origin," which were not included in ICD 171 but which, by some classifications, belong in the group of tumors under consideration (Mack, 1995). It is difficult to evaluate this finding, because of the problem of estimating a comparable expected incidence for the same tumors, but the authors note that 1.4 cases would be expected in this cohort when cancers including ICD 171 and cancers of parenchymal origin are combined. In the larger but less exposed group from Zone B, there were again no cases of ICD 171 cancers observed, while about 0.5 cases were expected. Zone R is the largest group, with considerably lower exposures to TCDD on average. Two cases of STS (ICD 171) were observed in females (RR = 1.6, 95 percent CI 0.3-7.4). In males, six cases were observed, yielding an RR of 2.8 (95 percent CI 1.0-7.3). There appeared to be a trend in increasing risk with increasing duration of residence in Zone R.

A PMR study that examined the causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently reported (Visintainer et al., 1995). The mortality rates of 3,364 Vietnam veterans were compared to the morality rates of 5,229 veterans who served elsewhere. Based on eight deaths from STS, the PMR was 1.1 (CI 0.5-2.2). No data were available to identify whether individual Vietnam veterans had been exposed to herbicides.

Summary

The reports issued since the publication of VAO, notably the Kogevinas et al. Case-control study (1995), provide additional evidence for an association between exposure to herbicides and STS.

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 soft-tissue sarcoma. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

TCDD has been shown to have a wide range of effects in laboratory animals on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. In addition, TCDD has been shown to cause cancer in laboratory animals at a variety of sites. If TCDD has similar effects on cell regulation in humans, it is plausible that it could have an effect on human cancer incidence. TCDD administration increased fibrosarcoma formation in both rats and mice (NTP, 1982a,b). In contrast to TCDD, there is no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides, although they have not been studied as extensively as TCDD.



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--> origin," which were not included in ICD 171 but which, by some classifications, belong in the group of tumors under consideration (Mack, 1995). It is difficult to evaluate this finding, because of the problem of estimating a comparable expected incidence for the same tumors, but the authors note that 1.4 cases would be expected in this cohort when cancers including ICD 171 and cancers of parenchymal origin are combined. In the larger but less exposed group from Zone B, there were again no cases of ICD 171 cancers observed, while about 0.5 cases were expected. Zone R is the largest group, with considerably lower exposures to TCDD on average. Two cases of STS (ICD 171) were observed in females (RR = 1.6, 95 percent CI 0.3-7.4). In males, six cases were observed, yielding an RR of 2.8 (95 percent CI 1.0-7.3). There appeared to be a trend in increasing risk with increasing duration of residence in Zone R. A PMR study that examined the causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently reported (Visintainer et al., 1995). The mortality rates of 3,364 Vietnam veterans were compared to the morality rates of 5,229 veterans who served elsewhere. Based on eight deaths from STS, the PMR was 1.1 (CI 0.5-2.2). No data were available to identify whether individual Vietnam veterans had been exposed to herbicides. Summary The reports issued since the publication of VAO, notably the Kogevinas et al. Case-control study (1995), provide additional evidence for an association between exposure to herbicides and STS. 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 soft-tissue sarcoma. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. TCDD has been shown to have a wide range of effects in laboratory animals on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. In addition, TCDD has been shown to cause cancer in laboratory animals at a variety of sites. If TCDD has similar effects on cell regulation in humans, it is plausible that it could have an effect on human cancer incidence. TCDD administration increased fibrosarcoma formation in both rats and mice (NTP, 1982a,b). In contrast to TCDD, there is no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides, although they have not been studied as extensively as TCDD.

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--> Skin Cancers Background Skin cancers are generally divided into two broad categories—malignant melanomas and nonmelanotic skin cancers. According to the American Cancer Society, approximately 34,100 new cases of melanoma (ICD-9 172.0-172.9) were diagnosed in the United States in 1995, and some 7,200 persons died of this cancer (ACS, 1995). The incidence is similar in men and women, but men account for about 60 percent of deaths. Other skin cancers (basal-cell and squamous-cell carcinomas) led to about 800,000 new cases and 2,100 deaths. According to the committee's calculations, assuming that veterans have the same cancer rates as those of the general U.S. population, 486 cases of melanoma were expected among male Vietnam veterans and 1.1 among female veterans in the year 1995. For the year 2000, the expected numbers are 632 cases in male veterans and 1.3 in female veterans. No calculations were made for the very common and highly curable nonmelanotic skin cancers. Epidemiologic Studies Most of the epidemiologic studies reviewed in VAO did not find an excess risk of skin cancer among TCDD-exposed workers or veterans. These included studies of chemical production workers in the United States and other countries (Suskind and Hertzberg, 1984; Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991), agricultural workers (Burmeister, 1981; Alavanja et al., 1988; Wigle et al., 1990; Hansen et al., 1992; Ronco et al., 1992), pesticide applicators (Blair, 1983; Swaen et al., 1992), Seveso residents (Pesatori et al., 1992), and Vietnam veterans (Lawrence et al., 1985; Boyle et al., 1987; Breslin et al., 1988; CDC, 1988; Anderson et al., 1986a,b). The lack of association was also seen in a study in which the cohort observed consisted of those with chloracne (Moses et al., 1984). One exception is melanoma mortality following the Seveso accident. Bertazzi et al. (1989a,b) found an elevated risk in males from Zones B and R, but this was based on two and one melanoma deaths, respectively. In addition, the Ranch Hand study (Wolfe et al., 1990) found a relative risk of 1.5 (CI 1.1-2.0) for nonmelanomic skin cancer. One study of agricultural workers in Sweden (Wiklund, 1983) found an elevated risk for skin cancer excluding melanoma (RR = 1.1, 99 percent CI 1.0-1.2), but these results may be confounded by sun exposure in these groups. One more recent study reviewed by this committee did find an excess risk of skin cancer (Lynge, 1993). Melanoma was studied in employees of two phenoxy herbicide manufacturing facilities in Denmark. There were 1,651 men and 468 women who were judged to have had potential exposure to phenoxy herbicides.

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--> 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 latancy cannot be put into context. 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 244 deaths from melanoma in white male farmers, the PCMR was 1.0 (CI 0.8-1.1). Based on 425 deaths from other types of skin cancer in white male farmers, the PCMR was 1.1 (CI 1.0-1.2). The numbers for these two types of cancer were very small and nonsignificant for the other racial and gender groups: nonwhite males and white and nonwhite females. The cancer incidence (including the rates of melanoma and other skin cancers) in the Seveso population was investigated for the first ten years after its potential exposure to TCDD (Bertazzi et al., 1993). No cases of melanoma were reported in Zones A or B. There was also no increase in the risk of nonmelanotic skin cancer in any of the zones. There was no increase in the risk of melanoma in men or women in Zone R, the least contaminated area. These risks were calculated based on only one or two cases, except for Zone R, there were larger numbers of both types of skin cancer. Three other studies calculated SMRs for skin cancer, all of which were too small to have sufficient statistical power to give definitive results (Asp et al. 1994; Bueno de Mesquita et al., 1993; and Collins et al., 1993). These authors observed zero, one, and one cases of skin cancer, respectively. Summary Some of the studies have utilized melanoma as the end point of interest, whereas others have utilized skin cancer, which primarily reflects melanoma. While the studies are fairly evenly distributed between positive and negative studies, one recent study (Lynge et al., 1993) did find an excess risk of skin cancer. 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 studies, while not even suggestive evidence about an association, undermined the evidence of no association in VAO, and thus warranted changing skin cancer from the "limited/suggestive evidence of no association" category to the "inadequate/insufficient evidence to determine whether an association exists" category. Conclusions There is inadequate or insufficient evidence to determine whether an association

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--> exists between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant, TCDD; cacodylic acid; and picloram) and skin 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. Cancers of the Female Reproductive System Background According to the American Cancer Society, new cases and deaths in the United States in 1995 for each of these cancers were as follows (ACS, 1995): Site New Cases Deaths Cervix 15,800* 4,800 Corpus uteri 32,800 5,900 Ovary 26,600 14,500 Other genital 5,700 1,200 * Excludes carcinoma in situ (65,000 cases of cervical cancer). According to the committee's calculations, 1.6 cases of cancer of the uterine corpus were expected among female Vietnam veterans in 1995; For the year 2000, the expected number of cases is 2.8. For cervical cancer, 1.2 cases are expected among female Vietnam veterans in 1995; for the year and in 2000, the expected number of cases is 1.2 cases. For ovarian cancer, 1.5 cases were expected among female Vietnam veterans; for the year 2000, the expected number of cases is 1.9 cases. Summary of VAO Studies that examined exposure to herbicides and uterine and ovarian cancers were extremely limited. In a case-control study specifically designed to address the relation between herbicide exposure and risk of ovarian cancer, Donna et al. (1984) compared exposure histories among 60 women with ovarian cancer to controls (women with cancers at other sites, including breast, endometrium, cervix, and other organs). Overall, 18 women with ovarian cancer were classified as definitely or probably exposed, compared to 14 controls, giving an odds ratio of 4.4 (CI 1.9-16.1). These data provide the most direct evidence of an association between herbicides and ovarian cancer. Bertazzi et al. (1989b) followed the Seveso population for ten years after the 1976 accident. If the TCDD did initiate cancers of female reproductive organs, the elapsed time is probably insufficient for these tumors to have come to clinical

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--> attention. In particular, women exposed to TCDD, during adolescence may be at increased risk for cancers that could not be detected for 20 or more years after the exposure. Other studies examining the association between ovarian or uterine cancer and exposure to herbicides are Wiklund, 1983; Saracci et al., 1991; Ronco et al., 1992. Update of the Scientific Literature A cohort study of cancer incidence was conducted among employees of two phenoxy herbicide manufacturing facilities in Denmark (Lynge, 1993). This cohort included 1,071 women who were followed for the period from 1947 to 1987. A statistically significant increase in the risk of cervical cancer was found, based on seven cases (SIR = 3.2; CI 1.3-6.6). A cohort study of cancer incidence and mortality was conducted among 701 women in the IARC cohort, who were occupationally exposed to chlorophenoxy herbicides, chlorophenols and dioxins (Kogevinas et al., 1993). Of these 701 women, 468 (66 percent) worked at two herbicide plants in Denmark, so there is considerable overlap with the cohort investigated by Lynge (1993). One death was observed from each of the following types of cancer: cervical cancer (SMR = 80); uterus nonspecified (SMR = 192); and ovary (SMR = 74). Cancer incidence during the first ten years following exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). There were no significant increases in the rates of uterine cancer among female residents of Zones A, B, or R, based on two, two, and 21 cases, respectively; the relative risks were 2.6, 0.4, and 0.6, respectively. No cases of ovarian cancer were diagnosed among women in Zones A or B. Based on 20 cases, the relative risk for ovarian cancer in Zone R, the least contaminated area, was 1.1 (CI 0.7-1.7). 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 21 deaths from cervical cancer in nonwhite female farmers, the PCMR was significantly elevated at 2.0 (CI 0.3-3.1). This may partially reflect the increased risk for this cancer type among both nonwhite women and women in the lower socioeconomic groups. Based on six deaths from cervical cancer in white female farmers, the PCMR was 0.9 (CI 0.3-2.0). The numbers of deaths from cancer of the uterine corpus were small and nonsignificant for both white and nonwhite female farmers. The cancer mortality rates among 4,586 female Vietnam veterans were recently evaluated, as well as the rates among 5,325 female veterans who had served elsewhere (Dalager et al., 1995). Based on four cases of cancer of the uterine corpus, the relative risk for Vietnam veterans was 2.1 (CI 0.6-5.4), compared to that of the general U.S. population.

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--> Summary There has been considerable recent interest in the potential association of exposure to chlorinated hydrocarbons, including TCDD, and female reproductive cancers and other health outcomes in women. For example, teratogenic effects due to maternal exposures to TCDD have been well-documented in experimental animals (see Chapter 3). Endometriosis has recently been demonstrated in monkeys exposed to TCDD (Rier et al., 1993), and research on this disease has been proposed for women in the Seveso cohort (Bois and Eskenazi, 1994). The available epidemiologic evidence, however, is inconclusive. The committee concludes that more research is needed on populations of women with documented exposure to herbicides and TCDD. 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 uterine and ovarian cancers. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Breast Cancer Background Approximately 11 percent of U.S. women will develop breast cancer sometime during their lifetimes. Among U.S. women 40 to 55 years of age, breast cancer is the leading cause of death (U.S. DHHS, 1987). Rates of breast cancer increase rapidly up to the time of menopause. After menopause, incidence rates continue to increase with age but more slowly than before. Long-term increases in incidence rates have been observed. An analysis of SEER data indicates that the incidence of breast cancer increased 4 to 6 percent annually between 1980 and 1987. Only some of the increase can be attributed to more extensive screening and earlier diagnosis (Miller et al., 1991; Harris et al., 1992). Mortality patterns vary by age and race, with decreases seen among white women under age 65 and increases among older white women and black women of all ages (Miller et al., 1992). Earlier detection of tumors and improved treatments have kept increases in mortality lower than increases in incidence. According to the committee's calculations, assuming that veterans have the same rates of cancer as those as the general U.S. population, 13.2 cases of breast cancer were expected among female Vietnam veterans in 1995. For the year 2000, the expected number of cases is 15.5.

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--> Because of the public health significance of breast cancer, this discussion integrates the studies reviewed in VAO with those published more recently. By far the most common histological type of breast cancer is adenocarcinoma, derived from the epithelium of breast ducts. Lobular carcinoma derived from gland lobule epithelium is a separate category (less than 5 percent of breast cancer). Lobular cancers are usually bilateral and grow very aggressively. Other malignant, although somewhat less invasive, cancers include medullary, mucinous, and tubular carcinomas. Noninvasive carcinomas are found in breast ducts (e.g., comedocarcinoma) and lobules. Intraductal papillomas, another histological variant, are nearly always benign and do not appreciably alter the overall statistics. Risk factors for breast cancer include early age at menarche, late age at first birth and low parity (or nulliparity), late age at menopause, and family history of breast cancer and personal history of benign cystic breast disease (Henney and DeVita, 1987). Women living in the United States who are of northern European heritage have four to five times more breast cancer than women of Asian heritage living in Asian countries. Dietary factors have been postulated to modify risk, but only alcohol intake is consistently related to increased risk of breast cancer (Henderson, 1991). Investigations into the relationship between stress and breast cancer have not been conclusive. Age is an important modifier of risk, in that exposure to radiation between the onset of menses and first pregnancy creates a greater risk than a similar exposure at older ages. Epidemiologic Studies The data relating exposure to herbicides to cancer among women are extremely limited. The committee attempted to examine cancer among women separately from cancer among men. However, compared with the sparse data available for men, data for women are almost nonexistent. Many studies have excluded women from analysis because of their small numbers in the groups under study. For example, in their follow-up of workers from 12 companies, Fingerhut et al. (1991) identified 67 women who were then excluded from the report. Likewise, Moses et al. (1984) excluded three women from their follow-up analysis of workers, and Zack and Suskind (1980) excluded the one woman who was living at the end of the study. Among the studies that were based on follow-up of workers, women contribute a minor portion of the data, and the results are accordingly even less precise than those reported for men. Occupational Studies Manz et al. (1991) describe a retrospective cohort of chemical workers employed in an herbicide plant in Hamburg, Germany. The standardized mortality ratio for breast cancer was elevated, at 2.2 (CI 1.0-4.1). This SMR, however, was

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--> based on only nine deaths. Only 7 percent of the women in this study worked in high exposure departments, and the small number of women precluded separate examination of those with high exposure. In a study focusing on all persons employed in the manufacture of phenoxy herbicides in Denmark before 1982, Lynge (1985) linked employment records for 1,069 women (contributing 17,624 person-years of follow-up) with the National Cancer Register. Thirteen cases of breast cancer were diagnosed, giving an SMR of 0.9. As described in Chapter 6, Saracci et al. (1991) have established a study population comprising members of 20 cohorts from ten countries other than the United States who were likely to have had exposure to phenoxy herbicides or TCDD. Among the more than 18,000 workers included in this cohort, 1,527 were women. Follow-up continued for an average of 17 years. It is assumed that the follow-up rates were similar for women and for men, although details are not reported. Among the exposed women, there was one death from breast cancer—a lower mortality rate than expected. Among nonexposed women, four deaths were observed due to breast cancer. This mortality was not significantly different from that expected. Additional data have been reported by Kogevinas et al. (1993), who identified and followed the subset of women in the IARC cohort who had been occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Saracci et al., 1991). Among the 701 women who were followed, 29 cases of cancer were diagnosed. Overall, no increase in total cancer was observed (SIR = 1.0, CI 0.6-1.4). Among those workers exposed to chlorophenoxy herbicides contaminated with TCDD, excess cancer incidence was observed, based on nine cases (SIR = 2.2, CI 1.0-4.2). However, no excess of breast cancer was observed among these 701 women; seven cases resulted in an SIR of 0.9 (CI 0.4-1.9). When the 169 women who were probably exposed to TCDD were analyzed separately, only one case of breast cancer was diagnosed (SIR = 0.9, CI 0.0-4.8). Among women farm workers in Denmark, the standardized incidence ratios for breast cancer, ovarian cancer, and uterine cancer were all less than 1.0 (Ronco et al., 1992). There were 429 cases of breast cancer diagnosed, and the standardized incidence ratio of 0.8 was significantly less than unity. In this group, the standardized ratios for cervical cancer, uterine cancer, and ovarian cancer were all based on 100 or more cases, and all were significantly less than 1.0. The actual level of exposure of these women to herbicides is not defined, however, and it is possible that the reduced incidence of reproductive cancers reflects general patterns of female cancers seen elsewhere, in which rates are lower for rural than for urban populations. In a similar occupational study based on census data for economically active women in Sweden (Wiklund, 1983), the SIR for breast cancer was 0.8. This result is not adjusted for reproductive risk factors for these cancers, and the actual exposures of interest are not defined.

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--> In the United States, a PCMR study was performed using death certificate data from male and female farmers from 23 states (Blair et al., 1993). Occupation and industry data were coded based on the information listed on the death certificates. Based on the 71 deaths from breast cancer among white female farmers, the PCMR was 1.0 (CI 0.8-1.3). Based on 30 deaths from breast cancer among nonwhite female farmers, the PCMR was significantly decreased, at 0.7 (0.5-1.0). In Seveso, one study includes cancer mortality among women (Bertazzi et al., 1989b). The ten year mortality follow-up provides limited information for women in the high- and medium-exposure groups. Person-years of follow-up were 2,490 in Zone A (high exposure), 16,707 in Zone B, 114,558 in Zone R, and 726,014 in the reference area. There were only three deaths due to any cancer in females in Zone A; therefore, no conclusions are possible. Among the 14 deaths of Zone B women, 5 were due to breast cancer, resulting in a mortality ratio of 0.9 (CI 0.4-2.1). In Zone R, the least contaminated area, 28 women died from breast cancer, giving a significantly reduced estimated relative risk of 0.6 (CI 0.4-0.9). Cancer incidence in the Seveso cohort during the first ten years following exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). One case of breast cancer was diagnosed among women in Zone A (RR = 0.5, CI 0.1-3.3). Among women in Zone B, there were 10 cases of breast cancer diagnosed (RR = 0.7, CI 0.4-1.4). Among women in Zone R, the least contaminated area, there were 106 cases of breast cancer diagnosed (RR = 1.1, CI 0.9-1.3). Vietnam Veterans Studies Thomas et al. (1991) assembled a list of female Vietnam veterans and followed them from 1973 to 1987. Cause-specific estimates of mortality risk among women Vietnam veterans relative to those for Vietnam-era veterans who served elsewhere were derived from proportional hazards multivariate models adjusted for rank (officer, enlisted), occupation (nurse, nonnurse), duration of service (at least ten years), age at entry to follow-up, and race. Of these women, 80 percent were classified as officers/nurses, and the majority served between three and 19 years. Slightly more than one-fourth of the cancer deaths were due to breast cancer among the Vietnam veterans. The relative risk was not significantly elevated (RR = 1.2, CI 0.6-2.5) compared to that among the other Vietnam-era veterans. Cancer mortality rates among 4,586 female Vietnam veterans were recently compared with the rates among 5,325 female veterans who had served elsewhere (Dalager et al., 1995). This extended the follow-up of Thomas et al. (1991) an earlier study for four additional years, through 1991. There were 196 deaths observed among the Vietnam veterans. Based on 26 deaths from breast cancer among the Vietnam veterans, the relative risk was 1.0 (CI 0.6-1.8).

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--> Summary 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 (Table 7-4). 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. TCDD appears to exert a protective effect on the incidence of mammary tumors in experimental animals (see Chapter 3), which is consistent with the tendency for the relative risks to be less than 1.0. In summary, however, the committee believes that there is insufficient evidence to determine whether an association exists between exposure to herbicides and breast cancer. Conclusions Strength of Evidence in Epidemiologic Studies 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 breast 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. Biologic Plausibility TCDD has been shown to have a wide range of effects in laboratory animals on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. Although animal data suggest TCDD may act as an antiestrogen, and it has been shown to inhibit growth of breast cancer cell lines in tissue culture, the extrapolation to prevention of breast cancers is plausible, but has not been clearly demonstrated in humans. Prostate Cancer Background According to the American Cancer Society, approximately 132,000 new cases of prostate cancer (ICD-9 185) were diagnosed in the United States in 1992, and some 34,000 persons died of prostate cancer (ACS, 1992). According to the committee's calculations, assuming that veterans have the same cancer rates as those in the general U.S. population, 179 cases of prostate cancer were expected

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--> TABLE 7-4 Selected Epidemiologic Studies—Breast Cancer Reference Study Population Exposed Casesa Estimated Risk (95% CI)a Occupational Cohort studies Ronco et al., 1992 Danish family farm workers 429 0.8 (p<.05) Wiklund, 1983 Swedish economically active agricultural workers 444 0.8 (0.7-0.9)b Donna et al., 1984 Female residents near Alessandria, Italy     Lynge, 1985 Danish production workers 13 0.9 Manz et al., 1991 German production workers 9 2.2 (1.0-4.1) Kogevinas et al., 1993 701 women from IARC cohort 7 0.9 (0.4-1.9) Saracci et al., 1991 IARC cohort 1 0.3 (0.01-1.7) Blair et al., 1993 Female farmers from 23 states       -white 71 1.0 (0.8-1.3)   -nonwhite 30 0.7 (0.5-1.0) Environmental Bertazzi et al., 1993c Seveso female residents—Zone A 1 0.5 (0.1-3.3)   —Zone B 10 0.7 (0.4-1.4)   —Zone R 106 1.1 (0.9-1.3) Vietnam Veterans Thomas et al., 1991 Women Vietnam veterans 17 1.2 (0.6-2.5) Dalager et al., 1995d Women Vietnam veterans 26 1.0(0.6-1.8) a Given when available. b 99% CI. c This is further follow-up of women included in Bertazzi et al., 1989. d This is further follow-up of women included in Thomas et al., 1991. among male Vietnam veterans in 1995. For the year 2000, the expected number of cases is 855. Because this type of cancer is of special interest to the DVA, this discussion integrates the studies reviewed in VAO with those published more recently. One in 11 men develops prostate cancer, and it is the most common cancer in men (excluding skin cancers) and the second leading cause of cancer death (Pienta and Esper, 1993). Increased age is the major risk factor; more than 80 percent of cases occur in men over 65. The incidence of prostate cancer increases sharply at about age 40. Among men 65 and older, it occurs at higher rates than in any other

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--> cancer. With advancing age, the incidence of noninvasive prostate cancer increases. The percentage of these that undergo invasive transformation remains unknown. Prostate cancer occurs about twice as often in black men as in to white men. Incidence has increased since 1973 at an annual rate of about 3 percent for whites and about 2 percent for blacks. Between 1985 and 1989, the rate of increase for whites had reached 6 percent per year. Specific causes of prostate cancer are unknown, but associations have been observed with family history of prostate cancer, having had a vasectomy, hormonal factors, a high-fat diet, a history of untreated venereal diseases, multiple sex partners, cigarette smoking, certain occupations, and possibly exposure to ionizing radiation or cadmium (Nomura and Kolonel, 1991; Pienta and Esper, 1993). Improved detection accounts for some of the increase in incidence, but mortality rates are increasing as well. Early detection is the most important consideration for a cure. Hormonal treatment, radiation, and/or surgery remain the methods of choice. Epidemiologic Studies Occupational Studies For prostate cancer, several studies have shown elevated risk in agricultural or forestry workers. Mortality was increased in studies of USDA agricultural extension agents (PMR = 1.5, CI 1.1-2.0) and forest and soil conservationists (PMR = 1.6, CI 1.1-2.0) (Alavanja et al., 1988, 1989). However, subsequent case-control analysis of these deaths showed no increased risk of prostate cancer for ever being an extension agent (OR = 1.0, CI 0.7-1.5) or a soil conservationist (OR = 1.0, CI 0.6-1.8), although the risk was elevated for forest conservationists (OR = 1.6, CI 0.9-3.0). The risk of prostate cancer was more highly elevated for those whose employment ended prior to 1960 and who had worked for at least 15 years as a conservationist (OR = 2.1 for forest workers and 2.9 for soil workers). A case-control study of white male Iowans who died of prostate cancer (Burmeister et al., 1983) found a significant association (OR = 1.2) with farming; this was not connected to a specific agricultural exposure. Higher relative risks were observed after restricting analysis to those born before 1890 (OR = 1.5) and for those age 65 or older (OR = 1.3). A PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 3,765 deaths from prostate cancer in white male farmers (total N = 119,648), the PCMR was significantly increased, at 1.2 (CI 1.1-1.2). Based on 564 deaths from prostate cancer in nonwhite male farmers (total N = 11,446), the PCMR was also significantly increased at 1.1 (CI 1.1-1.2). This increased risk for prostate cancer was observed in 22 of the 23 states studied. In a large cohort study of Canadian farmers, Morrison et al. (1993) found

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--> that an increased risk of prostate cancer was associated with herbicide spraying, and the risk was found to rise with increasing number of acres sprayed. For the entire cohort, the relative risk for prostate cancer and spraying at least 250 acres was 1.2 (CI 1.0-1.5). Adjustment for potential confounders showed no evidence of confounding for the association. Additional analyses were restricted to a one-third sample of farmers most likely to be exposed to phenoxy herbicides or other herbicides (RR = 1.3, CI 1.0-1.8 for ≥250 acres sprayed). To focus on farmers who were most likely to be exposed to herbicides, additional analyses were restricted to those with no employees (RR = 1.4, CI 1.0-1.9 for ≥250 acres sprayed); no customary expenses for assisting in work, which might include spraying (RR = 1.6, CI 1.1-2.2 for ≥250 acres sprayed); age between 45-69 years (RR = 1.7, CI 1.1-2.8 for ≥250 acres sprayed); and a combination of the three restrictions (RR = 2.2, CI 1.3-3.8 for ≥250 acres sprayed). For each of these comparisons, a statistical test for trend (increasing risk) over increasing number of acres sprayed was significant. Other occupational and environmental studies of prostate cancer generally have been consistent. These include studies of chemical production workers in the United States and other countries (Bond et al., 1983; Lynge, 1985; Coggon et al., 1986; Zober et al., 1990), agricultural workers (Burmeister, 1981; Wigle et al., 1990; Ronco et al., 1992), pesticide applicators (Blair, 1983; Swaen et al., 1992), and paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989; Solet et al., 1989). Cancer mortality was evaluated for employees of two Dutch companies that produced several chlorophenoxy herbicides; these men were a subgroup of the IARC Registry (Bueno de Mesquita et al., 1993). Mortality rates for 963 exposed and 1,111 nonexposed men were evaluated. Based on three deaths from prostate cancer among the exposed men, the SMR was 2.6 (CI 0.5-7.7). The mortality experience was evaluated for employees of a Monsanto Company trichlorophenol plant, that had an accidental release of TCDD in 1949 (Collins et al., 1993). The mortality rates in 754 men with varying degrees of exposure to TCDD and 4-aminobiphenyl were compared to rates in the local population. Based on nine deaths from prostate cancer, the SMR was 1.6 (CI 0.7-3.0). An 18-year prospective follow-up of cancer morbidity and mortality for 1,909 Finnish herbicide applicators was reported (Asp et al., 1994). These 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 five deaths from prostate cancer, the SMR was 0.8 (CI 0.3-1.8). The SIR was 0.9 (CI 0.1-1.3) based on 6 cases.

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--> Environmental Studies Cancer incidence and mortality were described for the Seveso population in three previous studies (Bertazzi et al., 1989a,b; Pesatori et al., 1992). Cancer incidence for the first ten years after exposure to TCDD was thoroughly updated in the Seveso cohort (Bertazzi et al., 1993). In Zone A and Zone B (the more highly exposed areas), 4 cases of prostate cancer were diagnosed, and the relative risk was 1.4 (0.5-3.9) (Pesatori et al., 1992). In Zone R (the less exposed area), based on 16 cases of prostate cancer (Bertazzi et al., 1993), the relative risk was 0.9 (CI 0.5-1.5). Vietnam Veterans Studies Studies of prostate cancer among Vietnam veterans or following environmental exposures have not consistently shown an association (Anderson et al., 1986a,b; Breslin et al., 1988). However, prostate cancer is generally a disease of older men, and the risk among Vietnam veterans might not be detectable yet in epidemiologic studies. A proportionate mortality study examining causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently reported (Visintainer et al., 1995). The cause-specific mortality rates among 3,364 Vietnam veterans were compared with the rates among 5,229 age-matched veterans who had served elsewhere. There were 19 deaths from male genital cancer among the Vietnam veterans (PMR = 1.1, CI 0.6-1.7). Rates for prostatic cancer were not reported separately from testicular cancer. Summary Most of the agricultural studies indicate some elevation in risk of prostate cancer. One large, high-quality study in farmers showed an increased risk, and subanalyses in this study indicated that the increased risk is specifically associated with herbicide exposure (Morrison et al., 1993). In addition, a significantly increased risk of prostate cancer was observed in both white and nonwhite farmers in another large study (Blair et al., 1993). The three major studies of production workers (Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991) showed a small, but not statistically significant, elevation in risk. In the NIOSH study, the subcohort with at least 20 years latency and at least one year of exposure had a slightly increased risk, (SMR = 1.5, CI 0.7-2.9) (Fingerhut et al. 1991). Most of the studies used mortality as an outcome, so detection bias is not likely to explain these results. It should be noted, however, that most of the associations are relatively weak (RR < 1.5). Most Vietnam veterans have not yet reached the age when this cancer tends to appear. Results are summarized in Table 7-5.

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--> TABLE 7-5 Selected Epidemiologic Studies—Prostate Cancer Reference Study Population Exposed Casesa Estimated Risk (95% CI)a Occupational Cohort studies Fingerhut et al., 1991 NIOSH cohort 17 1.2 (0.7-2.0)   ≥20 year latency, ≤1 year exposure 9 1.5 (0.7-2.9) Bond et al., 1988 Dow 2,4-D production workers 1 1.0 (0.0-5.8) Coggon et al., 1986 British MCPA production workers 18 1.3 (0.8-2.1) Lynge, 1985 Danish production workers 9 0.8 Manz et al., 1991 German production workers 7 1.4 (0.6-2.9) Zober et al., 1990 BASF production workers 0 —(0-7.5) Saracci et al., 1991 IARC cohort 30 1.1 (0.8-1.6) Burmeister, 1981 Iowa farmers 1,138 1.1 (p<.01) Morrison et al., 1993 Canadian farmers Age 45-69 years, no employees, or custom workers, sprayed ³250 acres 20 2.2 (1.3-3.8) Ronco et al., 1992 Danish self-employed farm workers 399 0.9 (p<.05) Wiklund, 1983 Swedish agricultural workers 3,890 1.0 (0.9-1.0)b Blair, 1983 Florida pesticide applicators 2 0.5 Swaen et al., 1992 Dutch herbicide applicators 1 1.3 (0.0-7.3) Solet et al., 1989 Paper and pulp workers 4 1.1 (0.3-2.9) Robinson et al., 1986 Paper and pulp workers 17 1.2 (0.7-2.0) Henneberger et al., 1989 Paper and pulp workers 9 1.0 (0.7-2.0) Asp et al., 1994 Finnish herbicide applicators 5 0.8 (0.3-1.8) Bueno de Mesquita et al., 1993 Dutch Production Workers 3 2.6 (0.5-7.7) Blair et al., 1993 Farmers in 23 states -whites 3,765 1.2 (1.1-1.2)   -nonwhites 564 1.1 (1.1-1.2) Collins et al., 1993 Monsanto 2,4-D production workers 9 1.6 (0.7-3.0) Case-control studies Burmeister et al., 1983 Iowa residents   1.2 (p<.05) Alavanja et al., 1988 USDA agricultural extension agents   1.0 (0.7-1.5) Alavanja et al., 1989 USDA forest conservationists   1.6 (0.9-3.0)   Soil conservationists   1.0 (0.6-1.8) Environmental Bertazzi et al., 1993 Seveso male residents - Zone R 16 0.9 (0.5-1.5) Pesatori et al., 1992 Seveso male residents - Zones A and B 4 1.4 (0.5-3.9)

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--> Reference Study Population Exposed Casesa Estimated Risk (95% CI)a Vietnam veterans Breslin et al., 1988 Army Vietnam veterans 30 0.9 (0.6-1.2)   Marine Vietnam veterans 5 1.3 (0.2-10.3) Anderson et al., 1986b Wisconsin Vietnam veterans 2   Visintainer et al., 1995 Michigan Vietnam veterans 19 1.1 (0.6-1.7) a Given when available. b 99% CI. 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 prostate 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. Renal, Bladder, And Testicular Cancers Background Genitourinary cancers include renal (kidney), bladder, and testicular cancer, as well as prostate cancer. Cancers of the female reproductive organs are discussed in the section on female reproductive cancers. According to the American Cancer Society, approximately 50,500 new cases of bladder cancer (ICD-9 188.0-188.9) and 28,800 new cases of kidney and other urinary cancers (ICD-9 189.0, 189.1) were diagnosed in the United States in 1995, and some 11,200 and 11,700 men and women died of these cancers (ACS, 1995). These cases are slightly more common in men than in women. Unlike breast and cervical cancers, in situ bladder cancers, as well as invasive cancers, are included in these numbers (Miller et al., 1992). According to the committee's calculations, if veterans have rates similar to those of the U.S. population, 374 cases of bladder cancer and 307 cases of renal cancer were expected among male Vietnam veterans and 0.4 and 0.3, respectively, among female veterans in 1995. For the year 2000, the expected numbers are 777 cases of bladder cancer and 497 cases of renal cancer in male veterans and 0.7 cases and 0.6 cases, respectively, in female veterans. For testicular

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--> cancer, 117 cases were expected among male Vietnam veterans in 1995, and 86 cases are expected in the year 2000. Renal Cancer Summary of VAO Alavanja et al. (1988, 1989) found excess mortality due to renal cancer in studies of USDA agricultural extension agents (PMR = 2.0, CI 1.2-3.3) and forest and soil conservationists (PMR = 2.1, CI 1.2-3.3). In subsequent case-control studies of these deaths, comparing ''ever" versus "never" being an extension agent resulted in a relative risk of 1.7 (CI 0.9-3.3). The relative risk for being a soil conservationist was 2.4 (CI 1.0-5.9) and for being a forest conservationist was 1.7 (CI 0.5-5.5). Other studies of renal cancer have generally produced inconclusive results, in some cases because of small sample sizes. These include 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; Manz et al., 1991; Saracci et al., 1991), agricultural workers (Burmeister, 1981; Wiklund, 1983; Ronco et al., 1992), pesticide applicators (Blair, 1983), paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989), the Seveso population (Pesatori et al., 1992), and Vietnam veterans (Anderson et al., 1986a,b; Breslin et al., 1988; Kogan and Clapp, 1985, 1988; Clapp et al., 1991). Update of the Scientific Literature A PCMR study was performed using death certificate data from male and female farmers from 23 states (Blair et al., 1993). Occupational data were coded, based on information on the death certificates, and nonfarmers in each state were used as the comparison group. There were 522 deaths due to renal cancer in white males, six deaths in white females, 30 deaths in nonwhite males, and six in nonwhite females. The PCMR among white males was marginally elevated at 1.1 (CI 1.0-1.2). The PCMRs among the other three groups were not significantly different from 1.0. A case-control study of occupational risk factors and renal cell carcinoma included 365 cases identified from the Denmark Cancer Registry and from pathology records and 396 controls selected from the country's Central Population Registry (Mellemgaard et al., 1994). Detailed occupational histories were obtained, including exposure to herbicides and pesticides. Exposure histories were only considered positive if exposure had lasted more than one year. Based on 13 cases, the odds ratio for men for herbicide exposure was 1.7 (CI 0.7-4.3). Based on three cases, the odds ratio for herbicide exposure for women was 5.7 (CI 0.6-5.8). Because of the wide confidence limits, these data are highly uncertain. Two other occupational studies reported too few cases of renal cancer to

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--> provide substantial information on risk (Asp et al., 1994; Bueno de Mesquita et al., 1993). Cancer incidence during the first ten years after exposure to TCDD was investigated in the Seveso cohort (Bertazzi et al., 1993). There were no cases of renal cancer diagnosed in Zones A or B, the most heavily exposed areas. Based on ten cases of renal cancer in men in Zone R, the least exposed area, the relative risk was 0.9 (CI 0.4-1.7). Based on seven cases of renal cancer in women in Zone R, the relative risk was 1.2 (0.5-2.7). A PMR study examining causes of death among veterans on the state of Michigan's Vietnam-era Bonus list was recently reported (Visintainer et al., 1995). This study compared 3,364 Vietnam veterans with 5,229 age-matched veterans who served elsewhere. Based on 21 cases of renal cancer among Vietnam veterans, the PMR was 1.4 (0.9-2.2). Summary The studies reviewed since the publication of VAO indicate marginally positive results. They are not, however, significant enough to suggest any change in the committee's view that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and renal cancer. 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 renal 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. Bladder Cancer Summary of VAO For bladder cancer, Fingerhut et al. (1991) found a small excess in mortality in their study of chemical production workers exposed to TCDD. In the total cohort of 5,172 workers, there was an SMR of 1.6 (CI 0.7-3.0), based on nine cases. In workers with at least one year of employment and 20 years latency, there were four cases (SMR = 1.9, CI 0.5-4.8). Other studies of bladder cancer have produced inconclusive results. Occupational studies include studies of chemical production workers in the United States and other countries (Moses et al., 1984; Suskind and Hertzberg, 1984; Bond et al., 1988; Zober et al., 1990; Saracci et al., 1991), agricultural and forestry workers (Burmeister, 1981;