8

Reproductive Effects and Impacts on Future Generations

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2008, hereafter referred to as Update 2008 (IOM, 2009), 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, 2002, 2004, and 2006 [IOM, 1996, 1999, 2001, 2003, 2005, 2007] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Because some polychlorinated biphenyls (PCBs), some polychlorinated dibenzofurans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs).

As in previous updates, the adverse outcomes evaluated include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant mortality, and such other adverse birth outcomes as low birth weight, preterm birth, and birth defects. In addition to the more delayed problem of childhood cancer in their offspring, this update also addresses the concern of Vietnam veterans that their military exposures may contribute to other problems that their children experience later in life or that are manifested in later generations. Finally, as suggested in Update 2008, endometriosis and pregnancy loss will no



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8 Reproductive Effects and Impacts on Future Generations This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2008, hereafter referred to as Update 2008 (IOM, 2009), 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, 2002, 2004, and 2006 [IOM, 1996, 1999, 2001, 2003, 2005, 2007] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) The categories of as- sociation and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Because some polychlori- nated biphenyls (PCBs), some polychlorinated dibenzofurans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like bio- logic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs). As in previous updates, the adverse outcomes evaluated include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant mortality, and such other adverse birth outcomes as low birth weight, preterm birth, and birth defects. In addition to the more delayed problem of childhood cancer in their offspring, this update also addresses the concern of Vietnam veterans that their military exposures may contribute to other problems that their children experience later in life or that are manifested in later generations. Finally, as suggested in Update 2008, endometriosis and pregnancy loss will no 540

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541 REPRODUCTIVE EFFECTS AND IMPACTS longer be fully evaluated after this update. It is unlikely, given the age of the Vietnam veteran cohort, that any newly published data on those two outcomes will provide additional information that would be directly relevant to that cohort. However, if new research suggests that the two outcomes may be influenced by epigenetic changes, their relevance to transgenerational effects will be assessed in future updates. To reduce repetition throughout the report, Chapter 5 presented design in - formation on new studies that report findings on multiple health outcomes. To provide context for publications that present new results on study populations that were addressed in publications reviewed in earlier updates, Chapter 5 also dis - cussed the overall characteristics of those populations with details about design and analysis relevant to individual publications. Design information on new stud- ies that report only reproductive health outcomes and are not revisiting previously studied populations is summarized in this chapter with results. This chapter’s primary emphasis is on the potential adverse reproductive effects of herbicide exposure of men because the vast majority of Vietnam vet- erans are men. However, 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. Whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately. Exposure scenarios in human populations and experimental animals studied differ in their applicability to our population of concern according to whether the exposed parent was a male or female veteran. In addition, for published epidemiologic or experimental results to be fully rel - evant to evaluation of the plausibility of reproductive effects in Vietnam veterans, whether female or male, the timing of exposure needs to correspond to the vet - erans’ experience (that is, it must have occurred only before conception). With the possible exception of female veterans who became pregnant while serving in Vietnam, pregnancies that might have been affected occurred after deployment, when primary exposure had ceased. BIOLOGIC PLAUSIBILITY OF REPRODUCTIVE EFFECTS This chapter opens with a general discussion of factors that influence the plausibility that TCDD and the four herbicides used in Vietnam could have ad - verse reproductive effects. There have been few reproductive studies of the four herbicides in question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the preponderance of the following discussion concerns TCDD, which outside of controlled experi - mental circumstances usually occurred in a mixture of dioxins (dioxin congeners in addition to TCDD). Because TCDD is stored in fat tissue and has a long biologic half-life, inter- nal exposure at generally constant concentrations may continue after episodic,

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542 VETERANS AND AGENT ORANGE: UPDATE 2010 high-level exposure to external sources has ceased. If a person had high exposure, there may still be high amounts of dioxins stored in fat tissue, which may be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid. A father’s contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg and any damage to the embryo or offspring would result from either genetic or epigenetic changes of the sperm DNA. Epigenetic effects are ones that result in permanent (heritable) changes in gene expression without a change in DNA sequence. Dioxins have not been shown to mutate DNA se- quence, so any damage to an embryo or offspring from a dioxin-exposed father would be limited to epigenetic effects. A mother’s contribution to a pregnancy is obviously more extensive, and any damage to an embryo or offspring can result from epigenetic changes of the egg DNA or from direct effects of exposure on the fetus during gestation and on the neonate during lactation. Dioxin in the mother’s bloodstream can cross the placenta and expose the developing embryo and fetus. Furthermore, mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus or nursing infant. In humans, TCDD has been measured in circulating maternal blood, cord blood, placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as that in an infant not breastfed (Lorber and Phillips, 2002). On the basis of laboratory animal studies, TCDD can affect reproduction and development, so a connection between TCDD exposure and human reproductive and developmental effects is biologically plausible. However, definitive conclu- sions based on animal studies about the potential for TCDD to cause reproductive and developmental toxicity in humans are complicated by differences in sensi - tivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-dichlorophen - oxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (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 their repro - ductive or developmental effects. The biologic-plausibility sections on the specific outcomes considered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed.

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543 REPRODUCTIVE EFFECTS AND IMPACTS ENDOMETRIOSIS Endometriosis (International Classification of Diseases, 9th revision [ICD- 9], code 617) affects 5.5 million women in the United States and Canada at any given time (National Institute of Child Health and Human Development, 2007). The endometrium is the tissue that lines the inside of the uterus and is built up and shed each month during menstruation. In endometriosis, endometrial cells are found outside the uterus―usually in other parts of the reproductive system, in the abdomen, or on surfaces near the reproductive organs. The ectopic tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with the menstrual cycle. Unlike blood released during normal shedding of the endometrium lining the uterus, blood released from endometrial lesions has no way to leave the body, and results in inflammation and internal bleeding. The degeneration of blood and tissue can cause scarring, pain, infertility, adhesions, and intestinal problems. There are several theories of the etiology of endometriosis, including a ge - netic contribution, but the cause remains unknown. Estrogen dependence and im- mune modulation are established features of endometriosis but do not adequately explain its cause. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those with immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometrio - sis, diagnosis is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure. Conclusions from VAO and Previous Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies, and Update 2004 examined three environmental studies. Three additional environmental studies considered in Update 2008 did not change the conclusion that the evidence was inadequate or insufficient to support an association with herbicide exposure. Table 8-1 provides a summary of relevant studies that have been reviewed. Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and endometriosis have been published since Update 2008.

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544 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 8-1 Selected Epidemiologic Studies—Endometriosis Reference Study Population Study Results ENVIRONMENTAL Studies Conducted in the United States Niskar Case–control study of Results for cases vs controls: et al., 2009 women in Atlanta, GA Total TEQ (determined by GC/MS): OR = 01.00 (95% with endometriosis; CI 0.930–1.07) 60 cases and 64 controls Studies Conducted in Belgium Heilier 88 matched triads (264 Results for pelvic endometriosis vs controls: et al., 2007 total); patients with deep Dietary fat: OR = 1.0 (95% CI 1.0–1.0) endometriotic nodules, BMI: OR = 1.0 (95% CI 0.9–1.0) pelvic endometriosis, Occupation: OR = 0.5 (95% CI 0.2–1.1) controls matched for age, Traffic: OR = 1.0 (95% CI 0.3–2.8) gynecologic practice Incinerator: OR = 1.0 (95% CI 1.0–1.1) in Belgium; routes of exposure to DLCs examined Heilier Serum DLC and No association between TEQs (determined by GC/MS) et al., 2006 aromatase activity in of DLCs in serum and aromatase activity by regression endometriotic tissue from analyses. 47 patients in Belgium p-values = 0.37–0.90 for different endometriosis subgroups Heilier Endometriosis in Belgian 50 exposed cases, risk of increase of 10 pg/g lipid of et al., 2005 women with overnight TEQ compounds (determined by GC/MS); OR = 2.6 fasting serum levels of (95% CI 1.3–5.3) PCDD, PCDF, PCB Fierens Belgian women with Mean concentration of TEQ (determined by GC/MS): et al., 2003 environmental exposure Cases (n = 10), 26.2 (95% CI 18.2–37.7) to PCDDs, PCDFs; Controls (n = 132), 25.6 (95% CI 24.3–28.9) compared analyte No significant difference concentrations in cases vs controls Pauwels Patients undergoing Six exposed cases: OR = 4.6 (95% CI 0.5–43.6) et al., 2001 infertility treatment in Belgium; compared number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay)

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545 REPRODUCTIVE EFFECTS AND IMPACTS TABLE 8-1 Endometriosis, continued Reference Study Population Study Results Studies Conducted in Italy Porpora Case–control study of Results for endometriosis vs controls: dl-PCB 118 compared to ≤ 13.2 ng/g: et al., 2009 Italian women with endometriosis; 80 cases 13.3–24.2 ng/g; OR = 3.17 (95% CI 1.36–7.37) ≥ 24.3 ng/g; OR = 3.79 (95% CI 1.61–8.91) and 78 controls (TEQs Total TEQ compared to ≤ 15.6 pgC-TEQ/g fat: determined by CALUX bioassay) 15.7–29.5 pgC-TEQs/g fat; OR = 0.52 (95% CI 0.18–1.48) ≥ 29.6 pgC-TEQ/g fat; OR = 0.73 (95% CI 0.26–2.01) Porpora Case–control study of Mean total PCBs (ng/g) et al., 2006 Italian women with Cases, 410 ng/g endometriosis, measured Control, 250 ng/g serum PCBs All PCB congeners: OR = 4.0 (95% CI 1.3–13) De Felip Pilot study of Italian, Mean concentration of TCDD (ppt of lipid): et al., 2004 Belgian women of Italy: reproductive age; Controls (10 pooled samples), 1.6 compared concentrations Cases (two sets of 6 pooled samples), 2.1, 1.3 of TCDD, total TEQ Belgium: (determined by GC/MS) Controls (7 pooled samples), 2.5 in pooled blood samples Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), from women who had 2.3, 2.3 diagnosis endometriosis Mean concentration of TEQ (ppt of lipid): with controls Italy: Controls (10 pooled samples), 8.9 ± 1.3 (99% CI 7.2–11.0) Cases (two sets of 6 pooled samples), 10.7 ± 1.6; 10.1 ± 1.5 Belgium: Controls (7 pooled samples), 24.7 ± 3.7 (99% CI 20–29) Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 18.1 ± 2.7; 27.1 ± 4.0 Eskenazi Residents of Seveso Serum TCDD (ppt): ≤ 20 (n = 2 cases), RR = 1.0 (reference) et al., Zones A and B up 2002a to 30 years old in 20.1–100, (n = 8), RR = 1.2 (90% CI 0.3–4.5) > 100, (n = 9), RR = 2.1 (90% CI 0.5–8.0) 1976; population- based historical cohort comparing incidence of endometriosis across serum TCDD concentrations continued

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546 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 8-1 Endometriosis, continued Reference Study Population Study Results Studies Conducted in Israel Mayani Residents of Jerusalem 8 exposed cases: OR = 7.6 (95% CI 0.9–169.7) et al., 1997 being evaluated for infertility; compared number of women with high TCDD who had (n = 44), did not have (n = 35) diagnosis of endometriosis Studies Conducted in Japan Tsuchiya 138 infertility patients Results for advanced endometriosis: et al., 2007 in Japan; laproscopically Total TEQ: OR = 0.5 (95% CI 0.2–1.7) confirmed case–control Genotype-specific: ORs = 0.3–0.6 status, serum dioxin, No significant interaction between genotype, dioxin TEQ PCB TEQ (determined by GC/MS); P450 genetic polymorphism ABBREVIATIONS: BMI, body mass index; CALUX, chemical activated luciferase gene expres - sion; CI, confidence interval; dl, dioxin-like; DLC, dioxin-like compound; GA, Georgia; GC/MS, gas chromatography/mass spectrometry; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent. Environmental Studies Niskar et al. (2009) recruited 144 women who lived in Atlanta, Georgia, during 1998–1999 for a case–control study of endometriosis. TCDD TEQs were calculated on the basis of the serum concentration of each of the dioxin-like PCDDs, PCDFs, and PCBs; total PCBs were calculated on the basis of the sum of 36 PCB congeners measured in serum. Persons who had endometriosis (n = 60) and controls who did not (n = 64) were selected from patients seeking con- sultation at a reproductive-medicine clinic. At the time of enrollment, cases had been recently diagnosed, confirmed with biopsy, and staged as minimal, mild, moderate, or severe. No difference was observed between cases and controls with regard to TEQ or total PCBs on the basis of either lipid-adjusted or non–lipid- adjusted values. A second case–control study of endometriosis was completed in Rome, Italy (Porpora et al., 2009). Women scheduled for laparoscopy were recruited from a reproductive-medicine clinic. Cases (n = 80) were confirmed and staged with

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547 REPRODUCTIVE EFFECTS AND IMPACTS histologic analyses. Controls (n = 78) were women who had no known infertility and underwent laparoscopy for unrelated gynecologic conditions. An increased risk of endometriosis was observed with increasing serum concentrations of the dioxin-like PCB 118. When they were compared with women who had the low - est concentrations of PCB 118 (≤ 13.3 ng/g serum lipid), the adjusted odds ratios (ORs) for endometriosis were 3.14 (95% confidence interval [CI] 1.36–7.37) and 3.79 (95% CI 1.61–8.91) for women who had serum PCB 118 concentrations of 13.3–24.2 ng/g lipid and more than 24.2 ng/g lipid, respectively. However, no association was observed with total TEQs: an OR of 0.73 (95% CI 0.26–2.01) in women who had the highest concentration of total TEQ (> 29.6 pg TEQ/g lipid). Biologic Plausibility Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. The first sug - gestion that TCDD exposure may be linked to endometriosis came as a secondary finding of a study that exposed female rhesus monkeys (Macaca mulatta) chroni- cally to low concentrations of dietary TCDD for 4 years (Rier et al., 1993). Ten years after the exposure ended, the investigators documented an increased inci - dence of endometriosis in the monkeys that correlated with the TCDD exposure concentration. The small sample prevented a definitive conclusion that TCDD was a causal agent of endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of pre-existing endometriotic lesions. A number of proposed mechanisms by which TCDD may promote endome - trial lesions provide additional biologic plausibility of the link between TCDD and endometriosis. Human endometrial tissue expresses the aryl hydrocarbon receptor (AHR) and its dimerization partner, the aryl hydrocarbon nuclear trans - locator (ARNT) (Khorram et al., 2002), and three AHR target genes: CYP1A1, 1A2, and 1B1 (Bulun et al., 2000); this suggests that endometrial tissue is re - sponsive to TCDD. Recently, it was shown that CYP1A1 expression increases in ectopic endometrial tissue from women, compared with eutopic uterine tissue, in the absence of TCDD exposure, and this suggests that CYP1A1 may play a role in disease etiology (Singh et al., 2008). Other mechanisms by which TCDD may promote endometriosis include altering the ratio of progesterone receptor A to B and blocking the ability of progesterone to suppress matrix metalloproteinase (MMP) expression—actions that promote endometrial-tissue invasion and that are observed in women who have endometriosis (Igarashi et al., 2005). TCDD also induces changes in gene expression that mirror those observed in endometrial lesions. In addition to the induction of CYP1A1 noted above, TCDD can induce expression of histamine-releasing factor, which is increased in endo - metrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). Simi - larly, TCDD stimulates expression of RANTES (regulated on activation, normal

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548 VETERANS AND AGENT ORANGE: UPDATE 2010 T-cell–expressed, and secreted) in endometrial stromal cells, and RANTES con- centration and bioactivity are increased in women who have endometriosis (Zhao et al., 2002). The two CC-motif chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory protein 1α (MIP-1α), have been identified as potential contributors to the pathogenesis and progression of endometriosis. Pre - vious studies showed that the combination of 17β-estradiol and TCDD increased the secretion of RANTES and MIP-1α in endometrial stromal cells (Yu et al., 2008), and a more recent study showed that the same combination increased ex- pression of the chemokine C receptor 9 (CCR9) and the secretion of its ligand, thymus-expressed chemokine (TECK), in endometriosis-associated cells (Wang et al., 2010). Those results support the idea that TCDD in combination with estra - diol may contribute to the development of endometriosis by increasing invasive - ness of endometrial cells. Despite that compelling evidence, chronic exposure of rats to TCDD, a dioxin-like PCB, or PCDF or a mixture of the three fails to alter endometrial histology in a consistent manner (Yoshizawa et al., 2009). Differ- ences between the rodent uterus and human endometrium could account for that lack of observed effects in rats. In summary, experimental studies, particularly those using human eutopic and ectopic endometrial tissue provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. Synthesis The new epidemiologic studies described above were contradictory in their findings and did not assess dioxin directly. Overall, the studies linking dioxin exposure with endometriosis are few and inconsistent. The association in animal studies is biologically plausible, but it is possible that human exposures are too low to show an association consistently. Conclusion On the basis of the evidence reviewed here, in VAO, and in the previous VAO updates, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and human endometriosis. 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 health outcomes related to male fertility, including reproductive hor- mones and sperm characteristics, can be studied as indicators of fertility. The reproductive neuroendocrine axis involves the central nervous system, the an -

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549 REPRODUCTIVE EFFECTS AND IMPACTS terior 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 se - creted 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 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). Studies of the relationship between chemicals and fertility are less common in women than in men. 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 that result in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and meno- pause, and impairment of fertility (Bretveld et al., 2006a,b). Conclusions from VAO and Previous Updates The committee responsible for the original VAO report (IOM, 1994) con- cluded that there was inadequate or insufficient evidence of an association be - tween exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility. Additional information available to the com - mittees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Reviews of the relevant studies are presented in the earlier reports. Tables 8-2 and 8-3 summarize the studies related to male and female fertility, respectively. Update of the Epidemiologic Literature Male Fertility No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and male fertility have been published since Update 2008. Environmental Studies Since Update 2008, two studies published on semen quality and exposure to organochlorine compounds have been published. The first, by Cok et al. (2010), explored associations between PCBs measured in adi - pose tissue and fertility status in 25 infertile men and 21 healthy men. Infertile

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550 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 8-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility) Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population VIETNAM VETERANS US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs Gupta Coefficient (p-value) et al., 2006 for ln(Testosterone) vs AFHS (964 Ranch Hands, 1,259 comparison) ln(TCDD) in 1987 Comparison TCDD quartile I nr 0 (referent) (mean, 2.14 ppt) Comparison TCDD quartile II nr –0.063 (0.004) (mean, 3.54 ppt) Ranch Hand TCDD quartile I nr 0.002 (0.94) (mean, 4.14 ppt) Comparison TCDD quartile III nr –0.048 (0.03) (mean, 4.74 ppt) –0.079 (< 0.001) Comparison TCDD quartile IV nr (mean, 7.87 ppt) Ranch Hand TCDD quartile II nr –0.052 (0.03) (mean, 8.95 ppt) Ranch Hand TCDD quartile III nr –0.029 (0.22) (mean, 18.40 ppt) Ranch Hand TCDD quartile IV nr –0.056 (0.02) (mean, 76.16 ppt) Henriksen Effects on specific hormone concentrations or et al., 1996 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)

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