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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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FIGURE 7-1 Organization of the epidemiologic studies.

FIGURE 7-2 Hydrocarbon compounds including herbicides. NOTE: * = compounds contaminated by TCDD.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.,

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

employees of the company. This comparison was adjusted for age, interval since entry into follow-up, and pay status.

In the only case-control study of the Dow Chemical Company, in Midland, Michigan, STS cases were identified among more than 37,000 chemical workers who had been employed for at least one year between 1940 and 1979 (Sobel et al., 1987). Cases were identified from death certificates listing diagnosis of STS as the underlying or contributing cause; where possible, medical records, pathology reports, and tissue specimens were obtained and reviewed. A combination of the best available information from death certificates, medical records, and histopathology reports was used to determine case definition. Controls were matched from among other Dow employees who had been employed for at least one year and had not died from an STS-related disease. Nine controls were individually matched to cases on sex, race, birth, and year of hire within one year; survival of controls had to have been at least as long as that of cases. As described for other studies, exposure history was determined from a number of sources. Information on potential confounders was obtained from medical record review. Analyses were based on 14 cases (4 women, 10 men) and 126 matched controls.

As part of Dow Chemical Company's surveillance program, reproductive outcomes among employees were evaluated for possible association with paternal exposure to TCDD or other polychlorinated dioxins (Townsend et al., 1982). Wives whose husbands had been potentially exposed for at least one month to dioxins during 1939-1975 were identified through company census lists. There were 930 male employees qualified according to potential exposure to dioxin, and 586 had potentially eligible wives; 370 agreed to be interviewed. A control group of equal size was established from among lists of male employees who had worked for Dow for at least one month, but not in potentially exposed areas; of 559 wives potentially eligible as controls, 345 were interviewed. Tracing was accomplished by using company benefit records. Estimation of father's exposure was through methods similar to those described for earlier Dow studies. Women were interviewed in person where possible, and questionnaire responses included information on demographics, marital and familial history, and relevant pregnancy outcomes. Congenital malformations were coded as to whether diagnosis had occurred prior to one year after birth or whether the time of diagnosis was uncertain. If conditions were diagnosed after the first year, the information was reviewed by a physician blind to the exposure group, to determine if the malformation could be diagnosed in the first year of life. If conception occurred before the father's exposure to dioxin, the conceptus was assigned to a "no-exposure" group, although the father had been exposed. Therefore, because of these regroupings, the final analysis was based on whether the conceptus was potentially exposed to dioxin through

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

paternal job exposure, rather than whether the employee was exposed. Outcomes of interest were live births, miscarriages, and stillbirths; birth defects were coded only among live births.

BASF

In Germany, an uncontrolled reaction during a trichlorophenol process at BASF Aktiengesellschaft on November 17, 1953, resulted in the exposure to TCDD of workers in the plant, who were identified and followed for mortality, along with additional workers who were potentially exposed in the building following the accident. The BASF study cohort originally identified by Thiess and colleagues (1982), described below, is later subsumed by Zober and colleagues (1990) for extended follow-up; therefore, in the health outcome chapters, the results of Zober et al. are discussed.

Investigators reported results of a mortality study undertaken 27 years after persons were exposed to TCDD in the explosion during trichlorophenol processing at BASF (Thiess et al., 1982). There were 70 persons initially exposed and 4 persons involved in cleanup operations for a cohort of 74; no data on direct exposure to TCDD were available because no TCDD measurements had been taken at the time of the accident. Follow-up of the cohort was maintained by the company and was complete; death certificates were obtained from public offices. Comparisons were made with external population control groups (town of Ludwigshafen, governmental district of Rhinehessia-Palatinate, and country of former West Germany) and two internal comparison groups selected from participants in other studies who were unexposed to TCDD; all were matched to the exposed subjects by age and date of entry to the factory.

Additional mortality of BASF employees was evaluated by Zober and colleagues (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 at the BASF plant 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 on the May 5, 1954, list as being exposed during the accident (N = 69); of the 69 in this cohort, 66 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, according to the authors, than the basic cohort. The second additional cohort was assembled (1984 through December 1987) through the "Dioxin Investigation Programme," which informed

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

employees of potential hazards from exposure and identified, through a variety of methods, other employees, investigators, and demolition workers potentially 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 a subcohort of members of the three cohorts described above with chloracne or erythema for cancer outcomes.

Other Chemical Plants

All workers in a Hamburg-Moorfleet, German herbicide plant contracted to Boehringer for at least three months between 1952 and 1984 were identified from company and union records for follow-up (1,184 men, 399 women) through 1989 (Manz et al., 1991). Community registries were used to identify deaths, and medical records were also reviewed for cause of death. Comparisons were made to the national West German mortality experience as well as, for men, to a control group of men employed at a Hamburg gas supply company (N = 3,120). This control cohort had been used for a previous study and had been followed only through 1985; therefore, comparisons to this population were limited to follow-up through 1985 for the study group, as well. This control group was required to have been employed in the gas company for at least 10 years, whereas inclusion in the Boehringer cohort required 3 months of employment. The gas company control group was selected to account for potential bias from the healthy worker effect. Exposure to TCDD was determined by production processes in which employees were involved; exposed workers were classified as having high, medium, or low exposure according to work department. Duration of employment and year employment began were also considered in relation to TCDD exposure. A sample of workers (N = 48) was also tested for TCDD levels in adipose tissue for comparison to the categorizations listed.

A study involving numerous cohorts from different countries was conducted by the International Agency for Research on Cancer (IARC) (Saracci et al., 1991). Independently conducted studies of various cohorts exposed to phenoxy herbicides and chlorophenols were combined for this study cohort. Several of the individual studies are also described in this section. Although several studies in this section have been included in the overall cohort, they are of sufficiently different potential exposure that some of these individual study results are discussed in the health outcome chapters.

The cohort of international workers, the "International Register of Workers

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Exposed to Phenoxy Herbicides and Their Contaminants," included information on mortality and exposures of 18,390 workers, which includes 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 (1991) at the IARC created a multinational registry of phenoxy herbicide- and chlorophenol-exposed workers. The Danish production worker cohort studied by Lynge (1985) is included in this larger study, as are the cohorts of Green (1991), Coggon et al. (1986, 1991), and Bueno de Mesquita and colleagues (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 counted as STS [International Classification of Disease (ICD) 171]. Workers are included from 20 cohorts who had ever been involved in herbicide production or spraying, except for 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 that country or from medical records and cancer registries.

Questionnaires were sent to factories producing chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts; job histories were examined if available. The cohort was subdivided according to whether members were exposed, whether they were producers or sprayers, and the group of chemicals produced. 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 "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 additionally classified by chemical produced or sprayed (9,377 chlorophenoxy herbicides, 408 chlorinated phenols, 4,133 both) and by department within manufacturing cohort (3,034 main production; 1,522 maintenance and cleaning; 1,665 other; 1,907 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 or

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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 workers assembled by Saracci et al. may have been exposed to multiple chemicals.

In Britain, a cohort of 5,754 males employed between 1947 and 1975 by a company that manufactured, formulated, and sprayed 2-methyl-4-chlorophenoxyacetic acid (MCPA) and other phenoxy acid herbicides was followed for mortality through 1983 (Coggon et al., 1986). The exposed men were employed at the factory or spray depots, and were identified from personnel records. The recorded job title allowed for classification of potential exposure to phenoxy acids into high (chemical process workers, spray operatives, some lab occupations), low (maintenance staff, chemical stores, transport workers), and background categories (clerical, sales staff, managers). The National Health Service Central Register at Southport was the source for tracing the cohort, with the Office of Population Censuses and Surveys providing copies of death certificates. Expected numbers of deaths for age and calendar period were calculated using England and Wales national death rates; a second comparison group of rates was formed for rural areas of England and Wales for 1968-1978.

Six British cohorts contributed members to the IARC study described above (Saracci et al., 1991); results of mortality from one of those cohorts is reported above (Coggon et al., 1986), and mortality of four of the six cohorts was assessed through December 31, 1987 (Coggon et al., 1991). The four cohorts represent workers at four factories manufacturing a range of chemicals through similar manufacturing processes. A total of 2,239 men employed were included according to the following definitions: (1) factory A (N = 1,104), all manual employees during April 1975-October 1985; (2) factory B (N = 271), all weekly paid employees during March 1969-November 1985; (3) factory C (N = 345), all process workers in phenoxy plants during January 1963-December 1984, and all formulators and packers during January 1982-December 1984; (4) factory D (N = 519), all weekly paid employees during April 1969-December 1985. Personnel or wage files were used to identify workers at factories A, B, and D; workers at factory C were identified from bound registers kept by shift foremen and from personnel records. Potential exposure to phenoxy herbicides and chlorophenol was determined from job history information; those who worked only in nonphenoxy plants were considered as "background" exposed. The National Health Service Central Register and National Insurance Index were used to trace the cohorts; cancers among living workers were obtained from registered notification. Two comparisons were done, one with the national death rates for England and Wales and one using expected numbers of deaths from 1974 to 1985 for the local authority area in which the factory was located.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Eighteen workers in the United Kingdom who were exposed to TCDD as a result of an industrial accident on April 24, 1968, underwent a complete clinical assessment and laboratory series to determine immunological abnormalities 17 years later (Jennings et al., 1988). Workers may have been exposed in the building when the accident occurred, during cleanup after the explosion, or while washing and repainting the building. Fifteen controls were selected from the portering and estate management at the plant, and were matched for age, sex, percentage of ideal body weight, social class, alcohol consumption, and smoking habits.

Workers exposed and possibly exposed to the above accident were also examined 10 years later, and compared to a control group for differences in health outcomes, including reproductive outcomes and biochemical and hematological tests (May, 1982). Workers selected for examination included those reporting chloracne after the accident, those who worked regularly at the TCP plant (including laboratory workers and management personnel), and a control group (recruited from remaining laboratory staff and management). Of those with chloracne who were considered to be definitely exposed to dioxin, 41 participated; 54 employees with possible exposure were included, along with 31 having no dioxin exposure. Along with the medical examination, a complete work history was obtained; contact with TCP and related chemicals was confirmed from company records.

In the Netherlands, the National Institute of Public Health and Environmental Protection contributed a cohort to the IARC registry described above, with workers from two companies that produced several chlorophenoxy herbicides; this cohort 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, which can result in exposure to TCDD contamination; 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 for study inclusion; 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], with 2,4-D produced in smaller amounts; 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 provided 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.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Workers were considered exposed if they worked in synthesis, finishing, formulation, packing, maintenance/repair, laboratory, chemical effluent/waste, 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 the former USSR, 292 workers involved in the production of 2,4-D were studied through examinations for the frequency of negative health outcomes (Bashirov, 1969). A more comprehensive examination was conducted on 50 exposed individuals and 20 controls, presumed unexposed to toxic substances, to specifically study the effects of exposure on the cardiovascular system and digestive organs. Details of exposure assessment are not given.

A cohort study of cancer incidence was conducted among employees of manufacturing facilities in Denmark that produced phenoxy herbicides, including 2,4-D, 2,4,5-T, MCPA, and MCPP (Lynge, 1985). All workers in the manufacture of phenoxy herbicides in Denmark before 1982 were eligible for inclusion in the exposed study cohort; two factories were the source of identifying 4,459 workers (3,390 men and 1,069 women) who were followed for vital status and cancer incidence through 1982. Vital status was ascertained by using the Central Population Register, and cancer incidence was determined by using 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.

A descriptive study followed 55 men in Prague, Czechoslovakia, for symptoms of TCDD intoxication 10 years after occupational exposure during the production of 2,4,5-T (Pazderova-Vejlupkova et al., 1981). There were originally 400 workers involved in production, 80 of whom became ill with a variety of symptoms; the 55 men described were from this original 80 and were available for long-term follow-up. TCDD was not measured in individuals; however, its presence was noted in the company product and the building structure. Medical lesions, neurological lesions, skin lesions, and psychological changes were evaluated as indicating TCDD intoxication.

Physical examination and medical histories in 1969 of volunteers who had worked in a factory producing 2,4-D and 2,4,5-T are reported (Poland et al., 1971). Workers who volunteered for physical exam (N = 73) were divided into groups based on present work location: administrators, lab technicians, and janitors (N = 20), production supervisors (N = 11), production workers (N = 28), and maintenance workers (N = 14). Comparisons between these groups were made for various portions of the report. In

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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addition to physical exam and laboratory tests for presence of porphyria cutanea tarda (PCT), chloracne, hepatotoxicity, and neuropsychiatric symptoms, medical history included occupational history, smoking, drinking, and medication history; physical exams were conducted by three separate physicians, and diagnoses were considered final. The Minnesota Multiphasic Personality Inventory was also administered.

A cohort of 1,412 white male workers employed for at least one day between 1945 and 1965 at a chemical plant manufacturing flavors and fragrances was followed to determine potential excess overall mortality and mortality from cancer (Thomas, 1987). Men were exposed to multiple chemicals in the manufacture of fragrances, flavors, aroma chemicals, and other organic substances; traces of TCDD had been found in and around plant buildings that used trichlorophenol in the production of hexachlorophene. Workers were identified from company records, and information concerning work history, as indicated by job title, was abstracted. No information was available on buildings in which the employees worked, and not all buildings were involved in the production of hexachlorophene; therefore, there was no way to identify those workers specifically exposed to TCDD. Jobs were categorized into chemical operator, maintenance worker, compounder/weigher/bulker/labeler, shipping and receiving, laboratory worker, plant chemist, engineer/draftsman, research and development, clerk/administrator, warehouse worker, and safety worker. Multiple chemical exposures were possible. Vital status as of January 1, 1981, was established, using company, SSA, credit bureau, and state motor vehicle records; person-years were accrued from January 1, 1945, or date of hire (whichever was later) through date last known alive. Deaths reported after January 1, 1981, were considered to be alive for the analysis. Cause-specific standardized mortality ratios (SMRs) were calculated for the entire study population and for several subsets by likelihood of exposure to chemicals, duration of employment, and year of hire. Rates for U.S. white men, adjusted for sex, race, age, and calendar time were used to calculate cause-specific mortality; local rates for the state in which the factory was located were used to obtain expected numbers of cancers.

Agricultural/Forestry Workers

Cohort Studies

Agricultural Workers By using both proportionate mortality and standardized mortality analyses, the mortality experience of white, male, Iowan farmers was compared to that projected from the population of white men, employed, more than 20 years old, and living in Iowa in January 1975 (Burmeister, 1981). White male death certificates for the years 1971-1978

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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were examined to establish coded causes of death and usual occupation. Proportionate mortality ratios (PMRs) were computed separately for all men, for men under age 65, and for men 65 and over. Exposure was "farming," with categorization of type of farming, where available. This cohort study formed the basis for further case-control studies of tumors for which the PMR was significantly elevated.

In Canada, the Mortality Study of Canadian Male Farm Operators covering the years 1971-1985 was undertaken to investigate the relationship of farm work practices, especially herbicide spraying, to the risk of all causes of mortality (Wigle et al., 1990; Morrison et al., 1992, 1993). The cohort was established by linking records from the 1971 Census of Agriculture, the 1971 Census of Population, and the 1971 Central Farm Register, which combined agricultural, population, and personal identifying information on the cohort. A second step linked the 1971 Central Farm Register to the 1981 Farm Register as a follow-up of the cohort; a third step linked the cohort to the Mortality Data Base (1971-1985) for the mortality experience. The agriculture census included information on individual number of acres sprayed with herbicides (types not specified) and insecticides, total acreage of land operated, and surrogate measures for pesticide exposure. In order to determine duration of exposure, indices for individual farmers were developed from 1971 and 1981 data; farmers appearing in both censuses on the same farm had a continuing exposure for those years. Farmers not appearing in both censuses had more uncertain continual exposure to herbicides. Also, subgroups of farmers who did not employ workers or who did not hire outside workers to do work on the farm were assumed to be more likely to be exposed, as the sole and primary worker on the farm. Other than these assumptions, no information on individual exposures was available. The Farm Register, established as a mailing list for agricultural questionnaires, contained all farm operators in the 1971 agriculture census, in addition to agricultural variables and personal identifiers.

In Saskatchewan, Canada, a total of 69,513 men over 35 were identified in this manner for study. A detailed multivariate analysis of the risk of death from non-Hodgkin's lymphoma (NHL) was undertaken (Wigle et al., 1990).

Also from the Mortality Study of Canadian Male Farm Operators, farmers in Manitoba, Saskatchewan, and Alberta, Canada, were evaluated for prostate cancer mortality (Morrison et al., 1993). Mortality records between June 1, 1971, and 1987 were linked with these names to identify all those who were at least 45 years at census or at some time in the follow-up period and who had died. Additionally, information from the 1971 registry compilation was linked with 1966, 1976, 1981, and 1986 Central Farm Registers and corresponding censuses of agriculture to examine farming practices and exposures reported, which included herbicide information except

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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for 1966 or 1976. Thus, individual exposure to herbicides was not determined, except as these methods allow for assumption of exposure.

A total of 145,383 farmers were eligible according to the age criterion of 45 years at some point in the follow-up period for inclusion and contribution of person-years data. Expected numbers of deaths were obtained from the Canadian prairie mortality rates, which include the three provinces from which the farmers were obtained. Potential confounders included calendar period and age, and were included in all statistical models; other variables, although not known to be associated with prostate cancer, were considered as potential confounders.

The Canadian farmer cohort was also studied further for brain cancer mortality using methods described above (Morrison et al., 1992). A total of 155,547 male farm operators from Alberta, Saskatchewan, and Manitoba provinces who were at least 35 years old at some point in the study period were followed between June 1971 and December 1987. Brain cancers and histologic information were obtained through the National Cancer Incidence Reporting System of Statistics Canada.

Two cohorts of farmers, one in Denmark and one in Italy, were evaluated for cancer experience through linkage of occupational census data with incidence of cancer in Denmark and with cancer mortality in Italy (Ronco et al., 1992). In Denmark, male and female farmers between 15 and 74 years were identified from the Danish Occupational Cancer Register for a 10 year cancer follow-up in the 1970 census population and the Danish Cancer Registry. Categories of male farmers in Denmark were "self-employed" and "employees"; for women, an additional category of "family workers'' was included. In Italy, the cohort of male and female farmers was 18-74 years, identified from the 1981 census; cancer mortality was established by linking the death certificates with the census after 6 months of follow-up from the time of the census. In the Italian cohort, the two categories "self-employed" and "employees" were considered. For each of these cohorts, the respective Danish or Italian population base provided comparison rates for expected numbers. The exposure of interest was farming, with type of farming available to a limited degree. More detailed occupational groups were considered in evaluating associations with lymphatic cancers in Denmark.

In the southern Piedmont area of Italy, the use of chlorophenoxyacetic herbicides was higher than the national average, and this was therefore the site of a cohort study of cancer risk in farmers licensed to spray pesticides (Corrao et al., 1989). An original cohort of male farmers licensed between 1970 and 1974 to buy and use pesticides was established. Given the design of Italian law obligating licensure, this cohort also included agricultural workers with an exposure. Additionally, a computer file of records of all admissions to public hospitals and private clinics between January 1976 and

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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December 1983 in the Piedmont area was available. A linkage of the hospital admissions for malignant neoplasms (N = 44,494) with the licensed pesticide users (N = 25,945) resulted in a final exposed cohort of 642 hospitalized users of pesticides and an unexposed cohort of 18,839 hospitalized nonusers. Diagnoses were verified for birth of the study subject before 1952, and a diagnosis of bone, connective tissue, or skin tumor; tumor of the brain or other part of the nervous system; and lymphatic or hematopoietic tissue tumors. Exposure, as represented by having a license, was classified in clusters, according to type of agricultural activity in the villages; the clusters represented arable farming, woodland, and mixed areas.

Farmers who were considered to be exposed to 2,4-D (N = 32) as measured by gas chromatography testing of the urine, were compared to a group of men unexposed to herbicides (N = 25) for abnormalities in their sperm (Lerda and Rizzi, 1991). How the study groups were obtained was not detailed in the report. Exposure was possible through either oral, inhalation, or dermal contact. The study was conducted over the period of March through July 1989, with exposure periods defined as (1) exposure from August to September; (2) effect in March; and (3) possible recovery in July. Laboratory testing was done for sperm collected four days after abstaining from intercourse, and included sperm volume measured within two hours, necrospermia, sperm count, sperm motility, and morphologic sperm abnormalities.

The cancer incidence among a cohort of male and female Danish gardeners was investigated, to assess the risk of cancer among these workers highly exposed to pesticides and other chemicals (Hansen et al., 1992). The cohort was established to include all members on May 1, 1975, of a gardeners trade union, associated with the Danish Union of General Workers; 859 women and 3,156 men were identified. All identified cohort members were traced for 10 years with respect to emigration and vital status through the Danish Central Population Registre, accumulating person-years at risk from identification date through date of death, emigration, or January 1, 1985. The Danish Cancer Registry provided information on cancer incidence; additional surrogate exposure data for cases of STS, hematopoietic, or lymphatic tumors were assessed through contact with the local union, which maintained data on type of work area and duration of union membership. Exposure as a gardener included workers in greenhouses, nurseries, public parks, gardens, and cemeteries; greenhouse workers were primarily exposed to fungicides and insecticides, including chlorinated compounds, whereas outdoor gardeners were primarily exposed to herbicides, including phenoxyacetic acids (2,4-D, 2,4,5-T, and MCPA) and amitrole. Outdoor gardeners were also reported to have been exposed to insecticides and fungicides. Comparison rates were based on national incidence rates for five year age-, sex-, and period-specific groups.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Several studies involving pesticide, forestry, agricultural, and railroad workers have been conducted in Sweden. A cohort study was undertaken, based on data from the Swedish Cancer Environment Register (CER), which links population census data, including occupation, with the Swedish Cancer Registry (Wiklund, 1983). Both men and women were included in the study. A comparison was made to expected numbers of cases based on five year birth cohort and gender-specific rates of the general Swedish population. The CER is formed for a decade of census data; for example, the CER 60 links the 1961-1973 cancer data with the 1960 census. Agriculture was the primary economic activity of 19,490 of the 331,767 people with cancers listed in the CER, which defined the study cohort. Cancers observed among this cohort of 19,490 were compared to the number expected based on the 1960 Swedish census. Exposure was agricultural economic activity as indicated in the data. This study formed the basis for subsequent studies discussed.

The risk of STS among male agricultural and forestry workers with possible exposure to phenoxy acid herbicides (MCPA; 2,4-D; 2,4,5-T and some of their esters) was also studied in the cohort identified above, with additional years of diagnosis (1974-1979) available for supplementing the CER (Wiklund and Holm, 1986). The cohort consisted of 354,620 men born between 1891 and 1940, who had indicated in the 1960 census that they were agricultural and forestry workers. The reference cohort was 1,725,845 men born in the same years who had not indicated these occupations as primary economic activity. A total of 331 cases of STS were observed in the study cohort and 1,508 cases in the reference group. The greatly increased use of phenoxy acid herbicides from 1947 to 1970 was the exposure of interest, and assumptions were made as to the types of possible exposures that occurred based on subcohorts in the agriculture and forestry industries. As there was heterogeneity in exposures among the subcohorts, the categories described below were considered rough estimates of exposure in each group. These subcohorts included land and/or animal husbandry (MCPA; 2,4-D; 2,4,5-T), horticulture (herbicides other than phenoxy acids), other agricultural occupations (heterogeneous herbicide exposure), silviculture (planting and thinning of young trees; 2,4-D; 2,4,5-T), timber cutting (passive 2,4,5-T and 2,4-D), and other forestry occupations (heterogeneous herbicide exposure). The most commonly used phenoxy acid in Sweden was MCPA (also called 4-chloro-2-methylphenoxyacetic acid; Chemical Abstracts Service No. 94-74-6). Also examined in further detail among this cohort of agricultural and forestry workers was the risk of malignant lymphoma (Wiklund et al., 1988a).

A later cohort study was undertaken, based on data from the Swedish Cancer Environment Register (Eriksson et al., 1992). Similarly, the CER 70 links 1970 census data with the cancer incidence from 1971 to 1984.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Using the CER 70, associations between occupations (farming, farming-related activities, forestry, horticulture, electrical and electronics workers, sawmill workers, carpenters, pulp mill workers, paper mill workers, and health care employees) and non-Hodgkin's lymphoma, Hodgkin's disease (HD), and multiple myeloma were evaluated. Trends over time were considered by using both the CER 60 and the CER 70. Occupational group was the surrogate for exposure to phenoxy acids and chlorinated phenols.

Forestry Workers A cohort mortality study was conducted to evaluate the mortality experience for 1,222 men employed six months or more in forestry work at a Canadian public utility during the period 1950-1982 (Green, 1987, 1991). Mortality was determined for the follow-up period (1950-1982) from internal company records, drivers' license records, and the Canadian Mortality Data Base. Death certificate data were used for cause of death for the population comparison. The occupational cohort consisted of 1,222 males who were assumed to have been exposed to herbicides, including, 2,4-D; 2,4,5-T; and picloram, based on herbicide use data reported within the utility during the period of interest. Prior to 1974 it is estimated that the 2,4,5-T may have been contaminated by 60-120 ppm of TCDD; in 1975 the levels were required to be less than 0.1 ppm. The mortality experience of the workers was compared to the total male population of Ontario.

A short account of the suicide experience of this cohort was reported, as well as the number of years subjects worked as a forestry worker. This was done as a surrogate for possible years of exposure to the phenoxy herbicides (Green, 1987).

A briefly outlined study of a selected sample of 54 forestry workers exposed to 2,4,5-T compared to 54 workers not exposed presents comparisons for prevalence of acne and liver dysfunction (van Houdt et al., 1983). A high prevalence of tumors in a small village in the Netherlands prompted this investigation from among 400 persons who had used 2,4,5-T. Very few details on sampling, exposure, or disease assessment, and very little discussion, are provided.

Herbicide/Pesticide Applicators Mortality (1957-1972), specifically from cancer, among railroad workers spraying herbicides in Sweden was evaluated, compared to the mortality expected in the general population (Axelson and Sundell, 1974). Four exposure cohorts were established based on a minimum total exposure to herbicides of 45 days, which was approximately the length of a spraying season: (1) total herbicide exposure > 45 days (N = 348); (2) phenoxy acids and combinations exposure (2,4-D and 2,4,5-T) > 45 days (N = 207); (3) amitrole and combinations exposure > 45 days (N = 152); and (4) other herbicides and combinations exposure > 45 days (N = 28). These were not mutually exclusive cohorts. Information on

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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persons involved in herbicide spraying and on duration of spraying was obtained for the state-owned Swedish railways. Mortality was determined from the National Central Bureau of Statistics, and cause of death was obtained from death certificates. Mortality from additional person-years of follow-up through 1978 was reported (Axelson et al., 1980).

A cohort of 3,827 white men who were licensed with the Florida Department of Health and Rehabilitative Services to apply pesticides in Florida during 1965-1966 were traced through January 1, 1977, and their mortality was compared with U. S. and Florida general population rates (Blair et al., 1983). Among the pesticides used were 2,4-D; 2,4,5-T; and Silvex. With the exception of those licensed only to control lawn and ornamental pests, all other categories were not exclusive but included applicators with multiple-category licenses. Workers were exposed to a multiplicity of chemicals; the individual or group exposure to phenoxy herbicides or to any TCDD is unknown. Multivariate analyses based on the Cox proportional hazards model were undertaken.

In Finland, 1,971 male herbicide applicators were identified from the personnel records of the four main Finnish employers involved with chemical brushwood control, who had been exposed for at least two weeks during 1955-1971 to 2,4-D and 2,4,5-T (Riihimaki et al., 1982). After excluding 45 individuals who had died before 1971, the final cohort of 1,926 persons was followed prospectively from 1972 to 1980 for mortality, by checking the names with the population register of the Social Insurance Institution. Underlying cause of death was determined from death certificates. Expected numbers of deaths were determined by using age- and cause-specific death rates for the nation in 1975. Since data on exposure were collected from personnel records, files did not always contain assignment information, and in some cases, recall of exposures was based on the memory of clerks or foremen. Cancer morbidity and mortality in this cohort were reported separately (Riihimaki et al., 1983).

A study of chemical applicators in New Zealand, as well as a follow-up to the original study, examined the reproductive outcomes of births to families where the husband was potentially exposed as compared to outcomes of births where the husband was unexposed (Smith et al., 1981, 1982). All chemical applicators registered (N = 652) at any time between 1973 and 1979 with the Agricultural Chemicals Board in New Zealand were identified, along with a control group of agricultural contractors (N = 532) for inclusion in the study. A detailed questionnaire assessed demographic data, duration of chemical spray use, and number of months of spraying 2,4,5-T during 1969-1979; for those currently married, information was completed by wives of births from that marriage about any defects, miscarriages, or stillbirths. The overall response yielded 459 married chemical applicators and 422 married agricultural contractors. Rates of congenital

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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defects, stillbirths, and miscarriages among the 1,172 chemical applicator births were compared with the rates among 1,122 agricultural contractor births.

These study results (Smith et al., 1981) indicated that among the chemical sprayers, there were some who had not been exposed to chemicals, and among the agricultural contractors, there were those who had been exposed. Therefore, the combined group of 989 respondents was categorized by exposure to chemicals: no chemical exposure; chemicals sprayed, but not 2,4,5-T; and 2,4,5-T exposure (Smith et al., 1982). The numbers of births, congenital defects, and miscarriages from 1969 to 1980 were identified by a postal questionnaire, and each pregnancy outcome was classified according to whether or not the father sprayed 2,4,5-T during the year of the pregnancy outcome or the previous year.

A cohort of 20,245 pesticide/herbicide applicators in Sweden, licensed between 1965 and 1976, was followed, with results reported after the 1982 and 1984 follow-ups (Wiklund et al., 1987, 1988b, 1989a,b). For each follow-up period, cancers were ascertained from the Swedish Cancer Register, from date of license through 1982 or 1984. A questionnaire was mailed to a sample of the cohort to assess the use of pesticides, protective clothing, tobacco, and occupations from the 1950s through the 1970s. Expected numbers of cases were determined using the 5 year age-specific incidence for the entire Swedish population. Although the study methods did not utilize individual exposure estimates, helpful qualitative data on the use of phenoxy herbicides by pesticide applicators were provided. The principal chemicals used were MCPA, mecoprop (MCPP), and dichloroprop; 2,4-D and 2,4,5-T were also used, but to a lesser extent. Since 1965, all of the above herbicides have been applied by licensed applicators. Their exposure, as a group, exceeds that of other agriculture or forestry workers.

Risk for all cancers in this cohort through 1982 has been reported (Wiklund et al., 1989a). Results for HD and NHL through 1982 (Wiklund et al., 1987) and STS through 1984 (Wiklund et al., 1988b) have been reported. Additional follow-up through 1984 evaluated the risk for STS, HD, and NHL by number of years since license, birth cohort, and whether protective clothing was used (Wiklund et al., 1989b).

A cohort study of male licensed herbicide applicators in the Netherlands evaluated the mortality experience, particularly from cancer, among the cohort, compared to the population of Dutch men (Swaen et al., 1992). The cohort was identified from a central agency of herbicide applicators who were certified before 1980; follow-up was until January 1, 1988. When fact of mortality was determined, cause of death was requested from the Central Bureau of Statistics. Subclassification by type of job was possible based on information obtained at the time of licensing. Data on municipality use of herbicides were obtained and are presented to convey an idea of

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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the kinds of chemicals sprayed, although data on individual exposures could not be obtained.

The cancer mortality experience of Minnesota highway maintenance workers was evaluated compared to the numbers expected for white men in Minnesota (Bender et al., 1989). Highway workers are exposed to a number of potentially harmful substances, and herbicides were among the list of potential exposures, although no assessment of actual exposures was made. Personnel records were abstracted to accumulate employment and allow for discontinuous years of employment. Men who worked one or more years as highway maintenance workers in Minnesota for the Department of Transportation, with at least one day after January 1, 1945, were eligible for inclusion; vital status was determined as of December 31, 1984. Cause of death was determined from the death certificate. A total of 4,849 men were included in the follow-up; comparisons were to expected numbers of cancers in Minnesota white men.

Lung cancer morbidity was investigated among 1,658 male subjects who had been employed as agricultural plant protection workers for at least 5 years in 14 districts of the former German Democratic Republic during 1948-1972 (Barthel, 1981). The cohort was identified from lists compiled by plant production offices, personnel records, and colleagues of the subjects; extensive exposure to a variety of pesticides, fungicides, and herbicides (including 2,4-D and MCPA) was possible. On average, 130 days per year were spent applying pesticides (May through September). During the rest of the year, subjects repaired and cleaned equipment and stored or moved pesticides, resulting in potential year-round exposure. The cancer deaths during the years 1970-1978 were obtained from county tumor reference centers, with cause of death from death certificates obtained from county medical officers or the Central Statistics Administration: autopsy reports were obtained from pathology institutes and patient records. The expected deaths were calculated for lung cancer, based on 1973 incidence data for the population. An investigation of the smoking patterns of plant protection workers indicated that they are similar to the general population.

Case-Control Studies

Sweden In 1977, a case series report in Sweden (Hardell, 1977, 1979) of a potential connection between STS and exposure to phenoxyacetic acids prompted several case-control studies throughout Sweden to further investigate this potential association These studies are presented together in a separate section, because many of the methods used are similar between studies, and the discussion is facilitated.

The first case-control study (Hardell and Sandstrom, 1979) identified 52 male cases of STS (21 living and 31 deceased) between the ages of 26

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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and 80 years who were admitted to the Department of Oncology, University Hospital, Umea, between 1970 and 1977. Four controls were matched to each case by vital status. Living controls were selected from the National Population Registry and matched on sex, residence in the same municipality as the case at the time of admission to the hospital, and age within five years. Deceased controls were selected from the National Registry for Causes of Death and matched on the same variables in addition to year of death; deaths from tumors and suicides were excluded. Controls were required to have been working until two years before retirement of the case or, if the case was not retired, until two years before death; this was done to allow for the probability of controls having opportunity for comparable time for occupational exposure.

A questionnaire was mailed to study subjects or next of kin for deceased subjects, following a telephone call regarding the upcoming mailing. After the form was returned, information in the questionnaire was supplemented by telephone by an investigator blind to case or control status. The questionnaire included items about past and present occupations, chemical and other exposures in the workplace, and smoking. Those with low levels of exposure (less than one day) or late exposure (i.e., less than five years before tumor diagnosis) were not considered exposed to the chemical groups of interest, phenoxyacetic acids and chlorophenols. A questionnaire was also sent to employers of study subjects, who indicated forest work or sawmill/pulp industry work, to verify exposures to phenoxyacetic acids and chlorophenols, respectively. Chlorophenols can be contaminated by polychlorinated dibenzodioxins (PCDDs; including TCDD) and dibenzofurans (PCDFs). Exposures occur from contact with cutting oils or wood-protection agents and in shoe or leather industries. Response rates from employers in the forest industry were low, and not based on records, whereas responses from sawmill/pulp industries were at 97 percent, with good agreement with statements from the interview.

To verify the findings of the first case-control study, a case-control study of STS was conducted in southern Sweden, where MCPA, 2,4-D, and phenoxypropionic acids are used in agricultural areas (Eriksson et al., 1979, 1981). Pathologically confirmed cases of STS diagnosed between 1974 and 1988 among residents in the five most southern counties of Sweden and reported to the National Social Welfare Board Cancer Registry were eligible. Two controls were selected for each living and deceased case using methods described above. The total number of subjects included 110 cases and 219 controls for analysis. Questionnaire assessment of exposure was the same as described above.

A later study repeats the study methods described, and evaluates the association between STS and phenoxyacetic acids without overlapping the previous series of cases (N = 55), using cases diagnosed between 1978 and

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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1983, and reported to the Regional Cancer Registry in Umea, Sweden (Hardell and Eriksson, 1988); the three most northern counties in Sweden were included in this reporting. Two control groups were used: the first was population-based and selected as previously described; the second was drawn at random from the Regional Cancer Registry, excluding lymphomas and nasopharyngeal cancers.

The Regional Cancer Registry at the University Hospital in Linkoping, Sweden, was the source of STS cases in southeastern Sweden diagnosed between 1975 and 1982 (Wingren et al., 1990). Cases were men between the ages of 25 and 80 years at diagnosis. Two control groups were chosen, one selected randomly from the population and one selected from among those with other cancers residing in the same three counties in southeast Sweden as the cases. A total of 71 cases, 164 cancer controls, and 315 population-based controls or their next of kin responded to the study questionnaire. Exposure was evaluated by a mail questionnaire for the occupations that had potential exposure to phenoxy herbicides and chlorophenols. Telephone interviews followed for some occupations, and detailed questions about the pesticides were asked at that time.

The last case-control study, chronologically, of STS in Sweden included cases diagnosed in central Sweden and reported to the Regional Cancer Registry in Uppsala between 1978 and 1986 (Eriksson et al., 1990). A population-based control series was used, and responses for analysis were available from 218 cases and 212 controls or their next of kin. Study methods and exposures of interest were the same as for the other Swedish case-control studies of STS.

A matched case-control study of patients with lymphomas including HD (N = 60) and NHL (N = 109) was conducted in northern Sweden (Hardell et al., 1980, 1981); four unclassifiable lymphomas were included in the NHL case series. Methods for sample identification and exposure were as described previously (Hardell and Sandstrom, 1979). Cases were males 25-85 years old with histologically verified malignant lymphoma, admitted to the hospital between 1974 and 1978. Two controls (N = 338) were matched to each case. Analyses were done both for phenoxy acids/chlorophenols and for organic solvents. A later study examined the HD cases in a separate analysis (Hardell and Bengtsson, 1983).

In an attempt to address criticism regarding potential observer bias in the Swedish case-control series, another case-control study was done using colon cancer (N = 154), both as an index case and as controls in a comparison with the original STS and malignant lymphoma cases (Hardell, 1981). The referent groups from the two earlier studies (Hardell and Sandstrom, 1979; Hardell et al., 1981) were used as the referent group for the colon cancer case evaluation. Similar study methods were employed, and the questionnaire was similar; however, results were compared for those who

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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responded by questionnaire to those responding with a combination of questionnaire and telephone follow-up answers, to evaluate potential bias.

By using a study design and methods similar to those described in this section, males aged 25-85 were identified from the northern Swedish Cancer Registry having nasal (N = 44) and nasopharyngeal (N = 27) carcinomas reported between 1970 and 1979 (Hardell et al., 1982); controls were the same 541 referents combined from the STS and malignant lymphoma studies (Hardell and Sandstrom, 1979; Hardell et al., 1981). Cases of primary or unspecified liver cancer (N = 98) diagnosed between 1974 and 1981 were also studied (Hardell et al., 1984). The controls were from the national population register (N = 200) and the cases were mailed questionnaires identical to those sent for earlier studies.

In Sweden, potential risk factors for HD and for NHL were evaluated in a case-control study; phenoxy acids were included in the occupational exposures potentially associated with disease (Persson et al., 1989). Cases diagnosed between 1964 and 1986 who were still alive and listed in the Department of Oncology at Orebro Medical Center Hospital registry, at least 20 years old at diagnosis and less than 80 years old at interview, were included. A total of 175 Swedish-born men and women were eligible; a total of 160 were in the final interviewed sample. Controls were 275 subjects enrolled in other studies who met eligibility set for cases. Information about various occupational exposures including solvents, welding, wood preservatives, phenoxy acids, and fresh wood (sawmill workers, lumberjacks, paper/pulp workers) was obtained by questionnaires mailed to the subjects; a minimum exposure of one year was required.

In a case-control study of NHL, 167 cases were evaluated for association with exposure to organic solvents, phenoxy acids, and chlorophenol from information obtained by interview, compared to two groups of healthy men (Olsson and Brandt, 1988). Cases were identified from the Department of Oncology, University Hospital, Lund, Sweden, between 1978 and 1981; all were men between 20 and 81 years of age. Controls were identified from control series used for other studies; 50 were included from the same geographic area as the cases, and 80 were identified from other parts of Sweden. Cases and controls were interviewed concerning occupational history and exposure to various chemicals, including phenoxy acids and cholorophenol. Exposure was considered to be at least one day minimum for phenoxy acids and chlorophenol used occupationally. Analysis was also conducted by duration of herbicide and chlorophenol exposure.

New Zealand Prompted by the Swedish studies of STS and exposure to phenoxy herbicides, a case-control study was undertaken in New Zealand including all male cases of STS reported to the New Zealand Cancer Registry by public hospitals between 1976 and 1980, and preliminary results

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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were reported (Smith et al., 1983). Ninety-eight eligible male cases and 111 controls were identified; 80 cases and 92 controls actually participated in the interview. Controls were obtained by a random selection of other cancer patients listed on the cancer registry, matched to the case for year of registration and age of birth within 2 years. Each patient or next of kin was interviewed; questions included whether the subject had sprayed phenoxyacetic acids or had contact with phenoxy herbicides and were classified for analysis as definitely, probably, or possibly exposed. When the specific compounds used were known, 2,4,5-T and 2,4-D were the predominating exposures reported. Another classification included individuals who had sprayed agricultural chemicals of unknown type. If the specific chemical was unknown but vegetation including gorse and blackberry was sprayed, the subject was classified as potentially exposed, as 2,4,5-T was the compound most widely used on these plants. For those who reported having done spraying, their primary occupation when exposed to the herbicides was also noted. Analyses were also undertaken excluding those who were exposed during the 5 or 10 years prior to cancer registration.

Results of further investigation of phenoxy herbicides as well as chlorophenols for association with STS incidence and mortality were reported by Smith and colleagues (Smith et al., 1984). The incidence data were obtained from 1955 to 1979 from the New Zealand National Cancer Registry, and mortality data were obtained from the National Health Statistics Center; trends showed increases in STS over time. Therefore, further study of this increase as related to occupation was done for the STS cases. The cases and controls described above (Smith et al., 1983), plus two additional cases that had next-of-kin interviews, were evaluated for associations with phenoxy herbicides and chlorophenols. Interviews were conducted by telephone by a single interviewer; for 50 subjects who were dead or too ill, the next of kin were interviewed. The questionnaire included items on occupational history and chemical exposure, including use of phenoxy herbicides and chlorophenols, in a number of occupations. Questions on use of herbicides or involvement in spraying activities were used as prompts to ask further questions about specific chemicals involved.

An updated extension of this study was conducted with cases identified through 1982 from the New Zealand Cancer Registry (Smith and Pearce, 1986). A control series interviewed for another study (of multiple myeloma and lymphoma) was used for this study, rather than the cancer controls described above. The updated series included an additional 51 cases and 315 controls; combined with the previous study, 133 cases and 407 controls were available for study. Questions regarding phenoxy herbicide use were the same as those used in the earlier study. A portion of the analysis for exposure to phenoxy herbicides included a definition of probable or definite, for more than 1 day, but not in the 5 years before cancer registration.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Additional studies were conducted of malignant lymphoma and multiple myeloma for association with agricultural occupations and phenoxy herbicides (Pearce et al., 1985, 1986a,b). The New Zealand Cancer Registry was used to identify all males 20 years or older at registration, between 1977 and 1981, with HD, NHL, and multiple myeloma. Four controls per case were selected from other cancer patients (excluding NHL, HD, STS, and multiple myeloma) registered in the same year who were within 2 years of age. Death and cancer registry data were utilized to obtain the study subject's most recent or current occupation. A total of 734 cases of malignant lymphoma and multiple myeloma, along with 2,936 controls, constituted the study population (Pearce et al., 1985). The vast majority of agricultural workers were classified as general or unspecified farm workers. Exposure to herbicides was not indicated as being of primary interest in this study; however, it provides a basis for subsequent studies, particularly with respect to study methods.

A second phase involved a series of case-control studies that investigated farming and phenoxy herbicide association with NHL and multiple myeloma (Pearce et al., 1986a,b, 1987). From the study described above, 106 cases of NHL (ICD 202) were identified (1977-1981) and 83 were ultimately included in the sample; similarly, 168 of the 212 other cancer controls were included (Pearce et al., 1986b). A population control sample of 300 male registrants on the New Zealand electoral roll was identified for comparison to living, interviewed cases; 228 were in the final sample. A second control group of 168 males with other cancers was also used for comparison in the analysis. Cases and controls were interviewed by telephone and questioned about their occupation, specifically about potential spraying exposure to phenoxy herbicides and treatment exposures to chlorophenols (Pearce et al., 1986b). The questionnaire used was similar to that used in the study of STS described above (Smith et al., 1983, 1984).

This study was expanded to include additional NHL cases diagnosed under ICD 200, and additional controls were included from the same years (1977-1981) (Pearce et al., 1987). The expanded case series was combined with the original NHL series (Pearce et al., 1986b), and exposures of interest were reexamined, with some additional details in the questionnaire including type of farming, contact with animals, and medical conditions and allergies. Questionnaire information related to phenoxy herbicides and chlorophenol exposure was obtained as described above.

A separate study of the 76 cases of multiple myeloma and 315 controls with other types of cancer, all of whom had been included in the earlier study (Pearce et al., 1985), were interviewed concerning their occupation, with particular interest in potential exposure to phenoxy herbicides and chlorophenol, as previously described (Pearce et al., 1986a).

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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United States An early study in Nebraska was to become the basis for later studies of farmers and mortality. Geographic mortality patterns for white males indicated elevated leukemia mortality in the central part of the United States, which prompted a study of leukemia mortality of Nebraska farmers (Blair and Thomas, 1979). Computerized mortality listings in Nebraska between 1957-1974 were the source of white male deaths 30 years or older from leukemia as the underlying cause of death (N = 1,084). Two deaths from other causes (N = 2,168) were matched to leukemia cases by sex, race, county of usual residence, age at death (±2 years), and exact calendar year of death. Occupation was as noted on death certificates, with farm owners, tenants, and laborers classified as farmers. Risk associated with being a farmer was not established on an individual basis but according to demographics and agricultural practices in the usual county of residence. Counties (N = 30) with the highest levels of different agricultural products as well as fertilizer, herbicide, and pesticide use were identified; cases of leukemia and matched controls in the county groupings (considered ''highest" or other) were compared, with farming as the exposure of interest.

To further evaluate farming as a potential exposure for risk of leukemia, a case-control study was conducted of 1,084 white men 30 years or older, with cause of death listed as leukemia, in Nebraska from 1957 to 1974 (Blair and White, 1985). Controls (N = 2,168) were nonleukemia deaths, matched by sex, race, county of usual residence, and age and calendar year at death within two years. Analyses were made of the risks of acute lymphatic, chronic lymphatic, acute myeloid, and chronic myeloid leukemia across birth cohorts and Nebraska agricultural regions distinguished by predominant type of farming as surrogate for various exposures. Agricultural region surrogate measures included multiple possible exposures. Occupation as a farmer was determined from the death certificate with farm owners, tenants, and laborers classified together.

In response to these early studies indicating possible associations between farming and leukemia, a large case-control study of leukemia was conducted in Iowa and Minnesota (Brown et al., 1990). Cases of leukemia newly diagnosed in white men aged 30 years or older were identified from tumor registries and hospital records for one year prior to the study and for two years prospectively. In Iowa, cases were identified through the Iowa Tumor Registry from March 1981 to October 1983; in Minnesota, cases were identified between October 1980 and September 1982 through a special network established by the state in hospitals and laboratories. Major city residents were excluded from the study, because farming exposures were of interest. Controls were identified from the population of white men, without leukemia or NHL, based on a stratified sample, in five year age groups, and considering state of residence and vital status. Cases included 578 men from both states combined, who were interviewed or for

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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whom a surrogate was interviewed; 1,245 controls were in the final population. An extensive questionnaire obtained information on a variety of farming exposures, including insecticides, herbicides, and fungicides.

A population-based case-control study of NHL in men from Iowa and Minnesota was conducted (Cantor et al., 1992). Cases of NHL newly diagnosed between March 1981 and October 1983 in men 30 years or older were identified in Iowa from the Iowa State Health Registry records; in Minnesota, men diagnosed between October 1980 and September 1982 were identified from a special surveillance of Minnesota hospital and pathology laboratory records. Cases from the entire state of Iowa were eligible; cases residing outside of the major cities of Minneapolis, St. Paul, Duluth, or Rochester were eligible in Minnesota. Case histologic specimens were reviewed by a panel of pathologists, and confirmed from diagnosis (N = 622) as well as subtype: follicular, diffuse, small lymphocytic, and "other NHL." Controls (N = 1,245) were randomly selected from the population of white men without hematopoietic or lymphatic cancer, and frequency matched to cases by 5 year age group, vital statistics at interview, and state of residence using random-digit dialing for living subjects under 65 at diagnosis; a 1 percent random Medicare files listing from HCFA for living subjects 65 or older; and death certificates for deceased subjects. Interviewers obtained comparable data on sociodemographic characteristics, medical diagnosis, and other known and suspected risk factors from subjects, next of kin, or friend for deceased or incompetent subjects. For those who had lived on a farm at least 6 months since age 18, detailed farming and pesticide use history were obtained as well as information on 38 specific herbicides (including phenoxy herbicides, 2,4-D, 2,4,5-T). Information on ever use, first/last year use, and method of application (aerial, surface, incorporated in soil, other), whether subject had personally applied, mixed or handled and use of protective equipment. Analysis obtained ORs adjusted for confounders and other possible risk factors.

Additional case-control studies have evaluated other cancers as well as leukemia for association with farming. A case-control study of white men 21 years or older residing in 66 counties of eastern Nebraska and diagnosed between July 1, 1983, and June 30, 1986, with NHL (Zahm et al., 1990) was conducted. Cases in eastern Nebraska were identified through the Nebraska Lymphoma Study Group and area hospitals. Histologically confirmed cases were eligible for inclusion (N = 220); interviews were successfully completed with 201 cases or their next of kin. Residents of the same 66-county area were eligible as controls, and were matched 3:1 by race, sex, vital status, and age (±2 years). Living controls less than 65 years of age were selected by random-digit dialing; controls were selected from Medicare records to be matched to living cases 65 years or older. Controls were selected from the Nebraska mortality files by matching for year of death

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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with deceased cases. Deaths due to NHL, HD, multiple myeloma, leukemia, unknown malignancy site, aplastic anemia, suicide, or homicide were excluded as controls. A total of 725 white male controls or their next of kin were interviewed. The interview was designed to obtain information on all agricultural exposures, including 2,4-D, to determine potential association with NHL. Herbicide use, application method, use of protective equipment, years of use for each herbicide and insecticide, average annual number of days of use on the farm, duration of time wearing work clothes after handling pesticides, and personal handling were among the questions included in the interview.

Incident and prevalent cases of multiple myeloma identified from death certificates obtained in a follow-up study of cancer mortality were compared to a control series for association with several occupational exposures (Boffetta et al., 1989). A volunteer cohort of 508,637 men and 676,613 women who had been enrolled by the American Cancer Society (ACS) in a prospective study of mortality in 1982 completed a questionnaire which obtained information on medical history including cancer, medication and vitamin use, menstrual and reproductive history, diet, drinking, smoking, and occupational history and exposures. Exposures in or outside of the workplace to 12 groups of substances, including pesticides and herbicides, and duration of exposure were ascertained. Follow-up of the cohort occurred in 1984 and 1986 for mortality, with volunteers checking on vital status and recording date and place of death. Nosologists coded cause of death from death certificates. From this mortality study, all cases of MM reported on death certificates as underlying or contributing cause of death were the cases for the nested case-control study. Controls (4 per case) were randomly selected from the cohort and matched to the cases on sex, ACS division, year of birth, and ethnic group. Cases were determined to be incident or prevalent based on whether the cancer had been mentioned in completing the questionnaires for the cohort mortality follow-up. There were a total of 282 cases (128 incident, 154 prevalent) and 1,128 controls (512 matched to incident and 616 matched to prevalent) studied. Exposure of interest for analysis was considered to be "pesticides and herbicides." Subanalysis examined these exposures among those who were reported to be farmers and among nonfarmers.

As an extension of a previous cohort study of cancer associated with farm employment in Iowa (Burmeister, 1981), a case-control study of leukemia mortality in white males in Iowa (Burmeister et al., 1982) was conducted. Deaths of white males who were at least 30 years old at the time of death from leukemia (N = 1,675) were obtained from computer listings in Iowa (1964-1978). Two controls (N = 3,350) were selected from among white male deaths other than leukemia, matched to cases on county of usual residence, age at death within two years, and calendar year of death. The

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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death certificate was the source of usual occupation for the years 1964-1970 as coded by the 1960 U.S. Census, and according to the U.S. Bureau of Labor for 1971-1978. "Farmers" were defined as farm owners, tenants, and laborers and were evaluated separately in the analysis for associations between exposures, including herbicide use, and leukemia. Agricultural data were provided by the Iowa Crop and Livestock Reporting Service, and pesticide use was provided by the 1964 agricultural census; herbicide use was also available by county distribution for those classified as farmers. No individual exposures were ascertained.

In a later study, the relationship of cancers of the stomach, prostate, NHL, and multiple myeloma to agricultural practices and farm products was examined (Burmeister et al., 1983). Deaths of white male Iowa residents, 30 years of age or older, occurring between 1964 and 1978 from any of the four cited cancers were abstracted from computer listings. Two deaths of white men, from any other cause, including other cancers, were selected as controls, matched by county of residence, age of death within two years, and calendar year of death. The usual occupation indicated on the certificate of death was coded according to census criteria; farm owners, tenants, and laborers were all categorized as "farmers." The geographic distribution by county of selected farm commodities was reviewed, and counties were classified as to their status in the top third or otherwise for production of each selected commodity. Odds ratios were computed according to birth cohort and production levels for the following: egg-laying chickens, milk products sold, number of cattle and hogs, and amount of soybeans or corn per acre, as well as herbicide or insecticide use and amount of fertilizer applied. As with the study above, no individual measure of exposure was available.

In an attempt to replicate the Swedish studies of Hardell and colleagues, a population-based case-control study of STS, HD, and NHL in relation to farm use of herbicides was conducted in Kansas (Hoar et al., 1986). Use of 2,4-D and 2,4,5-T is heavy in Kansas, with minimal use of insecticides, compared to other states with high phenoxy herbicide use. White, male residents of Kansas, 21 years of age or older, were identified by using a population-based, statewide cancer registry for the years 1976-1982, with STS, HD, and NHL for study inclusion as cases; pathological review confirmed diagnosis. Controls were obtained by using a random-digit dialing technique for controls under age 65 and Medicare records for controls 65 or over. Study participants or their next of kin were interviewed by telephone regarding employment and specific types of farm work, including crops raised and herbicide or insecticide use. Herbicide and pesticide use was confirmed for each case and control by contact with suppliers; duration and frequency of use were also examined. 2,4-D was the most commonly used herbicide, although 2,4,5-T and many other herbicides

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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were also used. The interviewed cases totaled 133 for STS, 121 for HD, and 170 for NHL.

A total of 774 cases of NHL in white male residents of Wisconsin counties other than Milwaukee were identified from computerized mortality records of Wisconsin deaths, 1968-1976 (Cantor, 1982). Cases were 30-89 years of age at time of death. Controls dying from other causes were frequency matched in a 4:1 ratio, within strata based on county size, by year of death, five year age group, and residence county population group; smoking-related cancers among controls were excluded. Because an individual's farming activity was unknown, county data were used as a surrogate for farm-related exposures, including data on measures of agriculture activity, such as total acreage, type of crops, tons of fertilizer applied, areas sprayed for weed control or with insecticides, and inventory of hogs, cattle, and chickens. Trends with age and calendar year were examined.

A case-control study was conducted of NHL (N = 61) and HD (N = 15), with cases identified from 1958 to 1983 using death certificates of white male residents of Hancock County, Ohio, which is an area of reported heavy herbicide use (Dubrow et al., 1988). Controls were selected as a stratified (by age at death and year of death) random sample from other causes of mortality (N = 304). Cases and controls were compared for usual occupation and industry, as listed on the death certificates, and adjusted for age at death and year of death. Exposures of interest were farming as an occupation or agriculture as the industry in which subject worked.

A population-based case-control study of all persons under 80 years of age with multiple myeloma diagnosed between July 1, 1977, and June 30, 1981, was conducted through cancer registries serving four Surveillance, Epidemiology, and End Results (SEER) areas (Detroit, Washington State, Atlanta, Utah) (Morris et al., 1986). Controls were individuals selected at random from the same geographic areas as the cases; the method of control selection varied according to study area. Three of the areas used random-digit dialing, while one (Washington) used standard area sampling methods. Controls were matched by age (W5 years), sex, and race. Interviews were conducted with study subjects or next of kin if the subject was unable to be interviewed. Information on risk factors hypothesized to be associated with multiple myeloma was ascertained through interview questions on specific occupational and chemical exposures, particularly from herbicide use. A total of 698 cases or their next of kin were interviewed; 1,683 controls or next of kin completed the interview. Of cases, 69 percent were interviewed themselves, whereas 99 percent of the controls interviewed were the study subjects.

A case-control study of spontaneous abortions compared to live births was undertaken in Oregon and Washington to evaluate the association with father's occupational exposure to 2,4-D (Carmelli et al., 1981). Employers

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

in the Northwest (Oregon and Washington) were contacted to sample, from the worker population, married men 35 years or younger, living in these states. Employers included farm groups, forest industry, forest service, licensed applicators, transportation, utilities, formulators, and manufacturers; of a total of 14,747 questionnaires sent, 8,287 responded. From those responses, a total of 3,787 were considered eligible, with both husband and wife under 35 years of age. For a subsample of 1,098 couples reporting either late, heavy period, or pregnancy within the past two years, a telephone interview was conducted. This interview included questions on reproductive history; work history; birth control; smoking, marijuana, and medication use; and exposure to herbicides. The final study sample included 134 cases of miscarriage and 311 control live births. Validation of a reported miscarriage was attempted through the review of physician or hospital records; records were obtained for 75 (56 percent) of the cases, and 69 miscarriages were confirmed. The critical period of exposure was taken to be the month of the last menstrual period plus the month of the first missed period. Questions were asked about exposure to herbicides around the home, as well, Exposure was classified as "high" exposure (directly exposed in the manufacture, formulation, mixing, or application of 2,4-D), "medium" exposure (indirectly exposed by being in an area in which 2,4-D was sprayed or being in the area after it had been sprayed), and ''low" exposure (not exposed at work). Attempts were made to validate exposures, including verification using written records of exposure dates, signed statements from coworkers and supervisors, and other sources.

A population-based case-control study was conducted in western Washington where phenoxyacetic acid herbicides and chlorophenol are widely used by agricultural, forestry, and wood product industries (Woods et al., 1987; Woods and Polissar, 1989). Cases of STS and NHL were identified between 1983 and 1985 from a population-based tumor registry covering 13 counties of western Washington. Eligible cases were men diagnosed between the ages of 20 and 79 years, during 1981 to 1984, according to International Classification of Diseases for Oncology (ICD-O) coding; pathologic review was also obtained for cases. Live controls aged 20 to 64 were selected from the population by random-digit dialing; living controls aged 65 to 79 were randomly selected from the files of the Health Care Financing Administration. Death certificates were used to identify deceased controls with date of death during the study period and residence within the study area, for noncancer deaths, excluding homicides and suicides, of persons aged 20 to 79. The final study population included 97 living and 31 dead STS cases, 402 living and 174 dead NHL cases, and 475 living and 219 dead controls. Study subjects or their proxies were interviewed in person; the interview included residential, military, and medical history, as well as a detailed occupational history. Information about specific activities involving

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

the manufacture or use of phenoxy herbicides or chlorophenol was obtained in the interview. Confirmation of the self-reported occupational exposure to phenoxy herbicides, chlorophenol, and other chemicals was sought by telephone contact with former employers or coworkers. Generally there was good agreement with the self-reports. A later study using this case series evaluated the associations between NHL and the exposures of interest among farmers only (Woods and Polissar, 1989).

In a two-part study the mortality experience of all U.S. Department of Agriculture (USDA), white, male employees who died between 1970 and 1979 and who had ever been employed as extension agents (Alavanja et al., 1988) was evaluated (N = 1,495). PMR analysis examined causes of death, with detailed cancer causes noted. Excess mortality at specific organ sites identified from the PMR analysis resulted in a case-control study for the following: colon, prostate, kidney, brain, HD, NHL, multiple myeloma, and leukemia. Four controls were selected for each case from the mortality analysis who died from any cause of death different from the case, and matched on date of birth (±2 years) and race. Exposure of interest for the case-control analysis included extension agent status, duration, time period, and location of employment as an extension agent.

The mortality experience of males employed as forest or soil conservationists (N = 1,411) was evaluated for the same period and utilized the two-part study methods described above (Alavanja et al., 1989). Case-control studies of NHL, pancreas, kidney, colon, and prostate cancers were conducted. Trends with duration of employment as either a forest or a soil conservationist were also examined.

Under the hypothesis that exposure to dioxins may result in immunosuppression and subsequently decrease host resistance to infection, the association between exposure to TCDD and Kaposi's sarcoma in AIDS patients was evaluated (Hardell et al., 1987). AIDS patients with Kaposi's sarcoma (N = 50) and 50 homosexual controls matched to cases by age were identified at outpatient clinics and interviewed. Interviews included questions on occupational exposure to pesticides, service in Vietnam, exposure to Agent Orange, home use of pesticides, and smoking.

Other Case-Control Studies In the Piedmont region of Italy, the association between occupational exposure to herbicides used in the rural areas and ovarian neoplasms arising from the serosal surfaces of the ovary, which are of mesothelial or mesodermic origin, was investigated (Donna et al., 1984). Subjects for this case-control study consisted of 66 newly diagnosed cases of histologically confirmed primary mesothelial ovarian tumors diagnosed between January 1, 1974, and June 30, 1980, in the Department of Pathology of the City Hospital in Alessandria. Sixty women or their next of kin were successfully interviewed in 1981 regarding their occupational history

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

to assess herbicide exposure. Controls consisted of newly diagnosed cases of cancer in sites other than the ovary, selected from the same file in the Pathology Department, matched to the cases by year of diagnosis, age (±2.5 years), and district of residence. One hundred and thirty-five controls were obtained, with a variable matching ratio from 1:4 per case. Of these, 127 were successfully interviewed in 1982. Many of these controls were breast cancer cases, whereas the others were a variable mix of other types of malignancies in females. Exposure was defined by three categories: definite exposure (subject or next of kin described personal herbicide use and could name brands), probable exposure (subject was farmer after 1960 when herbicides were in heavy use, or resided in areas of known herbicide use), and no exposure (denied herbicide use).

Incident brain gliomas (N = 240) from two hospitals in Milan, Italy, were evaluated in comparison to patients with nonglioma nervous system tumors (N = 465) and patients with other neurologic diseases (N = 277) for association with chemical exposures among farmers (Musicco et al., 1988). Two of the major centers in Milan for treatment and diagnosis of brain tumors were the source of cases for this Italian study; all newly hospitalized cases were enrolled between January 1983 and December 1984 who were 20-74 years old. Cases were patients with gliomas; tumor controls had nonglioma tumors, and neurologic controls had nonneoplastic neurologic diagnoses. Subjects were interviewed concerning all occupations for six months or more, with additional information collected on agricultural occupations, including the use of fertilizers, herbicides, insecticides, and fungicides.

Incidence of STS was investigated in the highly agricultural area of northern Italy, where exposure to phenoxy herbicides by rice weeders was quite common (Vineis et al., 1986). All persons diagnosed with STS between 1981 and 1983 who were at least 20 years old were identified from the pathology departments of the three northern province hospitals. After histologic confirmation and other exclusions, 68 of the 135 potential cases were interviewed: 31 cases were diagnosed among women, and 37 were diagnosed in men. A total of 158 controls were interviewed of the 208 originally identified. Living controls were randomly sampled from population electoral rosters; deceased controls were identified from the demographic offices of the same municipality as the deceased case. Interviews were obtained with subjects or their next of kin and included demographic information, smoking history, occupational history, radiological therapy treatment, and history of residence changes, including periods of time in rice-growing areas. For those who had worked in agriculture, including rice-growing, additional information was obtained concerning the handling, transportation, distribution, and spraying of herbicides. Exposure was categorized by potential for phenoxy herbicide exposure, based partially on the

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

assumption that certain occupational groups would be exposed to those chemicals during certain time periods.

Data from 15 regional cancer registries, which constitute the National Cancer Register in England, 1968-1976, were used to identify cases of STS and other cancers as controls to evaluate association with farming, agricultural, and forestry occupations as surrogates for exposure to phenoxy herbicides (Balarajan and Acheson, 1984). Cases were men at least 15 years old, for whom occupational information was available in the registry data base; similarly, controls were registrants with other cancers and occupational data, matched to cases within five years of age and by region of residence (N = 1,961 pairs).

A case-control study of STS and malignant lymphoma was also conducted in Australia to evaluate potential association between the cancer and exposure to phenoxy herbicides and chlorophenol in a number of occupations (Smith and Christophers, 1992). Living cases of STS and malignant lymphoma, and other cancer controls, registered in the Victoria Cancer Registry after January 1, 1982, who were male, 30 years or older at registration, and patients at any of six major Melbourne hospitals, were selected. The study progressed until 30 patients with STS and 52 patients with malignant lymphomas had been interviewed; diagnoses were confirmed through review of hospital records. One control with another type of cancer was randomly selected from the cancer registry, and matched for sex, age within three years, and area of current residence; patients with leukemia, multiple myeloma, or bone sarcomas were excluded. An additional control group was selected at random from the population by using the electoral register and matching on the same criteria as the cancer controls. Interviews regarding occupational herbicide and chemical exposure were conducted either in person or by telephone and asked about comprehensive occupational history, leisure activity, and alcohol and tobacco use; details on the nature and duration of exposure were determined by the interviewer when the subject reported any occupation or activity that might have involved use of phenoxy herbicides or chlorophenol. Additional questions included work or living on a farm, work with asbestos, use of pesticides, herbicides, or wood preservatives, with further details obtained by interviewer probing. Exposures within five years prior to diagnosis were ignored for both the case and the matched control; lifetime exposure of less than one day was counted as not exposed. In the analysis, exposure was assessed with two indicator variables, one for possible exposure and one for definite exposure, such that the risk for one was adjusted for the other. Exposure to phenoxy herbicides or chlorophenols was classified as none, possible, or definite/probable for analysis.

As part of an ongoing study of neoplasms in Milan, Italy, incident cases between 1983 and October 1988, aged 15-74 and histologically confirmed,

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

were identified along with hospital controls to evaluate occupational exposures for association with lymphoid cancers (LaVecchia et al., 1989). Cases of HD (N = 69), NHL (N = 153), and multiple myeloma (N = 110) were included for study along with 396 patients admitted for acute conditions to the same hospitals from which cases were identified. Diagnoses for controls included traumatic conditions, nontraumatic orthopedic conditions, acute surgical conditions, and miscellaneous ailments. The questionnaire included items on demographic characteristics, life-style habits, selected diet, medical history, menstrual and reproductive history, start and stop date for 16 industries or occupations, role in the industry, and exposure to occupational agents including herbicides.

Paper/Pulp Workers

Four studies of paper and pulp workers are included, which hypothesize and evaluate potential exposures to dioxins in the processing of wood to form pulp, and patterns of mortality among workers (Robinson et al., 1986; Henneberger et al., 1989; Solet et al., 1989; Jappinen and Pukkala, 1991).

A cohort of 3,572 white, male, pulp and paper workers employed for at least one year between 1945 and 1955 was identified from 5 mills selected from a possible 37 paper and pulp mills in the states of Washington, Oregon, and California, to be followed through March 1977 for mortality experience (Robinson et al., 1986). Three mills produced sulfate pulp and two produced sulfite pulp; four of the five mills used different bleaching processes as well. Men were identified from personnel records, which also contained demographic data and detailed work histories; vital status was determined through the SSA, Internal Revenue Service (IRS), state motor vehicle departments, telephone directories, and other sources. Those of unknown vital status on March 31, 1977, were assumed to be living for analyses. Comparisons were made with expected numbers of cause-specific mortality from U.S. standardized mortality rates. Analyses were not specific for individuals involved in processes with potential dioxins exposure.

Participants in a cohort study to evaluate respiratory health in Berlin, New Hampshire, in 1961 were identified for inclusion in a cohort to evaluate mortality (Henneberger et al., 1989). Occupational histories were available for those in the 1961 cohort, which were used to determine employment in the paper and pulp mill in Berlin, New Hampshire, as well as exposures. Those who participated in the 1961 study who had worked in the mill for at least one year, and who had worked in another paper and pulp mill for less than five years, were eligible as the cohort for the mortality study; a total of 883 white men were included. Exposure groupings were defined for the cohort as (1) pulp mill work for at least one year; (2) paper mill work for at least one year; and (3) other paper company work for at

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 7-1 Epidemiologic Studies—Occupational Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Production Workers

NIOSH

Fingerhut et al., 1991

Cohort

Cancer mortality in male workers from 12 plants producing TCDD-contaminated chemicals (1942-1984), compared to U.S. population

5,172

Calvert et al., 1991

Cohort

Study of workers employed at one of two plants manufacturing substances contaminated with TCDD 15 years or more prior to assessment of chronic bronchitis, COPD, ventilatory function, thorax, and lung abnormalities, compared to neighborhood controls without exposure to TCDD

281

260

Calvert et al., 1992

Cohort

Assessment of liver and gastrointestinal systems in same group as Calvert et al. (1991)

281

260

Alderfer et al., 1992

Cohort

Assessment of psychological variables to determine depression in same group as Calvert et al. (1991)

281

260

Sweeney et al., In press

Cohort

Peripheral neuropathy in same group as Calvert et al. (1991)

281

260

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Monsanto

Zack and Suskind, 1980

Cohort

Evaluation of mortality experience among employees with chloracne exposed to TCP process accident in 1949 at Monsanto, compared to U.S. male population standard

121

Zack and Gaffey, 1983

Cohort

Study of mortality experience of all white male workers (1955-1977) employed at a Monsanto plant through Dec. 31, 1977, compared to mortality of standardized U.S. population rates

884

Suskind and Hertzberg, 1984

Cohort

Evaluation of health outcomes (1979) at clinical examination among workers exposed to 2,4,5-T (1948-1969) compared to nonexposed workers at same Monsanto plant

204

163

Moses et al., 1984

Cohort

Study of health outcomes in Monsanto workers (1948-1969) with chloracne reported as a surrogate to 2,4,5-T exposure compared to health outcomes in workers without chloracne as surrogate for no exposure

117

109

Collins et al., 1993

Cohort

Mortality of workers (through 1987) exposed and unexposed to dioxin between March 8, 1949 and November 22, 1949 as indicated by presence of chloracne, compared to local population mortality rates

122 with chloracne

632 without chloracne

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Dow

Ott et al., 1980

Cohort

Mortality experience among workers exposed to 2,4,5-T in manufacturing (1950-1971) compared to mortality experience of U.S. white men

204

Cook et al., 1980

Cohort

Mortality experience (through 1978) of male workers involved in a chloracne incident (1964) from TCDD exposure, compared to mortality experience of U.S. white men

61

Bond et al., 1987

Cohort

Extension of Cook et al. (1980) study, mortality through 1982

322

(1) U.S. white male population

(2) 2,026 employees without chloracne

Bond et al., 1983

Cross-sectional

Study of differences in workers potentially exposed and unexposed to TCDD during chemical production for (1) morbidity and (2) medical examination frequency between 1976 and 1978

(1) 183;

(2) 114

(1) 732

(2) 456

Cook et al., 1986

Cohort

Mortality experience (1940-1979) of men manufacturing chlorinated phenols compared to U.S. white men

2,189

Ott et al., 1987; Cook et al., 1987

Cohort

Expanded Cook et al. (1986) study an additional three years, through 1982

2,187

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Bond et al., 1989b

Cohort

Extension of Ott et al. (1987) study through 1984

2,187

Bond et al., 1989a

Cohort

Study of incidence of chloracne among a cohort of workers potentially exposed to TCDD, and association with other risk factors

2,072

Internal comparison

Bond et al., 1988

Cohort

Study of mortality (through 1982) among workers potentially exposed to 2,4-D (1945-1983) compared to U.S. white males and all other male employees not exposed

878

(1) U.S. white male population

(2) 36,804 employees not exposed

Sobel et al., 1987

Case-control

Study of STS among Dow chemical employees (1940-1979) compared to employees without STS for possible association with several chemical exposures

14

126

Townsend et al., 1982

Cohort

Study of adverse reproductive outcomes among wives of Dow chemical employees potentially exposed to TCDD (1939-1975) compared to reproductive outcomes among wives whose husbands were not exposed

370

345

Other chemical plants

Thiess et al., 1982

Cohort

Study of mortality experience among BASF employees potentially exposed to TCDD during Nov. 17, 1953 accident compared to population and other workers not exposed

74

External controls: 180,000 town 1.8 million district 60.5 million Federal Republic of Germany Two groups of 74 each from other cohort studies

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Zober et al., 1990

Cohort

Mortality experience of workers exposed to TCDD (1954-1987) at BASF plant compared to population of Federal Republic of Germany

247

Manz et al., 1991

Cohort

Mortality experience of workers (1952-1984) at Hamburg plant of Boehringer exposed to TCDD compared to national mortality and workers from another company

1,184 men

399 women

(a) population

(b) 3,120 gas workers

Saracci et al., 1991

Cohort

Study of mortality experience of 20 international cohorts of herbicide sprayers and production workers compared to mortality experience expected for the nation

16,863 men 1,527 women

Coggon et al., 1986

Cohort

Study of mortality experience (through 1983) among workers manufacturing and spraying MCPA (1947-1975) compared to expected numbers of deaths among men of England and Wales and for rural areas

5,754

Coggon et al., 1991

Cohort

Mortality experience among four cohorts of workers potentially exposed (1963-1985) to phenoxy herbicides and chlorophenols compared to national (England and Wales) expected numbers and to the local population where factory is located

1,104 Factory

A 271 Factory

B 345 Factory

C 519 Factory

D

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Jennings et al., 1988

Cohort

Assessment of immunological abnormalities among workers exposed to TCDD during accident manufacturing 2,4,5-T compared to matched controls

18

15

May, 1982, 1983

Cohort

Health outcomes among workers exposed and probably exposed to TCDD following a 1968 accident, compared to unexposed workers

41 exposed

54 possibly exposed

31

Bueno de Mesquita et al., 1993

Cohort

Mortality experience of production workers exposed to phenoxy herbicides and chlorophenols in the Netherlands compared to national rates

2,310

Bashirov, 1969

Cross-sectional

Descriptive results of examination of workers involved in production of herbicides and study of workers at examination of cardiovascular and digestive systems compared to unexposed controls

292 (descriptive)

50 (examined)

20 (examined)

Lynge, 1985

Cohort

Study of cancer incidence among Danish workers exposed to phenoxyherbicides compared to expected results from the general population

3,390 men

1,069 women

Pazderova-Vejlupkova et al., 1981

Descriptive

Study of development of TCDD intoxication among men in Prague (1965-1968)

55

No comparison group

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Poland et al., 1971

Cross-sectional

Assessment of PCT, chloracne, hepatotoxicity, and neuropsychiatric symptoms among 2,4-D and 2,4,5-T workers compared to other plant workers

73 total;

20 administrators;

11 production supervisors;

28 production workers;

14 maintenance workers

Internal comparison

Thomas, 1987

Cohort

Assessment of mortality experience as of Jan. 1, 1981, for white men employed in fragrance and flavors plant with possible exposure to TCDD, compared to U.S. white men and for cancers compared to local men

1,412

Agricultural/Forestry Workers

Cohort studies

Agricultural workers

Burmeister, 1981

Cohort

Study of mortality of farmers compared to nonfarmers in Iowa (1971-1978)

6,402

13,809

Wigle et al., 1990

Cohort

Mortality experience of male farmers 35 years or older (1971-1985) in Saskatchewan, Canada, compared to age-and period-specific mortality rates expected for Saskatchewan males

69,513

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Morrison et al., 1993

Cohort

Mortality experience of male Canadian farmers 45 years or older in Manitoba, Saskatchewan, and Alberta, Canada (1971-1987), compared to Canadian prairie province mortality rates

145,383

Morrison et al., 1992

Cohort

Mortality experience of male farmers 35 years or older (1971-1987) compared to Canadian prairie province rates

155,547

Ronco et al., 1992

Cohort

Study of cancer incidence (1970-1980) among male and female Danish farm workers 15 to 74 years old, compared to expected numbers of cancers among persons economically active, and study of cancer mortality (November 1981-April 1982) among male and female Italian farmers 18 to 74 years old compared to persons in other occupational groups

No Ns given

No Ns given

Corrao et al., 1989

Cohort

Study of cancer incidence among male farmers licensed (1970-1974) to use pesticides, compared to number of cancers expected among licensed nonusers

642

18,839

Lerda and Rizzi, 1991

Cohort

Study of farmers exposed to 2,4-D as measured in urine, compared to men unexposed for differences in sperm volume, death, count, motility, and abnormalities between March and June 1989

32

25

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Hansen et al., 1992

Cohort

Study of cancer incidence among male and female Danish gardeners compared to incidence expected among the general population

4,015;

859 women, 3,156 men

Wiklund, 1983

Cohort

Study of cancer incidence (diagnosed 1961-1973) among agricultural workers in Sweden compared to rates expected from the 1960 population census

19,490

Wiklund and Holm, 1986

Cohort

STS incidence among agricultural and forestry workers in Sweden compared to the general population of men, 1960 census

354,620

1,725,845

Wiklund et al., 1988a

Cohort

Malignant lymphoma incidence among agricultural and forestry workers in Sweden compared to the general population of men, 1960 census

354,620

1,725,845

Eriksson et al., 1992

Cohort

Study of incidence of NHL, HD, and multiple myeloma (1971-1984) among selected occupational groups in Swedish men and women, compared to expected rates of disease in general population

Number in occupational group unknown

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Forestry workers

Green, 1987

Cohort

Suicide experience in a cohort of Canadian forestry workers by number of years in forestry trade as a surrogate for exposure to phenoxy herbicides compared to population

1,222

Green, 1991

Cohort

Mortality experience of male forestry workers (1950-1982) in Ontario, compared to the expected mortality of the male Ontario population

1,222

van Houdt et al., 1983

Cross-sectional

Study of acne and liver dysfunction in a select group of Dutch forestry workers exposed to 2,4,5-T and unexposed

54

54

Herbicide/Pesticide Sprayers

Axelson and Sundell, 1974

Cohort

Study of mortality and cancer incidence among cohorts of Swedish railroad workers spraying herbicides (> 45 days) compared to the expected number of deaths (1957-1972) from Swedish age- and sex-specific rates

348 total herbicide exposure 207 phenoxy acids and combinations 152 amitrole and combinations 28 other herbicides and combinations

Axelson et al., 1980

Cohort

Additional years of follow-up to cohort established in Axelson and Sundell (1974)

348

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Blair et al., 1983

Cohort

Mortality experience of white male Florida pesticide applicators compared to U.S. and Florida men

3,827

Riihimaki et al., 1982

Cohort

Study of mortality among herbicide applicators exposed to 2,4-D and 2,4,5-T in Finland compared to mortality expected in the population

1,926

Riihimaki et al., 1983

Cohort

Cancer morbidity and mortality in cohort (Riihimaki et al., 1982)

1,926

Smith et al., 1981

Cohort

Study of chemical applicators (1973-1979) in New Zealand compared to agricultural contractors for differences in adverse reproductive outcomes

459

422

Smith et al., 1982

Cohort

Study of adverse reproductive outcomes among chemical applicators and agricultural contractors by category of exposure: none; chemicals not 2,4,5-T; 2,4,5-T

113 pregnancies (chemicals not 2,4,5-T)

486 pregnancies (2,4,5-T)

401 pregnancies (not exposed)

Wiklund et al., 1987

Cohort

Risk of HD and NHL among Swedish pesticide applicators from date of license through 1982, compared to expected number of cases in the total population

20,245

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Wiklund et al., 1988b

Cohort

Risk of STS in Wiklund et al. (1987) cohort through 1984

20,245

Wiklund et al., 1989a

Cohort

Risk of cancer in Wiklund et al. (1987) cohort through 1982

20,245

Wiklund et al., 1989b

Cohort

Risk of STS, HD, and NHL in Wiklund et al., 1987 cohort through 1984

20,245

Swaen et al., 1992

Cohort

Cancer mortality experience (through 1987) among Dutch male herbicide applicators licensed before 1980, compared to the total male Dutch population

1,341

Bender et al., 1989

Cohort

Cancer mortality of Minnesota highway maintenance workers compared to expected numbers based on white Minnesota men

4,849

Barthel, 1981

Cohort

Study of male agricultural production workers (1948-1972) for incidence of cancer, compared to incidence rates expected in the population

1,658

Case-control studies

Hardell and Sandstrom, 1979

Case-control

Study of male cases of STS (26-80 years) diagnosed between 1970 and 1977 in northern Sweden, compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

52

206

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Eriksson et al., 1979, 1981

Case-control

Study of cases of STS diagnosed between 1974 and 1978 in southern Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

110

219

Hardell and Eriksson, 1988

Case-control

Study of male cases of STS (25-80 years) diagnosed between 1978-1983 in northern Sweden compared to two referent groups: (1) population-based, (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 1975-1982 in southeast Sweden, compared to two referent groups: (1) population-based sample, (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 1978-1986 in central Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

218

212

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Case-control

Study of malignant lymphomas (HD, NHL, unknown) diagnosed in men age 25-85, between 1974 and 1978 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 in men 28-85, between 1974 and 1978 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 1970-1979 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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Hardell et al., 1984

Case-control

Study of primary liver cancer diagnosed 1974-1981 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

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 1976-1980 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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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 1977-1981 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 1971-1981 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 (Pearce et al., 1986b) study 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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

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, chronic lymphocytic leukemia for association with herbicides (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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Burmeister et al., 1983

Case-control

Study of multiple myeloma, NHL, 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, 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 males (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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group(N)

Comparison Group (N)a

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

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

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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 1983-1984 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., 1986

Case-control

Study of cases of STS in men and women diagnosed 1981-1983 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 1982-1988 in Australia, compared to other cancers for association with exposure to phenoxy herbicides and chlorophenols

82

82 other cancers;

82 population

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

LaVecchia et al., 1989

Case-control

Study of Italian men and women with HD, NHL, and MM (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

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

Approximately 135,000

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

a The dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

least one year, with no work in either the paper or the pulp mill. Vital status was determined through August 1, 1985, using information from the 1961 study follow-ups, contacts with relatives and friends, telephone books, city directories, SSA, and the NDI. Comparisons were made to death rates from U.S. vital statistics.

The third study was a PMR analysis of 201 white males who died between 1970 and 1984 and who had been employed in pulp and paper production plants (Solet et al., 1989). The workers were identified from the United Paperworkers International Union and were vested (employed at least 10 years) in the union's Paper Industry Union-Management Pension Fund. Data were obtained from the pension fund files for those who were deceased; employment history consisted of the plant and years worked there. Expected mortality, adjusted for sex, race, age at death, and calendar year of death, among U.S. males was used as a comparison. No data on potential exposure to processes involving TCDD were available.

A small cohort study of Finnish paper mill workers investigated the association of potential exposure to PCDD compounds, including TCDD, with lung cancer as well as all sites combined (Jappinen and Pukkala, 1991). One hundred fifty-two male pulp and paper mill workers in Finland who had been exposed to TCDD and dibenzofurans in bleach (organic chlorine compounds) for one year or more from 1945 to 1961 were followed from January 1, 1953, until December 31, 1987, for cancer incidence. Data from the Finnish Cancer Registry were used to identify incident cancers; the National Population Register was used to identify mortality. Expected numbers were obtained from rates of the local central hospital district. Exposure assessment was not performed, but association was studied specifically among subgroups chosen to have different levels of exposure to chlorinated compounds. No smoking data were available.

Other Occupational Studies

Following an electrical transformer fire in 1981, in a building in Binghamton, New York, TCDD was identified in the soot samples analyzed; 482 persons potentially exposed to polychlorinated biphenyls (PCBs), dibenzo-p-dioxins, and dibenzofurans were followed for adverse health effects (Fitzgerald et al., 1989). Of those potentially exposed, 155 were not actually in the building, but in the vicinity. A questionnaire was sent in April 1984 to all participants who had been identified originally. Questions concerning health status and reproductive history were asked; repeated attempts were made to contact those not known to be deceased. Hospital, physician, and pediatric reports were sought to verify medical and reproductive outcomes reported; computer linkages of the cohort with New York State vital records and the Cancer Registry were used to identify deaths (including spontaneous abortions

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

and fetal or infant deaths) and cancers between 1981 and 1984. Expected numbers for comparison were obtained from corresponding population rates of upstate New York (state of New York exclusive of New York City). The final study sample included 377 respondents.

ENVIRONMENTAL STUDIES

The occurrence of accidents and industrial disasters has offered opportunities to evaluate the long-term health effects of exposure to dioxin and other potentially hazardous chemicals. Among these disasters is the accidental explosion, on July 10, 1976, of a factory in Seveso, Italy, that produced trichlorophenol, which resulted in the release of TCDD-containing compounds into the surrounding environment, exposing those living in the area. Details of the accident and exposure are included in Chapter 2. The epidemiologic studies on these populations are summarized in Table 7-2.

Seveso

The incidence of neurological disorders following exposure to TCDD was the focus of one study initiated shortly after the Seveso accident on July 10, 1976 (Boeri et al., 1978). The accident resulted in what are subsequently referred to as exposure zones based on contamination of the soil: zone A included residents who were evacuated from the area around the plant (N = 734); zone B included residents who were exposed, but to a lesser extent (N = 4,699); and zone R included residents who had the lowest exposure (N = 31,800). Residents from zone A were invited for neurological examination, and 470 of 723 residents volunteered; invitation was by letter or personal invitation during home screening visits (Filippini et al., 1981). Residents of zone R requested examination, although not originally designated for inclusion in the study, however, since examinations of controls were not completed, volunteers from this zone (N = 152) were examined for comparison with the zone A participants. Neurologic testing occurred in March 1977. Although actual individual exposures were unknown, residence in a high- versus low-exposure potential area was considered as the exposure. As a follow-up to the screening above, residents were invited to return in April 1978 for a second neurological screening, to be compared with results from neurological tests of those in unpolluted areas around Seveso (Filippini et al., 1981). Of the 709 Seveso residents invited, 308 who attended the second screening were eligible for inclusion; subjects were examined clinically, completed a medical history questionnaire, and underwent an electrophysiologic investigation. A nonexposed population of 305 provided referent levels of neurological functioning. Analyses were done by comparing those with symptoms of neuropathy or previously studied

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

indicators of TCDD exposure (chloracne, gamma-glutamyl transpeptidase, glutamic-oxalacetic transaminase, or glutamic-pyruvic transaminase) to those with neither symptoms nor indicators.

With chloracne being used as a marker of exposure to TCDD, 152 Seveso residents with chloracne or a history of the lesions agreed to be examined for the presence of peripheral nervous system involvement as a long-term effect of exposure (Barbieri et al., 1988). The control group consisted of 123 age- and sex-matched subjects living in nearby towns with similar environmental pollution. The study was conducted from October 1982 to May 1983; medical history, occupational exposures to neurotoxic agents, dermatologic exam, laboratory testing, and neurological examination were completed on all study participants.

Descriptive data results of selected health outcomes that occurred among residents of the Seveso area after July 10, 1976, were reported (Bisanti et al., 1980). The number of residents included in this report differs slightly from the numbers presented above; here, for zone A, N = 730; zone B, N = 4,737; and zone R, N = 31,800. Health outcomes reported included chloracne, birth defects, and spontaneous abortions, as well as crude birth and death rates.

The distribution of chloracne among the population exposed in zones A, B, and R, especially among children, and associations with other diseases among those with and without chloracne are presented (Caramaschi et al., 1981). After the accident, reports of skin lesions were made, and cases of chloracne were diagnosed; data regarding dermatological conditions were collected by the Department of Dermosyphilopatic Diseases of the University of Milan; additionally, dermatological screening of children under 15 years was conducted between February and April 1977. Two groups of children, one with chloracne (N = 146) and one without symptoms (N = 182), were clinically followed with medical examinations and biochemical tests. Cases of chloracne were included from each of the three zones, as well as from non-ABR zones.

Children in the zones around Seveso were examined periodically for chloracne and were tested for laboratory levels of several chemicals in the blood and urine, to compare them to normal levels expected among children not exposed to TCDD (Mocarelli et al., 1986). Children residing in zone A (N = 69), zone B (N = 528), a subset of more highly exposed children in zone B (N = 83), zone R (N = 874), and a subset from zone R as a control group (N = 241) were followed over six years for levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, cholesterol and triglycerides, and amino levulinic acid in urine; these values were compared to a sample of 1,000 subjects used by the laboratory to establish ''normal" values.

In a follow-up to these studies (Caramaschi et al., 1981; Mocarelli et

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

al., 1986) in children, dermatologic findings and laboratory tests were conducted among a group of the children with chloracne compared to controls (Assennato et al., 1989a).

Adults and children in the area of Seveso and surrounding unexposed communities were the subjects of a study of urinary d-glucaric acid as an indicator of induced hepatic enzymes associated with the TCDD exposures in the area (Ideo et al., 1985); an earlier study evaluated these enzymes in children with and without chloracne (Ideo et al., 1982). As part of the monitoring plan of the Seveso area, residents of zone B had blood drawn for testing, and for one week in February 1978, urine was collected from 117 adults as well; 127 residents of an unexposed community contributed urine specimens as a control group. Nonparametric statistical methods were used to compare levels of liver enzyme activity between groups because of the relatively small size of the sample.

A 10-year follow-up of individuals exposed to TCDD following the accidental explosion in Seveso has been reported (Bertazzi et al., 1989a,b). All persons who resided in any of the 11 towns included in the two health districts that were in the contaminated zones of Seveso (A, B, and R) were eligible for study follow-up; information collected included demographics, residence at time of the accident and subsequently, and date of first residence for those moving into the area. Classification of exposed residents of the Seveso area was according to zones A (N = 556), B (N = 3,920), and R (N = 26,227), or outside the contaminated boundaries, based on residence at the time of the accident or at first entry to the area. Study subjects were followed through national records throughout the country as of December 31, 1986; cause of death for those deceased was as certified by the attending physician and reported to the National Statistics Institute of Italy. The reference population was the cohort residing outside the contaminated A, B, and R zones (N = 167,391).

Cancer incidence over the same period for this cohort has also been evaluated, using rates for the Lombardy region from hospital discharge registration as a comparison (Pesatori et al., 1992).

Reported separately are the results of a 10 year follow-up mortality study (1976-1986) of children age 1-19 at the time of the accidental explosion in Seveso of the TCDD factory (Bertazzi et al., 1992), with methods similar to those used for adults described previously. The 19,637 subjects that were exposed (zones A, B, and R) and a reference group of 95,339 people living in the surrounding districts formed the basis of this study. The follow-up was nearly 99 percent for vital status as of December 31, 1986. Exposure data are reasonably good for the amount of TCDD on the ground in different zones beyond the factory. However, there is no individual quantification of exposures.

A two year prospective controlled study was conducted of workers potentially

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

exposed to TCDD during the cleanup of the most highly contaminated areas following the Seveso accident (Assennato et al., 1989b). Preemployment examinations were performed from March to June 1980 to select the study groups. Workers who met certain criteria (age and certain health characteristics) were assigned to either the cleanup group or the comparison group. Periodic examinations were conducted every six months. The cleanup group was provided with protective clothing and was subject to safety measures designed to minimize the potential for exposure. At the conclusion of the study, hypothesized TCDD-related clinical disease (i.e., chloracne, liver disease, peripheral neuropathy, porphyria cutanea tarda) and differences in biochemical outcomes were compared between the two groups.

All live and stillbirths from January 1, 1977, to December 31, 1982, to women who were residents in zones A, B, R, and non-ABR were reported to an ad hoc birth defects registry, the Seveso Congenital Malformation Registry (Mastroiacovo et al., 1988). Classification of infant exposure was based on residence of the mother; ascertainment of the malformation data was obtained from maternity hospitals, pediatric departments, and primary care pediatric services. A special team examined all reports to the registry. Registered infant malformations were considered as major or mild. A total of 15,291 births were included in the registry for this time period.

A cytogenetic analysis of maternal and fetal tissues from a control sample of women not exposed to environmental mutagens, who underwent an induced abortion between 8 and 11 weeks gestation, was compared to similar tissues from women exposed to TCDD around Seveso (Tenchini et al., 1983). The frequencies of aberrant cells, the relative proportions of individual types of chromosomal aberration, the average number of lesions per damaged cell, and the frequencies of polyploids were compared in maternal blood and placenta in the two samples.

Times Beach and Quail Run

During early 1971, by-products of a hexachlorophene and 2,4,5-T production facility in Verona, Missouri, were mixed with waste oils and sprayed on various sites around the state for dust control. TCDD was a contaminant of the mixtures sprayed, and the contamination was reported by the Environmental Protection Agency (EPA). A pilot study to evaluate health effects from potential exposure was conducted in the state in 1983, and results were reported (Stehr et al., 1986; Webb et al., 1987). At the time the pilot was designed, the environmental data available were limited, direct measures of TCDD body burden were not available, and health effects to be investigated were uncertain; the pilot was designed to potentially direct future research. Assessment of potential health effects was determined through

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

three means, including a health effects survey questionnaire that included information on exposure-risk (residence, recreation, occupation), medical history, and potential confounding variables. Individuals were given the questionnaire if they lived near, worked at, or participated in activities near a contaminated site; persons were so identified from response to a media announcement. The second assessment of health effects was through a dermatology screening clinic for anyone in the population suspecting exposure, and the third assessment of health effects was through a pilot medical study from among completed questionnaire respondents. A high-risk group (N = 68) consisted of those who had lived or worked at least six months in highly TCDD-contaminated areas; low-risk comparison subjects (N = 36) were selected from among the lowest exposed of the 800, and matched on type of exposure site, age, sex, race, and socioeconomic status (SES). The clinical protocol included physical, neurologic, and dermatologic exams; lab analysis; immune response tests; and storage of serum. All comparisons made were between low- and high-risk exposure groups.

Participants from the original study who did not respond to any of the delayed-type hypersensitivity skin test antigens or who responded to only one antigen (50 exposed and 27 unexposed) were invited back for retesting, and results are reported for 28 exposed and 15 unexposed individuals (Evans et al., 1988).

One of the sites with extremely high levels [2,200 parts per billion (ppb)] of TCDD from the study described above, was the area of Quail Run Mobile Home Park; residents were followed for long-term health effects between 1971 and 1983 (Hoffman et al., 1986; Stehr-Green et al., 1987). Residents were eligible for inclusion in the study if they had lived at Quail Run for at least six months between April 1971 and May 1983; of 207 potentially eligible households, 95 were located and a total of 154 persons enrolled in the study. A comparison group consisted of residents for at least six months of another mobile home park of comparable size, with similar homes and upkeep; three mobile home parks with no TCDD contaminants in the soil on testing constituted 515 households. Of those eligible to participate, 155 individuals agreed. Medical examinations of all participants were conducted from November 1984 to January 1985 by one of two physicians, blinded to subject's exposure status. Additionally, urine and blood samples were collected, delayed-type hypersensitivity testing was done, sensory peripheral neuropathy was tested, neurobehavioral tests were administered, and a standard interview of SES and household occupation was conducted. Comparisons were made between the exposed and unexposed mobile home residents; for physician-diagnosed medical conditions, 137 of the 154 exposed subjects were matched to unexposed subjects on sex, race, and age (within five years for those > 15 years of age, within two years for those <15 years old). Diagnoses of medical conditions for both pair members

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

were included only if the diagnosis occurred after the participant's first residence in Quail Run until November 1984.

Further epidemiologic investigation examined adverse human reproductive outcomes associated with exposure to soil contaminated during 1971 with TCDD in residential areas of Missouri (Stockbauer et al., 1988). A pregnancy was considered as potentially "exposed" to TCDD if the mother's address on the birth or fetal death certificate was in an area with documented TCDD contamination equal to or greater than 1 ppb in proximity to the house. Missouri vital statistics data for live births and fetal deaths between January 1, 1972, and December 31, 1982, were linked to map and environmental sampling data for nine residential sites determined to have been contaminated by TCDD. The linkage resulted in 410 potentially exposed pregnancies. The majority (N = 319) of the births were from residents of the Times Beach area. For comparison, two births from unaffected areas of Missouri were selected for each exposed birth matched on maternal age, race, hospital of birth, and year of birth. Further exclusions, such as one member from each twin set or unavailable medical records, resulted in 402 exposed and 804 unexposed births that were reviewed for the presence of birth defects. Newborn medical records were reviewed (blind to exposure status) for the presence of selected structural, chromosomal, and biochemical defects. In addition, a statewide search of every hospital and major clinic in Missouri was undertaken to identify cases of birth defects. Variables obtained from the birth certificates included birthweight, sex of the infant, maternal education, parity, marital status, prepregnancy weight, smoking during pregnancy, and history of previous spontaneous or induced abortions. An attempt was made to classify exposed births further on the basis of the extent of potential TCDD exposure. First, the birth data set was compared with a Missouri central listing of TCDD-exposed persons. This list was derived from self-reported information from persons who thought they had been exposed to TCDD. Individuals on this list were divided into a high-risk group (lived at least six months in TCDD > 100 ppb contaminated areas or two years in 20-100 ppb contaminated areas) and a low-risk group (similar contamination levels, but lived there for less than stated time or lived where contamination was 1-19 ppb), based on time lived in the area and soil concentrations of TCDD. The investigators also compared births from 1972 to 1974 with births from 1975 to 1982, assuming a higher likelihood of exposure during the period of spraying of dirt roads with TCDD-contaminated oil prior to 1974.

Vietnam

Studies of the population of Vietnam who were exposed to the spraying that occurred during the Vietnam conflict have been conducted by Vietnamese

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

investigators, and the unpublished results of these studies have been summarized in a review paper by Constable and Hatch (1985). These studies focus primarily on reproductive outcomes, since the early laboratory studies indicated that adverse pregnancy outcomes could result from exposure to TCDD. Studies were conducted comparing couples who lived in sprayed areas in the South with couples living in unsprayed areas; some studies compared couples living in the North with couples living in the South of Vietnam; other studies compared couples living in the North in which husbands did and did not serve in the South. There were nine reports included in the review article, which are summarized as follows: (1) Khoa (1983): rates of obstetric events 1965-1982 among Montagnards living in a heavily sprayed area of southern Vietnam; (2) Nguyen (1983): rates of obstetric events 1979-1981 in a provincial hospital in a heavily sprayed area of southern Vietnam; (3) Trung and Chien (1983): comparison of rates of miscarriage and birth defects before and after spraying in an exposed and an unexposed village in southern Vietnam; (4) Huong and Phuong (1983): time trends analysis of reproductive events 1952-1981 with a case-control study of herbicide exposure and hydatidiform mole in Obstetric Hospital, Ho Chi Minh City; (5) Phuong and Huong (1983): comparison of reproductive problems in women exposed to herbicides in southern Vietnam and unexposed in southern and northern Vietnam; (6) Lang et al. (1983a): comparison of birth defects in offspring of soldiers from agricultural villages in northern Vietnam who did and did not serve in the South; (7) Lang et al. (1983b): comparison of miscarriage rates according to degree of northern Vietnam veterans' herbicide exposure; (8) Can et al. (1983b): comparison of reproductive events among wives of exposed and unexposed northern Vietnam veterans from three areas; (9) Can et al. (1983a): case-control study of birth defects in relation to northern Vietnam veterans' service in the South. Three studies in Vietnam were later published, and detailed methods follow.

The mortality experience from 1966 to 1986, in two villages that were sprayed with Agent Orange in Vietnam was compared with mortality in a village that remained unsprayed (Dai et al., 1990). Estimates of amount of exposure received during spraying for the three villages were obtained from published spray records; the village was considered as having been hit if the mission passed within 10 km of the village center. Since most babies in Vietnam are breast-fed, the possible effects of exposure of the mother on the offspring were of concern. Study subjects from the villages were interviewed on residential history, life-style, demographics, economic status, occupational history, chemical exposures (fertilizer and insecticides at least once a year), health status, medical history, and births and deaths of children; interviewers were not blinded to exposure status. Classification of exposure was into four groups, with two criteria to be met for each level of

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

exposure; if only one criterion per level was met, the exposure level assigned was the next lower. The categories were "heavy" (lived more than three years in sprayed area, and directly sprayed three or more times); "moderate" (lived in sprayed area one to three years, and directly sprayed one or two times); "light" (lived less than one year in sprayed areas, and not directly sprayed); "none" (lived in nonsprayed area during the Vietnam conflict).

To evaluate the potential association between mother's exposure to Agent Orange and TCDD during the Vietnam conflict, and the occurrence of birth defects or hydatidiform mole, a case-control study was conducted in Ho Chi Minh City, Vietnam (Phuong et al., 1989a). Cases were babies born with gross congenital anomalies during the period May 1-June 14 and July 18-August 25, 1982, in the Ob-Gyn Hospital of Ho Chi Minh City; also included were patients producing placentas with hydatidiform mole, with or without choriocarcinoma. Controls for birth defect cases were live births in the same time period; controls for the hydatidiform mole were patients admitted for vaginitis or exocervicitis. Matching variables for cases and controls included date of admission within seven days, SES, and residing originally in the southern part of Vietnam. Exposure was determined by mother's residence in villages known to be heavily sprayed primarily between 1965 and 1970.

Another study in southern Vietnam (May 2, 1982-June 15, 1982) evaluated reproductive abnormalities occurring among births to families resident in the heavily sprayed village of Thanh Phong, compared to births from families in Ho Chi Minh City (Phuong et al., 1989b). Mothers were interviewed for demographic information including residence from 1952 to 1982 and possible herbicide exposure. Data on behavioral habits including diet, smoking, and alcohol were also collected. Obstetrical history and determination of incidence of congenital anomalies were obtained in a separate interview. A total of 7,327 births occurred to Thanh Phong families and 6,690 births in commune 10, Ho Chi Minh City. Exposure in Thanh Phong was historically estimated to be heavy, moderate, or light. Heavy exposure included multiple spraying episodes and always resident in Thanh Phong. Moderate exposure included two sprayings and resident at least two years in Thanh Phong. Light or no exposure included less than two sprayings or indirect spraying, or residence in Thanh Phong after 1971.

Other Environmental Studies

In response to the concern of women in Alsea, Oregon, who believed their miscarriages were associated with local herbicide spraying, a study was undertaken by the Human Effects Monitoring Branch in the EPA Office of Pesticide Programs (U.S. EPA, 1979). An initial health questionnaire

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

survey (Alsea I) of nine women who had experienced 13 confirmed miscarriages from May 1973 to March 1978 prompted a study of the six year spontaneous abortion rates in three areas of Oregon (Alsea II). The definition of the study area, which was primarily rural, was around the "Alsea basin" in Oregon, as defined by U.S. Postal Service zip codes. Four hospitals in the largest towns were the source of birth information for the Alsea II study. The control study area was a primarily rural area, with little or no reported use of 2,4,5-T, where hospital facilities and physician practices were anticipated to be similar to those in the "exposed" area; the two hospitals in the control area were located in the two largest towns. Additionally, an urban area located in the agricultural nonforested Willamette Valley of Oregon was identified. The main hospital in this area was used by women delivering babies; it was used by women in other study areas as well. Spraying in the area of interest was determined through information supplied by major organizations using the chemicals, and consisted of date of application, rate of application, formulation, number of acres sprayed, and location of the sprayed areas. The areas sprayed were plotted on a map; seasonal usage patterns were also noted. All hospitals noted above were sources of spontaneous abortion data; for each spontaneous abortion, ICD code, age of patient, date of spontaneous abortion, gestation period, and patient's zip code were obtained from all records between 1972 and 1977. Physicians in the area were also contacted to assess their estimates of the number of spontaneous abortions that had been treated in the time period of interest; these interviews were not conducted in the control area. Computer tapes of births per month were obtained from the Vital Statistics Section of the Oregon State Health Department; birth certificate data were also obtained from this source. A spontaneous abortion index was developed for each area to account for number of births occurring in the area.

In an area of Northland, New Zealand, rates of occurrence of all diagnosed malformations, excluding miscarriages less than 28 weeks, were correlated with densities of 2,4,5-T sprayed during the same period (Hanify et al., 1981). Seven areas, as defined by location of the hospitals, were used in determining births in the hospitals and spraying as indicated by company records for those doing the spraying. Little spraying was done between 1959 and 1965; therefore, January 1, 1960-August 31, 1966, was used as the "unexposed" period, and September 1, 1972-August 31, 1977, as the "exposed" period.

An ecological study design was used to examine the relationship between the prevalence of oral cleft palate and the use of 2,4,5-T in Arkansas (Nelson et al., 1979). In order to estimate 2,4,5-T exposure, herbicide application reports were obtained from the Arkansas State Plant Board for 1970-1974. It was found that 58 percent of the acreage treated with 2,4,5-T was planted with rice; since rice is the major crop treated with 2,4,5-T, the

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

investigators assumed that the ratio of rice acreage to total acreage could be used to divide the 75 Arkansas counties into high (5 percent or more of total acreage planted with rice in 1974), medium (1.3-4.5 percent), and low exposure (0-0.9 percent). Ascertainment of oral clefts was conducted by using birth certificates (1943-1974) and records from the Crippled Children's Services of Arkansas.

A case-control study in Iowa and Michigan was undertaken to evaluate the potential association between agricultural use of chemicals and cleft lip or palate (Gordon and Shy, 1981). Based on a number of criteria (number of births, adequate birth defect reporting, agricultural status), Iowa and Michigan were chosen as the study area; National Center for Health Statistics data for 1974-1975 were used to identify cases and controls. Cases were infants born with cleft lip and/or palate in either Iowa or Michigan in 1974 or 1975. Controls were a random sample (2 percent) of live births in each state, which yielded approximately a 5:1 ratio of controls to cases. The study sample was restricted to white, liveborn singletons from rural areas; children with multiple malformations were excluded, for a final sample of 187 case and 985 control births. Two surrogate measures of exposure were used. The first was a ratio of the number of acres of a specific crop to the number of acres of farmland by county. The second measure was a ratio of the number of acres of cropland in which chemicals (herbicides and pesticides) were applied to the number of acres of farmland by county. For each state, exposures were categorized as crops only, all pesticide chemicals and fertilizers, and "suspect" chemicals (pesticides only). Within each of these categories, each county was assigned either a high or a low score on each crop and chemical. Finally, the county score, the sum of the high and low scores, was calculated within the three exposure categories and assigned to each study subject in that county. Further rescoring of the exposure variables was done, resulting in a dichotomous variable with 0 equal to a high score on no more than two chemicals and 1 for a high score on three or more chemicals.

Stillbirths and birth defects were compared to control births for association with exposure to chemicals used in agriculture in areas where the births occurred in New Brunswick, Canada, between 1973 and 1979 (White et al., 1988). Statistics Canada was the source of stillbirth information, and the Canadian Congenital Anomalies Surveillance System was the source of birth defect data. Chemical use data were compiled from the New Brunswick Department of Environment through maps and records from the spray application companies. Since there were no records for most of the period in question for chemical use in agriculture, an index of chemical exposure opportunity was developed based on where agricultural production might occur. Included in the pesticides under consideration as exposures were fentrothion formulations, aminocarb formulation, other forest insecticides,

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

herbicides with some phenoxy component, herbicides with only phenoxy, chlorinated herbicides, and nonchlorinated herbicides. Birth defects identified included neural tube defects, facial clefts, and bilateral renal agenesis. Correlational analyses, comparisons of mean rates of birth defects by periods of spraying, and a case-control analysis were conducted. For the case-control study, controls were identified from the Provincial Registry of Live-births and Statistics Canada; approximately two controls per case were selected and matched in one set by date of birth and sex, and in another set by county and date of birth, but from a different year. The residence in which the mother lived when giving birth determined the "exposure-risk window," calculated for the first trimester as the 2 weeks before and the 13 weeks after conception, and in the second trimester, from 14 to 27 weeks gestation. To calculate the exposure, (1) the occurrence of the spraying and the mother's residence were plotted on a map; (2) a radius was centered on the residence; and (3) potential exposure to forestry insecticides was quantified by the number of dots in the circle that occurred in the sprayed area.

A case study and a registry-based study were conducted in the county of Skaraborg, Sweden, in 18 boroughs with incinerators (Jansson and Voog, 1989). The case study was a patient investigation for six children born with cleft lip and/or palate between April and August 1987, and an exposure assessment including meteorological and dispersal calculations. The registry study compared numbers of cleft lip and palate occurring in the county of Skaraborg and the constituent boroughs between 1975 and 1987, compared to expected numbers. Rates of cleft lip before and after incinerators were introduced were compared during 1973-1986 for boroughs with cities excluded. The exposure of interest was municipal incinerators that were suspected of discharging high doses of TCDD in the area.

Since the mortality rates from STS and connective tissue cancers were apparently elevated in Midland County, Michigan, between 1970 and 1979, compared to the state of Michigan, an investigation of this potential excess was evaluated in conjunction with residence of the cases (Michigan Department of Public Health, 1983). Between 1960 and 1981, 20 deaths were coded as STS or connective tissue cancer in the Michigan Death Statistics. Rates of mortality were compared for each Michigan county, based on data for the period 1970-1981 from Michigan death certificates; comparisons were made with national and state rates. Residence for cases reported was investigated beyond what was reported on the death certificate as last known residence. Residence history, particularly for the period of interest (1960-1981), was obtained through interviews with next of kin; occupational history information was also obtained. Of particular interest was whether the decedent had been employed at Dow Chemical or Dow Corning, which would have potentially involved exposure to TCDD. Mortality rates were therefore examined for the 29 U.S. counties in which

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 7-2 Epidemiologic Studies—Environmental Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Seveso

Boeri et al., 1978

Cohort

Evaluation of neurological disorders among Seveso residents exposed to TCDD on July 10, 1976, compared to residents in unexposed areas

470 zone A

152 zone R

Filippini et al., 1981

Cohort

Comparison of prevalence of peripheral neuropathy on two screening examinations among Seveso residents, compared to residents in unexposed areas

308

305

Barbieri et al., 1988

Cohort

Comparison of prevalence of peripheral nervous system involvement among Seveso residents with chloracne, compared to residents in unexposed areas

152

123

Bisanti et al., 1980

Descriptive

Descriptive report of selected health outcomes among residents of Seveso located in zones A, B, R

730 zone A;

4,737 zone B;

31,800 zone R

No comparison group

Caramaschi et al., 1981

Cohort

Evaluation of chloracne among children in Seveso, compared to children with no chloracne, and association with other health outcomes between chloracne and no chloracne groups

146

182

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Mocarelli et al., 1986

Cross-sectional

Study of laboratory measures of serum and urine in Seveso zone A and B children measured over 6 years (1977-1982), compared to zone R children

69 zone A;

528 zone B;

874 zone R

241, subset of zone R

Assennato et al., 1989a

Cohort

Comparison of dermatologic and laboratory findings in children during periodic exams following accident in Seveso

193 with chloracne

123

Ideo et al., 1982

Cross-sectional

Evaluation of hepatic enzymes in children exposed to Seveso compared to normal values

16 zone A;

51 zone B

60 Bristo Assizio;

26 Cannero

Ideo et al., 1985

Cross-sectional

Evaluation of levels of enzyme activity among residents of Seveso zone B and an uncontaminated community

117 adults

127 adults

Bertazzi et al., 1989a,b

Cohort

Comparison of mortality experience (1976-1986) of residents of contaminated zones (A, B, R) around Seveso to the mortality experience of unexposed residents in neighboring towns

556 zone A;

3,920 zone B;

26,227 zone R

167,391

Pesatori et al., 1992

Cohort

Cancer incidence (1976-1986) among those in zones A, B, R around Seveso compared to residents of uncontaminated surrounding areas

Data given in person-years

Data given in person-years

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Bertazzi et al., 1992

Cohort

Comparison of mortality of children (1976-1986) exposed during Seveso accident compared to children in uncontaminated areas

306 zone A;

2,727 zone B;

16,604 zone R

95,339

Assennato et al., 1989b

Cohort

Study of health outcomes in workers assigned to cleanup or referent group following Seveso accident

36

36

Techini et al., 1983

Cross-sectional

Cytogenetic analysis of maternal and fetal tissue among Seveso exposed compared to control sample

19

16

Mastroiacovo et al., 1988

Cohort

Comparison of birth defects occurring among zone A, B, R mothers with live and stillbirths to mothers with births from non-A, B, or R residents

26 zone A;

435 zone B;

2,439 zone R

12,391 (non-A, -B, -R)

Times Beach/Quail Run

Stehr et al., 1986;

Webb et al., 1987

Cross-sectional

Pilot study of Missouri residents exposed to TCDD in the environment (1971) for health effects, comparing potentially high-exposed to low-exposed residents

68 high-exposed

36 low-exposed

Evans et al., 1988

Cross-sectional

Comparison of retesting for skin delayed-type hypersensitivity among nonresponders in earlier test (Stehr et al., 1986)

28

15

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Hoffman et al., 1986; Stehr-Green et al., 1987

Cohort

Study of the health effects (1971-1984) of residents of Quail Run Mobile Home Park compared to residents in uncontaminated mobile parks

154

155

Stockbauer et al., 1988

Cohort

Study of adverse reproductive outcomes (1972-1982) among mothers potentially exposed to TCDD-contaminated areas of Missouri (1971) compared to births among unexposed mothers

402 births

804 births

Vietnam

Dai et al., 1990

Cohort

Study of infant mortality (1966-1986) in two South Vietnam villages exposed to Agent Orange spraying compared to infant mortality in unsprayed area

5,609

3,306

Phuong et al., 1989b

Cohort

Comparison of reproductive anomalies among births to women (May 1982-June 1982) living in areas heavily sprayed with herbicides in southern Vietnam, to women from Ho Chi Minh city

7,327 births

6,690 births

Phuong et al., 1989a

Case-control

Study of deformed babies and hydatidiform mole compared to normal births (1982) in Ho Chi Minh City for association with mother's exposure to Agent Orange and TCDD in Vietnam conflict

15 birth defects

50 hydatidiform moles

104;

134

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Constable and Hatch, 1985

Review

Summaries of reproductive outcomes among Vietnamese populations, includes nine unpublished studies

 

 

Other environmental studies

Cartwright et al., 1988

Case-control

Study of living cases of NHL (1979-1984) in Yorshire, England, compared to other hospitalized patients for association with a range of exposures including fertilizers/herbicides

437

724

Gordon and Shy, 1981

Case-control

Study of agricultural chemical exposures and potential association with cleft palate/lip in Iowa and Michigan, compared to other live births

187

985

Hanify et al., 1981

Ecological design

Study of adverse birth outcomes occurring 1960-1966, compared to 1972-1977 for association with 2,4,5-T spraying in the later time period

9,614 births

15,000 births

Jansson and Voog, 1989

Cohort/Case study

Case study of facial cleft (April-August 1987) and study of facial clefts (1975-1987) compared to the rates expected in Swedish county with incinerators

20,595 births after incineration 6 case study

71,665 births before incineration

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Lampi et al., 1992

Nested case-control/Cohort

Study of cancer incidence among a community in Finland exposed to water and food contaminated with chlorophenols (1987), compared to other communities; study of several cancers compared to population controls for association with potential risk factors including food and water consumption

56 colon cancer;

40 bladder cancer;

8 STS;

7 HD;

23 NHL;

43 leukemia

688

Nelson et al., 1979

Ecological design

Study of prevalence of oval cleft palates in high, medium, and low 2,4,5-T-sprayed areas in Arkansas (1948-1974)

Vineis et al., 1991

Ecological

Presentation of rates (1985-1988) of NHL, HD, and STS in men and women 15-74 years living in provinces in Italy where phenoxy herbicides are used in riceweeding and defined in two categories

63 HD;

253 NHL;

49 STS

No control/unexposed

White et al., 1988

Case-control and ecological

Study of chemical exposures in agricultural activity for potential association with birth defects and stillbirths in New Brunswick, Canada, 1973-1979

(a) 392 defects;

(b) 298 stillbirths

(a) 384 matched date of birth/sex; 386 matched county/date of birth;

(b) 299 matched date of birth/sex; 302 matched county/date of birth

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Michigan, 1983

Descriptive

Comparison of Michigan county rates of mortality for STS and connective tissue cancer (1960-1981), compared to state and national rates for potential excess in areas where dioxin may be in the environment

County rates

State and national rates

U.S. EPA, 1979

Ecological design

Study of spontaneous abortions occurring during 1972-1977 in herbicide-sprayed areas around Alsea, Oregon, compared to spontaneous abortions occurring in unsprayed areas

2,344 births

(a) 1,666 control births—unsprayed area

(b) 4,120 births—urban area

a The dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

chemical manufacturing may have produced dioxin contaminants; also examined were U.S. counties where STS death rates were in the 95th percentile, where rates in 1970-1979 were increased over those between 1950 and 1959, and where in 1970-1978 an excess of deaths occurred compared to national rates. Although these national comparisons were made, no information was available concerning possible dioxin contamination in the environment around these areas. There were no comparison groups for the cases examined in this study.

A case-control study was conducted in the Yorkshire Health Region where cases of NHL were identified from pathology departments in hospitals in Yorkshire between October 1979 and December 1984 (Cartwright et al., 1988). All pathology was reviewed and confirmed. The Yorkshire Regional Cancer Registry and the Regional Histopathology Lymphoma Panel were also checked for potential additional cases. The controls were selected from in-patients with a wide variety of nonmalignant conditions, and matched 2:1 to each case by residential health district, sex, and age ±3 years. Identical interviews were conducted by trained interviewers for cases and controls; information included a variety of occupational, personal, life-style, hobby, medical history, and drug history questions. The exposure of relevance was an item reported concerning use of fertilizers/herbicides for at least three months at work or at home. The study included 437 living cases and 724 living controls.

A study of a community in Finland exposed to chlorophenol through drinking water and fish contamination in 1987, and through occupational exposure in a lumber mill, was conducted, with both cohort (the entire town) and nested case-control components (Lampi et al., 1992). The cancer incidence for the health care district of interest, as obtained from files in the Finnish Cancer Registry between 1953 and 1986, was compared to the cancer incidence for neighboring municipalities and for the larger Cancer Control Region (CCR) (approximately 1.1 million population); neighboring municipalities were also compared to the expected incidence of the CCR. Additionally, a case-control study of cancers of the colon, bladder, ureter and urethra, soft tissues, lymphomas, and leukemia occurring in the health care district between 1967 and 1986 was conducted. The national population registry was the source of random selection of four controls per case, living in the same health care district at the time the cancer was diagnosed, of the same sex, and within two years of age. The study subjects or next of kin responded to a mailed questionnaire with items focused on work history, particularly in sawmills or on farms; source and duration of drinking and other household water supplies; source and quantity of fish eaten; frequency of eating soup; and smoking habits. Exposures were combined into groups, related to work in the sawmill, fungicide exposure, exposure to contaminated water source, and eating fish from contaminated lakes. A person was

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

exposed to the grouped variable if any item constituting the group had a positive response. Additional information on probable drinking water exposure was added based on history of residence, by a study member blinded to case or control status.

An ecological study of lymphomas and STS correlated with environmental exposures to phenoxy herbicides in two northern Italian provinces was conducted where phenoxy herbicides have been used since 1950 in rice weeding (Vineis et al., 1991). Cases of HD, NHL, and STS diagnosed between 1985 and 1988 in men and women between the ages of 15 and 74, living in the two provinces of interest, were identified. Hospitals in the provinces and a referral hospital outside the province were contacted for reports of newly diagnosed cases; a total of 63 cases of HD, 253 cases of NHL, and 49 cases of STS were identified. Soil and water contaminated by 2,4-D and 2,4,5-T, as indicated in analyses performed in 1974-1975, were used to indicate exposure areas. Categories of exposure were defined as category A, where 2,4-D or 2,4,5-T were detected in water or soil in at least one measurement, or category B, where the highest levels of water contamination were found. Areas did overlap partially. Rates were compared between the areas for men and women separately. No unexposed areas were identified as control areas for comparison.

VIETNAM VETERAN STUDIES

Studies of Vietnam veterans who were potentially exposed to Agent Orange have been conducted in the United States at the national and state levels, as well as in Australia (see Table 7-3). Exposure measures in these studies have been done on a variety of levels, and evaluations of health outcomes have been made utilizing a variety of different comparison or control groups. This section is organized primarily by the sponsors of the research, as this format was more conducive to the methodologic presentations of the articles. Within these studies, the exposure measures fall along a crude scale of measurement, from the individual level for the Ranch Hands, as reflected in the serum measurements of the amount of dioxin present, to some of the individual state studies, which examined groups of veterans serving in Vietnam as a surrogate for TCDD exposure.

It should also be noted that comparison groups for the veteran cohort studies vary to include unexposed Vietnam veterans who were stationed in areas essentially not exposed to active herbicide missions, and were unlikely to have been in areas sprayed with herbicides; Vietnam-era veterans, who were in the service at the time of the Vietnam conflict, but did not serve in Vietnam; non-Vietnam veterans, who served in other wars or conflicts, such as Korean or World War II; and various U.S. male populations (either state or national).

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

United States

Ranch Hands

The men responsible for the majority of the aerial spraying of herbicides were volunteers from the Air Force who participated in Operation Ranch Hand. Participants in this operation are referred to as ''Ranch Hands." To determine whether there are adverse health effects associated with exposure to herbicides, including Agent Orange, the Air Force made a commitment to the Congress and the White House in 1979 to conduct an epidemiologic study of the Ranch Hand participants (AFHS, 1982).

A retrospective matched cohort study design was implemented to examine morbidity and mortality, with follow-up scheduled to continue until 2002. The National Personnel Records Center and the U.S. Air Force Human Resources Laboratory records were searched and cross-referenced to completely ascertain all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990). A total of 1,269 participants were originally identified through this process (AFHS, 1983). A control population of 24,971 C-130 crew members and support personnel assigned to duty in Southeast Asia but not occupationally exposed to herbicides (AFHS, 1983) was selected from the same data sources as used to identify the Ranch Hand population. Controls were matched on age, type of job using Air Force specialty code, and race (white/not white). The rationale for matching on these variables was to control for the clinical aging process, education and socioeconomic status, and potential differences by race in development of chronic disease. Since Ranch Hands and controls performed similar combat or combat-related jobs, many potential confounders related to the physical/psychophysiologic effects of combat stress and the Southeast Asia environment were potentially controlled (AFHS, 1982).

Ten matches for each exposed subject formed a control set. For the mortality study, each exposed subject and a 50 percent random sample of the subject's control set is being followed for 20 years, in a 1:5 matched design. The morbidity component of follow-up consists of a 1:1 matched design, using the first control randomized to the mortality ascertainment component of the study. If a control is noncompliant, another control from the matched "pool" will be selected; controls that die will not be replaced.

The baseline exam occurred in 1982, and future exams are scheduled until 2002. Morbidity is ascertained through questionnaire and physical examination, which emphasizes dermatologic, neuropsychiatric, hepatic, immunologic, reproductive, and neoplastic conditions. There were 1,208 Ranch Hands and 1,668 comparison subjects eligible for baseline examination. Initial questionnaire response rates were 97 percent for the exposed

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

cohort and 93 percent for the unexposed; baseline physical exam responses were 87 and 76 percent, respectively (Wolfe et al., 1990). For the 1987 examination and questionnaire (Wolfe et al., 1990), 84 percent of the Ranch Hands (N = 955) and 75 percent of the comparison subjects (N = 1,299) were fully compliant. Mortality outcome was obtained and reviewed by using U.S. Air Force Military Personnel Center records, Veterans Administration (VA) Death Beneficiary Identification and Record Location System (BIRLS), and the IRS database of active Social Security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990).

The Ranch Hands were potentially exposed to large quantities of herbicides and categories were developed to account for their potential exposures:

  1. low potential, including pilots, copilots, and navigators—exposure was primarily through preflight checks and during actual dissemination of the spray;

  2. moderate potential, including crew chiefs, aircraft mechanics, and support personnel—exposure was possible by contact during dedrumming and aircraft loading operations, on-site repair of aircraft, and spray equipment;

  3. high potential, including spray console operators and flight engineers.

Exposure occurred in loading the aircraft, from ground test equipment, from tank leakage, and during dissemination. An exposure index was calculated by evaluating known factors that would influence exposure, such as date of tour with Ranch Hands in Vietnam; number and length of tours with Ranch Hands; number of herbicide dissemination missions (as reflected by flying hours and air medals); herbicides employed; crew position; and routes of personal exposure. Data from spray mission tapes were employed to estimate the amount of herbicide used by the Ranch Hands, based on time and month active. Details on the exposure index are given in Chapter 6.

Results have been published for the baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983); first (1984) and second (1987) follow-up examinations (AFHS, 1987, 1990); and reproductive outcomes study (AFHS, 1992). Mortality updates have been published for 1984-1986, 1989, and 1991 (AFHS, 1984b, 1985, 1986, 1989, 1991a). Serum dioxin levels were measured in 1982 (36 Ranch Hands) (Pirkle et al., 1989), 1987 (866 Ranch Hands) (AFHS, 1991b), and 1992 (results have not yet been published). The serum dioxin analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b). Details on serum dioxin studies are discussed further in Chapter 6. Continued follow-up and results will be forthcoming.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Centers for Disease Control

The Centers for Disease Control has undertaken a series of studies to examine various health outcomes of Vietnam veterans, as directed by Congress (Veterans Health Programs Extension and Improvement Act of 1979, Public Law 96-151, and Veterans' Health Care, Training, and Small Business Loan Act of 1981, Public Law 97-72). One of the first studies of Vietnam veterans was of birth defects among offspring of fathers serving in Vietnam (Erickson et al., 1984a,b). In response to the congressional mandate, the Vietnam Experience Study (VES; CDC, 1989b) was initiated. Since the cohort was young and the incidence of cancers reported was low, it was not possible to evaluate the association with Vietnam experience in a cohort study design; therefore, the Selected Cancers Study (SCS; CDC, 1990a) was initiated to evaluate the association among several rare cancers, Agent Orange exposure, and military service in Vietnam. To examine the concerns about Agent Orange more directly, the CDC originally proposed a study of the health of Vietnam veterans exposed to Agent Orange, compared to unexposed veterans, by using records of military unit locations and herbicide spray locations to assess exposure; this assessment was eventually determined by CDC not to be feasible. To make this determination, the Agent Orange Validation Study was conducted to evaluate TCDD levels in U.S. Army veterans, compared to exposure estimates based on military records and TCDD levels of veterans who did not serve in Vietnam. The Agent Orange Validation Study (CDC, 1989a) is discussed in Chapter 6 of this report.

Birth Defects Study The birth defects study by CDC was a case-control interview study (Erickson et al., 1984a,b) using cases and controls ascertained in the Atlanta area. Cases were selected from the Metropolitan Atlanta Congenital Defects Program (MACDP) registry, which has attempted to ascertain all liveborn and stillborn babies with structural and biochemical congenital defects. Mothers of these babies had to be residents of a five-county metropolitan Atlanta area at the time of the baby's birth. Cases were identified by a regular search of all records at hospitals that have obstetric or pediatric services, including examination of pathology department records, obstetric logs, and hospital disease indices. Initial identification of cases was also based on state of Georgia vital records and cytogenetic laboratories. Hospital charts were examined and abstracted for a confirmation of the initial diagnosis. A congenital anomaly was included if it was diagnosed prior to 1 year of age and occurred in a child who weighed > 500 grams with > 20 weeks' gestation.

Only cases with serious or major birth defects were included in this study. These defects are generally considered to include defects that affect survival or result in serious physical or psychological handicaps. Birth

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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defect diagnoses (coded according to the ICD-8 system) were grouped into three categories, namely: category 1, which included any baby with one or more "serious" or "major" defects; category 2, which mostly included defects coded as ''other specified …," or "anomalies of …," and defects such as syndactyly and hip dislocation; and category 3, relatively minor defects and "unspecified" defects of organs. Babies with only category 3 minor defects were excluded. The initial ascertainment included a total of 7,529 cases; after exclusions, a final sample of 7,133 cases was eligible for the interview study.

The control group consisted of babies born without birth defects, chosen from among the 323,421 live births that occurred in hospitals in the MACDP surveillance area from 1968 to 1980. The control group was chosen by a stratified random sampling procedure to frequency match the controls on race, year and quarter of birth, and hospital of birth. This sampling process identified 4,246 eligible control babies.

After efforts to locate respondents, telephone interviews of parents of case and control babies were conducted in 1982 and 1983. Trained interviewers conducted a two-part interview with each parent. Two different interviewers conducted parts of the computer-assisted telephone interview. The first part of the interview with each parent asked about pregnancy history, and the second part covered items such as medical history, medication use, alcohol and tobacco use, and occupational history. The interviewer that conducted the second part of the interview was blinded to case or control status. For many exposures, mothers were asked about fathers, and vice versa.

The father's interview also involved a detailed history of military service including occupational specialties, periods, and locations of service. The potential for an individual Vietnam veteran exposure to Agent Orange was estimated in this study by using interview information and a review of military records. A task force of military specialists (Agent Orange Task Force) reviewed the interview data and military records, and estimated the Agent Orange "exposure opportunity" for each veteran without knowledge of case or control status. The exposure opportunity index (EOI) that was created represented five ordered categories from no or minimal exposure to numerous Agent Orange exposure opportunities. One EOI was developed based on interview data, another from military records. The records-based EOI used location data derived from the Operations Reports-Lessons Learned, which were prepared quarterly, indicating general battalion-sized unit locations. Information on day-to-day location of units was not available for this study. The general unit locations were compared to various Agent Orange and herbicide applications by using the Ranch Hand HERBS tapes and other data such as base perimeter spraying records. The EOI based on interviews used self-reported data on service locations, service periods, and

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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occupational specialties. The EOI ranged from a value of 1 (e.g., service in Vietnam prior to Agent Orange, stationed offshore) to a value of 5 (e.g., Ranch Hand personnel).

Vietnam Experience Study The VES was a historical cohort study of the health experience of Vietnam veterans. The study was divided into three parts: physical health; reproductive outcomes and child health; and psychosocial characteristics (CDC, 1987, 1988a-c, 1989b). The VES involved a health assessment of Vietnam veterans based on a random sample of enlisted men who served in the U.S. Army from 1965 through 1971. A random sample of U.S. Army veterans was ascertained, of whom 9,078 Vietnam veterans and 8,789 Vietnam era veterans who served only one term of enlistment and were discharged as enlisted men were eligible for telephone interview (CDC, 1988a, 1989b). Of these, 7,924 Vietnam (87 percent) and 7,364 Vietnam era (84 percent) veterans completed telephone health interviews. A random subsample of the veterans underwent extensive physical and psychological health examinations, involving 2,490 Vietnam (75 percent) and 1,972 Vietnam era (63 percent) veterans (CDC, 1989b). All examinations were conducted at a single medical facility, according to standardized procedures. To the extent possible, examiners did not know the status of the examinee. At the time of the study, the two groups of veterans were similar in terms of level of education, employment, income, marital status, and satisfaction with personal relationships (CDC, 1988a, 1989b). As Agent Orange exposure was not a focus of the study, military service in Vietnam was regarded as a surrogate for herbicide exposure. Results of the physical examination study have been reported (CDC, 1988a,b, 1989b).

The VES assessment of reproductive outcomes and child health included three components: (1) a telephone interview; (2) hospital record review of birth defects for a subsample of veterans who underwent a medical examination; and (3) a medical record review of selected birth defects for all study subjects (CDC, 1988c). A total of 28,724 eligible pregnancies (15,009 Vietnam veterans, 13,715 Vietnam era veterans), 24,698 eligible births (12,788 Vietnam veterans, 11,910 Vietnam era veterans), and 24,436 eligible live births (12,659 Vietnam veterans, 11,777 Vietnam era veterans) were reported. The telephone interview with veterans included pregnancy history (miscarriage, induced abortion, tubal pregnancy, live birth, stillbirth, birth defects), cancer, infant and childhood death, and other major health conditions in the first five years of life. In addition, information on a number of covariates (potential confounders and/or effect modifiers) was obtained from either military records or interview. These covariates included paternal age at birth of a child, veteran's race, the Army general technical placement exam score, enlistment status, primary military occupational

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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specialty, year of entry into the Army, years between entry and child's birth, paternal smoking history, alcohol use, educational attainment, marital status at interview, and illicit drug use in the service.

The interim results of the VES interview study prompted the CDC to conduct two substudies as an attempt to validate or verify the veterans' self-reports of birth defects among their offspring. The first substudy (the General Birth Defects Study) involved the comparison of the occurrence of birth defects recorded on hospital records of the children of Vietnam and Vietnam era veterans. The veterans chosen for this study were already part of the medical exam component of the VES, the veterans (1,237 Vietnam, 1,045 Vietnam era veterans) who attended the Lovelace Medical Foundation from January 1 through September 30, 1986.

There were a total of 4,462 veterans who participated in both the telephone interview and the medical examination. Of these, 2,282 veterans were examined after January 1, 1986, and were asked to provide information on the birth and hospital for each offspring. After excluding births prior to entry into the Army, 3,683 births (1,945 Vietnam veterans, 1,738 Vietnam era veterans) were ascertained. An attempt was made to obtain birth and hospital records for each veteran's offspring, and a variety of information was abstracted from eligible records. A total of 3,366 birth records were obtained. For 1,791 Vietnam veterans (92 percent) and 1,575 Vietnam era veterans (91 percent), birth records were obtained.

The second substudy (the Cerebrospinal Malformation Study, CSM) involved the acquisition of medical records for all active and suspected cases of cerebrospinal malformations (spina bifida, anencephalus, hydrocephalus) and stillbirths reported by veterans in the interview study. All veterans who reported a cerebrospinal malformation in the telephone interview study were included in the CSM substudy. Birth records were sought for all children with a reported or suspected CSM and all reported still-births. There were a total of 294 eligible births in this substudy (154 Vietnam veterans, 140 Vietnam era veterans), and 221 birth records were received overall, with 127 (83 percent) records obtained for Vietnam veterans and only 94 (67 percent) for Vietnam era veterans.

In both substudies, information on potential birth defects (major and minor) was abstracted, along with data on perinatal mortality, low birthweight, and maternal age and gravidity (number of pregnancies). A birth defect was defined as a structural abnormality present at birth or diagnosed prior to hospital discharge or transfer during the first 28 days after birth among liveborn or stillborn infants.

The CDC also examined the postservice mortality (through 1983) of a cohort of 9,324 U.S. Army veterans who served in Vietnam, compared to 8,989 Vietnam era Army veterans who served in Korea, Germany, or the United States (Boyle et al., 1987; CDC, 1987). The veterans came from all

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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branches of the service. Mortality follow-up was conducted from the time of discharge until January 1, 1984, by using a variety of methods, including personal contact with next of kin and computer linkages to the SSA, VA, IRS, and the NDI (Boyle et al., 1987). A veteran had to have served in Vietnam at any time during his term of enlistment, with no minimum. Results were also calculated by using the total U.S. male population as the reference group. Analyses were conducted utilizing both the cause of death recorded on the death certificate and the cause of death assigned by a medical review panel from supplemental sources including hospital records and autopsy reports.

An additional study (O'Brien et al., 1991) combined the mortality and interview data to identify all veterans with NHL. Medical reports and records were obtained for all self-reported cases. Four veterans who had stated in the interview that they had cancer had been diagnosed with NHL. All four were Vietnam veterans. In the mortality study, three Vietnam veterans and one Vietnam era veteran were found to have NHL. In total, therefore, seven Vietnam veterans and one Vietnam era veteran had some type of NHL. No information was available regarding specific exposure to Agent Orange, because none of the NHL cases had military job titles that suggested they had been exposed to herbicides while in Vietnam.

To evaluate whether self-reported assessment of exposure to herbicides influences the reporting of adverse health outcomes, a study was designed using VES subjects (Decoufle et al., 1992). Respondents from the VES cohort were asked to report patterns of health outcomes as well as exposure to combat and herbicides in Vietnam. An index of combat exposure and herbicide exposure was developed. Six questions were asked to determine ways in which veterans believed they were exposed to herbicides in Vietnam, including whether they had actually sprayed herbicides, handled spray equipment or containers, been present when others were spraying, gotten herbicides on skin or clothing, passed through areas that appeared defoliated, or been exposed in any "other" way. Crude comparisons between Vietnam and Vietnam era veterans for health effects were reported, as well as comparisons of differences in reported health outcomes by herbicide and combat exposure indices.

Selected Cancers Study The Selected Cancers Study (CDC, 1990a-d) was undertaken by the CDC to investigate the effects of military service in Vietnam and exposure to herbicides on the health of American veterans. This was a population-based case-control study. Cases were restricted to men born between 1929 and 1953. All cases of NHL; soft tissue and other sarcomas; HD; nasal, nasopharyngeal, and primary liver cancers diagnosed from December 1984 to November 1988 in the geographic regions covered by eight tumor registries were considered eligible. The tumor registries

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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covered three states (Connecticut, Kansas, Iowa) and five large metropolitan areas (Miami, Detroit, San Francisco, Seattle, Atlanta), comprising approximately 10 percent of the U.S. population (CDC, 1990a). The control group was selected by random-digit dialing, and was frequency matched to the cases for geographic area covered by the tumor registry and five year date-of-birth intervals. A second control group, pair matched to deceased cases, consisted of deceased individuals from the same registry area, date of birth, race, and time interval between death and proxy interview. Pathology experts confirmed the diagnosis for each of the cases by independent review of the microscopic slides and tissue blocks. Trained personnel interviewed study participants by telephone with the use of a standardized questionnaire, collecting information on medical history, occupation, contact with pesticides, personal characteristics and habits, and military service. The participation rate for the controls identified through random-digit dialing was 83 percent and averaged 87 percent for all types of cancer cases combined. Participation of cases was indicated by consent to interview, either by subject or next of kin. Subjects who reported having served on active duty in the U.S. military were asked if they had been stationed in Vietnam or off the coast of Vietnam. Information was also obtained regarding rank, dates, and branch of service. Military records were reviewed for the men who reported that they had been stationed in Vietnam. Any exposure to phenoxy acid herbicides and chlorophenols other than in Vietnam was ascertained from answers to questions. The interviewed cases included 310 men with HD, 48 with nasal cancer, 80 with nasopharyngeal cancer, 130 with primary liver cancer, 342 with STS, 1,157 with NHL, and 1,776 controls. The same control group was used for comparison to each series of cancer site cases. Potential AIDS cases were excluded from the analysis.

Exposure was indirectly assessed as Vietnam service. Study participants were classified by branch of service, duration of service, calendar year of service, job duties, self-perceived exposure to herbicides, and location in Vietnam according to military region or in the Navy, whether blue water, brown water, or on shore. The units were categorized as support, combat support, or combat units. This classification was done by the U.S. Army and Joint Services Environmental Support Group (ESG) (CDC, 1990a-d).

Analyses were conducted using three statistical models: (1) controlling only for simple design variables such as age; (2) controlling for socioeconomic factors (race and educational achievement); and (3) including characteristics that could be found in association with herbicides (e.g., occupational contact other than in Vietnam). For most analyses, the referent group was composed of men who did not serve in Vietnam. The authors stress that probably few of the Vietnam veterans were actually exposed to Agent Orange, so this is not a study of Agent Orange per se. Results are reported

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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for an association between military service in Vietnam and NHL (CDC, 1990b), STS and other sarcomas (CDC, 1990c), and HD, nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d).

Department of Veterans Affairs

A proportionate mortality study was conducted by the U.S. Veterans Administration, (Breslin et al., 1988; Burt et al., 1987); a nested case-control study of the cases of NHL was conducted by Burt and colleagues, with controls selected from among the cardiovascular disease mortality deaths. The study subjects were ground troops who served in the U.S. Army or Marine Corps at any time from July 4, 1965, through March 1, 1973. Air Force, Navy, and Coast Guard personnel were excluded. The VA's BIRLS was used to select potential study subjects. This file is estimated to be 94 percent complete. A list of 186,000 Vietnam era veterans who served in the Army or Marine Corps, whose service dates included 1964-1975, and who were reported deceased as of July 1, 1982, was assembled from BIRLS. A random sample of 75,617 names was selected from this group, the aim being to get a sample size of approximately 50,000 eligible veterans. The military personnel records of these 75,617 potential study subjects were obtained and reviewed, and there were 52,253 men who died between July 4, 1965, and July 1, 1982, and who had served in the U.S. Army or Marine Corps during the period in question. Death certificates were obtained for 97 percent of the cases (881 were not obtained), and the cause of death was ascertained for 51,421 veterans. Sources of death certificates included the VA, Federal Archives Records Centers, and state vital statistics offices. Of these 51,421 men, 26,685 had not served in Southeast Asia, whereas 24,235 had served in Vietnam. Of those excluded from the analysis, 501 had served elsewhere in Southeast Asia, or their place of service was unknown. No data were available regarding exposure to herbicides. The analyses in this study compared 24,235 Vietnam veterans and 26,685 Vietnam era veterans. More than 50 percent of the veterans died between the ages of 25 and 34.

An additional study was conducted by the Department of Veterans Affairs, using the Vietnam veteran mortality experience reported above compared with three different referent groups and with additional follow-up through 1984 (Watanabe et al., 1991). Of these 62,068 men, 32,422 had not served in Southeast Asia, while 29,646 had served in Vietnam, and 711 had served elsewhere in Southeast Asia (Watanabe et al., 1991) or their place of service was unknown; the final group was excluded. The final study group of 62,068 veterans included 50,743 from an earlier mortality study (Breslin et al., 1988). Adjustments were made for age, race, and calendar year of death. Separate analyses were performed for Army and Marine Vietnam

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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veterans, because of potential differences in environmental exposures among those serving in the different military branches. Three separate comparison groups were identified: (1) branch-specific (Army, Marine) Vietnam era veterans, (2) all Vietnam era veterans combined, and (3) the U.S. male population.

A study examined whether Army I Corps Vietnam veterans had cancer mortality experiences similar to other Army Vietnam era veterans (Bullman et al., 1990). Army I Corps experience is the exposure surrogate measure. Information regarding the location of military service was obtained from military personnel records regarding the unit to which the veterans had been assigned in Vietnam, matched with a computerized file containing grid coordinates for the geographic location of each unit in Vietnam over time. In addition, station listings of units in Vietnam and the Vietnam Order of Battle (Stanton, 1981) were used to assign locations. There were 6,668 Army veterans who served in I Corps at least once during their tour of duty in Vietnam; 27,917 Army Vietnam era veterans were used as a comparison group. Mortality was standardized by age, race, and calendar year; data were analyzed by calendar year (five year intervals).

The DVA also examined the morbidity and mortality experience of a subgroup of Vietnam veterans potentially exposed to high levels of herbicides (Thomas and Kang, 1990). There were 22 U.S. Army Chemical Corps units assigned to South Vietnam between 1966 and 1971. These units were responsible for the storage, handling, mixing, and application of riot control agents (tear gas, burning agents) and herbicides. The Chemical Corps applied herbicides around the perimeters of base camps and was responsible for aerial spraying from helicopters. Morning reports for all Army Chemical Corps units known to have been assigned to Vietnam between 1966 and 1971 were examined, and a roster of information on all men who served in at least one of these units was created. The result was information on 954 men. Military service records were all obtained from the National Personnel Records Center and from the U.S. Army. The final study size was 894 men who were eligible and had available records. Their vital status on December 31, 1987, was determined through computer searches of the VA, SSA, IRS, and NDI data bases. Death certificates for those men determined to be deceased were obtained. Standardized mortality ratios were calculated by comparing the Chemical Corps cohort to mortality rates among U.S. men. Adjustment was made for race, age, and calendar period. Information on morbidity was obtained from VA hospital records and the Agent Orange Registry medical examinations.

The veterans' studies described up to this point include only men in the analysis. The DVA also conducted a study of mortality among women Vietnam veterans (Thomas et al., 1991). Women who served in Vietnam were identified from the service branches by various means: (1) Army

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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women were identified from morning report records of 91 Army hospital and administrative support units that were likely to have had female personnel; (2) Air Force women were identified from a computerized personnel file maintained by the Air Force Human Resources Laboratory; (3) Navy women were identified through a review of all personnel on the muster rolls of the four Navy facilities in Vietnam; (4) the Marine Corps provided listings of all women assigned to Vietnam. Women Vietnam veterans were eligible for inclusion in the study if they were on active duty in the U.S. Armed Forces at any time between 1964 and 1972, and had a tour of duty that included service in Vietnam during that same period.

Women who had never served in Vietnam were selected in a manner similar to that for the Vietnam cohort to serve as a comparison group. For the Army, ESG identified 90 units with female personnel stationed in the United States between 1964 and 1972; the other service branches selected women at random who had never served in Vietnam from their automated personnel files. These women were frequency matched to the Vietnam veterans by rank and military occupation. All personnel records for the potential study subjects were obtained from the National Personnel Records Center and the Army Reserve Personnel Center; 89 percent of the records were available for abstracting. Initially, 4,644 of the Vietnam cohort and 6,575 of the comparison cohort met the eligibility criteria. Vital status on December 31, 1987, was determined for study subjects using the DVA Beneficiary Records and the SSA, IRS, National Death Index, and military personnel records. An official certificate of death was obtained for deceased subjects. Deaths on active military duty before March 28, 1973, were excluded from the analyses.

The final study cohorts consisted of 4,582 women Vietnam veterans and 5,324 women who had served in the U.S. military but not in Vietnam or the Pacific theater. Person-years for risk of dying were calculated for each study subject starting with either the date she left military service or March 28, 1973. Analyses were adjusted for rank, military occupation (nurse or non-nurse), duration of military service, age at entry, and race. The mortality experiences in the cohort of women serving in Vietnam and the non-Vietnam cohort were each compared to the mortality experience of U.S. women, adjusted for race, age and calendar year. No information on any individual exposures, particularly to herbicides, was available.

Specific diseases and health outcomes have also been evaluated in studies conducted by the DVA, including case-control studies of STS (Kang et al., 1986, 1987) and NHL (Dalager et al., 1991), posttraumatic stress disorder (True et al., 1988; Bullman et al., 1991), and suicide (Farberow et al., 1990) as well as a co-twin study of self-reported physical health in a series of Vietnam era monozygotic twins (Eisen et al., 1991).

The DVA conducted two case-control studies of STS (Kang et al., 1986,

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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1987). In the first study, the Veterans Administrations patient treatment file (PTF) was used to identify all Vietnam era veterans diagnosed with STS between 1969 and 1983 (Kang et al., 1986) for a case-control study of these tumors. The PTF is a computerized hospital discharge abstract system covering all in-patient discharges from 172 VA medical centers. Vietnam era veterans were defined as veterans who served in the military sometime between August 5, 1964, and May 7, 1975. In all, 418 cases were identified; a pathology report was obtained for each case and reviewed by the study pathologist. After review, there were 234 remaining STS cases available for analysis. The comparison group consisted of 14,931 patients systematically sampled from the same Vietnam era veteran patient population. Military service information, particularly regarding Vietnam service, was obtained for STS cases and controls by review of the military personnel records. Records were located and abstracted for all of the 234 STS cases and 13,496 (90 percent) of the controls. Branch of service was used as a surrogate for exposure to Agent Orange.

In the second study, cases were drawn from the files of the Armed Forces Institute of Pathology (AFIP) (Kang et al., 1987). STS cases were restricted to men who were diagnosed between January 1, 1975, and December 31, 1980, and who were born between 1940 and 1955 (i.e., were between 18 and 25 years of age during the Vietnam conflict). In addition, their cancer specimens would have been referred for diagnostic evaluation before the publicity regarding Agent Orange. Controls were selected from the patient logs of referring pathologists or referring pathology departments, excluding patients with STS, NHL, and HD. For each case, a pathologist in the referring pathology department was asked to select three male patients born between 1940 and 1955. A total of 440 STS cases were identified. A letter was then sent to the attending physicians of the STS cases and controls for permission to approach the study subjects or their next of kin for a telephone interview. The telephone interview elicited information on occupational exposure, medical exposure, and life-style and sociodemographic factors. Interviews with study subjects or next of kin were conducted for 217 of the cases (78 percent) and 599 of the controls (74 percent).

Information was also obtained on military history. Military and Vietnam service was documented by reviewing military personnel records. As a surrogate for Agent Orange exposure, service in the Army or Marine Corps was used; military occupation, broad geographical location of the individual's unit in Vietnam in reference to recorded herbicide spray missions, and a combination of the above were identified.

By use of the PTF, a review for the years 1969 through 1985 identified all malignant lymphomas among male Vietnam era veterans born between 1937 and 1954 (Dalager et al., 1991). Pathology reports were requested from VA medical centers that had 10 or more lymphoma cases. These

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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reports were reviewed by a pathologist who identified 450 cases that were consistent with the diagnosis of NHL. Two controls were selected from the PTF from the same Vietnam era veteran population discharged from the VA in-patient hospital as the cases, matched by hospital, discharge year of hospitalization for NHL, and birth date. Persons with a diagnosis of lymphoma were excluded from the control group. In this way, 900 matched controls were identified. For both groups, the National Personnel Records Center was searched for military personnel records, and information was obtained on dates of service, military occupational specialty codes, and military region of service. These were found for 91 percent of the cases and 88 percent of the controls. The study population was restricted to men serving in the military sometime between July 1965 and March 1973. Because of the possibility of selection bias for those who were wounded during the Vietnam conflict, those persons who were first seen at a VA medical center as an immediate consequence of Vietnam duty were excluded.

Surrogate measures of Agent Orange exposure were specific military branch of service, with Army and Marine ground troops considered most likely to have been exposed directly and indirectly to Agent Orange; certain military regions (I, II, III, and IV) in Vietnam; or combat role determined by military occupation specialty (Dalager et al., 1991). The analysis in this study was limited to those persons who had been discharged from military service at least 5 years before their first hospitalization at a VA medical center. The final study population consisted of 201 NHL cases and 358 controls.

Psychological and behavioral outcomes among Vietnam veterans have also been examined by the DVA (True et al., 1988; Faberow et al., 1990; Bullman et al., 1991). In many of these studies, exposure to Agent Orange is not discussed, but exposure to "combat" is evaluated as the risk factor of interest. Some of the readjustment problems of Vietnam veterans have been attributed to posttraumatic stress disorder (PTSD). A case-control study of PTSD compared demographic and military characteristics of 374 Vietnam veterans' cases of PTSD to 373 healthy Vietnam veterans (Bullman et al., 1991). A computerized data base of approximately 200,000 Vietnam veterans who volunteered for physical examinations is maintained as the Agent Orange Registry in the Department of Veterans Affairs. Veterans were selected from this registry; cases and controls were frequency matched by age, year of registry exam, and race. Additional details of the Agent Orange Registry are given in Chapter 2. Crude odds ratios were used to evaluate the risk of PTSD associated with certain characteristics of Vietnam service, since there was no apparent confounding by other military factors. Combat exposure is evaluated for association with PTSD; it does not appear that combat is used as a surrogate for herbicide exposure.

A sample of 1,787 Army, Navy, and Marine veterans who entered the

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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service after August 4, 1965, was identified from the Survey of Veterans II conducted in 1979 by the VA and the U.S. Bureau of the Census (True et al., 1988). A summary index of combat exposure was developed from nine questions on combat roles and experiences. This index along with service in the Southeast Asia war zone was used to evaluate stresses of war. Symptoms related to PTSD were also measured. As with the previous study of PTSD, combat exposure was not used as a surrogate for herbicide exposure. Potential confounding effects of military service and demographic factors were adjusted in the analysis.

The DVA computer file of Vietnam veteran mortality (Breslin et al., 1988) was used to identify all Vietnam era veterans who died from suicide and motor vehicle accidents in Los Angeles county between 1977 and 1982 (Farberow et al., 1990). By searching backward from 1982, 100 consecutive veteran suicides and 100 consecutive veteran motor vehicle accidents were selected from the lists. The 175 veteran deaths that were matched to the medical examiner's data were divided into 38 Vietnam veteran suicides, 46 Vietnam veteran motor vehicle accidents, 43 Vietnam era veteran suicides, and 48 Vietnam era veteran motor vehicle accidents. The actual numbers available for analysis were less, as complete data were not available for all study subjects. Information on demographic data, toxicology tests, and police and suicide notes obtained from the medical examiner's record was combined with data abstracted from military personnel records. Unblinded psychological autopsies were conducted for 82 of the 175 veterans. Comparisons were done for demographic, military, and psychological factors and for preservice variables between (1) Vietnam veteran suicides and Vietnam veteran motor vehicle accidents; (2) Vietnam era veteran suicides and Vietnam era veteran motor vehicle accidents; (3) Vietnam veteran suicides and Vietnam era veteran suicides; and (4) Vietnam veteran motor vehicle accidents and Vietnam era veteran motor vehicle accidents. No information on individual exposures to herbicides was available.

Finally, the DVA studied monozygotic twins, born between 1939 and 1957, both of whom served during the Vietnam era (1965-1975), which defined a unique cohort to minimize differences in genetic and early environmental experiences. The twins were identified from the Vietnam Era Twin Registry (Eisen et al., 1991). One twin of the pair served in Southeast Asia, defined as being stationed in Vietnam, Laos, or Cambodia; serving in the waters around these countries; or flying missions over these areas. Individuals who were too ill to be interviewed or who had died were excluded. A questionnaire survey in 1987 by mail, telephone, or in-person interview asked about selected aspects of military service, physical health (hearing; skin, cardiovascular, gastrointestinal, and respiratory conditions; joint or skeletal disorders; kidney, bladder, or urinary disorders; blood; and cancer), symptoms, and use of alcohol and cigarettes. Included were twin pairs in

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

which the siblings were monozygotic and both members of the pair responded to the questionnaire, totaling 2,260 pairs.

A combat exposure index was developed by asking each veteran about 18 specific types of combat activities, resulting in a five-level index of exposure for analysis, which approximated quartiles of the combat index score distribution. The index of combat exposure was defined as the sum of all positive responses of an individual to each item. A pilot study of 150 twin pairs was conducted to test the methodology used in the full survey. This also provided a validation for those responding in both the pilot and the full study.

American Legion

The American Legion conducted a cohort study concerning the health and well-being of Vietnam veterans that belonged to the American Legion, a voluntary veterans service organization. Approximately 700,000 Vietnam era veterans are members of the American Legion at that time (Stellman et al., 1988a) Participants were selected from the membership rosters as of October 15, 1983, in six departments of the American Legion, encompassing the states of Colorado, Indiana, Maryland, Minnesota, Ohio, and Pennsylvania (Stellman et al., 1988a). Each man was given a self-administered questionnaire that included questions regarding medical history as well as combat exposure and possible Agent Orange exposure. Questionnaire return rates varied from a high of 64 percent in Minnesota to a low of 53 percent in Pennsylvania (Stellman et al., 1988a). Extensive discussion of the exposure measurement is included in Chapter 6. The questionnaire-derived service locations in Vietnam were compared with combined Air Force and U.S. Army joint services environmental records or spraying locations (HERBS tapes). Based on this, a numerical probability score was assigned to each subject. Subjects were stratified by combat (three levels) or by herbicide score (three levels). Age adjustment was not done because of the narrow age range within the study group. Of the 6,810 Vietnam era veterans who returned completed questionnaires, 2,858 had served in Southeast Asia and 3,933 served elsewhere (Stellman et al., 1988b). A series of studies examined physical health and reproductive outcomes (Stellman et al., 1988b), social-behavioral consequences (Stellman et al., 1988c), and PTSD (Snow et al., 1988).

State Studies

Several states including Hawaii, Iowa, Maine, Massachusetts, New Jersey, New Mexico, New York, Pennsylvania, Texas, West Virginia, and Wisconsin

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

have conducted studies of Vietnam veterans. Most of these studies remain unpublished in the scientific literature.

Hawaii A random sample of Vietnam era veterans residing in Hawaii was generated (Rellahan, 1985). Of 511 Vietnam era veterans agreeing to participate in the study, 418 questionnaire responses were received. The Vietnam experience group consisted of 232 respondents who had been stationed in Vietnam between 1962 and 1972. The control group was 186 respondents whose Vietnam era service was not in Southeast Asia. Respondents received general health questionnaires. Exposure of interest was the Vietnam experience (Rellahan, 1985).

Iowa The report prepared for the Iowa State Department of Health in 1985 was based on a questionnaire survey of Iowa Vietnam veterans in the Iowa Agent Orange Registry (Wendt, 1985). An Agent Orange Exposure Questionnaire was mailed to 45,181 veterans who served in Southeast Asia, listed in the Iowa Agent Orange Registry. There were 10,846 respondents (24 percent). Percentages of self-reported direct exposure to Agent Orange, length of exposure, and illness within 48 hours of exposure are reported. There was no comparison group.

Maine Vietnam veterans in Maine were surveyed by the Maine Commission on Vietnam and Atomic Veterans to assess health status, risk factors, and reproductive experience compared to veterans who were exposed during atomic nuclear weapons tests, and to compare observations from previous population studies examining similar outcomes (Deprez et al., 1991). Of 1,700 surveys sent to veterans in Maine, 249 were received from Vietnam veterans and 113 from atomic test veterans. Exposure to herbicides in Vietnam was by self-report, through descriptions of passing through sprayed areas, ingesting water or food in local areas, or clearing vegetation.

Massachusetts In Massachusetts, computerized statewide mortality files for 1972 to 1983 were linked to the computerized list of veterans who applied for a military service bonus, which was available through the Massachusetts Office of Veterans Services; the results were compiled for overall mortality (Kogan and Clapp, 1985), as well as for cause-specific mortality, with a focus on STS (Kogan and Clapp, 1988). To be eligible for a bonus, veterans must have served for at least six months between July 1, 1958, and April 1, 1973; must have been Massachusetts residents for at least six months immediately prior to entering the service; must have applied for the bonus; and must have been honorably discharged. It was estimated that 95 percent of all eligible Massachusetts residents received the bonus. A mortality file provided information on age at death, sex, race, cause and year of death, and Vietnam service. Cause of death codes on the mortality file were found to be 99 percent accurate compared to death certificates. The report is

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

limited to white males, because nonwhites and females constituted less than 2 percent of the population. The cause-specific mortality (1972-1983) was compared among deceased Vietnam veterans (N = 840), deceased Vietnam era veterans (N = 2,515), and all other deceased Massachusetts resident white men (excluding Vietnam era veterans). The standardized PMRs were calculated. The standardized mortality odds ratios were also calculated in certain instances by using circulatory disease as the comparison. No information was available regarding actual exposure to herbicides in Vietnam; the Vietnam experience is assumed to be the exposure. Information on potential confounding factors, such as smoking and drinking habits, and complete occupational histories were not available for analysis.

As a follow-up to the mortality study of veterans in Massachusetts (Kogan and Clapp, 1985, 1988), cases of selected cancers were identified from the Massachusetts Cancer Registry between 1982 and 1988 (Clapp et al., 1991). The data were linked to status as Vietnam era veterans or Vietnam bonus recipients. Controls for each cancer site analysis were veterans with other cancers, excluding STS, NHL, and kidney cancer. The study focused on males between the ages of 30 and 59 at the time of cancer diagnosis. There were 727 male Vietnam era veterans and 214 Vietnam veterans identified for inclusion in the analysis. STS and NHL were evaluated in greater detail in the analysis. Exposure of interest was Vietnam service.

Vietnam veterans receiving bonuses as previously described in Massachusetts and living in the greater Boston area were contacted regarding the presence of chloracne skin lesions as a surrogate for exposure to TCDD (Levy, 1988). Six current cases of chloracne and 25 control subjects from the same bonus list were identified. Controls were matched to cases on age, education, and time of Vietnam service. Neuropsychological tests were administered to all study subjects to determine the presence of PTSD in association with exposure to TCDD, as indicated by the presence of chloracne.

New Jersey The Agent Orange Commission in the state of New Jersey developed and supported what is known as the Pointman Project (I and II), which investigated exposure among veterans handling herbicides (Part I) (Kahn et al., 1988) and among ground combat troops (Part II) (Fiedler and Gochfeld, 1992; Kahn et al., 1992a,c). The first Pointman project was not considered a valid epidemiologic study, because it was based on only 10 Vietnam herbicide-exposed veterans, 10 Vietnam nonexposed veterans, and 7 Vietnam era veterans; immune status testing results have been reported (Kahn et al., 1992b). The second Pointman study, which focused on ground troops not specifically handling herbicides, involved 15 Army and 20 Marine veterans from battalion units that operated in heavily defoliated areas, and 20 Navy veterans from units operating on canals and rivers in heavily

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

defoliated areas (Fielder and Gochfeld, 1992). Vietnam veterans with no known exposure were chosen as controls (N = 15). Study subjects had blood drawn and tested for serum levels of 14 dioxins and furans (Kahn et al., 1992a). Outcomes evaluated included neurobehavioral assessments (Fielder and Gochfeld, 1992), semen analysis (Kahn et al., 1992c), and dibenzodioxin and dibenzofuran congener levels (Kahn et al., 1992a).

New Mexico A cohort study of Vietnam veterans in the Agent Orange registry of the VA medical center in Albuquerque, New Mexico, was designed to ascertain the presence of abnormal pulmonary pathology on radiographs among this cohort compared to an unexposed group of veterans who did not serve in Vietnam (Pollei et al., 1986). The exposure of interest was service in Vietnam. Veterans (N = 422) were between 18 and 45 years at the time of service and between 26 and 62 years at radiographic examination. Control, unexposed veterans were Air Force staff who did not serve in Vietnam, between 19 and 45 years of age, who had received a flight physical examination. A subset of films was available and analyzed separately for 27 veterans who reported handling Agent Orange.

New York A mortality study of New York State veterans used New York State Vital Records, Defense Manpower Data Center (DMDC) military information, and the VA BIRLS data base. Service in Vietnam was considered indicative of dioxin-contaminated herbicide exposure. In the first analysis, all deaths that occurred from 1965 to 1967, and 1970 to 1980, among males who were 18 to 29 years of age during the Vietnam era (1965-1971) were identified (Lawrence et al., 1985). Military service information was obtained from death certificates. Adjusted mortality odds ratios for 26 different causes of death were calculated for Vietnam era veterans (N = 4,558) and nonveterans (N = 17,936). Verification of veteran status as indicated on the death certificate was 90 percent accurate compared to next of kin interview. However, Vietnam service information showed a high degree of misclassification and needed to be assessed elsewhere. Therefore the DMDC and the BIRLS were used to obtain information on Vietnam service. A separate comparison was made of mortality (1970-1980) of veterans who served in Vietnam (N = 555) compared to mortality of non-Vietnam veterans of the same era (N = 941).

The New York State Cancer Registry (Greenwald et al., 1984) was used to identify all men with STS diagnosed from 1962 to 1980 who in 1962-1971 were between the ages of 18 and 29 years. Of the cases identified, 281 patients or their next of kin agreed to be interviewed; 151 cases were alive and 130 had died. Living controls were matched to all cases by five year age groups and zip code of residence, and identified by New York State Department of Motor Vehicle files. Additionally, deceased controls were matched to deceased cases from death certificates for year of death,

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

five year age group, years of education, race, and health systems area. Cancer deaths were excluded. Information for deceased controls was collected in a similar manner as for deceased cases, through interviews with next of kin. Medical records and hospital pathology information were collected for all cases. STS specimens were reviewed by a pathologist. Of the cases, 9 percent were not STS. All cases and controls or next of kin were interviewed by telephone using a standardized questionnaire. Information was obtained about military service experience, occupational history involving herbicide exposure (chemical production, highway or railroad maintenance or construction, park or garden maintenance, farming, herbicide spraying, outdoor or rural work); exposure to a list of specific chemicals including Agent Orange, dioxin, or 2,4,5-T; past illnesses; family medical history; and smoking and drinking histories. Dose information was not available for chemical exposures.

Pennsylvania A case-control study on the association of STS, NHL, and other selected rare cancers in Pennsylvania males who had served in Vietnam was conducted through a review of Pennsylvania death records of men dying between 1969 and 1983 at the ages of 18 to 50 (Goun and Kuller, 1986). A total of 349 deceased men and 349 men dying of other cancers excluding the cancers of interest and HD, were identified from the Pennsylvania death records, with matching on year of death, age of death, race, and county of residence. A living control group was also selected from the Pennsylvania Department of Transportation drivers' license files, matched for sex, year of birth, and county of residence. Military service information for cases and deceased controls was determined by using death certificates, questionnaires mailed to next of kin, official military personnel files, and records of the Pennsylvania Vietnam Conflict Veterans Compensation Bureau. Military service data for the living controls were obtained from computerized record linkage to the Pennsylvania Vietnam Conflict Veterans Compensation Bureau and the National Personnel Records Center. Vietnam military service was accepted as a surrogate for herbicide exposure, because no data on Agent Orange exposure were available.

Texas Preliminary studies of cytogenetics, sperm, and immune response were conducted among Texas Vietnam veterans compared to a control group (Newell, 1984). The exposure of interest was Agent Orange; military, medical, and other supporting documents were reviewed to determine Vietnam Agent Orange exposure and how it occurred. Included in the exposure evaluation was a determination of amount of exposure to herbicides (other than from Operation Ranch Hand), reported symptoms of chloracne at and after exposure, current medical problems believed to be associated with Agent Orange exposure, current or past chemical exposure (in fact an exclusion criterion), miscarriages, stillbirths, birth defects, and dates and

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

types of service duty. Exposures were categorized into six levels; those in the ''highly exposed" category were included in these studies reported. The study group was intentionally skewed by researchers to reflect high Agent Orange doses. The amount of herbicide sprayed in the area in which the veteran was assigned was noted. Controls were selected as having no possible Agent Orange exposure in Vietnam. All three laboratory studies were performed on Vietnam veterans and controls, although total samples varied by test. Study 1 examined chromosome changes including breaks, exchanges, fragment rings, etc.; study 2 examined semen specimens for sperm count and morphologic abnormalities; and study 3 examined measures of T cells and blood lymphocytes.

West Virginia The West Virginia Health Department conducted a proportionate mortality study among veterans of the Vietnam era for the purposes of generating hypotheses regarding the possible association of specific causes of death with service in Vietnam (Holmes et al., 1986). A record of all deaths by cause was compiled from the death records of the Health Statistics Center of the state of West Virginia (1968-1983). This record was matched with a list of all individuals who had qualified for a bonus under the state's Vietnam era bonus program. Four groups of deaths were used for comparison purposes: all deceased male veterans, deceased male Vietnam era veterans, deceased Vietnam veterans, and all nonveteran West Virginia males. The analyses conducted were proportionate mortality analyses stratified on age at death (by five year period) and on year of death (by two year intervals). Of the total of 1,225 male veteran deaths identified, 610 were Vietnam era veterans and 615 were Vietnam veterans. No exposure data were available.

Wisconsin The Wisconsin Division of Health examined the mortality of Vietnam veterans in a study conducted in three phases. Phase 1 compared all Wisconsin veteran deaths (1960-1979) to Wisconsin nonveterans for white men, black men, and white women. Death records from the Wisconsin Center for Health Statistics were used to identify mortality (Anderson et al., 1986a,b). Phase 2 compared Wisconsin Vietnam veterans and Wisconsin Vietnam era veterans to Wisconsin nonveterans, and other Wisconsin veterans, for mortality experience from 1964 to 1983. Cause of mortality information was obtained from the Wisconsin Department of Veterans Affairs Grave Registration files. A Vietnam veteran was defined as someone serving for a minimum of six months on active duty in Vietnam at some time between January 1964 and December 1975. Vietnam era veterans did not serve in the Vietnam theater but served during the Vietnam era (Anderson et al., 1986a).

Phase 3 of the Wisconsin study of a cohort of Vietnam era veterans was an SMR study (Anderson et al., 1986b). Veterans were followed in this

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

phase through December 1984. Follow-up started at the time of discharge and ended at the time of death or December 1984. Mortality was evaluated by using four reference populations: U.S. men, Wisconsin men, male Wisconsin nonveterans, and Wisconsin veterans. There was no information regarding exposure, specifically, to Agent Orange or other herbicides.

Other U.S. Vietnam Veteran Studies

Additional studies have been conducted in Vietnam veterans to examine a number of health outcomes including testicular cancer (Tarone et al., 1991), spontaneous abortion in spouses of veterans (Aschengrau and Monson, 1989), late adverse pregnancy outcomes (Aschengrau and Monson, 1990), and PTSD (Goldberg et al., 1990).

A case-control study of testicular cancer in men was conducted following a published study indicating a potential association with testicular cancer in dogs that served in Vietnam (Hayes et al., 1990). Incident cases, newly diagnosed with testicular cancer between the ages of 18 and 42 years, between January 1, 1976, and June 30, 1981, and referred to one of three Washington, D.C., area hospitals (the National Naval Medical Center, Walter Reed Army Medical Center, and the National Institutes of Health Clinical Center) were identified (Tarone et al., 1991). Controls were male patients at the same hospital as the case but newly diagnosed during the same period with cancers other than cancer of the genital tract, matched to the cases by age (±2 years). A questionnaire was administered to each study participant, and included information on military service and occupational history. Successful interviews were obtained for 271 testicular cancer patients (88 percent) and 259 controls (90 percent). All patients with either cryptorchidism or low birthweight were eliminated from the study. Analysis was restricted also to the 137 testicular cancer cases and 156 controls who were born before 1955. NHL cases were also excluded as controls because of a potential association with Vietnam service, resulting in 130 controls for the study. Service in Vietnam was considered to be the exposure of interest.

Women with spontaneous abortion loss at Boston Hospital for Women between July 1976 and July 1978 were eligible for inclusion in a study comparing husband's military occupational service to husbands of women having full-term babies during this same time (Aschengrau and Monson, 1989). Cases were women with spontaneous abortions through 27 weeks; controls were randomly selected from those patients with delivery within one week of the case's pregnancy loss. Following exclusion, 201 cases and 1,119 controls were selected for study. Paternal military service was identified from patient medical record information, Massachusetts bonus records, and national military records. Military service for veterans was classified as Vietnam veteran, Vietnam era veteran, and no known military service.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Aspects of interest of Vietnam service were branch, rank, occupational specialty, and calendar years; combat jobs were designated by the Director of the Massachusetts Agent Orange Program.

By using methods similar to those described above (Aschengrau and Monson, 1989), the relationship between paternal military service in Vietnam and the risk of three late adverse pregnancy outcomes, was evaluated in women who delivered infants from August 1977 until March 1980 at Boston Hospital for Women (Aschengrau and Monson, 1990). Paternal military service was compared among 857 cases of congenital anomaly, 61 stillbirth cases, and 48 neonatal death cases with paternal military service for 998 normal control births.

A cohort of 2,092 male monozygotic twin pairs, in which both twins served during the Vietnam era (1965-1975), was identified (Goldberg et al., 1990). Evaluation of the presence of PTSD among twin pairs was determined from responses to a health survey, and compared among pairs of twins discordant for Vietnam service (N = 715); that is, one twin served in Southeast Asia, and one did not. Twins were identified for study from the Vietnam Era Twin Registry, and detailed study methods are described earlier in the chapter (Eisen et al., 1991).

Australia

In 1980, the Commonwealth Institute of Health at the University of Sydney was commissioned by the Australian government to investigate Agent Orange claims (Evatt, 1985). In 1981, the scope of the investigation broadened to enable examination of all aspects of Vietnam service. The intention of the commission was to undertake three studies, involving birth defects, mortality, and morbidity. The morbidity protocol was denied by the coalition government, and only the birth defects and mortality studies were conducted. Several initial informal sessions were designed to ascertain, anecdotally, how service personnel were potentially exposed to Agent Orange. Formal hearings that were related to matters of toxicity, birth defects, morbidity, mortality, and neuropsychology followed (Evatt, 1985).

The study of birth anomalies was designed as a case-control study (Donovan et al., 1983, 1984; Evatt, 1985). Infants with anomalies diagnosed at birth, or in the first week of life, were individually matched to control infants born without an anomaly in the same hospital, to a mother of similar age, and at about the same date. The fathers of 8,517 cases and controls were identified (1966-1979) and compared with a list of men who served in the Australian Army during Australia's involvement in Vietnam (1962-1972). Fathers who served in the Army during the Vietnam era were classified according to the following: National Service or Australian Regular Army, Vietnam veteran status, year of first tour in Vietnam, length of

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 7-3 Epidemiologic Studies—Vietnam Veterans

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Ranch Hands

AFHS, 1983, 1984b, 1985, 1986, 1989, 1991a

Cohort

Mortality updates of Ranch Hands tasked with herbicide spraying operations during the Vietnam conflict, compared with Air Force C-130 air and ground crew veterans in Southeast Asia who did not participate in herbicide spraying missions

1,261 (original cohort)

19,101 (original cohort)

AFHS, 1984a, 1987, 1990, 1991b

Cohort

Baseline morbidity and follow-up exam results of the Air Force Health Study

1,208 (baseline)

1,668 (baseline)

AFHS, 1992

Cohort

Reproductive outcomes of participants in the Air Force Health Study

791

942

Michalek et al., 1990

Cohort

Mortality of Ranch Hands compared with Air Force C-130 air and ground crew veterans in Southeast Asia

1,261

19,101

Wolfe et al., 1990

Cohort

Health status of Ranch Hands at second follow-up, compared with Air Force C-130 air and ground crew veterans in Southeast Asia

995

1,299

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Centers for Disease Control

Erickson et al., 1984a,b

Case-control

CDC birth defects study of children born in the Atlanta area between 1968-1980, comparing fathers' Vietnam experience and potential Agent Orange exposure between birth defects cases and normal controls

7,133

4,246

CDC, 1989b

Cohort

Vietnam Experience Study—random sample of U.S. Army enlisted men 1965-1971

2,490

1,972

CDC, 1988a

Cohort

Vietnam Experience Study—random sample of U.S. Army enlisted men 1965-1971: psychosocial outcomes

2,490

1,972

CDC, 1988b

Cohort

Vietnam Experience Study: physical health outcomes

2,490

1,972

CDC, 1988c

Cohort

Vietnam Experience Study: reproductive outcomes

12,788 children

11,910 children

CDC, 1987; Boyle et al., 1987

Cohort

Vietnam Experience Study: mortality

9,324

8,989

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

O'Brien et al., 1991

Cohort

Interview report and mortality for NHL based on Vietnam Experience Study

8,170

7,564

Decoufle et al., 1992

Cohort

Association between self-reported health outcomes and perception of exposure to herbicides based on Vietnam Experience Study

7,924

7,364

CDC, 1990a

Case-control

Selected Cancers study—population-based case-control study of all men born between 1921 and 1953; cases diagnosed area covered by eight cancer registries and controls selected by random-digit dialing

1,157 NHL; 342 STS;

310 HD;

48 Nasal carcinoma;

80 Nasopharyngeal carcinoma; 130 Primary liver cancer

1,776

CDC, 1990b

Case-control

Selected Cancers study—population-based case-control study of all men born between 1921 and 1953; cases diagnosed area covered by eight cancer registries and controls selected by random-digit dialing: NHL

1,157

1,776

CDC, 1990c

Case-control

Selected Cancers study: soft tissue sarcomas

342

1,776

CDC, 1990d

Case-control

Selected Cancers Study: HD, nasal cancer, nasopharyngeal cancer, and primary liver cancer

310 HD;

48 Nasal carcinoma;

80 Nasopharyngeal carcinoma; 130 Primary liver cancer

1,776

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Dept. of Veterans Affairs

Burt et al., 1987; Breslin et al., 1988

Cohort

Mortality experience (1965-1982) of Army and Marine Corps Vietnam veterans, compared to Vietnam era veterans who did not serve in Southeast Asia standardized by age and race; nested case-control study of NHL

24,235

26,685

Bullman et al., 1990

Cohort

Mortality experience of Army I Corps Vietnam veterans compared to Army Vietnam era veterans

6,668

27,917

Watanabe et al., 1991

Cohort

Mortality experience (1965-1984) of Army and Marine Corps Vietnam veterans compared to: (1) branch-specific (Army and Marine) Vietnam-era veterans; (2) all Vietnam-era veterans combined; (3) the U.S. male population

24,145 Army;

5,501 Marines

(1) 27,145 Army;

4,505 Marines;

(2) 32,422 Combined Vietnam era;

(3) U.S. male population

Thomas and Kang, 1990

Cohort

Morbidity and mortality experience (1968-1987) of Army Chemical Corps Vietnam veterans compared to U.S. men

894

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Thomas et al., 1991

Cohort

Mortality experience (1973-1987) among women Vietnam veterans compared to women non-Vietnam veterans and for each cohort compared to U.S. women

4,582

5,324

Kang et al., 1986

Case-control

STS cases (1969-1983) in Vietnam era veterans for association with branch of Vietnam service as a surrogate for Agent Orange exposure

234

13,496

Kang et al., 1987

Case-control

STS cases (1975-1980) diagnosed at the Armed Forces Institute of Pathology, compared to controls identified from patient logs of referring pathologists or their departments for association with Vietnam service and likelihood of Agent Orange exposure

217

599

Dalager et al., 1991

Case-control

Cases of NHL diagnosed 1969-1985 among Vietnam era veterans compared to cases of other malignancies among Vietnam era veterans for association with Vietnam service

201

358

True et al. 1988

Cross-sectional

PTSD and Vietnam combat experience evaluated among Vietnam era veterans

775

1,012

Bullman et al., 1991

Case-control

PTSD cases in Vietnam veterans compared to Vietnam veterans without PTSD for association with traumatic combat experience

374

373

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Farberow et al., 1990

Case-control

Psychological profiles and military factors associated with suicide and motor vehicle accident (MVA) fatalities in Los Angeles County Vietnam era veterans (1977-1982)

22 Vietnam suicides;

19 Vietnam era suicides

21 Vietnam MVA;

20 Vietnam era MVA

Eisen et al., 1991

Cohort

Health effects of male monozygotic twins serving in the armed forces during Vietnam era (1965-1975)

2,260

2,260

American Legion

Snow et al., 1988

Cohort

Assessment of PTSD in association with traumatic combat experience among American Legionnaires serving in Southeast Asia (1961-1975)

2,858

Study group subdivided for internal comparison

Stellman et al., 1988b

Cohort

Assessment of physical health and reproductive outcomes among American Legionnaires who served in Southeast Asia (1961-1975) for association with combat and herbicide exposure

2,858

3,933

Stellman et al., 1988c

Cohort

Assessment of social and behavioral outcomes among American Legionnaires who served in Southeast Asia (1961-1975) for association with combat and herbicide exposure

2,858

3,933

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

State studies

Rellahan, 1985

Cohort

Study of health outcomes in Vietnam era (1962-1972) veterans residing in Hawaii associated with Vietnam experience

232

186

Wendt, 1985

Descriptive

Descriptive findings of health effects and potential exposure to Agent Orange among Iowa veterans who served in Southeast Asia

10,846

None

Kogan and Clapp, 1985, 1988

Cohort

Mortality experience (1972-1983) among white male Massachusetts Vietnam veterans, compared to non-Vietnam veterans, and to all other nonveteran white males in Massachusetts

840 deaths

2,515 deaths in Vietnam era veterans

Clapp et al., 1991

Case-control

Selected cancers identified (1982-1988) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam era veterans with cancers of other sites

214

727

Levy, 1988

Cross-sectional

Study of PTSD in chloracne as indicator of exposure to TCDD and control Vietnam veterans in Massachusetts

6

25

Fiedler and Gochfeld, 1992; Kahn et al., 1992a,b,c

Cohort

New Jersey study of outcomes in select group of herbicide-exposed Army, Marine, and Navy Vietnam veterans, compared to veterans self-reported as unexposed

10 Pointman I;

55 Pointman II

17 Pointman I;

15 Pointman II

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Pollei et al., 1986

Cohort

Study of chest radiographs of New Mexico Agent Orange Registry Vietnam veterans, compared to control Air Force servicemen radiographs for pulmonary and cardiovascular pathology

422

105

Lawrence et al., 1985

Cohort

Mortality experience of New York State (1) Vietnam era veterans compared to nonveterans and (2) Vietnam veterans compared to Vietnam era veterans

(1) 4,558;

(2) 555

17,936;

941

Greenwald et al., 1984

Case-control

Cases of STS in New York State compared to controls without cancer for Vietnam service and herbicide exposure including Agent Orange, dioxin, or 2,4,5-T

281

281 live controls;

130 deceased controls

Goun and Kuller, 1986

Case-control

Cases of STS, NHL, and selected rare cancers compared to controls without cancer for Vietnam experience in Pennsylvania men (1968-1983)

349

349 deceased

Anderson et al., 1986a

Cohort

Mortality experience of Wisconsin veterans compared to nonveterans (Phase 1); mortality experience of Wisconsin Vietnam veterans and Vietnam era veterans compared to nonveterans and other veterans (Phase 2)

110,815 white male veteran deaths;

2,494 white male Vietnam era veteran deaths;

923 white male Vietnam veteran deaths

342,654 white male nonveteran deaths; 109,225 white male other veteran deaths

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Anderson et al., 1986b

Cohort

Mortality experience of Wisconsin Vietnam era veterans and Vietnam veterans compared to U.S. men, Wisconsin men, Wisconsin nonveterans, and Wisconsin other veterans

122,238 Vietnam era veterans; 43,398 Vietnam veterans

Holmes et al., 1986

Cohort

Mortality experience (1968-1983) of West Virginia veterans, Vietnam veterans, Vietnam era veterans compared to nonveterans; Vietnam veterans compared to Vietnam era veterans

615 Vietnam veterans;

610 Vietnam era veterans

Newell, 1984

Cross-sectional

Preliminary (1) cytogenetic, (2) sperm, and (3) immune response tests in Texas Vietnam veterans compared to controls

(1) 30

(2) 32

(3) 66

30

32

66

Deprez et al., 1991

Descriptive

Study of Maine Vietnam veterans compared to atomic test veterans and general population for health status and reproductive outcomes

249

113 atomic test veterans

Other U.S. veteran studies

Aschengrau and Monson, 1989

Case-control

Association between husband's military service and women having spontaneous abortion at 27 weeks compared to women delivering at 37 weeks

201

1,119

Aschengrau and Monson, 1990

Case-control

Study of cases with late adverse pregnancy outcomes compared to normal control births for association with paternal Vietnam service (1977-1980)

857 congenital anomalies

61 stillbirths

48 neonatal deaths

998

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Goldberg et al., 1990

Cohort

Study of male twin pairs who served in Vietnam era (1965-1975) for association between Vietnam service and PTSD

2,092

2,092

Tarone et al., 1991

Case-control

Study of cases between January 1976 and June 1981 with testicular cancer (18-42 years old) compared to hospital controls for association with Vietnam service

137

130

Australian studies

Donovan et al., 1983, 1984

Case-control

Australian study of cases of congenital anomalies in children born (1969-1979), compared to infants born without anomalies for association with paternal Vietnam service

8,517

8,517

Fett et al., 1987a

Cohort

Australian study of mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981

19,205

25,677

Fett et al., 1987b

Cohort

Australian study of cause-specific mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981

19,205

25,677

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Forcier et al., 1987

Cohort

Australian study of mortality in Vietnam veterans by job classification, location, and time of service

19,205

Internal comparison

Field and Kerr, 1988

Cohort

Tasmanian study of Vietnam veterans compared to neighborhood controls for adverse reproductive and childhood health outcomes

357

281

a The dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.

Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Vietnam service before conception, and time to conception following return from Vietnam. Of the men identified with Army service, there were a total of 127 fathers of infants who were born with anomalies and 123 fathers of control infants who were Vietnam veterans. Numbers of specific defects were given.

An independent study in Tasmania evaluated numerous reproductive and childhood health problems for association with paternal Vietnam service (Field and Kerr, 1988). Tasmanian servicemen serving in Vietnam between 1965 and 1972 were identified and asked to identify a neighborhood control family with children in which the father was of similar age to the veteran. Of 1,395 Tasmanian servicemen identified as serving in this period, 357 veterans agreed and had conceived one or more children since service. Interviews of veterans and control families focused on 22 aspects of reproductive and childhood health, veterans' Vietnam service including rank and type of service, father's exposure to chemicals during civilian life, and family history of disease.

Mortality (Commonwealth Institute of Health, 1984a-c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987) was examined in a retrospective cohort study among men drafted into the Australian National Service during the Vietnam era (1965-1971). Excluded from the study were those who died in Vietnam or within two years of enlistment, those less than 18 years old at enlistment, and those serving fewer than 90 days. The final study population consisted of 19,205 Vietnam veterans and 25,677 Vietnam era veterans who had served at least 12 months. Type of service within the Army (infantry, engineers, armor, artillery, minor field presence, nonfield corps), dates, and lengths of service were obtained from military records. Follow-up was from discharge through January 1, 1982. Vital status was determined by matching study subjects against death certificates from the State Registrar-General; information on where death occurred and whether from external causes was obtained from transcripts of court proceedings, police investigations, and reports of postmortems from hospital and clinical records. Analyses were also examined in each corps group by calendar year of Vietnam service or duration of service, with mortality rates of Vietnam veterans compared to those of Vietnam era veterans. Deaths from all causes (Fett et al., 1987b) and cause-specific mortality (Fett et al., 1987a) have been reported. An additional publication using the study methods described cross-tabulates veteran corps groups by phase of Vietnam conflict service for differences in mortality patterns (Forcier et al., 1987).

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×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Suggested Citation:"7 Epidemiologic Studies." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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