7

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 7-1), however, the risk of dying from cancer exceeds the risk of dying from heart disease, the leading 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 570,000 Americans of all ages were expected to die from cancer in 2010—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2010).

This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to

TABLE 7-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (numbers in thousands)


Vietnam Era Vietnam Theater


Age Group (Years) n (%) n (%)

All ages 7,805 3,816
≤ 54 133 (1.8) 32 (0.9)
55-59 1,109 (15.1) 369 (10.4)
60-64 3,031 (41.3) 1,676 (47.0)
65-69 2,301 (31.3) 1,090 (30.6)
70-74 675 (9.2) 280 (7.9)
75-84 511 (6.9) 322 (9.0)
≥ 85 178 (2.4) 83 (2.4)

SOURCE: IOM, 1994, Table 3-3, updated by 20 years.



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7 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 7-1), however, the risk of dying from cancer exceeds the risk of dying from heart dis - ease, the leading 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 570,000 Ameri - cans of all ages were expected to die from cancer in 2010—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2010). This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to TABLE 7-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (numbers in thousands) Vietnam Era Vietnam Theater Age Group (Years) n (%) n (%) All ages 7,805 3,816 ≤ 54 133 (1.8) 32 (0.9) 55–59 1,109 (15.1) 369 (10.4) 60–64 3,031 (41.3) 1,676 (47.0) 65–69 2,301 (31.3) 1,090 (30.6) 70–74 675 (9.2) 280 (7.9) 75–84 511 (6.9) 322 (9.0) ≥ 85 178 (2.4) 83 (2.4) SOURCE: IOM, 1994, Table 3-3, updated by 20 years. 265

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266 VETERANS AND AGENT ORANGE: UPDATE 2010 the chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlo - rophenoxyacetic 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. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. If a new study reported on only a single type of cancer and did not revisit a previously studied population, its design information is sum - marized here with its results; design information on all other new studies can be found in Chapter 5. The objective of this chapter is assessment of whether the occurrence of various cancers in Vietnam veterans themselves may be associated with exposure they may have received during military service. Therefore, studies of childhood cancers in relation to parental exposure to the chemicals of interest are discussed in Chapter 8, which addresses possible adverse effects in the veterans’ offspring. Studies that consider only childhood exposure are not considered relevant to the committee’s charge. In an evaluation of a possible connection between herbicide exposure and risk of cancer, the approach used to assess the exposure of study subjects is of critical importance in determining the overall relevance and usefulness of find - ings. As noted in Chapters 3 and 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 presence of a chemical 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, not predictions for the Vietnam-veteran cohort. The data reported are for 2004–2008 and are from the most recent dataset available (NCI, 2010). Incidence data are given for all races combined and separately for blacks and whites. The age range of 55–69 years now includes about 80% of Vietnam-era veterans, and incidences are presented for three 5-year age groups: 55–59 years, 60–64 years, and 65–69 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 2.6 times as high in men who are 65–69 years old as in men 55–59 years old and almost twice as high in blacks 55–64 years old as in whites in the same age group (NCI, 2010).

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267 CANCER 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, re- ferred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003); Update 2004 (IOM, 2005); Update 2006 (IOM, 2007); and Update 2008 (IOM, 2009). That is followed by a discus- sion 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 Chapters 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 are presented. It is of note that in this update we have explicitly included an examination of the contribution of epigenetic mechanisms in assess - ing the carcinogenicity of TCDD. A large literature indicates that carcinogenesis is a process that involves not only genetic changes but also epigenetic changes (Johnstone and Baylin, 2010). There is emerging evidence that TCDD and the chemicals of interest may disturb epigenetic processes (see Chapter 4), and ref - erence to this evidence, as it applies to cancers is included where it exists, by cancer site. Considerable uncertainty remains about the magnitude of risk posed by exposure to the chemicals of interest. Many of the veteran, occupational, and en - vironmental studies reviewed by the committee did not control fully for important

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268 VETERANS AND AGENT ORANGE: UPDATE 2010 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 studies 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 in deriving useful quantitative esti - mates of the risks of various health outcomes in 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 GROUPS 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. The organization of cancer groups follows major and minor categories of cause of death related to cancer sites established by the National Institute for Occupa - tional Safety and Health (NIOSH). The NIOSH 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). For the present update, the committee gave more attention to the World Health Organization’s classification for lymphohematopoietic neo - plasms (WHO, 2008), which stresses partitioning of these disorders first accord - ing to the lymphoid or myeloid lineage of the transformed cells rather than into lymphomas and leukemias. 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 on 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.

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269 CANCER BIOLOGIC PLAUSIBILITY The studies considered with respect to the biologic plausibility of associa - tions between exposure to the chemicals of interest and human cancers have been performed primarily in laboratory animals (rats, mice, hamsters, and monkeys) or cultured cells. Collectively, the evidence obtained from studies of TCDD indi - cates that a connection between human exposure to this chemical 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 individual cancers. Recent reviews have affirmed the now well-established mechanistic roles of the aryl hydrocarbon receptor (AHR) in cancer (Androutsopoulos et al., 2009; Barouki and Coumoul, 2010; Dietrich and Kaina, 2010; Ray and Swanson, 2009), and the data have firmly established the biologic plausibility of an association between TCDD exposure and cancer. 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 of whether the highest doses (generally 30–50 mg/kg) in some of these studies reached a maximum tolerated dose (MTD). It is not possible to have absolute confidence that these chemicals have no carcinogenic potential. Further evidence of a lack of carcinogenic potential is provided, however, by negative findings on 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 cytochrome P450–derived metabolites of benzo[a]pyrene, most available evidence indicates that 2,4,5-T is genotoxic only at high concentrations. Recently, Hernández et al. (2009) have reviewed the mechanisms of action of nongenotoxic carcinogens, including TCDD in this category 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, lungs, 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 cancer (Davis et al., 2000), liver cancer (Beebe et al., 1995), and skin cancers

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270 VETERANS AND AGENT ORANGE: UPDATE 2010 (Wyde et al., 2004). As to the mechanisms by which TCDD exerts its carcino - genic 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 epithelial tissues. In addition, in both laboratory animals and cul - tured 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 ani - mal studies, TCDD has been characterized as a nongenotoxic carcinogen because it does not have obvious DNA-damaging potential, but it is a potent “promoter” 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 AHR. For many years, it has been known that TCDD is a potent tumor-promoter. Recent evidence has shown that AHR activa - tion by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleukin-6 (IL-6) cytokine, which has tumor-promoting effects in numerous tissues—including breast, prostate, ovary, and malignant cholangiocytes—and opens up the possibility that TCDD would promote carci - nogenesis in these and possibly other tissues (Hollingshead et al., 2008). TCDD has been shown to downregulate reduced folate carrier (Rfc1) mRNA and protein in rat liver, which is essential in maintaining folate homeostasis (Halwachs et al., 2010). Reduced Rfc1 activity and a functional folate deficiency may contribute to the risk of carcinogenesis posed by TCDD exposure. Mechanisms by which TCDD induces G1 arrest in hepatic cells (Mitchell et al., 2006; Weiss et al., 2008) and decreases viability of endometrial endothe - lial cells (Bredhult et al., 2007), insulin-secreting beta cells (Piaggi et al., 2007), peripheral T cells (Singh et al., 2008), and neuronal cells (Bredhult et al., 2007) have recently been identified, and these results suggest possible carcinogenic mechanisms. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants via the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2 (“four and a half LIM protein 2,” where the LIM domain is a highly conserved protein structure) (Kollara and Brown, 2009). Borlak and Jenke (2008) demonstrated that the AHR is a major regulator of c-raf and proposed that there is cross-talk

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271 CANCER between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. TCDD inhibits ultraviolet-C (UV-C) radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepa - toma cells, and this supports the hypothesis that TCDD acts as a tumor-promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009). Additional in vitro work with mouse hepatoma cells has shown that activation of the AHR results in increased concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG), 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). Mitochon- drial reactive-oxygen production depends on the AHR. Electronics-dismantling workers, experiencing complex exposures including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), had elevated levels of urinary 8-OHdG indicative of oxidative stress and genotoxicity; this cannot, however, be ascribed directly to the dioxin-like chemicals (DLCs) (Wen et al., 2008). In a 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) in mean SCE frequency between the experimental group and 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 PCBs make up a group of chemicals with carcinogenic potential includes unequivocal animal carcino - genesis and biologic plausibility based on mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be established, the intracellular factors and mechanistic pathways involved in dioxin’s cancer- promotion mode of action all have parallels in animals and humans. No qualita - tive 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. Thus, the toxicologic evidence indicates that a connection of TCDD and per- haps cacodylic acid with cancer in humans is, in general, biologically plausible, but (as discussed below) it must be determined case by case whether such poten- tial 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.

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272 VETERANS AND AGENT ORANGE: UPDATE 2010 THE COMMITTEE’S VIEW OF “GENERAL” HUMAN CARCINOGENS 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 and the various genetic and environmental factors that can influence the occurrence of a particular type of cancer. Before considering each site in turn, however, it is important to address the concept that cancers share some characteristics among organ sites and to clarify the committee’s view regarding the implications of a chemical’s being a “general” human carcinogen. All cancers share phenotypic characteristics: uncontrolled cell proliferation, increased cell survival, invasion outside normal tissue boundaries, and eventually metastasis. The current under- standing of cancer development holds that a cell or group of cells must acquire a series of sufficient genetic mutations to progress and that particular epigenetic events (events that affect gene function but do not involve a change in gene cod- ing 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 genetic (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 acquisi - tion of important mutations is a continuing process in tumors and that promoters, or epigenetic processes that favor cancer growth, enhance the accumulation of genotoxic damage, which traditionally would be regarded as initiating activity. 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. However, cacodylic acid and TCDD have shown the capacity to increase cancer development in animal experiments, particularly as promoters rather than as pure genotoxic agents. Ex- trapolating organ-specific results from animal experiments to humans is problem- atic because of important differences between species in overall susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments about the “general” carcinogenicity of a compound in humans are based heavily on the results of epidemiologic studies, par- ticularly on the question of whether there is evidence of excess cancer risk at mul- tiple organ sites. As the evaluations of particular types of cancer in the remainder of this chapter indicate, the committee finds that TCDD in particular appears to be

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273 CANCER 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 Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans.” It is important to emphasize that the goals and methods of IARC and EPA in making their determinations were different from those of the present committee; the mis- sions of those organizations focus on evaluating risk to minimize future exposure, whereas this committee focuses on risk after exposure. 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 cancer types observed and the extent to which specific types can be analyzed. For instance, the present update includes an analysis of cumulative results on diabetes 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 presents 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. It acknowledges that the highly stratified analyses conducted suggest that some increase in the incidence of some cancers did occur in the Ranch Hand subjects, but it views the “all cancers” results as a conglomeration of information on specific cancers—most important, melanoma and prostate cancer, on 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 the 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 sites, includ- ing the structures of the mouth (inside lining of the lips, cheeks, gums, tongue,

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274 VETERANS AND AGENT ORANGE: UPDATE 2010 and hard and soft palate) (ICD-9 140–145), oropharynx (ICD-9 146), nasophar- ynx (ICD-9 147), hypopharynx (ICD-9 148), other buccal cavity and pharynx (ICD-9 149), and nasal cavity and paranasal sinuses (ICD-9 160). Until recently, cancers that occur in the oral cavity and pharynx have been thought to be similar in descriptive epidemiology and risk factors, whereas cancer of the nasopharynx is known to have a different epidemiologic profile. However, we now recognize that human papilloma virus (HPV) is an important risk factor for squamous-cell carcinoma of the head and neck, with the risk estimates being highest for the base of the tongue and tonsils (Marur et al., 2010). The American Cancer Society (ACS) estimated that about 36,540 men and women would receive diagnoses of oral, nasal, or pharyngeal cancer in the United States in 2010 and that 7,880 men and women would die from these diseases (Jemal et al., 2010). 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 7-2 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 (d’Errico et al., 2009; Feron et al., 2001; Grimsrud and Peto, 2000), wood dust (d’Errico et al., 2009), leather dust (Bonneterre et al., 2007), and high doses of formaldehyde (Nielsen and Wolkoff, 2010). 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, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Up- date 2008 did not change that conclusion. In Update 2006 at the request of the the Department of Veterans Affairs (VA), the committee attempted to evaluate tonsil-cancer cases separately, but it was able to identify 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. Since then, no studies have offered any important additional insight into this question. The committee

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275 CANCER TABLE 7-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in United Statesa 55–59 Years Old 60–64 Years Old 65–69 Years Old All Races White Black All Races White Black All Races White Black Nose, Nasal Cavity, and Middle Ear: Men 1.4 1.3 2.4 2.2 1.8 4.0 2.7 2.4 3.5 Women 1.2 1.1 0.9 1.0 1.0 1.6 2.0 2.3 1.3 Nasopharynx: Men 2.5 1.4 2.6 1.9 1.3 0.8 3.2 1.8 2.3 Women 1.1 0.6 0.4 0.8 0.7 0.3 1.1 1.0 0.4 Oral Cavity and Pharynx: Men 42.1 42.7 44.9 50.2 52.1 46.8 55.9 55.9 64.5 Women 12.7 12.8 11.9 15.1 15.8 14.2 20.7 21.8 18.2 Oropharynx: Men 1.9 1.7 4.2 1.9 1.8 4.0 2.4 2.2 3.5 Women 0.3 0.3 0.2 0.6 0.6 1.0 0.4 0.5 0.0 aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010). 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 that committee suggested a potential association between the expo - sures in Vietnam and tonsil cancer. The new evidence indicating that cancer of the tonsils can have a viral (HPV) etiology underscores a reasonable mechanistic hypothesis for an excess of cancers in Vietnam-era veterans exposed to Agent Or- ange; as a result of immune alterations associated with exposure, veterans may be susceptible to HPV infection in the oral cavity and tonsils. The present committee strongly reiterates the 2006 and 2008 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans. Studies evaluated previously and in the present report are summarized in Table 7-3. Update of the Epidemiologic Literature Vietnam-Veteran Studies Cypel and Kang (2010) updated the study of Vietnam-era Army Chemical Corps (ACC) veterans, comparing mortality through 2005 among ACC veterans by Vietnam service. They reported six cases of oral-cavity and pharyngeal cancer in the deployed cohort compared with two cases in the nondeployed cohort for an

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