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Veterans and Agent Orange: Update 2000 (2001)

Chapter: 8 Reproductive Effects

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Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

8
Reproductive Effects

INTRODUCTION

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) on exposure to herbicides and adverse reproductive or developmental effects. The literature includes papers describing environmental, occupational, and Vietnam veteran studies that evaluated herbicide exposure and the risk of adverse outcomes, including spontaneous abortion, birth defects, stillbirths, neonatal and infant mortality, childhood cancer, low birthweight, and sperm quality and infertility. Besides studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) are also reviewed when relevant, since TCDD is a ubiquitous contaminant of PCBs.

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

In addition to studies of specific health and developmental outcomes associated with reproduction, there have been several reports investigating reproductive hormones in relation to exposures to TCDD or related compounds such as PCBs, which are contaminated with TCDD when they occur in the human environment. Sweeney et al. (1998) measured several reproductive hormones, namely serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in workers exposed to TCDD through their involvement in chemical pro-

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

duction. These authors found that among 479 male workers, as the serum concentration of 2,3,7,8-TCDD increased, so did the odds of having a high level of LH or FSH; the odds of having a low testosterone level also increased with the concentration of TCDD. A study of women from Seveso is in progress (Eskenazi et al., 2000). This investigation will examine serum TCDD concentration in relation to (1) endometriosis, (2) menstrual cycle characteristics, (3) age at menarche, (4) birth outcomes, (5) time to conception and infertility, and (6) age at menopause.

The following specific categories of reproductive effects have been reviewed in previous Veterans and Agent Orange (VAO) reports (IOM, 1994, 1996, 1999): fertility, sex ratio, spontaneous abortion, stillbirth and infant mortality, low birthweight and preterm delivery, and birth defects. New data since Update 1998 are available for spontaneous abortion, sex ratio, birth defects, childhood cancer, low birthweight, and early postnatal growth.

BIRTH DEFECTS

Background

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 with birth defects are “congenital anomalies” and “congenital malformations.” Major birth defects are usually defined as those abnormalities that are present at birth and severe enough to interfere with viability or physical well-being. Major birth defects are seen in approximately 2 to 3 percent of live births. An additional 5 percent of birth defects can be detected with follow-up through the first year of life. The cause of most birth defects is unknown. In addition to genetic factors, a number of other factors and exposures including medication, environmental, occupational, and life-style have long been implicated in the etiology of some birth defects (Kalter and Warkany, 1983). Historically, most etiologic research focused on the effect of maternal and fetal exposures, but work on paternal exposures is receiving increased attention. Paternal exposures could exert an effect through direct genetic damage to the male germ cell that is transmitted to the offspring and expressed as a birth defect; through transfer of chemicals via seminal fluid, with subsequent fetal exposure; or by indirect exposure from household contamination.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and birth defects among

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

offspring. Additional information available to the committee responsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association between the exposures and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. There was no change in these findings in Update 1998. Reviews of the studies underlying these findings may be found in the earlier reports.

Update of the Scientific Literature

Garcia et al. (1998) conducted a case-control study based on births in eight hospitals located in agricultural areas in Spain. Cases consisted of infants with any of the following malformations: nervous system defects, cardiovascular defects, epispadias or hypospadias, musculoskeletal defects, and unspecified defects. Some cases fell into more than one group. Controls were matched (1:1) with cases by hospital and date of birth. Interviews were conducted with parents of the cases and controls by telephone where possible and inperson otherwise. The questions covered potential confounders and activities that would involve potential exposure to pesticides. The critical exposure period for fathers was considered to be 3 months before conception through the first trimester of pregnancy, and for mothers, 1 month before conception through the first trimester. Interviewees who were involved in agricultural activities during this critical period were interviewed a second time to collect detailed information about their work and their potential exposures. Reliability and accuracy were assessed by gathering information from several sources, including employers and previously completed questionnaires. Several experts independently reviewed the interview information on exposures, and when discrepancies arose, a meeting was held to reach consensus. Overall, the adjusted odds ratio (OR) was 0.9 (95 percent confidence interval [95% CI] 0.3–2.7) for exposure to organochlorines. 2-Methyl-4-chlorophenoxyacetic acid (MCPA), a chlorophenoxy herbicide, showed an adjusted OR of 1.2 (0.4–3.8). When analyzed by a semiquantitative scale based on probability and intensity of exposure, the highest category of exposure to chlorophenoxy herbicides, compared to no exposure, showed an adjusted OR of 2.1 (0.5–9.8); the OR for MCPA was 2.6 (0.4–17.1). When analyzed according to an index based on months of work in agriculture and intensity of exposure, chlorophenoxy herbicides above the median had an OR of 3.1 (0.6–16.9), while for MCPA, the OR was 3.5 (0.6–21.8). When analyzed for involvement in pesticide treatments, those above the median level of exposure to chlorophenoxy herbicides had an OR of 0.6 (0.1–2.9), and a similar OR was seen for MCPA. Overall, this study provides little evidence for an association between herbicides chemically related to or potentially contaminated by TCDD and the risk of nervous system, cardiovascular, genital, musculoskeletal, or unspecified defects. However, because of the small number of exposed cases (N=21), the statistical power and precision were poor.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

In July 1998, the National Technical Information Service (NTIS) released a report that was apparently completed in 1984 regarding reproductive outcomes in Air Force personnel exposed to herbicides (Michalek et al., 1998a). The data concern the Ranch Hand cohort and a corresponding comparison group; comparisons are made for conceptions taking place in two time periods: pre- and post-Southeast Asia. The fathers were interviewed, and their reports of birth defects in their children were verified by reviewing birth and other medical records and birth and death certificates. The most common defects were of the musculoskeletal and the circulatory systems. About one-third of the reported defects had not been verified; this percentage was equal for Ranch Hands and comparisons. The analysis used only verified defects. No verification had been conducted for those responding that their children had no defects. In the pre-Southeast Asia period, those in the Ranch Hand group had a lower percentage of children with birth defects than the comparison group (OR=0.7). In the post-Southeast Asia period, the percentage of children with birth defects was higher (OR=1.5). These were significantly different; however, after adjustment for occupation; the test for homogeneity gave a p-value of 0.6. The differences between Ranch Hands and comparisons were found for the enlisted flying and enlisted ground crews but not for officers. When stratified by smoking, the strongest differences were found among children whose mothers smoked. Overall, this study suggests a possible association between service in Southeast Asia and birth defects but is limited because of the low verification of reported birth defects and the lack of verification of reports of no defects. The use of a heterogeneous group of defects could have reduced statistical power if exposure were associated with malformations in one system or of one type only.

The Australian Vietnam veterans Validation Study also examined spina bifida in the offspring of male Vietnam veterans (AIHW, 1999). In this study, an attempt was made to validate self-reported medical conditions. For each condition or disease, medical documents, physician certification, and records on disease or death registers were used. Three categories were created: (1) a condition was considered “validated” if sufficient information was found that confirmed the existence of the condition; (2) a condition was considered “not validated” if information from the validation source indicated that the condition did not or had not existed to the best of its knowledge; (3) a condition was considered “not able to be validated” when the source could not be contacted or accessed, or the source indicated was not able to confirm or deny the existence of the condition. The study made an adjustment to estimate the number that fell in the third category but would be expected to be validated based on information in reports in the first two categories. A total of 34 spina bifida cases were validated, and the adjustment brought this figure to an estimated 50. The expected number of cases, for comparison, was 33, for which a CI of 22–44 is given in the report. Thus, there appears to be a significant excess of spina bifida cases in children born to Australian Vietnam veterans. Cleft palate also showed an excess, with 94 estimated validated conditions, where 64 were expected.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Conclusions

Strength of Evidence in Epidemiologic Studies

The committee continues to believe that the available scientific literature provides limited/suggestive evidence of an association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and spina bifida in offspring. The Australian veterans Validation Study lends further support to this conclusion. Given the limitations in this study, including the extrapolation of validation rates to cases with inadequate data, the information available is not strong enough to reclassify this outcome in the category of “sufficient evidence.”

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and other birth defects.

Biologic Plausibility

Laboratory studies of potential male-mediated developmental toxicity of TCDD and herbicides, specifically with regard to birth defects, are too limited to permit conclusions. Research on chemical production workers with TCDD exposure suggests that some hormonal changes are associated with such exposure, but it is unclear whether these changes could be responsible for an increase in spina bifida or other birth defects.

A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The new data from the Validation Study of Australian Vietnam veterans provides further evidence of an elevated risk for spina bifida among the offspring of men who served in Vietnam. Other data that have come to the attention of the committee are contained in a report from the Air Force Health Study, which indicates that among children conceived after service in Southeast Asia, birth defects may have been greater in the Ranch Hand group than in the comparison group. However, about one-third of reported birth defects were of unknown verification status, severely limiting the conclusions that can be drawn. Thus, the previous conclusion that there is limited/suggestive evidence for an increased risk of spina bifida among offspring of Vietnam veterans remains, but there are no changes with regard to other birth defects.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 8-1 Selected Epidemiologic Studies—Neural Tube Defects

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies reviewed in Update 1998

Blatter et al., 1997

Offspring of Dutch farmers—spina bifida

 

Pesticide use (moderate or heavy exposure)

9

1.7 (0.7–4.0)

 

Herbicide use (moderate or heavy exposure)

7

1.6 (0.6–4.0)

Kristensen et al., 1997

Offspring of Norwegian farmers—spina bifida

 

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

 

Spina bifida or anencephaly

22b

2.4 (1.1–5.3)

 

Spina bifida

18b

1.8 (0.8–4.1)

Garry et al., 1996

Private pesticide appliers

 

Central nervous system defects

6

1.1 (0.5–2.4)

ENVIRONMENTALc

Studies Reviewed in VAO

Stockbauer et al., 1988

TCDD soil contamination in Missouri

 

Central nervous system defects

3

3.0 (0.3–35.9)

Hanify et al., 1981

Spraying of 2,4, 5-T in New Zealand

 

Anencephaly

10

1.4 (0.6–3.3)

 

Spina bifida

13

1.1 (0.6–2.3)

VIETNAM VETERANS

New Studies

AIHW, 1999

Australian Vietnam veterans—Validation Study (spina bifida)

50

1.5 (NR)

Studies Reviewed in Update 1996

Wolfe et al., 1995

Follow-up of Air Force Ranch Hands

 

Neural tube defects among Ranch Hands childrend

4

 

 

Neural tube defects among comparison children

0

 

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study

 

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

 

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Erickson et al., 1984a, b

Birth Defects Study

 

Vietnam veterans: spina bifida

19

1.1 (0.6–1.7)

 

Vietnam veterans: anencephaly

12

0.9 (0.5–1.7)

 

EOI-5: spina bifida

19e

2.7 (1.2–6.2)

 

EOI-5: anencephaly

7e

0.7 (0.2–2.8)

Australia Department of Veteran Affairs, 1983

Australian Vietnam veterans—Neural tube defects

16

0.9

NOTE: EOI=score based on interview; NR=not reported; 2,4,5-T=2,4,5-trichlorophenoxyacetic acid.

aGiven when available.

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

cEither or both parents potentially exposed.

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

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

FERTILITY

Background

Male reproductive function is a complex system under the control of several components whose proper coordination is important for normal fertility. There are several components or end points related to male fertility, including reproductive hormones and sperm parameters. Only a brief description of male reproductive hormones is given here; more detailed reviews can be found elsewhere (Yen and Jaffe, 1991; Knobil et al., 1994). The reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates gonadotropins (luteinizing hormone and follicle-stimulating hormone). Both of these hormones are necessary for normal spermatogenesis. Luteinizing hormone and follicle-stimulating hormone are secreted in episodic bursts by the anterior pituitary gland into the circulation. LH interacts with receptors on the Leydig cells, which leads to increased testosterone synthesis. FSH and testosterone from the Leydig cells interact with the Sertoli cells in the seminiferous tubule epithelium to regulate spermatogenesis. Several agents, such

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

as lead and dibromochloropropane, have been shown to affect the neuroendocrine system and spermatogenesis (Bonde and Giwercman, 1995; Tas et al., 1996).

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and altered sperm parameters or infertility. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports.

Update of the Scientific Literature

A few new studies have appeared in the literature in relation to fertility. A study of Danish farmers compared those who used pesticides with those who did not in relation to the “fecundability ratio (FR)” (Larsen et al., 1998). This ratio represents a means of assessing how long it takes a sexually active couple to achieve a pregnancy while not using any form of contraceptive. A low FR (i.e., an FR less than 1.0) suggests that it takes longer for the exposed group to achieve pregnancy. In this study, the farmers were questioned about their use of pesticides during the year before their youngest child was born. A specific list of pesticides with potential for spermatotoxicity was presented, which included 2,4-dichlorophenoxyacetic acid (2,4-D), benomyl, carbendazim, iprodione, isoproturon, atrazine, chlormequat chloride, glyphosate, deltamethrin, fenvalerate, dimethoate, mancozeb, manep, and dinoseb. Several variables were constructed that reflected farm practices known to be associated with exposure levels. Those exposed to pesticides at the start of unprotected coitus had similar fecundability to those who were not (i.e., pregnancies occurred at a similar rate for the two groups [FR=1.0, 0.8–1.4]). A tendency toward reduced fecundability was observed for those who used three or more pesticides with spermatotoxic effects (FR=0.9, 0.7–1.2), and similarly for those using a manually controlled sprayer (FR=0.8, 0.6–1.1). The main weaknesses of the study were the relatively small number who were not using pesticides, the use of self-reported recall of pesticide use, and for the purposes of this report, the lack of information on TCDD level as a contaminant of the pesticides investigated. It should also be noted that studies limited to couples who achieve a pregnancy can be biased, because the most severe cases, those who are infertile, are excluded (Sallmén et al., 2000).

Abell et al. (2000) also report on fecundability, in an investigation of female greenhouse workers in Denmark. The study compared women members of the gardener’s trade union who were employed in flower greenhouses with other

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

members of the union and also evaluated different work activities or the use of protective gloves. Although it did not take longer for the flower greenhouse workers to become pregnant, those with higher exposures to pesticides did take longer. The FR was 0.7 (0.5–1.0) for those with more than 20 hours contact compared to those with less than 20 hours contact, 0.7 (0.5–1.0) for those who never used gloves versus those who used them always, and 0.6 (0.5–0.9) for those with high exposure based on several work practices versus those with low exposure. However, data on specific pesticide exposures or on TCDD contamination of such pesticides were not available.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and altered hormone levels, decreased sperm count or quality, subfertility, or infertility.

Biologic Plausibility

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

A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

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

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 8-2 Selected Epidemiologic Studies—Fertility

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Abell et al., 2000b

Female greenhouse workers in Denmark >20 hours manual contact per week

220

0.7 (0.5–1.0)

 

Never used gloves

156

0.7 (0.5–1.0)

 

High exposure

202

0.6 (0.5–0.9)

Larsen et al., 1998b

Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D

523

1.0 (0.8–1.4)

 

Used three or more pesticides

 

0.9 (0.7–1.2)

 

Used manual sprayer

 

0.8 (0.6–1.1)

Studies Reviewed in Update 1998

Heacock et al., 1998

Workers at sawmills using chlorophenates

18,016 (births)

0.9 (0.8–0.9)

 

Workers at sawmills using chlorophenates

18,016

0.7 (0.7–0.8)c

 

Cumulative exposure (hours)

 

120–1,999

7,139

0.8 (0.8–0.9)

 

2,000–3,999

4,582

0.9 (0.8–0.9)

 

4,000–9,999

4,145

1.0 (0.9–1.1)

 

≥10,000

1,300

1.1 (0.9–1.2)

Studies Reviewed in Update 1996

Henriksen et al., 1996

Ranch Hands

 

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)

 

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)

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study

 

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

 

Difficulty having children

349

1.3 (p< .01)

aGiven when available.

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

cStandardized fertility ratio.

SPONTANEOUS ABORTION

Background

Spontaneous abortion refers to the expulsion of a nonviable fetus, generally before 20 weeks of gestation, not induced through physical or pharmacologic means. The background risk for recognized spontaneous abortion is generally around 7–15 percent (Hertz-Picciotto and Samuels, 1988), although it is established that many more pregnancies terminate before the woman is aware that she has become pregnant (Wilcox et al., 1988); the latter are known as subclinical pregnancy losses. Estimates of the risk of recognized spontaneous abortion will vary according to the design and method of analysis. Major types of study designs include cohorts of women asked retrospectively about their pregnancy history, cohorts of pregnant women, usually those receiving prenatal care, and cohorts of women who are monitored for future pregnancies. Retrospective reports may be limited by memory loss, particularly of spontaneous abortions that took place a long time before. Studies enrolling women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for the varying times during pregnancy when women seek medical care. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but because of very demanding protocols, this may attract nonrepresentative study groups.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and spontaneous abortion. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports.

Update of the Scientific Literature

A survey of women employed by the U.S. Forest Service assessed job exposures and reproductive outcomes (Driscoll, 1998). A mail questionnaire was sent to more than 10,000 women aged 18–52 who were full-time employees with at least a year of service. The questionnaire collected information on job duties and reproductive histories for a 10-year period. Questions inquired about use of herbicides, pesticides, and specific paints, as well as potential confounders including smoking, alcohol, hobbies, home pesticide applications, and so forth. A 59 percent response rate was achieved. The initial analysis showed foresters to have a greater proportion of pregnancies ending in miscarriage (18 percent) than non-foresters (14 percent), with an adjusted OR of 1.4 (1.1–1.9). When analyses were conducted for specific work exposures and adjusted for maternal age, self-reported strenuous work, smoking, and alcohol consumption, use of herbicides was associated with an increased risk of spontaneous abortion, OR=2.0 (1.1–3.5). The primary weaknesses of this study were the low response rate with consequent possible selection bias and the lack of information regarding specific herbicides used.

Petrelli et al. (2000) conducted a small study of pregnancies among wives of pesticide appliers. Fifty-one workers were engaged in mixing pesticides manually, then applying them, with applications occurring for 6 hours daily. A comparison group consisted of food retailers, who had no direct exposure to pesticides through work or hobbies. Reproductive histories were collected by interviews. Pesticide appliers reported a greater proportion of spontaneous abortions among their wives’ pregnancies, but the men were also less educated and more likely to smoke, although their wives were less likely to do so. Although multiple logistic regression analyses were conducted, education was not controlled and insufficient information was provided regarding models with interactions. Due to these weaknesses combined with the small sample size, the study provides little information relevant to this report. The list of pesticides applied during the period of employment of these workers included several that may have been contaminated by TCDD, but the published report did not address particular exposures.

A study of miscarriages among wives of Swedish fishermen, a group with a relatively high consumption of fish contaminated with PCBs, ascertained preg-

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

nancy outcomes by questionnaire (Axmon et al., 2000). After adjustment for numerous potential confounders, the women who consumed high quantities of fish had a lower risk of miscarriage than those with no fish consumption.

In a doctoral dissertation, Schwartz (1998) conducted an interview study with three groups of women: female veterans who served in Vietnam, female veterans of the Vietnam era who did not serve in Vietnam, and female civilians who were matched by age and occupation to the group who served in Vietnam. Ninety-five percent of the veterans were located, and a high response was achieved. The Vietnam era veterans differed markedly in age and occupation from the Vietnam veterans, who tended to be older and consisted mostly of nurses (84 percent versus 10 percent among Vietnam era veterans). Interviews were conducted, with questions taken from several sources, including the National Survey of the Vietnam Generation and the National Health Interview Survey. The former asked questions on demographics, financial status, and reproductive outcomes, while the latter asked about health. Results showed that spontaneous abortions occurred more frequently in women who had served in Vietnam than in comparable civilians, but not more frequently than in women veterans who did not serve in Vietnam. However, major demographic differences between the two veteran groups make it difficult to interpret the comparisons that were made.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and spontaneous abortion.

Biologic Plausibility

Experimental animal evidence suggests that dioxin can alter hormones but does not provide direct clues about the reproductive significance of these hormonal changes and the risk of recognized pregnancy loss before 20 weeks of gestation.

A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Few studies have addressed spontaneous abortion in Vietnam veterans. The recent doctoral dissertation examining female veterans provides weak evi-

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

dence of an association between herbicides used in Vietnam and risk of spontaneous abortion among exposed women. Unfortunately, interpretation of the results is hampered by problems of comparability of the referent groups. Given the relatively weak data and the great uncertainties regarding the level of exposures experienced by servicepersons in Vietnam, it is not possible for the committee to quantify the degree of risk for spontaneous abortion likely to be or to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Background

The term stillbirth or late fetal death is typically defined as the delivery of a fetus occurring at or after 28 weeks of gestation that shows no signs of life at birth, although a more recent definition includes deaths among all fetuses weighing more than 500 grams at birth, regardless of gestational age at delivery (Kline et al., 1989). Neonatal death refers to the death of a live-born infant within the first 28 days of life. Because the causes of stillbirths and early neonatal deaths overlap considerably, these are commonly analyzed as one group, referred to as perinatal mortality (Kallen, 1988). Stillbirths occur in less than 1 percent of all births (CDC, 2000). Among low-birthweight live- and stillborn infants (500– 2,500 grams), placental and delivery complications such as abruptio placentae, placenta previa, malpresentation, and umbilical cord complications are the most common causes of perinatal mortality (Kallen, 1988). Among infants weighing more than 2,500 grams 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, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and stillbirth, neonatal death, and infant death. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports.

Update of the Scientific Literature

No new relevant data regarding stillbirths or infant mortality have come to the attention of the committee.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and stillbirth, neonatal death, and infant death.

Biologic Plausibility

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

A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk of stillbirth, neonatal death, and infant death, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. It is also possible that if such a risk exists, it would decline with time since service.

LOW BIRTHWEIGHT AND PRETERM BIRTH

Background

The World Health Organization (WHO) recommends a 2,500-gram cutpoint for the determination of low birthweight (Alberman, 1984). Reduced infant weight at birth is one of the most important causes of neonatal mortality and morbidity in the United States. Although often treated as a single entity, the concept of low birthweight actually encompasses two different causal pathways: (1) low birthweight secondary to intrauterine growth retardation (IUGR) or small for gestational age, and (2) low birthweight secondary to preterm delivery, which may have more long-term consequences. The concept of IUGR represents birthweight adjusted for gestational age. The currently used definition of preterm delivery (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

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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(Bryce, 1991). Approximately 7 percent of live births have low birthweight. The incidence of IUGR is much more difficult to quantify since there are no universally applied standards for dividing the distribution of birthweight for gestational age. When no distinction is made between the causes of low birthweight (i.e., IUGR versus PTD), the factors most strongly associated with reduced birthweight are maternal smoking during pregnancy, multiple births, and race or ethnicity. Other potential risk factors for low birthweight include socioeconomic status (SES), maternal size, birth order, maternal complications during pregnancy (e.g., severe preeclampsia) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Kallen, 1988). Established risk factors for preterm birth include race (black); marital status (single); low SES; previous low birthweight or preterm birth; multiple gestations; cigarette smoking; and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993).

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and low birthweight. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports.

Update of Scientific Literature

A number of earlier studies found that mothers with high exposures to PCBs gave birth to infants that were lower in weight and remained smaller at later ages. These included the Yusho and Yucheng children, born to mothers in Japan and Taiwan, respectively, who were exposed accidentally when cooking oil with high concentrations of PCBs was sold commercially (Kuratsune et al., 1972; Chen et al., 1994). Infants born to women who consumed contaminated fish from Lake Michigan experienced a decrease in birthweight, a smaller head circumference, and a weight deficit at age 4 years (Fein et al., 1984; Jacobson et al., 1990). It was recognized that the cooking oil in Taiwan and Japan also was contaminated with dioxins; similarly, fish with PCBs are contaminated with dioxins.

More recently, Patandin et al. (1998) have been following a group of children with exposures to PCBs and dioxins beginning in utero. Cord and maternal plasma samples were used to estimate prenatal PCB exposures, and breast milk was collected for measurement of TCDD and other poly chlorinated dibenzodioxin or dibenzofuran (PCDD/F) congeners, as well as three planar PCBs, three monoortho PCBs, two diortho PCBs, and eighteen nonplanar PCBs. A toxic equivalent (TEQ) was estimated according to the approach of Safe (1994), by applying the congener concentration in breast milk (nanograms per kilogram of milk fat) to the

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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TEQ factor and summing over all congeners. PCBs in cord plasma, expressed as the sum of the International Union of Pure and Applied Chemistry (IUPAC) numbers 118, 138, 153, and 180 (the four most abundant PCBs in human samples) were inversely associated with birthweight; findings were similar for maternal plasma. The authors also found that the rate of growth between birth and 3 months, among those who were not breast-fed, was negatively associated with prenatal PCB exposures. However, among breast-fed children, neither PCBs nor TEQs were associated with decreased rates of growth. No associations were found with the rate of growth after 3 months. Although no measurements of TCDD were made in the blood specimens collected at birth, dioxins are a contaminant of PCBs, and their presence in breast milk samples indicates clearly that these pregnant women also carried body burdens to which the fetus was exposed in utero. However, it is not possible to distinguish an effect of the dioxins from that of PCBs, some of which may operate by similar mechanisms. Planar PCBs and mono-ortho PCBs bind to the aryl hydrocarbon receptor (AhR) and may exert toxic effects through this same mechanism, believed to be a primary one for TCDD.

Rylander et al. (1998) conducted a study of low birthweight among children whose fathers were fishermen. The exposures were estimated by collecting blood samples in 1995 and extrapolating back to the time of pregnancies in 1973–1991. Cases of low birthweight (1,500–2,750 grams) were matched with controls on gender, parity, and calendar year of birth, and PCB 153 was used as a marker of exposure. In previous work, these authors had found that the correlation coefficient between PCB 153 and the total PCB toxic equivalent was 0.9 (Grimvall et al., 1997). Several extrapolation models were examined for the estimation of exposures during the pregnancies of interest. These were validated against a group of women for whom two blood samples in different years were available, although there were limitations to this validation. The analysis of low birthweight indicated an increase in risk with increasing exposure. The authors emphasized the strength of the association at the upper end of the exposure range and suggested that the effect might follow a threshold model. However there seemed to be an elevated risk (ORs of 1.8, 2.1, and 2.3) above several different cutpoints from different extrapolation models. The primary limitation of this study follows from uncertainties in the exposure assessment, which would likely have reduced the precision of this already small study.

Vartiainen et al. (1998) also analyzed PCBs, PCDDs, and PCDFs measured in breast milk samples in relation to birthweight. Their study was conducted in a Finnish population exposed primarily through consumption of contaminated fish in the Baltic Sea. Birthweight decreased slightly with increasing concentrations of PCDDs, PCDFs, and PCBs, including an index of the TEQ based on the WHO equivalencies; this difference was stronger in boys. When restricted to primiparous pregnancies, the association was not observed. This finding is difficult to interpret for several reasons. First, none of the analyses of

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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birthweight and organochlorine compounds adjusted simultaneously for other factors. Second, fish consumption has been found in some studies to increase birthweight, probably because of the presence of omega-3 fatty acids (Olsen et al., 1992). Thus, any deficits in growth related to contaminants may have been offset by the benefits of fish consumption. This issue is further complicated by the fact that educated mothers consumed more fish (and hence had higher TEQs), which might partially explain the lack of association between education and birthweight among boys. There was an association of birthweight with education among girls; however, some data suggest that boys are more susceptible to the developmental effects of PCBs or dioxins. Finally, after the authors stratified on parity and sex of the child, the numbers of observations were small.

No studies appear to have examined the risk for preterm delivery associated with TCDD or related compounds.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and either low birthweight or preterm birth. A handful of studies of populations with exposures to TCDD have observed some association with low birthweight, although these investigations are not fully consistent. All of the new studies addressing this outcome involved exposures to a variety of compounds other than dioxins, such as poly chlorinated biphenyls and poly chlorinated dibenzofurans. Additionally, for most of these studies, only maternal exposure was addressed. For these reasons, the evidence is weak regarding an association between herbicides used in Vietnam and low birthweight among offspring.

Biologic Plausibility

Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are too limited to permit conclusions. Regarding female-mediated developmental toxicity, TCDD and herbicides are found in follicular fluid (Tsutsumi et al., 1998), suggesting exposure of embryos, and are known to cross the placenta, leading to direct exposure of the fetus.

A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the exposure levels of Vietnam veterans and the magnitude of potential risk of low birthweight and preterm birth, it is not possible for the committee to quantify the degree of risk likely to be experienced by the offspring of Vietnam veterans because of exposure to herbicides in Vietnam.

CHILDHOOD CANCERS

Background

The American Cancer Society (ACS) estimates that approximately 8,600 children under the age of 15 will be diagnosed with cancer in the United States in 2001. Nearly half of these cases will be in children aged 0 to 4 years. Treatment and supportive care for children with cancer have greatly improved, leading to a decline in mortality rates by 50 percent over the last 3 decades. Despite these advances, cancer remains the leading cause of death from disease in children under the age of 15, with 1,500 deaths projected in 2001.

Leukemia is the most common cancer in children. It accounts for about one-third of all childhood cancer cases, with nearly 2,700 children projected to be diagnosed in 2001 (ACS, 2001). Of these children, nearly 2,000 will be diagnosed with acute lymphocytic leukemia (ALL) and most of the rest with acute myelogenous leukemia (AML).1 The former is most common in early childhood, peaking between ages 2 and 3, while the latter is most common during the first two years of life. ALL incidence is consistently higher in males than females, while AML shows similar incidence for boys and girls (NCI, 2001). Through early adulthood, ALL rates are about twice as high in whites as in African Americans, whereas there is no consistent pattern for AML. Chapter 7 contains additional information on leukemia as part of the discussion of adult cancer outcomes.

The second most common group of cancers in children are those of the central nervous system—brain and spinal cord. Other cancers occurring in children include lymphomas, bone cancers, soft-tissue sarcomas, kidney cancers, eye cancers, and adrenal gland cancers. Compared with adult cancers, relatively little

1  

Acute myelogenous leukemia (ICD•9 205) is referred to by other names as well, including acute myeloid leukemia and acute nonlymphocytic leukemia. There are also numerous subtypes of the disease. For consistency, this report uses “acute myelogenous leukemia,” or the abbreviation AML, no matter how the disease is referred to in the work being reviewed.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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is known about the etiology of most childhood cancers and especially about potential environmental risk factors and the impact of parental exposures.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 8–3 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of Scientific Literature

Occupational Studies

An earlier study, not previously summarized in Veterans and Agent Orange reports, examined occupational herbicide exposures in relation to acute myelogenous leukemia (Buckley et al., 1989). This study was assembled by the Children’s Cancer Study Group and included cases diagnosed from 1980 to 1984. Initial analyses focused on self-reported job titles, with linkage to exposures based on a previously developed job-exposure matrix (Hoar et al., 1980). One hundred seventy-eight case-control pairs provided information regarding paternal occupational pesticide exposures, including weed killers. Using the job-title linkage, pesticide exposures were associated with a 2.3-fold increased risk. Using self-reported information on workplace exposure to specific types of products and on duration of exposure, a 2.7-fold increased risk of fathering a child who developed AML was found for men exposed more than 1,000 days. Results were comparable when interviews conducted with surrogates for the fathers were excluded from the analysis. An elevated risk was seen for exposure before, during, and after the pregnancy, but since these were highly correlated, it was not possible to determine which time period might have been most important.

A second study addressed childhood cancer in children born to male sawmill workers in British Columbia, Canada (Heacock et al., 2000). The primary exposures in these plants were to chlorophenate fungicides, which are contaminated with PCDDs and PCDFs formed during the production of these chemicals. Employees who worked at least 1 year at any of 11 such lumber mills in 1950–1985 formed the cohort of 23,829. Estimates of exposure were made from job title in each mill using information from mill records and interviews with persons knowledgeable about technology and formulation changes; a validation study that compared urinary chlorophenates with job-based estimates yielded a correlation of 0.5. The cohort was linked to birth files and also to marriage files that were linked

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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to birth files (since the mother’s name is on all birth certificates, whereas the father’s name is not always), in order to identify the cohort of workers’ children. The children’s cohort was then linked to the British Columbia Cancer Registry to determine cancer diagnoses by age 20. Cancer cases in children born to sawmill plant workers from 1952 through 1988 and diagnosed in 1969–1993 were included. There were a total of 40 such cases, of which 22 were female and 18 male.

The initial analysis proceeded by calculation of a standardized incidence ratio (SIR), in which the cancer experience of these children was compared to that of the general population of the province of British Columbia, adjusted for age and sex of the children and calendar year. Results showed no elevation of risk for all cancers (SIR=1.0, 0.7–1.4) or for leukemia (SIR=1.0, 0.5–1.8); a slight but imprecise excess was observed for brain cancer (SIR=1.3, 0.6–2.5). An internal comparison was conducted using a nested case-control design. For each case, five controls were selected from within the cohort matched on sex and year of birth. These results compared risks for differing cumulative exposure groups within four time windows: (1) more than 90 days prior to conception; (2) 90 days before conception to conception; (3) conception to birth; and (4) after birth. The risks for all cancers combined and for brain cancer were greater in the high-exposure groups than in the low-exposure groups for all windows except the first (more than 90 days before conception); however, these findings were not stable (i.e., all confidence intervals included values consistent with no effect or even a lowered risk in those with high exposures). The risk for leukemia was not elevated. The main limitations of the study were the small number of cases and the lack of quantitative data on chlorophenate or TCDD exposure.

Environmental Studies

Infante-Rivard et al. (1999) examined the risk of childhood acute lymphocytic leukemia associated with pesticide use: 491 cases in 0–9-year-old children were identified from tertiary care centers in the province of Quebec, Canada, over the years 1980–1993. These were age, gender, and location matched with controls. Interviewers administered questionnaires to the parents of all subjects to gather information on potential influencing and confounding variables, including home use of pesticides. Cases were significantly more likely than controls to be from households that used herbicides while the subject was in utero (OR=1.8, 1.3–2.6) or during the subject’s childhood (OR=1.4, 1.1–1.9). Risk increased with frequency of use, although this observation was based on a very small number of cases in the higher of two use categories. The authors suggested that 2,4-D was probably the ingredient most frequently contained in the chlorophenoxy herbicides used at home. Because exposures were based entirely on self-reports after the diagnosis (and hence, for most cases, years after pregnancy), controls may have been less attuned to recalling events of the past than cases,

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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producing recall bias. Additionally, specific products were not recorded (i.e., no analysis by chlorophenoxy herbicide use was possible).

A much larger population-based case-control interview study of several childhood cancers was conducted in West Germany by Meinert et al. (2000). The children were diagnosed at less than 15 years of age, and there were 1,184 cases of leukemia. Parental occupational exposures to herbicides, insecticides, or fungicides were found to be related to childhood cancer regardless of the time period of exposure and the type of cancer (lymphoma or leukemia) (see Table 8–3). Of particular note is the finding that there was a statistically significant association between paternal exposure in the year before pregnancy and leukemia (OR=1.5, 1.1–2.2, based on 62 cases). Statistically significant associations were also found between leukemia and paternal exposure during pregnancy (1.6, 1.1–2.3) and “ever” (1.6, 1.1–2.3). However the strongest associations were in relation to maternal exposures during pregnancy (e.g., leukemia OR=3.6, 1.5–8.8). No analyses of the separate types of leukemia were reported.

The data provide some evidence of an increased leukemia risk for children exposed in utero to herbicides, insecticides, or fungicides and also for children whose fathers were exposed preconceptionally. While this study may have been the largest ever to examine this hypothesis, the possibility of recall bias could not be ruled out, and there was some evidence suggesting that parents of cases consistently reported more occupational exposures than parents of controls. Neither study reported the effect of paternal preconception exposures independent of maternal exposures (or vice versa). The relevance of this study to exposures to the herbicides used in Vietnam and their contaminants is uncertain because the data did not permit analysis by specific herbicides.

Pearce and Parker (2000) compared children who died of kidney cancer with children who died of other causes with regard to paternal occupation in agriculture at the time of the child’s birth. No association was found, although the relatively small number of deaths (21) from kidney cancer complicates the analysis. However, the analysis compared these children to children who died of other causes, rather than to the full cohort. If other children who died were more (or perhaps less) likely to have had fathers who worked in agriculture, the results could be biased.

Vietnam Veteran Studies

In a large case-control study, Wen et al. (2000) examined service in Vietnam or Cambodia as a risk factor for childhood leukemia. The study included 1,805 cases of ALL and 528 cases of AML, including cases diagnosed through 17 years of age. It combined data from three studies conducted by the Children’s Cancer Group, which represents a consortium of hospitals and medical centers in the United States and Canada that pool their cases to enable large studies of rare childhood cancers to achieve sufficient statistical power. The cases were matched

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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to controls on year of birth, location of residence, sex, and race. Controls were found through random-digit dialing, and cases were restricted to those with a telephone in the home. The overall response rates were 89 percent for cases and 77 percent for controls, and they were slightly lower for those with paternal interviews (83 percent for cases, 70 percent for controls). Analyses were conducted using conditional logistic regression for all leukemias combined, for ALL and AML separately, and stratified by age at diagnosis. Regression models adjusted for potential confounders, including education, race, family income, smoking, exposure to X-rays, and paternal marijuana use.

The results indicated no increased risk of either leukemia subtype associated with military service in general. However, for service in Vietnam or Cambodia, the risk of AML, but not ALL, was increased: OR=1.7 (1.0–2.9). Analyses examining tours in Vietnam or Cambodia led to small numbers, although the highest risk was for those with two or more tours there; for those serving less than or equal to 1 year in these countries, the OR was 2.4 (1.1–5.4), whereas those with more than 1 year had an OR of 1.5 (0.7–3.2). When stratified by years between service and conception of the child, the association was strongest in those who had served more than 15 years earlier; however, the numbers in this stratum were small. Self-reported exposure to Agent Orange showed no association. The strongest association was for cases diagnosed under the age of 2 years. It is believed that childhood cancers at very young ages are more likely to be etiologically related to preconception or in utero exposures than those diagnosed at later ages. Limitations of the study include possible residual confounding from not having detailed exposure data on smoking and marijuana use; the unexplained stronger association with increasing interval between service and conception; and possible other factors associated with service in Vietnam or Cambodia, including postwar exposures. The authors point out that the inconsistency in results for number of tours of duty versus number of years in Vietnam or Cambodia could have been related to exposures being correlated with movement in and out of these areas, rather than with duration, or to other exposures in Southeast Asian countries. Longer duration in Vietnam or Cambodia does not necessarily mean higher exposure to herbicides, since no information is available on the nature of these veterans’ activities during their service.

Close to 50,000 Australian Vietnam veterans were surveyed about their and their children’s health, and an 80 percent response rate was achieved (Commonwealth Department of Veterans’ Affairs [CDVA], 1998). A follow-up validation study of selected conditions was conducted that included children’s cancers (AIHW, 1999); a later supplement (AIHW, 2000) had, as one of its aims, the collection and analysis of data on specific subtypes of leukemia among children of veterans. Validation sources included pathology reports, doctor certifications, or records from a disease or death registry. Australia has had, since 1982, a cancer registry. Nine cases of reported AML were confirmed through clinical records. The investigators used various assumptions to adjust for nonrespondents

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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in the validation study and for circumstances in which it was not possible to validate a reported case (e.g., physician could not be located or medical records were incomplete). Depending on the specific assumptions, up to nine additional cases of AML were estimated for the full cohort (for a total of from 9 to 18 cases). The assumptions adopted by the study’s authors estimated 4 additional cases (i.e., 13 validated cases where 3 [range 0–6] were expected) using community standards. This represents a statistically significant 4.3-fold increased risk. All of the alternative analyses, including those with the most restrictive assumptions (i.e., assuming zero cases among nonrespondents and no valid AML diagnoses among reported cases for which validation was not possible), also yielded large, precise, and hence statistically significant excesses of AML. These analyses did not adjust for any sociodemographic or life-style factors associated with increased risk of AML, although adjustment for age and gender was achieved through the methods used to derive expected numbers of cases in Australia’s community standard. As in the study of Wen et al., no excess risk was observed for childhood ALL. The number of cases of chronic lymphocytic leukemia (CLL) and chronic myelocytic leukemia (CML) was well within the range of the expected number of cases.

The study also examined adrenal gland cancer in the children of veterans. It found a much higher-than-expected incidence of the disease, reporting 10 cases where 1 (range 0 to 3) was expected, using community standards.

Synthesis

No firm evidence links exposures to the herbicides used in Vietnam with most childhood cancers, including acute lymphocytic leukemia, chronic leukemias, non-Hodgkin’s lymphoma, brain tumors, neuroblastoma, and cancers at other sites. A cohort study reports a slight elevation in risk to children of sawmill workers (Heacock et al., 2000), but the estimate of effect is very imprecise, and it is unclear how the exposures studied inform the question of the effect of exposure to the chemicals of concern in this report. One case-control study shows elevated risks for all leukemias with either maternal or paternal occupational use of herbicides, pesticides, or fungicides, specifically during the year prior to conception (Meinert et al., 2000). A similar association, but with much less precision, was seen for non-Hodgkin’s lymphoma. Another case-control study showed elevated risks for ALL with household herbicide use during pregnancy (Infante-Rivard et al., 1999) but did not address exposures prior to pregnancy. Both of these studies relied on self-reports of exposure, which can entail biased reporting: for example, parents of children without cancer may be less likely to recall having used pesticides some years in the past, whereas parents of children with cancer might have thought about it more and therefore be likely to recall such activities. Self-report of use of herbicides, pesticides, or fungicides does not necessarily imply that exposures to dioxin or the herbicides used in Vietnam occurred. Overall, the

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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literature lacks consistency for most types of cancer in children of exposed persons. The one study that separated herbicides from pesticides or fungicides did not examine exposures prior to conception, the time period most relevant for births to Vietnam veterans.

Three studies provide evidence regarding an association between exposure to the herbicides used in Vietnam and acute myelogenous leukemia in the children of veterans. The first is a case-control study of AML and parental occupational exposures conducted by the Children’s Cancer Study Group (Buckley et al., 1989). Use of pesticides by either the mother or the father, as reported in detailed interviews, was associated with an elevated risk. However, because of a high correlation among exposures in the three periods studied (before, during, and after pregnancy), it was not possible to determine whether exposure uniquely prior to the pregnancy was associated with increased risk of AML in the children. The strongest associations were for children diagnosed before 5 years of age and for children with M4/M5 morphology.

In a second case-control study of AML conducted by the Children’s Cancer Group (Wen et al., 2000), self-reported service in Vietnam or Cambodia was associated with an elevated risk (OR=1.7, CI 1.0–2.9), after adjusting for potential confounders including education, race, income, smoking, X-ray exposure, and paternal marijuana use. Since service in Vietnam or Cambodia would be an extremely memorable event, underreporting by controls or overreporting by cases seems unlikely. Also arguing against recall bias was the lack of association with ALL in this study, as well as the lack of association of AML with general paternal military service. When stratified by time spent in Vietnam or Cambodia, those with 1 year or less of service there showed a greater risk than those with more than 1 year; additionally, self-reported exposure to Agent Orange was not associated with AML. However, these outcomes are not particularly convincing evidence against a causal association since neither length of service in Vietnam or Cambodia nor self-reported exposure is known to be strongly related to the actual level of herbicide exposure. Two or more tours of duty in Vietnam showed a stronger association than a single tour, although the numbers were small. This study showed the strongest association to be with childhood AML diagnosed before the age of 2 years (OR=4.6, 1.3–16.1). One concern was the apparent lack of adjustment for maternal marijuana use, which has been shown to be related to AML (Robison et al., 1989). Additionally, the authors point out that an unexplained increase in risk with longer time since service in Vietnam or Cambodia might have been due to random fluctuations, but could also have been due to an unmeasured postwar exposure that was different from those who did not serve in the military or those who served elsewhere.

A third study on this topic is that of the Australian Vietnam veterans. Investigators surveyed veterans regarding their medical conditions and the health of their children (CDVA, 1998), with a follow-up validation of the self-reported conditions and a calculation of the expected number of cases based on Australian

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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community standards (AIHW, 1999, 2000). The results were thereby adjusted for age and gender but not for other potential confounding factors. Among respondents, 9 cases of AML were successfully validated, where 3 (range 0–6) were expected based on the community standard. Taking into account possible additional cases among nonrespondents and cases that might have been validated had the information been obtainable, the authors estimated that there were 13 cases of AML among the veterans’ children, representing a 4.3-fold increased risk. As in the study of Wen et al., no excess risk was observed for ALL among the children. Sensitivity analyses were conducted using a variety of strategies for assignment of nonrespondent cases. These analyses yielded relative risks, compared to a community standard, that varied from 3.0 to 6.0—in all cases, these were significant.

The relatively thorough control for confounders in the study by Wen et al. combined with the magnitude of association among Australian veterans diminishes the likelihood of explanations unrelated to service in Vietnam. The results of the Buckley et al. study suggest that exposure to the herbicides used in Vietnam is a credible candidate for producing the observed outcomes.

Conclusions

Strength of Evidence in Epidemiologic Studies

Based on the scientific evidence reviewed above, the committee finds there is limited/suggestive evidence of an association between exposure to the herbicides of concern in this report and acute myelogenous leukemia (AML) in the children of veterans. This is a change in classification from previous Veterans and Agent Orange reports, which found inadequate/insufficient evidence to determine whether an association existed for AML and other cancers.

When the whole of the literature was considered, the committee found that it met the definition established for limited/suggestive evidence—that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence. Two studies, in particular, support this conclusion. One is a case-control study of AML conducted by the Children’s Cancer Group (Wen et al., 2000) in which self-reported service in Vietnam or Cambodia was associated with an elevated risk after adjusting for numerous potentially confounding lifestyle and sociodemographic factors. The other, a study of the children of Australian Vietnam veterans (AIHW, 2000), found a greater than fourfold risk, although confounding factors other than age and gender were not controlled. While direct measures of exposure are lacking, the committee found the following characteristics of these studies to be particularly persuasive: (1) both studies were conducted in Vietnam veteran populations; (2) the association was specific for AML, with no excess risk for ALL; (3) one study adjusted for

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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numerous confounders, while the other had an association of sufficiently large magnitude to reduce the likelihood of being completely due to confounding; and (4) the strongest association was seen in children diagnosed at the youngest ages—cases that are considered the strongest candidates for an etiology of parental origin. These characteristics of the studies and their findings reduce the likelihood of alternative explanations.

A 1989 case-control study of AML and parental occupational exposures by Buckley et al. reported a 2.7-fold increased risk in the children of fathers with self-reported exposure of more than 1,000 days to pesticides or weed killers. The study also found an association with maternal occupational exposures of more than 1,000 days and a high correlation among parental exposures in different time periods (before, during, and after pregnancy). It is thus not possible to determine whether paternal exposure uniquely prior to the pregnancy was associated with increased risk of AML in the children.

The Meinert et al. (2000) study finds a statistically significant excess of leukemia in children whose fathers were exposed to herbicides, insecticides, or fungicides in the year preceding the pregnancy, but does not separate the types of leukemia for analysis. It is therefore not possible to assess whether this study provides additional supportive evidence regarding AML. If the information is available, the committee encourages these researchers to conduct separate analyses of ALL and AML (the two most common forms of childhood leukemia) and publish the results.

None of the studies of childhood cancer outcomes reviewed in previous Veterans and Agent Orange reports provide specific information regarding AML. The Centers for Disease Control Vietnam Experience Study (CDC, 1989) found an elevated risk for childhood leukemia in its veterans’ cohort (OR=1.6, 0.6–4.0, based on 12 cases), but the types of leukemia found were not reported. A study reviewed in Update 1996 of subjects aged 0–19 living in the area surrounding Seveso, Italy—site of a 1976 industrial accident that released dioxin into the environment—found 3 cases of myelogenous leukemia in the 10 years following the event where 1.1 was expected (RR=2.7, 0.7–11.4) (Pesatori et al., 1993). However, all were in individuals born prior to the accident.

There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this report or the contaminant dioxin and most childhood cancers, including acute lymphocytic leukemia, chronic leukemias, non-Hodgkin’s lymphoma, brain tumors, neuroblastoma, and cancers at other sites. Although two moderately sized investigations did observe associations with ALL, all leukemia, or non-Hodgkin’s lymphoma in children, these studies were still problematic, because of reliance on self-reports for exposure assessment and/or a lack of information on exposures prior to the child’s conception, the time period relevant for cancer among children of Vietnam veterans. Additionally, both Vietnam veterans’ studies (AIHW, 2000; Wen et al., 2000) observed no association with ALL.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Biologic Plausibility

As noted in Chapter 3, the reproductive systems of adult male laboratory animals are considered to be relatively insensitive to TCDD because high doses are required to elicit effects. Two animal studies reviewed in Update 1998 have investigated developmental effects following paternal exposure to the chemicals of interest. No paternally mediated effects were observed in the offspring of mice exposed to a mixture of 2,4-D, 2,4,5-T, and dioxin (Lamb et al., 1980). The offspring of mice exposed to a mixture of 2,4-D and picloram, however, showed some effects but at doses that also caused paternal toxicity (Blakley et al., 1989).

The mechanism by which herbicide or TCDD exposures could lead to childhood cancer in the offspring of persons exposed many years previously is unclear. One possible mechanism would involve germ cell mutations whereby damaged cells might later undergo spermatogenesis and result in fertilization, leading to the birth of a genetically susceptible child. However, assays do not indicate that the herbicides of interest or TCDD are genotoxic except at very high doses or concentrations. The link between Down’s syndrome and AML appears to imply some genetic origin for at least a portion of AML cases. Leukemias in younger children, the period during which childhood AML cases are more common, are believed to have a different etiology from those of older children because the genetic abnormalities underlying them are more likely to have been present at birth.

Given the present lack of information, the committee believes that further research aimed at evaluating long-term effects of herbicide exposures on male reproductive organs would be useful.

Increased Risk of Disease Among Vietnam Veterans

Recently published studies reported an increased incidence of AML in the children of U.S. and Australian veterans of Vietnam. Although the committee’s finding regarding the strength of evidence for AML derives primarily from this research, there remain large uncertainties about the exposure levels both of the subjects who participated in the cited studies and of Vietnam veterans generally. There are additional uncertainties regarding the magnitude of risk for AML in the children of Vietnam veterans. For these reasons, it is not possible for the committee to quantify the degree of risk for AML likely to be experienced by the children of Vietnam veterans because of their fathers’ exposure to herbicides in Vietnam.

There remains insufficient information to quantify the degree of risk for other childhood cancers in the children of veterans resulting from their fathers’ exposures to herbicides in Vietnam.

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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TABLE 8-3 Selected Epidemiologic Studies—Childhood Cancers

Reference

Study Population

Exposed Cases

RR, OR, or SIR (95% CI)

OCCUPATIONAL STUDIES

Heacock et al., 2000

Cohort of sawmill workers’ offspring; exposure via fungicides contaminated with PCDDs and PCDFs

 

Leukemia, all workers

11

SIR=1.0 (0.5–1.8)

 

Brain cancer, all workers

9

SIR=1.3 (0.6–2.5)

 

Leukemia, high chlorophenate exposure

5

OR=0.8 (0.2–3.6)

 

Brain cancer, high chlorophenate exposure

5

OR=1.5 (0.4–6.9)

Buckley et al., 1989

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

 

AML in children with any paternal exposure

27

OR=2.3 (p=.05)

 

AML in children with paternal exposure >1,000 days

17

OR=2.7 (1.0–7.0)

 

AML in children with maternal exposure > 1,000 days

7

OR undefined (no cases in controls)

ENVIRONMENTAL STUDIES

New Studies

Meinert et al., 2000

Population-based case-control study of childhood cancer

 

Leukemias, paternal exposure, year before pregnancy

62

1.5 (1.1–2.2)

 

Leukemias, paternal exposure, during pregnancy

57

1.6 (1.1–2.3)

 

Lymphomas, paternal exposure, year before pregnancy

11

1.5 (0.7–3.1)

 

Lymphomas, paternal exposure, during pregnancy

10

1.6 (0.7–3.6)

 

Leukemias, maternal exposure, year before pregnancy

19

2.1 (1.1–4.2)

 

Leukemias, maternal exposure, during pregnancy

15

3.6 (1.5–8.8)

 

Lymphomas, maternal exposure, year before pregnancy

3

2.9 (0.7–13)

 

Lymphomas, maternal exposure, during pregnancy

4

11.8 (2.2–64)

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Reference

Study Population

Exposed Cases

RR, OR, or SIR (95% CI)

Pearce and Parker, 2000

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

Paternal agricultural occupation

(total cases= 21)

0.9 (0.2–3.8)

Infante-Rivard et al., 1999

Population-based case-control study of childhood ALL and household herbicide use during pregnancy

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 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 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

New Studies

AIHW, 2000

Australian Vietnam veterans’ children— Validation Study

 

AML

13 (estimated)

3 expected (0–6)

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)

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Reference

Study Population

Exposed Cases

RR, OR, or SIR (95% CI)

Studies Reviewed in VAO

CDC, 1989

Vietnam Experience Study

 

Cancer in children of veterans

25

1.5 (0.7–2.8)

 

Leukemia in children of veterans

12

1.6 (0.6–4.0)

Field and Kerr, 1988

Cancer in children of Australian Vietnam veterans

4

Erikson et al, 1984b

CDC Birth Defects Study

 

“Other” neoplasms—children of Vietnam veterans

87

1.8 (1.0–3.3)

SEX RATIO

Background

Sex ratio (ratio of males to females at birth, about 105–107 males per 100 females, or 51.4 percent males among all births) has been used for a number of years as a potential marker of genetic damage. It has been hypothesized that the induction of lethal mutations prior to birth will alter the sex ratio at birth. In general, it was thought that with paternal exposure that there would be a reduction in the frequency of female offspring since sex-linked lethals on the paternal X chromosome would differentially affect female conceptuses. Investigators have evaluated the sex ratio among various species in relation to exposures such as radiation for a number of years. More recently, it has been suggested that the sex ratio is controlled by parental hormone levels at conception, and changes in gonadotropin and steroid levels may result in an altered sex ratio (James, 1996). The specific mechanisms involved (zygote formation, implantation, regulation of sex-determining factors, selective fetal loss) are uncertain, and direct experimental evidence for or against the hypothesis is lacking. James (1997) has suggested that a reduction in testosterone and high gonadotropin levels after dioxin exposure would result in an excess of female offspring. Potential confounding factors for altered sex ratio are uncertain, but parental age, social class, illness, race, smoking, and stress have been considered.

Summary of VAO, Update 1996, and Update 1998

The potential association between exposure to herbicides used in Vietnam or the contaminant dioxin and altered sex ratio was not explored in the VAO and Update 1996 reports. The committee responsible for Update 1998 reviewed papers addressing altered sex ratio as part of its examination of the literature on

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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fertility. That committee found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and health outcomes related to fertility.

Update of Scientific Literature

Mocarelli et al. (2000) have recently published new findings on the sex ratio of births to parents from Seveso, Italy, where an explosion of a chemical plant resulted in widespread environmental exposure in 1976. The study was based on a total of 674 births, to parents aged 3 to 45 at the time of the accident. Birth records for all persons in zones A and B and for a part of zone R were investigated, and all available serum samples from these parents or persons living outside these zones were analyzed for TCDD. Those who lived outside the three zones or whose TCDD measurement was less than 15 parts per trillion (ppt) were considered unexposed. Couples were analyzed according to whether the mother alone, the father alone, or both were exposed, based on the TCDD value in the 1976 serum specimen. The sex ratio was 0.6 if both parents were unexposed, 0.6 if only the mother was exposed, and 0.4 if only the father or if both parents were exposed. When only the father’s exposure was considered, there was a decreasing trend (p=.008) for increasing concentration of TCDD in serum in 1976. When the authors stratified by age of the father in 1976, those who were younger than 19 years had a lower sex ratio than those older than 19, although for both groups the sex ratio was significantly different from that expected.

An interesting finding from this study is that the sex ratio within zone A was decreased not only from 1977 to 1984, but also in the period 1973–1976, the 4 years before the accident occurred. The authors argue that TCDD contamination of the environment surrounding the plant occurred even before the explosion. As evidence, they report that five men living in zone A from 1964 to 1967, who left before the accident and never returned, had TCDD levels in 1976 ranging from 138 to 352 ppt. In contrast, the sex ratio in a nearby comparison town with similar types of industrial and socioeconomic conditions was normal throughout 1966– 1996.

In contrast to the Seveso findings, Michalek et al. (1998b) failed to find a reduction in male births among Ranch Hand personnel. This study included 2,157 live births, of whom 903 were to Ranch Hand servicemen and 1,254 to comparison servicemen. Ranch Hand veterans were divided into those having background, low, or high dioxin levels. The sex ratio was actually higher in those with high exposure than in the comparison group. This held true for births whose conception occurred in four different time periods: up to 1 month postservice, up to 1 year postservice, up to 5 years postservice, and during the entire postservice period.

The sex ratio results from the Seveso study have been compared with changes

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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in wildlife sexual differentiation and mating behaviors hypothesized to be due to environmental contamination by hormonally active compounds such as DDT, dichlorodiphenyldichloroethylene (DDE), PCBs, and dioxin. In the case of the Seveso studies, only TCDD was present, rendering it less likely that the findings are due to other environmental contaminants. The discrepancy with the Ranch Hand study could be due to higher exposures in Seveso.

Conclusions

Strength of the Evidence in Epidemiologic Studies

Newly available information from the Seveso cohort, although interesting, does not change the committee’s conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and altered sex ratio.

Biologic Plausibility

Laboratory studies of the potential developmental toxicity of TCDD and herbicides using male animals are too limited to permit conclusions. A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk of altered sex ratio, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. Furthermore, giving birth to a higher-than-expected number of females is not in itself an adverse event. This outcome should be viewed as indicative of hormonal disruption with other potential adverse consequences, rather than as an outcome in itself.

SUMMARY

Strength of the Evidence in Epidemiologic Studies

The committee responsible for Update 1996 found that there was limited/ suggestive evidence of an association between exposure to the herbicides considered in this report and spina bifida in the children of veterans. The Australian veterans Validation Study lends further support to this conclusion. The commit-

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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tee therefore upholds the designation reached in Update 1996. Also, as detailed earlier in the text, the committee concludes there is also limited/suggestive evidence of an association between exposure to these herbicides and AML in the children of veterans.

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and altered hormone levels, semen quality, or infertility; spontaneous abortion; late-fetal, neonatal, or infant death; low birthweight or preterm delivery; birth defects other than spina bifida; childhood cancers other than AML; and altered sex ratio.

Biologic Plausibility

This section summarizes the general biologic plausibility of a connection between exposure to dioxin or herbicides and reproductive and developmental effects on the basis of data from animal and cellular studies. Details of the committee’s evaluation of data from these studies are presented in Chapter 3. Some of the preceding discussions of reproductive and developmental outcomes include references to papers relevant to specific reproductive and developmental effects.

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

In addition, there is some evidence in animals that TCDD can exacerbate or cause endometriosis. Although a recent study did not show any increase in surgically induced endometriosis with TCDD exposure, early studies have demonstrated an association between TCDD exposure and endometriosis. Recent evidence does demonstrate that TCDD inhibits progesterone-associated transforming growth factor-β2 (TGFβ2) expression and endometrial matrix metalloproteinase suppression, which the authors suggest could be a mechanism underlying an association between TCDD and endometriosis. Animal data, therefore, support a possible association between exposure to TCDD and endometriosis.

Experiments have examined the effects of TCDD on the adult female reproductive system. TCDD exposure did not increase egg mortality, nor did it affect time-to-hatching of newly fertilized zebrafish eggs. However, pericardial edema

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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and craniofacial malformations were observed in zebrafish larvae. In ovo TCDD exposure adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron.

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

TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that coexposure with either of two other chemicals, hydrocortisone or retinoic acid, synergistically enhances expression of cleft palate. This synergy suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. Several reports describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity, with evidence suggesting that cytochrome P450 1A1 (CYP1A1) induction in the endothelium might mediate the early lesions that result in TCDD-induced vascular derangements. Antioxidant treatment provides significant protection against TCDD-induced embryotoxicity, suggesting that reactive oxygen species might be involved in the teratogenic effects of TCDD.

Studies in female rats show that a single dose of TCDD results in malformations of the external genitalia and functional reproductive alterations in female progeny (e.g., decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, increased incidences of constant estrus). These effects were dependent 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 varying concentrations of simulated Agent Orange mixtures concluded there were no adverse effects in offspring. A statistically significant excess of fused sternebrae in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of this defect in the controls.

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

Studies in female animals are limited but demonstrate that in utero and

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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lactational exposure reduced fertility, decreased the ability to carry pregnancy to term, decreased litter size, increased fetal death, impaired ovary function, and decreased levels of hormones such as estradiol and progesterone. Most of these effects may have occurred as a result of TCDD’s general toxicity to the pregnant animal, however, and not as a result of a TCDD-specific mechanism that acted directly on the reproductive system. TCDD also induced changes in serum concentrations of reproductive hormones in immature female rats administered TCDD by gastric intubation, partially because of the action of TCDD on the pituitary gland.

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

Most studies are consistent with the hypothesis that the effects of TCDD are mediated by the AhR, a protein in animal and human cells to which TCDD can bind. Following the binding of TCDD, the TCDD-AhR complex has been shown to bind DNA, leading to changes in transcription (i.e., genes are differentially regulated). Modulation of these genes may alter cell function.

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

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

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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pregnant rats, mice, and hamsters. The ability of 2,4,5-T 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 evidence suggests that a connection between TCDD exposure and human reproductive and developmental effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of such toxicity by TCDD in humans. Experiments with 2,4-D and 2,4,5-T indicate that these chemicals can have effects on cells at the subcellular level that could provide a biologically plausible mechanism for reproductive and developmental effects. Evidence in animals, however, indicates that these chemicals do not have reproductive effects and have developmental effects only at very high doses. There is inadequate information on picloram and cacodylic acid to assess the biologic plausibility of these compounds’ having reproductive or developmental effects.

Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure. Investigating the biological mechanisms underlying TCDD’s toxic effects continues to be a very active area of research, and subsequent updates of this report might have more and better information on which to base conclusions, at least for that compound.

Increased Risk of Disease Among Vietnam Veterans

As discussed in Update 1998, there are some data suggesting that the highest risks for spina bifida occur in the children of those veterans estimated to have been exposed to Agent Orange (e.g., Ranch Hands). It therefore follows that there is limited/suggestive evidence for an increased risk of spina bifida among offspring of Vietnam veterans. Recently published studies reviewed in this report reported an increased incidence of AML in the children of U.S. and Australian veterans of Vietnam.

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

Suggested Citation:"8 Reproductive Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Veterans and Agent Orange: Update 2000 examines the state of the scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. It is the fourth in a series of comprehensive reviews of epidemiologic and toxicologic studies of the agents used as defoliants during the Vietnam War. Over forty health outcomes in veterans and their children are addressed.

Among the report's conclusions is that there is sufficient evidence of a link between exposure and the development of soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne in veterans. Additionally, it found that scientific studies offer "limited or suggestive" evidence of an association with other diseases in veterans—including Type 2 diabetes, respiratory cancers, prostate cancer, multiple myeloma and some forms of transient peripheral neuropathy—as well as the congenital birth defect spina bifida in veterans' children.

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