Alavanja et al., 1988, 1989; Green, 1991; Ronco et al., 1992), pesticide applicators (Blair, 1983), and paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989). Environmental studies of bladder cancer and herbicide or TCDD exposure include the Pesatori et al. (1992) study of Seveso residents and the Lampi et al. (1992) study of a Finnish community exposed to chlorophenols. Studies in Vietnam veterans examining bladder cancer include the Breslin et al. (1988) study of Army and Marine Corps Vietnam veterans and a study of veterans in Wisconsin (Anderson et al., 1986a,b). On the basis of this evidence, the committee concluded in VAO that there was limited/suggestive evidence of no association between exposure to herbicides and urinary bladder cancer.

Update of the Scientific Literature

As a subgroup of the IARC cohort, a cohort of workers was identified who manufactured chlorophenoxy herbicides in two factories in the Netherlands (Bueno de Mesquita et al., 1993). Among 963 exposed male workers, there was only one case of bladder cancer (SMR = 1.2, CI 0.0-6.7).

The mortality experience of 754 male production workers at a Monsanto Company plant was evaluated (Collins et al., 1993). One hundred and twenty-two of these workers had developed chloracne as a result of an accidental release of TCDD in 1949. Many of the employees studied were also exposed to 4-aminobiphenyl, a known bladder carcinogen. Based on 16 deaths due to bladder cancer, the SMR was 6.8 (CI 3.9-11.1). Eleven of these cases had documented exposure to 4-aminobiphenyl; therefore, TCDD exposure was not the primary suspected risk factor for them. The SMR was not significantly elevated for the other five cases nonexposed to 4-aminobiphenyl.

An 18-year follow-up study of cancer incidence and mortality in 1,909 Finnish herbicide applicators was reported (Asp et al., 1994). These employees had previously been identified as having exposure to 2,4-D and 2,4,5-T (Riihimaki et al., 1982). The median total exposure to herbicides was six weeks. Based on 12 cases of bladder cancer, the SIR was 1.6 (CI 0.8-2.8).

In the United States, a PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). The number of bladder cancer cases among four subgroups of farmers were: 733 among white males, four among white females, 47 among nonwhite males, and three among nonwhite females. None of the four PCMR was not elevated. For example, the PCMR for white males was 0.9 (CI 0.9-1.0). Because of the large sample sizes, the confidence intervals were relatively narrow.

The cancer incidence for the first ten years after potential TCDD exposure was reported for the population in Seveso (Bertazzi et al., 1993). In Zone A, there were two and zero bladder cancers diagnosed in men and women, respectively. In Zone B, there were eight and one bladder cancers diagnosed in men and



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--> Alavanja et al., 1988, 1989; Green, 1991; Ronco et al., 1992), pesticide applicators (Blair, 1983), and paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989). Environmental studies of bladder cancer and herbicide or TCDD exposure include the Pesatori et al. (1992) study of Seveso residents and the Lampi et al. (1992) study of a Finnish community exposed to chlorophenols. Studies in Vietnam veterans examining bladder cancer include the Breslin et al. (1988) study of Army and Marine Corps Vietnam veterans and a study of veterans in Wisconsin (Anderson et al., 1986a,b). On the basis of this evidence, the committee concluded in VAO that there was limited/suggestive evidence of no association between exposure to herbicides and urinary bladder cancer. Update of the Scientific Literature As a subgroup of the IARC cohort, a cohort of workers was identified who manufactured chlorophenoxy herbicides in two factories in the Netherlands (Bueno de Mesquita et al., 1993). Among 963 exposed male workers, there was only one case of bladder cancer (SMR = 1.2, CI 0.0-6.7). The mortality experience of 754 male production workers at a Monsanto Company plant was evaluated (Collins et al., 1993). One hundred and twenty-two of these workers had developed chloracne as a result of an accidental release of TCDD in 1949. Many of the employees studied were also exposed to 4-aminobiphenyl, a known bladder carcinogen. Based on 16 deaths due to bladder cancer, the SMR was 6.8 (CI 3.9-11.1). Eleven of these cases had documented exposure to 4-aminobiphenyl; therefore, TCDD exposure was not the primary suspected risk factor for them. The SMR was not significantly elevated for the other five cases nonexposed to 4-aminobiphenyl. An 18-year follow-up study of cancer incidence and mortality in 1,909 Finnish herbicide applicators was reported (Asp et al., 1994). These employees had previously been identified as having exposure to 2,4-D and 2,4,5-T (Riihimaki et al., 1982). The median total exposure to herbicides was six weeks. Based on 12 cases of bladder cancer, the SIR was 1.6 (CI 0.8-2.8). In the United States, a PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). The number of bladder cancer cases among four subgroups of farmers were: 733 among white males, four among white females, 47 among nonwhite males, and three among nonwhite females. None of the four PCMR was not elevated. For example, the PCMR for white males was 0.9 (CI 0.9-1.0). Because of the large sample sizes, the confidence intervals were relatively narrow. The cancer incidence for the first ten years after potential TCDD exposure was reported for the population in Seveso (Bertazzi et al., 1993). In Zone A, there were two and zero bladder cancers diagnosed in men and women, respectively. In Zone B, there were eight and one bladder cancers diagnosed in men and

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--> women, respectively. In Zone R, the least contaminated area, there were 39 and four bladder cancers diagnosed in men and women, respectively. None of these subgroups demonstrated a significant increase in relative risk. These results are very similar to the previous reports on bladder cancer incidence and mortality in the Seveso population (Bertazzi et al., 1989 a,b; Pesatori et al., 1992). Summary The additional evidence since publication of VAO does not warrant changing the conclusion on bladder cancer and herbicide exposure. Conclusions There is limited/suggestive evidence of no association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and urinary bladder cancer. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Testicular Cancer Summary of VAO A case-control study of 137 testicular cancer cases and 130 hospital controls (Tarone et al., 1991) found an odds ratio of 2.3 (CI 1.0-5.5) for service in Vietnam. Risk for testicular cancer was not significantly elevated by service branch. In general, the other veteran studies and most of the occupational and environmental studies have shown no association between exposure and outcome, but the sample size of some of these studies may have been too small to detect an elevated risk. Other studies of testicular cancer have generally been inconsistent. These include studies of chemical production workers in the United States and other countries (Bond et al., 1988; Saracci et al., 1991), agricultural workers (Wiklund, 1983; Ronco et al., 1992), residents of Seveso (Pesatori et al., 1992), and Vietnam veterans (Anderson et al., 1986a,b; Boyle et al., 1987; Breslin et al., 1988; Watanabe et al., 1991). Update of the Scientific Literature A PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 32 deaths from testicular cancer in white male farmers, the PCMR was 0.8 (CI 0.6-1.2). Based on six deaths from testicular cancer in nonwhite male farmers, the PCMR was 1.3 (CI 0.5-2.9).

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--> Cancer incidence during the first ten years after exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). There were zero and one cases (nonsignificant) of testicular cancer in Zone A and B, respectively. There were nine male cases in Zone R, the least contaminated area (RR = 1.4, CI 0.7-3.0). A recent case-control study investigated the association between potential Agent Orange exposure and the risk of testicular cancer (Bullman et al., 1994). The subjects were chosen from the DVA's Agent Orange Registry; by definition, all of them were Vietnam veterans. This included 97 veterans with testicular cancer and 311 veterans with no clinical diagnosis recorded on the registry. Risk of testicular cancer was not significantly increased for ground troops, for combat duty, for service in the III Corps area (a heavily sprayed area), or for being close to other areas where Agent Orange was sprayed. Only Navy veterans had a statistically significant increased risk of testicular cancer (OR = 2.6, CI 1.1-6.2), based on 12 cases among 27 Navy veterans. Only one of these 27 Navy veterans served in the "brown water" Navy and may have had Agent Orange exposure due to spraying of riverbanks. Summary The new scientific evidence does not warrant changing the conclusions of VAO on testicular cancer and herbicide exposure. Conclusions There is inadequate or insufficient evidence to determine whether an association exists between the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and testicular cancer. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Brain Tumors Background According to the American Cancer Society, approximately 17,200 new cases of brain and other nervous system cancers (ICD-9 191.0-191.9, 192.0-192.3, 192.8-192.9) were diagnosed in the United States in 1995, and some 13,300 persons died of these cancers (ACS, 1995). These cancers are slightly more common in men than in women. According to the committee's calculations, assuming that veterans have the same cancer rates as those in the general U.S. population, 226 cases of cancers of brain and nervous system were expected among male Vietnam veterans and 0.4 among female veterans in 1995. For the

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--> year 2000, the expected numbers are 268 cases in male veterans and 0.4 cases in female veterans. Summary of VAO A case-control study of gliomas and occupational exposure to chemical carcinogens was conducted in Italy (Musicco et al., 1988). Farmers had an increased risk of gliomas (RR = 1.6, CI 1.1-2.4) compared to all controls; this was found to be associated with the farmers' use of chemicals, including insecticides and herbicides. Another occupational study (Alavanja et al., 1988) found a PMR of 2.1 (CI 1.2-3.7) among USDA agricultural extension agents. A subsequent case-control analysis comparing "ever" versus "never" being an extension agent resulted in an OR of 1.0 (CI 0.4-2.4). A study of Wisconsin veterans (Anderson et al., 1986a) showed an excess risk (RR = 1.6, CI 0.9-2.7). On the other hand, no excess risk of central nervous system tumors has been found among other occupational groups or in other studies. Other relevant reports on brain cancers included studies of chemical production workers in the United States and other countries (Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Fingerhut et al., 1991; Saracci et al., 1991), agricultural workers (Burmeister, 1981; Wigle et al., 1990; Morrison et al., 1992; Ronco et al., 1992), pesticide applicators (Blair, 1983; Swaen et al., 1992), paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989), the Seveso population (Bertazzi et al., 1989a,b; Pesatori et al., 1992), and Vietnam veterans (Lawrence et al., 1985; Anderson et al., 1986a,b; Boyle et al., 1987; Breslin et al., 1988; Thomas and Kang, 1990). The only epidemiological study in VAO that had quantitative exposure measurements on serum TCDD levels was the NIOSH study of occupational workers, who had an estimated mean maximum TCDD level of 1,434 ppt (Fingerhut et al., 1991). Five deaths from brain cancer were observed, compared to an expected number of 7.3 deaths. For workers with more than 20 years latency, two such deaths were observed, compared to an expected number of 3.2. Update of the Scientific Literature Since VAO, a number of new studies on brain cancer have been published. A PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). No information on individual exposures to herbicides was available. Based on 447 deaths due to brain cancer in white male farmers, the PCMR was marginally increased at 1.2 (CI 1.1-1.3). Based on much smaller numbers of brain cancer deaths, the rates were not elevated in other race and gender groups. In Finland, an 18-year prospective follow-up of cancer morbidity and mortality for 1,909 herbicide applicators was reported (Asp et al., 1994). These

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--> employees had previously been identified as being exposed to 2,4-D and 2,4,5-T for at least two weeks between 1955 and 1971 (Riihimaki et al., 1982). The median total duration of exposure was six weeks. Based on three deaths from brain cancer and eye cancer combined, the SMR was 1.2 (CI 0.3-3.6). A cohort study of cancer mortality in Ireland was performed using occupation information on death certificates from the years 1971 to 1987 (Dean, 1994). There were 195 and 72 deaths due to brain cancer among men and women in farming occupations, respectively. These numbers were significantly less than the 226.1 and 90.5 deaths expected in men and women due to brain cancer. No specific information on herbicide use was available. The cancer incidence for the first ten years after potential TCDD exposure was recently published for the Seveso population (Bertazzi et al., 1993). No cases of brain cancer were diagnosed among residents of the more highly contaminated areas (Zones A and B). In the less contaminated area, Zone R, six cases of brain cancer occurred in men (RR = 0.6, CI 0.3-1.4); and six cases of brain cancer occurred in women (RR = 1.4, CI 0.6-3.4). A PMR study examining causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently published (Visintainer et al., 1995). The mortality rates among 3,364 Vietnam veterans were compared with the rates among 5,229 veterans who served elsewhere. Based on 36 deaths due to brain cancer, the PMR was 1.1 (CI 0.8-1.5). There was no information on documented herbicide exposure among the Vietnam veterans. The cancer mortality rates in 4,586 female Vietnam veterans were compared to the rates in 5,325 female veterans who served elsewhere (Dalager et al., 1995). More than 80 percent of the Vietnam veterans were nurses, so their exposure to herbicides was probably low. Based on four cases of brain cancer, the SMR was 1.4 (CI 0.4-3.7). Summary Although the number of cases of brain tumors is small in many studies, it is apparent that the risks associated with herbicide exposure are fairly evenly distributed around the null, and the confidence intervals are relatively narrow. Conclusions There is limited/suggestive evidence of no association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and brain tumors. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

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--> Malignant Lymphomas And Myeloma Background According to the American Cancer Society, approximately 60,900 new cases of lymphomas and myelomas were diagnosed in the United States in 1992, and 30,100 persons died from these cancers. These diseases are slightly more common in men than women. According to the committee's calculations, assuming that veterans have the same cancer rates as those in the general U.S. population, 94 new cases of Hodgkin's disease (HD), 380 new cases of non-Hodgkin's lymphoma (NHL), and 57 new cases of multiple myeloma (MM) were expected among male Vietnam veterans in 1995. Among women Vietnam veterans, a total of 0.8 of all these cancers were expected in 1995. For the year 2000, 109, 494, and 133 cases, respectively, are expected in male veterans and a total of 1.1 cases in female veterans. Non-Hodgkin's Lymphoma Summary of VAO Non-Hodgkin's lymphoma includes a group of malignant lymphomas—that is, neoplasms derived from lymphoreticular cells in lymph nodes, bone marrow, spleen, liver, or other sites in the body. One large, well-conducted case-control study in Sweden by Hardell et al. (1981) examined NHL and Hodgkin's disease together and found an odds ratio of 6.0 (CI 3.7-9.7) for exposure to phenoxy acids or chlorophenols, based on 105 cases. These results were replicated in further investigations of the validity of exposure assessment and other potential biases (Hardell, 1981). A more recent case-control study by Persson et al. (1989) showed increased risk for NHL in those exposed to phenoxy acids (OR = 4.9, CI 1.0-27.0), based on a logistic regression analysis of 106 cases. Other studies of farmers and agricultural workers are generally positive for an association between NHL and herbicides/TCDD; however, only some are statistically significant. All of the studies of U.S. agricultural workers reviewed showed elevated relative risks (although none was significant), and two National Cancer Institute studies of farmers in Kansas and Nebraska (Hoar et al., 1986; Zahm et al., 1990) show patterns of increased risk linked to use of 2,4-D. The CDC Selected Cancers Study found an increased risk of NHL in association with service in Vietnam; other studies of veterans, generally with small sample sizes, are consistent with an association. In contrast, studies of production workers—including the largest, most heavily exposed cohorts (Fingerhut et al., 1991; Saracci et al., 1991; Zober et al., 1990; Manz et al., 1991)—indicate no increased risk. Thus, unlike most of the other cancers studied in VAO the data did not distinguish between the effects of herbicides and TCDD; rather the data suggested that the

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--> phenoxy herbicides (including 2,4-D) rather than TCDD may be associated with non-Hodgkin's lymphomas. Update of the Scientific Literature Occupational Studies Production Studies Mortality from malignant lymphomas was examined in the IARC registry, which included 18,390 production workers or sprayers from 10 countries (Kogevinas et al., 1992). Exposure to chlorophenoxy herbicides and chlorophenols was evaluated from job histories and company records. Mortality from NHL among 13,898 workers who were classified as exposed or probably exposed to these chemicals was not elevated, based on 11 deaths (SMR = 1.0, CI 0.5-1.7). No difference in risk was seen in relation to potential exposure to TCDD, based on history of exposure to 2,4,5-T or 2,4,5-trichlorophenol. A nested case-control study of 32 cases of NHL and 158 controls was performed, using the IARC registry (Kogevinas et al., 1995), which at the time contained information on 21,183 workers in 11 countries. Exposure to 21 chemicals or mixtures was estimated by industrial hygienists who evaluated individual job histories. None of the exposures was significantly associated with an increased risk of NHL, but there was a threefold increased risk in subjects with medium or high exposure to 2,4,5-T or TCDD. The odds ratio was 1.9 for any exposure to 2,4,5-T (CI 0.7-4.8) and 1.9 for any exposure to TCDD (CI 0.7-5.1). These results run counter to the trend discussed in VAO that suggested that 2,4-D rather than TCDD may be associated with NHL. Two other studies focused on subgroups of production workers in the IARC registry. In the Netherlands, Bueno de Mesquita and colleagues (1993) demonstrated a nonsignificant increased risk of NHL among workers exposed to herbicides based on 2 deaths (SMR = 3.0, CI 0.4-10.8). In Denmark, Lynge (1993) found an increased but nonsignificant risk of NHL among male workers exposed to herbicides based on 10 incident cases (SIR = 1.7, CI 0.5-4.5), but no increase when men and women are combined (figures not given). Similarly, an update of mortality among 878 Dow Chemical workers exposed to 2,4-D demonstrated a nonsignificant increased risk of NHL, based on 2 cases (SMR = 2.0; CI 0.2-7.1) (Bloemen et al., 1993). All of these studies were limited by low statistical power. Agricultural/Forestry Workers The mortality experience from NHL was recently evaluated for 155,547 male farm operators in Saskatchewan, Manitoba, and Alberta (Morrison et al., 1994). Overall, the observed number of deaths from NHL was significantly lower than expected (SMR = 0.8, CI 0.7-0.9). There was no association between the number of acres sprayed with herbicides in 1970 and the relative risk of NHL. For farm operators who lived on the same farm in both 1971 and 1981, an increased risk of NHL mortality was associated with the

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--> number of acres sprayed with herbicides in 1970. The relative risk for the highest quartile of acres sprayed, 380 acres or more, was 2.1 (CI 1.1-3.9). The relative risk for the highest quartile of spraying for both 1970 and 1980, relative to farmers who reported no herbicide spraying in either 1970 or 1980, was 3.0 (CI 1.1-8.1). Because this was a cohort study and the health and agricultural data were collected by separate agencies, the risk of recall bias on the use of herbicides was reduced. In the United States, a PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 843 deaths from NHL in white male farmers, the PCMR was significantly increased, at 1.2 (CI 1.1-1.3). Twenty states had two or more deaths from NHL; 15 of these states, a statistically significant proportion, had PCMRs greater than 1.0. The numbers of deaths due to NHL were small and did not significantly increase in other race and gender subgroups. A cohort study of cancer mortality in Ireland was performed using occupational information on death certificates from the years 1971 to 1987 (Dean, 1994). Among men in farming occupations, there were 244 deaths due to all lymphomas combined, a significantly decreased risk compared to the 265.7 deaths expected. Among women in farming occupations, there were 84 deaths from all lymphomas, compared to 88.9 expected. An 18-year follow-up study of cancer incidence in 1,909 Finnish herbicide applicators was recently reported (Asp et al., 1994). The median total duration of exposure to herbicides, including 2,4-D and 2,4,5-T, was six weeks. There was only one case of NHL diagnosed (SIR = 0.4, CI 0.0-2.0). A recent Swedish case-control study compared the occupational histories of 93 men who were diagnosed with NHL between 1975 and 1984 with 204 male control subjects (Persson et al., 1993). Based on ten cases and 14 controls, logistic regression analysis revealed an odds ratio of 2.3 for a history of exposure to phenoxy herbicides for at least one year (90 percent CI 0.7-7.2). Work as a lumberjack was significantly associated with the risk of NHL (OR = 6.0, 90 percent CI 1.1-31.0), but there was no association with exposure to chlorophenols or creosote, which are used as wood preservatives. Another Swedish case-control study compared the occupational histories of 105 cases who were diagnosed with NHL between 1974 and 1978 with 335 control subjects (Hardell et al., 1994). Previously published data (Hardell et al. 1981) that had combined both types of lymphomas was reanalyzed by removal of the data on Hodgkin's disease. Exposure to phenoxyacetic acids was reported by 25 cases and 24 controls (OR = 5.5, CI 2.7-11.0). Most of these 49 individuals had been exposed to a combination of 2,4-D and 2,4,5-T. Thirty-five cases and 35 controls reported exposure to chlorophenols (OR = 4.8, CI 2.7-8.8). An increased risk due to exposure to either class of chemical was found for all histological subtypes of NHL, according to the Rappaport classification. A population-based case-control study conducted in eastern Nebraska compared

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--> the occupational histories of 184 women diagnosed with NHL with 707 control subjects (Zahm et al., 1993). The risk of NHL was not increased in women who had ever lived or worked on a farm (OR = 1.0, CI 0.7-1.4). No class of herbicide, whether used on the farm or personally handled, was associated with a significantly increased risk of NHL. Only a few women, however, reported personally handling herbicides (four cases and 11 controls). Environmental Studies Cancer incidence during the first ten years after potential exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). No cases of NHL were found in the most heavily exposed population residing in Zone A; only 0.4 cases were expected. For women in Zone B, the relative risk of NHL was 0.9 (CI 0.1-6.4), based on one case. For men in Zone B, the corresponding relative risk was 2.3 (CI 0.7-7.4), based on three cases. Larger numbers of cases were found in the lower-exposed and much larger Zone R population. Relative risks for NHL were 1.2 (CI 0.6-2.3) in women, based on ten cases, and 1.3 (CI 0.7-2.5) in men, based on 12 cases. Vietnam Veterans Studies A PMR study that examined the causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently published (Visintainer et al., 1995). The mortality rates of 3,364 Vietnam veterans were compared to the mortality rates of 5,229 veterans who served elsewhere. No data were available to identify whether individual veterans had been exposed to herbicides. Based on 32 deaths from NHL, the PMR was significantly increased, at 1.5 (CI 1.0-2.1). Summary The recent scientific literature continues to support the conclusion that there is a positive association between exposure to herbicides and non-Hodgkin's lymphoma. Conclusions Evidence is sufficient to conclude that there is a positive association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and non-Hodgkin's lymphoma. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

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--> Hodgkin's Disease Summary of VAO Hodgkin's disease, also a malignant lymphoma, is a neoplastic disease characterized by painless, progressive enlargement of lymph nodes, spleen, and general lymphoid tissues. Fewer studies have been conducted of HD in relation to exposure to herbicides or TCDD than have been conducted of soft-tissue sarcoma or non-Hodgkin's lymphoma, but the pattern of results is strikingly consistent. The 60 HD cases in the study by Hardell et al. (1981) were later examined by Hardell and Bengtsson (1983), who found odds ratios of 2.4 (CI 0.9-6.5) for low-grade exposure to chlorophenols and 6.5 (CI 2.7-19.0) for high-grade exposures. The study by Persson et al. (1989) of 54 HD cases showed a large, but not statistically significant, OR of 3.8 (CI 0.5-35.2) for exposure to phenoxy acids. Furthermore, nearly all of the 13 case-control and agricultural worker studies show increased risk for HD, although only a few of these results are statistically significant for HD. As with NHL, even the largest studies of production workers exposed to TCDD do not indicate an increased risk. The few studies of HD in Vietnam veterans tend to show elevated risks; all but one are statistically insignificant. Update of the Scientific Literature Occupational Studies Mortality from malignant lymphomas was examined in the IARC registry, which included 18,390 production workers or sprayers from ten countries (Kogevinas et al., 1992). Among the 13,898 workers classified as exposed or probably exposed to chlorophenoxy herbicides or chlorophenols, there were three deaths from HD (SMR = 0.6, CI 0.1-1.7). One of these deaths occurred in a female employee (Kogevinas et al., 1993). In the United States, a PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 56 deaths due to HD among white male farmers, the PCMR was 1.0 (CI 0.8-13.). The numbers of deaths due to HD were very small and nonsignificant for the other race and gender subgroups. An 18-year follow-up study of cancer incidence in 1,909 Finnish herbicide applicators was recently reported (Asp et al., 1994). The median total duration of exposure to herbicides, including 2,4-D and 2,4,5-T, was six weeks. Two cases of HD were diagnosed (SIR = 1.7, CI 0.2-6.0). A recent Swedish-case-control study compared the occupational histories of 31 men who were diagnosed with HD with 204 male control subjects (Persson et al., 1993). Five cases and 14 controls reported a history of at least one year of

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--> exposure to phenoxy herbicides, which yielded a significantly increased adjusted odds ratio of 7.4 (90 percent CI 1.4-40.0). Environmental Studies Cancer incidence during the first ten years after exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). No HD cases were reported among residents in Zone A, which was the most heavily contaminated but had the smallest population. Among women in Zone B, one HD case occurred (RR = 2.1, CI 0.3-15.7); among men in Zone B, one HD case occurred (RR = 1.7, CI 0.2-12.8). Among women residents of Zone R, the zone with the lowest exposure, three cases of HD occurred (RR = 1.0, CI 0.3-3.2); there were four cases in men (RR = 1.1, CI 0.4-3.1). This study, which has one of the highest documented human exposures to TCDD, is limited by the relatively small size of the population in Zone A and by a short period of follow-up. Vietnam Veterans Studies A recent PMR study examined the causes of death among veterans on the state of Michigan's Vietnam-era bonus list (Visintainer et al., 1995). The mortality rates were compared between 3,364 Vietnam veterans and 5,229 veterans who served elsewhere. No data were available to identify whether individual veterans had been exposed to herbicides. Based on 20 deaths from HD, the PMR was not significantly elevated, at 1.1 (CI 0.7-1.8). Summary The recent scientific evidence continues to support the conclusions of a positive association between exposure to herbicides and Hodgkin's disease. Conclusions Evidence is sufficient to conclude that there is a positive association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and Hodgkin's disease. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Multiple Myeloma Background Because VAO classified multiple myeloma in the category of limited/suggested

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--> Reference Study Population Exposed Casesa Estimated Risk (95% CI)a Zahm et al., 1992 Eastern Nebraska users of herbicides       Male 8 0.6 (0.2-1.7)   Female 10 2.3 (0.8-7.0)   Eastern Nebraska users of insecticides       Male 11 0.6 (0.2-1.4)   Female 21 2.8 (1.1-7.3) Brown et al., 1993 Iowa male users of pesticides or herbicides 111 1.2 (0.8-1.7) Environmental Studies Bertazzi et al., 1993 Seveso residents       Zone A - male 0     Zone A - female 0     Zone B - male 2 3.2 (0.8-13.3)   Zone B - female 2 5.3 (1.2-22.6)   Zone R - male 1 0.2 (0.0-1.6)   Zone R - female 2 0.6 (0.2-2.8) a Given when available. used on the most acres, the odds ratio for farmers was also 1.4 (CI 0.8-2.3), suggesting no special herbicide-related risk. A case-control study of herbicide and insecticide use by Nebraska residents presented some unusual results (Zahm et al., 1992). The odds ratios for use of either herbicides or insecticides was 0.6 for men. But, for women, the odds ratio for herbicide use was 2.3 (C.I = 0.8-7.0) and 2.8 (CI 1.1-7.3). The observed gender-related effect is interesting, but given that relatively few cases were considered, it may be the result of chance and requires confirmation by other studies. It is noteworthy that the comparison category, nonfarmers, contained only seven female cases. In another U.S. study that examined farm use of herbicides in relation to the risk of cancer, Morris et al. (1986) used data from cancer registries in Washington, Utah, metropolitan Detroit, and metropolitan Atlanta. Results indicated an adjusted odds ratio of 2.6 (CI 1.5-4.6) for exposure to pesticides when data from all cases and controls were used. When only self-respondent interviews were used, the adjusted odds ratio was 2.9 (CI 1.5-5.5); the only other exposures with odds ratios in which the confidence intervals did not include 1.0 were to paints or solvents, metals, and carbon monoxide. The odds ratio for having lived on a farm was 1.3 (CI 1.0-1.6). Explicit exposure to herbicides gave an odds ratio of 4.8 but was based on only four cases.

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--> A proportionate mortality study by Blair et al. (1993), which included 23 states, demonstrated a slightly increased risk of MM among white male farmers. Based on 413 deaths due to MM, the PMR was 1.2 (CI 1.0-1.3). However, no information was available on herbicide usage by individuals or groups. Twenty states had two or more deaths from MM; of these, 15 states had a PMR for MM that was greater than 1.0. This is a significant proportion of states. The numbers of deaths due to MM was small and nonsignificant in other racial and gender groups. A cohort study of cancer mortality in Ireland was performed using death certificate information from the years 1971 to 1987 (Dean, 1994). There were 170 deaths due to multiple myeloma among men in farming occupations, which was less than the 177.9 deaths expected. There were 72 deaths due to MM among women in farming occupations, which was slightly more than the 67 deaths expected. A cohort of 155,547 male farmers in Saskatchewan, Manitoba, and Alberta was followed from 1971 to 1987 (Semenciw et al., 1993). Based on 160 deaths due to MM, the SMR for farmers was significantly decreased at 0.8 (CI 0.7-1.0). There was a small, nonsignificant increase in risk of MM among farmers who had reported using herbicides in 1970. In New Zealand, two studies by Pearce et al. (1985, 1986) found no evidence of an association between MM and herbicide exposure. In the initial study (Pearce et al., 1985), odds ratios for agricultural employment were 2.2 (CI 1.3-3.8) for MM cases identified at 20 to 64 years of age and 1.3 (CI 0.8-2.0) for cases identified over age 64, compared with correspondingly aged cases of other cancer in the New Zealand cancer registry during the period 1977-81. These odds ratios were the highest found in this study, which also considered NHL and HD, but no individual data on exposure to herbicides were given. However, in a follow-up case-control study (Pearce et al., 1986), interviews and a detailed questionnaire on use of herbicides were completed. The study produced an odds ratio of 1.7 (CI 1.0-2.9) for MM in relation to farming, an odds ratio of 1.3 (CI 0.7-2.5) for any agricultural use of chemical spray, and an odds ratio of 1.6 (CI 0.8-3.1) for spraying of specific plants on which phenoxy herbicides (specifically 2,4,5-T) are generally used. Potential exposure to chlorophenols found in wood preservatives used in fencing work gave an odds ratio of 1.6 (CI 0.9-2.7), and potential exposure in a sawmill gave an odds ratio of 1.4 (CI 0.5-3.9) for sawmill workers or timber merchants, although the odds ratio for explicit exposure to chlorophenols was 1.1 (CI 0.4-2.7), based on six cases. Eriksson and Karlsson (1992) undertook a case-control study of MM in relation to occupation and exposures in northern Sweden between 1982 and 1986. An odds ratio of 1.7 (CI 1.2-2.6) was found for farmers and an odds ratio of 2.2 (CI 1.0-5.7) for exposure to phenoxy herbicides. An analysis by the number of days that phenoxyacetic acid was used showed no clear trend with exposure; the odds ratio for each of three exposure categories was 2.0 or greater.

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--> In a multivariate analysis involving 22 exposure factors, the odds ratio for phenoxyacetic acids was 1.9 (CI 0.7-5.7). The multivariate analysis eliminated the raising of sheep, hogs, and poultry as risk factors and decreased the odds ratio for raising horses, cattle, and goats. A case-control study of MM was undertaken in the region surrounding Milan, Italy, by LaVecchia et al. (1989). A multivariate regression analysis with terms for age, gender, area of residence, and smoking gave a relative risk of 2.0 (CI 1.1-3.5) among those employed in agriculture. An 18-year follow-up study of cancer incidence and mortality in 1,909 Finnish herbicide applicators was reported (Asp et al., 1994). These employees had previously been identified as having exposure to 2,4-D and 2,4,5-T (Riihimaki et al., 1983). The median total duration of exposure to herbicides was six weeks. Based on three deaths from MM, the SMR was 2.6 (CI 0.5-7.7). The SIR was 1.5 (CI 0.2-5.2) based on 2 cases. A Dutch study by Swaen et al. (1992) observed three deaths from MM among licensed herbicide applicators (0.4 was expected), yielding an SMR of 8.2 (CI 1.6-23.8). Another small study of Canadian herbicide applicators (Green 1991) found no deaths from MM. However, only about 0.3 deaths would have been expected. Summary of Agricultural/Forestry Worker Studies Several studies of agricultural and forestry workers provide specific information on MM risk in relation to herbicide or pesticide exposure. Most studies demonstrated an odds ratio or SMR greater than 1.0, nine did so at a statistically significant level. Paper/Pulp Workers Three studies of pulp and paper workers observed that some cohort members may have had exposure to low levels of dioxins (Robinson et al., 1986; Henneberger et al., 1989; Solet et al., 1989). Grouping MM from these studies with lymphomas other than lymphosarcoma, reticulum cell sarcoma, and Hodgkin's disease resulted in a combined number of four cases; 4.4 were expected. Environmental Studies Cancer incidence for the Seveso cohort during the first ten years following exposure to TCDD was reported in more detail by Bertazzi et al. (1993). There were no cases of MM in Zone A. In Zone B, there were two cases of MM among men, a nonsignificant increase (RR = 3.2, CI 0.8-13.3). There were also two cases of MM among women in Zone B, a significant increase (RR = 5.3, CI 1.2-22.6). There was a deficit of MM cases in Zone R, the least exposed area, based on one case in men and two cases in women, (RR = 0.2 in men and 0.6 in women).

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--> Vietnam Veterans Studies The major study of multiple myeloma among veterans is the DVA's proportionate mortality study by Breslin et al. (1988). The authors found a PMR of 0.8 (CI 0.2-2.5) for Army Vietnam veterans and a PMR of 0.5 (CI 0.0-17.1) for Marine veterans (the latter was based on two cases). Each group was compared to Vietnam-era veterans of the same service. No MMs were noted in the CDC Vietnam Experience Study (Boyle et al., 1987) or the Air Force Ranch Hand study (Wolfe et al., 1990). Goun and Kuller (1986) reported that the odds ratio for MM among Pennsylvania Vietnam veterans was less than 1.0. The veteran studies are particularly limited, because of the small numbers of MM deaths in the few analyses that have been conducted and because they use such a broad exposure category: service in Vietnam. With the exception of the Ranch Hands, no definitively exposed groups were categorized. Summary Although multiple myeloma has been less extensively studied than the lymphomas, a consistent pattern of elevated risks appears in the studies. Several studies of agricultural and forestry workers provide information on MM risk in relation to herbicide or pesticide exposure. Most studies demonstrated an odds ratio or SMR greater than 1.0; nine did so at a statistically significant level. The committee determined that the evidence for this association was limited/suggestive, because the individuals in the existing studies (mostly farmers) have by the nature of their occupation probably been exposed to a range of potentially carcinogenic agents other than herbicides and TCDD. Multiple myeloma—like non-Hodgkin's lymphoma and Hodgkin's disease for which there is stronger epidemiologic evidence of an association—is derived from lymphoreticular cells, which adds to the biologic plausibility of an association. The new data available on MM do not change the committee's view that there is a limited/suggestive association between exposure to herbicides and multiple myeloma. Conclusions There is limited/suggestive evidence of an association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and multiple myeloma. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

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--> Leukemia Background According to the American Cancer Society, approximately 25,700 new cases of leukemia (ICD-9 202.4, 203.1, 204.0-204.9, 205.0-205.9, 206.0-206.9, 207.0-207.2, 207.8, 208.0-208.9) were diagnosed in the United States in 1995, and about 20,400 persons died of this cancer (ACS, 1995). It is somewhat more common among men than women. According to the committee's calculations, assuming that veterans have the same cancer rates as those in the general U.S. population, 205 cases of leukemia were expected among male Vietnam veterans and 0.4 among female veterans in 1995. For the year 2000, the expected numbers are 259 cases among male veterans and 0.5 cases among female veterans. Summary of VAO The epidemiologic evidence for an association between exposure to herbicides and leukemia comes primarily from studies of farmers and residents of Seveso, Italy. The observed overall relative risk for leukemia mortality and incidence in Seveso was elevated, but not significantly. The increase was significant, however, for cases who were in the most highly exposed zone and died five to ten years after the accident. A number of studies of farmers also show a consistently elevated risk of leukemia, but these results are not necessarily due to herbicide use, because confounding exposures were not controlled for adequately in the analyses. Also, when farmers are stratified by suspected use of herbicide, the incidence of leukemia is generally not elevated. Some studies of chemical workers found an increased risk of leukemia, but the number of cases was small in all of these studies. The available data on Vietnam veterans are generally not conclusive, because the exposure data are inadequate for the cohort being studied. Small sample sizes weaken the studies of the Ranch Hands or Chemical Corps; therefore, excess risks are not likely to be detected. Since no study has adequately differentiated between exposure solely to either herbicides or TCDD, or demonstrated a dose-response for any subtype of leukemia, it is not possible to attribute any symptom or subtype of leukemia as a result of exposure. Update of Scientific Literature Since the publication of VAO, a number of new studies have been published. There have been two reports on the female subgroup of the IARC registry, but they contain too few leukemia cases to allow for definite statements about risk. Kogevinas et al. (1993) reported one case of myeloid leukemia among 701 female

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--> production workers (not significant). Similarly, the 18-year follow-up of a cohort of 1,909 Finnish herbicide applicators reported two cases of leukemia (not significant) (Asp et al., 1994). Both of these studies have low statistical power. A cohort mortality study of 155,547 male farmers in Saskatchewan, Manitoba, and Alberta has been conducted over the period 1971-87 (Semenciw et al., 1994). The SMR for leukemia was 0.9, based on 357 cases, a significant decrease (CI 0.8-1.0). The risk of death from leukemia did not vary by herbicide use, based on reported numbers of acres sprayed with herbicides in 1970. A cohort study of cancer mortality in Ireland was performed using death certificate information from the years 1971 to 1987 (Dean, 1994). Among men in farming occupations, there were 138 deaths due to lymphoid leukemia, 114 due to myeloid leukemia, and 46 due to monocytic and other leukemias. The corresponding numbers for women in farming occupations were 39, 37, and 24. None of these categories was significantly elevated. In the United States, a PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 1,072 deaths from leukemia in white male farmers, the PCMR was significantly increased at 1.3 (CI 1.2-1.4). Twenty-two states had two or more deaths from leukemia. Sixteen states had risks that were greater than 1.0. The numbers of leukemia deaths were small and the PCMRs were nonsignificant in other gender and racial groups. Cancer incidence in the Seveso cohort during the first ten years following exposure to TCDD was investigated (Bertazzi et al., 1993). There were no cases of leukemia in Zone A. Among men in Zone B, there were two cases of leukemia (RR = 1.6, CI 0.4-6.5). Among women in Zone B, there were also two cases of leukemia (RR = 1.8, CI 0.4-7.3). In Zone R, where residents had much less potential for exposure to TCDD than in Zones A and B, there were eight cases of leukemia in men (RR = 0.9, CI 0.4-1.9) and three cases in women (RR = 0.4, CI 0.1-1.2). A PMR study that examined the causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently published (Visintainer et al., 1995). The mortality rates of 3,364 Vietnam veterans were compared with 5,229 veterans who served elsewhere. No data were available to identify whether individual Vietnam veterans had been exposed to herbicides. Based on 30 deaths from leukemia, the PMR was 1.0 (CI 0.7-1.5). Summary The committee concluded in VAO that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and leukemia. The updated scientific studies do not provide enough information to change this classification.

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--> Conclusions There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and leukemia. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Overall Summary For Cancer Based on the occupational, environmental, and veterans studies reviewed, the committee has reached one of four standard conclusions about the strength of the epidemiological evidence regarding association between exposure to herbicides and/or TCDD and each of the cancers under study. As explained in Chapter 4, these distinctions reflect the committee's judgment that if an association between exposure and an outcome were ''real," it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or dioxin was sufficiently high, well-characterized, and appropriately measured on an individual basis. Consistent with the charge to the Committee by the Secretary of Veterans Affairs in Public Law 102-4, the distinctions between these standard conclusions are based on statistical association, not on causality, as is common in scientific reviews. The committee used the same criteria to categorize diseases by the strength of the evidence as were used in VAO. Health Outcomes with Sufficient Evidence of an Association In VAO, the committee found sufficient evidence of an association with herbicides and/or TCDD for three cancers: soft-tissue sarcoma, non-Hodgkin's lymphoma, and Hodgkin's disease. The recent scientific literature continues to support the classification of these three cancers in the category of sufficient evidence. Based on the literature, there are no additional cancers that satisfy the criteria necessary for this category. Health Outcomes with Limited/Suggestive Evidence of Association In VAO, the committee found limited/suggestive evidence of an association for three cancers: respiratory cancer, prostate cancer, and multiple myeloma. The recent scientific literature continues to support the classification of these three diseases in the category of limited/suggestive evidence. For outcomes in this category, the evidence must be suggestive of an association between herbicides and the outcome, but may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study

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--> indicates a positive association, but the results of other studies may be inconsistent. Among the many epidemiologic studies of respiratory cancers (specifically cancers of the lung, larynx, and trachea), positive associations were found consistently only when TCDD or herbicide exposures were probably high and prolonged. This was especially true in the largest, most heavily exposed cohorts of chemical production workers exposed to TCDD (Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991). Studies of farmers tended to show a decreased risk of respiratory cancers (perhaps due to lower smoking rates), and studies of Vietnam veterans are inconclusive. The committee felt that the evidence for this association was limited/suggestive rather than sufficient, because of the inconsistent pattern of positive findings across populations with various degrees of exposure and because the most important risk factor for respiratory cancers—cigarette smoking—was not fully controlled for or evaluated in all studies. Several studies have shown an elevated risk for prostate cancer in agricultural or forestry workers. In a large cohort study of Canadian farmers (Morrison et al., 1993), an increased risk of prostate cancer was associated with herbicide spraying, and the risk was shown to rise with increasing number of acres sprayed. The mortality risk was elevated in a study of USDA forest conservationists (PMR = 1.6, CI 0.9-3.0) (Alavanja et al., 1989), and a case-control study of white male Iowans who died of prostate cancer (Burmeister et al., 1983) found a significant association (OR = 1.2) that was not linked with any particular agricultural practice. These results are strengthened by a consistent pattern of elevated, though nonsignificant, risks in studies of chemical production workers in the United States and other countries, agricultural workers, pesticide applicators, paper and pulp workers, and the Seveso population. The most important recent study demonstrated a significantly increased risk of death from prostate cancer in both white and nonwhite farmers in 22 of the 23 states that were studied (Blair et al., 1993). Studies of prostate cancer among Vietnam veterans and studies of environmental exposures have not consistently shown an association. However, prostate cancer is generally a disease of older men, and the risk among Vietnam veterans would not be detectable in current epidemiologic studies. Because there was a strong indication of a dose-response relationship in one study and a consistent positive association in a number of others, the committee felt that the evidence for association with herbicide exposure was limited/suggestive for prostate cancer. Multiple myeloma, a cancer of specific bone marrow cells, has been less extensively studied than other lymphomas, but a consistent pattern of elevated risks appears in the studies. Several studies of agricultural and forestry workers provide information on MM risk in relation to herbicide or pesticide exposure. Most demonstrated an odds ratio or SMR greater than 1.0; nine did so at a statistically significant level. The committee determined that the evidence for

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--> this association was limited/suggestive, because the individuals in the existing studies (mostly farmers) have by the nature of their occupation probably been exposed to a range of potentially carcinogenic agents other than herbicides and TCDD. Multiple myeloma—like non-Hodgkin's lymphoma and Hodgkin's disease, for which there is stronger epidemiologic evidence of an association—is derived from lymphoreticular cells, which adds to the biologic plausibility of an association. Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists The scientific data for the remainder of the cancers reviewed by the committee were inadequate or insufficient to determine whether an association exists. For these cancers, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding or have inadequate exposure assessment. This category includes hepatobiliary cancers, nasal/nasopharyngeal cancer, bone cancer, female reproductive cancers (cervical, uterine, ovarian), breast cancer, renal cancer, testicular cancer, leukemia, and skin cancer. A recently published study reviewed by the committee (Lynge, 1993) contained enough evidence to warrant moving skin cancer from the "limited/suggestive evidence of no association" category to this one. The scientific evidence for four cancers will be summarized here. Hepatobiliary cancer and nasopharyngeal cancer are of special interest to the Department of Veterans Affairs. The evidence for skin cancer will be presented because it has changed categories. Breast cancer also deserves attention, because of its public health importance. There are relatively few occupational, environmental, and veterans studies of hepatobiliary cancer, and most of these are small in size and have not controlled for lifestyle-related factors. The estimated relative risk in the various studies range from 0.3 to 3.3, usually with broad confidence intervals. Given the methodological difficulties associated with most of the few existing studies, the evidence regarding hepatobiliary cancer is not convincing with regard to either an association with herbicides/TCDD or the lack of an association. The few studies that have been published since VAO do not change the conclusion that there is inadequate evidence to determine whether an association exists between exposure to herbicides and hepatobiliary cancer (Asp et al., 1994; Bertazzi et al., 1993; Blair et al., 1993; Collins et al., 1993; and Cordier et al., 1993). There are only a few occupational studies, one environmental study, and one veterans study of nasal and/or nasopharyngeal cancer, including two recently published studies (Asp et al., 1994; and Bertazzi et al., 1993). The estimated relative risks in the various studies range from 0.6 to 6.7, usually with broad confidence intervals. The few studies published since VAO do not change the

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--> conclusion that there is inadequate evidence to determine whether an association exists between exposure to herbicides and nasal/nasopharyngeal cancer. One recent study (Lynge et al., 1993) found an excess risk of skin cancer. Based on four cases, a statistically significant increase in the risk of melanoma was observed in the subgroup of men who had been employed for at least one year, using a ten year latency period (SIR = 4.3, CI 1.2-10.9). However, no information is given about the risk in men with less than 10 years of latency and expected numbers for women are not reported so observed elevated risk in the men with 10+ years of latency cannot be put into context. Another study also found a significant excess risk in men from the Seveso area (SMR = 3.3), based on only three cases (Bertazzi et al., 1989a,b). The committee felt that these results, while not even suggestive evidence about an association, undermined the evidence of no association in VAO, and thus warranted changing skin cancer to the "inadequate/insufficient evidence to determine whether an association exists" category. There have been a few occupational studies, two environmental studies, and two veterans studies of breast cancer among women exposed to herbicides and/or TCDD. These include four recently published studies (Bertazzi et al., 1993; Blair et al., 1993; Dalager et al., 1995; and Kogevinas et. al., 1993). Most of these studies reported a relative risk of approximately 1.0 or less, but it is uncertain whether or not the female members of these cohorts had substantial chemical exposure. For example, more than 80 percent of the women Vietnam veterans in the two studies were nurses (Thomas et al., 1991; Dalager et. al., 1995). There continues to be inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and breast cancer. Health Outcomes with Limited/Suggestive Evidence of No Association In VAO, the committee found a sufficient number and variety of well-designed studies to conclude that there is limited/suggestive evidence of no association between a small group of cancers and exposure to TCDD or herbicides. This group includes gastrointestinal tumors (colon, rectal, stomach, and pancreatic), brain tumors, and bladder cancer. The recent scientific evidence continues to support the classification of these cancers in this category. Based on the literature, there are no additional cancers that satisfy the criteria necessary for this category. For outcomes in this category, several adequate studies covering the full range of levels of exposure that human beings are known to encounter are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. These studies have relatively narrow confidence intervals. A conclusion of "no association" is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded.

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--> Increased Risk in Vietnam Veterans Although there have been numerous health studies of Vietnam veterans, most have been hampered by relatively poor or nonexistent measures of exposure to herbicides or TCDD, in addition to other methodologic problems. Most of the evidence on which the conclusions in this chapter are based comes from studies of people exposed to dioxin or herbicides in occupational and environmental settings, rather than from studies of Vietnam veterans. The committee found this body of evidence adequate for reaching the conclusions about statistical associations between herbicides and health outcomes in this chapter. However, the lack of adequate data on Vietnam veterans per se complicates the determination of the increased risk of disease among individuals exposed to herbicides during service in Vietnam. Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed, the inadequate control for important confounders, and the uncertainty about the nature and magnitude of exposure to herbicides in Vietnam (as discussed in Chapter 5), none of the ingredients necessary for a quantitative risk assessment is available. Thus, the committee cannot quantify the degree of risk likely to be experienced by veterans because of their exposure to herbicides in Vietnam. The available quantitative and qualitative evidence about herbicide exposure among various groups studied suggests that Vietnam veterans as a group (except those with documented high exposures, such as participants in Operation Ranch Hand) had lower exposure to herbicides and TCDD than did the subjects in many occupational and environmental studies. However, individual veterans who had very high exposures to herbicides could have risks approaching those in the occupational and environmental studies. References Ablashi DV. 1978. Meeting report: international symposium on etiology and control of nasopharyngeal carcinoma. Cancer Research 38:3114-3115. 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. American Cancer Society (ACS). 1992. Cancer Facts and Figures: 1992. Atlanta: American Cancer Society. American Cancer Society (ACS). 1995. Cancer Facts and Figures: 1995. Atlanta: American Cancer Society. Andersen HC, Andersen I, Selgaard J. 1997. Nasal cancers, symptoms, and upper airway function in woodworkers. British Journal of Industrial Medicine 34:201-207. Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986a. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Study Results. State of Wisconsin, Department of Health and Social Sciences.