7
Cancer

Cancer is the second leading cause of death in the United States. Among males aged 45–64, the group that describes most Vietnam veterans, the risk of dying from cancer nearly equals the risk from heart disease, the overall leading cause of death in the United States (U.S. Census, 1999). This year about 552,200 Americans are expected to die of cancer—more than 1,500 people a day. In the United States, one of every four deaths is from cancer (ACS, 2000b).

In this chapter, the committee summarizes and reaches conclusions about the strength of the evidence in epidemiologic studies regarding associations between exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and each type of cancer under consideration in this report. 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 a standardized means of classifying medical conditions used by physicians and researchers around the world. Appendix B lists ICD•9 codes for the major forms of cancer.

In assessing a possible relation between herbicide exposure and risk of cancer, one key issue is the level of exposure of those included in a study. As noted in Chapter 5, the detail and accuracy of exposure assessment vary widely among the studies reviewed by the committee. A small number of studies use a biomarker of exposure, for example, the presence of dioxin in serum or tissues; some develop an index of exposure from employment or activity records; and others use a surrogate measure 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.



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Veterans and Agent Orange: Update 2000 7 Cancer Cancer is the second leading cause of death in the United States. Among males aged 45–64, the group that describes most Vietnam veterans, the risk of dying from cancer nearly equals the risk from heart disease, the overall leading cause of death in the United States (U.S. Census, 1999). This year about 552,200 Americans are expected to die of cancer—more than 1,500 people a day. In the United States, one of every four deaths is from cancer (ACS, 2000b). In this chapter, the committee summarizes and reaches conclusions about the strength of the evidence in epidemiologic studies regarding associations between exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and each type of cancer under consideration in this report. 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 a standardized means of classifying medical conditions used by physicians and researchers around the world. Appendix B lists ICD•9 codes for the major forms of cancer. In assessing a possible relation between herbicide exposure and risk of cancer, one key issue is the level of exposure of those included in a study. As noted in Chapter 5, the detail and accuracy of exposure assessment vary widely among the studies reviewed by the committee. A small number of studies use a biomarker of exposure, for example, the presence of dioxin in serum or tissues; some develop an index of exposure from employment or activity records; and others use a surrogate measure 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.

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Veterans and Agent Orange: Update 2000 The outcomes reviewed in this chapter follow a common format. Each section begins by providing some background information about the cancer under discussion, including data concerning its incidence in the general U.S. population. A brief summary of the findings described in the first three Agent Orange reports—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996), and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) —is then presented, followed by a discussion of the most recent scientific literature and a synthesis of the material reviewed. Where appropriate, reviews are separated by the type of exposure (occupational, environmental, Vietnam veteran) being addressed. Each section concludes with the committee’s finding regarding the strength of the evidence in epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. Expected Number of Cancer Cases Among Vietnam Veterans in the Absence of Any Increase in Risk Due to Herbicide Exposure To provide some background for the consideration of cancer risks in Vietnam veterans, this chapter also reports information on cancer incidence in the general U.S. population. Incidence rates are reported for individuals between the ages of 45 and 59 because most Vietnam era veterans are in this age group. The data, which were collected as part of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Center for Health Statistics (NCHS), are categorized by sex, age, and race because these factors can have a profound effect on the estimated level of risk. Prostate cancer incidence, for example, is nearly 11 times higher in men age 55–59 than in 45–49-year-olds and more than twice as high in African Americans age 45–59 as in whites of this age group (NCI, 2000). The figures presented for each cancer are estimates for the entire U.S. population, not precise predictions for the Vietnam veteran cohort. It should be remembered that numerous factors may influence the incidence reported here—including personal behavior (e.g., smoking and diet), genetic predisposition, and other risk factors such as medical history. These factors may make a particular individual more or less likely than average to contract a given cancer. Incidence data are reported for all races and also separately for African Americans and whites. The data reported are for 1993–1997, the most recent data available at the time this report was written. As detailed in Chapter 6, here, and in the following chapters, great uncertainties remain about the magnitude of potential risk from exposure to herbicides and dioxin in the occupational, environmental, and veteran studies reviewed by the committee. Many have inadequate controls for important confounders, and the information needed to extrapolate from the level of exposure in the studies to that of individual Vietnam veterans is lacking. The committee therefore cannot quan-

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Veterans and Agent Orange: Update 2000 tify the degree of risk likely to have been experienced by Vietnam veterans due to exposure to herbicides in Vietnam. It offers qualitative observations where data permit. GASTROINTESTINAL TRACT TUMORS Background As a group, this category includes some of the major cancers in the United States and the world. The committee reviewed the data on colon cancer (ICD•9 153.0–153.9), rectal cancer (ICD•9 154.0–154.1), stomach cancer (ICD•9 151.0– 151.9), and pancreatic cancer (ICD•9 157.0–157.9). According to American Cancer Society estimates, approximately 180,000 individuals will be diagnosed with these cancers in the United States in 2000 and some 97,500 individuals will die from them (ACS, 2000a). Colon cancer accounts for about half of these diagnoses and deaths. Collectively, gastrointestinal (GI) tract tumors are expected to account for 15 percent of new diagnoses and 18 percent of cancer deaths in 2000. Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa Selected Gastrointestinal Cancers   45–49 Years of Age 50–54 Years of Age 55–59 Years of Age   All Races White Black All Races White Black All Races White Black Stomach Males 6.0 4.9 11.1 10.9 9.8 20.9 20.0 16.7 35.2 Females 2.6 2.0 4.7 4.4 3.5 7.3 7.8 6.6 14.1 Colon Males 15.6 14.6 23.7 34.2 31.4 59.8 62.9 61.7 81.4 Females 14.8 13.0 24.1 27.1 23.9 49.0 49.9 48.3 72.7 Rectal Males 7.7 6.9 10.1 14.8 13.6 17.9 24.8 24.6 27.1 Females 4.9 4.6 5.4 9.4 8.8 12.7 13.7 12.8 16.6 Pancreatic Males 5.4 4.9 10.6 12.5 11.7 24.7 21.6 19.6 46.7 Females 3.9 3.5 6.7 8.1 7.5 13.7 13.8 13.4 22.6 aSEER nine standard registries, crude age-specific rate, 1993–1997. The incidence of stomach, colon, rectal, and pancreatic cancers increases with age for individuals between 45 and 59. In general, incidence in males is higher than in females, and incidence in African Americans exceeds that in whites. Risk factors besides age and race vary for these cancers but always include family history of the same form of cancer, certain diseases of the affected organ, and dietary factors. Cigarette smoking is a risk factor for pancreatic cancer and may also increase the risk of stomach cancer (Miller et al., 1996).

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Veterans and Agent Orange: Update 2000 Infection with the bacterium Helicobacter pylori also increases the risk of stomach cancer. Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found there to be limited or suggestive evidence of no association between exposure to herbicides used in Vietnam or the contaminant dioxin and gastrointestinal tumors. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Tables 7-1, 7-2, 7-3, and 7-4 provide summaries of the results of studies underlying these findings and a list of reports that contain details of the research. Update of the Scientific Literature Occupational Studies The largest industrial cohort exposed to dioxins is the group of 5,132 U.S. workers known as the NIOSH (National Institute of Occupational Safety and Health) cohort. This group was assembled from employees of 12 major chemical manufacturers that produced 2,4,5-trichlorophenol, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), Silvex, Erbon, Ronnel, and hexachlorophene. Workers engaged in production and maintenance were exposed to TCDD as a contaminant of these chemicals. The first study of mortality through 1987 among these workers (Fingerhut, 1991) found a slight excess cancer mortality for all cancers combined (standardized mortality ratio [SMR]=1.2, 95 percent confidence interval [95% CI] 1.0–1.3); however, no elevated risk was observed for cancers of the stomach, colon, rectum, or pancreas. This cohort has been updated through 1993, and an exposure-response analysis on a subcohort (approximately 69 percent of the population) has been conducted (Steenland et al., 1999). In that study, mortality from cancer of the small intestine and colon (1.2, 0.8–1.6), rectum (0.9, 0.3–1.9), stomach (1.0, 0.6–1.8), and pancreas (1.0, 0.6– 1.6) is not different from expected. Similar results are reported for a subcohort of 608 workers whose medical records stated that they had chloracne, indicating higher TCDD exposures during their working years. A quantitative exposure assessment was conducted on workers employed in 8 (of a total of 12) plants that had sufficient information on the level of TCDD contamination in their products and detailed work histories. For this subcohort, a job-exposure matrix was constructed, and exposure scores were calculated using three factors: (1) the concentration of TCDD in the process materials, (2) the fraction of the day each worker spent in the specific process that resulted in contact with these materials, and (3) a weighting factor for the level of contact by skin contamination or inhalation of TCDD-containing material. In the analysis of

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Veterans and Agent Orange: Update 2000 this subcohort, several exposure metrics were calculated including a cumulative exposure score, the log of this score, the average exposure score (cumulative divided by duration), and cumulative exposure categorized into septiles. Excess cancer risk was confined largely to the highest two exposure class septiles, with an all-cancer SMR of 1.5 (1.2–1.8). Site-specific GI cancers are not reported, and for all digestive cancers (ICD•9 150–159), this highest-exposure class (the two highest septiles) had a nonsignificantly elevated excess risk (1.4, 0.9–2.2). In a study of a cohort of Danish paper mill workers, Rix et al. (1998) examined mortality from a wide range of causes. Substantial dioxin exposure among these workers is unlikely, since paper pulp was never produced at the three mills studied. Rather, they manufactured paper from imported bleached and unbleached pulp. There are no direct measures of exposure for these workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. For two of the mills, the period of follow-up was January 1, 1943, to December 31, 1993, while for the third mill, follow-up started at January 1, 1965. Incident cancer cases were identified from the Danish Cancer Register, and expected numbers of cases were calculated using the rates for the total Danish population by gender, 5-year age group, and calendar time. For cancer sites of specific interest, Poisson regression models were used to analyze by duration and years since first employment and by department of employment. For GI cancers, no statistically significant excesses were observed in men or women (standardized incidence ratios [SIRs] reported separately for esophagus, stomach, colon, rectum, and pancreas). When analyzed by department of work, men employed in maintenance and repair had a nonsignificantly elevated risk of stomach cancer (SIR=1.5, CI not reported, 15 cases), while men employed in the power station had an SIR of 1.7 (4 cases). For pancreatic cancer, men in the paper machine department had an SIR of 1.6 (6 cases), while men in the storage and transport departments had an SIR of 1.6 (8 cases). Hooiveld et al. (1998) reported on an update of a mortality study of workers at two chemical factories in the Netherlands. This group is included in the multinational International Agency for Research on Cancer (IARC) study of cancer and exposure to organochlorine compounds. This update of the Dutch cohort added 6.5 years of follow-up to a previous study of these workers (Bueno de Mesquita et al., 1993) and included analysis by estimated maximum TCDD serum level. This value was estimated for each member of the cohort by measuring serum TCDD levels for 144 subjects, including production workers known to be exposed to dioxins, workers in herbicide production, nonexposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963. By assuming first-order TCDD elimination with an estimated half-life of 7.1 years, TCDDmax was extrapolated for 47 of these workers, and a regression model was constructed to estimate the effect of exposure as a result of

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Veterans and Agent Orange: Update 2000 the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970 on the estimated TCDDmax for each cohort member. For gastrointestinal cancers (esophagus, 1 case; stomach, 3 cases; intestine, 3 cases; rectum, 1 case; pancreas, 4 cases; other sites, 1 case), no excess mortality was observed among 549 exposed male workers by comparison to national (Dutch) death rates. For workers known to be exposed as a result of the 1963 accident, a nonsignificant elevation of cancer of the esophagus was reported (SMR=4.3, 0.1–24.0, 1 case); the other GI sites were not reported. Gastrointestinal cancer was not reported in the results of the comparison between exposed and unexposed male workers in the cohort or by comparison of workers with low, medium, and high levels of predicted TCDDmax. In a meta-analysis of occupational exposures and pancreatic cancer, Ojajärvi et al. (2000) surveyed publications for the period 1969–1998, searching Medline, Toxline, and Cancerlit for studies addressing occupational exposure and pancreatic cancer. They reduced the number of studies from 1,902 to 92 studies of 161 populations after excluding studies that did not report on pancreatic cancer, did not include sufficient information for meta-analysis, were not the most recent update, or did not include verifiable information on exposure to one or more of 23 specific chemical and physical agents. This information on exposure may have been direct estimates of risk for one or more of the 23 agents or information on job title that verified exposure to one or more of these agents. Herbicides were among the 23 specific agents included; however this broad class of chemical agents was not stratified by type of herbicide. Other agents of interest included chlorinated hydrocarbon solvents, fungicides, insecticides, and polycyclic aromatic hydrocarbons, as well as several heavy metals (cadmium, chromium, iron, lead, and nickel). The set of studies included in the meta-analysis consisted of 23 studies described as administrative (linkage of administrative records or proportional mortality ratio [PMR], proportionate cancer mortality ratio, or mortality odds ratio studies); 88 studies of industrial cohorts; 7 industry-based nested case-control studies; and 43 population- or hospital-based case-control studies. Most studies included were mortality studies. Studies were analyzed using simple random effects models to calculate meta-risk ratios (MRRs). In cases where excesses were observed, population etiological fractions and etiological fractions among the exposed groups were calculated. Data were reported based on exposed populations rather than by study. For the 10 studies in which herbicide exposure was reported, the MRR was 1.0 (0.8–1.3), and the range of point estimates in these studies was 0.6–5.9. The p-value for heterogeneity by agent (herbicides) was .3. These results were virtually unchanged when stratified for gender and quality of diagnosis (MRR=1.2, 0.8–2.0 for men, not reported for women; 0.9, 0.7–1.2 when gender was unspecified or both). None of the studies included information on the histological verification of the pancreatic cancer diagnosis. When examined by study type, the MRRs for the nine SMR or SIR studies (1.1,

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Veterans and Agent Orange: Update 2000 0.8–1.5) were virtually identical to the one case-control study (0.9, 0.7–1.8). Population etiological fraction and etiological fraction among the exposed groups were not calculated for herbicides. The authors concluded that the meta-analysis suggested increased risk of pancreatic cancer with exposure to chlorinated hydrocarbon solvents, nickel and its compounds, and chromium and its compounds. There was more limited evidence of increased risk for organochlorine pesticides, silica, and aliphatic and alicyclic hydrocarbon solvents. There was no evidence of increased risk with herbicide exposure. Environmental Studies In a review of early, mid-term, and long-term health effects, Bertazzi et al. (1998) continued the follow-up of people environmentally exposed to TCDD in the Seveso accident. The events that led to the exposure and the methods used to study this population have been fully described previously. Their 1998 report reviews the full range of indicators of exposure and effects on animal and human health. At least in the case of GI cancer mortality, the report does not appear to add any new information to Bertazzi et al. (1997), which was reviewed in Update 1998. After 15 years’ follow-up (1976–1991), death from cancer of the rectum was significantly elevated for men in zone B (relative risk [RR]=2.9, 1.3–6.2, 7 observed deaths). A statistically significant increase in stomach cancer in women in Zone B observed after 10 years (RR=2.4, 1.0–6.0, 5 deaths) was not seen in the 15-year follow-up (RR=1.0, 0.5–2.2, 7 observed deaths). Excess mortality from esophageal cancer (RR=1.6, 1.1–2.4, 30 deaths) was reported among men in zone R (considered to be the low-exposure region). No other significant elevation of death from digestive cancer overall or at any of the GI sites was observed in men or women in any exposure zone. In another report, Bertazzi et al. (2001) extended the mortality analysis through the end of 1996. They examined mortality from GI cancer and found a pattern of mixed results, similar to those seen in their earlier studies of the Seveso population. In this study, digestive cancer overall (ICD•9 150–159) was not elevated in either zone A or zone B. When examined on a site-specific basis, cancer of the rectum (ICD•9 154) was elevated in zone B (RR=1.9, 1.1–3.5, 11 cases) but not in zone A (1.2, 0.2–8.6, 1 case). Digestive cancers classified as “other” (ICD•9 159) were nonsignificantly elevated in zones A and B, while all other digestive cancer sites had RRs of 1.0 or less. More detailed examination including stratification of the zone A and zone B populations (done both separately and combined) by 5-year intervals of latency did not reveal any significant excess risk estimates, except for an excess in stomach cancer for zone B women in the 10– 14-year latency group (2.5, 1.1–5.7, 6 cases). Cancer of the rectum was also elevated among all zone B men (2.4, 1.2–4.9, 8 cases).

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Veterans and Agent Orange: Update 2000 Vietnam Veteran Studies In the Air Force Health Study final report (AFHS, 2000), gastrointestinal cancers as a group are not addressed; however, results for esophageal cancer and cancer of the colon and rectum are reported. Because of the absence of cases of malignant neoplasms of the esophagus in Ranch Hands, statistical analysis was not performed. A malignant neoplasm of the esophagus was observed in two members of the comparison group. For malignant neoplasms of the colon and rectum, no excess risk was seen for the Ranch Hand veterans after analyses were adjusted for covariates. Approximately 50,000 members of the Australian Defence Force and Citizen Military Forces served in the Vietnam theater over the war years. The government of Australia conducted mail surveys of all individuals with Vietnam service, which included those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a, b). Questionnaires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate). The self-reported data gathered were compared with age-matched Australian national data. The study found that 405 male veterans and 1 female veteran indicated a doctor had told them they had colorectal cancer since their first day of service in Vietnam. For male veterans, this was higher than the expected number of 117 (96–138), while for female veterans, it corresponded to expected community rates. The authors cited possible reporting errors such as misclassification of intestinal and rectal cancers as colon cancers and reporting pre- or nonmalignant polyps as possible explanations for the high number of cases reported by male veterans. A follow-up to the Commonwealth Department of Veterans’ Affairs (CDVA) study of male Vietnam veterans was conducted to medically confirm selected conditions reported in the survey study described above (AIHW, 1999). Sources used to validate reported conditions included clinicians, several Australian morbidity and mortality data bases, CDVA data, and documentation provided by veterans. Results from this study showed there was no significant difference in prevalence of colorectal cancer between the veterans and an Australian community standard. Synthesis With only rare exceptions, studies on gastrointestinal cancers and exposure to herbicide in production, from agricultural use, from environmental sources, and among veteran populations found RRs close to 1.0, providing no evidence of any increase in risk. Most of the recent studies were occupational. The updated analysis of mortality among U.S. chemical workers did not report site-specific GI cancers, and there was a nonsignificantly elevated excess

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Veterans and Agent Orange: Update 2000 risk for all GI cancers in the highest-exposed subgroups. A study of Danish paper mill workers found some nonsignificant elevations of GI cancers, but the possible link with dioxin exposure was not well established. An update of a cohort of Dutch chemical workers found no significant excess of GI cancer among the workers exposed to phenoxy herbicides or chlorophenols. A meta-analysis of studies of pancreatic cancer and occupational exposures found no evidence of associations with herbicide exposures. Updates of the Seveso cohort found some statistically significant excess risks, but these were based on relatively small numbers of cases and do not seem to occur with any consistency over the range of latency periods and exposure zones for the cohort. Among studies of Vietnam veterans, there is no significant evidence of an association between exposure and any gastrointestinal cancer. Conclusions Strength of Evidence in Epidemiologic Studies VAO and the previous updates concluded that there is limited/suggestive evidence of no association between exposure to herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and gastrointestinal cancers (stomach, pancreatic, rectal, and colon cancers). The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. There is no evidence found by this committee to suggest that the conclusion of limited/suggestive evidence of no association should be changed. Biologic Plausibility No animal studies have found an increased incidence of gastrointestinal cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3. Increased Risk of Disease Among Vietnam Veterans The available data on Vietnam veterans do not suggest there is an association between TCDD or herbicide exposure and any gastrointestinal cancers.

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Veterans and Agent Orange: Update 2000 TABLE 7-1 Selected Epidemiologic Studies—Stomach Cancer Reference Study Population C Exposed Casesa Estimated Risk (95% CI)a OCCUPATIONAL New Studies Steenland et al., 1999 U.S. 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 body wt 0   TCDD 0.1–0.99 µg/kg body wt 1 1.3 (0.0–7.0) TCDD >1 µg/kg 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 U.S. 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   NS Collins et al., 1993 Monsanto 2,4-D production workers   NS Kogevinas et al., 1993 IARC cohort—female   NS 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)

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Veterans and Agent Orange: Update 2000 Reference Study Population Exposed Casesa Estimated Risk (95% CI)a 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   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   1.3 (p < .05) Wiklund, 1983 Swedish agricultural workers 2,599 1.1 (1.0–1.2)c Burmeister, 1981 Farmers in Iowa 338 1.1 (p <.01) Axelson et al., 1980 Swedish railroad workers—total exposure 3 2.2 ENVIRONMENTAL New Studies 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)

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Veterans and Agent Orange: Update 2000 Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee’s general findings regarding this charge. Where more specific information about particular health outcomes is available, this information can be found in the preceding discussions of those diseases. REFERENCES ACS (American Cancer Society). 1998. Cancer Facts and Figures. http://www.cancer.org/statistics/cff98/graphicaldata.html (accessed March 12). ACS. 2000a. Cancer Facts and Figures. http://www3.cancer.org/cancerinfo/sitecenter.asp?ct=1&ctid=8&scp=8.3.10.40038&scs=4&scss=3&scdoc=41170&pnt=2&language=english.html (accessed October 20). ACS. 2000b. Basic Facts. http://www3.cancer.org/cancerinfo/sitecenter.asp?ct=1&ctid=8&scp=8.3.1.40029&scs=4&scss=6&scdoc=40044&pnt=2&language=english.html (accessed December 21). AFHS (Air Force Health Study). 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996–0068. 31 pp. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination and Results. Reston, VA: Science Application International Corporation. F41624–96-C1012. AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community, Volume 3: Validation Study. Canberra. Alavanja MC, Blair A, Merkle S, Teske J, Eaton B. 1988. Mortality among agricultural extension agents. American Journal of Industrial Medicine 14:167–176. Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservationists. Archives of Environmental Health 44:94–101. Amadori D, Nanni O, Falcini F, Saragoni A, Tison V, Callea A, Scarpi E, Ricci M, Riva N, Buiatti E. 1995. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: a population case-control study based on job titles. Occupational and Environmental Medicine 52(6):374–379. Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986a. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison: Wisconsin Division of Health. Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986b. Wisconsin Vietnam Veteran Mortality Study: Final Report. Madison: Wisconsin Division of Health. Aparaso NE. 2000. Pharmacogenetic Studies. Bethesda, MD: Crisp Data Base, National Institutes of Health. Armstrong BG, Kazantzis G. 1983. The mortality of cadmium workers. Lancet 1(8339):1425–1427. Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year prospective follow-up. American Journal of Industrial Medicine 26:243–253.

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