Hardell and Eriksson, 1988

Case-control

Study of male cases of STS (25-80 years) diagnosed between 1978 and 1983 in northern Sweden compared to two referent groups: (1) population-based and (2) with other cancers, for association with occupational exposure to phenoxyacetic acids and chlorophenols

55

330 Population-based

190 Other cancers

Wingren et al., 1990

Case-control

Study of male cases of STS (25-80 years) diagnosed between 1975 and 1982 in southeast Sweden compared to two referent groups: (1) population-based sample and (2) with other cancers, for association with phenoxyacetic acids and chlorophenols

71

315 Population-based 164 Other cancers

Eriksson et al., 1990

Case-control

Study of male cases of STS (25-80 years) diagnosed between 1978 and 1986 in central Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

218

212

Hardell et al., 1980 Hardell et al., 1981

Case-control

Study of malignant lymphomas (HD, NHL, unknown) diagnosed between 1974 and 1978 in men age 25-85 in northern Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

60 HD 109 NHL

338

Hardell and Bengtsson, 1983

Case-control

Study of HD diagnosed between 1974 and 1978 in men 25-85 in northern Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acid and chlorophenols

60

335

Hardell, 1981

Case-control

Study (1) of cases of STS (Hardell and Sandstrom, 1979) and malignant lymphomas (Hardell et al., 1981) compared to colon cancer cases, and (2) study of colon cancer compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

(1) 221 (2) 154

154 541

Hardell et al., 1982

Case-control

Study of nasal and nasopharyngeal cancers diagnosed between 1970 and 1979 in men 25-85 years residing in northern Sweden compared to controls selected from previous studies (Hardell and Sandstrom, 1979; Hardell et al., 1981) for association with occupational exposure to phenoxyacetic acids and chlorophenols

44 Nasal 27 Nasopharyngeal

541

Hardell et al., 1984

Case-control

Study of primary liver cancer diagnosed between 1974 and 1981 in men 25-80 years residing in northern Sweden compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

98

200

Persson et al., 1989

Case-control

Study of HD and NHL among living men and women in Sweden compared with those without these cancers for association with occupational exposures, including phenoxy herbicides

54 HD 106 NHL

275



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--> Hardell and Eriksson, 1988 Case-control Study of male cases of STS (25-80 years) diagnosed between 1978 and 1983 in northern Sweden compared to two referent groups: (1) population-based and (2) with other cancers, for association with occupational exposure to phenoxyacetic acids and chlorophenols 55 330 Population-based 190 Other cancers Wingren et al., 1990 Case-control Study of male cases of STS (25-80 years) diagnosed between 1975 and 1982 in southeast Sweden compared to two referent groups: (1) population-based sample and (2) with other cancers, for association with phenoxyacetic acids and chlorophenols 71 315 Population-based 164 Other cancers Eriksson et al., 1990 Case-control Study of male cases of STS (25-80 years) diagnosed between 1978 and 1986 in central Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols 218 212 Hardell et al., 1980 Hardell et al., 1981 Case-control Study of malignant lymphomas (HD, NHL, unknown) diagnosed between 1974 and 1978 in men age 25-85 in northern Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols 60 HD 109 NHL 338 Hardell and Bengtsson, 1983 Case-control Study of HD diagnosed between 1974 and 1978 in men 25-85 in northern Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acid and chlorophenols 60 335 Hardell, 1981 Case-control Study (1) of cases of STS (Hardell and Sandstrom, 1979) and malignant lymphomas (Hardell et al., 1981) compared to colon cancer cases, and (2) study of colon cancer compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols (1) 221 (2) 154 154 541 Hardell et al., 1982 Case-control Study of nasal and nasopharyngeal cancers diagnosed between 1970 and 1979 in men 25-85 years residing in northern Sweden compared to controls selected from previous studies (Hardell and Sandstrom, 1979; Hardell et al., 1981) for association with occupational exposure to phenoxyacetic acids and chlorophenols 44 Nasal 27 Nasopharyngeal 541 Hardell et al., 1984 Case-control Study of primary liver cancer diagnosed between 1974 and 1981 in men 25-80 years residing in northern Sweden compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols 98 200 Persson et al., 1989 Case-control Study of HD and NHL among living men and women in Sweden compared with those without these cancers for association with occupational exposures, including phenoxy herbicides 54 HD 106 NHL 275

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--> Reference Study Design Description Study Group (N) Comparison Group (N)a Olsson and Brandt, 1988 Case-control Study of NHL (1978-1981) in Swedish men compared to two groups of men without NHL for association with occupational exposures including phenoxy acids 167 50 Same area 80 Other parts of Sweden Smith et al., 1983 Case-control Preliminary report of men with STS reported between 1976 and 1980 in New Zealand compared to controls with other cancers for association with phenoxyacetic acid exposure 80 92 Smith et al., 1984 Case-control Study of STS among New Zealand residents (1976-1980) compared to those without these cancers for association with occupational exposures, including phenoxy herbicides 82 92 Smith and Pearce, 1986 Case-control Update of Smith et al. (1983) with diagnoses through 1982 51 In updated study 133 When combined with Smith et al., 1983 315 407 Pearce et al., 1985 Case-control Study of malignant lymphoma and multiple myeloma in men diagnosed between 1977 and 1981 in New Zealand compared to men with other cancers for association with agricultural occupations 734 2,936 Pearce et al., 1986b Case-control Study of NHL cases (ICD 202) in men diagnosed between 1977 and 1981 in New Zealand compared to sample with other cancers and population sample, for association with occupational exposure to phenoxy herbicides and chlorophenols 83 168 Other cancers 228 General population Pearce et al., 1986a Case-control Study of male multiple myeloma cases diagnosed between 1971 and 1981 in New Zealand compared to controls for other cancers for potential association with phenoxy herbicides and chlorophenols 76 315 Pearce et al., 1987 Case-control Expanded study (Pearce et al., 1986b) of NHL to include ICD 200-diagnosed cases and additional controls for association with farming exposures 183 338 Blair and Thomas, 1979 Case-control Study of leukemia cases in Nebraska (1957-1974) compared to deaths from other causes for association with agricultural practices 1,084 2,168 Blair and White, 1985 Case-control Study of leukemia cases by cell type in Nebraska (1957-1974) compared to nonleukemia deaths for association with agricultural practices 1,084 2,168 Brown et al., 1990 Case-control Population-based case-control study of leukemia in Iowa and Minnesota men for association with farming exposures 578 1,245

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--> Cantor et al., 1992 Case-control Population-based case-control study of NHL in Iowa and Minnesota men for association with farming exposures 622 1,245 Zahm et al., 1990 Case-control Study of white men 21 years or older diagnosed with NHL (1983-1986) in Nebraska compared to residents of the same area without NHL, HD, multiple myeloma, and chronic lymphocytic leukemia for association with herbicide use (2,4-D) on farms 201 725 Boffetta et al., 1989 Nested case-control National study of multiple myeloma compared to other cancer controls for association with exposures including pesticides and herbicides 282 1,128 Burmeister et al., 1982 Case-control Study of leukemia deaths (1964-1978) in white men 30 years or older in Iowa compared to nonleukemia deaths for association with farming 1,675 3,350 Burmeister et al., 1983 Case-control Study of multiple myeloma, NHL, and prostate and stomach cancer mortality (1964-1978) in white men 30 years or older compared to mortality from other causes for association with farming practices including herbicide use in Iowa 550 Multiple myeloma 1,101 NHL 4,827 Prostate 1,812 Stomach 1,100 2,202 9,654 3,624 Hoar et al., 1986 Case-control Study of STS, NHL, and HD in Kansas (1976-1982) compared to controls without cancer for association with 2,4-D, 2,4,5-T, and other herbicides in white men 21 years or older 133 STS 121 HD 170 NHL 948 Cantor, 1982 Case-control Study of NHL in Wisconsin among men (1968-1976) compared to men dying from other causes for association with farming exposures 774 1,651 Dubrow et al., 1988 Case-control Death certificate study (1958-1983) of NHL and HD among white male residents of Hancock County, Ohio, compared to a random sample of those dying from other causes for association with farming 61 NHL 15 HD 304 Morris et al., 1986 Case-control Study of multiple myeloma (1977-1981) in four SEER areas compared to population controls for risk factors associated with the disease, including farm use of herbicides 698 1,683 Carmelli et al., 1981 Case-control Cases of spontaneous abortions occurring to women (1978-1980) compared to live births for association with father's exposure to 2,4-D 134 311 Woods et al., 1987 Case-control Study of STS or NHL in men 20-79 years old (1983-1985) in western Washington State compared to a population sample without these cancers for association with occupational exposure to phenoxy herbicides and chlorinated phenols 128 STS 576 NHL 694

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--> Reference Study Design Description Study Group (N) Comparison Group (N)a Woods and Polissar, 1989 Case-control Study of NHL from the Woods et al. (1987) study for association with phenoxy herbicides in farm workers 576 694 Alavanja et al., 1988 PMR analysis with nested case-control Mortality experience of USDA extension agents (1970-1979) evaluated for specific cancer excess; case-control study of specific cancers identified from PMR analysis 1,495 — Alavanja et al., 1989 PMR analysis with nested case-control Mortality experience of USDA forest/soil conservationists (1970-1979) evaluated for specific cancer excess; case-control study of specific cancers identified from PMR analysis 1,411 — Hardell et al., 1987 Case-control Study of Kaposi's sarcoma in AIDS patients (23-53 years of age) compared to controls for association with TCDD and pesticide exposure in Sweden 50 50 Donna et al., 1984 Case-control Study of ovarian cancer in women (1974-1980) for association with herbicide use compared to women without ovarian cancer 60 127 Musicco et al., 1988 Case-control Study of brain gliomas diagnosed between 1983 and 1984 in men and women in Italy compared to (1) patients with nonglioma nervous system tumors and (2) patients with other neurologic diseases, for association with chemical exposures in farming 240 (1) 465 (2) 277 Vineis et al., 1987 Case-control Study of cases of STS in men and women diagnosed between 1981 and 1983 in northern Italy compared to population sample of controls for association with phenoxy herbicide exposure 37 Men 31 Women 85 Men 73 Women Balarajan and Acheson, 1984 Case-control Study of STS (1968-1976) diagnosed in men in England and Wales compared to men with other cancers for association with farming, agriculture, and forestry occupations 1,961 1,961 Smith and Christophers, 1992 Case-control Study of STS and malignant lymphomas in men diagnosed between 1982 and 1988 in Australia compared to other cancers for association with exposure to phenoxy herbicides and chlorophenols 82 82 Other cancers 82 Population LaVecchia et al., 1989 Case-control Study of Italian men and women with HD, NHL, and multiple myeloma (1983-1988) compared to population of Italy for association with occupations and herbicide use 69 HD 153 NHL 110 MM 396 Paper/Pulp Workers Robinson et al., 1986 Cohort Mortality experience through March 1977 of white male workers employed in five paper/pulp mills compared to expected number of deaths among U.S. population 3,572 —

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--> Henneberger et al., 1989 Cohort Mortality experience through August 1985 of white men employed in Berlin, N.H., paper and pulp industry compared to expected mortality in U.S. white men 883 — Solet et al., 1989 Cohort Mortality (1970-1984) among white male United Paperworkers International Union members compared to expected number of deaths in U.S. men 201 — Jappinen and Pukkala, 1991 Cohort Cancer incidence (through 1987) among male Finnish pulp and paper workers (1945-1961) compared to rates in the local central hospital district 152 Approx. 135,000 Other Occupational Studies Fitzgerald et al., 1989 Cohort Health outcomes in group exposed to electrical transformer fire in 1981 compared to standardized rates among upstate New York residents 377 — NOTE: COPD = chronic obstructive pulmonary disease; HD = Hodgkin's disease; IARC = International Agency for Research on Cancer; ICD = International Classification of Diseases; NHL = non-Hodgkin's lymphoma; PMR = proportionate mortality ratio; SEER = surveillance, epidemiology, and end results; STS = soft-tissue sarcoma; and VAO = Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (Institute of Medicine, 1994). a The dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), and details are given in the text for specifics of the actual population.

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--> Production Workers National Institute for Occupational Safety and Health In 1978, the National Institute for Occupational Safety and Health (NIOSH) began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,000 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their exposure resulted from working with certain contaminated chemicals, including 2,4,5-trichlorophenol and in which TCDD was a contaminant included 2,4,5-trichlorophenoxyacetic acid, Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. TCDD was also measured in serum from a sample of 253 workers. The health status of the workers was determined as of December 31, 1987, and death certificates were used to establish numbers of deaths from each cause. Person-years were calculated from the first documented assignment to a process involving TCDD contamination until date of death or December 31, 1987. Vital status was determined for all but 77 members (2 percent) of the cohort. Those with unknown vital status were assumed to be alive. General U.S. population rates were used to calculate the number of expected deaths. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many of the study subjects probably were exposed to many other chemicals, some of which could be carcinogenic. Data were analyzed for mortality according to duration of exposure to processes involving TCDD contamination (determined from personnel records) and latency; total years of employment at the plant were also considered. A number of studies were later conducted that looked at health outcomes in the exposed worker population. Prior to this study, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in the manufacture of chemicals with TCDD contamination at chemical plants in Newark, New Jersey (from 1951 through 1969), and in Verona, Missouri (from 1968 through 1969, and from 1970 through 1972) (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The plant in New Jersey manufactured TCP and 2,4,5-T (N = 490 eligible); the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene (N = 96 eligible). TCDD is formed as a contaminant during the production of each of these chemicals. The workers were interviewed to collect information on health status, occupational history, time in Vietnam, time in agriculture, residential history, hospitalizations, medications, demographics, and life-style variables. Health outcomes of interest included peripheral neuropathies, neurobehavioral effects, chloracne, pigmentary changes, skin cancer, hepatic enzyme changes,

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--> porphyria, angina, myocardial infarction, ulcers, lipid changes, diabetes, lymphocyte cell types and function, and such adverse reproductive outcomes as fetal loss, reduced fertility, and major malformations (Sweeney et al., 1989). Physical examination included clinical assessment of respiratory function and adverse health outcomes, including chronic bronchitis, chronic obstructive pulmonary disease (COPD), ventilatory function, and thorax and lung abnormalities (Calvert et al., 1991); assessment of hepatic and gastric systems, including determination of laboratory tests associated with liver function, hepatitis, cirrhosis, fatty liver, gastritis, gastrointestinal hemorrhage, and ulcer disease (Calvert et al., 1992); psychological testing to determine the presence of depression (Alderfer et al., 1992); and assessment of peripheral neuropathy through examination, electrophysiologic and quantitative sensory tests, and symptoms (Sweeney et al., 1993). Serum levels of TCDD were determined as indicating exposure and were adjusted for lipids. The matched comparison group consisted of individuals who had no occupational exposure to phenoxy herbicides, who lived in the same communities as the workers, and who were within five years of age and of the same sex and race as the exposed workers. Comparison subjects underwent the same series of medical examinations and interviews as workers exposed to TCDD (Sweeney et al., 1993). A total of 281 workers and 260 unexposed subjects participated in the medical examination; 360 exposed worker interviews and 325 neighborhood interviews were completed. Data on important confounders, including cigarette and alcohol consumption, were collected and adjusted for in the analyses. The data were further analyzed to evaluate the association between occupational exposure to TCDD and porphyria cutanea tarda (Calvert et al., 1994). Unadjusted odds ratios were calculated to assess the relationship between TCDD exposure and urinary porphyrin and other outcomes of interest. Total serum testosterone and gonadotrophin levels in 248 dioxin-exposed chemical production workers in New Jersey (1951-69) and Missouri (1968-72) were compared with the same parameters in 231 nonexposed individuals from neighborhoods near the plants who participated in a medical evaluation in 1987 (Egeland et al., 1994). The plants in this study are two of the 12 plants in the original NIOSH study at which serum TCDD measurements were performed on workers. A total of 586 workers were identified in these two plants, and 281 (48 percent) participated in the medical examination. Questionnaires on occupational exposures and demographics were administered to study participants by trained interviewers, and serum dioxin, follicle-stimulating hormone, luteinizing hormone, and total serum testosterone were determined by laboratory analyses. The association of each of the hormonal parameters with serum dioxin exposure was analyzed by multiple linear regression analysis.

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--> Dow Chemical Company Dow Chemical Company undertook a cohort mortality study of workers exposed to 2,4-dichlorophenoxyacetic acid (Bond et al., 1988). The herbicide was manufactured in several Dow plants; in some plants it was the only chemical produced, while other plants also produced 2,4,5-T and other herbicides containing TCDD. It was estimated that 77 percent of the group worked in proximity to 2,4-D manufacturing, and thus had opportunity for exposure to TCDD or H/OCDD. Prior to 1950, levels of 2,4-D ranged from 0.5 to 3.0 mg/m3. Thereafter, concentrations decreased to 0.2-0.8 mg/m3, depending on the job classification. After 1978, 2,4-D concentrations were below the detection limit of 0.01 mg/m3. The cohort consisted of 878 workers from four production areas and was followed from 1945 until employee death, loss to follow-up, or December 31, 1982. Analysis was conducted according to cumulative dose of 2,4-D, as determined from such information as job history lists, industrial hygiene data, and years on the job. Allowance for latent period was made by lagging exposures by an interval of 15 years. Expected numbers were calculated for two comparison groups. The first comparison group consisted of white American males, adjusted for age and calendar year, and the second comparison group consisted of all other male workers at the manufacturing location (N = 36,804) who were employed between 1945 and 1982. This comparison was adjusted for age, interval since entry into follow-up, and pay status. The study was updated with four additional years of follow-up of the cohort of 878 workers, through December 31, 1986 (Bloeman et al., 1993). The method of analysis corresponded closely with that of the first study. Vital status was successfully ascertained for all of the original cohort members through 1986, using company records, the files of Social Security Administration, and the National Death Index. BASF In Germany, an accident on November 17, 1953, during the manufacture of trichlorophenol at BASF Aktiengesellschaft, resulted in the exposure to TCDD of some of the workers in the plant. These workers were identified and followed for mortality; other workers who were potentially exposed in the building following the accident were also studied. Mortality of the employees was evaluated by Zober et al. (1990). Of the 247 employees followed, three study cohorts—a basic cohort and two additional cohorts—were assembled to establish all those exposed during the accident as well as during cleanup operations, for follow-up over 34 years. The potential amount and reliability of exposure information were the defining factors in compiling the cohorts. The basic cohort consisted of those workers who were listed as being exposed during the accident (N = 69); of the 69 workers in this group, 66

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--> were included in the cohort of Thiess et al. (1982). The first additional cohort identified by the BASF Occupational Safety and Employee Protection Department consisted of those workers who had been potentially exposed by August 31, 1983, since more people were reporting potential exposures to the company medical department (N = 84); the degree of exposure for this group was less clear than the basic cohort. The second additional cohort was assembled (1984 through December 1987) through the ''Dioxin Investigation Programme," which informed employees of potential hazards from exposure and identified, through a variety of methods, other employees, investigators, and demolition workers who had potentially been exposed (N = 94). Occupational descriptions of jobs held by these employees were investigated, and for those included in the "Dioxin Investigation Programme," medical examinations were conducted. Vital status for the final cohort of 247 persons was established as of December 31, 1987. The cohort mortality was compared with the national mortality rates in the Federal Republic of Germany for different periods of time since the first exposure. Analysis included cancer outcomes for a subcohort of members of the three cohorts described above who experienced chloracne or erythema. Morbidity follow-up of 151 members of the original cohort, as well as seven additional employees later identified as part of the accident cohort, was continued by Zober and colleagues through 1989 (Zober et al., 1994). Cohort members were assigned to one of three subcohorts based on chloracne status following the accident. Subgroup I consisted of 52 workers with extensive or severe chloracne; Subgroup II consisted of 61 workers with either moderate chloracne or a diagnosis of "erythyema" but no chloracne; and Subgroup III consisted of 45 men without chloracne. Blood lipid TCDD concentrations in the cohort members were also used to assess exposure. Cohort morbidity was compared with a referent group comprised of male employees hired before November 1953. Episodes of acute illness were assessed on the basis of number of illness episodes per time period for each employee; while for chronic illness, an "ever" or "never" basis was used. International Register of Workers Exposed to Phenoxy Herbicides A study involving numerous cohorts from different countries was conducted by the International Agency for Research on Cancer (IARC) (Saracci et al., 1991). The cohort of international workers, the "International Register of Workers Exposed to Phenoxy Herbicides and Their Contaminants," included information on mortality and exposures of 18,390 workers—16,863 men and 1,527 women. In an effort to avoid the problems of small studies with insufficient power to detect increased cancer risks, Saracci and colleagues at the IARC created a multinational registry of workers exposed to phenoxy herbicide and chlorophenol (Saracci et al., 1991). The Danish production worker cohort studied by Lynge (1985) is included in this registry, as are the cohorts of Green

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--> (1991), Coggon et al. (1986, 1991), and Bueno de Mesquita et al. (1993). The cohort of Lynge (1985) contributes a very large fraction of all the person-years in the IARC study, and all four of the deaths found in the study were attributed to soft-tissue sarcoma (International Classification of Disease [ICD] 171). The studies are reported in detail in Chapter 8 of VAO. Workers are included from 20 cohorts who had ever been involved in herbicide production or spraying, with the exception of the Australian, Canadian, and New Zealand cohorts, which required a minimum employment of one year, six months, and one month, respectively. Follow-up for all cohorts was either through the computerized systems for the particular country or from medical records and cancer registries. In the study, questionnaires were distributed to workers in factories producing chlorophenoxy herbicides or chlorinated phenols and to workers involved in spraying operations at the plants; job histories were examined if available. The cohort was subdivided according to whether members were exposed and whether they were producers or sprayers. Workers who sprayed chlorophenoxy herbicides or worked in factory departments in contact with these chemicals were considered "exposed" (N = 13,482); workers "probably exposed" had no job title but were judged to have been exposed (N = 416). Workers with no exposure status information were considered as having "unknown" exposure (N = 541), and those who never worked in factory departments with exposure to chlorophenoxy herbicides or who never sprayed these chemicals were considered "nonexposed'' (N = 3,951). There were 12,492 workers categorized as producers and 5,898 as sprayers. Exposed and probably exposed workers were subclassified according to the chemical they produced or sprayed (9,377 worked with chlorophenoxy herbicides; 408 worked with chlorinated phenols; and 4,133 worked with both) and according to their department (3,034 were in main production; 1,522 in maintenance and cleaning; 1,665 in other departments; and 1,907 were unclassifiable). For the analysis, results are presented for the potential categories of exposure, with the "exposed" category combining production workers and sprayers into one category. Comparison mortality rates were calculated from the World Health Organization Mortality Data Bank, standardized for sex, age, and calendar-year period; mortality coding was done nationally, with a conversion table developed to allow pooling over ICD revisions. Determination of vital status began in 1955 or the date of first exposure thereafter and continued for an average of 17 years. Exposure to TCDD was assumed to be possible for those who worked producing or spraying 2,4,5-TCP and 2,4,5-T (other products). Because certain factories produced no or very little 2,4,5-T, it was possible to differentiate workers by probable TCDD exposure. Exposure was not exclusively focused on TCDD, as in the NIOSH-assembled cohort (Fingerhut et al., 1991), and the workers may have been exposed to multiple chemicals. In the Netherlands, the National Institute of Public Health and Environmental Protection contributed a cohort to the IARC registry, consisting of workers from two companies that produced several chlorophenoxy herbicides; this cohort

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--> was also evaluated apart from the IARC registry for cancer mortality (Bueno de Mesquita et al., 1993). Factory A produced primarily 2,4,5-T; in March 1963, an uncontrolled reaction in the factory resulted in an explosion in which polychlorinated dibenzodioxins (PCDDs), including TCDD, were released. Anyone employed at this factory between 1955 and June 30, 1985, was eligible to be included in the study; workers contracted to clean up after the accident were also included in the cohort. Factory B produced primarily MCPA and MCPP (2-[4-chloro-2-methylphenoxy]propanoic acid), plus smaller amounts of 2,4-D; all persons employed between 1965 and June 30, 1986, were included in the cohort. The total cohort included 2,310 workers, and follow-up was 97 percent complete; analysis was presented for the 2,074 male workers who were exposed and unexposed in the factories. The causes of death were taken from the Netherlands Central Bureau of Statistics. The important steps for phenoxy herbicide exposure, which might occur in a number of different departments, included synthesis of the chemical, formulation of the herbicide, and packaging. Since individual measures of exposure were not available, occupational history, including working in the above departments and exposure to the accident, was used to define exposure. Workers were considered exposed if they worked in departments involving synthesis, finishing, formulation, packing, maintenance/repair, the laboratory, chemical effluent/waste handling, cleaning, shipping/transport, or plant supervision; if they were exposed to the accident; or if they were exposed by proximity to the above departments. Comparisons were made to total and cancer-specific mortality using expected numbers standardized for the Netherlands; exposed and unexposed workers were also compared by selected mortality causes. In Denmark, cohort study of cancer incidence was conducted among employees of manufacturing facilities that produced phenoxy herbicides, including 2,4-D, 4-chloro-2-methylphenoxyacetic acid (CMPP), 2-[4-chloro-2-methylphenoxy]-propanoic acid (MCPA), and 2-[2,4-dichlorophenoxy]-propanoic acid (2,4-DP) (Lynge, 1985). All workers involved in the manufacture of phenoxy herbicides in Denmark before 1982 were eligible for the exposed study cohort; two factories were the source of identification of 4,461 workers (3,390 men and 1,071 women) who were followed for vital status and cancer incidence through 1982. Vital status was ascertained through the Central Population Register, and cancer incidence was determined through the Danish Cancer Registry. The incidence of cancer in the cohort was compared to the expected incidence in the entire Danish population, by sex, five year age group, and calendar period. Individual exposure was not indicated; however, department worked in the factory was used as a means of classifying those exposed. Two groups were considered to be potentially exposed to phenoxy herbicides: those in the "phenoxy herbicidal manufacturing and packaging departments"; and those in "manual service functions." The cohort was followed for cancer incidence for five years, through December 31, 1987 (Lynge, 1993). Workers at each plant were classified according to estimated potential herbicide exposure. Exposure measurement data for the cohort

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--> (1991). When just those three studies are combined, the pooled SMR is somewhat elevated: 1.4 (CI 1.2-1.8). The studies of Coggon and Lynge are largely subsumed under the European registry of Saracci et al. and so should not be viewed as independent measurements of effect. Note, however, that certain findings in these two studies that are suggestive of an association with lung cancer are lost when the combined cohort of Saracci is presented. In the Coggon study (1986), weak evidence of a trend of increasing risk with increasing category of exposure was observed (see above). In the Lynge study (1985), an elevated risk of lung cancer was observed, and this elevation was consistent over the two plants studied. In addition, the rural population from which the workforce was derived would be expected to have had lower than average smoking rates, thus indirectly reducing the likelihood that the lung cancer excess could be explained by smoking. Because many of the workers smoked and were exposed to other chemicals, it is not possible to rule out alternative explanations for this small excess risk. It is unlikely, however, that smoking explains the entire effect, since the studies of Fingerhut et al. (1991) and Manz et al. (1991) both found that smoking rates were only slightly different in samples of their study populations and in the comparison populations. Chemical production workers are often exposed to asbestos, which until recently was widely used wherever an industrial process involved high temperature. This well-known lung carcinogen might confound the observed association with herbicide and TCDD exposure in many of these studies. But it is also unlikely that asbestos could fully explain these findings, because the lung cancer risk from asbestos among chemical workers in general (as distinct from those whose occupations brought them into frequent and direct contact with the substance) is not elevated (Wong and Raabe, 1989). Thus, although tobacco and asbestos cannot be ruled out, the more likely explanation for the observed elevations in risk involves one or more agents associated with the production of phenoxy herbicides and related compounds. Agricultural/Forestry Workers Studies that compare the lung cancer experience of farmers as a group to that of other occupations or the general population show a consistent deficit of lung cancer among farmers. For example, studies by Burmeister (1981) and by Wigle et al. (1990) in North America, and by Wiklund (1983) in Sweden, provide strong evidence for a reduced risk of lung or respiratory cancer in farmers. A cohort study of Danish gardeners (Hansen et al., 1992) observed neither a deficit nor an excess of lung cancer. In the United States, a recent PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Because of the large population size, the confidence intervals are relatively narrow. Based on 6,473 deaths from lung cancer in white male farmers, the PCMR was significantly decreased, at 0.9 (CI 0.9-0.9). Based on 664 deaths in nonwhite male farmers, the PCMR was 1.0 (CI 0.9-1.1). The numbers of deaths in women

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--> of all races were small and nonsignificant. The PCMR for death from lung cancer was less than 1.0 in 18 of 23 states, a significant finding. Several authors have attributed this observed deficit in lung cancer among male farmers to decreased smoking among this group, and there is evidence to support this supposition, at least in the United States (Sterling and Weinkam, 1976) and Sweden (Rylander, 1990). Another causal hypothesis that has been proposed is that farmers are exposed to high levels of bacterial endotoxins in a wide variety of organic dusts (Rylander, 1990); these biologically active compounds have been shown to retard cancer growth in laboratory animals and have been proposed as anticancer drugs (Engelhardt et al., 1991). Several studies of cohorts whose members were engaged in agriculture-related activities have examined lung cancer risk, but the connection to herbicides is tenuous and does not add to the evidence of an association (Alavanja et al., 1988, 1989). Herbicide and Pesticide Applicators Studies of pesticide applicators are more relevant than those studies just discussed, because it can be presumed that applicators had more sustained exposures to herbicides than did members of the other groups, and the types of herbicides and durations of exposure can often be quantified generally. There are several weaknesses in many of these studies, however, including a lack of individual estimates of exposure, the fact that many different kinds of herbicides were often used, and limited sample sizes. Axelson and Sundell (1974) conducted a cohort study of herbicide sprayers who tended railroad rights-of-way in Sweden; the study initially covered the period 1957-72, and was extended until 1978 (Axelson et al., 1980). Based on follow-up through 1978, the results for lung cancer were ambiguous because of the very small numbers of both observed and expected cancers; for example, the SMR for lung cancer was 1.4 (CI 0.3-4.0), based on three observed cases for all types of exposure. A cohort of Finnish workers who sprayed the herbicides 2,4-D and 2,4,5-T was followed by Riihimaki et al. (1982). Good employment records were available, and follow-up through 1980 was nearly complete. Additional strengths of this study include the apparent lack of confounding by other chemical exposures (although the authors do not explore what the cohort members did when they were not spraying) and the relatively high exposures that the subjects probably experienced during spraying seasons. No information on smoking habits for the cohort is available. By applying a ten year latency period (the shortest latency for which data were provided), 12 lung cancer deaths were observed, compared to 11.1 expected (SMR = 1.1, CI 0.6-1.9). Lung cancer incidence for the period 1972-78, with ten year latency applied, resulted in the SIR = 1.4 (nine cases observed versus 6.6 expected, CI 0.6-2.6) (Riihimaki et al., 1983). Asp et al. (1994) extended this study by adding ten years of follow-up to the original eight years (Riihimaki et al., 1982, 1983). In both studies, the ten years

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--> following first exposure were not counted as time at risk, to allow time for disease to develop. The median duration of exposure was six weeks. While the number of respiratory cancer deaths among the 10+ years of latency group nearly tripled—from 12 to 33—the relative risk estimate of 1.1 was nearly unchanged, and the confidence interval narrowed (CI 0.7-1.5) with additional follow-up. The corresponding SIR, however, dropped to 1.0 based on 33 cases (CI 0.7-1.3). In a study of licensed pesticide applicators in Florida (Blair et al., 1983), the overall lung cancer SMR was 1.4 (34 observed deaths versus 25.1 expected, CI 0.9-1.9). The risk estimate rose with the number of years licensed, from 1.0 for less than ten years licensed, to 1.6 for 10 to 19 years, to 2.9 for 20 years or more (in a test for trend, p = .13). Increased lung cancer SMRs were found for workers licensed to apply fumigants and to apply pesticides for termites and other wood-infesting organisms, general household pests, rodents, and lawn and ornamental pests. In applicators employed by a small group of firms that were licensed to treat lawns and ornamental plants, the SMR was not elevated (SMR = 0.9), but the numbers were small (seven observed deaths versus 7.6 expected, CI 0.4-1.9). However, workers were exposed to numerous chemicals, including some known carcinogens; individual exposure to phenoxy herbicides or to any TCDD-contaminated compound cannot be determined. It is unlikely that the elevated lung cancer risk in the entire cohort can be entirely attributable to smoking. The SMRs for other smoking-related diseases were depressed, the risk was related to duration of pesticide use, and implausibly high smoking prevalences would be necessary among this cohort to explain a lung cancer risk of this magnitude. A cohort study by Green (1991) of right-of-way sprayers in Ontario, Canada, was based on records of spraying activities, but the number of subjects was small. Lung cancer mortality was essentially normal (five deaths versus 4.6 expected, RR = 1.1, CI 0.4-2.5), but the small numbers of observed deaths preclude strong conclusions. Minnesota highway workers (Bender et al., 1989) were at reduced risk of lung cancer (SMR = 0.7, CI 0.5-0.9), as were Swedish pesticide applicators (Wiklund et al., 1989); the standardized incidence ratio was 0.5 (CI 0.4-0.7), with 38 observed cases. No association with lung cancer was found when the cohort was subdivided by years since license or by year of birth. Licensed herbicide applicators in the Netherlands were studied by Swaen et al. (1992). The study is about the same size as that of Riihimaki et al. (1982) in Finland and yielded similar results for lung cancer: 12 deaths observed compared to 11.2 expected (SMR = 1.1, CI 0.6-1.9). Summary of Pesticide Applicator Studies If the cohorts of Axelson (at second follow-up), Riihimaki (with minimum ten year latency—all others have no latency restriction), Blair (lawn and ornamental sprayers only), and Green are considered roughly comparable studies of workers with likely exposure to phenoxy herbicides through manual spraying, the observed and expected deaths

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--> could be combined to yield a more precise estimate of risk. This yields 27 observed and 25.5 expected deaths and an SMR = 1.1 (CI 0.8-1.5). Paper/Pulp Workers Unlike the studies of farmers, the reports of paper worker are not consistent with respect to their estimates of lung cancer risk. Some studies do report an excess, although usually without adequate control for potential confounding by smoking (Solet et al., 1989; Jappinen and Pukkala, 1991), while others do not (Robinson et al., 1986; Henneberger et al., 1989). Case-Control Studies A case-control study that investigated lung cancer herbicide exposures was published by McDuffie et al. (1990). The occupational histories of chemical exposure for 273 male cases of primary lung cancer from the tumor registry in Saskatchewan, Canada, were compared to the histories of 187 male controls. Subjects were questioned about their use of many chemicals, including phenoxy herbicides. The response rate was rather low (74 percent), and duration of exposure appears not to have been considered in the exposure assessment. No association was found between reported use of phenoxy herbicides and lung cancer, either in the unadjusted analyses (OR = 0.5) or after controlling for cigarette smoking (OR = 0.6). Environmental Studies Studies of the population exposed to TCDD the 1976 industrial accident in Seveso, Italy, to TCDD include estimates of lung cancer risk (Bertazzi et al., 1989b, 1993; Pesatori et al., 1992). Ten years of follow-up for mortality and cancer incidence demonstrate an inconsistent pattern of lung cancer rates in the different exposed groups, as well as between males and females. People most heavily exposed (those living in Zone A at the time of the accident, but subsequently permanently evacuated) are too few in number (two observed lung cancer deaths in ten years) to provide any information. In Zone B, the lung cancer incidence in males was slightly elevated, based on 18 observed cases (RR = 1.1, CI 0.7-1.8), while there were no observed cases among women (expected number not given). The largest and least contaminated area, Zone R, was not found to have elevated lung cancer incidence rates in males (96 observed cases, RR = 0.8, CI 0.7-1.0), whereas a slight excess was observed in females (16 observed cases, RR = 1.5, CI 0.8-2.5). Smoking is not likely to explain differences in lung cancer rates in people living in the zones around Seveso and the comparison population, because the latter consists of the residents of nearby towns that are economically and culturally similar to the contaminated region. The Seveso studies followed the population only until ten years after the

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--> accident. If the TCDD release did increase the risk for lung cancers, one might not expect to see the full impact on tumor incidence for some years to come. At least another ten years is needed before the impact of the accident on cancer incidence can be meaningfully assessed. Vietnam Veterans Studies Ranch Hands The follow-up study of Ranch Hand veterans is too small to evaluate excess cancer risks (Michalek et al., 1990). Lung cancer mortality was similar in Ranch Hands and the comparison group, although the study was based on only five Ranch Hand lung cancer deaths (incidence density ratio = 0.9, CI 0.3-2.1). CDC The Vietnam Experience Study (Boyle et al., 1987) was too small to consider lung cancer risk; only one lung cancer death occurred in the comparison group of Vietnam era veterans. DVA Studies Breslin et al. (1988) and Watanabe et al. (1991) have studied Army and Marine Vietnam veterans and Vietnam-era veterans, and both studies found a small increase in lung cancer risk in Army and Marine Corps veterans who served in Vietnam. For both groups combined, the PMR is 1.1 (CI 1.0-1.2), and the risk is only slightly higher in Marine than in Army veterans. No smoking data are available on this cohort, but other studies have suggested that the smoking habits of Vietnam and Vietnam-era veterans were not significantly different from each other. Investigators at the DVA designed an additional PMR study based on deceased Army veterans who served in Military Region I (I Corps), where the majority of Marines were stationed (Bullman et al., 1990). Lung cancer risk was comparable in Army I Corps veterans and Army Vietnam-era veterans (PMR = 0.9, CI 0.8-1.1, based on 187 observed deaths). The mortality experience of women who served in Vietnam has been studied by DVA investigators (Thomas et al., 1991). Lung cancer mortality was comparable or perhaps somewhat reduced in Vietnam veterans, although based on only eight lung cancer deaths in the exposed group; after adjusting for potential confounding factors, the relative risk was 0.6, CI 0.3-1.5. The cancer mortality rates in 4,586 female Vietnam veterans were compared to the rates in 5,325 female veterans who served elsewhere (Dalager et al., 1995). This is an update of a previous study with four additional years of follow-up (Thomas et al., 1991). Based upon 15 cases of lung cancer, the adjusted SMR was 0.9 (CI 0.4-1.7). More than over 80 percent of the Vietnam cohort were nurses; therefore, their exposure to herbicides was probably low. Twenty-two U.S. Army Chemical Corps units assigned to Vietnam between 1966 and 1971 have been followed for vital status through 1987 (Thomas and

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--> Kang, 1990). In the final cohort of 894 men, there were only two deaths from lung cancer, against 1.8 expected based on the entire U.S. male population (SMR = 1.1, CI 0.1-4.0). State Studies Studies of Vietnam veterans in several states have examined lung cancer mortality rates. There include Wisconsin (Anderson et al., 1986a,b), Massachusetts (Kogan and Clapp, 1985, 1988), New York (Lawrence et al., 1985), and West Virginia (Holmes et al., 1986). In each case, lung cancer mortality rates were comparable between Vietnam veterans and Vietnam-era veterans. A proportionate mortality study examining causes of death among veterans on 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 served elsewhere. There were 80 deaths from lung cancer among the Vietnam veterans (PMR = 0.9; CI 0.7-1.1). Australian Vietnam Veterans In a study that compared Australian Vietnam veterans to Australian Vietnam-era veterans who served elsewhere, the relative risk for lung cancer was 2.7 (CI 0.2-30.0) (Fett et al., 1987). This association is based on only two cases among the Vietnam veterans. Summary of Veterans Studies Current studies of lung cancer risk in veterans are of limited usefulness for evaluating the effect of herbicide exposure, either because the studies are too small or because it is not possible to identify those soldiers who were likely to have been exposed to herbicides. Epidemiologic Studies of Laryngeal Cancer In nearly all studies analyzing respiratory cancers, the authors either group all of the different types of cancer in this broad group together (ICD codes 161 to 165, which include trachea, bronchus, lung, larynx) or present data for the largest category within this group (ICD code 162, which includes trachea, bronchus, and lung). Cancers of the latter three sites are often simply called "lung cancer." In only a few cases are the data broken out to allow assessment of other respiratory sites. Of note are five studies of production workers in which data for laryngeal cancer (ICD 161) are presented separately (Fingerhut et al., 1991; Bond et al., 1988; Coggon et al., 1986; Manz et al., 1991; Saracci et al., 1991). Although the numbers are too small to draw strong conclusions, the consistency of a mild elevation in relative risk is suggestive of an association for laryngeal cancer. Pooling all but the Coggon data (Coggon et al., 1986, 1991) yields an odds ratio of 1.8 (CI 1.0-3.2). Potential confounders of an occupational risk for this cancer

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--> include tobacco and alcohol consumption. As noted previously, these studies did not directly control for smoking, although its magnitude in Manz et al. (1991) and Fingerhut et al. (1991) is not likely to be large. There is no information on alcohol consumption in any of the studies. Other than these studies of production workers, there is only one other study that reported separate results for cancer of the larynx. A PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 162 deaths from laryngeal cancer in white male farmers, the PCMR was significantly decreased, at 0.7 (CI 0.6-0.8). This was consistent with a significant decrease in lung cancer in the same subgroup. Based on 32 deaths from laryngeal cancer in nonwhite male farmers, the PCMR was 1.1 (CI 0.8-1.5). There were no deaths from this cancer in female farmers. Summary Among the many epidemiologic studies of respiratory cancers reviewed by the committee (see Table 7-3), positive associations were found consistently only when TCDD or herbicide exposures were probably high and prolonged. This was especially true in the largest, most heavily exposed cohorts of chemical production workers exposed to TCDD (Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991). Studies of farmers tended to show a decreased risk of respiratory cancers (perhaps due to lower smoking rates), and studies of Vietnam veterans were inconclusive. 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 factor for respiratory cancers—cigarette smoking—was not fully controlled for or evaluated in all studies. The update of scientific literature continues to support these conclusions. 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) and respiratory cancers (lung, larynx, trachea). The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

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--> Bone Cancer Background According to the American Cancer Society, approximately 2,070 new cases of bone and joint cancer (ICD-9 170.0-170.9) were diagnosed in the United States in 1995, and some 1,280 persons died of this cancer (ACS, 1995). These cases are divided approximately equally between men and women. According to the committee's calculations, assuming that veterans have the same cancer rates as those of the general U.S. population, ten cases of bone cancer are expected among male Vietnam veterans and 0.1 among female veterans in 1995. For the year 2000, the expected numbers are 21 cases in male veterans and less than 0.05 cases in female veterans. Primary bone cancers are among the least common malignancies. The bones are, however, a frequent site for secondary tumors of other cancers that have metastasized, meaning that they have spread from another site. Only the primary cancers are considered here. Summary of VAO 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); agricultural workers (Burmeister, 1981; Wiklund, 1983; Ronco et al., 1992); and Vietnam veterans (Lawrence et al., 1985; Anderson et al., 1986a,b; Breslin et al., 1988). The studies regarding bone cancer were evenly distributed between positive and negative studies. Because of its rarity, this cancer is particularly difficult to study; very few of the studies were of sufficient size to have much statistical power, and the confidence limits were typically large. Case-control studies focusing on populations with potentially heavy exposure, such as production workers, might conceivably change this situation, but none had been published for bone cancer. Update of the Scientific Literature Bone cancer mortality was evaluated for a cohort of 754 white male employees of a Monsanto Company trichlorophenol plant at which an explosion occurred in 1949 (Collins et al., 1993). As a result of the accident, 122 employees developed chloracne. SMRs were calculated, based on a follow-up period through 1987 and using mortality rates in the local general population. Based on two observed cases of bone cancer, the SMR was 5.0 (0.6-18.1). The authors did not mention whether these two bone cancer cases had developed chloracne. A PCMR study was performed for farmers in 23 states, using occupational information from death certificates (Blair et al., 1993). Based on 49 deaths from

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--> bone cancer in white male farmers, the PCMR was 1.3 (CI 1.0-1.8). The numbers of bone cancer were very small and nonsignificant in the other racial and gender groups: nonwhite males and white and nonwhite females. Summary The committee found only two new studies that reported bone cancer as an endpoint. These studies do not change the VAO's conclusions concerning bone 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 bone 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. Soft-Tissue Sarcomas Background According to the American Cancer Society, 6,000 new cases of soft-tissue sarcoma (STS) (ICD-9 171.0-171.9, 164.1) were diagnosed in the United States in 1995, and some 3,600 persons died of these cancers (ACS, 1995). New cases were slightly more common in men than in women, but similar numbers of deaths occurred. According to the committee's calculations, assuming that veterans have the same cancer rates as those of the general U.S. population, 65 cases of STS are expected among male Vietnam veterans and 0.1 among female veterans in 1995. For the year 2000, the expected numbers are 86 cases in male veterans and 0.2 in female veterans. STSs arise in the soft somatic tissues that occur within and between organs. Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis can be difficult. A recent review of U.S. cancer registry data (the SEER program) clarifies many of the difficulties in the classification of the sarcomas (Mack, 1995), and underscores the challenges facing epidemiologic analyses of this cancer. Summary of VAO The strongest evidence for an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies conducted in Sweden (Hardell and Sandstrom, 1979; Eriksson et al., 1981, 1990; Hardell and

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--> Eriksson, 1988). The studies, involving a total of 506 cases, show an association between STS and exposure to phenoxy herbicides, chlorophenols, or both. The committee concluded that although these studies have been criticized, there is insufficient justification to discount the consistent pattern of elevated risks and the clearly described and sound methods employed. These findings are supported by a significantly increased risk in the NIOSH study (SMR = 9.2, CI 1.9-27.0) for the production workers most highly exposed to TCDD (Fingerhut et al., 1991), and a similar increased risk in the IARC cohort (SMR = 6.1, CI 1.7-15.5) for deaths that occurred between ten and 19 years after the first exposure (Saracci et al., 1991). These are the two largest, as well as the most highly exposed, occupational cohorts. Some studies in other occupational, environmental, and veterans groups showed an increased risk for STS, but the results were commonly nonsignificant, possibly because of small sample sizes (related to the relative rarity of STS in the population). An exception was the significantly elevated risk for males in Zone R of Seveso, which is consistent with the findings supporting an association. Because of difficulties in diagnosing this group of tumors, the epidemiologic studies reviewed by the committee were inconsistent with regard to the specific types of tumors included in the analyses. The available data did not permit the committee to determine whether specific forms of STS are or are not associated with TCDD and/or herbicides. Therefore, the committee's findings relate to the class of STS as a whole. Update of the Scientific Literature Cancer mortality from STS was evaluated in the IARC cohort of 16,863 male and 1,527 female workers in ten countries, who were employed in the production or spraying of pesticides (Kogevinas et al., 1992). Exposure to chlorophenoxy herbicides and chlorophenols was evaluated on the basis of job histories and company questionnaires. Based on four deaths from STS, a nonsignificant two-fold increased risk was observed for the total cohort. The deaths occurred ten to 19 years after first exposure (SMR = 6.1, CI 1.7-15.5). A nested case-control study of STS within the IARC multicountry worker cohort has recently been published (Kogevinas et al., 1995). There were 11 cases of STS and five controls chosen per case. In the full cohort study, Saracci et al. (1991) had detected an elevated risk with a very crude exposure classification. A 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. There were associations between STS risk and exposure to ''any phenoxy herbicide," "any dioxin," and several other definitions of exposure. The authors noted that because many of the workers had multiple exposures and few had single exposures,

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--> it is difficult to conclude with confidence that the risk is more strongly associated with any specific exposure in the broad class of phenoxy acids and related compounds. There was evidence of increasing risk with increasing cumulative exposure to several agents, including TCDD, and 2,4-D, a herbicide that does not contain TCDD. Collins et al. (1993) point out that "All but one of the confirmed STS cases among more than 5000 workers in 12 plants mentioned in the Fingerhut et al. [(1991]) study occurred among the 754 persons in the [Monsanto] study," and, based on a detailed analysis of the exposure histories of the STS cases, argue that the TCDD is unlikely to be responsible and that 4-aminobiphenyl may be. Several authors have added additional years of follow-up to occupational cohort studies (Bloemen et al., 1993; Lynge, 1993; Asp et al., 1994). Lynge (1993) found the risk of STS similar to that reported in the earlier study of this cohort of Danish herbicide manufacturers (Lynge, 1985). There were five cases of STS observed, versus 2.5 expected (relative risk = 2.0, CI 0.7 to 4.8). When the definition of exposure was restricted to those with at least one year of work in exposed areas, and a ten year interval was applied between the start of exposure and the start of follow-up time considered to be at risk, there were 3 observed cases, compared to 0.5 cases expected (RR = 6.4, CI 1.3 to 18.7). These workers were engaged in the manufacture of 2,4-D and a related herbicide, 4-chloro-2-methylphenoxyacetic acid (MCPA), but not 2,4,5-T. Despite additional follow-up, the Bloemen et al. (1993) study of 2,4-D workers was still of insufficient size to be useful for an evaluation of STS. This study was an extension of a cohort mortality study of 878 Dow Chemical Company workers exposed to 2,4-D (Bond et al., 1988). There were no deaths observed from this cancer, and considerably less than one case would have been expected. Similarly, the Asp et al. (1994) study was too small to be useful for detecting an evaluation in risk of STS. This study was an update of a cancer incidence and mortality study of 1,909 herbicide applicators in Finland (Riihimaki et al., 1982, 1983). The authors noted that with 0.8 cases of STS expected, their study had sufficient power to detect only relative risks of 7.0 or greater with 90 percent confidence. 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 98 deaths from STS in white male farmers, the PCMR was 0.9 (CI 0.8-1.1). The numbers of deaths due to STS were small and nonsignificant in the other racial and gender groups: nonwhite males and white and nonwhite females. The Bertazzi et al. (1993) study of cancer incidence at Seveso yielded results similar to those reported in earlier publications from this group and summarized in VAO (Bertazzi et al., 1989a,b; Pesatori et al., 1992). In the small, most heavily exposed group (Zone A), there were no cases of STS observed, when the class is defined as those tumors in ICD 171: "malignant neoplasms of connective and other soft-tissues." There were two cases of "soft-tissue sarcomas of parenchymal