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6 Cancer Cancer is the second-leading cause of death in the United States. Among men 50–64 years old, the group that includes most Vietnam veterans (see Table 6-1), 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

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20 CANCER 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

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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

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20 CANCER groups map the full range of International Classification of Diseases, Reision 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.

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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

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20 CANCER 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

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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.

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209 CANCER 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

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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.

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211 CANCER 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 tonsil-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

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212 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 6-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer Estimated Exposed Relative Risk Study Populationa Casesb (95% CI)b Reference 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 Australian Vietnam veterans vs Australian CDVA, population—incidence 199a 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)

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

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

OCR for page 202
426 VETERANS AND AGENT ORANGE: UPDATE 2008 Liu J, Singh B, Tallini G, Carlson DL, Katabi N, Shaha A, Tuttle RM, Ghossein RA. 2006. Follicular variant of papillary thyroid carcinoma: A clinicopathologic study of a problematic entity. Cancer 107:1255–1264. Lynge E. 1985. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. British Journal of Cancer 52(2):259–270. Lynge E. 1993. Cancer in phenoxy herbicide manufacturing workers in Denmark, 1947–87—an update. Cancer Causes and Control 4(3):261–272. Mack TM. 1995. Sarcomas and other malignancies of soft tissue, retroperitoneum, peritoneum, pleura, heart, mediastinum, and spleen. Cancer 75(1):211–244. Magnani C, Coggon D, Osmond C, Acheson ED. 1987. Occupation and five cancers: A case–control study using death certificates. British Journal of Industrial Medicine 44(11):769–776. Mahan CM, Bullman TA, Kang HK, Selvin S. 1997. A case–control study of lung cancer among Vietnam veterans. Journal of Occupational and Enironmental Medicine 39(8):740–747. Mantovani A, Allavena P, Sica A, Balkwill F. 2008. Cancer-related inflammation. Nature 454: 436–444. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338(8773):959–964. Marlowe JL, Fan Y, Chang X, Peng L, Knudsen ES, Xia Y, Puga A. 2008. The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Molecular Biology of the Cell 19:3263–3271. McDuffie HH, Klaassen DJ, Dosman JA. 1990. Is pesticide use related to the risk of primary lung cancer in Saskatchewan? Journal of Occupational Medicine 32(10):996–1002. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW. 2001. Non-Hodgkin’s lymphoma and specific pesticide exposures in men: Cross- Canada study of pesticides and health. Cancer Epidemiology, Biomarkers and Preention 10(11): 1155–1163. McGee SF, Lanigan F, Gilligan E, Groner B. 2006. Mammary gland biology and breast cancer. Conference on Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer Progression. EMBO Reports 7(11):1084–1088. McLean D, Pearce N, Langseth H, Jäppinen P, Szadkowska-Stanczyk I, Person B, Wild P, Ki- shi R, Lynge E, Henneberger P, Sala M, Teschke K, Kauppinen T, Colin D, Kogevinas M, Boffetta P. 2006. Cancer mortality in workers exposed to organochlorine compounds in the pulp and paper industry: An international collaborative study. Enironmental Health Perspec- ties 114(7):1007–1012. Mellemgaard A, Engholm G, McLaughlin JK, Olsen JH. 1994. Occupational risk factors for renal- cell carcinoma in Denmark. Scandinaian Journal of Work, Enironment, and Health 20(3): 160–165. Merletti F, Richiardi L, Bertoni F, Ahrens W, Buemi A, Costa-Santos C, Eriksson M, Guenel P, Kaerlev L, Jockel K-H, Llopis-Gonzalez A, Merler E, Miranda A, Morales-Suarez-Varela, MM, Olsson H, Fletcher T, Olsen J. 2006. Occupational factors and risk of adult bone sarcomas: A multicentric case–control study in Europe. International Journal of Cancer 118(3):721–727. Michalek JE, Pavuk M. 2008. Diabetes and cancer in Veterans of Operation Ranch Hand after ad- justment for calendar period, days of sprayings, and time spent in Southeast Asia. Journal of Occupational and Enironmental Medicine 50(3):330–340. Michalek JE, Wolfe WH, Miner JC. 1990. Health status of Air Force veterans occupationally ex- posed to herbicides in Vietnam. II. Mortality. Journal of the American Medical Association 264(14):1832–1836. Miligi L, Costantini AS, Bolejack V, Veraldi A, Benvenuti A, Nanni O, Ramazzotti V, Tumino R, Stagnaro E, Rodella S, Fontana A, Vindigni C, Vineis P. 2003. Non-Hodgkin’s lymphoma, leu- kemia, and exposures in agriculture: Results from the Italian Multicenter Case–Control Study. American Journal of Industrial Medicine 44:627–636.

OCR for page 202
42 CANCER Miligi L, Costantini AS, Veraldi A, Benvenuti A, Will, Vineis P. 2006. Cancer and pesticides: An overview and some results of the Italian multicenter case–control study on hematolymphopoietic malignancies. Annals of the New York Academy of Sciences 1076:366–377. Miller BA, Kolonel LN, Bernstein L, Young JL Jr, Swanson GM, West D, Key CR, Liff JM, Glover CS, Alexander GA, et al. (eds). 1996. Racial/Ethnic Patterns of Cancer in the United States 1988–1992. Bethesda, MD: National Cancer Institute. NIH Pub. No. 96-4104. Mills PK, Yang R. 2005. Breast cancer risk in Hispanic agricultural workers in California. Interna- tional Journal of Occupational and Enironmental Health 11(2):123–131. Mills PK, Yang RC. 2007. Agricultural exposures and gastric cancer risk in Hispanic farm workers in California. Enironmental Research 104(2):282–289. Mills PK, Yang R, Riordan D. 2005. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988–2001. Cancer Causes and Control 16(7):823–830. Morris PD, Koepsell TD, Daling JR, Taylor JW, Lyon JL, Swanson GM, Child M, Weiss NS. 1986. Toxic substance exposure and multiple myeloma: A case–control study. Journal of the National Cancer Institute 76(6):987–994. Morrison H, Semenciw RM, Morison D, Magwood S, Mao Y. 1992. Brain cancer and farming in western Canada. Neuroepidemiology 11(4-6):267–276. Morrison H, Savitz D, Semenciw RM, Hulka B, Mao Y, Morison D, Wigle D. 1993. Farming and prostate cancer mortality. American Journal of Epidemiology 137(3):270–280. Morrison HI, Semenciw RM, Wilkins K, Mao Y, Wigle DT. 1994. Non-Hodgkin’s lymphoma and agricultural practices in the prairie provinces of Canada. Scandinaian Journal of Work, Eni- ronment, and Health 20(1):42–47. Mulero-Navarro S, Carvajal-Gonzalez JM, Herranz M, Ballestar E, Fraga MF, Ropero S, Esteller M, Fernandez-Salguero PM. 2006. The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding. Carcinogenesis 27(5):1099–1104. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. 1988. A case–control study of brain gliomas and occupational exposure to chemical carcinogens: The risks to farmers. American Journal of Epidemiology 128:778–785. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, Buiatti E. 1996. Chronic lympho- cytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breed- ing workers: A population case–control study based on a priori exposure matrices. Occupational and Enironmental Medicine 53(10):652–657. Nascimento MG, Suzuki S, Wei M, Tiwari A, Arnold LL, Lu X, Le XC, Cohen SM. 2008. Cytotox- icity of combinations of arsenicals on rat urinary bladder urothelial cells in vitro. Toxicology 249(1):69–74. NCI (National Cancer Institute). 2008. Sureillance, Epidemiology, and End Results (SEER) Incidence and US Mortality Statistics: SEER Incidence—Crude Rates for White/Black/Other 2000–200. http://www.seer.cancer.gov/canques/incidence.html (Accessed February 2, 2009). Nordby KC, Andersen A, Kristensen P. 2004. Incidence of lip cancer in the male Norwegian agricul- tural population. Cancer Causes and Control 15(6):619–626. NTP (National Toxicology Program). 1982a. Technical Report Series No. 209. Carcinogenesis Bio- assay of 2,,,8-Tetrachlorodibenzo-p-dioxin (CAS No. 146-01-6) in Osborne-Mendel Rats and B6cF1 Mice (Gaage Study). NIH Publication No. 82-1765. 195 pp. National Toxicology Program, Research Triangle Park, NC, and Bethesda, MD. NTP. 1982b. Technical Report Series No. 201. Carcinogenesis Bioassay of 2,,,8-Tetrachloro- dibenzo-p-dioxin (CAS No. 146-01-6) in Swiss-Webster Mice (Dermal Study). National Toxi- cology Program, Research Triangle Park, NC, and Bethesda, MD. NTP. 2006. NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,,,8- Tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 146-01-6) in Female Harlan Sprague-Dawley Rats (Gaage Studies). Issue 521:4–232. National Toxicology Program, Research Triangle Park, NC, and Bethesda, MD.

OCR for page 202
428 VETERANS AND AGENT ORANGE: UPDATE 2008 Nyska A, Jokinen MP, Brix AE, Sells DM, Wyde ME, Orzech D, Haseman JK, Flake G, Walker NJ. 2004. Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Enironmental Health Perspecties 112(8):903–909. Nyska A, Yoshizawa K, Jokinen MP, Brix AE, Sells DM, Wyde ME, Orzech DP, Kissling GE, Walker NJ. 2005. Olfactory epithelial metaplasia and hyperplasia in female Harlan Sprague- Dawley rats following chronic treatment with polychlorinated biphenyls. Toxicologic Pathology 33(3):371–377. O’Brien TR, Decoufle P, Boyle CA.1991. Non-Hodgkin’s lymphoma in a cohort of Vietnam veterans. American Journal of Public Health 81:758–760. Ojajärvi IA, Partanen TJ, Ahlbom A, Boffetta P, Hakulinen T, Jourenkova N, Kauppinen TP, Kogevinas M, Porta M, Vainio HU, Weiderpass E, Wesseling CH. 2000. Occupational exposures and pan- creatic cancer: A meta-analysis. Occupational and Enironmental Medicine 57:316–324. Olsson H, Brandt L. 1988. Risk of non-Hodgkin’s lymphoma among men occupationally exposed to organic solvents. Scandinaian Journal of Work, Enironment, and Health 14:246–251. Omoti C, Omoti A. 2008. Richter syndrome: A review of clinical, ocular, neurological and other manifestations. British Journal of Haematology 142:709–716. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Enironmental Medicine 53:606–612. Pahwa P, McDuffie HH, Dosman JA, McLaughlin JR, Spinelli JJ, Robson D, Fincham S. 2006. Hodgkin lymphoma, multiple myeloma, soft tissue sarcomas, insect repellents, and phenoxy- herbicides. Journal of Occupational and Enironmental Medicine 48(3):264–274. Park JY, Shigenaga MK, Ames BN. 1996. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachloro- dibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage. Proceed- ings of the National Academy of Sciences of the United States of America 93(6):2322–2327. Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. 2005. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange? Journal of Occupational and Enironmental Medicine 47(4):335–342. Pavuk M, Michalek JE, Ketchum NS. 2006. Prostate cancer in US Air Force veterans of the Vietnam War. Journal of Exposure Science and Enironmental Epidemiology 16(2):184–190. Pearce NE, Smith AH, Fisher DO. 1985. Malignant lymphoma and multiple myeloma linked with agricultural occupations in a New Zealand cancer registry-based sudy. American Journal of Epidemiology 121:225–237. Pearce NE, Smith AH, Howard JK, Sheppard RA, Giles HJ, Teague CA. 1986. Non-Hodgkin’s lymphoma and exposure to phenoxyherbicides, chlorophenols, fencing work, and meat works employment: A case control study. British Journal of Industrial Medicine 43:75–83. Pearce NE, Sheppard RA, Smith AH, Teague CA. 1987. Non-Hodgkin’s lymphoma and farming: An expanded case–control study. International Journal of Cancer 39:155–161. Percy C, Ries GL, Van Holten VD. 1990. The accuracy of liver cancer as the underlying cause of death on death certificates. Public Health Reports 105:361–368. Persson B, Dahlander AM, Fredriksson M, Brage HN, Ohlson CG, Axelson O. 1989. Malignant lym- phomas and occupational exposures. British Journal of Industrial Medicine 46:516–520. Persson B, Fredriksson M, Olsen K, Boeryd B, Axelson O. 1993. Some occupational exposures as risk factors for malignant lymphomas. Cancer 72:1773–1778. Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C, Bertazzi PA. 1992. Cancer morbidity in the Seveso area, 1976–1986. Chemosphere 25:209–212. Poland A, Palen D, Glover E. 1982. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300(5889):271–273. Pu YS, Yang SM, Huang YK, Chung CJ, Huang SK, Chiu AW, Yang MH, Chen CJ, Hsueh YM. 2007. Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure. Toxicology and Applied Pharmacology 218(2):99–106.

OCR for page 202
429 CANCER Rajkumar SV, Dispenzieri A, Kyle RA. 2006. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: Diagnosis and treatment. Mayo Clinic Proceedings 81(5):693–703. Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940–1989. American Journal of Indus- trial Medicine 30:180–194. Read D, Wright C, Weinstein P, Borman B. 2007. Cancer incidence and mortality in a New Zea- land community potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin from 2,4,5-tri- chlorophenoxyacetic acid manufacture. Australian and New Zealand Journal of Public Health 31(1):13–18. Reif JS, Pearce N, Fraser J. 1989. Occupational risks of brain cancer: A New Zealand cancer registry- based study. Journal of Occupational Medicine 31(10):863–867. Revich B, Aksel E, Ushakova T, Ivanova I, Zhuchenko N, Klyuev N, Brodsky B, Sotskov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 243(4-7):951–966. Reynolds P, Hurley SE, Goldberg DE, Anton-Culver H, Bernstein L, Deapen D, Horn-Ross PL, Peel D, Pinder R, Ross RK, West D, Wright WE, Ziogas A. 2004. Residential proximity to agri- cultural pesticide use and incidence of breast cancer in the California Teachers Study cohort. Enironmental Research 96(2):206–218. Reynolds P, Hurley SE, Petreas M, Goldberg DE, Smith D, Gilliss D, Mahoney ME, Jeffrey SS. 2005a. Adipose levels of dioxins and risk of breast cancer. Cancer Causes and Control 16(5): 525–535. Richardson DB, Terschuren C, Hoffmann W. 2008. Occupational risk factors for non-Hodgkin’s lymphoma: A population-based case–control study in Northern Germany. American Journal of Industrial Medicine 51(4):258–268. Riedel D, Pottern LM, Blattner WA. 1991. Etiology and epidemiology of multiple myeloma. In: Wiernick PH, Camellos G, Kyle RA, Schiffer CA, eds. Neoplastic Disease of the Blood and Blood Forming Organs. New York: Churchill Livingstone. Riihimaki V, Asp S, Hernberg S. 1982. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5- trichlorophenoxyacetic acid herbicide applicators in Finland: First report of an ongoing prospec- tive cohort study. Scandinaian Journal of Work, Enironment, and Health 8:37–42. Rix BA, Villadsen E, Engholm G, Lynge E. 1998. Hodgkin’s disease, pharyngeal cancer, and soft tissue sarcomas in Danish paper mill workers. Journal of Occupational and Enironmental Medicine 40(1):55–62. Robinson CF, Waxweiler RJ, Fowler DP. 1986. Mortality among production workers in pulp and paper mills. Scandinaian Journal of Work, Enironment, and Health 12:552–560. Ronco G, Costa G, Lynge E. 1992. Cancer risk among Danish and Italian farmers. British Journal of Industrial Medicine 49:220–225. Roulland S, Navarro J-M, Grenot P, Milili M, Agopian J, et al. 2006. Follicular lymphoma-like B cell in healthy individuals: A novel intermediate step in early lymphomagenesis. The Journal of Experimental Medicine 203(11):2425–2431. Rowland RE, Edwards LA, Podd JV. 2007. Elevated sister chromatid exchange frequencies in New Zealand Vietnam War veterans. Cytogenetic and Genome Research 116(4):248–251. Ruder AM, Waters MA, Butler MA, Carreon T, Calvert GM, Davis-King KE, Schulte PA, Sanderson WT, Ward EM, Connally LB, Heineman EF, Mandel JS, Morton RF, Reding DJ, Rosenman KD, Talaska G. 2004. Gliomas and farm pesticide exposure in men: The Upper Midwest Health Study. Archies of Enironmental Health 59(12):650–657. Salehi F, Turner MC, Phillips KP, Wigle DT, Krewski D, Aronson KJ. 2008. Review of the etiology of breast cancer with special attention to organochlorines as potential endocrine disruptors. Journal of Toxicology and Enironmental Health—Part B: Critical Reiews 11(3–4):276–300.

OCR for page 202
40 VETERANS AND AGENT ORANGE: UPDATE 2008 Samanic C, Rusiecki J, Dosemeci M, Hou L, Hoppin JA, Sandler DP, Lubin J, Blair A, Alavanja MC. 2006. Cancer incidence among pesticide applicators exposed to dicamba in the agricultural health study. Enironmental Health Perspecties 114(10):1521–1526. Samanic CM, De Roos AJ, Stewart PA, Rajaraman P, Waters MA, Inskip PD. 2008. Occupational exposure to pesticides and risk of adult brain tumors. American Journal of Epidemiology 167(8):976–985. Saracci R, Kogevinas M, Bertazzi PA, Bueno de Mesquita BH, Coggon D, Green LM, Kauppinen T, L’Abbe KA, Littorin M, Lynge E, Mathews JD, Neuberger M, Osman J, Pearce N, Winkelmann R. 1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 338:1027–1032. Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH. 2006. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biological Chemistry 387(9):1175–1187. Semenciw RM, Morrison HI, Morison D, Mao Y. 1994. Leukemia mortality and farming in the prairie provinces of Canada. Canadian Journal of Public Health 85:208–211. Senft AP, Dalton TP, Nebert DW, Genter MB, Puga A, Hutchinson RJ, Kerzee JK, Uno S, Shertzer HG. 2002. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radical Biology and Medicine 33(9):1268–1278. Sharma-Wagner S, Chokkalingam AP, Malker HS, Stone BJ, McLaughlin JK, Hsing AW. 2000. Occupation and prostate cancer risk in Sweden. Journal of Occupational and Enironmental Medicine 42(5):517–525. Shertzer HG, Nebert DW, Puga A, Ary M, Sonntag D, Dixon K, Robinson LJ, Cianciolo E, Dalton TP. 1998. Dioxin causes a sustained oxidative stress response in the mouse. Biochemical and Biophysical Research Communications 253(1):44–48. Siemiatycki J, Wacholder S, Dewar R, Wald L, Bégin D, Richardson L, Rosenman K, Gérin M. 1988. Smoking and degree of occupational exposure: Are internal analyses in cohort studies likely to be confounded by smoking status? American Journal of Industrial Medicine 13(1):59–69. Simanainen U, Haavisto T, Tuomisto JT, Paranko J, Toppari J, Tuomisto J, Peterson RE, Viluksela M. 2004a. Pattern of male reproductive system effects after in utero and lactational 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) exposure in three differentially TCDD-sensitive rat lines. Toxicological Sciences 80(1):101–108. Simanainen U, Adamsson A, Tuomisto JT, Miettinen HM, Toppari J, Tuomisto J, Viluksela M. 2004b. Adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and effects on male re- productive organs in three differentially TCDD-susceptible rat lines. Toxicological Sciences 81(2):401–407. Smith AH, Pearce NE. 1986. Update on soft tissue sarcoma and phenoxyherbicides in New Zealand. Chemosphere 15:1795–1798. Smith AH, Fisher DO, Giles HJ, Pearce NE. 1983. The New Zealand soft tissue sarcoma case–control study: Interview findings concerning phenoxyacetic acid exposure. Chemosphere 12:565–571. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. 1984. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. Journal of the National Cancer Institute 73:1111–1117. Smith JG, Christophers AJ. 1992. Phenoxy herbicides and chlorophenols: A case control study on soft tissue sarcoma and malignant lymphoma. British Journal of Cancer 65:442–448. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ. 1998. Alcohol and breast cancer in women: A pooled analysis of cohort studies. Journal of the American Medical Association 279(7):535–540. Solet D, Zoloth SR, Sullivan C, Jewett J, Michaels DM. 1989. Patterns of mortality in pulp and paper workers. Journal of Occupational Medicine 31:627–630.

OCR for page 202
41 CANCER Spinelli JJ, Ng CH, Weber JP, Connors JM, Gascoyne RD, Lai AS, Brooks-Wilson AR, Le ND, Berry BR, Gallagher RP. 2007. Organochlorines and risk of non-Hodgkin lymphoma. International Journal of Cancer 121(12):2767–2775. Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI. 1999. Cancer, heart disease, and diabe- tes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the National Cancer Institute 91(9):779–786. Stott WT, Johnson KA, Landry TD, Gorzinski SJ, Cieszlak FS. 1990. Chronic toxicity and onco- genicity of picloram in Fischer 344 rats. Journal of Toxicology and Enironmental Health 30:91–104. Svensson BG, Mikoczy Z, Stromberg U, Hagmar L. 1995. Mortality and cancer incidence among Swedish fishermen with a high dietary intake of persistent organochlorine compounds. Scandi- naian Journal of Work, Enironmental, and Health 21(2):106–115. Swaen GMH, van Vliet C, Slangen JJM, Sturmans F. 1992. Cancer mortality among licensed herbi- cide applicators. Scandinaian Journal of Work, Enironment, and Health 18:201–204. Swaen GM, van Amelsvoort LG, Slangen JJ, Mohren DC. 2004. Cancer mortality in a cohort of li- censed herbicide applicators. International Archies of Occupational and Enironmental Health 77(4):293–295. ’t Mannetje A, McLean D, Cheng S, Boffetta P, Colin D, Pearce N. 2005. Mortality in New Zealand workers exposed to phenoxy herbicides and dioxins. Occupational and Enironmental Medicine 62(1):34–40. Tarone RE, Hayes HM, Hoover RN, Rosenthal JF, Brown LM, Pottern LM, Javadpour N, O’Connell KJ, Stutzman RE. 1991. Service in Vietnam and risk of testicular cancer. Journal of the National Cancer Institute 83:1497–1499. Teitelbaum SL, Gammon MD, Britton JA, Neugut AI, Levin B, Stellman SD. 2007. Reported resi- dential pesticide use and breast cancer risk on Long Island, New York. American Journal of Epidemiology 165(6):643–651. Thiess AM, Frentzel-Beyme R, Link R. 1982. Mortality study of persons exposed to dioxin in a tri- chlorophenol-process accident that occurred in the BASF AG on November 17, 1953. American Journal of Industrial Medicine 3:179–189. Thomas TL. 1987. Mortality among flavour and fragrance chemical plant workers in the United States. British Journal of Industrial Medicine 44:733–737. Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veter- ans: A preliminary report. American Journal of Industrial Medicine 18:665–673. Thomas TL, Kang H, Dalager N. 1991. Mortality among women Vietnam veterans, 1973–1987. American Journal of Epidemiology 134:973–980. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. 2003. The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 349(3):215–224. Thörn Å, Gustavsson P, Sadigh J, Westerlund-Hännerstrand B, Hogstedt C. 2000. Mortality and can- cer incidence among Swedish lumberjacks exposed to phenoxy herbicides. Occupational and Enironmental Medicine 57:718–720. Torchio P, Lepore AR, Corrao G, Comba P, Settimi L, Belli S, Magnani C, di Orio F. 1994. Mortal- ity study on a cohort of Italian licensed pesticide users. The Science of the Total Enironment 149(3):183–191. Toth K, Somfai-Relle S, Sugar J, Bence J. 1979. Carcinogenicity testing of herbicide 2,4,5-tri- chlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature 278(5704): 548–549. Tuomisto JT, Pekkanen J, Kiviranta H, Tukiainen E, Vartiainen T, Tuomisto J. 2004. Soft-tissue sar- coma and dioxin: A case–control study. International Journal of Cancer 108(6):893–900.

OCR for page 202
42 VETERANS AND AGENT ORANGE: UPDATE 2008 van Grevenynghe J, Bernard M, Langouet S, Le Berre C, Fest T, Fardel O. 2005. Human CD34- positive hematopoietic stem cells constitute targets for carcinogenic polycyclic aromatic hydro- carbons. Journal of Pharmacology and Experimental Therapeutics 314(2):693–702. Van Miller JP, Lalich JJ, Allen JR. 1977. Increased incidence of neoplasms in rats exposed to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chemosphere 9:537–544. Viel JF, Arveux P, Baverel J, Cahn JY. 2000. Soft-tissue sarcoma and non-Hodgkin’s lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels. American Journal of Epidemiology 152(1):13–19. Viel JF, Clement MC, Hagi M, Grandjean S, Challier B, Danzon A. 2008. Dioxin emissions from a municipal solid waste incinerator and risk of invasive breast cancer: A population-based case–control study with GIS-derived exposure. International Journal of Health Geographics [Electronic Resource] 7:4. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, Maffi L, Pisa R, Ricci P, Zanini E, Comba P. 1986. Phenoxy herbicides and soft-tissue sarcomas in female rice weeders. A population-based case-referent study. Scandinaian Journal of Work, Enironment, and Health 13:9–17. Vineis P, Faggiano F, Tedeschi M, Ciccone G. 1991. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides. Journal of the National Cancer Institute 83:362–363. Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnam-era veterans of Michigan. Journal of Occupational and Enironmental Medicine 37(4):423–428. Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence BP. 2004. A novel effect of dioxin: Exposure during pregnancy severely impairs mammary gland differentiation. Toxicological Sciences 78(2):248–257. Walker NJ, Wyde ME, Fischer LJ, Nyska A, Bucher JR. 2006. Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats. Molecular Nutrition and Food Research 50(10):934–944. Wang S-L, Chang Y-C, Chao H-R, Li C-M, Li L-A, Lin L-Y, Papke O. 2006. Body burdens of poly- chlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls and their relations to estrogen metabolism in pregnant women. Enironmental Health Perspecties 114(5):740–745. Wanibuchi H, Salim E, Kinoshita A, Shen J, Wei M, Morimura K, Yoshida K, Kuroda K, Endo G, Fukushima S. 2004. Understanding arsenic carcinogenicity by the use of animal models. Toxi- cology and Applied Pharmacology 198(3):366–376. Warner M, Eskenazi B, Mocarelli P, Gerthoux PM, Samuels S, Needham L, Patterson D, Brambilla P. 2002. Serum dioxin concentrations and breast cancer risk in the Seveso Women’s Health Study. Enironmental Health Perspecties 110(7):625–628. Watanabe KK, Kang HK. 1995. Military service in Vietnam and the risk of death from trauma and selected cancers. Annals of Epidemiology 5:407–412. Watanabe KK, Kang HK. 1996. Mortality patterns among Vietnam veterans: A 24-year retrospective analysis. Journal of Occupational and Enironmental Medicine 38(3):272–278. Watanabe KK, Kang HK, Thomas TL. 1991. Mortality among Vietnam veterans: With methodological considerations. Journal of Occupational Medicine 33:780–785. Waterhouse D, Carman WJ, Schottenfeld D, Gridley G, McLean S. 1996. Cancer incidence in the rural community of Tecumseh, Michigan: A pattern of increased lymphopoietic neoplasms. Cancer 77(4):763–770. Wei M, Wanibuchi H, Morimura K, Iwai S, Yoshida K, Endo G, Nakae D, Fukushima S. 2002. Carci- nogenicity of dimethylarsinic acid in make F344 rats and genetic alterations in incuded urinary bladder tumors. Carcinogenesis 23(8):1387–1397. Weiderpass E, Adami HO, Baron JA, Wicklund-Glynn A, Aune M, Atuma S, Persson I. 2000. Or- ganochlorines and endometrial cancer risk. Cancer Epidemiology, Biomarkers and Preention 9:487–493.

OCR for page 202
4 CANCER Weinberg RA. 2008. Twisted epithelial-mesenchymal transition blocks senescence. Nature Cell Biol- ogy 10(9):1021–1023. Wen S, Yang FX, Gong Y, Zhang XL, Hui Y, Li JG, Liu AIL, Wu YN, Lu WQ, Xu Y. 2008. Elevated levels of urinary 8-hydroxyl-2’-deoxyguanosine in male electrical and electronic equipment dismantling workers exposed to high concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans, polybrominated diphenyl ethers, and polychlorinated biphenyls. Enironmental Science and Technology 42(11):4202–4207. Wigle DT, Semenciw RB, Wilkins K, Riedel D, Ritter L, Morrison HI, Mao Y. 1990. Mortality study of Canadian male farm operators: Non-Hodgkin’s lymphoma mortality and agricultural practices in Saskatchewan. Journal of the National Cancer Institute 82:575–582. Wiklund K. 1983. Swedish agricultural workers: A group with a decreased risk of cancer. Cancer 51:566–568. Wiklund K, Lindefors BM, Holm LE. 1988. Risk of malignant lymphoma in Swedish agricultural and forestry workers. British Journal of Industrial Medicine 45:19–24. Wiklund K, Dich J, Holm LE, Eklund G. 1989a. Risk of cancer in pesticide applicators in Swedish agriculture. British Journal of Industrial Medicine 46:809–814. Wiklund K, Dich J, Holm LE. 1989b. Risk of soft tissue sarcoma, Hodgkin’s disease and non- Hodgkin’s lymphoma among Swedish licensed pesticide applicators. Chemosphere 18: 395–400. Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH, Williams DE. 1990. Health status of Air Force veterans occupationally ex- posed to herbicides in Vietnam. I. Physical health. Journal of the American Medical Association 264:1824–1831. Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. 1987. Soft tissue sarcoma and non- Hodgkin’s lymphoma in relation to phenoxy herbicide and chlorinated phenol exposure in western Washington. Journal of the National Cancer Institute 78:899–910. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. 2002. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro-Oncology 4(4):278–299. Wu CH, Chen HL, Su HJ, Lee CC, Shen KT, Ho WL, Ho SY, Ho YS, Wang YJ. 2004. The topical application of 2,3,7,8-tetrachlorodibenzo-p-dioxin lacks skin tumor-promoting potency but induces hepatic injury and tumor necrosis factor-alpha expression in ICR male mice. Food and Chemical Toxicology 42(8):1217–1225. Wyde ME, Braen AP, Hejtmancik M, Johnson JD, Toft JD, Blake JC, Cooper SD, Mahler J, Vallant M, Bucher JR, Walker NJ. 2004. Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. Toxicological Sciences 82(1):34–45. Xu JX, Hoshida Y, Yang WI, Inohara H, Kubo T, Kim GE, Yoon JH, Kojya S, Bandoh N, Harabuchi Y, Tsutsumi K, Koizuka I, Jia XS, Kirihata M, Tsukuma H, Aozasa K. 2007. Life-style and environmental factors in the development of nasal NK/T-cell lymphoma: A case–control study in East Asia. International Journal of Cancer 120(2):406–410. Yamamoto S, Konishi Y, Matsuda T, Murai T, Shibata MA, Matsui-Yuasa I, Otani S, Kuroda K, Endo G, Fukushima S. 1995. Cancer incidence by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carginogens. Cancer Research 55(6):1271–1276. Yamanaka K, Ohtsubo K, Hasegawa A, Hayashi H, Ohji H, Kanisawa M, Okada S. 1996. Exposure to dimethylarsinic acid, a main metabolite of inorganic arsenics, strongly promotes tumorigenesis initiated by 4-nitroquinoline 1-oxide in the lungs of mice. Carcinogenesis 17(4):767–770. Yang X, Solomon S, Fraser LR, Trombino AF, Liu D, Sonenshein GE, Hestermann EV, Sherr DH. 2008. Constitutive regulation of CYP1B1 by the aryl hydrocarbon receptor (AhR) in pre- malignant and malignant mammary tissue. Journal of Cellular Biochemistry 104(2):402–417.

OCR for page 202
44 VETERANS AND AGENT ORANGE: UPDATE 2008 Yoshizawa K, Walker NJ, Jokinen MP, Brix AE, Sells DM, Marsh T, Wyde ME, Orzech D, Haseman JK, Nyska A. 2005a. Gingival carcinogenicity in female Harlan Sprague-Dawley rats follow- ing two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like com- pounds. Toxicological Sciences 83(1):64–77. [erratum appears in Toxicological Sciences 2005; 83(2):405–406]. Yoshizawa K, Marsh T, Foley JF, Cai B, Peddada S, Walker NJ, Nyska A. 2005b. Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo- p-dioxin in female Harlan Sprague-Dawley rats. Toxicological Sciences 85(1):594–606. Yoshizawa K, Heatherly A, Malarkey DE, Walker NJ, Nyska A. 2007. A critical comparison of murine pathology and epidemiological data of TCDD, PCB126, and PeCDF. Toxicologic Pathology 35(7):865–879. Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to tetrachlorodibenzo- dioxin in a trichlorophenol process accident. Journal of Occupational Medicine 22:11–14. Zahm SH, Fraumeni JF Jr. 1997. The epidemiology of soft tissue sarcoma. Seminars in Oncology 24(5):504–514. Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, Blair A. 1990. A case– control study of non-Hodgkin’s lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1:349–356. Zahm SH, Blair A, Weisenburger DD. 1992. Sex differences in the risk of multiple myeloma associ- ated with agriculture (2). British Journal of Industrial Medicine 49:815–816. Zahm SH, Weisenburger DD, Saal RC, Vaught JB, Babbitt PA, Blair A. 1993. The role of agricultural pesticide use in the development of non-Hodgkin’s lymphoma in women. Archies of Eniron- mental Health 48:353–358. Zambon P, Ricci P, Bovo E, Casula A, Gattolin M, Fiore AR, Chiosi F, Guzzinati S. 2007. Sarcoma risk and dioxin emissions from incinerators and industrial plants: A population-based case– control study (Italy). Enironmental Health: A Global Access Science Source 6:19. Zhong Y, Rafnsson V. 1996. Cancer incidence among Icelandic pesticide users. International Journal of Epidemiology 25(6):1117–1124. Zober A, Messerer P, Huber P. 1990. Thirty-four-year mortality follow-up of BASF employees ex- posed to 2,3,7,8-TCDD after the 1953 accident. International Archies of Occupational and Enironmental Health 62:139–157.