6
Epidemiologic Studies
In seeking evidence for associations between health outcomes and exposure to herbicides and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), many 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 7, 9, 10, and 11. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The historical basis for the groups studied was examined in Chapter 2 of Veterans and Agent Orange (henceforth called VAO) (IOM, 1994). A discussion of the criteria for inclusion in the review is detailed in Appendix A of VAO.
This chapter summarizes the epidemiologic studies and reports reviewed by the committee. Included are new studies published after Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996), studies that were not reviewed by the committees that wrote the prior reports; and studies that have been updated since publication of Update 1996. Tables 6-1, 6-2, and 6-3 give a brief overview of the epidemiologic studies reviewed for both the prior reports and this document. The summaries include the study method used and, if available, how the study subjects were selected; how the data were collected; the inclusion criteria; and how exposure was determined. The tables also list the numbers of subjects in the study and comparison populations and provide a brief description of the study. No studies are evaluated in this chapter; rather, a methodologic framework is provided for the health outcome chapters that follow. Qualitative critique of the study design, population size, methods of data collection, case and control ascertainment, or quality of exposure assessment has been
TABLE 6-1 Epidemiologic Studies—Occupational Exposure
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
PRODUCTION WORKERS |
||||
NIOSH |
||||
New Studies |
||||
Sweeney et al., 1996, 1997 |
Cross-sectional |
Study of numerous noncancer endpoints for liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in same group as Calvert et al. (1991) |
281 |
260 |
Halperin et al., 1995 |
Cross-sectional |
Study of surrogates for cytochrome P-450 induction in same group as Calvert et al. (1991) |
281 |
260 |
Studies Reviewed in Update 1996 |
||||
Calvert et al., 1994 |
Cross-sectional |
Study of porphyria cutanea tarda in same group as Calvert et al. (1991) |
281 |
260 |
Egeland et al., 1994 |
Cohort |
Study of total serum testosterone and gondadotropin levels in chemical production workers exposed to dioxin, in same group as Calvert et al. (1991) |
248 |
231 |
Studies Reviewed in VAO |
||||
Sweeney et al., 1993 |
Cohort |
Peripheral neuropathy 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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Calvert et al., 1992 |
Cohort |
Assessment of liver and gastrointestinal systems in same group as Calvert et al. (1991) |
281 |
260 |
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 |
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 |
— |
Monsanto |
||||
Studies Reviewed in VAO |
||||
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 |
— |
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 |
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 non-exposed workers at same Monsanto plant |
204 |
163 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
— |
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 |
— |
Dow |
||||
New Studies |
||||
Ramlow et al., 1996 |
Cohort |
Study of mortality in a cohort of workers exposed to pentachlorophenol (PCP) |
770 |
(1) U.S. population (2) 36,804 unexposed workers |
Studies Reviewed in Update 1996 |
||||
Bloeman et al., 1993 |
Cohort |
Additional years of follow-up of Bond et al. (1988) study cohort through 1986 |
878 |
(1) U.S. population (2) 36,804 unexposed workers |
Studies Reviewed in VAO |
||||
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., 1989b |
Cohort |
Extension of Ott et al. (1987) study through 1984 |
2,187 |
— |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Ott et al., 1987 Cook et al., 1987 |
Cohort |
Expanded Cook et al. (1986) study an additional three years, through 1982 |
2,187 |
— |
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 |
Cook et al., 1986 |
Cohort |
Mortality experience (1940-1979) of men manufacturing chlorinated phenols compared to U.S. white men |
2,189 |
— |
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 |
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 |
Cook et al., 1980 |
Cohort |
Mortality experience (through 1978) of male workers involved m a chloracne incident (1964) from TCDD exposure, compared to mortality experience of U.S. white men |
61 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Oft 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 |
— |
BASF |
||||
New Studies |
||||
Ott and Zober, 1996 |
Cohort |
Cancer incidence and mortality experience (through 1992) of workers exposed to TCDD after the BASF accident, during reactor cleanup, maintenance, or demolition; based on the cohort of Zober et al. (1990) |
243 |
— |
Studies Reviewed in Update 1996 |
||||
Zober et al., 1994 |
Cohort |
Morbidity experience in the same group as Zober et al. (1990) |
158 |
161 |
Studies Reviewed in VAO |
||||
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 |
— |
Thicss 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: (1) 180,000 town (2) 1.8 million district (3) 60.5 million Federal Republic of Germany (4) Two groups of 74 each from other cohort studies |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
IARC |
||||
New Studies |
||||
Kogevinas et al., 1997 |
Cohort |
Mortality study (through 1992) of workers engaged in the production or application of phenoxy herbicides and composed of (1) the Saracci et al. (1991) cohorts, (2) the German cohorts of Becher et al. (1996), and (3) the NIOSH cohorts of Fingerhut et al. (1991) |
26,615 total (21,863 exposed; 4,160 probably exposed; 592 unknown exposure) |
— |
Becher et al., 1996 |
Cohort |
Cancer mortality (through 1989) among German workers in four chemical factories exposed to 2,4,5-T and/or trichlorophenol (subcohorts I and II), and phenoxy herbicides and chlorophenols (subcohorts III and IV) |
2,479 |
— |
Flesch-Janys et al., 1995 |
Cohort |
Cancer and circulatory system mortality among workers in a chemical plant in Hamburg, Germany, exposed in varying degrees to herbicides contaminated with PCDD/F |
1,189 |
(1) population (2) 2,528 gas workers |
Studies Reviewed in Update 1996 |
||||
Kogevinas et al., 1995 |
Case-control |
Two nested case-control studies of the relationship between STS and NHL and occupational exposures in members of the IARC cohort |
STS: 11 cases NHL: 32 cases |
5 controls per case |
Kogevinas et al., 1993 |
Cohort |
Cancer incidence and mortality experience of female workers in seven countries, potentially exposed to chlorophenoxy herbicides, chlorophenols, and dioxin compared to national death rates and cancer incidence rates |
701 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Lynge, 1993 |
Cohort |
Cancer incidence in the same group as Lynge (1985), with follow-up extended through 1987 |
3,390 men 1,071 women |
— |
Kogevinas et al., 1992 |
Cohort |
Study of mortality from STS and malignant lymphomas in an international cohort of production workers and herbicide sprayers (same group as Saracci et al., 1991) |
14,439 (13,482 exposed 416 probably exposed 541 unknown exposure) |
3,951 non-exposed employees |
Studies Reviewed in VAO |
||||
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 |
— |
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 |
— |
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 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
— |
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 |
— |
Other Chemical Plants |
||||
New Studies |
||||
Tonn et al., 1996 |
Cohort |
Study of the long-term immune system effects of TCDD in industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T between 1966 and 1976 |
11 |
10 |
Studies Reviewed in VAO |
||||
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 |
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 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Pazderova-Vejlupkova et al., 1981 |
Descriptive |
Study of development of TCDD intoxication among men in Prague (1965-1968) |
55 |
No comparison group |
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 |
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) |
AGRICULTURAL/FOREST PRODUCTS |
||||
Cohort Studies of Agricultural Workers |
||||
New Studies |
||||
Gambini et al., 1997 |
Cohort |
Cancer mortality (1957-1992) among a cohort of rice growers in the Novara Province of northern Italy |
958 |
— |
Kristensen et al., 1997 |
Cohort |
Birth defects among the offspring of Norwegian farmers born after 1924 |
192,417 births |
61,351 births |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Faustini et al., 1996 |
Cohort |
Study of immune system components and functions among farmers who mixed and applied commercial formulations containing the chlorophenoxy herbicides 2,4-D and MCPA |
10 |
Internal comparison |
Studies Reviewed in Update 1996 |
||||
Dean, 1994 |
Cohort |
Study of mortality from brain and hematopoietic cancers of agricultural workers compared to non-agricultural workers in Ireland (1971-1987) |
(population size unclear) |
— |
Morrison et al., 1994 |
Cohort |
Update of mortality experience in Wigle et al. (1990) cohort, through 1987, with addition of farmers from Alberta and Manitoba. |
155,547 |
— |
Semenciw et al., 1994 |
Cohort |
Study of leukemia mortality in same group as Morrison et al. (1993) |
155,547 |
— |
Blair et al., 1993 |
Cohort |
Study of causes of death, including cancer, among farmers in 23 states (1984-1988) |
119,648 white men 2,400 white women 11,446 nonwhite men 2,066 nonwhite women |
— |
Semenciw et al., 1993 |
Cohort |
Study of multiple myeloma mortality of male farmers compared to male population of the three prairie provinces of Canada (1971-1987) |
155,547 |
— |
Senthilselvan et al., 1992 |
Cross-sectional |
Study of the association between pesticide exposure and asthma in male farmers |
1,939 |
No comparison group |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Studies Reviewed in VAO |
||||
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 |
— |
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 |
— |
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 |
— |
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 I talian farmers 18 to 74 years old compared to persons in other occupational groups |
No Ns given |
No Ns given |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Wigle et al., 1990 |
Cohort |
Mortality experience from non-Hodgkin's lymphoma 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 |
— |
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 |
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 |
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, 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 |
— |
Burmeister, 1981 |
Cohort |
Study of mortality of farmers compared to nonfarmers in Iowa (1971-1978) |
6,402 |
13,809 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Cohort Studies of Forestry Workers |
||||
Studies Reviewed in VAO |
||||
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 |
— |
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 |
— |
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 |
Cohort Studies of Herbicide/Pesticide Sprayers |
||||
New Studies |
||||
Heacock et al., 1998 |
Cohort |
Fertility study among British Columbia workers potentially exposed chlorophenate wood preservatives in 14 sawmillls between 1955-1988; Includes the cohort of Hertzman et al. (1997) |
18,016 births |
1,668 births |
Hertzman et al, 1997 |
Cohort |
Mortality study among British Columbia workers potentially exposed chlorophenate wood preservatives in 11 sawmillls between 1950-1985 |
23,829 |
2,658 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Dimich-Ward et al., 1996 |
Cohort; Nested case-control |
Analysis of birth defects among the offspring (born between 1952-1988) of the Hertzman et al. (1997) cohort |
19,675 births among 2 fathers |
5 non-defect births controls per case |
Garry et al., 1996a |
Cohort |
Study of chromosome abnormalities based on the cohort of Garry et al. (1994) |
23 fumigant appliers; nsecticide appliers erbicide appliers |
33 |
Garry et al., 1996b |
Cohort |
Birth defects among the offspring born between 1989-1992 of male pesticide appliers in Minnesota |
4,935 births among 72 pesticide appliers with birth anomalies |
3,666 births with anomalies in the general population |
Zhong and Rafnsson, 1996 |
Cohort |
Cancer mortality among various subgroups of pesticide users m Iceland |
2,449 (1,860 male and 589 female) |
— |
Studies Reviewed in Update 1996 |
||||
Asp et al., 1994 |
Cohort |
Mortality and cancer morbidity experience of male chlorophenoxy herbicide appliers (same cohort as Riihimaki et al., 1982 and 1983) in Finland (1955-1971), through 1989, compared to general population rates for morbidity and mortality. |
1,909 |
— |
Garry et al., 1994 |
Cross-sectional |
Evaluation of health outcomes resulting from exposure to pesticides by male pesticide appliers in Minnesota |
719 |
No comparison group |
Studies Reviewed in VAO |
||||
Swaen et al., 1992 |
Cohort |
Cancer mortality experience (through 1987) among Dutch male herbicide appliers licensed before 1980, compared to the total male Dutch population |
1,341 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Bender et al., 1989 |
Cohort |
Cancer mortality of Minnesota highway maintenance workers compared to expected numbers based on white Minnesota men |
4,849 |
— |
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 |
— |
Wiklund et al., 1988b |
Cohort |
Risk of STS in Wiklund et al. (1987) cohort through 1984 |
20,245 |
— |
Wiklund et al., 1987 |
Cohort |
Risk of HD and NHL among Swedish pesticide appliers from date of license through 1982, compared to expected number of cases in the total population |
20,245 |
|
Blair et al., 1983 |
Cohort |
Mortality experience of white male Florida pesticide appliers compared to U.S. and Florida men |
3,827 |
— |
Riihimaki et al., 1983 |
Cohort |
Cancer morbidity and mortality in cohort (Riihimaki et al., 1982) through 1980. |
1,926 |
— |
Riihimaki et al., 1982 |
Cohort |
Study of mortality among herbicide appliers exposed to 2,4-D and 2,4,5-T in Finland compared to mortality expected in the population |
1,926 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Smith et al., 1982 |
Cohort |
Study of adverse reproductive outcomes among chemical appliers and agricultural contractors by category of exposure: none; chemicals not 2,4,5-T; 2,4,5-T 486 pregnancies (2,4,5-T) |
113 pregnancies chemicals not 2,4,5-T) |
401 pregnancies (not exposed) |
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 |
— |
Smith et al., 1981 |
Cohort |
Study of chemical appliers (1973-1979) in New Zealand compared to agricultural contractors for differences in adverse reproductive outcomes |
459 |
422 |
Axelson et al., 1980 |
Cohort |
Additional years of follow-up to cohort established in Axelson and Sundell (1974) |
348 |
— |
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 |
— |
Case-Control Studies |
||||
New Studies |
||||
Blatter et al., 1997 |
Case-control |
Multicenter Dutch study of paternal occupation and risk of spina bifida in offspring (1980-1992) |
222 |
764 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Liou et al., 1997 |
Case-control |
Study of occupational and environmental risk factors and Parkinson's disease (PD) in Taiwan (1993-1995) |
120 |
240 |
Tatham et al., 1997 |
Nested case-control |
Population based study of the occupational risk factors for subgroups of NHL patients based on the CDC's Selected Cancers Study (CDC, 1990a-d) |
1,048 |
1,659 |
Nanni et al., 1996 |
Case-control |
Population-based study in northeastern Italy of occupational and chemical risk factors for chronic lymphocytic leukemia (CLL) and NHL lymphomas (1987-1990) |
187 |
977 |
Schulte et al., 1996 |
PMR analysis with nested case-control |
Study of neurodegenerative diseases and occupational risk factors from 27 states |
|
|
Seidler et al., 1996 |
Case-control |
Study of Parkinson's disease and various rural factors, including exposure to herbicides and wood preservatives in Germany |
380 |
(1) 379 neighborhood controls (2) 376 regional controls |
Studies Reviewed in Update 1996 |
||||
Hardell et al., 1994 |
Case-control |
Study of the association between occupational exposures and parameters related to NHL in white males in Sweden |
105 |
335 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Mellemgaard et al., 1994 |
Case-control |
Study of cases of renal-cell carcinoma (20-79 years) in Denmark, compared to population-based sample without cancer for identification of occupational risk factors |
365 |
396 |
Nurminen et al., 1994 |
Case-control |
Study of structural defect infants born to mothers engaged in agricultural work during the first trimester of pregnancy, compared to infants with structural defects born to mothers who did not engage in agricultural work during the first trimester |
1,306 |
1,306 |
Brown et al., 1993 |
Case-control |
Population-based case-control study of multiple myeloma m Iowa men for association with pesticide exposures |
173 |
650 |
Persson et al., 1993 |
Case-control |
Study of risk factors potentially associated with HD and NHL in males identified from the Regional Cancer Registry in Sweden |
HD: 31 NHL: 93 |
204 |
Semchuk et al., 1993 |
Case-control |
Study of cases of Parkinson's disease (36-90 years) in Canada, compared to population-based sample for association with occupational exposure to herbicides and other exposures |
75 men 55 women |
150 men 110 women |
Zahm et al., 1993 |
Case-control |
Study of NHL and exposure to pesticides in white women diagnosed with NHL between July 1, 1983, and June 30, 1986 |
206 |
824 |
McDuffie et al., 1990 |
Case-control |
Study of pesticide exposure m male cases of primary lung cancer in Saskatchewan, compared to control subjects matched by age, sex, and location of residence |
273 |
187 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Studies Reviewed in VAO |
||||
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 |
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 |
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 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
— |
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 |
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 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
— |
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 |
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 |
Musicco et al., 1988 |
Case-control |
Study of brain gliomas diagnosed 1983-1984 m 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 |
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 |
167 |
50 same area 80 other parts of Sweden |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Pearce et al., 1987 |
Case-control |
Expanded study (Pearce et al., 1986b) of NHL to include ICD 200 diagnosed cases, and additional controls for association with farming exposures |
183 |
338 |
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 |
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 m white men 21 years or older |
133 STS 121 HD 170 NHL |
948 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
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 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
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 |
Hardell and Bengtsson, 1983 |
Case-control |
Study of HD diagnosed in men 25-85, 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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
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 |
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 |
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, 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., 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 HNL |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
PAPER/PULP WORKERS |
||||
Studies Reviewed in VAO |
||||
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 |
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 |
— |
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 |
— |
NOTE: COPD = chronic obstructive pulmonary disease; HD = Hodgkin's disease; IARC = International Agency for Research on Cancer; ICD = International Classification of Diseases; NHL = non-Hodgkin's lymphoma; PMR = proportionate mortality ratio; SEER = surveillance, epidemiology, and end results; STS = soft-tissue sarcoma; Update 1996 = Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO = Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). a The dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), and details are given in the text for specifics of the actual population. |
TABLE 6-2 Epidemiologic Studies—Environmental Exposure
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
SEVESO |
||||
New Studies |
||||
Bertazzi et al., 1997 |
Cohort |
Study of cancer incidence among Seveso residents in contaminated zones (A, B, R) after 15 years of follow-up through 1991 |
45,373 total: 805 in zone A; 5,943 in zone B; 38,625 in zone R |
232,747 |
Mocarelli et al., 1996 |
Cohort |
Study of sex ratio among the offspring of Seveso residents born in zone A from (1) 1977-1984 and (2) 1985-1994 |
(1) 74 births (28 male, 48 female) (2) 124 births (60 male, 48 female) |
— |
Studies Reviewed in Update 1996 |
||||
Bertazzi et al., 1993 |
Cohort |
Study of cancer incidence in Seveso residents (aged 20 to 74 years) in contaminated zones (A, B, R) exposed to TCDD on July 10, 1976, compared to neighboring residents in unexposed areas |
724 zone A 4,824 zone B 31,647 zone R |
181,579 |
Pesatori et al., 1993 |
Cohort |
Evaluation of cancer incidence in Seveso residents aged 1-19 years m the first post-accident decade compared to age-matched residents of neighboring unexposed areas |
Approximately 20,000 |
167,391 |
Studies Reviewed in VAO |
||||
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Assennato et al., 1989a |
Cohort |
Comparison of dermatologic and laboratory findings in children during periodic exams following accident in Seveso |
193 with chloracne |
123 |
Assennato et al., 1989b |
Cohort |
Study of health outcomes in workers assigned to cleanup or referent group following Seveso accident |
36 |
36 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Mastroiacovo et al., 1988 |
Cohort |
Comparison of birth defects occurring among zone A, B, and 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, or -R) |
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 |
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 |
Tenchini et al., 1983 |
Cross-sectional |
Cytogenetic analysis of maternal and fetal tissue among Seveso exposed compared to control sample |
19 |
16 |
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 |
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 |
Filippini et al., 1981 |
Cohort |
Comparison of prevalence of peripheral neuropathy on two screening examinations among Seveso residents, compared to residents m unexposed areas |
308 |
305 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
TIMES BEACH/QUAIL RUN |
||||
Studies Reviewed in VAO |
||||
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 |
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 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Stehr et al., 1986 |
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 |
Vietnam |
||||
Studies Reviewed in Update 1996 |
||||
Cordier, et al. 1993 |
Case-control |
Study of cases of hepatocellular carcinoma (1989-1992) m males living in Vietnam, compared to other hospitalized patients for association with a range of exposures including herbicides |
152 |
241 |
Studies Reviewed in VAO |
||||
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., 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 |
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 |
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 |
||||
New Studies |
||||
Gallagher et al., 1996 |
Case-control |
Community-based study of primary basal cell carcinoma (BCC) and patients with primary squamous cell carcinoma (SCC) in Alberta, Canada |
BCC: 226 SCC: 180 |
406 |
Lovik et al., 1996 |
Cohort |
Study of immune system parameters in hobby fishermen in the Frierfjord m southeastern Norway |
24 |
10 |
Masala et al., 1996 |
Case-control |
Multicenter study of NHL, HD, multiple myelomas (MM), and acute myeloid leukemias (AML) in Italy by region |
HD: 421 NHL: 1822 MM: 325 AML: 263 |
Internal comparison by region |
Waterhouse et al., 1996 |
PMR analysis with nested case-control |
Study of NHL, HD, and CLL in a rural Michigan community |
42 males 32 females |
4 controls per case |
Svensson et al., 1995 |
Cohort |
Mortality and cancer incidence experience in East coast: two cohorts of Swedish fishermen |
2,896 |
West coast: 8,477 |
Weisglas-Kuperus et al., 1995 |
Cohort |
Study of the immunological effects of pre-and postnatal PCB or TCDD exposure in 207 Dutch infants from birth to 18 months |
105 breast-fed |
102 bottle-fed |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Wolf and Karmaus, 1995 |
Cross-sectional |
Study of the effects of inhalative exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day care center employees |
221 |
189 |
Studies Reviewed in Update 1996 |
||||
Butterfield et al., 1993 |
Case-control |
Study of possible environmental risk factors associated with young-onset Parkinson's disease |
63 |
68 |
Peper et al., 1993 |
Descriptive |
Study of environmental exposure to dioxins and furans and potential association with adverse neuropsychological effects in Germany |
19 |
None |
Studies Reviewed in VAO |
||||
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 |
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 rice weeding and defined in two categories |
63 HD 253 NHL 49 STS |
No control/unexposed |
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 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Cartwright et al., 1988 |
Case-control |
Study of living cases of NHL (1979-1984) in Yorkshire, England, compared to other hospitalized patients for association with a range of exposures including fertilizers/herbicides |
437 |
724 |
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 |
Michigan Department of Public Health, 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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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) |
— |
— |
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 |
NOTE: HD = Hodgkin's disease; NHL = non-Hodgkin's lymphoma; STS = soft-tissue sarcoma; Update 1996 = Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO = Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). 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. |
TABLE 6-3 Epidemiologic Studies—Vietnam Veterans
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
UNITED STATES STUDIES |
||||
Ranch Hands |
||||
New Studies |
||||
Michalek et al., 1998a |
Cohort |
Paternal serum dioxin levels and infant death among the offspring of Ranch Hands |
859 children: 323 background exposure, 267 low exposure, 269 high exposure |
1,223 children |
Henriksen et al., 1997 |
Cohort |
Study of the relationship between serum dioxin and glucose and insulin levels and diabetes mellitus in Ranch Hands through 1992 |
989 |
1,276 |
AFHS, 1996 |
Cohort |
Mortality update of Ranch Hands through the end of 1993 m the same cohort as AFHS (1983, 1984b, 1985, 1986, 1989, 1991a, 1995) |
1,261 |
19,080 |
Michalek et al., 1998b |
|
|
|
|
Henriksen et al., 1996 |
Cohort |
Study of serum dioxin and reproductive hormones in Ranch Hands in 1982, 1985, 1987, and 1992 |
1,045 (participants, 1982) 474 (provided semen) |
1,224 (participants, 1982) 532 (provided semen) |
Studies Reviewed in Update 1996 |
||||
AFHS, 1995 |
Cohort |
Mortalּty 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 inherbicide spraying missions |
1,261 (original cohort) |
19,101 (original cohort) |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Wolfe et al., 1995 |
Cohort |
Paternal serum dioxin levels and reproductive outcomes of Ranch Hand veterans compared with Air Force veterans from Southeast Asia who did not participate in herbicide spraying missions |
932 |
1202 |
Studies Reviewed in VAO |
||||
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, 1995 |
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 followup, compared with Air Force C-130 air and ground crew veterans in Southeast Asia |
995 |
1,299 |
Centers for Disease Control (CDC) |
||||
Studies Reviewed in VAO |
||||
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
O'Brien et al., 1991 |
Cohort |
Interview report and mortality for NHL based on Vietnam Experience Study |
8,170 |
7,564 |
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 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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
Department of Veterans Affairs (DVA) |
||||
New Studies |
||||
Dalager and Kang, 1997 |
Cohort |
Morbidity and mortality experience (1968-1987) of Army Chemical Corps Vietnam veterans compared to U.S. men; Extension of Thomas and Kang (1990) |
2,872 |
2,737 |
Mahan et al., 1997 |
Case-control |
Study of lung cancer among Vietnam veterans (1983-1990) |
329 |
269 111 |
McKinney et al., 1997 |
Cross-sectional |
Study of the smoking behavior of veterans and nonveterans using the 1987 National Medical Expenditure Survey (NMES) |
15,000 |
— |
Bullman and Kang, 1996 |
Cohort |
Mortality study of veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam war |
34,534 |
— |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Watanabe and Kang, 1996 |
Cohort |
Mortality experience (1965-1988) of Army and Marine Corps Vietnam veterans; Extension of Breslin et al. (1988) and Watanabe et al. (1991) |
33,833 |
36,797 |
Dalager et al., 1995b |
Case-control |
Cases of HD diagnosed 1969-1985 among Vietnam-era veterans |
283 |
404 |
Watanabe and Kang, 1995 |
Cohort |
Post service mortality among Marine Vietnam veterans |
10,716 |
9,346 |
Studies Reviewed in Update 1996 |
||||
Dalager et al., 1995a |
Cohort |
Update of Thomas et al. (1991) through December 31, 1995 |
4586 |
5325 |
Bullman et al., 1994 |
Case-control |
Study of the association between testicular cancer and surrogate measures of exposure to Agent Orange in male Vietnam veterans |
97 |
311 |
Studies Reviewed in VAO |
||||
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
Bullman et al., 1990 |
Cohort |
Mortality experience of Army I Corps Vietnam veterans compared to Army Vietnam era veterans |
6,668 deaths |
27,917 deaths |
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 |
Thomas and Kang, 1990 |
Cohort |
Morbidity and mortality experience (1968-1987) of Army Chemical Corps Vietnam veterans compared to U.S. men |
894 |
— |
True et al., 1988 |
Cross-sectional |
PTSD and Vietnam combat experience evaluated among Vietnam-era veterans |
775 |
1,012 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Breslin et al., 1988 Burr et al., 1987 |
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 |
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 |
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 |
American Legion |
||||
Studies Reviewed in VAO |
||||
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
State Studies |
||||
New Studies |
||||
Clapp, 1997 |
Case-control |
Selected cancers identified (1988-1993) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam-era veterans with cancers of other sites; Update of Clapp et al. (1991) |
245 |
999 |
Studies Reviewed in Update 1996 |
||||
Visintainer et al., 1995 |
Cohort |
Mortality experience (1965-1971) among male Michigan Vietnam veterans, compared to non-Vietnam veterans from Michigan |
3,364 deaths |
5,229 deaths |
Studies Reviewed in VAO |
||||
Fiedler and Gochfeld, 1992 Kahn et al., 1992a-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 |
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 |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
Levy, 1988 |
Cross-sectional |
Study of PTSD in chloracne as indicator of exposure to TCDD and control Vietnam veterans in Massachusetts |
6 |
25 |
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) veteran deaths |
110,815 white male veteran deaths 2,494 white male Vietnam-era veteran deaths 923 white male Vietnam |
342,654 white male nonveteran deaths 109,225 white male other veteran deaths Vietnam veteran deaths |
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 |
— |
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 |
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 |
— |
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
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 |
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 |
Other U.S. Veteran Studies |
||||
Studies Reviewed in VAO |
||||
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 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
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 |
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 |
AUSTRALIAN STUDIES |
||||
New Studies |
||||
Crane et al., 1997a |
Cohort |
Mortality experience (through 1994) of Australian veterans who served in Vietnam |
59,036 males 484 females |
— |
Crane et al., 1997b |
Cohort |
Mortality experience (through 1994) of Australian national servicemen who served in Vietnam |
18,949 |
24,646 |
O'Toole et al., 1996a-c |
Cross-sectional |
Survey of self-reported health status (1989-1990) of Australian Army Vietnam veterans |
641 |
— |
Studies Reviewed in VAO |
||||
Field and Kerr, 1988 |
Cohort |
Study of Tasmanian Vietnam veterans compared to neighborhood controls for adverse reproductive and childhood health outcomes |
357 |
281 |
Reference |
Study Design |
Description |
Study Group (N) |
Comparison Group (N)a |
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 |
Forcier et al., 1987 |
Cohort |
Australian study of mortality in Vietnam veterans by job classification, location, and time of service |
19,205 |
Internal comparison |
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 |
OTHER VIETNAM VETERANS STUDIES |
||||
New Studies |
||||
Chinh et al., 1996 |
Cohort |
Study of antinuclear antibodies and sperm autoantibodies among Vietnamese veterans who served 5-10 years in a ''dioxin-sprayed |
25 |
63 36 |
NOTE: HD = Hodgkin's disease; NHL = non-Hodgkin's lymphoma; PTSD = posttraumatic stress disorder; STS = soft-tissue sarcoma; Update 1996 = Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO = Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). 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. |
reserved for the individual health outcome chapters in which the results of these studies are discussed.
The text and tables in this chapter are organized in three basic sections— occupational studies, environmental studies, and studies in Vietnam veterans— with subsections included under each heading. The studies address exposures to 2,4-D (2,4-dichlorophenoxyacetic acid); 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD; cacodylic acid; and picloram. In some cases, the committee examined studies addressing compounds chemically related to the herbicides used in Vietnam, such as 2-methyl-4-chlorophenoxyacetic acid (MCPA), hexachlorophene, and chlorophenols, including trichlorophenol. In other instances, investigators did not indicate specific herbicides to which study participants were exposed, or the level of exposure. These complicating factors were considered when the committee weighed the relevance of a study to its findings. Where available, details are given with regard to exposure assessment and how exposure was subsequently used in the analysis.
The occupational section includes studies of production workers, agricultural and forestry workers (including herbicide and pesticide appliers), and paper and pulp workers, as well as case-control studies of specific cancers and the association with exposures to herbicides or related compounds. The environmental section includes studies of populations accidentally exposed to unusual levels of herbicides or dioxin as a result of the location in which they live, for example, the residents of Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans includes studies conducted in the United States by the Air Force; the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (DVA; formerly the Veterans Administration [VA]); the American Legion; and the State of Michigan, as well as other groups. Studies of Australian Vietnam veterans are also presented there.
Many cohorts potentially exposed to dioxin and the herbicides used in Vietnam are monitored on an ongoing basis. Studies of the groups that are assessed regularly include the National Institute for Occupational Safety and Health (NIOSH), International Agency for Research on Cancer (IARC), National Cancer Institute (NCI), Seveso, and Ranch Hand cohorts. Typically, the risks between exposure to herbicides and specific health outcomes are updated every three to five years. For example, the health of the Ranch Hands cohort was assessed in 1982, 1987, 1992, and 1997. For such studies, the committee has chosen to focus on the most recent update available when multiple comparisons are made across years. For the sake of thoroughness, the discussion of specific health outcomes in Chapters 7-10 includes reference to all studies, including those subsumed by the most recent update.
Similarly, researchers investigating the constituent cohorts used in some large multicenter studies may publish reports based solely on the individuals they monitor. Examples include the IARC and NCI cohort studies. The committee has chosen to focus on the studies of the larger multicenter cohorts. However, for the
sake of thoroughness, Chapters 7-11 reference all of these studies, including those subsumed by the larger multicenter cohorts.
OCCUPATIONAL STUDIES
Several occupational groups in the United States and elsewhere have been exposed to the types of herbicides used in Vietnam and, more specifically, to TCDD, a contaminant of some herbicides and other products. Occupational groups exposed to these chemicals include farmers, agricultural and forestry workers, herbicide sprayers, workers in chemical production plants, and workers involved in paper and pulp manufacturing. In addition, studies that use job titles as broad surrogates of exposure and studies that rely on disease registry data have been conducted. Exposure characterization varies widely in these studies in terms of measurement, quantification, level of detail, confounding by other exposures, and individual versus surrogate or group (ecological) measures.
Production Workers
National Institute for Occupational Safety and Health (NIOSH)
In 1978, NIOSH began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,000 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many of the study subjects probably were exposed to many other chemicals, some of which could be carcinogenic.
Prior to this study, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in the manufacture of chemicals with TCDD contamination at chemical plants in Newark, New Jersey, from 1951 to 1969, and in Verona, Missouri, from 1968 to 1969 and from 1970 to 1972 (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The plant in New Jersey manufactured TCP and 2,4,5-T; the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene.
A number of studies were later conducted that looked at specific health outcomes among the larger cohort, including pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et
al., 1992), the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and reproductive hormones (Egeland et al., 1994). VAO and Update 1996 describe the details of each of these studies.
Based on a previous exposure characterization study (Sweeney et al., 1990) of this cohort, Halperin et al. (1995) conducted a cross-sectional medical survey of chemical workers at the New Jersey and Missouri plants. Of the 586 workers eligible for participation, 357 completed an occupational history, and 281 of these participated in a medical exam. Urine and serum samples were collected from 58 of the latter individuals, who served as cases. Two hundred sixty non-exposed individuals from neighborhoods near the plants participated in the medical exam. Of these 125 had urine samples collected and served as controls. Surrogates for cytochrome P-450 induction (5-acetylamino-6-formylamino-3-methyluracil [AMFU] and cotinine levels) were measured in the urine samples of cases and controls. Blood serum TCDD levels were measured in all 58 cases and a subset of the 260 individual who participated in the medical exam. The median TCDD level in these 260 participants was used for the controls that did not themselves give blood samples.
Sweeney et al. (1996, 1997) evaluated other noncancer end points for liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in 281 of the 586 workers first identified by Calvert et al. (1991) in New Jersey and Missouri. In addition, 260 controls were examined.
Monsanto
Included in the study cohort of Fingerhut et al. (1991) are a number of individual cohort members from Monsanto's production facilities. These are discussed in more detail in VAO. One set of Monsanto studies are based on a violent reaction that occurred on March 8, 1949, in the trichlorophenol (TCP) production process at the Nitro, West Virginia, plant of Monsanto (Zack and Suskind, 1980; Moses et al., 1984; Collins et al., 1993). Other studies focused on exposure of Monsanto workers involved in numerous aspects of producing 2,4,5-T (Suskind and Hertzberg, 1984; Moses et al., 1984; Zack and Gaffey, 1983).
Dow Chemical Company
Several studies of Dow Chemical Company production workers are summarized in VAO and Update 1996. These study populations, except for one article by Bond and colleagues (1988), is included in the NIOSH study (Fingerhut et al., 1991). Originally, Dow Chemical Company conducted a study on the work force engaged in the production of 2,4,5-T (Ott et al., 1980) and later on TCP manufacturing workers exhibiting chloracne (Cook et al., 1980). A extension and follow-up study compared medical examination results and morbidity (Bond et al., 1983) as well as reproductive outcomes from paternal TCDD (Townsend et al., 1982).
Dow employees with chloracne, established on the basis of past diagnosis or clinical description were later enrolled in a prospective mortality study (Bond et al., 1987).
Dow Chemical Company assembled a large cohort at the Midland, Michigan, plant (Cook et al., 1986; Cook et al., 1987; Bond et al., 1989b). Based on this large Midland cohort, a cohort study of women (Ott et al., 1987) and a case-control study of STS (Sobel et al., 1987) was conducted. Exposure to TCDD was better characterized in this cohort based on chloracne diagnosis (Bond et al., 1989a). Dow Chemical Company has also undertaken a large-scale cohort mortality study of workers exposed to herbicides in several Dow plants (Bond et al., 1988; Bloemen et al., 1993).
As part of this ongoing Dow study, Ramlow et al. (1996) examined mortality in a cohort of workers exposed to pentachlorophenol (PCP). The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential polychlorinated dibenzodioxin (PCDD) exposure between 1937 and 1980. From this cohort, 770 workers were identified who were considered to have potential PCP exposure based on work history records. Exposure to PCP was assessed using historical industrial hygiene and process data, which resulted in a strategy for ranking jobs by exposure intensity on a scale of 1 to 3. Exposure assessment to PCDD was performed using the process described by Ott et al. (1987), in which semiquantitative, logarithmic exposure intensity scores ranging from 1 to 4 for TCDD and 0 to 2 for hexa- or octachlorodibenzodioxins (H/OCDD) were assigned to each job title. Cumulative exposure indices for PCP and dioxin were calculated using these assigned scores. In the study analysis, the U.S. white male death rates (5-year age and calendar time specific) and the non-PCP and PCDD male Dow Michigan employees for 1940 to 1989 were both used as reference values to calculate expected deaths. Four exposure groups were developed for TCDD (1 unit = very low; 1-1.9 = low; 2-2.9 = medium; 3 = high). Standardized mortality ratios (SMRs) were calculated with exposure lagged by 15 years, using both the U.S. and the Dow referent populations.
BASF
In Germany, an accident on November 17, 1953, during the manufacture of trichlorophenol at BASF Aktiengesellschaft, resulted in the exposure of some workers in the plant to TCDD. VAO and Update 1996 summarize studies of these workers, including a mortality study of persons initially exposed or later involved in clean-up operations, conducted 27 years after the accident (Thiess et al., 1982), an update and expansion of this study (Zober et al., 1990), and a morbidity follow up (Zober et al., 1994).
More recently, Ott and Zober (1996) examined another cohort of workers exposed to TCDD after the accident during reactor cleanup, maintenance, or
demolition. They studied cancer incidence and mortality up to 1992 for a group of 243 men and developed TCDD dose estimates based upon work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. Expected numbers of incident cancer cases and cancer deaths were obtained from German sources by five-year age and calendar intervals. Analysis included proportional hazard modeling to include estimated TCDD dose, diagnosis of chloracne, smoking history, body mass index (BMI), time since first exposure, and potential confounders including exposure to asbestos and aromatic amines.
International Register of Workers Exposed to Phenoxy Herbicides (IARC)
To avoid problems of small studies with insufficient power to detect increased cancer risks, IARC created this multinational registry of workers exposed to phenoxy herbicides, chlorophenols, and their contaminants (Saracci et al., 1991). The IARC register included information on mortality and exposures of 18,390 workers—16,863 men and 1,527 women. Update 1996 describes the individual national cohorts included in this multinational registry.
In a study covering ten countries, cancer mortality from soft-tissue sarcoma and malignant lymphoma was evaluated on the entire cohort (Kogevinas et al., 1992). Two nested case-control studies were also undertaken to evaluate the relationship between soft-tissue sarcoma and non-Hodgkin's lymphoma (Kogevinas et al., 1995). A cohort study of cancer incidence and mortality was conducted among 701 women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins from seven countries (Kogevinas et al., 1993). VAO and Update 1996 highlight these studies.
In an update and expansion, Kogevinas et al. (1997) assembled national studies from 12 countries using the same core protocol jointly developed by study participants and coordinated by IARC. The expanded study consisted of 26,615 male and female workers engaged in the production or application of phenoxy herbicides and was composed of (1) the Saracci et al. (1991) cohort, (2) the German cohorts of Becher et al. (1996), and (3) the NIOSH cohorts of Fingerhut et al. (1991).
Of the total study population, 21,863 (20,851 men and 1,012 women) were classified as exposed to phenoxy herbicides or chlorophenols based on individual job records and company exposure questionnaires; 4,160 were unexposed; and 592 were classified as "unknown exposure." Most workers were classified as exposed if they had ever worked in production or spraying of phenoxy herbicides or chlorophenols (for four cohorts, a minimum employment period of 1 to 12 months was specified). The period of follow-up also varied between cohorts; overall, it extended from 1939 to 1992 (488,482 person years at report). Overall, 4.4 percent (970 workers) were lost to follow-up. Exposure information varied between cohorts, but in general, exposures were reconstructed from job records.
The exposed workers were aggregated into five groups: main production, maintenance, other exposed jobs, unspecified tasks, and sprayers. Based on these categories and information on production processes and the composition of the materials used, the exposed workers were further classified into three categories: (1) exposed to TCDD or higher chlorinated dioxins; (2) unexposed to the same; and (3) unknown exposure to the same. Analysis was performed by calculating SMRs and 95 percent confidence intervals (95% CI), using the World Health Organization (WHO) mortality data bank to calculate national mortality rates by sex, age (five-year intervals), and calendar period (five years). Within-cohort analysis was also performed using Poisson regression adjusting for time since first exposure, duration of exposure, and employment status.
A number of these individual cohorts were evaluated apart from the IARC coordinated efforts. These cohorts included Danish production workers studied by Lynge (1985, 1993); the British production workers of Coggon et al. (1986, 1991); the Dutch production workers of Bueno de Mesquita et al. (1993); and the German production workers of Manz et al. (1991). VAO and Update 1996 discuss these studies in more detail.
More recently, Becher et al. (1996) assessed cancer mortality among German workers in four phenoxy herbicide-and chlorophenol-producing facilities. The population included workers who had a least one month of employment, resulting in a cohort consisting of 2,479 male workers. The cohort was assembled from four plants, and the analysis was conducted on the total cohort divided into four subcohorts corresponding to each plant considered separately. The period of follow-up varied between plants, and 100 workers were lost to follow-up. The nature of the chemicals produced varied substantially between plants and over time; some facilities synthesized and formulated a wide range of phenoxy herbicides and chlorophenols (subcohorts III and Iv); others produced primarily 2,4,5-T and/or TCP (subcohorts I and II). Manz et al. (1991) previously reported on subcohort I. SMRs and 95% CI were calculated using West German mortality rates by five-year age and calendar intervals. Cox regression was performed to evaluate the effect of smoking in the one subcohort where smoking information was available. Each subcohort was analyzed separately because the exposure pattern was judged to be characteristic of each facility. Based on production information and limited blood dioxin measurements, subcohorts I and II are supposed to have higher TCDD exposures than subcohorts III and IV.
Flesch-Janys et al. (1995) described cancer and circulatory system mortality among 1,189 male workers in a chemical plant in Hamburg, Germany. Workers had been exposed in varying degrees to herbicides contaminated with PCDD/F. The authors developed a quantitative estimate of polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) exposure for the entire cohort derived from blood and adipose tissue levels measured in a subgroup of 190 workers. An unexposed cohort of gas workers served as an external reference group.
Other Chemical Plants
Other studies have reviewed health outcomes among chemical workers in the United Kingdom exposed to TCDD as a result of an industrial accident in 1968 (Jennings et el., 1988; May, 1982, 1983); production workers in the former USSR involved in the production of 2,4-D (Bashirov, 1969); factory workers in Prague, Czechoslovakia, who exhibited symptoms of TCDD intoxication 10 years after occupational exposure to 2,4,5-T (Pazderova-Vejlupkova et el., 1981); 2,4-D and 2,4,5-T productions workers in the U.S. (Poland et el., 1971); and white male workers employed at a chemical plant manufacturing flavors and fragrances (Thomas, 1987). VAO details these studies.
More recently, Tonn et el. (1996) examined the long-term immune system effects of TCDD in 11 industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T. Members of this group worked at the factory for several years between 1966 and 1976. In 1989 or 1992, the research team took blood samples from these workers and from 10 aged-matched healthy male volunteers with no known exposure to TCDD. The exposed cohort had TCDD body burdens at least ten times higher than the general population. A number of immune system parameters, including lymphocyte subsets and lympoproliferative responses were characterized.
Agricultural and Forestry Workers
Cohort Studies of Agricultural Workers
VAO and Update 1996 details a number of cohort studies examining health effects among those involved in agricultural activity, including proportionate mortality among Iowa farmers (Burmeister, 1981), cancer mortality among Danish and Italian farmers (Ronco et al., 1992), cancer incidence among farmers licensed to spray pesticides in the southern Piedmont area of Italy (Corrao et al., 1989), sperm abnormalities among Argentinian farmers (Lerda and Rizzi, 1991), and cancer among Danish gardeners (Hansen et al., 1992). A set of Canadian studies called the Mortality Study of Canadian Male Farm Operators, evaluated the risk to farmers of general mortality and specific health outcomes including NHL (Wigle et al., 1990; Morrison et al., 1994), prostate cancer (Morrison et al., 1992), brain cancer (Morrison et al., 1993), multiple myeloma (Semenciw et al., 1993), leukemia (Semenciw et al., 1994), and asthma (Senthilselvan et al., 1992). Based on data from the Swedish Cancer Environment Register (which links population census data, including occupation, with the Swedish Cancer Registry), cohorts studies evaluated cancer mortality and farmwork (Wiklund, 1983), STS and malignant lymphoma among agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a), the risk of NHL, HD, and multiple myeloma in relation to numerous occupational activities (Eriksson et al., 1992), and brain, lymphatic, and hematopoietic cancers in Irish agricultural workers
(Dean, 1994). In the United States, a large-scale proportionate mortality study was performed using data on more than 100,000 male and female farmers from 23 states (Blair et al., 1993).
More recently, Gambini and colleagues (1997) investigated cancer mortality among a cohort of rice growers in the Novara Province of northern Italy. Using a set of registered farm owners, they evaluated 1,493 males who worked on farms from 1957 to 1992. The cause of death was identified for 958 subjects and compared with the expected numbers calculated from national rates for five-year period and age group. No direct exposure information was available, so employment on the farm was used as a surrogate for exposure to the range of phenoxy herbicides used during the study period.
Kristensen et al. (1997) investigated birth defects among the offspring of Norwegian farmers by linking several Norwegian national registries. Farm holders born after 1924 were identified from the computerized files of national agricultural censuses held in 1969, 1979, 1989, and horticultural censuses in 1974 and 1985. Linkages with the Central Population Register and Medical Birth Registry identified a total of 192,417 births in 1967-1991 to farm holders. A comparison group consisted of 61,351 births to mothers residing in agricultural municipalities but determined not to be farm holders. Birth defects were identified from the Medical Birth Registry, a national registry of all births of 16 completed weeks gestation with up to three birth defects recorded. In addition, data were available on potential confounding factors including maternal age, birth order, parental consanguinity, geographic location, and maternal chronic diseases. Exposure information for each farm was obtained from the agricultural censuses. Exposure variables used in the analysis were based on the type of farming (animal husbandry, grain farming, and orchard or greenhouse farming) and use indicators (amount of money spent on pesticides, tractor pesticide spraying equipment, and amount of phosphorus and nitrogen in fertilizers). Exposure information was derived from the census closest to the time of birth. The sensitive period for exposure was considered to be three months before the estimated date of conception.
Faustini and colleagues (1996) carried out a study of 10 farmers who mixed and applied commercial formulations containing the chlorophenoxy herbicides 2,4-D and MCPA during March 1994. Researchers collected blood samples one week before herbicide exposure, and 1-12 and 50-70 days after exposure. A number of immune system components and functions were assessed, including lymphocyte count, natural killer cell-mediated cytotoxicity, and lymphoproliferative response. The farmers served as their own controls.
Cohort Studies of Forestry Workers
Studies have been conducted among forestry workers potentially exposed to herbicides used in Vietnam. These studies include a cohort mortality study among
men employed at a Canadian public utility (Green, 1987, 1991) and a briefly outlined Dutch study of forestry workers exposed to 2,4,5-T which compared the prevalence of acne and liver dysfunction (van Houdt et al., 1983). VAO describes these studies in greater detail.
Cohort Studies of Herbicide/Pesticide Appliers
A number of cohort studies have assessed health outcomes among herbicide and pesticide appliers including cancer mortality among Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980), mortality among pesticide appliers in Florida (Blair et al., 1983), general and cancer mortality and morbidity measured prospectively among Finnish male 2,4-D and 2,4,5-T appliers (Riihimaki et al., 1982, 1983; Asp et al., 1994), and reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982). Other studies examined the risk of cancer including STS, HD, and NHL among pesticide and herbicide appliers in Sweden (Wiklund et al., 1987, 1988b, 1989a,b), general and cancer mortality among Dutch male herbicide appliers (Swaen et al., 1992), cancer mortality among Minnesota highway maintenance workers (Bender et al., 1989), and lung cancer morbidity in male agricultural plant protection workers in the former German Democratic Republic (Barthel, 1981). Some of these studies include agricultural and forestry worker cohorts.
More recently, Garry et al. (1994) conducted a cross-sectional study of 1,000 pesticide appliers in Minnesota to evaluate health outcomes associated with pesticide use. Study participants were selected from a current list of licensed pesticide appliers obtained from the state Department of Agriculture. All persons certified and/or recertified within the past five years were eligible to participate in the study. One thousand pesticide appliers were chosen by random selection and contacted by telephone. Seven hundred and nineteen individuals who chose to participate in the study received a questionnaire in the mail regarding general health, occupation, pesticide use, and use of protective gear. Update 1996 describes this study in more detail.
Using this base population of 719 licensed pesticide appliers, Garry et al. (1996a) obtained blood samples from 23 fumigant appliers, 18 insecticide appliers, and 20 herbicide appliers; 33 subjects who were not involved in applying pesticides were used as controls and frequency-matched on age and smoking status. Although blood samples were collected at various times in the year, only the samples obtained during the traditional pesticide application season were evaluated.
Garry et al. (1996b) further conducted a series of analyses using data on birth defects among the offspring of these male pesticide appliers in Minnesota. Information on private state-licensed pesticide appliers registered with the Minnesota Department of Agriculture in 1991 (N = 34,772) were linked with live birth data for the state of Minnesota (1989-1992). Birth defect data were contained in these
birth files. Analyses of the relationship between birth defect rates and county-specific agricultural data were also performed. Pesticide data for units or clusters of Minnesota counties with similar geologic features and crops served to provide use data for 12 herbicides (including 2,4-D). An additional analysis was conducted to evaluate specific pesticide use. Based on pounds of active ingredient per county, low-and high-use categories were defined for the 12 specific pesticides, and comparisons were made of the birth defect rates within each region.
Hertzman and colleagues (1997) conducted a large retrospective cohort study of British Columbia sawmill workers potentially exposed chlorophenate wood preservatives. The researchers selected 23,829 cases from 11 sawmills that used chlorophenates, and 2,658 controls from 3 other sawmills. Study participants worked in these sawmills for at least one year or, for those who worked only intermittantly, 260 days between 1950 and 1985. These data were linked to the British Columbia Death File and the British Columbia Cancer Incidence File. Researchers conducted a second link to the Canadian Mortality Database and also to data provided by Statistics Canada. Based on a protocol from a previous exposure study (Hertzman et al., 1988; Teschke et al., 1989), a retrospective exposure assessment was conducted and combined with worker estimates of frequency and duration of exposure, to yield a quantitative measure of exposure. Standardized mortality and incidence ratio analysis were conducted between cases and control, with the male population of British Columbia serving a external controls. Cancer latency was assessed using 5-, 15-, and 20-year time interval categories. A separate standardized rate ratio analysis was conducted for NHL.
As part of the larger cohort study of Hertzman et al. (1997), Dimich-Ward et al. (1996) conducted a nested case-control analysis of birth defects among offspring of fathers employed in these British Columbia sawmills. The cohort included 9,512 fathers who had worked at least one year in sawmills where chlorophenate wood preservatives had been used. Chlorophenates are known to be contaminated by dioxin. Births (1952-1988) to these men were identified by linkage with the British Columbia (BC) live and stillbirth records. Further linkage with the BC Health Surveillance Registry identified cases of birth defects. The registry system is population based and uses multiple sources of identification. A case-control analysis was conducted, matching five controls (non-defect births) per case on year of birth and gender. Covariates included mother's and father's age. Exposure to chlorophenates for specific time periods was assessed by a team of industrial hygienists based on job title. Continuous estimates of cumulative hours of chlorophenate exposure were calculated for time windows relative to conception and pregnancy. Estimates of maximal exposure were determined for the most exposed job in each time period.
Heacock et al. (1998) further evaluated fertility in the sawmill worker cohort in British Columbia. The worker cohort was linked with provincial marriage and birth files. The person-year contributions and live births of workers less than 55 years of age, who had worked for at least one year between 1950 and 1985 (N =
26,487), were included. The exposure of these workers to chlorophenates, possibly contaminated by dioxin, was estimated for each worker and an index of cumulative chlorophenate exposure duration was developed (<120, 120-1,999, 2,000-3,999, 4,000-9,999, and >10,000 hours). For the external analysis, exposure was defined as sawmills in which chlorophenates were used; for the internal analysis, the cumulative exposure index was used. Among those exposed to chlorophenates, 18,016 births were recorded, while 1,668 births were recorded for the comparison group. The internal analysis estimated the rate ratio to evaluate the effects of chlorophenate exposure and time since hire, adjusting for age and calendar period.
Zhong and Rafnsson (1996) examined cancer risk among pesticide users in Iceland. Based on data provided by the Icelandic Cancer Registry, the researchers followed a cohort of 2,449 people, including 1,860 men and 589 women, who had all come into contact with pesticides. Six subcohorts were formed based on previous contact with pesticides, including (1) specially licensed pesticide users, (2) students of the Icelandic Horticultural College, (3) members of the Icelandic Market Gardeners' Association Pension Fund, (4) members of the Horticulturist's Association, (5) members of the Association of Vegetable Farmers, and (6) vegetable producers of the Farmers' Association of Iceland. Only a group of 594 of the specially license pesticide users were assumed to have been heavily exposed to pesticides. While it is not known whether study participants were exposed to the herbicides used in Vietnam, data from the Icelandic Committee on Toxic Substances suggest that 2,4-D was used heavily in agricultural during 1976-1993. The data from the Icelandic Cancer Registry were linked to the National Registry and the Register of Deaths to ascertain vital statistics of study participants. Standardized incidence ratios were calculated based on observed and expected number of cancers for each subgroup.
Case-Control Studies
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 included studies of STS from data provided by the Department of Oncology, University Hospital, Umea (Hardell and Sandstrom, 1979); the Cancer Registry of five southern counties, where MCPA, 2,4-D, and phenoxypropionic acids are used in agricultural areas (Eriksson et al., 1979, 1981); the Regional Cancer Registry in Umea, Sweden (Hardell and Eriksson, 1988); the Regional Cancer Registry at the University Hospital in Linkoping in southeastern Sweden (Wingren et al., 1990); and the Regional Cancer Registry in Uppsala in central Sweden (Eriksson et al., 1990).
Based on these results, other researchers conducted cases-control studies of other health outcomes including HD, NHL, and other lymphomas from the north-
ern Sweden cancer registry in Umea (Hardell et al., 1980, 1981; Hardell and Bengtsson, 1983); HD and NHL from the Orebro Medical Center Hospital registry (Persson et al., 1989); NHL from the Lund University Hospital registry (Olsson and Brandt, 1988); HD and NHL from the Regional Cancer Registry at the University Hospital in Linkoping (Persson et al., 1993); and nasal and nasopharyngeal carcinomas (Hardell et al., 1982), and primary or unspecified liver cancer (Hardell et al., 1984) from the northern Swedish Cancer Registry. To address criticism regarding potential observer bias in some of these Swedish case-control series, Hardell (1981) conducted another case-control study on colon cancer. Later, Hardell et al. (1994) examined the relationship between occupational exposure to phenoxyacetic acids and chlorophenols and various parameters related to NHL, including histopathology, stage, and anatomical location, based on the NHL cases from a previous study (Hardell et al., 1981).
Prompted by the Swedish studies of STS and exposure to phenoxy herbicides, a set of case-control studies was undertaken in New Zealand to evaluate the risks of phenoxyherbicide and chlorophenol exposure and STS incidence and mortality (Smith et al., 1983, 1984; Smith and Pearce, 1986). Additional case-control studies and an expanded case series were conducted of phenoxy herbicide and chlorophenol exposure find the risks of malignant lymphoma, NHL, and multiple myeloma (Pearce et al., 1985, 1986a,b, 1987).
Geographic mortality patterns for white males indicated elevated leukemia mortality in the central part of the United States, which prompted a study of the leukemia mortality of Nebraska farmers (Blair and Thomas, 1979). Additional case-control studies were later conducted on leukemia in Nebraska (Blair and White, 1985); Iowa (Burmeister et al., 1982), based on the cohort study of Burmeister (1981); Iowa and Minnesota (Brown et al., 1990); and leukemia associated with NHL in eastern Nebraska (Zahm et al., 1990). VAO and Update 1996 summarize these studies in greater detail.
Case-control studies have been conducted on other cancers, including NHL in Iowa and Minnesota (Cantor et al., 1992); multiple myeloma in a nation-wide American Cancer Society Cancer Prevention Study (Boffetta et al., 1989); cancers of the stomach, prostate, NHL, and multiple myeloma in Iowa (Burmeister et al., 1983); STS, HD, and NHL in Kansas (Hoar et al., 1986); multiple myeloma in Iowa (Brown et al., 1993); and NHL among white women in Nebraska. (Zahm et al., 1993).
Other researchers have conducted additional studies on NHL among white male residents of certain Wisconsin counties (Cantor, 1982); NHL and HD in Hancock County, Ohio, an area of reported heavy herbicide use (Dubrow et al., 1988); multiple myeloma in four Surveillance, Epidemiology, and End Results (SEER) areas from Detroit, Washington State, Atlanta, and Utah (Morris et al., 1986); and STS and NHL 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).
Numerous case-control studies have examined other health effects, including spontaneous abortions in Oregon and Washington (Carmelli et al., 1981); immunosuppression and subsequently decreased host resistance to infection among AIDS patients with Kaposi's sarcoma (Hardell et al., 1987); and mortality of U.S. Department of Agriculture extension agents (Alavanja et al., 1988, 1989).
More recently, Blatter and colleagues (1997) recently conducted a multicenter case-control study of paternal occupation and risk of spina bifida in offspring. The study identified live-born cases of spina bifida by medical records review at seven hospitals and two rehabilitation centers in the Netherlands (1980-1992). Controls were children who were born healthy, but developed trauma capitis or meningitis during early childhood and were diagnosed at three of the hospitals where cases were identified (N = 456). Birth registries were used to identify another group of controls (N = 1,894). Case and control parents were initially mailed a questionnaire to collect data on occupational histories and potentially confounding factors. A follow-up telephone interview was conducted for fathers that had an occupation involving potential environmental exposures. This second interview included items on the frequency of tasks and exposures and the use of protective gear. Agricultural workers were included in the second interview. Estimation of exposure level was based on the self-reported information and the judgment of industrial hygienists. Exposure was analyzed for the time period from three months prior to the estimated date of conception to one month after. Response to the initial questionnaire included 77 percent of cases and 68 percent of controls. The final sample, including the second interview, totaled 222 cases and 764 controls. Data were collected on a number of potentially confounding factors including medication use, maternal diabetes, parity, family history of neural tube defects, and parental smoking and alcohol consumption. No analyses were presented on specific pesticides, especially herbicides of interest such as 2,4-D, probably because of the small numbers of exposed subjects.
Based on the work of Amadori et al. (1995), Nanni et al. (1996) conducted a population-based case-control study in northeastern Italy of occupational and chemical risk factors for lymphocytic leukemia and non-Hodgkin's lymphomas. Between 1987 and 1990, the population tumor registry of the Forli Province was consulted to identify all hematologically or histologically diagnosed cases of NHL and chronic lymphocytic leukemia (CLL) among 15-75 year olds (N = 187). Controls (N = 977) were selected randomly using a residents' list and were frequency matched by sex and five-year age interval. Study participants were mailed a questionnaire regarding occupational history, potential pesticide exposure and confounders. Exposure recall and a priori matrices of occupational status and exposure were used to define exposure. Unconditional logistic analysis was performed with adjustment for confounders.
Tatham et al. (1997) conducted a population-based case-control study of the occupational risk factors for subgroups of NHL patients using information contained in the CDC's Selected Cancers Study, a multicenter case-control study
(CDC, 1990a-d). In 1983, the CDC undertook the Selected Cancers Study to investigate the health effects of Vietnam military service and exposure to herbicides. Tumor registries covering three states and five large metropolitan areas were reviewed to identify all cases of several types of cancers diagnosed from December 1984 to November 1988. Controls were selected by random-digit dialing and were frequency matched for geographic area covered by the tumor registry and five-year date-of-birth intervals. A second control group consisted of deceased individuals from the same registry area, who were pair matched to deceased cases by date of birth, race, and time interval between death and proxy interview. Researchers interviewed study participants, collecting information on medical history, occupation, contact with chemicals, personal characteristics and habits, and military service in Vietnam (CDC, 1990a-d). VAO describes the study design in more detail.
Based on these controls and a subset of cases diagnosed with NHL, Tatham et al. (1997) conducted another study. In all, 1,048 cases and 1,659 controls were identified. Cases were categorized into three subgroups representing different histological types of NHL: (1) small-cell diffuse lymphomas, (2) follicular lymphomas, and (3) large-cell diffuse lymphomas. Comparisons were made between these three subgroups and controls for chemical exposure and occupation using conditional logistic regression.
Schulte et al. (1996) conducted a proportionate mortality study of neurodegenerative diseases and occupational risk factors. The researchers collected 130,420 death certificates for the years 1982-1991 from 27 states in the National Occupational Mortality Surveillance System. They coded occupation or industry of employment according to Bureau of Census standards. Subsequently, a certified industrial hygienist and senior epidemiologist grouped these occupational codes based on common exposures and tasks. Age-standardized proportionate mortality ratios (PMRs) were calculated for the each occupational group for four neurodegenerative diseases: (1) presenile dementia, (2) Alzheimer's disease, (3) Parkinson's disease, and (4) motor neuron disease.
Liou et al. (1997) conducted a case-control study of occupational and environmental risk factors and Parkinson's disease (PD) in Taiwan. The researchers recruited 120 PD patients from the Movement Disorder Clinic of National Taiwan University Hospital from 1993 to 1995 along with 240 controls matched on age and sex. Interviewers obtained data on demographic and residential history and potential exposure to occupational and environmental agents. Although the structured interview included questions about pesticide or herbicide use, no specific information about phenoxy herbicide exposure was obtained. Subjects were asked about exposure to the herbicide paraquat. Researchers calculated chi square and odds ratios for matched subjects. In addition, conditional logistic regression was employed in the multivariate analysis.
Seidler et al. (1996) conducted a case-control study of Parkinson's disease and various rural factors, including exposure to herbicides and wood preserva-
tives. Researchers recruited 380 PD patients from nine German neurologic clinics, along with 379 neighborhood and 376 regional controls. Trained interviewers collected data on demographic, residential, and occupational variables and on exposures to numerous chemical agents. Subjects were questioned about frequency and length of herbicide use and contact with wood preservatives. Researchers used a job exposure matrix to more objectively assess exposure to these chemicals. They controlled educational status and smoking through the use of conditional logistic regression.
VAO and Update 1996 describe a number of other studies that look at various health outcomes and associated exposures to phenoxyherbicides or surrogate measures of exposure. The examined health outcomes include including ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988); STS and other cancers from the 15 regional cancer registries that constitute the National Cancer Register in England (Balarajan and Acheson, 1984); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); STS among rice weeders in northern Italy (Vineis et al., 1986); primary lung cancer among pesticide users in Saskatchewan (McDuffie et al., 1990); renal cell carcinoma from the Denmark Cancer Registry (Mellemgaard et al., 1994); Parkinson's disease in relation to occupational risk factors in Canada (Semchuk et al., 1993); and birth defects among agricultural workers in Finland (Nurminen et al., 1994).
Paper and Pulp Workers
VAO describes studies of workers potentially exposed to TCDD at paper and pulp mills and various health outcomes, including general mortality of workers at five mills in Washington, Oregon, and California (Robinson et al., 1986); cancer incidence among male Finnish paper mill workers (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality among white males employed in plants identified by the United Paperworkers International Union (Solet et al., 1989).
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.
Seveso
One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled
reaction during trichlorophenol production. A variety of indicators were used to estimate individual exposure; soil contamination by TCDD has been the most extensively used. On the basis of soil sampling, three areas were defined about the release point: zone A, the most heavily contaminated, from which all residents were evacuated within 20 days; zone B, an area of lesser contamination that children and pregnant women in their first trimester were urged to avoid during daytime; and zone R, a region with some contamination, in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b).
Several cohort studies based on these exposure categories have been conducted. These studies are reviewed extensively in VAO and Update 1996 and summarized here. Caramaschi et al. (1981) presented the distribution of chloracne among Seveso children, while Mocarelli et al. (1986) tested the children for laboratory levels of several chemicals in the blood and urine based on previous chloracne. In a follow-up to these studies, dermatologic findings and laboratory tests were conducted among a group of the children with chloracne compared to controls (Assennato et al., 1989a).
Other studies looked at specific health effects associated with TCDD exposure among Seveso residents, including chloracne, birth defects, spontaneous abortions, crude birth and death rates (Bisanti et al., 1980), chloracne and peripheral nervous system conditions (Barbieri et al., 1988), hepatic enzyme associated conditions (Ideo et al., 1982, 1985), abnormal birth outcomes (Mastroiacovo et al., 1988), cytogenetic abnormalities in maternal and fetal tissues (Tenchini et al., 1983), neurological disorders (Boeri et al., 1978; Filippini et al., 1981), and cancer incidence (Pesatori et al., 1992, 1993; Bertazzi et al., 1993). A two-year prospective controlled study was conducted of workers potentially exposed to TCDD during cleanup of the most highly contaminated areas following the accident (Assennato et al., 1989b).
Mocarelli et al. (1996) recently evaluated the sex ratio among offspring who were born in zone A of Seveso from 1977-1984 (74 births) and from 1985-1994 (124 births). Stored serum samples were used to determine the TCDD levels in 13 families in which both parents were from zone A to further examine the relationship with sex ratio.
The Seveso residents have had long-term follow-up of their health outcomes, especially cancer. For example, Bertazzi et al. (1989a,b, 1992) conducted ten-year mortality follow-up studies among adults and children age 1 to 19 at the time of the accident.
More recently, Bertazzi et al. (1997) evaluated the Seveso population after 15 years of follow-up through the end of 1991. Study subjects were assigned to one of the exposure zones previously described: 45,373 cases (805 in zone A; 5,943 in zone B; and 38,625 in zone R) and 232,747 controls were identified. Poisson regression was employed to compare age-adjusted rates in each exposure and control zone. Additional analyses were conducted using a surrogate of duration of exposure and time since first exposure within each exposure group.
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 number of studies were conducted to evaluate health effects from the potential exposure (Hoffman et al., 1986; Stehr et al., 1986; Stehr-Green et al., 1987; Webb et al., 1987; Evans et al., 1988; Stockbauer et al., 1988). VAO discusses these studies in greater detail.
Vietnam
Vietnamese researchers have conducted studies of the native population exposed to the spraying that occurred during the Vietnam conflict. In a review paper, Constable and Hatch (1985) have summarized the unpublished results of these studies. The review article included nine reports that focus primarily on reproductive outcomes (Can et al., 1983a,b; Huong and Phuong, 1983; Khoa, 1983; Lang et al., 1983a,b; Nguyen, 1983; Phuong and Huong, 1983; Trung and Chien, 1983). Vietnamese researchers later published results of four additional studies conducted in Vietnam, two focusing on reproductive abnormalities (Phuong et al., 1989a,b), one on mortality (Dai et al., 1990), and one on hepatocellular carcinoma (Cordier et al., 1993). VAO and Update 1996 discuss these studies in more thorough detail.
Other Environmental Studies
VAO and Update 1996 reported on numerous studies focusing on reproductive outcomes of potential environmental exposure in Oregon (U.S. EPA, 1979); Arkansas (Nelson et al., 1979); Iowa and Michigan (Gordon and Shy, 1981); New Brunswick, Canada (White et al., 1988); Skaraborg, Sweden (Jansson and Voog, 1989); and Northland, New Zealand (Hanify et al., 1981).
Numerous studies have focused on other outcomes due to environmental exposure, including STS and connective tissue cancers in Midland County, Michigan (Michigan Department of Public Health, 1983); NHL in Yorkshire, England (Cartwright et al., 1988); cancer in Finland (Lampi et al., 1992); and lymphomas and STS in Italy (Vineis et al., 1991). Additional studies were conducted on neuropsychological effects in Germany (Peper et al., 1993); young-onset Parkinson's disease in Oregon and Washington (Butterfield et al., 1993); and adverse health effects following an electrical transformer fire in Binghamton, New York (Fitzgerald et al., 1989).
More recently, Gallagher et al. (1996) conducted a community case-control study of skin cancer in Alberta, Canada. Using pathological reports obtained
from the Alberta Cancer Registry, researchers identified and interviewed 226 male patients diagnosed during 1983-1984 with primary basal cell carcinoma (BCC) and 180 male patients with primary squamous cell carcinoma (SCC). By randomly sampling the Alberta Health Care Insurance Plan patient files, 406 age-matched controls were identified and interviewed. Interview questions included self-reported duration, intensity, and source of exposure to numerous chemical agents. To better characterize total lifetime exposure, the duration of exposure was weighted by its source (direct job, workplace environment, hobby, or home) and intensity (duration per week: <1 hour, 1-4 hours, 5-19 hours, or >20 hours). Exposed subjects were dichotomized into low and high exposure levels based on this total lifetime exposure. Adjustments were made for age, skin and hair color, mother's ethnic origin, and sunlight exposure in 10 years prior to diagnosis by use of conditional logistic regression.
Based on a longitudinal cohort study of residents of Tecumseh, Michigan, Waterhouse et al. (1996) conducted a nested case-control study of NHL, HD, and CLL in a rural Michigan community. Researchers identified 7,016 study participants who had been involved in earlier rounds of the longitudinal cohort study, and sent health surveillance questionnaires to them or their living relatives. Cause of death was determined for 99 percent of the individuals. Researchers collected death certificates and those indicating cancer as the cause of death were placed into several categories (definite, probably, suspect, unconfirmed, and misclassified cases) based on medical confirmation of tumor type. Comparisons were made between the observed incidence of cancer in these categories and that expected based on a referent population in the Connecticut tumor registry. A nested case-control study was then conducted based on risk factors obtained in the longitudinal study, including smoking history, family cancer history, and occupational and environmental exposure to numerous chemicals. Four sets of controls were matched to each case (N = 42 males and 32 females) with leukemia or lymphoma by sex and year of birth. Exposure to pesticides and herbicides was evaluated by geographic coding of acreage sprayed in 1978 or 1982-1987 by Michigan county.
Masala et al. (1996) conducted a large multicenter case-control study of HD (N = 421), NHL (N = 1822), multiple myelomas (N = 325) and acute myeloid leukemias (N = 263) in various regions of Italy. Cases were ascertained from data provided by cancer registries, hospitals in the regions studied, and referral hospitals. Cases were categorized based on area of residence, including the heavily industrialized regions in the north of Italy, rural areas, and mixed rural and urban settings. Based on these data, annual incidence rates were calculated according to five-year age groups. Comparison were made across area of residence.
Wolf and Karmaus (1995) reported on a cross-sectional study of the effects of inhalative exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day care center employees. The study population consisted of 221 exposed persons and an unexposed control group of 189 persons who worked at neighboring day-care centers not treated with wood pre-
servatives. Research staff conducted physical exams, administered clinical tests on cell-mediated immunity, and interviewed study participants about occupational exposure. Measurements of the indoor air concentrations of the wood preservatives and the contaminant, dioxin were taken. Researchers also took into account other sources of exposure to dioxin and wood preservatives.
A number of studies evaluated TCDD exposure among fishermen It is assumed that diet constitutes the primary exposure route in these cases. Svensson et al. (1995) assessed mortality and cancer incidence in two cohorts of Swedish fishermen. One group (2,896 men) resided on the east coast of Sweden and consumed fish from the Baltic Sea. These fatty fish (particularly salmon and herring) are reported to contain elevated levels of PCBs, PCDDs, and PCDFs. The other group of fishermen (8,477) resided on the west coast of Sweden and were presumed to have a higher intake of lean (and less contaminated) fish, including cod and flat fish. This distinction of exposure by place of residence is reportedly confirmed by the finding that blood levels of dioxin-like compounds were two times higher among east coast than west coast fishermen; however, no supporting data are provided relating to this point.
Lovik and colleagues (1996) conducted a cohort study of hobby fishermen in the Frierfjord in southeastern Norway. The researchers recruited 24 fishermen with possible dietary exposure to a number of halogenated aromatic hydrocarbons, such as PCDD and PCF, through crab consumption. The locally caught crabs are known to contain high levels of these organochlorine compounds. Ten control subjects were randomly selected from the Population Registry. All study participants were asked detailed questions about health status, potential occupational and environmental exposure to PCDDs, PCDFs, and PCBs, and fish and crab consumption. The researchers also collected blood samples, measuring levels of the organochlorine compounds and various biological parameters.
Based on the previous study of Dutch infants (Koopman-Esseboom et al., 1994), Weisglas-Kuperus et al. (1995) explored the immunological effects of pre-and postnatal PCB or TCDD exposure in 207 Dutch infants from birth to 18 months of age. Mother-infant pairs were selected from the Rotterdam area and 102 infants were exclusively bottle-fed, while the remaining 105 were breast-fed for at least 6 weeks. Postnatal dioxin and PCB exposure for breastfed infants was estimated from the total toxic equivalent level of each compound in human milk multiplied by the weeks of breastfeeding. Prenatal exposure to the compounds was estimated for all infants based on PCB-plasma levels for individual mother-infant pairs. Blood samples were collected on a subgroup of infants and immunological tests conducted. Mothers were questioned about health status and history.
VIETNAM VETERANS STUDIES
Studies of Vietnam veterans who were potentially exposed to herbicides, including Agent Orange, have been conducted in the United States at the national
and state levels, as well as in Australia. Exposure measures in these studies have been done on a variety of levels, and evaluations of health outcomes have been made using a variety of different comparison or control groups. This section is organized primarily by the sponsors of the research, because this format is more conducive to methodologic presentation of the articles. In these studies, exposure measures fall along a crude scale from individual levels for Ranch Hands, as reflected in serum dioxin measurements, to use of service in Vietnam as a surrogate for TCDD exposure in some state studies.
It should also be noted that comparison groups for the veteran cohort studies vary to include 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 military at the time of the conflict but did not serve in Vietnam; non-Vietnam veterans who served in other wars or conflicts such as the Korean War or World War II; and various U.S. male populations (either state or national).
United States
Ranch Hands
The men responsible for the majority of the aerial spraying of herbicides in Vietnam were volunteers from the Air Force who participated in Operation Ranch Hand. 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 Ranch Hands (AFHS, 1982). VAO and Update 1996 discuss the cohort in more detail.
A retrospective matched cohort study design was implemented to examine morbidity and mortality, with follow-up scheduled to continue until 2002. National Personnel Records Center and U.S. Air Force Human Resources Laboratory records were searched and cross-referenced to ascertain completely all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990). A total of 1,269 participants were originally identified (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 used to identify the Ranch Hand population. Controls were matched on age, type of job (using Air Force specialty code), and race (white or not white). The rationale for matching on these variables was to control for the clinical aging process, educational 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 con-founders related to the physical and 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 random sample of half of each subject's control set are 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" is selected; controls who die are not replaced.
The baseline exam occurred in 1982, and future exams are scheduled until 2002. Morbidity is ascertained through questionnaire and physical examination, which emphasize 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 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, the DVA's Death Beneficiary Identification and Record Location System (BIRLS), and the Internal Revenue Service's data base of active social security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990). Eighty-four percent of the 1,148 eligible Ranch Hands (N = 952), 76 percent of the original comparison group (N = 912), and 65 percent of the 567 replacement comparisons (N = 369) invited to the 1992 follow-up chose to participate in the examination and questionnaire (AFHS, 1995). The methods used to assess mortality and morbidity were identical to the methods described previously for the 1982 and 1987 examinations.
Ranch Hands were divided into three categories on the basis of their potential exposures:
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Low potential: This group included pilots, copilots, and navigators. Exposure was primarily through preflight checks and during actual spraying.
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Moderate potential: This group included crew chiefs, aircraft mechanics, and support personnel. Exposure could occur by contact during dedrumming and aircraft loading operations, on-site repair of aircraft, and repair of spray equipment.
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High potential: This group included spray console operators and flight engineers.
Results have been published for the baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983); first (1984b), second (1987), and third (1992) follow-up examinations (AFHS, 1987, 1990, 1995); and reproductive outcomes study (AFHS, 1992; Wolfe et al., 1995). 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 (455 Ranch Hands; AFHS, 1995). Serum dioxin analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b). Continued follow-up and results will be forthcoming.
In an interim technical report, the Air Force Health Study (AFHS, 1996; Michalek et al., 1998b) updated the cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 controls through the end of 1993. Study design followed that of the previous Ranch Hand studies. The study team reported few other details.
A recent Ranch Hand publication addressed the relationship between serum dioxin and reproductive hormones (Henriksen et al., 1996). The Air Force investigators measured serum testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testicular abnormality in clinic visits by Ranch Hand and comparison participants in 1982, 1985, 1987, and 1992. In the baseline year of 1982, a total of 1,045 Ranch Hands and 1,224 comparisons participated in the study. Serum dioxin was measured in 1987, testicular volume in 1992, and sperm count and percentage of abnormal sperm in 1982. The semen data was collected from 474 Ranch Hands and 532 comparisons. Potential confounding factors adjusted for in the analysis included age, race, personality type, diabetes, current alcohol consumption, current cigarette smoking, and percentage of body fat. Sperm count and sperm abnormality were adjusted only for age and exposure to industrial chemicals.
Henriksen and colleagues (1997) analyzed the Ranch Hand data to address the relationship between TCDD and diabetes mellitus and glucose and insulin levels. For this analysis, a total of 989 Ranch Hands and 1,276 comparisons were clinically examined. Blood samples were collected and medical records were reviewed to determine diabetes status, severity and time-to-diabetes onset. Serum insulin and glucose levels were calculated from blood samples taken in 1992. Exposure to TCDD was classified on the basis of original exposure calculated from serum (lipid-adjusted) dioxin levels determined in 1987 or 1992. At follow-up (1992), the mean age of the comparison group was 53.5 years (±7.6), and the mean ages of the exposed groups were 54.6 ± 7.2, 54.9 ± 7.6, and 50.9 ± 7.4 years by increasing exposure category.
A recent Ranch Hand publication reported results for the analysis of dioxin levels in relation to infant death (Michalek et al., 1998a). Infant death was ascertained from medical records, vital statistics, and autopsy records. Cause of death was coded based on record review. The analysis included a total of 2,082 children (859 children of Ranch Hands and 1,223 children of comparisons) conceived before the father's service in Southeast Asia. The 859 Ranch Hands children were stratified into four exposure categories including children of comparison veterans (current dioxin levels less than 10 ppt), "background" Ranch Hand children (< 10 ppt), "low" Ranch Hand children (>10 and <79 ppt), and "high" Ranch Hand children (> 79 ppt). The cutpoint of 79 ppt is the median initial dioxin level based on the extrapolated current levels (in 1987 or 1992). The stratified analyses
adjusted for father's race, mother's smoking and alcohol consumption during pregnancy, parental age, and father's military occupation. The investigators also examined the distribution of post-SEA infant deaths in the low and high categories by quintile of initial dioxin. Another analysis was conducted excluding infants whose mothers had medical conditions such as hypertension during pregnancy, abruptio placentae, placenta previa, and Ranch Hand incompatibility.
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) 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). VAO and Update 1996 describe these studies in more detail. The first of these was a case-control interview study of birth defects among offspring of fathers serving in Vietnam (Erickson et al., 1984a,b).
To examine the concerns about Agent Orange more directly, the CDC conducted the Agent Orange Validation Study 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 (CDC, 1989a). Using the exposure estimates from this study, the CDC subsequently conducted the Vietnam Experience Study (VES), a historical cohort study of the health experience of Vietnam veterans (CDC, 1989b). The study was divided into three parts: (1) physical health; (2) reproductive outcomes and child health; and (3) psychosocial characteristics (CDC, 1987, 1988a-c, 1989b).
Using data from the VES, 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). An additional study (O'Brien et al., 1991) combined the mortality and interview data to identify all veterans with NHL. To evaluate whether self-reported assessment of exposure to herbicides influences the reporting of adverse health outcomes, the CDC designed a study using VES subjects (Decoufle et al., 1992).
Finally, the CDC undertook the Selected Cancers Study (CDC, 1990a) to investigate the effects of military service in Vietnam and exposure to herbicides on the health of American veterans. Outcomes studied were NHL (CDC, 1990b); STS and other sarcomas (CDC, 1990c); and HD, nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d).
Department of Veterans Affairs
The DVA has conducted numerous cohort and case-control studies, which VAO and Update 1996 discuss in greater detail. One of the first of these was a
proportionate mortality study conducted by Breslin et al. (1988). 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. A list of 186,000 Vietnam era veterans who served in the Army or Marine Corps 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. Cause of death was ascertained for 51,421 men, including 24,235 who served in Vietnam. Based on this proportionate mortality study (Breslin et al., 1988), Burt et al. (1987) conducted a nested case-control study of NHL with controls selected from among the cardiovascular disease mortality deaths. Later, Bullman et al. (1990) examined whether Army I Corps Vietnam veterans had cancer mortality experiences similar to other Army Vietnam era veterans, based on the study design of Breslin et al. (1988).
Watanabe et al. (1991) conducted an additional study using this Vietnam veteran mortality experience (Breslin et al., 1988) compared with three different referent groups and with additional follow-up through 1984. The final study group of 62,068 veterans included 50,743 from the earlier mortality study of Breslin et al. (1988).
Watanabe and Kang (1996) conducted a third follow-up proportionate mortality study using the 75,617 veterans from Breslin et al. (1988) arid the 15,038 veterans from Watanabe et al. (1991). Using the original study design, a random sample of 11,851 veterans was selected from a BIRLS-generated file of 59,259 veterans who died between July 1, 1984, and June 30, 1988. The three groups were combined to yield a final sample of 102,506 veterans. Excluding those who served in Southeast Asia but not in Vietnam, the researchers collected detailed demographic and military records and ascertained the cause of death for 70, 630 of these veterans, including 33,833 who served in Vietnam and 36,797 era veterans. Adjustments were made for age, race, and calendar year of death. Separate analyses were performed for Army and Marine Vietnam veterans because of potential differences in environmental exposures among those serving in different branches of the military. Three separate comparison groups were identified: (1) branch-specific Vietnam era veterans; (2) all Vietnam era veterans combined; arid (3) for external comparisons, the U.S. male population.
The DVA also examined the morbidity and mortality experience of a sub-group of Vietnam veterans potentially exposed to high levels of herbicides from certain U.S. Army Chemical Corps units (Thomas and Kang, 1990). VAO discusses the study in greater detail.
In an extension of Thomas and Kang (1990), Dalager and Kang (1997) recently compared veterans of the Chemical Corps specialties, including 2,872 Vietnam veterans and 2,737 non-Vietnam veterans. All study subjects served at least 18 months active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. Direct exposure information on the two cohorts was not available, and the presumption that Vietnam veterans had potentially higher levels of dioxin exposure because of their duties (which involved
Agent Orange and other dioxin-contaminated herbicides) than non-Vietnam veterans has not been verified. The effects of race, military rank, duration of service, and age at entry to follow-up were adjusted using proportional hazards modeling.
A recent DVA cohort study (Watanabe and Kang, 1995) examined post-service mortality among 10,716 Marine Vietnam veterans compared to 9,346 Vietnam era Marines who did not actually serve in Vietnam. The researchers first linked files of a sample of all active-duty (1967-1969) Marines to military records from the National Personnel Records Centers and then checked the vital status of these Marines using BIRLS. BIRLS identified 701 cases and 562 controls as deceased between 1973-1991. Subsequently, the researchers located death certificates, and evaluated and coded the cause of death for each Marine. Comparisons of cause-specific mortality were made between cases and controls using relative frequency of death along with a proportional hazards multivariate model. Comparisons were also made to mortality rates of U.S. males by adjusting for age, race, and calendar year period. Finally, follow-up categories of less than 16 years and 16 years or more were created and used to compare cancer latency.
The DVA has also evaluated specific disease and health outcomes, including case-control studies of STS (Kang et al., 1986, 1987), NHL (Dalager et al., 1991), and testicular cancer (Bullman et al., 1994), as well as a co-twin study of self-reported physical health in a series of Vietnam era monozygotic twins (Eisen et al., 1991). Mortality among women Vietnam veterans was assessed by Thomas et al. (1991) and Dalager et al. (1995a). VAO and Update 1996 provide more detail.
Using the study design of Dalager et al. (1991), a case-control study assessed the risk of Vietnam service for the development of Hodgkin's disease (Dalager et al., 1995b). A review of the DVA Patient Treatment File (PTF) from 1969 to 1985 identified all malignant lymphomas among male Vietnam era veterans. A pathologist reviewed pathology reports from VA medical centers that had 10 or more lymphoma cases and identified 770 cases of HD. Using the PTF, 1,540 controls were selected from the same Vietnam-era veteran population as the cases, matched by hospital, discharge year of hospitalization for HD, and birth date. Researchers linked these data with military personnel records provided by the National Personnel Records Center. After exclusion of some individuals due to potential bias, 283 cases and 404 controls were identified. Surrogate measures of Agent Orange exposure were specified for cases based on military branch, duration of service, region of military assignment in Vietnam, and occupational specialty. A multiple logistic regression model was employed for comparisons.
Mahan et al. (1997) conducted a case-control study of lung cancer among veterans. Using the VA's Patient Treatment File (PTF), 329 Vietnam era veterans with a diagnosis of lung cancer made between 1983-1990 were identified. Variables abstracted from the military record include education, race, branch of service, Military Occupational Specialty Code, rank, and units served within Vietnam. Two groups of controls were randomly selected from the PTF file of (1) men hospitalized for a reason other than cancer (N = 269), and (2) patients with
colon cancer (N = 111). The researchers characterized the veterans' exposure to Agent Orange by assessing information on the location of each individual ground troop veteran's unit in relation to an area sprayed and the time elapsed since that area was sprayed.
Other outcomes including posttraumatic stress disorder (True et al., 1988; Bullman et al., 1991), suicide, and motor vehicle accidents (Farberow et al., 1990) among Vietnam veterans have also been examined by the DVA. VAO discusses these studies in greater detail. In many of these studies, exposure to Agent Orange is not discussed, but exposure to "combat" is evaluated as the risk factor of interest.
More recently, Bullman and Kang (1996) assessed the risk of cause-specific mortality among 34,534 veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam war. This study did not evaluate or control for chemical exposures.
McKinney et al. (1997) compared the smoking behavior of veterans and non-veterans using the 1987 National Medical Expenditure Survey (NMES). The NMES is designed to explore trends in health service utilization. Based on a stratified area probability design, 15,000 households were asked to participate in the five rounds of NMES interviews. Self-reported smoking status or history and service status or history were compared using covariance and chi squared analysis and adjusting for age, ethnicity, and sex. The study did not evaluate or control for any chemical exposures.
American Legion
The American Legion conducted a cohort study of the health and well-being of Vietnam veterans who belonged to the American Legion, a voluntary veterans service organization. A series of studies examining physical health and reproductive outcomes, social-behavioral consequences, and PTSD was conducted on 2,858 veterans who had served in Southeast Asia and 3,933 who served elsewhere (Snow et al., 1988; Stellman et al., 1988a-c).
State Studies
Several states have conducted studies of Vietnam veterans. Most of these studies remain unpublished in the scientific literature. VAO and Update 1996 review studies from Hawaii (Rellahan, 1985); Iowa (Wendt, 1985); Maine (Deprez et al., 1991); Massachusetts (Kogan and Clapp, 1985, 1988; Levy, 1988; Clapp et al., 1991); Michigan (Visintainer et al., 1995); New Jersey (Kahn et al., 1988; Fielder and Gochfeld, 1992; Kahn et al., 1992a-c); New Mexico (Pollei et al., 1986); New York (Greenwald et al., 1984; Lawrence et al., 1985); Pennsylvania (Goun and Kuller, 1986); Texas (Newell, 1984); West Virginia (Holmes et al., 1986); and Wisconsin (Anderson et al., 1986a,b).
Recently, Clapp (1997) updated the Massachusetts veterans cancer surveillance study reported six years earlier (Clapp et al., 1991). In the first study, detailed in VAO, the researchers identified cases of selected cancers from the Massachusetts Cancer Registry between 1982 and 1988 (Clapp et al., 1991). Data were linked to status as Vietnam era veterans or Vietnam bonus recipients. Controls for each cancer site analysis included veterans with other cancers, excluding STS, NHL, and kidney cancer. The study identified 727 male Vietnam era veterans and 214 Vietnam veterans. Study participants were males between the ages of 30 and 59 at the time of cancer diagnosis, and Vietnam service served as the exposure of interest.
For the update, Clapp (1997) conducted an additional records linkage covering the years 1988 to 1993. During this six-year period, researchers identified 245 and 999 cases of cancer in Vietnam veterans and Vietnam era veterans, respectively. Age-adjusted odds ratios for selected cancers were calculated and used in the comparison.
Other U.S. Vietnam Veteran Studies
Additional studies have been conducted to examine a number of health outcomes including spontaneous abortion (Aschengrau and Monson, 1989), late adverse pregnancy outcomes (Aschengrau and Monson, 1990) in spouses of veterans, and PTSD among monozygotic twins who served during the Vietnam era (Goldberg et al., 1990). After a published study indicating a potential association with testicular cancer in dogs that served in Vietnam (Hayes et al., 1990), Tarone et al. (1991) conducted a case-control study of testicular cancer in male veterans. VAO summarizes these studies.
Australia
The Australian government has also commissioned studies to investigate the health risks of Australian veterans. Studies of birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985); mortality (Commonwealth Institute of Health, 1984a-c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987); deaths from all causes (Fett et al., 1987b); and cause-specific mortality (Fett et al., 1987a) have been conducted. An independent study in Tasmania evaluated numerous reproductive and childhood health problems for association with paternal Vietnam service (Field and Kerr, 1988). VAO describes these Australian studies.
More recently, the Australian Department of Veterans' Affairs conducted a mortality study of more than 59,000 male Australian veterans who served in Vietnam (Crane et al., 1997a). Based on data provided by the Australian Department of Defense and civilian agencies, researchers created a nominal list of all members of the Army, Navy, and Air Force and some civilian personnel who served on land or in Vietnamese waters for at least one day during the period of
the Vietnam war—59,036 in all. In addition, 484 females were identified. Vital statistics, including cause of death, collected from Department of Defense records, Department of Veterans' Affairs records, the National Death Index, Electoral Commission rolls, and the Health Insurance Medicare data base were matched to the nominal list. Of the 59,036 male veterans on the nominal list, 6.5 percent (3,840) died between the end of their service and December 31, 1994; 90.4 percent (53,391) were alive. Vital status of the remaining 3.1 percent (1,805) was unknown. There were no direct measures or indirect estimates of veterans' exposure to herbicides or other chemical agents, and the authors suggest that any variations in mortality found in the study would "probably need to be attributed to service in Vietnam rather than exposure to particular agents." Cause-specific standardized mortality ratios were calculated and compared to death rates for the Australian male population.
A second cohort study of Australian veterans compared mortality for the period 1982-1994 for 18,949 national servicemen who had served in Vietnam (veterans) with that of 24,646 national servicemen who had not served in Vietnam (nonveterans) (Crane et al., 1997b).
O'Toole and colleagues (1996a-c) describe the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-1990, and illness rates were compared to the age-and sex-matched Australian population. The researchers also adjusted these illness rates for the effects of nonresponse bias based on the 950 veterans who were initially eligible for participation as cases.
Other Vietnam Veterans Studies
A team of Vietnamese scientists recently examined 25 Vietnamese veterans who served 5-10 years in a "dioxin-sprayed zone" (Chinh et al., 1996). Few other details of the cohort were provided. The researchers administered tests to detect antinuclear antibodies in the veterans and 63 age-matched controls. Additionally, tests to detect sperm autoantibodies were conducted on the veterans and 36 male controls.
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