7
Epidemiologic Studies

In seeking evidence for associations between health outcomes to be considered in subsequent chapters and exposure to herbicides and TCDD, a variety of different kinds of epidemiologic studies must be considered. Each study has varying degrees of strengths and weaknesses, and contributes evidence to an association with the health outcomes considered in Chapters 8 through 11 in accord with a balance of these factors. The historical basis for the variety of groups studied with respect to herbicides and TCDD has been discussed in Chapter 2. How the actual articles reviewed were selected from the literature for this study is described in Appendix A.

In this chapter, the epidemiologic studies and reports that were reviewed by the committee are summarized to present the study methods used, including, where available in the articles, how the study subjects were ascertained; how the data were collected; the inclusion criteria; and how the exposure, including 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), 2,4-D (2,4-dichlorophenoxyacetic acid), chlorophenols, and the TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) contaminant, was determined. Additionally, the numbers in the study and comparison populations, when available, are given along with a brief description of the study in Tables 7-1, 7-2, and 7-3. No results are presented here; rather the chapter provides a methodologic framework for the health outcome chapters that follow. Qualitative critique of the study design, population size, methods of data collection, case and control ascertainment, or exposure quality has been reserved for the individual health outcome chapters in which the results of these studies are discussed. To allow for cross-references, Appendix E provides an index



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 7 Epidemiologic Studies In seeking evidence for associations between health outcomes to be considered in subsequent chapters and exposure to herbicides and TCDD, a variety of different kinds of epidemiologic studies must be considered. Each study has varying degrees of strengths and weaknesses, and contributes evidence to an association with the health outcomes considered in Chapters 8 through 11 in accord with a balance of these factors. The historical basis for the variety of groups studied with respect to herbicides and TCDD has been discussed in Chapter 2. How the actual articles reviewed were selected from the literature for this study is described in Appendix A. In this chapter, the epidemiologic studies and reports that were reviewed by the committee are summarized to present the study methods used, including, where available in the articles, how the study subjects were ascertained; how the data were collected; the inclusion criteria; and how the exposure, including 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), 2,4-D (2,4-dichlorophenoxyacetic acid), chlorophenols, and the TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) contaminant, was determined. Additionally, the numbers in the study and comparison populations, when available, are given along with a brief description of the study in Tables 7-1, 7-2, and 7-3. No results are presented here; rather the chapter provides a methodologic framework for the health outcome chapters that follow. Qualitative critique of the study design, population size, methods of data collection, case and control ascertainment, or exposure quality has been reserved for the individual health outcome chapters in which the results of these studies are discussed. To allow for cross-references, Appendix E provides an index

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam that lists where each study is discussed in this and the health outcome chapters. The organizational structure of the chapter is indicative of the exposure groupings subsequently used in considering the evidence for individual health outcomes. The chapter text and tables are organized in three basic sections, occupational studies, environmental studies, and studies in Vietnam veterans, with subsections included under each major heading. Figure 7-1 provides a simplified basic scheme of how the chapter is organized. Each of these three major sections is organized, for the most part, with studies having the most specific or intense exposures discussed first, moving to less specific, and in many cases, group determination of exposure as compared to individual exposure determination. Studies have been reviewed that include exposures to herbicides, TCDD, and sometimes other chemicals; in several instances, it has not been indicated by the study authors to which specific chemicals study participants were exposed, or to how much. Where available in the papers reviewed, details are given with regard to exposure assessment and how exposure was subsequently used in the analysis. In order to aid interpretation, Figure 7-2 indicates the relationships among the groups of chemicals to which study subjects may have been exposed, and also indicates which are contaminated with TCDD. Among the herbicides or chemicals of special interest to this review are those which were sprayed in Vietnam, or were potentially contaminated with TCDD, including: 2,4-D, 2,4,5-T, MCPA, picloram, hexachlorophene, and chlorophenols including trichlorophenol. The subsections in the occupational studies section include production workers, agricultural/forestry workers (including herbicide/pesticide applicators), paper/pulp workers, and case-control studies of specific cancers and the association with exposures to herbicides and related compounds in many of these occupations. The environmental section includes studies of populations exposed to excessive herbicides in the environment, including the residents of Seveso, Times Beach and Quail Run, Vietnam, and other areas. The Vietnam veteran studies include those conducted in the United States by the Air Force, Centers for Disease Control (CDC), Department of Veterans Affairs (DVA, formerly the Veterans Administration), American Legion, and several individual states, as well as other groups. Vietnam veteran studies were also conducted in Australia and are presented here. For each section of the chapter, there is an extensive table (Tables 7-1 through 7-3) that lists and briefly describes each of the epidemiologic studies that was brought to the attention of the committee. The studies are presented in the same general order as in the text. Studies that were published with only minor modifications in multiple publications are cited in the text with the earliest publication date, although multiple citations appear in the table.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam FIGURE 7-1 Organization of the epidemiologic studies. FIGURE 7-2 Hydrocarbon compounds including herbicides. NOTE: * = compounds contaminated by TCDD.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam OCCUPATIONAL STUDIES Several occupational groups in the United States and elsewhere have been exposed to the herbicides of concern in this review (i.e., the ones used in Vietnam) and, more specifically, to TCDD, a contaminant of some herbicides and other products (see Table 7-1). Occupational groups exposed to chemicals in question, including herbicides, are farmers, agricultural/forestry workers, herbicide sprayers, workers in chemical production plants, and workers involved in paper/pulp manufacturing. In addition, studies linking job titles as broad surrogates of exposure and disease registry data have been conducted. Exposure measures vary widely in these occupational studies, in terms of measurement, quantification, level of detail, confounding by other exposures, and individual versus surrogate or group (ecological) measures. The National Institute for Occupational Safety and Health (NIOSH) study by Fingerhut and colleagues (1991) described below includes in the cohort analyzed many of the individual study cohorts discussed and presented in this section of the chapter (Ott et al., 1980, 1987; Zack and Suskind, 1980; Zack and Gaffey, 1983; Moses et al., 1984; Suskind and Hertzberg, 1984; Cook et al., 1980, 1986, 1987; Townsend et al., 1982; Bond et al., 1983, 1987, 1989a,b; Sobel et al., 1987; Thomas, 1987; Calvert et al., 1991, 1992; Alderfer et al., 1992; Collins et al., 1993; Sweeney et al., in press). In the cancer health outcome chapter (Chapter 8), only the NIOSH study is referenced, because, except for one Dow cohort of 2,4-D production workers, the individual cohorts are subsumed into the larger cohort. As described below, a subset of the NIOSH cohort was selected to have serum TCDD measurements, and the NIOSH research team carried out studies of these subcohorts for outcomes other than cancer. The results of these subcohort studies are discussed, where appropriate, in Chapters 9, 10, and 11. There are numerous studies of farmers and their mortality and morbidity experience to be found in the literature. The committee has included studies of farmers in which keywords in literature searches indicated herbicide exposure, or in which the authors of the articles state in their introduction that such exposures are hypothesized to be associated with the disease outcome, or which were identified through searches of the secondary literature. Production Workers National Institute for Occupational Safety and Health In 1978, NIOSH undertook to identify all U.S. workers potentially exposed to TCDD in the manufacture of contaminated products between 1942 and 1984 (Fingerhut et al., 1991). For 12 chemical companies, 5,000 workers

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam were identified from personnel and payroll records indicating that the workers had been involved in production or maintenance processes associated with TCDD contamination. Derivatives in the process of producing 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 previously identified 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. Vital status as of December 31, 1987, was determined; 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 for calculation of expected deaths. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many of the study subjects had exposures to many other chemicals, some of which could be carcinogenic. Data were analyzed for mortality according to duration of exposure in processes involving TCDD contamination (determined from personnel records) and latency; total years of employment at the plant was also considered. A cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function was conducted on workers employed more than 15 years earlier in the manufacture of chemicals with TCDD contamination at chemical plants in Newark, New Jersey (1951-1969) and Verona, Missouri (1968-1969, 1970-1972) (Sweeney et al., 1989, in press; 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). Production of these chemicals produces TCDD in the process as a contaminant, which was the actual exposure of interest. Information on health status, occupational history, time in Vietnam, time in agriculture, residential history, hospitalizations, medications, demographics, and life-style variables was collected through interview. Health outcomes of interest included peripheral neuropathies, neurobehavioral effects, chloracne, pigmentary changes, skin cancer, hepatic enzyme changes, porphyria, angina, myocardial infarction, ulcers, lipid changes, diabetes, lymphocyte cell types and function, and adverse reproductive outcomes including fetal loss, reduced fertility, and major malformations (Sweeney et al., 1989). Physical examination included (1) 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); (2) assessment of hepatic and gastric

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam systems including determination of laboratory tests associated with liver function, hepatitis, cirrhosis, fatty liver, gastritis, gastrointestinal hemorrhage, and ulcer disease (Calvert et al., 1992); (3) psychological testing to determine presence of depression (Alderfer et al., 1992); (4) assessment of peripheral neuropathy through examination, electrophysiologic and quantitative sensory tests, and symptoms (Sweeney et al., in press). Serum levels of TCDD were determined as indicating exposure and were adjusted for lipids. The matched comparison group consisted of individuals with no occupational exposure to phenoxy herbicides who lived in the same communities as the workers and were within five years of age, and of the same sex and race as the exposed worker; comparison subjects underwent the same series of medical examinations and interviews as workers exposed to TCDD (Sweeney et al., in press). A total of 281 workers and 260 unexposed referents 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. Monsanto Cohort members of studies of Monsanto workers described in this section are included in the assembled cohort by Fingerhut et al. (1991) described above. On March 8, 1949, a violent reaction occurred in the trichlorophenol (TCP) production process at the Nitro, West Virginia, plant of Monsanto (Zack and Suskind, 1980). Fumes and tarry residues were discharged into the atmosphere and building interior when a relief valve opened. One hundred and twenty-one male workers who developed chloracne following this accident were identified for inclusion in the study cohort from plant safety records at the time of the accident, plant medical records, and workers' compensation records. Chloracne was used as an indicator of TCDD exposure. Vital status of all cohort members was determined as of December 31, 1978; death certificate-coded causes of death were compared with expected deaths, based on U.S. population rates. Information is not provided about the magnitude of the exposures any individual might have experienced. Each person was assumed to have entered the study on March 8, 1949, the date of the accident. The group was selected for exposure to TCDD, and potential exposure to other chemicals is not discussed. No information is provided on the total number of individuals in the process area at the time of explosion or on the number involved in the cleanup. An additional Monsanto study evaluated health outcomes among a group of active and retired workers involved in any aspect of producing 2,4,5-T, including maintenance, and employed between 1948 and 1969 at the Nitro, West Virginia, plant (Suskind and Hertzberg, 1984). The exposed group

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam included men who had been exposed to the accident described above, as well as workers potentially exposed during manufacturing processes; comparison subjects were male workers at the same plant who, according to interview and work history, had never been exposed to 2,4,5-T processing. A total of 436 individuals who worked at the plant volunteered to be interviewed and examined during the week of July 11-18, 1979. The participation rate among the exposed group, those who worked in the 2,4,5-T process, was 61 percent and among the unexposed group 46 percent. Of the 436 examined, 69 were excluded because of demographic considerations or because their exposure history could not be adequately documented. Of the remaining 367 participants, 204 had a history of exposure and 163 had never worked in 2,4,5-T production or maintenance. Data on health outcomes were determined from laboratory results, physical examination, and medical history; smoking and alcohol use histories were also obtained. All comparisons were between these two cohorts. All workers, current and retired, identified by union records as occupationally exposed to 2,4,5-T production were invited to participate in a health survey in April 1979 in Nitro, West Virginia; workers without known exposure were invited to participate in a control group (Moses et al., 1984). The exposure source included a factory explosion in 1949 and daily exposure through work from 1948 to 1969; the comparison group was factory workers from the same plant. Of the 425 workers invited to participate, who were potentially exposed and unexposed, 235 actually participated; after exclusions, 226 subjects were available for analysis. The final cohorts consisted of 117 men with current or reported history of chloracne and 109 men with no chloracne. Of interest to investigators was the difference in health outcomes reported among those indicating the presence of chloracne as a surrogate of exposure, compared to those who reported no chloracne. It was recognized that those without chloracne may have been exposed to TCDD and were not "unexposed controls." Participants were interviewed on lifetime occupational history, current symptoms, past medical history, reproductive history, medication, and tobacco and alcohol use; examination included dermatologic, neurologic, and laboratory tests. Worker recall was originally used to determine exposure to 2,4,5-T, but this classification was not useful for analyses, which motivated development of a different mechanism for classifying exposed versus unexposed: the result was classification of exposure based on chloracne as a surrogate. All workers at the Nitro, West Virginia, Monsanto plant who worked for at least one day between March 8, 1949 (date of accident), and November 22, 1949 (date last chloracne case from cleanup was reported), were identified from work records and Internal Revenue Service Form 941 and followed for mortality through December 31, 1987 (Collins et al., 1993). Vital status for the cohort of 754 workers was determined from Monsanto

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam files, the Social Security Administration (SSA), the National Death Index (NDI), state motor vehicle records, and credit bureaus; death certificates were obtained for 99 percent of the 363 deceased cohort members. Exposure to TCDD was of interest in the study and was determined from company records of chloracne or chloracne-like events and review of company processes for additional cases exposed. A comparison with local population rates was conducted for mortality differences with the exposed group experiencing chloracne and the group presumed to be unexposed because they did not have chloracne. To examine the effects of exposure to 4-aminobiphenyl, a potential carcinogen to which workers may have been exposed, subcohorts of the original study population were determined. A cohort mortality study was undertaken to evaluate the mortality experience of the entire white, male Monsanto hourly work force with one or more years of employment on or after January 1, 1955, and prior to December 31, 1977, in Nitro, West Virginia (Zack and Gaffey, 1983). A total of 884 men were followed for mortality and compared to mortality rates in the U.S. population. For those deceased, an additional proportionate mortality analysis was conducted among those potentially exposed to 2,4,5-T and those unexposed; exposure was based on assignment to a 2,4,5-T operation in the company as indicated in work history records. Government earnings reports were used to identify eligible cohort members on company file between 1951 and 1977; mortality was ascertained for the cohort through December 31, 1977. Dow Several studies of workers in the Dow chemical plant have been published and are described in this section. It should be noted, however, that the population discussed here, except for one article by Bond and colleagues (1988) is included in the NIOSH study by Fingerhut and colleagues (1991), and results of the subsumed studies are addressed in the individual health outcome chapters as described in the introduction. The first publication examining the Dow Chemical Company's work force engaged in the production of 2,4,5-T was a study of the mortality experience of 204 persons exposed to the chemical during manufacturing (Ott et al., 1980). Ott and colleagues reported on a cohort that manufactured 2,4,5-T from March 1950 until May 1971, along with several other chemicals to which workers were potentially exposed. 2,4,5-T manufacturing was done by a crew of four, including a reactor operator, a salt wheel operator, an acid wheel operator, and a dryer operator; the 2,4,5-T dust in the plant was suspected to be a result of the final drying process. Identification of study subjects involved determining, from census lists for 1951-1971, who was in the departments where the process was organized; secondly, the work histories

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam of each person were reviewed to determined experience in any of the four jobs listed above. This constituted the exposed cohort of 204 members, with exposure determined by length of time on the four jobs. Vital status of the cohort was determined through the SSA and verified by study subject or relative; comparisons in outcome were to the mortality rates of the U.S. white male population by five year intervals. Follow-up of the population extended from first exposure to 2,4,5-T until December 31, 1976. An outbreak of chloracne among employees from a trichlorophenol manufacturing area of the Dow Chemical Company, with possible exposure to TCDD, occurred in 1964 (Cook et al., 1980). All 61 employees who worked in the particular production area during 1964 constituted the cohort, as identified from company census lists. Study subjects were assigned by an industrial hygienist to high (N - 39, including workers involved in production, sampling, and maintenance of the immediate area) and low (N = 22, including workers who worked away from the most highly contaminated areas) potential exposure to TCDD by job classification. Acne-like lesions were observed in 49 of the 61 employees; 34 of 39 highly exposed and 15 of 22 low-exposed workers had chloracne. Exposure groups were further divided into those employed in the process area before June 1964 or during July to December 1964. Workers were followed for ascertainment of vital status through December 31, 1978, and comparisons were to expected numbers of death according to cause-specific and age-specific rates for the U.S. white male population. One worker with fibrosarcoma who died in 1975 appears in later studies (Bond et al., 1987; Ott et al., 1987; Fingerhut et al., 1991) as the individual with a death certificate diagnosis of soft tissue sarcoma (STS) that was later determined to be a renal clear cell carcinoma based on review of tissue specimens. In an extension of the earlier study (Cook et al., 1980), Dow employees with chloracne, established on the basis of past diagnosis or clinical description, were enrolled in a prospective mortality study (Bond et al., 1987). The cohort consisted of 322 chemical workers with chloracne, out of 2,192 Dow employees with medical records in the NIOSH Dioxin Registry. Chloracne was graded as ''definite," "probable based on recorded diagnosis," "probable based on clinical description," "possible," and "none." Only those diagnosed as definite or probable constituted the chloracne group. Follow-up for chloracne cases extended from the year of diagnosis and continued until they were lost, died, or January 1, 1983. Mortality was compared to the U.S. white male population, adjusted for age and calendar year, as well as to a group of employees who did not have chloracne. Follow-up of Dow employees, using cohorts previously studied for potential manufacturing exposure to TCDD (Cook et al., 1980; Ott et al., 1980), compared medical examination and morbidity surveillance from 1976 to 1978 with those of matched unexposed employees (Bond et al.,

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 1983). From the original cohorts of 204 (Ott et al., 1980) and 61 participants (Cook et al., 1980), 135 and 48, respectively, were included for this study based on whether they were eligible to participate in the medical examination surveillance available at the company between 1976 and 1978. Controls were selected from others who had participated in the surveillance, but who were not exposed to high levels of chemicals potentially containing TCDD. Four controls were matched to each exposed worker by year of birth within five years, salary or hourly payment, smoking habits, and year and month of most recent health examination. Outcomes of interest were results of medical laboratory tests and prevalence of disease. With growing concern about health effects of TCDD exposure, Dow Chemical Company assembled a cohort of 2,189 men identified from company census lists and personnel records at the Midland, Michigan, plant. Workers identified were involved in TCP production, neutralization, and distillation; 2,4,5-T and Silvex production and support; 2,4,5-T formulation; Ronnel production and support; Erbon production; and chlorophenol production and finishing. These processes potentially involved contamination with TCDD. Workers were followed to determine patterns of mortality between 1940 and 1979 (Cook et al., 1986). A detailed exposure profile was developed by Dow industrial hygienists, which included job and process descriptions, analyses of process and product streams, and all available industrial hygiene records. Intensity of exposure to TCDD was measured on a scale of 0 to 4 for every relevant job; each increase in score represented approximately a tenfold relative increase in exposure. Additionally, duration of exposure was calculated to complete the cumulative exposure index used for analyses. The U.S. national mortality rates for white males were used for comparisons. Vital status was obtained for all but six of the 2,189 men who comprised the cohort, and death certificates were obtained and reviewed by a nosologist for all 298 known deaths. A cause-specific dose-response analysis was undertaken according to five categories of the TCDD exposure index. In an extension of the cohort mortality study described above, an additional three years of follow-up were included (through 1982), and more detailed analyses by exposure categories were undertaken among 2,192 Dow chemical workers (including 5 women who were subsequently excluded from the analysis) who had potential exposure to chlorinated dioxins (Cook et al., 1987; Ott et al., 1987). Comparisons, as done previously, were with U.S. white male mortality rates. Eligible employees were included as previously described, for the period 1940-1980, with an exposure profile developed for each employee. The assessment included (1) description of activities or tasks of job classifications; (2) development of process flow diagrams and potential changes; (3) review of analytic and bioassay data

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam related to dioxin in process streams and end products; (4) compilation of available industrial hygiene data; (5) assessment of TCDD and hexa- to octachlorodibenzodioxin (H/OCDD) exposure intensity score; and (6) development of an exposure profile using computer algorithm (Ott et al., 1987). No air exposure data were available, but some data on TCDD content of wipe tests and contamination of process streams or product content were given. Average concentrations for all samples of TCDD in each of four herbicides ranged from 0.3 to 5.1 parts per million (ppm) over various periods from 1964 to 1979. Higher average concentrations, up to 1,818 ppm, were present in process streams. The same TCDD exposure intensity index was used as previously described (Cook et al., 1986). Additionally, scoring of 0 to 2 was made for H/OCDD. Latency analysis was done using the serially added expected dose model, which compares the cumulative dose of individuals exposed to TCDD with others not so exposed over years of employment. A later study provided two additional years of follow-up through 1984 for this group of 2,192 employees identified as having potential exposure to chlorinated dioxins (Bond et al., 1989b). Among this Dow cohort of 2,192, company medical charts were reviewed to determine whether they were ever diagnosed as having chloracne (Bond et al., 1989a). A study of risk factors for chloracne among these cases, compared to those without chloracne, was conducted. Chloracne cases were considered as definite or probable, according to clinical description in the company medical records. Logistic regression analysis was used to adjust for factors including demographics, work history, and exposure data, previously described. Dow also 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, and in others, formulation of 2,4,5-T and other herbicides containing TCDD also took place. It was estimated that 77 percent of the group had opportunity for exposure to TCDD or H/OCDD, due to the proximity to 2,4-D manufacturing. 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 concentrates were below the detection limit of 0.01 mg/m3. The cohort was comprised 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 information including 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 U.S. white men, adjusted for age and calendar year, and the second comparison group was with all other male

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