Veterans and Agent Orange Update 1998 (1999) / Chapter Skim
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7 Cancer
7 Cancer
Pages 265-406
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From page 265... ...
Appendix B lists ICD.9 codes for the major forms of cancer. In assessing a possible relation between herbicide exposure and risk of cancer, one key issue is the level of exposure of those included in a study.
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From page 266... ...
Prostate cancer incidence, for example, is 14 times higher in men age 55-59 than in 45-49 year olds and nearly twice as high in African Americans age 45-59 than in whites of this age group (NCI, 1998~. The figures presented for each cancer are estimates for the entire U.S.
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From page 267... ...
Collectively, GI tract tumors are expected to account for 15 percent of new diagnoses and 18 percent of cancer deaths in 1998. Average Annual Cancer Incidence (per 100,000 individuals)
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From page 268... ...
(1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides.
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From page 269... ...
(1996) examined cancer mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols.
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From page 270... ...
, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential polychlorinated dibenzodioxin (PCDD)
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From page 271... ...
and long latency (37 percent of deaths observed beyond the age of 80~. It is limited by very crude exposure assessment, however, and the degree to which the study subjects were actually exposed to phenoxy herbicides cannot be established with any certainty.
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From page 272... ...
Direct exposure information on the two cohorts was not available, and the presumption that Vietnam veterans had potential for higher levels of dioxin exposure because of their duties involving Agent Orange and other dioxin-contaminated herbicides (compared to non-Vietnam Chemical Corps veterans) has not been verified.
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From page 273... ...
The study authors have described the strengths and limitations of this cohort study of Australian veterans, including virtually complete identification of the study population, a period of follow-up ranging from 22 to 32 years, and vital status ascertainment of 96.9 percent. Among the weaknesses of the study are the possibility of underascertainment of death and the uncertain quality of exposure assessment regarding a variety of risk factors, including smoking and alcohol consumption, as well as herbicide and dioxin exposure.
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From page 274... ...
1986 Robinson et al., 1986 Danish male self-employed farm workers 286 Dutch herbicide applicators NIOSH cohort German production workers IARC cohort Canadian farmers BASF production workers basic cohort USDA forest/soil conservationists Paper and pulp workers Paper and pulp workers USDA agricultural extension agents Dow 2,4-D production workers Flavor and fragrance chemical production workers British MCPA production workers Paper and pulp workers 0.9 0.5 (0_2.7)
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From page 275... ...
58 1.0 (0.8-1.3) Svensson et al., 1995 Males zone A Males zone B Males zone R Females zone A Females zone B Females zone R Swedish fishermen mortality East coast West coast Swedish fishermen incidence East coast West coast Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso male residents zone B 7 Female residents zone B 2 Seveso male residents zone R 45 Female residents zone R 25 1.4 (0.8-2.2)
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From page 276... ...
farmers in 23 states White males Bueno de Mesquita et al., Phenoxy herbicide workers 1993 Collins et al., 1993 Studies reviewed in VAO Swaen et al., 1992 Ronco et al., 1992 Fingerhut et al., 1991 Manz et al., 1991 Saracci et al., 1991 Zober et al., 1990 Alavanja et al., 1989 Henneberger et al., 1989 Solet et al., 1989 Alavanja et al., 1988 Bond et al., 1988 Thomas, 1987 Coggon et al., 1986 Hoar et al., 1986 1.0 (0.9-1.0) NS Monsanto 2,4-D production workers Dutch herbicide applicators 4 Danish male self-employed farm workers 277 NIOSH cohort German production workers IARC cohort BASF production workers basic cohort USDA forest conservationists USDA soil conservationists Paper and pulp workers Paper and pulp workers USDA agricultural extension agents Dow 2,4-D production workers 4 Flavor and fragrance chemical production workers British MCPA production workers 19 Kansas residents No herbicide use Herbicide use NS 2.6 (0.7-6.5)
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From page 277... ...
ENVIRONMENTAL New studies Bertazzi et al., 1997 Svensson et al., 1995 Seveso male residents zone A zone B zone R Seveso female residents zone A zone B zone R Swedish fishermen mortality East coast West coast Swedish fishermen incidence East coast West coast Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso male residents zone B 2 Female residents zone B 2 Seveso male residents zone R 32 Female residents zone R 23 Studies reviewed in VAO Lampi et al., 1992 Bertazzi et al., 1989a Pesatori et al., 1992 o 5 0.8 (0.3-2.0)
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From page 278... ...
TABLE 7-3 Selected Epidemiologic Studies Rectal Cancer Estimated Exposed Risk Reference Study PopulationCasesa (95% CI) a OCCUPATIONAL New studies Kogevinas et al., 1997 IARC cohort Workers exposed to TCDD (or higher chlorinated dioxins)
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From page 279... ...
Lynge, 1985 Danish male production workers14 1.5 Blair, 1983 Florida pesticide applicators2 1.0 Wiklund, 1983 Swedish agricultural workers1,083 o.g (o.g_l.o) b ENVIRONMENTAL New studies Bertazzi et al., 1997 Svensson et al., 1995 Seveso male residents zone A zone B zone R Seveso female residents zone A zone B zone R Swedish fishermen mortality East coast West coast Swedish fishermen incidence East coast West coast Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso male residents zone B Female residents zone B Seveso male residents zone R Female residents zone R Studies reviewed in VAO Pesatori et al., 1992 Bertazzi et al., 1989a Bertazzi et al., 1989b VIETNAM VETERANS New studies Crane et al., 1997a Crane et al., 1997b Studies reviewed in VAO Anderson et al., 1986a Anderson et al., 1986b 7 2.9 (1.2-5.9)
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From page 280... ...
farmers in 23 states White males Bueno de Mesquita et al., Phenoxy herbicide workers 1993 Studies reviewed in VAO Ronco et al., 1992 Swaen et al., 1992 Fingerhut et al., 1991 Saracci et al., 1991 Alavanja et al., 1989 Henneberger et al., 1989 Solet et al., 1989 Alavanja et al., 1988 Thomas, 1987 Coggon et al., 1986 Robinson et al., 1986 Lynge, 1985 Blair, 1983 Wiklund, 1983 Burmeister, 1981 ENVIRONMENTAL New studies Bertazzi et al., 1997 1,133 1.1 (1.1-1.2) NS Danish self-employed male farm workers 137 Dutch herbicide applicators 3 NIOSH cohort 10 NIOSH cohort 26 USDA forest conservationists USDA soil conservationists Paper and pulp workers Paper and pulp workers USDA agricultural extension agents 21 Flavor and fragrance chemical production workers British MCPA production workers Paper and pulp workers Danish male production workers Florida pesticide applicators Swedish agricultural workers Farmers in Iowa Seveso residents Males zone A Males zone B 0.6 (p < .05)
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From page 281... ...
Anderson et al., 1986b Wisconsin Vietnam veterans 4 a Given when available. b 99% CI and its contaminant TCDD, cacodylic acid, and picloram)
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From page 282... ...
According to American Cancer Society estimates, 9,300 men and 4,600 women will be diagnosed with liver cancer in the United States in 1998; 7,900 men and 5,100 women will die from the disease (ACS, 1998~. Liver cancer is expected to account for about 1 percent of new diagnoses and 2 percent of cancer deaths in the United States in 1998.
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From page 283... ...
Environmental Studies A follow-up of the population involved in the Seveso incident (Bertazzi et al., 1989b and Bertazzi et al., 1993) reported a statistically significant excess in liver cancer mortality for female residents of zone B (RR = 3.3, CI 1.3-8.1~.
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From page 284... ...
(1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides.
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From page 285... ...
East and west coast fishermen were found to have nonsignificantly decreased mortality from liver cancer. East coast fishermen had a nonsignificantly increased incidence of liver cancer (SIR = 1.31, CI 0.48-2.85, 6 cases)
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From page 286... ...
Among the weaknesses of the study are the possibility of underascertainment of death, and uncertain quality of exposure assessment regarding a variety of risk factors, including smoking and alcohol consumption, as well as herbicide and dioxin exposure. The examination of mortality among Australian National Service Vietnam veterans (Crane et al., 1997b)
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From page 287... ...
2 1.4 (0.2-5.2) 20 years latency IARC cohort Paper and pulp workers Dow 2,4-D production workers Danish production workers Male residents of northern Sweden Swedish agricultural workers Monsanto production workers Seveso male residents zone A zone B zone R Seveso female residents zone A zone B zone R 23 0.4 9 0.8 5 0.5 6 1.2 (0.4-2.5)
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From page 288... ...
A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and hepatobiliary cancer is contained in Chapter 3; a summary is presented in the conclusion to this chapter. NASAL/NASOPHARYNGEAL CANCER Background There are many types of nasal (ICD-9 160.0-160.9)
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From page 289... ...
There are also serous and mucous glands and lymphoid aggregates in close association with the epithelium. The American Cancer Society estimates that approximately 4,100 men and 1,200 women will be diagnosed with nasal, pleural, tracheal, and other respiratory system cancers in the United States in 1998 and that some 700 men and 500 women will die from the diseases (ACS, 1998~.
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From page 290... ...
This cohort contains 26,976 workers and was divided into those who were exposed to TCDD or higher chlorinated dioxins and those who were not so. The combined cohort study showed no effect of phenoxy herbicide exposure on oral cavity and pharyngeal cancers (26 cases coded ICD.9 140-149)
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From page 291... ...
Coggon et al., 1986 British MCPA production workers 3 4.9 (1.0-14.4) Robinson et al., 1986 Paper and pulp workers 0 Wiklund, 1983 Swedish agricultural workers 64 0.8 (0.6-1.2)
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From page 292... ...
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 A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and nasal or nasopharyngeal cancer is contained in Chapter 3; a summary is presented in the conclusion to this chapter.
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From page 293... ...
There is no information on alcohol consumption in any of the studies. Other than these studies of production workers, only one study reported separate results for cancer of the larynx: a proportional cancer mortality ratio (PCMR)
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From page 294... ...
based on 12 laryngeal cancer deaths. A second study examining the TABLE 7-7 Selected Epidemiologic Studies Laryngeal Cancer Estimated Exposed Risk Reference Study PopulationCasesa (95% CI)
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From page 295... ...
The committee concluded 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 and types of exposure and because the most important risk factors for laryngeal cancers cigarette smoking and alcohol consumption were not fully controlled for or evaluated in the studies. Conclusions Strength of Evidence in Epidemiologic Studies 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)
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From page 296... ...
The rate for AfricanAmerican males is consistently higher than for females or white males. The American Cancer Society estimates that more than 90 percent of lung cancers in males are the result of tobacco smoking (ACS, 1998~.
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From page 297... ...
Employment on the farm was used as a surrogate for exposure to the range of phenoxy herbicides including 2,4D and 2,4,5-T. Researchers reported an SMR for lung cancer of 0.8 (CI 0.6-1.1)
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From page 298... ...
, 11 lung cancer deaths among Vietnam units were found, compared to 3 among units not in Vietnam, for an RR of 1.4 (CI 0.4-5.4~. A case-control study of lung cancer mortality in Vietnam veterans (Mahan et al., 1997)
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From page 299... ...
The primary evidence comes from studies of individuals occupationally exposed to phenoxy herbicides. Although studies show an increase in lung cancer among Vietnam veterans in the United States and Australia, the lack of information regarding herbicide exposure and cigarette smoking limits their usefulness.
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From page 300... ...
farmers in 23 states White males Nonwhite males Dow 2,4-D production workers Female herbicide sheaving and Bloemen et al., 1993 Kogevinas et al., 1993 production workers Lynge, 1993 Danish male production workers Studies reviewed in VAO Bueno de Mesquita et al., Phenoxy herbicide workers 45 0.8 (0.6-1.1)
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From page 301... ...
0.7 (0.5-0 9) Seveso residents zone A males zone A females zone B males zone B females zone R males zone R females Swedish fishermen mortality East coast West coast Seveso residents first ten years after accident zone A males zone A females zone B males zone B females zone R males zone R females Australian military veterans Australian national service veterans Army Chemical Corps Veterans Case-control Vietnam service Army Non-Vietnam Vietnam service Marines Non-Vietnam Vietnam service Marines v.
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From page 302... ...
in the United Statesa Bone and Joint Cancer 50-54 years of age all races white black 45~9 years of age all races white black 55-59 years of age all races white black males 1.0 1.1 0.3 0.8 0.8 0.4 1.2 1.2 1.1 females 0.5 0.5 0.5 0.6 0.6 0.4 0.7 0.6 0.4 a SEER nine standard registries crude, age-specific rate, 1990-1994. Summary of VAO and Update 1996 Studies of bone cancer and herbicide exposure have included chemical production workers (Coggon et al., 1986; Bond et al., 1988; Zober et al., 1990; Fingerhut et al., 1991; Collins et al., 1993~; agricultural workers (Burmeister, 1981; Wiklund, 1983; Ronco et al., 1992; Blair et al., 1993~; and Vietnam veterans (Lawrence et al., 1985; Anderson et al., 1986a,b; Breslin et al., 1988~.
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From page 303... ...
Hertzman's study of 26,000 Canadian sawmill workers presumptively exposed to dioxin-contaminated chlorophenate (Hertzman et al., 1997) reported five bone cancer deaths, with an SMR of 1.3 (CI 0.5-2.7~.
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From page 304... ...
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 A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and bone cancer is contained in Chapter 3; a summary is presented in the conclusion to this chapter.
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From page 305... ...
Workers exposed to TCDD (or higher chlorinated dioxins) 1.1 Workers not exposed to TCDD (or higher chlorinated dioxins)
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From page 306... ...
Several chemical exposures have also been identified as possible risk factors (Zahm and Fraumeni, 1997~. Average Annual Cancer Incidence (per 100,000 individuals)
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From page 307... ...
Detailed exposure reconstruction was performed for all cases of STS and a set of controls by a team of industrial hygienists who did not know case or control status (Kauppinen et al., 1994~. The team estimated cumulative exposures to TCDD and numerous phenoxy herbicides and related chemicals.
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From page 308... ...
The SMR was essentially unchanged when the cohort was restricted to workers exposed to TCDD or higher chlorinated dioxins, although this was based on six deaths (CI 0.8-4.4~. Workers not exposed to TCDD had an SMR of 1.35, based on two deaths.
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From page 309... ...
In this subgroup, the SMR was 2.1 (CI 0.6-5.4~. Svensson's study of cancer incidence and mortality among approximately 11,400 Swedish fishermen (Svensson et al., 1995)
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From page 310... ...
Because soft-tissue sarcomas are rare, it is difficult to discern whether the small increases in the number of cases observed in these studies are due to dioxin TABLE 7-10 Selected Epidemiologic Studies All (or unspecified) Skin Cancer Mortality Estimated Exposed Risk Reference Study PopulationCasesa (95% CI)
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From page 311... ...
and those that do not. The common nonmelanocytic skin cancers, which include basal cell and squamous cell carcinomas, have a far higher incidence rate than malignant melanoma but are considered less aggressive and therefore more treatable.
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From page 312... ...
, primarily basal cell and squamous cell carcinomas, are diagnosed in the United States each year (ACS, 1998~. The American Cancer Society estimates that 1,200 men and 700 women will die from these diseases in 1998.
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From page 313... ...
Certain skin diseases and chemical exposures have also been identified as potential risk factors. SEER incidence data are not available for nonmelanocytic skin cancers.
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From page 314... ...
of production workers exposed to phenoxy herbicides, chlorophenols, and dioxins reported no increased risk of malignant melanoma among workers exposed to phenoxy herbicides contaminated with TCDD or higher chlorinated dioxins (SMR = 0.5, CI 0.2-3.2) , or among workers with exposure to phenoxy herbicides and chlorophenols but minimal or no exposure to TCDD or higher chlorinated dioxins (SMR = 1.0, CI 0.3-2.4~.
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From page 315... ...
These include a study of phenoxy herbicide production workers, with four cases of melanoma (Lynge, 1985) , and two Vietnam veteran studies.
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From page 316... ...
a OCCUPATIONAL New Studies Hertzman et al., 1997 Kogevinas et al., 1997 Sawmill workers IARC cohort Workers exposed to TCDD (or higher chlorinated dioxins) Workers not exposed to TCDD (or higher chlorinated dioxins)
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From page 317... ...
CYPlAl, a P450 isozyme under the control of the AhR, is expressed in the skin and has been linked to the development of skin cancer and skin sensitization by PAHs (Gonzalez et al., 1996~. Since TCDD toxicity is also mediated by the AhR, it is plausible that TCDD exposures could be associated with increased risk of melanoma.
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From page 318... ...
Since nonmelanocytic skin cancers are highly curable, studies of cancer incidence may be more helpful than mortality studies in evaluating the risk of basal and squamous cell skin cancers. A study of Danish farmers showed significantly reduced risk of these "other" skin cancers (Ronco et al., 1992~.
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From page 319... ...
of workers exposed to phenoxy herbicides, chlorophenols, and dioxins reported an SMR of 1.2 (CI 0.3-3.2) for nonmelanocytic skin cancer among workers exposed to phenoxy herbicides contaminated with TCDD or higher chlorinated dioxins, based on four cases.
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From page 320... ...
Since TCDD toxicity is also mediated by the AhR, it is plausible that TCDD exposures could be associated with increased risk of skin cancer. In VAO and Update 1996, an increased risk of mortality from nonmelanoma skin cancers was found among agricultural workers.
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From page 321... ...
Skin Cancer Mortality Reference Study Population Estimated Exposed Risk Casesa (95% CI) a OCCUPATIONAL New Studies Hertzman et al., 1997 Kogevinas et al., 1997 Sawmill workers IARC cohort Workers exposed to TCDD (or higher chlorinated dioxins)
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From page 322... ...
Since TCDD toxicity is also mediated by the AhR, it is plausible that TCDD exposures could be associated with increased risk of skin cancer. A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and skin cancer is contained in Chapter 3; a summary is presented in the conclusion to this chapter.
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From page 323... ...
a OCCUPATIONAL New Studies Zhong and Rafnsson, 1996 Icelandic pesticide users Svensson et al., 1995 Swedish fisherman East coast West coast Studies reviewed in VAO Ronco et al., 1992 Danish self-employed farmers ENVIRONMENTAL New Studies Gallagher et al., 1996 Alberta, Canada, residents Squamous cell Carcinoma All herbicide exposure Low herbicide exposure High herbicide exposure All fungicide exposure Low fungicide exposure High fungicide exposure Alberta, Canada, residents Basal cell Carcinoma All herbicide exposure All fungicide exposure Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso male residents zone A zone B zone R Studies reviewed in VAO Pesatori et al., 1992 VIETNAM VETERANS Studies reviewed in VAO Wolfe et al., 1990 5 2.8 (0.9-6.6)
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From page 324... ...
In the age groups that characterize most Vietnam veterans, the incidence for whites is slightly higher than for African Americans. Risk factors other than aging include a personal or family history of breast cancer and reproductive history (specifically, early onset of menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after 30 years of age)
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From page 325... ...
Among those female workers exposed to chlorophenoxy herbicides contaminated with TCDD (N= 169) , there was an excess overall cancer incidence, based on nine cases (SIR = 2.2, CI 1.0-4.2)
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From page 326... ...
and 2.6 for male breast cancers (CI 0.3-9.3) , for workers exposed to TCDD or higher chlorinated dioxins (Kogevinas et al., 1997~.
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From page 327... ...
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.
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From page 328... ...
farmers in 23 states Whites Nonwhites Kogevinas et al., 1993 Studies reviewed in VAO Ronco et al., 1992 Manz et al., 1991 Saracci et al., 1991 Lynge, 1985 Wiklund, 1983 ENVIRONMENTAL New Studies Bertazzi et al., 1997 Seveso female residents, mortality zone A zone B zone R Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso female residents; follow-up of Bertazzi et al., 1989b zone A zone B zone R Female herbicide spraying and production workers Probable exposed to TCDD Danish family farm workers 429 German production workers IARC cohort Danish production workers 1 Swedish agricultural workers 444 Studies reviewed in VAO Bertazzi et al., 1989b VIETNAM VETERANS New Studies Crane et al., 1997a Australian military veterans Studies reviewed in Update 1996 Dalager et al., 1995a Women Vietnam veterans Studies reviewed in VAO Thomas et al., 1991 Women Vietnam veterans Seveso female residents zone B zone R 9 2.2 (1.0-4.1)
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From page 329... ...
A more thorough discussion of TCDD's antiestrogenic properties and of the effect of TCDD or herbicides on breast cells is contained in Chapter 3; a summary discussion of biologic plausibility is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans Studies in female Vietnam veterans have not shown an elevated risk of breast cancer, but the length of follow-up may not have been sufficient for an effect, if it exists, to become evident.
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From page 330... ...
the least contaminated area, was 1.1 (CI 0.7-1.7~. A cohort study of cancer incidence was conducted among employees of two phenoxy herbicide manufacturing facilities in Denmark (Lynge, 1993~.
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From page 331... ...
Cancer mortality rates among 4,586 female Vietnam veterans were recently evaluated, as well as rates among 5,325 female veterans who had served elsewhere (Dalager et al., 1995a)
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From page 332... ...
The committee concludes that more research is needed on populations of women with documented exposure to herbicides and TCDD. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides used in Vietnam (2,4-D, 2,4,5-T and its TABLE 7-17 Selected Epidemiologic Studies Cancers of the Cervix Reference Study Population Estimated Exposed Risk Cases (95% CI)
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From page 333... ...
farmers in 23 states Whites15 1.2 Nonwhites17 1.4 Ronco et al., 1992 Danish farmers Self-employed farmers8 0.6 Family workers103 0.8 Employees9 0.9 Wiklund, 1983 Swedish agricultural workers135 0.9 ENVIRONMENTAL New Studies Bertazzi et al., 1997 Seveso residents0 0.0 VIETNAM VETERANS Studies reviewed in Update 1996 Dalager et al., 1995a Women Vietnam veterans 4 2.1 (0.6-5.4) TABLE 7-19 Selected Epidemiologic Studies Ovarian Cancer Estimated Exposed Risk Reference Study Population Cases (95% CI)
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From page 334... ...
This makes prostate cancer the most common cancer among men, excluding nonmelanocytic skin cancers. It is expected to account for approximately 29 percent of new diagnoses and 13 percent of cancer deaths in 1998.
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From page 335... ...
Based on 564 deaths from prostate cancer in nonwhite male farmers, out of 11,446 studied, the PCMR was also significantly increased to 1.1 (CI 1.1-1.2~. This increased risk for prostate cancer was observed in 22 of the 23 states studied.
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From page 336... ...
, the RR was 0.9 (CI 0.5-1.5~. Vietnam Veteran Studies Studies of prostate cancer mortality among Vietnam veterans have not consistently shown an association (Anderson et al., 1986a,b; Breslin et al., 1988~.
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From page 337... ...
None of these provides strong evidence of increased risk for prostate cancer. The smallest study involved 243 workers exposed during and after a 1953 reactor accident in a West German plant that produced trichlorophenol (Ott and Zober, 1996~.
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From page 338... ...
The SIR for prostate cancer was 1.0 (CI 0.9-1.1~. Although data were collected on sawmill workers not exposed to chlorophenates, the size of this unexposed group was much smaller than for exposed workers, and data were not presented on its prostate cancer incidence or mortality that would have enabled internal comparisons to be made for prostate cancer.
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From page 339... ...
Additional agricultural studies published since Update 1996, one on rice growers in northern Italy and the other on Icelandic pesticide users, show no evidence of increased risk of prostate cancer, although it should be noted that exposure information was poor and both cohorts demonstrated a rather strong healthy worker effect. The earlier major studies of production workers (Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991)
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From page 340... ...
In the cohort study of Australian male veterans, which had a much stronger design, an elevated rate of prostate cancer mortality was observed among those who served in Vietnam (SMR = 1.5, CI 1.1-2.1, based on 36 prostate cancer deaths)
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From page 341... ...
farmers in 23 states Whites Nonwhites Bueno de Mesquita et al., 1993 Collins et al., 1993 Studies reviewed in VAO Morrison et al., 1993 Ronco et al., 1992 Swaen et al., 1992 Fingerhut et al., 1991 Manz et al., 1991 Saracci et al., 1991 Zober et al., 1990 Alavanja et al., 1989 Henneberger et al., 1989 Solet et al., 1989 Alavanja et al., 1988 Bond et al., 1988 Coggon et al., 1986 Robinson et al., 1986 Lynge, 1985 Blair et al., 1983 Burmeister et al., 1983 Wiklund, 1983 Burmeister, 1981 5 0.8 (0.3-1.8) Dutch production workers Monsanto 2,4-D production workers Canadian farmers, age 45-69 years, no employees, or custom workers, sprayed 2250 acres Danish self-employed farm workers Dutch herbicide applicators NIOSH cohort 20 year latency, 1 year exposure German production workers IARC cohort BASE production workers USDA forest conservationists Soil conservationists Paper and pulp workers Paper and pulp workers USDA agricultural extension agents Dow 2,4-D production workers British MCPA production workers Paper and pulp workers Danish production workers Florida pesticide applicators Iowa residents Swedish agricultural workers 3,890 Iowa farmers 1,138 3,765 1.2 (1.1-1.2)
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From page 342... ...
The evidence regarding association is drawn from occupational studies in which subjects were exposed to a variety of herbicides and herbicide components and is also based on data from studies of Vietnam veterans. An important consideration is the fact that prostate cancer tends not to be fatal; thus, mortality studies have lower statistical power to detect a comparable effect than a similar-sized morbidity study would have.
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From page 343... ...
The statistically significantly elevated prostate cancer SMR for Australian male Vietnam veterans suggests that U.S. Vietnam veterans may be at increased risk.
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From page 344... ...
These include studies of chemical production workers in the United States and other countries (Bond et al., 1988; Saracci et al., l991~; agricultural workers (Wiklund, 1983; Ronco et al., 1992; Blair et al., 1993~; residents of Seveso (Pesatori et al., 1992; Bertazzi et al., 1993~; 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 Occupational Studies The IARC study (Kogevinas et al., 1997)
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From page 345... ...
Residents zone R 9 1.5 (0.7-3-0) VIETNAM VETERANS New Studies Clapp, 1997 Crane et al., 1997a Crane et al., 1997b Dalager and Kang, 1997 Army Chemical Corps veterans 2 Watanabe and Kang, 1996 Vietnam service Army Vietnam service Marines Studies reviewed in Update 1996 Bullman et al., 1994 Navy veterans Studies reviewed in VAO Tarone et al., 1991 Massachusetts Vietnam veterans .
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From page 346... ...
Conclusions Strength of Evidence in Epidemiologic Studies 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.
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From page 347... ...
(1991) found a small excess mortality in their study of chemical production workers exposed to TCDD.
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From page 348... ...
Occupational studies include 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; Alavanja et al., 1988, 1989; Green, 1991; Ronco et al., 1992; Blair et al., 1993~; pesticide appliers (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.
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From page 349... ...
A second study of the mortality experience of conscripted Australian veterans relative to military personnel who did not serve in the conflict reported a statistically significant RR of 0.6 based on one death among Vietnam veterans and two in the comparison population (Crane et al., 1997b)
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From page 350... ...
Incidence 94 1.0 (0.8-1.2) Kogevinas et al., 1997 IARC cohort Workers exposed to TCDD (or higher chlorinated dioxins)
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From page 351... ...
changed to "inadequate/insufficient evidence to determine whether an association exists." Biologic Plausibility A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and bladder cancer is contained in Chapter 3; a summary is presented in the conclusion to this chapter. RENAL CANCER Background Cancers of the kidney (ICD.9 189.0)
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From page 352... ...
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; Bueno de Mesquita et al., 1993; Asp et al., 1994~; agricultural workers (Burmeister, 1981; Wiklund, 1983; Ronco et al., 1992; Blair et al., 1993~; pesticide applicators (Blair, 1983~; paper and pulp workers (Robinson et al., 1986; Henneberger et al., 1989~; the Seveso population (Pesatori et al., 1992; Bertazzi et al., 1993~; and Vietnam veterans (Anderson et al., 1986a,b; Breslin et al., 1988; Kogan and Clapp, 1985, 1988; Clapp et al., l991~. Alavanja et al.
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From page 353... ...
for all workers exposed to any phenoxy herbicide or chlorophenol. In a study of 770 pentachlorphenol workers (Ramlow, 1996)
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From page 354... ...
Workers exposed to any phenoxy herbicide or chlorophenol Studies reviewed in Update 1996 Mellemgaard et al., 1994 Danish Cancer Registry patients Occupational herbicide exposure among males Occupational herbicide exposure among females U.S. farmers in 23 states White males Nonwhite males White females Nonwhite females Danish male self-employed farm workers NIOSH cohort German production workers IARC cohort USDA forest conservationists Soil conservationists Paper and pulp workers USDA agricultural extension agents Dow 2,4-D production workers Paper and pulp workers British MCPA production workers Danish male production workers Swedish agricultural workers Florida pesticide applicators Farmers in Iowa Blair et al., 1993 Studies reviewed in VAO Ronco et al., 1992 Fingerhut et al., 1991 Manz et al., 1991 Saracci et al., 1991 Alavanja et al., 1989 Henneberger et al., 1989 Alavanja et al., 1988 Bond et al., 1988 Robinson et al., 1986 Coggon et al., 1986 Lynge, 1985 Wiklund, 1983 Blair, 1983 Burmeister, 1981 26 1.6(1.1-2.4)
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From page 355... ...
However, although this result is mildly suggestive, because of the marginal significance, lack of trend data, and heterogeneity of the cohorts it is not strong enough to outweigh the equivocal results from other studies. Conclusions Strength of Evidence in Epidemiologic Studies In the judgment of the committee there is still 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)
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From page 356... ...
Several other potential factors have been examined, but the American Cancer Society notes that the majority of brain cancers are not associated with any known risk factors. Average Annual Cancer Incidence (per 100,000 individuals)
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From page 357... ...
(1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides.
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From page 358... ...
East coast fishermen were found to have nonsignificantly decreased mortality and incidence of brain cancer, whereas west coast fishermen had nonsignificantly decreased incidence and nonsignificantly increased mortality (SMR = 1.0, CI 0.6-1.7,15 deaths observed) compared to Swedish national rates In a comparison of mortality between Army Chemical Corps Vietnam and non-Vietnam veterans, Dalger and Kang (1997)
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From page 359... ...
Study authors have described the strengths and limitations of the Australian veterans cohort study, including virtually complete identification of the study population, a period of follow-up ranging from 22 to 32 years, and vital status ascertainment of 96.9 percent. Among the weaknesses of the study are the possibility of underascertainment of death and the uncertain quality of exposure assessment to a variety of risk factors, including smoking and alcohol consumption, as well as herbicide and dioxin exposure.
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From page 360... ...
Gambini et al., 1997 Italian rice growers4 0.9 (0.2-2.3) Becher et al., 1996 German chemical production workers Subcohort I3 2.3 (0.5-6.8)
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From page 361... ...
Boyle et al., 1987 Vietnam Experience Study3 Studies reviewed in VAO Thomas and Kang, 1990 Army Chemical Corps Vietnam veterans2 5.0 Breslin et al., 1988 Army Vietnam veterans116 1.0 (0.3-3.2) Marine Vietnam veterans25 1.1 (0.2-7.1)
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From page 362... ...
A number of behavioral, occupational, and environmental risk factors have also been proposed (Blair et al., 1997~. Average Annual Cancer Incidence (per 100,000 individuals)
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From page 363... ...
indicated no increased risk. Thus, unlike most of the other cancers studied in VAO, where the data did not distinguish between the effects of herbicides and TCDD, these data suggested that the phenoxy herbicides (including 2,4-D)
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From page 364... ...
Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with TCDD or higher chlorinated dioxins, mortality increased from all malignant neoplasms (SMR = 1.1,95% CI 1.0-1.2,710 deaths)
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From page 365... ...
However, exposures to herbicides nonsignificantly elevated the risk of only follicular NHL (farming exposure: OR = 1.1, CI 0.8-1.5; non-farming exposure: OR = 1.3, CI 0.8-1.9~. No variance from null was observed for the overall NHL cohort or for specific exposure to chlorophenoxy herbicides.
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From page 366... ...
Synthesis The recent scientific literature continues to support the conclusion of a positive association between exposure to herbicides and non-Hodgkin's lymphoma and provides a biological rationale that includes the possible interaction between environmental toxins such as phenoxyacid herbicides and oncogene abnormalities of bcl- 1 and bc1-2 found in follicular NHL, a tumor that is sharply increasing in incidence in Western countries. Conclusions Strength of Evidence in Epidemiologic Studies Evidence continues to accumulate to conclude of a positive association between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram)
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From page 367... ...
Dow 2,4-D production workers2 Dutch production workers Workers exposed to phenoxy herbicides 2 Danish male production workers10 Swedish NHL patients Exposure to phenoxy herbicides Occupation as a lumberjack Females in eastern Nebraska farms IARC cohort Workers exposed to any phenoxy herbicide or chlorophenol Asp et al., 1994 Dean, 1994 Hardell et al., 1994 Morrison et al., 1994 Blair et al., 1993 Bloemen et al., 1993 Bueno de Mesquita et al., 1993 Lynge, 1993 Persson et al., 1993 Zahm et al., 1993 Kogevinas et al., 1992 Studies reviewed in VAO Hansen et al., 1992 Danish gardeners men and women 164 1.8 (1.2-2.6)
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From page 368... ...
Woods et al., 1987 Male residents of Washington State Phenoxy herbicide use 1.1 (0.~-1.4) Chlorophenol use 1.0 (0.8-1.2)
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From page 369... ...
CANCER TABLE 7-25 Continued 369 Reference Study Population Male residents of New Zealand Agricultural sprayers Male residents of New Zealand Agricultural occupations, ages 20-64 Iowa residents Farmers Farmers in 33 counties with highest herbicide use: Born before 1890 Born 1890-1900 Born after 1900 Exposed Casesa Estimated Risk (95% CI) a Pearce et al., 1986b Pearce et al., 1985 Burmeister et al., 1983 Riihimiki et al., 1983 Wiklund, 1983 Cantor, 1982 Hardell et al., 1980 Finnish herbicide applicators Swedish agricultural workers Wisconsin residents Umea Hospital patients Exposed to phenoxy acids Exposed to chlorophenols ENVIRONMENTAL New Studies Bertazzi et al., 1997 Seveso residents Males in zone B Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents Males in zone B Females in zone B Males in zone R Females in zone R Studies reviewed in VAO Lampi et al., 1992 Pesatori et al., 1992 Bertazzi et al., 1989b gc 1.5 (0.7-3.3)
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From page 370... ...
Marine Vietnam veterans (service 1967-1969) Australian Vietnam veterans Wisconsin Vietnam veterans Wisconsin Vietnam veterans compared to Wisconsin nonveterans 370 TABLE 7-25 Continued VETERANS AND AGENT ORANGE: UPDATE 1998 Reference VIETNAM VETERANS New Studies Crane et al., 1997a Australian military veterans Watanabe and Kang, 1996 Marine Vietnam veterans Studies reviewed in Update 1996 Visintainer et al., 1995 Michigan Vietnam veterans Studies reviewed in VAO Clapp et al., 1991 Dalager et al., 1991 O'Brien et al., 1991 Thomas et al., 1991 Watanabe et al., 1991 Study Population Exposed Casesa Estimated Risk (95% CI)
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From page 371... ...
According to American Cancer Society estimates, 3,700 men and 3,400 women will be diagnosed with the disease in the United States in 1998, and 700 men and an equal number of women will die from it (ACS, 1998)
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From page 372... ...
As with NEIL, 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 significant.
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From page 373... ...
Although not as clearly demonstrated as for NHL, biologic plausibility also exists for a positive association between TCDD and the development of HD due to their common lymphoreticular origin and association with common risk factors.
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From page 374... ...
Studies reviewed in VAO Eriksson et al., 1992 Swedish Cancer Registry patients Male sawmill workers 10 2.2 Male farmers 97 1.2 Male forestry workers 35 1.2 Male horticulture workers 11 1.2 Ronco et al., 1992 Danish and Italian farm workers Swaen et al., 1992 Fingerhut et al., 1991 Green, 1991 Saracci et al., 1991 Zober et al., 1990 Alavanja et al., 1989 Male Danish farmers self-employed 27 Male Italian farmers self-employed Male Italian farmers employees Male Italian farmers self-employed and employees Female Italian farmers self-employed Dutch herbicide applicators NIOSH cohort 20 years latency, 1+ years exposure 1 Herbicide sprayers in Ontario IARC cohort BASE production workers USDA forest/soil conservationists 0.6 10 2.9 1 0.4 1.9 1.9 3.3 3 1.2 (0.3-3.5)
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From page 375... ...
Exposed to low-grade chlorophenols5 2.4 (0.9-6.5) Riihimaki et al., 1983 Finnish herbicide applicators0 Wiklund, 1983 Swedish agricultural workers226 1.0 (0.9-1.2)
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From page 376... ...
men born between 1921 and 1953 Vietnam veterans Army Vietnam veterans Marine Vietnam veterans Air Force Vietnam veterans Navy Vietnam veterans Air Force Ranch Hand veterans mortality Army Vietnam veterans compared to Vietnam-era Army veterans Marine Vietnam veterans compared to Marine Vietnam-era veterans Vietnam Experience Study Australian Vietnam veterans Wisconsin Vietnam veterans compared to Wisconsin nonveterans Wisconsin Vietnam veterans compared to non-Vietnam-era veterans Wisconsin Vietnam veterans compared to Vietnam-era veterans Wisconsin Vietnam veterans West Virginia Vietnam veterans compared to West Virginia Vietnamera veterans New York Vietnam veterans compared to New York Vietnam-era veterans 116 1.0 25 1.9 116 1.1 25 1.0 28 12 4 5 7 o 1.2 (0.7-2.4)
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From page 377... ...
Evidence regarding other risk factors is mixed. Average Annual Cancer Incidence (per 100,000 individuals)
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From page 378... ...
(1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides.
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From page 379... ...
No direct exposure information was available, so employment on the farm was used as a surrogate for exposure to the range of phenoxy herbicides employed during the study period. Cancer mortality was evaluated for MM and observed and expected deaths were O and 1.9 for the overall cohort (SMR = 0.0, CI 0.0-2.0~.
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From page 380... ...
It is limited by crude exposure assessment, however, and the degree to which study subjects were actually exposed to phenoxy herbicides can not be established with any certainty. Environmental Studies Bertazzi et al.
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From page 381... ...
1.2 (0.6-2.3 Workers not exposed to TCDD (or higher chlorinated dioxins) 1.6 (0.7-3.1 Workers exposed to any phenoxy herbicide or chlorophenol17 1.3 (0.8-2.1)
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From page 382... ...
a LaVecchia et al., 1989 Morris et al., 1986 Pearce et al., 1986 Cantor and Blair, 1984 Burmeister et al., 1983 Riihimaki et al., 1983 ENVIRONMENTAL New Studies Bertazzi et al., 1997 Seveso residents zone B female Studies reviewed in Update 1996 Bertazzi et al., 1993 Seveso residents zone A male zone A female zone B male zone B female zone R male zone R female Finnish herbicide applicators Studies reviewed in VAO Pesatori et al., 1992 Seveso residents Males zones A and B Female zones A and B Males zone R Females zone R VIETNAM VETERANS New Studies Crane et al., 1997a Australian military veterans Crane et al., 1997a Australian military veterans Watanabe and Kang, 1996 Army Vietnam veterans Marine Vietnam veterans Studies reviewed in VAO Breslin et al., 1988 Army Vietnam veterans Marine Vietnam veterans 2.0 (1.1-3.5)
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From page 383... ...
According to American Cancer Society estimates, 16,100 men and 12,600 women will be diagnosed with some form of the disease in the United States in 1998, and 12,000 men and 9,600 women will die from it (ACS,1998~. Collectively, leukemias are expected to account for slightly more than 2 percent of all new cancer diagnoses and nearly 4 percent of cancer deaths in 1998.
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From page 384... ...
White males have a higher incidence that white females; the lifetime incidence in African-American males and females is roughly equal. Risk factors associated with an increased risk of AML include high doses of ionizing radiation, occupational exposure to benzene, and some medications used in cancer chemotherapy (melphalan, for example)
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From page 385... ...
The available data on Vietnam veterans are generally not conclusive, because exposure data were inadequate for the cohort being studied. Small sample sizes weaken the studies of the Ranch Hand or Chemical Corps veterans; therefore, excess risks were not likely to be detected.
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From page 386... ...
(1997) examined cancer mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides.
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From page 387... ...
Leukemia was not included in the more detailed analysis by the four categories of cumulative exposure. Agricultural Workers Cancer mortality among a cohort of rice growers in northern Italy was investigated by Gambini et al.
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From page 388... ...
Finally, because of the availability of information on lifestyle risk factors that had been collected in the 1960s on all participants, a nested case-control study was implemented. A significantly increased risk for males and females combined was demonstrated in the incidence of lymphopoietic neoplasms, namely, NHL, HD, and CLL; the combined SIR was 1.4 (95% CI 1.001.9; p = .03~.
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From page 389... ...
Synthesis As in VAO and Update 1996, the studies reviewed in this report found a small number of cases of leukemia, and it is apparent that the risks associated with herbicide exposure are fairly evenly distributed around the null, with relatively narrow confidence intervals. Some data on agricultural workers suggest an increased risk for all hematopoietic neoplasms (including NEIL and MM, as well
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From page 390... ...
Biologic plausibility would suggest an association of risk for hematopoietic and lymphoreticular malignancies, as would the Biologic similarity of CLL and NHL; however, the overall incidence and small number of positive studies are inadequate to change the previous classification. Conclusion 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)
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From page 391... ...
Kogevinas et al., 1993 Female herbicide spraying and production workers1 Studies reviewed in VAO Bueno de Mesquita Dutch production workers et al., 1993 Workers exposed to phenoxy herbicides2 2.2 (0.3-7.9) Hansen et al., 1992 Danish gardeners All gardeners CLL6 2.5 (0.9-5.5)
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From page 392... ...
and R Females zones A, B and R VIETNAM VETERANS New Studies Dalager and Kang, 1997 Crane et al., 1997a Army Chemical Corps veterans Australian military veterans Studies reviewed in Update 1996 Visintainer et al., 1995 Michigan Vietnam veterans 138 0.9 (0.7-1.0)
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From page 393... ...
, nasal and nasopharyngeal cancer, bone cancer, skin cancers (including basal cell carcinoma, squamous cell carcinoma, and nonmelanocytic skin cancers) , breast cancer, cancers of the female reproductive system (including cervix, endometrium, and ovaries)
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From page 394... ...
In studies in which liver cancer incidence was enhanced, other adverse changes in the ~ i~ver were observed. Decreased rates of some cancers including those of the uterus; pancreas; and pituitary and mammary glands were also reported.
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From page 395... ...
This also suggests that TCDD tumor promotion may be due to interference with gap junctional intercellular communications. Controversy exists about the TCDD exposure levels required to induce adverse health outcomes.
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From page 396... ...
may induce DNA modifications that sensitize it to free radical injury, whereas another study concluded that it is a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats. In particular, cacodylic acid may promote rat urinary bladder carcinogenesis by stimulating cell proliferation in the urinary bladder epithelium.
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From page 397... ...
1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins [see comments]
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From page 398... ...
1997. Occupational and environmental risk factors for chronic lymphocytic leukemia and non-Hodgkin's lymphoma.
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From page 399... ...
1993. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands.
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From page 400... ...
1997. Interpreting recent trends in prostate cancer incidence and mortality.
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From page 401... ...
1994. Retrospective assessment of exposure through modeling in a study on cancer risks among workers exposed to phenoxy herbicides, chlorophenols and dioxins.
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From page 402... ...
1992. Cancer mortality from soft-tissue sarcoma and malignant lymphomas in an international cohort of workers exposed to chlorophenoxy herbicides and chlorophenols.
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From page 403... ...
1993. Farming and prostate cancer mortality.
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From page 404... ...
1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.
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From page 405... ...
1991. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides.
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From page 406... ...
1980. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident.
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Key Terms
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