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Veterans and Agent Orange: Update 2002 (2003)

Chapter: 7. Reproductive and Developmental Effects

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Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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7

Reproductive and Developmental Effects

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2000 (hereafter, Update 2000; IOM, 2001) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed in this chapter includes papers that describe environmental, occupational, and Vietnam-veteran studies that evaluate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirths, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. Besides studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) are also reviewed when relevant, because TCDD is sometimes a contaminant of PCBs.

The primary emphasis of this chapter is on the potential adverse reproductive effects of herbicide exposure in men, because the vast majority of Vietnam veterans are men. Because about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), findings relevant to female reproductive health are also included.

BIRTH DEFECTS

The March of Dimes defines a birth defect as “an abnormality of structure, function or metabolism, whether genetically determined or as the result of an environmental influence during embryonic or fetal life” (Bloom, 1981). Other

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

terms often used interchangeably with birth defects are congenital anomalies and congenital malformations. Major birth defects are usually defined as abnormalities that are present at birth and are severe enough to interfere with viability or physical well-being. Major birth defects are seen in about 2– 3% of live births. Birth defects can be detected in an additional 5% of babies with follow-up through the first year of life. The causes of most birth defects are unknown. In addition to genetic factors, a number of exposures—including medications and environmental, occupational, and lifestyle factors—have long been implicated in the etiology of birth defects (Kalter and Warkany, 1983). Historically, most etiologic research focused on the effect of maternal and fetal exposures, but some work has addressed paternal exposures. Paternally mediated exposures could occur via several routes, and therefore exert an effect in various ways. One is through direct genetic damage to the male germ cell that is transmitted to the offspring and expressed as a birth defect. A second is through transfer of chemicals from the work, home, or general environment via seminal fluid with subsequent fetal exposure during gestation. A third route is via indirect exposure from household contamination by take-home exposures.

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and birth defects among offspring. Additional information available to the committee responsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association between at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. There was no change in those findings in Update 1998 or Update 2000. Reviews of the studies underlying the findings may be found in the earlier reports (see Tables 7-1 and 7-2).

Update of the Scientific Literature
Occupational Studies

No relevant occupational studies have been published since Update 2000 (IOM, 2001).

Environmental Studies

In a pilot study of 30 Vietnamese women who were known or whose spouses were known to be exposed to Agent Orange, Le and Johansson (2001) reported

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 7-1 Selected Epidemiologic Studies—Birth Defects

Reference

Study Population

Estimated Casesa

Exposed Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Dimich-Ward et al., 1996

Sawmill workers (paternal exposure)

 

Cataracts

11b

5.7 (1.4–22.6)

 

Genital organs

105b

1.3 (0.9–1.5)

Garry et al., 1996

Private pesticide appliers (paternal exposure)

   
 

Circulatory–respiratory

17

1.7 (1.0–2.8)

 

Gastrointestinal

6

1.7 (0.8–3.8)

 

Urogenital

20

1.7 (1.1–2.6)

 

Musculoskeletal–integumental

30

 
 

Maternal age < 30 years

11

0.9 (0.5–1.7)

 

Maternal age > 30 years

19

2.5 (1.6–2.1)

 

Chromosomal

8

1.1 (0.5–2.1)

 

Other

48

 
 

Maternal age < 35 years

36

1.1 (0.8–1.6)

 

Maternal age > 35 years

12

3.0 (1.6–5.3)

 

All births with anomalies

125

1.4 (1.2–1.7)

Kristensen et al., 1997

Offspring of Norwegian farmers (maternal and paternal exposure)

4,189c

1.0 (1.0–1.1)

Studies Reviewed in VAO

Townsend et al., 1982

Follow-up of Dow Chemical plant workers (paternal exposure)

30

0.9 (0.5–1.4)

Smith et al., 1982

Follow-up of 2,4,5-T sprayers (paternal exposure)—sprayers

 

compared with nonsprayers

13

1.2 (0.5–3.0)

Suskind and Hertzberg, 1984

Follow-up of 2,4,5-T production workers (paternal exposure)

18

1.1 (0.5–2.2)

Moses et al., 1984

Follow-up of 2,4,5-T production workers (paternal exposure)

11

1.3 (0.5–3.4)

ENVIRONMENTAL

New Studies

Loffredo et al., 2001

Infants exposed to herbicides during the first trimester (maternal exposure)

66

2.8 (1.3–7.2)

Revich et al., 2001

Residents of Chapaevsk, Russia— congenital malformations

*

(*) NS

ten Tusscher et al., 2000

Infants born in Zeeburg, Amsterdam, clinics in 1963–1965 with orofacial cleft (maternal exposure)

   
 

Births in 1963

5

(*) SS

 

Births in 1964

7

(*) SS

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Estimated Cases

Exposed Relative Risk (95% CI)

Studies Reviewed in VAO

Fitzgerald et al., 1989

Follow-up of an electric transformer fire—total birth defects (maternal and paternal exposure)

1

SIR = 212 (5.4–1,185.1)

Hanify et al., 1981

All birth malformationsd

164

1.7 (1.4–2.2)

 

All heart malformations

20

3.9 (1.7–8.9)

 

Hypospadias, epispadias

18

5.6 (2.1–15.1)

 

Talipes

52

1.7 (1.1–2.4)

 

Anencephaly

10

1.4 (0.6–3.3)

 

Spina bifida

13

1.1 (0.6–2.3)

 

Cleft lip

6

0.6 (0.2–1.5)

 

Isolated cleft palate

7

1.4 (0.5–3.8)

Mastroiacovo et al., 1988

Reproductive outcomes of Seveso, Italy, residents (maternal, paternal, and in utero exposure)

   
 

Zones A, B total defects

27

1.2 (0.8–1.8)

 

Zones A, B, R total defects

137

1.0 (0.8–1.2)

 

Zones A, B mild defects

14

1.4 (0.9–2.6)

Stockbauer et al., 1988

TCDD soil contamination in Missouri (all exposures)

   
 

Total birth defects

17

0.8 (0.4–1.5)

 

Major defects

15

0.8 (0.4–1.7)

 

Midline defects

4

0.6 (0.2–2.3)

 

Central nervous system defects

3

3.0 (0.3–35.9)

Studies Reviewed in Update 2000

Garcia et al., 1998

Infants born with various birth defects in agricultural areas in Spain

21

 
 

Index based on months of work in agriculture and intensity of exposure to chlorophenoxy herbicides

 

3.1 (0.6–16.9)

VIETNAM VETERANS

New Studies

Kang et al., 2000

Female Vietnam veterans

4,140

 
 

“Llikely” birth defects

 

1.7 (1.2–2.2)

 

“Moderate-to-severe” birth defects

 

1.5 (1.1–2.0)

Studies Reviewed in Update 2000

AIHW, 1999

Australian Vietnam veterans— Validation Study (paternal exposures)

   
 

Down syndrome

67

92 expected (73–111)

 

Tracheoesophageal fistula

10

23 expected (14–32)

 

Anencephaly

13

16 expected (8–24)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Estimated Cases

Exposed Relative Risk (95% CI)

 

Cleft lip or palate

94

64 expected (48–80)

 

Absent external body part

22

34 expected (23–45)

 

Extra body part

74

74 expected (*)

Michalek et al., 1998

Children with birth defects born to Air Force Ranch Hand veterans (paternal exposures)

   
 

Pre-Southeast Asia

*

0.7 (*)

 

Post-Southeast Asia

*

1.5 (*)

Studies Reviewed in Update 1996

Wolfe et al., 1995

High-exposure Ranch Hands relative to comparisons (paternal exposure)

   
 

Nervous system

3

(*)

 

Eye

3

1.6 (0.4–6.0)

 

Ear, face, and neck

5

1.7 (0.6–4.7)

 

Circulatory system, heart

4

0.9 (0.3–2.7)

 

Respiratory system

2

(*)

 

Digestive system

5

0.8 (0.3–2.0)

 

Genital system

6

1.2 (0.5–3.0)

 

Urinary system

7

2.1 (0.8–5.4)

 

Musculoskeletal

31

0.9 (0.6–1.2)

 

Skin

3

0.5 (0.2–1.7)

 

Chromosomal anomalies

1

(*)

 

All anomalies

57

1.0 (0.8–1.3)

Studies Reviewed in VAO

Erikson et al., 1984a

Birth defects study (paternal exposure)

 

Any major birth defects

428

1.0 (0.8–1.1)

 

Multiple birth defects with reported exposure

25

1.1 (0.7–1.7)

 

EOI-5: spina bifida

1

2.7 (1.2–6.2)

 

EOI-5: cleft lip with or without cleft palate

5

2.2 (1.0–4.9)

CDC, 1989

Vietnam Experience Study (paternal exposure)

 

Interview study

 

Any congenital anomaly

826

1.3 (1.2–1.4)

 

Nervous system defects

33

2.3 (1.2–4.5)

 

Ear, face, neck defects

37

1.6 (0.9–2.8)

 

Integument

41

2.2 (1.2–4.0)

 

Musculoskeletal

426

1.2 (1.1–1.5)

 

Hydrocephalus

11

5.1 (1.1–23.1)

 

Spina bifida

9

1.7 (0.6–5.0)

 

Hypospadias

10

3.1 (0.9–11.3)

 

Multiple defects

71

1.6 (1.1–2.5)

 

Defects with high exposure

46

1.7 (1.2–2.4)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Estimated Cases

Exposed Relative Risk (95% CI)

CDC, 1989

General Birth Defects Study (paternal exposure)

   
 

Birth defects

130

1.0 (0.8–1.3)

 

Major birth defects

51

1.2 (0.8–1.9)

 

Black Vietnam veterans with children with birth defects

21

3.4 (1.5–7.6)

 

Digestive system defects

18

2.0 (0.9–4.6)

Aschengrau and Monson, 1990

Birth defects and father's Vietnam service

   
 

Vietnam veterans compared with men without known military service

55

1.3 (0.9–1.9)

 

Vietnam veterans compared with non-Vietnam veterans

55

1.2 (0.8–1.9)

 

Major malformations

 

Vietnam veterans compared with men without known military service

18

1.8 (1.0–3.1)

 

Vietnam veterans compared with non-Vietnam veterans

18

1.3 (0.7–2.4)

Donovan et al., 1984

Birth defects and father's Vietnam service (Australia)

   
 

Vietnam veterans vs all other men

127

1.02 (0.8–1.3)

 

National Service veterans

Vietnam service vs no Vietnam service

69

1.3 (0.9–2.0)

AFHS, 1992

Follow-up of Air Force Ranch Hand personnel

   
 

Birth defects in conceptions after service in Southeast Asia Congenital anomalies

229

1.3 (1.1–1.6)

 

Nervous system

5

1.9 (0.5–7.2)

 

Respiratory system

5

2.6 (0.6–10.7)

 

Circulatory system or heart

19

1.4 (0.7–2.6)

 

Urinary system

21

2.5 (1.3–5.0)

 

Chromosomal

6

1.8 (0.6–6.1)

 

Other

5

2.6 (0.6–10.7)

a Given when available.

b Number of workers with maximal index of exposure (upper three quartiles) for any job held up to three months prior to conception.

c 95% confidence intervals contained one for all outcomes. Anencephaly and spina bifida included in this calculation.

d Excludes stillbirths, neonatal death, or dislocated or dislocatable hip.

* Information not provided by study authors.

ABBREVIATIONS: AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; NS, not significant; SIR, standardized incidence ratio; SS, statistically significant.

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 7-2 Selected Epidemiologic Studies—Neural Tube Defects

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Blatter et al., 1997

Offspring of Dutch farmers—spina bifida (paternal exposure)

   
 

Pesticide use (moderate or heavy exposure)

9

1.7 (0.7–4.0)

 

Herbicide use (moderate or heavy exposure)

7

1.6 (0.6–4.0)

Kristensen et al., 1997

Offspring of Norwegian farmers—spina bifida (paternal exposure)

   
 

Tractor spraying equipment

28

1.6 (0.9–2.7)

 

Tractor spraying equipment, orchards or greenhouses

5

2.8 (1.1–7.1)

Dimich-Ward et al., 1996

Sawmill workers (paternal exposure)

 

Spina bifida or anencephaly

22b

2.4 (1.1–5.3)

 

Spina bifida

18b

1.8 (0.8–4.1)

Garry et al., 1996

Private pesticide appliers— central nervous system defects

6

1.1 (0.5–2.4)

ENVIRONMENTALc

Studies Reviewed in VAO

Stockbauer et al., 1988

TCDD soil contamination in Missouri— central nervous system defects (all exposures)

3

3.0 (0.3–35.9)

Hanify et al., 1981

Spraying of 2,4,5-T in New Zealand (all exposures)

   
 

Anencephaly

10

1.4 (0.6–3.3)

 

Spina bifida

13

1.1 (0.6–2.3)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AIHW, 1999

Australian Vietnam veterans—validation study, spina bifida (paternal exposure)

50

1.5 (NR)

Studies Reviewed in Update 1996

Wolfe et al., 1995

Follow-up of Air Force Ranch Hands (paternal exposure)

   
 

Neural tube defects among Ranch Hand personnel childrend

4

(*)

 

Neural tube defects among comparison children

0

(*)

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study (paternal exposure)

 

Spina bifida among Vietnam veterans' children

9

1.7 (0.6–5.0)

 

Spina bifida among non-Vietnam veterans' children

5

(*)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Anencephaly among Vietnam veterans' children

3

(*)

 

Anencephaly among non-Vietnam veterans' children

0

(*)

Erickson et al., 1984a,b

Birth Defects Study (paternal exposure)

 

Vietnam veterans: spina bifida

19

1.1 (0.6–1.7)

 

Vietnam veterans: anencephaly

12

0.9 (0.5–1.7)

 

EOI-5: spina bifida

19e

2.7 (1.2–6.2)

 

EOI-5: anencephaly

7e

0.7 (0.2–2.8)

Australia Department of Veterans Affairs, 1983

Australian Vietnam veterans—neural tube defects (paternal exposure)

16

0.9

a Given when available.

b Number of workers with maximal index of exposure (upper three quartiles) for any job held up to 3 months before conception.

c Either or both parents potentially exposed.

d Four neural tube defects among Ranch Hand offspring include two spina bifida (high dioxin), one spina bifida (low dioxin), and one anencephaly (low dioxin). Denominator for Ranch Hand group is 792 and for comparison group 981.

e Number of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index.

*Information not provided by study authors.

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AIWI, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; EOI, exposure opportunity index; NR, not reported.

that two-thirds of their children had congenital malformations or developed disabilities within the first few years of life. However, by the authors' own admission, the study subjects were purposely selected to be those who had given birth to at least one disabled child. So, although suggestive for future research, the results may not be amenable to serious interpretation.

Loffredo et al. (2001) reported results from the Baltimore-Washington Infant Study. This case–control study of congenital heart defects in liveborn infants, conducted in 1981–1989, included 1,832 cases of congenital heart defects—66 with transdisposition of the great arteries (TGA) and 114 with non-TGA outflow-tract anomalies—and 771 controls. In 1987–1989, information on exposure was obtained by expanding the original questionnaire to include questions on pesticide exposure for the 1987–1989 period. Information was obtained on type, mode, location, frequency, and time of exposure. A mother was said to be exposed to pesticides if exposure occurred during the 3 months preceding pregnancy or the first trimester, a period of pregnancy considered critical for cardiovascular devel-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

opment. The mothers were further classified into four mutually exclusive groups: mothers not exposed to pesticides at any time 6 months before pregnancy or during pregnancy, mothers exposed to any pesticides 4–6 months before pregnancy, mothers exposed to pesticides during the 3 months preceding pregnancy or during the first trimester, and mothers exposed during the last 4–9 months of pregnancy (late gestational exposures).

The authors report significant associations between TGA and exposures to any pesticide (odds ratio [OR] = 2.0, 1.2–3.3), herbicides (OR = 2.8, 1.3–7.2), or rodenticidal chemicals (OR = 4.7, 1.4–12.1) but not insecticides (OR = 1.5, 0.9– 2.6). Of those, only the models for herbicides and rodenticidal chemicals were adjusted for race of infant, socioeconomic status, maternal age, maternal smoking and alcohol use, family history of heart defects, maternal diabetes, maternal solvent exposures, and paternal pesticide exposures. Non-TGA cardiac outflow-tract anomalies were significantly associated with pesticide exposure (OR = 3.8, 1.4–10.6). All other associations were not statistically significant, and ORs ranged from 0.8 to 1.5. The effect on TGA was stronger among those who used pellet, powder, or food imitators (OR = 4.0, 0.7– 9.8); and effects generally were also stronger with more frequent use of pesticides. For both herbicides and rodenticides, the effects on TGA were pronounced if they occurred during the critical period of pregnancy for cardiovascular development, i.e., the 3 months preceding pregnancy and the first trimester. No data were collected on specific chemicals used, although the authors specifically mention chlorophenoxy herbicides being sold commercially during the period of interest. A major strength of this study is the high response rate, even among controls. Also notable are the specificity for exposures early but not late in pregnancy and the lack of association of herbicides with other heart defects.

ten Tusscher et al. (2000) reported results of a retrospective observational epidemiologic study that compared trends in incidence of nonsyndromal orofacial clefts during 1961–1969 in clinics in the communities of Zeeberg, Amsterdam, and Wilhelmina Gasthuis, Amsterdam. The two locations were different. Zeeberg was highly exposed to potentially toxic chemicals, including dioxins, because of its proximity to open chemical combustion in a nearby incinerator. In fact, the area was still a prohibited terrain as late as 1998 because of the toxic chemical present. Wilhelmina Gasthuis was a clean control location. The authors showed that the trend in incidence of orofacial clefts was consistently higher in the exposed communities than in the control community. There was also a suggestion of a dose–response relationship in that a higher volume of combustion tended to be followed by higher incidence. Note, however, that information on combusted quantities was sketchy. Combusted quantities were generally under-reported (by up to 70%) and unknown for 5 of the 10 years of interest (1960– 1969). In 1961–1969, the incidence in Zeeberg averaged about 2.4 per 1,000 births, with a peak of about 7.1 per 1,000 births in 1963–1965; it later plateaued at 1.7 per 1,000 births (a figure that is still higher than that in the control commu-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

nity in that period). In Wilhelmina, the maximal incidence over the entire 10-year period was 2.3 per 1,000 births. The differences in incidence between the Zeeberg and Wilhelmina Gasthuis clinics were found to be statistically significant for 1963 and 1964.

The results are not based on multivariate models that account for confounding, but the authors outline the comparability of the two populations. Both clinics served communities with low socioeconomic status; hence the need for delivery at the clinics instead of at home. In addition to the social indications that were common to the two clinics, the Wilhelmina clinic handled all pathologic pregnancies. That indicates that the Zeeberg clinic handled healthier pregnancies, despite the observed higher incidence of orofacial clefts. The authors argue, but do not present data, that the two populations are comparable with respect to smoking, socioeconomic status, and alcohol consumption. The study is relevant to the charge of the committee in that chemical emissions from incineration are known to contain TCDD and dioxin-like compounds. Moreover, eels and rabbits from the vicinity of the incinerator were found to have very high concentrations of dioxins in their bodies. The combustion processes, however, were likely to produce multiple chemicals with potential adverse health effects. The nonspecific nature of the exposure information and lack of direct information on potential confounders limit the usefulness of the results of this study for the charge of this committee.

Revich et al. (2001) studied the relationship between the relatively high dioxin concentrations in the air, soil, drinking water, and cows' milk of Chapaevsk, Russia, due to pollution from a chemical plant in the area and its effects on the reproductive health status of the study population. In 369 children born in 1990–1995, the average number of congenital morphogenetic conditions (CMGCs) per child was higher in Chapaevsk, Russia (4.5 in boys and 4.4 in girls), than reported previously in other comparably polluted industrial towns. The most frequent CMGCs were sandals chack, epicanthus, shawl scrotum (in boys), clinodactyly, and broad first fingers. Fequencies of congenital malformations in Chapaevsk were not statistically significantly different from the data reported for the entire continent in the European register.

Vietnam-Veteran Studies

In a historical cohort study of 4,140 female Vietnam veterans and 4,140 female non-Vietnam (but contemporary) veterans, Kang et al. (2000) assessed potential associations between various self-reported pregnancy outcomes and the Vietnam experience or lack thereof. Statistically significant associations were detected only with “likely” (OR = 1.7, 1.2 –2.2) and “moderate-to-severe” (OR = 1.5, 1.1–2.0)] birth defects. Here, “likely” birth defects were defined as congenital anomalies—including structural, metabolic, or hereditary defects—based on an initial 11-category grouping of birth defects. “Moderate-to-severe” birth de-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

fects were defined according to the severity of the diagnosis or were conditions that had any history of surgical or medical treatment or functional impairment or were related to death. The “moderate-to-severe ” category was constructed to analyze possibly teratogenic defects. When analysis was restricted to the nonnurse veterans in both groups, the associations between serving in Vietnam and birth defects became stronger for both “likely” (OR = 3.1, 1.8–5.6) and “moderate-to-severe” (OR = 2.6, 1.4–4.9) birth defects. This study has very high relevance to the assessment of effects of Agent Orange and other herbicides used in the Vietnam era, but its usefulness is somewhat limited by the definition of exposure as service in Vietnam. In addition, a serious attempt to validate the self-reported pregnancy outcomes was not generally successful, possibly because of the long gap between the reported events and data collection. However, the rather strong association with birth defects, in the absence of a significant association with any other pregnancy outcome, is rather convincing. Reanalysis of the data in conjunction with forthcoming data from a current study (which is being overseen by the National Academies) characterizing herbicide exposure in Vietnam could yield information valuable for understanding the effects of Agent Orange and other herbicides on birth defects.

Synthesis

The interpretation of the increased risk of CMGCs due to high concentrations of dioxin that was reported in Revich et al. (2001) suffers from poor study design (it used an ecologic study design) and inadequate control for confounding factors. Similarly, the findings of Le and Johansson (2001) suffer from an admitted bias in selection of study subjects.

Of the three relatively well-designed recent studies (Kang et al., 2000; Loffredo et al., 2001; ten Tusscher et al., 2000), Loffredo et al. (2001) and ten Tusscher et al. (2000) do not deal with effects that are directly associated with Vietnam veterans. The positive associations between TGA and use of pesticides and herbicides give some evidence of increased risks that may be relevant to exposure of Vietnam veterans to Agent Orange and other herbicides. However, the stronger results that were associated with exposures during critical periods may not be relevant to Vietnam veterans unless pregnancies occurred during periods of active duty, although the persistence of TCDD implies that direct exposure during pregnancy might not be required.

The results of ten Tusscher et al. (2000) provide evidence of increased risk of nonsyndromal orofacial clefts and a possible dose–response relationship with exposures to potentially high concentrations of dioxins. This study suffers from lack of adjustment for confounders, but its two populations appear to be comparable with respect to potential confounders, such as sociodemographic factors. It is also not possible to rule out confounding by the effects of exposures other than

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TCDD and dioxin-like compounds. The nonspecific nature of the exposure information might limit the usefulness of the results of the study.

Perhaps the evidence most relevant to the charge of the committee is that reported by Kang et al. (2000). The statistically significant association of the “Vietnam experience” with increased risks of birth defects, in the absence of associations with any of the other pregnancy outcomes, needs further attention. The importance of the results is attenuated by the nonspecific nature of the exposure; until more specific information on exposure is available, the results will remain intriguing but inconclusive.

Conclusions
Strength of Evidence from Epidemiologic Studies

There were no new relevant studies on the association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and spina bifida in offspring. The committee believes that the evidence is still limited or suggestive of an association between exposure the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and spina bifida. On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there remains inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, and cacodylic acid) and all other birth defects. Although there are reports of increased risks of TGA, nonsyndromal orofacial clefts, and CMGCs in the various studies reviewed for this update, those studies suffer from various pitfalls with respect to study design, sample size, and nonspecific exposure ascertainment.

Biologic Plausibility

Laboratory studies of potential male-mediated developmental toxicity of TCDD and herbicides, specifically with regard to birth defects, are too limited to permit conclusions. Research on chemical production workers with TCDD exposure suggests that some hormonal changes are associated with such exposure, but it is unclear whether the changes could be responsible for an increase in spina bifida or other birth defects. Notably, one recent investigation did not show evidence that paternal exposure to a herbicide formation containing 2,4-D and picloram caused birth defects or any other adverse reproductive outcomes in experimental animals.

A summary of the biologic plausibility of reproductive effects of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties about the exposure of Vietnam veterans and the magnitude of potential risk, if any, of the various birth defects, it is not possible for the committee to quantify the degree of risk to Vietnam veterans of having children born with birth defects.

FERTILITY

Male reproductive function is a complex system under the control of several components whose proper coordination is important for normal fertility. Several components and end points related to male fertility, including reproductive hormones and sperm characteristics, can be studied as indicators of fertility. Briefly, the reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. In the central nervous system, the hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both those hormones are secreted in episodic bursts by the anterior pituitary gland into the circulation and are necessary for normal spermatogenesis. In the testis, LH interacts with receptors on Leydig cells, where it leads to increased testosterone synthesis. FSH and the testosterone from the Leydig cells interact with the Sertoli cells in the seminiferous tubule epithelium to regulate spermatogenesis. More-detailed reviews of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, have been shown to affect the neuroendocrine system and spermatogenesis (Bonde and Giwercman, 1995; Tas et al., 1996).

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and altered sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying those findings may be found in the earlier reports (see Table 7-3 for summaries of studies).

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 7-3 Selected Epidemiologic Studies—Fertility

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2000

Abell et al., 2000

Fecundibility ratios in female greenhouse workers in Denmark (maternal exposure)

   
 

>20 hours of manual contact per week

220

0.7 (0.5–1.0)b

 

Never used gloves

156

0.7 (0.5–1.0)b

 

High exposure

202

0.6 (0.5–0.9)b

Larsen et al., 1998

Fecundibility ratios in Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D (paternal exposure)

523

1.0 (0.8–1.4)b

 

Used three or more pesticides

 

0.9 (0.7–1.2)b

 

Used manual sprayer

 

0.8 (0.6–1.1)b

Studies Reviewed in Update 1998

Heacock et al., 1998

Standardized fertility ratios in workers at sawmills using chlorophenates (paternal exposure)

18,016 (births)

0.9 (0.8–0.9)c

 

Mantel-Haenszel rate ratio estimator in workers at sawmills using chlorophenates (paternal exposure)

18,016 (births)

0.7 (0.7–0.8)c

 

Cumulative exposure (hours)

 

120–1,999

7,139

0.8 (0.8–0.9)c

 

2,000–3,999

4,582

0.9 (0.8–0.9)c

 

4,000–9,999

4,145

1.0 (0.9–1.1)c

 

≥10,000

1,300

1.1 (0.9–1.2)c

VIETNAM VETERANS

New Studies

Staessen et al., 2001

Delays in sexual maturity in adolescents from highly exposed areas

   
 

In Antwerp, Belgium

15

4 (*)

 

In Wilrik, Belgium

8

1.7 (*)

Studies Reviewed in Update 1996

Henriksen et al., 1996

Effects on specific hormone levels in Ranch Hands (paternal exposure)

   
 

Low testosterone

 

High dioxin (1992)

18

1.6 (0.9–2.7)

 

High dioxin (1987)

3

0.7 (0.2–2.3)

 

Low dioxin (1992)

10

0.9 (0.5–1.8)

 

Low dioxin (1987)

10

2.3 (1.1–4.9)

 

Background (1992)

9

0.5 (0.3–1.1)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

High FSH

 

High dioxin (1992)

8

1.0 (0.5–2.1)

 

Low dioxin (1992)

12

1.6 (0.8–3.0)

 

Background (1992)

16

1.3 (0.7–2.4)

 

High LH

 

High dioxin (1992)

5

0.8 (0.3–1.9)

 

Low dioxin (1992)

5

0.8 (0.5–3.3)

 

Background (1992)

8

0.8 (0.4–1.8)

 

Low sperm count

 

High dioxin

49

0.9 (0.7–1.2)

 

Low dioxin

43

0.8 (0.6–1.0)

 

Background

66

0.9 (0.7–1.2)

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study (paternal exposure)

   
 

Lower sperm concentration

42

2.3 (1.2–4.3)

 

Proportion of abnormal sperm

51

1.6 (0.9–2.8)

 

Reduced sperm motility

83

1.2 (0.8–1.8)

Stellman et al., 1988

American Legionnaires who served in Southeast Asia (paternal exposure)

   
 

Difficulty in having children

349

1.3 (p < 0.01)

a Given when available.

b For this study, relative risk has been replaced with the fecundability ratio, a value of which less than 1.0 indicates an adverse effect.

c Standardized fertility ratio, for which a value less than 1.0 indicates an adverse effect.

* Information not provided by study authors.

ABBREVIATIONS: CDC, Centers for Disease Control and Prevention; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

Update of the Scientific Literature
Occupational Studies

No relevant occupational studies have been published since Update 2000 (IOM, 2001).

Environmental Studies

Staessen et al. (2001) used biomarkers to assess whether exposure to heavy metals, PCBs, volatile organic compounds, and polycyclic aromatic hydrocarbons is related to early reproductive effects. They compared 100 17-year-old

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

lifetime residents of two highly exposed suburbs of Antwerp, Belgium, with 100 17-year-old lifetime residents of a rural control community. The two suburban locations (Hoboken and Wilrijk) are 11–13 km southeast of the chemical industry of Antwerp and were characterized by pollution from a lead smelter and two waste incinerators. The control town of Peer is far from any busy highways and lies 15–25 km east of the nearest nonferrous-metal smelters and chemical plants. Information was collected on medical history, Tanner staging was conducted and testicular volume measured (in boys), and questionnaires were used to collect data on lifestyle, use of tobacco and alcohol, food intake, dietary habits, medication use and socioeconomic status. Concentrations of several environmental agents, including dioxin-like compounds in serum samples, were found to be higher in the two suburban locations than in the control community, after adjustment for sex, body-mass index (BMI), weeks of breastfeeding, parental social class, and dietary fat intake. The results indicate that children in the two suburban locations experienced substantial and statistically significant delays in sexual maturation and (in boys) lower testicular volume, after adjustment for age, BMI, parental social class, and use of oral contraceptives (by girls).

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

In a recent review article, Figà-Talamanca et al. (2001) summarize the most up-to-date evidence on the relationship between male fertility and occupational exposure to pesticides, metals, and solvents. After a careful review of the literature, they conclude that there is insufficient evidence to conclude that use of pesticides leads to significantly higher risk to human reproduction. More specifically, results on the effects of dioxins, including TCDD, appear to be conflicting and open to debate.

That the delayed sexual maturation and (in boys) lower testicular volume in adolescents is associated with higher concentrations of dioxin-like compounds (Staessen et al., 2001) supports a potential effect on male reproductive capacity, but the implication for Vietnam veterans remain unclear, inasmuch as most veterans were past their pubertal development during their terms of duty. Moreover, there were numerous exposures of the Belgian adolescents, and attribution of effects to TCDD is not possible. However, the overall effect of dioxin-like compounds on human reproduction increases the evidence of adverse effects of dioxin-like compounds. The new findings since Update 2000 do not appear to be strong enough to change the overall conclusions of the previous reports regarding fertility.

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Conclusions
Strength of Evidence from Epidemiological Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and altered hormone concentrations, decreased sperm counts or quality, subfertility, or infertility.

Biologic Plausibility

Experimental-animal evidence suggests that TCDD can alter testosterone synthesis, generally at relatively high doses, but does not provide direct clues to the reproductive significance of alterations in hormone concentrations of the magnitude found in available studies.

A summary of the biologic plausibility of reproductive effects of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of exposures in Vietnam and about the potential risk, if any, for altered hormones, semen quality, and subfertility or infertility, it is not possible for the committee to quantify the degree of risk of infertility likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

SPONTANEOUS ABORTION

Spontaneous abortion refers to the expulsion of a nonviable fetus, generally before 20 weeks of gestation, not induced through physical or pharmacologic means. The background risk of recognized spontaneous abortion is generally around 7–15% (Hertz-Picciotto and Samuels, 1988), but it is established that many more pregnancies terminate before the woman is aware that she has become pregnant (Wilcox et al., 1988); the latter are known as subclinical pregnancy losses and are generally not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Major types of study design include cohorts of women asked retrospectively about their pregnancy history, cohorts of pregnant women (usually those receiving prenatal care), and cohorts of women who are monitored for future pregnancies. Retrospective reports can be limited by memory loss, particu-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

larly of spontaneous abortions that took place a long time before. Studies enrolling women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for differences in the times at which women seek medical care during pregnancy. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it may attract nonrepresentative study groups because the protocols are demanding.

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and spontaneous abortion. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports (see Table 7-4 for summary of studies).

Update of the Scientific Literature
Occupational Studies

Schnorr and colleagues (2001) at the National Institute for Occupational Safety and Health (NIOSH) conducted an investigation of pregnancy outcomes of the wives and partners of men in the NIOSH cohort (see Chapter 4 for a description of the cohort). A brief interview was conducted with the male study subjects, and contact information on current and former wives and partners was collected. In-depth telephone interviews with these partners were conducted to collect reproductive history and medical, lifestyle, and occupational data. All pregnancies after the date of the father's first exposure at the plant were considered exposed. Pharmacokinetic models applied to paternal serum TCDD were used to estimate exposure at the time of each conception. Serum TCDD was measured in 79 of the referents (controls). Those concentrations were assumed to represent lifetime background environmental exposures and were assumed for all pregnancies. The median serum TCDD concentration of the 79 referents (6 ppt) was assigned to the remaining referents. Statistical analyses examined exposure as the log of TCDD at the time of the conception or in five categories (referents, and exposed at <20, at 20 to <255, at 255 to <1,120, and at ≥1,120 ppt).

Multiple births, induced abortions, tubal and other ectopic pregnancies, and pregnancies exposed to oral contraceptives, intrauterine devices, or injections to induce menstruation were excluded. All remaining pregnancies were classified as live birth, stillbirth, or spontaneous abortion (termination no later than 20 weeks

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 7-4 Selected Epidemiologic Studies—Spontaneous Abortion

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Schnorr et al., 2001

NIOSH cohort

 

Levels of Exposure

 

<20 ppt

29

0.8 (0.5–1.2)

 

20 to <255 ppt

11

0.8 (0.4–1.6)

 

255 to <1120

11

0.7 (0.3–1.6)

 

≥1120 ppt

8

1.0 (0.4–2.2)

Arbuckle et al., 2001

Ontario farm families

 

Phenoxyacetic acid herbicide exposure in the pre-conception period and risk of first-trimester spontaneous abortion

48

1.5 (1.1–2.1)

Studies Reviewed in Update 2000

Driscoll, 1998

Women employed by US Forest Service—pregnancies ending in miscarriage

141

2.0 (1.1–3.5)

Studies Reviewed in VAO

Townsend et al., 1982

Wives of men employed at Dow involved in chlorophenol processing (paternal exposure)

85

1.0 (0.8–1.4)

Smith et al., 1982

Follow-up of 2,4,5-T sprayers— sprayers compared to non-sprayers (paternal exposure)

43

0.9 (0.6–1.5)

Carmelli et al., 1981

Spontaneous abortion among wives of men occupationally exposed to 2,4-D (paternal exposure)

   
 

All reported work exposure to herbicides (high and medium)

63

0.8 (0.5–1.2)

 

Farm exposure

32

0.7 (0.3–1.8)

 

Forest and commercial exposure

31

0.9 (0.5–1.6)

 

Exposure during conception period

 

Farm exposure

15

1.0 (0.4–2.1)

 

Forest and commercial exposure

16

1.6 (0.7–3.3)

 

All exposures, father 18–25 years old

 

Forest and commercial exposure

8

3.1 (0.9–9.6)

 

Exposure during conception period

 

Father 31–35 years old, farm exposure

10

2.9 (0.8–10.9)

Suskind and Hertzberg, 1984

Follow-up of 2,4,5-T production workers (paternal exposure)

69

0.9 (0.6–1.2)

Moses et al., 1984

Follow-up of 2,4,5-T production workers (paternal exposure)

14

0.9 (0.4–1.8)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

Tuyet and Johansson, 2001

Women whose husbands were exposed to Agent Orange

*

(*)

Revich et al., 2001

Residents of Chapaevsk, Russia

*

(*)

 

Spontaneous abortion per 100 full-term pregnancies for “the last seven years”

Chapaevsk 24.4%

Samara 15.2%

Toliatti 10.6%

Syzran 15.6%

Novokuibyshevsk 16.9%

Other small towns 11.3%

   

Studies Reviewed in Update 2000

Petrelli et al., 2000

Wives of pesticide appliers

26

3.8 (1.2–12.0)

Axmon et al., 2000

Wives of Swedish fishermen

 

Miscarriages before week 12

 

0.5 (0.3–1.0)

 

East coast

12

(*)

 

West coast

54

(*)

VIETNAM VETERANS

New Studies

Kang et al., 2000

Female Vietnam veterans

 

Vietnam veteran spontaneous abortions or stillbirths (1,665 pregnancies)

278

(*)

 

Non-Vietnam spontaneous abortions or stillbirths (1,912 pregnancies)

317

(*)

Studies Reviewed in Update 2000

Schwartz, 1998

Female Vietnam veterans— miscarriages

63

(*)

Studies Reviewed in Update 1996

Wolfe et al., 1995

Air Force Ranch Hand veterans

157

 
 

Background

 

(*) (0.8–1.5)

 

Low-level exposure

 

(*) (1.0–1.7)

 

High-level exposure

 

1.0 (0.7–1.3)

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study (paternal exposure)

1,566

1.3 (1.2–1.4)

 

Self-reported low exposure

489

1.2 (1.0–1.4)

 

Self-reported medium exposure

406

1.4 (1.2–1.6)

 

Self-reported high exposure

113

1.7 (1.3–2.1)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Stellman et al., 1988

Assessment of reproductive effects among American Legionnaires who served in Southeast Asia (1961–1975), (paternal exposure)

   
 

Vietnam veterans compared with Vietnam-era veterans

   
 

All Vietnam veterans

231

1.4 (1.1–1.6)

 

Low exposure

72

1.3 (1.0–1.7)

 

Medium exposure

53

1.5 (1.1–2.1)

 

High exposure

58

1.7 (1.2–2.4)

 

Herbicide handlers compared with Vietnam-era veterans

9

1.6 (0.7–3.3)

 

Vietnam veterans with medium or high exposure compared to Vietnam veterans with low exposure

   
 

Medium exposure

53

1.2 (0.8–1.7)

 

High exposure

58

1.4 (0.9–1.9)

Aschengrau and Monson, 1989

Spontaneous abortion and husband's Vietnam service— spontaneous abortions

*

0.9 (0.4–1.9)

 

First-trimester abortions

10

1.2 (0.6–2.8)

Field and Kerr, 1988

Follow-up of Australian Vietnam veterans (paternal exposure)

195

1.6 (1.3–2.0)

a Given when available.

* Information not provided by study authors.

ABBREVIATIONS: CDC, Centers for Disease Control and Prevention; CI, confidence interval; NIOSH, National Institute for Occupational Safety and Health.

after the last menstrual period). Workers' wives and partners had a total of 332 pregnancies during or after the workers' exposure, and 300 conceived before exposure; 707 pregnancies in the wives and partners of the referent group were included. Of those, 35, 25, and 89 miscarriages, respectively, occurred by 20 weeks of gestation, and four, three, and six stillbirths (after 20 weeks gestation) occurred, respectively. Generalized estimating equations were used to adjust for multiple pregnancies per woman. Many covariates were evaluated for inclusion as confounders. For the four levels of exposure, the adjusted ORs were 0.8, 0.8, 0.7 and 1.0, respectively; the confidence intervals had widths of 2.5–5 and included the null in all cases. Early and late spontaneous abortions did not differ with respect to the OR for TCDD exposure.

The strengths of this study include the pharmacokinetically based quantita-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

tive exposure data on the fathers, the wide range of paternal exposure, the confirmation of all pregnancies, and the collection of and adjustment for many potential confounders. Limitations include the moderate response rate (73% and 78% among referents' and workers' wives, respectively) and the relatively small number of exposed cases of fetal loss (35 spontaneous abortions and four stillbirths). The literature on retrospective interviews for recall of pregnancies suggests that live births are remembered well but some spontaneous abortions are not recalled and that recall worsens as time elapses (Wilcox and Horney, 1984; Heidam and Olsen, 1985). Most of the pregnancies in this study occurred during the 1950s and 1960s, so the women were recalling events that occurred 3 or 4 decades previously. No measure of take-home contamination was available, and the results should not be construed as providing evidence regarding the effect of maternal exposure on pregnancy outcome.

Environmental Studies

Tuyet and Johansson (2001) conducted a series of semistructured interviews with women who were or whose husbands were exposed to Agent Orange. The goal was to determine the impact of Agent Orange exposure on the women's lives. This was a case series and provides insight into the lives of individual Vietnamese women and their children, many of whom had congenital malformations or developed disabilities within the first years of life. For those whose husbands came back from the war as invalids, the hardship was both physical and emotional. The paper does not attempt to generate quantitative data.

The Ontario Farm Family Health Study conducted by Arbuckle et al. (2001) collected data on pesticide use, medical and reproductive history, and lifestyle retrospectively from farm operators and couples living on farms. Eligible couples were those in which the wife was 44 years old or younger and at least one member was working on the farm. In this analysis, the outcome of interest was self-reported spontaneous abortion at less than 20 weeks of gestation. The husband, wife, and farm operator (if other than husband or wife) were all interviewed, with both open-ended and checklist questions, and the resulting information was pooled to construct a history of monthly agricultural and residential pesticide use. The active ingredients of each pesticide were identified and grouped into use categories and chemical families. For each pregnancy, exposure to pesticides was analyzed for two periods: preconception, representing the 4-month period from 3 months before conception to the calendar month of conception, and postconception, the period from the first calendar month after conception to the end of the pregnancy or through the end of the first trimester, whichever came first. Crude ORs were calculated, comparing those exposed to the pesticide of interest during the period with those not exposed to that pesticide during the same period. The authors found that no variables confounded the associations and therefore reported only crude analyses. In addition, the classification and regres-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

sion tree (CART) method was used to examine interactions between pesticides and other factors.

Phenoxyacetic acid herbicide exposure in the preconception period was associated with a higher risk of first-trimester spontaneous abortion (OR = 1.5, 1.1– 2.1, based on 48 exposed cases). The authors note that in an earlier publication on the same cohort, a referent group consisting of those with no pesticide exposure during the period yielded a higher OR of 2.3. The “use” class of herbicides (78 exposed cases) also showed a modestly increased risk (OR = 1.4, 1.1–1.9). For exposure in the postconception period in relation to first-trimester spontaneous abortion, all ORs but one (miscellaneous pesticides) were less than 1.0. For exposure in the postconception period in relation to second-trimester spontaneous abortion, 2,4-D was associated with a moderately increased risk (OR = 1.6, 0.9–2.7, based on 16 exposed cases). In the analysis of interactions, the authors found that women who were 35 years old or older were most susceptible to the effects of pesticides: those exposed to both carbaryl and 2,4-D in the preconception period were 27 times more likely to have a spontaneous abortion than those with only carbaryl exposure, although the confidence interval was extremely wide (2.0–368). An analysis of chemical classes demonstrated an interaction of phenoxy herbicides with triazines.

Several methodologic concerns affect the interpretation of those results. One is the assignment of postconception exposure, a time-dependent variable: the opportunity to be exposed is longer among noncases than among cases (Hertz-Picciotto et al., 1996). Exposure for a first-trimester pregnancy termination could occur only before the spontaneous abortion, but for noncases it could occur at any time during the full first trimester, so it is not surprising that all ORs for this period were less than 1.0. In other words, those ORs are downwardly biased estimates of the effect of exposure. A survival analysis could have eliminated the problem if the information on timing of exposure had been exact (Hertz-Picciotto et al., 1989). This concern would apply only to the analysis of first-trimester spontaneous abortions and not to the analysis of late spontaneous abortions (weeks 12–19) or the analysis of preconception exposure in relation to first- or second-trimester losses, in that all pregnancies would have the same opportunity for exposure in this period. Overall, the study was based on a thorough interview to develop exposure indexes and involved a large cohort (3,936 pregnancies among 2,000 farm couples). Self-reports of spontaneous abortion have been found to have high validity (Wilcox and Horney, 1984; Lindbohm and Hemminki, 1988), but some are not remembered, and memory worsens as time elapses (Wilcox and Horney, 1984; Heidam and Olsen, 1985). Also, it is not clear whether self-reports of the timing of pregnancy loss are accurate. The authors did not account for the multiple pregnancies per woman, and the reported standard errors are downwardly biased in that the propensity to abort is known to cluster in pregnancies of the same woman (Watier et al., 1997). Generalized estimating equations should have been used to produce correct confidence limits, but the effect on precision of

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

not using those equations is usually not large in populations with small family sizes. The point estimates of the OR would not be affected. The authors did not address how induced abortions were handled. In spite of some concerns about the analysis, this study suggests reproductive toxicity of phenoxy herbicides. Spontaneous abortions occur at a higher rate in women exposed to them during the preconception period, including the month of conception, and this effect is particularly strong in women 35 years old or older. The findings are characterized by internal consistency in that the individual pesticide (2,4-D), the chemical class (phenoxyacetic acids), and the “use” category of herbicides all produce similar results.

Numerous studies of populations with high dietary intake of PCBs from consumption of fatty fish in the Baltic Sea have examined reproductive outcomes. Axmon et al. (2000) collected information on miscarriages and stillbirths from a cohort of fishermen's wives from the Swedish east coast (N = 438) and a referent cohort of west coast fishermen's wives (N = 983) with a retrospective self-administered questionnaire. Demographic, lifestyle, and occupational information was also collected. To avoid using nonindependent observations resulting from multiple pregnancies per woman, only the first planned pregnancy was included in the analysis. Only physician-confirmed or home-pregnancy-test-confirmed pregnancies were included. Initial comparisons were between the east and west coast women. Fish consumption was also assessed for the current period, and the 179 women who consumed at least two meals of fish per week were compared with the 73 who consumed no fatty fish.

After adjustment for confounders, the east coast fishermen's wives experienced a deficit of miscarriages in the first trimester (OR = 0.5, 0.3–1.0). A similarly lower risk was observed for high consumers of fatty fish compared with nonconsumers. Those results suggest that the risk of spontaneous abortion or stillbirth is not increased in women who consume fatty fish contaminated with PCBs. Whether there is no adverse effect of PCBs and other concomitant contaminants or some adverse effect is outweighed by the benefits of fatty-fish consumption remains unclear.

The association between TCDD exposure and spontaneous abortion was examined in a study conducted in Chapaevsk, a town in Russia that is the site of a chemical plant that produced hexachlorocyclohexane (lindane) and its derivatives in 1967–1987. Mustard gas and other chemical blister agents were produced there previously, and crop-protection chemicals now (Revich et al., 2001). Contamination of air, water, cows' milk, and human serum and breast milk has been documented; exposure declines with increasing distance from the factory. In a report that surveyed a variety of exposure and public-health indicators, Revich and colleagues obtained official medical statistics for Chapaevsk, for the surrounding region of Samara, and for several other areas. The mean frequency, defined as number of spontaneous abortions per 100 full-term pregnancies in the preceding 7 years, was 24.4 in Chapaevsk, 15.2 in Samara, 10.6 in Toliatti, 15.6

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

in Syzran, 16.9 in Novokuibyshevsk, and 11.3 in small towns. It is difficult to interpret those results, because there are no demographic or lifestyle data comparing Chapaevsk with other areas.

Vietnam-Veteran Studies

Kang et al. (2000) conducted a survey of female Vietnam veterans. A cohort was assembled on the basis of records from all branches of the military and consisted of both Vietnam veterans and women who served in the military during the Vietnam War but were stationed at bases in the United States. Military-service data were abstracted from personnel records. After record review, 4,643 women met eligibility criteria of having had a permanent tour of duty in Vietnam in the period July 4, 1965, through March 28, 1973, a period of substantial US military involvement in Vietnam. Of them, 4,390 were alive on January 1, 1992. A comparison group of female veterans whose tour of duty did not include service in Vietnam but who were assigned a military unit in the United States during the Vietnam War was identified, and 4,390 were randomly selected from among those still alive on January 1, 1992. After exclusion of 250 from each group who participated in a pilot study, an attempt was made to locate the remaining 4,140 in each group, for a total eligible cohort of 8,280. Various location strategies were used; 370 (less than 5%) were not located, and another 339 were deceased. A full telephone interview was conducted on 6,430, after 775 refused (13% of Vietnam veterans and 17% of non-Vietnam veterans) and another 336 completed only a short written questionnaire, which collected information on demographic background, lifestyle factors, reproductive history, military experience, use of oral contraceptives and hormone-replacement therapy, and health status.

For each pregnancy, information on smoking, drinking, complications, infections, medications, exposure to x-rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides was collected. An index pregnancy was defined for each woman. For the Vietnam veterans, it was the first pregnancy after entry into Vietnam service; for the non-Vietnam veterans, it was the first pregnancy after July 4, 1965, the starting date for US ground-troop involvement in Vietnam, or after the entrance date into military service, whichever came later. Fetal loss included both spontaneous abortion and stillbirth; these were not separated. The logistic-regression models for those adverse outcomes of pregnancy vs a live birth adjusted for age at conception, education, race, marital status, military characteristics of the mother's service (branch, rank, and military nursing), and lifestyle factors (smoking, drinking, and average number of hours worked during pregnancy). There were 278 spontaneous abortions or stillbirths among 1,665 Vietnam-veteran index pregnancies, and 317 out of 1,912 among the non-Vietnam-veteran pregnancies, representing rates of 16.7% and 16.6%. Although a smaller number of Vietnam than non-Vietnam veterans re-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

ported ever having been pregnant, that was because more of them never tried; the main reasons for never having tried to become pregnant were “never married” and “never wanted children.” Those data do not suggest an association between service in Vietnam and pregnancy loss. However, because the authors had no indexes of exposure to the chemicals of interest, the study does not provide evidence on whether TCDD or the herbicides 2,4-D and 2,4,5-T affect the likelihood of spontaneous abortion or stillbirth. The authors did not state how they handled induced abortions.

Synthesis

Because the literature on TCDD shows different results with regard to spontaneous abortion than does the evidence on herbicides, this discussion addresses the two exposures separately. In light of two well-conducted studies that were recently published (Schnorr et al., 2001; Arbuckle et al., 2001), the committee reexamined in detail all the studies relevant to spontaneous abortion and the exposures of interest in that light.

The strongest evidence to date regarding preconception paternal exposures to TCDD in relation to spontaneous abortion comes from the occupational study by Schnorr et al. (2001). That study was able to assign exposures and corresponding pregnancies to a sizable number of men. Despite a large range of exposures, no association was observed, even for the most highly exposed. Some earlier studies have shown slight increases in risk of spontaneous abortion among those who served in Vietnam (Stellman et al., 1988; CDC, 1989), among the low- but not the high-exposure Ranch Hand Air Force personnel (Wolfe et al., 1995), and in a study of Tasmanian men who served in the Australian services in Vietnam (Field and Kerr, 1988). However, control selection and outcome definition were weak in the Australian veteran study. The Stellman and Centers for Disease Control (CDC) studies, although stronger, used paternal reports of pregnancy outcomes of partners, which are known to be error-prone and the errors could be in the direction of creating artifactual associations. CDC also conducted a validation substudy of reported birth defects and found evidence of reporting bias in comparisons of Vietnam with non-Vietnam veterans. In the analysis of miscarriages, the association was stronger among those who reported herbicide exposure, and this was interpreted by the authors as evidence of reporting bias due to the inaccuracy of self-reports of herbicide exposure. Given the lack of an increased risk among highly exposed men in the Air Force Health Study, the other studies are not of sufficient quality to strengthen the evidence of an effect of TCDD or herbicides on spontaneous abortion.

The strengths of the study by Schnorr et al. (2001) provide convincing evidence that TCDD is unlikely to increase the risk of spontaneous abortion. That does not, however, rule out the possibility that herbicides used in Vietnam, such as 2,4-D and 2,4,5-T, are associated with an increased risk. The results of

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Arbuckle et al. (2001), who used thorough exposure assessment, are remarkably consistent for various measures of phenoxy-herbicide exposures during the preconception period. Increased risks of spontaneous abortion were observed for the use category of “herbicides” and specifically for phenoxyacetic acid, and the numbers of exposed cases were 78 and 48, respectively. Whether maternal or paternal exposure or both played a role remains unclear, in that the analysis pooled the information for an overall “farm” exposure. An earlier study of women working for the Forest Service also showed an increased risk in those with herbicide exposure although it suffered from a low response rate (Driscoll, 1998).

In contrast, a case–control study of an occupational cohort constructed to include a high proportion of workers with 2,4-D exposure observed no association with paternal exposure either during the 2–3 years before conception or during the 2-month period consisting of the month before conception and the month of conception (Carmelli et al., 1981). This study also suffered from a low response rate. No association was observed with maternal occupational or environmental exposure.

Overall, it is difficult to determine whether the biases in those two studies would have attenuated or magnified an association. In a small study, Petrelli et al. (2000) found that pesticide appliers reported more spontaneous abortions among their wives than did a comparison group of food retailers, but confounders were not all controlled. The list of pesticides applied during the period of employment of these workers included several that may have been contaminated by TCDD, but the published report did not address particular exposures.

Several other studies were too weak to provide evidence of an association or of no association. The present report reviews the negative study by Kang et al. (2000), which compared women who served in Vietnam with those who served elsewhere but had no direct measures of exposure to TCDD or herbicides, and the ecological comparisons by Revich et al. (2001), which failed to provide any data on potential confounding variables. Earlier inadequate investigations that the committee reviewed include a report on the wives of men who were employed by Dow Chemical Company, in which an obscure, nonstandard method of analysis was used (the overall results showed no association, but an association was observed in a specific stratum of women with high gravidity) (Townsend et al., 1982); a small study of 2,4,5-T sprayers, which had very crude data on the timing of exposure and failed to adjust for Maori ethnicity in spite of a difference between exposed and nonexposed (Smith et al., 1982); and a report on 2,4,5-T production workers, which relied on men's reports of their spouses' pregnancy outcomes (Suskind and Hertzberg, 1984).

On the basis of the NIOSH study, the evidence is therefore strong that paternal exposure to TCDD is not associated with an increased risk of spontaneous abortion among partners. Despite the strengths of the study by Arbuckle et al. (2001), the evidence regarding herbicides and spontaneous abortion remains inadequate to determine whether an association exists, primarily because of the

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

limitations of the numerous studies that have attempted to evaluate pesticides and spontaneous abortion.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic literature examining spontaneous abortion reviewed in this and previous Veterans and Agent Orange reports, the committee notes that the evidence on TCDD and the evidence on herbicides used in Vietnam are divergent. For TCDD, the data suggest that paternal exposure to TCDD is not associated with risk of spontaneous abortion, but the data are inadequate to determine whether an association with maternal exposure to TCDD exists. For herbicides—namely 2,4-D and 2,4,5-T—the committee finds that there is inadequate or insufficient evidence to determine whether an association exists. Overall, the committee finds that the data are inadequate or insufficient to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and the risk of spontaneous abortion in pregnancies that begin after exposure.

Biologic Plausibility

Experimental-animal evidence suggests that TCDD can alter hormones after low-dose exposure and can cause fetal lethality after high doses. However, the reproductive significance of those effects and the risk of recognized pregnancy loss before 20 weeks of gestation in humans are not clear. There is no evidence to suggest a relationship between paternal exposure to TCDD and spontaneous abortion. In experimental animals, 2,4-D and 2,4,5-T have been shown to cause fetal toxicity and lethality following maternal exposure. However, this occurs only at high doses and in the presence of maternal toxicity. No fetal toxicity or lethality has been found following paternal exposure to 2,4-D.

A summary of the biologic plausibility of the reproductive effects of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Studies of the outcomes of pregnancies of female Vietnam veterans or women whose partners were Vietnam veterans have provided uncertain results because of methodologic limitations. It is therefore not possible for the committee to quantify the degree of risk of spontaneous abortion due to exposure to herbicides

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

or the contaminant TCDD in pregnancies that began after such exposure in Vietnam.

STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Stillbirth or late fetal death typically refers to the delivery of a fetus at or after 20 weeks of gestation that shows no signs of life, although a more recent definition includes deaths among all fetuses that weigh more than 500 g at birth, regardless of gestational age at delivery (Kline et al., 1989). Neonatal death refers to the death of a liveborn infant within the first 28 days after birth.

Because the causes of stillbirth and early neonatal death overlap considerably, they are commonly analyzed as one group, referred to as perinatal mortality (Kallen, 1988). Stillbirths occur in less than 1% of all births (CDC, 2000). Among low-birthweight (500–2,500 g) liveborn and stillborn infants, placental and delivery complications—such as abruptio placentae, placenta previa, malpresentation, and umbilical-cord complications —are the most common causes of perinatal mortality (Kallen, 1988). Among infants weighing more than 2,500 g at birth, the most common causes of perinatal death are complications of the cord, placenta, and membranes and lethal congenital malformations (Kallen, 1988).

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, and cacodylic acid) and stillbirth, neonatal death, and infant death. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying those findings may be found in the earlier reports.

Update of the Scientific Literature

No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TCDD, picloram, and cacodylic acid) and stillbirth, neonatal death, and infant death.

Biologic Plausibility

Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are too limited to permit conclusions.

A summary of the biologic plausibility of reproductive effects of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk of stillbirth, neonatal death, and infant death, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

LOW BIRTHWEIGHT AND PRETERM DELIVERY

The World Health Organization (WHO) recommends a cut point of 2,500 g for the determination of low birthweight (Alberman, 1984). Low infant weight at birth is one of the most important predictors of neonatal mortality and morbidity in the United States, and preterm delivery is one of the most important causes. The concept of low birthweight actually encompasses two different causal pathways often treated as a single entity: low birthweight secondary to intrauterine growth retardation (IUGR), in which case a fetus or baby is referred to as small for gestational age, and low birthweight secondary to preterm delivery (PTD), which may have other long-term consequences. The concept of IUGR represents birthweight adjusted for gestational age. The current definition of PTD is delivery at less than 259 days, or 37 completed weeks, of gestation, calculated on the basis of the date of the first day of the last menstrual period (Bryce, 1991). About 7% of live births have low birthweight. The incidence of IUGR is much more difficult to quantify because there are no universally applied standards for distributing birthweight by gestational age. When no distinction is made between the causes of low birthweight (IUGR vs PTD), the factors most strongly associated with reduced birthweight are maternal smoking during pregnancy, multiple births, and race or ethnicity. Other potential risk factors for low birthweight include socioeconomic status (SES), maternal weight, birth order, maternal complications during pregnancy (such as severe preeclampsia) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Kallen, 1988). Established risk factors for PTD include race (black), marital status (single), low SES, previ-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

ous low birthweight or PTD, multiple gestations, cigarette-smoking, and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993).

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and low birthweight. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying those findings may be found in the earlier reports.

Update of Scientific Literature
Occupational Studies

No relevant occupational studies have been published since Update 2000 (IOM, 2001).

Environmental Studies

The possible association between TCDD exposure and spontaneous abortion was examined in a study conducted in Chapaevsk, a town in Russia that is the site of a chemical plant that produced hexachlorocyclohexane (lindane) and its derivatives in 1967–1987. Mustard gas and other chemical blister agents were produced there previously, and crop-protection chemicals now (Revich et al., 2001). Contamination of air, water, cows' milk, and human serum and breast milk has been documented; exposure declines with increasing distance from the factory. In a report that surveyed a variety of exposure and public-health indicators, Revich and colleagues obtained official medical statistics for Chapaevsk, for the surrounding region of Samara, and for several other areas. The average rate of PTD was 45.7 per 1,000 deliveries in Chapaevsk, 39.9 in Samara, 45.8 in Toliatti, 36.5 in Novokuibyshevsk, and 30.0 –38.4 in small towns. The authors report a prevalence of low birthweight of 7.1%, compared with 5.1–6.2% in Russia and in most of the Samara towns. It is difficult to interpret those results, because there are no demographic or lifestyle data comparing Chapaevsk with the other areas. The rate of PTD in Chapaevsk, however, is not high by US standards.

Vietnam-Veteran Studies

Kang et al. (2000) conducted a survey of female Vietnam veterans. A cohort was assembled on the basis of records from all branches of the military and

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

consisted of both Vietnam veterans and women who served in the military during the Vietnam War but were stationed at bases in the United States. Military-service data were abstracted from personnel records. After record review, 4,643 women met eligibility criteria of having had a permanent tour of duty in Vietnam in the period July 4, 1965, through March 28, 1973, a period of substantial US military involvement in Vietnam. Of them, 4,390 were alive on January 1, 1992. A comparison group of female veterans whose tour of duty did not include service in Vietnam but who were assigned to a military unit in the United States during the Vietnam War was identified, and 4,390 were randomly selected from among those still alive on January 1, 1992. After exclusion of 250 from each group who participated in a pilot study, an attempt was made to locate the remaining 4,140 in each group, for a total eligible cohort of 8,280. Various location strategies were used; 370 (less than 5%) were not located, and another 339 were deceased. A full telephone interview was conducted on 6,430, after 775 refused (13% of Vietnam veterans and 17% of non-Vietnam veterans) and another 336 completed only a short written questionnaire, which collected information on demographic background, lifestyle factors, reproductive history, military experience, use of oral contraceptives and hormone-replacement therapy, and health status.

For each pregnancy, information on smoking, drinking, complications, infections, medications, exposure to x-rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides was collected. An index pregnancy was defined for each woman. For the Vietnam veterans, it was the first pregnancy after entry into Vietnam service; for the non-Vietnam veterans, it was the first pregnancy after July 4, 1965, the starting date for US ground-troop involvement in Vietnam, or after the entrance date into military service, whichever came later. Low birthweight was defined as <2,500 g (5 lb, 8 oz) in a singleton delivery. PTD was defined as delivery at no more than 37 weeks or 8 months (if reported in months) of gestation. Logistic-regression analyses were adjusted for age at conception, education, race, marital status, military characteristics of the mother's service (branch, rank, and military nursing), lifestyle factors (smoking, drinking, and average number of hours worked during pregnancy), and pregnancy complications (toxemia, diabetes, high blood pressure, bleeding, or threatened miscarriage).

Of 1,229 index live births among Vietnam veterans, the rates of low birthweight and PTD were 6.3% and 9.1%, respectively; of 1,460 non-Vietnam-veteran pregnancies, the figures were 6.6% and 8.6%. Adjusted ORs were 1.1 (95% CI 0.8–1.5) for low birthweight and 1.2 (95% CI 0.9–1.6) for preterm delivery.

Synthesis

Of the two newly published studies on low birthweight and PTD, the environmental study does not adjust for possible differences among communities, and

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

the Vietnam-veteran study shows small non-significant elevations in risk of these outcomes between women who served in Vietnam and women who served elsewhere.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and low birthweight or PTD.

Biologic Plausibility

Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are too limited to permit conclusions. Regarding female-mediated developmental toxicity, TCDD and herbicides are found in follicular fluid (Tsutsumi et al., 1998), suggesting exposure of embryos, and are known to cross the placenta and lead to direct exposure of the fetus. A more detailed discussion of biologic plausibility is found at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

Given the uncertainties about the exposure of Vietnam veterans and the magnitude of potential risk of low birthweight and PTD, it is not possible for the committee to quantify the degree of risk to Vietnam veterans of having pre-term deliveries or children with low birthweight.

CHILDHOOD CANCER

The American Cancer Society estimates that about 8,600 children under the age of 15 years will be diagnosed with cancer in the United States in 2001. Nearly half the cases will be in children 0–4 years old. Treatment and supportive care of children with cancer have greatly improved, and mortality rates have declined by 50% over the last 3 decades. Despite those advances, cancer remains the leading cause of death from disease in children under the age of 15 years, with 1,500 deaths projected in 2001.

Leukemia is the most common cancer in children. It accounts for about one-third of all childhood cancer cases; nearly 2,700 children are projected to be

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

diagnosed in 2001 (ACS, 2001). Of those, nearly 2,000 will be diagnosed with acute lymphocytic leukemia (ALL) and most of the rest with acute myelogenous leukemia (AML)1. ALL is most common in early childhood, peaking between the ages of 2 and 3 years, and AML is most common during the first 2 years of life. ALL incidence is consistently higher in boys than in girls, whereas AML has a similar incidence in boys and girls (NCI, 2001). Through early adulthood, ALL rates are about twice as high in whites as in blacks, whereas AML has no consistent pattern. Chapter 6 contains additional information on leukemia as part of the discussion of adult cancer.

The second-most common group of cancers in children are those of the central nervous system—the brain and the spinal cord. Other cancers in children include lymphomas, bone cancers, soft-tissue sarcomas, kidney cancers, eye cancers, and adrenal gland cancers. Compared with adult cancers, relatively little is known about the etiology of most childhood cancers, especially about potential environmental risk factors and the effect of parental exposures.

Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. The committee responsible for Update 2000 reviewed the material in earlier Veterans and Agent Orange reports and newly available published literature and determined there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and AML. After the release of Update 2000, researchers from one of the studies discovered an error in their published data. The committee reconvened to evaluate the previously reviewed and new literature regarding that illness, and the Acute Myelogenous Leukemia (IOM, 2002) report was produced. It reclassified AML from “limited/suggestive evidence of an association” to “inadequate evidence to determine whether an association exists.” Table 7-5 provides summaries of the results of the studies underlying that conclusion.

1  

Acute myelogenous leukemia (ICD-9 205) is also commonly referred to as “acute myeloid leukemia” and “acute nonlymphocytic leukemia.” There are also numerous subtypes of the disease. For consistency, this report uses acute myelogenous leukemia, or the abbreviation AML, regardless of usage in the source materials.

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 7-5 Selected Epidemiologic Studies—Childhood Cancers

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL STUDIES

Heacock et al., 2000

Cohort of sawmill workers' offspring— exposure via fungicides contaminated with PCDDs and PCDFs

   
 

Leukemia all workers (paternal exposure)

11

SIR = 1.0 (0.5–1.8)

 

Brain cancer all workers (paternal exposure)

9

SIR = 1.3 (0.6–2.5)

 

Leukemia, high chlorophenate exposure (paternal exposure)

5

OR = 0.8 (0.2–3.6)

 

Brain cancer, high chlorophenate exposure (paternal exposure)

5

OR = 1.5 (0.4–6.9)

Buckley et al., 1989

Children's Cancer Study Group—case– control study of children of parents exposed to pesticides or weed killers

   
 

AML in children with any paternal exposure

27

OR = 2.3 (p = 0.05)

 

AML in children with paternal exposure >1,000

17

OR = 2.7 days (1.0–7.0)

 

AML in children with maternal exposure >1,000 days

7

OR undefined (no cases in controls)

ENVIRONMENTAL STUDIES

New Studies

Buckley et al., 2000

Cases of NHL diagnosed at the age of ≥ 20 years in 1986–1990

*

(*)

Daniels et al., 2001

Case–control study of neuroblastoma in children whose:

   
 

Parents reported using pesticides in the home

*

1.6 (1.0–2.3)

 

Parents reported using herbicides in the garden

*

1.9 (1.1–3.2)

 

Mothers reported applying herbicides in the garden

*

2.2 (1.3–3.8)

Kerr et al., 2000

Neuroblastoma risk in children

 

Mothers whose occupation involves handling insecticides

40

2.3 (1.4–3.7)

 

Fathers exposed to dioxin

7

6.9 (1.3–68.4)

Studies Reviewed in Update 2000

Meinert et al., 2000

Population-based case-control study of childhood cancer

   
 

Leukemia, paternal exposure, year before pregnancy

62

1.5 (1.1–2.2)

 

Leukemia, paternal exposure, during pregnancy

57

1.6 (1.1–2.3)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Lymphoma, paternal exposure, year before pregnancy

11

1.5 (0.7–3.1)

 

Lymphoma, paternal exposure, during pregnancy

10

1.6 (0.7–3.6)

 

Leukemia, maternal exposure, year before pregnancy

19

2.1 (1.1–4.2)

 

Leukemia, maternal exposure, during pregnancy

15

3.6 (1.5–8.8)

 

Lymphoma, maternal exposure, year before pregnancy

3

2.9 (0.7–13)

 

Lymphoma, maternal exposure, during pregnancy

4

11.8 (2.2–64)

Pearce and Parker, 2000

Cohort study examining paternal occupation on death certificate of children who died of kidney cancer

(total cases = 21)

0.9 (0.2–3.8)

 

Paternal agricultural occupation

   

Infante-Rivard et al., 1999

Population-based case–control study of childhood ALL and household herbicide use during pregnancy, in utero exposure, others not excluded

118

1.8 (1.3–2.6)

Studies Reviewed in Update 1996

Pesatori et al., 1993

Seveso residents 0–19 years old—10-year follow-up, morbidity, all exposures

   
 

All cancer

17

1.2 (0.7–2.1)

 

Ovary and uterine adnexa

2

— (0 expected)

 

Brain

3

1.1 (0.3–4.1)

 

Thyroid

2

4.6 (0.6–32.7)

 

Hodgkin's lymphoma

3

2.0 (0.5–7.6)

 

Lymphatic leukemia

2

1.3 (0.3–6.2)

 

Myeloid leukemia

3

2.7 (0.7–11.4)

Bertazzi et al., 1992

Seveso residents 0–19 years old—10-year follow-up, mortality, all exposures

   
 

All cancer

10

7.9 (3.8–13.6)

 

Leukemia

5

3.9 (1.2–1.8)

 

Lymphatic leukemia

2

1.6 (0.1–4.5)

 

Myeloid leukemia

1

0.8 (0.0–3.1)

 

Leukemia, others

2

1.6 (0.1–4.6)

 

Central nervous system tumors

2

1.6 (0.1–4.6)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AIHW, 2000

Australian Vietnam veterans' children— Validation Study

   
 

AML

13 (estimated)

3 expected (0–6)

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Wen et al., 2000

Case–control study of children's leukemia

   
 

AML and ALL

 

Father ever served in Vietnam or Cambodia

117

1.2 (0.9–1.6)

 

<1 year in Vietnam or Cambodia

61

1.4 (0.9–2.0)

 

>1 year in Vietnam or Cambodia

49

1.2 (0.8–1.7)

 

AML only

 

Father ever served in Vietnam or Cambodia

40

1.7 (1.0–2.9)

 

<1 year in Vietnam or Cambodia

13

2.4 (1.1–5.4)

 

>1 year in Vietnam or Cambodia

16

1.5 (0.7–3.2)

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study

 

Cancer in children of veterans (paternal exposure)

25

1.5 (0.7–2.8)

 

Leukemia in children of veterans (paternal exposure)

12

1.6 (0.6–4.0)

Field and Kerr, 1988

Cancer in children of Australian Vietnam veterans (paternal exposure)

4

(*)

Erikson et al, 1984b

CDC Birth Defects Study

 

“Other” neoplasms—children of Vietnam veterans (paternal exposure)

87

1.8 (1.0–3.3)

a Given when available.

* Information not provided by study authors.

—When information was denoted by a dash in the original study.

ABBREVIATIONS: AIHW, Australian Institute of Health and Welfare; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CDC, Centers for Disease Control and Prevention; CI, confidence interval; NHL, non-Hodgkin's lymphoma; OR, odds ratio; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurons; SIR, standardized incidence ratio.

Update of Scientific Literature
Occupational Studies

No relevant occupational studies have been published since Update 2000 (IOM, 2001).

Environmental Studies

Two recent papers address risk factors for neuroblastoma in children (Daniels et al., 2001; Kerr et al., 2000). Children in New York state, excluding New York

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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City, who developed this form of brain cancer were significantly more likely than community-matched controls to have mothers whose occupation involved handling insecticides (OR = 2.3, 1.4–3.7) or fathers who were exposed to dioxins (6.9, 1.3–68.4). Similarly increased risks were observed in association with mother's employment in retail trade and maternal exposure to lead (Kerr et al., 2000).

Daniels et al. (2001) found that children enrolled in treatment for neuroblastoma in one of two major clinical-trial groups were significantly more likely than community-matched controls to have both parents report having ever used pesticides in the home (1.6, 1.0–2.3); estimated risks did not achieve statistical significance for pesticide use during specific periods (preconception, pregnancy, or during childhood) and for use of pesticides by one of the parents. Among people who used pesticides in the garden, the association was strongest for reports of herbicide use (1.9, 1.1–3.2); when they were asked who had applied the chemicals in the garden, the association was strongest in the subset of mothers who reported applying the pesticide (2.2, 1.3–3.8).

Buckley et al. (2000) examined childhood non-Hodgkin's lymphoma (NHL) in relation to a wide array of exposures during gestation and childhood. The authors participate with a consortium of hospitals that conduct epidemiologic studies of rare childhood cancers. Cases of NHL diagnosed at the age of 20 years or less in 1986-1990 were eligible. The case definition also included those with “‘lymphomatous leukemia,' defined as leukemia with bulk disease in the mediastinum, peripheral lymph nodes, liver, spleen or other abdominal site and at least 25% lymphoblasts in the bone marrow.” The final analysis included 268 cases and an equal number of controls who were matched, to the extent feasible, on date of birth, race, and sex. The questionnaire included a broad array of characteristics, including childhood infections, allergies, vaccinations and immune-related disorders, family history of malignancies, and other lifestyle and exposure-related factors.

Five main questions addressed pesticide exposure: household insecticide use by the mother, garden sprays by the mother, exterminations around the home, herbicide or pesticide exposure of the child, and occupational pesticide exposure of either parent. Statistical analyses evaluated NHL combined with the lymphomatous leukemias and in immunologic, histologic, and age-at-diagnosis categories. Cases were similar to controls with respect to age, sex, race, and education. For each of the five questions, cases were more likely to have been exposed than controls. No question addressed herbicides alone. Subtype analyses revealed similar risks for B-cell and T-cell lineage of the lymphoma. Some variation was seen in histologic subtypes for associations with large ORs, for example, household insecticide use with lymphoblastic histology, insect extermination with large-cell and Burkitt lymphoma, child's exposure with large-cell and Burkitt lymphoma, and occupational exposure with Burkitt lymphoma. Overall, the primary

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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focus of the study was childhood infections, so the questions regarding pesticide exposure were few. Most important for the purposes of this update, no information on herbicides as a class, distinct from insecticides or other pesticides, was available. In addition, exposures before conception were not singled out, nor was a distinction between maternal and paternal exposure made. Another point of concern is the omission of response rates for cases and controls.

Vietnam-Veteran Studies

Pham and Lannigan (2001) reported a single case of carcinoma of the larynx in a 7-year old child born in Australia, whose father, of Vietnamese origin, was exposed to herbicides during the Vietnam conflict. Cancer of the larynx is rare but not unknown in children, and most cases are of squamous-cell origin. Historically, such cases were associated with radiation. The authors do not itemize the risk factors that they believe were ruled out but state “further inquiries with regards to family history, social and demographic factors and environmental exposure to cigarette smoke or toxic substances were negative.” The conclusion that there is limited or suggestive evidence of an association between laryngeal cancer and the exposure of concern in adults is presented elsewhere in this volume. Adult risk factors may not apply to children in this case as in other malignancies. However, one case report of a young adolescent (cited in Pham and Lannigan, 2001) suggests at least one shared risk factor in cigarette-smoking. There is insufficient evidence to assess the risk posed by paternal exposure to Agent Orange or arsenic compounds on the basis of a single case.

Synthesis

A single case study of a malignancy, even a rare cancer, among the many children of Vietnam-era veterans does not constitute evidence of an association. It suggests only that such an event is possible. Whether such an event may occur by chance alone or there is an underlying association cannot be determined from a single case report. Such case reports are generally regarded as hints that it would be prudent to look for more cases or to conduct a study. In this situation, however, the medical community is alert, public interest is high and the outcome is very unusual. There are many incentives to identify and report such cases, but the absence of other reported cases in such situations is usually taken as evidence that the event is unlikely to be frequent.

The evidence of an association between pesticides, possibly including herbicides or TCDD exposure, and neuroblastoma in children conceived around the time of exposure is suggestive. The evidence of such an effect among offspring of Vietnam veterans conceived months or years later is inadequate and insufficient.

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and childhood cancers.

Biologic Plausibility

Susceptibility to cancers in childhood following environmental exposures may be influenced by several factors, one of which is that the child may inherit a genetic susceptibility trait that would increase the likelihood of developing cancer after exposure to a carcinogen. The mother or father would have to transmit an acquired genetic defect that predisposed the child to cancer, and the child could be exposed to a carcinogen in utero or by exposure to a potent carcinogen in infancy or early childhood either directly or by exposure in breast milk. TCDD and dioxin-like compounds cross the placenta and are present in breast milk, so a pathway of exposure is demonstrated. Women who were breastfed as infants appear to have a lower incidence of endometriosis, a finding that has led to speculation that the effects of TCDD and dioxin-like compounds with estrogen-like activity may persist beyond childhood, even into adult life (Tsutsumi et al., 2000). However, laryngeal carcinoma has not been considered an estrogen-responsive malignancy.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the exposure of Vietnam veterans and the magnitude of risk, if any, of childhood cancers, it is not possible for the committee to quantify the risk likely to be experienced by the offspring of Vietnam veterans because of exposure to herbicides in Vietnam.

SEX RATIO

Sex ratio (ratio of males to females at birth)—about 106 males per 100 females (Pyeritz, 1998), or about 0.51 percent males among all births—has been used for a number of years as a potential marker of genetic damage. It has been hypothesized that the induction of lethal mutations before birth will alter the sex ratio at birth. For instance, a lethal mutation on the paternal X chromosome would differentially affect female conceptuses. Investigators have evaluated the sex ratio among various species in relation to such exposures as radiation for

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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some years. More recently, it has been suggested that the sex ratio is controlled by parental hormones at conception and that changes in gonadotropin and steroid concentrations may affect it (James, 1996). The specific mechanisms involved (such as zygote formation, implantation, regulation of sex-determining factors, and selective fetal loss) are uncertain, and direct experimental evidence supporting or refuting the hypothesis is lacking. James (1997) has suggested that a reduction in testosterone and high gonadotropin after TCDD exposure would result in an excess of female offspring. Potential confounding factors for this altered sex ratio are uncertain, but parental age, social class, illness, race, smoking, and stress have been considered.

Summary of VAO, Update 1996, Update 1998, and Update 2000

The potential association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and altered sex ratio was not explored in the VAO and Update 1996 reports. The committees responsible for Update 1998 and Update 2000 reviewed papers addressing altered sex ratio as part of their examination of literature on fertility. There was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and sex ratio.

Update of Scientific Literature
Occupational Studies

Okubo et al. (2000) reported results of an examination of the offspring of 15 male industrial workers. In 1980-1997, the workers were employed by a company in Japan that made plastic products and were also engaged in the recovery of dicyclopentadiene. The workers were exposed to several chemical materials— dicyclopentadiene, cyclopentadiene, epoxy resin, and such raw materials as bisphenol A epichlorohydrin. Using a binomial test, they reported a statistically significant (p < 0.01) excess number of female births (18 of 24) compared with the 1980 sex ratio of 0.5 in Japan. They also reported that there was no association between the sex ratio and several characteristics on the basis of information obtained from personal interviews. Those characteristics included year of birth of the offspring, paternal age at the birth of offspring, paternal age when joining the company (19–22 years), and the period of employment until the birth of offspring (mean = 9.5 years; SD = 3.7 years). This study, although interesting enough to warrant a more careful look at the study population, suffers from potential shortcomings. The results may not be specifically attributed to any of the chemicals to which the workers were exposed. Moreover, the results may be, at least partially,

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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due to the heat to which they were also exposed. The study results are also based on a small sample size, further limiting their usefulness.

In a letter to Lancet, Moshammer and Neuberger (2000) report on the effect of occupational exposure to TCDD on the sex ratio, on the basis of the Austrian chloracne cohort. After exposure to TCDD in the early 1970s, the number of live births showed a slight tendency toward having a lower sex ratio (that is, having fewer boys): 0.46 (26 boys in 56 births) compared with 0.61 (19 boys in 31 births). But no statistically significant trend was found with respect to TCDD load or the period between exposure and date of birth. Moreover, the large number of female births was mainly to fathers who were younger than 20 years old during the exposure. Those findings support findings from earlier studies (such as those of Seveso, Italy).

On the basis of data on participants in a cross-sectional medical study, Schnorr et al. (2001) investigated whether pregnancy outcomes (spontaneous abortions or altered sex ratio) were associated with paternal occupational exposure to TCDD. The study was conducted on a highly exposed population whose serum TCDD measurements were available. The medical study was conducted on 325 nonexposed controls that were matched for race, age (within 5 years), and neighborhood to 281 workers at two plants who were exposed to TCDD while engaged in the production of sodium trichlorophenol or any of its derivatives, most notably the derivative 2,4,5-T, which was one of the herbicides used in Vietnam. Health and risk-factor information were obtained from questionnaires and medical examination. For the reproductive study, additional information was obtained on reproductive outcomes and related characteristics from the fathers (via a brief questionnaire) and mothers (via telephone interview). A pharmacokinetic model was used to estimate serum TCDD at the time of conception for each pregnancy. The models used time-dependent BMI information to account for body burden. Paternal exposures were modeled as logarithms and also by categorizing into <20, 20–255, 255–1120, and ≥1120 ppt. Extrapolated TCDD concentrations at times of conception in this cohort were high (3–16,340 ppt) compared with those in other studies (the range in the Ranch Hand cohort was 0–1,424 ppt).

The analysis on sex ratios was limited to 1,191 live births (544 fathered by workers and 647 by nonexposed controls) from the 200 wives of the 259 male workers and 220 wives of the 243 controls with eligible pregnancies and whose serum TCDD measurements were available. Sex ratio was not significantly different between the two groups. On the basis of a logistic-regression paradigm that used a generalized-estimation-equations approach to account for multiple pregnancies, the probability of a male birth was modeled. In a model that adjusted for potential confounders (father's race and mother's education), there also was no significant trend with magnitude of paternal exposure to TCDD. In contrast with other prior studies (such as that of Seveso, Italy), there was no difference in sex ratio by age at first exposure. The sex ratios among those first exposed when

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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younger than 20 years old and those first exposed when older than 20 years were 0.6 (0.5–0.7) and 0.6 (0.5–0.6), respectively.

The strengths of that study include the availability of extensive questionnaire and interview information on potential risk factors and pregnancy outcomes and characteristics, the use of pharmacokinetic models to quantify fathers' exposure data, and confirmation of all pregnancies. One of its limitations is the modest rate of response (73% and 78% among controls' and workers' wives, respectively).

Savitz et al. (1997) reported results of the Ontario Farm Family Health Study. The study was conducted by using the 1986 Canadian census of agriculture as a sampling frame for selection of farms. Of the 2,693 farm couples that were eligible for the study (year-round occupants of the farm where the female was no older than 44 years at the time of interview), 1,898 couples provided questionnaire data; they had 3,984 eligible pregnancies (occurring on the study farm with known time intervals of pregnancy, and where questionnaire data were provided by the fathers). Of reported farm activities over the preceding 5 years, direct pesticide exposure was said to have occurred if activities involved mixing or applying crop herbicides, crop insecticides and fungicides, livestock chemicals, yard herbicides, or building pesticides. For exposure during the period from 3 months before conception to the time of conception (to account for sperm-mediated effects), men were grouped for each pregnancy into “chemical activity” if involved in activities with direct pesticide exposure for at least 1 month, “nonchemical activity” if involved in farm activities that were not associated with direct pesticide exposure (such as milking cows), or “no activity ” if not involved in any farm-related activity during the period of interest. Exposure information was further refined by asking about use of protective equipment and about specific pesticides applied on the farm. On the basis of logistic-regression models that used the generalized-estimation-equations approach to account for within-woman across-pregnancies correlation, sex ratio was not found to be associated with farm chemical activities. There was a trend toward lower sex ratio for fathers who did not report using protective equipment, with an OR of 0.8 for all classifications of specific activities. But none of the trends was statistically significant. The models adjusted for mother's age, father's age, and father's off-farm job. The study has the strength of having a detailed exposure assessment, and the advantage of maternally reported pregnancy outcomes. The authors report that TCDD is not likely to be present to any substantial degree in the pesticides considered, but they also list the types of chemicals that were involved, including relevant exposures, such as to phenoxy herbicides.

Environmental Studies

Yoshimura et al. (2001) reported results of a study on the sex ratio of live births (during 1968–1977) to parents that were accidentally exposed to PCBs and

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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polychlorinated dibenzofurans (PCDFs) in 1968 in Yusho, Japan. The study focused on two regions of Japan that were affected by the exposure: Fukuoka and a region of Nagasaki. Using a two-sided binomial test and 85 live births to affected parents in the study area in February 1968 to December 1977, they showed that the sex ratio was not statistically different from the ratio of 0.5 in the general Japanese population. That result is different than the findings in Seveso, Italy, and Yucheng, Taiwan. But, as the authors rightly acknowledged, the exposure in this Japanese study and in the Yucheng study was to PCBs and PCDFs, not to TCDD, as in Seveso (Italy). The study seems to have used appropriate statistical methods for testing the main null hypotheses. It also appears that the study period was too brief to allow for possible effects on sex ratio in offspring of victims who were younger than 19 years old at the time of the incident.

Revich et al. (2001) studied the relationship between the relatively high dioxin concentrations in Chapaevsk, Russia (as detected in the air, the soil, drinking water, and cows' milk because of pollution from a chemical plant in the area), and its effects on the reproductive health of the study population. The sex ratio of births in Chapaevsk was examined with demographic data. The overall sex ratio for 1983 –1997 was 0.5. The year-specific sex ratio ranged from 0.4 for 1989 to 0.6 for 1987 and 1995. The authors conclude that these results support the decline in sex ratio that has been shown in other industrial countries. However, the pattern is not clear. Moreover, the nonspecific nature of the exposure and the poor study design limit the usefulness of these results.

Karmaus et al. (2002) examined the relationship between environmental parental exposure to PCBs and dichlorophenyl dichloroethene (DDE) in Michigan fish-eaters and sex ratio in their offspring. The study was based on a cohort of 1,177 people who were recruited as a result of three surveys (1973–1974, 1979– 1982, and 1989–1991) that assessed total serum PCB concentrations in Michigan anglers. Notably, dioxin-like activity was not assessed in this investigation. A telephone interview was conducted in 2000 to collect data on their children's birth characteristics, such as birth date, sex, birthweight, and gestational age. Exposure data were obtained from analyses of serum PCB and DDE in samples obtained in each of the three surveys. For each birth of a child, the paternal and maternal exposures (dichotomized at the median) that were closest to the birth were used as the most relevant exposures. Logistic-regression models that used the generalized-estimation-equations approach to account for multiple births in a family were fitted to estimate the OR for sex ratio after adjustment for calendar period of the child 's birth, age of the mother at the child's birth, and whether there was an older brother in the family. The models were based on 101 families, which had 208 offspring born after 1963 and paternal measurements of PCB and DDE. The results indicate that a significantly higher OR (with a higher sex ratio) was associated with paternal PCB concentrations over 8.1 µg/L serum (OR = 2.3, 1.1 –4.7). There was no significant association with maternal PCB concentration, but the estimated OR was in the opposite direction (OR = 0.7, 0.4 –1.5). Some of

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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the strengths of the study are the attempt to assess the reliability of questionnaire information on a sample of 30 parents (yielding a kappa statistic of 91% and complete agreement on the sex of the children) and the use of appropriate statistical techniques to account for multiple births in a family. But PCB concentrations were determined only at the times of the three surveys, and it was not possible to study the effects of PCB congeners, such as those that display dioxin-like activity.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

Of the four occupational studies evaluated in this section, the two larger studies (Savitz et al., 1997; Schnorr et al. 2001) are of sufficient size to yield results that may be reliable and hence amenable to serious interpretation. Savitz et al. (1997) is a well-designed and well-analyzed case-control study. Schnorr et al. (2001) dealt with a study population with high TCDD exposures, and hence this study is relevant to the charge of the committee. In any case, both studies give evidence of no association of the exposures with sex ratio.

The intriguing finding of excess number of female births in the relatively small study of Okubo et al. (2000) suffers from the shortcomings of the study, one of which is the results may not be specifically attributed to any of the chemicals involved. Moshammer and Neuberger (2000) reported that excess female births were observed after exposures to TCDD in the 1970s, but the results were significantly linked to TCDD load or the interval between exposure and date of birth.

The results from Yoshimura et al. (2001) show lack of association of exposures to sex ratio, contradicting previous results from Seveso, Italy, and Yucheng, Taiwan, but the exposures were to PCBs and PCDFs, not to TCDD. The results from Revich et al. (2001) support previous findings of declining sex ratios in other industrial countries, but this study suffers from poor design. The results from Karmaus et al. (2002) indicate higher sex ORs (more male births) after exposure to PCB and DDE, but exposure data were based on data from three surveys, and it was not possible to study whether the effects were the result of PCB congeners that may have dioxin-like activity.

There is not enough data to determine whether an association exists between exposure to the chemicals of interest and altered sex ratio, but regardless the committee does not necessarily consider this an adverse health outcome. Although a large change in the sex ratio would have adverse effects on the population as a whole, a higher-than-expected number of females may not in itself be an

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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adverse event in terms of social or personal capacity on an individual veteran basis. Altered sex ratio might indicate an underlying functional abnormality in one or both parents that might be adverse, such as loss of male fetuses, or alteration of motility of sperm, but altered sex ratio is not necessarily associated with functional deficit in affected persons. Therefore, the committee has reviewed the data but does not treat sex ratio as a health outcome but not an adverse one.

SUMMARY

Strength of the Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and altered hormone concentrations, semen quality, or infertility; spontaneous abortion; late-fetal, neonatal, or infant death; low birthweight or preterm delivery; birth defects other than spina bifida; and childhood cancers.

Biologic Plausibility

This section summarizes the general biologic plausibility of a connection between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and reproductive and developmental effects on the basis of data from animal and cellular studies. Details of the committee's evaluation of data from the recent studies are presented in Chapter 3.

TCDD is reported to cause a number of reproductive and developmental effects in laboratory animals. In males, sperm count and production and seminal vesicle weight have been affected by TCDD. Effects on female reproductive organs have also been seen. The mechanisms of these effects are not known, but one hypothesis is that they are mediated through effects on hormones. Effects on male and female reproductive organs are not always accompanied by effects on reproductive outcomes. On the basis of animal data, there is a biologically plausible mechanism of male and female reproductive effects in humans. In animal studies, offspring of female hamsters given TCDD orally on gestation day 15 had reduced body weight. Although body weight is not consistently reduced in mice and rats exposed to TCDD in utero, those data are suggestive that exposure to TCDD in utero could affect the body weight of newborn humans.

Experiments have examined the effects of TCDD on the adult female reproductive system. TCDD exposure did not increase egg mortality or affect time to hatching of newly fertilized zebrafish eggs, but pericardial edema and craniofacial malformations were observed in zebrafish larvae. In ovo TCDD exposure adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron. Immature

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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female rats treated with TCDD have been shown to produce significantly fewer ova; the reduction might have a number of pathways, including direct effects on the ovaries and effects on the ovaries that are secondary to effects on other hormone-producing tissues.

Administration of TCDD to male rats, mice, guinea pigs, marmosets, monkeys, and chickens elicits reproductive toxicity by affecting testicular function, decreasing fertility, and decreasing the rate of sperm production. Effects on the prostate have been seen after TCDD exposure. TCDD decreased the concentrations of hormones, such as gonadotropin and testosterone, in rats. High doses of TCDD, however, are required to elicit many of those effects.

TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that coexposure with either of two other chemicals, hydrocortisone or retinoic acid, synergistically enhances expression of cleft palate. The synergy suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. Several reports describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity; cytochrome P450 1A1 induction in the endothelium might mediate the early lesions that result in TCDD-related vascular derangements. That antioxidant treatment provides substantial protection against TCDD-induced embryotoxicity suggests that reactive oxygen species might be involved in the teratogenic effects of TCDD.

Studies in female rats show that a single dose of TCDD results in malformations of the external genitalia and in functional reproductive alterations in female progeny, such as decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and increased incidence of constant estrus. Those effects depend on the timing of exposure.

Little research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed various concentrations of simulated Agent Orange mixtures concluded that there were no adverse effects in offspring. A statistically significant excess of fused sternebrae in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of this defect in the controls.

The effects of in utero and lactational exposure on the male reproductive system have been investigated. In utero and lactational exposure to TCDD led to decreased daily sperm production and cauda epididymal sperm number in male rat and hamster offspring. Research suggests that in utero and lactational TCDD exposure selectively impairs rat prostatic growth and development without inhibiting testicular androgen production or consistently decreasing prostatic dihydrotestosterone concentrations. In utero exposure to TCDD also caused decreased seminal vesicle weight and branching and decreased sperm production and increased sperm transit time in male offspring.

Studies in female animals are few but demonstrate that in utero and lacta-

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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tional exposure reduced fertility, decreased the ability to carry pregnancy to term, decreased litter size, increased fetal death, impaired ovarian function, and decreased concentrations of hormones, such as estradiol and progesterone. Most of those effects may have occurred as a result of TCDD's general toxicity to the pregnant animal, however, and not as a result of a TCDD-specific mechanism that acted directly on the reproductive system. TCDD also induced changes in serum concentrations of reproductive hormones in immature female rats given TCDD by gastric intubation, partially because of the action of TCDD on the pituitary gland.

The mechanism by which TCDD could exert reproductive and developmental effects is not established. Extrapolating results to humans is not straightforward, because the factors that determine susceptibility to reproductive and developmental effects vary among species. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; these effects in turn could lead to reproductive or developmental toxicity.

Most studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex has been shown to bind DNA and lead to changes in transcription; that is, genes are differentially regulated. Modulation of those genes may alter cell function.

Although structural differences in the AhR have been identified among species, it operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the toxic effects of TCDD in humans and animals, and data in animals support a biologic basis of TCDD's toxic effects. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the TCDD exposure that causes reproductive or developmental effects.

Little information is available on reproductive and developmental effects of the herbicides discussed in this report. Studies indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities. However, when pregnant rats or mice are exposed to 4-(2,4-dichlorophenoxy)butyric acid (2,4-DB), of which 2,4-D is a major metabolite, the rate of growth of offspring is reduced, and their mortality increased (Charles et al., 1999); very high doses of 2,4-D and 2,4-DB were required to elicit these effects. 2,4-D has also been shown to alter the concentration and function of reproductive hormones and prostaglandins. One study reported an increased incidence of malformed offspring of male mice exposed to a mixture of 2,4-D and picloram in drinking water. However, paternal toxicity was observed in the high-dose group, and there was no clear dose–response relationship; both findings were a concern in that study. Data have suggested that picloram alone may produce fetal abnormalities in rabbits at doses that are also toxic to the pregnant animals, but that effect has not been seen in many studies. 2,4,5-T was toxic to fetuses when administered to pregnant rats,

Suggested Citation:"7. Reproductive and Developmental Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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mice, and hamsters. Its ability to interfere with calcium homeostasis in vitro has been documented and linked to its teratogenic effects on the early development of sea urchin eggs. Cacodylic acid is toxic to rat, mouse, and hamster fetuses at high doses that are also toxic to the pregnant mother.

The foregoing suggests that a connection between TCDD exposure and human reproductive and developmental effects is, in general, biologically plausible. However, more-definitive conclusions about the presence or absence of a mechanism for the induction of such toxicity by TCDD in humans is complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; the lack of strong evidence of organ-specific effects among species; and differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they can have effects on cells at the subcellular level that could provide a biologically plausible mechanism for reproductive and developmental effects. Evidence in animals, however, indicates that they do not have reproductive effects and that they have developmental effects only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of these compounds' reproductive or developmental effects.

Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicide or TCDD exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animal and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure. The biologic mechanisms underlying TCDD's toxic effects continues to be an active field of research, and future updates of this report might have more and better information on which to base conclusions, at least for TCDD.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk of reproductive and developmental outcomes associated with exposure to herbicides in the studies that have been reviewed, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

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This book updates and evaluates the available scientific evidence regarding statistical associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam, focusing on new scientific studies and literature.

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