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-



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Veterans and Agent Orange: Update 2000 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-

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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.

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Veterans and Agent Orange: Update 2000 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.

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Veterans and Agent Orange: Update 2000 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.

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Veterans and Agent Orange: Update 2000 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  

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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.

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Veterans and Agent Orange: Update 2000 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)

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Veterans and Agent Orange: Update 2000 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.

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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-

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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

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Veterans and Agent Orange: Update 2000 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.

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