6
Cancer

Cancer is the second leading cause of death in the United States. Among men aged 45–64, the group that includes most Vietnam veterans, the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). In 2004, about 563,700 Americans are expected to die from cancer—more than 1,500 people per day. In the United States, one of every four deaths is from cancer (ACS, 2004a).

In this chapter, the Veterans and Agent Orange: Update 2004 committee summarizes and reaches conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds of interest (2,4-dichlorophenoxyacetic acid [2,4-D]; 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] or its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]; picloram; cacodylic acid) and each type of cancer under consideration in the report. For any new study that reports on just a single type of cancer and that does not revisit a previously studied population, its design information is summarized here with its results; design information for all other new studies can be found in Chapter 4, and tables that summarize the major studies are in Appendix A. The cancer types are, with minor exceptions, discussed in the order in which they are listed in the International Classification of Diseases, Ninth Edition (ICD-9). ICD-9 is the classification used to code and classify mortality data from death certificates. ICD-9 CM (clinical modification) is used to code and classify morbidity data from medical records, hospital records, and surveillance surveys. Appendix C lists ICD-9 codes (and corresponding ICD-10 codes) for the major forms of cancer. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.



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Veterans and Agent Orange: Update 2004 6 Cancer Cancer is the second leading cause of death in the United States. Among men aged 45–64, the group that includes most Vietnam veterans, the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). In 2004, about 563,700 Americans are expected to die from cancer—more than 1,500 people per day. In the United States, one of every four deaths is from cancer (ACS, 2004a). In this chapter, the Veterans and Agent Orange: Update 2004 committee summarizes and reaches conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds of interest (2,4-dichlorophenoxyacetic acid [2,4-D]; 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] or its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]; picloram; cacodylic acid) and each type of cancer under consideration in the report. For any new study that reports on just a single type of cancer and that does not revisit a previously studied population, its design information is summarized here with its results; design information for all other new studies can be found in Chapter 4, and tables that summarize the major studies are in Appendix A. The cancer types are, with minor exceptions, discussed in the order in which they are listed in the International Classification of Diseases, Ninth Edition (ICD-9). ICD-9 is the classification used to code and classify mortality data from death certificates. ICD-9 CM (clinical modification) is used to code and classify morbidity data from medical records, hospital records, and surveillance surveys. Appendix C lists ICD-9 codes (and corresponding ICD-10 codes) for the major forms of cancer. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

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Veterans and Agent Orange: Update 2004 In assessing a possible connection between herbicide exposure and risk of cancer, one important issue is the magnitude of exposure for the people included in a study. As noted in Chapter 5, there is a great variety in detail and accuracy of exposure assessment among the studies the committee reviewed. A small number used biologic markers of exposure, such as the presence of a compound in serum or tissues; some developed an index of exposure from employment or activity records; others used surrogate measures of exposure, such as being present when herbicides were used. Inaccurate assessment of exposure can obscure the presence or absence of exposure–disease associations and thus make it less likely that a true risk will be identified. In this chapter, background information about each cancer, including data on its incidence in the general US population, is followed by a summary of the findings described in the previous Agent Orange reports (Veterans and Agent Orange, hereafter referred to as VAO [IOM, 1994]; Veterans and Agent Orange: Update 1996, hereafter, Update 1996 [IOM, 1996]; Veterans and Agent Orange: Update 1998, hereafter, Update 1998 [IOM, 1999]; Veterans and Agent Orange: Update 2000, hereafter, Update 2000 [IOM, 2001]; and Veterans and Agent Orange: Update 2002, hereafter, Update 2002 [IOM, 2003]), a discussion of the most recent scientific literature, and a synthesis of the material reviewed. Where appropriate, the literature is discussed by exposure type (occupational, environmental, service in Vietnam). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding epidemiology and Vietnam veterans. Cancer incidence data for the general US population are included in the background sections to provide a context for consideration of cancer risk in Vietnam veterans. Incidences are reported for people 50–64 years old because most Vietnam-era veterans are in this age group. The data, which were collected for the Surveillance, Epidemiology, and End Results (SEER) Program of the National Institutes of Health—National Cancer Institute, are categorized by sex, age, and race, all of which can have a profound effect on risk. Prostate cancer incidence, for example, is approximately 4.4 times higher in men between the ages of 60 and 64 than it is in men 50–54 years old; it is approximately twice as high in blacks 50–64 years old as it is in whites in the same age group (NCI, 2004). The figures presented for each cancer are estimates for the entire US population, not predictions for the Vietnam-veteran cohort. Many factors can influence incidence, among them personal behavior (tobacco use, diet), genetic predisposition, and medical history. Those factors can make someone more or less likely than average to contract a given cancer. Incidence data are reported for all races and also separately for blacks and whites. The data reported are for 1997–2001, the most recent data set available to the committee. Incidence figures given here are not directly comparable to the figures listed in earlier Updates. Earlier reports used 1990 US Census data; this report used data from the 2000 Census, so some of the differences in incidence estimates

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Veterans and Agent Orange: Update 2004 resulted from changes in demographics rather than from changes in the factors that determine cancer rates. There is still considerable uncertainty about the magnitude of potential risk posed by exposure to the compounds of interest as shown by the occupational, environmental, and veterans’ studies reviewed by the committee. Many of those studies provided inadequate controls for important confounders, and there is not enough information to extrapolate from exposure as presented in those studies to that of individual Vietnam veterans. The committee therefore cannot measure the likely risk to Vietnam veterans that is attributable to exposure to the compounds of interest in Vietnam. Where the data permit, qualitative observations are offered. Information about biologic mechanisms that could contribute to carcinogenic activity by any of the agents of interest is summarized in the Biologic Plausibility section at the conclusion of this chapter. It distills toxicologic information concerning how any of the chemicals of interest impact general mechanisms of carcinogenesis, which is presented in detail in Chapter 3. Such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is addressed for a particular site, the generic information is implicit, and only toxicologic information specific to carcinogenesis at the site in question is presented. GASTROINTESTINAL TRACT CANCERS Gastrointestinal tract tumors are among the most common of cancers. The committee reviewed data on esophageal cancer (ICD-9 150.0–150.9), stomach cancer (ICD-9 151.0–151.9), pancreatic cancer (ICD-9 157.0–157.9), colon cancer (ICD-9 153.0–153.9), and rectal cancer (ICD-9 154.0–154.9). According to American Cancer Society (ACS) estimates, about 255,640 people will be diagnosed with those cancers in the United States in 2004, and 134,840 people will die from them (ACS, 2004a). Colon cancer accounts for about 40% of those diagnoses and deaths. Collectively, gastrointestinal tract tumors are expected to account for 19% of new diagnoses and 24% of cancer deaths in 2004. Colorectal cancer is the third most common form of cancer in men and in women, excluding basal- and squamous-cell skin cancers. The average annual incidences for gastrointestinal cancers are shown in Table 6-1. Carcinoma of the esophagus has great geographic variation. The region of the world extending from Iran through the steps of Central Asia, Mongolia, and northern portion of China has cancer frequencies that are 10 times those of the rest of the world. In northern China, the incidence is 160 cases per 100,000, compared with 4–8 per 100,000 in North America, Europe, Southeast Asia, and Japan. In addition to a different disease incidence, there is a difference in the histopathologic type of cancer; squamous-cell carcinoma is predominant in the high-endemic areas, adenocarcinoma makes up approximately 50% of cases in the low-incidence areas of the United States, Europe, Southeast Asia, and Japan.

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Veterans and Agent Orange: Update 2004 TABLE 6-1 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in United Statesa   50–54 Years of Age 55–59 Years of Age 60–64 Years of Age All Races White Black All Races White Black All Races White Black Stomach Males 9.7 8.7 17.3 16.4 14.9 20.9 27.1 22.7 47.4 Females 4.6 3.5 8.8 6.8 5.8 9.3 10.8 8.6 19.0 Esophagus Males 9.7 9.0 20.6 16.8 16.1 31.2 24.8 24.7 35.5 Females 1.5 1.2 5.1 3.3 2.7 9.0 5.8 5.0 16.4 Colon (excluding the rectum) Males 33.3 31.1 53.6 59.4 58.7 82.4 105.7 102.8 148.5 Females 27.5 25.4 41.0 44.6 41.6 74.5 78.2 77.5 111.4 Rectum and rectosigmoid junction Males 23.3 22.2 24.1 36.9 36.8 34.7 55.1 54.2 58.7 Females 14.0 13.3 17.5 22.0 21.2 30.6 29.6 30.3 35.0 Pancreas Males 12.7 12.1 22.5 20.3 18.8 34.7 33.7 33.4 48.4 Females 7.7 7.5 11.3 13.6 12.7 21.3 24.0 22.5 38.0 a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001. The incidences of stomach, colon, rectal, and pancreatic cancers increase with age in people 50–64 years old. In general, incidence is higher in men than it is in women, and is higher in blacks than in whites. Other risk factors for those cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and dietary factors. Tobacco use is a risk factor for pancreatic cancer that might also increase the risk of stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori increases the risk of stomach cancer. Type 2 diabetes is associated with an increased risk of cancers of the colon and pancreas (ACS, 2004a). Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the compounds of interest and gastrointestinal tumors. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Tables 6-2, 6-3, 6-4, 6-5, and 6-6 summarize the results of the relevant studies.

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Veterans and Agent Orange: Update 2004 TABLE 6-2 Selected Epidemiologic Studies—Stomach Cancer Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL New Studies Bodner et al., 2003 Dow chemical production workers—mortality — 1.5 (0.7–2.7) Swaen et al., 2004 Dutch licenced herbicide applicators—mortality 3 0.4 (0.1–1.3) b Studies Reviewed in Update 2002 Burns et al., 2001 Dow 2,4-D production workers—cancer of the digestive organs—mortality 16 0.7 (0.4–1.2) Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers 13 1.0 (0.6–1.8) Hooiveld et al., 1998 Dutch chemical production workers 3 1.0 (0.2–2.9) Rix et al., 1998 Danish paper mill workers     Male 48 1.1 (0.8–1.4) Female 7 1.0 (0.4–2.1) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 39 0.9 (0.7–1.3) Kogevinas et al., 1997 IARC cohort     Workers exposed to TCDD (or higher-chlorinated dioxins) 42 0.9 (0.6–1.2) Workers not exposed to TCDD (or higher-chlorinated dioxins) 30 0.9 (0.6–1.3) Workers exposed to any phenoxy herbicide or chlorophenol 72 0.9 (0.7–1.1) Becher et al., 1996 German chemical production workers     Plant I 12 1.3 (0.7–2.2) Plant II 0   Plant III 0   Plant IV 2 0.6 (0.1–2.3) Ott and Zober, 1996 BASF cleanup workers 3 1.0 (0.2–2.9)   TCDD <0.1 µg/kg of body wt 0   TCDD 0.1–0.99 µg/kg of body wt 1 1.3 (0.0–7.0) TCDD >1 µg/kg of body wt 2 1.7 (0.2–6.2) Ramlow et al., 1996 Pentachlorophenol production workers     0-year latency 4 1.7 (0.4–4.3) 15-year latency 3 1.8 (0.4–5.2) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states     White males 657 1.0 (1.0–1.1) Nonwhite females 23 1.9 (1.2–2.8) Bueno de Mesquita et al., 1993 Phenoxy herbicide workers 2 0.7 (01.–2.7) Collins et al., 1993 Monsanto 2,4-D production workers 0 0 (0.0–1.1) Kogevinas et al., 1993 IARC cohort—females   NS

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Veterans and Agent Orange: Update 2004 Reference Study Population Estimated Casesa Exposed Relative Risk (95% CI)a Studies Reviewed in VAO Ronco et al., 1992 Danish male self-employed farm workers 286 0.9 (*) Swaen et al., 1992 Dutch herbicide appliers 1 0.5 (0.0–2.7)b Fingerhut et al., 1991 NIOSH cohort 10 1.0 (0.5–1.9) Manz et al., 1991 German production workers 12 1.2 (0.6–2.1) Saracci et al., 1991 IARC cohort 40 0.9 (0.6–1.2) Wigle et al., 1990 Canadian farmers 246 0.9 (0.8–1.0) Zober et al., 1990 BASF production workers—basic cohort 3 3.0 (0.8–11.8) Alavanja et al., 1989 USDA forest or soil conservationists 9 0.7 (0.3–1.3) Henneberger et al., 1989 Paper and pulp workers 5 1.2 (0.4–2.8) Solet et al., 1989 Paper and pulp workers 1 0.5 (0.1–3.0) Alavanja et al., 1988 USDA agricultural extension agents 10 0.7 (0.4–1.4) Bond et al., 1988 Dow 2,4-D production workers 0 —(0.0–3.7) Thomas, 1987 Flavor and fragrance chemical production workers 6 1.4 (*) Coggon et al., 1986 British MCPA production workers 26 0.9 (0.6–1.3) Robinson et al., 1986 Paper and pulp workers 17 1.2 (0.7–2.1) Lynge, 1985 Danish male production workers 12 1.3 (*) Blair et al., 1983 Florida pesticide appliers 4 1.2 (*) Burmeister et al., 1983 Iowa residents—farming exposures 1,812 1.3 (p < 0.05) Wiklund, 1983 Swedish agricultural workers 2,599 1.1 (1.0–1.2)c Burmeister, 1981 Iowa Farmers 338 1.1 (p < 0.01) Axelson et al., 1980 Swedish railroad workers—total exposure 3 2.2 (*) ENVIRONMENTAL New Studies Fukuda et al., 2003 Residents of municipalities in Japan with or without waste incineration plants in males     Age-adjusted mortality (100,000)   38.2 ± 7.8 vs 39.0 ± 8.8 (p = 0.28) Age-adjusted mortality (100,000) in females 20.7 ± 5.0 vs 20.7 ± 5.8 (p = 0.92) Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia   45.3 in Chapaevsk; 44.0 in Samara Regiond   Age-adjusted incidence (100,000) of stomach cancer in males   Age-adjusted incidence (100,000) of stomach cancer in females   33.9 in Chapaevsk; 17.6 in Samara Regiond

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a   Mortality standardized to Samara Region     Males 59 1.7 (1.3–2.2) Females 45 0.7 (0.5–0.9) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up     Zone A males 1 0.5 (0.1–3.2) Zone A females 2 1.4 (0.3–5.5) Zone B males 15 1.0 (0.6–1.6) Zone B females 9 1.0 (0.5–1.9) Bertazzi et al., 1998 Seveso residents—15-year follow-up     Zone A females 1 0.9 (0.1–6.7) Zone B males 10 0.8 (0.4–1.5) Zone B females 7 1.0 (0.5–2.2) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up     Zone A females 1 0.9 (0.0–5.3) Zone B males 10 0.8 (0.4–1.5) Zone B females 7 1.0 (0.4–2.1) Zone R males 76 0.9 (0.7–1.1) Zone R females 58 1.0 (0.8–1.3) Svensson et al., 1995 Swedish fishermen—mortality     East coast 17 1.4 (0.8–2.2) West coast 63 0.9 (0.7–1.2) Swedish fishermen—incidence   East coast 24 1.6 (1.0–2.4) West coast 71 0.9 (0.7–1.2) Studies Reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents—10-year follow-up—morbidity     Zone B males 7 1.0 (0.5–2.1) Zone B females 2 0.6 (0.2–2.5) Zone R males 45 0.9 (0.7–1.2) Zone R females 25 1.0 (0.6–1.5) Studies Reviewed in VAO Pesatori et al., 1992 Seveso residents     Zones A, B males 7 0.9 (0.4–1.8) Zones A, B females 3 0.8 (0.3–2.5) Bertazzi et al., 1989a Seveso residents—10-year follow-up     Zones A, B, R males 40 0.8 (0.6–1.2) Zones A, B, R females 22 1.0 (0.6–1.5) Bertazzi et al., 1989b Seveso residents—10-year follow-up     Zone B males 7 1.2 (0.6–2.6)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a VIETNAM VETERANS New Studies Akhtar et al., 2004 White Air Force Ranch Hand veterans—cancer of the digestive system     All Ranch Hand veterans Incidence (SIR) 16 0.6 (0.4–1.0) Mortality (SMR) 6 0.4 (0.2–0.9) Veterans, tours 1966–1970—incidence 14 0.6 ((0.4–1.1) White Air Force comparison veterans—cancer of the digestive system   All comparison veterans Incidence (SIR) 31 0.9 (0.6–1.2) Mortality (SMR) 14 0.7 (0.4–1.1) Veterans, tours 1966–1970—incidence 24 0.9 (0.6–1.3) Studies Reviewed in Update 1998 Crane et al., 1997a Australian military Vietnam veterans 32 1.1 (0.7–1.5) Crane et al., 1997b Australian national service Vietnam veterans 4 1.7 (0.3–10) Studies Reviewed in VAO Breslin et al., 1988 Army Vietnam veterans 88 1.1 (0.9–1.5)   Marine Vietnam veterans 17 0.8 (0.4–1.6) Anderson et al., 1986a Wisconsin Vietnam veterans 3 —* Anderson et al., 1986b Wisconsin Vietnam veterans 1 —* a Given when available. b Risk estimate is for stomach and small intestine. c 99% CI. d Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity. * Information not provided by study authors. —Information denoted by a dash in the original study. ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; USDA, US Department of Agriculture.

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Veterans and Agent Orange: Update 2004 TABLE 6-3 Selected Epidemiologic Studies—Esophageal Cancer Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 1998 Kogevinas et al., 1997 IARC cohort     Esophagus 28 1.0 (0.7–1.4) Studies Reviewed in Update 1996 Asp et al., 1994 Finnish herbicide applicators—incidence 3 1.6 (0.3–4.6)   Finnish herbicide applicators—mortality 2 1.3 (0.2–4.7) Studies Reviewed in VAO Ronco et al., 1992 Danish male self-employed—incidence farmworkers 32 0.4 (NS) Saracci et al., 1991 IARC cohort 8 0.6 (0.3–1.2) Coggon et al., 1986 British MCPA production workers 8 0.9 (0.6–1.3) Wiklund, 1983 Swedish agricultural workers 169 0.6 (0.5–0.7) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia     Age-adjusted incidence (100,000) in males   4.1 in Chapaevsk; 4.0 in Samara Regionb Age-adjusted incidence (100,000) in females 0.0 in Chapaevsk; 1.4 in Samara Regionb VIETNAM VETERANS Studies Reviewed in Update 1998 Crane et al. 1997a Australian military Vietnam veterans     Esophagus 23 1.2 (0.7–1.8) Crane et al. 1997b Australian national service Vietnam veterans     Esophagus 1 1.3 (0.0–10) a Given when available. b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity. ABBREVIATION: CI, confidence interval; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Edition; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not significant.

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Veterans and Agent Orange: Update 2004 TABLE 6-4 Selected Epidemiologic Studies—Colon Cancer Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 2000 Steenland et al., 1999 US chemical production workers 34 1.2 (0.8–1.6) Hooiveld et al., 1998 Dutch chemical production workers 3 1.4 (0.3–4.0) Rix et al., 1998 Danish paper mill workers     Males 58 1.0 (0.7–1.2) Females 23 1.1 (0.7–1.7) Studies Reviewed in Update 1998 Gambini et al., 1997 Italian rice growers 27 1.1 (0.7–1.6) Kogevinas et al., 1997 IARC cohort     Workers exposed to TCDD (or higher-chlorinated dioxins) 52 1.0 (0.8–1.3) Workers not exposed to TCDD (or higher-chlorinated dioxins) 33 1.2 (0.8–1.6) Workers exposed to any phenoxy herbicide or chlorophenol 86 1.1 (0.8–1.3) Becher et al., 1996 German chemical production workers     Plant I 2 0.4 (0.0–1.4) Plant II 0   Plant III 1 2.2 (0–12) Plant IV 0   Ott and Zober, 1996b BASF cleanup workers 5 1.0 (0.3–2.3)   TCDD <0.1 µg/kg of body wt 2 1.1 (0.1–3.9) TCDD 0.1–0.99 µg/kg of body wt 2 1.4 (0.2–5.1) TCDD >1 µg/kg of body wt 1 0.5 (0.0–3.0) Ramlow et al., 1996 Pentachlorophenol production workers     0-year latency 4 0.8 (0.2–2.1) 15-year latency 4 1.0 (0.3–2.6) Studies Reviewed in Update 1996 Blair et al., 1993 US farmers in 23 states—white males 2,291 1.0 (0.9–1.0) Bueno de Mesquita et al., 1993 Phenoxy herbicide workers 3 1.8 (0.4–5.4) Collins et al., 1993 Monsanto 2,4-D production workers 3 0.5 (0.1–1.3) Studies Reviewed in VAO Swaen et al., 1992 Dutch herbicide applicators 4 2.6 (0.7–6.5) Ronco et al., 1992 Danish male self-employed farm workers 277 0.7 (p < 0.05) Fingerhut et al., 1991 NIOSH cohort 25 1.2 (0.8–1.8) Manz et al., 1991 German production workers 8 0.9 (0.4–1.8) Saracci et al., 1991 IARC cohort 41 1.1 (0.8–1.5) Zober et al., 1990b BASF production workers—basic cohort 2 2.5 (0.4–14.1) Alavanja et al., 1989 USDA forest conservationists * 1.4 (0.7–2.8)   USDA soil conservationists * 1.2 (0.7–2.0) Henneberger et al., 1989 Pulp and paper workers 9 1.0 (0.5–2.0) Solet et al., 1989 Pulp and paper workers 7 1.5 (0.6–3.0) Alavanja et al., 1988 USDA agricultural extension agents * 1.0 (0.7–1.5) Bond et al., 1988 Dow 2,4-D production workers 4 2.1 (0.6–5.4)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a Thomas, 1987 Flavor and fragrance chemical production workers 4 0.6 (*) Coggon et al., 1986 British MCPA production workers 19 1.0 (0.6–1.6) Robinson et al., 1986 Pulp and paper workers 7 0.4 (0.2–0.9) Lynge, 1985 Male Danish production workers 10 1.0 (*) Blair et al., 1983 Florida pesticide applicators 5 0.8 (*) Wiklund, 1983 Swedish agricultural workers 1,332 0.8 (0.7–0.8)c Thiess et al., 1982 BASF production workers 1 0.4 (*) Burmeister, 1981 Iowa farmers 1,064 1.0 (NS) Hardell, 1981 Sweden residents     Exposed to phenoxy acids 11 1.3 (0.6–2.8) Exposed to chlorophenols 6 1.8 (0.6–5.3) ENVIRONMENTAL Studies Reviewed in Update 2002 Revich et al., 2001 Residents of Chapaevsk, Russia   22.7 in Chapaevsk; 21.7 in Samara regiond   Age-adjusted incidence (100,000) in males     Age-adjusted incidence (100,000) in females   13.3 in Chapaevsk; 15.4 in Samara regiond   Mortality standardized to Samara region     Males 17 1.3 (0.8–2.2) Females 24 1.0 (0.7–1.5) Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents—20-year follow-up     Zone A females 2 1.8 (0.4–7.0) Zone B males 10 1.2 (0.6–2.2) Zone B females 3 0.4 (0.1–1.3) Bertazzi et al., 1998 Seveso residents—15-year follow-up     Zone A females 2 2.6 (0.6–10.5) Zone B males 5 0.8 (0.3–2.0) Zone B females 3 0.6 (0.2–1.9) Studies Reviewed in Update 1998 Bertazzi et al., 1997 Seveso residents—15-year follow-up     Zone A females 2 2.6 (0.3–9.4) Zone B males 5 0.8 (0.3–2.0) Zone B females 3 0.6 (0.1–1.8) Zone R males 34 0.8 (0.6–1.1) Zone R females 33 0.8 (0.6–1.1)

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