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Veterans and Agent Orange: Update 1998 7 Cancer INTRODUCTION 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, 1997). Almost one-half of all men and slightly more than one in three women in the United States will develop an invasive cancer at some time in their lives; approximately one in five Americans will die from cancer (Ries, 1997). 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 varies 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
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Veterans and Agent Orange: Update 1998 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. A second key issue for herbicide exposure and cancer risks is latency, the effect of timing of exposure on subsequent risk of disease. Chapter 8 addresses this issue in detail. 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 scientific evidence described in the first two Agent Orange reports—Veterans and Agent Orange (1994; hereafter referred to as VAO), and Veterans and Agent Orange: Update 1996 (hereafter, Update 1996)—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. The Department of Veterans Affairs (DVA) asked the committee to specifically address the classification of chondrosarcomas of the skull as part of its work. This is done in the discussion of bone cancer below. 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 14 times higher in men age 55-59 than in 45-49 year olds and nearly twice as high in African Americans age 45-59 than in whites of this age group (NCI, 1998). 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 the years 1990-1994, the most recent available at the time this report was written.
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Veterans and Agent Orange: Update 1998 Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veteran studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies to that of individual Vietnam veterans, the committee cannot quantify the degree of risk likely to have been experienced by Vietnam veterans due to exposure to herbicides in Vietnam. GASTROINTESTINAL TRACT TUMORS Background As a group, the category of gastrointestinal (GI) tract tumors includes some of the most common cancers in the United States and the world. The committee reviewed the data on stomach cancer (ICD·9 151.0-151.9), colon cancer (ICD·9 153.0-153.9), rectal cancer (ICD·9 154.0-154.1), and pancreatic cancer (ICD·9 157.0-157.9). According to American Cancer Society estimates, approximately 183,000 individuals will be diagnosed with these cancers in the United States in 1998 and some 99,000 individuals will die from them (ACS, 1998). Colon cancer accounts for about half of these diagnoses and deaths. The cases are divided approximately equally between men and women. Collectively, GI tract tumors are expected to account for 15 percent of new diagnoses and 18 percent of cancer deaths in 1998. 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 5 10 12 10 23 20 17 39 females 3 2 4 5 4 7 9 7 14 Colon males 18 16 27 37 35 49 69 68 92 females 16 14 21 28 24 52 15 49 77 Rectal males 9 9 15 15 15 20 21 20 23 females 7 6 11 7 7 6 12 12 14 Pancreatic males 5 5 10 12 11 23 21 20 40 females 4 3 7 8 8 10 14 13 25 a SEER nine standard registries crude, age-specific rate, 1990-1994. The incidence of stomach, colon, rectal, and pancreatic cancers increases with age for individuals between 45 and 59 years of age. In general, incidence in males is higher than in females, and incidence in African Americans exceeds that
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Veterans and Agent Orange: Update 1998 of 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). Infection with the bacterium Helicobacter pylori also increases the risk of stomach cancer. Summary ofVAO andUpdate 1996 Numerous studies were considered in VAO and Update 1996 that examined one or more gastrointestinal tract cancers; no consistent associations between herbicide exposure and these cancers were found. These included studies of chemical production workers in the United States and other countries (Lynge, 1985; Coggon et al., 1986; Thomas, 1987; Bond et al., 1988; Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991; Bloemen et al., 1993; Bueno de Mesquita et al., 1993; Collins et al., 1993; Kogevinas et al., 1993); agricultural workers (Burmeister, 1981; Hardell, 1981; Burmeister et al., 1983; Wiklund, 1983; Hoar et al., 1986; Alavanja et al., 1988, 1989; Wigle et al., 1990; Hansen et al., 1992; Ronco et al., 1992; Blair et al., 1993; Garry et al., 1994; Asp et al., 1994); pesticide appliers (Axelson et al., 1980; Blair et al., 1983; Swaen et al., 1992); paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989; Solet et al., 1989); the population of Seveso, Italy (Bertazzi et al., 1989a,b; Pesatori et al., 1992; Bertazzi et al., 1993); others subjected to environmental exposure (Lampi et al., 1992); and Vietnam veterans (Kogan and Clapp, 1985; Lawrence et al., 1985; Anderson et al., 1986a,b; Boyle et al., 1987; Breslin et al., 1988; CDC, 1988; Dalager et al., 1995a; Visintainer et al., 1995). VAO and Update 1996 found that, with rare exceptions, studies of GI cancers and herbicide exposure reported relative risks (RRs) close to 1.0, providing no evidence of any increased risk. They concluded that there is limited/suggestive evidence of no association between exposure to the herbicides (2,4-dichlorophenoxyacetic acid [2,4-D]; 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] and its contaminant TCDD; cacodylic acid; and picloram) and GI cancers (stomach, pancreatic, rectal, and colon cancers). The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicide and herbicide components. Update of the Scientific Literature Occupational Studies In an update and expansion of the International Agency for Research on Cancer (IARC) cohort study, Kogevinas et al. (1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides. The workers for this cohort were assembled
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Veterans and Agent Orange: Update 1998 from 12 countries, drawn from national studies that followed the same core protocol developed jointly by the participants and coordinated by IARC. No excess risk of death from GI cancer of any site was observed among the group comprised of all workers exposed to any phenoxy herbicide or chlorophenol (stomach: standardized mortality ratio [SMR] = 0.9, 95 percent confidence interval [95% CI] 0.7-1.1, 72 deaths; colon: SMR = 1.1, CI 0.8-1.3, 86 deaths; rectum: SMR = 1.1, CI 0.8-1.4, 44 deaths; pancreas: SMR = 0.9, CI 0.7-1.2, 47 deaths). When this group was divided into those exposed and unexposed to TCDD or higher chlorinated dioxins, slight elevations were seen for certain cancers, but they were found in both the exposed and the unexposed groups, and none achieved statistical significance. More detailed analysis by exposure variables such as duration and time since first exposure was not conducted for GI cancers. Although the study includes large numbers of workers who were likely to be exposed at levels substantially higher than general population exposures, the lack of information about actual exposures limits the investigator's ability to examine exposure-response relationships within the cohort. In addition, the inclusion of workers in the exposed group based on ever having worked in a job considered exposed makes it impossible to distinguish heavily exposed workers from those with very minor exposures. Becher et al. (1996) examined cancer mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols. The population included workers who had a least one month of employment, resulting in a cohort consisting of 2,479 male workers. The cohort was assembled from four plants; analysis was conducted on the total cohort, divided into four subcohorts that corresponded to each plant considered separately. Based on production information and limited blood dioxin measurements, subcohorts I and II are supposed to have higher TCDD exposures than subcohorts III and IV. Of the four subcohorts, only group I had at least one observed or expected death at each of the GI cancer sites. Of these, stomach (SMR = 1.3, 95% CI 0.7-2.2, 12 cases) and rectum (SMR = 1.9, CI 0.7-4.0, 6 cases) were nonsignificantly elevated. The small numbers in the other three subcohorts resulted in few reportable results for GI cancers, and none of these demonstrated a significant excess risk. Ott and Zober (1996) updated the experience of workers exposed to TCDD during the cleanup of a trichlorophenol (TCP) reactor, which exploded in 1953 at a BASF plant in Ludwigshafen, Germany. They studied cancer incidence and mortality up to 1992 for the group of 243 men and developed TCDD dose estimates based on work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. The analysis of cancer mortality showed a nonsignificant elevation of death for cancer of the digestive organs in the total cohort (SMR = 1.2, CI 0.6-2.1, 11 cases) with the lowest risk (SMR = 0.6) observed in the lowest-dose group (<0.1 µg/kg
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Veterans and Agent Orange: Update 1998 body weight). The medium-dose group (0.1-0.99 µg/kg body weight) reported an SMR of 1.7 (CI 0.5-4.3), whereas the highest dose group (>1 µg/kg body weight) had an SMR of 1.5 (CI 0.5-3.4). Incident cancer cases showed a similar pattern, with a nonsignificant elevation of cancer of the digestive tract in the total cohort (standardized incidence ratio [SIR] = 1.1, CI 0.6-1.9, 12 cases). The lowest risk (SIR = 0.7) was observed in the lowest-dose group (<0.1 µg/kg body weight). The medium-dose group (0.1-0.99 µg/kg body weight) reported an SIR of 1.4 (CI 0.4-3.6), whereas the highest-dose group (>1 µg/kg body weight) showed an SIR of 1.2 (CI 0.4-2.9). Separate analysis for incidence of stomach cancer within this class revealed three cases overall (SIR = 1.0, CI 0.2-2.9), with no cases observed in the lowest-dose group, one case in the medium-dose group (SIR = 1.3, CI 0.0-7.0), and two cases in the highest-dose group (SIR = 1.7, CI 0.2-6.2). Internal analysis of the cohort by proportional hazard analysis showed that TCDD dose was significantly associated with both death from cancer of the digestive tract (conditional regression ratio 1.5, CI 1.1-1.9) and incidence of digestive cancer (conditional risk ratio 1.4, CI 1.1-1.7). Review of these cases revealed that three had occurred among the four most highly exposed workers in the cohort and that one (stomach cancer) involved a worker with an estimated TCDD dose of 6.8 µg/kg and a second (pancreatic cancer), with an estimated dose of 6.1 µg/kg. However, information provided for the third case classified as a digestive cancer raises concerns. This case was a primary liver cancer with a dose estimate of 8.3 µg/kg. It is unclear why this case was not classified as a hepatobiliary cancer. Had it been, its exclusion from the digestive cancer analysis would probably have weakened the reported association in the proportional hazard analysis. Ramlow et al. (1996) examined mortality in a cohort of workers exposed to pentachlorophenol (PCP), as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential polychlorinated dibenzodioxin (PCDD) exposure between 1937 and 1980. In the study analysis, U.S. white male death rates (five-year age and calendar specific) and the non-PCP and PCDD male Dow Michigan employees for 1940 to 1989 were both used as reference values to calculate expected deaths. Four exposure groups were developed for TCDD (1 unit = very low, 1-1.9 units = low, 2-2.9 units = medium, 3 units = high). Calculation of SMRs with exposure lagged by 15 years using both the U.S. and the Dow referent populations found no significant excess mortality for digestive cancer (SMR = 0.9, CI 0.4-1.6, 10 deaths). The vast majority of deaths observed were among the unexposed group, leaving very few deaths distributed over the four categories of cumulative exposure (unexposed, 517 deaths from digestive cancer; very low exposure, 1 death; low exposure, 5 deaths; medium exposure, 4 deaths; high exposure, none).
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Veterans and Agent Orange: Update 1998 For the hepta- or octa-chlorinated dibenzodioxin (H/OCDD) groups, 2 units was the low-exposure category; 2-2.9, units medium; and 3 or more units, high. SMRs for cancers of the digestive system (15-year lagged exposure) showed no significant excess compared to the U.S. and Dow referent populations. As for TCDD, a very small proportion of the population was considered to have any exposure, and very few cases were observed. Gambini et al. (1997) investigated cancer mortality among a cohort of rice growers in northern Italy. Using a set of registered farm owners consisting of 1,493 males who worked on farms from 1957 to 1992, they examined the cause of death for 958 subjects and compared this with expected numbers calculated from national rates. No direct exposure information was available, so employment on the farm was used as a surrogate for exposure to the range of phenoxy herbicides employed during the study period. Cancer mortality was evaluated for three GI sites (stomach, pancreas, and intestines), and observed and expected deaths did not differ significantly for any of these sites in the overall cohort (stomach: SMR = 0.9, CI 0.7-1.3, 39 deaths; pancreas: SMR = 0.9, CI 0.4-1.9, 7 deaths; intestines: SMR = 1.1, CI 0.7-1.6, 27 deaths). Stratification by age at death and duration of exposure (employment as a farmer) did not change the finding of nonsignificant differences. Although the study population is small, it does describe the experience of a cohort with good follow-up (99 percent) and long latency (37 percent of deaths observed beyond the age of 80). It is limited by very crude exposure assessment, however, and the degree to which the study subjects were actually exposed to phenoxy herbicides cannot be established with any certainty. Environmental Studies Bertazzi et al. (1997) continued the follow-up of people environmentally exposed to TCDD in Seveso, Italy. The events that led to the exposure and the methods used to study this population have been described fully in the earlier reports. This report updates the population after 15 years follow-up. Death from cancer of the rectum was significantly elevated for men in zone B (SMR = 2.9, CI 1.2-5.9, 7 observed deaths). No other significant elevation of death from digestive cancer overall or at any GI sites was observed in men or women in any exposure zone. More detailed investigation of subjects in zone B showed that there were nonsignificant elevations of death from digestive cancers overall for women in the longest-latency (>10 years; overall digestive cancer: SMR = 1.5, CI 0.7-2.7, 10 deaths; stomach: SMR = 2.4, CI 0.8-5.7, 5 deaths) and length of stay (>10 years; overall digestive cancer: SMR = 1.6, CI 0.8-2.9, 9 deaths; stomach: SMR = 2.3, CI 0.6-6.0, 4 deaths) groups, whereas men showed significant excesses of rectal cancer in the group with the longest length of stay (SMR = 7.2, CI 1.9-18.4, 4 deaths) and the longest-latency group (SMR = 6.2, CI 1.7-15.9, 4 deaths). Svensson et al. (1995) studied mortality and cancer incidence in two cohorts of Swedish fishermen. One group (2,896 men) resided on the east coast of Swe-
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Veterans and Agent Orange: Update 1998 den and consumed fish from the Baltic Sea. These fatty fish (particularly salmon and herring) are reported to contain elevated levels of polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and PCDDs. The other group of fishermen (8,477) resided on the west coast of Sweden and was presumed to have a higher intake of lean (and less contaminated) fish, including cod and flat fish. This distinction in exposure by place of residence is reportedly confirmed by the finding that blood levels of ''dioxin-like compounds" were two times higher among east coast than west coast fishermen; however, no data are provided to support this point. East coast fishermen were found to have nonsignificantly increased mortality from stomach cancer (SMR = 1.4, CI 0.8-2.2, 17 deaths) and increased incidence of stomach cancer (SIR = 1.6, CI 1.0-2.4, 24 cases) compared to Swedish national rates. No significant excess incidence or mortality was seen among west coast fishermen. When the two groups were compared directly, the east coast excess incidence of stomach cancer was 2.2 (incidence rate ratio [IRR], CI 1.3-3.5). East coast fishermen were found to have significantly decreased incidence and mortality of cancer of the colon, which was not observed in west coast fishermen. The degree to which the difference in stomach cancer between east and west coast fishermen can be attributed to organochlorine exposure is limited by the lack of any direct information on exposure, aside from the above (unreferenced) statement that blood levels of dioxin-like compounds were twice as high among east coast as west coast fishermen. The authors also report that east coast fishermen consume smoked fish twice as often as west coast fishermen, so the role of confounding exposures cannot be discounted. Vietnam Veteran Studies In a comparison of mortality between Army Chemical Corps Vietnam and non-Vietnam veterans, Dalager et al. (1997) reported a significant excess of death from digestive diseases, primarily cirrhosis, among Vietnam veterans. The study compared 2,872 Vietnam veterans with 2,737 non-Vietnam veterans (all of whom served in Chemical Corps specialties). All study subjects served at least 18 months' active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. Nonsignificant decreases in deaths from digestive system cancer were observed in both groups when compared to general U.S. population rates. When Vietnam and non-Vietnam cohorts were compared directly, the crude rate ratio of GI cancer death was 4.8 (Vietnam versus non-Vietnam). The adjusted RR calculated by proportional hazards modeling to include the effect of race, military rank, duration of service, and age at entry to follow-up was 2.2 (CI 0.2-19.8). Direct exposure information on the two cohorts was not available, and the presumption that Vietnam veterans had potential for higher levels of dioxin exposure because of their duties involving Agent Orange and other dioxin-contaminated herbicides (compared to non-Vietnam Chemical Corps veterans) has not been verified.
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Veterans and Agent Orange: Update 1998 The Australian study Mortality of Vietnam Veterans: The Veteran Cohort Study (Crane et al., 1997a) examined the mortality experience of male Australian Vietnam veterans from 1980 to 1994. This cohort consists of 59,036 male veterans, who were followed for a period ranging from 22 to 32 years. There were 2067 deaths recorded among this group from 1980 to 1994, and vital status was ascertained for 96.9 percent of the cohort. There was a statistically significant excess of death for all cancer (SMR = 1.2, CI 1.1-1.3) in the cohort, by comparison to the Australian white male population and by calculation of a standardized relative mortality ratio (SRMR), which is the ratio of the cause-specific SMR and the SMR for all other causes combined (SRMR = 1.2, CI 1.1-1.3). No excess mortality was observed from cancer at any of the four GI sites. Death from cancer of the colon (SMR = 1.2, CI 1.0-1.5), rectum (SMR = 0.6, CI 0.4-1.0), stomach (SMR = 1.1, CI 0.7-1.5), and pancreas (SMR = 1.4, CI 1.0-1.9) did not exceed expected numbers for all military Vietnam veterans, and when analyzed separately by branch of service, only Navy veterans were reported to have excess mortality for any GI site (colon cancer: SMR = 1.8, CI 1.0-2.8), which was not statistically significant. The study authors have described the strengths and limitations of this cohort study of Australian veterans, including virtually complete identification of the study population, a period of follow-up ranging from 22 to 32 years, and vital status ascertainment of 96.9 percent. Among the weaknesses of the study are the possibility of underascertainment of death and the uncertain quality of exposure assessment regarding a variety of risk factors, including smoking and alcohol consumption, as well as herbicide and dioxin exposure. The examination of mortality among Australian National Service Vietnam veterans (Crane et al., 1997b) reported similar findings for GI cancer. Synthesis With rare exceptions, studies on GI cancers and exposure to herbicide in production, in agricultural use, from environmental sources, and among veteran populations found RRs close to 1.0, providing no evidence of any increase in risk. A reported statistically significant positive association in the BASF cohort is rendered problematic by the inclusion of a liver cancer in the analysis. The positive association reported for rectal cancer in males in zone B of the Seveso cohort is not by itself compelling, and is not supported by findings in any other zone or for females in the cohort. Conclusions Strength of Evidence in Epidemiologic Studies This report, like its predecessors, concludes that there is limited/suggestive evidence of no association between exposure to the herbicides (2,4-D, 2,4,5-T
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Veterans and Agent Orange: Update 1998 TABLE 7-1 Selected Epidemiologic Studies—Stomach Cancer Reference Study Population Exposed Casesa Estimated Risk (95% CI)a OCCUPATIONAL New Studies 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) Gambini et al., 1997 Italian rice growers 39 0.9 (0.7-1.3) 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 Female herbicide spraying and production workers NS Studies reviewed in VAO Ronco et al., 1992 Danish male self-employed farm workers 286 0.9 Swaen et al., 1992 Dutch herbicide applicators 1 0.5 (0-2.7)c 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/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 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)
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Veterans and Agent Orange: Update 1998 Reference Study Population Exposed Casesa Estimated Risk (95% CI)a Lynge, 1985 Danish male production workers 12 1.3 Blair, 1983 Florida pesticide applicators 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)b 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., 1997 Seveso residents Males—zone A 0 Males—zone B 10 0.8 (0.4-1.5) Males—zone R 76 0.9 (0.7-1.1) Females—zone A 1 0.9 (0.0-5.3) Females—zone B 7 1.0 (0.4-2.1) Females—zone R 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 male residents—zone B 7 1.0 (0.5-2.1) Female residents—zone B 2 0.6 (0.2-2.5) Seveso male residents—zone R 45 0.9 (0.7-1.2) Female residents—zone R 25 1.0 (0.6-1.5) Studies reviewed in VAO Pesatori et al., 1992 Seveso male residents—zones A and B 7 0.9 (0.4-1.8) Female residents—zones A and B 3 0.8 (0.3-2.5) Bertazzi et al., 1989a Seveso male residents—zones A, B, R 40 0.8 (0.6-1.2) Female residents—zones A, B, R 22 1.0 (0.6-1.5) Bertazzi et al., 1989b Seveso male residents—zone B 7 1.2 (0.6-2.6) VIETNAM VETERANS New Studies Crane et al., 1997a Australian military veterans 32 1.1 (0.7-1.5) Crane et al., 1997b Australian national service 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 99% CI. c Risk estimate is for stomach and small intestine.
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Veterans and Agent Orange: Update 1998 Limited information is available on health effects of exposure to the herbicides discussed in this report. Several studies of the carcinogenicity of 2,4-D, 2,4,5-T, picloram, and cacodylic acid have been performed in laboratory animals. In general, they produced negative results. However, because some studies do not meet present-day standards for cancer bioassays, and some produced equivocal results, it is not possible to draw confident conclusions at this time. 2,4-D was administered to rats, mice, and dogs in their food, by injecting it under their skin, or placing it directly into their stomachs. All results were negative, except for one study that found an increased rate of brain tumors in male, but not female, rats receiving the highest dose. These tumors also occurred in the control group and thus may have occurred spontaneously and not as a result of 2,4-D exposure. In a recent mutagenicity study, 2,4-D induced significant numbers of mutations in at least one of the cell types tested, either spermatocytes or spermatogonia. Because these results differ from earlier studies, it was hypothesized that different germ cell stages and treatment regimens may account for the observed inconsistencies. Similar results were obtained in a 2,4,5-T mutagenicity study. 2,4,5-T has been administered to rats and mice in their food, in their drinking water, by injecting it under their skin, or by placing it directly into their stomachs. In a recent study, 2,4,5-T exposure increased the formation of DNA adducts by cytochrome P450-derived metabolites of benzo[a]pyrene. The latter effects are particularly interesting since they are strikingly similar to those elicited by dioxin. Picloram has been tested in rats and mice in their food. Results of all of these studies were negative, with the exception of one study in which liver tumors appeared. These were attributed to the presence of a picloram contaminant, hexachlorobenzene. A recent study indicates that cacodylic acid (also known as dimethylarsinic acid) may induce DNA modifications that sensitize it to free radical injury, whereas another study concluded that it is a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats. In particular, cacodylic acid may promote rat urinary bladder carcinogenesis by stimulating cell proliferation in the urinary bladder epithelium. An exposure study in mice produced negative results. The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human health effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of site-specific cancers by TCDD. Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from
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Veterans and Agent Orange: Update 1998 animals and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning, and subsequent updates of this report may have more and better information on which to base conclusions. 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 American Cancer Society (ACS) Cancer Facts and Figures [WWW site]. 1998. URL http://www.cancer.org/statistics/cff98/graphicaldata.html (accessed March 12, 1998). 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. 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. 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. Axelson O, Sundell L, Andersson K, Edling C, Hogstedt C, Kling H. 1980. Herbicide exposure and tumor mortality: an updated epidemiologic investigation on Swedish railroad workers. Scandinavian Journal of Work, Environment, and Health 6:73-79. Becher H, Flesch-Janys D, Kauppinen T, et al. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins [see comments]. Cancer Causes Control. 7:312-321. Bender AP, Parker DL, Johnson RA, Scharber WK, Williams AN, Marbury MC, Mandel JS. 1989. Minnesota highway maintenance worker study: cancer mortality. American Journal of Industrial Medicine 15:545-556.
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Representative terms from entire chapter: