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)

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