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), the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). About 564,830 Americans of all ages were expected to die from cancer in 2006—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2006).

This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds 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 reports on only a single type of cancer and does 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; Appendix C contains cumulative tables that summarize studies that looked at multiple endpoints or involved repeatedly investigated populations that have contributed evidence to this series of reports.

In an evaluation of a possible connection between herbicide exposure and risk of cancer, how exposures of study subjects were assessed is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapter 5, there is a 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 compound in serum or tissues; some developed an index of exposure from employment or activity records; and others used surrogate mea-



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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), the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). About 564,830 Americans of all ages were expected to die from cancer in 2006—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2006). This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds 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-tetrachloro- dibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. If a new study reports on only a single type of cancer and does 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; Appendix C contains cumulative tables that summarize studies that looked at multiple endpoints or involved repeatedly investigated populations that have contributed evidence to this series of reports. In an evaluation of a possible connection between herbicide exposure and risk of cancer, how exposures of study subjects were assessed is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapter 5, there is a great variety in detail and accuracy of exposure as- sessment among studies. A few studies used biologic markers of exposure, such as the presence of a compound in serum or tissues; some developed an index of exposure from employment or activity records; and others used surrogate mea- 261

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262 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans 2004–2005 (numbers in thousands) Vietnam Era Vietnam Theater Ages Group (Years) N (%) N (%) All ages 7,934 3,853 49 133 (1.6) 32 (0.1) 50–54 1,109 (13.8) 369 (9.4) 55–59 3,031 (37.6) 1,676 (43.1) 60–64 2,301 (28.5) 1,090 (28.0) 65–69 675 (8.4) 280 (7.2) 70–79 511 (6.3) 322 (8.3) 80 178 (2.2) 83 (2.1) SOURCE: Table 3-3 (IOM, 1994), updated by 15 years. sures of exposure, such as presence in a geographic 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 for the entire US popula- tion, however, not predictions for the Vietnam-veteran cohort. The incidence figures in this update are adapted to the demographic patterns defined by the 2000 US census data. The data reported are for 1998–2002, the most recent data set available (NCI, 2006). 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 percent 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 of the National Institutes of Health and are cat- egorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostatic cancer is about 4.3 times as high in men who are 60–64 years old than in men 50–54 years old; it is about twice as high in blacks 50–64 years old as in whites in the same age group (NCI, 2006). Many factors can influence incidence, including behavior (such as tobacco and alcohol use and 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 compounds of interest. The body of each section on a specific type of cancer includes a summary of the findings described in the previous Agent Orange reports: Veterans and

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263 CANCER 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 2000 (IOM, 2001); Update 2002 (IOM, 2003); and Update 2004 (IOM, 2005). That is fol- lowed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. Where appropri- ate, the literature is discussed by exposure type (occupational, environmental, or service in Vietnam). Each section ends with the committee’s conclusion regard- ing 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. As explained in the following paragraphs, this committee has slightly modified the format in which it has satisfied the other two aspects of its charge. Biologic plausibility corresponds to the third element of the committee’s congressionally mandated statement of task. In previous updates, it had been discussed in the conclusion section for each health outcome after a statement of the committee’s judgment about the adequacy of the epidemiologic evidence of an association between exposure to the compounds of interest and the outcome. In fact, the degree of biologic plausibility itself influences whether the commit- tee perceives positive findings to be indicative of a pattern of association or the product of statistical fluctuations. To provide the reader with a more logical se- quence, in this update sections on biologic plausibility have been placed between the presentation of epidemiologic evidence and the synthesis of the evidence, which leads to the committee’s conclusion about the adequacy of the evidence to support an association. Information on biologic mechanisms that could contribute to the generic (rather than tissue- or organ-specific) carcinogenic potential of the compounds of interest is summarized in the section on biologic plausibility that precedes the synopsis of conclusions for the entire chapter. It distills toxicologic information concerning the mechanisms by which the compounds of interest affect carcino- genesis, as presented in more detail in Chapter 3; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in the chapter’s sections on particular cancer types, the generic information is implicit, and only toxicologic information peculiar to carcinogenesis at the site in question has been presented. Considerable uncertainty remains about the magnitude of potential risk posed by exposure to the compounds of interest. Many of the occupational, environ- mental, and veterans studies reviewed by the committee did not control fully for important confounders. There is not enough information about individual Viet- nam veterans to compare with exposures presented in scientific research studies. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the compounds of interest. Previous reports in the VAO series have had a rather formulaic statement to that effect as the third

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264 VETERANS AND AGENT ORANGE: UPDATE 2006 entry in the conclusion section for each cancer type, corresponding to the second element in the committee’s statement of task as dictated by the congressional mandate. The (at least currently) insurmountable problems of deriving meaning- ful 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 no longer reiterated for every health outcome addressed. AN EXHAUSTIVE AND UNAMBIGUOUS SYSTEM FOR ADDRESSING CANCER TYPES The Department of Veterans Affairs (VA) requested that the present commit- tee ensure that evaluations of the possibility of associations between exposures to the compounds of interest and various types of cancer be framed in such a fashion that a corresponding conclusion would be available for any type of cancer that might be diagnosed in a veteran and that it would be clear which conclusion would be applicable when a veteran filed a claim. VA also expressed concern that the episodic nature of the VAO series may have interfered with recognition and evaluation of cumulatively usable amounts of epidemiologic information on some uncommon cancers; in particular, VA asked for a focused examination of available information on cancer of the tonsil and acute myelogenous leukemia (AML). The committee therefore screened the studies that contributed results on the cancer types discussed in prior updates for results on tonsil cancer, AML, and other uncommon sites while gaining an over- view of how cancer sites are typically grouped to report findings. VA had indicated that a grouping system for reporting the committee’s con- clusions based on the International Classification of Diseases (ICD) codes would be appropriate to match the diagnostic information presented in veterans’ claims. ICD is used to code and classify mortality data from death certificates. ICD CM (clinical modification) is used to code and classify morbidity data from medical records, hospital records, and surveillance surveys. The 10th edition (ICD-10) came into use in 1999 and constitutes a marked change from the previous four versions that evolved into the ninth edition (ICD-9). ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research re- viewed in this series, it has been used when codes are given for a specific health outcome. The first modification made in this update toward addressing VA’s request was to change the order in which cancer types are discussed, which had evolved from the original VAO report. The more systematic order of major and minor categories of cause of death for cancer sites established by the National Institute for Occupational Safety and Health (NIOSH) is now followed with minor ex- ceptions. The NIOSH groups map the full range of ICD-9 codes for malignant neoplasms (140–208), and this somewhat coarser gradient has been adopted as an exhaustive organizing principle for the present chapter. Appendix B discusses

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265 CANCER the issue in more detail and delineates the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (Table B-1); the groupings for mortal- ity 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 groups provide a comprehensive framework for software routinely used by epidemiologists to generate expected values based on the demographics of the cohort being studied and have well-documented correspondence with the more detailed ICD coding system in its successive iterations (Robinson et al., 2006). When conditions reported on in epidemiologic research are specified in ICD ranges, the specificity may not be as refined as might be desired for some purposes, and errors of misclassification in the research process cannot be ex- cluded, but the grouping intended is unambiguous. This rearrangement following a largely anatomic sequence should make locating a particular cancer easier for readers and facilitated the committee’s iden- tification of ICD codes for malignancies that had not been explicitly addressed in previous updates (as noted in italics in Table B-1). VAO reports’ default cat- egory 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. In this update, it still is the case that failure to review a specific cancer or other condition separately reflects the paucity of information, so there is indeed inadequate or insufficient information to categorize such a disease outcome. However, in response to VA’s request and in light of our review of how “rare cancers” are grouped or presented when they do have reported results, we state here how each of these previously overlooked ICD codes will be treated in this and future updates: • ICD-9 149, other buccal cavity and pharynx—routinely included in full buccal cavity and pharynx range, 140–149. • ICD-9 152, small intestine—rarely reported individually; to be encom- passed in conclusions for colorectal cancers. • ICD-9 156, gallbladder and extrahepatic bile ducts—to be tracked under hepatobiliary cancers. • ICD-9 158–159, retroperitoneum and other and unspecified digestive cancers—rarely reported individually; to be encompassed in conclusions for colorectal cancers. • ICD-9 162.0, trachea—intended grouping with lung and bronchus has not always been explicitly stated. • ICD-9 163, pleura—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with mediastinum and other and unspecified respiratory cancers. • ICD-9 164.0, thymus—to be considered with thyroid and other endocrine cancers. • ICD-9 164.2–164.9, mediastinum—rarely reported individually and not

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266 VETERANS AND AGENT ORANGE: UPDATE 2006 as yet seen for the chemicals of interest; would be considered with pleura and other and unspecified respiratory cancers. • ICD-9 165, other and unspecified respiratory cancers—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with pleura and mediastinum as other respiratory cancers. • ICD-9 179, unspecified parts of uterus—to be considered with female reproductive system. • ICD-9 181, placenta—to be considered with female reproductive system. • ICD-9 183.2–183.9, fallopian tube and other uterine adnexa—to be con- sidered with female reproductive system. • ICD-9 184, other female genital organs—to be considered with female reproductive system. • ICD-9 187, penis and other male genital organs—to be considered with testis as other male reproductive organs (excluding prostate). • ICD-9 189.3–189.9, urethra, paraurethral glands, and other and unspeci- fied urinary—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with bladder cancer. • ICD-9 190, eye—to be considered with brain and other parts of nervous system. • ICD-9 193, thyroid—to be considered with thymus and other endocrine cancers. • ICD-9 194, other endocrine cancers—to be considered with thyroid and thymus as endocrine cancers. • ICD-9 195, other and ill-defined sites—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with other and unspecified cancers. • ICD-9, 196–198, stated or presumed to be secondary of specified sites— rarely reported individually and not as yet seen for the chemicals of inter- est; would be considered with other and unspecified cancers. • ICD-9, 199, site unspecified—rarely reported individually and not as yet seen for the chemicals of interest; would be considered with other and unspecified cancers. This committee’s search of previously reviewed studies for results on ton- sil cancer and AML also identified sets of previously considered papers with reported findings specifically on lip cancer (ICD-9 140) and on tongue cancer (ICD-9 141), which both fall within the range for cancers of the oral (buccal) cavity. The current update includes separate sections discussing the site-specific results. In future updates, however, findings for these sites will be tracked on the results tables for the broader grouping that contains them: buccal cavity, nose, and pharynx (ICD-9 140–149, 160) for tonsil, tongue, and lip, and leukemias (ICD- 9 204–208) for AML. For the digestive cancers, in future updates esophageal,

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267 CANCER stomach, colorectal, hepatobiliary, and pancreatic cancers will be broken out into sections with individual conclusions. Care will be taken to specify as precisely as possible in results tables when findings are being reported for a subsite of a particular grouping. ORAL, NASAL, AND PHARYNGEAL CANCER Oral, nasal, and pharyngeal cancers (ICD-9 140–149, 160) 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). Although 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 different epidemiologic profile. The American Cancer Society (ACS) estimated that about 30,990 men and women would receive a diagnosis of oral or pharyngeal cancer in the United States in 2006 and 7,430 men and women would die from these diseases (Jemal et al., 2006). Less than 10 percent as many cancers originate in the nasal cavity. Most oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Naso- pharyngeal carcinoma (NPC) is the most common malignant tumor of the naso- pharynx; it is relatively rare in the United States, where it accounts for about 0.25 percent of all cancers. 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 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 compounds of interest and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Studies evaluated previously and in this report are summarized in Table 6-3.

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268 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral Cavity and Pharynx, and Oropharynx Cancers in United Statesa 50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All All All Races White Black Races White Black Races White Black Nose, Nasal Cavity, and Middle Ear: Men 1.2 1.1 1.2 1.6 1.5 1.8 2.0 2.0 3.0 Women 0.6 0.6 0.4 1.0 1.1 0.3 1.1 1.1 1.6 Nasopharynx: Men 1.8 1.0 1.7 2.3 1.5 1.8 3.1 1.6 4.5 Women 0.7 0.3 0.8 0.6 0.3 0.3 1.2 0.6 0.4 Oral Cavity and Pharynx: Men 28.4 27.6 42.0 37.2 36.4 53.1 47.9 47.3 66.1 Women 9.2 8.7 11.6 12.6 12.7 15.5 17.3 17.5 19.0 Oropharynx: Men 1.0 0.8 3.1 1.1 1.0 3.2 2.2 2.0 6.5 Women 0.1 0.1 0.2 0.6 0.5 1.8 0.2 0.2 0.0 a SEER (Surveillance, Epidemiology, and End Results program) nine standard registries, crude age- specific rates, 1999–2003. Update of the Epidemiologic Literature Occupational Studies McLean et al. (2006) reported on a multinational International Agency for Research on Cancer (IARC) cohort of 60,468 pulp and paper industry workers. A job–exposure matrix (JEM) was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlorine compounds (which would include TCDD). Deaths from cancers of the oral cavity and pharynx were signifi- cantly fewer among those who had been exposed to nonvolatile organochlorine compounds (n 15; standardized mortality ratio [SMR] 0.51, 95% confidence interval [CI] 0.29–0.85) but not among those who had never been exposed (n 33; SMR 0.92, 95% CI 0.63–1.29). Alavanja et al. (2005) reported that among the private pesticide applicators in the Agricultural Health Study (AHS), there were 66 cases of buccal-cavity can- cer, which represented a significant deficit compared with the general population (standardized incidence ratio [SIR], 0.66, 95% CI 0.51–0.83). The correspond- ing results for commercial pesticide applicators were based on much smaller numbers of cases, so the confidence interval on the SIR was wide. Among the spouses of private applicators, the SIR for buccal cavity cancer was 0.73 (95% CI 0.40–1.22) on the basis of 14 cases. Nasal and pharyngeal cancers were not

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269 CANCER TABLE 6-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer Estimated Exposed Relative Risk Study Population a,b Casesc (95% CI)c Reference OCCUPATIONAL New Studies 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) Alavanja US Agriculture Health Study—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 Agriculture Health Study (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 (0–25.4) ’t Mannetje Phenoxy herbicide producers (men and women) (ICD-9 et al., 2005 140–149) 2 2.8 (0.3–9.9) Lip (ICD-9 140) 0 * Mouth (ICD-9 141–145) 2 5.4 (0.7–20) Oropharynx (ICD-9 146) 0 * Nasopharynx (ICD-9 147) 0 0.0 (0.0–42) Hypopharynx and other (ICD-9 148–149) 0 * Phenoxy herbicide sprayers ( 99% men) (ICD-9 140–149) 1 1.0 (0.0–5.7) Lip (ICD-9 140) 0 * Mouth (ICD-9 141–145) 0 0.0 (0.0–7.5) Oropharynx (ICD-9 146) 0 * Nasopharynx (ICD-9 147) 1 8.3 (0.2–46) Hypopharynx and other (ICD-9 148–149) 0 * Torchio Italian licensed pesticide users et al., 1994 Buccal cavity and 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) Nasopharyngeal 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 * 0.7 (0.4–1.0) Swaen Dutch licensed herbicide applicators et al., 2004 Nose 0 — Mouth and pharynx 0 — continued

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270 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 6-3 Continued Estimated Exposed Relative Risk Study Population a,b Casesc (95% CI)c Reference Studies Reviewed in Update 2000 Caplan Case–control study of US men born 1929–1953, all 70 et al., 2000 nasal cancers (carcinomas, plus 11 lymphomas and 5 sarcomas) from CDC (1990a) study population Selected landscaping and forestry occupations 26 1.8 (1.1–3.1) Living or working on farm 23 0.5 (0.3–0.8) Herbicides or pesticides 19 0.7 (0.4–1.3) Phenoxy herbicides 5 1.2 (0.4–3.3) Studies Reviewed in Update 1998 Hooiveld Workers at Dutch chemical factory (lip, oral cavity, et al., 1998 pharynx) All working any time 1955–1985 1 2.3 (0.1–12.4) Cleaned up 1963 explosion 1 7.1 (0.2–39.6) Rix et al., Danish men and women 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 Kogevinas IARC cohort (men and women)—Workers exposed to et al., 1997 any phenoxy herbicide or chlorophenol Oral cavity and pharynx cancer (ICD-9 140–149) 26 1.1 (0.7–1.6) Exposed to TCDD 22 1.3 (0.8–2.0) Not exposed to TCDD 3 0.5 (0.1–1.3) Nose and nasal sinuses cancer (ICD-9 160) 3 1.6 (0.3–4.7) Exposed to TCDD 0 0.0 (0.0–3.5) Not exposed to TCDD 3 3.8 (0.8–11.1) Studies Reviewed in Update 1996 Becher German phenoxy herbicide production workers (included et al., 1996 in the IARC cohort) Buccal cavity, pharynx (ICD-9 140–149) 9 3.0 (1.4–5.6) Tongue 3 * Floor of mouth 2 * Tonsil 2 * Pharynx 2 * Asp et al., Finnish herbicide applicators 1994 Buccal and 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)

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271 CANCER TABLE 6-3 Continued Estimated Exposed Relative Risk Study Population a,b Casesc (95% CI)c Reference Studies Reviewed in VAO Blair et al., White male farmers from 23 state—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 (*) Employees 4 0.5 (*) Danish self-employed farmers—incidence Lip 182 1.8 (p 0.05) Tongue 9 0.6 (*) Salivary glands 13 0.9 (*) Mouth 14 0.5 (p 0.05) Pharynx 13 0.3 (p 0.05) Nasal cavities and sinuses 11 0.6 (*) Danish farming employees—incidence Lip 43 2.1 (p 0.05) Tongue 2 0.6 (*) Salivary glands 0 0.0 (*) Mouth 0 0.0 (p 0.05) Pharynx 9 1.1 (*) Nasal cavities and sinuses 5 1.3 (*) Saracci IARC cohort—exposed subcohort (men and women) et al., 1991 Buccal cavity and pharynx (ICD-8 140–149) 11 1.2 (0.6–2.1) Nose and nasal cavities (ICD-8 160) 3 2.9 (0.6–8.5) Zober BASF Aktiengesellschaft accident cohort—33 cancers et al., 1990 among 247 workers at 34-yr follow-up Squamous-cell carcinoma of tonsil 1 * Wiklund Licensed Swedish pesticide applicators— et al., incidence 1989a Lip 14 1.8 (1.0–2.9) Coggon British MCPA production workers (included in the IARC et al., 1986 cohort) Lip (ICD-9 140) 0 * 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 et al., 1986 Buccal cavity and pharynx (ICD-7 140–148) 1 0.1 (0.0–0.7) Nasal (ICD-7 160) 0 —* Wiklund, Swedish men and women agricultural 1983 workers—incidence 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 and nasal sinuses 64 0.8 (0.6–1.2) continued

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