National Academies Press: OpenBook

Veterans and Agent Orange: Update 2008 (2009)

Chapter: 6 Cancer

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Suggested Citation:"6 Cancer." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

6 Cancer Cancer is the second-leading cause of death in the United States. Among men 50–64 years old, the group that includes most Vietnam veterans (see Table 6-1), however, the risk of dying from cancer exceeds the risk of dying from heart disease, the main cause of death in the United States, and does not fall to second place until after the age of 75 years (Heron et al., 2009). About 565,650 Ameri- cans of all ages were expected to die from cancer in 2008—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2008a). This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations be- TABLE 6-1  Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2004–2005 (numbers in thousands) Vietnam Era Vietnam Theater Age Group (Years) n (%) n (%) All ages 7,938 3,852 ≤ 49 133 (1.7) 32 (0.8) 50–54 1,109 (14.0) 369 (9.6) 55–59 3,031 (38.2) 1,676 (43.5) 60–64 2,301 (29.0) 1,090 (28.3) 65–69 675 (8.5) 280 (7.3) 70–79 511 (6.4) 322 (8.4) ≥ 80 178 (2.2) 83 (2.2) SOURCE: IOM, 1994, Table 3-3, updated by 15 years. 202

CANCER 203 tween exposure to the chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-tri­chlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8- tetrachlorodi­benzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. If a new study reported on only a single type of cancer and did not revisit a previously studied population, its design information is summarized here with its results; design information on all other new studies can be found in Chapter 4. In an evaluation of a possible connection between herbicide exposure and risk of cancer, the approach used to assess study subjects is of critical impor- tance in determining the overall relevance and usefulness of findings. As noted in Chapter 5, there is great variety in detail and accuracy of exposure assessment among studies. A few studies used biologic markers of exposure, such as the pres- ence of a compound in serum or tissues; some developed an index of exposure from employment or activity records; and some used other surrogate measures of exposure, such as presence in a locale when herbicides were used. As noted in Chapter 2, inaccurate assessment of exposure can obscure the relationship between exposure and disease. Each section on a type of cancer opens with background information, includ- ing data on its incidence in the general US population and known or suspected risk factors. Cancer-incidence data on the general US population are included in the background material to provide a context for consideration of cancer risk in Vietnam veterans; the figures presented are estimates of incidence in the entire US population, however, not predictions for the Vietnam-veteran cohort. The data reported are for 2000–2005 and are from the most recent dataset available (NCI, 2008). Incidence data are given for all races combined and separately for blacks and whites. The age range of 50–64 years now includes about 80% of Vietnam- era veterans, so incidences are presented for three 5-year age groups: 50–54 years, 55–59 years, and 60–64 years. The data were collected for the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and are categorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostate cancer is about 4.1 times as high as men who are 60–64 years old than in men 50–54 years old and about twice as high in blacks 50–64 years old as in whites in the same age group (NCI, 2008). Many other factors can influence cancer incidence, including screening methods, tobacco and alcohol use, diet, genetic predisposition, and medical history. Those factors can make someone more or less likely than the average to contract a given kind of cancer; they also need to be taken into account in epidemiologic studies of the possible contributions of the chemicals of interest. Each section of this chapter pertaining to a specific type of cancer includes a summary of the findings described in the previous Agent Orange reports: Veter- ans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update

204 VETERANS AND AGENT ORANGE: UPDATE 2008 2000 (IOM, 2001); Update 2002 (IOM, 2003); Update 2004 (IOM, 2005); and Update 2006 (IOM, 2007). That is followed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. When it is appropriate, the literature is discussed by exposure type (service in Vietnam, occupational exposure, or environmental exposure). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chap- ters 1 and 2. Biologic plausibility corresponds to the third element of the committee’s congressionally mandated statement of task. In fact, the degree of biologic plau- sibility itself influences whether the committee perceives positive findings to be indicative of an association or the product of statistical fluctuations (chance) or bias. Information on biologic mechanisms by which exposure to TCDD could contribute to the generic (rather than tissue-specific or organ-specific) carcino- genic potential of the chemicals of interest is summarized in Chapter 4. It distills toxicologic information concerning the mechanisms by which TCDD affects the basic process of carcinogenesis; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in this chapter’s sections on particular cancer types, the generic infor- mation is implicit, and only experimental data peculiar to carcinogenesis at the site in question is presented. Considerable uncertainty remains about the magnitude of potential risk posed by exposure to the chemicals of interest. Many of the veteran, occupational, and environmental studies reviewed by the committee did not control fully for impor- tant confounders. There is not enough information about the exposure experience of individual Vietnam veterans to permit combining exposure estimates for them with any potency estimates that might be derived from scientific research stud- ies in order to quantify risk. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the chemicals of interest. The (at least currently) insurmountable problems of deriving useful quantitative estimates of the risks of various health outcomes to Vietnam veterans are explained in Chapter 1 and the summary of this report, but the point is not reiterated for every health outcome addressed. ORGANIZATION OF CANCER GROUPINGS For Update 2006, a system for addressing cancer types was described to clarify how specific cancer diagnoses were grouped for evaluation by the com- mittee and to ensure that the full array of cancer types would be considered. As described in Update 2006, the organization of cancer groups follows ma- jor and minor categories of cause of death related to cancer sites established by the National Institute for Occupational Safety and Health (NIOSH). The NIOSH

CANCER 205 groups map the full range of International Classification of Diseases, Revision 9 (ICD-9) codes for malignant neoplasms (140–208). The ICD system is used by physicians and researchers to group related diseases and procedures in a standard form for statistical evaluation. Revision 10 (ICD-10) came into use in 1999 and constitutes a marked change from the previous four revisions that evolved into the ninth ICD-9. ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it has been used when codes are given for a specific health outcome. Appendix B describes the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (Table B-1); the groupings for mortality are largely congruent with those of the SEER program for cancer incidence (see Table B-2, which presents equivalences between the ICD-9 and ICD-10 systems). The system of organization used by the committee simplifies the process for locating a particular cancer for readers and facilitated the committee’s iden- tification of ICD codes for malignancies that had not been explicitly addressed in previous updates. VAO reports’ default category for any health outcome for which no epidemiologic research findings have been recovered has always been “inadequate evidence” of association, which in principle is applicable to specific cancers. Failure to review a specific cancer or other condition separately reflects the paucity of information, so there is indeed inadequate or insufficient informa- tion to categorize such a disease outcome. BIOLOGIC PLAUSIBILITY The studies considered with respect to the biologic plausibility of an asso- ciation between exposure to the chemicals of interest and human cancers have been performed primarily in either laboratory animals (rats, mice, hamsters, and monkeys) or cultured cells. Collectively, the evidence obtained from studies of TCDD indicates that a connection between human exposure to this compound and cancers is biologically plausible, as will be discussed more fully in a generic sense below and more specifically in the biologic-plausibility sections on indi- vidual cancers. With respect to 2,4-D, 2,4,5-T, and picloram, several studies have been performed in laboratory animals. In general, the results were negative although some would not meet current standards for cancer bioassays; for instance, there is some question whether the highest doses (generally 30–50 mg/kg) in some of these studies achieved a maximum tolerated dose (MTD). It is not possible to have absolute confidence that these compounds have no carcinogenic potential. Further evidence of a lack of carcinogenic potential is provided, however, by negative findings for genotoxic effects in assays conducted primarily in vitro. The evidence indicates that 2,4-D is genotoxic only at very high concentrations. Although 2,4,5-T was shown to increase the formation of DNA adducts by cy- tochrome P450–derived metabolites of benzo[a]pyrene, most available evidence indicates that 2,4,5-T is genotoxic only at high concentrations.

206 VETERANS AND AGENT ORANGE: UPDATE 2008 There is some evidence that cacodylic acid is carcinogenic. Studies per- formed in laboratory animals have shown that it can induce neoplasms of the kid- ney (Yamamoto et al., 1995) and bladder (Arnold et al., 2006; Wei et al., 2002). In the lung, treatment with cacodylic acid induced formation of neoplasms when administered to mouse strains that are genetically susceptible to them (Hayashi et al., 1998). Other studies have used the two-stage model of carcinogenesis in which animals are exposed first to a known genotoxic agent and then to a sus- pected tumor-promoting agent. With that model, cacodylic acid has been shown to act as a tumor-promoter with respect to lung cancer (Yamanaka et al., 1996). Studies in laboratory animals in which only TCDD has been administered have reported that it can increase the incidence of a number of neoplasms, most notably of the liver, lung, thyroid, and oral mucosa (Kociba et al., 1978; NTP, 2006). Some studies have used the two-stage model of carcinogenesis and shown that TCDD can act as a tumor-promoter and increase the incidence of ovarian (Davis et al., 2000), liver (Beebe et al., 1995), and skin cancers (Wyde et al., 2004). As to the mechanisms by which TCDD exerts its carcinogenic effects, it is thought to act primarily as a tumor-promoter. In many of the animal studies reviewed, treatment with TCDD has resulted in hyperplasia or metaplasia of epi- thelial tissues. In addition, in both laboratory animals and cultured cells, TCDD has been shown to exhibit a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes that involve growth, maturation, and differentiation. Thus, it may be that TCDD increases the incidence or progression of human cancers through an interplay between multiple cellular factors. Tissue-specific protective cellular mechanisms may also affect the response to TCDD and complicate our understanding of its site-specific carcinogenic effects. As shown with long-term bioassays in both sexes of several strains of rats, mice, hamsters, and fish, there is adequate evidence that TCDD is a carcinogen in laboratory animals, increasing the incidence of tumors at sites distant from the site of treatment at doses well below the maximum tolerated. On the basis of animal studies, TCDD has been characterized as a nongenotoxic carcinogen because it does not have obvious DNA-damaging potential, but it is a potent “pro- moter” and a weak initiator in two-stage initiation–promotion models for liver, skin, and lung. Early studies demonstrated that TCDD is 2 orders of magnitude more potent than the “classic” promoter tetradecanoyl phorbol acetate and that TCDD skin-tumor promotion depends on the aryl hydrocarbon receptor (AHR). For many years, it has been known that TCDD is a potent tumor-promoter. Recent evidence has shown that AHR activation by TCDD in human breast and endocer- vical cell lines induces sustained high concentrations of the interleukin–6 (IL–6) cytokine, which has tumor-promoting effects in numerous tissues—including breast, prostate, ovarian, and malignant cholangiocytes—and opens up the pos- sibility that TCDD would promote carcinogenesis in these and possibly other tissues (Hollingshead et al., 2008). In vitro work with mouse hepatoma cells has shown that activation of

CANCER 207 the AHR results in increased concentrations of 8-hydroxydeoxyguanosine—a product of DNA-base oxidation and later excision repair and a marker of DNA damage. Induction of cytochrome P4501A1 (CYP1A1) by TCDD or indolo(3,2- b)carbazole is associated with oxidative DNA damage (Park et al., 1996). In vivo experiments in mice corroborated those findings by showing that TCDD caused a sustained oxidative stress, as determined by measurements of urinary 8-hydroxydeoxyguanosine (Shertzer et al., 2002), involving AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reac- tive oxygen production depends on the AHR. Recent work designed to measure DNA damage in humans has also found high urinary 8-hydroxydeoxyguanosine in workers dismantling electronic equipment who were exposed to high concen- trations of dioxins and dioxin-like compounds (Wen et al., 2008). In a recent study of New Zealand Vietnam War veterans (Rowland et al., 2007), clastogenic genetic disturbances arising as a consequence of confirmed exposure to Agent Orange were determined by analyzing sister-chromatid ex- changes (SCEs) in lymphocytes from a group of 24 New Zealand Vietnam War veterans and 23 control volunteers. The results showed a highly significant dif- ference (p < 0.001) between the mean of the experimental group and the mean of the control group. The Vietnam War veterans also had a much higher proportion of cells with SCE frequencies above the 95th percentile than the controls (11.0 and 0.07%, respectively). The weight of evidence that TCDD and dioxin-like polychlorinated biphenyls make up a group of compounds with carcinogenic potential includes unequivocal animal carcinogenesis and biologic plausibility based on mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be es- tablished, the intracellular factors and mechanistic pathways involved in dioxin’s cancer-promotion mode of action all have parallels between animals and humans. No qualitative differences have been reported to indicate that humans should be considered as fundamentally different from the multiple animal species in which bioassays have demonstrated dioxin-induced neoplasia. In conclusion, the toxicologic evidence indicates that a connection of TCDD and perhaps cacodylic acid with cancer in humans is, in general, biologically plausible, but (as discussed below) it must be determined case-by-case whether such potential is realized in a given tissue. Experiments with 2,4-D, 2,4,5-T, and picloram in animals and cells have not provided a strong biologic basis of the presence or absence of carcinogenic effects. The Committee’s View of “General” Human Carcinogens In order to address its charge, the committee weighed the scientific evidence linking the chemicals of interest to specific individual cancer sites. That was appropriate given the different susceptibilities of various tissues and organs to cancer development and the various genetic and environmental factors that can influence the occurrence of a particular type of cancer. Before considering each

208 VETERANS AND AGENT ORANGE: UPDATE 2008 site in turn, however, it is important to address the concept that cancers share cer- tain features among organ sites and to clarify the committee’s view regarding the implications of a compound’s being a “general” human carcinogen. All cancers share phenotypic features: uncontrolled cell proliferation, increased cell survival, invasion outside normal tissue boundaries, and eventually metastasis. The current model for understanding cancer development holds that a cell or group of cells must acquire a series of sufficient genetic mutations to progress and that particu- lar epigenetic events (events that affect gene function but do not involve a change in gene coding sequence) must occur to accelerate the mutational process and provide growth advantages for the more aggressive clones of cells. That means that a carcinogen can stimulate the process of cancer development by either ge- netic (mutational) or epigenetic (nonmutational) activities. In classic experiments based on the induction of cancer in mouse skin that were conducted over 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and promot- ers, those capable of promoting the growth of initiated tumor cells, generally through nonmutational events. Some carcinogens, such as those found in tobacco smoke, were considered “whole carcinogens”; that is, they were capable of both initiation and promotion. Today, cancer researchers recognize that the acquisition of important mutations is a continuing process in tumors, and that promoters, or epigenetic processes that favor cancer growth, influence the accumulation of genotoxic damage and vice versa. As discussed above and in Chapter 4, 2,4-D, 2,4,5-T, and picloram have shown little evidence of genotoxicity in laboratory studies, except at very high doses, and little ability to facilitate cancer growth in laboratory animals. How- ever, cacodylic acid and TCDD have shown the capacity to increase cancer de- velopment in animal experiments, particularly as promoters rather than as pure genotoxic agents. Extrapolating organ-specific results from animal experiments to humans is problematic because of important differences between species in over- all susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments about the gen- eral carcinogenicity of a compound are based heavily on the results of epidemio- logic studies, particularly on the question of whether there is evidence of excess cancer risk at multiple organ sites. As the cancer-type evaluations indicate in the remainder of this chapter, the committee finds that TCDD in particular appears to be a multisite carcinogen. That finding is in agreement with the International Agency for Research on Cancer (IARC), which has determined that TCDD is a category 1 “known human carcinogen,” and with the US Environmental Protec- tion Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans.” It is important to emphasize that the goals and methodology of the IARC and EPA in making their determinations were different from those of this committee; the mission of those organizations focuses on evaluating risk to minimize future exposure, whereas this committee focuses on risk after exposure.

CANCER 209 Furthermore, recognition that TCDD and cacodylic acid are multisite carcinogens does not imply that they cause human cancer at every organ site. The distinction between general carcinogen and site-specific carcinogen is more difficult to grasp in light of the common practice of beginning analyses of epidemiologic cohorts with a category of “all malignant neoplasms,” which is a routine first screen for any unusual cancer activity in the study population rather than a test of a biologically-based hypothesis. When the distribution of cancers among anatomic sites is lacking in the report of a cohort study, a statistical test for an increase in all cancers is not meaningless, but it is usually less scientifically supportable than analyses based on specific sites, for which more substantial bio- logically based hypotheses can be developed. The size of a cohort and the length of the observation period often constrain the number of cases of individual cancer types observed and the extent to which specific cancer types can be analyzed. For instance, this present update includes an analysis of cumulative results on diabe- tes and cancer from a report of the prospective Air Force Health Study (Michalek and Pavuk, 2008). For the fairly common condition of diabetes, that publication represents important information summarizing previous findings, but the cancer analysis does not go beyond “all cancers.” The committee does not accept those findings as an indication that exposure to Agent Orange increases the risk of every variety of cancer. The committee acknowledges that the highly stratified analy- ses conducted suggest that some increase in the incidence of some cancers did occur in some of the Ranch Hand subjects, but it views the “all cancers” results as a conglomeration containing information on specific cancers—most impor- tant, melanoma and prostate cancer—for which provocative results have been published (Akhtar et al., 2004; Pavuk et al., 2006) and which merit individual longitudinal analysis to resolve outstanding questions. The remainder of this chapter deals with the committee’s review of the evi- dence on each individual cancer site in accordance with its charge to evaluate the statistical association between exposure and cancer occurrence, the biologic plausibility and potential causal nature of that association, and the relevance to US veterans of the Vietnam War. ORAL, NASAL, AND PHARYNGEAL CANCER Oral, nasal, and pharyngeal cancers are found in many anatomic subsites, including the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and hard and soft palate) (ICD-9 140–145), oropharynx (ICD-9 146), nasopharynx (ICD-9 147), hypopharynx (ICD-9 148), other buccal cavity and pharynx (ICD-9 149), and nasal cavity and paranasal sinuses (ICD-9 160). Al- though those sites are anatomically diverse, cancers that occur in the nasal cavity, oral cavity, and pharynx are for the most part similar in descriptive epidemiology and risk factors. The exception is cancer of the nasopharynx, which has a differ- ent epidemiologic profile. The American Cancer Society (ACS) estimated that about 35,310 men and

210 VETERANS AND AGENT ORANGE: UPDATE 2008 women would receive diagnoses of oral, nasal, or pharyngeal cancer in the United States in 2006 and 7,590 men and women would die from these diseases (Jemal et al., 2008a). Almost 91% of those cancers originate in the oral cavity or oropharynx. Most oral, nasal, and pharyngeal cancers are squamous-cell carcino- mas. Nasopharyngeal carcinoma (NPC) is the most common malignant epithelial tumor of the nasopharynx although it is relatively rare in the United States. There are three types of NPC: keratinizing squamous-cell carcinoma, nonkeratinizing carcinoma, and undifferentiated carcinoma. The average annual incidences reported in Table 6-2 show that men are at greater risk than women for those cancers and that the incidences increase with age although there are few cases, and care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (Hayes, 1997), wood dust (Demers et al., 1995), and formaldehyde (Blair and Kazerouni, 1997). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, TABLE 6-2  Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Nose, Nasal Cavity, and Middle Ear: Men 1.3 1.2 1.5 1.5 1.4 1.5 2.2 2.3 2.7 Women 0.5 0.5 0.5 1.0 1.1 0.0 1.1 1.1 1.3 Nasopharynx: Men 1.8 1.0 1.3 2.6 1.4 2.4 2.8 1.6 3.1 Women 0.7 0.3 0.8 0.7 0.3 0.4 1.1 0.5 0.6 Oral Cavity and Pharynx: Men 29.4 29.2 38.3 39.0 38.3 50.4 48.9 49.5 56.1 Women 9.0 8.7 11.7 12.6 12.6 13.9 16.0 16.3 17.5 Oropharynx: Men 1.9 1.0 2.3 1.6 1.4 3.2 2.0 1.9 4.7 Women 0.2 0.1 0.6 0.5 0.4 1.1 0.2 0.2 0.6 a Surveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

CANCER 211 Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. For Update 2006, the Department of Veterans Affairs (VA) made the specific request that the committee screened studies that had reported the number of t ­ onsil-cancer cases observed. Given the small number of cases diagnosed in the general population, it is often not possible to evaluate tonsil-cancer cases sepa- rately in epidemiologic studies; therefore, they are grouped in the more general category of oral, nasal, and pharyngeal cancers. The committee was able to iden- tify only three cohort studies that provided the number of tonsil-cancer cases in their study populations and concluded that these studies did not provide sufficient evidence to determine whether an association existed between exposure to the chemicals of interest and tonsil cancer. The committee responsible for Update 2006 recommended that VA evaluate the possibility of studying health outcomes, including tonsil cancer, in Vietnam-era veterans by using existing administrative and health-services databases. Anecdotal evidence provided to the present com- mittee by the veterans suggests a potential association between the exposures in Vietnam and tonsil cancer, so this committee strongly reiterates the 2006 recom- mendation that VA develop a strategy for evaluating tonsil cancer in Vietnam-era veterans with existing databases. Studies evaluated previously and in this report are summarized in Table 6-3. Update of the Epidemiologic Literature No studies of Vietnam veterans or of populations exposed to the chemicals of interest environmentally and oral, nasal, or pharyngeal cancers have been published since Update 2006. Occupational Studies Hansen et al. (2007) evaluated cancer incidence from May 1975 through 2001 in an occupational cohort of the Danish Union of General Workers identified from men working in 1973; their cancer incidence from 1975 to 1984 was reported in Hansen et al. (1992). The cohort of 3,156 male gardeners—whose pesticide ex- posure was primarily to herbicides, including phenoxyacetic acids—was matched to the Danish Cancer Registry to determine the observed cancer incidence; cancer cases were coded with ICD-7. The expected number of cancers was calculated by using national cancer incidences. The standardized incidence ratios (SIRs) were controlled for age and calendar time. The cohort was divided by year of birth, a proxy for exposure because pesticide use decreased over time. Three subcohorts were evaluated: high, early-birth cohort (born before 1915); low, late-birth co- hort (born after 1934); and medium (born in 1915–1934). A total of 521 cancer cases were identified; nine were classified as originating in the buccal cavity or pharynx (ICD-7 140–148). The observed incidence of pharyngeal cancers was

212 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-3  Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian Vietnam veterans vs Australian 2005a population—incidence Head and neck 247 1.5 (1.3–1.6) Navy 56 1.6 (1.1–2.0) Army 174 1.6 (1.3–1.8) Air Force 17 0.9 (0.5–1.5) ADVA, Australian Vietnam veterans vs Australian 2005b population—mortality Head and neck 101 1.4 (1.2–1.7) Navy 22 1.5 (0.9–2.1) Army 69 1.5 (1.1–1.8) Air Force 9 1.1 (0.5–2.0) Nasal 3 0.8 (0.2–2.2) ADVA, Australian conscripted Army National Service Vietnam- 2005c era veterans: deployed vs nondeployed Head and neck Incidence 44 2.0 (1.2–3.4) Mortality 16 1.8 (0.8–4.3) Nasal Mortality 0 0.0 (0.0–48.2) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 (ICD-9 140–149) 6 nr Studies Reviewed in Update 2004 Akhtar White AFHS subjects vs national rates (buccal cavity) et al., 2004 Ranch Hand veterans Incidence 6 0.9 (0.4–1.9) With tours in 1966–1970 6 1.1 (0.5–2.3) Mortality 0 0.0 (nr) Comparison veterans Incidence 5 0.6 (0.2–1.2) With tours in 1966–1970 4 0.6 (0.2–1.4) Mortality 1 0.5 (nr) Studies Reviewed in Update 2000 AFHS, Air Force veterans participating in 1997 examination 2000 cycle, Ranch Hands vs comparisons (oral cavity, pharynx, and larynx) 4 0.6 (0.2–2.4) Studies Reviewed in Update 1998 CDVA, Australian Vietnam veterans vs Australian 1997a population—incidence Lip (ICD-9 140) 0 nr Nasopharyngeal cancer (ICD-9 147) 2 0.5 (0.1–1.7) Nasal cavities (ICD-9 160) 2 1.2 (0.1–4.1)

CANCER 213 TABLE 6-3  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b CDVA, Australian conscripted Army National Service Vietnam- 1997b era veterans—deployed vs nondeployed Nasopharyngeal cancer 1 1.3 (0.0– > 10) Nasal cavities 0 0.0 (0.0– > 10) Visintainer PM study of deaths (1974–1989) of Michigan Vietnam- et al., 1995 era veterans—deployed vs nondeployed Lip, oral cavity, and pharynx 12 1.0 (0.5–1.8) Studies Reviewed in VAO CDC, Case–control study of US males born 1929–1953 1990a 89 nasopharyngeal carcinomas Vietnam service 3 0.5 (0.2–1.8) 62 nasal carcinomas Vietnam service 2 0.7 (0.2–2.9) OCCUPATIONAL New Studies Hansen Danish gardeners—incidence et al., 2007 (buccal cavity and pharynx, ICD-7 140–148) 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 6 1.1 (0.4–2.5) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 3 0.7 (0.2–2.3) Born 1915–1934 (medium exposure) 6 0.7 (0.3–1.4) Born after 1934 (low exposure) 0 0.0 (0.0–1.0) Studies Reviewed in Update 2006 Alavanja US AHS—incidence (buccal cavity) et al., 2005 Private applicators (men and women) 66 0.7 (0.5–0.8) Lip 25 1.4 (0.9–2.1) Spouses of private applicators (> 99% women) 14 0.7 (0.4–1.2) Lip 2 1.4 (0.2–5.1) Commercial applicators (men and women) 5 0.9 (0.3–2.2) Lip 3 2.7 (0.6–8.0) Blair et al., US AHS (buccal cavity, and pharynx) 2005a Private applicators (men and women) 5 0.3 (0.1–0.7) Spouses of private applicators (> 99% women) 0 0.0 (0.0–25.4) McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds (oral cavity, and pharynx) Never 33 0.9 (0.6–1.3) Ever 15 0.5 (0.3–0.9) ’t Mannetje Phenoxy herbicide producers (men and women) et al., 2005 (ICD-9 140–149) 2 2.8 (0.3–9.9) Lip (ICD-9 140) 0 nr Mouth (ICD-9 141–145) 2 5.4 (0.7–20) Oropharynx (ICD-9 146) 0 nr Nasopharynx (ICD-9 147) 0 0.0 (0.0–42) continued

214 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-3  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Hypopharynx, other (ICD-9 148–149) 0 nr Phenoxy herbicide sprayers (> 99% men) (ICD-9 140–149) 1 1.0 (0.0–5.7) Lip (ICD-9 140) 0 nr Mouth (ICD-9 141–145) 0 0.0 (0.0–7.5) Oropharynx (ICD-9 146) 0 nr Nasopharynx (ICD-9 147) 1 8.3 (0.2–46) Hypopharynx, other (ICD-9 148–149) 0 nr Torchio Italian licensed pesticide users et al., 1994 Buccal cavity, pharynx 18 0.3 (0.2–0.5) Reif et al., New Zealand forestry workers—incidence 1989 Buccal cavity 3 0.7 (0.2–2.2) Nasopharynx 2 5.6 (1.6–19.5) Studies Reviewed in Update 2004 Nordby Norwegian farmers born 1925–1971—incidence, lip et al., 2004 Reported pesticide use nr 0.7 (0.4–1.0) Swaen Dutch licensed herbicide applicators et al., 2004 Nose 0 nr Mouth, pharynx 0 nr Studies Reviewed in Update 2000 Caplan Case–control study of US males born 1929–1953, all 70 et al., 2000 nasal cancers (carcinomas, 11 lymphomas, 5 sarcomas) in CDC (1990a) study population Selected landscaping, forestry occupations 26 1.8 (1.1–3.1) Living, working on farm 23 0.5 (0.3–0.8) Herbicides, pesticides 19 0.7 (0.4–1.3) Phenoxy herbicides 5 1.2 (0.4–3.3) Studies Reviewed in Update 1998 Hooiveld Dutch chemical production workers included in IARC et al., 1998 cohort (lip, oral cavity, pharynx) All working any time in 1955–1985 1 2.3 (0.1–12.4) Cleaned up 1963 explosion 1 7.1 (0.2–39.6) Rix et al., Danish male, female paper-mill workers 1998 Buccal cavity (ICD-7 140–144) Men 24 1.0 (0.7–1.5) Women 4 1.5 (0.4–3.8) Pharynx (ICD-7 145–149) Men 15 2.0 (1.1–3.3) Women 2 2.1 (0.2–7.6) Tonsil cancers among pharyngeal cancers 11 nr Kogevinas IARC cohort, male and female workers exposed to any et al., 1997 phenoxy herbicide or chlorophenol Oral cavity, pharynx cancer (ICD-9 140–149) 26 1.1 (0.7–1.6) Exposed to highly chlorinated PCDDs 22 1.3 (0.8–2.0) Not exposed to highly chlorinated PCDDs 3 0.5 (0.1–1.3)

CANCER 215 TABLE 6-3  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Nose, nasal sinus cancer (ICD-9 160) 3 1.6 (0.3–4.7) Exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.5) Not exposed to highly chlorinated PCDDs 3 3.8 (0.8–11.1) Studies Reviewed in Update 1996 Becher German phenoxy herbicide production workers (included et al., 1996 in IARC cohort) Buccal cavity, pharynx (ICD-9 140–149) 9 3.0 (1.4–5.6) Tongue 3 nr Floor of mouth 2 nr Tonsil 2 nr Pharynx 2 nr Asp et al., Finnish herbicide applicators 1994 Buccal, pharynx (ICD-8 140–149) Incidence 5 1.0 (0.3–2.3) Mortality 0 0.0 (0.0–3.0)  “Other respiratory” (ICD-8 160, 161, 163)— nose, larynx, pleura Incidence 4 1.1 (0.3–2.7) Mortality 1 0.5 (0.0–2.9) Studies Reviewed in VAO Blair et al., White male farmers in 23 states—deaths 1984–1988 1993 Lip 21 2.3 (1.4–3.5) Ronco Italian farmers (lip, tongue, salivary glands, mouth, et al., 1992 pharynx)—mortality Self-employed 13 0.9 (nr) Employees 4 0.5 (nr) Danish self-employed farmers—incidence Lip 182 1.8 (p < 0.05) Tongue 9 0.6 (nr) Salivary glands 13 0.9 (nr) Mouth 14 0.5 (p < 0.05) Pharynx 13 0.3 (p < 0.05) Nasal cavities, sinuses 11 0.6 (nr) Danish farming employees—incidence Lip 43 2.1 (p < 0.05) Tongue 2 0.6 (nr) Salivary glands 0 0.0 (nr) Mouth 0 0.0 (p < 0.05) Pharynx 9 1.1 (nr) Nasal cavities and sinuses 5 1.3 (nr) Saracci IARC cohort—exposed subcohort (males, females) et al., 1991 Buccal cavity, pharynx (ICD-8 140–149) 11 1.2 (0.6–2.1) Nose, nasal cavities (ICD-8 160) 3 2.9 (0.6–8.5) Zober BASF Aktiengesellschaft accident cohort—33 cancers in et al., 1990 247 workers at 34-year follow-up Squamous-cell carcinoma of tonsil 1 nr continued

216 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-3  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Wiklund Licensed Swedish pesticide applicators—incidence et al., Lip 14 1.8 (1.0–2.9) 1989a Coggon British MCPA production workers (included in IARC et al., 1986 cohort) Lip (ICD-9 140) 0 nr Tongue (ICD-9 141) 1 1.1 (0.0–6.2) Pharynx (ICD-9 146–149) 1 0.5 (0.0–3.0) Nose (ICD-9 160) 3 4.9 (1.0–14.4) Robinson Northwestern US paper and pulp workers 90% CI et al., 1986 Buccal cavity, pharynx (ICD-7 140–148) 1 0.1 (0.0–0.7) Nasal (ICD-7 160) 0 nr Wiklund, Swedish male and female agricultural 1983 workers—incidence 99% CI Lip 508 1.8 (1.6–2.1) Tongue 32 0.4 (0.2–0.6) Salivary glands 68 1.0 (0.7–1.4) Mouth 70 0.6 (0.5–0.8) Throat 84 0.5 (0.4–0.7) Nose, nasal sinuses 64 0.8 (0.6–1.2) Hardell Residents of northern Sweden (44 nasal, 27 et al., 1982 nasopharyngeal cancers) Phenoxy acid exposure 8 2.1 (0.9–4.7) Chlorophenol exposure 9 6.7 (2.8–16.2) Burmeister Iowa farmers—deaths in 1971–1978 et al., 1981 Lip 20 2.1 (p < 0.01) ENVIRONMENTAL Studies Reviewed in VAO Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Buccal cavity (ICD-9 140–149) Zone B— enM 6 1.7 (0.8–3.9) Women 0 nr Zone R— enM 28 1.2 (0.8–1.7) Women 0 nr Nose, nasal cavities (ICD-9 160) Zone R— enM 0 nr Women 2 2.6 (0.5–13.3) ABBREVIATIONS: AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2 methyl-4-chlorophenoxyacetic acid; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. a Subjects are male and outcome is mortality unless otherwise noted. b Given when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort.

CANCER 217 lower than the expected incidence for all birth cohorts examined. For men born before 1915, the SIR was 0.74 (95% confidence interval [CI] 0.24–2.29). A re- duced incidence was also observed in men born in 1915–1934 (SIR = 0.65, 95% CI 0.29–1.44). No cases were observed in men born after 1934. Nasal cancers were grouped in the respiratory-cancer category (ICD-7 160–165). The SIRs for respiratory cancers were also lower than expected, with SIRs of 0.90 (95% CI 0.64–1.26), 0.98 (95% CI 0.78–1.23), and 0.84 (95% CI 0.42–1.69) in the early-, intermediate-, and late-birth cohorts, respectively. The study was limited by the inability to examine incidence by pesticide class (for example, herbicides) and the lack of confounder data. Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). A recent National Toxicology Program study (Yoshizawa et al., 2005a) reported an increase in the incidence of gingival squamous-cell carcinoma in female rats treated orally (by gavage) with TCDD at 100 ng/kg 5 days/week for 104 weeks. Incidences of gingival squamous-cell hyperplasia were significantly increased in all groups treated at 3–46 ng/kg. In addition, squamous-cell carcinoma in the oral mucosa of the palate was increased. Increased neoplasms of the oral mucosa were previously observed and described as carcinomas of the hard palate and nasal turbinates (Kociba et al., 1978). Kociba et al. (1978) also reported a small increase in the incidence of tongue squamous- cell carcinoma. A similar 2-year study performed in female rats failed to reveal a pathologic effect of TCDD on nasal tissues (Nyska et al., 2005). The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The single study reporting on oral, nasal, and pharyngeal cancers found noth- ing suggestive of an association with the herbicides sprayed in Vietnam. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and oral, nasal, or pharyngeal cancers.

218 VETERANS AND AGENT ORANGE: UPDATE 2008 CANCERS OF THE DIGESTIVE ORGANS Until Update 2006, VAO committees had reviewed “gastrointestinal tract tumors” as a group consisting of stomach, colorectal, and pancreatic cancers, with esophageal cancer being formally factored in only since Update 2002. With more evidence from occupational studies available, VAO updates now address cancers of the digestive organs individually. Findings on cancers of the digestive organs as a group (ICD-9 150–159) are too broad for useful etiologic analysis and will no longer be considered. Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 224,460 people would receive diagnoses of those cancers in the United States in 2008 and 109,410 people would die from them (Jemal et al., 2008a). When other digestive cancers (for example, small intestine, anal, and hepatobiliary) were included, the 2008 estimates for the United States were about 271,290 new diagnoses and 135,130 deaths (Jemal et al., 2008a). Collectively, tumors of the digestive organs were expected to account for 19% of new diagnoses and 24% of cancer deaths in 2008. The average annual incidences of gastrointestinal cancers are presented in Table 6-4. TABLE 6-4  Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Stomach: Men 9.2 8.0 16.8 15. 8 14.0 22.3 24.1 21.0 44.1 Women 4.7 3.8 7.9 7.0 5.7 11.7 9.5 7.6 17.5 Esophagus: Men 9.4 9.5 12.8 16.8 16.9 25.2 23.9 24.2 33.7 Women 1.7 1.5 4.6 3.2 2.8 8.0 4.9 5.0 9.4 Colon (excluding rectum): Men 35.8 34.2 50.0 57.1 54.9 85.6 94.9 91.1 144.4 Women 28.5 26.3 44.1 43.9 39.8 77.3 69.9 66.5 112.4 Rectum and rectosigmoid junction: Men 25.0 23.9 27.3 33.6 32.6 31.3 49.5 49.3 47.2 Women 15.1 14.6 19.5 21.0 20.4 27.0 26.5 25.8 34.6 Liver and intrahepatic bile duct: Men 19.0 15.3 34.3 21.2 15.7 49.6 24.9 18.0 44.1 Women 3.4 2.5 6.6 5.1 4.1 9.1 8.1 5.8 11.2 Pancreas: Men 13.1 12.6 20.7 21.4 20.7 32.1 34.6 33.5 48.0 Women 8.1 7.7 12.5 14.2 13.5 18.6 24.2 23.3 39.0

CANCER 219 TABLE 6-4  Continued 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Small Intestine: Men 3.3 3.1 5.5 5.1 4.8 10.3 5.9 5.6 8.5 Women 2.0 1.9 4.0 3.2 3.2 4.6 4.4 4.2 8.1 Anus, anal canal, and anorectum: Men 2.4 2.3 4.3 2.7 2.9 2.6 3.5 3.8 2.3 Women 3.2 3.6 3.5 3.7 3.8 5.5 4.3 4.7 3.2 Other digestive organs: Men 0.7 0.6 0.9 1.1 1.0 2.1 1.3 1.4 1.2 Women 0.6 0.6 0.8 0.8 0.8 0.9 1.2 1.2 1.3 Gallbladder: Men 0.4 0.4 0.2 1.0 0.8 1.3 1.6 1.6 1.6 Women 1.1 1.0 1.6 2.1 1.9 2.2 2.9 2.8 2.8 Other Biliary: Men 1.4 1.2 2.1 2.6 2.4 3.7 4.7 4.6 4.3 Women 1.1 1.1 1.3 1.6 1.5 1.3 3.1 3.1 2.8 a Surveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, incidence is higher in men than in women and higher in blacks than in whites. Other risk factors for the cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and diet. Tobacco use is a risk factor for pancreatic cancer and possibly stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori in- creases the risk of stomach cancer. Type 2 diabetes is associated with an increased risk of cancers of the colon and pancreas (ACS, 2006). Esophageal Cancer Epithelial tumors of the esophagus (squamous-cell carcinomas and adeno- carcinomas) are responsible for more than 95% of all esophageal cancers (ICD-9 150); 16,470 newly diagnosed cases and 14,280 deaths were estimated for 2008 (Jemal et al., 2008a). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. Rates of esophageal cancer have been increasing in the last 2 decades. Adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esopha-

220 VETERANS AND AGENT ORANGE: UPDATE 2008 geal malignancy in the United States and western Europe (Blot and McLaughlin, 1999). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized to explain the link between GERD and esophageal adenocarcinoma. Conclusions from VAO and Previous Updates The committee responsible for VAO explicitly excluded esophageal cancer from the group of gastrointestinal tract tumors, for which it was concluded that there was limited or suggestive evidence of no association with exposure to the herbicides used by the US military in Vietnam. Esophageal cancers were not separately evaluated and were not categorized with this group until Update 2004. For Update 2006, the committee concluded that there was not enough evidence on each of the chemicals of interest to sustain this negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Esophageal cancer was thus reclassified to the default category of inadequate or insufficient evidence to determine whether there is an association. Table 6-5 summarizes the results of the relevant studies concerning esophageal cancer. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and esophageal cancer have been published since Update 2006. Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of esophageal cancer has been reported in laboratory animals after exposure to them. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

CANCER 221 TABLE 6-5  Selected Epidemiologic Studies—Esophageal Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 70 1.2 (0.9–1.5) Navy 19 1.6 (0.9–2.4) Army 40 1.1 (0.7–1.4) Air Force 11 1.5 (0.8–2.8) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 67 1.1 (0.8–1.3) Navy 13 1.0 (0.5–1.7) Army 42 1.0 (0.7–1.3) Air Force 12 1.5 (0.8–2.6) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 9 1.9 (0.6–6.6) Mortality 10 1.3 (0.5–3.6) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 6 1.2 (0.4–4.0) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 23 1.2 (0.7–1.7) 1997a CDVA, Australian National Service Vietnam veterans 1 1.3 (0.0– > 10) 1997b Visintainer PM study of deaths (1974–1989) of Michigan Vietnam- et al., 1995 era veterans—deployed vs nondeployed 9 0.9 (0.4–1.6) OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 27 0.7 (0.4–1.0) Ever 26 0.8 (0.5–1.2) ’t Mannetje Phenoxy herbicide producers (men and women) 2 2.0 (0.2–7.0) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 1 0.7 (0.0–4.0) Blair et al., US AHS 2005a Private applicators (men and women) 16 0.5 (0.3–0.9)  Spouses of private applicators (> 99% women) 1 0.3 (0.1–1.9) Lee et al., Population-based case–control—agricultural pesticide 2004a use and adenocarcinoma of the esophagus 137 Insecticides 0.7 (0.4–1.1) Herbicides 0.7 (0.4–1.2) Reif et al., New Zealand forestry workers—nested case–control 1989 (incidence) correspondence 4 1.8 (0.7–4.8) Magnani UK case–control et al., 1987 Herbicides   nr 1.6 (0.7–3.6) Chlorophenols   nr 1.2 (0.7–2.2) continued

222 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-5  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1998 Kogevinas IARC cohort, male and female workers exposed to any et al., 1997 phenoxy herbicide or chlorophenol 28 1.0 (0.7–1.4) Exposed to highly chlorinated PCDDs 20 1.3 (0.8–1.9) Not exposed to highly chlorinated PCDDs 6 0.5 (0.2–1.1) Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators—incidence 3 1.6 (0.3–4.6) 1994 Finnish herbicide applicators—mortality 2 1.3 (0.2–4.7) Studies Reviewed in VAO Ronco Danish farm workers—incidence et al., 1992 Male— elf-employed S 32 0.4 (p < 0.05) Employee 13 0.9 (nr) Female— elf-employed S 1 1.4 (nr) Family worker 2 0.4 (nr) Saracci IARC cohort—exposed subcohort (men and women) et al., 1991 8 0.6 (0.3–1.2) Coggon British MCPA production workers (included in IARC et al., 1986 cohort) 8 0.9 (0.4–1.9) Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 169 0.6 (0.5–0.7) ENVIRONMENTAL None ABBREVIATIONS: AHS, Agricultural Health Study; CDC, Centers for Disease Control and Preven- tion; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl- 4-chlorophenoxyacetic acid; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines). a Subjects are male and outcome is mortality unless otherwise noted. b Given when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort. Synthesis No epidemiologic evidence concerning the chemicals of interest and esopha- geal cancer has been published since Update 2006. No toxicologic studies pro- vide evidence of the biologic plausibility of an association between the chemicals of interest and tumors of the esophagus. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to

CANCER 223 determine whether there is an association between exposure to the chemicals of interest and esophageal cancer. Stomach Cancer The incidence of stomach cancer (ICD-9 151) increases in people 50–64 years old. ACS estimated that 13,190 men and 8,310 women would develop new cases of stomach cancer in the United States in 2008 and 6,450 men and 4,430 women would die from it (Jemal et al., 2008a). In general, the incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history of this cancer, some diseases of the stomach, and diet. Infection with the bacterium Helicobacter pylori increases the risk of stomach cancer. Tobacco use and consumption of nitrite- and salt-preserved food may also increase the risk of stomach cancer (Brenner et al., 2009; Key et al., 2004; Miller et al., 1996). Conclusions from VAO and Previous Updates Update 2006 considered stomach cancer independently for the first time. Prior updates developed a table of results for stomach cancer, but conclusions about the adequacy of the evidence of its association with herbicide exposure had been reached in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including stomach cancer. The com- mittee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain this negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Stomach cancer was thus reclassified to the default category of inadequate or insufficient evidence to determine whether there was an association. Table 6-6 summarizes the results of the relevant studies concerning stomach cancer. Update of the Epidemiologic Literature Vietnam-Veteran Studies  No studies of exposure to the chemicals of inter- est and stomach cancer in Vietnam veterans have been published since Update 2006. Occupational Studies  Mills and Yang (2007) conducted a nested case–control study of gastric cancer in the United Farm Workers of America (UFW) cohort and identified 100 cases of gastic cancer newly diagnosed during 1988–2003.

224 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-6  Selected Epidemiologic Studies—Stomach Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 104 0.9 (0.7–1.1) Navy 28 1.1 (0.7–1.6) Army 66 0.9 (0.7–1.1) Air Force 10 0.7 (0.3–1.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 76 0.9 (0.7–1.2) Navy 22 1.3 (0.8–1.8) Army 50 0.9 (0.7–1.2) Air Force 4 0.4 (0.1–1.0) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 11 0.6 (0.2–1.2) Mortality 7 0.7 (0.2–2.0) Pavuk et al., Comparison subjects only from AFHS (digestive 2005 system)—incidence  Serum TCDD (pg/g) based on model with exposure variable loge(TCDD) Per unit increase of -loge(TCDD) (pg/g) 24 1.8 (0.8–3.9) Quartiles (pg/g) 0.4–2.6 4 nr 2.6–3.8 3 1.0 (0.2–4.8) 3.8–5.2 7 2.0 (0.5–8.2) > 5.2 10 3.3 (0.9–12.5) Number of years served in SEA Per year of service 24 1.2 (1.0–1.4) Quartiles (years in SEA) 0.8–1.3 4 nr 1.3–2.1 4 1.0 (0.2–3.8) 2.1–3.7 5 1.1 (0.3–4.2) 3.7–16.4 11 2.1 (0.6–7.3) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 (stomach) 5 nr Studies Reviewed in Update 2004 Akhtar White AFHS subjects vs national rates (digestive et al., 2004 system) Ranch Hand veterans Incidence 16 0.6 (0.4–1.0) Tours 1966–1970 14 0.6 (0.4–1.1) Mortality 6 0.4 (0.2–0.9) Comparison veterans Incidence 31 0.9 (0.6–1.2) Tours 1966–1970 24 0.9 (0.6–1.3) Mortality 14 0.7 (0.4–1.1)

CANCER 225 TABLE 6-6  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 32 1.1 (0.7–1.4) 1997a CDVA, Australian National Service Vietnam veterans 4 1.7 (0.3– > 10) 1997b Studies Reviewed in VAO Breslin Army Vietnam veterans 88 1.1 (0.9–1.5) et al., 1988 Marine Vietnam veterans 17 0.8 (0.4–1.6) Anderson Wisconsin Vietnam veterans 1 nr et al., 1986 OCCUPATIONAL New Studies Mills and Nested case–control study of agricultural exposure Yang, 2007 and gastric cancer in UFW cohort Ever worked in area where 2,4-D used 42 1.9 (1.1–3.3) Quartile of lifetime exposure to 2,4-D (lb) 0 58 1.0 1–14 17 2.2 (1.0–4.6) 15–85 14 1.6 (0.7–3.5) 86–1,950 11 2.1 (0.9–5.1) Ekström Case–control study of Swedish residents with gastric et al., 1999 adenocarcinoma All occupational herbicide exposure 75 1.6 (1.1–2.2) Phenoxyacetic acid exposure 62 1.8 (1.3–2.6) Hormoslyr (2,4-D and 2,4,5-T) 48 1.7 (1.2–2.6) 2,4-D only 3 nr (vs 0 controls) MCPA 11 1.8 (0.8–4.1) Duration of exposure Nonexposed to all herbicides 490 1.0 < 1 month 11 1.6 (0.7–3.5) 1–6 months 30 1.9 (1.1–3.2) 7–12 months 7 1.7 (0.6–4.7) > 1 year 13 1.4 (0.6–3.0) Other herbicide exposure 13 1.0 (0.5–1.9) Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 146 0.9 (0.8–1.1) Ever 98 0.9 (0.7–1.1) ’t Mannetje Phenoxy herbicide producers (men and women) 2 1.1 (0.1–4.0) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 3 1.4 (0.3–4.0) continued

226 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-6  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Alavanja AHS—incidence (all digestive cancers) et al., 2005 Private applicators (men and women) 462 0.8 (0.8–0.9) Spouses of private applicators (> 99% women) 161 0.9 (0.7–1.0) Commercial applicators (men and women) 24 1.0 (0.6–1.4) Blair et al., AHS (stomach cancers) 2005a Private applicators (men and women) 10 0.5 (0.2–1.0) Spouses of private applicators (> 99% women) 4 1.1 (0.3–2.8) Lee et al., Population-based case–control—agricultural 2004a pesticide use and adenocarcinoma of stomach 170 Insecticides 0.9 (0.6–1.4) Herbicides 0.9 (0.5–1.4) Torchio Italian licensed pesticide users 126 0.7 (0.6–0.9) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 (incidence) 13 2.2 (1.3–3.9) Studies Reviewed in Update 2004 Bodner Dow production workers (included in the IARC et al., 2003 cohort, NIOSH Dioxin Registry) nr 1.5 (0.7–2.7) Swaen Dutch licensed herbicide applicators (stomach and et al., 2004 small intestine) 3 0.4 (0.1–1.3) Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in the 2001 IARC cohort, NIOSH Dioxin Registry) Digestive organs, peritoneum 16 0.7 (0.4–1.2) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 13 1.0 (0.6–1.8) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) 3 1.0 (0.2–2.9) Rix et al., Danish paper-mill workers—incidence 1998 Men 48 1.1 (0.8–1.4) Women 7 1.0 (0.4–2.1) Studies Reviewed in Update 1998 Gambini Italian rice growers 39 1.0 (0.7–1.3) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 72 0.9 (0.7–1.1) Exposed to highly chlorinated PCDDs 42 0.9 (0.7–1.2) Not exposed to highly chlorinated PCDDs 30 0.9 (0.6–1.3) Becher German production workers (included in IARC et al., 1996 cohort) Plant I 12 1.3 (0.7–2.2) Plant II 0 nr Plant III 0 nr Plant IV 2 0.6 (0.1–2.3)

CANCER 227 TABLE 6-6  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Ott and BASF employees—incidence 3 1.0 (0.2–2.9) Zober, 1996 TCDD < 0.1 µg/kg of body weight 0 0.0 (0.0–3.4) TCDD 0.1–0.99 µg/kg of body weight 1 1.3 (0.0–7.0) TCDD ≥ 1 µg/kg of body weight 2 1.7 (0.2–6.2) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0-year latency 4 1.7 (0.5–4.3) 15-year latency 3 1.8 (0.4–5.2) Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 657 1.0 (1.0–1.1) White women 12 1.2 (0.6–2.0) Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort) 2 0.7 (0.1–2.7) et al., 1993 Collins Monsanto Company workers (included in NIOSH et al., 1993 cohort) 0 0.0 (0.0–1.1) Kogevinas IARC cohort—women et al., 1993 1 1.4 (nr) Studies Reviewed in VAO Ronco et al., Danish farm workers—incidence 1992 Men 286 0.9 (nr) Women 5 1.0 (nr) Swaen Dutch licensed herbicide applicators (stomach and et al., 1992 small intestine) 1 0.5 (0.0–2.7) Fingerhut NIOSH—entire cohort 10 1.0 (0.5–1.9) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 4 1.4 (0.4–3.5) Manz et al., German production workers—men, women 1991 (included in IARC cohort) Men 12 1.2 (0.6–2.1) Saracci IARC cohort—exposed subcohort (men and women) 40 0.9 (0.6–1.2) et al., 1991 Wigle et al., Canadian farmers 246 0.9 (0.8–1.0) 1990 Zober et al., 90% CI 1990 BASF employees—basic cohort 3 3.0 (0.8–7.7) Alavanja USDA forest, soil conservationists 9 0.7 (0.3–1.3) et al., 1989 Henneberger New Hampshire pulp and paper workers 5 1.2 (0.4–2.8) et al., 1989 Solet et al., US paper and pulp workers 1 0.5 (0.1–3.0) 1989 Alavanja USDA agricultural extension agents 10 0.7 (0.4–1.4) et al., 1988 continued

228 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-6  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 0 nr (0.0–3.7) Thomas, Expected exposed 1987 US flavor and fragrance chemical plant workers 6 cases 4.2 Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 26 0.9 (0.6–1.3) Robinson 90% CI et al., 1986 Northwestern US paper and pulp workers 17 1.2 (0.8–1.9) Lynge, 1985 Danish production workers—incidence (included in IARC cohort) Men 12 1.3 (nr) Women 1 0.7 (nr) Blair et al., Expected exposed 1983 cases Florida pesticide applicators 4 3.3 Burmeister Iowa residents—farming exposures et al., 1983 1,812 1.3 (p < 0.05) Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 2,599 1.1 (1.0–1.2) Burmeister, Iowa farmers 1981 338 1.1 (p < 0.01) Axelson Swedish railroad workers—total exposure 3 2.2 (nr) et al., 1980 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 3 0.7 (0.2–2.0) Zone B 24 0.8 (0.5–1.2) Zone R 212 1.0 (0.8–1.1) Studies Reviewed in Update 2004 Fukuda Residents of Japanese municipalities with and Age-adjusted et al., 2003 without waste-incineration plants mortality (per Men 100,000) With 38.2 ± 7.8 vs 39.0 Without ± 8.8 (p = 0.29) Women With 20.7 ± 5.0 vs 20.7 Without ± 5.8 (p = 0.92) Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia et al., 2001 Men 59 1.7 (1.3–2.2) Women 45 0.7 (0.5–0.9) Studies Reviewed in Update 2000

CANCER 229 TABLE 6-6  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B— en m 16 0.9 (0.5–1.5) women 11 1.0 (0.6–1.9) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone A—women 1 0.9 (0.0–5.3) Zone B— en m 10 0.8 (0.4–1.5) women 7 1.0 (0.4–2.1) Zone R— en m 76 0.9 (0.7–1.1) women 58 1.0 (0.8–1.3) Svensson Swedish fishermen—mortality (men and women) et al., 1995 East coast 17 1.4 (0.8–2.2) West coast 63 0.9 (0.7–1.2) Swedish fishermen—incidence (men and women) East coast 24 1.6 (1.0–2.4) West coast 71 0.9 (0.7–1.2) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone B— en m 7 1.0 (0.5–2.1) women 2 0.6 (0.2–2.5) Zone R— en m 45 0.9 (0.7–1.2) women 25 1.0 (0.6–1.5) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 7 0.9 (0.4–1.8) women 3 0.8 (0.3–2.5) Bertazzi Seveso residents—10-year follow-up et al., 1989a Zones A, B, R— en m 40 0.8 (0.6–1.2) women 22 1.0 (0.6–1.5) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone B—men 7 1.2 (0.6–2.6) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; UFW, United Farm Workers of America; USDA, US Department of Agriculture. a Subjects are male and outcome is mortality unless otherwise noted. b Given when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort.

230 VETERANS AND AGENT ORANGE: UPDATE 2008 California has maintained a pesticide-reporting program since the early 1970s for many restricted-use chemicals and implemented full-use reporting in 1990. Union records indicate when and where the workers were employed, and grower contracts indicate in what crop or commodity the workers were involved. Link- ages with the Department of Pesticide Regulation were used to determine what pesticides were applied to the crops in a given county or month and year. Controls (n = 210) were matched on age, sex, ethnicity (predominantly Hispanic), and being alive and a California resident up to the date of the cases’ diagnoses. Ever working in areas with high use of 2,4-D was associated with gastric cancer (odds ratio [OR], 1.85, 95% CI 1.05–3.25). The ORs for 2,4-D exposure and gastric cancer were about twice as high in the second and fourth quartiles of use as in the nonexposed (first quartile), but a pattern of increased risk was not seen when the low-exposure group (second quartile) was used as the referent. Gastric cancer was also associated with use of the insecticide chlordane (OR = 2.96, 95% CI 1.48–5.94), use of the acaricide propargite (OR = 2.86, 95% CI 1.56–5.23), use of the herbicide triflurin (OR = 1.69, 95% CI 0.99–2.89), and citrus-crop employ- ment (OR = 2.88, 95% CI 1.02–8.12). The authors were not able to adjust their data for socioeconomic status (SES), alcohol intake, or smoking. The association with 2,4-D did not differ between cardia and noncardia gastric cancers or between diffuse and intestinal cancers. Mills and Yang (2007) compared their results with those of Ekström et al. (1999). The publication by Ekström et al. was reviewed with the epidemiologic studies in Update 2000, but specific results for gastric cancer were not included in the cancer chapter of that review. The Ekström et al. study included all Swedish- born people who were 40–79 years old and living in either of two areas with different rates of gastric cancer (total population, 1.3 million) during 1989–1995. In-person interviews were conducted with 567 people who had histologically confirmed gastric adnenocarcinoma newly diagnosed in the study period and 1,165 population-based controls who were frequency-matched for age and sex. All employment of at least 1 year’s duration was coded with a five-digit clas- sification of occupational titles. Work in each industry was analyzed as ever vs never and stratified by duration (1–10 years vs more than 10 years). Interviewers asked open-ended questions about exposures to occupational chemicals, includ- ing pesticides. Occupational epidemiologists who were blinded to case–control status assigned exposure status to subjects and estimated cumulative duration of exposure to each agent. Pesticides were divided into herbicides (phenoxyacetic acids and others), insecticides (DDT and others) and fungicides, and the year of withdrawal or banning was considered when applicable. The risk of gastric cancer was increased after exposure to herbicides (OR = 1.56, 95% CI 1.13–2.15). Further stratification by herbicide type revealed that those ever exposed to phenoxyacetic acids had an 80% excess risk (OR = 1.80, 95% CI 1.26–2.57) after adjustment for age and sex. With additional adjustment for SES, place of residence, number of siblings, and diet, the results of exposure

CANCER 231 to phenoxyacetic acid herbicides were similar among tumor subtypes and were not affected by smoking, alcohol consumption, body-mass index, or Helicobacter pylori status. The maximum risk was observed in cases exposed to both H. pylori and phenoxyacetic acids (OR = 3.42, 95% CI 1.41–8.26). The cases that had been exposed to Hormoslyr, a combination of 2,4-D and 2,4,5-T, had a risk (OR = 1.73, 95% CI 1.16–2.58) similar to that of the smaller number who had been exposed to 2-methyl-4-chlorophenoxyacetic acid (OR = 1.84, 95% CI 0.82–4.10). Although there was a marginally significant trend (p = 0.03) with duration of exposure to phenoxyacetic acid herbicides, there was no marked indication of a dose–response relationship. There was no association between exposure to other herbicides or insecticides and gastric cancer. An earlier study by Cocco et al. (1999) was reviewed by the current commit- tee. This case–control study focused on gastric-cancer mortality in 24 US states in 1984–1996. “Herbicide” was one of 12 workplace exposures encoded from occupation and industry information on death certificates. Type and intensity of exposure was determined by applying job exposure matrices to the occupation and industry combinations. Intensity of exposure was estimated on the basis of industrial-hygiene and occupational-health references and NIOSH and Occupa- tional Safety and Health Administration databases. The ORs for men (white or black) and for black women fluctuated around 1.0, but findings were significant for white women with high probability of exposure to herbicides (OR = 1.71, 95% CI 1.18–2.46) or medium (OR = 3.26, 95% CI 1.07–9.99) or high (OR = 1.60, 95% CI 1.11–2.31) intensity of exposure to herbicides. No specific informa- tion was obtained regarding the specificity of the herbicides and whether the cases were exposed to any of the chemicals of interest for this review. Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso cohort of 273,108 subjects resident at the time of the accident or immigrating or born in the 10 years thereafter. Analyses were performed accord- ing to three zones with increasing TCDD contamination in the soil. In the overall sample, no statistically significant increases in deaths related to stomach cancer were observed. In the zone with greatest TCDD contamination, three stomach- cancer deaths were observed (relative risk [RR] = 0.65, 95% CI 0.21–2.03). The middle-contamination zone had 24 stomach-cancer deaths (RR = 0.78, 95% CI 0.52–1.17), and the lowest-contamination zone had 212 stomach-cancer deaths (RR = 0.95, 95% CI 0.82–1.09). Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest (2-4-D and TCDD) on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of gastrointestinal cancer has been reported in laboratory animals.

232 VETERANS AND AGENT ORANGE: UPDATE 2008 However, studies performed in laboratory animals have observed dose-dependent increases in the incidence of squamous-cell hyperplasia of the forestomach or fundus of the stomach after administration of TCDD (Hebert et al., 1990; Walker et al., 2006). Similarly, in a long-term TCDD-treatment study performed in monkeys, hypertrophy, hyperplasia, and metaplasia were observed in the gastric epithelium (Allen et al., 1977). In addition, a transgenic mouse bearing a con- stitutively active form of the AHR has been shown to develop stomach tumors (Andersson et al., 2002a). The tumors are neither dysplastic nor metaplastic but are indicative of both squamous and intestinal metaplasia (Andersson et al., 2005). The validity of the transgenic-animal model is indicated by the similarities in the phenotype of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of the AHR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006). The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The two occupational studies reporting significant findings regarding a rela- tionship between stomach cancer and exposure to phenoxyacetic acid herbicides considered in this review have several strengths. The Swedish study by Ekström et al. (1999) is based on a large number of cases on which data were available for dietary factors, lifetime SES, smoking, alcohol intake, and infection by H. pylori. Data were available for specific pesticide groups, and the increased risk was observed for the phenoxyacetic acids and not other herbicides. The Mills and Yang (2007) case–control study also included employment history on dates, loca- tion, and primary crop. Pesticide reporting in California was used to determine what pesticides a worker was most likely to be exposed to and thereby avoided potential errors in self-reporting but resulted in a somewhat ecologic exposure assessment. The exposures occurred in the 2 decades before the diagnosis of cancer and are used extensively in California agriculture. The significant findings were dampened somewhat by the reported findings of a significant relationship of gastric cancer with agents not included in the chemicals of interest for this review, including the insecticide chlordane, the acaricide propargite and the her- bicide triflurin. The study by Cocco et al. (1999) was not specific as to type of herbicide, and Update 2006 reviewed a study by Reif et al. (1989) that reported a significant relationship between stomach cancer and the nonspecific exposure of being a forestry worker. The Mills and Yang (2007) and Ekström et al. (1999) occupational studies are well done and indicative of an association between the chemicals of interest and stomach cancer, but there has been no suggestion of an association between the chemicals of interest and stomach cancer in the studies of Vietnam-veteran cohorts, the IARC cohort studies, or the US Agricultural Health Study (AHS).

CANCER 233 There is some evidence of biologic plausibility in animal models, but overall the epidemiologic studies do not support an association between exposure to the chemicals of interest and stomach cancer. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and stomach cancer. Colorectal Cancer Colorectal cancers include malignancies of the colon (ICD-9 153) and of the rectum and anus (ICD-9 154); less prevalent tumors of the small intestine (ICD-9 152) are often included. Findings on cancers of the retroperitoneum and other unspecified digestive organs (ICD-9 159) are considered in this category. Colorectal cancers account for about 55% of digestive tumors; ACS estimated that 159,990 people would develop new cases in the United States in 2008 and 51,750 would die from the cancers (Jemal et al., 2008a). Excluding basal-cell and squamous-cell skin cancers, colorectal cancer is the third-most common form of cancer both in men and in women. The incidence of colorectal cancer increases with age; it is higher in men than in women and higher in blacks than in whites. Because it is recommended that all persons over 50 years old receive colon-cancer screening, screening can affect the incidence. Other risk factors include family history of this form of can- cer, some diseases of the intestines, and diet. Type 2 diabetes is associated with an increased risk of cancer of the colon (ACS, 2007a). Conclusions from VAO and Previous Updates Update 2006 considered colorectal cancer independently for the first time. Prior updates developed tables of results on colon and rectal cancer, but conclu- sions about the adequacy of the evidence of their association with herbicide ex- posure had been reached only in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including colorectal cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain this negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Colorectal cancer was thus reclassified to

234 VETERANS AND AGENT ORANGE: UPDATE 2008 the default category of inadequate or insufficient evidence to determine whether there is an association. Table 6-7 summarizes the results of the relevant studies concerning colon and rectal cancers. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed data on two cohorts of female veterans who served in Vietnam (the Vietnam- veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-causes mortality and cause-specific mortality in the Vietnam-veteran and era-veteran cohorts, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Eleven cases of large intestine–cancer deaths were observed in the Vietnam veterans (crude rate, 0.75/10,000) compared with 29 in the era veterans, for an adjusted standardized mortality ratio (SMR) of 0.50 (95% CI 0.24–1.04). No excess risk was observed in the nurses-only analysis (SMR = 0.59, 95% CI 0.26–1.37). Occupational Studies  Lee WJ et al. (2007) analyzed 305 incident cases of colorectal cancer (212 colon and 93 rectal) diagnosed in 1993–2005 in the AHS. The association with self-reported exposures to 50 pesticides (including 2,4-D, 2,4,5-T, and 2,4,5-trichlorophenoxypropionic acid) was studied. Some, including chlorpyrifos and aldicarb, were associated with an increased risk for rectal cancer and colon cancer, respectively. 2,4-D had a significant inverse association with colon cancer. The lack of a monotonic exposure–response pattern with lifetime exposure weakens somewhat the argument for a true protective relationship, but further evaluation of this inverse association in the AHS cohort is planned. Samanic et al. (2006) reported on the incidence of all cancers, including those of the colon, in male pesticide applicators in the AHS with respect to re- ported exposures to dicamba (3,6-dichloro-2-methoxybenzoic acid), a benzoic acid herbicide with a chemical structure similar to that of phenoxy herbicides. Dicamba is used in combination with other herbicides, such as 2,4-D. The au- thors reported significant trends of increasing risk of colon cancer with lifetime exposure days and with intensity-weighted lifetime days when the referent group comprised low-exposed applicators. Only the RRs for the highest-exposure cat- egory were significant (lifetime days RR = 3.29, 95% CI 1.40–7.73; p trend, 0.02; intensity-weighted lifetimes days RR = 2.57, 95% CI 1.28–5.17; p trend, 0.002). That trend was not observed when the referent group comprised applicators who never used dicamba. There were no differences when analysis was restricted to only applicators who first applied dicamba before 1990. Hansen et al. (2007) included colorectal-cancer deaths in their historical co- hort study of 3,156 male gardeners followed from 1975 until 2002. Although their study did not include specific types of pesticide exposure, the Danish National Environmental Board reports that 2,4-D and other chlorophenoxy acids were

CANCER 235 TABLE 6-7  Selected Epidemiologic Studies—Colon and Rectal Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women 29 0.5 (0.2–1.0) Kang, 2008 Vietnam-veteran nurses 11 0.6 (0.2–1.4) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population Colon—incidence 376 1.1 (1.0–1.2) Navy 91 1.3 (1.0–1.5) Army 239 1.1 (0.9–1.2) Air Force 47 1.1 (0.8–1.5) Rectum—incidence Navy 54 1.1 (0.8–1.4) Army 152 1.0 (0.8–1.1) Air Force 28 1.0 (0.6–1.4) ADVA, Australian male Vietnam veterans vs Australian 2005b population Colon—mortality 176 1.0 (0.8–1.1) Navy 49 1.3 (0.9–1.6) Army 107 0.9 (0.7–1.0) Air Force 21 0.9 (0.5–1.3) Rectum—mortality Navy 13 0.8 (0.4–1.4) Army 44 0.9 (0.6–1.1) Air Force 12 1.3 (0.6–2.2) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Colon Incidence 54 0.9 (0.7–1.4) Mortality 29 0.8 (0.5–1.3) Rectum Incidence 46 1.4 (0.9–2.2) Mortality 10 1.8 (0.6–5.6) Boehmer Follow-up of CDC Vietnam Experience et al., 2004 Cohort—mortality Colon, rectum, and anus 9 1.0 (0.4–2.6) Studies Reviewed in Update 2000 AFHS, 2000 Ranch Hand veterans from AFHS—mortality Colon, rectum combined 7 1.5 (0.4–5.5) AIHW, 1999 Australian Vietnam veterans (men)—incidence Expected number (validation study) of exposed cases (95% CI) Colorectal cancer 188 221 (191–251) CDVA, Australian Vietnam veterans (men)—incidence 1998a Self-reported colon cancer 405 117 (96–138) continued

236 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b CDVA, Australian Vietnam veterans (women)—incidence 1998b Self-reported colon cancer 1 1.0 (0–5) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans—mortality 1997a Colon 78 1.2 (0.9–1.5) Rectum 16 0.6 (0.4–1.0) CDVA, Australian National Service Vietnam 1997b veterans—mortality Colon 6 0.6 (0.2–1.5) Rectum 3 0.7 (0.2–9.5) Studies Reviewed in Update 1996 Dalager US Vietnam veterans (women)—mortality et al., 1995 Colon 4 0.4 (0.1–1.2) Vietnam-veteran nurses—mortality Colon 4 0.5 (0.2–1.7) Studies Reviewed in VAO Breslin Army and Marine Vietnam veterans—mortality et al., 1988 Army Vietnam veterans  Colon, other gastrointestinal (ICD-8 152–154, 158, 159) 209 1.0 (0.7–1.3) Marine Vietnam veterans  Colon, other gastrointestinal (ICD-8 152–154, 158, 159) 33 1.3 (0.7–2.2) Anderson Wisconsin Vietnam veterans—mortality et al., 1986 Colon 6 1.0 (0.4–2.2) Rectum 1 nr OCCUPATIONAL New Studies Lee WJ Pesticide applicators (men and women) in AHS— et al., 2007 colorectal-cancer incidence (enrollment–2002) and any use before enrollment of: 2,4-D 204 0.7 (0.2–0.9) 2,4,5-T 65 0.9 (0.5–1.5) 2,4,5-TP 24 0.8 (0.4–1.5) Dicamba 110 0.9 (0.7–1.2) Samanic Pesticide applicators in AHS—colon-cancer et al., 2006 incidence (enrollment–2002) Dicamba—days of use None 76 1.0 1– < 20 9 0.4 (0.2–0.9) 20– < 56 20 0.9 (0.5–1.5) 56– < 116 13 0.8 (0.4–1.5) ≥ 116 17 1.4 (0.8–2.9) p-trend = 0.10

CANCER 237 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Dicamba—intensity-weighted  quartiles None 76 1.0 Lowest 16 0.6 (0.4–1.1) Second 17 0.7 (0.4–1.2) Third 6 0.5 (0.2–1.2) Highest 20 1.8 (1.0–3.1) p-trend = 0.02 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers—mortality et al., 2006  Ever exposed to nonvolatile organochlorine compounds Colon 62 0.7 (0.6–1.0) Rectum 60 0.9 (0.7–1.1) ’t Mannetje Phenoxy herbicide producers, sprayers—mortality et al., 2005 Phenoxy herbicide producers (men and women) Colon 2 0.6 (0.0–2.3) Rectum, rectosigmoid junction, anus 5 2.5 (0.8–5.7) Phenoxy herbicide sprayers (> 99% men) Colon 8 1.9 (0.8–3.8) Rectum, rectosigmoid junction, anus 4 1.5 (0.4–3.8) Alavanja US AHS—incidence et al., 2005 Colon Private applicators (men and women) 208 0.9 (0.8–1.0) Spouses of private applicators (> 99% women) 87 0.9 (0.7–1.1) Commercial applicators (men and women) 12 1.2 (0.6–2.1) Rectum Private applicators (men and women) 94 0.8 (0.7–1.0) Spouses of private applicators (> 99% women) 23 0.6 (0.4–0.9) Commercial applicators (men and women) 7 1.3 (0.5–2.6) Blair et al., US AHS—mortality 2005a Colon Private applicators (men and women) 56 0.7 (0.6–1.0) Spouses of private applicators (> 99% women) 31 1.2 (0.8–1.6) Rectum Private applicators (men and women) nr nr Spouses of private applicators (> 99% women) nr nr Torchio Italian licensed pesticide users—mortality et al., 1994 Colon 84 0.6 (0.5–0.7) Rectum nr nr Reif et al., New Zealand forestry workers—nested case–control 1989 (incidence) Colon 7 0.5 (0.2–1.1) Small intestine 2 5.2 (1.4–18.9) Rectum 10 1.2 (0.6–2.3) continued

238 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators—mortality et al., 2004 Colon 7 1.0 (0.4–2.1) Rectum 5 2.1 (0.7–4.8) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) Small intestine and colon 34 1.2 (0.8–1.6) Rectum 6 0.9 (0.3–1.9) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) Intestine (except rectum) 3 1.4 (0.3–4.0) Rectum 1 1.0 (0.0–5.6) Rix et al., Danish paper-mill workers—incidence 1998 Men Colon 58 1.0 (0.7–1.2) Rectum 43 0.9 (0.6–1.2) Women Colon 23 1.1 (0.7–1.7) Rectum 15 1.5 (0.8–2.4) Studies Reviewed in Update 1998 Gambini Italian rice growers—mortality et al., 1997 Intestines 27 1.1 (0.7–1.6) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol Colon 86 1.1 (0.9–1.3) Rectum 44 1.1 (0.8–1.4) Exposed to highly chlorinated PCDDs Colon 52 1.0 (0.8–1.3) Rectum 29 1.3 (0.9–1.9) Not exposed to highly chlorinated PCDDs Colon 33 1.2 (0.8–1.6) Rectum 14 0.7 (0.4–1.2)

CANCER 239 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Becher German production workers (included in IARC et al., 1996 cohort)—mortality Plant I Colon 2 0.4 (0.1–1.4) Rectum 6 1.9 (0.7–4.0) Plant II Colon 0 nr Rectum 0 nr Plant III Colon 1 2.2 (0.1–12.2) Rectum 0 nr Plant IV Colon 0 nr Rectum 1 0.9 (0.0–4.9) Ott and BASF employees—colorectal—incidence 5 1.0 (0.3–2.3) Zober, 1996 TCDD < 0.1 µg/kg of body weight 2 1.1 (0.1–3.9) TCDD 0.1–0.99 µg/kg of body weight 2 1.4 (0.2–5.1) TCDD ≥ 1 µg/kg of body weight 1 0.5 (0.0–3.0) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) —mortality 0-year latency Colon 4 0.8 (0.2–2.1) Rectum 0 nr 15-year latency Colon 4 1.0 (0.3–2.6) Rectum 0 nr Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states—mortality 1993 White men Colon 2,291 1.0 (0.9–1.0) Rectum 367 1.0 (0.9–1.1) White women Colon 59 1.0 (0.8–1.3) Rectum 4 0.5 (0.1–1.3) Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort)—mortality et al., 1993 Colon 3 1.8 (0.4–5.4) Rectum 0 nr Collins Monsanto Company workers (included in NIOSH et al., 1993 cohort)—mortality Colon 3 0.5 (0.1–1.3) Studies Reviewed in VAO Swaen Dutch licensed herbicide applicators—mortality et al., 1992 Colon 4 2.6 (0.7–6.5) continued

240 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Ronco et al., Danish workers—incidence 1992 Men—self-employed Colon 277 0.7 (p < 0.05) Rectum 309 0.8 (p < 0.05) Men—employees Colon 45 0.6 (p < 0.05) Rectum 55 0.8 (nr) Women—self-employed Colon 14 0.9 (nr) Rectum 5 0.6 (nr) Women—employees Colon 112 0.9 (nr) Rectum 55 0.8 (nr) Women—family worker Colon 2 0.2 (p < 0.05) Rectum 2 0.4 (nr) Fingerhut NIOSH cohort—mortality et al., 1991 Entire NIOSH cohort Small intestine, colon 25 1.2 (0.8–1.8) Rectum 5 0.9 (0.3–2.1) ≥ 1-year exposure, ≥ 20-year latency Small intestine, colon 13 1.8 (1.0–3.0) Rectum 2 1.2 (0.1–4.2) Manz et al., German production workers (included in IARC 1991 cohort)—mortality Colon 8 0.9 (0.4–1.8) Saracci IARC cohort—exposed subcohort (men and et al., 1991 women)—mortality Colon (except rectum) 41 1.1 (0.8–1.5) Rectum 24 1.1 (0.7–1.6) Zober et al., BASF employees—basic cohort—mortality 90% CI 1990 Colon, rectum 2 2.5 (0.4–7.8) Alavanja USDA forest or soil conservationists—mortality et al., 1989 Colon 44 1.5(1.1–2.0) Rectum 9 1.0 (0.5–1.9) Henneberger New Hampshire pulp and paper workers—mortality et al., 1989 Colon 9 1.0 (0.5–2.0) Rectum 1 0.4 (0.0–2.1) Solet et al., US pulp and paper workers—mortality 1989 Colon 7 1.5 (0.6–3.0) Alavanja USDA agricultural extension agents—mortality et al., 1988 Colon 41 1.0 (0.7–1.5) Rectum 5 nr

CANCER 241 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry)—mortality Colon 4 2.1 (0.6–5.4) Rectum 1 1.7 (0.0–9.3) Thomas, US flavor and fragrance chemical plant 1987 workers—mortality Colon 4 0.6 (nr) Rectum 6 2.5 (nr) Coggon British MCPA production workers (included in the et al., 1986 IARC cohort)—mortality Colon 19 1.0 (0.6–1.6) Rectum 8 0.6 (0.3–1.2) Robinson Northwestern US pulp and paper workers et al., 1986 Intestines (ICD-7 152, 153) 7 0.4 (0.2–0.7) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence Men Colon 10 1.0 (nr) Rectum 14 1.4 (nr) Women Colon 1 0.3 (nr) Rectum 2 1.0 (nr) Blair et al., Florida pesticide applicators—mortality 1983 Colon 5 0.8 (nr) Rectum 2 nr Wiklund, Swedish male and female agricultural 1983 workers—incidence 99% CI Colon 1,332 0.8 (0.7–0.8) Rectum 1,083 0.9 (0.9–1.0) Thiess et al., BASF production workers—mortality 1982 Colon 1 0.4 (nr) Burmeister, Iowa farmers—mortality 1981 Colon 1,064 1.0 (nr) Hardell, Swedish residents—incidence 1981 Colon Exposed to phenoxy acids 11 1.3 (0.6–2.8) Exposed to chlorophenols 6 1.8 (0.6–5.3) continued

242 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A Colon 3 1.0 (0.3–3.0) Rectum 1 0.9 (0.1–6.4) Zone B Colon 12 0.6 (0.3–1.1) Rectum 11 1.5 (0.8–2.8) Zone R Colon 137 0.9 (0.7–1.3) Rectum 50 0.9 (0.7–1.3) Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia—mortality et al., 2001 Men Colon 17 1.3 (0.8–2.2) Rectum 21 1.5 (1.0–2.4) Women Colon 24 1.0 (0.7–1.5) Rectum 24 0.9 (0.6–1.4) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up—mortality et al., 2001 Zones A, B—men Colon 10 1.0 (0.5–1.9) Rectum 9 2.4 (1.2–4.6) Zones A, B—men Colon 5 0.6 (0.2–1.4) Rectum 3 1.1 (0.4–3.5) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up—mortality et al., 1997 Zone A—women Colon 2 2.6 (0.3–9.4) Zone B—men Colon 5 0.8 (0.3–2.0) Rectum 7 2.9 (1.2–5.9) Zone B—women Colon 3 0.6 (0.1–1.8) Rectum 2 1.3 (0.1–4.5) Zone R—men Colon 34 0.8 (0.6–1.1) Rectum 19 1.1 (0.7–1.8) Zone R—women Colon 33 0.8 (0.6–1.1) Rectum 12 0.9 (0.5–1.6)

CANCER 243 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Svensson Swedish fishermen—mortality (men and women) et al., 1995 East coast Colon 1 0.1 (0.0–0.7) Rectum 4 0.7 (0.2–1.9) West coast Colon 58 1.0 (0.8–1.3) Rectum 31 1.0 (0.7–1.5) Swedish fishermen—incidence (men and women) East coast Colon 5 0.4 (0.1–0.9) Rectum 9 0.9 (0.4–1.6) West coast Colon 82 1.0 (0.8–1.2) Rectum 59 1.1 (0.8–1.4) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—morbidity et al., 1993 Zone B—men Colon 2 0.5 (0.1–2.0) Rectum 3 1.4 (.04–4.4) Zone B—women Colon 2 0.6 (0.1–2.3) Rectum 2 1.3 (0.3–5.4) Zone R—men Colon 32 1.1 (0.8–1.6) Rectum 17 1.1 (0.7–1.9) Zone R—women Colon 23 0.8 (0.5–1.3) Rectum 7 0.6 (.03–1.3) Studies Reviewed in VAO Lampi et al., Finnish community exposed to chlorophenol 1992 contamination—incidence Colon—men, women 9 1.1 (0.7–1.8) Pesatori Seveso residents—incidence et al., 1992 Zones A, B—men Colon 3 0.6 (0.2–1.9) Rectum 3 1.2 (0.4–3.8) Zones A, B—women Colon 3 0.7 (0.2–2.2) Rectum 2 1.2 (0.3–4.7) Bertazzi Seveso residents—10-year follow-up—mortality et al., 1989a Zones A, B, R—men Colon 20 1.0 (0.6–1.5) Rectum 10 1.0 (0.5–2.7) Zones A, B, R—women Colon 12 0.7 (0.4–1.2) Rectum 7 1.2 (0.5–2.7) continued

244 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-7  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Bertazzi Seveso residents—10-year follow-up—mortality et al., 1989b Zone B—men Rectum 2 1.7 (0.4–7.0) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; AFHS, Air Force Health Study; AHS, Ag- ricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort. used during the periods when the older members of the cohort were working. No excess deaths from digestive cancers were found in any of the three age cohorts in the study. Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso, Italy, cohort exposed to large amounts of environmental con- tamination with TCDD. The study cohort of 273,108 subjects resident at the time of the accident or immigrating or born in the 10 years thereafter were analyzed according to three zones with increasing levels of soil TCDD. In the overall sample, no statistically significant increases in deaths related to colon or rectal cancer were observed. In the zone with intermediate TCDD contamination, there was a 50% nonsignificant increase in rectal-cancer mortality; the excesses were in males (eight deaths; RR = 1.81, 95% CI 0.89–3.67). Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of colorectal cancer in laboratory animals exposed to the chemicals of interest has been reported. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

CANCER 245 Synthesis The epidemiologic studies reviewed yielded no evidence to suggest an as- sociation between the chemicals of interest and colorectal cancer. There is no evidence of biologic plausibility of an association between exposure to any of the chemicals of interest and the development of tumors of the colon or rectum. Overall, the available evidence does not support an association between the chemicals of interest and colorectal cancer. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and colorectal cancer. Hepatobiliary Cancers Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). ACS estimated that 15,190 men and 6,180 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2008 and 12,570 men and 5,840 women would die from these cancers (Jemal et al., 2008a). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon and are often grouped with liver cancers when they are addressed. In the United States, liver cancers account for about 1.5% of new cancer cases and 3.3% of cancer deaths. Misclassification of metastatic cancers as pri- mary liver cancer can lead to overestimation of the number of deaths attributable to liver cancer (Percy et al., 1990). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. The known risk factors for liver cancer include chronic infection with hepatitis B or C virus and exposure to the carcinogens aflatoxin and vinyl chloride. Alcohol cirrhosis and obesity-associated metabolic syndrome may also contribute to the risk of liver cancer. In the general popula- tion, the incidence of liver and intrahepatic bile duct cancer increases slightly with age; at the ages of 50–64 years, it is greater in men than in women and greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 6-4. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between

246 VETERANS AND AGENT ORANGE: UPDATE 2008 exposure to the chemicals of interest and hepatobiliary cancers. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-8 summarizes the results of the relevant studies. Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies addressing exposure to the chemicals of interest and hepatobiliary cancer have been published since Update 2006. Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso, Italy, cohort exposed to large amounts of environmental con- tamination with TCDD. The study cohort of 273,108 subjects resident at the time of the accident or immigrating or born in the 10 years thereafter were analyzed according to three zones with increasing levels of soil TCDD. In the overall sam- ple, no statistically significant increases in deaths related to biliary tract cancer or liver cancer were observed. In Zone A (very high TCDD contamination), no bili- ary tract cancer deaths were observed; there were three liver-cancer deaths (RR = 1.03, 95% CI 0.33–3.20). The middle-contamination zone (Zone B, high TCDD contamination) had two biliary cancer deaths (RR = 0.56, 95% CI 0.14–2.26) and 16 liver-cancer deaths (RR = 0.86, 95% CI 0.52–1.40). The lowest-contamination zone (Zone R) had 31 biliary cancer deaths (RR = 1.16, 95% CI 0.79–1.70) and 107 liver-cancer deaths (RR = 0.80, 95% CI 0.65–0.98). Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). Studies performed in laboratory animals have consistently demonstrated that long-term exposure to TCDD results in the formation of liver adenomas and carcinomas (Knerr and Schrenk, 2006; Walker et al., 2006). Furthermore, TCDD increases the growth of hepatic tumors that are initiated by the treatment with a complete carcinogen. In addition, changes in liver pathology have been observed after exposure to TCDD and include nodular hyperplasia and massive inflammatory cell infiltration (Walker et al., 2006; Yoshizawa et al., 2007). Inflammation and cancer are strongly intertwined in the development and progression of many cancers, including liver cancers (Mantovani et al., 2008). Similarly, in monkeys treated with TCDD, hyperplasia and an increase in cells that stain positive for alpha-smooth muscle actin have been observed (Korenaga et al., 2007). Postive staining for alpha-smooth muscle actin is thought to be indicative of a process (epithelial–mesenchymal transition) that is associated with the progression of malignant tumors (Weinberg, 2008).

CANCER 247 TABLE 6-8  Selected Epidemiologic Studies—Hepatobiliary Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 27 0.7 (0.4–1.0) Navy 8 1.0 (0.4–1.9) Army 18 0.7 (0.4–1.1) Air Force 1 0.2 (0.0–1.2) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality (liver, gallbladder) 48 0.9 (0.6–1.1) Navy 11 1.0 (0.5–1.7) Army 33 0.9 (0.6–1.2) Air Force 4 0.6 (0.2–1.5) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 2 2.5 (0.1–147.2) Mortality (liver, gallbladder) 4 2.5 (0.4–27.1) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 (liver, intrahepatic bile ducts [ICD-9 155]) 5 nr Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence 2 1.6 (0.2–11.4) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 1997a Liver (ICD-9 155) 8 0.6 (0.2–1.1) Gallbladder (ICD-9 156) 5 1.3 (0.4–2.8) CDVA, Australian National Service Vietnam veterans 1 nr 1997b Studies Reviewed in VAO CDC, 1990a US men born 1921–1953—incidence 8 1.2 (0.5–2.7) Breslin Army Vietnam veterans (liver, bile duct) 34 1.0 (0.8–1.4) et al., 1988 Marine Vietnam veterans (liver, bile duct) 6 1.2 (0.5–2.8) Anderson Wisconsin Vietnam veterans 0 nr et al., 1986 OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 27 0.9 (0.6–1.3) Ever 16 0.7 (0.4–1.1) ’t Mannetje New Zealand phenoxy herbicide workers et al., 2005 (ICD-9 155) Producers (men and women) 1 1.6 (0.0–8.8) Sprayers (> 99% men) 0 0.0 (0.0–4.2) continued

248 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-8  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Alavanja US AHS—incidence et al., 2005 Liver Private applicators (men and women) 35 1.0 (0.7–1.4) Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5) Commercial applicators (men and women) nr 0.0 (0.0–4.2) Gallbladder Private applicators (men and women) 8 2.3 (1.0–4.5) Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5) Commercial applicators (men and women) nr 0.0 (0.0–35.8) Blair et al., US AHS 2005a Liver Private applicators (men and women) 8 0.6 (0.2–1.1) Spouses of private applicators (> 99% women) 4 1.7 (0.4–4.3) Gallbladder Private applicators (men and women) 3 2.0 (0.4–5.7) Spouses of private applicators (> 99% women) 2 1.3 (0.1–4.6) Torchio Italian licensed pesticide users et al., 1994 Liver 15 0.6 (0.3–0.9) Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence Liver 1 0.8 (0.1–5.8) Gallbladder 3 4.1 (1.4–12.0) Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators 0 nr et al., 2004 Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) Liver, biliary tract (ICD-9 155–156) 7 0.9 (0.4–1.6) Rix et al., Danish paper mill workers—incidence 1998 Liver— enm 10 1.1 (0.5–2.0) women 1 0.6 (0.0–3.2) Gallbladder— enm 9 1.6 (0.7–3.0) women 4 1.4 (0.4–3.7) Studies Reviewed in Update 1998 Gambini Italian rice growers 7 1.3 (0.5–2.6) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 15 0.7 (0.4–1.2) Exposed to highly chlorinated PCDDs 12 0.9 (0.5–1.5) Not exposed to highly chlorinated PCDDs 3 0.4 (0.1–1.2) Becher German production workers (included in IARC et al., 1996 cohort) Liver and biliary tract 1 1.2 (0.0–6.9)

CANCER 249 TABLE 6-8  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Ott and BASF employees—incidence 2 2.1 (0.3–7.5) Zober, 1996 Liver, gallbladder, and bile duct TCDD < 0.1 µg/kg of body weight 1 2.8 (0.1–15.5) TCDD 0.1–0.99 µg/kg of body weight 0 0.0 (0.0–15.4) TCDD ≥ 1 µg/kg of body weight 1 2.8 (0.1–15.5) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) Liver, primary (ICDA-8 155–156) 0-year latency 0 nr 15-year latency 0 nr Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators—liver, biliary tract 1994 Incidence 3 0.9 (0.2–2.6) Mortality 2 0.6 (0.1–2.2) Blair et al., US farmers in 23 states 1993 White men 326 1.0 (0.9–1.1) White women 6 0.7 (0.3–1.6) Collins Monsanto Company 2,4-D production workers et al., 1993 (included in NIOSH cohort) Liver, biliary tract 2 1.4 (0.2–5.2) Studies Reviewed in VAO Ronco et al., Danish farm workers—incidence 1992 Liver Men— elf-employed s 23 0.4 (p < 0.05) employees 9 0.8 (nr) Women— amily workers f 5 0.5 (nr) Gallbladder Men— elf-employed s 35 0.8 (nr) employees 7 0.8 (nr) Women— elf-employed s 7 2.7 (p < 0.05) employees 1 0.7 (nr) family workers 17 1.0 (nr) Fingerhut NIOSH—entire cohort (liver, biliary tract)— 6 1.2 (0.4–2.5) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 1 0.6 (0.0–3.3) Saracci IARC cohort—exposed subcohort (men and women) et al., 1991 Liver, gallbladder, bile duct (ICD-8 155–156) 4 0.4 (0.1–1.1) Solet et al., US pulp and paper workers (ICD-8 155–156) 2 2.0 (0.2–7.3) 1989 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) Liver, biliary tract (ICDA-8 155–156) 0 1.2 (nr) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence Men 3 1.0 (nr) Women 0 nr continued

250 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-8  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Hardell Swedish residents—incidence, mortality combined et al., 1984 102 1.8 (0.9–4.0) Wiklund, Swedish male and female agricultural 1983 workers—incidence 99% CI Liver (primary) 103 0.3 (0.3–0.4) Biliary tract 169 0.6 (0.5–0.7) Liver (unspecified) 67 0.9 (0.7–1.3) Zack and Monsanto Company production workers (included in Suskind, NIOSH cohort) 1980 0 nr ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Liver (ICD-9 155) Zone A 3 1.0 (0.3–3.2) Zone B 16 0.9 (0.5–1.4) Zone R 107 0.8 (0.7–1.0) Biliary tract (ICD-9 156) Zone A 0 0.0 (nr) Zone B 2 0.6 (0.1–2.3) Zone R 31 1.2 (0.8–1.7) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B—men  liver, gallbladder) ( 6 0.5 (0.2–1.0) (liver) 6 0.5 (0.2–1.1) women  liver, gallbladder) ( 7 1.0 (0.5–2.2) (liver) 6 1.3 (0.6–2.9) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B—men  liver, gallbladder) ( 4 0.6 (0.2–1.4) (liver) 4 0.6 (0.2–1.6) women  liver, gallbladder) ( 4 1.1 (0.3–2.9) (liver) 3 1.3 (0.3–3.8) Zone R—men  liver, gallbladder) ( 35 0.7 (0.5–1.0) (liver) 31 0.7 (0.5–1.0) women  liver, gallbladder) ( 25 0.8 (0.5–1.3) (liver) 12 0.6 (0.3–1.1) Svensson Swedish fishermen (men and women)—mortality et al., 1995 East coast 1 0.5 (0.0–2.7) West coast (liver, bile ducts) 9 0.9 (0.4–1.7) Swedish fishermen (men and women)—incidence East coast 6 1.3 (0.5–2.9) West coast (liver, bile ducts) 24 1.0 (0.6–1.5)

CANCER 251 TABLE 6-8  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone B—men  liver) ( 4 2.1 (0.8–5.8) (gallbladder—ICD-9 156) 1 2.3 (0.3–17.6) women (gallbladder—ICD-9 156) 4 4.9 (1.8–13.6) Zone R—men  liver) ( 3 0.2 (0.1–0.7) (gallbladder—ICD-9 156) 3 1.0 (0.3–3.4) women  liver) ( 2 0.5 (0.1–2.1) (gallbladder—ICD-9 156) 7 1.0 (0.5–2.3) Cordier Military service in South Vietnam for ≥ 10 years et al., 1993 after 1960 11 8.8 (1.9–41.0) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zone A, B— en (liver) m 4 1.5 (0.5–4.0) (gallbladder—ICD-9 156) 1 2.1 (0.3–15.6) women  liver) ( 1 1.2 (0.2–9.1) (gallbladder—ICD-9 156) 5 5.2 (2.1–13.2) Zone R—men  liver) ( 8 0.5 (0.2–0.9) (gallbladder—ICD-9 156) 3 1.0 (0.3–3.4) women  liver) ( 5 0.8 (0.3–2.1) (gallbladder—ICD-9 156) 7 1.0 (0.5–2.3) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone A—women (gallbladder—ICD-9 156) 1 12.1 (1.6–88.7) Zone B— en (liver) m 3 1.2 (0.4–3.8) women (gallbladder—ICD-9 156) 2 3.9 (0.9–16.2) Zone R— en (liver) m 7 0.4 (0.2–0.8) women  liver) ( 3 0.4 (0.1–1.4) (gallbladder—ICD-9 156) 5 1.2 (0.5–3.1) Hoffman Residents of Quail Run Mobile Home Park (men et al., 1986 and women) 0 nr ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; ICDA, International Classification of Diseases, Adapted for Use in the United States; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of the same cohort.

252 VETERANS AND AGENT ORANGE: UPDATE 2008 With respect to cancers of the bile duct, bile duct hyperplasia, but not tumors, has been reported (Knerr and Schrenk, 2006; Walker et al., 2006; Yoshizawa et al., 2007). Similarly, monkeys treated with TCDD developed metaplasia, hyperplasia, and hypertrophy of the bile duct (Allen et al., 1977). Hollingshead et al. (2008) recently showed that TCDD-activated AHR in human breast and endocervical cell lines induces sustained high concentrations of the IL–6 cytokine, which has tumor-promoting effects in numerous tissues, including cholangiocytes, so TCDD might promote carcinogenesis in biliary tissue. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis For this update, no new reports of a definitive link between exposure to the chemicals of interest and hepatobiliary tumors were found. Despite the evi- dence of TCDD’s activity as a hepatocarcinogen in animals, the evidence from epidemiologic studies remains inadequate to link the chemicals of interest with hepatobiliary cancer, which occurs at a relatively low incidence in Western populations. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and hepatobiliary cancer. Pancreatic Cancer The incidence of pancreatic cancer (ICD-9 157) increases with age. ACS estimated that 18,770 men and 18,910 women would develop pancreatic cancer in the United States in 2008 and that 17,500 men and 16,790 women would die from it (Jemal et al., 2008a). The incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history, diet, and tobacco use; the incidence is about twice as high in smokers as in nonsmokers (Miller et al., 1996). Chronic pancreatitis, obesity, and type 2 diabetes are also associated with an increased risk of pancreatic cancer (ACS, 2006). Conclusions from VAO and Previous Updates Update 2006 considered pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer but reached con- clusions about the adequacy of the evidence of its association with herbicide

CANCER 253 exposure in the context of gastrointestinal tract cancers. The committee respon- sible for VAO concluded that there was limited or suggestive evidence of no as- sociation between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including pancreatic cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Pancreatic cancer was thus reclassified to the default category inadequate or insufficient evidence of an association. That com- mittee reviewed the increased rates of pancreatic cancer in Australian National Service Vietnam veterans but concluded that the increased rates could be attrib- uted to the rates of smoking in the cohort (ADVA, 2005c). The committee also noted the report of increased rates of pancreatic cancer in US female Vietnam nurse veterans (Dalager et al., 1995). Table 6-9 summarizes the results of the relevant studies concerning pancreatic cancer. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam- veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-causes mortality and cause-specific mortality through 2004 in the Vietnam-veteran and era-veteran cohorts and earlier research were compared. Similar analyses were performed for nurses only. Seventeen deaths from pancreatic cancer were observed in the Vietnam-veteran groups and 16 in the era-veteran group, for an adjusted RR of 2.12 (95% CI 0.99–4.51). The nurse-only group had 14 cases compared with 11 in the corresponding era group (adjusted RR = 2.45, 95% CI 1.00–6.00). A limitation of the study was the in- ability to control for diet and smoking behavior. Occupational Studies  No occupational studies concerning exposure to the chemicals of interest and pancreatic cancer have been published since Update 2006. Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso, Italy, cohort exposed to large amounts of environmental con- tamination with TCDD. The study cohort of 273,108 subjects resident at the time of the accident or immigrating or born in the 10 years thereafter were analyzed according to three zones with increasing levels of soil TCDD. In the overall sam- ple, no statistically significant increase in deaths related to pancreatic cancer was observed. In Zone A (very high TCDD contamination), two pancreatic-­cancer deaths were observed (RR = 1.17, 95% CI 0.29–4.68). The middle-­contamination

254 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-9  Selected Epidemiologic Studies—Pancreatic Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women 17 2.1 (1.0–4.5) Kang, 2008 Vietnam-veteran nurses 14 2.5 (1.0–6.0) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 86 1.2 (0.9–1.4) Navy 14 0.9 (0.5–1.5) Army 60 1.2 (0.9–1.5) Air Force 12 1.3 (0.7–2.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 101 1.2 (1.0–1.5) Navy 18 1.0 (0.6–1.6) Army 71 1.3 (1.0–1.6) Air Force 11 1.1 (0.5–1.8) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 17 2.5 (1.0–6.3) Mortality 19 3.1 (1.3–8.3) Boehmer Follow-up of CDC Vietnam Experience Cohort 5 1.0 (0.3–3.5) et al., 2004 Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 38 1.4 (0.9–1.8) 1997a CDVA, Australian National Service Vietnam veterans 6 1.5 (nr) 1997b Studies Reviewed in Update 1996 Dalager US Vietnam veterans—women 7 2.8 (0.8–10.2) et al., 1995 Vietnam-veteran nurses 7 5.7 (1.2–27.0) Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 14 1.0 (0.6–1.7) Non-black 9 0.7 (0.3–1.3) Black 5 9.1 (2.9–21.2) Studies Reviewed in VAO Thomas US Vietnam veterans—women 5 2.7 (0.9–6.2) et al., 1991 Breslin Army Vietnam veterans 82 0.9 (0.6–1.2) et al., 1988 Marine Vietnam veterans 18 1.6 (0.5–5.8) Anderson Wisconsin Vietnam veterans et al., 1986 4 nr OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 67 0.8 (0.7–1.1) Ever 69 1.1 (0.9–1.4)

CANCER 255 TABLE 6-9  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ’t Mannetje Phenoxy herbicide producers (men and women) 3 2.1 (0.4–6.1) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 0 0.0 (0.0–2.1) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 46 0.7 (0.5–1.0) Spouses of private applicators (> 99% women) 20 0.9 (0.6–1.4) Commercial applicators (men and women) 3 1.1 (0.2–3.2) Blair et al., US AHS 2005a Private applicators (men and women) 29 0.6 (0.4–0.9) Spouses of private applicators (> 99% women) 10 0.7 (0.3–1.2) Torchio Italian licensed pesticide users 32 0.7 (0.5–1.0) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 6 1.8 (0.8–4.1) Magnani UK case–control et al., 1987 Herbicides nr 0.7 (0.3–1.5) Chlorophenols nr 0.8 (0.5–1.4) Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators 5 1.2 (0.4–2.7) et al., 2004 Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 16 1.0 (0.6–1.6) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) 4 2.5 (0.7–6.3) Rix et al., Danish paper-mill workers—incidence 1998 Men 30 1.2 (0.8–1.7) Women 2 0.3 (0.0–1.1) Studies Reviewed in Update 1998 Gambini Italian rice growers 7 0.9 (0.4–1.9) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 47 0.9 (0.7–1.3) Exposed to highly chlorinated PCDDs 30 1.0 (0.7–1.4) Not exposed to highly chlorinated PCDDs 16 0.9 (0.5–1.4) Becher German production workers (included in IARC et al., 1996 cohort) Plant I 2 0.6 (0.1–2.3) Plant II 0 nr Plant III 0 nr Plant IV 2 1.7 (0.2–6.1) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0-year latency 2 0.7 (0.1–2.7) 15-year latency 2 0.9 (0.1–3.3) continued

256 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-9  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 1,133 1.1 (1.1–1.2) White women 23 1.0 (0.6–1.5) Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort) 3 2.2 (0.5–6.3) et al., 1993 Studies Reviewed in VAO Ronco et al., Danish farm workers—incidence 1992 Men— elf-employed s 137 0.6 (p < 0.05) employees 23 0.6 (p < 0.05) Women— elf-employed s 7 1.2 (nr) employees 4 1.3 (nr) family workers 27 0.7 (p < 0.05) Swaen Dutch licensed herbicide applicators et al., 1992 3 2.2 (0.4–6.4) Fingerhut NIOSH—entire cohort 10 0.8 (0.4–1.6) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 4 1.0 (0.3–2.5) Saracci IARC cohort—exposed subcohort (males, females) et al., 1991 26 1.1 (0.7–1.6) Alavanja USDA forest, soil conservationists et al., 1989 22 1.5 (0.9–2.3) Henneberger New Hampshire paper and pulp workers et al., 1989 9 1.9 (0.9–3.6) Solet et al., US pulp and paper workers 1989 1 0.4 (0.0–2.1) Alavanja USDA agricultural extension agents et al., 1988 21 1.3 (0.8–1.9) Thomas, US flavor and fragrance chemical plant workers 1987 6 1.4 (nr) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 9 0.7 (0.3–1.4) Robinson 90% CI et al., 1986 Northwestern US paper and pulp workers 4 0.3 (0.1–0.8) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence Men 3 0.6 (nr) Women 0 nr Blair et al., Expected exposed 1983 cases Florida pesticide applicators 4 4.0 Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 777 0.8 (0.8–0.9) Burmeister, Iowa farmers 416 1.1 (nr) 1981

CANCER 257 TABLE 6-9  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ENVIRONMENTAL New Studies Consonni Seveso residents (men and women)—25-year et al., 2008 follow-up Zone A 2 1.2 (0.3–4.7) Zone B 5 0.5 (0.2–1.1) Zone R 76 1.0 (0.7–1.7) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B—men 4 0.7 (0.3–1.9) women 1 0.3 (0.0–2.0) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone A—men 1 1.9 (0.0–10.5) Zone B— en m 2 0.6 (0.1–2.0) women 1 0.5 (0.0–3.1) Zone R— en m 20 0.8 (0.5–1.2) women 11 0.7 (0.4–1.3) Svensson Swedish fishermen (men and women)—mortality et al., 1995 East coast 5 0.7 (0.2–1.6) West coast 33 0.8 (0.6–1.2) Swedish fishermen (men and women)—incidence East coast 4 0.6 (0.2–1.6) West coast 37 1.0 (0.7–1.4) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 2 1.0 (0.3–4.2) women 1 1.6 (0.2–12.0) Bertazzi Seveso residents—10-year follow-up et al., 1989a Zones A, B, R— en m 9 0.6 (0.3–1.2) women 4 1.0 (0.3–2.7) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone B—men 2 1.1 (0.3–4.5) ABBREVIATIONS: AHS, Agricultural Health Study; CDC, Centers for Disease Control and Preven- tion; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl- 4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort.

258 VETERANS AND AGENT ORANGE: UPDATE 2008 zone (Zone B, high TCDD contamination) had five pancreatic-cancer deaths (RR = 0.45, 95% CI 0.19–1.09), and the lowest-contamination zone (Zone R) had 76 (RR = 0.95, 95% CI 0.74–1.21). Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of pancreatic cancer in laboratory animals after the administration of cadodylic acid, 2-4-D, or picloram has been reported. A 2-year study of female rats has reported increased incidences of pancreatic adenomas and carcinomas after treatment at the highest dose of TCDD (100 ng/kg per day) (Nyska et al., 2004). Other studies have observed chronic active inflammation, acinar-cell vacuolation, and an increase in proliferation of the acinar cells surrounding the vacuolated cells (Yoshizawa et al., 2005b). As previously discussed, both chronic inflammation and hyperproliferation are closely linked to the formation and progression of cancers, including that of the pancreas (Hahn and Weinberg, 2002; Mantovani et al., 2008). Metaplastic changes in the pancreatic ducts were also observed in female monkeys treated with TCDD (Allen et al., 1977). The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The large excess of pancreatic cancers in female Vietnam veterans vs their nondeployed counterparts observed by Thomas et al. (1991) and Dalager et al. (1995) has prevailed and is now significant for all the female Vietnam veterans, as well as for the nursing subset. The committee responsible for Update 2006 also reported a higher incidence of and mortality from pancreatic cancer in deployed Australian National Service veterans than in nondeployed veterans (ADVA, 2005c). No increase in risk has been reported to date in US male Vietnam veter- ans or in agricultural cohorts or IARC follow-up studies. A limitation of all of the veteran studies has been the lack of control for the effect of smoking and a lack of supportive data from occupational or environmental studies. The association that has been observed, particularly in women, is moderately plausible. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and pancreatic cancer.

CANCER 259 LARYNGEAL CANCER ACS estimated that 9,680 men and 2,570 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2008 and that 2,910 men and 760 women would die from it (Jemal et al., 2008a). Those numbers constitute a little more than 0.9% of new cancer diagnoses and 0.7% of cancer deaths. The incidence of cancer of the larynx increases with age, and it is more common in men than in women, with a sex ratio in the United States of about 4:1 in people 50–64 years old. The average annual incidence of laryngeal cancer is shown in Table 6-10. Established risk factors for laryngeal cancer are tobacco use and alcohol use, which are independent and act synergistically. Occupational exposures—long and intense exposures to wood dust, paint fumes, and some chemicals used in the metalworking, petroleum, plastics, and textile industries—also could increase risk (ACS, 2007b). An Institute of Medicine committee recently concluded that asbestos is a causal factor in laryngeal cancer (IOM, 2006); infection with hu- man papilloma virus might also raise the risk of laryngeal cancer (Hobbs and Birchall, 2004). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest and laryngeal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-11 summarizes the results of the relevant studies. TABLE 6-10  Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 9.4 9.0 18.3 14.6 13.7 29.7 21.8 21.3 39.9 Women 2.2 2.1 3.7 3.2 3.1 7.1 4.7 4.8 7.5 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

260 VETERANS AND AGENT ORANGE: UPDATE 2008 Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies addressing exposure to the chemicals of interest and laryngeal cancer have been published since Update 2006. Environmental Studies Investigators in Italy completed a 25-year mortality follow-up of people ex- posed to the industrial accident in Seveso (Consonni et al., 2008). Mortality from respiratory cancer (ICD 160–165) in residents in three exposure zones—very high (Zone A), high (Zone B), and low (Zone R)—was compared with that in a nonexposed reference population. Laryngeal-cancer mortality was not evalu- ated independently; however, excluding lung-cancer cases (ICD-162) from all respiratory-cancer cases results in a maximum of no, eight, and 49 deaths in Zones A, B, and R, respectively, that could possibly be attributed to laryngeal cancer. There was no evidence of increased mortality in any of the exposure groups. Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of laryngeal cancer in laboratory animals after the administration of any of the chemicals of interest have been reported. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The present committee, as part of its reassessment of all health outcomes, had concerns that the conclusion of limited/suggestive evidence for classify- ing the associations for laryngeal cancer did not meet the current criterion. The original VAO committee had few studies to draw on (see VAO Table 8-10, reproduced here). It stated that “positive associations were found consistently only in those studies in which TCDD or herbicide exposures were probably high and prolonged, especially the largest, most heavily exposed cohorts of chemical production workers exposed to TCDD (Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991) and herbicide applicators (Axelson and Sundell, 1974; Riihimaki et al., 1982; Blair et al., 1983; Green, 1991).” Moreover, the committee conducted a pooled analysis of the data in the table and stated that “although the numbers are too small to draw strong conclusions, the consistency

CANCER 261 TABLE 6-11  Selected Epidemiologic Studies—Laryngeal Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian Vietnam veterans vs Australian 2005a population—incidence 97 1.5 (1.2–1.8) Navy 21 1.5 (0.9–2.1) Army 69 1.6 (1.2–1.9) Air Force 7 0.8 (0.3–1.7) ADVA, Australian Vietnam veterans vs Australian 2005b population—mortality 28 1.1 (0.7–1.5) Navy 6 1.1 (0.4–2.4) Army 19 1.1 (0.7–1.7) Air Force 3 0.9 (0.2–2.5) ADVA, Australian men conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 8 0.7 (0.2–1.6) Mortality 2 0.4 (0.0–2.4) Boehmer CDC Vietnam Experience Cohort 0 0.0 (nr) et al., 2004 Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence Oral cavity, pharynx, larynx 4 0.6 (0.2–2.4) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 12 1.3 (0.7–2.2) 1997a CDVA, Australian National Service Vietnam veterans 0 0 (0– > 10) 1997b Watanabe Army Vietnam veterans compared with US men 50 1.3 (nr) and Kang, Marine Vietnam veterans 4 0.7 (nr) 1996 Army Vietnam veterans 50 1.4 (p < 0.05) OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine chemicals Never 18 0.9 (0.5–1.5) Ever 20 1.2 (0.8–1.9) ’t Mannetje Phenoxy herbicide producers (men and women) 0 nr et al., 2005 Phenoxy herbicide sprayers (> 99% men) 0 nr Torchio Italian farmers licensed to use pesticides 25 0.5 (0.3–0.7) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 2 1.1 (0.3–4.7) Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators 1 1.0 (0.0–5.1) et al., 2004 continued

262 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-11  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2002 Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides Foremen—incidence 0 nr Studies Reviewed in Update 1998 Gambini Italian rice growers 7 0.9 (0.4–1.9) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 21 1.6 (1.0–2.5) Exposed to highly chlorinated PCDDs 15 1.7 (1.0–2.8) Not exposed to highly chlorinated PCDDs 5 1.2 (0.4–2.9) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 2 2.9 (0.3–10.3) 0-year latency 2 2.9 (0.4–10.3) 15-year latency 1 nr Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 162 0.7 (0.6–0.8) White women 0 nr (0.0–3.3) Studies Reviewed in VAO Fingerhut NIOSH—entire cohort 7 2.1 (0.8–4.3) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 3 2.7 (0.6–7.8) Manz et al., German production workers—men, women 1991 (included in IARC cohort) 2 2.0 (0.2–7.1) Saracci IARC cohort (men and women)—exposed subcohort 8 1.5 (0.6–2.9) et al., 1991 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 1 3.0 (0.0–16.8) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 4 1.7 (0.5–4.5) ENVIRONMENTAL New Studies Consonni Seveso residents (men and women)—25-year et al., 2008 follow-up—all respiratory cancers (ICD-9 160–165) excluding reported lung cancers (ICD-9 162) Zone A 0 nr Zone B ≤8 nr Zone R ≤ 49 nr Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia et al., 2001 Men 13 2.3 (1.2–3.8) Women 1 0.1 (0.0–0.6)

CANCER 263 TABLE 6-11  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2000 Bertazzi Seveso residents (men and women)—20-year et al., 2001 follow-up—all respiratory cancers (ICD-9 160–165) excluding reported lung cancers (ICD-9 162) Zone A 0 nr Zone B 8 nr Bertazzi Seveso residents—15-year follow-up—all et al., 1998 respiratory cancers (ICD-9 160–165) excluding reported lung cancers (ICD-9 162) Zone B— enm 6 nr women 0 nr Zone R— ales m 32 nr women 6 nr ABBREVIATIONS: CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr = not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. of a mild elevation in relative risk is suggestive of an association for laryngeal cancer. Pooling all but the Coggon data (Coggon et al., 1986, 1991) yields an OR of 1.8 (95% CI 1.0–3.2).” Since then, a combined analysis of many of the separate cohorts has been conducted (the IARC study, Kogevinas et al., 1997) and has shown significant effects in workers exposed to any phenoxyacetic acid herbicide or chlorophenol (RR = 1.6, 95% CI 1.0–2.5; 21 deaths), especially workers exposed to TCDD (or higher-chlorinated dioxins) (RR = 1.7, 95% CI 1.0–2.8; 15 deaths). Those RRs are remarkably close to the pooled estimate computed by the committee respon- sible for VAO. The study by Kogevinas et al. was a high-quality study that used an excellent method for assessing exposure, and its results were unlikely to be af- fected by confounding, because the distribution of smoking in working cohorts is not likely to differ in exposure (Siemiatycki et al., 1988). Another cohort of pulp and paper workers also showed an increase in risk (RR = 1.2, 95% CI 0.8–1.9; 20 deaths; McLean et al., 2006). With regard to veteran studies, a positive association was found in the study of veterans in Australia that compared mortality with that in the general popula- tion (ADVA, 2005a) but not in the study that compared Australian veterans of

264 VETERANS AND AGENT ORANGE: UPDATE 2008 the Vietnam conflict with nondeployed soldiers (ADVA, 2005c). In contrast, Watanabe and Kang (1996) found a significant 40% excess of mortality in Army personnel deployed to the Vietnam theater. The Ranch Hand study is not large enough to have sufficient power to detect an association if one exists. An environmental study (Revich et al., 2001) of residents of Chapaevsk, Russia, which was heavily contaminated by many industrial pollutants, including dioxin, showed an association in men (RR = 2.3, 95% CI 1.2–3.8). Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one chemical of interest and laryngeal cancer. LUNG CANCER Lung cancer (carcinoma of the lung or bronchus, ICD-9 162.2–162.9) is the leading cause of cancer death in the United States. ACS estimated that 114,690 men and 100,330 women would receive diagnoses of lung cancer in the United States in 2008 and that about 90,810 men and 71,030 women would die from it (Jemal et al., 2008a). Those numbers represent roughly 15% of new cancer diag- noses and 29% of cancer deaths in 2008. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma (the bronchi are the two main branches of the trachea) and carcinoma of the lung. Cancer of the trachea (ICD-9 162.0) is often grouped with cancer of the lung and bronchus under ICD-9 162. The lung is also a common site of the development of metastatic tumors. In men and women, the incidence of lung cancer increases greatly beginning at about the age of 40 years. The incidence in people 50–54 years old is double that in people 45–49 years old, and it doubles again in those 55–59 years old. The incidence is consistently higher in black men than in women or white men. The average annual incidence of lung cancer in the United States is shown in Table 6-12. ACS estimates that 85–90% of lung-cancer deaths are attributable to cigarette- smoking (Jemal et al., 2008b). Smoking increases the risk of all histologic types of lung cancer, but the associations with squamous-cell and small-cell carcinomas are strongest. Other risk factors include exposure to asbestos, uranium, vinyl chlo- ride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic. The latter statement does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor. Important environmental risk factors include exposure to tobacco smoke and radon (ACS, 2007c).

CANCER 265 TABLE 6-12  Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 56.7 52.8 110.5 115.7 107.0 222.4 213.7 208.5 333.4 Women 45.2 44.6 66.8 89.7 90.8 116.5 154.5 162.5 172.0 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and lung cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-13 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam-veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-cause mortality and cause-specific mortality in the Vietnam-veteran and era- veteran cohorts, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Fifty lung-cancer deaths were observed in the Vietnam veterans (crude rate per 10,000, 3.4) and 66 in the era veterans, for an adjusted SMR of 0.96 (95% CI 0.65–1.42). No excess risk was observed in the nurses-only analysis (SMR = 0.76, 95% CI 0.48–1.18). Occupational Studies Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union (the study was first reported in VAO as Hansen et al., 1992). Subjects were then followed up with population and cancer registries, and the incidence of cancer was ascertained from 1975 until the end of 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides, with earlier cohorts representing higher potential exposures. No

266 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-13  Selected Epidemiologic Studies—Lung and Bronchus Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women (lung) 50 1.0 (0.7–1.4) Kang, 2008 Vietnam veteran nurses 35 0.8 (0.5–1.2) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 576 1.2 (1.1–1.3) Branch of service Navy 141 1.4 (1.2–1.7) Army 372 1.2 (1.1–1.3) Air Force 63 1.0 (0.7–1.2) Histologic type—all service branches combined Adenocarcinoma 188 1.5 (1.2–1.7) Squamous 152 1.2 (1.0–1.4) Small-cell 87 1.2 (0.97–1.5) Large-cell 79 1.1 (0.8–1.3) Other 70 1.1 (0.8–1.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 544 1.2 (1.1–1.3) Branch of service Navy 135 1.4 (1.2–1.6) Army 339 1.1 (1.0–1.3) Air Force 71 1.1 (0.9–1.4) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence (1982–2000) 78 1.2 (1.0–1.5) Histologic type Adenocarcinoma 27 1.4 (0.8–1.9) Squamous 19 1.5 (0.9–2.3) Small-cell 14 1.4 (0.8–2.4) Large-cell 8 0.7 (0.3–1.3) Other 10 1.2 (0.6–2.2) Mortality (1966–2001) 67 1.8 (1.2–2.7) Pavuk et al., Comparison subjects only from AFHS (respiratory 2005 system)—incidence Serum TCDD (pg/g) based on model with exposure variable loge(TCDD) Per unit increase of -loge(TCDD) (pg/g) 36 1.7 (0.9–3.2) Quartiles (pg/g) 0.4–2.6 6 1.0 (nr) 2.6–3.8 8 1.1 (0.3–3.4) 3.8–5.2 9 1.2 (0.4–3.5) > 5.2 13 1.9 (0.7–5.5)

CANCER 267 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Number of years served in SEA Per year of service 36 1.1 (0.9–1.2) Quartiles (years in SEA) 0.8–1.3 8 1.0 (nr) 1.3–2.1 4 0.5 (0.2–1.8) 2.1–3.7 11 0.7 (0.3–2.0) 3.7–16.4 13 0.7 (0.3–2.0) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 (trachea, bronchus, and lung) 41 1.0 (0.6–1.5) Low pay grade at time of discharge nr 1.6 (0.9–3.0) Studies Reviewed in Update 2004 Akhtar White AFHS subjects vs national rates (respiratory et al., 2004 system) Ranch Hand veterans Incidence 33 1.1 (0.8–1.6) With tours between 1966–1970 26 1.1 (0.7–1.6) Mortality 21 0.9 (0.6–1.3) Comparison veterans Incidence 48 1.2 (0.9–1.6) With tours 1966–1970 37 1.2 (0.9–1.6) Mortality 38 1.1 (0.8–1.5) Studies Reviewed in Update 2000 AFHS, 2000 Ranch Hand veterans from AFHS (lung and bronchus)—incidence 10 3.7(0.8–17.1) Expected number of exposed cases Australian Vietnam veterans—(lung cancer)— (95% CI) AIHW, 1999 incidence (validation study) 46 65 (49–81) CDVA, Australian Vietnam veterans (lung)—incidence 120 65 (49–89) 1998a Studies Reviewed in Update 1998 CDVA, Australian Vietnam veterans—mortality 1997a Lung (ICD-9 162) 212 1.3 (1.1–1.4) Respiratory systems (ICD-9 163–165) 13 1.8 (1.0–3.0) CDVA, Australian National Service Vietnam veterans 1997b (lung)—mortality 27 2.2 (1.1–4.3) Dalager and Army Chemical Corps veterans (respiratory Kang, 1997 system)—mortality 11 1.4 (0.4–5.4) Mahan Case–control of Vietnam-era Vietnam veterans et al., 1997 (lung)—incidence 134 1.4 (1.0–1.9) Watanabe US Army and Marine Corps Vietnam veterans and Kang, (lung)—mortality 1996 Army Vietnam service 1,139 1.1 (nr) (p < 0.05) Non-Vietnam 1,141 1.1 (nr) (p < 0.05) Marine Vietnam service 215 1.2 (1.0–1.3) Non-Vietnam 77 0.9 (nr) continued

268 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Watanabe Marine Vietnam service vs non-Vietnam (lung) 42 1.3 (0.8–2.1) and Kang, 1995 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed (lung) 80 0.9 (0.7–1.1) OCCUPATIONAL New Studies Hansen Danish gardeners (nasal, laryngeal, lung, and et al., 2007 bronchus, ICD-7 160–165)—incidence  10-year follow-up (1975–1984) reported in Hansen et al. (1992) 41 1.0 (0.7–1.3) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 34 0.9 (0.6–1.3) Born 1915–1934 (medium exposure) 72 1.0 (0.8–1.2) Born after 1934 (low exposure) 8 0.8 (0.4–1.7) Samanic Pesticide applicators in AHS—lung-cancer incidence et al., 2006 from enrollment through 2002 Dicamba—lifetime days exposure None 95 1.0 1– < 20 14 0.8 (0.5–1.5) 20– < 56 11 0.6 (0.3–1.3) 56– < 116 12 1.0 (0.5–1.9) ≥ 116 15 1.5 (0.8–2.7) p-trend = 0.13 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers—exposure et al., 2006 to nonvolatile organochlorine compounds Lung (ICD-9 162) Never 356 1.0 (0.9–1.1) Ever 314 1.0 (0.9–1.2) Pleura (ICD-9 163) Never 17 2.8 (1.6–4.5) Ever 4 0.8 (0.2–2.0) Other respiratory (ICD-9 164–165) Never 8 2.1 (0.9–4.2) Ever 2 0.7 (0.1–2.4) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) Lung 266 0.5 (0.4–0.5) Respiratory system 294 0.5 (0.4–0.5) Spouses of private applicators (> 99% women) Lung 68 0.4 (0.3–0.5) Respiratory system 71 0.4 (0.3–0.5)

CANCER 269 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Commercial applicators (men and women) Lung 12 0.6 (0.3–1.0) Respiratory system 14 0.6 (0.3–1.0) Blair et al., US AHS (lung)—mortality 2005a Private applicators (men and women) 129 0.4 (0.3–0.4) Years handled pesticides ≤ 10 years 25 0.4 (nr) (p < 0.05) > 10 years 80 0.3 (nr) (p < 0.05) Spouses of private applicators (> 99% women) 29 0.3 (0.2–0.5) ’t Mannetje New Zealand phenoxy herbicide workers—mortality et al., 2005 Producers (men and women) Trachea, bronchus, lung (ICD-9 162) 12 1.4 (0.7–2.4) Other respiratory system sites (ICD-9 163–165) 1 3.9 (0.1–21.5) Sprayers (> 99% men) Trachea, bronchus, lung (ICD-9 162) 5 0.5 (0.2–1.1) Other respiratory system sites (ICD-9 163–165) 1 2.5 (0.1–13.7) Torchio Italian licensed pesticide users—mortality et al., 1994 Lung 155 0.5 (0.4–0.5) Reif et al., New Zealand forestry workers—incidence (nested 1989 case–control) Lung 30 1.3 (0.8–1.9) Studies Reviewed in Update 2004 Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry)—mortality Lung 54 0.8 (0.6–1.1) Swaen Dutch licensed herbicide applicators (trachea, and et al., 2004 lung)—mortality 27 0.7 (0.5–1.0) Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry)—mortality Respiratory system (ICD-8 160–163) 31 0.9 (0.6–1.3) Thörn et al., Swedish lumberjacks exposed to phenoxy herbicides 2000 Foremen (bronchus and lung)—incidence 1 4.2 (0.0–23.2) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry)—mortality Lung 125 1.1 (0.9–1.3) Studies Reviewed in Update 1998 Gambini Italian rice growers—mortality et al., 1997 Lung 45 0.8 (0.6–1.1) Pleura 2 2.2 (0.2–7.9) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol Lung (ICD-9 162) 380 1.1 (1.0–1.2) Other respiratory organs (ICD-9 163–165) 12 2.3 (1.2–3.9) continued

270 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Exposed to highly chlorinated PCDDs Lung (ICD-9 162) 225 1.1 (1.0–1.3) Other respiratory organs (ICD-9 163–165) 9 3.2 (1.5–6.1) Not exposed to highly chlorinated PCDDs Lung (ICD-9 162) 148 1.0 (0.9–1.2) Other respiratory organs (ICD-9 163–165) 3 1.2 (0.3–3.6) Becher German production workers (included in IARC et al., 1996 cohort) (lung) 47 1.4 (1.1–1.9) Ott and BASF employees—incidence Zober, 1996 Respiratory system 13 1.2 (0.6–2.0) TCDD 0.1–0.99 µg/kg of body weight 2 0.7 (0.1–2.5) TCDD ≥ 1 µg/kg of body weight 8 2.0 (0.9–3.9) Lung, bronchus 11 1.1 (0.6–2.0) TCDD 0.1–0.99 µg/kg of body weight 2 0.8 (0.1–2.8) TCDD ≥ 1 µg/kg of body weight 8 2.2 (1.0–4.3) Ramlow Dow pentachlorophenol production workers et al., 1996 (Included in IARC cohort, NIOSH Dioxin Registry)—mortality 0-year latency Respiratory system (ICD-8 160–163) 18 1.0 (0.6–1.5) Lung (ICD-8 162) 16 0.9 (0.5–1.5) 15-year latency Respiratory system (ICD-8 160–163) 17 1.1 (0.6–1.8) Lung (ICD-8 162) 16 1.1 (0.6–1.8) Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators, 1972–1989 1994 Incidence Trachea, bronchus, lung (ICD-8 162) 39 0.9 (0.7–1.3) Other respiratory (ICD-8 160, 161, 163) 4 1.1 (0.7–1.3) Mortality Trachea, bronchus, lung (ICD-8 162) 37 1.0 (0.7–1.4) Other respiratory (ICD-8 160, 161, 163) 1 0.5 (0.0–2.9) Blair et al., US farmers in 23 states (lung)—mortality 1993 White men 6,473 0.9 (0.9–0.9) White women 57 0.8 (0.6–1.1) Bloemen Dow 2,4-D production workers (included in IARC et al., 1993 cohort, NIOSH Dioxin Registry) Respiratory system (ICD-8 162–163) 9 0.8 (0.4–1.5) Kogevinas IARC cohort, women (lung)—incidence 2 1.4 (0.2–4.9) et al., 1993 Lynge, 1993 Danish production workers (included in IARC cohort)—incidence Lung 13 1.6 (0.9–2.8)

CANCER 271 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort)—mortality et al., 1993 Trachea, bronchus, lung (ICD-8 162) 9 0.8 (0.4–1.5) Respiratory system (ICD-8 160–163) 9 1.7 (0.5–6.3) Swaen Dutch herbicide applicators—mortality et al., 1992 Trachea and lung 12 1.1 (0.6–1.9) Coggon British phenoxy herbicide workers (included in et al., 1991 IARC cohort)—mortality Lung 19 1.3 (0.8–2.1) Workers with exposure above background 14 1.2 (0.7–2.1) Fingerhut NIOSH workers exposed to TCDD—mortality et al., 1991 Entire cohort Trachea, bronchus, lung (ICD-9 162) 89 1.1 (0.9–1.4) Respiratory system (ICD-9 160–165) 96 1.1 (0.9–1.4) ≥ 1-year exposure, ≥ 20-year latency Trachea, bronchus, lung (ICD-9 162) 40 1.4 (1.0–1.9) Respiratory system (ICD-9 160–165) 43 1.4 (1.0–1.9) Green, 1991 Herbicide sprayers in Ontario (lung)—mortality 5 nr Manz et al., German production workers (included in IARC 1991 cohort)—mortality Lung 26 1.7 (1.1–2.4) Saracci IARC cohort, men, women—mortality et al., 1991 Trachea, bronchus, lung 173 1.0 (0.9–1.2) McDuffie Saskatchewan farmers applying et al., 1990 herbicides—incidence Lung 103 0.6 (nr) Zober et al., BASF employees—incidence 90% CI 1990 Trachea, bronchus, lung 4 2.0 (0.7–4.6) Bender Herbicide sprayers in Minnesota—mortality et al., 1989 Trachea, bronchus, lung (ICD-9 162.0–162.8) 54 0.7 (0.5–0.9) All respiratory (ICD-9 160.0–165.9) 57 0.7 (0.5–0.9) Wiklund Swedish pesticide applicators—incidence et al., 1989a Trachea, bronchus, lung 38 0.5 (0.4–0.7) Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry)—mortality Lung (ICD-8 162–163) 8 1.0 (0.5–2.0) Respiratory (ICD-8 160–163) (exposure lagged 15 years) Low cumulative exposure 1 0.7 (nr) Medium cumulative exposure 2 1.0 (nr) High cumulative exposure 5 1.7 (nr) continued

272 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Coggon British MCPA production workers (included in et al., 1986 IARC cohort)—mortality Lung, pleura, mediastinum (ICD-8 162–164) 117 1.2 (1.0–1.4) Background exposure 39 1.0 (0.7–1.4) Low-grade exposure 35 1.1 (0.8–1.6) High-grade exposure 43 1.3 (1.0–1.8) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence Lung Men 38 1.2 (nr) Women 6 2.2 (nr) Blair et al., Licensed pesticide applicators in Florida, lawn, 1983 ornamental pest category only—mortality Lung (ICD-8 162–163) 7 0.9 (nr) Axelson Swedish herbicide sprayers (lung)—mortality 3 1.4 (nr) et al., 1980 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 (lung ICD-9 162) Zone A 11 1.1 (0.6–2.0) Zone B 62 1.1 (0.9–1.4) Zone R 383 1.0 (0.8–1.1) Studies Reviewed in Update 2004 Fukuda Residents of Japanese municipalities with and Age-adjusted et al., 2003 without waste-incineration plants mortality (per Men 100,000) With 39.0 ± 6.7 vs 41.6 Without ± 9.1 (p = 0.001) Women With 13.7 ± 3.8 vs 14.3 Without ± 4.6 (p = 0.11) Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia (lung) et al., 2001 Men 168 3.1 (2.6–3.5) Women 40 0.4 (0.3–0.6) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 (lung)—incidence Zones A, B— en m 57 1.3 (1.0–1.7) women 4 0.6 (0.2–1.7) Bertazzi Seveso residents—15-year follow-up et al., 1998 (lung)—incidence Zone A— en m 4 1.0 (0.4–2.6) women 0 nr

CANCER 273 TABLE 6-13  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Zone B— en m 34 1.2 (0.9–1.7) women 2 0.6 (0.1–2.3) Zone R— en m 176 0.9 (0.8–1.1) women 29 1.0 (0.7–1.6) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 (lung)—incidence Zone A—men 4 1.0 (0.3–2.5) Zone B— en m 34 1.2 (0.9–1.7) women 2 0.6 (0.1–2.1) Zone R— en m 176 0.9 (0.8–1.0) women 29 1.0 (0.7–1.5) Svensson Swedish fishermen et al., 1995 East coast (lung, larynx) 16 0.8 (0.5–1.3) West coast (lung, larynx) 77 0.9 (0.7–1.1) Studies Reviewed in VAO Bertazzi Seveso residents—10-year follow-up (trachea, et al., 1993 bronchus, lung)—incidence Zone A—men 2 0.8 (0.2–3.4) Zone B—men 18 1.1 (0.7–1.8) Zone R— en m 96 0.8 (0.7–1.0) women 16 1.5 (0.8–2.5) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International ­ Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Insitute for Occu- pational Safety and Health; nr = not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly c ­ hlorinated, if four or more chlorines); PM, proportionate mortality; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. associations between the exposures and all respiratory cancers were found; RRs were roughly unity. In a report on the US AHS, Samanic et al. (2006) conducted an analysis of the incidence of lung cancer and exposure to dicambin male pesticide applicators. When a metric defined as lifetime exposure–days was used, rate ratios comparing subjects exposed to dicamba were less than unity for all categories of exposure except the highest quintile, at least 166 exposure–days (RR = 1.47, 95% CI 0.79– 2.72), and there was no trend with increasing exposure (p for linear trend = 0.13).

274 VETERANS AND AGENT ORANGE: UPDATE 2008 When a metric defined as “intensity-weighted lifetime exposure–days” (data not shown) was used, there was no evidence of a monotonic association with mortal- ity from lung cancer (p for linear trend = 0.58), and the largest RR was 1.10 (for the category of at least 739.2 weighted exposure–days vs no exposure). Environmental Studies Investigators in Italy completed a 25-year mortality follow-up of people exposed to the industrial accident in Seveso (Consonni et al., 2008). Mortality from lung cancer in residents in three exposure zones—very high (Zone A), high (Zone B), and low (Zone R)—was compared with that in a nonexposed reference population. The RRs for lung-cancer mortality in the exposure groups were 1.26 (95% CI 0.7–2.29) in Zone A, 1.11 (95% CI 0.87–1.43) in Zone B, and 0.98 (95% CI 0.88–1.09) in Zone R. There were 11, 62, and 383 lung-cancer deaths during the follow-up period in Zones A, B, and R, respectively. Biologic Plausibility Long-term animal studies have examined the effect of exposure to the chemi- cals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). As noted in previous VAO reports, there is evidence of increased incidence of squamous-cell carcinoma of the lung in male and female rats exposed to TCDD at high concentrations (Kociba et al., 1978; Van Miller et al., 1977). A more recent study reported a significant increase in cystic keratinizing epitheliomas in female rats exposed to TCDD for 2 years (NTP, 2006; Walker et al., 2006) and increases in the incidences of bronchiolar metaplasia, acinar vacuolization, and inflammation in the high-dose (100 ng/kg) group. A recent 2-year study of F344 rats exposed to cacodylic acid at 0–100 ppm and B6C3F1 mice exposed at 0–500 ppm failed to detect neoplasms in the lung at any dose (Arnold et al., 2006); this finding is consistent with those of previous studies. However, exposure to cacodylic acid has previously been shown to in- crease tumor multiplicity in mouse strains susceptible to developing lung tumors (for example, A/J strain; Hayashi et al., 1998) or mice pretreated with an intitiat- ing agent (4-nitroquinoline 1-oxide; Yamanaka et al., 1996). The data indicate that cacodylic acid may act as a tumor promoter in the lung. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The evidence remains limited but suggestive of an association between exposure to at least one chemical of interest and the risk of developing or dying

CANCER 275 from lung cancer. The most compelling evidence comes from studies of heavily exposed occupational cohorts, including British 2-methyl-4-chlorophenoxyacetic acid production workers (Coggon et al., 1986), German production workers (Becher et al., 1996; Manz et al., 1991), a BASF cohort (Ott and Zober, 1996), a NIOSH cohort (Fingerhut et al., 1991; Steenland et al., 1999), and Danish production workers (Lynge, 1993). The latest findings from the US Air Force Health Study suggest an increase in risk with the concentration of serum TCDD even in subjects who made up the comparison group, whose TCDD exposure was considerably lower (but not zero) than that of the Ranch Hand cohort. The American and Australian cohort studies of Vietnam veterans, which presumably cover a large proportion of exposed soldiers, show higher than expected incidence of and mortality from lung cancer. The main limitations of those studies are that there was no assessment of exposure—as there was in, for example, the Ranch Hand study—and that some potential confounding variables, notably smoking, could not be accounted for. The committee believes that it is unlikely that the distribution of smoking differed greatly between the two cohorts of veterans, so confounding by smoking is probably minimal. The studies therefore lend support to the findings of the Ranch Hand study. The methodologically sound AHS did not show any increased risks of lung cancer, but, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of the con- temporary farmers was probably negligible. Results of the environmental studies were mostly consistent with no association. Also supportive of an association are the numerous lines of mechanistic evidence, discussed in the section on biologic plausibility, which provide fur- ther support for the conclusion that the evidence of an association is limited or suggestive. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one chemical of interest and carcinomas of the lung, bronchus, and trachea. BONE AND JOINT CANCER ACS estimated that about 1,270 men and 1,110 women would receive diag- noses of bone or joint cancer (ICD-9 170) in the United States in 2008 and that 820 men and 650 women would die from these cancers (Jemal et al., 2008a). Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 6-14.

276 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-14  Average Annual Incidence (per 100,000) of Bone and Joint Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 0.9 0.9 0.8 1.2 1.2 0.5 1.2 1.2 1.6 Women 0.9 1.0 0.3 1.0 1.1 0.4 1.2 1.1 1.6 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (50–64 years). Among the risk factors for adults’ contracting of bone or joint cancer are exposure to ionizing radiation in treatment for other cancers and a history of some noncancer bone diseases, including Paget disease. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and bone and joint cancer. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-15 summarizes the results of the relevant studies. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and bone and joint cancers have been published since Update 2006. Biologic Plausibility No animal studies have reported an increased incidence of bone and joint cancers after exposure to the chemicals of interest. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

CANCER 277 TABLE 6-15  Selected Epidemiologic Studies—Bone and Joint Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 4 0.9 (0.1–11.3) AFHS, 1996 Air Force Ranch Hand veterans 0 nr Studies Reviewed in VAO Breslin Army Vietnam veterans 27 0.8 (0.4–1.7) et al., 1988 Marine Vietnam veterans 11 1.4 (0.1–21.5) Anderson Wisconsin Vietnam veterans 1 nr et al., 1986 Lawrence New York Vietnam veterans 8 1.0 (0.3–3.0) et al., 1985 OCCUPATIONAL Studies Reviewed in Update 2006 Merletti Association between occupational exposure and risk et al., 2006 of bone sarcoma 18 2.6 (1.5–4.6) ’t Mannetje Phenoxy herbicide producers and sprayers (men and et al., 2005 women) 0 nr Torchio Italian licensed pesticide users 10 0.8 (0.4–1.4) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 1 1.7 (0.2–13.3) Studies Reviewed in Update 2004 Swaen Dutch licenced herbicide applicators 0 nr et al., 2004 Studies Reviewed in Update 2000 Rix et al., Danish paper-mill workers—incidence 1998 Men 1 0.5 (0.0–2.7) Women 0 nr Studies Reviewed in Update 1998 Gambini Italian rice growers 1 0.5 (0.0–2.6) et al., 1997 Hertzman British Columbia sawmill workers et al., 1997 Mortality 5 1.3 (0.5–2.7) Incidence 4 1.1 (0.4–2.4) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 5 1.2 (0.4–2.8) Exposed to highly chlorinated PCDDs 3 1.1 (0.2–3.1) Not exposed to highly chlorinated PCDDs 2 1.4 (0.2–5.2) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0 nr 0-year latency 0 nr 15-year latency 0 nr Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 49 1.3 (1.0–1.8) White women 1 1.2 (0.0–6.6) continued

278 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-15  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Collins Monsanto Company workers (included in NIOSH et al., 1993 cohort) 2 5.0 (0.6–18.1) Studies Reviewed in VAO Ronco et al., Danish, Italian farm workers 1992 Male Danish farmers 9 0.9 (nr) Female Danish farmers 0 nr Fingerhut NIOSH—entire cohort 2 2.3 (0.3–8.2) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 1 5.5 (0.1–29.0) Zober et al., 90% CI 1990 BASF employees—basic cohort 0 0 (0.0–65.5) Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 0 nr (0.0–31.1) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 1 0.9 (0.0–5.0) Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 44 1.0 (0.6–1.4) Burmeister, Iowa farmers 56 1.1 (nr) 1981 ENVIRONMENTAL Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia et al., 2001 Mortality standardized to Samara region (bone, soft- tissue cancer) Men 7 2.1 (0.9–4.4) Women 7 1.4 (0.6–3.0) Studies Reviewed in Update 2000 Bertazzi Seveso residents—15-year follow-up et al., 1998 Zone B women 1 2.6 (0.3–19.4) Zone R men 2 0.5 (0.1–2.0) Zone R women 7 2.4 (1.0–5.7) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B women 1 2.6 (0.0–14.4) Zone R men 2 0.5 (0.1–1.7) Zone R women 7 2.4 (1.0–4.9) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, Interna- tional Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of the same cohorts.

CANCER 279 Synthesis There are no new data concerning the chemicals of interest and bone cancer, and the previous body of results summarized in Table 6-15 does not indicate an association between exposure to the chemicals of interest and bone cancer. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and bone and joint cancers. SOFT-TISSUE SARCOMAS Soft-tissue sarcoma (STS) (ICD-9 164.1, 171) arises in soft somatic tissues in and between organs. Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that about 5,720 men and 4,670 women would receive diagnoses of STS in the United States in 2008 and that about 1,880 men and 1,800 women would die from it (Jemal et al., 2008a). The average annual incidence of STS is shown in Table 6-16. Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers and some inherited conditions, including Gardner syn- drome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical expo- sures have been identified as possible risk factors (Zahm and Fraumeni, 1997). Conclusions from VAO and Previous Updates The committee responsible for VAO judged that the strong findings in the IARC and NIOSH cohorts and the extensive Scandinavian case–control studies, complemented by consistency in preliminary reports on the Seveso population TABLE 6-16  Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in United States a 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 4.5 4.5 4.0 5.0 4.8 7.4 6.7 7.2 3.5 Women 3.1 3.2 3.9 4.3 4.1 6.4 5.1 4.8 7.2 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

280 VETERANS AND AGENT ORANGE: UPDATE 2008 and one statistically significant finding in a state study of Vietnam veterans, con- stituted sufficient information to determine that there is an association between exposure to at least one of the chemicals of interest and STS. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-17 summarizes the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies No Vietnam-veteran studies concerning exposure to the chemicals of interest and soft tissue sarcomas have been published since Update 2006. Occupational Studies Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union. The study by Hansen et al. (1992), which followed the cohort for 10 years through 1984, was reported in VAO. Subjects were followed-up by using population and cancer registries, and the incidence of cancer was ascertained from 1975 until the end of 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides, with earlier cohorts representing higher potential exposures. Although the analysis was based on only three cases, the risk of dying from STS was 6 times higher in men born before 1915 (RR = 5.9, 95% CI 1.9–18.2). Environmental Studies Consonni et al. (2008) conducted a follow-up of the population in the area of the accident that occurred in Seveso in 1976. The follow-up was extended until 2001, and no associations with deaths from STS were found in any of the three exposure zones. There were only four deaths from STS, all of which occurred in Zone R (RR = 0.76, 95% CI 0.27–2.14). Read et al. (2007) conducted a study of residents of the coastal community of Paritutu, New Plymouth, New Zealand, near the Ivon Watkins-Dow Limited plant, which had manufactured the herbicide 2,4,5-T during 1962–1987. It was reported that the body burden of TCDD was comparable with that in residents living in Zone B of the Seveso area. Incidence and mortality were ascertained for the period 1970–2001. No association between exposure to 2,4,5-T or TCDD and the incidence of STS was found, but there was a 20% increase in mortality (95% CI 0.8–1.8). Zambon et al. (2007) conducted a population-based case–control study in Venice, Italy. Confirmed cases of sarcoma (ICD-9 171, 173, 158) were identi- fied from a population cancer registry. The cases were divided by anatomic site

CANCER 281 TABLE 6-17  Selected Epidemiologic Studies—Soft-Tissue Sarcoma Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian Vietnam veterans vs Australian 2005a population—incidence 35 1.0 (0.7–1.3) Navy 6 0.8 (0.3–1.7) Army 29 1.2 (0.8–1.6) Air Force 0 0.0 (0.0–1.1) ADVA, Australian Vietnam veterans vs Australian 2005b population—mortality 12 0.8 (0.4–1.3) Navy 3 0.9 (0.2–2.4) Army 9 0.8 (0.4–1.5) Air Force 0 0.0 (0.0–2.3) ADVA, Australian men conscripted Army National Service 2005c Vietnam era veterans—deployed vs nondeployed Incidence 10 1.0 (0.4–2.4) Mortality 3 0.5 (0.1–2.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.8 (0.1–12.8) AIHW, 1999 Expected number of exposed cases Male Australian Vietnam veterans—incidence (95% CI) (validation study) 14 27 (17–37) CDVA, Male Australian Vietnam veterans—self-reported 1998a incidence 398 27 (17–37) CDVA, Female Australian Vietnam veterans—self-reported 1998b incidence 2 0 (0–4) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 18 1.6 (0.5–5.4) CDVA, Australian military Vietnam veterans 9 1.0 (0.4–1.8) 1997a CDVA, Australian National Service Vietnam veterans 2 0.7 (0.6–4.5) 1997b AFHS, 1996 Ranch Hand veterans 0 nr Watanabe US Marines in Vietnam 0 nr and Kang, 1995 Studies Reviewed in Update 1996 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 8 1.1 (0.5–2.2) Studies Reviewed in VAO Watanabe Army Vietnam veterans 43 1.1 et al., 1991 Marine Vietnam veterans 11 0.7 Bullman Army I Corps Vietnam veterans 10 0.9 (0.4–1.6) et al., 1990 Michalek Ranch Hand veterans 1 nr et al., 1990 Comparisons 1 nr continued

282 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Breslin Army Vietnam veterans 30 1.0 (0.8–1.2) et al., 1988 Marine Vietnam veterans 8 0.7 (0.4–1.3) Kogan and Massachusetts Vietnam veterans 9 5.2 (2.4–11.1) Clapp, 1988 Fett et al., Australian Vietnam veterans 1 1.3 (0.1–20.0) 1987 Anderson Wisconsin Vietnam veterans 4 nr et al., 1986 Breslin US Vietnam veterans et al., 1986 Army 30 1.0 (nr) Marines 8 0.7 (nr) Kang et al., Vietnam veterans vs Vietnam-era veterans 86 0.8 (0.6–1.1) 1986 Lawrence New York State Vietnam veterans 2 1.1 (0.2–6.7) et al., 1985 Greenwald New York State Vietnam veterans 10 0.5 (0.2–1.3) et al., 1984 OCCUPATIONAL New Studies Hansen Danish gardeners (ICD-7 197)—incidence et al., 2007  10-year follow-up (1975–1984) reported in Hansen et al. (1992) 3 5.3 (1.1–15.4) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 3 5.9 (1.9–18.2) Born 1915–1934 (medium exposure) 0 0.0 (0.0–3.8) Born after 1934 (low exposure) 1 1.8 (0.3–12.9) Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds Never 8 1.2 (0.5–2.4) Ever 4 0.8 (0.2–2.0) ’t Mannetje Phenoxy herbicide producers (men and women) 0 0.0 (0.0–19.3) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 1 4.3 (0.1–23.8) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 10 0.7 (0.3–1.2) Spouses of private applicators (> 99% women) 3 0.5 (0.1–1.4) Commercial applicators (men and women) nr 0.0 (0.0–3.8) Blair et al., US AHS 2005a Private applicators (men and women) 4 0.7 (0.2–1.8) Spouses of private applicators (> 99% women) 3 1.4 (0.3–4.1) Torchio Italian licensed pesticide users 2 1.0 (0.1–3.5) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 4 3.2 (1.2–9.0)

CANCER 283 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2004 Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry) 2 2.4 (0.3–8.6) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 0 nr Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) 0 nr Rix et al., Danish paper-mill workers—incidence 1998 Women employed in sorting and packing 8 4.0 (1.7–7.8) Men employed in sorting and packing 12 1.2 (0.6–2.0) Studies Reviewed in Update 1998 Hertzman Canadian sawmill workers 11 1.0 (0.6–1.7) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 9 2.0 (0.9–3.8) Exposed to highly chlorinated PCDDs 6 2.0 (0.8–4.4) Not exposed to highly chlorinated PCDDs 2 1.4 (0.2–4.9) Ott and Expected number Zober, 1996 of exposed cases BASF employees—incidence 0 0.2 Ramlow Expected number et al., 1996 Dow pentachlorophenol production workers of exposed cases (included in IARC cohort, NIOSH Dioxin Registry) 0 0.2 Studies Reviewed in Update 1996 Kogevinas IARC cohort (men and women)—incidence 11 nr et al., 1995 Mack, 1995 US cancer registry data (SEER program) review Men 3,526 nr Women 2,886 nr Blair et al., US farmers in 23 states 98 0.9 (0.8–1.1) 1993 Lynge, 1993 Danish production workers (included in the IARC cohort)—updated incidence for men, women 5 2.0 (0.7–4.8) Kogevinas IARC cohort (men and women) et al., 1992 10–19 years since first exposure 4 6.1 (1.7–15.5) Studies Reviewed in VAO Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort) 0 0.0 (0.0–23.1) et al., 1993 Hansen Danish gardeners—incidence 3 5.3 (1.1–15.4) et al., 1992 Smith and Australia residents 30 1.0 (0.3–3.1) Christophers, 1992 continued

284 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Fingerhut NIOSH cohort—entire cohort 4 3.4 (0.9–8.7) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 3 9.2 (1.9–27.0) Manz et al., German production workers (included in IARC 1991 cohort)—men, women 0 nr Saracci IARC cohort—exposed subcohort (men and et al., 1991 women) 4 2.0 (0.6–5.2) Zober et al., BASF employees—basic cohort 0 nr 1990 Alavanja USDA forest and soil conservationists 2 1.0 (0.1–3.6) et al., 1989 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 0 nr Wiklund et al., 1988, 99% CI 1989b Swedish agricultural workers (men and women) 7 0.9 (0.4–1.9) Woods et al., Washington state residents—incidence 1987 High phenoxy exposure nr 0.9 (0.4–1.9) Self-reported chloracne nr 3.3 (0.8–14.0) Coggon British MCPA chemical workers (included in IARC et al., 1986 cohort) 1 1.1 (0.03–5.9) Hoar et al., Kansas residents—incidence 1986 All farmers 95 1.0 (0.7–1.6) Farm use of herbicides 22 0.9 (0.5–1.6) Smith and 90% CI Pearce, 1986 Reanalysis of New Zealand workers 133 1.1 (0.7–1.8) Vineis et al., Italian rice growers 1986 Among all living females 5 2.4 (0.4–16.1) Smith et al., 90% CI 1984 Update of New Zealand workers 17 1.6 (0.7–3.8) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence Men 5 2.7 (0.9–6.3) Women 0 nr Balarajan Agricultural workers in England and Overall 42 1.7 (1.0–2.9) Acheson, Under 75 years old 1984 33 1.4 (0.8–2.6) Blair et al., Florida pesticide applicators 1983 0 nr Smith et al., 90% CI 1983 New Zealand workers exposed to herbicides 17 1.6 (0.8–3.2) Hardell, Swedish residents 1981 Exposed to phenoxy acids 13 5.5 (2.2–13.8) Exposed to chlorophenols 6 5.4 (1.3–22.5)

CANCER 285 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Eriksson Swedish workers et al., 1979, (2.5–10.4) 1981 25 5:1 matched ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 0 nr Zone B 0 nr Zone R 4 0.8 (0.3–2.1) Read et al., Residents of New Plymouth Territorial Authority, 2007 New Zealand near plant manufacturing 2,4,5-T in 1962–1987 Incidence 56 1.0 (0.8–1.4)c 1970–1974 7 1.0 (0.4–2.1) 1975–1979 3 0.4 (0.1–2.1) 1980–1984 10 1.3 (0.6–2.4) 1985–1989 11 1.2 (0.6–2.2) 1990–1994 9 0.9 (0.4–1.7) 1995–1999 14 1.3 (0.7–2.2) 2000–2001 2 0.8 (0.1–3.0) Mortality 27 1.2 (0.8–1.8)c 1970–1974 5 1.8 (0.6–4.3) 1975–1979 1 0.4 (0.0–2.0) 1980–1984 4 1.1 (0.3–2.9) 1985–1989 5 1.5 (0.5–3.6) 1990–1994 5 1.3 (0.4–3.0) 1995–1999 5 1.3 (0.4–3.0) 2000–2001 2 0.9 (0.1–3.1) Zambon Population-based Veneto Tumour Registry, Italy, et al., 2007 average exposure based on duration and distance of residence from 33 industrial sources—incidence Sarcoma (ICD-9 158, 171, 173, visceral sites) Men < 4 TCDD (fg/m3) 31 1.0 4–6 39 1.1 (0.6–2.0) ≥ 6 17 1.9 (0.9–4.0) p-trend = 0.15 Women < 4 TCDD (fg/m3) 24 1.0 4–6 44 1.5 (0.8–2.7) ≥ 6 17 2.4 (1.0–5.6) p-trend = 0.04 continued

286 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Men, women combined Connective, other soft tissue (ICD-9 171) < 4 TCDD (fg/m3) 25 1.0 4–6 39 1.4 (0.7–2.5) ≥ 6 17 3.3 (1.4–7.9) p-trend = 0.01 Skin (ICD-9 173) < 4 TCDD (fg/m3) 5 1.0 4–6 10 0.0 (0.3–4.7)d ≥ 6 2 0.3 (0.0–3.4) p-trend = 0.48 Retroperitoneum, peritoneum (ICD-9 158) < 4 TCDD (fg/m3) 6 1.0 4–6 12 1.1 (0.3–3.4) ≥ 6 3 0.8 (0.1–4.5) p-trend = 0.86 Visceral sites < 4 TCDD (fg/m3) 19 1.0 4–6 22 1.2 (0.6–2.6) ≥ 6 12 2.5 (1.0–6.3) p-trend = 0.08 Studies Reviewed in Update 2006 Pahwa et al., Any phenoxyherbicide 46 1.1 (0.7–1.5) 2006 2,4-D 41 1.0 (0.6–1.5) Mecoprop 12 1.0 (0.5–1.9) MCPA 12 1.1 (0.5–2.2) Studies Reviewed in Update 2004 Comba Residents near industrial-waste incinerator in et al., 2003 Mantua, Italy—incidence Residence within 2 km of incinerator 5 31.4 (5.6–176.1) Tuomisto Finnish STS patients vs controls within quintiles et al., 2004 based on TEQ in subcutaneous fat—incidence 110 Quintile 1 (median, ~12 ng/kg TEQ) nr 1.0 Quintile 2 (median, ~20 ng/kg TEQ) nr 0.4 (0.2–1.1) Quintile 3 (median, ~28 ng/kg TEQ) nr 0.6 (0.2–1.7) Quintile 4 (median, ~40 ng/kg TEQ) nr 0.5 (0.2–1.3) Quintile 5 (median, ~62 ng/kg TEQ) nr 0.7 (0.2–2.0) Studies Reviewed in Update 2002 Costani Residents near chemical plant in Mantua, et al., 2000 Italy—incidence 20 2.3 (1.3–3.5) Studies Reviewed in Update 2000 Bertazzi Seveso—20-year follow-up (men and women) 0 nr et al., 2001

CANCER 287 TABLE 6-17  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Viel et al., Residents near French solid-waste 2000 incinerator—incidence Spatial cluster 45 1.4 (p = 0.004) 1994–1995 12 3.4 (p = 0.008) Bertazzi Seveso—15-year follow-up (men and women) et al., 1998 Zone R men 4 2.1 (0.7–6.5) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up (men and et al. 1997 women) Zone R men 4 2.1 (0.6–5.4) Gambini Italian rice growers et al., 1997 1 4.0 (0.1–22.3) Svensson Swedish fishermen—incidence (men and women) et al., 1995 West coast 3 0.5 (0.1–1.4) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—morbidity et al., 1993 Zone R men 6 2.8 (1.0–7.3) Zone R women 2 1.6 (0.3–7.4) Studies Reviewed in VAO Lampi et al., Finnish community exposed to chlorophenol 1992 contamination (men and women) 6 1.6 (0.7–3.5) Bertazzi Seveso residents—10-year follow-up et al., 1989a Zone A, B, R men 2 5.4 (0.8–38.6) Zone A, B, R women 1 2.0 (0.2–1.9) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone R men 2 6.3 (0.9–45.0) Zone B women 1 17.0 (1.8–163.6) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophen- oxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, propor- tionate mortality; SEER, Surveillance, Epidemiology, and End Results; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods. dThere appears to be an error in this entry because lower 95% CL (0.3) is not smaller than odds ratio (0.0). Studies in italics have been superseded by newer studies of same cohorts.

288 VETERANS AND AGENT ORANGE: UPDATE 2008 (connective and soft tissue, skin, peritoneum, and viscera) and by morphologic type (fibrosarcoma, myxosarcoma, liposarcoma, myosarcoma, mixed mesen- chymal sarcoma, synovial sarcoma, blood vessel sarcoma, lymphatic vessel sar- coma, nerve sheath sarcoma, alveolar sarcoma, and not otherwise specified). Three controls, individually matched on sex and age at the time of diagnosis, were sought from the population for each of the identified 205 cases; 172 cases and 405 controls met all eligibility criteria and were included in the analyses. Residential histories were obtained from a population registry and were linked to assessments of exposure to dioxin that made use of the locations of incinerators. The exposures were attributed by estimating total emissions from the incinerators and the proportion of TCDD emitted. Environmental estimates of exposure were derived by using EPA’s Industrial Source Complex Model, which is a dispersion model that provides estimates of deposition at different places. The estimates were linked to subjects’ addresses. With a metric defined by average exposure at each subject’s address, monotonic increases in risk of all types of sarcoma were found in both men and women and of sarcomas of the connective and other soft tissue and in organs in the cavities of the body (visceral sites) in men and women combined. Biologic Plausibility In a 2-year study, dermal application of TCDD to Swiss-Webster mice led to an increase in fibrosarcomas in females but not males (NTP, 1982b). There is some concern that the increase in fibrosarcomas may be associated with the treatment protocol rather than with TCDD. The National Toxicology Progam gavage study (1982a) also found increased incidences of fibrosarcomas in male and female rats and in female mice. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Previous committees have concluded that the occupational, environmental, and Vietnam-veteran studies showed sufficient evidence to link herbicide expo- sure to STS. That conclusion is strengthened by one of the new studies (Zambon et al., 2007), which showed an increased risk in persons living in the vicinity of incinerators in Venice, Italy. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest and STS.

CANCER 289 SKIN CANCER—MELANOMA Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma, or simply melanoma) and neoplasms that do not. Nonmelanoma skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 6-18. The committee responsible for Update 1998 first chose to address melanoma studies separately from those of non-melanoma skin cancer. Some researchers report results by combining all types of skin cancer without specifying type. The present committee believes that such information is not interpretable (although there is a supposition that mortal- ity figures refer predominantly to melanoma and that sizable incidence figures refer to nonmelanoma skin cancer); therefore, the committee is interpreting data only on results that are specified as applying to melanoma or to non-melanoma skin cancer. ACS estimated that about 34,950 men and 27,530 women would receive diagnoses of cutaneous melanoma (ICD-9 172) in the United States in 2008 and that about 5,400 men and 3,020 women would die from it (Jemal et al., 2008a). More than a million cases of nonmelanoma skin cancer (ICD-9 173), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2006); it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. ACS reports that although melanoma accounts for only about 4% of skin-cancer cases, it is responsible for about 79% of skin-cancer deaths (2006). It estimates that 1,000–2,000 people die each year from nonmelanoma skin cancer. Melanoma occurs more frequently in fair-skinned people than in dark- skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks. The incidence increases with age; the increase is more striking in males than in females. Other risk factors include the presence of particular kinds of moles on TABLE 6-18  Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal-Cell and Squamous-Cell Cancers) in United States a 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Melanomas of the Skin: Men 34.4 41.3 1.1 48.5 57.3 3.2 63.3 74.4 5.0 Women 26.9 33.1 2.1 30.1 36.7 3.3 32.7 39.6 2.2 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. SEER incidence data not available for nonmelanocytic skin cancer.

290 VETERANS AND AGENT ORANGE: UPDATE 2008 the skin, suppression of the immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun-exposure patterns. Excessive exposure to UV radiation is the most important risk factor for nonmelanoma skin cancer; some skin diseases and chemical exposures have also been identified as potential risk factors. Exposure to inorganic arsenic is a risk factor for skin cancer; this does not imply that exposure to cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that con- clusion. The committee responsible for Update 1998 considered the literature on melanoma separately from that of nonmelanoma skin cancer. It found that there was inadequate or insufficient information to determine whether there is an association between the chemicals of interest and melanoma. The committees responsible for Update 2000, Update 2002, and Update 2004 concurred with the findings of Update 1998. The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the chemicals of interest and melanoma or inadequate or insufficient evidence to determine whether there is an association, so melanoma was left in the lower category. Table 6-19 summarizes the relevant melanoma studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies No Vietnam-veteran studies concerning exposure to the chemicals of interest and melanoma have been published since Update 2006. Occupational Studies Samanic et al. (2006) observed no strong association with melanoma and ex- posure to dicamba in the AHS cohort. When exposure was defined as the number of lifetime days of applications, Poisson regression found the largest association for applications of 20–56 days, with a rate ratio of 1.59 (95% CI 0.84–3.00). The association decreased as the number of exposure days increased, with an estimated risk of 0.83 (95% CI 0.33–2.13) for greater than 116 lifetime days of

CANCER 291 TABLE 6-19  Selected Epidemiologic Studies—Melanoma Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 Pavuk et al., White Air Force comparison subjects 2005 only—incidence Serum TCDD (pg/g), based on model with exposure variable loge(TCDD) Per unit increase of -loge(TCDD) 25 2.7 (1.1–6.3) Quartiles (pg/g) 0.4–2.6 3 1.0 2.6–3.8 5 2.1 (0.4–11.0) 3.8–5.2 8 3.2 (0.7–15.5) > 5.2 9 3.6 (0.7–17.2) Number years served SEA Per year of service 25 1.1 (0.9–1.3) Quartiles (years in SEA) 0.8–1.3 3 1.0 1.3–2.1 4 1.9 (0.3–10.3) 2.1–3.7 8 3.2 (0.7–15.3) 3.7–16.4 10 4.1 (0.9–19.7) ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 756 1.3 (1.2–1.4) Navy 173 1.4 (1.2–1.6) Army 510 1.2 (1.2–1.4) Air Force 73 1.4 (1.1–1.7) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 111 1.1 (0.9–1.3) Navy 35 1.6 (1.0–2.1) Army 66 1.0 (0.7–1.2) Air Force 10 1.0 (0.5–1.8) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs nondeployed Incidence 204 1.1 (0.9–1.4) Mortality 14 0.6 (0.3–1.1) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 6 1.4 (0.4–4.9) Studies Reviewed in Update 2004 Akhtar AFHS subjects vs national rates et al., 2004 White AFHS Ranch Hand veterans Incidence 17 2.3 (1.4–3.7) With tours between 1966–1970 16 2.6 (1.5–4.1) Mortality nr White AFHS comparison veterans Incidence 15 1.5 (0.9–2.4) With tours between 1966–1970 12 1.5 (0.8–2.6) Mortality nr continued

292 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-19  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b White AFHS subjects—incidence Who spent at most 2 years in SEA Per unit increase of -loge(TCDD) (pg/g) 14 2.2 (1.3–3.9) Comparison group 3 1.0 Ranch Hand— < 10 TCDD pg/g in 1987 4 3.0 (0.5–16.8)  Ranch Hand— < 118.5 TCDD pg/g at end of service 4 7.4 (1.3–41.0)  Ranch Hand— > 118.5 TCDD pg/g at end of service 3 7.5 (1.1–50.2)  Only Ranch Hands with 100% service in Vietnam, comparisons with 0% service in Vietnam Per unit increase of -loge(TCDD) in pg/g 14 1.7 (1.0–2.8) Comparison group 2 1.0 Ranch Hand— < 10 TCDD pg/g in 1987 5 3.9 (0.4–35.3)  Ranch Hand— < 118.5 TCDD pg/g at end of service 4 7.2 (0.9–58.8)  Ranch Hand— > 118.5 TCDD pg/g at end of service 3 5.5 (0.6–46.1) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence 16 1.8 (0.8–3.8) Ketchum Ranch Hand veterans, comparisons through June et al., 1999 1997—incidence Comparisons 9 1.0 Ranch Hand background exposure 4 1.1 (0.3–4.5) Ranch Hand low exposure 6 2.6 (0.7–9.1) Ranch Hand high exposure 2 0.9 (0.2–5.6) AIHW, Expected number 1999 of exposed cases Australian Vietnam veterans—incidence (validation (95% CI) study) 483 380 (342–418) CDVA, Australian Vietnam veterans (men)—self-reported 1998a incidence 2,689 380 (342–418) CDVA, Australian Vietnam veterans (women)—self-reported 1998b incidence 7 3 (1–8) Studies Reviewed in Update 1998 CDVA, Australian Vietnam veterans (men) 51 1.3 (0.9–1.7) 1997a CDVA, Australian national service Vietnam veterans 16 0.5 (0.2–1.3) 1997b Clapp, 1997 Massachusetts Vietnam veterans—incidence 21 1.4 (0.7–2.9) Studies Reviewed in VAO Wolfe et al., Air Force Ranch Hand veterans—incidence 4 1.3 (0.3–5.2) 1990 Breslin Army Vietnam veterans 145 1.0 (0.9–1.1) et al., 1988 Marine Vietnam veterans 36 0.9 (0.6–1.5)

CANCER 293 TABLE 6-19  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL New Studies Hansen Danish gardeners—incidence et al., 2007 (skin, ICD-7 190–191)  10-year follow-up (1975–1984) reported in Hansen et al. (1992) 31 1.3 (0.9–1.8) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 28 0.9 (0.6–1.4) Born 1915–1934 (medium exposure) 36 0.6 (0.4–0.9) Born after 1934 (low exposure) 5 0.3 (0.1–0.7) Samanic Pesticide applicators in AHS—melanoma incidence et al., 2006 from enrollment through 2002 Dicamba—lifetime days exposure None 32 1.0 1– < 20 10 1.0 (0.5–2.1) 20– < 56 18 1.6 (0.8–3.0) 56– < 116 6 0.7 (0.3–1.8) ≥ 116 6 0.8 (0.3–2.1) p-trend = 0.51 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds Never 20 0.8 (0.5–1.3) Ever 21 1.2 (0.7–1.8) ’t Mannetje Phenoxy herbicide producers (men and women) 0 0.0 (0.0–3.0) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 1 0.6 (0.0–3.4) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 100 1.0 (0.8–1.2) Spouses of private applicators (> 99% women) 67 1.6 (1.3–2.1) Commercial applicators (men and women) 7 1.1 (0.4–2.2) Blair et al., US AHS 2005a Private applicators (men and women) 13 0.7 (0.4–1.3) Spouses of private applicators (> 99% women) 2 0.4 (0.1–1.6) Torchio Italian licensed pesticide users 9 1.2 (0.6–2.3) et al., 1994 Magnani UK case–control et al., 1987 Herbicides nr 1.2 (0.4–4.0) Chlorophenols nr 0.9 (0.4–2.3) Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators et al., 2004  Melanoma, squamous-cell carcinoma, unknown skin cancer (mortality presumably attributable to melanoma) 5 3.6 (1.2–8.3) continued

294 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-19  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2002 Thörn et al., Swedish lumberjack workers exposed to 2000 phenoxyacetic herbicides—incidence Women 1 3.5 (0.1–19.2) Men 0 nr Studies Reviewed in Update 2000 Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) 1 2.9 (0.1–15.9) Studies Reviewed in Update 1998 Hertzman British Columbia sawmill workers et al., 1997 Incidence 38 1.0 (0.7–1.3) Mortality 17 1.4 (0.9–2.0) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 9 0.6 (0.3–1.2) Exposed to highly chlorinated PCDDs 5 0.5 (0.2–3.2) Not exposed to highly chlorinated PCDDs 4 0.0 (0.3–2.4) Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 244 1.0 (0.8–1.1) White women 5 1.1 (0.4–2.7) Lynge, 1993 Danish production workers (included in IARC cohort)—updated incidence 4 4.3 (1.2–10.9) Studies Reviewed in VAO Ronco et al., Danish workers—incidence 1992 Men 72 0.7 (p < 0.05) Women 5 1.2 (nr) Wigle et al., Canadian farmers 24 1.1 (0.7–1.6) 1990 Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 268 0.8 (0.7–1.0) ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 1 3.1 (0.4–22.0) Zone B 2 1.0 (0.2–3.9) Zone R 12 0.8 (0.4–1.5) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B— en m 1 1.5 (0.2–12.5) women 2 1.8 (0.4–7.3) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone A—women 1 9.4 (0.1–52.3) Zone R— en m 3 1.1 (0.2–3.2) women 3 0.6 (0.1–1.8)

CANCER 295 TABLE 6-19  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Svensson Swedish fishermen (men and women) et al., 1995 East coast Incidence 0 0.0 (0.0–0.7) Mortality 0 0.0 (0.0–1.7) West coast Incidence 20 0.8 (0.5–1.2) Mortality 6 0.7 (0.3–1.5) Studies Reviewed in VAO Bertazzi Seveso residents—10-year follow-up et al., 1989a Zones A, B, R— en m 3 3.3 (0.8–13.9) women 1 0.3 (0.1–2.5) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin. aCohorts are male and outcome mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. exposure. A similar inverse pattern with increasing exposure was observed when exposure categories were weighted by intensity. Hansen et al. (2007) evaluated cancer incidence from May 1975 through 2001 in an occupational cohort of Danish union workers identified from men working in 1973; their incidence from 1975 to 1984 was reported earlier by Hansen et al. (1992). The cohort of 3,156 male gardeners was matched to the Danish Cancer Registry to measure cancer incidence in the cohort. All skin can- cers (ICD-7 190–191) were examined as one group. SIRs, with control for age and calendar time, were calculated by using the national cancer incidences as the standards. Given the reduction in pesticide use over time, birth cohorts were used as a proxy definition of exposure. Three subcohorts were evaluated: high exposure, early-birth cohort (born before 1915); low exposure, late-birth cohort (born after 1935); and medium exposure (births in 1915–1935). Overall, 521 cancer cases were identified, of which 69 were coded as skin cancer. The SIRs decreased with birth-cohort period (the SIRs were lowest in the late-birth cohort), but the observed incidence for all skin cancers combined was lower than the expected incidence in all birth cohorts examined. In men born before 1915, the cohort assumed to have the greatest exposure potential, the SIR was 0.93 (95% CI 0.64–1.35). A lower incidence than expected was also observed in men born after 1935, when exposures were hypothesized to be lower because there were fewer applications and better safety measures (SIR = 0.28, 95% CI 0.12–0.67).

296 VETERANS AND AGENT ORANGE: UPDATE 2008 Environmental Studies The 25-year follow-up of the Seveso cohort was reported by Consonni et al. (2008). Person-years were calculated for 278,108 cohort members from July 10, 1976 (or entry date), until death or the end of the study (December 31, 2001) for all 278,108 study members. A total of 15 melanoma deaths were identified, of which 12 occurred in residents in the low-exposure zone (Zone R). Compared with the incidence in the reference zone, melanoma incidence was decreased in the high exposure Zone B (RR = 0.97, 95% CI 0.24–3.93) and low-exposure Zone R (RR = 0.83, 95% CI 0.45–1.51). One melanoma death was observed in Zone A, which had the highest TCDD exposure (RR = 3.06, 95% CI 0.43–22.01). Fortes et al. (2007) examined residential use of pesticides and melanoma in a hospital-based case–control study; however, the lack of exposure specificity in the study precluded inclusion of its results in this review. Biologic Plausibility There have been no new studies of animal models of skin cancer. TCDD and related herbicides have not been found to cause melanoma in animal models. In general, rodents, which are used in most toxicology studies, are not a good model for studying melanoma. TCDD does produce nonmelanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation. However, no experiments have been conducted specifically to examine that potential mechanism. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis No association between the chemicals of interest and melanoma was ob- served in either of the two new occupational studies. Of the two new environmen- tal studies, that by Fortes et al. observed a weak association between self-reported residential use of pesticides and melanoma, but the numbers were not sufficient to examine herbicides separately. Finally, although the risk of melanoma was increased in those living in the highest-exposure zone in the Seveso cohort, this finding was based on only one melanoma death. The new studies do not provide evidence to support moving melanoma to the category of limited or suggestive evidence. The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the chemicals of interest and melanoma or inadequate or insufficient evidence to determine whether there is an association. That committee recognized that the findings from the Air Force Health Study (AFHS), including the evalu-

CANCER 297 ation of TCDD measurements and melanoma (Akhtar et al., 2004; Pavuk et al., 2005), were of prime interest. However, the data from the final AFHS examina- tion cycle indicate that many more melanoma cases were diagnosed in the com- parison veterans than in the Ranch Hand subjects, so the committee responsible for Update 2006 recommended that the Akhtar et al. analyses be rerun on the final AFHS dataset. The final data on the Ranch Hand and comparison subjects still have not been analyzed in a satisfactory and uniform manner, so the pres- ent committee also strongly encourages that such an analysis be performed and published to provide documentation of the full melanoma experience revealed by the AFHS and to permit definitive evaluation of the possible association between the chemicals of interest and melanoma. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and melanoma. SKIN CANCER—BASAL-CELL CANCER AND SQUAMOUS-CELL CANCER (NONMELANOMA SKIN CANCERS) The preceding section on melanoma presented background information on nonmelanoma skin cancers (ICD-9 173). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and skin cancer, and additional informa- tion available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on nonmelanocytic skin cancer separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and basal-cell or squamous-cell cancer. The committees responsible for Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-20 summarizes the relevant studies. Update of the Epidemiologic Literature No Vietnam-veteran studies or environmental studies concerning exposure to the chemicals of interest and basal-cell or squamous-cell cancer have been published since Update 2006.

298 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-20  Selected Epidemiologic Studies—Other Nonmelanoma (Basal- Cell and Squamous-Cell) Skin Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 Pavuk et al., White Air Force comparison subjects only (basal 2005 cell and squamous cell)—incidence Serum TCDD (pg/g), based on model with exposure variable loge(TCDD) Per unit increase of -loge(TCDD) 253 1.2 (0.9–1.4) Quartiles (pg/g) 0.4–2.6 50 nr 2.6–3.8 59 1.2 (0.8–1.8) 3.8–5.2 71 1.5 (1.1–2.3) > 5.2 73 1.4 (0.9–2.0) Number of years served in SEA Per year of service 253 1 (0.9–1.1) Quartiles (years in SEA) 0.8–1.3 55 nr 1.3–2.1 50 0.9 (0.6–1.4) 2.1–3.7 73 1.1 (0.8–1.6) 3.7–16.4 75 1.2 (0.8–1.7) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence Basal-cell carcinoma 121 1.2 (0.9–1.6) Squamous-cell carcinoma 20 1.5 (0.8–2.8) CDVA, Australian Vietnam veterans (men)—self-reported 1998a incidence 6,936 nr CDVA, Australian Vietnam veterans (women)—self-reported 1998b incidence 37 nr Studies Reviewed in VAO Wolfe et al., Air Force Ranch Hand veterans—incidence 1990 Basal-cell carcinoma 78 1.5 (1.0–2.1) Squamous-cell carcinoma 6 1.6 (0.5–5.1) OCCUPATIONAL New Studies Hansen Danish gardeners—incidence et al., 2007 (skin, ICD-7 190–191)  10-year follow-up (1975–1984) reported in Hansen et al. (1992) 31 1.3 (0.9–1.8) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 28 0.9 (0.6–1.4) Born 1915–1934 (medium exposure) 36 0.6 (0.4–0.9) Born after 1934 (low exposure) 5 0.3 (0.1–0.7) Studies Reviewed in Update 2006 Torchio Italian licensed pesticide users 3 0.6 (0.1–1.8) et al., 1994

CANCER 299 TABLE 6-20  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators et al., 2004 Melanoma, squamous-cell carcinoma, unknown skin cancer (mortality presumably attributable to melanoma) 5 3.6 (1.2–8.3) Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) Nonmelanoma skin cancer 0 nr Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides—incidence Foremen 1 16.7 (0.2–92.7) Studies Reviewed in Update 1998 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 4 0.9 (0.3–2.4) Exposed to highly chlorinated PCDDs 4 1.3 (0.3–3.2) Not exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.4) Zhong and Icelandic pesticide users (men, women—incidence) Rafnsson, Men 5 2.8 (0.9–6.6) 1996 Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 Skin (including melanoma) White men 425 1.1 (1.0–1.2) White women 6 1.0 (0.4–2.1) Studies Reviewed in VAO Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 493 0.7 (p < 0.05) employee 98 0.7 (p < 0.05) Women— elf-employed s 5 0.3 (p < 0.05) employee 10 0.9 (nr) family worker 90 0.6 (p < 0.05) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 3 3.1 (0.6–9.0) ENVIRONMENTAL Studies Reviewed in Update 1998 Gallagher Alberta, Canada, residents—squamous-cell et al., 1996 carcinoma—incidence All herbicide exposure 79 1.5 (1.0–2.3) Low herbicide exposure 33 1.9 (1.0–3.6) High herbicide exposure 46 3.9 (2.2–6.9) Alberta, Canada, residents—basal-cell carcinoma All herbicide exposure 70 1.1 (0.8–1.7) continued

300 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-20  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Svensson Swedish fishermen et al., 1995 East coast Incidence 22 2.3 (1.5–3.5) Mortality 0 0.0 (0.0–15.4) West coast Incidence 69 1.1 (0.9–1.4) Mortality 5 3.1 (1.0–7.1) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone A— en m 1 2.4 (0.3–17.2) women 1 3.9 (0.5–28.1) Zone B— en m 2 0.7 (0.2–2.9) women 2 1.3 (0.3–5.1) Zone R— en m 20 1.0 (0.6–1.6) women 13 1.0 (0.6–1.9) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 3 1.0 (0.3–3.0) women 3 1.5 (0.5–4.9) Zone R— en m 20 1.0 (0.6–1.6) women 13 1.0 (0.5–1.7) Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 708 1.1 (1.0–1.2) ABBREVIATIONS: CI, confidence interval; IARC, International Agency for Research on ­Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetra­chloro­dibenzo-p-dioxin. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. Occupational Studies The study by Hansen et al. (2007), which examined the incidence of all skin cancers combined (see section on melanoma above), is the only new one related to skin cancer published since Update 2006. No association was observed in this occupational cohort of Danish gardeners when cancer incidence was compared with national rates by birth cohort (a proxy for pesticide exposure). The study was limited by the inability to examine incidence by pesticide class (such as her- bicides) and to evaluate nonmelanoma cancer separately from melanoma.

CANCER 301 Biologic Plausibility There are no new studies on animal models of skin cancer to report. TCDD does produce nonmelanoma skins cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation, but no experiments have been conducted specifically to support this potential mechanism. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis In accord with the results of reports previously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and basal- cell or squamous-cell cancer. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and basal-cell or squamous-cell cancer. BREAST CANCER Breast cancer (ICD-9 174 for females, ICD-9 175 for males) is the second- most common type of cancer (after nonmelanoma skin cancer) in women in the United States. ACS estimated that 182,460 women would receive diagnoses of breast cancer in the United States in 2008 and that 40,480 would die from it (Jemal et al., 2008a). Overall, those numbers represent about 26% of the new cancers and 15% of cancer deaths in women. Incidence data on breast cancer are presented in Table 6-21. Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence is higher in whites than in blacks. Established risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after the age of 30 years. A pooled analysis of six large-scale pro- spective studies of invasive breast cancer showed that alcohol consumption over the range of consumption reported by most women was associated with a small, linear increase in incidence in women (Smith-Warner et al., 1998). It is now generally accepted that breast-cancer risk is increased by prolonged use of hormone-replacement therapy, particularly use of preparations that combine es-

302 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-21  Average Annual Incidence (per 100,000) of Breast Cancer in Females in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 1.2 1.3 1.7 2.3 2.9 4.5 3.5 3.5 6.6 Women 240.5 248.2 224.6 309.0 321.5 270.7 372.4 391.0 321.8 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. trogen and progestins (Chlebowski et al., 2003). The potential of other personal behavioral and environmental factors (including use of exogenous hormones) to affect breast-cancer incidence is being studied extensively. Most of the roughly 10,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have recently reached menopause. Given the high incidence of breast cancer in older and postmeno- pausal women in general, on the basis of demographics alone it is expected that the breast-cancer burden in female Vietnam veterans will increase in the near future. The vast majority of breast-cancer epidemiologic studies involve women, but the disease also occurs rarely in men, with 1,990 new cases expected in 2008 (Jemal et al., 2008a). Reported instances of male breast cancer are noted, but the committee’s conclusions are based on the studies in women. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and breast cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. The com- mittee responsible for Update 2006 was unable to reach consensus as to whether there was limited or suggestive evidence of an association between the chemicals of interest and breast cancer or inadequate or insufficient evidence to determine whether an association exists, and so breast cancer was left in the lower category. Table 6-22 summarizes the relevant research. Update of the Epidemiologic Literature Vietnam-Veteran Studies Cypel and Kang (2008) compared breast-cancer mortality in female veterans who served in Vietnam with that in veterans, matched on rank and type of du-

CANCER 303 TABLE 6-22  Selected Epidemiologic Studies—Breast Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women 57 1.0 (0.7–1.4) Kang, 2008 Vietnam-veteran nurses 44 0.9 (0.6–1.4) Studies Reviewed in Update 2006 Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 0 nr ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 7 0.9 (0.4–1.9) Navy 1 0.6 (0.0–3.3) Army 5 1.0 (0.3–2.2) Air Force 1 1.1 (0.0–6.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 4 2.2 (0.6–5.4) Navy 1 2.5 (0.0–13.5) Army 3 2.5 (0.5–7.2) Air Force 0 0.0 (0.0–14.6) ADVA, Australian male conscripted Army National Service 2005c Vietnam era veterans—deployed vs nondeployed 0 nr Incidence 0 0.0 (0.0–2.4) Mortality nr Studies Reviewed in Update 2002 Kang et al., Female US Vietnam veterans 2000 170 1.2 (0.9–1.5) CDVA, Expected number 1998b of exposed cases Australian Vietnam veterans (women)—self-reported (95% CI) incidence 17 5 (2–11) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans (men) 3 5.5 (1.0– > 10.0) 1997a Studies Reviewed in Update 1996 Dalager Female US Vietnam veterans 26 1.0 (0.6–1.8) et al., 1995 Studies Reviewed in VAO Thomas Female US Vietnam veterans 17 1.2 (0.6–2.5) et al., 1991 OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 21 0.9 (0.6–1.4) Ever 32 0.9 (0.6–1.3) continued

304 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-22  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ’t Mannetje Phenoxy herbicide producers (men and women) et al., 2005 Women 1 1.3 (0.0–7.2) Men 1 32 (0.8–175) Phenoxy herbicide sprayers (> 99% men) 0 0.0 (nr) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 27 1.1 (0.7–1.6) Spouses of private applicators (> 99% women) 474 1.0 (0.9–1.1) Commercial applicators (men and women) 1 0.6 (0.1–3.5) Engel et al., US AHS, wives of private applicators—incidence 2005 Wives’ own use of phenoxy herbicides 41 0.8 (0.6–1.1) 2,4-D 41 0.8 (0.6–1.1) Husbands’ use of phenoxy herbicides 110 1.1 (0.7–1.8) 2,4-D 107 0.9 (0.6–1.4) 2,4,5-T 44 1.3 (0.9–1.9) 2,4,5-TP 19 2.0 (1.2–3.2) Blair et al., US AHS—mortality 2005a Private applicators (men and women) 3 0.9 (0.2–2.7) Spouses of private applicators (> 99% women) 54 0.9 (0.7–1.1) Mills and Hispanic agricultural farm workers (women) Yang, 2005 Cancer diagnosis 1987–1994 Low 2,4-D use 12 0.6 (0.2–1.9) High 2,4-D use 8 0.6 (0.2–1.7) Cancer diagnosis 1995–2001 Low 2,4-D use 19 2.2 (1.0–4.9) High 2,4-D use 21 2.1 (1.1–4.3) Studies Reviewed in Update 2000 Duell et al., Female farm workers, residents in North Carolina 2000 Used pesticides in garden 228 2.3 (1.7–3.1) Laundered clothes for pesticide user 119 4.1 (2.8–5.9) Studies Reviewed in Update 1998 Kogevinas IARC cohort, workers exposed to any phenoxy et al., 1997 herbicide or chlorophenol Women (identical with Manz et al. [1991]) 12 1.2 (0.6–2.1) Exposed to highly chlorinated PCDDs 9 2.2 (1.0–4.1) Not exposed to highly chlorinated PCDDs 3 0.5 (0.1–1.6) Men 2 1.6 (0.2–5.6) Exposed to highly chlorinated PCDDs 2 2.6 (0.3–9.3) Not exposed to highly chlorinated PCDDs 0 nr Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 Men— hite w 18 0.7 (0.4–1.2) nonwhite 4 1.7 (0.5–4.4) Women— hite w 71 1.0 (0.8–1.3) nonwhite 30 0.7 (0.5–1.0) Kogevinas IARC cohort—women 7 0.9 (0.4–1.9) et al., 1993

CANCER 305 TABLE 6-22  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Ronco et al., Danish, Italian farm workers 1992 Male farmers 5 0.5 (nr) Female farmers 41 0.9 (nr) Female family workers 429 0.8 (p < 0.05) Manz et al., German production workers—men, women 1991 (included in IARC cohort) Women 9 2.2 (1.0–4.1) Saracci IARC cohort—exposed subcohort (men and women) et al., 1991 Men 2 3.5 (0.4–12.5) Women 1 0.3 (0.0–1.7) Lynge, 1985 Danish male and female production workers (included in IARC cohort)—incidence Women 13 0.9 (nr) Wiklund, Swedish agricultural workers—incidence 99% CI 1983 Men and women 444 0.8 (0.7–0.9) Men only nr 1.0 (nr) ENVIRONMENTAL New Studies Consonni Seveso residents (men and women)—25-year et al., 2008 follow-up Zone A 2 0.6 (0.2–2.4) Zone B 13 0.6 (0.3–1.2) Zone R 133 0.9 (0.7–1.1) Teitelbaum Case–control study in Long Island, New et al., 2007 York—incidence Used lawn and garden pesticides Never 240 1.0 Ever 1,254 1.3 (1.1–1.6) Product for weeds 1,109 1.4 (1.2–1.8) Viel et al., Case–control study in Besançon, France—incidence 2008  Residence in zones of dioxin exposure around solid-waste incinerator Women, 20–59 years old Very low 41 1.0 Low 81 1.1 (0.7–1.6) Intermediate 64 1.3 (0.8–1.9) High 11 0.9 (0.4–1.8) Women, at least 60 years old Very low 50 1.0 Low 111 0.9 (0.6–1.3) Intermediate 72 1.0 (0.7–1.4) High 4 0.3 (0.1–0.9) continued

306 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-22  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2006 Reynolds Total TEQs (pg/g) in adipose breast tissue et al., 2005 ≤ 14.0 24 1.0 14.1–20.9 22 0.7 (0.3–1.9) ≤ 21.0 33 0.3 (0.3–2.0) p-trend = 0.99 Reynolds California Teachers Study cohort et al., 2004  Residential proximity to use of “endocrine disruptors” (including 2,4-D, cacodylic acid) Quartiles of use (lb/mi2) < 1 1,027 1.0 1–21 274 1.0 (0.8–1.1) 22–323 114 0.9 (0.7–1.1) ≥ 324 137 1.0 (0.9–1.3) Studies Reviewed in Update 2002 Holford Patients at Yale–New Haven hospital with breast- et al., 2000 related surgery; dioxin-like congener 156 nr 0.9 (0.8–1.0) Revich Residents of Chapaevsk, Russia—women 58 2.1 (1.6–2.7) et al., 2001 Warner SWHS—981 women who were infants to 40 years et al., 2002 old when exposed—incidence With 10-fold increase in TCDD 15 2.1 (1.0–4.6) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B—females 14 0.7 (0.4–1.3) Bagga et al., Women receiving medical care in Woodland Hills, 2000 California 73 nr Demers Women in Quebec City—newly diagnosed 314 nr et al., 2000 Høyer et al., Overall survival 2000 relative risk Female participants in Copenhagen City Heart Study 195 2.8 (1.4–5.6) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al. 1997 Zone A—women 1 0.6 (0.0–3.1) Zone B—women 9 0.8 (0.4–1.5) Zone R—women 67 0.8 (0.6–1.0) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone A—women 1 0.5 (0.1–3.3) Zone B—women 10 0.7 (0.4–1.4) Zone R— omen w 106 1.1 (0.9–1.3) men 1 1.2 (0.1–10.2)

CANCER 307 TABLE 6-22  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone A—women 1 1.1 (0.1–7.5) Zone B—women 5 0.9 (0.4–2.1) Zone R—women 28 0.6 (0.4–0.9) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2 (2,4,5-trichlorophenoxy) propionic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent quotient. aSubjects are female and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. ties, who served outside Vietnam during the same era. The RR of breast-cancer mortality was 1.00 (95% CI 0.69–1.44). The RR posed by Vietnam service was similar when the analysis was restricted to those serving as nurses (RR = 0.92, 95% CI 0.61–1.41). That study therefore provides no support of an association between Agent Orange exposure and breast-cancer risk. However, although its fo- cus on Vietnam veterans is germane, the analysis did not consider actual exposure to herbicides and was unable to adjust for variables, such as reproductive history, that can confound the relationships of exposures to breast cancer. Occupational Studies No occupational studies concerning exposure to the chemicals of interest and breast cancer have been published since Update 2006. Environmental Studies In a case–control study in France, 434 women who had breast cancer were compared with 2,170 community controls according to the proximity of their residence to emissions from a waste incinerator that generated polychlorinated dibenzodioxins and polychlorinated dibenzofurans (Viel et al., 2008). Four expo- sure categories were created on the basis of emission data and a wind-dispersion model. Separate analyses were carried out for women 20–59 years old and women at least 60 years old. For the younger women, the OR for the highest ex- posure relative to the lowest was 0.88 (95% CI 0.43–1.79). In older women, that OR was 0.31 (95% CI 0.08–0.89); however, this was based on only four cases,

308 VETERANS AND AGENT ORANGE: UPDATE 2008 and there was no evidence of a dose–response trend. Furthermore, the study did not adjust for any potential confounders. Teitelbaum et al. (2007) reported results of the large case–control study of breast cancer in Long Island, New York. Over 1,500 cases and a similar number of matched controls provided information on their exposure to several categories of household pesticides. The OR for those who reported ever using antiweed chemicals vs those who never used any lawn or garden chemicals was 1.43 (95% CI 1.17–1.75). However, similar ORs were obtained for several other categories of lawn and garden chemicals when those who never used any such chemicals were the referent group. That suggests that recall bias (higher recall of all expo- sures of cases relative to controls) might have played a role. Although ever vs never use of lawn and garden chemicals was significantly associated with breast- cancer risk, there was no dose–response relationship with respect to number of lifetime applications, and the degree of specificity regarding exposure to the chemicals of interest was rather weak. The relatively low response rate among potential controls (63% of those eligible agreed to participate) further reduces the value of this case–control analysis. Investigators in Italy completed a 25-year mortality follow-up of people exposed to the industrial accident in Seveso (Consonni et al., 2008). Mortality from breast cancer was compared in residents in three exposure zones—very high (Zone A), high (Zone B), and low (Zone R)—and a nonexposed reference population. There was no evidence of increased breast-cancer mortality in any of the exposure groups. The RRs were 0.60 (95% CI 0.15–2.41) in Zone A, 0.65 (95% CI 0.37–1.12) in Zone B, and 0.87 (95% CI 0.73–1.05) in Zone R. There were two, 13, and 133 breast-cancer deaths during the follow-up period in Zones A, B, and R, respectively. It should be noted that the analysis did not include data on established risk factors for breast cancer and was therefore unable to adjust for potential confounding. Biologic Plausibility All the experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are at most weakly genotoxic. However, TCDD is a demonstrated carcinogen in animals and is recognized as having carcinogenic potential in humans because of the mechanisms discussed in Chapter 4. With respect to breast cancer, studies performed in laboratory animals (Sprague-Dawley rats) indicate that the effect of TCDD may depend on the age of the animal. For example, TCDD exposure was found to inhibit mammary- tumor growth in the adult rat (Holcombe and Safe, 1994), but to increase tumor growth in the neonatal rat (21 days old) (Desaulniers et al., 2001). Other studies have failed to demonstrate an effect of TCDD on mammary-tumor incidence or growth (Desaulniers et al., 2004). Those observations may indicate a close association between the develop- ment of mammary cancers and mammary gland differentiation. Agents capable of

CANCER 309 disrupting the ability of the normal mammary epithelial cell to enter or maintain its appropriate status (a proliferative, differentiated, apoptotic state), to maintain its appropriate architecture, or to conduct normal hormone (estrogen) signal- ing are likely to act as carcinogenic agents (Fenton, 2006; McGee et al., 2006). In that light, it is interesting that postnatal exposure of pregnant rats to TCDD has been found to alter proliferation and differentiation of the mammary gland (Birnbaum and Fenton, 2003; Vorderstrasse et al., 2004). In a recent publication, Jenkins et al. (2007) used a carcinogen-induced rat mammary-cancer model to show that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility to mammary cancer by altering the expression of estrogen-receptor genes and of genes involved in oxidative-stress defense. Thus, the effect of TCDD may depend on the timing of the exposure and on the level of gene expression at the time of exposure; TCDD may affect mammary-tumor development only if exposure to it occurs during a specific window during breast development. The breast is the only human organ that does not fully differentiate until it becomes ready for use; nulliparous women have less-differentiated breast lobules, which are presumably more susceptible to carcinogenesis. Activation of the AHR by dioxin or by the nondioxin ligand indole-3-carbinol is believed to be protective against breast cancer by mechanisms that disrupt mi- gration and metastasis (Bradlow, 2008; Hsu et al., 2007). TCDD has been shown to modulate the induction of DNA chain breaks in human breast-cancer cells by regulating the activity of the enzymes respon- sible for estradiol catabolism and generating more reactive intermediates, which might contribute to TCDD-induced carcinogenesis by altering the ratios of 4- OH-estradiol to 2-OH-estradiol (Lin et al., 2007, 2008). A similar imbalance in metabolite ratios has been observed in pregnant Taiwanese women, in whom the ratio of 4-OH-estradiol to 2-OH-estradiol, a breast-cancer–risk marker, decreased with increasing exposure to TCDD (Wang et al., 2006). Expression of CYP1B1, the cytochrome P450 enzyme responsible for 2-OH-estradiol formation, but not CYP1A1, the one responsible for 4-OH estradiol formation, was found to be highly increased in premalignant and malignant rat mammary tissues in which the AHR was constitutively active in the absence of ligand (Yang et al., 2008). On the basis of recent mechanistic data, it has been proposed that the AHR con- tributes to mammary-tumor cell growth by inhibiting apoptosis while promoting transition to an invasive, metastatic phenotype (Marlowe et al., 2008; Schlezinger et al., 2006). Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the IL–6 cy- tokine, which has tumor-promoting effects in numerous tissues, including breast tissue, so TCDD might promote carcinogenesis in these tissues (Hollingshead et al., 2008). The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

310 VETERANS AND AGENT ORANGE: UPDATE 2008 Synthesis In the early 1990s, it was suggested that exposure to some environmental chemicals, such as organochlorine compounds, might play a role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast-cancer risk has been studied extensively especially in the last decade; TCDD and dioxin-like compounds have been among the organo- chlorines so investigated. Today there is no clear evidence to support a causal role of most organochlorines in human breast cancer (Salehi et al., 2008). The committee responsible for Update 2006 was unable to reach a consen- sus regarding whether the evidence of an association between the chemicals of interest and breast cancer was suggestive or inadequate. Only a few studies have been published in the interim, but, although each of them has limitations and cannot be considered definitive, they tend to weigh against the conclusion that the herbicides in question cause breast cancer in humans. The study by Cypel and Kang (2008) on mortality in female Vietnam-era veterans, especially nurses, is particularly relevant to the mission of the committee. Even though the study did not include any details of specific chemical exposures or confounding factors, the failure to observe any increase in breast-cancer mortality in women who served in Vietnam is revealing. Meanwhile, the analysis by Consonni et al. (2008), a long-term mortality follow-up in Seveso, was specific with regard to exposure to dioxin, and it also had null findings. In fact, breast-cancer mortality was lower in exposed residents than in the nonexposed reference population, and the lower risk—although still consistent with a chance finding—begins to approach statistical significance in the Zone B (high-exposure) and Zone R (low-exposure) groups. We note the contrast between that result and the results of an earlier study on Seveso in which a positive association between serum TCDD and breast-cancer risk reached borderline statistical significance (Warner et al., 2002). The study by Viel et al. (2008) of women who lived near a waste incinerator had too few cases and too little control for confounding to provide strong evidence, but it, too, found only inverse associations with breast-cancer risk, especially in older women. The study by Teitelbaum et al. (2007), which reported some increase in risk associated with reports of having used lawn or garden chemicals, may have been affected by the recall bias that is common in case–control studies and also lacked details of specific chemical exposures. Conclusion Having considered the new evidence and the results of studies reviewed in previous updates, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association (either positive or negative) between exposure to the chemicals of interest and breast cancer.

CANCER 311 CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM This section addresses cancers of the cervix (ICD-9 180), endometrium (also referred to as the corpus uteri; ICD-9 182.0–182.1, 182.8), and ovary (ICD-9 183.0). Other cancers of the female reproductive system that are infrequently reported separately are unspecified cancers of the uterus (ICD-9 179), placenta (ICD-9 181), fallopian tube and other uterine adnexa (ICD-9 183.2–183.9), and other female genital organs (ICD-9 184); findings on these cancers are included in this section. It also presents statistics on other cancers of the female reproductive system. ACS estimates of the numbers of new female reproductive-system can- cers in the United States in 2008 are presented in Table 6-23, with genital-system cancers representing roughly 11% of new cancer cases and 10% of cancer deaths in women (Jemal et al., 2008a). The incidences of and risk factors for those diseases vary (Table 6-24). Cervi- cal cancer occurs more often in blacks than in whites, whereas whites are more likely to develop endometrial and ovarian cancer. The incidence of endometrial and ovarian cancer is increased in older women and in those with positive fam- ily histories. Use of unopposed estrogen-hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of en- dometrial cancer. Human papilloma virus (HPV) infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer. Use of oral contraceptives is associated with a substantial reduction in the risk of ovarian cancer. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Tables 6-25, 6-26, and 6-27 summarize the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies The long-term mortality study of female Vietnam veterans by Cypel and Kang (2008) found no increase in risk of death from uterine or ovarian cancer in those who served in Vietnam; however, the number of deaths due to these cancers was small, so these estimates lack precision.

312 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-23  Estimates of New Cases of Deaths from Selected Cancers of the Female Reproductive System in the United States in 2008 Site New Cases Deaths Cervix 11,070 3,870 Endometrium 40,100 7,470 Ovary 21,650 15,520 Other female genital 5,670 1,630 SOURCE: Jemal et al., 2008. Occupational Studies No occupational studies concerning exposure to the chemicals of interest and cancers of the female reproductive system have been published since Update 2006. Environmental Studies Consonni et al. (2008) studied mortality of various causes in women exposed to dioxin during the Seveso incident in Italy. Very few deaths from those specific cancers occurred in women in the more heavily exposed areas, so those risk es- timates lack precision and are not very informative. Biologic Plausibility No animal studies have reported an increased incidence of female reproduc- tive cancer after exposure to the chemicals of interest. One study (Kociba et al., 1978), however, showed a reduced incidence of uterine tumors in rats fed TCDD at 0.1 mg/kg of diet for 2 years. TABLE 6-24  Average Annual Incidence (per 100,000) of Female Genital System Cancers in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black All genital sites 84.3 87.6 64.2 119.4 125.5 84.0 148.7 153.2 146.1 Cervix 11.6 10.9 15.2 11.9 10.9 17.5 12.3 10.5 22.8 Endometrium 45.5 48.8 24.6 68.6 73.7 36.6 88.6 93.0 77.1 Ovary 22.3 23.6 15.1 29.9 32.1 19.7 38.3 41.1 29.3 Other genital organs 1.2 1.2 1.0 1.6 1.7 1.1 2.5 2.7 1.6 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

CANCER 313 TABLE 6-25  Selected Epidemiologic Studies—Cervical Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., Female Vietnam veterans 57 1.1 (0.7–1.7) 2000 Studies Reviewed in Update 2000 CDVA, Expected number 1998b of exposed cases Australian Vietnam veterans—self-reported (95% CI) incidence 8 1 (0–5) OCCUPATIONAL Studies Reviewed in Update 1998 Kogevinas IARC cohort, female workers exposed to any et al., 1997 phenoxy herbicide or chlorophenol 3 1.1 (0.2–3.3) Exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.8) Not exposed to highly chlorinated PCDDs 3 1.8 (0.4–5.2) Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 Whites 6 0.9 (0.3–2.0) Nonwhites 21 2.0 (1.3–3.1) Lynge, 1993 Danish phenoxy herbicide workers 7 3.2 (1.3–6.6) Studies Reviewed in VAO Ronco et al., Danish farmers—incidence 1992 Self-employed farmers 7 0.5 (p < 0.05) Family workers 100 0.5 (p < 0.05) Employees 12 0.8 (nr) Wiklund, 99% CI 1983 Swedish female agricultural workers—incidence 82 0.6 (0.4–0.8) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia 13 1.8 (1.0–3.1) et al., 2001 ABBREVIATIONS: CI, confidence interval; IARC, International Agency for Research on Cancer; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines). aSubjects are female and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Hollingshead et al. (2008) recently showed that TCDD activation of the AHR in human breast and endocervical cell lines induces sustained high concentrations of the IL–6 cytokine, which has tumor-promoting effects in numerous tissues, including ovarian, so TCDD might promote carcinogenesis in these tissue. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

314 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-26  Selected Epidemiologic Studies—Uterine Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US non-Vietnam veterans vs non-Vietnam veterans 5 0.8 (0.2–2.8) Kang, 2008 Vietnam nurses vs non-Vietnam nurses 5 1.3 (0.3–5.0) Studies Reviewed in Update 2002 Kang et al., US Vietnam veterans—incidence 41 1.0 (0.6–1.6) 2000 Studies Reviewed in Update 2000 CDVA, Australian Vietnam veterans—self-reported 4 Expected number 1998b incidence of exposed cases (95% CI) 1 (0–5) Studies Reviewed in Update 1996 Dalager US Vietnam veterans 4 2.1 (0.6–5.4) et al., 1995 OCCUPATIONAL Studies Reviewed in Update 1998 Kogevinas IARC cohort, female workers exposed to any et al., 1997 phenoxy herbicide or chlorophenol (includes cancers of endometrium) 3 3.4 (0.7–10.0) Exposed to highly chlorinated PCDDs 1 1.2 (0.0–6.5) Not exposed to highly chlorinated PCDDs 4 2.3 (0.6–5.9) Studies Reviewed in VAO Blair et al., US farmers in 23 states 1993 Whites 15 1.2 (0.7–2.1) Nonwhites 17 1.4 (0.8–2.2) Ronco et al., Danish farmers—incidence 1992 Self-employed farmers 8 0.6 (nr) Family workers 103 0.8 (p < 0.05) Employees 9 0.9 (nr) Wiklund, Swedish female agricultural workers—incidence 99% CI 1983 135 0.9 (0.7–1.1) ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up et al., 2008 Zone A 0 0 Zone B 2 0.5 (0.1–1.9) Zone R 41 1.3 (0.9–1.8) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B 2 0.5 (0.1–1.9) Weiderpass Swedish women 154 1.0 (0.6–2.0) et al., 2000 continued

CANCER 315 TABLE 6-26  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Bertazzi Seveso residents—15-year follow-up et al., 1998 Zone B 1 0.3 (0.0–2.4) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B 1 0.3 (0.0–1.9) Zone R 27 1.1 (0.8–1.7) ABBREVIATIONS: CI, confidence interval; IARC, International Agency for Research on ­Cancer; nr = not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines). aSubjects are female; outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. Synthesis New information concerning female reproductive cancers since Update 2006 has been sparse, especially because the two new analyses deal with mortality rather than incidence. Together, they add little weight to the existing body of evidence. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and uterine, ovarian, or cervical cancer. TABLE 6-27  Selected Epidemiologic Studies—Ovarian Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., Vietnam veterans 16 1.8 (0.7–4.6) 2000 Studies Reviewed in Update 2000 CDVA, Expected number 1998b of exposed cases Australian Vietnam veterans—self-reported (95% CI) incidence 1 0 (0–4) continued

316 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-27  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL Studies Reviewed in Update 2006 Blair et al., US AHS 2005a Private applicators (men and women) 4 3.9 (1.1–10.1) Spouses of private applicators (> 99% women) 13 0.7 (0.4–1.2) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 8 3.0 (1.3–5.9) Spouses of private applicators (> 99% women) 32 0.6 (0.4–0.8) Commercial applicators (men and women) 0 0.0 (0.0–16.0) Studies Reviewed in Update 1998 Kogevinas IARC cohort, female workers exposed to any et al., 1997 phenoxy herbicide or chlorophenol 1 0.3 (0.0–1.5) Exposed to highly chlorinated PCDDs 0 0.0 (0.0–2.6) Not exposed to highly chlorinated PCDDs 1 0.5 (0.0–2.5) Studies Reviewed in Update 1996 Kogevinas IARC cohort et al., 1993 1 0.7 (nr) Studies Reviewed in VAO Ronco et al., Danish farmers—incidence 1992 Self-employed farmers 12 0.9 (nr) Family workers 104 0.8 (p < 0.05) Employees 5 0.5 (nr) Donna Female residents near Alessandria, Italy 18 4.4 (1.9–16.1) et al., 1984 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up et al., 2008 Zone A 1 1.2 (0.2–8.5) Zone B 2 0.4 (0.1–1.6) Zone R 37 1.0 (0.7–1.4) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B 3 0.7 (0.2–2.0) Bertazzi Seveso residents—15-year follow-up et al., 1998 Zone A 1 2.3 (0.3–16.5) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone A—women 1 2.3 (0.0–12.8) Zone R—women 21 1.0 (0.6–1.6) ABBREVIATIONS: AHS, Agricultural Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; nr = not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines). aSubjects are female and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts.

CANCER 317 PROSTATE CANCER ACS estimated that 186,320 new cases of prostate cancer (ICD-9 185) would be diagnosed in the United States in 2008 and that 28,660 men would die from it (Jemal et al., 2008a). That makes prostate cancer the second-most common cancer in men (after nonmelanoma skin cancers); it is expected to account for about 25% of new cancer diagnoses and 10% of cancer deaths in men in 2008. The average annual incidence of prostate cancer is shown in Table 6-28. The incidence of prostate cancer varies dramatically with age and race. The risk more than doubles between the ages of 50–54 years and 55–59 years, and it nearly doubles again between the ages of 55–59 years and 60–64 years. As a group, American black men have the highest recorded incidence of prostate cancer in the world (Miller et al., 1996); their risk is roughly twice that in whites in the United States, 5 times that in Alaska natives, and nearly 8.5 times that in Korean Americans. Little is known about the causes of prostate cancer. Other than race and age, risk factors include a family history of the disease and possibly some elements of the Western diet, such as high consumption of animal fats. The drug finasteride, which has been widely used to treat benign enlargement of the prostate, was found to decrease the prevalence of prostate cancer substantially in a major randomized trial (Thompson et al., 2003). Finasteride acts by decreasing the formation of potent androgen hormones in the prostate. The study of the incidence of and mortality from prostate cancer is compli- cated by trends in screening for the disease. The widespread adoption of serum prostate-specific antigen (PSA) screening in the 1990s led to very large increases in prostate cancer incidence in the United States, which have recently subsided as exposure to screening has become saturated. The long-term influence of better screening on incidence and mortality in any country or population is difficult to predict and will depend on the rapidity with which the screening tool is adopted, its differential use in men of various ages, and the aggressiveness of tumors de- tected early with this test (Gann, 1997). Because exposure to PSA testing is such a strong determinant of prostate-cancer incidence, epidemiologic studies must be careful to exclude differential PSA testing as an explanation of a difference in risk observed between two populations. TABLE 6-28  Average Annual Incidence (per 100,000) of Prostate Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black 146.7 140.9 269.9 350.5 337.5 633.8 600.6 587.8 1,002.5 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

318 VETERANS AND AGENT ORANGE: UPDATE 2008 Prostate cancer tends not to be fatal, so mortality studies might miss an in- creased incidence of the disease. Findings that show an association between an exposure and prostate-cancer mortality should be examined closely to determine whether the exposed group might have had poorer access to treatment that would have increased the likelihood of survival. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was limited or sug- gestive evidence of an association between exposure to the chemicals of interest and prostate cancer. Additional information available to the committees respon- sible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-29 summarizes results of the relevant studies, including both morbidity and mortality studies. The type, quality, and specificity of each study must be considered in the interpretation and weighing of evidence. Because of study heterogeneity, simply examining all the estimated risks in the table together will not yield a good assessment of the risks. Update of the Epidemiologic Literature Vietnam-Veteran Studies Chamie et al. (2008) published a study of prostate cancer incidence in Vietnam-era veterans who were receiving care in the Northern California Vet- erans Affairs Health System. A total of 6,214 veterans reported having been ex- posed to Agent Orange while serving in Vietnam, and another 6,930 men served on active duty in Vietnam but reported no exposure. Men categorized as exposed had to have reported it on their initial application to VA for medical benefits. A total of 239 cases of prostate cancer were identified in the exposed group and 124 in the nonexposed group. In Cox proportional-hazards modeling, the hazard ratio was 2.87 (95% CI 2.31–3.57) with a mean time between exposure and diagnosis of 407 months. The proportion of cases with high-grade or advanced cancer at diagnosis was higher in the exposed group. Some 38 cases in the exposed group reported their exposure after receiving a diagnosis of prostate cancer; exclusion of these cases reduces the magnitude of the association, but it remains significant. Occupational Studies Investigators in the AHS evaluated the association between exposure to dicamba, a benzoic acid herbicide that is often mixed with 2,4-D when sprayed, and cancer incidence (Samanic et al., 2006). Neither cumulative exposure nor

CANCER 319 TABLE 6-29  Selected Epidemiologic Studies—Prostate Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Chamie Vietnam-era veterans in northern California Veterans et al., 2008 Affairs Health System—self-reported exposure to Agent Orange 239 2.9 (2.3–3.6) Studies Reviewed in Update 2006 Leavy et al., 606 prostate cancer cases in Western Australia 2006 Vietnam service 25 2.1 (0.9–5.1) Pavuk et al., AFHS subjects—incidence 2006 20-year cumulative TCDD (ppt-year) Comparison group 81 1.0 Ranch Hand low (≤ 434 ppt-year) 31 1.0 (0.7–1.6) Ranch Hand high (> 434 ppt-year) 28 1.2 (0.8–1.9) p-trend = 0.42 Last tour in SEA before 1969 (heavy spraying) Yes Comparison group 17 1.0 Ranch Hand low (≤ 434 ppt-year) 9 1.0 (0.4–2.3) Ranch Hand high (> 434 ppt-year) 15 2.3 (1.1–4.7) p-trend = 0.04 No Comparison group 64 1.0 Ranch Hand low (≤ 434 ppt-year) 22 1.1 (0.7–1.8) Ranch Hand high (> 434 ppt-year) 13 0.9 (0.5–1.6) p-trend = 0.75 Less than 2 years served in SEA Yes Comparison group 16 1.0 Ranch Hand low (≤ 434 ppt-year) 20 1.9 (1.0–3.7) Ranch Hand high (> 434 ppt-year) 14 2.2 (1.0–4.5) p-trend = 0.03 No Comparison group 65 1.0 Ranch Hand low (≤ 434 ppt-year) 11 0.8 (0.4–1.5) Ranch Hand high (> 434 ppt-year) 14 1.1 (0.6–1.9) p-trend = 0.89 Pavuk et al., White Air Force comparison subjects 2005 only—incidence Serum TCDD (pg/g) based on model with exposure variable loge(TCDD) Per unit increase of -loge(TCDD) 83 1.1 (0.7–1.5) Quartiles (pg/g) 0.4–2.6 13 1.0 2.6–3.8 24 1.7 (0.8–3.3) 3.8–5.2 24 1.5 (0.7–2.9) > 5.2 22 1.2 (0.6–2.4) Number of years served in SEA Per year of service 83 1.1 (1.0–1.2) continued

320 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Quartiles (years in SEA) 0.8–1.3 8 1.0 1.3–2.1 11 1.3 (0.5–3.2) 2.1–3.7 28 2.2 (1.0–4.9) 3.7–16.4 36 2.4 (1.1–5.2) ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 692 1.3 (1.2–1.3) Navy 137 1.2 (1.0–1.4) Army 451 1.8 (1.2–1.4) Air Force 104 1.3 (1.0–1.5) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 107 1.2 (1.0–1.5) Navy 22 1.3 (0.8–1.8) Army 65 1.2 (0.9–1.5) Air Force 19 1.4 (0.8–2.1) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs nondeployed Incidence 65 1.2 (0.9–1.5) Mortality 0 0.0 (0.0–0.7) Boehmer Follow-up of CDC Vietnam Experience Cohort 1 0.4 (nr) et al., 2004 Studies Reviewed in Update 2004 Akhtar AFHS subjects vs national rates et al., 2004 White AFHS Ranch Hand veterans Incidence 36 1.5 (1.0–2.0) With tours in 1966–1970 34 1.7 (1.2–2.3) Mortality 2 0.7 (0.1–2.3) White AFHS comparison veterans Incidence 54 1.6 (1.2–2.1) With tours between 1966–1970 42 1.6 (1.2–2.2) Mortality 3 0.8 (0.2–2.1) White AFHS subjects—incidence Who spent at most 2 years in SEA Per unit increase of -loge(TCDD) 28 1.5 (0.9–2.4) Comparison group 7 1.0 Ranch Hand— < 10 TCDD pg/g in 1987 10 1.5 (0.5–4.4) Ranch Hand—< 118.5 TCDD pg/g at end of service 6 2.2 (0.7–6.9) Ranch Hand— > 118.5 TCDD pg/g at end of  service 5 6.0 (1.4–24.6) Only Ranch Hands with 100% service in Vietnam and comparisons with no service in Vietnam Per unit increase of -loge(TCDD) 20 1.1 (0.6–1.8) Comparison group 3 1.0 Ranch Hand— < 10 TCDD pg/g in 1987 9 2.5 (0.4–16.1) Ranch Hand— < 118.5 TCDD pg/g at end of  service 4 2.4 (0.4–16.0)

CANCER 321 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Ranch Hand—> 118.5 TCDD pg/g at end of service 4 4.7 (0.8–29.1) Giri et al., Veterans using the VA Medical Center in Ann Arbor, 2004 Michigan All cases 11 OR 2.1 (0.8–5.2) Cases in white veterans only nr OR 2.7 (0.9–8.2) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 26 0.7(0.4–1.3) AIHW, Expected number 1999 of exposed cases Australian Vietnam veterans—incidence (validation (95% CI) study) 212 147 (123–171) CDVA, Australian Vietnam veterans—self-reported 1998a incidence 428 147 (123–171) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans—incidence 15 0.8 (0.4–1.6) CDVA, Australian military Vietnam veterans 36 1.5 (1.0–2.0) 1997a AFHS, 1996 Air Force Ranch Hand veterans 2 0.6 expected Watanabe US Army and Marine Corps Vietnam veterans and Kang, Army Vietnam Service 58 1.1 (nr) 1996 Non-Vietnam 1 1.2 (nr)c Marine Vietnam Service 9 1.2 (nr) Non-Vietnam 6 1.3 (nr) Studies Reviewed in Update 1996 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed (male genital system) 19 1.1 (0.6–1.7) Studies Reviewed in VAO Breslin Army Vietnam veterans 30 0.9 (0.6–1.2) et al., 1988 Marine Vietnam veterans 5 1.3 (0.2–10.3) Anderson et al., 1986 Wisconsin Vietnam veterans 0 nr OCCUPATIONAL New Studies Hansen Danish gardeners (male genital organs, ICD-7 et al., 2007 177–178)—incidence 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 20 1.2 (0.7–1.8) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 39 1.3 (1.0–1.8) Born 1915–1934 (medium exposure) 35 0.9 (0.6–1.2) Born after 1934 (low exposure) 3 0.4 (0.1–1.3) continued

322 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Samanic Pesticide applicators in AHS—prostate cancer et al., 2006 incidence from enrollment through 2002 Dicamba—lifetime days exposure None 343 1.0 1– < 20 106 1.0 (0.8–1.3) 20– < 56 102 0.9 (0.7–1.2) 56– < 116 76 1.0 (0.7–1.3) ≥ 116 67 1.1 (0.8–1.5) p-trend = 0.45 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds Never 117 0.9 (0.7–1.0) Ever 84 0.9 (0.7–1.2) ’t Mannetje Phenoxy herbicide producers 1 0.4 (0.0–2.1) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 2 0.6 (0.1–2.2) Alavanja US AHS—incidence et al., 2005 Private applicators 1,046 1.3 (1.2–1.3) Spouses of private applicators (> 99% women) 5 1.2 (0.4–2.8) Commercial applicators 41 1.4 (1.0–1.9) Blair et al., US AHS 2005a Private applicators 48 0.7 (0.5–0.8) Spouses of private applicators (> 99% women) 0 0.0 (0.0–1.6) Torchio Italian licensed pesticide users 66 1.0 (0.7–1.2) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 12 0.7 (0.4–1.3) Studies Reviewed in Update 2004 Alavanja US AHS—pesticide appliers in Iowa and North et al., 2003 Carolina—incidence 566 1.1 (1.1–1.2) Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry) nr 1.7 (1.0–2.6) Swaen Dutch licensed herbicide applicators 6 1.0 (0.4–2.2) et al., 2004 Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 7 1.3 (0.5–2.8) Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides Foremen—incidence 2 4.7 (nr) Male lumberjacks—incidence 3 0.9 (nr)

CANCER 323 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2000 Sharma- Swedish citizens Wagner Agriculture, stock raising 6,080 1.1 (1.0–1.1) et al., 2000 (p < 0.01) Farmers, foresters, gardeners 5,219 1.1 (1.0–1.1) (p < 0.01) Paper-mill workers 304 0.9 (0.8–1.0) Pulp grinding 39 1.4 (1.0–1.9) (p < 0.05) Fleming Florida pesticide appliers 353 1.9 (1.7–2.1) et al., 1999a Fleming Florida pesticide appliers 64 2.4 (1.8–3.0) et al., 1999b Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 28 1.2 (0.8–1.7) Dich and Swedish pesticide appliers 401 1.1 (1.0–1.2) Wiklund, Born 1935 or later 7 2.0 (0.8–4.2) 1998 Born before 1935 394 1.1 (1.0–1.2) Studies Reviewed in Update 1998 Gambini Italian rice growers 19 1.0 (0.6–1.5) et al., 1997 Hertzman Canadian sawmill workers et al., 1997 Morbidity 282 1.0 (0.9–1.1) Mortality from male genital tract cancers 116 1.2 (1.0–1.4) Kogevinas IARC cohort, workers exposed to any phenoxy et al., 1997 herbicide or chlorophenol 68 1.1 (0.9–1.4) Exposed to highly chlorinated PCDDs 43 1.1 (0.8–1.5) Not exposed to highly chlorinated PCDDs 25 1.1 (0.7–1.6) Becher German production workers (included in IARC et al., 1996 cohort) 9 1.3 (nr) Ott and BASF employees—incidence Zober, 1996 TCDD < 0.1 µg/kg of body weight 4 1.1 (0.3–2.8) TCDD 0.1–0.99 µg/kg of body weight 1 1.1 (0.0–5.9) Zhong and Icelandic pesticide users 10 0.7 (0.3–1.3) Rafnsson, 1996 Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators 1994 Incidence 6 0.4 (0.1–0.8) Mortality 5 0.8 (0.3–1.8) Blair et al., US farmers in 23 states 1993 Whites 3,765 1.2 (1.1–1.2) Nonwhites 564 1.1 (1.1–1.2) Bueno de Dutch phenoxy herbicide workers (included in 3 2.6 (0.5–7.7) Mesquita IARC cohort) et al., 1993 continued

324 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Collins Monsanto Company workers (included in NIOSH et al., 1993 cohort) 9 1.6 (0.7–3.0) Studies Reviewed in VAO Morrison Canadian farmers, 45–69 years old, no employees, et al., 1993 or custom workers, sprayed ≥ 250 acres 20 2.2 (1.3–3.8) Ronco et al., Danish workers—incidence 1992 Self-employed 399 0.9 (p < 0.05) Employee 63 0.8 (p < 0.05) Swaen Dutch licensed herbicide applicators 1 1.3 (0.0–7.3) et al., 1992 Fingerhut NIOSH—entire cohort 17 1.2 (0.7–2.0) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 9 1.5 (0.7–2.9) Manz et al., German production workers (included in IARC 1991 cohort)—men, women 7 1.4 (0.6–2.9) Saracci IARC cohort—exposed subcohort 30 1.1 (0.8–1.6) et al., 1991 Zober et al., 90% CI 1990 BASF employees—basic cohort 0 nr (0.0–6.1) Alavanja USDA forest conservationists nr 1.6 (0.9–3.0) et al., 1989 Soil conservationists nr 1.0 (0.6–1.8) Henneberger New Hampshire pulp and paper workers 9 1.0 (0.5–1.9) et al., 1989 Solet et al., US paper and pulp workers 4 1.1 (0.3–2.9) 1989 Alavanja USDA agricultural extension agents nr 1.0 (0.7–1.5) et al., 1988 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 1 1.0 (0.0–5.8) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 18 1.3 (0.8–2.1) Robinson 90% CI et al., 1986 Northwestern US paper and pulp workers 17 1.2 (0.7–1.7) Lynge, 1985 Danish production workers—incidence (included in the IARC cohort) 9 0.8 (nr) Blair et al., Expected number 1983 of exposed cases (95% CI) Florida pesticide applicators 2 3.8 (nr) Burmeister Iowa residents—farm exposures 4, 827 1.2 (p < 0.05) et al., 1983 Wiklund, 99% CI 1983 Swedish male agricultural workers 3,890 1.0 (0.9–1.0) Burmeister, Iowa farmers 1,138 1.1 (p < 0.01) 1981

CANCER 325 TABLE 6-29  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 1 0.9 (0.1–6.2) Zone B 8 0.9 (0.4–1.8) Zone R 65 1.1 (0.8–1.4) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B—men 8 1.1 (0.5–2.2) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B—men 6 1.2 (0.5–2.7) Zone R—men 39 1.2 (0.8–1.6) Svensson Swedish fishermen—mortality et al., 1995 East coast 12 1.0 (0.5–1.8) West coast 123 1.1 (0.9–1.3) Swedish fishermen—incidence East coast 38 1.1 (0.8–1.5) West coast 224 1.0 (0.9–1.1) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone R—men 16 0.9 (0.5–1.5) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B—men 4 1.4 (0.5–3.9) Zone R—men 17 0.9 (0.6–1.5) Bertazzi Seveso residents—10-year follow-up et al., 1989a Zones A, B, R—men 19 1.6 (1.0–2.7) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone B—men 3 2.2 (0.7–6.9) Zone R—men 16 1.6 (0.9–2.7) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence in- terval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OR, odds ratio; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture; VA, Department of Veterans Affairs. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cStatistically significant with the 95% CI not including 1.0. Studies in italics have been superseded by newer studies of same cohorts.

326 VETERANS AND AGENT ORANGE: UPDATE 2008 intensity-weighted cumulative exposure was associated with prostate-cancer risk. Hansen et al. (2007) evaluated a cohort consisting of members of a Danish gardeners union, who were followed from 1975 until 2002. Because herbicide and pesticide exposures were reduced over successive calendar periods, year of birth was used as a proxy for magnitude of exposure. Previous analyses had detected an excess of STS in the older workers, which suggested that phenoxy herbicides might have been responsible. Prostate cancers were included in a more general category (male genital organs), and there was some evidence of increased risk compared with that in the general Danish population in the early, most heav- ily exposed subcohort (SIR = 1.34, 95% CI 0.97–1.81) but no association in the later, less-exposed subcohorts. Environmental Studies Consonni et al. (2008) compared prostate cancer mortality over 25 years in men exposed to dioxins in Seveso, Italy, with that in a nearby but nonexposed reference population. The number of deaths due to prostate cancer was too small in residents in the very-high-exposure and high-exposure zones (Zones A and B) to provide informative estimates. There was no evidence of an association in resi- dents in Zone R, the larger, low-exposure area (RR = 1.06, 95% CI 0.81–1.38). Biologic Plausibility Prostate cells and prostatic-cancer cell lines are responsive to TCDD in induc- tion of various genes, including those involved in drug metabolism. Simanainen et al. (2004a) used different rat lines (TCDD-resistant Hans/Wistar and TCDD- sensitive Long Evans) and showed that TCDD treatment resulted in a significant decrease in the weight of prostate lobes, but the effect did not appear to be line-specific. In contrast, the TCDD-related reduction in sperm appears to be line-specific and not fully related to the effects of TCDD on serum testosterone (Simanainen et al., 2004b). TCDD effects appear to occur through actions on the urogenital sinus (Lin et al., 2004). In utero and lactational exposure to TCDD ap- pears to retard the aging process in the prostate (Fritz et al., 2005). Progeny mice of a genetic cross between AHR-null mice and the transgenic adenocarcinoma of the mouse prostate (TRAMP) strain that models prostate cancer showed that the presence of the AHR inhibited the formation of prostate tumors that have a neuroendocrine phenotype. In a follow-up, Fritz et al. (2008) used the TRAMP model to show that the presence of the AHR inhibits prostate carcinogenesis. In agreement with a possible potential protective role, negative associations were found in the AFHS between the risk of benign prostate hyperplasia and both TCDD exposure and serum testosterone concentration (Gupta et al., 2006).

CANCER 327 The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Among the few studies published since Update 2006, the study published by Chamie et al. (2008) stands out because of its direct focus on the relation- ship between exposure to Agent Orange in Vietnam and prostate cancer risk. The findings support the existence of an association. However, several features of the study limit the strength of its conclusions. First, although exposure was presumably self-reported at the time of application for initial medical benefits, those who reported exposure had more detailed exposure histories taken, and it is not clear how or whether their detailed histories influenced the final exposure categorization. Second, the methods used to control for confounding by PSA testing are unclear. It appears that the groups compared had similar prevalence of ever having received a PSA test, but the frequency of PSA testing during the long follow-up interval and the means used to adjust for PSA-testing differences were not explained in detail. As mentioned above, small differences in the frequency of PSA testing can have a profound effect on prostate-cancer detection rates. There is a particular concern in this case because veterans who reported exposure and therefore entered the Agent Orange medical program were likely to have received additional PSA testing. Third, as acknowledged in the paper, 38 men reported their exposure to Agent Orange after receiving a diagnosis of prostate cancer, although the association appears to have remained significant after exclusion of these cases, further analyses need to be done to determine the extent of any bias that their inclusion might have caused. The study by Chamie et al. offers an important basic blueprint for similar analyses that can be conducted in the VA medical system. However, despite the relatively strong association between Agent Orange and prostate cancer risk in their report on northern California vet- erans, the committee believes that unresolved questions regarding the methods used in the study warrant caution in interpreting the results. The existing body of epidemiologic evidence supporting an association be- tween exposure to the chemicals of interest and prostate cancer is robust enough that the committee’s judgment that there is limited or suggestive evidence of an association is not reversed by the largely negative results in experimental systems. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there remains limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest and prostate cancer.

328 VETERANS AND AGENT ORANGE: UPDATE 2008 TESTICULAR CANCER ACS estimated that 8,090 men would receive diagnoses of testicular cancer (ICD-9 186.0–186.9) in the United States in 2008 and that 380 men would die from it (Jemal et al., 2008a). Other cancers of the male reproductive system that are infrequently reported separately are cancers of the penis and other male genital organs (ICD-9 187). The average annual incidence of testicular cancer is shown in Table 6-30. Testicular cancer occurs more often in men younger than 40 years old than in older men. On a lifetime basis, the risk in white men is about 4 times that in black men. Cryptorchidism (undescended testes) is a major risk factor for testicu- lar cancer. Family history of the disease also appears to be a risk factor. Several other hereditary, medical, and environmental risk factors have been suggested, but the results of research are inconsistent (Bosl and Motzer, 1997). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and testicular cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclu- sion. Table 6-31 summarizes the results of the relevant studies. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and testicular cancer have been published since Update 2006. Biologic Plausibility No animal studies of the incidence of testicular cancer after exposure to any of the chemicals of interest have been published since Update 2006. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. TABLE 6-30  Average Annual Incidence (per 100,000) of Testicular Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black 4.0 4.6 1.0 2.4 2.6 1.3 1.5 1.6 0.8 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

CANCER 329 TABLE 6-31  Selected Epidemiologic Studies—Testicular Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 54 0.9 (0.6–1.1) Navy 17 1.2 (0.7–1.8) Army 34 0.8 (0.5–1.0) Air Force 3 0.8 (0.2–2.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 14 0.9 (0.4–1.4) Navy 3 0.8 (0.2–2.4) Army 10 0.9 (0.4–1.7) Air Force 0 0.0 (0.0–3.3) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs non-deployed Incidence 17 0.7 (0.4–1.2) Mortality 4 0.8 (0.2–2.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 3 nr AIHW, Australian Vietnam veterans—incidence (validation Expected number 1999 study) of exposed cases (95% CI) 59 110 (89–139) CDVA, Australian Vietnam veterans—self-reported 1998a incidence 151 110 (89–131) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans—incidence 30 1.2 (0.4–3.3) CDVA, Australian military Vietnam veterans 4 ns 1997a CDVA, Australian National Service Vietnam veterans 1 1.3 1997b Dalager and Army Chemical Corps veterans 2 4.0 (0.5–14.5) Kang, 1997 Watanabe Army Vietnam service 114 1.1 (nr) and Kang, Marine Vietnam service 1996 28 1.0 (nr) Studies Reviewed in Update 1996 Bullman Navy veterans 12 2.6 (1.1–6.2) et al., 1994 Studies Reviewed in VAO Tarone Patients in three Washington, DC, area hospitals 31 2.3 (1.0–5.5) et al., 1991 Watanabe Army Vietnam veterans 109 1.2 (ns) et al., 1991 Marine Vietnam veterans 28 0.8 (ns) Breslin Army Vietnam veterans 90 1.1 (0.8–1.5) et al., 1988 Marine Vietnam veterans 26 1.3 (0.5–3.6) continued

330 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-31  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Anderson Wisconsin Vietnam veterans 9 1.0 (0.5–1.9) et al., 1986 OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds Never 2 1.1 (0.1–4.1) Ever 5 3.6 (1.2–8.4) Alavanja US AHS—incidence et al., 2005 Private applicators 23 1.1 (0.7–1.6) Spouses of private applicators (> 99% women) nr 0.0 (0.0–50.2) Commercial applicators 4 1.2 (0.3–3.2) Blair et al., US AHS 2005a Private applicators 0 nr Spouses of private applicators (> 99% women) 0 nr Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 6 1.0 (0.4–2.6) Studies Reviewed in Update 2002 Burns et al., Dow chemical production workers 1 2.2 (0.0–12.5) 2001 Studies Reviewed in Update 2000 Flemming Florida pesticide appliers 23 2.5 (1.6–3.7) et al., 1999b Hardell Swedish workers exposed to herbicides 4 0.3 (0.1–1.0) et al., 1998 Studies Reviewed in Update 1998 Hertzman British Columbia sawmill workers et al., 1997 Mortality (male genital cancers) 116 1.0 (0.8–1.1) Incidence 18 1.0 (0.6–1.4) Kogevinas IARC cohort, workers exposed to any phenoxy et al., 1997 herbicide or chlorophenol 68 1.1 (0.9–1.4) Exposed to highly chlorinated PCDDs 43 1.1 (0.8–1.5) Not exposed to highly chlorinated PCDDs 25 1.1 (0.3–1.6) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0 nr Zhong and Icelandic pesticide users 2 1.2 (0.1–4.3) Rafnsson, 1996 Studies Reviewed in Update 1996 Blair et al., US farmers in 23 states 1993 White men 32 0.8 (0.6–1.2) Nonwhite men 6 1.3 (0.5–2.9)

CANCER 331 TABLE 6-31  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 74 0.9 (nr) employee 23 0.6 (p < 0.05) Saracci IARC cohort—exposed subcohort 7 2.3 (0.9–4.6) et al., 1991 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 1 4.6 (0.0–25.7) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 4 2.2 (0.6–5.7) Wiklund, 99% CI 1983 Swedish male agricultural workers—incidence 101 1.0 (0.7–1.2) ENVIRONMENTAL Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B—men 17 1.0 (0.6–1.7) Bertazzi Seveso residents—15-year follow-up (genitourinary et al., 1998 tract) Zone B—men 10 1.0 (0.5–1.8) Zone R—men 73 1.0 (0.8–1.3) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone B—men 1 1.0 (0.1–7.5) Zone R—men 9 1.4 (0.7–3.0) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B—men 1 0.9 (0.1–6.7) Zone R—men 9 1.5 (0.7–3.0) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlo- rophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not re- ported; ns, not significant; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines). aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of the same cohorts. Synthesis The evidence from epidemiologic studies is inadequate to link herbicide exposure and testicular cancer. The relative rarity of this cancer makes it difficult to develop risk estimates with any precision. Most cases occur in men 25–35 years old, and men who have received such a diagnosis could be excluded from military service; this could explain the slight reduction in risk observed in some veteran studies.

332 VETERANS AND AGENT ORANGE: UPDATE 2008 Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and testicular cancer. BLADDER CANCER Urinary bladder cancer (ICD-9 188) is the most common urinary tract cancer. Cancers of the urethra, paraurethral glands, and other and unspecified urinary cancers (ICD-9 189.3–189.9) are infrequently reported separately; findings on these cancers would be reported in this section. ACS estimated that 51,230 men and 17,580 women would receive a diagnosis of bladder cancer in the United States in 2008 and that 9,950 men and 4,150 women would die from it (Jemal et al., 2008a). In males, in whom this cancer is about twice as common as it is in females, those numbers represent about 5% of new cancer diagnoses and 3% of cancer deaths. Overall, bladder cancer is fourth in incidence in men in the United States. Bladder-cancer risk rises rapidly with age. In men in the age groups that characterize most Vietnam veterans, bladder-cancer incidence is about twice as high in whites as in blacks. The average annual incidence of urinary bladder cancer is shown in Table 6-32. The most important known risk factor for bladder cancer is tobacco use, which accounts for about half the bladder cancers in men and one-third of them in women (Miller et al., 1996). Occupational exposure to aromatic amines (also called arylamines), polycyclic aromatic hydrocarbons (PAHs), and some other organic chemicals used in the rubber, leather, textile, paint-products, and print- ing industries is associated with higher incidence. In some parts of Africa and Asia, infection with the parasite Schistosoma haematobium contributes to the high incidence. TABLE 6-32  Average Annual Incidence (per 100,000) of Bladder Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 23.4 25.6 14.3 46.7 51.3 30.8 81.8 91.1 42.6 Women 6.9 7.6 4.0 13.3 15.1 7.7 22.0 24.7 14.4 aSurveillance,Epidemiology, and End Results program. nine standard registries, crude age-specific rates, 2000–2005.

CANCER 333 Exposure to inorganic arsenic is also a risk factor for bladder cancer. Al- though cacodylic acid is a metabolite of inorganic arsenic, as discussed in Chapter 4, the data are insufficient to conclude that studies of inorganic-arsenic exposure are directly relevant to exposure to cacodylic acid, so the literature on inorganic arsenic is not considered in this section. Conclusions from VAO and Previous Updates The committees responsible for VAO and Update 1996 concluded that there was limited or suggestive evidence of no association between exposure to the chemicals of interest and urinary bladder cancer. Additional information available to the committee responsible for Update 1998 led it to change that conclusion to one of inadequate or insufficient information to determine whether there is an association. The committee responsible for Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-33 summarizes the results of the relevant studies. Update of Epidemiologic Literature Vietnam-Veteran Studies No Vietnam-veteran studies concerning exposure to the chemicals of interest and bladder cancer have been published since Update 2006. Occupational Studies Hansen et al. (2007) studied cancer incidence in Danish professional garden- ers compared with the general Danish population. For cancer of the urinary sys- tem (presumably including bladder cancer and kidney cancer), the RR was 1.07 (95% CI 0.72–1.59) in the older workers with the highest exposure to herbicides. There was evidence of a lower risk in workers in the intermediate and recent birth cohorts, whose exposure to herbicides and pesticides was considered to be lower than that of the older workers. That suggests that there may have been a histori- cal exposure that increased bladder-cancer rates; however, no details of specific chemicals were reported, so it is difficult to attribute the lower risk to any of the chemicals of interest. Samanic et al. (2006) looked at bladder-cancer occurrence in pesticide applicators in the AHS according to their exposure to dicamba, a benzoic acid herbicide often mixed with 2,4-D. There was no evidence of an as- sociation between cumulative dicamba exposure and bladder-cancer incidence. Environmental Studies Consonni et al. (2008), who compared mortality in residents of Seveso in various zones of exposure to dioxin, found no relationship with bladder-cancer

334 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-33  Selected Epidemiologic Studies—Urinary Bladder Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 164 1.0 (0.9–1.2) Navy 34 1.0 (0.7–1.4) Army 104 1.0 (0.8–1.2) Air Force 26 1.3 (0.8–1.8) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 22 0.7 (0.4–1.0) Navy 4 0.6 (0.2–1.6) Army 13 0.7 (0.3–1.1) Air Force 5 1.1 (0.4–2.5) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 19 0.7 (0.4–1.1) Mortality 1 0.3 (0.0–1.7) Boehmer Follow-up of CDC Vietnam Experience Cohort 1 nr et al., 2004 Studies Reviewed in Update 2004 Akhtar AFHS subjects vs national rates et al., 2004 White AFHS Ranch Hand veterans Incidence 14 1.1 (0.6–1.7) With tours between 1966–1970 14 1.3 (0.7–2.1) Mortality 1 0.9 (nr) White AFHS comparison veterans Incidence 8 0.4 (0.2–0.8) With tours in 1966–1970 4 0.3 (0.1–0.7) Mortality 1 0.6 (nr) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans Bladder, kidney 11 3.1 (0.9–11.0) Studies Reviewed in Update 1998 Clapp, 1997 Massachusetts Vietnam veterans 80 0.6 (0.2–1.3) CDVA, Australian military Vietnam veterans 11 1.1 (0.6–1.9) 1997a CDVA, Australian national service Vietnam veterans 1 0.6 (nr) 1997b Studies Reviewed in VAO Breslin Army Vietnam veterans 9 0.6 (0.3–1.2) et al., 1988 Marine Vietnam veterans 4 2.4 (0.1–66.4) Anderson Wisconsin Vietnam veterans 1 nr et al., 1986

CANCER 335 TABLE 6-33  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL New Studies Hansen Danish gardeners (urinary system, ICD-7 et al., 2007 180–181)—incidence 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 18 0.9 (0.7–1.8) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 25 1.1 (0.7–1.6) Born 1915–1934 (medium exposure) 23 0.5 (0.4–0.8) Born after 1934 (low exposure) 1 0.2 (0.0–1.1) Samanic Pesticide applicators in AHS—bladder-cancer et al., 2006 incidence from enrollment through 2002 Dicamba—lifetime days exposure None 43 1.0 1– < 20 6 0.5 (0.2–1.3) 20– < 56 9 0.7 (0.3–1.4) 56– < 116 6 0.6 (0.3–1.5) ≥ 116 8 0.8 (0.4–1.9) p-trend = 0.66 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006  Exposure to nonvolatile organochlorine compounds Never 50 1.0 (0.7–1.3) Ever 43 1.1 (0.8–1.5) Alavanja US AHS (urinary system)—incidence et al., 2005 Private applicators (men and women) 184 0.7 (0.6–0.8) Spouses of private applicators (> 99% women) 17 0.7 (0.4–1.1) Commercial applicators (men and women) 13 1.1 (0.6–1.8) ’t Mannetje Phenoxy herbicide producers (men and women) 0 nr et al., 2005 Phenoxy herbicide sprayers (> 99% men) 0 nr Blair et al., US AHS 2005a Private applicators (men and women) 7 0.4 (0.1–0.7) Spouses of private applicators (> 99% women) 2 0.8 (0.1–2.7) Torchio Italian licensed pesticide users 31 0.5 (0.4–0.8) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 4 0.7 (0.3–1.8) Studies Reviewed in Update 2004 Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry) nr 0.7 (0.1–2.0) Swaen Dutch licensed herbicide applicators 2 0.7 (0.1–2.4) et al., 2004 continued

336 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-33  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 1 0.5 (0.1–2.8) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) Total cohort 16 2.0 (1.1–3.2) High-exposure cohort 6 3.0 (1.4–8.5) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) Total cohort 4 3.7 (1.0–9.5) Accidentally exposed subcohort 1 2.8 (0.1–15.5) Studies Reviewed in Update 1998 Hertzman Canadian sawmill workers et al., 1997 Mortality 33 0.9 (0.7–1.2) Incidence 94 1.0 (0.8–1.2) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 34 1.0 (0.7–1.5) Exposed to highly chlorinated PCDDs 24 1.4 (0.9–2.1) Not exposed to highly chlorinated PCDDs 10 0.7 (0.3–1.2) Ott and BASF employees (bladder, kidney)—incidence 2 1.4 (0.4–3.2) Zober, 1996 Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators—incidence 12 1.6 (0.8–2.8) 1994 Bueno de Dutch phenoxy herbicide workers (included in 1 1.2 (0.0–6.7) Mesquita IARC cohort) et al., 1993 Collins Monsanto Company workers (included in IARC et al., 1993 cohort) (many also exposed to 4-aminobiphenyl, a known bladder carcinogen) Bladder, other urinary 16 6.8 (3.9–11.1) Studies Reviewed in VAO Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 300 0.6 (p < 0.05) employee 70 0.7 (p < 0.05) Women— elf-employed s 1 0.2 (nr) employee 2 0.6 (nr) family worker 25 0.6 (p < 0.05) Fingerhut NIOSH—entire cohort (bladder, other) 9 1.6 (0.7–3.0) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 4 1.9 (0.5–4.8) Green, 1991 Herbicide sprayers in Ontario Diseases of genitourinary system 1 1.0 (0.0–5.6) Saracci IARC cohort—exposed subcohort (men and women) 13 0.8 (0.4–1.4) et al., 1991

CANCER 337 TABLE 6-33  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Zober et al., BASF employees—basic cohort 90% CI 1990 0 nr (0.0–15.0) Alavanja USDA forest, soil conservationists 8 0.8 (0.3–1.6) et al., 1989 Henneberger New Hampshire pulp and paper workers 4 1.2 (0.3–3.2) et al., 1989 Alavanja USDA agricultural extension agents 8 0.7 (0.4–1.4) et al., 1988 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 0 nr (0.0–7.2) Coggon British MCPA production workers (included in et al., 1986 IARC cohort) 8 0.9 (0.4–1.7) Robinson Northwestern US paper and pulp workers et al., 1986 8 1.2 (0.6–2.6) Lynge, 1985 Danish production workers (included in IARC cohort)—incidence 11 0.8 (nr) Blair et al., Florida pesticide applicators 3 1.6 (nr) 1983 Burmeister, Iowa farmers 274 0.9 (nr) 1981 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men and et al., 2008 women Zone A 1 1.0 (0.2–7.4) Zone B 6 0.9 (0.4–2.0) Zone R 42 0.9 (0.6–1.2) Studies Reviewed in Update 2002 Revich Residents of Chapaevsk, Russia (urinary organs) et al., 2001 Men 31 2.6 (1.7–3.6) Women 17 0.8 (0.5–1.3) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B—men 6 1.2 (0.5–2.7) Bertazzi Seveso residents—15-year follow-up et al., 1998 Zone B— en m 1 2.4 (0.3–16.8) women 3 0.9 (0.3–3.0) Zone R— en m 21 0.9 (0.6–1.5) women 4 0.6 (0.2–1.8) Studies Reviewed in Update 1998 Gambini Italian rice growers 12 1.0 (0.5–1.8) et al., 1997 continued

338 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-33  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Svensson Swedish fishermen (men and women)—mortality et al., 1995 East coast 5 1.3 (0.4–3.1) West coast 20 1.0 (0.6–1.6) Swedish fishermen (men and women)—incidence East coast 10 0.7 (0.4–1.3) West coast 55 0.9 (0.7–1.1) Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 10 1.6 (0.9–3.1) women 1 0.9 (0.1–6.8) Zone R— en m 39 1.0 (0.7–1.4) women 4 0.6 (0.2–1.5) Lampi et al., Finnish community exposed to chlorophenol 1992 contamination (men and women) 14 1.0 (0.6–1.9) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. mortality, but the small number of relevant deaths in the highly exposed zone greatly limits the interpretability of this result. Biologic Plausibility In laboratory animals, cacodylic acid has been shown to induce primarily bladder tumors (Cohen et al., 2006). In a study of male F344 rats, cacodylic acid administered in drinking water resulted in formation of bladder tumors at the highest concentrations (50 and 200 ppm) (Wei et al., 2002). In another re- port (Arnold et al., 2006), administration of cacodylic acid in the diet resulted in formation of papillomas and carcinomas in the bladders of female and male F344 rats but not B6C3F1 mice. Experimental work since Update 2006 has shown that cacodylic acid (dimethyl arsenic acid, DMA) is cytotoxic at very high concentrations in rat urothelial cells in vitro (Nascimento et al., 2008); such concentrations are unlikely to be environmentally relevant. Other recent

CANCER 339 studies have shown DMA concentrations to be lower in bladder-cancer patients than in matched controls (Pu et al., 2007) and to be associated with a lower incidence of urinary cancer (Huang et al., 2008). In contrast, greater oxidative DNA damage has been found in association with higher DMA concentrations in urothelial-cancer patients (Chung et al., 2008), although this was not the case in primary human hepatocytes (Dopp et al., 2008). In a study that used a rat cancer initiation–promotion model, DMA was found to be a weak cancer-initiator but a tumor-promoter at high dose (Fukushima et al., 2005). No studies have reported an increased incidence of urinary bladder cancer in TCDD-treated animals. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Available analyses of an association between exposure to the chemicals of interest and bladder-cancer risk are characterized by low precision because of the small numbers, low exposure specificity, and lack of ability to control for confounding. The data that have emerged since Update 2006 suggest that DMA may be a bladder-tumor-promoter and that DMA concentrations are lower in patients with urinary cancer. The evidence in either direction is still too prelimi- nary to alter the conclusion that the cumulative evidence of such an association is inadequate or insufficient. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and bladder cancer. RENAL CANCER Cancers of the kidney (ICD-9 189.0) and renal pelvis (ICD-9 189.1) are often grouped in epidemiologic studies; cancer of the ureter (ICD-9 189.2) is sometimes also included. Although diseases of those organs have different char- acteristics and could have different risk factors, there is some logic to grouping them: the structures are all exposed to filterable chemicals, such as PAHs, that ap- pear in urine. ACS estimated that 33,130 men and 21,260 women would receive diagnoses of renal cancer (ICD-9 189.0, 189.1) in the United States in 2008 and that 8,100 men and 4,910 women would die from it (Jemal et al., 2008a). Those figures represent 2–4% of all new cancer diagnoses and cancer deaths. The aver- age annual incidence of renal cancer is shown in Table 6-34.

340 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-34  Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 23.8 23.2 35.8 36.9 36.4 49.0 55.5 56.2 66.2 Women 12.6 12.8 13.8 18.6 19.1 20.8 24.8 26.0 28.1 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. Renal cancer is twice as common in men as in women. In the age groups that include most Vietnam veterans, black men have a higher incidence than white men. With the exception of Wilms’ tumor, which is more likely to occur in chil- dren, renal cancer is more common in people over 50 years old. Tobacco use is a well-established risk factor for renal cancer. People with some rare syndromes—notably, von Hippel–Lindau syndrome and tuberous scle- rosis—are at higher risk. Other potential risk factors include obesity, heavy acetaminophen use, kidney stones, and occupational exposure to asbestos, cad- mium, and organic solvents. Firefighters, who are routinely exposed to numerous pyrolysis products, are in a known higher-risk group. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and renal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclu- sion. Table 6-35 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies No Vietnam-veteran studies concerning exposure to the chemicals of interest and renal cancer have been published since Update 2006. Occupational Studies Hansen et al. (2007) reported the results of a follow-up on mortality in an historical cohort of Danish professional gardeners. In the younger workers, the

CANCER 341 TABLE 6-35  Selected Epidemiologic Studies—Renal Cancer Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 125 1.0 (0.8–1.2) Navy 34 1.3 (0.9–1.7) Army 77 0.9 (0.7–1.1) Air Force 14 1.1 (0.6–1.8) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 50 1.0 (0.7–1.2) Navy 12 1.1 (0.6–1.9) Army 33 0.9 (0.6–1.3) Air Force 5 0.8 (0.3–1.8) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs nondeployed Incidence 19 0.7 (0.4–1.0) Mortality 4 0.4 (0.1–1.1) Boehmer Follow-up of CDC Vietnam Experience Cohort 1 nr et al., 2004 Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 11 3.1 (0.9–11.0) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 22 1.2 (0.7–1.8) 1997a CDVA, Australian National Service Vietnam veterans 3 3.9 (nr) 1997b Studies Reviewed in Update 1996 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 21 1.4 (0.9–2.2) Studies Reviewed in VAO Breslin Army Vietnam veterans 55 0.9 (0.5–1.5) et al., 1988 Marine Vietnam veterans 13 0.9 (0.5–1.5) Kogan and Massachusetts Vietnam veterans 9 1.8 (1.0–3.5) Clapp, 1988 Anderson Wisconsin Vietnam veterans 2 nr et al., 1986 OCCUPATIONAL New Studies Hansen Danish gardeners—incidence et al., 2007 (urinary system, ICD-7 180–181) 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 18 0.9 (0.7–1.8) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 25 1.1 (0.7–1.6) Born 1915–1934 (medium exposure) 23 0.5 (0.4–0.8) Born after 1934 (low exposure) 1 0.2 (0.0–1.1) continued

342 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-35  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2006 McLean Exposure to nonvolatile organochlorine compounds et al., 2006 Never 41 0.9 (0.7–1.3) Ever 18 0.5 (0.3–0.8) ’t Mannetje Phenoxy herbicide producers (men and women) 1 1.2 (0.0–6.6) et al., 2006 Phenoxy herbicide sprayers (> 99% men) 3 2.7 (0.6–8.0) Torchio Italian licensed pesticide users 16 0.6 (0.4–1.0) et al., 1994 Reif et al., New Zealand forestry workers—nested case–control 1989 —incidence 2 0.6 (0.2–2.3) Magnani UK case–control et al., 1987 Herbicides nr 1.3 (0.6–3.1) Chlorophenols nr 0.9 (0.4–1.9) Studies Reviewed in Update 2004 Swaen et al., Dutch licensed herbicide applicators 4 1.3 (0.4–3.4) 2004 Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 2 0.9 (0.1–3.3) Studies Reviewed in Update 2000 Steenland US chemical workers (included in IARC cohort, et al., 1999 NIOSH Dioxin Registry) 13 1.6 (0.8–2.7) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) Total cohort—kidney cancer 4 4.1 (1.1–10.4) Total cohort—“urinary organs” 8 3.9 (1.7–7.6) Studies Reviewed in Update 1998 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 29 1.1 (0.7–1.6) Exposed to highly chlorinated PCDDs 26 1.6 (1.1–2.4) Not exposed to highly chlorinated PCDDs 3 0.3 (0.1–0.9) Studies Reviewed in Update 1996 Mellemgaard Danish Cancer Registry patients et al., 1994 Occupational herbicide exposure, men 13 1.7 (0.7–4.3) Occupational herbicide exposure, women 3 5.7 (0.6–58.0) Blair et al., US farmers in 23 states 1993 White men 522 1.1 (1.0–1.2) White women 6 0.8 (0.3–1.7) Studies Reviewed in VAO Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 141 0.6 (p < 0.05) employee 18 0.4 (p < 0.05) Women— elf-employed s 4 0.9 (nr) employee 3 1.0 (nr) family worker 30 0.8 (nr)

CANCER 343 TABLE 6-35  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Fingerhut NIOSH cohort—entire cohort 8 1.4 (0.6–2.8) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 2 1.1 (0.1–3.8) Manz et al., German production workers—men, women 1991 (included in IARC cohort) 3 1.6 (0.3–4.6) Saracci IARC cohort—exposed subcohort (men and women) 11 1.0 (0.5–1.7) et al., 1991 Alavanja USDA forest conservationists nr 1.7 (0.5–5.5) et al., 1989 Soil conservationists nr 2.4 (1.0–5.9) Henneberger New Hampshire paper and pulp workers et al., 1989 3 1.5 (0.3–4.4) Alavanja USDA agricultural extension agents et al., 1988 nr 1.7 (0.9–3.3) Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 0 nr (0.0–6.2) Robinson Northwestern US paper and pulp workers et al., 1986 6 1.2 (0.5–3.0) Coggon British MCPA production workers (included in the et al., 1986 IARC cohort) 5 1.0 (0.3–2.3) Lynge, 1985 Danish production workers—incidence 3 0.6 (nr) Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 775 0.8 (0.7–0.9) Blair et al., Florida pesticide applicators 1 0.5 (nr) 1983 Burmeister, Iowa farmers 178 1.1 (ns) 1981 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 0 nr Zone B 3 0.6 (0.2–2.0) Zone R 39 1.2 (0.8–1.6) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B— en m 3 0.8 (0.3–2.6) women 3 1.8 (0.6–5.8) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up (kidney, other et al., 1993 urinary organs)—incidence Zone R— en m 10 0.9 (0.4–1.7) women 7 1.2 (0.5–2.7) continued

344 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-35  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 0 nr women 1 1.1 (0.2–8.1) Zone R— en m 11 0.9 (0.5–1.7) women 7 1.2 (0.5–2.6) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, Inter- national Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. incidence of those cancers was significantly lower than the general population, which probably represents a healthy worker effect. In older workers (who may have been exposed to higher concentrations of pesticides than younger workers), however, the incidence of urinary system cancers (presumably including blad- der and kidney cancer) was comparable to that in the general population. That provides a weak suggestion that older workers may have been exposed to some chemicals that increased renal-cancer risk. The Danish National Environmental Board reports that 2,4-D and other chlorophenoxy acids were used during the periods when the older members of the cohort were working, but the study contained no details regarding specific chemical exposures, so relevance to the chemicals of interest here is limited. Environmental Studies Consonni et al. (2008) reported on mortality from kidney cancer in residents of Seveso who were exposed to dioxin at various concentrations. The number of deaths due to kidney cancer in residents in the highly exposed areas was too small to permit useful conclusions regarding any association. Biologic Plausibility No animal studies have reported an increased incidence of renal cancer after exposure to the chemicals of interest. The biologic plausibility of the carcino-

CANCER 345 genicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Available analyses of an association between exposure to the chemicals of interest and renal-cancer risk are limited by the small number of cases and lack of exposure specificity. No data have emerged since Update 2006 to alter the committee’s conclusion that the evidence is inadequate or insufficient to deter- mine whether there is an association. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and renal cancer. BRAIN CANCER Brain and other nervous system cancers (ICD-9 191–192) involve the central nervous system (CNS) and include tumors of the brain and spinal cord, the cranial nerves, and the meninges (the outer coverings of the brain and spinal cord). Any of the cell types in the CNS can produce cancer. Tumors of the peripheral nerves and autonomic nervous system are considered soft-tissue tumors (ICD-9 171). Most cancers in the CNS originate in other parts of the body, such as the lung or breast, but have metastasized to the brain or spinal cord. This section focuses on cancers that originate in the CNS. Cancer of the eye (ICD-9 190) was considered retrospectively in Update 2006, but the present committee decided that findings concerning cancer of the eye would be tracked with results on brain cancer because, when it is reported, it is often grouped with brain cancer. The average annual incidence of CNS cancer is shown in Table 6-36. About 95% of cases derive from the brain, cranial nerves, and cranial meninges. In people over 45 years old, about 90% of tumors that originate in the brain are gliomas—astrocytoma, ependymoma, oligodendroglioma, or glioblastoma multi- forme. Astrocytoma is the most common; glioblastoma multiforme has the worst prognosis. Meningioma accounts for 20–40% of CNS cancers. It tends to occur in middle age and more commonly in women. Most meningiomas are benign and can be removed surgically. ACS estimated that about 11,780 men and 10,030 women would receive diagnoses of brain and other nervous system cancers in the United States in 2008 and that 7,420 men and 5,650 women would die from them (Jemal et al., 2008a). Those numbers represent about 1.5% of new cancer

346 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-36  Average Annual Incidence (per 100,000) of Brain and Other Nervous System Cancers in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 9.1 10.1 4.9 13.1 14.5 8.2 16.3 18.6 6.6 Women 6.4   7.2 3.5   8.6   9.2 6.6 10.6 11.4 5.9 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. diagnoses and 2.3% of cancer deaths. ACS estimated that 1,340 men and 1,050 women would receive diagnoses of cancers of the eye and orbit in the United States in 2008 and that 130 men and 110 women would die from them (Jemal et al., 2008a). In reviewing the descriptive epidemiology of these cancers, it is important to recognize the variation with which specific cancers are included in published re- ports, many of which distinguish between benign and malignant cancers. Another variation is whether cancer derived from related tissues (such as the pituitary or the eye) is included. Various types of cancer are usually grouped; although this may bias results in unpredictable ways, the most likely consequence is dilution of risk estimates toward the null. The only well-established environmental risk factor for brain tumors is ex- posure to high doses of ionizing radiation (ACS, 2007d; Wrensch et al., 2002). Other environmental exposures—such as to vinyl chloride, petroleum products, and electromagnetic fields—are unproved as risk factors. The causes of most cancers of the brain and other portions of the nervous system are not known. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was limited or sug- gestive evidence of no association between exposure to the chemicals of interest and brain cancer. The committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. The committee responsible for Update 2006 changed the classification for brain cancer (formally expanded to include cancers of the eye and orbit) to inadequate or insufficient information to determine an association between exposure to the chemicals of interest and brain cancer. That committee considered one study that suggested a relationship between adult gliomas and phenoxy acid herbicides (Lee et al., 2005), studies that reported slightly but not statistically significantly higher risks of brain cancer in deployed than in nondeployed Australian Vietnam-era vet- erans (ADVA, 2005a,b) and in pesticide applicators in the AHS (Alavanja et al.,

CANCER 347 2005), and several studies with essentially neutral findings (Carreon et al., 2005; Magnani et al., 1987; McLean et al., 2006; Ruder et al., 2004; Torchio et al., 1994). Overall, the studies discussed in Update 2006 suggested that a conclusion of no association between exposure to the chemicals of interest and brain cancer was too definitive. Table 6-37 summarizes the results of the relevant studies. Update of Epidemiologic Literature Vietnam-Veteran Studies Since Update 2006, Cypel and Kang (2008) have evaluated mortality from all causes among female Vietnam veterans. The vital status through 2004 of the 4,390 veterans who had been alive in 1991 was assessed; overall, mortality from cancer was not higher than that in a control group of era veterans or the general population. Eight deaths attributed to cancer of the brain and CNS were observed in the Vietnam veterans (crude rate, 0.54 per 10,000) and seven in the era-veteran cohort, giving an adjusted RR of 1.97 (95% CI 0.67–5.86). In a comparison of Vietnam nurses with non-Vietnam nurses, there were eight and three deaths, respectively (RR = 3.55, 95% CI 0.87–14.53). Occupational Studies Samanic et al. (2008) conducted a case–control study of 462 patients with gliomas (43.5% in women) and 195 patients with meningiomas (76.4% in women) diagnosed at three major cancer-referral centers in 1994–1998 and 765 controls treated for nonneoplastic conditions in the same hospitals. Cumulative lifetime exposure to insecticides and herbicides was estimated by applying a job–exposure matrix to the occupational histories reported in interviews with the subjects or proxies for 15.2% of the gliomas, 7.2% of the meningiomas, and 2.4% of the controls. There was no relationship between herbicide exposure and incidence of gliomas in men or women. For the meningiomas, only the number of cases in women was adequate to perform the analysis. Among the cases, the women had a significantly increased risk of meningiomas in association with herbicide exposure (OR = 2.4, 95% CI 1.4–4.3); risk increased with estimated cumulative dose (p < 0.01) and years of exposure (p < 0.01). The increase in me- ningioma risk in women exposed to herbicides is of concern, given the apparent dose–response relationship, but there was no specification of the herbicides to which subjects were exposed. Environmental Studies Consonni et al. (2008) evaluated mortality in a follow-up period of 1997– 2001 in 278,108 people exposed to TCDD as a result of the industrial accident in

348 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-37  Selected Epidemiologic Studies—Brain Tumors Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans (brain and CNS)—women 8 2.0 (0.7–5.9) Kang, 2008 Vietnam veteran nurses 8 3.6 (0.9–14.5) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population (brain)—incidence 97 1.1 (0.9–1.2) Navy 24 1.2 (0.7–1.7) Army 63 1.0 (0.8–1.3) Air Force 10 1.1 (0.6–2.1) ADVA, Australian male Vietnam veterans vs Australian 2005b population (brain, CNS)—mortality 99 1.0 (0.8–1.1) Navy 23 1.0 (0.6–1.4) Army 66 0.9 (0.7–1.2) Air Force 9 0.9 (0.4–1.6) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs nondeployed (brain, CNS) Incidence (1982–2000) 23 1.4 (0.7–2.6) Mortality (1966–2001) 27 1.6 (0.9–3.1) Boehmer Follow-up of CDC Vietnam Experience Cohort et al., 2004 (meninges, brain, other CNS) 9 1.2 (0.4–3.2) Studies Reviewed in Update 2004 Akhtar White AFHS subjects vs national rates et al., 2004 Ranch Hand veterans Incidence (brain and nervous system) 5 1.8 (0.7–4.1) With tours in 1966–1970 5 2.2 (0.8–4.8) Mortality (CNS) 3 1.3 (0.3–3.6) Comparison veterans Incidence (brain and nervous system) 2 0.5 (0.1–1.8) With tours in 1966–1970 2 0.7 (0.1–2.3) Mortality (CNS) 1 0.3 (nr) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 39 1.1 (0.7–1.4) 1997a CDVA, Australian National Service Vietnam veterans 13 1.4 (nr) 1997b Dalager and Army Chemical Corps veterans (crude rate ratio vs Kang, 1997 nondeployed) 2 1.9 (nr) Studies Reviewed in Update 1996 Dalager US Vietnam veterans—women 4 1.4 (0.4–3.7) et al., 1995 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 36 1.1 (0.8–1.5) Boyle et al., Vietnam Experience Study 3 nr 1987

CANCER 349 TABLE 6-37  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Thomas and Army Chemical Corps Vietnam veterans 2 nr Kang, 1990 Breslin Army Vietnam veterans 116 1.0 (0.3–3.2) et al., 1988 Marine Vietnam veterans 25 1.1 (0.2–7.1) Anderson Wisconsin Vietnam veterans 8 0.8 (0.3–1.5) et al., 1986 Lawrence New York Vietnam veterans (brain and CNS) 4 0.5 (0.2–1.5) et al., 1985 OCCUPATIONAL New Studies Samanic US hospital-based case–control study et al., 2008 Cumulative lifetime occupational exposure to herbicides vs unexposed Gliomas Men 65 0.9 (0.6–1.3) Low quartile 20 1.0 (0.5–1.9) Second quartile 16 1.0 (0.5–2.1) Third quartile 12 0.6 (0.3–1.3) Fourth quartile 17 0.8 (0.4–1.6) p-trend = 0.50 Women 35 1.3 (0.8–2.0) Below median 23 1.5 (0.8–2.7) Above median 12 1.0 (0.5–2.1) p-trend = 0.91 Meningiomas (women only) 33 2.4 (1.4–4.3) Below median 16 2.1 (1.0–4.4) Above median 17 2.9 (1.3–6.2) p-trend = 0.01 Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 44 1.0 (0.7–1.4) Ever 28 0.8 (0.5–1.2) ’t Mannetje New Zealand phenoxy herbicide workers et al., 2005 Phenoxy herbicide producers (men and women) 1 0.8 (0.0–4.6) Phenoxy herbicide sprayers (> 99% men) 1 0.6 (0.0–3.4) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 33 0.8 (0.6–0.8) Spouses of private applicators (> 99% women) 15 0.9 (0.5–1.4) Commercial applicators (men and women) 5 1.9 (0.6–4.3) continued

350 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-37  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Blair et al., US AHS 2005a Private applicators (men and women) 19 0.7 (0.4–1.1) Years handled pesticides ≤ 10 years 5 0.9 (ns) > 10 years 12 0.6 (ns) Spouses of private applicators (> 99% women) 11 1.1 (0.5–1.8) Torchio Italian licensed pesticide users et al., 1994 Brain, nervous system 15 0.5 (0.3–0.9) Eye 4 2.4 (0.7–6.1) Lee et al., Nebraska case–control study (gliomas)—incidence 2005  Phenoxy herbicides—combined reports (identical with results for 2,4-D specifically) 32 1.8 (1.0–3.3) By self 7 0.6 (0.2–1.6) By proxy 25 3.3 (1.5–7.2) 2,4,5-T—combined reports 7 1.3 (0.5–3.6) By self 2 0.4 (0.1–2.3) By proxy 5 2.7 (0.7–9.8) Carreon NIOSH UMHS—case–control et al., 2005 Women Arsenicals 13 1.0 (0.5–1.9) Phenoxy herbicides 25 0.9 (0.5–1.5) 2,4-D 24 0.9 (0.5–1.6) Ruder et al., Men 2004 Arsenicals 15 0.7 (0.4–1.4) Phenoxy herbicides 67 0.9 (0.6–1.2) 2,4-D nr nr Reif et al., Case–control study, all men with occupation entered 1989 into New Zealand Cancer Registry 1980–1984 (brain, CNS cancers) Forestry workers 4 1.2 (0.4–3.3) Magnani UK case–control, JEM used on occupation given on et al., 1987 death certificate Herbicides nr 1.2 (0.7–2.1) Chlorophenols nr 1.1 (0.7–1.8) Studies Reviewed in Update 2004 Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry) (brain and CNS) nr 0.6 (0.1–1.8) Swaen Dutch licensed herbicide applicators 4 1.6 (0.4–4.1) et al., 2004 Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 3 1.1 (0.2–3.2) Thörn et al., Swedish lumberjacks exposed to phenoxy acetic 2000 herbicides Foreman—incidence 0 nr

CANCER 351 TABLE 6-37  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2000 Steenland US chemical workers (included in IARC cohort, et al., 1999 NIOSH Dioxin Registry) (brain and CNS) 8 0.8 (0.4–1.6) Studies Reviewed in Update 1998 Gambini Italian rice growers (brain and CNS) 4 0.9 (0.2–2.3) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 22 0.7 (0.4–1.0) Exposed to highly chlorinated PCDDs 12 0.6 (0.3–1.1) Not exposed to highly chlorinated PCDDs 10 0.8 (0.4–1.5) Becher German production workers (included in IARC et al., 1996 cohort)—cohort I 3 2.3 (0.5–6.8) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) (brain and CNS) 0-year latency 1 nr 15-year latency 1 nr Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators (eye, brain) 1994 Incidence 3 0.7 (0.1–2.0) Mortality 3 1.2 (0.3–3.6) Dean, 1994 Irish farmers, farm workers Men 195 nr Women 72 nr Blair et al., US farmers in 23 states 1993 White men 447 1.2 (1.1–1.3) White women 9 1.1 (0.5–2.1) Studies Reviewed in VAO Morrison Farmers in Canadian prairie province et al., 1992 250+ acres sprayed with herbicides 24 0.8 (0.5–1.2) Ronco et al., Danish farmers (brain and CNS)—incidence 1992 Men 194 1.1 (nr) Women 5 1.0 (nr) Swaen Dutch licensed herbicide applicators 3 3.2 (0.6–9.3) et al., 1992 Fingerhut NIOSH cohort—entire cohort (brain and CNS) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 2 1.1 (0.1–3.8) Saracci IARC cohort (men and women)—exposed subcohort 6 0.4 (0.1–0.8) et al., 1991 Wigle et al., Canadian farmers 96 1.0 (0.8–1.3) 1990 Alavanja USDA forest, soil conservationists 6 1.7 (0.6–3.7) et al., 1989 Henneberger New Hampshire pulp and paper workers 2 1.2 (0.1–4.2) et al., 1989 continued

352 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-37  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Alavanja USDA agricultural extension agents nr 1.0 (0.4–2.4) et al., 1988 Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) Brain, other system tissues 0 nr (0.0–4.1) Musicco Brain-tumor patients in Milan, Italy (male, female et al., 1988 farmers) 61 1.6 (1.1–2.4) Coggon British MCPA chemical workers (included in IARC et al., 1986 cohort) (brain and CNS) 11 1.2 (0.6–2.2) Robinson Northwestern US paper and pulp workers 4 0.6 (0.2–2.1) et al., 1986 Lynge, 1985 Danish production workers (included in IARC cohort)—incidence 4 0.7 (nr) Blair et al., Florida pesticide applicators 5 2.0 (nr) 1983 Burmeister, Iowa farmers 111 1.1 (ns) 1981 ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 0 nr Zone B 3 0.7 (0.2–2.1) Zone R 34 1.1 (0.8–1.6) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B— en m 1 0.4 (0.1–3.0) women 3 1.9 (0.6–6.0) Bertazzi Seveso residents—15-year follow-up et al., 1998 Zone B— en m 1 0.8 (0.1–5.5) women 3 3.2 (1.0–10.3) Zone R— en m 12 1.3 (0.7–2.5) women 8 1.1 (0.5–2.4) Studies Reviewed in Update 1998 Svensson Swedish fishermen (men and women)—mortality et al., 1995 East coast 2 0.6 (0.1–2.1) West coast 15 1.1 (0.6–1.7) Swedish fishermen (men and women)—incidence East coast 3 0.5 (0.1–1.5) West coast 24 0.9 (0.6–1.4) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone R— en m 6 0.6 (0.3–1.4) women 6 1.4 (0.6–3.4)

CANCER 353 TABLE 6-37  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Pesatori Seveso residents—incidence et al., 1992 Zones A, B—women 1 1.5 (0.2–11.3) Zone R— en m 6 0.6 (0.3–1.4) women 5 1.2 (0.4–3.0) Bertazzi Seveso residents—10-year follow-up et al., 1989a Zones A, B, R— en m 5 1.2 (0.4–3.1) women 5 2.1 (0.8–5.9) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; CNS, central nervous system; IARC, International Agency for Research on Cancer; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not sig- nificant; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; UMHS, Upper Midwest Health Study; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts. Seveso, Italy, in 1976. Compared with that in residents in a nonexposed adjacent area, there was no increase in mortality from brain cancer in any of the three exposed zones with increasing exposure and no indication of a dose–response relationship. Biologic Plausibility No animal studies have reported an association between exposure to the chemicals of interest and brain cancer. The biologic plausibility of the carcino- genicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Since Update 2006, several studies relevant to the possibility of an asso- ciation between the chemicals of interest and brain cancer have been identified, including cohort and case–control studies. All recent studies are consistent in identifying no relationship between exposure to the chemicals of interest and the development of gliomas. Samanic et al. (2008) did identify a possible rela-

354 VETERANS AND AGENT ORANGE: UPDATE 2008 tionship between herbicide exposure and meningiomas in women, but lack of identification of specific chemicals of interest makes the interpretation of this result uncertain. Conclusion On the basis of the epidemiologic evidence from new and previously re- ported studies of populations with potential exposure to the chemicals of inter- est, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and brain cancer and other nervous system cancers. ENDOCRINE CANCERS Cancers of the endocrine system as grouped by the SEER program (see Table B-2 in Appendix B) make up a disparate group of ICD codes: thymus cancer (ICD-9 164.0), thyroid cancer (ICD-9 193), and other endocrine cancer (ICD-9 194). ACS estimated that 8,930 men and 28,410 women would receive diagnoses of thyroid cancer in the United States in 2008 and that 680 men and 910 women would die from it and estimated that 1,100 men and 1,070 women would receive diagnoses of other endocrine cancers in 2008 and that 430 men and 410 women would die from them (Jemal et al., 2008a). Incidence data on cancers of the en- docrine system are presented in Table 6-38. Thyroid cancer is the most prevalent of the endocrine cancers. Many types of tumors can develop in the thyroid gland; most are benign. The thyroid gland contains two main types of cells: follicular cells, which make and store thyroid hormones and that make thyroglobulin, and C cells, which make the hormone calcitonin, which helps to regulate calcium metabolism. Different cancers can de- velop from each kind of cell, and the classification of thyroid cancer is still evolv- ing (Liu et al., 2006). The several types into which thyroid cancer is currently TABLE 6-38  Average Annual Incidence (per 100,000) of Endocrine System Cancer in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 6.7 9.3 7.2 11.1 11.4 7.2 12.5 12.7 7.0 Women 23.5 24.4 14.1 22.2 22.1 18.3 21.7 22.5 15.0 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

CANCER 355 classified differ in their seriousness. Papillary carcinoma is the most common and usually affects women of childbearing age; it metastasizes slowly and is the least malignant type of thyroid cancer. Follicular carcinoma accounts for about 30% of all cases and has a greater rate of recurrence and metastasis. Medullary carcinoma is a cancer of nonthyroid cells in the thyroid gland and tends to occur in families; it requires treatment different from other types of thyroid cancer. Ana- plastic carcinoma (also called giant-cell cancer and spindle-cell cancer) is rare but is the most malignant form of thyroid cancer; it does not respond to radioiodine therapy and metastasizes quickly, invading such nearby structures as the trachea and causing compression and breathing difficulties. Thyroid cancer can occur in all age groups. People who have had radia- tion therapy directed at the neck are at higher risk. That therapy was commonly used in the 1950s in treatment for enlarged thymus glands, adenoids, and tonsils and for skin disorders. People who received radiation therapy as children have a higher incidence of thyroid cancer. Other risk factors are a family history of thyroid cancer and chronic goiter. Conclusions from VAO and Previous Updates The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not consider endocrine cancers sepa- rately and therefore reached no conclusion as to whether there was an associa- tion between exposure to the chemicals of interest and endocrine cancers. The committee responsible for Update 2006 considered endocrine cancers separately and concluded that there was inadequate or insufficient evidence to determine whether there was an association between the chemicals of interest and endocrine cancers. Table 6-39 summarizes the pertinent results of the relevant studies. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and thyroid or other endocrine cancers have been published since Update 2006. Biologic Plausibility The National Toxicology Program (NTP) conducted carcinogenesis bioas- says in Osborne-Mendel rats and B6C3F1 mice exposed to TCDD by gavage (NTP, 1982a). The incidence of follicular-cell adenoma, but not of carcinoma, increased with increasing TCDD dose in male and female rats; the increase was significant in male but not female rats. There was a significant increase in follicular-cell adenoma in female but not male mice. The NTP carried out a similar study in female Sprague-Dawley rats more recently (NTP, 2006), and Walker et al. (2006) compared the data from that study and the results of the Dow

356 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-39  Selected Epidemiologic Studies—Endocrine Cancers (Thyroid, Thymus, and Other) Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS ADVA, Australian male Vietnam veterans vs Australian 2005a population (thyroid)—incidence 17 0.6 (0.3–0.9) Navy 3 0.5 (0.1–1.3) Army 11 0.5 (0.3–1.0) Air Force 3 1.2 (0.2–3.5) ADVA, Australian male Vietnam veterans vs Australian 2005b population (thyroid)—mortality 2 0.5 (0.0–1.8) Navy 1 1.2 (0.0–6.5) Army 1 0.4 (0.0–2.0) Air Force 0 0.0 (0.0–7.8) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans—deployed vs nondeployed Thyroid—incidence 4 0.6 (0.1–2.2) Thyroid—mortality 1 1.2 (0.0–91.7) Breslin Veterans with service in Vietnam vs. era veterans et al., 1988 (thyroid and other endocrine, ICD-9 193–194) Army 15 0.6 (0.3–1.2) Marine Corps 4 0.6 (0.1–3.4) Clapp, 1997 Massachusetts male Vietnam veterans vs era veterans (thyroid)—incidence 1988–1993 4 1.2 (0.3–4.5) OCCUPATIONAL Alavanja US AHS (thyroid, other endocrine)—incidence et al., 2005 Private applicators (men and women) 29 1.3 (0.8–1.8) Spouses of private applicators (> 99% women) 24 0.9 (0.5–1.4) Commercial applicators (men and women) 3 1.6 (0.3–5.0) ’t Mannetje Phenoxy herbicide producers (men and women) 0 nr et al., 2005 Phenoxy herbicide sprayers (> 99% men) 0 nr Blair et al., US AHS (thyroid)—mortality 2005a Private applicators (men and women) 3 1.8 (0.4–5.3) Spouses of private applicators (> 99% women) 0 0.0 (0.0–2.2) Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol Thyroid (ICD-9 193) 4 1.7 (0.5–4.3) Exposed to highly chlorinated PCDDs 2 1.4 (0.2–4.9) Not exposed to highly chlorinated PCDDs 2 2.2 (0.3–7.9) Other endocrine organs (ICD-9 194) 5 3.6 (1.2–8.4) Exposed to highly chlorinated PCDDs 2 2.3 (0.3–8.1) Not exposed to highly chlorinated PCDDs 3 6.4 (1.3–18.7) Zhong and Icelandic men, women exposed to agricultural Rafnsson, pesticides, primarily 2,4-D (other endocrine organs, 1996 ICD-9 194)—incidence 2 1.3 (0.1–4.7) Ramlow Dow cohort of pentachlorophenol factory workers et al., 1996 employed in 1940–1989 in Michigan Division 0 nr

CANCER 357 TABLE 6-39  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Asp et al., Finnish phenoxy herbicide applicators (thyroid, 1994 other endocrine)—incidence No latency 2 1.9 (0.3–7.0) 10-year latency 2 2.4 (0.3–8.6) 15-year latency 2 3.4 (0.4–12.2) Mortality (thyroid) No latency 1 3.8 (0.1–21.3) 10-year latency 1 4.7 (0.1–26.4) 15-year latency 1 6.5 (0.2–36.2) Hallquist Case–control study of male, female thyroid cancers et al., 1993 from Swedish Cancer Registry, 1980–1989 Phenoxy herbicide exposure 3 0.5 (0.0–2.0) Chlorophenol exposure 4 2.8 (0.5–18) Blair et al., US farmers in 23 states (thyroid) 1993 White men 39 1.3 (1.0–1.8) White women 1 0.8 (0.0–4.4) Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 13 0.7 (nr) employee 5 1.1 (nr) Women— elf-employed s 1 1.3 (nr) employee 1 1.4 (nr) family worker 15 1.7 (p < 0.05) Green, 1991 Cohort mortality study of forestry workers exposed to phenoxy acid herbicides 1 nr Wiklund Cancer risk in licensed pesticide applicators in et al., 1989a Sweden 6 1.1 (0.4–2.4) Bond et al., Workers engaged in manufacture of phenoxy 1988 herbicides 0 nr Coggon British MCPA procuction workers (thyroid) et al., 1986 (included in IARC cohort) 1 1.8 (0.4–9.8) Wiklund, Swedish male and female agricultural 1983 workers—incidence 99% CI Thyroid 126 0.9 (0.7–1.1) Other endocrine gland 117 0.7 (0.5–0.9) ENVIRONMENTAL Bertazzi Cancer mortality after Seveso incident et al., 1998 Zone A nr nr Zone B— en m 1 4.9 (0.6–39.0) women 1 3.2 (0.4–24.5) Zone R— en m 0 nr women 2 0.8 (0.2–3.6) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD, International Clas- sification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; nr, not reported; PCDDs, c ­ hlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines). aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually.

358 VETERANS AND AGENT ORANGE: UPDATE 2008 Chemical assessment of TCDD carcinogenicity (Kociba et al., 1978). In the NTP and Dow studies, the incidence of thyroid cancer (C-cell adenoma and carcinoma) decreased with increasing dose of TCDD. However, an increased incidence of minimal thyroid follicular-cell hypertrophy was noted in rats given TCDD at 22 ng/kg of body weight or more. As indicated in Chapter 4, 2,4-D and 2,4,5-T are at most only weakly muta- genic or carcinogenic. No studies that addressed a possible association between exposure to those herbicides and thyroid cancer in animal models have been identified. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The studies reviewed previously did not provide sufficient evidence to de- termine whether there is an association between exposure to the chemicals of interest and thyroid cancer or other endocrine cancers, and no new additional information was found by the present committee. Conclusion On the basis of the epidemiologic evidence reviewed here, the committee concludes that there is insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and thyroid or other endocrine cancers. LYMPHOHEMATOPOIETIC CANCERS (LYMPHOMAS AND LEUKEMIAS) As in the case of other cancers that are subject to idiosyncratic grouping in the results reported from epidemiologic studies (notably, head and neck cancers and gastrointestinal cancers), the conclusions that the VAO committees have been able to draw about associations between herbicide exposure and specific lympho- hematopoietic cancers are complicated and curtailed by the lack of specificity and the occasional inconsistency of groupings in the available evidence. Categoriza- tion of cancers of the lymphatic and hematopoietic systems continues to evolve on the basis of increasing insight into the lineage of the clonal cancer cells that characterize each of a broad spectrum of neoplasms arising in these tissues. Stem cells in the bone marrow generate two major lineages of leukocytes: myeloid and lymphoid. Myeloid cells include monocytes and three types of granulocytes (neutrophils, eosinophils, and basophils). Lymphoid cells include T and B lymphocytes and a smaller subset of cells called natural killer cells. All those cells circulate in the blood and are collectively referred to as white blood cells. Monocytes move out of the bloodstream into inflamed tissues, where they

CANCER 359 differentiate into macrophages or dendritic cells. Stem cells that are destined to become T lymphocytes migrate from the bone marrow to the thymus, where they acquire antigen-specific receptors. Antigen stimulation induces the T cells to differentiate into the several types involved in cell-mediated immunity. Pre-B cells mature in the bone marrow into antigen-specific B cells. On encountering their cognate antigens, B cells differentiate into antibody-secreting plasma cells involved in humoral immunity. Lymphoma is a general term for cancers that arise from B or T lymphocytes. As stem cells mature into B or T cells, they pass through several developmental stages, each with unique functions. The developmental stage at which a cell be- comes malignant defines the kind of lymphoma. About 85% of lymphomas are of B-cell origin, and 15% of T-cell origin. Lymphomas grow as circumscribed solid tumors in the lymph nodes. If a cell that becomes cancerous resides in the bone marrow, its daughter cells may crowd normal cells in the bone marrow or be released from the bone marrow and circulate in the blood. Such cancers are called leukemias. Leukemias are generally classified as myeloid or lymphoid, depending on the differentiation pathway of the original mutated cell. If the original mutated cell of a cancer of the blood arises in a lymphocytic cell line, the cancer is called lymphocytic leu- kemia; lymphocytic leukemias are further partitioned into acute (ALL) forms if they are derived from precursor B or T lymphoid cells and chronic (CLL) forms derived from more mature lymphoid cells, which tend to replicate less rapidly. Similarly, myeloid leukemias are portioned into acute and chronic forms, AML and CML, respectively. B lymphocytes (B cells) give rise to a number of types of neoplasms that are given names based on the stage at which B-cell development was arrested when the cells became cancerous. Follicular, large-cell, and immunoblastic lymphomas result when a malignancy develops after a B cell has been exposed to antigens (such as bacteria and viruses). CLL is now believed to be a tumor of antigen- experienced (memory) B cells, not naive B cells (Chiorazzi et al., 2005); small lymphocytic lymphoma (SLL), which presents primarily in lymph nodes rather than in the bone marrow and blood, is now considered to be the same disease as CLL at a different stage (Jaffe et al., 2008). (Although some may now prefer to designate the two closely related entities as CLL/SLL, the committee has opted to continue using the abbreviation CLL to refer to this condition in its more in- clusive sense.) Some of those stages are more common than others and therefore have been subclassified for diagnostic purposes. However, why one stage of B-cell development rather than another is affected by a cancerous mutation is not known; it may reflect individual genetic predispositions or other environmental exposures. The more common cancers of the hematopoietic system are described in the sections below on Hodgkin’s disease; non-Hodgkin’s lymphomas; multiple my- eloma, followed by a separate section on the related condition, AL amyloidosis; and leukemias. An additional section on CLL has been included in light of VA’s

360 VETERANS AND AGENT ORANGE: UPDATE 2008 request that it be considered separately for Update 2002. The introduction to the CLL section includes an explanation of why the committee accepts the epide- miologic and toxicologic data on CLL to be applicable to hairy-cell leukemia (HCL). Hodgkin’s Disease Hodgkin’s disease (HD) (ICD-9 201) is now often designated as Hodgkin’s lymphoma, but the present committee continues its use of disease to maintain consistency throughout the VAO reports. HD is distinguished from non-Hodgkin’s lymphoma (NHL) primarily on the basis of its neoplastic cells, mononucleated Hodgkin cells and multinucleated Reed–Sternberg cells originating in germinal center B cells (Kuppers et al., 2002). HD’s demographics and genetics are also characteristic. ACS estimated that 4,400 men and 3,820 women would receive diagnoses of HD in the United States in 2008 and that 700 men and 650 women would die from it (Jemal et al., 2008a). The average annual incidence is shown in Table 6-40. The possibility that HD has an infectious etiology has been a topic of discus- sion since its earliest description. An increased incidence in people with a history of infectious mononucleosis has been observed in some studies, and a link with Epstein–Barr virus has been proposed. In addition to the occupational associa- tions discussed below, higher rates of the disease have been observed in people who have suppressed or compromised immune systems. Conclusions from VAO and Previous Updates The committee responsible for VAO determined that there were sufficient epidemiologic data to support an association between exposure to the chemicals of interest and HD. Additional studies available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-41 summarizes the results of the relevant studies. TABLE 6-40  Average Annual Incidence (per 100,000) of Hodgkin’s Disease in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 3.3 3.4 4.3 2.8 2.9 2.4 3.3 3.5 4.3 Women 1.7 1.7 1.6 1.6 1.7 1.8 2.0 2.2 0.3 aSurveillance,Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005.

CANCER 361 TABLE 6-41  Selected Epidemiologic Studies—Hodgkin’s Disease Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans (lymphopoietic Kang, 2008 cancersc)—women 18 0.7 (0.4–1.3) Vietnam-veteran nurses 14 0.7 (0.3–1.3) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 51 2.1 (1.5–2.6) Navy 7 1.3 (0.5–2.6) Army 40 2.3 (1.6–3.0) Air Force 4 2.1 (0.6–5.3) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 13 0.9 (0.5–1.5) Navy 2 0.6 (0.1–2.1) Army 11 1.1 (0.5–1.9) Air Force 0 0.0 (0.0–2.9) ADVA, Australian male conscripted Army National Service 2005c Vietnam era veterans: deployed vs non-deployed Incidence 12 0.9 (0.4–2.0) Mortality 4 1.7 (0.3–11.8) Boehmer Vietnam Experience Cohort 2 0.9 (nr) et al., 2004 Studies Reviewed in Update 2004 Akhtar White Air Force Ranch Hand veterans vs national et al., 2004 rates (lymphopoietic cancerc)—incidence Ranch Hand veterans 10 0.9 (0.4–1.5) Comparison Air Force veterans 9 0.6 (0.3–1.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 1 0.3 (0.0–3.2) Studies Reviewed in Update 1998 Watanabe Marine Vietnam veterans 25 1.9 (1.2–2.7) and Kang, 1996 Studies Reviewed in Update 1996 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 20 1.1 (0.7–1.8) Studies Reviewed in VAO Watanabe Army Vietnam veterans et al., 1991 Vs Army non-Vietnam veterans 116 1.0 (nr) Vs all non-Vietnam veterans 116 1.1 (nr) Marine Vietnam veterans Vs Marine non-Vietnam veterans 25 1.9 (nr) Vs all non-Vietnam veterans 25 1.0 (nr) CDC, 1990a US men born 1921–1953 Vietnam veterans 28 1.2 (0.7–2.4) Army 12 1.0 (0.5–2.0) Marine Corps 4 1.7 (0.5–5.9) Air Force 5 1.7 (0.6–4.9) Navy 7 1.1 (0.4–2.6) continued

362 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-41  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Michalek Air Force Ranch Hand veteran 0 nr et al., 1990; Wolfe et al., 1990 Breslin Vietnam-era veterans—deployed vs nondeployed et al., 1988 Army 92 1.2 (0.7–1.9) Marine Corps 22 1.3 (0.7–2.6) Boyle et al., Vietnam Experience Study 0 nr 1987 Fett et al., Australian Vietnam veterans 0 nr 1987 Anderson Wisconsin Vietnam veterans 4 nr et al., 1986 Holmes West Virginia Vietnam veterans compared with West et al., 1986 Virginia Vietnam-era veterans 5 8.3 (2.7–19.5) Lawrence New York Vietnam veterans compared with New 99% CI et al., 1985 York Vietnam-era veterans (lymphoma and HD) 10 1.0 (0.4–2.2) OCCUPATIONAL Studies Reviewed in Update 2006 McLean IARC cohort of pulp and paper workers et al., 2006 Exposure to nonvolatile organochlorine compounds Never 7 0.6 (0.2–1.2) Ever 17 1.8 (1.0–2.8) ’t Mannetje Phenoxy herbicide producers (men and women) 1 5.6 (0.1–31.0) et al., 2006 Phenoxy herbicide sprayers (> 99% men) 0 0.0 (0.0–16.1) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 11 0.9 (0.4–1.6) Spouses of private applicators (> 99% women) 4 0.7 (0.2–1.9) Commercial applicators (men and women) 1 0.8 (0.1–4.2) Blair et al., US AHS 3 1.1 (0.2–3.3) 2005a Private applicators (men and women) 3 1.7 (0.3–4.8) Spouses of private applicators (> 99% women) 0 0.0 (0.0–2.5) Torchio Italian licensed pesticide users 11 1.0 (0.5–1.7) et al., 1994 Studies Reviewed in Update 2004 Swaen Dutch licensed herbicide applicators 0 nr et al., 2004 Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 1 1.5 (0.0–8.6) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 3 1.1 (0.2–3.2) Hooiveld Dutch chemical production workers (included in et al., 1998 IARC cohort) 1 3.2 (0.1–17.6) Rix et al., Danish paper mill workers—incidence 1998 Men 18 2.0 (1.2–3.2) Women 2 1.1 (0.1–3.8)

CANCER 363 TABLE 6-41  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1998 Gambini Italian rice growers 1 0.7 (0.0–3.6) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 10 1.0 (0.5–1.8) Exposed to highly chlorinated PCDDs 8 1.3 (0.6–2.5) Not exposed to highly chlorinated PCDDs 1 0.3 (0.0–1.5) Becher German production workers (included in IARC et al., 1996 cohort) 0 nr Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0 nr Waterhouse Residents of Tecumseh, Michigan 13 2.0 (1.1–3.4) et al., 1996 Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators 2 1.7 (0.2–6.0) 1994 Blair et al., US farmers in 23 states 56 1.0 (0.8–1.3) 1993 Kogevinas IARC cohort—females—incidence 1 nr et al., 1993 Persson Swedish NHL patients—exposure to phenoxy 90% CI et al., 1993 herbicides 5 7.4 (1.4–40.0) Kogevinas IARC cohort (men and women) 3 0.6 (0.1–1.7) et al., 1992 Studies Reviewed in VAO Eriksson Swedish Cancer Registry patients (men and women) et al., 1992 Male sawmill workers 10 2.2 (nr) Male farmers 97 1.2 (nr) Male forestry workers 35 1.2 (nr) Male horticulture workers 11 1.2 (nr) Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 27 0.6 (p < 0.05) employee 13 1.0 (nr) Female— elf-employed s 1 1.1 (nr) employee 1 1.2 (nr) family worker 9 0.9 (nr) Swaen Dutch licensed herbicide applicators 1 3.3 (0.04–18.6) et al., 1992 Fingerhut NIOSH cohort—entire cohort 3 1.2 (0.3–3.5) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 1 2.8 (0.1–15.3) Green, 1991 Ontario herbicide sprayers 0 nr Saracci IARC cohort—exposed subcohort (men and women) 2 0.4 (0.1–1.4) et al., 1991 Zober et al., BASF employees—basic cohort 0 nr 1990 continued

364 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-41  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Alavanja USDA forest, soil conservationists 4 2.2 (0.6–5.6) et al., 1989 LaVecchia Residents of the Milan, Italy, area (men and women) et al., 1989 Agricultural occupations nr 2.1(1.0–3.8) Chemical-industry occupations nr 4.3 (1.4–10.2) Persson Orebro (Sweden) Hospital patients (men and et al., 1989 women) 90% CI Farming 6 1.2 (0.4–3.5) Exposed to phenoxy acids 4 3.8 (0.7–21.0) Wiklund Swedish pesticide applicators 15 1.5 (0.8–2.4) et al., 1989b Alavanja USDA agricultural extension agents et al., 1988 PM analysis 6 2.7 (1.2–6.3) Case–control analysis 6 1.1 (0.3–3.5) Bond et al., Dow 2,4-D production workers (included in IARC 1988 cohort, NIOSH Dioxin Registry) 1 2.7 (0.0–14.7) Dubrow Hancock County, Ohio, residents—farmers 3 2.7 (nr) et al., 1988 Wiklund Swedish agricultural and forestry workers (men and et al., 1988 women) Workers in land or in animal husbandry 242 1.0 (0.9–1.2) Workers in silviculture 15 2.3 (1.3–3.7) Hoar et al., Kansas residents 1986 All farmers 71 0.8 (0.5–1.2) Farm use of herbicides (phenoxy acids and others) 28 0.9 (0.5–1.5) Farmers using herbicides > 20 days/year 3 1.0 (0.2–4.1) Farmers using herbicides > 15 years 10 1.2 (0.5–2.6) Pearce New Zealand residents with agricultural et al., 1985 occupations, 20–64 years old 107 1.1 (0.6–2.0) Hardell and Umea (Sweden) Hospital patients—incidence Bengtsson, Exposed to phenoxy acids 14 5.0 (2.4–10.2) 1983 Exposed to high-grade chlorophenols 6 6.5 (2.2–19.0) Exposed to low-grade chlorophenols 5 2.4 (0.9–6.5) Riihimaki Finnish herbicide applicators 0 nr et al., 1982 Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 226 1.0 (0.9–1.2) Burmeister, Iowa farmers 47 1.2 (ns) 1981 Hardell Umea (Sweden) Hospital patients (all et al., 1981 lymphomas)—incidence Exposed to phenoxy acids 41 4.8 (2.9–8.1) Exposed to chlorophenols 50 4.3 (2.7–6.9)

CANCER 365 TABLE 6-41  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ENVIRONMENTAL New Studies Consonni Seveso residents (men and women)—25-year et al., 2008 follow-up Zone A 0 nr Zone B  Bertazzi et al. [2001, 1997] reported 4 ( HD cases in Zone B) 3 2.2 (0.7–6.9) Zone R 9 0.9 (0.5–1.9) Miligi et al., Italian case–control study—herbicide exposure in 2006 men, women with diagnosis of HD 6 0.4 (0.2–1.2) Read et al., Residents of New Plymouth Territorial Authority, 2007 New Zealand near plant manufacturing 2,4,5-T (1962–1987) Incidence 49 1.1 (0.8–1.5)d 1970–1974 9 1.2 (0.6–2.3) 1975–1979 9 1.1 (0.5–2.2) 1980–1984 8 1.1 (0.5–2.1) 1985–1989 9 1.3 (0.6–2.5) 1990–1994 7 1.3 (0.5–2.7) 1995–1999 4 0.7 (0.2–1.7) 2000–2001 3 1.0 (0.2–3.1) Mortality 22 1.3 (0.8–2.0)d 1970–1974 7 1.6 (0.7–3.3) 1975–1979 4 1.2 (0.3–3.0) 1980–1984 6 2.1 (0.8–4.5) 1985–1989 3 1.2 (0.2–3.5) 1990–1994 1 0.6 (0.0–3.5) 1995–1999 1 0.6 (0.0–3.6) 2000–2001 0 nr Studies Reviewed in Update 2006 Pahwa Canadian men (at least 19 years old) in any of 6 et al., 2006 provinces Any phenoxy herbicide 65 1.0 (0.7–1.4) 2,4-D 57 1.0 (0.7–1.4) Mecoprop 20 1.3 (0.7–2.2) MCPA 11 1.2 (0.6–2.6) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B— en m 2 2.6 (0.6–10.9) women 2 3.7 (0.9–16.0) Viel et al., Residents around French municipal solid-waste 2000 incinerator—incidence 9 1.5 (nr) Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B— enm 2 3.3 (0.4–11.9) women 2 6.5 (0.7–23.5) Zone R—women 4 1.9 (0.5–4.9) continued

366 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-41  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone B— en m 1 1.7 (0.2–12.8) women 1 2.1 (0.3–15.7) Zone R— en m 4 1.1 (0.4–3.1) women 3 1.0 (0.3–3.2) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CI, confidence interval; HD, Hodgkin’s disease; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHL, non-Hodgkin’s lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; PCDDs, chlori- nated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cLymphopoietic cancers comprise all forms of lymphoma (including Hodgkin’s disease and non- Hodgkin’s lymphoma) and leukemia (ALL, AML, CLL, CML). dCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years, 95% CIs on these total ratios were computed with exact methods. Studies in italics have been superseded by newer studies of same cohorts. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam- veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-cause mortality and cause-specific mortality in the Vietnam-veteran cohort, the era-veteran cohort, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Eighteen deaths attributed to lymphopoietic cancer were observed in the Vietnam veterans (crude rate, 1.22/10,000), and 29 in the era-veterans, for an adjusted RR of 0.68 (95% CI 0.37–1.25). No excess risk was observed in the nurses-only analysis (RR = 0.65, 95% CI 0.32–1.30). Occupational Studies  Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union and reported their findings in terms of lymphohematopoietic cancers (ICD-7 200–2005), which include HD. In the 10-year follow-up (Hansen et al., 1992), the 15 cases of lym- phohematopoietic cancers observed had included no cases of HD. The 25-year follow-up did not specify the breakdown of the lymphohematopoietic cancers,

CANCER 367 so it is not certain whether the additional 27 cases observed in the last 15 years included any cases of HD. The statistics on NHL in Table 8-43 are not repeated here in Table 8-41, because if any cases of HD did occur, it is not known how they were distributed over the three birth periods that were used as surrogates for potential exposure to pesticides and herbicides in the more recent analysis. Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso cohort of 273,108 subjects who were resident at the time of the accident or immigrated or were born in the 10 years thereafter. Analyses were performed according to three zones with increasing soil TCDD contamination. In the overall sample, no statistically significant increases in deaths from HD were observed. No deaths from HD were observed in Zone A, the zone with very high TCDD contamination. Zone B, the high-contamination zone, had three HD deaths (RR = 2.15, 95% CI 0.67–6.86), and Zone R, the low contamination zone, had nine HD deaths (RR = 0.94, 95% CI 0.46–1.89). Miligi et al. (2006) reported further results of a population-based case– control study carried out in 11 areas of Italy that was included in Update 2004 (Miligi et al., 2003). Newly diagnosed cases of hematolymphopoietic malignan- cies (NHL, CLL, leukemia, HD, and multiple myeloma) were identified during 1991–1993. The control group comprised a random sample of the residents of each area. No significant association was found between exposure to herbicides and HD in men (OR = 0.4, 95% CI 0.1–1.3), in women (OR = 0.5, 95% CI 0.1–4.0), or in men and women combined (OR = 0.4, 95% CI 0.2–1.2). Read et al. (2007) conducted a follow-up of residents of the coastal com- munity of Paritutu, New Plymouth, near the Ivon Watkins–Dow Limited plant in which 2,4,5-T was manufactured. They reported that the body burden of TCDD was comparable with that in residents of Zone B in the Seveso area. Incidence and mortality were ascertained for the period 1970–2001, and increased risks were found especially for mortality (SMR = 1.3, 95% CI 0.8–2.0), but the confi- dence intervals were wide and included the null. There was also a weaker, posi- tive association with incidence (SIR = 1.11, 95% CI 0.8–1.5). Biologic Plausibility HD arises from the malignant transformation of a germinal center B cell and is characterized by malignant cells that have a distinctive structure and pheno- type; these binucleate cells are known as Reed–Sternberg cells (Jaffe et al., 2008). No animal studies have shown an increase in HD after exposure to the chemicals of interest. Reed–Sternberg cells have not been demonstrated in mice or rats, so there is no good animal model of HD. Thus, there are no specific animal data to support the biologic plausibility of the development of HD after exposure to the chemicals of interest.

368 VETERANS AND AGENT ORANGE: UPDATE 2008 The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The relative rarity of HD complicates the evaluation of epidemiologic studies because their statistical power is generally quite low. Earlier studies (Eriksson et al., 1992; Hardell et al., 1981; Holmes et al., 1986; LaVecchia et al., 1989; Persson et al., 1993; Rix et al., 1998; Waterhouse et al., 1996; Wiklund et al., 1988) were generally well conducted and included excellent characterization of exposure, and they formed the basis of previous committees’ conclusions. The present committee believes that the small amount of additional information avail- able to it does not contradict those findings, especially given that most studies had low statistical power. Although it has not been demonstrated as clearly as for NHL, a positive association between the chemicals of interest and the develop- ment of HD is biologically plausible because of the common lymphoreticular origin of HD and NHL and their common risk factors. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest and HD. Non-Hodgkin’s Lymphoma NHL (ICD-9 200.0–200.8, 202.0–202.2, 202.8–202.9) is a general name for cancers of the lymphatic system other than HD. NHL comprises a large group of lymphomas that can be partitioned into acute, aggressive (fast-growing) or chronic, indolent (slow-growing) types of either B-cell or T-cell origin. B-cell NHL includes Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lym- phoma, large-cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle- cell lymphoma. T-cell NHL includes mycosis fungoides, anaplastic large-cell lymphoma, and precursor T-lymphoblastic lymphoma. Although CLL and HCL share many traits with NHL (including B-cell origin and immunohistochemical properties) and may progress to an acute aggressive form of NHL, they have usu- ally been classified with leukemias; in response to requests from VA, CLL and HCL are discussed separately after the general section on leukemia. ACS estimated that 35,450 men and 30,670 women would receive diagnoses of NHL in the United States in 2008 and that 9,790 men and 9,370 women would die from it (Jemal et al., 2008a). The incidence of NHL is uniformly higher in men than in women and typically higher in whites than in blacks. In the groups

CANCER 369 TABLE 6-42  Average Annual Incidence (per 100,000) of Non-Hodgkin’s Lymphoma in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 27.2 27.9 29.6 38.0 39.3 38.4 53.1 56.1 38.7 Women 19.1 19.5 18.9 28.3 29.2 23.6 38.4 41.1 30.0 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. that characterize most Vietnam veterans, incidence increases with age. Average annual incidences are shown in Table 6-42. The causes of NHL are poorly understood. People with suppressed or com- promised immune systems are known to be at higher risk, and some studies show an increased incidence in people who have HIV, human T-cell leukemia virus type I, Epstein–Barr virus, and gastric Helicobacter pylori infections. Be- havioral, occupational, and environmental risk factors also have been proposed (Blair et al., 1997). Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was sufficient evidence to support an association between exposure to at least one of the chemi- cals of interest and NHL. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-43 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam- veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-causes mortality and cause-specific mortality in the Vietnam-veteran and era-veteran cohorts, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Eigh- teen deaths attributed to lymphopoietic cancer were observed in the Vietnam vet- erans (crude rate, 1.22/10,000) and 29 deaths in the era-veterans, for an adjusted RR of 0.68 (95% CI 0.37–1.25). No excess risk was observed in the nurses-only analysis (RR = 0.65, 95% CI 0.32–1.30).

370 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Selected Epidemiologic Studies—Non-Hodgkin’s Lymphoma Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women (lymphopoietic Kang, 2008 cancersc) 18 0.7 (0.4–1.3) Vietnam-veteran nurses 14 0.7 (0.3–1.3) Studies Reviewed in Update 2006 ADVA, Australian male Vietnam veterans vs Australian 2005a population—incidence 126 0.7 (0.6–0.8) Navy 31 0.8 (0.5–1.0) Army 86 0.7 (0.5–0.8) Air Force 9 0.5 (0.2–0.9) ADVA, Australian male Vietnam veterans vs Australian 2005b population—mortality 70 0.8 (0.6–1.0) Navy 10 0.5 (0.3–0.9) Army 52 0.9 (0.6–1.1) Air Force 8 0.9 (0.4–1.6) ADVA, Australian male conscripted Army National Service 2005c Vietnam-era veterans: deployed vs nondeployed Incidence 35 1.1 (0.7–1.9) Mortality 21 1.4 (0.7–2.8) Boehmer Vietnam Experience Cohort 6 0.9 (0.3–2.9) et al., 2004 Studies Reviewed in Update 2004 Akhtar et al., White Air Force Ranch Hand veterans 2004 (lymphopoietic cancerc)—incidence Ranch Hand veterans 10 0.9 (0.4–1.5) Comparison Air Force veterans 9 0.6 (0.3–1.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans—incidence 1 0.2 (0.0–2.6) AIHW, 1999 Expected number of exposed cases Australian Vietnam veterans—incidence (validation (95% CI) study) 62 48 (34–62) CDVA, Australian Vietnam veterans—self-reported 1998a incidence 137 48 (34–62) CDVA, Australian Vietnam veterans (women)—self-reported 1998b incidence 2 0 (0–4) Studies Reviewed in Update 1998 CDVA, Australian military Vietnam veterans 1997a NHL deaths, 1980–1994 33 0.9 (0.6–1.2) Watanabe Marine Vietnam veterans (ICDA-8 200, 202) 46 1.7 (1.2–2.2) and Kang, 1996 Studies Reviewed in Update 1996 Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 32 1.5 (1.0–2.1)

CANCER 371 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Clapp et al., Massachusetts Vietnam veterans 1.2 (0.6–2.4) 1991 Dalager US Vietnam veterans—incidence 100 1.0 (0.7–1.5) et al., 1991 O’Brien Army enlisted Vietnam veterans (all lymphomas) 7 1.8 (nr) et al., 1991 Thomas US Vietnam veterans—women (NHL, ICD-8 200, et al., 1991 200–203, 208) 3 1.3 (0.3–1.8) Watanabe Army Vietnam veterans vs non-Vietnam veterans et al., 1991 (ICD-8 200, 202) 140 0.8 (nr) Army Vietnam veterans vs combined Army and Marine Vietnam-era veterans (ICD-8 200, 202) 140 0.9 (nr) Marine Vietnam veterans vs non-Vietnam veterans (ICD-8 200, 202) 42 1.8 (1.3–2.4) Marine Vietnam veterans vs combined Army and Marine Vietnam-era veterans (ICDA-8 200, 202) 42 1.2 (nr) CDC, 1990b US Vietnam veterans born 1921–1953—incidence 99 1.5 (1.1–2.0) Army Vietnam veterans 45 1.2 (0.8–1.8) Marine Vietnam veterans 10 1.8 (0.8–4.3) Air Force Vietnam veterans 12 1.0 (0.5–2.2) Navy Vietnam veterans 32 1.9 (1.1–3.2) Blue Water Navy Vietnam veterans 28 2.2 (1.2–3.9) Michalek Air Force Ranch Hand veterans—mortality et al., 1990 Lymphatic and hematopoietic tissue 0 nr Wolfe et al., Air Force Ranch Hand veterans—incidence 1 nr 1990 Breslin Army Vietnam veterans (ICDA-8 200, 202) 108 0.8 (0.6–1.0) et al., 1988 Marine Vietnam veterans (ICDA-8 200, 202) 35 2.1 (1.2–3.8) Garland Navy enlisted personnel (white males, et al., 1988 1974–1983)—incidence 68 0.7 (0.5–0.9) Burt et al., Army combat Vietnam veterans 39 1.1 (0.7–1.5) 1987 Marine combat Vietnam veterans 17 3.2 (1.4–7.4) Army Vietnam veterans (service 1967–1969) 64 0.9 (0.7–1.3) Marine Vietnam veterans (service 1967–1969) 17 2.5 (1.1–5.8) Fett et al., Australian Vietnam veterans (ICD-8 200, 202) 4 1.8 (0.4–8.0) 1987 Anderson Wisconsin Vietnam veterans (includes et al., 1986 lymphosarcoma, reticulosarcoma) 4 nr Holmes West Virginia Vietnam veterans vs West Virginia et al., 1986 Vietnam-era veterans 2 1.1 (nr) Lawrence New York Vietnam veterans vs New York Vietnam- et al., 1985 era veterans (all lymphomas) 10 1.0 (0.4–2.2) continued

372 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b OCCUPATIONAL New Studies Hansen Danish gardeners (lymphohematopoietic, ICD-7 et al., 2007 200–205)—incidence 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 15 1.4 (0.8–2.4) NHL (ICD-7 200, 202, 205) 6 1.7 (0.6–3.8) HD (ICD-7 201) 0 nr Multiple myeloma (ICD-7 203) 0 nr CLL (ICD-7 204.0) 6 2.8 (1.0–6.0) Other leukemias (ICD-7 204.1–204.4) 3 1.4 (0.3–4.2) 25-year follow-up (1975–2001) Born before 1915 (high exposure) 16 1.4 (0.9–2.3) Born 1915–1934 (medium exposure) 25 1.2 (0.8–1.8) Born after 1934 (low exposure) 1 0.2 (0.0–1.0) Richardson German case–control study, occupational factors et al., 2008 associated with NHL Chlorophenols NHL—high-grade malignancy 61 2.0 (1.3–2.9) NHL—low-grade malignancy 77 1.3 (1.0–1.8) CLL 44 0.9 (0.6–1.3) Herbicides NHL—high-grade malignancy 56 2.2 (1.4–3.3) NHL—low-grade malignancy 79 1.4 (1.0–1.9) CLL 43 1.2 (0.8–1.7) Samanic Pesticide applicators in AHS—NHL incidence from et al., 2006 enrollment through 2002 Dicamba—lifetime days exposure None 39 1.0 1– < 20 18 1.8 (1.0–3.2) 20– < 56 14 1.3 (0.7–2.5) 56– < 116 7 0.9 (0.4–2.2) ≥ 116 7 1.2 (0.5–2.9) p-trend = 0.92 Studies Reviewed in Update 2006 Chiu et al., Nebraska residents (men and women), NHL 2006 (based reclassified according to specific chromosomal on Zahm translocation (t(14;18)(q32;q21))—incidence et al., 1990, Translocation present in cases 1993) Herbicides 25 2.9 (1.1–7.9) Translocation absent in cases Herbicides 22 0.7 (0.3–1.2)

CANCER 373 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b McLean IARC cohort of pulp and paper workers—men, et al., 2006 women (ICD-9 200, 202)  Exposure to nonvolatile organochlorine compounds Never 35 0.9 (0.7–1.3) Ever 25 0.9 (0.6–1.3) ’t Mannetje Phenoxy herbicide producers (men and women) 1 0.9 (0.0–4.9) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 1 0.7 (0.0–3.8) Alavanja US AHS—incidence et al., 2005 Private applicators (men and women) 114 1.0 (0.8–1.2) Spouses of private applicators (> 99% women) 42 0.9 (0.6–1.2) Commercial applicators (men and women) 6 1.0 (0.4–2.1) Blair et al., US AHS 2005a Private applicators (men and women) 33 0.9 (0.6–1.2) Spouses of private applicators (> 99% women) 16 1.2 (0.7–2.0) Fritschi Population-based case–control study in New South et al., 2005 Wales, Australia, 2000–2001 Phenoxy herbicides Nonsubstantial exposure 10 0.7 (0.3–1.7) Substantial exposure 5 1.8 (0.4–7.4) Mills et al., Nested case–control analyses of Hispanic workers in 2005 cohort of 139,000 California United Farm Workers Ever used 2,4-D nr 3.8 (1.9–7.8) Chiu et al., Herbicide use—incidence 2004 Farmers (no herbicide use) 294 1.2 (1.0–1.5) Farmers (herbicide use) 273 1.0 (0.8–1.2) Lee et al., Asthmatics—incidence 2004b Herbicide exposure—phenoxyacetic acid 17 1.3 (0.7–2.4) Exposures among farmers 2,4-D 17 1.3 (0.7–2.5) 2,4,5-T 7 2.2 (0.8–6.1) Nonasthmatics—incidence Herbicide exposure—phenoxyacetic acid 176 1.0 (0.8–1.3) Exposures among farmers 2,4-D 172 1.0 (0.8–1.3) 2,4,5-T 36 1.1 (0.7–1.8) Hardell Pooled analysis of Swedish case–control studies of et al., 2002 NHL, hairy-cell leukemia Herbicide exposure 77 1.8 (1.3–2.4) Phenoxyacetic acids 64 1.7 (1.2–2.3) MCPA 21 2.6 (1.4–4.9) 2,4-D, 2,4,5-T 48 1.5 (1.0–2.2) Other 15 2.9 (1.3–6.4) Torchio Italian licensed pesticide users (ICD-8 202.0–202.9) 15 0.9 (0.5–1.5) et al., 1994 continued

374 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Reif et al., New Zealand forestry workers—nested case–control 7 1.8 (0.9–4.0) 1989 (ICD-9 200, 202)—incidence Studies Reviewed in Update 2004 Miligi et al., Residents of 11 areas in Italy (NHL other than 2003 lymphosarcoma and reticulosarcoma)—incidence Phenoxy acid herbicides exposure Men 18 1.0 (0.5–2.0) Women 11 1.3 (0.5–3.7) 2,4-D exposure Men 6 0.7 (0.3–1.9) Women 7 1.5 (0.4–5.7) Bodner Dow chemical production workers (included in et al., 2003 IARC cohort, NIOSH Dioxin Registry) nr 1.4 (0.6–2.7) Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 3 1.0 (0.2–2.9) Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides—incidence 2 2.3 (0.3–8.5) Studies Reviewed in Update 2000 Steenland US chemical production workers (included in IARC et al., 1999 cohort, NIOSH Dioxin Registry) 12 1.1 (0.6–1.9) Hooiveld Dutch phenoxy herbicide workers (included in et al., 1998 IARC cohort) 3 3.8 (0.8–11.0) Studies Reviewed in Update 1998 Gambini Italian rice growers 4 1.3 (0.3–3.3) et al., 1997 Keller-Byrne Farmers in central United States nr 1.3 (1.2–1.6) et al., 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 34 1.3 (0.9–1.8) Exposed to highly chlorinated PCDDs 24 1.4 (0.9–2.1) Not exposed to highly chlorinated PCDDs 9 1.0 (0.5–1.9) Becher German production workers (included in IARC et al., 1996 cohort) 6 3.3 (1.2–7.1) Nanni et al., Italian farming and animal-breeding workers (men 1996 and women) (NHL other than lymphosarcoma and reticulosarcoma)—incidence Exposure to herbicides 3 1.4 (0.4–5.7) Ramlow Dow pentachlorophenol production workers et al., 1996 (included in IARC cohort, NIOSH Dioxin Registry) All lymphopoietic cancer (ICDA-8 200–209) 0-year latency 7 1.4 (0.6–2.9) 15-year latency 5 1.3 (0.4–3.1)  Other, unspecified lymphopoietic cancer (ICDA-8 200, 202–203, 209) 0-year latency 5 2.0 (0.7–4.7) 15-year latency 4 2.0 (0.5–5.1)

CANCER 375 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Amadori Italian farming, animal-breeding workers (men and et al., 1995 women)—incidence NHL, CLL combined 164 1.8 (1.2–2.6) Studies Reviewed in Update 1996 Kogevinas IARC cohort (men and women)—incidence et al., 1995 Exposed to 2,4,5-T 10 1.9 (0.7–4.8) Exposed to TCDD 11 1.9 (0.7–5.1) Asp et al., Finnish herbicide applicators—incidence 1994 No latency 1 0.4 (0.0–2.0) 10-year latency 1 0.4 (0.0–2.4) Dean, 1994 Irish farmers and farm workers  Other malignant neoplasms of lymphoid and histiocytic tissue (including some types of NHL) (ICD–9 202) Men 244 nr Women 84 nr Hardell Umea (Sweden) Hospital patients—incidence et al., 1994 Exposure to phenoxy herbicides 25 5.5 (2.7–11.0) Exposure to chlorophenols 35 4.8 (2.7–8.8) Morrison Farm operators in three Canadian provinces et al., 1994 All farm operators nr 0.8 (0.7–0.9) Highest quartile of herbicides sprayed 19 2.1 (1.1–3.9)  Highest quartile of herbicides sprayed relative to no spraying 6 3.0 (1.1–8.1) Blair et al., US farmers in 23 states (white men) 843 1.2 (1.1–1.3) 1993 Bloemen Dow 2,4-D production workers (included in IARC et al., 1993 cohort, NIOSH Dioxin Registry) 2 2.0 (0.2–7.1) Bueno de Dutch phenoxy herbicide workers (included in Mesquita IARC cohort) 2 3.0 (0.4–10.8) et al., 1993 Lynge, 1993 Danish male and female production workers (included in IARC cohort)—updated incidence Exposure to phenoxy herbicides (men) 10 1.7 (0.5–4.5) Persson Swedish NHL patients et al., 1993 Exposure to phenoxy herbicides 10 2.3 (0.7–7.2) Occupation as lumberjack 9 6.0 (1.1–31.0) Zahm et al., Females on eastern Nebraska farms 119 1.0 (0.7–1.4) 1993 Kogevinas IARC cohort (men and women) et al., 1992  Workers exposed to any phenoxy herbicide or chlorophenol 11 1.0 (0.5–1.7) Studies Reviewed in VAO Ronco et al., Danish farm workers—incidence 147 1.0 (nr) 1992 Italian farm workers—mortality 14 1.3 (nr) continued

376 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Smith and Australian residents Christophers, Exposure > 1 day 15 1.5 (0.6–3.7) 1992 Exposure > 30 days 7 2.7 (0.7–9.6) Swaen et al., Dutch herbicide applicators 0 nr 1992 Vineis et al., Residents of selected Italian provinces 1991 Male residents of contaminated areas nr 2.2 (1.4–3.5) Wigle et al., Canadian farmers 1990 All farmers 103 0.9 (0.8–1.1) Spraying herbicides on 250+ acres 10 2.2 (1.0–4.6) Zahm et al., Eastern Nebraska residents—incidence 1990 Ever done farm work 147 0.9 (0.6–1.4) Ever mixed or applied 2,4-D 43 1.5 (0.9–2.5) Alavanja USDA forest, soil conservationists 22 2.4 (1.5–3.6) et al., 1989 Corrao et al., Italian farmers licensed to apply pesticides 1989 Lymphatic tissue (ICD-8 200–202.9) Licensed pesticide users and nonusers 45 1.4 (1.0–1.9) Farmers in arable land areas 31 1.8 (1.2–2.5) LaVecchia Residents of Milan, Italy, area (men and et al., 1989 women)—incidence Agricultural occupations nr 2.1 (1.3–3.4) Persson Örebro (Sweden) Hospital (men and et al., 1989 women)—incidence Exposed to phenoxy acids 6 4.9 (1.0–27.0) Wiklund Swedish pesticide applicators (men and et al., 1989b women)—incidence 27 1.1 (0.7–1.6) Alavanja USDA agricultural extension agents nr 1.2 (0.7–2.3) et al., 1988 Dubrow Hancock County, Ohio, residents—farmers 15 1.6 (0.8–3.4) et al., 1988 Olsson and Lund (Sweden) Hospital patients—incidence Brandt, 1988 Exposed to herbicides nr 1.3 (0.8–2.1) Exposed to chlorophenols nr 1.2 (0.7–2.0) Wiklund Swedish agricultural, forestry workers (men and et al., 1988 women) Workers in land, animal husbandry 1.0 (0.9–1.1) Timber cutters 0.9 (0.7–1.1) Pearce et al., New Zealand residents—incidence 1987 Farming occupations 33 1.0 (0.7–1.5) Fencing work 68 1.4 (1.0–2.0) Woods et al., Washington state residents—incidence 1987 Phenoxy herbicide use nr 1.1 (0.8–1.4) Chlorophenol use nr 1.0 (0.8–1.2) Farming occupations nr 1.3 (1.0–1.7) Forestry herbicide appliers nr 4.8 (1.2–19.4)

CANCER 377 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Hoar et al., Kansas residents—incidence 1986 Farmers compared with nonfarmers 133 1.4 (0.9–2.1) Farmers using herbicides at least 21 days/year 7 6.0 (1.9–19.5) Pearce et al., New Zealand residents (ICD-9 202 only)—incidence 1986 Agricultural sprayers (phenoxy herbicides) 19 1.5 (0.7–3.3) Pearce et al., New Zealand residents with agricultural 1985 occupations, 20–64 years old—incidence 224 1.4 (0.9–2.0) Burmeister Iowa residents—farming exposures 1,101 1.3 (nr) et al., 1983 Riihimaki Finnish herbicide applicators 0 nr et al., 1982 Wiklund, Swedish male and female agricultural 99% CI 1983 workers—incidence 476 1.1 (0.9–1.2) Cantor, 1982 Wisconsin residents—farmers (ICD-8 200.0, 200.1, 202.2) 175 1.2 (1.0–1.5) Hardell Umea (Sweden) Hospital patients (lymphoma and et al., 1981 HD)—incidence Exposed to phenoxy acids 41 4.8 (2.9–8.1) Exposed to chlorophenols 50 4.3 (2.7–6.9) ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, women et al., 2008 Zone A 3 3.4 (1.1–10.5) Zone B 7 1.2 (0.6–2.6) Zone R 40 1.0 (0.7–1.4) Eriksson NHL case–control study of exposure to pesticides in et al., 2008 Sweden (men and women)—incidence Herbicides, total 74 1.7 (1.2–2.5) ≤ 20 days 36 1.6 (1.0–2.7) > 20 days 38 1.9 (1.1–3.2) Phenoxyacetic acids 47 2.0 (1.2–3.4) ≤ 45 days 32 2.8 (1.5–5.5) > 45 days 15 1.3 (0.6–2.7) MCPA 21 2.8 (1.3–6.2) ≤ 32 days 15 3.8 (1.4–10.5) > 32 days 6 1.7 (0.5–6.0) 2,4,5-T, 2,4-D 33 1.6 (0.9–3.0) ≤ 29 days 21 2.1 (1.0–4.4) > 29 days 12 1.3 (0.6–3.1) continued

378 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Miligi et al., Italian case–control study of hematolymphopoietic 2006 malignancies NHL or CLL—ever exposed to herbicides Men and women 73 1.0 (0.7–1.4) Men 49 0.8 (0.5–1.3) Women 24 1.3 (0.7–2.5) NHL (men and women) Phenoxy herbicides—ever 32 1.1 (0.6–1.8)  Probability of use more than “low,” lack of protective equipment 13 2.4 (0.9–7.6) 2,4-D—ever 17 0.9 (0.5–1.8)  Probability of use more than “low,” lack of protective equipment 9 4.4 (1.1–29.1) MCPA—ever 18 0.9 (0.4–1.8)  Probability of use more than “low,” lack of protective equipment 7 3.4 (0.8–23.2) Read et al., Residents of New Plymouth Territorial Authority, 2007 New Zealand near plant manufacturing 2,4,5-T (1962–1987) Incidence 223 1.0 (0.9–1.1)d 1970–1974 33 1.8 (1.2–2.5) 1975–1979 29 1.3 (0.9–1.9) 1980–1984 22 0.8 (0.5–1.3) 1985–1989 24 0.7 (0.5–1.1) 1990–1994 35 0.8 (0.6–1.1) 1995–1999 61 1.1 (0.8–1.4) 2000–2001 19 0.8 (0.5–1.3) Mortality 138 1.1 (0.9–1.3)d 1970–1974 19 1.6 (0.9–2.4) 1975–1979 24 1.6 (1.0–2.4) 1980–1984 14 1.0 (0.5–1.6) 1985–1989 25 1.3 (0.9–2.0) 1990–1994 23 0.9 (0.6–1.4) 1995–1999 21 0.7 (0.4–1.1) 2000–2001 12 1.0 (0.5–1.8) Spinelli Case–control study in British Columbia, Canada et al., 2007 Total dioxin-like PCBs Lowest quartile 82 1.0 Second quartile 96 1.4 (0.9–2.2) Third quartile 82 1.6 (1.0–2.5) Highest quartile 143 2.4 (1.5–3.7) p-trend < 0.001

CANCER 379 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Xu et al., Case–control study of nasal NK/T-cell lymphomas 2007 in East Asia (men and women)—incidence Pesticide use 23 4.0 (2.0–8.1) Herbicide 13 3.2 (1.4–7.4) Insecticide 20 3.5 (1.7–7.1) Fungicide 10 6.1 (2.0–18.5) Studies Reviewed in Update 2006 Hartge et al., NCI SEER case–control study (Iowa, Los Angeles 2005 County, Detroit, Seattle) 1998–2000 Exposures to 2,4-D in carpet dust (ng/g) Under detection limit 147 1.0 < 500 257 1.1 (0.8–1.6) 500–999 86 0.9 (0.6–1.5) 1,000–9,999 165 0.7 (0.5–1.0) > 10,000 24 0.8 (0.4–1.7) Kato et al., Population-based case–control study in upstate New 2004 York, women, 20–79 years old, 1995–1998 Home use only of herbicides, pesticides (times) 0 231 1.0 1–4 33 0.9 (0.5–1.5) 5–17 30 0.7 (0.4–1.3) 18–39 27 1.0 (0.6–1.7) ≥ 40 40 0.9 (0.5–1.5) Studies Reviewed in Update 2004 Floret et al., Residents near French municipal solid-waste 2003 incinerator—incidence High exposure category 31 2.3 (1.4–3.8) Studies Reviewed in Update 2002 Hardell Case–control study of NHL—TEQ > 27.8, EA > 80 8 2.8 (0.5–18.0) et al., 2001 McDuffie Case–control study of NHL in Canada et al., 2001 Exposed to phenoxy herbicides 131 1.4 (1.1–1.8) 2,4-D 111 1.3 (1.0–1.7) Mecoprop 53 2.3 (1.6–3.4) Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zone A, B— enm 3 1.2 (0.4–3.9) women 4 1.8 (0.7–4.9) Viel et al., Residents near French solid-waste 2000 incinerator—incidence Spatial cluster 286 1.3 (p = 0.00003) 1991–1994 109 1.8 (p = 0.00003) continued

380 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-43  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1998 Bertazzi Seveso residents—15-year follow-up et al., 1997 Zone B—men 2 1.5 (0.2–5.3) Zone R— en m 10 1.1 (0.5–2.0) women 8 0.9 (0.4–1.7) Studies Reviewed in Update 1996 Bertazzi Seveso residents—10-year follow-up—incidence et al., 1993 Zone B— en m 3 2.3 (0.7–7.4) women 1 0.9 (0.1–6.4) Zone R— en m 12 1.3 (0.7–2.5) women 10 1.2 (0.6–2.3) Studies Reviewed in VAO Lampi et al., Finnish community exposed to chlorophenol 1992 contamination (men and women)—incidence 16 2.8 (1.4–5.6) Pesatori Seveso residents—incidence et al., 1992 Zones A, B— en m 3 1.9 (0.6–6.1) women 1 0.8 (0.1–5.5) Zone R— en m 13 1.4 (0.7–2.5) women 10 1.1 (0.6–2.2) Bertazzi Seveso residents—10-year follow-up et al., 1989b Zone B—women (ICD-9 200–208) 2 1.0 (0.3–4.2) Zone R— en (ICD-9 202) m 3 1.0 (0.3–3.4) women (ICD-9 202) 4 1.6 (0.5–4.7) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; CI, confidence interval; CLL, chronic lymphocytic leukemia; EA, Epstein-Barr virus early antigen; HD, Hodgkin’s disease; IARC, International Agency for Re- search on Cancer; ICD, International Classification of Diseases; ICDA, International Classification of Diseases, Adapted for Use in the United States; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NCI, National Cancer Institute; NHL, non-Hodgkin’s lymphoma; NIOSH, National Institute for Oc- cupational Safety and Health; nr, not reported; PCB, polychlorinated biphenyl; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEER, Surveillance, Epidemiology, and End Results; SIR, standard incidence ratio; TEQ, toxicity equivalent quotient; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cLymphopoietic cancers comprise all of forms of lymphoma (including Hodgkin’s disease and non- Hodgkin’s lymphoma) and leukemia (ALL, AML, CLL, CML). dCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods. Studies in italics have been superseded by newer studies of same cohorts.

CANCER 381 Occupational Studies  Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union (the study was first reported in VAO as Hansen et al., 1992). Subjects were then followed up by using population and cancer registries, and the incidence of cancer from 1975 until the end of 2001 was ascertained. Birth date served as a surrogate for po- tential exposure to pesticides and herbicides; earlier cohorts represented higher potential exposures. An association in those born before 1915 (presumptive high exposure) was found for cancers of the lymphatic and hematopoietic tissue (ICD 200–205) (RR = 1.40, 95% CI 0.86–2.28). Richardson et al. (2008) conducted a population-based case–control study of incident NHL and CLL in men and women 15–75 years old who lived in six Ger- man counties during 1986–1998. Control subjects were selected randomly from German population registries and were matched individually to cases by sex, age, and region; two controls per case were recruited. The job–exposure matrix developed by Pannett and co-workers in the middle 1990s was used to assign exposures to chemicals that subjects were presumably exposed to occupationally. NHL was classified as “high” or “low” grade by using the Kiel classification. On the basis of an analysis whereby cumulative exposure (the sum across jobs of the product of the number of hours exposed, intensity, and probability of exposure) was categorized in three levels, there was some evidence that risk increased with increasing cumulative exposure. This metric of cumulative exposure is difficult to interpret because it combines duration of exposure (continuous) with rank- ordered scales of intensity and probability; for example, an intensity coded as 2 and a probability coded as 1 yield the same product as an intensity coded as 1 and a probability coded as 2. Moreover, simple categorization of exposure can obscure trends in the data that can be seen with other techniques that make use of the continuous nature of the data (such as natural cubic spline functions). In a report on the AHS, Samanic et al. (2006) conducted an analysis of the incidence of NHL and exposure to dicamba in male pesticide applicators. With a metric defined as a lifetime exposure days, the rate ratios comparing subjects ex- posed to dicamba with those not exposed, a 75% excess risk was observed in the lowest quintile (less than 20 exposure days) (RR = 1.75, 95% CI 0.96–3.21), but the rate ratios declined with higher exposures (p for linear trend = 0.92). Similar results were obtained by using a metric defined as “intensity-weighted lifetime exposure days” (data not shown; p for linear trend = 0.68). Environmental Studies  Consonni et al. (2008) reported on a 25-year follow- up through 2001 conducted on the population in the area of the accident that occurred in Seveso in 1976. The number of deaths from NHL in Zones A (very high TCDD contamination) and B (high TCDD contamination) had increased to 10 from the seven reported in the 20-year follow-up (Bertazzi et al., 2001), and the excess mortality from NHL in men and women combined in the zone closest

382 VETERANS AND AGENT ORANGE: UPDATE 2008 to the accident (SMR = 3.4, 95% CI 1.1–10.5) was now statistically significant but was based on only three deaths. Eriksson et al. (2008) conducted a population-based case–control study of histologically confirmed NHL in men and women 18–74 years old who lived in Sweden during 1999–2002. Controls were selected randomly from the Swedish population registry and were frequency-matched to cases by age and sex. Infor- mation was obtained from subjects with self-administered questionnaires and was followed up with interviews if information was lacking; thus, exposure to her- bicides was based on self-reports. Positive associations were found between all herbicides combined, phenoxyacetic acid, and 2-methyl-4-chlorophenoxyacetic acid (MCPA) and NHL, but there was no discernable gradient by duration of exposure. Miligi et al. (2006) reported further results of a population-based case–control study carried out in 11 areas of Italy that was included in Update 2004 (Miligi et al., 2003). Newly diagnosed cases of hematolymphopoietic malignancies that occurred (NHL, CLL, leukemia, HD, and multiple myeloma) were identified during 1991–1993. The control group comprised a random sample of the popu- lation of each area. The reported results combined NHL and CLL and showed an association with exposure (medium or high probability of use) to phenoxy herbicides (OR = 2.4, 95% CI 0.9–7.6), 2,4-D (OR = 4.4, 95% CI 1.1–29.1), and MCPA (OR = 3.4, 95% CI 0.8–23.2). Those associations are stronger than the ones reported in the author’s previous paper. Read et al. (2007) conducted a follow-up of residents of the coastal com- munity of Paritutu, New Plymouth, near the Ivon Watkins–Dow Limited plant in which 2,4,5-T was manufactured. It was reported that the body burden of TCDD was comparable with that in residents of Zone B of the Seveso area. Incidence and mortality were ascertained for the period 1970–2001, and RRs were no more than 10% greater than expected. Spinelli et al. (2007) conducted a population-based case–control study of histologically confirmed NHL in men and women 20–79 years old who lived in the greater metropolitan areas of Vancouver and Victoria, British Columbia, during 2000–2004. Population controls, frequency-matched to cases by 5-year age groups and area, were identified from the client registry of the provincial healthcare system. A random subset of controls was included in the analyses. The analyses were based on serum concentrations of organochlorines and related chemicals obtained from controls at the time of interview and from cases before chemotherapy. Cases who lost weight rapidly were excluded. Strong monotonic increases in risk by serum concentrations were found individually for two of the dioxin-like polychlorinated biphenyls (PCBs)—PCB-118 (p = 0.004) and PCB-156 (p = 0.004)—and for all three measured dioxin-like congeners com- bined (p < 0.001), but not for PCB-105 alone. Xu et al. (2007) conducted a hospital-based, incident case–control study of sinonasal NK/T-cell lymphoma, a lethal granuloma infrequently observed in

CANCER 383 Western populations, in 2000–2005 in selected cities in Japan, Korea, and China. They identified 126 cases and matched 305 control subjects who had a variety of other conditions (inflammatory diseases, hearing problems, benign cystic diseases, or otolaryngologic problems) by hospital. Subjects completed a self- administered questionnaire on a variety of possible risk factors. Little information was provided on the type of questions asked or on their validity or reliability. Increases in risks were found in association with ever using pesticides (OR = 4.0, 95% CI 2.0–8.1) and more specifically for any use of herbicides (OR = 3.2, 95% CI 1.4–7.4), but the risks associated with insecticide use (OR = 3.5, 95% CI 1.7–7.1) or fungicide use (OR = 6.1, 95% CI 2.0–18.5) were at least as high. Biologic Plausibility The diagnosis of NHL encompasses a wide variety of lymphoma subtypes. In humans, about 85% are of B-cell origin and 15% of T-cell origin. In commonly used laboratory mice, the lifetime incidence of spontaneous B-cell lymphomas is about 30% in females and about 10% in males. Although researchers seldom note the subtypes of B lymphomas observed, lymphoblastic, lymphocytic, fol- licular, and plasma-cell lymphomas are seen in mice and are similar to types of NHL seen in humans. Laboratory rats are less prone to develop lymphomas, but Fisher 344 rats have an increased incidence of spontaneous mononuclear cell leukemia of nonspecific origin. The lifetime incidence of leukemia is about 50% in male rats and about 20% in female rats. Neither mice nor rats develop T-cell lymphomas spontaneously at a predictable incidence, but T-cell–derived tumors can be induced by exposure to some carcinogens. Several long-term feeding studies of various strains of mice and rats have been conducted over the last 30 years to determine the effects of TCDD on cancer incidence. Few of them have shown effects of TCDD on lymphoma or leukemia incidence. The NTP (1982a) reported no increase in overall incidence of lym- phoma in female B6C3F1 mice exposed to TCDD at 0.04, 0.2, or 2.0 µg/kg per week for 104 weeks but found that histiocytic lymphomas (now considered to be equivalent to large B-cell lymphomas) were more common in the high-dose group. No effects on lymphoma incidence were seen in Osborne–Mendel rats treated with TCDD at 0.01, 0.05, or 0.5 µg/kg per week. Sprague–Dawley rats treated with TCDD at 0.003, 0.010, 0.022, 0.046, or 0.100 µg/kg per day showed no change in the development of malignant lymphomas. Long-term exposure to phenoxy herbicides or cacodylic acid also has not resulted in an increased incidence of lymphomas in laboratory animals. Thus, there are few laboratory animal data to support the biologic plausibility of promotion of NHL by TCDD or other chemicals of interest. In contrast, recent studies indicate that activation of the AHR by TCDD inhibits apoptosis, a mechanism of cell death that controls the growth of cancer cells. Vogel et al. (2007) studied human cancer cells in tissue culture and showed

384 VETERANS AND AGENT ORANGE: UPDATE 2008 that addition of TCDD inhibited apoptosis in histiocytic-lymphoma cells, Burkitt- lymphoma cells, and NHL cell lines. The reduced apoptosis was associated with an increase in the expression of Cox-2, C/EBP β, and Bcl-xL mRNA in the cells. Those expressed genes code for proteins that protect cells from apoptosis. The effects of TCDD on apoptosis were blocked when an AHR antagonist or a Cox-2 inhibitor was added to the culture, this demonstrated the underlying AHR- dependent mechanism of the effects. More important, when C57Bl/10J mice were given multiple doses of TCDD over a period of 140 days, premalignant lymphoproliferation of B cells was induced in the TCDD-treated mice before the appearance of any spontaneous lymphomas in the control mice. When the B cells were examined, they were found to manifest changes in gene expression similar to those induced by TCDD in the human cell lines, providing support for this mechanism of lymphoma promotion by TCDD. Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high levels of the IL–6 cytokine, which has tumor promotional effects in numerous tissues (Hollingshead et al., 2008). IL–6 plays a role in B-cell maturation and induces a transcriptional inflam- matory response. It is known to be elevated in B-cell neoplasms, including mul- tiple myeloma and various lymphomas, especially diffuse large B-cell lymphoma (Hussein et al., 2002; Kato et al., 1998; Kovacs, 2006). An alternative link that could help to explain the association between TCDD and NHL has been explored in human studies. Chromosomal rearrangements, with consequent expression dysregulation of various genes, are very prevelant in B-cell lymphomas, and the t(14;18) reciprocal translocation, which juxtaposes the BCL2 with the locus of the immunoglobin heavy chain, found in the tumor cells in most cases of follicular lymphoma. Roulland et al. (2004) investigated the prevalence of the t(14;18) transloca- tion characteristic of most cases of follicular lymphoma among a subset of 53 never-smoking and pesticide-using men from a cohort of French farmers whose pesticides exposures and confounding information had been previously well characterized; for 21 blood samples had been gathered during periods of high pes- ticide use, while for the other 32 the samples were drawn during a period of low pesticide use. They found a higher prevalence of cells carrying this translocation among the farmers whose blood had been drawn during a period of high pesticide use than among those with samples drawn during a low-use period. Baccarelli et al. (2006) reported an increase in t(14;18) chromosomal translo- cations in lymphocytes from humans exposed to TCDD in the Seveso explosion. In most cases of follicular lymphoma, the tumor cells carry the t(14;18) chromo- somal translocation, and there is evidence to suggest that an increased frequency of lymphocytes from the peripheral blood carrying this tumor marker may be a necessary but not sufficient step toward development of follicular lymphoma (Roulland et al., 2006).

CANCER 385 Synthesis Previous VAO committees found the evidence to be sufficient to support an association between exposure to at least one of the chemicals of interest and NHL. The evidence was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. New data generally strengthen the conclusion that there is an association with the chemicals of interest. Xu et al. (2007) reported an excess risk of nasal NK/T-cell lymphomas after uncharacterized herbicide exposure, and Miligi et al. (2006) found an increased risk in Italy after frequent and unprotected use of phenoxy herbicides. Much of the earlier epidemiologic evidence suggests that 2,4-D or 2,4,5-T, rather than TCDD, might be responsible for the associations observed in occupational cohorts, but the strongest new data available to the present commit- tee are related to TCDD exposure: a continuing increase in lymphoma mortality in the most highly exposed zone in Seveso (Consonni et al., 2008), increased risks with higher serum concentrations of dioxin-like congeners in British Columbia (Spinelli et al., 2007), and excess risks after occupational chlorophenol exposure in a German case–control study (Richardson et al., 2008). Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest and NHL. Multiple Myeloma Multiple myeloma (ICD-9 203.0) is characterized by proliferation of bone marrow stem cells that results in an excess of neoplastic plasma cells and in the production of excess abnormal proteins, usually fragments of immunoglobulins. Multiple myeloma is sometimes grouped with other immunoproliferative neo- plasms (ICD-9 203.8). ACS estimated that 11,190 men and 8,730 women would receive diagnoses of multiple myeloma in the United States in 2008 and that 5,640 men and 5,050 women would die from it (Jemal et al., 2008a). The average annual incidence of multiple myeloma is shown in Table 6-44. The incidence of multiple myeloma is highly age-dependent, with a rela- tively low rate in people under 40 years old. The incidence is slightly higher in men than in women, and the difference becomes more pronounced with age. An increased incidence of multiple myeloma has been observed in several occupational groups, including farmers and other agricultural workers and those with workplace exposure to rubber, leather, paint, and petroleum (Riedel et al., 1991). People with high exposure to ionizing radiation and those who suffer

386 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-44  Average Annual Incidence (per 100,000) of Multiple Myeloma in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black Men 7.2 6.2 17.2 11.9 11.0 23.6 18.9 18.2 33.3 Women 5.2 4.3 13.3 8.0 7.3 13.9 12.3 10.1 30.9 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. from other plasma-cell diseases, such as monoclonal gammopathy of unknown significance or solitary plasmacytoma, are also at greater risk. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the chemicals of in- terest and multiple myeloma. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 6-45 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam- v ­ eteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era- veteran cohort, n = 5,325). All causes mortality and cause-specific mortality in the Vietnam-veteran and era-veteran cohorts, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Although no separate analysis examined multiple myeloma mortality specifically, 18 deaths attributed to lymphopoietic cancer were observed in the Vietnam veterans (crude rate, 1.22/10,000) and 29 deaths in the era veterans, for an adjusted RR of 0.68 (95% CI 0.37–1.25). No excess risk was observed in the nurses-only analysis (RR = 0.65, 95% CI 0.32–1.30). Occupational Studies  Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union and reported their findings in terms of lymphohematopoietic cancers (ICD-7 200–2005), which include multiple myeloma. In the 10-year follow-up (Hansen et al., 1992), the 15 cases of lymphohematopoietic cancers observed included no cases of multiple

CANCER 387 myeloma. The 25-year follow-up did not specify a breakdown of the lymphohe- matopoietic cancers, so it is not certain whether the additional 27 cases observed in the last 15 years included any cases of multiple myeloma. The statistics for NHL in Table 6-43 are not repeated in Table 6-45, because if any cases of mul- tiple myeloma did occur, it is not known how they were distributed over the three birth periods that were used as surrogates for potential exposure to pesticides and herbicides in the more recent analysis. Environmental Studies  Consonni et al. (2008) conducted a follow-up of the population of the accident that occurred in Seveso in 1976. The follow-up was extended to 2001, and an association in the most highly exposed zone (Zone A) was found (RR = 4.3, 95% CI 1.1–17.5), but it was based on only two deaths from multiple myeloma. Miligi et al. (2006) reported further results of a population-based case–control study carried out in 11 areas of Italy that was included in Update 2004 (Miligi et al., 2003). Newly diagnosed cases of lymphohematopoietic cancers (NHL, CLL, leukemia, HD, and multiple myeloma) were identified during 1991–1993. The control group comprised a random sample of the population of each area. A nonsignificantly increased OR was seen in men and women who had multiple myeloma and were exposed to herbicides (OR = 1.6, 95% CI 0.8–3.5). Biologic Plausibility No animal studies have reported an association between exposure to the chemicals of interest and multiple myeloma. Thus, there are no specific animal data to support the biologic plausibility of an association between exposure to the chemicals of interest and multiple myeloma. Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high levels of the IL–6 cytokine, which has tumor promotional effects in numerous tissues (Hollingshead et al., 2008). IL–6 plays a role in B-cell maturation and induces a transcriptional inflam- matory response. It is known to be elevated in B-cell neoplasms, including mul- tiple myeloma and various lymphomas (Hussein et al., 2002; Kovacs, 2006). The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis Only one study provided updated information on the risk of dying from multiple myeloma, and it was the most recent analysis of the Seveso incident (Consonni et al., 2008). The main limitation of the study is the small number of deaths, which is always an issue for such a rare cancer.

388 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-45  Selected Epidemiologic Studies—Multiple Myeloma Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans—women (lymphopoietic Kang, 2008 cancers) vs nondeployed 18 0.7 (0.4–1.3) Vietnam-veteran nurses only 14 0.7 (0.3–1.3) Studies Reviewed in Update 2006 Boehmer Vietnam Experience Cohort et al., 2004 1 0.4 (nr) ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 31 0.7 (0.4–0.9) Navy 4 0.4 (0.1–1.0) Army 21 0.7 (0.4–1.0) Air Force 6 1.1 (0.4–2.4) ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 24 0.9 (0.5–1.2) Navy 3 0.5 (0.1–1.5) Army 15 0.8 (0.4–1.3) Air Force 6 1.7 (0.6–3.6) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans—deployed vs nondeployed Incidence 8 2.1 (0.7–6.0) Mortality 5 0.9 (0.2–3.4) Studies Reviewed in Update 2004 Akhtar et al., White Air Force Vietnam veterans (lymphopoietic 2004 cancers)—incidence Ranch Hand veterans—incidence 10 0.9 (0.4–1.5) Comparison Air Force veterans—incidence 9 0.6 (0.3–1.0) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 2 0.7 (0.1–5.0) Studies Reviewed in Update 1998 CDVA, 1997a Australian military Vietnam veterans 6 0.6 (0.2–1.3) CDVA, 1997b Australian military Vietnam veterans 0 Watanabe and Army Vietnam veterans 36 0.9 (nr) Kang, 1996 Marine Vietnam veterans 4 0.6 (nr) Studies Reviewed in VAO Breslin et al., Army Vietnam veterans 18 0.8 (0.2–2.5) 1988 Marine Vietnam veterans 2 0.5 (0.0–17.1) OCCUPATIONAL Studies Reviewed in Update 2006 McLean et al., IARC cohort of pulp and paper workers 2006  Exposure to nonvolatile organochlorine compounds Never 21 0.8 (0.5–1.3) Ever 20 1.1 (0.7–1.7)

CANCER 389 TABLE 6-45  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b ’t Mannetje Phenoxy herbicide producers (men and women) 3 5.5 (1.1–16.1) et al., 2005 Phenoxy herbicide sprayers (> 99% men) 0 0.0 (0.0–5.3) Alavanja et al., US AHS—incidence 2005 Private applicators (men and women) 43 1.3 (1.0–1.8) Spouses of private applicators (> 99% women) 13 1.1 (0.6–1.9) Commercial applicators (men and women) 0 0.0 (0.0–2.7) Blair et al., US AHS 2005a Private applicators (men and women) 11 0.6 (0.3–1.2) Spouses of private applicators (> 99% women) 5 0.9 (0.3–2.1) Torchio et al., Italian licensed pesticide users 5 0.4 (0.1–1.0) 1994 Reif et al., New Zealand forestry workers—nested 1989 case–control—incidence 1 0.5 (0.1–3.7) Studies Reviewed in Update 2004 Swaen et al., Dow chemical production workers (included in 2004 IARC cohort, NIOSH Dioxin Registry) 3 2.1 (0.4–6.1) Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in IARC 2001 cohort, NIOSH Dioxin Registry) 1 0.8 (0.0–4.5) Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides—incidence 0 nr Studies Reviewed in Update 2000 Steenland US chemical production workers (included in et al., 1999 IARC cohort, NIOSH Dioxin Registry) 10 2.1 (1.0–3.8) Hooiveld Dutch phenoxy herbicide workers (included in et al., 1998 IARC cohort) 0 0.0 (nr) Studies Reviewed in Update 1998 Gambini et al., Italian rice growers 0 nr 1997 Kogevinas IARC cohort, male and female workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol 17 1.3 (0.8–2.1) Exposed to highly chlorinated PCDDs 9 1.2 (0.6–2.3) Not exposed to highly chlorinated PCDDs 8 1.6 (0.7–3.1) Becher et al., German production workers (included in IARC 1996 cohort) Plant I 3 5.4 (1.1–15.9) Studies Reviewed in Update 1996 Asp et al., Finnish herbicide applicators 1994 Incidence 2 1.5 (0.2–5.2) Mortality 3 2.6 (0.5–7.7) Dean, 1994 Irish farmers and farm workers (men and women) Men 171 1.0 (nr) Semenciw Farmers in Canadian prairie provinces 160 0.8 (0.7–1.0) et al., 1994 Blair et al., US farmers in 23 states 413 1.2 (1.0–1.3) 1993 continued

390 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-45  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Brown et al., Iowa residents who used pesticides or herbicides 1993 111 1.2 (0.8–1.7) Lynge, 1993 Danish production workers (included in IARC cohort)—updated incidence Men 0 nr Women 2 12.5 (1.5–45.1) Zahm et al., Eastern Nebraska users of herbicides 1992 Men 8 0.6 (0.2–1.7) Women 10 2.3 (0.8–7.0) Eastern Nebraska users of insecticides Men 11 0.6 (0.2–1.4) Women 21 2.8 (1.1–7.3) Studies Reviewed in VAO Eriksson and 90% CI Karlsson, 1992 Residents of northern Sweden 20 2.2 (1.2–4.7) Swaen et al., Dutch herbicide applicators 3 8.2 (1.6–23.8) 1992 Fingerhut NIOSH cohort—entire cohort 5 1.6 (0.5–3.9) et al., 1991 ≥ 1-year exposure, ≥ 20-year latency 3 2.6 (0.5–7.7) Saracci et al., IARC cohort (men and women)—exposed 4 0.7 (0.2–1.8) 1991 subcohort Alavanja et al., USDA forest, soil conservationists 6 1.3 (0.5–2.8) 1989 Boffetta et al., ACS Prevention Study II subjects 12 2.1 (1.0–4.2) 1989 Farmers using herbicides, pesticides 8 4.3 (1.7–10.9) LaVecchia Residents (men and women) of Milan, Italy, area et al., 1989 Agricultural occupations nr 2.0 (1.1–3.5) Morris et al., Residents of four SEER program areas 2.9 (1.5–5.5) 1986 Pearce et al., New Zealand residents—agricultural sprayers 1986 Use of agricultural spray 16 1.3 (0.7–2.5) Likely sprayed 2,4,5-T 14 1.6 (0.8–3.1) Cantor and Wisconsin residents—farmers in counties with Blair, 1984 highest herbicide use nr 1.4 (0.8–2.3) Burmeister Iowa residents—farming exposures et al., 1983 Born 1890–1900 nr 2.7 (p < 0.05) Born after 1900 nr 2.4 (p < 0.05) Riihimaki Finnish herbicide applicators Expected et al., 1982 number of exposed cases 1 0.2 (nr) ENVIRONMENTAL New Studies Consonni Seveso residents—25-year follow-up—men, et al., 2008 women Zone A 2 4.3 (1.1–17.5)

CANCER 391 TABLE 6-45  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Zone B 5 1.7 (0.7–4.1) Zone R 24 1.1 (0.7–1.7) Miligi et al., Italian case–control study—herbicide exposure 2006 among men, women with diagnosis of multiple myeloma 11 1.6 (0.8–3.5) Studies Reviewed in Update 2006 Pahwa et al., Canadian men (at least 19 years old) in any of 6 2006 provinces Any phenoxy herbicide 62 1.2 (0.8–1.8) 2,4-D 59 1.3 (0.9–1.9) Mecoprop 16 1.2 (0.7–2.8) MCPA 7 0.5 (0.2–1.2) Studies Reviewed in Update 2000 Bertazzi et al., Seveso residents—20-year follow-up 2001 Zone A, B— en m 1 0.6 (0.1–4.3) women 4 3.2 (1.2–8.8) Studies Reviewed in Update 1998 Bertazzi et al., Seveso residents—15-year follow-up 1997 Zone B— enm 1 1.1 (0.0–6.2) women 4 6.6 (1.8–16.8) Zone R— enm 5 0.8 (0.3–1.9) women 5 1.0 (0.3–2.3) Studies Reviewed in Update 1996 Bertazzi et al., Seveso residents—10-year follow-up—incidence 1993 Zone B— enm 2 3.2 (0.8–13.3) women 2 5.3 (1.2–22.6) Zone R— enm 1 0.2 (0.0–1.6) women 2 0.6 (0.2–2.8) Studies Reviewed in VAO Pesatori et al., Seveso residents—incidence 1992 Zones A, B— en m 2 2.7 (0.6–11.3) women 2 4.4 (1.0–18.7) Zone R— enm 1 0.2 (0.0–1.5) women 3 0.9 (0.3–3.1) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ACS, American Cancer Society; AHS, Agricultural Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); SEER, Surveillance, Epidemiology, and End Results; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohorts.

392 VETERANS AND AGENT ORANGE: UPDATE 2008 Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an associa- tion between exposure to at least one of the chemicals of interest and multiple myeloma. AL Amyloidosis The committee responsible for Update 2006 moved the discussion of AL amyloidosis from the chapter on miscellaneous nonneoplastic health conditions to the cancer chapter to put it closer to related neoplastic conditions, such as multiple myeloma and some types of B-cell lymphoma. The conditions share sev- eral biologic features, most notably clonal hyperproliferation of B-cell-derived plasma cells and production of abnormal amounts of immunoglobulins. The primary feature of amyloidosis (ICD-9 277.3) is the accumulation and deposition in various tissues of insoluble proteins historically denoted by the generic term “amyloid.” Amyloid protein accumulates in the extracellular spaces of various tissues. The pattern of organ involvement depends on the nature of the protein; some amyloid proteins are more fibrillogenic than others. Amyloidosis is classified according to the biochemical properties of the fibril-forming protein. Excessive amyloid protein can have limited clinical consequences or can produce severe, rapidly progressive multiple–organ-system dysfunction. The annual inci- dence is estimated at 1/100,000; there are about 2,000 new cases each year in the United States. Amyloidosis occurs mainly in people 50–70 years old and occurs more often in males than in females. AL amyloidosis is the most common form of systemic amyloidosis; the A stands for amyloid, and the L indicates that the amyloid protein is derived from immunoglobin light chains. That links AL amyloidosis with other B-cell disor- ders that involve overproduction of immunoglobin, such as multiple myeloma and some types of B-cell lymphomas. AL amyloidosis results from the abnor- mal overproduction of immunoglobulin light-chain protein from a monoclonal population of plasma cells. Clinical findings can include excessive AL protein or immunoglobulin fragments in the urine or serum, renal failure with nephrotic syndrome, liver failure with hepatomegaly, heart failure with cardiomegaly, mar- croglossia, carpal tunnel syndrome, and peripheral neuropathy. Bone marrow biopsies commonly show an increased density of plasma cells, suggesting a pre- malignant state. Historically, that test emphasized routine histochemical analysis, but modern immunocytochemistry and flow cytometry now commonly identify monoclonal populations of plasma cells with molecular techniques. AL amyloi- dosis can progress rapidly and is often far advanced by the time it is diagnosed (Buxbaum, 2004).

CANCER 393 Conclusions from VAO and Previous Updates VA identified AL amyloidoisis as of concern after the publication of Update 1998. The committees responsible for Update 2000, Update 2002, and Update 2004 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and AL amyloidosis. Although there are few epidemiologic data specifically on AL amyloidosis, the committee responsible for Update 2006 changed the categoriza- tion to limited or suggestive evidence of an association on the basis of common- alities in its cellular lineage with multiple myeloma and B-cell lymphomas. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and amyloidosis of any sort have been published since Update 2006. Biologic Plausibility A 1979 study reported the dose-dependent development of a “generalized lethal amyloidosis” in Swiss mice that were treated with TCDD for 1 year (Toth et al., 1979). That finding has not been validated in 2-year carcinogenicity studies of TCDD in mice or rats. Thus, there are few animal data to support an associa- tion between TCDD exposure and AL amyloidosis in humans. And there are no animal data to support an association between the other chemicals of interest and AL amyloidosis. It is known, however, that AL amyloidosis is associated with B-cell diseases and 15–20% of cases of AL amyloidosis occur with multiple myeloma. Other diagnoses associated with AL amyloidosis include B-cell lymphomas (Cohen et al., 2004), monoclonal gammopathies, and agammaglobulinemia (Rajkumar et al., 2006). Thus, AL amyloidosis can occur with such medical conditions as multiple myeloma and B-cell lymphomas. Synthesis AL amyloidosis is very rare and it is not likely that population-based epi- demiology will ever provide substantial direct evidence regarding its causation. However, the biologic and pathophysiologic features linking AL amyloidosis, multiple myeloma, and some types of B-cell lymphomas—especially clonal hy- perproliferation of plasma cells and abnormal immunoglobulin production—indi- cate that AL amyloidosis is pathophysiologically related to those conditions.

394 VETERANS AND AGENT ORANGE: UPDATE 2008 Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to the chemicals of interest and AL amyloidosis. Leukemia There are four primary types of leukemia (ICD-9 202.4, 203.1, 204.0–204.9, 205.0–205.9, 206.0–206.9, 207.0–207.2, 207.8, 208.0–208.9): acute and chronic lymphocytic leukemia and acute and chronic myelogenous (or granulocytic) leukemia. AML (ICD-9 205) is also commonly called acute myeloid leukemia or acute nonlymphocytic leukemia. There are numerous subtypes of AML; for consistency, the present report uses acute myelogenous leukemia, regardless of designations in the source materials. ACS estimated that 25,180 men and 19,090 women would receive diagnoses of some form of leukemia in the United States in 2008 and that 12,460 men and 9,250 women would die from it (Jemal et al., 2008a). Collectively, leukemia was expected to account for 3.1% of all new diagnoses of cancer and 3.8% of deaths from cancer in 2008. The different forms of leukemia have different patterns of incidence and in some cases different risk factors. The incidences of the various forms of leukemia are presented in Table 6-46. In adults, acute leukemia is nearly always in the form of AML (ICD-9 205.0, 207.0, 207.2). ACS estimated that about 7,200 men and 6,090 women would receive new diagnoses of AML in the United States in 2008 and that 5,100 men and 3,720 women would die from it (Jemal et al., 2008a). In the age groups that include most Vietnam veterans, AML makes up roughly one-fourth of cases of leukemia in men and one-third in women. Overall, AML is slightly more com- mon in men than in women. Risk factors associated with AML include high doses of ionizing radiation, occupational exposure to benzene, and exposure to some medications used in cancer chemotherapy (such as melphalan). Fanconi anemia and Down syndrome are associated with an increased risk of AML, and tobacco use is thought to account for about 20% of AML cases. ALL is a disease of the young and of people over 70 years old. It is relatively uncommon in the age groups that include most Vietnam veterans. The lifetime incidence of ALL is slightly higher in whites than in blacks and higher in men than in women. Exposure to high doses of ionizing radiation is a known risk fac- tor for ALL, but there is little consistent evidence on other factors. CLL shares many traits with lymphomas (such as immunohistochemistry, B-cell origin, and progression to an acute, aggressive form of NHL), so the com- mittee reviews it below separately from the other leukemias. The incidence of CML increases steadily with age in people over 30 years old. Its lifetime incidence is roughly equal in whites and blacks and is slightly

CANCER 395 TABLE 6-46  Average Annual Incidence (per 100,000) of Leukemias in United Statesa 50–54 Years Old 55–59 Years Old 60–64 Years Old All All All Races White Black Races White Black Races White Black All leukemias: Men 13.2 13.6 12.1 20.7 21.7 18.0 32.7 34.0 30.2 Women 8.0 8.0 7.6 12.2 12.6 10.2 17.4 18.2 14.7 Acute lymphocytic leukemia: Men 0.9 0.9 0.8 0.9 0.8 0.8 1.2 1.3 0.7 Women 0.6 0.5 1.1 1.1 1.2 0.4 0.7 0.6 0.6 Acute myelogenous leukemia: Men 3.1 3.1 2.7 5.2 5.3 5.3 8.3 8.5 7.5 Women 2.8 2.4 2.4 4.4 4.4 3.8 5.4 5.3 6.2 Chronic lymphocytic leukemia: Men 5.2 5.7 5.3 9.4 10.1 6.1 15.7 16.8 12.4 Women 2.3 2.4 2.0 4.2 4.7 2.4 7.0 8.0 3.1 Chronic myelogenous leukemia: Men 1.9 2.0 0.9 2.3 2.3 2.7 3.6 3.6 4.3 Women 1.1 1.1 0.6 1.2 1.2 1.1 2.3 2.1 2.5 All other leukemia:b Men 0.5 0.4 0.8 0.7 0.5 2.1 1.2 1.2 1.6 Women 0.3 0.3 0.2 0.6 0.5 0.4 0.8 0.8 0.9 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2000–2005. bIncludes leukemic reticuloendotheliosis (hairy cell leukemia), plasma-cell leukemia, monocytic leukemia, and acute and chronic erythremia and erythroleukemia. higher in men than in women. CML accounts for about one-fifth of the cases of leukemia in people in the age groups that include most Vietnam veterans. It is associated with an acquired chromosomal abnormality known as the Philadelphia chromosome, for which exposure to high doses of ionizing radiation is a known risk factor. Little is known about the risk factors associated with other forms of leuke- mia. However, two human retroviruses have been linked to human leukemias: HTLV-1 causes adult T-cell leukemia or lymphoma, but early reports that HTLV-2 might play a role in the etiology of hairy cell leukemia (HCL) have not been substantiated. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and all types of leukemia. Additional infor-

396 VETERANS AND AGENT ORANGE: UPDATE 2008 mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. The committee responsible for Update 2002, however, considered CLL separately and judged that there was sufficient evidence of an association with the herbicides used in Vietnam and CLL alone. The committee responsible for Update 2006 considered AML individually but did not find evidence to sug- gest that its occurrence is associated with exposure to the chemicals of interest, so it was retained with other non-CLL leukemias in the category of inadequate and insufficient evidence. Table 6-47 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies  Cypel and Kang (2008) compiled and analyzed the data on two cohorts of female veterans who served in Vietnam (the Vietnam- veteran cohort, n = 4,586) or served elsewhere during the Vietnam War (the era-veteran cohort, n = 5,325). All-cause mortality and cause-specific mortality in the Vietnam-veteran and era-veteran cohorts, the US population, and earlier research were compared. Similar analyses were performed for nurses only. Al- though no separate analysis examined leukemia specifically, 18 deaths attributed to lymphopoietic cancer were observed in the Vietnam veterans (crude rate, 1.22/10,000) and 29 in the era-veteran cohort, for an adjusted RR of 0.68 (95% CI 0.37–1.25). No excess risk was observed in the nurses-only analysis (RR = 0.65, 95% CI 0.32–1.30). Occupational Studies  Hansen et al. (2007) conducted a historical-cohort study of 3,156 male gardeners who were members of a Danish union (the study was first reported in VAO as Hansen et al., 1992). Subjects were then followed up by using population and cancer registries, and the incidence of cancer was as- certained from 1975 until the end of 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides; earlier cohorts represented higher potential exposure. After the 25-year follow-up, no associations were found with pesticide and herbicide exposures and all lymphatic and hematopoietic tumors (ICD-7 200–205) (SIR = 1.1), but a positive association was observed for all leu- kemias (SIR = 1.4, 95% CI 0.9–2.1), especially in the presumptive high-exposure subcohort (SIR = 2.3, 95% CI 1.3–4.1). Environmental Studies  Consonni et al. (2008) conducted a follow-up of the population of the area of the accident that occurred in Seveso in 1976. The follow-up was extended until 2001, and an association was found in Zone B (high TCDD contamination) with mortality from all leukemias combined (RR = 1.7, 95% CI 1.0–3.0), myeloid leukemia (RR = 2.0, 95% CI 0.9–4.5), and unspecific leukemias (RR = 2.4, 95% CI 0.9–6.5). In addition, an association in Zone R was found for mortality from lymphatic leukemia (RR = 1.4, 95% CI 0.9–2.2).

CANCER 397 TABLE 6-47  Selected Epidemiologic Studies—Leukemia Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS New Studies Cypel and US Vietnam veterans (women)—lymphopoietic Kang, 2008 cancersc Deployed vs nondeployed 18 0.7 (0.4–1.3) Nurses only 14 0.7 (0.3–1.3) Studies Reviewed in Update 2006 ADVA, 2005a Australian Vietnam veterans vs Australian population—incidence All branches 130 1.1 (1.0–1.4) Lymphocytic leukemia 72 1.4 (1.1–1.7) Myelogenous leukemia 54 1.0 (0.8–1.3) Navy 35 1.5 (1.0–2.0) Lymphocytic leukemia 14 1.3 (0.7–2.1) Myelogenous leukemia 19 1.7 (1.0–2.6) Army 80 1.1 (0.8–1.3) Lymphocytic leukemia 50 1.4 (1.0–1.8) Myelogenous leukemia 28 0.8 (0.5–1.1) Air Force 15 1.2 (0.7–2.0) Lymphocytic leukemia 8 1.4 (0.6–2.7) Myelogenous leukemia 7 1.3 (0.5–2.6) ADVA, 2005b Australian Vietnam veterans vs Australian population—mortality All branches 84 1.0 (0.8–1.3) Lymphocytic leukemia 24 1.2 (0.7–1.7) Myelogenous leukemia 55 1.1 (0.8–1.3) Navy 17 1.3 (0.8–1.8) Lymphocytic leukemia 4 0.2 (0.0–1.2) Myelogenous leukemia 11 1.6 (0.9–2.5) Army 48 0.1 (0.7–1.2) Lymphocytic leukemia 17 1.3 (0.7–2.0) Myelogenous leukemia 30 0.8 (0.5–1.1) Air Force 14 1.6 (0.8–2.6) Lymphocytic leukemia 6 2.7 (1.0–5.8) Myelogenous leukemia 8 1.3 (0.5–2.5) ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans: deployed vs nondeployed Incidence 16 0.6 (0.3–1.1) Lymphocytic leukemia 9 0.8 (0.3–2.0) Myelogenous leukemia 7 0.5 (0.2–1.3) Mortality 11 0.6 (0.3–1.3) Lymphocytic leukemia 2 0.4 (0.0–2.4) Myelogenous leukemia 8 0.7 (0.3–1.7) Boehmer et al., Vietnam Experience Cohort 8 1.0 (0.4–2.5) 2004 continued

398 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 2004 Akhtar et al., White Air Force Ranch Hand veterans— 2004 lymphopoietic cancersc All Ranch Hand veterans Incidence 10 0.9 (0.4–1.5) Mortality 6 1.0 (0.4–2.0) Veterans with tours in 1966–1970—incidence 7 0.7 (0.3–1.4) White Air Force Comparison veterans— lymphopoietic cancersc All comparison veterans Incidence 9 0.6 (0.3–1.0) Mortality 5 0.6 (0.2–1.2) Veterans with tours in 1966–1970—incidence 4 0.3 (0.1–0.8) Studies Reviewed in Update 2000 AFHS, 2000 Air Force Ranch Hand veterans 2 0.7 (0.1–5.0) AIHW, 1999 Expected number of exposed cases Australian Vietnam veterans—incidence (95% CI) (validation study) 27 26 (16–36) CDVA, 1998a Australian Vietnam veterans (men)— self-reported incidence 64 26 (16–36) CDVA, 1998b Australian Vietnam veterans (women)— self-reported incidence 1 0 (0–4) Studies Reviewed in Update 1998 Dalager and Army Chemical Corps veterans 1.0 (0.1–3.8) Kang, 1997 CDVA, 1997a Australian military Vietnam veterans 33 1.3 (0.8–1.7) Studies Reviewed in VAO Visintainer PM study of deaths (1974–1989) of Michigan et al., 1995 Vietnam-era veterans—deployed vs nondeployed 30 1.0 (0.7–1.5) OCCUPATIONAL New Studies Hansen et al., Danish gardeners (all hematopoietic, ICD-7 2007 200–205—incidence) 10-year follow-up (1975–1984) reported in Hansen et al. (1992) 15 1.4 (0.8–2.4) NHL (ICD-7 200, 202, 205) 6 1.7 (0.6–3.8) HD (ICD-7 201) 0 nr Multiple myeloma (ICD-7 203) 0 nr CLL (ICD-7 204.0) 6 2.8 (1.0–6.0) Other leukemias (204.1–204.4) 3 1.4 (0.3–4.2)

CANCER 399 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b 25-year follow-up (1975–2001) 42 1.1 (0.8–1.4) Leukemia (ICD-7 204) 22 1.4 (0.9–2.1) Born before 1915 (high exposure) 16 1.4 (0.9–2.3) Leukemia (ICD-7 204) 12 2.3 (1.3­–4.1) Born 1915–1934 (medium exposure) 25 1.2 (0.8–1.8) Leukemia (ICD-7 204) 9 1.0 (0.5–2.0) Born after 1934 (low exposure) 1 0.2 (0.0–1.0) Leukemia (ICD-7 204) 1 0.5 (0.0–3.4) Studies Reviewed in Update 2006 McLean et al., IARC cohort of pulp and paper workers 2006  Exposure to nonvolatile organochlorine compounds Never 49 1.0 (0.7–1.3) Ever 35 0.9 (0.6–1.2) ’t Mannetje Phenoxy herbicide producers (men and women) 0 0.0 (0.0–5.3) et al., 2005 Phenoxy herbicide sprayers (> 99% men) (myelogenous leukemia) 1 1.2 (0.0–6.4) Alavanja et al., US AHS—incidence 2005 Private applicators (men and women) 70 0.9 (0.7–1.2) Spouses of private applicators (> 99% women) 17 0.7 (0.4–1.2) Commercial applicators (men and women) 4 0.9 (0.3–2.4) Blair et al., US AHS 2005a Private applicators (men and women) 27 0.8 (0.5–1.1) Spouses of private applicators (> 99% women) 14 1.4 (0.8–2.4) Mills et al., Cohort study of 139,000 United Farm Workers, 2005 with nested case–control analyses restricted to Hispanic workers in California Ever used 2,4-D Total leukemia nr 1.0 (0.4–2.6) Lymphocytic leukemia nr 1.5 (0.3–6.6) Granulocytic (myelogenous) leukemia nr 1.3 (0.3–5.4) Hertzman et al., British Columbia sawmill workers with 1997 chlorophenate process (more hexa-, hepta-, octa-chlorinated dibenzodioxins than TCDD), all leukemias—incidence 47 1.2 (0.9–1.5) ALL 2 1.0 (0.2–3.1) CLL 24 1.7 (1.2–2.4) AML 5 0.8 (0.3–1.7) CML 7 1.1 (0.5–2.0) Other, unspecified 5 0.5 (0.2–1.0) Torchio et al., Italian licensed pesticide users 27 0.8 (0.5–1.1) 1994 continued

400 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Reif et al., 1989 Case–control study of all men with occupation indicated entered into New Zealand Cancer Registry 1980–1984 (all leukemias) Forestry workers 4 1.0 (0.4–2.6) AML 3 2.2 (nr) Studies Reviewed in Update 2004 Miligi et al., Case–control study of residents of 11 areas in 2003 Italy—incidence of leukemia excluding CLL Exposure to phenoxy herbicides 2.1 (0.7–6.2) Swaen et al., Dutch licensed herbicide applicators—mortality 3 1.3 (0.3–3.7) 2004 Studies Reviewed in Update 2002 Burns et al., Dow 2,4-D production workers (included in 2001 IARC cohort, NIOSH Dioxin Registry)  Lymphopoietic mortality in workers with high 2,4-D exposure 4 1.3 (0.4–3.3) Thörn et al., Swedish lumberjacks exposed to phenoxyacetic 2000 herbicides 0 nr Studies Reviewed in Update 2000 Steenland et al., US chemical production workers (included in 1999 IARC cohort, NIOSH Dioxin Registry) 10 0.8 (0.4–1.5) Hooiveld et al., Dutch chemical production workers (included in 1998 IARC cohort) 1 1.0 (0.0–5.7) Rix et al., 1998 Danish paper mill workers—incidence Men 20 0.8 (0.5–1.2) Women 7 1.3 (0.5–2.7) Studies Reviewed in Update 1998 Gambini et al., Italian rice growers 4 0.6 (0.2–1.6) 1997 Kogevinas IARC cohort, male and female workers exposed et al., 1997 to any phenoxy herbicide or chlorophenol 34 1.0 (0.7–1.4) Exposed to highly chlorinated PCDDs 16 0.7 (0.4–1.2) Not exposed to highly chlorinated PCDDs 17 1.4 (0.8–2.3) Becher et al., German chemical production workers (included 1996 in IARC cohort)—Cohort I 4 1.8 (0.5–4.7) Ramlow et al., Dow pentachlorophenol production workers 1996 (included in IARC cohort, NIOSH Dioxin Registry) 0-year latency 2 1.0 (0.1–3.6) 15-year latency 1 nr Waterhouse Residents of Tecumseh, Michigan—incidence et al., 1996 All leukemias Men 42 1.4 (1.0–1.9) Women 32 1.2 (0.9–1.8) CLL 10 1.4 (1.0–1.9)

CANCER 401 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Amadori et al., Italian farming, animal-breeding workers—CLL 15 2.3 (0.9–5.8) 1995 Farmers 5 1.6 (0.5–5.2) Breeders 10 3.1 (1.1–8.3) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide applicators Mortality 2 nr Lymphatic 1 0.9 (0.0–5.1) Myelogenous 1 0.7 (0.0–3.7) Incidence Lymphatic 3 1.0 (0.2–3.0) Semenciw Farmers in Canadian prairie provinces 357 0.9 (0.8–1.0) et al., 1994 Lymphatic 132 0.9 (0.8–1.1) Myelogenous 127 0.8 (0.7–0.9) Blair et al., US farmers in 23 states 1993 White men 1,072 1.3 (1.2–1.4) White women 24 1.5 (0.9–2.2) Kogevinas IARC cohort (women only, myelogenous et al., 1993 leukemia) 1 2.0 (0.2–7.1) Studies Reviewed in VAO Bueno de Dutch phenoxy herbicide workers (included in Mesquita et al., IARC cohort) 1993 Leukemia, aleukemia (ICD-9 204–207) 2 2.2 (0.3–7.9) Myelogenous leukemia (ICD-8 205) 2 4.2 (0.5–15.1) Hansen et al., Danish gardeners—incidence 1992 All gardeners— LLC 6 2.5 (0.9–5.5) all other types of leukemia 3 1.2 (0.3–3.6) Men— LL C 6 2.8 (1.0–6.0) all other types of leukemia 3 1.4 (0.3–4.2) Ronco et al., Danish workers—incidence 1992 Men— elf-employed s 145 0.9 (nr) employee 33 1.0 (nr) Women— elf-employed s 8 2.2 (p < 0.05) employee 3 1.3 (nr) family worker 27 0.9 (nr) Fingerhut et al., NIOSH—entire cohort 6 0.7 (0.2–1.5) 1991 Saracci et al., IARC cohort—exposed subcohort (men and 1991 women) 18 1.2 (0.7–1.9) Brown et al., Case–control study on white men in Iowa, 1990 Minnesota, all types of leukemia—incidence 578 Ever farmed 335 1.2 (1.0–1.5) AML 81 1.2 (0.8–1.8) CML 27 1.1 (0.6–2.0) CLL 156 1.4 (1.1–1.9) ALL 7 0.9 (0.3–2.5) Myelodysplasias 32 0.8 (0.5–1.4) continued

402 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Any herbicide use 157 1.2 (0.9–1.6) AML 39 1.3 (0.8–2.0) CML 16 1.3 (0.7–2.6) CLL 74 1.4 (1.0–2.0) ALL 2 0.5 (0.1–2.2) Myelodysplasias 10 0.7 (0.3–1.5) Phenoxy acid use 120 1.2 (0.9–1.6) 2,4-D use 98 1.2 (0.9–1.6) 2,4,5-T use 22 1.3 (0.7–2.2) First use > 20 years before 11 1.8 (0.8–4.0) MCPA 11 1.9 (0.8–4.3) First use > 20 years before 5 2.4 (0.7–8.2) Wigle et al., Canadian farmers 138 0.9 (0.7–1.0) 1990 Zober et al., BASF employees at plant with 1953 explosion 90% CI 1990 All 3 cohorts (n = 247) 1 1.7 (nr) Cohort 3 1 5.2 (0.4–63.1) Incident case of AML in Cohort 1 Alavanja et al., USDA agricultural extension agents 23 1.9 (1.0–3.5) 1988 Lymphatic nr 2.1 (0.7–6.4) Trend over years worked (p < 0.01) Myelogenous nr 2.8 (1.1–7.2) Trend over years worked (p < 0.01) Bond et al., Dow 2,4-D production workers (included in 1988 IARC cohort, NIOSH Dioxin Registry) 2 3.6 (0.4–13.2) Blair and 1,084 leukemia deaths in Nebraska in White, 1985 1957–1974 Farmer—usual occupation on death certificate 1.3 (p < 0.05) 99 ALL cases nr 1.3 (nr) 248 CLL cases nr 1.7 (p < 0.05) 105 unspecified lymphatic cases nr 0.9 (nr) 235 AML cases nr 1.2 (nr) 96 CML cases nr 1.1 (nr) 39 unspecified myelogenous cases nr 1.0 (nr) 39 acute monocytic cases nr 1.9 (nr) 52 acute unspecified leukemia cases nr 2.4 (nr) 65 unspecified leukemia cases nr 1.2 (nr) Burmeister 1,675 leukemia deaths in Iowa 1968–1978 et al., 1982 Farmer—usual occupation on death certificate 1.2 (p < 0.05) ALL 28 0.7 (0.4–1.2) CLL 132 1.7 (1.2–2.4)  Lived in one of 33 counties with highest herbicide use nr 1.9 (1.2–3.1) Unspecified lymphatic 64 1.7 (1.0–2.7) AML 86 1.0 (0.8–1.5) CML 46 1.0 (0.7–1.7)

CANCER 403 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Unspecified myelogenous 36 0.8 (0.5–1.4) Acute monocytic 10 1.1 (0.4–2.6) Unspecified leukemia 31 1.1 (0.6–2.0) ENVIRONMENTAL New Studies Consonni et al., Seveso residents—25-year follow-up—men, 2008 women Leukemia (ICD-9 204–208) Zone A 1 0.9 (0.1–6.3) Zone B 13 1.7 (1.0–3.0) Zone R 51 1.0 (0.7–1.3) Lymphatic leukemia (ICD-9 204) Zone A 0 nr Zone B 3 1.3 (0.4–4.1) Zone R 23 1.4 (0.9–2.2) Myeloid leukemia (ICD-9 205) Zone A 1 2.1 (0.3–15.2) Zone B 6 2.0 (0.9–4.5) Zone R 16 0.7 (0.4–1.2) Monoccytic leukemia (ICD-9 206) 0 nr Leukemia, unspecified (ICD-9 208) Zone A 0 nr Zone B 4 2.4 (0.9–6.5) Zone R 10 0.8 (0.4–1.6) Studies Reviewed in Update 2002 Revich et al., Residents of Chapaevsk, Russia 2001 Mortality standardized to Samara Region Men 11 1.5 (0.8–2.7) Women 15 1.5 (0.8–2.4) Studies Reviewed in Update 2000 Bertazzi et al., Seveso residents—20-year follow-up 2001 Zones A, B— en m 9 2.1 (1.1–4.1) women 3 1.0 (0.3–3.0) Bertazzi et al., Seveso residents—15-year follow-up 1998 Zone B— en m 7 3.1 (1.4–6.7) women 1 0.6 (0.1–4.0) Zone R— ales m 12 0.8 (0.4–1.5) women 12 0.9 (0.5–1.6) Studies Reviewed in Update 1998 Bertazzi et al., Seveso residents—15-year follow-up 1997 Zone B— en m 7 3.1 (1.3–6.4) women 1 0.6 (0.0–3.1) Zone R— en m 12 0.8 (0.4–1.4) women 12 0.9 (0.4–1.5) continued

404 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-47  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in Update 1996 Swensson et al., Swedish fishermen 1995 All leukemias—mortality East coast (higher serum TEQs) 5 1.4 (0.5–3.2) West coast (lower serum TEQs) 24 1.0 (0.6–1.5) Lymphocytic—incidence East coast (higher serum TEQs) 4 1.2 (0.3–3.3) West coast (lower serum TEQs) 16 1.3 (0.8–2.2) Myelogenous—incidence East coast (higher serum TEQs) 2 0.9 (0.1–3.1) West coast (lower serum TEQs) 6 0.5 (0.2–1.1) Bertazzi et al., Seveso residents—10-year follow-up—incidence 1993 Zone B—men 2 1.6 (0.4–6.5) Myelogenous leukemia (ICD-9 205) 1 2.0 (0.3–14.6) women 2 1.8 (0.4–7.3) Myelogenous leukemia (ICD-9 205) 2 3.7 (0.9–15.7) Zone R—men 8 0.9 (0.4–1.9) Myelogenous leukemia (ICD-9 205) 5 1.4 (0.5–3.8) women 3 0.4 (0.1–1.2) Myelogenous leukemia (ICD-9 205) 2 0.5 (0.1–2.1) Studies Reviewed in VAO Bertazzi et al., Seveso residents—10-year follow-up 1992 Zones A, B, R— en m 4 2.1 (0.7–6.9) women 1 2.5 (0.2–27.0) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; HD, Hodgkin’s disease; IARC, International Agency for Research on Cancer; ICD, Interna- tional Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHL, non-Hodgkin’s lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr = not reported; PCDDs, chlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent quotient; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cLymphopoietic cancers comprise all forms of lymphoma (including Hodgkin’s disease and non- Hodgkin’s lymphoma) and leukemia (ALL, AML, CLL, CML). Studies in italics have been superseded by newer studies of same cohorts. For leukemia, the results presented by Miligi et al. (2006) on the Italian case–control study of lymphohematopoietic malignancies were not as informative for the purposes of the VAO series as those presented by Miligi et al. in 2003, as considered in Update 2004. The later publication reported estimated risk of all types of leukemia (ICD-9 204–208) in men and women who were exposed

CANCER 405 to any herbicide (OR = 1.4, 95% CI 0.8–2.3), whereas the earlier one had given findings on exposure to phenoxy herbicides specifically for leukemias excluding CLL (OR = 2.1, 95% CI 0.7–6.2). Biologic Plausibility Leukemia is a relatively rare spontaneous tumor in mice, but it is less rare in some strains of rats. A small study reported that five of 10 male rats fed TCDD at 1 ng/kg per week for 78 weeks showed an increased incidence of various cancers, one of which was lymphocytic leukemia (Van Miller et al., 1977). Later studies of TCDD’s carcinogenicity have not shown an increased incidence of lymphocytic leukemia in mice or rats. Two recent studies using cells in tissue culture suggest that TCDD exposure does not promote leukemia. Proliferation of cultured human bone marrow stem cells (the source of leukemic cells) was not influenced by addition of TCDD to the culture medium (van Grevenynghe et al., 2006). Likewise, Mulero-Navarro et al. (2006) reported that the AHR promoter is silenced in ALL—an effect that could lead to reduced expression of the receptor, which binds TCDD and medi- ates its toxicity. No reports of animal studies have noted an increased incidence of leukemia after exposure to the phenoxy herbicides or other chemicals of interest. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis The positive associations found in the most recent analyses of the Seveso accident (Consonni et al., 2008) suggest an association between residence in the high TCDD exposure zone and all types of leukemia combined. For lymphatic and myeloid leukemias, the committee is concerned about misclassification of causes of death of the few people whose deaths were attributed to lymphatic leukemia (three in Zone B), myeloid leukemia (six in Zone B), and unspecified types of leukemia (four in Zone B). The findings from the study of Danish gar- deners (Hansen et al., 2007) were consistent with a previous report (Hansen et al., 1992). The committee does not believe that the negative findings from Kang and Cypel are robust. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and leukemias in general. An exception is made for the specific leukemia

406 VETERANS AND AGENT ORANGE: UPDATE 2008 subtypes of chronic B-cell hematoproliferative diseases, including CLL and HCL; the rationale for this exception is discussed in the following section. Chronic Lymphocytic Leukemia and Hairy Cell Leukemia The proposed World Health Organization classification of NHL notes that CLL (ICD-9 204.1) and its lymphomatous form, small lymphocytic lymphoma, are both derived from mature B cells (Chiorazzi et al., 2005; IARC, 2001). (The committee has opted to continue using the abbreviation CLL to refer to this con- dition, although some now favor CLL/SLL.) ACS estimated that about 8,750 men and 6,360 women would receive diagnoses of CLL in the United States in 2008 and that 2,600 men and 1,790 women would die from it (Jemal et al., 2008a). Nearly all cases occur after the age of 50 years. For average annual incidence, see Table 6-46. The requirements for diagnosis of CLL include an absolute peripheral- blood count of more than 5 × 109 clonal lymphocytes per liter, a predominant population of mature-looking lymphocytes, and hypercellular or normal cellular bone marrow that contains more than 30% lymphocytes. The malignant cells in CLL exhibit a characteristic membrane phenotype with coexpression of pan- B-cell antigens—including CD19, CD20, and CD23—with CD5. However, the cell-surface membranes express only weak surface-membrane immunoglobulin (Hallek et al., 2008). Although it is now regarded as a different manifestation of the same disease, diffuse small lymphocytic lymphoma (SLL) is the term that has been used for the condition of patients who have lymphomatous CLL. Patients seek medical attention for painless generalized lymphadenopathy that in many cases has lasted for several years. Unlike the situation in other CLLs, the peripheral blood may be normal or reveal only mild lymphocytosis (fewer than 5 × 109 clonal lym- phocytes per liter). However, the bone marrow has abnormal cells in 75–95% of cases. Both SLL and CLL can transform into aggressive NHL, known as Richter’s syndrome (Omati and Omati, 2008). Richter’s syndrome is characterized by dif- fuse large-cell lymphoma or its immunoblastic variant. It is resistant to current therapies, and the median survival is about 6 months. For the present update, VA specifically asked that the committee address whether HCL should be considered to be in the group of neoplasms on which the evidence supports an association with herbicide exposure. As noted in Update 2004 and Update 2006, HCL has been classified as a rare form of CLL (AJCC, 2002). The committee’s response to VA’s request is based on considerations of the biology of HCL rather than its diagnosis because it is far too uncommon to be reported and analyzed individually in the cohort studies considered in the VAO series and has not been the subject of case–control investigations considering exposures to the chemicals of interest. HCL is a chronic B-cell lymphoproliferative disorder characterized by pan-

CANCER 407 cytopenia, splenomegaly, and the absence of lymphadenopathy. A leukemic blood profile is rare, occurring in about 8–10% of all cases. HCL is unique among the low-grade lymphomas not only because of its peculiar biologic properties but because treatment responses differ basically from those of all the other forms of NHL (König et al., 2000). The B–cell-derived tumor cells in the blood show many projections on their surface, hence the reference to “hairy”; the significance of the projections is not known. No studies have specifically described HCL in animals exposed to the chemi- cals of interest. Thus, in addition to there being no epidemiologic results on HCL and the chemicals of interest, no animal data support the biological plausibility of an association between the chemicals of interest and this rare cancer. The com- mittee sees no reason to exclude HCL or any other chronic hematoproliferative diseases of B-cell origin lacking their own specific epidemiologic evidence from the overaching broader groupings on which positive epidemiologic evidence is available. Because HCL is related to CLL, the committee explicitly includes it in the discussion and conclusions on CLL that follows. Conclusions from VAO and Previous Updates  Update 2002 was the first to discuss CLL separately from other leukemias. The epidemiologic studies indi- cated that farming, especially with exposure to 2,4-D and 2,4,5-T, is associated with significant mortality from CLL. Many more studies support the hypothesis that herbicide exposure can contribute to NHL risk. Most cases of CLL and NHL reflect malignant transformation of B-lymphocyte germinal center B cells, so these diseases could have a common etiology. Studies reviewed in Update 2002, Update 2004, Update 2006, and the present update are summarized in Table 6-48. Update of the Epidemiologic Literature Vietnam-Veteran Studies  No Vietnam-veteran studies addressing exposure to the chemicals of interest and CLL have been published since Update 2006. Occupational Studies  Richardson et al. (2008) conducted a population-based case–control study of incident NHL and CLL in men and women 15–75 years old and living in six German counties in 1986–1998. Control subjects were se- lected randomly from German population registries and were matched individu- ally to cases by sex, age, and region; two controls per case were recruited. The job–exposure matrix developed by Pannett and co-workers in the middle 1990s was used to assign chemicals that subjects were presumably exposed to occupa- tionally. On the basis of an analysis whereby cumulative exposure (the sum across jobs of the product of the number of hours exposed, intensity, and probability of exposure) was categorized in three levels, there was no evidence that risks of CLL increased with increasing cumulative exposure (all ORs were less than 1; p for

408 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-48  Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b VIETNAM VETERANS Studies Reviewed in Update 2006 ADVA, 2005a Australian Vietnam veterans vs Australian population—incidence All branches 58 1.2 (0.7–1.7) Navy 12 1.5 (0.8–2.6 Army 42 1.6 (1.2–2.2) Air Force 4 0.9 (0.2–2.2) OCCUPATIONAL New Studies Richardson et al., 2008 German residents, occupational factors associated with CLL—incidence Chlorophenols 44 0.9 (0.6–1.3) Lowest tertile cumulative exposure 12 0.9 (0.4–1.8) Middle tertile 15 0.9 (0.5–1.8) Highest tertile 17 0.9 (0.5–1.6) p-trend = 0.770 Herbicides 43 1.2 (0.8–1.7) Lowest tertile cumulative exposure 13 1.3 (0.7–2.7) Middle tertile 15 1.3 (0.7–2.5) Highest tertile 15 1.0 (0.5–1.9) p-trend = 0.755 Studies Reviewed in Update 2006 Hertzman et al., 1997 British Columbia sawmill worker with chlorophenate process (more hexa-, hepta-, and octa-chlorinated dibenzo-p-dioxins than TCDD), all leukemias—incidence 47 1.2 (0.9–1.5) ALL 2 1.0 (0.2–3.1) CLL 24 1.7 (1.2–2.4) AML 5 0.8 (0.3–1.7) CML 7 1.1 (0.5–2.0) Other, unspecified 5 0.5 (0.2–1.0) Studies Reviewed in Update 1998 Waterhouse et al., 1996 Residents of Tecumseh, Michigan (men and women)—incidence 10 1.8 (0.8–3.2) Amadori et al., 1995 Workers in northeast Italy (men and women) 15 2.3 (0.9–5.8) Farming workers only 5 1.6 (0.5–5.2) Breeding workers only 10 3.1 (1.1–8.3)

CANCER 409 TABLE 6-48  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b Studies Reviewed in VAO Hansen et al., 1992 Danish gardeners (men and women) All gardeners 6 2.5 (0.9–5.5) Male gardeners 6 2.8 (1.0–6.0) Brown et al., 1990 Residents of Iowa, Minnesota Ever farmed 156 1.4 (1.1–1.9) Any herbicide use 74 1.4 (1.0–2.0) Ever used 2,4,5-T 10 1.6 (0.7–3.4)  Use at least 20 years before interview 7 3.3 (1.2–8.7) Blair and White, 1985 1,084 leukemia deaths in Nebraska 1957–1974 Farmer usual occupation on death certificate nr 1.3 (p < 0.05) 248 CLL cases nr 1.7 (p < 0.05) Burmeister et al., 1982 1,675 leukemia deaths in Iowa 1968–1978 Farmer usual occupation on death certificate 1.2 (p < 0.05) CLL 132 1.7 (1.2–2.4)  Lived in 33 counties with highest herbicide use nr 1.9 (1.2–3.1) ENVIRONMENTAL New Studies Consonni et al., 2008 Seveso residents (men and women)— 25-year follow-up Lymphatic leukemia (ICD-9 204) Zone A 0 nr Zone B 3 1.3 (0.4–4.1) Zone R 23 1.4 (0.9–2.2) Read et al., 2007 Residents of New Plymouth Territorial Authority, New Zealand near plant manufacturing 2,4,5-T (1962–1987) Incidence 104 1.3 (1.1–1.6)c 1970–1974 16 2.5 (1.4–4.1) 1975–1979 7 0.9 (0.4–1.8) 1980–1984 21 2.6 (1.6–3.9) 1985–1989 16 1.4 (0.8–2.3) 1990–1994 13 0.9 (0.5–1.6) 1995–1999 19 0.9 (0.5–1.4) 2000–2001 12 1.1 (0.6–1.9) Mortality 40 1.3 (0.9–1.8)c 1970–1974 7 1.7 (0.7–3.5) 1975–1979 7 1.8 (0.7–3.6) 1980–1984 6 1.4 (0.5–3.0) 1985–1989 4 0.8 (0.2–2.2) continued

410 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-48  Continued Estimated Exposed Relative Risk Reference Study Populationa Casesb (95% CI)b 1990–1994 6 1.1 (0.4–2.5) 1995–1999 8 1.3 (0.6–2.6) 2000–2001 2 0.8 (0.1–2.8) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up Lymphatic leukemia Zones A, B— en m 2 1.6 (0.4–6.8) women 0 nr ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; ICD, International Classification of Diseases; nr, not reported; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aSubjects are male and outcome is mortality unless otherwise noted. bGiven when available; results other than estimated risk explained individually. cThe total SMR/SIR were computed by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods. Studies in italics have been superseded by newer studies of same cohort. linear trend = 0.77). This metric of cumulative exposure is difficult to interpret because it combines duration of exposure (continuous) with rank-ordered scales of intensity and probability; for example, an intensity coded as 2 and a probability coded as 1 yield the same product as an intensity coded as 1 and a probability coded as 2. Moreover, simple categorization of exposure can obscure trends in the data that can be seen with other techniques that make use of the continuous nature of the data (such as natural cubic spline functions). Environmental Studies  Consonni et al. (2008) reported on a mortality follow- up of the Seveso, Italy, cohort exposed to large amounts of environmental con- tamination with TCDD. The study cohort of 273,108 subjects who were resident at the time of the incident or immigrated or were born in the 10 years thereafter were analyzed according to three zones with increasing levels of soil TCDD. Mortality from leukemia was reported according to type of leukemia—lymphatic, myelocytic, and not reported—with no indication of acute or chronic subtypes. No deaths from lymphocytic leukemia were found in Zone A (the most highly ex- posed area), and no association with lymphocytic leukemia mortality was found in Zone B (RR = 1.3, 95% CI 0.4–4.1); however, an association was found in Zone R (RR = 1.4, 95% CI 0.9–2.2), the area with the lowest exposure. Although CLL is considerably less aggressive, it is considerable more prevalent than ALL,

CANCER 411 so it is not possible to infer that the statistics on mortality refer primarily to either of the two leukemia types. Read et al. (2007) studied residents of a community where a plant had manufactured 2,4,5-T from 1962–1987. They reported that the body burden of TCDD was comparable with that in residents of Zone B of the Seveso area. Can- cer incidence and mortality for the period 1970–2001 in the surrounding New Plymouth Territorial Authority were compared to those of the general population of New Zealand. Allowing for a latency period of about 10 years from the start of production, relative risks for incidence and mortality from CLL in this area were reported for five-year intervals starting in 1970. There was considerable fluctua- tion in the estimated risks, but significant increases in the incidence of CLL were noted during two intervals while production continued. The committee computed overall risks for the full 32-year observation period by dividing the sum of the observed values by the sum of the expected values over all years and derived 95% CIs on these total ratios by exact methods (SIR = 1.3, 95% CI 1.1–1.6; SMR = 1.3, 95% CI 0.9–1.8). Biologic Plausibility  No animal studies have reported on the occurrence spe- cifically of CLL after exposure to the chemicals of interest, but the information reported above in the biologic-plausibility section on all types of leukemias is rel- evant here. Given the similarities between CLL and B-cell lymphomas, a similar argument for biologic plausibility can be made for them. An increased incidence of lymphoma was reported in female B6C3F mice exposed to TCDD at 1 μg/kg of body weight via gavage twice a week for 2 years (NTP, 1982a). The finding was confirmed and extended in recent NTP studies in which a dose-related increase in the incidence of lymphoma was observed in female mice given TCDD orally at 0.04, 0.2, or 2.0 μg/kg twice a week for 104 weeks. Laboratory-animal studies of 2,4-D found no induction of lymphomas. The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter. Synthesis  The study by Read et al. (2007) suggested an association between 2.4.5-T and CLL in people who lived near a plant in which 2,4,5-T was manu- factured (RR = 1.3). In contrast, no excess risks of lymphatic leukemia in the two zones closest to the epicenter of the Seveso incident or of CLL in the German case–control study (Richardson et al., 2008) were found. Although considerably more studies support the hypothesis that herbicide exposure can contribute to the development of NHL, some high-quality studies show that exposure to 2,4-D and 2,4,5-T appears to be associated with the oc- currence of CLL, including the incidence study of Australian veterans (ADVA, 2005a), the high-quality case–control study by Hertzman et al. (1997) of Brit- ish Columbia sawmill workers exposed to chlorophenates, the Danish-gardener

412 VETERANS AND AGENT ORANGE: UPDATE 2008 study (Hansen et al., 1992), and the population-based case–control study in two US states by Brown et al. (1990) that showed increased risks associated with any herbicide use and use of 2,4,5-T at least 20 years before interview. Other studies that showed positive associations but do not contribute greatly to the overall conclusion include the population-based case–control study by Amadori et al. (1995) that made use of occupational titles but did not include specific as- sessments of exposure to the chemicals; the cancer-incidence study in Tecumseh County, Michigan, in which no exposure assessments were available (Waterhouse et al., 1996); and proportionate-mortality studies by Blair and White (1985) and Burmeister et al. (1982). Malignant transformation of B-lymphocyte germinal center B is apparent in most cases of CLL and NHL, so it is plausible that these diseases could have a common etiology. Conclusion  On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an associa- tion between exposure to the chemicals of interest and CLL, including HCL and all other chronic B-cell hematoproliferative diseases. SUMMARY The committee had four categories available to classify the strength of the evidence from the veteran, occupational, and environmental studies reviewed regarding an association between exposure to the chemicals of interest and each kind of cancer. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006. To be consistent with the charge to the committee from the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific reviews, the committee distinguished among the four categories on the basis of statistical association, not causality. Health Outcomes with Sufficient Evidence of an Association For outcomes in this category, a positive association with at least one of the chemicals of interest must be observed in studies in which chance, bias, and con- founding can be ruled out with reasonable confidence. The committee regarded evidence from several small studies that were free of bias and confounding and that showed an association that was consistent in magnitude and direction as suf- ficient evidence of an association. Previous VAO committees found sufficient evidence of an association be- tween exposure to at least one of the chemicals of interest and four kinds of

CANCER 413 cancer: soft-tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. The scientific literature continues to support the classification of those four kinds of cancers in the category of sufficient evidence. The current committee agreed with the findings of previous VAO committees but broadened the categorization of chronic lymphocytic leukemia to include hairy- cell leukemia and other chronic B-cell leukemias. Health Outcomes with Limited or Suggestive Evidence of an Association For outcomes in this category, the evidence must suggest an association with at least one of the chemicals of interest that could be limited because chance, bias, or confounding could not be ruled out with confidence. A high-quality study may have demonstrated a strong positive association amid a field of less convincing positive findings, or, more often, several studies yielded positive results, but the results of other studies were inconsistent. Previous VAO committees found limited or suggestive evidence of an asso- ciation between exposure to at least one of the chemicals of interest and laryngeal cancer; cancer of the lung, bronchus, or trachea; prostatic cancer; multiple my- eloma; and AL amyloidosis. The literature continues to support the classification of those diseases in the category of limited or suggestive evidence. Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association This is the default category for any disease outcome for which there is not enough information upon which to base a discussion. For many of the kinds of cancer reviewed by the committee, some scientific data were available, but they were inadequate or insufficient in quality, consistency, or statistical power to sup- port a conclusion as to the presence or absence of an association. Some studies fail to control for confounding or fail to provide adequate exposure assessment. In addition to any specific kinds of cancer that have not been directly addressed in the present report, this category includes hepatobiliary cancer (cancer of the liver, gallbladder, and bile ducts); cancer of the oral cavity, pharynx, and nose; cancer of the pleura, mediastinum, and other unspecified sites in the respiratory sys- tem and intrathoracic organs; cancer of the colon, rectum, esophagus, stomach, and pancreas; bone and joint cancer; melanoma and nonmelanoma skin cancer (including basal-cell carcinoma and squamous-cell carcinoma); breast cancer; cancer of the male and female reproductive systems (excluding prostate cancer); urinary bladder cancer; renal cancer (cancer of the kidney and renal pelvis); cancer of the brain and nervous system (including eye); and the various forms of leukemia other than chronic B-cell leukemias, including chronic lymphocytic leukemia and hairy cell leukemia.

414 VETERANS AND AGENT ORANGE: UPDATE 2008 Health Outcomes with Limited or Suggestive Evidence of No Association For outcomes in this category, several adequate studies covering the full known range of human exposure are consistent in not showing a positive associa- tion with exposure to one of the chemicals of interest. The studies have relatively narrow confidence intervals. A conclusion of no association is inevitably limited to the conditions, magnitude of exposure, and length of observation of the avail- able studies. The possibility of a very small increase in risk associated with a given exposure can never be excluded. Inclusion in this category does, however, presume evidence of a lack of association between each of the chemicals of interest and a particular health outcome, but there have been virtually no cancer- epidemiologic studies specifically evaluating the consequences of exposure to picloram or cacodylic acid. On the basis of evaluation of the scientific literature, no kinds of cancer satisfy the criteria for inclusion in this category. REFERENCES ACS (American Cancer Society). 2006. Cancer Facts and Figures 2006. Atlanta: American Cancer Society. http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf (Accessed March 6, 2007). ACS. 2007a. What are the risk factors for . . . http://www.cancer.org/docroot/CRI/content/CRI_2_4_ 2X_What_are_the_risk_factors_for . . . (Accessed September 18). ACS. 2007b. What are the risk factors for . . . http://www.cancer.org/docroot/CRI/content/CRI_2_2_ 2X_What_causes_laryngeal_and_hypopharyngeal_cancers . . . (Accessed September 18). ACS. 2007c. What are the risk factors for . . . http://www.cancer.org/docroot/CRI/content/CRI_2_2_ 2x_What_Causes . . . (Accessed September 18). ACS. 2007d. What are the risk factors for . . . . ������������������������������������������������ http://www.cancer.org/docroot/CRI/content/CRI_2_ 4_2X_What_are_the_risk_factors_for_brain������������������������������� . . . ������������������������ (Accessed��������������� September 18). �������������� ADVA (Australia Department of Veterans’ Affairs). 2005a. Cancer Incidence in Australian Vietnam Veteran Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epide- miologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-0068. 31 pp. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination and Results. Reston, VA: Science Ap- plication International Corporation. F41624–96–C1012.   Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

CANCER 415 AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community, Volume 3: Validation Study. Canberra, Australia. AJCC (American Joint Committee on Cancer). 2002. Lymphoid Neoplasms. AJCC Cancer Staging Manual, 6th Edition. New York: Springer-Verlag, pp. 393–406. Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. 2004. Cancer in US Air Force veterans of the Vietnam War. Journal of Occupational and Environmental Medicine 46(2):123–136. Alavanja MC, Blair A, Merkle S, Teske J, Eaton B. 1988. Mortality among agricultural extension agents. American Journal of Industrial Medicine 14(2):167–176. Alavanja MC, Blair A, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservationists. Archives of Environmental Health 44:94–101. Alavanja MC, Samanic C, Dosemeci M, Lubin J, Tarone R, Lynch CF, Knott C, Thomas K, ­Hoppin JA, Barker J, Coble J, Sandler DP, Blair A. 2003. Use of agricultural pesticides and ­prostate cancer risk in the Agricultural Health Study cohort. American Journal of Epidemiology 157(9):800–814. Alavanja MCR, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, Thomas K, Dosemeci M, Barker J, Hoppin JA, Blair A. 2005. Cancer incidence in the Agricultural Health Study. Scandinavian Journal of Work, Environment and Health 31(Suppl 1):39–45. Allen JR, Barsotti DA, Van MJP, Abrahamson LJ, Lalich JJ. 1977. Morphological changes in mon- keys consuming a diet containing low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Food and Cosmetics Toxicology 15:401–410. Amadori D, Nanni O, Falcini F, Saragoni A, Tison V, Callea A, Scarpi E, Ricci M, Riva N, Buiatti E. 1995. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: A population case–control study based on job titles. Oc- cupational and Environmental Medicine 52(6):374–379. Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Final Report. Madison: Wisconsin Division of Health. Andersson P, McGuire J, Rubioi C, Gradin K, Whitelaw ML, Pettersson S, Hanberg A, Poellinger L. 2002a. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proceedings of the National Academy of Sciences of the United States 99(15):9990–9995. Andersson P, Rubio C, Poellinger L, Hanberg A. 2005. Gastric hamartomatous tumours in a trans- genic mouse model expressing an activated dioxin/Ah receptor. Anticancer Research 25(2A): 903–911. Arnold LL, Eldan M, Nyska A, van Gemert M, Cohen SM. 2006. Dimethylarsinic acid: Results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice. Toxicology 223(1-2): 82–100. Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: An 18-year prospective follow-up. American Journal of Industrial Medicine 26(2):243–253. Axelson O, Sundell L. 1974. Herbicide exposure, mortality and tumor incidence. An epidemiological investigation on Swedish railroad workers. Scandinavian Journal of Work, Environment and Health 11:21–28. Axelson O, Sundell L, Andersson K, Edling C, Hogstedt C, Kling H. 1980. Herbicide exposure and tumor mortality. An updated epidemiologic investigation on Swedish railroad workers. Scandi- navian Journal of Work, Environment, and Health 6(1):73–79. Baccarelli A, Hirt C, Pesatori AC, Consonni D, Patterson DG Jr, Bertazzi PA, Dolken G, Landi MT. 2006. t(14;18) translocations in lymphocytes of healthy dioxin-exposed individuals from Seveso, Italy. Carcinogenesis 27(10):2001–2007. Bagga D, Anders KH, Wang HJ, Roberts E, Glaspy JA. 2000. Organochlorine pesticide content of breast adipose tissue from women with breast cancer and control subjects. Journal of the Na- tional Cancer Institute 92(9):750–753.

416 VETERANS AND AGENT ORANGE: UPDATE 2008 Balarajan R, Acheson ED. 1984. Soft tissue sarcomas in agriculture and forestry workers. Journal of Epidemiology and Community Health 38(2):113–116. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312–321. Beebe LE, Fornwald LW, Diwan BA, Anver MR, Anderson LM. 1995. Promotion of N- nitrosodiethylamine-initiated hepatocellular tumors and hepatoblastomas by 2,3,7,8-tetrachloro­ dibenzo-p-dioxin or Aroclor 1254 in C57BL/6, DBA/2, and B6D2F1 mice. Cancer Research 55(21):4875–4880. Bender AP, Parker DL, Johnson RA, Scharber WK, Williams AN, Marbury MC, Mandel JS. 1989. Minnesota highway maintenance worker study: Cancer mortality. American Journal of Indus- trial Medicine 15(5):545–556. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80(4):316–329. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989b. Ten-year mor- tality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129(6):1187–1200. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Consonni D, Tironi A, Landi MT. 1992. Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin. International Journal of Epidemiology 21(1):118–123. Bertazzi A, Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C. 1993. Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Epidemiology 4(5): 398–406. Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: A 15-year mortality study after the “Seveso accident.” Epidemiology 8(6):646–652. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives 106(Suppl 2):625–633. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: A 20-year mortality study. American Journal of Epidemiol- ogy 153(11):1031–1044. Birnbaum LS, Fenton SE. 2003. Cancer and developmental exposure to endocrine disruptors. Envi- ronmental Health Perspectives 111(4):389–394. Blair A, Kazerouni N. 1997. Reactive chemicals and cancer. Cancer Causes and Control 8(3): 473–490. Blair A, White DW. 1985. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 40(4):211–214. Blair A, Grauman DJ, Lubin JH, Fraumeni JF Jr. 1983. Lung cancer and other causes of death among licensed pesticide applicators. Journal of the National Cancer Institute 71(1):31–37. Blair A, Dosemeci M, Heineman EF. 1993. Cancer and other causes of death among male and female farmers from twenty-three states. American Journal of Industrial Medicine 23(5):729–742. Blair A, Zahm SH, Cantor KP, Ward MH. 1997. Occupational and environmental risk factors for chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. In: Marti GE, Vogt RF, Zenger VE, eds. Proceedings of the USPHS Workshop on Laboratory and Epidemiologic Approaches to Determining the Role of Environmental Exposures as Risk Factors for B-Cell Chronic Lympho- cytic and Other B-Cell Lymphoproliferative Disorders. US Department of Health and Human Services, Public Health Service.

CANCER 417 Blair A, Sandler DP, Tarone R, Lubin J, Thomas K, Hoppin JA, Samanic C, Coble J, Kamel F, Knott C, Dosemeci M, Zahm SH, Lynch CF, Rothman N, Alavanja MC. 2005a. Mortality among participants in the Agricultural Health Study. Annals of Epidemiology 15(4):279–285. Blair A, Sandler D, Thomas K, Hoppin JA, Kamel F, Coble J, Lee WJ, Rusiecki J, Knott C, Dosemeci M, Lynch CF, Lubin J, Alavanja M. 2005b. Disease and injury among participants in the Agri- cultural Health Study. Journal of Agricultural Safety and Health 11(2):141–150. Bloemen LJ, Mandel JS, Bond GG, Pollock AF, Vitek RP, Cook RR. 1993. An update of mortality among chemical workers potentially exposed to the herbicide 2,4-dichlorophenoxyacetic acid and its derivatives. Journal of Occupational Medicine 35(12):1208–1212. Blot WJ, McLaughlin JK. 1999. The changing epidemiology of esophageal cancer. Seminars in On- cology 26(5 Supplement 15):2–8. Bodner KM, Collins JJ, Bloemen LJ, Carson ML. 2003. Cancer risk for chemical workers ex- posed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Occupational and Environmental Medicine 60(9): 672–675. Boehmer TK, Flanders WD, McGeehin MA, Boyle C, Barrett DH. 2004. Postservice mortality in Vietnam veterans: 30-year follow-up. Archives of Internal Medicine 164(17):1908–1916. Boffetta P, Stellman SD, Garfinkel L. 1989. A case–control study of multiple myeloma nested in the American Cancer Society prospective study. International Journal of Cancer 43(4):554–559. Bond GG, Wetterstroem NH, Roush GJ, McLaren EA, Lipps TE, Cook RR. 1988. Cause specific mortality among employees engaged in the manufacture, formulation, or packaging of 2,4- dichlorophenoxyacetic acid and related salts. British Journal of Industrial Medicine 45(2): 98–105. Bosl GJ, Motzer RJ. 1997. Testicular germ-cell cancer. New England Journal of Medicine 337(4): 242–253. Boyle C, Decoufle P, Delaney RJ, DeStefano F, Flock ML, Hunter MI, Joesoef MR, Karon JM, Kirk ML, Layde PM, McGee DL, Moyer LA, Pollock DA, Rhodes P, Scally MJ, Worth RM. 1987. Postservice Mortality Among Vietnam Veterans. Atlanta, GA: Centers for Disease Control. CEH 86-0076. 143 pp. Bradlow H. 2008. Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo 22(4):441–445. Brenner J, Rothenbacher D, Arndt V. 2009. Epidemiology of stomach cancer. Methods in Molecular Biology 472:467–477. Breslin P, Lee Y, Kang H, Burt V, Shepard BM. 1986. A Preliminary Report: The Vietnam Vet- erans Mortality Study. Washington, DC: Veterans Administration, Office of Environmental Epidemiology. Breslin P, Kang H, Lee Y, Burt V, Shepard BM. 1988. Proportionate mortality study of US Army and US Marine Corps veterans of the Vietnam War. Journal of Occupational Medicine 30(5): 412–419. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, Burmeister LF, Van Lier SF, Dick F. 1990. Pesticide exposures and other agricultural risk factors for leukemia among men in Iowa and Minnesota. Cancer Research 50(20):6585–6591. Brown LM, Burmeister LF, Everett GD, Blair A. 1993. Pesticide exposures and multiple myeloma in Iowa men. Cancer Causes and Control 4(2):153–156. Brunnberg S, Andersson P, Lindstam M, Paulson I, Poellinger L, Hanberg A. 2006. The constitutively active Ah receptor (CA-Ahr) mouse as a potential model for dioxin exposure—effects in vital organs. Toxicology 224(3):191–201. Bueno de Mesquita HB, Doornbos G, Van der Kuip DA, Kogevinas M, Winkelmann R. 1993. Oc- cupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands. American Journal of Industrial Medicine 23(2):289–300. Bullman TA, Kang HK, Watanabe KK. 1990. Proportionate mortality among US Army Vietnam vet- erans who served in Military Region I. American Journal of Epidemiology 132(4):670–674.

418 VETERANS AND AGENT ORANGE: UPDATE 2008 Bullman TA, Watanabe KK, Kang HK. 1994. Risk of testicular cancer associated with surrogate measures of Agent Orange exposure among Vietnam veterans on the Agent Orange Registry. Annals of Epidemiology 4(1):11–16. Burmeister LF. 1981. Cancer mortality in Iowa farmers, 1971–1978. Journal of the National Cancer Institute 66(3):461–464. Burmeister LF, Van Lier SF, Isacson P. 1982. Leukemia and farm practices in Iowa. American Journal of Epidemiology 115(5):720–728. Burmeister LF, Everett GD, Van Lier SF, Isacson P. 1983. Selected cancer mortality and farm practices in Iowa. American Journal of Epidemiology 118(1):72–77. Burns CJ, Beard KK, Cartmill JB. 2001. Mortality in chemical workers potentially exposed to 2,4- dichlorophenoxyacetic acid (2,4-D) 1945–1994: An update. Occupational and Environmental Medicine 58(1):24–30. Burt VL, Breslin PP, Kang HK, Lee Y. 1987. Non-Hodgkin’s Lymphoma in Vietnam Veterans. Depart- ment of Medicine and Surgery, Veterans Administration, 33 pp. Buxbaum JN. 2004. The systemic amyloidoses. Current Opinion in Rheumatology 16(1):67–75. Cantor KP. 1982. Farming and mortality from non-Hodgkin’s lymphoma: A case–control study. International Journal of Cancer 29(3):239–247. Cantor KP, Blair A. 1984. Farming and mortality from multiple myeloma: A case control study with the use of death certificates. Journal of the National Cancer Institute 72(2):251–255. Caplan LS, Hall HI, Levine RS, Zhu K. 2000. Preventable risk factors for nasal cancer. Annals of Epidemiology 10(3):186–191. Carreon T, Butler MA, Ruder AM, Waters MA, Davis-King KE, Calvert GM, Schulte PA, Connally B, Ward EM, Sanderson WT, Heineman EF, Mandel JS, Morton RF, Reding DJ, Rosenman KD, Talaska G, Cancer B. 2005. Gliomas and farm pesticide exposure in women: The Upper Midwest Health Study. Environmental Health Perspectives 113(5):546–551. CDC (Centers for Disease Control and Prevention). 1990a. The association of selected cancers with service in the US military in Vietnam. III. Hodgkin’s disease, nasal cancer, nasopharyngeal cancer, and primary liver cancer. The Selected Cancers Cooperative Study Group. Archives of Internal Medicine 150(12):2495–2505. CDC. 1990b. The association of selected cancers with service in the US military in Vietnam. I. Non- Hodgkin’s lymphoma. Archives of Internal Medicine 150:2473–2483. CDVA (Commonwealth Department of Veterans’ Affairs). 1997a. Mortality of Vietnam Veterans: The Veteran Cohort Study. A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1998a. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 1: Male Vietnam Veterans Survey and Community Comparison Outcomes. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1998b. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 2: Female Vietnam Veterans Survey and Community Comparison Out- comes. Canberra, Australia: Department of Veterans’ Affairs. Chamie K, deVere White R, Volpp B, Lee D, Ok J, Ellison L. 2008. Agent Orange Exposure, Vietnam War Veterans, and the Risk of Prostate Cancer. Cancer 113(9):2464–2470. Charles JM, Bond DM, Jeffries TK, Yano BL, Stott WT, Johnson KA, Cunny HC, Wilson RD, Bus JS. 1996. Chronic dietary toxicity/oncogenicity studies on 2,4-dichlorophenoxyacetic acid in rodents. Fundamental and Applied Toxicology 33:166–172. Chiorazzi N, Rai KR, Ferrarini M. 2005. Mechanisms of disease: Chronic lymphocytic leukemia. The New England Journal of Medicine 352(8):804–815. Chiu BC, Weisenburger DD, Zahm SH, Cantor KP, Gapstur SM, Holmes F, Burmeister LF, Blair A. 2004. Agricultural pesticide use, familial cancer, and risk of non-Hodgkin lymphoma. Cancer Epidemiology, Biomarkers and Prevention 13(4):525–531.

CANCER 419 Chiu BC, Dave BJ, Blair A, Gapstur SM, Zahm SH, Weisenburger DD. 2006. Agricultural pesticide use and risk of t(14;18)-defined subtypes of non-Hodgkin lymphoma. Blood 108(4):1363–1369. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A, WHI Investigators. 2003. Influence of estrogen plus progestin on breast cancer and mammography in healthy post- menopausal women: The Women’s Health Initiative Randomized Trial. Journal of the American Medical Association 289(24):3243–3253. Chung CJ, Huang CJ, Pu YS, Su CT, Huang YK, Chen YT, Hsueh YM. 2008. Urinary 8-hydroxy­ deoxyguanosine and urothelial carcinoma risk in low arsenic exposure area. Toxicology and Applied Pharmacology 226(1):14–21. Clapp RW. 1997. Update of cancer surveillance of veterans in Massachusetts, USA. International Journal of Epidemiology 26(3):679–681. Clapp RW, Cupples LA, Colton T, Ozonoff DM. 1991. Cancer surveillance of veterans in Massachu- setts, 1982–1988. International Journal of Epidemiology 20(1):7–12. Cocco P, Heineman EF, Dosemeci M. 1999. Occupational risk factors for cancer of the central nervous system (CNS) among US women. American Journal of Industrial Medicine 36(1):70–74. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J. 1986. Mortality of workers exposed to 2-methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment, and Health 12(5):448–454. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48(3):173–178. Cohen AD, Zhou P, Xiao Q, Fleisher M, Kalakonda N, Akhurst T, Chitale DA, Moscowitz MV, Dhodapkar J, Teruya-Feldstein D, Filippa D, Comenzo RL. 2004. Systemic AL amyloidosis due to non-Hodgkin’s lymphoma: An unusual clinicopathologic association. British Journal of Haematology 124:309–314. Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD. 2006. Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Critical Reviews in Toxicology 36(2):99–133. Collins JJ, Strauss ME, Levinskas GJ, Conner PR. 1993. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident. Epidemiology 4(1):7–13. Comba P, Ascoli V, Belli S, Benedetti M, Gatti L, Ricci P, Tieghi A. 2003. Risk of soft tissue sarcomas and residence in the neighbourhood of an incinerator of industrial wastes. Occupational and Environmental Medicine 60(9):680–683. Consonni D, Pesatori AC, Zocchetti C, Sindaco R, D’Oro LC, Rubagotti M, Bertazzi PA. 2008. Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up. American Journal of Epidemiology 167(7):847–858. Cordier S, Le TB, Verger P, Bard D, Le CD, Larouze B, Dazza MC, Hoang TQ, Abenhaim L. 1993. Viral infections and chemical exposures as risk factors for hepatocellular carcinoma in Vietnam. International Journal of Cancer 55(2):196–201. Corrao G, Caller M, Carle F, Russo R, Bosia S, Piccioni P. 1989. Cancer risk in a cohort of licensed pesticide users. Scandinavian Journal of Work, Environment, and Health 15(3):203–209. Costani G, Rabitti P, Mambrini A, Bai E, Berrino F. 2000. Soft tissue sarcomas in the general popula- tion living near a chemical plant in northern Italy. Tumori 86(5):381–383. Cypel Y, Kang H. 2008. Mortality patterns among women Vietnam-era veterans: Results of a retro- spective cohort study. Annals of Epidemiology 18(3):244–252. Dalager NA, Kang HK. 1997. Mortality among Army Chemical Corps Vietnam veterans. American Journal of Industrial Medicine 31(6):719–726. Dalager NA, Kang HK, Burt VL, Weatherbee L. 1991. Non-Hodgkin’s lymphoma among Vietnam veterans. Journal of Occupational Medicine 33(7):774–779.

420 VETERANS AND AGENT ORANGE: UPDATE 2008 Dalager NA, Kang HK, Thomas TL. 1995. Cancer mortality patterns among women who served in the military: The Vietnam experience. Journal of Occupational and Environmental Medicine 37(3):298–305. Davis BJ, McCurdy EA, Miller BD, Lucier GW, Tritscher AM. 2000. Ovarian tumors in rats induced by chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Cancer Research 60(19):5414–5419. Dean G. 1994. Deaths from primary brain cancers, lymphatic and haematopoietic cancers in agri- cultural workers in the Republic of Ireland. Journal of Epidemiology and Community Health 48(4):364–368. Demers A, Ayotte P, Brisson J, Dodin S, Robert J, Dewailly E. 2000. Risk and aggressiveness of breast cancer in relation to plasma organochlorine concentrations. Cancer Epidemiology, Biomarkers and Prevention 9(2):161–166. Demers PA, Boffetta P, Kogevinas M, Blair A, Miller BA, Robinson CF, Roscoe RJ, Winter PD, Colin D, Matos E, et al. 1995. Pooled reanalysis of cancer mortality among five cohorts of workers in wood-related industries. Scandinavian Journal of Work, Environment and Health 21(3):179–190. Desaulniers D, Leingartner K, Russo J, Perkins G, Chittim BG, Archer MC, Wade M, Yang J. 2001. Modulatory effects of neonatal exposure to TCDD or a mixture of PCBs, p,p′-DDT, and p-p′- DDE on methylnitrosourea-induced mammary tumor development in the rat. Environmental Health Perspectives 109:739–747. Desaulniers D, Leingartner K, Musicki B, Cole J, Li M, Charboneau M, Tsang BK. 2004. Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the devel- opment of methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Journal of Toxicology and Environmental Health, Part A 67(18):1457–1475. Dich J, Wiklund K. 1998. Prostate cancer in pesticide applicators in Swedish agriculture. Prostate 34(2):100–112. Donna A, Betta P-G, Robutti F, Crosignani P, Berrino F, Bellingeri D. 1984. Ovarian mesothelial tumors and herbicides: A case–control study. Carcinogenesis 5(7):941–942. Dopp E, Von Recklinghausen U, Hartmann LM, Stueckradt I, Pollok I, Rabieh S, Hao L, Nussler A, Katier C, Hirner AV, Rettenmeier AW. 2008. Subcellular distribution of inorganic and methyl- ated arsenic compounds in human urothelial cells and human hepatocytes. Drug Metabolism and Disposition 36(5):971–979. Dubrow R, Paulson JO, Indian RW. 1988. Farming and malignant lymphoma in Hancock County, Ohio. British Journal of Industrial Medicine 45(1):25–28. Duell EJ, Millikan RC, Savitz DA, Newman B, Smith JC, Schell MJ, Sandler DP. 2000. A population- based case–control study of farming and breast cancer in North Carolina. Epidemiology 11(5): 523–531. Ekström AM, Eriksson M, Hansson L-E, Lindgren A, Signorello LB, Nyrén O, Hardell L. 1999. Occupational exposures and risk of gastric cancer in a population-based case–control study. Cancer Research 59:5932–5937. Engel LS, Hill DA, Hoppin JA, Lubin JH, Lynch CF, Pierce J, Samanic C, Sandler DP, Blair A, Alavanja MC. 2005. Pesticide use and breast cancer risk among farmers’ wives in the Agricul- tural Health Study. American Journal of Epidemiology 161(2):121–135. Eriksson M, Karlsson M. 1992. Occupational and other environmental factors and multiple myeloma: A population based case–control study. British Journal of Industrial Medicine 49(2):95–103. Eriksson M, Hardell L, Berg NO, Moller T, Axelson O. 1979. Case–control study on malignant mesenchymal tumor of the soft tissue and exposure to chemical substances. Lakartidningen 76(44):3872–3875. Eriksson M, Hardell L, Berg NO, Moller T, Axelson O. 1981. Soft-tissue sarcomas and expo- sure to chemical substances: A case-referent study. British Journal of Industrial Medicine 38(1):27–33.

CANCER 421 Eriksson M, Hardell L, Malker H, Weiner J. 1992. Malignant lymphoproliferative diseases in oc- ��������������������������������������������� cupations with potential exposure to phenoxyacetic acids or dioxins: A register-based study. American Journal of Industrial Medicine 22:305–312. Eriksson M, Hardell L, Carlberg M, Akerman M. 2008. Pesticide exposure as risk factor for non- Hodgkin lymphoma including histopathological subgroup analysis. International Journal of Cancer 123(7):1657–1663. Fenton SE. 2006. Endocrine-disrupting compounds and mammary gland development: Early expo- sure and later life consequences. Endocrinology 147(6):S18–S24. Fett MJ, Nairn JR, Cobbin DM, Adena MA. 1987. Mortality among Australian conscripts of the Viet- nam conflict era. II. Causes of death. American Journal of Epidemiology 125(15):878–884. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8- tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324(4):212–218. Fleming LE, Bean JA, Rudolph M, Hamilton K. 1999a. Mortality in a cohort of licensed pesticide applicators in Florida. Journal of Occupational and Environmental Medicine 56(1):14–21. Fleming LE, Bean JA, Rudolph M, Hamilton K. 1999b. Cancer incidence in a cohort of licensed pesticide applicators in Florida. Journal of Occupational and Environmental Medicine 41(4): 279–288. Floret N, Mauny F, Challier B, Arveux P, Cahn J-Y, Viel J-F. 2003. Dioxin emissions from a solid waste incinerator and risk of non-Hodgkin lymphoma. Epidemiology 14(4):392–398. Fortes C, Mastroeni S, Melchi F, Pilla MA, Alotto M, Antonelli G, Camaione D, Bolli S, Luchetti E, Pasquini P. 2007. The association between residential pesticide use and cutaneous melanoma. European Journal of Cancer 43(6):1066–1075. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, Grulich A, Milliken S, Kaldor J, Armstrong BK. 2005. Occupational exposure to pesticides and risk of non-Hodgkin’s lym- phoma. American Journal of Epidemiology 162(9):849–857. Fritz WA, Lin TM, Moore RW, Cooke PS, Peterson RE. 2005. In utero and lactational 2,3,7,8- tetrachlorodibenzo-p-dioxin exposure: Effects on the prostate and its response to castration in senescent C57BL/6J mice. Toxicological Sciences 86(2):387–395. Fritz WA, Lin T-M, Peterson RE. 2008. The aryl hydrocarbon receptor (AhR) inhibits vanadate- induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. Carcino- genesis 29(5):1077–1082. Fukuda Y, Nakamura K, Takano T. 2003. Dioxins released from incineration plants and mortality from major diseases: An analysis of statistical data by municipalities. Journal of Medical and Dental Sciences 50(4):249–255. Fukushima S, Morimura K, Wanibuchi H, Kinoshita A, Salim EI. 2005. Current and emerging challenges in toxicopathology: Carcinogenic threshold of phenobarbital and proof of arsenic carcinogenicity using rat medium-term bioassays for carcinogens. Toxicology and Applied Pharmacology 207(2 Suppl):225–229. Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe AR, Coldman A, McLean DI. 1996. Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiology, Biomarkers and Prevention 5(6):419–424. Gambini GF, Mantovani C, Pira E, Piolatto PG, Negri E. 1997. Cancer mortality among rice growers in Novara Province, northern Italy. American Journal of Industrial Medicine 31(4):435–441. Gann PH. 1997. Interpreting recent trends in prostate cancer incidence and mortality. Epidemiology 8(2):117–120. Garland FC, Gorham ED, Garland CF, Ferns JA. 1988. Non-Hodgkin’s lymphoma in US Navy per- sonnel. Archives of Environmental Health 43(6):425–429. Giri VN, Cassidy AE, Beebe-Dimmer J, Smith DC, Bock CH, Cooney KA. 2004. Association be- tween Agent Orange and prostate cancer: A pilot case–control study. Urology 63(4):757–760; discussion 760–761.

422 VETERANS AND AGENT ORANGE: UPDATE 2008 Green LM. 1991. A cohort mortality study of forestry workers exposed to phenoxy acid herbicides. British Journal of Industrial Medicine 48(4):234–238. Greenwald P, Kovasznay B, Collins DN, Therriault G. 1984. Sarcomas of soft tissues after Vietnam service. Journal of the National Cancer Institute 73(5):1107–1109. Gupta A, Ketchum N, Roehrborn CG, Schecter A, Aragaki CC, Michalek JE. 2006. Serum dioxin, testosterone, and subsequent risk of benign prostatic hyperplasia: A prospective cohort study of Air Force veterans. Environmental Health Perspectives 114(11):1649–1654. Hahn WC, Weinberg RA. 2002. Rules for making human tumor cells. New England Journal of Medicine 347(20):1593–1603. Hallek M, Cheson B, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keat- ing MJ, Montserrat E, Rai K, Kipps TJ. 2008. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lympho- cytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood 111(12):5446–5456. Hallquist A, Hardell L, Degerman A, Boquist L. 1993. Occupational exposures and thyroid cancer: Results of a case–control study. European Journal of Cancer Prevention 2(4):345–349. Hansen ES, Hasle H, Lander F. 1992. A cohort study on cancer incidence among Danish gardeners. American Journal of Industrial Medicine 21(5):651–660. Hansen ES, Lander F, Lauritsen JM. 2007. Time trends in cancer risk and pesticide exposure, a long- term follow-up of Danish gardeners. Scandinavian Journal of Work, Environment and Health 33(6):465–469. Hardell L. 1981. Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents. Scandinavian Journal of Work, Environment, and Health 7(2):119–130. Hardell L, Bengtsson NO. 1983. Epidemiological study of socioeconomic factors and clinical find- ings in Hodgkin’s disease, and reanalysis of previous data regarding chemical exposure. British Journal of Cancer 48(2):217–225. Hardell L, Eriksson M, Lenner P, Lundgren E. 1981. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids: A case–control study. British Journal of Cancer 43:169–176. Hardell L, Johansson B, Axelson O. 1982. Epidemiological study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. American Journal of Industrial Medicine 3(3):247–257. Hardell L, Bengtsson NO, Jonsson U, Eriksson S, Larsson LG. 1984. Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria: An epidemiological investigation. British Journal of Cancer 50(3):389–397. Hardell L, Eriksson M, Degerman A. 1994. Exposure to phenoxyacetic acids, chlorophenols, or or- ganic solvents in relation to histopathology, stage, and anatomical localization of non-Hodgkin’s lymphoma. Cancer Research 54(9):2386–2389. Hardell L, Nasman A, Ohlson CG, Fredrikson M. 1998. Case–control study on risk factors for tes- ticular cancer. International Journal of Oncology 13(6):1299–1303. Hardell L, Lindström G, van Bavel B, Hardell K, Linde A, Carlberg M, Liljegren G. 2001. Adipose tis- sue concentrations of dioxins and dibenzofurans, titers of antibodies to Epstein-Barr virus early antigen and the risk for non-Hodgkin’s lymphoma. Environmental Research 87(2):99–107. Hardell L, Eriksson M, Nordstrom M. 2002. Exposure to pesticides as risk factor for non-Hodgkin’s lymphoma and hairy cell leukemia: Pooled analysis of two Swedish case–control studies. Leu- kemia and Lymphoma 43(5):1043–1049. Hartge P, Colt JS, Severson RK, Cerhan JR, Cozen W, Camann D, Zahm SH, Davis S. 2005. Resi- dential herbicide use and risk of non-Hodgkin lymphoma. Cancer Epidemiology, Biomarkers and Prevention 14(4):934–937.

CANCER 423 Hayashi H, Kanisawa M, Yamanaka K, Ito T, Udaka N, Ohji H, Okudela K, Okada S, Kitamura H. 1998. Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice. Cancer Letters 125(1-2):83–88. Hayes RB. 1997. The carcinogenicity of metals in humans. Cancer Causes and Control 8(3): 371–385. Hebert CD, Harris MW, Elwell MR. Birnbaum LS. 1990. Relative toxicity and tumor-promoting abil- ity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) in hairless mice. Toxicology and Applied Pharmacology 102(2):362–377. Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46(9):658–664. Heron M, Hoyert D, Murphy S, Xu J, Kochanek K, Tejada-Vera B. 2009. Deaths: Final data for 2006. National Vital Statistics Reports 57(14):1–80. Hertzman C, Teschke K, Ostry A, Hershler R, Dimich-Ward H, Kelly S, Spinelli JJ, Gallagher RP, McBride M, Marion SA. 1997. Mortality and cancer incidence among sawmill workers exposed to chlorophenate wood preservatives. American Journal of Public Health 87(1):71–79. Hoar SK, Blair A, Holmes FF, Boysen CD, Robel RJ, Hoover R, Fraumeni JF. 1986. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. Journal of the American Medical Association 256(9):1141–1147. Hobbs CG, Birchall MA. 2004. Human papillomavirus infection in the etiology of laryngeal carci- noma. Current Opinion in Otolaryngology and Head and Neck Surgery 12(2):88–92. Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin. Journal of the American Medical Association 255(15):2031–2038. Holcombe M, Safe S. 1994. Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumor growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Letters 82(1):43–47. Holford TR, Zheng T, Mayne ST, Zahm SH, Tessari JD, Boyle P. 2000. Joint effects of nine polychlo- rinated biphenyl (PCB) congeners on breast cancer risk. International Journal of Epidemiology 29(6):975–982. Hollingshead BD, Beischlag TV, Dinatale BC, Ramadoss P, Perdew GH. 2008. Inflammatory signal- ing and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. Cancer Research 68(10):3609–3617. Holmes AP, Bailey C, Baron RC, Bosanac E, Brough J, Conroy C, Haddy L. 1986. West Virginia Department of Health Vietnam-Era Veterans Mortality Study: Preliminary Report. Charlestown: West Virginia Health Department. Hooiveld M, Heederik DJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG Jr, Bueno de Mesquita HB. 1998. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 147(9):891–901. Høyer AP, Jørgensen T, Brock JW, Grandjean P. 2000. Organochlorine exposure and breast cancer survival. Journal of Clinical Epidemiology 53(3):323–330. Hsu EL, Yoon D, Choi HH, Wang F, Taylor RT, Chen N, Zhang R, Hankinson O. 2007. A proposed mechanism for the protective effect of dioxin against breast cancer. Toxicological Sciences 98(2):436–444. Huang YK, Pu YS, Chung CJ, Shiue HS, Yang MH, Chen CJ, Hsueh YM. 2008. Plasma folate level, urinary arsenic methylation profiles, and urothelial carcinoma susceptibility. Food and Chemical Toxicology 46(3):929–938. Hussein MA, Juturi JV, Lieberman I. 2002. Multiple myeloma: Present and future. Current Opinions in Oncology 14(1):31–35. IARC (International Agency for Research on Cancer). 2001. Pathology and genetics of tumours of the haemopoietic and lymphoid tissues. In: Jaffe NL, Harris H, Stein, Vardiman JW, eds. World Health Organization, IARC. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

424 VETERANS AND AGENT ORANGE: UPDATE 2008 IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001.Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. IOM. 2006. Asbestos: Selected Cancers. Washington, DC: The National Academies Press. IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun M. 2008a. Cancer Statistics, 2008. CA: A Cancer Journal for Clinicians 58(2):71–96. Jemal A, Thun MJ, Ries L, Howe H, Weir HK, Center MM, Ward E, Wu X-C, Eheman C, Anderson R, Ajani UA, Kohler B, Edwards BK. 2008b. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. Journal of the National Cancer Institute 100(23):1672–1694. Jenkins S, Rowell C, Wang J, Lamartiniere CA. 2007. Prenatal TCDD exposure predisposes for mam- mary cancer in rats. Reproductive Toxicology 23(3):391–396. Kang HK, Weatherbee L, Breslin PP, Lee Y, Shepard BM. 1986. Soft tissue sarcomas and military service in Vietnam: A case comparison group analysis of hospital patients. Journal of Occupa- tional Medicine 28(12):1215–1218. Kang HK, Mahan CM, Lee KY, Magee CA, Selvin S. 2000. Prevalence of gynecologic cancers among female Vietnam veterans. Journal of Occupational and Environmental Medicine 42(11): 1121–1127. Kato H, Kinshita T, Suzuki S, Nagasaka T, Hatano S, Murate T, Saito H, Hotta T. 1998. Production and effects of interleukin–6 and other cytokines in patients with non-Hodgkin’s lymphoma. Leukemia and Lmphoma 29(1–2):71–79. Kato I, Watanabe-Meserve H, Koenig KL, Baptiste MS, Lillquist PP, Frizzera G, Burke JS, Moseson M, Shore RE. 2004. Pesticide product use and risk of non-Hodgkin lymphoma in women. En- vironmental Health Perspectives 112(13):1275–1281. Keller-Byrne JE, Khuder SA, Schaub EA, McAfee O. 1997. A meta-analysis of non-Hodgkin’s lym- phoma among farmers in the central United States. American Journal of Industrial Medicine 31(4):442–444. Ketchum NS, Michalek JE, Burton JE. 1999. Serum dioxin and cancer in veterans of Operation Ranch Hand. American Journal of Epidemiology 149(7):630–639. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. 2004. Diet, nutrition and the prevention of cancer. Public Health Nutrition 7(1A):187–200. Knerr S, Schrenk D. 2006. Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Molecular Nutrition and Food Research 50(10):897–907. Kociba RJ, Keys DG, Beyer JE, Careon RM, Wade CE, Dittenber DA, Kalnins RP, Frauson LE, Park CN, Barnar SD, Hummel RA, Humiston CG. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicology and Applied Pharmacology 46:279–303. Kogan MD, Clapp RW. 1988. Soft tissue sarcoma mortality among Vietnam veterans in Massachu- setts, 1972 to 1983. International Journal of Epidemiology 17(1):39–43. Kogevinas M, Saracci R, Bertazzi PA, Bueno de Mesquita BH, Coggon D, Green LM, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Osman J, Pearce N, Winkelmann R. 1992. Cancer mortality from soft-tissue sarcoma and malignant lymphomas in an international cohort of workers exposed to chlorophenoxy herbicides and chlorophenols. Chemosphere 25: 1071–1076.

CANCER 425 Kogevinas M, Saracci R, Winkelmann R, Johnson ES, Bertazzi PA, Bueno de Mesquita BH, Kaup- pinen T, Littorin M, Lynge E, Neuberger M. 1993. Cancer incidence and mortality in women oc- cupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins. Cancer Causes and Control 4(6):547–553. Kogevinas M, Kauppinen T, Winkelmann R, Becher H, Bertazzi PA, Bas B, Coggon D, Green L, Johnson E, Littorin M, Lynge E, Marlow DA, Mathews JD, Neuberger M, Benn T, Pannett B, Pearce N, Saracci R. 1995. Soft tissue sarcoma and non-Hodgkin’s lymphoma in workers exposed to phenoxy herbicides, chlorophenols and dioxins: Two nested case–control studies. Epidemiology 6(4):396–402. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno de Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061–1075. Korenaga T, Fukusato T, Ohta M, Asaoka K, Murata N, Arima A, Kubota S. 2007. Long-term effects of subcutaneously injected 2,3,7,8-tetrachlorodibenzo-p-dioxin on the liver of rhesus monkeys. Chemosphere 67(9):S399–S404. Kovacs E. 2006. Multiple myeloma and B cell lymphoma: Investigation of IL–6, IL–6 receptor antagonist (IL–6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model. The Scientific World Journal 6:888–898. Küppers R, Schwering I, Bräuninger A, Rajewsky K, Hansmann M. 2002. Biology of Hodgkin’s lymphoma. Annals of Oncology 13 (Supplement 1):11–18. Lampi P, Hakulinen T, Luostarinen T, Pukkala E, Teppo L. 1992. Cancer incidence following chlo- rophenol exposure in a community in southern Finland. Archives of Environmental Health 47(3):167–175. LaVecchia C, Negri E, D’Avanzo B, Franceschi S. 1989. Occupation and lymphoid neoplasms. British Journal of Cancer 60(3):385–388. Lawrence CE, Reilly AA, Quickenton P, Greenwald P, Page WF, Kuntz AJ. 1985. Mortality patterns of New York State Vietnam veterans. American Journal of Public Health 75(3):277–279. Leavy J, Ambrosini G, Fritschi L. 2006. Vietnam military service history and prostate cancer. BMC Public Health 6:75. Lee WJ, Lijinsky W, Heineman EF, Markin RS, Weisenburger DD, Ward MH. 2004a. Agricultural pesticide use and adenocarcinomas of the stomach and oesophagus. Occupational and Environ- mental Medicine 61(9):743–749. Lee WJ, Cantor KP, Berzofsky JA, Zahm SH, Blair A. 2004b. Non-Hodgkin’s lymphoma among asthmatics exposed to pesticides. International Journal of Cancer 111(2):298–302. Lee WJ, Colt JS, Heineman EF, McComb R, Weisenburger DD, Lijinsky W, Ward MH. 2005. Agricultural pesticide use and risk of glioma in Nebraska, United States. Occupational and Environmental Medicine 62(11):786–792. Lee WJ, Sandler DP, Blair A, Samanic C, Cross AJ, Alavanja MC. 2007. Pesticide use and colorectal cancer risk in the Agricultural Health Study. International Journal of Cancer 121(2):339–346. Lin PH, Lin CH, Huang CC, Chuang MC, Lin P. 2007. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines. Toxicology Letters 172(3):146–158. Lin PH, Lin CH, Huang CC, Fang JP, Chuang MC. 2008. 2,3,7,8-tetrachlorodibenzo-p-dioxin modu- lates the induction of DNA strand breaks and poly(ADP-ribose) polymerase-1 activation by 17beta-estradiol in human breast carcinoma cells through alteration of CYP1A1 and CYP1B1 expression. Chemical Research in Toxicology 21(7):1337–1347. Lin TM, Rasmussen NT, Moore RW, Albrecht RM, Peterson RE. 2004. 2,3,7,8-tetrachlorodibenzo- p-dioxin inhibits prostatic epithelial bud formation by acting directly on the urogenital sinus. Journal of Urology 172(1):365–368.

426 VETERANS AND AGENT ORANGE: UPDATE 2008 Liu J, Singh B, Tallini G, Carlson DL, Katabi N, Shaha A, Tuttle RM, Ghossein RA. 2006. Follicular variant of papillary thyroid carcinoma: A clinicopathologic study of a problematic entity. Cancer 107:1255–1264. Lynge E. 1985. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. British Journal of Cancer 52(2):259–270. Lynge E. 1993. Cancer in phenoxy herbicide manufacturing workers in Denmark, 1947–87—an update. Cancer Causes and Control 4(3):261–272. Mack TM. 1995. Sarcomas and other malignancies of soft tissue, retroperitoneum, peritoneum, pleura, heart, mediastinum, and spleen. Cancer 75(1):211–244. Magnani C, Coggon D, Osmond C, Acheson ED. 1987. Occupation and five cancers: A case–control study using death certificates. British Journal of Industrial Medicine 44(11):769–776. Mahan CM, Bullman TA, Kang HK, Selvin S. 1997. A case–control study of lung cancer among Vietnam veterans. Journal of Occupational and Environmental Medicine 39(8):740–747. Mantovani A, Allavena P, Sica A, Balkwill F. 2008. Cancer-related inflammation. Nature 454: 436–444. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338(8773):959–964. Marlowe JL, Fan Y, Chang X, Peng L, Knudsen ES, Xia Y, Puga A. 2008. The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Molecular Biology of the Cell 19:3263–3271. McDuffie HH, Klaassen DJ, Dosman JA. 1990. Is pesticide use related to the risk of primary lung cancer in Saskatchewan? Journal of Occupational Medicine 32(10):996–1002. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW. 2001. Non-Hodgkin’s lymphoma and specific pesticide exposures in men: Cross- Canada study of pesticides and health. Cancer Epidemiology, Biomarkers and Prevention 10(11): 1155–1163. McGee SF, Lanigan F, Gilligan E, Groner B. 2006. Mammary gland biology and breast cancer. Conference on Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer Progression. EMBO Reports 7(11):1084–1088. McLean D, Pearce N, Langseth H, Jäppinen P, Szadkowska-Stanczyk I, Person B, Wild P, Ki- shi R, Lynge E, Henneberger P, Sala M, Teschke K, Kauppinen T, Colin D, Kogevinas M, Boffetta P. 2006. Cancer mortality in workers exposed to organochlorine compounds in the pulp and paper industry: An international collaborative study. Environmental Health Perspec- tives 114(7):1007–1012. Mellemgaard A, Engholm G, McLaughlin JK, Olsen JH. 1994. Occupational risk factors for renal- cell carcinoma in Denmark. Scandinavian Journal of Work, Environment, and Health 20(3): 160–165. Merletti F, Richiardi L, Bertoni F, Ahrens W, Buemi A, Costa-Santos C, Eriksson M, Guenel P, Kaerlev L, Jockel K-H, Llopis-Gonzalez A, Merler E, Miranda A, Morales-Suarez-Varela, MM, Olsson H, Fletcher T, Olsen J. 2006. Occupational factors and risk of adult bone sarcomas: A multicentric case–control study in Europe. International Journal of Cancer 118(3):721–727. Michalek JE, Pavuk M. 2008. ����������������������������������������������������������������� Diabetes and cancer in Veterans of Operation Ranch Hand after ad- justment for calendar period, days of sprayings, and time spent in Southeast Asia. Journal of Occupational and Environmental Medicine 50(3):330–340. Michalek JE, Wolfe WH, Miner JC. 1990. Health status of Air Force veterans occupationally ex- posed to herbicides in Vietnam. II. Mortality. Journal of the American Medical Association 264(14):1832–1836. Miligi L, Costantini AS, Bolejack V, Veraldi A, Benvenuti A, Nanni O, Ramazzotti V, Tumino R, Stagnaro E, Rodella S, Fontana A, Vindigni C, Vineis P. 2003. Non-Hodgkin’s lymphoma, leu- kemia, and exposures in agriculture: Results from the Italian Multicenter Case–Control Study. American Journal of Industrial Medicine 44:627–636.

CANCER 427 Miligi L, Costantini AS, Veraldi A, Benvenuti A, Will, Vineis P. 2006. Cancer and pesticides: An overview and some results of the Italian multicenter case–control study on hematolymphopoietic malignancies. Annals of the New York Academy of Sciences 1076:366–377. Miller BA, Kolonel LN, Bernstein L, Young JL Jr, Swanson GM, West D, Key CR, Liff JM, Glover CS, Alexander GA, et al. (eds). 1996. Racial/Ethnic Patterns of Cancer in the United States 1988–1992. Bethesda, MD: National Cancer Institute. NIH Pub. No. 96-4104. Mills PK, Yang R. 2005. Breast cancer risk in Hispanic agricultural workers in California. Interna- tional Journal of Occupational and Environmental Health 11(2):123–131. Mills PK, Yang RC. 2007. Agricultural exposures and gastric cancer risk in Hispanic farm workers in California. Environmental Research 104(2):282–289. Mills PK, Yang R, Riordan D. 2005. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988–2001. Cancer Causes and Control 16(7):823–830. Morris PD, Koepsell TD, Daling JR, Taylor JW, Lyon JL, Swanson GM, Child M, Weiss NS. 1986. Toxic substance exposure and multiple myeloma: A case–control study. Journal of the National Cancer Institute 76(6):987–994. Morrison H, Semenciw RM, Morison D, Magwood S, Mao Y. 1992. Brain cancer and farming in western Canada. Neuroepidemiology 11(4-6):267–276. Morrison H, Savitz D, Semenciw RM, Hulka B, Mao Y, Morison D, Wigle D. 1993. Farming and prostate cancer mortality. American Journal of Epidemiology 137(3):270–280. Morrison HI, Semenciw RM, Wilkins K, Mao Y, Wigle DT. 1994. Non-Hodgkin’s lymphoma and agricultural practices in the prairie provinces of Canada. Scandinavian Journal of Work, Envi- ronment, and Health 20(1):42–47. Mulero-Navarro S, Carvajal-Gonzalez JM, Herranz M, Ballestar E, Fraga MF, Ropero S, Esteller M, Fernandez-Salguero PM. 2006. The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding. Carcinogenesis 27(5):1099–1104. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. 1988. A case–control study of brain gliomas and occupational exposure to chemical carcinogens: The risks to farmers. American Journal of Epidemiology 128:778–785. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, Buiatti E. 1996. Chronic lympho- cytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breed- ing workers: A population case–control study based on a priori exposure matrices. Occupational and Environmental Medicine 53(10):652–657. Nascimento MG, Suzuki S, Wei M, Tiwari A, Arnold LL, Lu X, Le XC, Cohen SM. 2008. Cytotox- icity of combinations of arsenicals on rat urinary bladder urothelial cells in vitro. Toxicology 249(1):69–74. NCI (National Cancer Institute). 2008. Surveillance, Epidemiology, and End Results (SEER) Incidence and US Mortality Statistics: SEER Incidence—Crude Rates for White/Black/Other 2000–2005. http://www.seer.cancer.gov/canques/incidence.html (Accessed February 2, 2009). Nordby KC, Andersen A, Kristensen P. 2004. Incidence of lip cancer in the male Norwegian agricul- tural population. Cancer Causes and Control 15(6):619–626. NTP (National Toxicology Program). 1982a. Technical Report Series No. 209. Carcinogenesis Bio- assay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in Osborne-Mendel Rats and B6c3F1 Mice (Gavage Study). NIH Publication No. 82-1765. 195 pp. National Toxicology Program, Research Triangle Park, NC, and Bethesda, MD. NTP. 1982b. Technical Report Series No. 201. Carcinogenesis Bioassay of 2,3,7,8-Tetrachloro­ dibenzo-p-dioxin (CAS No. 1746-01-6) in Swiss-Webster Mice (Dermal Study). National Toxi- cology Program, Research Triangle Park, NC, and Bethesda, MD. NTP. 2006. NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,3,7,8- Tetra­chlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in Female Harlan Sprague-Dawley Rats (Gavage Studies). Issue 521:4–232. National Toxicology Program, Research Triangle Park, NC, and Bethesda, MD.

428 VETERANS AND AGENT ORANGE: UPDATE 2008 Nyska A, Jokinen MP, Brix AE, Sells DM, Wyde ME, Orzech D, Haseman JK, Flake G, Walker NJ. 2004. Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Environmental Health Perspectives 112(8):903–909. Nyska A, Yoshizawa K, Jokinen MP, Brix AE, Sells DM, Wyde ME, Orzech DP, Kissling GE, Walker NJ. 2005. Olfactory epithelial metaplasia and hyperplasia in female Harlan Sprague- Dawley rats following chronic treatment with polychlorinated biphenyls. Toxicologic Pathology 33(3):371–377. O’Brien TR, Decoufle P, Boyle CA.1991. Non-Hodgkin’s lymphoma in a cohort of Vietnam veterans. American Journal of Public Health 81:758–760. Ojajärvi IA, Partanen TJ, Ahlbom A, Boffetta P, Hakulinen T, Jourenkova N, Kauppinen TP, Kogevinas M, Porta M, Vainio HU, Weiderpass E, Wesseling CH. 2000. Occupational exposures and pan- creatic cancer: A meta-analysis. Occupational and Environmental Medicine 57:316–324. Olsson H, Brandt L. 1988. Risk of non-Hodgkin’s lymphoma among men occupationally exposed to organic solvents. Scandinavian Journal of Work, Environment, and Health 14:246–251. Omoti C, Omoti A. 2008. Richter syndrome: A review of clinical, ocular, neurological and other manifestations. British Journal of Haematology 142:709–716. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Environmental Medicine 53:606–612. Pahwa P, McDuffie HH, Dosman JA, McLaughlin JR, Spinelli JJ, Robson D, Fincham S. 2006. Hodgkin lymphoma, multiple myeloma, soft tissue sarcomas, insect repellents, and phenoxy- herbicides. Journal of Occupational and Environmental Medicine 48(3):264–274. Park JY, Shigenaga MK, Ames BN. 1996. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachloro­ dibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage. Proceed- ings of the National Academy of Sciences of the United States of America 93(6):2322–2327. Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. 2005. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange? Journal of Occupational and Environmental Medicine 47(4):335–342. Pavuk M, Michalek JE, Ketchum NS. 2006. Prostate cancer in US Air Force veterans of the Vietnam War. Journal of Exposure Science and Environmental Epidemiology 16(2):184–190. Pearce NE, Smith AH, Fisher DO. 1985. Malignant lymphoma and multiple myeloma linked with agricultural occupations in a New Zealand cancer registry-based sudy. American Journal of Epidemiology 121:225–237. Pearce NE, Smith AH, Howard JK, Sheppard RA, Giles HJ, Teague CA. 1986. Non-Hodgkin’s lymphoma and exposure to phenoxyherbicides, chlorophenols, fencing work, and meat works employment: A case control study. British Journal of Industrial Medicine 43:75–83. Pearce NE, Sheppard RA, Smith AH, Teague CA. 1987. Non-Hodgkin’s lymphoma and farming: An expanded case–control study. International Journal of Cancer 39:155–161. Percy C, Ries GL, Van Holten VD. 1990. The accuracy of liver cancer as the underlying cause of death on death certificates. Public Health Reports 105:361–368. Persson B, Dahlander AM, Fredriksson M, Brage HN, Ohlson CG, Axelson O. 1989. Malignant lym- phomas and occupational exposures. British Journal of Industrial Medicine 46:516–520. Persson B, Fredriksson M, Olsen K, Boeryd B, Axelson O. 1993. Some occupational exposures as risk factors for malignant lymphomas. Cancer 72:1773–1778. Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C, Bertazzi PA. 1992. Cancer morbidity in the Seveso area, 1976–1986. Chemosphere 25:209–212. Poland A, Palen D, Glover E. 1982. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300(5889):271–273. Pu YS, Yang SM, Huang YK, Chung CJ, Huang SK, Chiu AW, Yang MH, Chen CJ, Hsueh YM. 2007. Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure. Toxicology and Applied Pharmacology 218(2):99–106.

CANCER 429 Rajkumar SV, Dispenzieri A, Kyle RA. 2006. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: Diagnosis and treatment. Mayo Clinic Proceedings 81(5):693–703. Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940–1989. American Journal of Indus- trial Medicine 30:180–194. Read D, Wright C, Weinstein P, Borman B. 2007. Cancer incidence and mortality in a New Zea- land community potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin from 2,4,5-tri­ chlorophenoxyacetic acid manufacture. Australian and New Zealand Journal of Public Health 31(1):13–18. Reif JS, Pearce N, Fraser J. 1989. Occupational risks of brain cancer: A New Zealand cancer registry- based study. Journal of Occupational Medicine 31(10):863–867. Revich B, Aksel E, Ushakova T, Ivanova I, Zhuchenko N, Klyuev N, Brodsky B, Sotskov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 243(4-7):951–966. Reynolds P, Hurley SE, Goldberg DE, Anton-Culver H, Bernstein L, Deapen D, Horn-Ross PL, Peel D, Pinder R, Ross RK, West D, Wright WE, Ziogas A. 2004. Residential proximity to agri- cultural pesticide use and incidence of breast cancer in the California Teachers Study cohort. Environmental Research 96(2):206–218. Reynolds P, Hurley SE, Petreas M, Goldberg DE, Smith D, Gilliss D, Mahoney ME, Jeffrey SS. 2005a. Adipose levels of dioxins and risk of breast cancer. Cancer Causes and Control 16(5): 525–535. Richardson DB, Terschuren C, Hoffmann W. 2008. Occupational risk factors for non-Hodgkin’s lymphoma: A population-based case–control study in Northern Germany. American Journal of Industrial Medicine 51(4):258–268. Riedel D, Pottern LM, Blattner WA. 1991. Etiology and epidemiology of multiple myeloma. In: Wiernick PH, Camellos G, Kyle RA, Schiffer CA, eds. Neoplastic Disease of the Blood and Blood Forming Organs. New York: Churchill Livingstone. Riihimaki V, Asp S, Hernberg S. 1982. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5- trichlorophenoxyacetic acid herbicide applicators in Finland: First report of an ongoing prospec- tive cohort study. Scandinavian Journal of Work, Environment, and Health 8:37–42. Rix BA, Villadsen E, Engholm G, Lynge E. 1998. Hodgkin’s disease, pharyngeal cancer, and soft tissue sarcomas in Danish paper mill workers. Journal of Occupational and Environmental Medicine 40(1):55–62. Robinson CF, Waxweiler RJ, Fowler DP. 1986. Mortality among production workers in pulp and paper mills. Scandinavian Journal of Work, Environment, and Health 12:552–560. Ronco G, Costa G, Lynge E. 1992. Cancer risk among Danish and Italian farmers. British Journal of Industrial Medicine 49:220–225. Roulland S, Navarro J-M, Grenot P, Milili M, Agopian J, et al. 2006. Follicular lymphoma-like B cell in healthy individuals: A novel intermediate step in early lymphomagenesis. The Journal of Experimental Medicine 203(11):2425–2431. Rowland RE, Edwards LA, Podd JV. 2007. Elevated sister chromatid exchange frequencies in New Zealand Vietnam War veterans. Cytogenetic and Genome Research 116(4):248–251. Ruder AM, Waters MA, Butler MA, Carreon T, Calvert GM, Davis-King KE, Schulte PA, Sanderson WT, Ward EM, Connally LB, Heineman EF, Mandel JS, Morton RF, Reding DJ, Rosenman KD, Talaska G. 2004. Gliomas and farm pesticide exposure in men: The Upper Midwest Health Study. Archives of Environmental Health 59(12):650–657. Salehi F, Turner MC, Phillips KP, Wigle DT, Krewski D, Aronson KJ. 2008. Review of the etiology of breast cancer with special attention to organochlorines as potential endocrine disruptors. Journal of Toxicology and Environmental Health—Part B: Critical Reviews 11(3–4):276–300.

430 VETERANS AND AGENT ORANGE: UPDATE 2008 Samanic C, Rusiecki J, Dosemeci M, Hou L, Hoppin JA, Sandler DP, Lubin J, Blair A, Alavanja MC. 2006. Cancer incidence among pesticide applicators exposed to dicamba in the agricultural health study. Environmental Health Perspectives 114(10):1521–1526. Samanic CM, De Roos AJ, Stewart PA, Rajaraman P, Waters MA, Inskip PD. 2008. Occupational exposure to pesticides and risk of adult brain tumors. American Journal of Epidemiology 167(8):976–985. Saracci R, Kogevinas M, Bertazzi PA, Bueno de Mesquita BH, Coggon D, Green LM, Kauppinen T, L’Abbe KA, Littorin M, Lynge E, Mathews JD, Neuberger M, Osman J, Pearce N, Winkelmann R. 1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 338:1027–1032. Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH. 2006. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biological Chemistry 387(9):1175–1187. Semenciw RM, Morrison HI, Morison D, Mao Y. 1994. Leukemia mortality and farming in the prairie provinces of Canada. Canadian Journal of Public Health 85:208–211. Senft AP, Dalton TP, Nebert DW, Genter MB, Puga A, Hutchinson RJ, Kerzee JK, Uno S, Shertzer HG. 2002. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radical Biology and Medicine 33(9):1268–1278. Sharma-Wagner S, Chokkalingam AP, Malker HS, Stone BJ, McLaughlin JK, Hsing AW. 2000. Occupation and prostate cancer risk in Sweden. Journal of Occupational and Environmental Medicine 42(5):517–525. Shertzer HG, Nebert DW, Puga A, Ary M, Sonntag D, Dixon K, Robinson LJ, Cianciolo E, Dalton TP. 1998. Dioxin causes a sustained oxidative stress response in the mouse. Biochemical and Biophysical Research Communications 253(1):44–48. Siemiatycki J, Wacholder S, Dewar R, Wald L, Bégin D, Richardson L, Rosenman K, Gérin M. 1988. Smoking and degree of occupational exposure: Are internal analyses in cohort studies likely to be confounded by smoking status? American Journal of Industrial Medicine 13(1):59–69. Simanainen U, Haavisto T, Tuomisto JT, Paranko J, Toppari J, Tuomisto J, Peterson RE, Viluksela M. 2004a. Pattern of male reproductive system effects after in utero and lactational 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) exposure in three differentially TCDD-sensitive rat lines. Toxicological Sciences 80(1):101–108. Simanainen U, Adamsson A, Tuomisto JT, Miettinen HM, Toppari J, Tuomisto J, Viluksela M. 2004b. Adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and effects on male re- productive organs in three differentially TCDD-susceptible rat lines. Toxicological Sciences 81(2):401–407. Smith AH, Pearce NE. 1986. Update on soft tissue sarcoma and phenoxyherbicides in New Zealand. Chemosphere 15:1795–1798. Smith AH, Fisher DO, Giles HJ, Pearce NE. 1983. The New Zealand soft tissue sarcoma case–control study: Interview findings concerning phenoxyacetic acid exposure. Chemosphere 12:565–571. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. 1984. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. Journal of the National Cancer Institute 73:1111–1117. Smith JG, Christophers AJ. 1992. Phenoxy herbicides and chlorophenols: A case control study on soft tissue sarcoma and malignant lymphoma. British Journal of Cancer 65:442–448. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ. 1998. Alcohol and breast cancer in women: A pooled analysis of cohort studies. Journal of the American Medical Association 279(7):535–540. Solet D, Zoloth SR, Sullivan C, Jewett J, Michaels DM. 1989. Patterns of mortality in pulp and paper workers. Journal of Occupational Medicine 31:627–630.

CANCER 431 Spinelli JJ, Ng CH, Weber JP, Connors JM, Gascoyne RD, Lai AS, Brooks-Wilson AR, Le ND, Berry BR, Gallagher RP. 2007. Organochlorines and risk of non-Hodgkin lymphoma. International Journal of Cancer 121(12):2767–2775. Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI. 1999. Cancer, heart disease, and diabe- tes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the National Cancer Institute 91(9):779–786. Stott WT, Johnson KA, Landry TD, Gorzinski SJ, Cieszlak FS. 1990. Chronic toxicity and onco- genicity of picloram in Fischer 344 rats. Journal of Toxicology and Environmental Health 30:91–104. Svensson BG, Mikoczy Z, Stromberg U, Hagmar L. 1995. Mortality and cancer incidence among Swedish fishermen with a high dietary intake of persistent organochlorine compounds. Scandi- navian Journal of Work, Environmental, and Health 21(2):106–115. Swaen GMH, van Vliet C, Slangen JJM, Sturmans F. 1992. Cancer mortality among licensed herbi- cide applicators. Scandinavian Journal of Work, Environment, and Health 18:201–204. Swaen GM, van Amelsvoort LG, Slangen JJ, Mohren DC. 2004. Cancer mortality in a cohort of li- censed herbicide applicators. International Archives of Occupational and Environmental Health 77(4):293–295. ’t Mannetje A, McLean D, Cheng S, Boffetta P, Colin D, Pearce N. 2005. Mortality in New Zealand workers exposed to phenoxy herbicides and dioxins. Occupational and Environmental Medicine 62(1):34–40. Tarone RE, Hayes HM, Hoover RN, Rosenthal JF, Brown LM, Pottern LM, Javadpour N, O’Connell KJ, Stutzman RE. 1991. Service in Vietnam and risk of testicular cancer. Journal of the National Cancer Institute 83:1497–1499. Teitelbaum SL, Gammon MD, Britton JA, Neugut AI, Levin B, Stellman SD. 2007. Reported resi- dential pesticide use and breast cancer risk on Long Island, New York. American Journal of Epidemiology 165(6):643–651. Thiess AM, Frentzel-Beyme R, Link R. 1982. Mortality study of persons exposed to dioxin in a tri- chlorophenol-process accident that occurred in the BASF AG on November 17, 1953. American Journal of Industrial Medicine 3:179–189. Thomas TL. 1987. Mortality among flavour and fragrance chemical plant workers in the United States. British Journal of Industrial Medicine 44:733–737. Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veter- ans: A preliminary report. American Journal of Industrial Medicine 18:665–673. Thomas TL, Kang H, Dalager N. 1991. Mortality among women Vietnam veterans, 1973–1987. American Journal of Epidemiology 134:973–980. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. 2003. The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 349(3):215–224. Thörn Å, Gustavsson P, Sadigh J, Westerlund-Hännerstrand B, Hogstedt C. 2000. Mortality and can- cer incidence among Swedish lumberjacks exposed to phenoxy herbicides. Occupational and Environmental Medicine 57:718–720. Torchio P, Lepore AR, Corrao G, Comba P, Settimi L, Belli S, Magnani C, di Orio F. 1994. Mortal- ity study on a cohort of Italian licensed pesticide users. The Science of the Total Environment 149(3):183–191. Toth K, Somfai-Relle S, Sugar J, Bence J. 1979. Carcinogenicity testing of herbicide 2,4,5-tri­ chlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature 278(5704): 548–549. Tuomisto JT, Pekkanen J, Kiviranta H, Tukiainen E, Vartiainen T, Tuomisto J. 2004. Soft-tissue sar- coma and dioxin: A case–control study. International Journal of Cancer 108(6):893–900.

432 VETERANS AND AGENT ORANGE: UPDATE 2008 van Grevenynghe J, Bernard M, Langouet S, Le Berre C, Fest T, Fardel O. 2005. Human CD34- positive hematopoietic stem cells constitute targets for carcinogenic polycyclic aromatic hydro- carbons. Journal of Pharmacology and Experimental Therapeutics 314(2):693–702. Van Miller JP, Lalich JJ, Allen JR. 1977. Increased incidence of neoplasms in rats exposed to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chemosphere 9:537–544. Viel JF, Arveux P, Baverel J, Cahn JY. 2000. Soft-tissue sarcoma and non-Hodgkin’s lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels. American Journal of Epidemiology 152(1):13–19. Viel JF, Clement MC, Hagi M, Grandjean S, Challier B, Danzon A. 2008. Dioxin emissions from a municipal solid waste incinerator and risk of invasive breast cancer: A population-based case–control study with GIS-derived exposure. International Journal of Health Geographics [Electronic Resource] 7:4. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, Maffi L, Pisa R, Ricci P, Zanini E, Comba P. 1986. Phenoxy herbicides and soft-tissue sarcomas in female rice weeders. A population-based case-referent study. Scandinavian Journal of Work, Environment, and Health 13:9–17. Vineis P, Faggiano F, Tedeschi M, Ciccone G. 1991. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides. Journal of the National Cancer Institute 83:362–363. Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnam-era veterans of Michigan. Journal of Occupational and Environmental Medicine 37(4):423–428. Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence BP. 2004. A novel effect of dioxin: Exposure during pregnancy severely impairs mammary gland differentiation. Toxicological Sciences 78(2):248–257. Walker NJ, Wyde ME, Fischer LJ, Nyska A, Bucher JR. 2006. Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats. Molecular Nutrition and Food Research 50(10):934–944. Wang S-L, Chang Y-C, Chao H-R, Li C-M, Li L-A, Lin L-Y, Papke O. 2006. Body burdens of poly- chlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls and their relations to estrogen metabolism in pregnant women. Environmental Health Perspectives 114(5):740–745. Wanibuchi H, Salim E, Kinoshita A, Shen J, Wei M, Morimura K, Yoshida K, Kuroda K, Endo G, Fukushima S. 2004. Understanding arsenic carcinogenicity by the use of animal models. Toxi- cology and Applied Pharmacology 198(3):366–376. Warner M, Eskenazi B, Mocarelli P, Gerthoux PM, Samuels S, Needham L, Patterson D, Brambilla P. 2002. Serum dioxin concentrations and breast cancer risk in the Seveso Women’s Health Study. Environmental Health Perspectives 110(7):625–628. Watanabe KK, Kang HK. 1995. Military service in Vietnam and the risk of death from trauma and selected cancers. Annals of Epidemiology 5:407–412. Watanabe KK, Kang HK. 1996. Mortality patterns among Vietnam veterans: A 24-year retrospective analysis. Journal of Occupational and Environmental Medicine 38(3):272–278. Watanabe KK, Kang HK, Thomas TL. 1991. Mortality among Vietnam veterans: With methodological considerations. Journal of Occupational Medicine 33:780–785. Waterhouse D, Carman WJ, Schottenfeld D, Gridley G, McLean S. 1996. Cancer incidence in the rural community of Tecumseh, Michigan: A pattern of increased lymphopoietic neoplasms. Cancer 77(4):763–770. Wei M, Wanibuchi H, Morimura K, Iwai S, Yoshida K, Endo G, Nakae D, Fukushima S. 2002. Carci- nogenicity of dimethylarsinic acid in make F344 rats and genetic alterations in incuded urinary bladder tumors. Carcinogenesis 23(8):1387–1397. Weiderpass E, Adami HO, Baron JA, Wicklund-Glynn A, Aune M, Atuma S, Persson I. 2000. Or- ganochlorines and endometrial cancer risk. Cancer Epidemiology, Biomarkers and Prevention 9:487–493.

CANCER 433 Weinberg RA. 2008. Twisted epithelial-mesenchymal transition blocks senescence. Nature Cell Biol- ogy 10(9):1021–1023. Wen S, Yang FX, Gong Y, Zhang XL, Hui Y, Li JG, Liu AIL, Wu YN, Lu WQ, Xu Y. 2008. Elevated levels of urinary 8-hydroxyl-2’-deoxyguanosine in male electrical and electronic equipment dismantling workers exposed to high concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans, polybrominated diphenyl ethers, and polychlorinated biphenyls. Environmental Science and Technology 42(11):4202–4207. Wigle DT, Semenciw RB, Wilkins K, Riedel D, Ritter L, Morrison HI, Mao Y. 1990. Mortality study of Canadian male farm operators: Non-Hodgkin’s lymphoma mortality and agricultural practices in Saskatchewan. Journal of the National Cancer Institute 82:575–582. Wiklund K. 1983. Swedish agricultural workers: A group with a decreased risk of cancer. Cancer 51:566–568. Wiklund K, Lindefors BM, Holm LE. 1988. Risk of malignant lymphoma in Swedish agricultural and forestry workers. British Journal of Industrial Medicine 45:19–24. Wiklund K, Dich J, Holm LE, Eklund G. 1989a. Risk of cancer in pesticide applicators in Swedish agriculture. British Journal of Industrial Medicine 46:809–814. Wiklund K, Dich J, Holm LE. 1989b. Risk of soft tissue sarcoma, Hodgkin’s disease and non- Hodgkin’s lymphoma among Swedish licensed pesticide applicators. Chemosphere 18: 395–400. Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH, Williams DE. 1990. Health status of Air Force veterans occupationally ex- posed to herbicides in Vietnam. I. Physical health. Journal of the American Medical Association 264:1824–1831. Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. 1987. Soft tissue sarcoma and non- Hodgkin’s lymphoma in relation to phenoxy herbicide and chlorinated phenol exposure in western Washington. Journal of the National Cancer Institute 78:899–910. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. 2002. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro-Oncology 4(4):278–299. Wu CH, Chen HL, Su HJ, Lee CC, Shen KT, Ho WL, Ho SY, Ho YS, Wang YJ. 2004. The topical application of 2,3,7,8-tetrachlorodibenzo-p-dioxin lacks skin tumor-promoting potency but induces hepatic injury and tumor necrosis factor-alpha expression in ICR male mice. Food and Chemical Toxicology 42(8):1217–1225. Wyde ME, Braen AP, Hejtmancik M, Johnson JD, Toft JD, Blake JC, Cooper SD, Mahler J, Vallant M, Bucher JR, Walker NJ. 2004. Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. Toxicological Sciences 82(1):34–45. Xu JX, Hoshida Y, Yang WI, Inohara H, Kubo T, Kim GE, Yoon JH, Kojya S, Bandoh N, Harabuchi Y, Tsutsumi K, Koizuka I, Jia XS, Kirihata M, Tsukuma H, Aozasa K. 2007. Life-style and environmental factors in the development of nasal NK/T-cell lymphoma: A case–control study in East Asia. International Journal of Cancer 120(2):406–410. Yamamoto S, Konishi Y, Matsuda T, Murai T, Shibata MA, Matsui-Yuasa I, Otani S, Kuroda K, Endo G, Fukushima S. 1995. Cancer incidence by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carginogens. Cancer Research 55(6):1271–1276. Yamanaka K, Ohtsubo K, Hasegawa A, Hayashi H, Ohji H, Kanisawa M, Okada S. 1996. Exposure to dimethylarsinic acid, a main metabolite of inorganic arsenics, strongly promotes tumorigenesis initiated by 4-nitroquinoline 1-oxide in the lungs of mice. Carcinogenesis 17(4):767–770. Yang X, Solomon S, Fraser LR, Trombino AF, Liu D, Sonenshein GE, Hestermann EV, Sherr DH. 2008. Constitutive regulation of CYP1B1 by the aryl hydrocarbon receptor (AhR) in pre- malignant and malignant mammary tissue. Journal of Cellular Biochemistry 104(2):402–417.

434 VETERANS AND AGENT ORANGE: UPDATE 2008 Yoshizawa K, Walker NJ, Jokinen MP, Brix AE, Sells DM, Marsh T, Wyde ME, Orzech D, Haseman JK, Nyska A. 2005a. Gingival carcinogenicity in female Harlan Sprague-Dawley rats follow- ing two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like com- pounds. Toxicological Sciences 83(1):64–77. [erratum appears in Toxicological Sciences 2005; 83(2):405–406]. Yoshizawa K, Marsh T, Foley JF, Cai B, Peddada S, Walker NJ, Nyska A. 2005b. Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats. Toxicological Sciences 85(1):594–606. Yoshizawa K, Heatherly A, Malarkey DE, Walker NJ, Nyska A. 2007. A critical comparison of murine pathology and epidemiological data of TCDD, PCB126, and PeCDF. Toxicologic Pathology 35(7):865–879. Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to tetrachlorodibenzo­ dioxin in a trichlorophenol process accident. Journal of Occupational Medicine 22:11–14. Zahm SH, Fraumeni JF Jr. 1997. The epidemiology of soft tissue sarcoma. Seminars in Oncology 24(5):504–514. Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, Blair A. 1990. A case– control study of non-Hodgkin’s lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1:349–356. Zahm SH, Blair A, Weisenburger DD. 1992. Sex differences in the risk of multiple myeloma associ- ated with agriculture (2). British Journal of Industrial Medicine 49:815–816. Zahm SH, Weisenburger DD, Saal RC, Vaught JB, Babbitt PA, Blair A. 1993. The role of agricultural pesticide use in the development of non-Hodgkin’s lymphoma in women. Archives of Environ- mental Health 48:353–358. Zambon P, Ricci P, Bovo E, Casula A, Gattolin M, Fiore AR, Chiosi F, Guzzinati S. 2007. Sarcoma risk and dioxin emissions from incinerators and industrial plants: A population-based case– control study (Italy). Environmental Health: A Global Access Science Source 6:19. Zhong Y, Rafnsson V. 1996. Cancer incidence among Icelandic pesticide users. International Journal of Epidemiology 25(6):1117–1124. Zober A, Messerer P, Huber P. 1990. Thirty-four-year mortality follow-up of BASF employees ex- posed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and Environmental Health 62:139–157.

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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2008 report is the eighth volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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