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Veterans and Agent Orange: Update 1998 (1999)

Chapter: 6 Epidemiologic Studies

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Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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)

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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).

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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 =

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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).

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(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-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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).

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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:

  1. Low potential: This group included pilots, copilots, and navigators. Exposure was primarily through preflight checks and during actual spraying.

  2. 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.

  3. 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);

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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).

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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.

REFERENCES

Air Force Health Study (AFHS). 1982. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides: Study Protocol, Initial Report. Brooks AFB, TX: USAF School of Aerospace Medicine. SAM-TR-82-44. 189 pp.

Air Force Health Study (AFHS). 1983. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Mortality Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A130 793.

Air Force Health Study (AFHS). 1984a. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results . Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. 362 pp.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Air Force Health Study (AFHS). 1984b. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1984. Brooks AFB, TX: USAF School of Aerospace Medicine.

Air Force Health Study (AFHS). 1985. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1985. Brooks AFB, TX: USAF School of Aerospace Medicine.

Air Force Health Study (AFHS). 1986. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1986. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-86-43. 12 pp.

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Veterans and Agent Orange: Update 1998 Get This Book
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Third in a series of six congressionally mandated studies occurring biennially, this book is an updated review and evaluation of the available scientific evidence regarding the statistical association between exposure to herbicides used in Vietnam and various adverse health outcomes suspected to be linked with such exposures. As part of the review, the committee convened a workshop at which issues surrounding the reanalysis and the combination of existing data on the health effects of herbicide and dioxin exposure were addressed.

This book builds upon the information developed by the IOM committees responsible for the 1994 original report, Veterans and Agent Orange, and Veterans and Agent Orange: Update 1996, but will focus on scientific studies and other information developed since the release of these reports. The two previous volumes have noted that sufficient evidence exists to link soft tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne with exposure. The books also noted that there is "limited or suggestive" evidence to show an association with exposure and a neurological disorder in veterans and with the congenital birth defect spina bifida in veterans' children. This volume will be critically important to both policymakers and physicians in the federal government, Vietnam veterans and their families, veterans organizations, researchers, and health professionals.

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