7
Reproductive and Developmental Effects

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2004, hereafter referred to as Update 2004 (IOM, 2005), on the association between exposure to herbicides and adverse reproductive or developmental effects. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, and 2002 [IOM, 1996, 1999, 2001, 2003].) The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed includes papers that describe environmental, occupational, and Vietnam-veteran studies that evaluate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirth, neonatal and infant mortality, low birth weight and preterm birth, and childhood cancer. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) were reviewed when relevant because TCDD is sometimes a contaminant of PCBs. For new studies that report only a single reproductive health outcome and that are not revisiting a previously studied population, design information is summarized here with the results; design information on all other new studies can be found in Chapter 4.

This chapter’s primary emphasis is on the potential adverse reproductive effects of herbicide exposure in men because the vast majority of Vietnam veterans are men. About 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so findings relevant to female reproductive health are also included. Studies that investigated the potential reproductive consequences of exposure of either parent were considered; whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately.



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7 Reproductive and Developmental Effects This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2004, hereafter referred to as Update 2004 (IOM, 2005), on the association between exposure to herbicides and adverse reproduc- tive or developmental effects. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, and 2002 [IOM, 1996, 1999, 2001, 2003].) The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed includes papers that describe environmental, occupational, and Vietnam-veteran studies that evalu- ate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirth, neonatal and infant mortality, low birth weight and preterm birth, and childhood cancer. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of popula- tions exposed to polychlorinated biphenyls (PCBs) were reviewed when relevant because TCDD is sometimes a contaminant of PCBs. For new studies that report only a single reproductive health outcome and that are not revisiting a previously studied population, design information is summarized here with the results; de- sign information on all other new studies can be found in Chapter 4. This chapter’s primary emphasis is on the potential adverse reproductive effects of herbicide exposure in men because the vast majority of Vietnam veter- ans are men. About 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so findings relevant to female reproductive health are also included. Studies that investigated the potential reproductive consequences of exposure of either parent were consid- ered; whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately. 517

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518 VETERANS AND AGENT ORANGE: UPDATE 2006 FERTILITY Male reproductive function is under the control of several components whose proper coordination is important for normal fertility. Several of the components and some endpoints related to male fertility, including reproductive hormones and sperm characteristics, can be studied as indicators of fertility. The reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the cen- tral and peripheral nervous systems and regulates the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both are secreted into the circulation in episodic bursts by the anterior pituitary gland and are neces- sary for normal spermatogenesis. In the testis, LH interacts with receptors on Leydig cells, where it stimulates increased testosterone synthesis. FSH and the testosterone from the Leydig cells interact with the Sertoli cells in the seminifer- ous tubule epithelium to regulate spermatogenesis. More detailed reviews of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde and Giwercman, 1995; Tas et al., 1996). Whereas many studies have investigated the relationship between chemi- cals and male fertility, studies among women are sparse. Some chemicals may disrupt the female hormonal balance necessary for proper functioning. Normal menstrual-cycle functioning is also important in the risk of hormonally related diseases, such as osteopenia, breast cancer, and cardiovascular disease. Chemicals can have multiple effects on the female system, including modulation of hormone concentrations, such menstrual- or ovarian-cycle irregularities as changes in men- arche and menopause, and impairment of fertility (Bretveld et al., 2006a,b). In this chapter, we discuss studies that have focused on menstrual-cycle characteris- tics and age of menarche or age of menopause. Studies of the association between the chemicals of interest and endometriosis are reviewed in Chapter 9. Conclusions from VAO and Updates The committee responsible for Veterans and Agent Orange, hereafter re- ferred to as VAO (IOM, 1994), concluded that there was inadequate or insuffi- cient evidence of an association between exposure to 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility. Additional in- formation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that finding. Reviews of the relevant studies are presented in the earlier reports. Table 7-1 summarizes the studies.

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519 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS TABLE 7-1 Selected Epidemiologic Studies—Fertility (altered hormone concentrations, decreased sperm counts or quality, subfertility, or infertility) Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population OCCUPATIONAL New Studies Farr et al., 2006 Age of menopause women who self-reported pesticide exposure 8,038 0.9 (0.8–1.0) Oh et al., 2005 Male fertility—dioxin exposure with air monitoring 31 1.4* Farr et al., 2004 Menstrual cycle characteristics of premenopausal women in AHS aged 21–40 1,754 Short menstrual cycle 0.8 (0.6–1.0) Long menstrual cycle 1.4 (0.9–2.1) Irregular 0.6 (0.4–0.8) Missed Period 1.6 (1.3–2.0) Intermenstrual bleeding 1.1 (0.9–1.4) Studies Reviewed in Update 2000 Abell et al., 2000 Female greenhouse workers in Denmark (maternal exposure) 0.7 (0.5–1.0)b 20 hours manual contact per week 220 0.7 (0.5–1.0)b Never used gloves 156 0.6 (0.5–0.9)b High exposure 202 Larsen et al., 1998 Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D Farmers using pesticides vs. organic 1.0 (0.8–1.4)b farmers 523 0.9 (0.7–1.2)b Used three or more pesticides 0.8 (0.6–1.1)b Used manual sprayer for pesticides Studies Reviewed in Update 1998 Heacock et al., Workers at sawmills using chlorophenates 0.7 (0.7–0.8)c 1998 Standardized fertility ratio 18,016 (births) 0.9 (0.8-0.9)c Mantel-Haenszel rate ratio estimator 18,016 (births) Cumulative exposure (hours) 0.8 (0.8–0.9)c 120–1,999 7,139 0.9 (0.8–1.0)c 2,000–3,999 4,582 1.0 (0.9–1.1)c 4,000–9,999 4,145 1.1 (1.0–1.2)c 10,000 1,300 continued

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520 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 7-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population Lerda and Rizzi, Argentinean farmers exposed to 2,4-D 32 1991 Sperm count (millions/ml) exposed: 49.0 vs. control: 101.6 Motility (%) exposed: 24.8 vs. control: 70.4 Sperm death (%) exposed: 82.9 vs. control: 37.1d Anomalies (%) exposed: 72.9 vs. control: 33.4 (p 0.01 overall) ENVIRONMENTAL New Studies Eskanazi et al., Seveso cohort-serum dioxin concentrations 2005 and age of menopause 616 Premenopause 260 43.6 (0.2–0.9) Natural Menopause 169 45.8 (0.3–1.0) Surgical menopause 83 43.4 (0.3–1.0) Impending menopause 13 43.8 (0.2–0.9) Perimenopause 33 36.5 (0.2–0.9) Other 58 39.6 (0.2–0.9) Warner et al., 2004 Age of menarche at time of exposure 282 1.0 (0.8–1.1) Greenlee et al., Women from Wisconsin, US infertility 2003 (maternal exposure) Mixed or applied herbicides 21 2.3 (0.9–6.1) Used 2,4,5-T 9 9 cases (2.7%) 11controls (3.4%) Used 2,4-D 4 4 cases (1.2%) 4 controls (1.2%) Swan et al., 2003 Men from Missouri, US low sperm quality Elevated urinary metabolite marker for 2,4-D 5 0.8 (0.2–3.0) Studies Reviewed in Update 2002 Staessen et al., Adolescents in communities close to industrial 2001 sources of heavy metals, PCBs, VOCs, and PAHs—delays in sexual maturity In Hoboken, Belgium 8 4.0 (*) In Wilrik, Belgium 15 1.7 (*)

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521 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS TABLE 7-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population VIETNAM VETERANS Studies Reviewed in Update 1996 Henriksen et al., Effects on specific hormone levels or sperm 1996 count in 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) Studies Reviewed in VAO CDC, 1989b 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., American Legionnaires who served in 1988 Southeast Asia Difficulty having children 349 1.3 (p 0.01) Unless otherwise indicated, studies show paternal exposure. a Given when available. b For this study, relative risk has been replaced with the fecundability ratio, for which a value less than 1.0 indicates an adverse effect. c For this study, relative risk has been replaced with the standardized fertility ratio, for which a value less than 1.0 indicates an adverse effect. d Table 1 in the reference reverses these figures—control: 82.9%; exposed: 37.1%—but the text (“The percentages of asthenospermia, mobility, necrosperma and teratospermia were greater in the exposed group than in controls…”) suggests that this is a typographic error. * Information not provided by study authors.

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522 VETERANS AND AGENT ORANGE: UPDATE 2006 Update of the Epidemiologic Literature Occupational Studies After exclusion of women who were pregnant, were nursing, were taking oral contraceptives, had extreme body-mass indexes, or had missing values, Farr et al. (2004) reported on the menstrual-cycle characteristics of 3,103 premeno- pausal women in the Agricultural Health Study (AHS) who were 21–40 years old when they completed a female health and family health questionnaire. They examined the association between pesticide mixing or applying and menstrual characteristics of short cycles, long cycles, irregular cycles, missed periods, and bleeding or spotting between periods in the preceding 12 months. Women who had never mixed or applied pesticides were considered the control group. The investigators reported a significant relationship between increased cycle length and ever mixing or applying any type of pesticide (p 0.02) and increased reports of missed periods (OR 1.6). There was a trend toward increased odds of long cycles (p 0.08) and missed periods (p 0.001) with increasing days of pesticide exposure. Although using hormonally active pesticides was found to be associ- ated with increased cycle length and increased frequency of missed cycles, the pesticides with this observed association did not include any of the chemicals of interest to the present review committee. The study used self-reported informa- tion on menstrual cycle that may have been unreliable, and no hormonal confir- mation of menstrual dysfunction was available. Overall, there was no indication of an association with menstrual-cycle characteristics and the specific chemicals of interest in this review. There also has been a report from the AHS (Farr et al., 2006) concerning age at menopause in 8,038 women who were 35–55 years old at the time of enroll- ment. Women were classified according to their self-reported pesticide exposure. Overall, women who ever mixed or applied pesticides were found to have a higher age at menopause (hazard ratio [HR] by Cox proportional hazard analysis 0.87, 95% CI 0.78–0.97) that translates into a delay of about 3 months. The estimate did not vary much when restricted to herbicides (HR 0.88, 95% CI 0.74–1.05) or to phenoxy herbicides (HR 0.85, 95% CI 0.65–1.11). One study of male fertility outcomes has been published since the last update. Oh et al. (2005) studied a group of 31 male incinerator workers and 84 controls in Seoul, South Korea. They measured dioxin exposure with air monitor- ing in the facility and found that levels were 100 times higher than those reported for the general Seoul area (31.17 ng TEQ/m3 compared with 0.32 ng TEQ/m3). Sperm characteristics were analyzed for eight controls and six workers. No sta- tistically significant differences were observed in the number of sperm (p = 0.05) or sperm mobility (p 0.35). The fractions of sperm with DNA damage in waste- incineration workers and control subjects were measured at 1.40% 0.08% and 1.26% 0.03%, respectively (p 0.001).

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523 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Environmental Studies The committee reviewed two reports from the Seveso Women’s Health Study (SWHS) published since the last update that focused on age at menarche and age at menopause in the Seveso population, which was exposed to high concentrations of TCDD as the result of an industrial explosion in 1976. Warner et al. (2004) examined age at menarche in 282 women who were premenarcheal at the time of the explosion. TCDD was measured in archived blood samples. Subjects had a mean age of 6.9 years at the time of the explosion. The median serum TCDD concentration was 140.3 ppt for all premenarcheal women. Serum TCDD did not vary with self-reported age at menarche in all subjects or in a group that were less than 8 years old at the time of the explosion. A major limi- tation of the study was that age at menarche was based on recall, and the time between onset of menarche and study interview ranged from 5 to 19 years. The finding of no association between age at menarche and exposure of young girls to TCDD may be related to the possibility that susceptibility is greater in utero than during childhood. The committee reviewed a second SWHS paper by Eskenazi et al. (2005) on serum dioxin concentrations and age at menopause in the Seveso cohort. The study included 616 women who were premenopausal at the time of the explo- sion and were older than 35 years at the time of the interview. The median lipid- adjusted serum TCCD concentration was 43.7 ppt and did not vary significantly among the menopausal categories of premenstrual, natural menopause, surgical menopause, impending menopause, and perimenopause. The HRs of the serum TCDD quintiles (1.0, 1.1, 1.4, 1.6, and 1.1) suggested a trend between TCDD exposure (up to about 100 ppt) and earlier onset of natural menopause but also suggested that women with the highest serum TCDD did not have the earliest onset of menopause. Age at which the subjects of this study were exposed rep- resents an appropriate match for the experience of female Vietnam veterans. The literature suggests, however, that ovarian follicles are most susceptible to effects in the prepubertal period. A publication by Swan (2006) only reiterated the findings in Swan et al. (2003), which were considered in Update 2004. Vietnam-Veteran Studies No new Vietnam-veteran studies concerning exposure to the compounds of interest and fertility were published since Update 2004. Biologic Plausibility There is little evidence that 2,4-D or 2,4,5-T has substantial effects on re- productive organs or fertility. One recent study has demonstrated that 2,4,5-T

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524 VETERANS AND AGENT ORANGE: UPDATE 2006 competes with 17 -estradiol for binding to estrogen receptor and can function as an antiestrogen in cell culture (Lemaire et al., 2006), suggesting 2,4,5-T may have the potential to disrupt female reproductive function. In contrast with the lack of evidence on 2,4-D and 2,4,5-T, many diverse laboratory studies provide evidence that TCDD can affect reproductive organ function and reduce fertility in both men and women. TCDD exposure can re- duce fertility in male rats and is associated with histologic changes in the testis (Chahoud et al., 1989). More recent studies of TCDD’s effects on the testis have shown that it can induce significant changes in gene expression (Kuroda et al., 2005; Lai et al., 2005a; Volz et al., 2005; Yamano et al., 2005), leading to modification of steroidogenesis in particular (Lai et al., 2005b). Those changes are associated with disruption or complete inhibition of spermatogenesis (Fisher et al., 2005; Simanainen et al., 2004; Volz et al., 2005). Furthermore, the TCDD- induced reduction in spermatogenesis has been associated with reduced erectile function in one study (Moon et al., 2004) and reduced serum testosterone in another (Simanainen et al., 2004). In women, TCDD has been shown to reduce reproductive success, and this reduction could be mediated by alterations in the ovaries, uterus, and placenta. TCDD has been shown to disrupt ovarian steroidogenesis, impair ovulation, re- duce circulating progesterone and estradiol, and decrease fertility (Li et al., 2006; Petroff and Mizinga, 2003; Ushinohama et al., 2001). Recent studies demonstrate that TCDD at low concentrations suppresses gene expression essential to ovarian function and downregulates estrogen-dependent signaling (Hombach-Klonisch et al., 2006; Miyamoto, 2004). TCDD-induced reduction in fertility in women could also be mediated by changes in the uterus. TCDD has antiestrogenic activ- ity on the uterus, causing impairment of uterine epithelial function (Buchanan et al., 2000) that may contribute to TCDD-induced reduction in the survival of implanted embryos early in gestation (Kitajima et al., 2004). TCDD-induced reduction in reproductive success may also be mediated by altered placental function, which can lead to fetal death. TCDD alters gene expression in the pla- centa, suppresses placental vascular remodeling, and induces placental hypoxia (Ishimura et al., 2002, 2006; Mizutani et al., 2004). The biologic plausibility of reproductive effects in general arising from ex- posure to the chemicals of interest is discussed at the end of this chapter. Synthesis Although there is much evidence of the biologic plausibility of disruption of male and female fertility by exposure to the chemicals of interest, there continues to be a lack of substantive epidemiologic data that demonstrate any association in human populations.

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525 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest and altered hormone concentrations, menstrual-cycle abnormalities, decreased sperm counts or sperm quality, subfertility, or infertility. SPONTANEOUS ABORTION Spontaneous abortion is the expulsion of a nonviable fetus, generally before 20 weeks of gestation, that is not induced by physical or pharmacologic means. The background risk of recognized spontaneous abortion is generally 7–15 per- cent (Hertz-Picciotto and Samuels, 1988), but it is established that many more pregnancies terminate before women become aware of them (Wilcox et al., 1988)—these terminations are known as subclinical pregnancy losses and gener- ally are not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Study designs include cohorts of women asked retrospectively about pregnancy history, cohorts of pregnant women (usually those receiving prenatal care), and cohorts of women who are monitored for future pregnancies. Retrospective re- ports can be limited by memory loss, particularly of spontaneous abortions that took place a long time before. Studies that enroll women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for differences in the times at which women seek medical care during pregnancy. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it can attract non-representative study groups because pro- tocols are demanding. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and spontaneous abortion. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion. Information available to the committee responsible for Update 2002, however, led to the conclusion that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion, but that there was insufficient information to determine whether an association exists between maternal exposure to TCDD and the risk of spontaneous abortion or between maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion. The additional information reviewed by the committee responsible for Update

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526 VETERANS AND AGENT ORANGE: UPDATE 2006 2004 did not change this conclusion. The relevant studies are reviewed in the earlier reports. Table 7-2 summarizes them. Update of the Epidemiologic Literature Environmental Studies Tango et al. (2004) studied the distribution of several birth outcomes around Japanese municipal-waste incinerators with elevated dioxin emissions. They found fetal death after the 12th week of gestation (with or without congenital malformations) was not associated with the distance the mother lived from an incinerator at the time of birth or whether her residence was in the area known to have the highest dioxin soil concentrations. No new occupational or Vietnam-veteran studies concerning exposure to the compounds of interest and spontaneous abortion were published since Update 2004. Biologic Plausibility Laboratory animal studies demonstrate that TCDD exposure during preg- nancy can alter circulating steroid hormone concentrations (Simanainen et al., 2004) and disrupt placental development and function (Ishimura et al., 2006; Mizutani et al., 2004) and thus contribute to a reduction in survival of implanted embryos and to fetal death (Kitajima et al., 2004). However, the reproductive significance of those effects and the risk of recognized pregnancy loss before 20 weeks of gestation in humans are not clear. There is no evidence of a relationship between paternal or maternal exposure to TCDD and spontaneous abortion. Ex- posure to 2,4-D or 2,4,5-T causes fetal toxicity and death after maternal exposure in experimental animals. However, that effect occurs only at high doses and in the presence of maternal toxicity. No fetal toxicity or death has been reported to occur after paternal exposure to 2,4-D. The biologic plausibility of reproductive effects in general arising from ex- posure to the chemicals of interest is discussed at the end of this chapter. Synthesis No additional information was available to the committee responsible for Update 2006 to motivate changing the assessment of the last two committees. Given the age of the Vietnam-veteran cohort, it is highly unlikely that additional information on this outcome among the population will appear.

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527 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS TABLE 7-2 Selected Epidemiologic Studies—Spontaneous Abortion Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population OCCUPATIONAL Studies Reviewed in Update 2002 Schnorr et al., Wives and partners of men in the NIOSH 2001 cohort Estimated paternal TCDD serum level at the time of conception 20 ppt 29 0.8 (0.5–1.2) 20 to 255 ppt 11 0.8 (0.4–1.6) 255 to 1,120 11 0.7 (0.3–1.6) 1,120 ppt 8 1.0 (0.4–2.2) Studies Reviewed in Update 2000 Driscoll et al., Women employed by the US Forest 1998 Service—miscarriages (maternal exposure) 141 2.0 (1.1–3.5) Studies Reviewed in VAO Moses et al., 1984 Follow-up of 2,4,5-T production workers 14 0.9 (0.4–1.8) Suskind and Hertzberg, 1984 Follow-up of 2,4,5-T production workers 69 0.9 (0.6–1.2) Smith et al., Follow-up of 2,4,5-T sprayers vs 1982 non-sprayers 43 0.9 (0.6–1.3)** Townsend et al., Wives of men employed involved in 1982 chlorophenol processing at Dow Chemical Company 85 1.0 (0.8–1.4) Carmelli et al., Wives of men occupationally exposed to 1981 2,4-D All reported work exposure to herbicides (high and medium) 63 0.8 (0.6–1.1)** Farm exposure 32 0.7 (0.4–1.5) Forest and commercial exposure 31 0.9 (0.6–1.4) Exposure during conception period Farm exposure 15 1.0 (0.5–1.8) Forest and commercial exposure 16 1.6 (0.9–1.8) All exposures, father aged 18–25 years Forest and commercial exposure 8 3.1 (1.2–7.8) Exposure during conception period Father aged 31–35 years, farm exposure 10 2.9 (0.8–10.9) ENVIRONMENTAL New Studies Eskenazi et al., Seveso (Italy) Women’s Health Study 2003 participants living in exposure Zones A and B in 1976 (maternal exposure) Pregnancies 1976–1998 97 0.8 (0.6–1.2) Pregnancies 1976–1984 44 1.0 (0.6–1.6) continued

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555 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS malformations of the external genitalia and functional reproductive alterations in female progeny, including decreased fertility rate, reduced fecundity, cystic en- dometrial hyperplasia, and disrupted estrous cycles. Those effects depend on the timing of exposure. Similarly, male progeny exhibit alterations in reproductive- organ development and function. Maternal exposure to TCDD impairs prostate growth and seminal vesicle weight and branching and decreases sperm production and caudal epididymal sperm number in offspring. Little research has been conducted on the offspring of male animals exposed to herbicides. Feeding of simulated Agent Orange mixtures to male mice pro- duced 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 (Lamb et al., 1981). Altered sex ratio might reflect the effects of exposure to the chemicals of interest on reproductive capability. It has been hypothesized that concentrations of parental hormones at conception or induction of lethal mutations before birth could affect sex ratio. There has been no work with experimental animals that specifically examined the effects of TCDD on sex ratios of offspring, nor have any alterations in sex ratio been reported in animal studies that examined devel- opmental effects of TCDD on offspring. The mechanisms by which TCDD induces birth defects have not been es- tablished and are probably species- and organ-specific. Nonetheless, studies have consistently demonstrated that TCDD-induced developmental toxicity required the AhR. That has been definitively established in mice that lack AhR expression. When pregnant AhR-null mice are exposed to TCDD, the fetuses fail to exhibit any of the typical developmental malformations associated with TCDD exposure. The activated AhR mediates changes in gene transcription, so the inappropriate and sustained activation of AhR by TCDD during development appears to be a key first step in mediating TCDD’s developmental toxicity. Although structural differences in the AhR have been identified among species, it functions similarly in animals and humans. Therefore, a common mechanism probably underlies the reproductive and developmental toxicity of TCDD in humans and animals, and data on animals support a biologic basis of TCDD’s toxic effects. Little information is available on the reproductive and developmental effects of exposure to the herbicides discussed in this report. Studies indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities. Offspring of pregnant rodents exposed to 4-(2,4-dichlorophenoxy)butyric acid (2,4- DB) exhibit a reduced growth rate and increased mortality (Charles et al., 1999), but only after very high doses. Exposure to 2,4-D also alters the concentration and function of reproductive hormones and prostaglandins. One study reported an increased incidence of malformed offspring of male mice exposed to a mixture of 2,4-D and picloram in drinking water; however, paternal toxicity was observed in the high-dose group, and there was no clear dose–response relationship (Blakley et al., 1989). Picloram alone produced fetal abnormalities in rabbits at doses that

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556 VETERANS AND AGENT ORANGE: UPDATE 2006 are also toxic to the pregnant animals (John-Greene et al., 1985), but that effect has not been seen in many studies. 2,4,5-T was toxic to fetuses when administered to pregnant rats, mice, and hamsters; its ability to interfere with calcium homeostasis in vitro has been documented and linked to its teratogenic effects on the early de- velopment 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. There is growing evidence from laboratory animal and human studies that exposures during fetal or postnatal development can lead to adverse effects later in life that are not immediately apparent as structural malformations or functional deficits. For example, exposure of humans and rats to TCDD in early postnatal life induces dental aberrations and reduces enamel maturation of teeth (Alaluusua et al., 2004; Gao et al., 2004). A study of human exposure to background con- centrations of dioxins, furans, and PCBs during prenatal development (Nakajima et al., 2006) suggests possibly more relationship with reduced motor development in 6-month-old infants than with their mental development; however, the few sig- nificant correlations found among dozens of comparisons made were for specific congeners with low relative potency (TEFs), so the study is essentially negative for developmental effects arising from prenatal exposure to TCDD. The foregoing suggests that a connection between TCDD exposure and hu- man reproductive and developmental effects is, in general, biologically plausible. However, more definitive conclusions about the potential for such TCDD toxic- ity in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; by differences in route, dose, duration, and timing of exposure; and by substantial differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-D and 2,4,5-T indicate that they have subcellular effects that could constitute a biologi- cally plausible mechanism for reproductive and developmental effects. Evidence from animals, however, indicates that they do not have reproductive effects and that they have developmental effects only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of those compounds’ reproductive or developmental effects. Considerable uncertainty remains about how to apply toxicologic informa- tion to the evaluation of potential health effects of herbicide or TCDD exposure on the offspring of Vietnam veterans. Scientists disagree over the extent to which information derived from animal and cellular studies can be used to predict hu- man health outcomes and over the extent to which the health effects of high-dose exposure can be extrapolated to low-dose exposure. The biologic mechanisms that underlie TCDD’s toxic effects continue to be a subject of active research, and future VAO updates are likely to have more and better information on which to base conclusions, at least for TCDD.

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557 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Synthesis The studies reviewed for this update did not find any significant associa- tions between the relevant exposures and reproductive outcomes. The scientific evidence supports the biologic plausibility of a connection between exposure to the chemicals of interest and reproductive effects, but the epidemiologic studies of occupational cohorts, exposed communities, and Vietnam veterans have not provided conclusive evidence of any additional associations between exposures and an array of reproductive outcomes and conditions among the offspring of exposed parents. The mechanisms by which the chemicals exert their biologic effects are still subjects of scientific investigation. With the aging of the Vietnam- veteran population, additional studies on fertility, spontaneous abortion, and sex ratio cannot be expected, although there may be additional studies of reproductive outcomes in other populations with exposure to the chemicals of interest. The possibility of structural or functional abnormalities in the offspring of exposed people will continue to be of interest. Conclusions There is inadequate or insufficient evidence of an association between expo- sure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations; semen quality; infertility; spontaneous abortion; late fetal, neo- natal, or infant death; low birth weight or preterm delivery; birth defects other than spina bifida; and childhood cancers. There is limited or suggestive evidence of an association between exposure to the compounds of interest and spina bifida. There is limited or suggestive evidence that the specific combination of pa- ternal exposure to TCDD is not associated with risk of spontaneous abortion. REFERENCES1 Abell A, Juul S, Bonde JP. 2000. Time to pregnancy among female greenhouse workers. Scandinavian Journal of Work, Environment and Health 26(2):131–136. ACS. 2004. Cancer Facts and Figures 2004. http://www.cancer.org/downloads/STT/CAFF_finalP- WSecured.pdf (Accessed September 13). ADVA (Australia Department of Veterans Affairs). 1983. Case–Control Study of Congenital Anoma- lies and Vietnam Service. Canberra. AFHS (Air Force Health Study). 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB, TX: USAF School of Aerospace Medicine. AL-TR-1992-0090. 602 pp. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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