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Veterans and Agent Orange: Update 2006 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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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 central 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 necessary 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 seminiferous tubule epithelium to regulate spermatogenesis. More detailed reviews of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde and Giwercman, 1995; Tas et al., 1996). Whereas many studies have investigated the relationship between chemicals 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 menarche and menopause, and impairment of fertility (Bretveld et al., 2006a,b). In this chapter, we discuss studies that have focused on menstrual-cycle characteristics 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 referred to as VAO (IOM, 1994), concluded that there was inadequate or insufficient 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 information 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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Veterans and Agent Orange: Update 2006 TABLE 7-1 Selected Epidemiologic Studies—Fertility (altered hormone concentrations, decreased sperm counts or quality, subfertility, or infertility) Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL 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) >20 hours manual contact per week 220 0.7 (0.5–1.0)b Never used gloves 156 0.7 (0.5–1.0)b High exposure 202 0.6 (0.5–0.9)b Larsen et al., 1998 Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D Farmers using pesticides vs. organic farmers 523 1.0 (0.8–1.4)b Used three or more pesticides 0.9 (0.7–1.2)b Used manual sprayer for pesticides 0.8 (0.6–1.1)b Studies Reviewed in Update 1998 Heacock et al., 1998 Workers at sawmills using chlorophenates Standardized fertility ratio 18,016 (births) 0.7 (0.7–0.8)c Mantel-Haenszel rate ratio estimator 18,016 (births) 0.9 (0.8-0.9)c Cumulative exposure (hours) 120–1,999 7,139 0.8 (0.8–0.9)c 2,000–3,999 4,582 0.9 (0.8–1.0)c 4,000–9,999 4,145 1.0 (0.9–1.1)c >10,000 1,300 1.1 (1.0–1.2)c
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Veterans and Agent Orange: Update 2006 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a Lerda and Rizzi, 1991 Argentinean farmers exposed to 2,4-D Sperm count (millions/ml) 32 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., 2005 Seveso cohort-serum dioxin concentrations 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., 2003 Women from Wisconsin, US ± infertility (maternal exposure) Mixed or applied herbicides 21 2.3 (0.9–6.1) Used 2,4,5-T 9 9 cases (2.7%) 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., 2001 Adolescents in communities close to industrial 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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Veterans and Agent Orange: Update 2006 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a VIETNAM VETERANS Studies Reviewed in Update 1996 Henriksen et al., 1996 Effects on specific hormone levels or sperm 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., 1988 American Legionnaires who served in 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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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 premenopausal 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 associated 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 information on menstrual cycle that may have been unreliable, and no hormonal confirmation 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 enrollment. 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 monitoring 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 statistically 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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Veterans and Agent Orange: Update 2006 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 limitation 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 explosion and were older than 35 years at the time of the interview. The median lipidadjusted 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 represents 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 reproductive organs or fertility. One recent study has demonstrated that 2,4,5-T
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Veterans and Agent Orange: Update 2006 competes with 17β-estradiol for binding to estrogen receptor α 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 reduce 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, reduce 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 activity 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 placenta, 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 exposure 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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Veterans and Agent Orange: Update 2006 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 percent (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 generally are not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Study designs include cohorts of women asked retrospectively about pregnancy history, cohorts of pregnant women (usually those receiving prenatal care), and cohorts of women who are monitored for future pregnancies. Retrospective reports can be limited by memory loss, particularly of spontaneous abortions that took place a long time before. Studies that enroll women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for differences in the times at which women seek medical care during pregnancy. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it can attract non-representative study groups because protocols 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 information 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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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 pregnancy 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. Exposure 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 exposure 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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Veterans and Agent Orange: Update 2006 TABLE 7-2 Selected Epidemiologic Studies—Spontaneous Abortion Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 2002 Schnorr et al., 2001 Wives and partners of men in the NIOSH 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., 1998 Women employed by the US Forest 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., 1982 Follow-up of 2,4,5-T sprayers vs non-sprayers 43 0.9 (0.6–1.3)** Townsend et al., 1982 Wives of men employed involved in chlorophenol processing at Dow Chemical Company 85 1.0 (0.8–1.4) Carmelli et al., 1981 Wives of men occupationally exposed to 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., 2003 Seveso (Italy) Women’s Health Study 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)
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Veterans and Agent Orange: Update 2006 malformations of the external genitalia and functional reproductive alterations in female progeny, including decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and disrupted estrous cycles. Those effects depend on the timing of exposure. Similarly, male progeny exhibit alterations in reproductiveorgan 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 produced no adverse effects in offspring; a statistically significant excess of fused sternebrae in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of this defect in the controls (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 developmental effects of TCDD on offspring. The mechanisms by which TCDD induces birth defects have not been established 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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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 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. 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 concentrations 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 significant 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 human reproductive and developmental effects is, in general, biologically plausible. However, more definitive conclusions about the potential for such TCDD toxicity 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 biologically 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 information 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 human 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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Veterans and Agent Orange: Update 2006 Synthesis The studies reviewed for this update did not find any significant associations 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 Vietnamveteran 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 exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations; semen quality; infertility; spontaneous abortion; late fetal, neonatal, 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 paternal 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_finalPWSecured.pdf (Accessed September 13). ADVA (Australia Department of Veterans Affairs). 1983. Case–Control Study of Congenital Anomalies 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. 1 Throughout the report the same alphabetic indicator following year of publication is used consistently 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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Veterans and Agent Orange: Update 2006 AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community: Volume 3: Validation Study. Canberra, Australia: AIHW. AIHW. 2000. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and Non-Hodgkin’s Lymphoma: Supplementary Report No. 2. (AIHW cat. no. PHE 28). Canberra, Australia: AIHW. AIHW. 2001. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and Non-Hodgkin’s Lymphoma: Supplementary Report No. 2. Revised edition (AIHW cat. No. PHE 34). Canberra, Australia: AIHW. Alaluusua S, Calderara P, Gerthoux PM, Lukinmaa PL, Kovero O, Needham L, Patterson DG Jr, Tuomisto J, Mocarelli P. 2004. Developmental dental aberrations after the dioxin accident in Seveso. Environmental Health Perspectives 112(13):1313–1318. Alberman E. 1984. Low birth weight. In: Bracken MB, ed. Perinatal Epidemiology. New York: Oxford University Press. Pp. 86–98. Arbuckle TE, Lin Z, Mery LS. 2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspectives 109(8):851–857. Aschengrau A, Monson RR. 1989. Paternal military service in Vietnam and risk of spontaneous abortion. Journal of Occupational Medicine 31(7):618–623. Aschengrau A, Monson RR. 1990. Paternal military service in Vietnam and the risk of late adverse pregnancy outcomes. American Journal of Public Health 80(10):1218–1224. Axmon A, Rylander L, Strömberg U, Hagmar L. 2000. Miscarriages and stillbirths in women with a high intake of fish contaminated with persistent organochlorine compounds. International Archives of Occupational and Environmental Health 73(3):204–208. Berkowitz GS, Papiernik E. 1993. Epidemiology of preterm delivery. Epidemiologic Reviews 15:414–443. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Consonni D, Tironi A, Landi MT. 1992. Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin. International Journal of Epidemiology 21(1):118–123. Blakley PM, Kim JS, Firneisz GD. 1989. Effects of paternal subacute exposure to Tordon 202c on fetal growth and development in CD-1 mice. Teratology 39(3):237–241. Blatter BM, Hermens R, Bakker M, Roeleveld N, Verbeek AL, Zielhuis GA. 1997. Paternal occupational exposure around conception and spina bifida in offspring. American Journal of Industrial Medicine 32(3):283–291. Bloom AD, ed. 1981. Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. White Plains, NY: March of Dimes Foundation. Bonde JP, Giwercman A. 1995. Occupational hazards to male fecundity. Reproductive Medicine Review 4:59–73. Bretveld RW, Thomas CMG, Scheepers PTJ, Zielhuis GA, Roeleveld N. 2006a. Pesticide exposure: The hormonal function of the female reproductive system disrupted? Reproductive Biology and Endocrinology 4:20. Bretveld RW, Thomas CM, Scheepers PT, Zielhuis GA, Roeleveld N 2006b. Pesticide exposure: The hormonal function of the female reproductive system disrupted? [Review] Reproductive Biology and Endocrinology 4:30. Brown NM, Manzolillo PA, Zhang JX, Wang J, Lamartiniere CA. 1998. Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19(9):1623–1629. Bryce R. 1991. The epidemiology of preterm birth. In: Kiely M, ed. Reproductive and Perinatal Epidemiology. Boca Raton, FL: CRC Press. Pp. 437–444. Buchanan DL, Sato T, Peterson RE, Cooke PS. 2000. Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse uterus: Critical role of the aryl hydrocarbon receptor in stromal tissue. Toxicological Sciences 57(2):302–311.
OCR for page 559
Veterans and Agent Orange: Update 2006 Buckley JD, Robison LL, Swotinsky R, Garabrant DH, LeBeau M, Manchester P, Nesbit ME, Odom L, Peters JM, Woods WG, Hammond GD. 1989. Occupational exposures of parents of children with acute nonlymphocytic leukemia: A report from the Childrens’ Cancer Study Group. Cancer Research 49(14):4030–4037. Buckley JD, Meadows AT, Kadin ME, Le Beau MM, Siegel S, Robison LL. 2000. Pesticide exposures in children with non-Hodgkin lymphoma. Cancer 89(11):2315–2321. Carmelli D, Hofherr L, Tomsic J, Morgan RW. 1981. A Case–Control Study of the Relationship Between Exposure to 2,4-D and Spontaneous Abortions in Humans. SRI International. Prepared for the National Forest Products Association and the US Department of Agriculture, Forest Service. CDC (Centers for Disease Control and Prevention). 1989a. Health Status of Vietnam Veterans Vols. I–V, Supplements A–C. Vietnam Experience Study. Atlanta, GA: US Department of Health and Human Services. CDC. 1989b. Health Status of Vietnam Veterans. Vietnam Experience Study, Vol. V, Reproductive Outcomes and Child Health. Atlanta, GA: US Department of Health and Human Services. CDC. 2000. National Center for Health Statistics. National Vital Statistics System. Vital Statistics of the United States, Vol. II, Mortality, Part A, for Data Years 1950–1993. Washington, DC: US Government Printing Office. Data for 1994 to 1998, data are available on the NCHS Web site at www.cdc.gov/nchs/datawh/statab/unpubd/mortabs.htm. Chahoud I, Krowke R, Schimmel A, Merker HJ, Neubert D. 1989. Reproductive toxicity and pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Effects of high doses on the fertility of male rats. Archives of Toxicology 63:432–439. Chahoud I, Krowke R, Bochert G, Burkle B, Neubert D. 1991. Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Problem of paternal-mediated abnormalities in the progeny of rat. Archives of Toxicology 65(1):27–31. Charles JM, Henwood SM, Leeming NM. 1999. Developmental toxicity studies in rats and rabbits and two-generation reproduction study in rats on 4-(2,4-dichlorophenoxy)butyric acid. International Journal of Toxicology 18:177–189. Chen Z, Stewart PA, Davies S, Giller R, Krailo M, Davis M, Robison L, Shu XO. 2005. Parental occupational exposure to pesticides and childhood germ-cell tumors. American Journal of Epidemiology 162(9):858–867. Chen Z, Robison L, Giller R, Krailo M, Davis M, Davies S, Shu XO. 2006. Environmental exposure to residential pesticides, chemicals, dusts, fumes, and metals, and risk of childhood germ cell tumors. International Journal of Hygiene and Environmental Health 209(1):31–40. Chia SE, Shi LM. 2002. Review of recent epidemiological studies on paternal occupations and birth defects. Occupational and Environmental Medicine 59(3):149–155. Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. 2004. Risk of congenital anomalies in the vicinity of municipal solid waste incinerators. Occupational and Environmental Medicine 61(1):8–15. Daniels JL, Olshan AF, Teschke K, Herz-Picciotto I, Savitz DA, Blatt J, Bondy ML, Neglia JP, Pollock BH, Cohn SL, Look AT, Seeger RC, Castleberry RP. 2001. Residential pesticide exposure and neuroblastoma. Epidemiology 12:20–27. Desaulniers D, Leingartner K, Musicki B, Cole J, Li M, Charboneau M, Tsang BK. 2004. Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the development of methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Journal of Toxicology and Environmental Health Part A 67(18):1457–1475. Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproductive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinavian Journal of Work, Environment and Health 22(4):267–273. Donovan JW, MacLennan R, Adena M. 1984. Vietnam service and the risk of cogenital anomalies: A case–control study. Medical Journal of Australia 140(7):394–397.
OCR for page 560
Veterans and Agent Orange: Update 2006 Driscoll R, Donovan B, Esswein E, Mattorano D. 1998. Health Hazard Evaluation Report. US Department of Agriculture, Pp. 1–72. Erickson J, Mulinare J, Mcclain P, Fitch T, James L, McClearn A, Adams M. 1984a. Vietnam Veterans’ Risks for Fathering Babies with Birth Defects. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control. Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Vietnam veterans’ risks for fathering babies with birth defects. Journal of the American Medical Association 252(7):903–912. Eskenazi B, Mocarelli P, Warner M, Chee WY, Gerthoux PM, Samuels S, Needham LL, Patterson DG Jr. 2003. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. Environmental Health Perspectives 111(7):947–953. Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, Mocarelli P. 2005. Serum dioxin concentrations and age at menopause. Environmental Health Perspectives 113(7):858–862. Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. 2004. Pesticide use and menstrual cycle characteristics among premenopausal women in the Agricultural Health Study. American Journal of Epidemiology 160(12):1194–1204. Farr SL, Cai J, Savitz DA, Sandler DP, Hoppin JA, Cooper GS. 2006. Pesticide exposure and timing of menopause: the Agricultural Health Study. American Journal of Epidemiology 163(8): 731–742. Field B, Kerr C. 1988. Reproductive behaviour and consistent patterns of abnormality in offspring of Vietnam veterans. Journal of Medical Genetics 25:819–826. Fisher MT, Nagarkatti M, Nagarkatti PS. 2005. Aryl hydrocarbon receptor-dependent induction of loss of mitochondrial membrane potential in epididydimal spermatozoa by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology Letters 157(2):99–107. Fitzgerald EF, Weinstein AL, Youngblood LG, Standfast SJ, Melius JM. 1989. Health effects three years after potential exposure to the toxic contaminants of an electrical transformer fire. Archives of Environmental Health 44:214–221. Flower KB, Hoppin JA, Lynch CF, Blair A, Knott C, Shore DL, Sandler DP. 2004. Cancer risk and parental pesticide application in children of Agricultural Health Study participants. Environmental Health Perspectives 112(5):631–635. Foster WG, Holloway AC, Hughes CL Jr. 2005. Dioxin-like activity and maternal thyroid hormone levels in second trimester maternal serum. American Journal of Obstetrics and Gynecology 193(6):1900–1907. Gao Y, Sahlberg C, Kiukkonen A, Alaluusua W, Pohjanvirta R, Tuomisto J, Lukinmaa PL. 2004. Lactational exposure of Han/Wistar rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin interferes with enamel maturation and retards dentin mineralization. Journal of Dental Research 83(2):139–144. García AM, Benavides FG, Fletcher T, Orts E. 1998. Paternal exposure to pesticides and congenital malformations. Scandinavian Journal of Work, Environment and Health 24(6):473–480. Garry VF, Schreinemachers D, Harkins ME, Griffith J. 1996. Pesticide appliers, biocides, and birth defects in rural Minnesota. Environmental Health Perspectives 104(4):394–399. Greenlee AR, Arbuckle TE, Chyou PH. 2003. Risk factors for female infertility in an agricultural region. Epidemiology 14(4):429–436. Hanify JA, Metcalf P, Nobbs CL, Worsley KJ. 1981. Aerial spraying of 2,4,5-T and human birth malformations: An epidemiological investigation. Science 212:349–351. Heacock H, Hogg R, Marion SA, Hershler R, Teschke K, Dimich-Ward H, Demers P, Kelly S, Ostry A, Hertzman C. 1998. Fertility among a cohort of male sawmill workers exposed to chlorophenate fungicides. Epidemiology 9(1):56–60.
OCR for page 561
Veterans and Agent Orange: Update 2006 Heacock H, Hertzman C, Demers PA, Gallagher R, Hogg RS, Teschke K, Hershler R, Bajdik CD, Dimich-Ward H, Marion SA, Ostry A, Kelly S. 2000. Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides. Environmental Health Perspectives 108(6):499–503. Henriksen GL, Michalek JE, Swaby JA, Rahe AJ. 1996. Serum dioxin, testosterone, and gonadotropins in veterans of Operation Ranch Hand. Epidemiology 7(4):352–357. Hertz-Picciotto I, Samuels SJ. 1988. Incidence of early loss of pregnancy. New England Journal of Medicine 319(22):483–484. Hombach-Klonisch S, Pocar P, Kauffold J, Klonisch T. 2006. Dioxin exerts anti-estrogenic actions in a novel dioxin-responsive telomerase-immortalized epithelial cell line of the porcine oviduct (TERT-OPEC). Toxicological Sciences 90(2):519–528. Infante-Rivard C, Labuda D, Krajinovic M, Sinnett D. 1999. Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 10:481–487. IOM (Institute of Medicine). 1994. Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam. Washington DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans. Washington, DC: The National Academies Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. Ishimura R, Ohsako S, Kawakami T, Sakaue M, Aoki Y, Tohyama C. 2002. Altered protein profile and possible hypoxia in the placenta of 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed rats. Toxicology and Applied Pharmacology 185(3):197–206. Ishimura R, Kawakami T, Ohsako S, Nohara K, Tohyama C. 2006. Suppressive effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vascular remodeling that takes place in the normal labyrinth zone of rat placenta during late gestation. Toxicological Sciences 91(1):265–274. John-Greene JA, Ouellette JH, Jeffries TK, Johnson KA, Rao KS. 1985. Teratological evaluation of picloram potassium salt in rabbits. Food and Chemical Toxicology 23(8):753–756. Kallen B. 1988. Epidemiology of Human Reproduction. Boca Raton, FL: CRC Press. Kalter H, Warkany J. 1983. Congenital malformations. Etiologic factors and their role in prevention (first of two parts). New England Journal of Medicine 308:424–431. Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy outcomes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4): 447–454. Kerr M, Nasca PC, Mundt KA, Michalek AM, Baptiste MS, Mahoney MC. 2000. Parental occupational exposures and risk of neuroblastoma: A case–control study (United States). Cancer Causes and Control 11:635–643. Khorram O, Garthwaite M, Jones J, Golos T. 2004. Expression of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in human spermatozoa. Medical Science Monitor 10(5):BR135–BR138. Kitajima M, Khan KN, Fujishita A, Masuzaki H, Ishimaru T. 2004. Histomorphometric alteration and cell-type specific modulation of arylhydrocarbon receptor and estrogen receptor expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in mouse experimental model of endometriosis. Reproductive Toxicology 18(6):793–801. Kline J, Stein Z, Susser M. 1989. Conception to Birth: Epidemiology of Prenatal Development. New York: Oxford University Press.
OCR for page 562
Veterans and Agent Orange: Update 2006 Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, eds. 1994. The Physiology of Reproduction. New York: Raven Press. Kristensen P, Andersen A, Irgens LM, Bye AS, Sundheim L. 1996. Cancer in offspring of parents engaged in agricultural activities in Norway: Incidence and risk factors in the farm environment. International Journal of Cancer 65(1):39–50. Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. 1997. Birth defects among offspring of Norwegian farmers, 1967–1991. Epidemiology 8(5):537–544. Kuroda M, Oikawa K, Ohbayashi T, Yoshida K, Yamada K, Mimura J, Matsuda Y, Fujii-Kuriyama Y, Mukai K. 2005. A dioxin sensitive gene, mammalian WAPL, is implicated in spermatogenesis. FEBS Letters 579(1):167–172. Lai KP, Wong MH, Wong CKC. 2005a. Effects of TCDD in modulating the expression of Sertoli cell secretory products and markers for cell-cell interaction. Toxicology 206(1):111–123. Lai KP, Wong MH, Wong CKC. 2005b. Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells. Journal of Endocrinology 185:519–527. Lamb JC 4th, Moore JA, Marks TA, Haseman JK. 1981. Development and viability of offspring of male mice treated with chlorinated phenoxy acids and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Toxicology and Environmental Health 8(5-6):835–844. Larsen SB, Joffe M, Bonde JP. 1998. Time to pregnancy and exposure to pesticides in Danish farmers. Occupational and Environmental Medicine 55(4):278–283. Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, Piacitelli LA, Sweeney MH, Connally LB. 2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects. Environmental Health Perspectives 112(14):1403–1408. Lemaire G, Mnif W, Pascussi J-M, Pillon A, Rabenoelina F, Fenet H, Gomez E, Casellas C, Nicolas J-C, Cavailles V, Duchesne M-J, Balaguer P. 2006. Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system. Toxicological Sciences 91(2):501–509. Lerda D, Rizzi R. 1991. Study of reproductive function in persons occupationally exposed to 2,4-dichlorophenoxyacetic acid (2,4-D). Mutation Research 262(1):47–50. Li B, Liu H-Y, Dai L-J, Lu J-C, Yang Z-M, Huang L. 2006. The early embryo loss caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin may be related to the accumulation of this compound in the uterus. Reproductive Toxicology 21(3):301–306. Lin C-M, Li C-Y, Mao I-F. 2006. Birth outcomes of infants born in areas with elevated ambient exposure to incinerator generated PCDD/Fs. Environment International 32(5):624–629. Loffredo CA, Silbergeld EK, Ferencz C, Zhang J. 2001. Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides. American Journal of Epidemiology 153(6):529–536. Lorber M, Phillips L. 2002. Infant exposure to dioxin-like compounds in breast milk. Environmental Health Perspectives 110(6):A325–A332. Mastroiacovo P, Spagnolo A, Marni E, Meazza L, Betrollini R, Segni G, Brogna-Pignatti C. 1988. Birth deffects in Seveso area after TCDD contamination. Journal of the American Medical Association 259:1668–1672 (published erratum appears in JAMA 1988, 260:792). Meinert R, Schüz J, Kaletsch U, Kaatsch P, Michaelis J. 2000. Leukemia and non-Hodgkin’s lymphoma in childhood and exposure to pesticides: Results of a register-based case–control study in Germany. American Journal of Epidemiology 151(7):639–646. Michalek JE, Albanese RA, Wolfe WH. 1998a. Project Ranch Hand II: An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides—Reproductive Outcome Update. US Department of Commerce: National Technical Information Service. Report number AFRL-HE-BR-TR-1998-0073. Michalek JE, Rahe AJ, Boyle CA. 1998b. Paternal dioxin, preterm birth, intrauterine growth retardation, and infant death. Epidemiology 9(2):161–167.
OCR for page 563
Veterans and Agent Orange: Update 2006 Miyamoto K. 2004. Effects of dioxin on gene expression in female reproductive system in the rat. Environmental Sciences 11(1):47–55. Mizutani T, Yoshino M, Satake T, Nakagawa M, Ishimura R, Tohyama C, Kokame K, Kangawa K, Miyamoto K. 2004. Identification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible and -suppressive genes in the rat placenta: Induction of interferon-regulated genes with possible inhibitory roles for angiogenesis in the placenta. Endocrine Journal 51(6):569–577. Moon DG, Lee KC, Kim YW, Park HS, Cho HY, Kim JJ. 2004. Effect of TCDD on corpus cavernosum histology and smooth muscle physiology. International Journal of Impotence Research 16(3):224–230. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5(3):161–182. Nakajima S, Saijo Y, Kato S, Sasaki S, Uno A, Kanagami N, Hirakawa H, Hori T, Tobiishi K, Todaka T, Nakamura Y, Yanagiya S, Sengoku Y, Iida T, Sata F, Kishi R. 2006. Effects of prenatal exposure to polychlorinated biphenyls and dioxins on mental and motor development in Japanese children at 6 months of age. Environmental Health Perspectives 114(5):773–778. NCI (National Cancer Institute). 2001. Surveillance, Epidemiology, and End Results (SEER) database. http://seer.cancer.gov/ScientificSystems/CanQues (Accessed March 19). Ngo AD, Taylor R, Roberts CL, Nguyen TV. 2006. Association between Agent Orange and birth defects: Systematic review and meta-analysis. International Journal of Epidemiology 35(5):1220–1230. Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immunoand reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 2(1):65–80. Pearce MS, Parker L. 2000. Paternal employment in agriculture and childhood kidney cancer. Pediatric Hematology and Oncology 17(3):223–230. Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. 1993. Cancer in a young population in a dioxin-contaminated area. International Journal of Epidemiology 22(6):1010–1013. Petrelli G, Figa-Talamanca I, Tropeano R, Tangucci M, Cini C, Aquilini S, Gasperini L, Meli P. 2000. Reproductive male-mediated risk: Spontaneous abortion among wives of pesticide applicators. European Journal of Epidemiology 16(4):391–393. Petroff BK, Mizinga KM. 2003. Pharmacokinetics of ovarian steroids in Sprague-Dawley rats after acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Reproductive Biology 3(2):131–141. Ray SS, Swanson HI. 2004. Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a. Journal of Biological Chemistry 279(26):27187–27193. Revich B, Aksel E, Ushakova T, Ivanova I, Zuchenko N, Lyuev N, Brodsky B, Sotsov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43(4–7):951–966. Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. 2005b. Agricultural pesticide use and childhood cancer in California. Epidemiology 16(1):93–100. Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally LB, Fingerhut MA. 2001. Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109(11):1127–1132. Schreinemachers DM. 2003. Birth malformations and other adverse perinatal outcomes in four US wheat-producing states. Environmental Health Perspectives 111(9):1259–1264. Schultz R, Suominen J, Varre T, Hakovirta H, Parvinen M, Toppari J, Pelto-Huikko M. 2003. Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator messenger ribonucleic acids and proteins in rat and human testis. Endocrinology 144(3):767–776.
OCR for page 564
Veterans and Agent Orange: Update 2006 Schwartz LS. 1998. Health Problems of Women Veterans of the Vietnam War. Doctoral dissertation, Yale University. Simanainen U, Adamsson A, Tuomisto JT, Miettinen HM, Toppari J, Tuomisto J, Viluksela M. 2004. Adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and effects on male reproductive organs in three differentially TCDD-susceptible rat lines. Toxicological Sciences 81(2):401–407. Smith AH, Fisher DO, Pearce N, Chapman CJ. 1982. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Archives of Environmental Health 37:197–200. Smith MT, McHale CM, Wiemels JL, Zhang L, Wiencke JK, Zheng S, Gunn L, Skibola CF, Ma X, Buffler PA. 2005. Molecular biomarkers for the study of childhood leukemia. Toxicology and Applied Pharmacology 206(2):237–245. Staessen JA, Nawrot T, Hond ED, Thijs L, Fagard R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, Van Hecke E, Verschaeve L, Vlietinck R, Roels HA. 2001. Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: A feasibility study of biomarkers. Lancet 357(9269):1660–1669. [Comment in Lancet. 2001. 358(9295):1816–1817.] Stellman SD, Stellman JM, Sommer JF Jr. 1988. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam. Environmental Research 47:150–174. Stockbauer JW, Hoffman RE, Schramm WF, Edmonds LD. 1988. Reproductive outcomes of mothers with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Epidemiology 128:410–419. Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372–2380. Suzuki G, Nakano M, Nakano S. 2005. Distribution of PCDDs/PCDFs and Co-PCBs in human maternal blood, cord blood, placenta, milk, and adipose tissue: Dioxins showing high toxic equivalency factor accumulate in the placenta. Bioscience, Biotechnology and Biochemistry 69(10):1836–1847. Swan SH. 2006. Semen quality in fertile US men in relation to geographical area and pesticide exposure. International Journal of Andrology 29(1):62–68; discussion 105–108. Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, Wang C, Brazil C, Overstreet JW; Study for Future Families Research Group. 2003. Semen quality in relation to biomarkers of pesticide exposure. Environmental Health Perspectives 111(12):1478–1484. Tango T, Fujita T, Tanihata T, Minowa M, Doi Y, Kato N, Kunikane S, Uchiyama I, Tanaka M, Uehata T. 2004. Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan. Journal of Epidemiology 14(3):83–93. Tas S, Lauwerys R, Lison D. 1996. Occupational hazards for the male reproductive system. Critical Reviews in Toxicology 26(3):261–307. ten Tusscher GW, Stam GA, Koppe JG. 2000. Open chemical combustions resulting in a local increased incidence of orofacial clefts. Chemosphere 40(9-11):1263–1270. Townsend JC, Bodner KM, Van Peenen PFD, Olson RD, Cook RR. 1982. Survey of reproductive events of wives of employees exposed to chlorinated dioxins. American Journal of Epidemiology 115:695–713. Tuyet LTN, Johansson A. 2001. Impact of chemical warfare with Agent Orange on women’s reproductive lives in Vietnam: A pilot study. Reproductive Health Matters 9(18):156–164. Ushinohama K, Son D, Roby KF, Rozman KK, Terranova PF. 2001. Impaired ovulation by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in immature rats treated with equine chorionic gonadotropin. Reproductive Toxicology 15(3):275–280.
OCR for page 565
Veterans and Agent Orange: Update 2006 Volz DC, Bencic DC, Hinton DE, Law MJ, Kullman SW. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces organ-specific differential gene expression in male Japanese medaka (Oryzias latipes). Toxicological Sciences 85(1):572–584. Wang S-L, Chang Y-C, Chao H-R, Li C-M, Li L-A, Lin L-Y, Papke O. 2006. Body burdens of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls and their relations to estrogen metabolism in pregnant women. Environmental Health Perspectives 114(5):740–745. Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, Eskenazi B. 2004. Serum dioxin concentrations and age at menarche. Environmental Health Perspectives 112(13):1289–1292. Wen WQ, Shu XO, Steinbuch M, Severson RK, Reaman GH, Buckley JD, Robison LL. 2000. Paternal military service and risk for childhood leukemia in offspring. American Journal of Epidemiology 151(3):231–240. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. 1988. Incidence of early pregnancy loss. New England Journal of Medicine 319:189–194. Wolfe WH, Michalek JE, Miner JC, Rahe AJ, Moore CA, Needham LL, Patterson DG Jr. 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6:17–22. Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C. 2004. Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2. Biological Reproduction 70(6):1790–1797. Yamano Y, Ohyama K, Ohta M, Sano T, Ritani A, Shimada J, Ashida N, Yoshida E, Ikehara K, Morishima I. 2005. A novel spermatogenesis related factor-2 (SRF-2) gene expression affected by TCDD treatment. Endocrine Journal 52(1):75–81. Yen SC, Jaffe RB. 1991. Reproductive Endocrinology. Philadelphia, PA: W.B. Saunders Company.