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Veterans and Agent Orange: Update 2004 (2005)

Chapter: 7 Reproductive and Developmental Effects

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Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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7
Reproductive and Developmental Effects

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2002 (hereafter, Update 2002; IOM, 2003) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed 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, stillbirth, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) were reviewed when relevant, because TCDD is sometimes a contaminant of PCBs. For studies new to this update that report only a single reproductive health outcome and that are not revisiting a previously studied population, their design information is summarized here with their results; the design information for all other new studies can be found in Chapter 4.

This chapter’s primary emphasis is 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 also were included. Studies investigating the potential reproductive consequences of exposure by either parent were considered; whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

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 terms, often used interchangeably, are congenital anomaly and congenital malformation. Major birth defects, which occur in 2–3% of live births, are abnormalities that are present at birth that are severe enough to interfere with viability or physical well-being. Birth defects are detected in another 5% of babies during follow-up through the first year of life. The causes of most birth defects are unknown. Genetic factors, exposure to some medications, exposure to environmental contaminants, occupational exposures, and lifestyle factors have been implicated in the etiology of birth defects (Kalter and Warkany, 1983). Most etiologic research has focused on the effect of maternal and fetal exposures, but some work has addressed paternal exposures. Paternally mediated exposures might occur by several routes and exert effects in various ways. One way is through direct genetic damage to the male germ cell transmitted to the offspring and dominantly expressed as a birth defect. A hypothesized route is the transfer of toxic compounds through a man’s body into his seminal fluid, resulting in fetal exposure during gestation (Chia and Shi, 2002). Another more indirect route of paternally mediated exposure could arise from contact of family members with contamination brought into the home from the workplace.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter, VAO; IOM, 1994) determined that there was inadequate or insufficient information to determine an association between exposure to 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (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 Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996) led it to conclude that there was limited or suggestive evidence of an association between at least one of the compounds of interest and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. Those findings were not modified further in Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999), Veterans and Agent Orange: Update 2000 (hereafter, Update 2000; IOM, 2001), or Veterans and Agent Orange: Update 2002 (hereafter, Update 2002; IOM, 2003).

Summaries of the studies of birth defects and neural tube defect specifically that were reviewed here and in earlier reports can be found in the Tables 7-1 and 7-2, respectively.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 7-1 Selected Epidemiologic Studies—Birth Defects

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kristensen et al., 1997

Norwegian farmers (maternal and paternal exposure)

4,189

1.0 (1.0–1.1)b

Dimich-Ward et al., 1996

Sawmill workers (paternal exposure)

 

 

Cataracts

11c

5.7 (1.4–22.6)

 

Genital organs

105c

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

11

0.9 (0.5–1.7)

 

Maternal age > 30

19

2.5 (1.6–2.1)

 

Chromosomal

8

1.1 (0.5–2.1)

 

Other

48

 

 

Maternal age < 35

36

1.1 (0.8–1.6)

 

Maternal age > 35

12

3.0 (1.6–5.3)

 

All births with anomalies

125

1.4 (1.2–1.7)

Studies Reviewed in VAO

Moses et al., 1984

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

11

1.3 (0.5–3.4)

Suskind and Hertzberg, 1984

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

18

1.1 (0.5–2.2)

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)

Townsend et al., 1982

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

30

0.9 (0.5–1.4)

ENVIRONMENTAL

New Studies

Cordier et al. 2004

Residents of the Rhône-Alpes region of France living near municipal solid waste incinerators (maternal and paternal exposure)

 

 

 

Minor anomalies

518

0.9 (0.8–1.1)

 

Chromosomal anomalies

204

1.0 (0.9–1.2)

 

Monogenic anomalies

83

1.1 (0.8-1.4)

 

Unknown or multifactoral etiology

964

1.1 (1.0–1.2)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Schreinemachers, 2003

Rural or farm residents of Minnesota, Montana, and North and South Dakota (maternal and paternal exposure)

 

 

 

Any birth anomaly

213

1.1 (0.9–1.3)

 

Central nervous system anomalies

12

0.8 (0.5–1.4)

 

Circulatory or respiratory anomalies

39

1.7 (1.1–2.6)

 

Digestive system anomalies

24

0.9 (0.6–1.5)

 

Urogenital anomalies

44

1.0 (0.7–1.5)

 

Musculoskeletal or integumental anomalies

70

1.5 (1.1–2.1)

 

Chromosomal anomalies

17

0.9 (0.6–1.6)

Studies Reviewed in Update 2002

Loffredo et al., 2001

Mothers in the Baltimore-Washington Infant Study exposed to herbicides during the first trimester (maternal exposures)

66

2.8 (1.3–6.9)

Revich et al., 2001

Residents of Chapaevsk, Russia—congenital malformations

*

(*) NS

ten Tusscher et al., 2000

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

 

 

 

Births in 1963

5

(*) SS

 

Births in 1964

7

(*) SS

Studies Reviewed in Update 2000

García et al., 1998

Residents of agricultural areas in Spain—≥median score on chlorophenoxy herbicides exposure duration (months) index (paternal)

14

3.1(0.6–16.9)

Studies Reviewed in VAO

Fitzgerald et al., 1989

Persons exposed to an electrical transformer fire—total birth defects (maternal or paternal exposure)—incidence

1

2.1 (0.05–11.85)

Mastroiacovo et al., 1988

Seveso residents (maternal, paternal, and in utero exposure)

 

 

 

Zones A and 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 and B mild defects

14

1.4 (0.9–2.6)

Stockbauer et al., 1988

Persons in Missouri with documented TCDD soil contamination near residence (maternal; paternal; in utero exposure)

 

 

 

Total birth defects

17

0.8 (0.4–1.5)

 

Major defects

15

0.8 (0.4–1.7)

 

Midline defects

4

0.7 (0.2–2.3)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Hanify et al., 1981

Residents of areas of Northland New Zealand subject to aerial 2,4,5-T sprayingd

 

 

 

All birth malformations

164

1.7 (1.4–2.1)e

 

All heart malformations

20

3.9 (2.1–7.4)e

 

Hypospadias, epispadias

18

5.6 (2.7–11.7)e

 

Talipes

52

1.7 (1.2–2.3)e

 

Cleft lip

6

0.6 (0.3–1.3)e

 

Isolated cleft palate

7

1.4 (0.6–3.2) e

VIETNAM VETERANS

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam veterans

4,140

 

 

“Likely” 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)

 

Tracheo-oesophageal fistula

10

23 expected (14–32)

 

Anencephaly

13

16 expected (8–24)

 

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., 1998a

Air Force Ranch Hand veterans (paternal exposures)

 

 

 

Before service in Southeast Asia

*

0.7 (*)

 

After service in 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 and 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)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

 

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 Update VAO

AFHS, 1992

Air Force Operation Ranch Hand veterans—birth defects in conceptions following 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)

Aschengrau and Monson, 1990

Vietnam veterans whose children were born at Boston Hospital for Women (paternal exposure)

 

 

 

All congenital anomalies (crude OR)

 

 

 

Vietnam veterans compared to men without known military service

55

1.3 (0.9–1.9)

 

Vietnam veterans compared to non-Vietnam veterans

55

1.2 (0.8–1.9)

 

One or more major malformations (crude OR)

 

 

 

Vietnam veterans compared to men without known military service

18

1.8 (1.0–3.1)

 

Vietnam veterans compared to non-Vietnam veterans

18

1.3 (0.7–2.4)

CDC, 1989

Vietnam Experience Study—interview data (paternal exposure)

 

 

 

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 defects

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)

 

Birth defects in childrens of veterans reporting high exposure

46

1.7 (1.2–2.4)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

CDC, 1989

General Birth Defects Study—hospital records (paternal exposure)

 

 

 

Birth defects

130

1.0 (0.8–1.3)

 

Birth defects—black Vietnam veterans only

21

3.4 (1.5–7.6)

 

Major birth defects

51

1.2 (0.8–1.9)

 

Digestive system defects

18

2.0 (0.9–4.6)

Donovan et al., 1984

Australian Vietnam veterans (paternal exposure)

 

 

 

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)

Erikson et al., 1984a

Vietnam veterans identified through the CDC Metropolitan Atlanta Congenital Defects Program (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)

a Given when available.

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

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

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

e 90% confidence interval

* 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; OR, oddds ratio; SIR, standardized incidence ratio; SS, statistically significant.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

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

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

Norwegian farmers—spina bifida (parental exposure)

 

 

 

Tractor spraying equipment

28

1.6 (0.9–2.7)

 

Tractor spraying equipment and 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 only

18b

1.8 (0.8–4.1)

Garry et al., 1996

Private pesticide appliers—central nervous system defects (paternal exposure)

6

1.1 (0.5–2.4)

ENVIRONMENTALc

New Studies

Cordier et al. 2004

Residents of the Rhône-Alpes region of France living near municipal solid-waste incinerators (maternal and paternal exposure)

49

0.9 (0.6–1.2)

Studies Reviewed in VAO

Stockbauer et al., 1988

Persons in Missouri with documented TCDD soil contamination near residence—central nervous system defects (maternal; paternal; in utero exposure)

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 (0.7–2.9)d

 

Spina bifida

13

1.1 (0.6–2.1)d

VIETNAM VETERANS

Studies Reviewed in Update 2000

AIHW, 1999

Australian Vietnam veterans—Validation Study (paternal exposure)

 

 

 

Spina bifida—maxima

50

33 expected (22–44)

 

Anencephaly

13

16 expected (8–24)

Studies Reviewed in Update 1996

Wolfe et al., 1995

Air Force Operation Ranch Hand personnel—neural tube defectse (paternal exposure)

4

(*)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

(*)

 

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

19f

2.7 (1.2–6.2)

 

EOI-5: anencephaly

7f

0.7 (0.2–2.8)

Australia Department of Veteran 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 prior to conception.

c Either or both parents potentially exposed.

d 90% confidence interval.

e Of the four neural tube defects reported among Ranch Hand offspring there were two spina bifida (high dioxin level), one spina bifida (low dioxin), and one anencephaly (low dioxin). No neural tube defects were reported in the comparison cohort. 454 post-service births were studied in Ranch Hand veterans; 570 in comparison cohort.

f 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; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; NR, not reported.

Update of the Scientific Literature

Occupational Studies

No relevant occupational studies have been published since Update 2002 (IOM, 2003).

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Enviromental Studies

Cordier et al. (2004) studied the impact of exposure to emissions from municipal solid-waste incinerators on birth defects in a region of southeast France for a 10-year period (1988–1997), under the assumption that such emissions increase the environmental load of dioxin and other hazardous compounds. Data on congenital malformations obtained from a regional registry were categorized into four groups: minor, chromosomal, monogenic, and other major anomalies. Communities with more than 50,000 residents were categorized by a detailed scoring system into 194 exposed and 2,678 unexposed. The rates of congenital malformations were compared in analyses adjusted for year of birth, maternal age, department of birth, population density, average family income, and local road traffic (when available). Congenital anomalies were not significantly associated with exposure overall (relative ratio [RR], 1.04; 95% confidence interval [CI], 0.97–1.11), but some specific anomalies (facial clefts, renal dysplasia, obstructive uropathies, cardiac anomalies) showed significant dose–response relationships. The defined exposure indicator could not, however, differentiate exposure to dioxins from exposure to metals in this ecologic study.

Schreinemachers (2003) conducted an ecologic study that compared rates of adverse birth outcomes in US agricultural states: Minnesota, Montana, North Dakota, and South Dakota. Counties, the unit of analysis, were included in the study if at least half of the population in the county was rural and if more than 20% of the land was dedicated to raising crops. The 147 counties were then classified according to their acreage of wheat fields, as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D) as high-wheat (N = 74) and low-wheat (N = 73). National birth and infant death data for 1995–1997 were used to derive gender-specific rates of malformations at birth for white singleton births, adjusting for several covariates, including maternal age, parity, maternal education, prenatal care, previous preterm or small-for-gestational-age (SGA) birth, tobacco use during pregnancy, alcohol use during pregnancy, sex of child, and season of conception. A strong association was observed for circulatory and respiratory anomalies (odds ratio [OR], 1.7; 95% CI, 1.1–2.6), which became even stronger after excluding heart malformations (OR, 2.0; 95% CI, 1.1–3.6). Conception during the season of heavy herbicide application (April–June) was the only significant adjustment covariate (OR, 1.7; 95% CI, 1.1–2.8). After covariate adjustment, increased risk for musculoskeletal and integumental anomalies was observed (OR, 1.5; 95% CI, 1.1–2.1). Boys appeared to be more susceptible to congenital anomalies than girls (male-to-female ratios of births with any congenital anomaly were 1.67 and 1.60 in the low- and high-wheat counties, respectively). The authors noted that the use of herbicides other than the chlorophenoxy herbicides should also be considered as a possible cause. Moreover, since acreage was used as an exposure surrogate, lack of directly measured herbicide exposure is a major limitation.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Vietnam-Veteran Studies

Correa-Villasenor et al. (2003) documented the methodology, use, and related results of the Metropolitan Atlanta Congenital Defects Program, in which 35 years of birth defects surveillance was done at the Centers for Disease Control and Prevention. Data from the registry were used by Erickson et al. (1984b), who showed that there was no greater risk among Vietnam veterans for fathering babies with serious birth defects. No health effects analysis was conducted by Correa-Villasenor et al. (2003).

Synthesis

Cordier et al. (2004) found significant associations with exposure to emissions from municipal solid-waste incinerators only for some facial cleft, renal dysplasia, and “other renal anomalies.” The validity of this ecologic study is limited considerably by the possibility of exposure misclassification and residual confounding. Furthermore, the researchers did not have actual dioxin measurements and the subjects were probably exposed to other toxic substances, particularly metals, in the incinerator emissions.

Schreinemachers (2003) reported increased incidences of circulatory or respiratory anomalies (possibly more pronounced among male children) in association with agricultural activity. Because of the study’s ecological design, its results are valid only for regional differences and might not translate to individual comparisons. The use of a county’s wheat-producing acreage as a surrogate for parental exposure to agricultural chemicals and, even more indirectly, for dioxin exposure severely limits the value of these findings in evaluating the exposure experience of Vietnam veterans.

Conclusions

Strength of Evidence from Epidemiologic Studies

There were no new relevant studies on the association between parental exposure to 2,4-D, 2,4,5-T, TCDD, cacodylic acid, or picloram and spina bifida in offspring. The committee concludes that the evidence is still limited or suggestive of an association between exposure to the compounds of interest and spina bifida.

Its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports leads the committee to conclude that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and all other birth defects.

Although there were reports of increased risks of transposition of the great arteries, non-syndromal orofacial clefts, and congenital morphogenetic condi-

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

tions in the various studies reviewed for Update 2004, those studies suffer from various pitfalls in design, sample size, and nonspecific exposure ascertainment. The two epidemiologic studies discussed in this report also suggest associations with specific groups of anomalies, as discussed above. But the studies have several limitations, and the associations might have been caused by other types of environmental contaminants that are not necessarily relevant to the charge of this committee.

Biologic Plausibility

Laboratory studies of potential male-mediated developmental toxicity attributable to exposure to TCDD and herbicides, specifically with regard to birth defects, are too limited to permit conclusions. Notably, one investigation that was reviewed for Update 2002 did not show evidence that paternal exposure to a herbicide formulation containing 2,4-D and picloram caused birth defects or any other adverse reproductive outcomes in experimental animals. Studies of chemical production workers exposed to TCDD suggest there are associated hormonal changes, but it is unclear whether those changes could be responsible for an increase in spina bifida or other birth defects.

A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and birth defects among offspring, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in the risk of this outcome in their children.

Although there are data to suggest an association between exposure to the chemicals of interest and spina bifida, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in the risk of this outcome (or other birth defects) in their children.

FERTILITY

Male reproductive function is under the control of several components whose proper coordination is important for normal fertility. Several of those components and some endpoints related to male fertility, including reproductive hormones and sperm characteristics, can be studied as indicators of fertility. 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

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both 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 Seretoli 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, affect the neuroendocrine system and spermatogenesis (for reviews see Bonde and Giwercman, 1995; Tas et al., 1996).

Summary of VAO, Update 1996, Update 1998 Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the relevant studies are presented in the earlier reports. Table 7-3 summarizes those studies.

Update of the Scientific Literature

Occupational Studies

No relevant occupational studies have been published since Update 2002 (IOM, 2003).

Environmental Studies

Greenlee et al. (2003) studied factors possibly associated with infertility in a case–control study of women living in an agricultural region of Wisconsin. A woman was considered infertile if she had 12 months of unprotected intercourse without conceiving a pregnancy that ended in live birth. Case subjects included women who were 18–35 years old and who sought treatment for infertility. They were identified through a review of medical records, and the group included women with endometriosis; infertility attributable to anovulation or pituitary–hypothalamic dysfunction; infertility of tubal, uterine, cervical, or vaginal origin; or infertility of other-specified or other-unspecified origin. Control subjects were identified through review of medical records of women with new visits to an obstetrics and gynecology department. Cases and controls were matched for age and clinic service date. Participants were asked about their activities during the 2 years before their pregnancy attempt. In 322 case subjects and 322 control

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 7-3 Selected Epidemiologic Studies—Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility)

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2000

Abell et al., 2000

Female greenhouse workers in Denmark—fecundibility ratio (maternal exposure)

 

 

 

>20 hours 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

Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D—fecundibility ratio (paternal exposure)

 

 

 

Farmers using pesticides vs organic farmers

523

1.0 (0.8–1.4)b

 

Used three or more pesticides

 

0.9 (0.7–1.2)b

 

Used manual sprayer for pesticides

 

0.8 (0.6–1.1)b

Studies Reviewed in Update 1998

Heacock et al., 1998

Workers at sawmills using chlorophenates (paternal exposure)

 

 

 

Standardized fertility ratio

18,016 (births)

0.9 (0.8–0.9)c

 

Mantel-Haenszel rate ratio estimator

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

Lerda and Rizzi, 1991

Argentinean farmers exposed to 2,4-D

32

 

 

Sperm count (millions/ml)

 

Exposed: 49.0 vs control: 101.6

 

Motility (%)

 

Exposed: 24.8 vs control: 70.4

 

Sperm death (%)

 

Exposed: 82.9 vs control: 37.1d

 

Anomalies (%)

 

Exposed: 72.9 vs control: 33.4 (p<0.01 overall)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

Greenlee et al., 2003

Women from Wisconsin, US ± infertility (maternal exposure)

 

 

 

Mixed or applied herbicides

21

2.3 (0.9–6.1)

 

Used 2,4,5-T

9

9 cases (2.7%)

11 controls (3.4%)

 

Used 2,4-D

4

4 cases (1.2%)

4 controls (1.2%)

Swan et al., 2003

Men from Missouri, US ± low sperm quality Elevated urinary metabolite marker for 2,4-D

5

0.8 (0.2–3.0)

Studies Reviewed in Update 2002

Staessen et al., 2001

Adolescents in communities close to industrial sources of heavy metals, PCBs, VOCs, and PAHs—delays in sexual maturity

 

 

 

In Antwerp, Belgium

15

4.0 (*)

 

In Wilrik, Belgium

8

1.7 (*)

VIETNAM VETERANS

Studies Reviewed in Update 1996

Henriksen et al., 1996

Effects on specific hormone levels or sperm count 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)

 

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)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

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 having children

49

1.3 (p < .01)

a Given when available.

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

c For this study, relative risk has been replaced with the standardized fertility ratio, for which a value less than 1.0 indicates an adverse effect.

d Table 1 in the reference reverses these figures—control: 82.9%; exposed: 37.1%—but the text (“The percentages of asthenospermia, mobility, necrosperma and teratospermia were greater in the exposed group than in controls…”) suggests that this is a typographic error.

* Information not provided by study authors.

subjects, when the broad category of “mix/apply herbicides” in the 2 years before trying to conceive, the crude OR was 2.3 (95% CI, 0.9–6.1) based on 21 exposed cases; adjustment for maternal education, maternal and paternal hours of passive smoke exposure, maternal and paternal time spent reviewing occupational and pesticide exposure lists, and per capita income was said to increase the OR to 26.9 (95% CI, 1.9–384.8). No equivalent data were presented for men. Numbers were too small to analyze individual pesticide products, but 9 case subjects (2.7%) and 11 control subjects (3.4%) reported being exposed to 2,4,5-T. Four case subjects (1.2%) and 4 controls (1.2%) reported exposure to 2,4-D.

Swan et al. (2003) performed a nested case–control study to examine whether previously observed poor semen quality in men from rural relative to urban areas was attributable to use of pesticides including herbicides, fungicides, and other pest control substances. Urine samples were analyzed for 15 non-persistent pesticide metabolites. None of the 36 subjects from Minnesota (9 cases and 27

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

controls) had detectable 2,4-D metabolites. Other pesticide metabolites were detected in the study—none of them were compounds of interest for this study. In the set of 25 cases and 25 controls from Missouri, the difference in the levels of the 2,4-D metabolite (means of 0.56 versus 0.10 micrograms/gram [µg/g] creatinine, respectively) was only of borderline statistical significance (p = 0.10). With exposure classification dichotomized at 0.10 µg/g, there was no association with semen quality (5 cases and 6 controls exposed; OR, 0.8; 95% CI, 0.2–3.0). Treating metabolite level and sperm quality parameters as continuous variables, 2,4-D was not association with sperm motility or concentration, but showed a weak association with sperm morphology (β = –2.36, p = 0.11). It should be noted that, because of the short half-life of 2,4-D, urine samples can be used to indicate exposures only for a few days.

Eskenazi et al. (2002a) studied the association between TCDD exposures, as measured first from serum samples collected immediately after an industrial explosion in 1976 at Seveso, Italy, and then in menstrual-cycle characteristics 20 years after the explosion. Several menstrual outcomes were analyzed, including length of menstrual cycle (in days), number of days of menstrual flow, regularity of menstrual cycle (binary: regular, irregular), and heaviness of menstrual flow (categorical: scanty, heavy, moderate). Multiple linear or logistic regression models were fitted (for continuous and categorical data, respectively), with heaviness of menstrual flow that was dichotomized in various ways; women with irregular cycles were excluded from analysis of length of menstrual flow.

A 10-fold increase in TCDD concentrations was marginally associated with about 0.40 day’s increase in estimated menstrual cycle length (95% CI, –0.14–0.94). In a model that included an interaction between TCDD concentration and menarchial status (interaction p = 0.08); that marginal association was present only in premenarchial women (adjusted β, 0.93; 95% CI, –0.01–1.86). For days of menstrual flow, no association was observed with TCDD concentration, even after stratification by menarchial status. In models for irregular flow and heaviness of flow, there was no significant association between TCDD concentration and heavy compared with moderate flow (adjusted OR, 0.95; 95% CI, 0.61–1.50). In models that compared the scanty flow category with others (moderate and heavy categories combined), there was a modest, but insignificant, association with TCDD concentration (adjusted OR, 0.84; 95% CI, 0.44–1.61). The association was significantly stronger for women who were premenarchial at the time of the explosion (interaction p = 0.03) with an adjusted OR of 0.33 (95% CI, 0.10–1.06), and completely absent for postmenarchial women (adjusted OR, 1.36; 95% CI, 0.70–2.64). After adjustment for age at interview and age at menarche, a 10-fold increase in serum TCDD concentration was significantly associated with reduced odds of having an irregular cycle (adjusted OR, 0.46; 95% CI, 0.23–0.95), with no apparent effect modification by menarchial status at the time of the explosion. It is possible that the finding was influenced by the exclusion of women who reported using hormones to regulate menstrual cycles. When those

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

29 women were included in the analysis, there was no longer a significant association with TCDD concentration (adjusted OR, 0.67; 95% CI, 0.40–1.10). The sensitivity analysis that refitted models after restricting to women aged 40 or younger did not result in any appreciable differences in conclusions. The main conclusion from the study was that serum TCDD concentration was associated with some menstrual cycle characteristics, with possible effect modification by menarchial status.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2002 (IOM, 2003).

Synthesis

Greenlee et al. (2003) presented intriguing findings with respect to female infertility, although the inability to examine the effects of specific herbicides because of the small sample sizes was a limitation. Moreover, information on risk factors was obtained from self-reports, which can be subject to recall bias.

Swan et al. (2003) conducted various statistical analyses in an effort to detect relationships between semen quality and the urinary metabolite levels of various herbicides. In that the results were at most of borderline statistical significance and rather inconsistent, they did not demonstrate a clear association between fairly recent exposure to 2,4-D and low semen quality.

The study by Eskenazi et al. (2002a) had several strengths, including its population-based (albeit historical) cohort design, the sophisticated and thorough analytic approaches employed, and the attempts to conduct a thorough sensitivity analysis. By using TCDD levels from previously gathered serum samples, they demonstrated some long-term effects of TCDD on current menstrual cycle. The menstrual-cycle characteristics, which were assessed retrospectively, are not directly predictive of fertility status. Eskenazi et al. (2002b) also investigated endometriosis, another outcome that does not actually measure fertility, but could be relevant to it.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations; decreased sperm counts; or sperm quality, subfertility, or infertility.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Biologic Plausibility

Evidence from tests with laboratory animals suggests that TCDD can alter testosterone synthesis, follicle development, and ova production. Those effects occur at relatively high doses. The reproductive significance of those changes to Vietnam veterans exposed to much lower concentrations of TCDD is not clear.

A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and altered sperm characteristics or infertility, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

SPONTANEOUS ABORTION

Spontaneous abortion is the expulsion of a nonviable fetus, generally before 20 weeks of gestation, that is not induced through physical or pharmacologic means. The background risk of recognized spontaneous abortion is generally 7–15% (Hertz-Picciotto and Samuels, 1988), but it is established that many more pregnancies terminate before women become aware of pregnancy (Wilcox et al., 1988); those are known as subclinical pregnancy losses and generally are not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Study designs include cohorts of women asked retrospectively about 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, particularly of spontaneous abortions that took place a long time before. Studies that enroll 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 can attract nonrepresentative study groups because protocols are demanding.

Summary of VAO, Update 1996, Update 1998, Update 2000 and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and spontaneous abortion. Additional information available to the committees responsible for Update 1996,

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Update 1998, and Update 2000 did not change that finding. Information available to the committee responsible for Update 2002, however, led to the conclusion that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion, but that there was insufficient information to determine whether an association exists between maternal exposure to TCDD and the risk of spontaneous abortion, or between maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion. The relevant studies are reviewed in the earlier reports. Table 7-4 summarizes the studies.

Update of the Scientific Literature

Eskenazi et al. (2003) evaluated data from the Seveso Women’s Health Study (SWHS) for an association between individual serum TCDD concentrations and birth outcomes in women who resided in Seveso at the time of the 1976 accident. For the analysis of spontaneous abortions, all pregnancies that ended in the period immediately after the explosion to the time of enrollment into the SWHS were considered, excluding those that ended by voluntary abortion (N = 108) or by ectopic or molar pregnancy (N = 11). The group of pregnancies that ended between 1976 and 1984—the first half-life of TCDD after the explosion—was analyzed separately. Exposure was based on serum TCDD concentrations, which were entered as a continuous variable in the statistical analyses (as a logarithmic function; an increase of 1 unit change corresponded to a 10-fold increase in TCDD concentration). The median maternal serum TCDD concentration at the time of the explosion was 46.6 parts per trillion (ppt) (range, 2.5–9,140 ppt). TCDD concentrations were highest for the youngest women, who were nulliparous at the time of the explosion. The analysis considered potential confounders and effect modifiers a priori from the literature, including maternal age at pregnancy, tobacco use, alcohol use, parity, and many other factors. Statistical adjustments were made for women who had multiple pregnancies during the study period. All information on pregnancy, pregnancy outcomes, and covariates was obtained in interviews conducted about 20 years after the explosion. The average length of recall between interview and pregnancy was 10.7 years. TCDD concentrations were highest for women with the shortest time of recall to pregnancy.

During the study period, 769 spontaneous abortions were reported (from 476 women; some had multiple spontaneous abortions). Those women had slightly lower TCDD concentrations than were found in women who had live births. No increase in rate was found in association with serum TCDD concentrations either in the group as a whole (adjusted OR, 0.8; 95% CI 0.6–1.2) or when the analysis was restricted to pregnancies that occurred between 1976 and 1984. However, almost one-third of the pregnancies reported within the first year of the explosion ended in voluntary abortions (a rate that decreased to 11% thereafter). Although it could be hypothesized that this could bias the results towards the null (assum-

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 7-4 Selected Epidemiologic Studies—Spontaneous Abortion

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Arbuckle et al., 2001

Ontario farm families (paternal and/or maternal exposure)

 

 

 

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

48

1.5 (1.1–2.1)

Schnorr et al., 2001

Wives and partners of men in the NIOSH cohort (paternal exposure)

 

 

 

Estimated paternal TCDD serum level at the time of conception

 

 

 

<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)

Studies Reviewed in Update 2000

Driscoll, 1998

Women employed by the US Forest Service—pregnancies ending in miscarriage

141

2.0 (1.1–3.5)

Studies Reviewed in VAO

Moses et al., 1984

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

14

0.9 (0.4–1.8)

Suskind and Hertzberg, 1984

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

69

0.9 (0.6–1.2)

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)

Townsend et al., 1982

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

85

1.0 (0.8–1.4)

Carmelli et al., 1981

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 aged 18–25 years Forest and commercial exposure

8

3.1 (0.9–9.6)

 

Exposure during conception period Father aged 31–35 years, farm exposure

10

2.9 (0.8–10.9)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

Eskenazi et al., 2003

Seveso (Italy) Women’s Health Study participants living in exposure Zones A and B in 1976

 

 

 

Spontaneous abortions in pregancies 1976–1998

97

0.8 (0.6–1.2)

 

Spontaneous abortions in pregancies 1976–1984

44

1.0 (0.6–1.6)

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia (maternal and paternal exposure)

*

24.4% (20.0–29.5%)b

 

Residents of surrounding towns in the Samara Region (maternal and paternal exposure)

 

 

 

Samara

*

15.2% (14.3–16.1%)b

 

Toliatti

*

10.6% (9.8–11.5%) b

 

Syzran

*

15.6% (13.4–18.1%)b

 

Novokuibyshevsk

*

16.9% (14.0–20.3%)b

 

Other small towns

*

11.3% (9.4–13.8%)b

Tuyet and Johansson, 2001

Vietnamese women who were or whose husbands were exposed to herbicides sprayed during the Vietnam war

*

(*) [anecdotal reports of miscarriage in pilot study]

Studies Reviewed in Update 2000

Axmon et al., 2000

Wives of Swedish fishermen Miscarriages and stillborn infants before week 12

 

0.5 (0.3–1.0)

 

East coast residents

12

(*)

 

West coast residents

54

(*)

Petrelli et al., 2000

Wives of pesticide appliers

26

3.8 (1.2–12.0)

VIETNAM VETERANS

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam-era veterans—spontaneous abortions or stillbirths

 

 

 

Vietnam veterans (1,665 pregnancies)

278

(*)

 

Vietnam-era veterans who did not serve in Vietnam (1,912 pregnancies)

317

(*)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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 (paternal exposure)

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

Aschengrau and Monson, 1989

Wives of Vietnam veterans presenting at Boston Hospital for Women

 

 

 

Spontaneous abortions through 27 weeks gestation

10

0.9 (0.4–1.9)

 

First-trimester (through 13 weeks gestation) spontaneous abortions only

*

1.2 (0.6–2.8)

CDC, 1989

Vietnam Experience Study (paternal exposure)

 

 

 

Overall

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)

Field and Kerr, 1988

Follow-up of Australian Vietnam veterans (paternal exposure)

195

1.6 (1.3–2.0)

Stellman et al., 1988

American Legionnaires who served in Southeast Asia 1961–1975 (paternal exposure)

 

 

 

Vietnam veterans compared to 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 to 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)

a Given when available.

b Spontaneous abortion rate per 100 full-term pregnancies for the years 1991–1997.

* 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.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

ing that perhaps if the pregnancies had not been ended voluntarily, they might have ended spontaneously). However, the rates of spontaneous abortion did not vary by exposure concentration of serum TCDD. If TCCD exposure were to increase preclinical early losses, the study could have missed the effect completely.

No relevant occupational or Vietnam-veteran studies have been published since Update 2002.

Synthesis

The only study reviewed for spontaneous abortion in relation to TCDD exposure did not reveal an association. The study of Eskenazi et al. (2003) reported on serum TCDD concentrations from the time of the Seveso accident for all study participants, carefully considered many potential confounders, and had a high participation rate. The outcomes and covariates related to pregnancy were all based on self-report, however, and on average they occurred 10 years after the pregnancy ended. In addition, although the range of exposures as measured by serum TCDD varied substantially within the study group, all women in the study had resided in the two most heavily contaminated areas in Seveso. It could be argued that more definitive results would have been produced if a truly unexposed control population had been included. Finally, because all spontaneous abortions were self-reported and referred to clinical loses, it could be hypothesized that the study does not rule out the possibility of a TCDD effect during the earliest period of gestation.

Conclusions

Strength of Evidence from Epidemiologic Studies

Additional information available to committee responsible for Update 2002 led that committee to note that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion, but that the information remained insufficient to determine whether an association exists between the risk of spontaneous abortion and maternal exposure to TCDD or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid. On the basis of its evaluation of the epidemiologic literature examining spontaneous abortion reviewed here and in previous VAO reports, the current committee concurs with the overall conclusion of the previous committees that the data are inadequate or insufficient to determine whether an association exists between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and the risk of spontaneous abortion.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Biologic Plausibility

Evidence from studies with laboratory animals suggests that TCDD can alter hormones after low-dose exposure and 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. Exposure to 2,4-D and 2,4,5-T causes fetal toxicity and lethality after maternal exposure in experimental animals. However, that effect occurs only at high doses and in the presence of maternal toxicity. No fetal toxicity or lethality has been reported to attend paternal exposure to 2,4-D.

A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and spontaneous abortion, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Stillbirth or late fetal death typically refers to the delivery at or after 20 weeks of gestation of a fetus that shows no signs of life; 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 28 days of birth.

Because the causes of stillbirth and early neonatal death overlap considerably, they are commonly analyzed together in a category, referred to as perinatal mortality (Kallen, 1988). Stillbirths occur in less than 1% of all births (CDC, 2000). The most common causes of perinatal mortality (Kallen, 1988) among low-birthweight (500–2,500 g) liveborn and stillborn infants are placental and delivery complications—abruptio placenta, placenta previa, malpresentation, and umbilical-cord complications. 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, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and stillbirth, neonatal death, or

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

infant death. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the relevant studies are presented in the earlier reports.

Update of the Scientific Literature

No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2002.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and stillbirth, neonatal death, or infant death.

Biologic Plausibility

Laboratory studies of the potential male-mediated developmental toxicity attributable to exposure to TCDD and herbicides in adult male animals are too limited to support conclusions.

A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and stillbirth, neonatal death, or infant death, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

BIRTHWEIGHT AND PRETERM DELIVERY

The World Health Organization recommends 2,500 g as the threshold determination for low birthweight (Alberman, 1984). Low infant weight at birth is among the important predictors of neonatal mortality and morbidity in the United States, and preterm delivery is a significant cause. The concept of low birthweight actually encompasses two 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 can have other long-term conse-

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

quences. 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 are low birthweight. The incidence of IUGR is much more difficult to quantify because there are no standards for distributing birthweight by gestational age. When no distinction is made between the causes of low birthweight (IUGR or PTD), the factors most strongly associated with reduced birthweight are maternal tobacco use during pregnancy, multiple births, and race or ethnicity. Other potential risk factors are 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; previous low birthweight or PTD; multiple gestations; tobacco use; and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest and low birthweight. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the relevant studies are presented in the earlier reports.

Update of Scientific Literature

Occupational Studies

Dabrowski et al. (2003) conducted a case–control study to examine birthweight in the offspring of women who were involved in farming for 7 or more days during pregnancy. The subjects were found originally at 25 maternity hospitals in the area of Lodz in central Poland. Sampling for the study was first cross-sectional and additional cases were added from 2 hospitals in other counties because the original group was small. In total, the study included 117 women who delivered low-birthweight infants (cases) and 377 women who delivered infants weighing at least 2,500 g (controls). Exposures were grouped by trimester, and because most women (83.6%) for whom pesticide exposure was reported for the first trimester also had exposure during the second trimester (95 women), those groups were combined. No significant differences were exhibited in the birthweights in the exposed and the non-exposed groups. The offspring of women who were exposed to phenoxyacetic acid derivatives during first or second trimester had a mean birthweight of 2,711 g (standard deviation [SD], 752); the

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

expected weight was 2,746 g (a difference of –35, p = 0.822). Pregnancy duration also was the same, with a mean of 38 weeks (SD, 2.5) in exposed women and in controls (p = 0.846). The study was limited by its retrospective nature; interviews were conducted after the birth by the physician. Although recall bias in favor of higher exposures among mothers of low birth weight infants is a potential problem in such studies, the bias usually tends to be away from the null, and hence does not explain the null finding.

Environmental Studies

Eskenazi et al. (2003) examined the association of TCDD exposure with reproductive outcomes among 510 SWHS participants. The women all had complete pregnancies within the 20 years after the accident. The analysis of birthweight and SGA was restricted to the 608 singleton live births (414 women). Exposure was based on individual TCDD serum measurements obtained from most women shortly after the explosion. Information on pregnancy outcomes and covariates was obtained by self-report in interviews conducted 20 years after the accident. The average length of recall between interview and pregnancy was 10.7 years.

Mean birthweight was 3,281 g, and there was a low-birth-weight (<2,500 g) rate of 5.1%. The mean gestational age was 39.4 weeks and a PTD rate of 4.9%; there were 59 (9.7%) SGA infants. There was no increase in association with serum TCDD concentrations after controlling for confounding factors. Overall, there was no decrease in birthweight with increasing serum TCDD (OR, -4 g; 95% CI, -68–60, for each 10-fold increase in maternal TCDD concentration). When the analysis was restricted to pregnancies that occurred during the first 8 years after the accident (corresponding to the first half-life of TCDD), there was a trend of decreased birthweight that was not statistically significant (adjusted OR, -92 g; 95% CI, -204–19). When data were analyzed for SGA, the results were consistent, with small, non-significant increases (OR, 1.2; 95% CI, 0.8–1.8 for the group; OR, 1.4; 95% CI, 0.6–2.9 for pregnancies in the earlier period). There was a similar trend for preterm births (<37 weeks of gestation) (OR, 1.3; 95% CI, 0.7–2.3 for the group as a whole, and OR = 1.5, CI, 0.7–3.2) for the earlier pregnancies). The results were slightly stronger for SGA when the analysis was confined further to first the post-explosion pregnancy (among women who had more than one pregnancy) during the earlier period, but they still did not reach statistical significance (OR, 1.8; 95% CI, 0.7–4.3).

The study presents individual serum TCDD concentrations, and outcome information based on personal interviews, on average 10 years after pregnancy. Recall biases therefore could affect the results, particularly if women suspected that their proximity to the plant could have adversely affected their pregnancies. Although they did not know their TCDD measurements at the time of the interview, zone of residence was positively associated with serum TCDD. The most

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

heavily exposed women were the youngest ones at the time of the explosion, and many of those younger women might not have had pregnancies by the time of enrollment in SWSH. Finally, the study included only those women who had resided closest to the Seveso plant (in zones A or B), and a totally unexposed control group was not available for comparison.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2002.

Synthesis

The study of reproductive outcomes among participants of the SWHS shows a small, non-significant association between maternal dioxin concentrations and decreased birthweight and prematurity among infants born during the 20 years after the explosion. Although the results could suggest an association, they should be interpreted with caution because of the possibility of recall and other biases. The study has several flaws: All information on pregnancy outcomes and covariates were obtained by self-report; the average recall time was more than 10 years after the pregnancy had ended; women living closest to the explosion might believe they were at greater risk of adverse pregnancy outcomes; about one-third of the pregnancies that began soon after the explosion were ended by elective abortion; no unexposed control group or measurement of background dioxin was included. Added to that list of uncertainties is a lack of statistical significance among the various outcomes investigated, despite the accurate measurements of exposure. Thus, no conclusion is possible with respect to a connection between dioxin exposures in the SWHS cohort and decreased birthweight or increased prematurity.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest 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. TCDD and herbicides are known to cross the placenta and lead to direct exposure of the fetus. Data from studies in experi-

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

mental animals also suggest that the preimplantation embryo and developing fetus are sensitive to the toxic effects of 2,4-D and TCDD after maternal exposure. However, the significance of those animal effects to humans is not clear.

A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and low birthweight, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

CHILDHOOD CANCER

The American Cancer Society estimated that 9,200 children under the age of 15 would be diagnosed with cancer in the United States in 2004 (ACS, 2004). Treatment and supportive care of children with cancer have greatly improved, and mortality rates have declined by 49% over the past 30 years. Despite those advances, cancer remains the leading cause of death from disease in children under the age of 15, and 1,510 deaths were projected for 2004 (ACS, 2004).

Leukemia is the most common cancer in children. It accounts for about one-third of all childhood cancer cases; nearly 2,760 children are expected to be diagnosed in 2004 (ACS, 2004). Of those, nearly 2,000 will be diagnosed with acute lymphocytic leukemia (ALL); most of the rest will have acute myelogenous leukemia (AML). AML (International Classification of Diseases, Ninth Edition [ICD-9] 205) also is commonly referred to as “acute myeloid leukemia” and “acute non-lymphocytic leukemia.” There are numerous subtypes of the disease. For consistency, this report uses acute myelogenous leukemia, or the abbreviation AML, regardless of usage in the source materials. ALL is most common in early childhood, peaking between the ages of 2 and 3, and AML is most common during the first 2 years of life. ALL incidence is consistently higher in boys than in girls; AML has a similar incidence rate in boys and girls (NCI, 2001). Through early adulthood, ALL rates are about twice as high in whites as in blacks; AML exhibits 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.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Summary of VAO, Update 1996, Update 1998, Update 2000 and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, 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 VAO 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 compounds of interest and AML. After the release of Update 2000, investigators from one study 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 summarizes the results of the relevant studies. The committees responsible for Update 2000 and Update 2002 reviewed the material in earlier VAO reports and in newly available published literature and agreed that there remained inadequate or insufficient evidence to determine an association between exposure and childhood cancers.

Update of Scientific Literature

As part of the Agricultural Health Study, Flower et al. (2004) examined childhood cancer in the offspring of male pesticide applicators in Iowa. Childhood cancer was defined as cancer diagnosed from birth through 19 years of age. The potential associations between pesticide exposure and individual types of cancer were not examined. Incidence was compared with the expected number of age-, sex-, race-, and time-period-specific cancer rates from Iowa Surveillance, Epidemiology, and End Result data. For maternal use of chlorophenoxy herbicides, there was a childhood cancer OR of 0.7 (95% CI, 0.3–1.5) based on 7 exposed cases. There was a higher rate of childhood cancers for paternal exposure to chlorophenoxy herbicides (OR, 1.3; 95% CI, 0.62–2.58) based on 28 exposed cases. Specifically, for 2,4-D, the OR was 0.7 (95% CI, 0.3–1.6) for maternal exposure based on 7 exposed cases. For paternal exposure, based on 6 exposed cases, the OR was 1.29 (95% CI, 0.71–2.35).

No relevant environmental or Vietnam-veteran studies have been published since Update 2002 (IOM, 2003).

Synthesis

The only new study reviewed for this update (Flower et al., 2004) does not show any significant association between the relevant exposures and childhood

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 7-5 Selected Epidemiologic Studies—Childhood Cancers

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Flower et al., 2004

Offspring of Male Pesticide Applicators in Iowa

 

 

 

Maternal exposure to chlorophenoxy herbicides

7

0.7 (0.3–1.5)

 

Paternal exposure to chlorophenoxy herbicides

28

1.3 (0.6–2.6)

 

Maternal exposure to 2,4-D

7

0.7 (0.3–1.6)

 

Paternal exposure to 2,4-D

6

1.3 (0.7–2.4)

Studies Reviewed in Update 2000

Heacock et al., 2000

Offspring of sawmill workers exposured to fungicides contaminated with PCDDs and PCDFs (paternal exposure)

 

 

 

Leukemia

 

 

 

All workers offspring—incidence

11

1.0 (0.5–1.8)

 

Offspring of workers with high chlorophenate exposure

5

0.8 (0.2–3.6)b

 

Brain cancer

 

 

 

All workers offspring—incidence

9

1.3 (0.6–2.5)

 

Offspring of workers with high chlorophenate exposure

5

1.5 (0.4–6.9)b

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

2.3 (p = .05)

 

AML in children with paternal exposure >1,000 days

17

2.7 (1.0–7.0)

 

AML in children with maternal exposure >1,000 days

7

undefined (no cases in controls)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

Studies Reviewed in Update 2002

Daniels et al., 2001

Neuroblastoma risk in children (case–control study)

 

 

 

Parents reported using pesticides in the home

*

1.6 (1.0–2.3)

 

Parents reported using herbicides in the home

*

1.9 (1.1–3.2)

 

Mother reported applying pesticides in the garden

*

2.2 (1.3–3.8)

Buckley et al., 2000

NHL diagnosed at the age of ≤ 20 years in children with potential prenatal exposure to herbicides

*

(*)c

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 Herbicide/Dioxin Exposure and AML in the Children of Veterans

Kristensen et al., 1996

Children of agricultural workers in Norway

 

 

 

Children with AML whose parents purchased pesticides

12

1.4 (0.6–2.9)

Studies Reviewed in Update 2000

Meinert et al., 2000

Childhood cancer—population-based case-control study

 

 

 

Leukemias

 

 

 

Paternal exposure; year before pregnancy

62

1.5 (1.1–2.2)

 

Paternal exposure; during pregnancy

57

1.6 (1.1–2.3)

 

Maternal exposure; year before pregnancy

19

2.1 (1.1–4.2)

 

Maternal exposure, during pregnancy

15

3.6 (1.5–8.8)

 

Lymphomas

 

 

 

Paternal exposure, year before pregnancy

11

1.5 (0.7–3.1)

 

Paternal exposure, during pregnancy

10

1.6 (0.7–3.6)

 

Maternal exposure, year before pregnancy

3

2.9 (0.7–13)

 

Maternal exposure, during pregnancy

4

11.8 (2.2–64)

Pearce and Parker, 2000

Kidney cancer in subjects (1–15 yrs) whose father listed an agricultural occupation on the child’s death certificate

21

0.9 (0.2–3.8)

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Infante-Rivard et al., 1999

Childhood ALL in households using herbicides during the pregnancy (in utero exposure, others not excluded)—population-based case-control study

118

1.8 (1.3–2.6)

Studies Reviewed in Update 1996

Pesatori et al., 1993

Seveso residents aged 0–19 years—10-year follow-up, morbidity, all exposure zones

 

 

 

All cancers

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 aged 0–19 years—10-year follow-up, mortality, all exposure zones

 

 

 

All cancers

10

7.9 (3.8–13.6)

 

Leukemias

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 Herbicide/Dioxin Exposure and AML in the Children of Veterans

AIHW, 2001

Australian Vietnam veterans’ children—Revised Validation Study

 

 

 

AML

12d

1.3 (0.8–4.0)

Studies Reviewed in Update 2000

AIHW, 2000

Australian Vietnam veterans’ children—Validation Study

 

 

 

AML

This study, which incorrectly calculated the expected number of AML cases, is superceded by AIHW, 2001 above.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

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—outcomes in the offspring of veterans (paternal exposure)

 

 

 

Cancer

25

1.5 (0.7–2.8)

 

Leukemia

12

1.6 (0.6–4.0)

Field and Kerr, 1988

Cancer in children of Australian Vietnam veterans (paternal exposure)

4

(*)

Erickson et al, 1984b

CDC Birth Defects Study—children of Vietnam veterans (paternal exposure)

 

 

 

“Other” neoplasms

87

1.8 (1.0–3.3)

a Given when available.

b OR estimated using low exposure subjects as the comparison cohort.

c No information on herbicides as a class, distinct from insecticides or other pesticides, was available; exposures before conception were not singled out, and no distinction between maternal and paternal exposure was made.

d Of the 12, 9 were observed and 3 additional cases were estimated to have occurred in the portion of the cohort whose data were not validated.

* 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; SS, statistically significant.

cancer. The lack of significance could be attributable to the very small number of cases and the attendant lack of statistical power.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

insufficient evidence of an association between exposure to the compounds of interest and childhood cancers.

Biologic Plausibility

Susceptibility to cancers in childhood after environmental exposures could be influenced by several factors, one of which is that a child could 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 during infancy or early childhood either directly or through breast milk. TCDD and dioxin-like compounds cross the placenta and are present in breast milk, so a pathway of exposure is demonstrated. Some data suggest that the effects of TCDD and dioxin-like compounds with estrogen like activity persist beyond childhood, even into adult life. For example, recent work indicates that animals exposed in utero to TCDD become more susceptible to mammary cancers induced by some polycyclic aromatic hydrocarbons but that the timing of exposure to TCDD is likely important for the development of malignancies.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and childhood cancers, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

SEX RATIO

Sex ratio (males to females at birth)—about 106 males per 100 females (Pyeritz, 1998), or about 51% males among all births—has been used as a potential marker of genetic damage. It has been hypothesized that the induction of lethal mutations before birth could alter sex ratio. For instance, a lethal mutation on the paternal X chromosome would differentially affect female conceptuses. For some years, investigators have evaluated the sex ratio among various species in relation to such exposures as radiation. More recently, it has been suggested that the ratio is controlled by parental hormones at conception and that changes in gonadotropin and steroid concentrations could exert an effect (James, 1996). The specific mechanisms, such as zygote formation, implantation, regulation of sex-determining factors, and selective fetal loss, are not clear, and direct experimental evidence to support or refute the hypothesis is lacking. James (1997) suggested that a reduction in testosterone and high gonadotropin after TCDD exposure would result in an excess of female offspring. Potential confounding factors for

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

an altered sex ratio are uncertain, but parental age, social class, illness, race, tobacco use, and stress have been considered.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The potential association between exposure to 2,4-D, 2,4,5-T, 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, Update 2000, and Update 2002 reviewed papers addressing altered sex ratio as part of their examination of literature on fertility. There was inadequate or insufficient information to determine an association between exposure to the compounds of interest and sex ratio. The relevant studies are summarized in Table 7-6.

Update of Scientific Literature

Ryan et al. (2002) studied the sex ratio of children of workers at agrochemical plants in Ufa, Bashkortostan, Russia. More than 650 workers produced the 2,4,5-trichlorophenol (TrCP) from 1961 to 1988, and more than 250 others produced 2,4,5-T from 1964 to 1967. Blood samples from 29 and 55 individuals from these two groups, respectively, were analyzed for TCDD and other dioxins. The median of toxic equivalent values over both cohorts was 243 ppt, with a range of 17–8,520 ppt. The concentrations were generally higher among the TrCP workers (median, 672 ppt) than in the 2,4,5-T workers (median, 177 ppt).

Information about the workers and their children was obtained from company archival records and later verified in personal or telephone interviews with the workers or with close relatives. Birth data were available for 110 and 88 workers, respectively, from the TrCP and 2,4,5-T groups. Only children born at least 9 months after the start of relevant employment (but including any who were deceased) were used in analysis. The sex ratio for the city of Ufa, estimated at 0.512 from data supplied by the State Regional Statistical Department of the Republic of Bashkortostan, was used as a basis for comparison. Statistical analysis was conducted via z-test for ratios and χ-square analysis of contingency. The two cohorts (2,4,5-T and TrCP) were analyzed separately and in combination. Comparisons were made for fathers and mothers separately (15 and 30% of the workers were females in the 2,4,5-T and TrCP groups, respectively) and for all parents combined. The sex ratio for the combined cohorts was 0.40 (z, 3.21, p < 0.001), indicating a significant excess of female births. Despite the comparable degree of exposure for fathers and mothers, that significant excess in female births was higher when only fathers were exposed (sex ratio, 0.38; z, 3.60, p < 0.001), and virtually nonexistent when the mothers alone were exposed (sex ratio, 0.51, not significant [NS]).

No relevant environmental or Vietnam-veteran studies have been published since Update 2002 (IOM, 2003).

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 7-6 Selected Epidemiologic Studies—Sex Ratio

Reference

Study Population

Sex Ratio of Offspring (boys/total)a

Comments

OCCUPATIONAL

New Studiesb

Ryan et al., 2002

Workers manufacturing 2,4,5,-trichlorophenol (1961–1988) or 2,4,5-T production (1964–1967)

0.40 (91 boys: 136 girls)

0.38 (71 boys: 117 girls)

0.51 (20 boys: 19 girls)

p < 0.001, either parent exposed; p < 0.001, only father exposed; NS, only mother exposed

Studies Reviewed in Update 2002

Schnorr et al., 2001

Workers producing trichlorophenol and derivatives, including 2,4,5-T: exposed

0.53 vs 0.54

NS overall; no difference on basis of age fathers vs unexposed at first exposure

Okubo et al., 2000

Japanese workers exposed to dicyclopentadiene, cyclopentadiene, epoxy resin, bisphenol A epichlorohydrin vs Japanese population

0.25 (6 boys: 18 girls)

p < 0.01

Moshammer and Neuberger, 2000

Austrian chloracne cohort (children born after start TCDD exposure in 1971 vs children born before 1971)

0.46 (26 boys: 30 girls) vs 0.70 (19 boys: 12 girls)

Fewer sons, especially if father was <20 yr when exposed (0.20 for 1 boy: 4 girls)

Savitz et al., 1997

Ontario Farm Family Health Study: fathers with “chemical activity” vs “no chemical activity” vs “no farm activity” during 3 mo before conception (some phenoxy herbicides)

 

NS overall; lower sex ratio if use of protective equipment not reported

Studies Reviewed in Update 1998

Heacock et al., 1998

Sawmill workers in British Columbia

0.515

Chlorophenate-exposed workers;

 

0.519

Unexposed workers;

0.512

Province overall

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Sex Ratio of Offspring (boys/total)a

Comments

ENVIRONMENTAL

Studies Reviewed in Update 2002

Karmaus et al., 2002

Michigan fish-eaters (serum PCBs and DDE levels)

>0.5

Significantly more sons, if paternal blood level PCBs >8.1 µg/L;

 

 

<0.5

NS more daughters, if maternal blood level PCBs >8.1 µg/L

Yoshimura et al., 2001

Births 1967–1977 among individuals exposed to PCBs and PCDFs in Yusho, Japan, in 1968

 

NS

Revich et al., 2001

Residents near chemical plant in Chapaevsk, Russia

0.5

0.4

0.6

1983-1997 min, 1989 max, 1987 and 1995

Studies Reviewed in Update 2000

Mocarelli et al., 2000

Individuals aged 3 to 45 and in Zones A, B, or R at time of Seveso accident

0.4

Father exposed (especially if had been <19 yr)

 

0.6

Only mother exposed

0.6

Neither parent exposed

Studies Reviewed in Update 1998

Mocarelli et al., 1996

Seveso—sex ratio of births in Zone A (1977–1984)

SR = 0.35 (26 boys: 48 girls)

p < 0.001

VIETNAM VETERANS

Studies Reviewed in Update 2000

Michalek et al., 1998b

Sex ratio of births to Ranch Hand personnel (high, low, or background dioxin level) vs other servicemen

 

SR higher for higher dioxin levels

a Given when available.

b VAO-series reports prior to Veterans and Agent Orange: Update 1998 did not address the association between to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and perturbations in the sex ratio of offspring.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: NS, not significant; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; TCDD, tetrachlorodibenzo-p-dioxin.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Synthesis

Despite some strengths, including the use of blood samples, and its obvious relevance to the charge of this committee, the study by Ryan et al. (2002) had several limitations. Samples were obtained many years after initial exposure, and no attempt was made to extrapolate concentrations at the time of employment. TCDD might be a strong candidate for explaining the altered sex ratios, but other compounds (perhaps with a shorter half-life) cannot be ruled out. The authors’ assertion that the hypothesis that youth at the time of exposure is an important factor could not be tested because “the mean age of the parents at the birth of their children was about 29 (range 20–43) years,” but the parents’ ages at the time of first exposure would be critical information for assessing the hypothesis. The nature of the analysis in the study did not allow for covariate adjustments for confounders or for effect modification. The results are similar to those observed for the Seveso population (Mocarelli et al., 1996, 2000, as reviewed in Update 1998 and Update 2000), but different from those reported for the US chlorophenol cohort (Schnorr et al., 2001, as reviewed in Update 2002).

Biologic Plausibility

There has been no work with experimental animals that specifically examined the effects of TCDD on sex ratios of offspring, nor have any alterations in sex ratio been reported for animal studies that have examined developmental effects of TCDD on offspring. However, several publications have suggested mechanisms by which an altered sex ratio might occur. James (2002), argued that paternal exposure to organochlorines could have different effects on sex ratios than does maternal exposure; because paternal and maternal exposures can lead to opposite effects on sex ratios, there could be confounding; and the effects of some organochlorines should be examined more closely because some could exhibit estrogenic behavior, whereas others could show antiestrogenic or antiandrogenic behavior. He also suggests that mammalian sex ratios depend partly on hormone concentrations in both parents around the time of conception: Low parental testosterone and high gonadotropin is associated with a higher prevalence of daughters. Numerous animal studies have shown that dioxin disrupts the production of several hormones and that it modulates hormone-dependent pathways, including those involved in reproduction (see Chapter 3). It is plausible that similar effects could disrupt the hormones that affect sex ratio.

Jongbloet et al. (2002) pointed out that experimental data are consistent with the possibility that the antiandrogenic effects of dioxin on male sperm (after paternal exposure) alter sperm transit time and mating behavior, causing fertilization of an “over-ripe” oocyte and leading to a reduced number of male progeny. Furthermore, the antiestrogenic properties of dioxin at the midcycle (after mater-

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

nal exposure) could result in preferential fertilization of non-optimally matured oocytes by Y-bearing sperm, thus resulting in more male offspring.

To have a better understanding of the issues involved, James (2002) suggested several lines of research focusing on closer examination of specific contaminants or congeners that could be associated with different exposure; endocrinologic assays of exposed women with different exposures, to study the hormonal profiles; and animal studies to obtain more decisive data on the effects of dioxin exposure on sex ratios under defined experimental conditions.

The above mechanisms are based on sex as determined by the chromosomal constitution of the fetus. The hormonal environment of the mother during gestation also might modify expression of developing genitalia, which are the likely basis of assignment of sex to children at birth. That would not, however, correspond to the tendency for any suggestive observed effects to be associated with paternal exposure.

SUMMARY

Strength of the Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, 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; altered sex ratio; and childhood cancers. There is limited or suggestive evidence for an association between spina bifida and exposure to the compounds of interest.

Overall Biologic Plausibility for Reproductive and Hormonal Effects

This section summarizes the general biologic plausibility of a connection between exposure to the compounds of interest 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 reproductive and developmental effects in laboratory animals. Effects on male and female reproductive organs are not always accompanied by adverse reproductive outcomes. The administration of TCDD to male animals elicits reproductive toxicity by affecting testicular and seminal vesicle weight and function and by decreasing the rate of sperm production. The mechanisms of those effects are not known, but a primary hypothesis is that they are mediated through effects on hormones. Exposure to TCDD has been accompanied by decreased concentrations of hormones such as gonadotropin and testosterone, which regulate sperm production. However, high doses of TCDD are required to elicit many of those effects. Furthermore, TCDD-exposed male rats

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

were able to sire viable fetuses. Many studies have examined the effects of TCDD on the female reproductive system. Abnormal follicle development and decreased numbers of ova have been observed. Although oocytes appear to be directly responsive to TCDD, effects on hormones, their metabolism, and the ability of hormones to act within the ovaries also are likely contributors to those effects. A recent study indicates that exposure of mice to TCDD during pregnancy disrupts mammary gland differentiation and lactation. 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 suggest that exposure to TCDD in utero could affect the body weight of newborn humans.

TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that coexposure with either of two other compounds, hydro-cortisone or retinoic acid, synergistically enhances expression of cleft palate. The synergy suggests that the pathways controlled by those 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. Some evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. Cytochrome P450 1A1 induction or alterations in pathways controlled by vascular endothelial growth factor might mediate the early lesions that result in TCDD-related vascular derangements. That antioxidant treatment provides protection against TCDD-induced embryo-toxicity in some systems suggests that reactive oxygen species might be involved in the teratogenic effects of exposure to TCDD. Several reports of studies in exposed animals and humans suggest that low perinatal exposure to TCDD and 2,4-D could impair brain development. Outcomes can be subtle, ranging from altered learning and memory to modified sex-related behavior. The mechanisms of those effects are unclear.

Studies in several rodent species show that administration of a single maternal dose of TCDD produces malformations of the external genitalia and functional reproductive alterations in female progeny, including decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and disrupted estrus cycles. 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 produced 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

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

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, decreasing prostatic dihydrotestosterone concentrations, or interfering with androgen-signaling pathways. In utero exposure to TCDD also caused decreased seminal vesicle weight and branching, and it decreased sperm production and increased sperm transit time in male offspring.

Studies in female offspring of TCDD-exposed dams are few but demonstrate that in utero and lactational exposure can reduce fertility, decrease the ability to carry pregnancy to term, decrease litter size, increase fetal death, impair ovarian function, and decrease concentrations of estradiol and progesterone. Most of those effects could occur as a result of TCDD’s general toxicity to the pregnant dam, however, and not as the result of any TCDD-specific mechanism. TCDD also induces changes in serum concentrations of reproductive hormones in immature female rats given TCDD by gastric intubation, partly because of the action of TCDD on the pituitary gland. As indicated above, some effects observed in the fetuses or offspring from TCDD-treated dams may be due to toxicity to the dams. However, it is clear that many effects of TCDD on development also occur at doses where there is no overt maternal toxicity.

The mechanism by which TCDD could exert reproductive and developmental effects is not established. Although the types of developmental effects reported in numerous toxicology experiments have been observed in highly exposed human populations, extrapolating results from animals to humans is difficult, because the factors that determine susceptibility to reproductive and developmental effects vary among species. TCDD has a variety of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; those effects in turn could lead to reproductive or developmental toxicity.

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 to lead to changes in transcription; that is, to genes that are differentially regulated. Modulation of those genes could alter cell function.

Although structural differences in the AhR have been identified among species, it operates similarly 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 for 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. However, biologic plausibility for effects of TCDD on development in humans is also supported by several studies reporting effects on children exposed in utero to PCBs containing dioxin-like compounds. Furthermore, some of these effects were reported to occur at near background levels of exposure.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Little information is available on the reproductive and developmental effects of exposure to 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 was reduced, and their mortality increased (Charles et al., 1999); very high doses of 2,4-D and 2,4-DB were required to elicit those effects. Exposure to 2,4-D also alters 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. Picloram alone could 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, 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; by the lack of strong evidence of organ-specific effects among species; and by differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they have subcellular effects 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 those 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 can be used to predict human health outcomes and about the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure. The investigation of the biologic mechanisms that underlie TCDD’s toxic effects continues to be an active field of research, and updates of this report could have more and better information on which to base conclusions, at least for TCDD.

Suggested Citation:"7 Reproductive and Developmental Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Increased Risk of Disease Among Vietnam Veterans

The lack of data supporting an association of reproductive and developmental effects with exposure to the chemicals of interest, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

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