Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam (1994) / Chapter Skim
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7 Epidemiologic Studies
7 Epidemiologic Studies
Pages 300-432
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From page 300... ...
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 (2,4dichlorophenoxyacetic acid)
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From page 301... ...
. The subsections in the occupational studies section include production workers, agricultural/forestry workers (including herbicide/pesticide applicators)
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From page 302... ...
Amines | Amitrole 1 Vietnam Veterans Studies | _ Ranch Hands Veterans involved in the aerial application of herbicides Other Vietnam Veteran Studies Military exposure to herbicides assessed through records-based measures (including Vietnam service, combat experience, branch of service, occupation, and spraying data) , biomarkers, and self-reported herbicide exposure.
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From page 303... ...
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.
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From page 304... ...
Information on health status, occupational history, time in Vietnam, time in agriculture, residential history, hospitalizations, medications, demographics, and lifestyle 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~.
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From page 305... ...
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)
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From page 306... ...
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, necrologic, 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.
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From page 307... ...
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, 19831. A total of 884 men were followed for mortality and compared to mortality rates in the U.S.
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From page 308... ...
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.
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From page 309... ...
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.
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From page 310... ...
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.
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From page 311... ...
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 (Sober 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.
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From page 312... ...
(19821. 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.
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From page 313... ...
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 = 3,1201. 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.
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From page 314... ...
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)
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From page 315... ...
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.
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From page 316... ...
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~.
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From page 317... ...
A cohort study of cancer incidence was conducted among employees of manufacturing facilities in Denmark that produced phenoxy herbicides, in cludin~ 2,4-D, 2,4,5-T, MCPA, and MCPP (Lynge, 19851. 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)
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From page 318... ...
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, 19811. White male death certificates for the years 1971-1978
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From page 319... ...
for the mortality experience. The agriculture census included information on individual number of acres sprayed with herbicides (types not specified)
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From page 320... ...
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.
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From page 321... ...
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)
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From page 322... ...
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)
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From page 323... ...
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~.
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From page 324... ...
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, 19821. All chemical applicators registered (N = 652)
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From page 325... ...
. 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~.
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From page 326... ...
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.
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From page 327... ...
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.
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From page 328... ...
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.
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From page 329... ...
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
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From page 330... ...
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.
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From page 331... ...
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)
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From page 332... ...
were matched to leukemia cases by sex, race, county of usual residence, age at death (+2 yearsJ, and exact calendar year of death. Occupation was as noted on death certificates, with farm owners, tenants, and laborers classified as farmers.
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From page 333... ...
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)
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From page 334... ...
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., 19893. A volunteer cohort of 508,637 men and 676,613 women who had been enrolled by the American Cancer Society (ACS)
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From page 335... ...
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.
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From page 336... ...
The for HD, and 170 for NHL. VETERANS AND AGENT ORANGE interviewed case s totaled 133 for S TS, 121 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, 19821.
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From page 337... ...
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 involv
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From page 338... ...
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., 19841.
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From page 339... ...
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.
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From page 340... ...
. 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, 19923.
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From page 341... ...
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., 19861. Three mills produced sulfate pulp and two produced sulfite pulp; four of the five mills used different bleaching processes as well.
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From page 342... ...
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From page 364... ...
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 abor
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From page 365... ...
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 Unexposed population of 305 provided referent levels of neurological functioning.
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From page 366... ...
N = 31,800. Health outcomes reported included chloracne, birth defects, and spontaneous abortions, as well as crude birth and death rates.
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From page 367... ...
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)
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From page 368... ...
R and non-ABR were reported to an ad hoc birth defects registry, the Seveso Congenital Malformation Registry (Mastroiacovo et al., 19881.
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From page 369... ...
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.
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From page 370... ...
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)
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From page 371... ...
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., 19901.
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From page 372... ...
. To evaluate the potential association between mother's exposure to Agent Orange and TODD 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)
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From page 373... ...
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.
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From page 374... ...
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.
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From page 375... ...
Correlational analyses, comparisons of mean rates of birth defects by periods of spraying, and a case-control analysis were conducted. For the casecontrol study, controls were identified from the Provincial Registry of Livebirths 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.
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From page 377... ...
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From page 383... ...
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)
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From page 384... ...
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.
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From page 385... ...
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.
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From page 386... ...
The Ranch Hands were potentially exposed to large quantities of herbicides and categories were developed to account for their potential expo sures: 1. low potential, including pilots, copilots, and navigators exposure was primarily through preflight checks and during actual dissemination of the spray; 2.
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From page 387... ...
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.
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From page 388... ...
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.
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From page 389... ...
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)
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From page 390... ...
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.
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From page 391... ...
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.
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From page 392... ...
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
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From page 393... ...
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.
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From page 394... ...
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.
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From page 395... ...
as well as a co-twin study of self-reported physical health in a series of Vietnam era monozygotic twins (Eisen et al., 19911. The DVA conducted two case-control studies of STS (Kang et al., 1986,
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From page 396... ...
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.
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From page 397... ...
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.
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From page 398... ...
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.
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From page 399... ...
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)
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From page 400... ...
Hawaii A random sample of Vietnam era veterans residing in Hawaii was generated (Rellahan, 19851. Of 511 Vietnam era veterans agreeing to participate in the study, 418 questionnaire responses were received.
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From page 401... ...
, 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.
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From page 402... ...
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)
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From page 403... ...
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.
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From page 404... ...
. 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.
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From page 405... ...
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.
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From page 406... ...
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., 19911.
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From page 418... ...
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.
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From page 419... ...
1986a. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results.
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From page 420... ...
1984. Soft tissue sarcomas in agriculture and forestry workers.
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From page 421... ...
1991. Posttraumatic stress disorder among Vietnam veterans on the Agent Orange Registry: a case-control analysis.
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From page 422... ...
1989a. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzop-Dioxin with Indirect Estimates of Agent Orange Exposure among Vietnam Veterans: Final Report.
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From page 423... ...
1986. Evaluation of: the mortality experience of workers exposed to the chlorinated dioxins.
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From page 424... ...
New Jersey Agent Orange Commission. Field B
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From page 425... ...
1986. Final Report: A Case-Control Mortality Study on the Association of Soft Tissue Sarcomas, Non-Hodgkin's Lymphomas, and Other Selected Cancers and Vietnam Military Service in Pennsylvania Males.
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From page 426... ...
1986. West Virginia Department of Health Vietnam-Era Veterans Mortality Study, Preliminary Report.
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From page 427... ...
1988. Agent Orange exposure and posttraumatic stress disorder.
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From page 428... ...
1985. Malignant lymphoma and multiple myeloma linked with agricultural occupations in a New Zealand cancer registry-based study.
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From page 429... ...
1992. Phenoxy herbicides and chlorophenols: a case-control study on soft tissue sarcoma and malignant lymphoma.
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From page 430... ...
1988b. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam.
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From page 431... ...
1985. Iowa Agent Orange Survey of Vietnam Veterans.
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From page 432... ...
1980. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident.
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