Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 540
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
OCR for page 541
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,
OCR for page 542
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.
OCR for page 543
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.
OCR for page 544
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)
OCR for page 545
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
OCR for page 546
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
OCR for page 547
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
OCR for page 548
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 -
OCR for page 549
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
OCR for page 550
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)
OCR for page 600
600 VETERANS AND AGENT ORANGE: UPDATE 2010 Cooney MA, Daniels JL, Ross JA, Breslow NE, Pollock BH, Olshan AF. 2007. Household pesticides and the risk of Wilms tumor. Environmental Health Perspectives 115(1):134–137. 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. Cordier S, Lehebel A, Amar E, Anzivino-Viricel L, Hours M, Monfort C, Chevrier C, Chiron M, Robert-Gnansia E. 2010. Maternal residence near municipal waste incinerators and the risk of urinary tract birth defects. Occupational and Environmental Medicine 67(7):493–499. 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. Darnerud PO, Lignell S, Glynn A, Aune M, Tornkvist A, Stridsberg M. 2010. POP levels in breast milk and maternal serum and thyroid hormone levels in mother-child pairs from Uppsala, Swe - den. Environment International 36(2):180–187. De Felip E, Porpora MG, di Domenico A, Ingelido AM, Cardelli M, Cosmi EV, Donnez J. 2004. Dioxin-like compounds and endometriosis: A study on Italian and Belgian women of reproduc - tive age. Toxicology Letters 150(2):203–209. del Rio Gomez I, Marshall T, Tsai P, Shao Y-S, Guo YL. 2002. Number of boys born to men exposed to polychlorinated byphenlys [sic]. The Lancet 360:143–144. 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 devel - opment of methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Journal of Toxicology and Environmental Health Part A 67(18):1457–1475. Dhooge W, van Larebeke N, Koppen G, Nelen V, Schoeters G, Vlietinck R, Kaufman JM, Comhaire F, Flemish E, Health Study Group. 2006. Serum dioxin-like activity is associated with repro - ductive parameters in young men from the general Flemish population. Environmental Health Perspectives 114(11):1670–1676. Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproduc- tive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinavian Journal of Work, Environment and Health 22(4):267–273. Dong B, Nishimura N, Vogel CF, Tohyama C, Matsumura F. 2010. TCDD-induced cyclooxygenase-2 expression is mediated by the nongenomic pathway in mouse MMDD1 macula densa cells and kidneys. Biochemical Pharmacology 79(3):487–497. 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. Dragin N, Dalton TP, Miller ML, Shertzer HG, Nebert DW. 2006. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1b1 are inconsequential. Journal of Biological Chemistry 281(27):18591–18600. Driscoll R, Donovan B, Esswein E, Mattorano D. 1998. Health hazard evaluation report. US Depart- ment of Agriculture 1–72. Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE. 1994. Total serum testosterone and gonadotropins in workers exposed to dioxin. American Journal of Epidemiol- ogy 139:272–281. Ergaz Z, Avgil M, Ornoy A. 2005. Intrauterine growth restriction—etiology and consequences: What do we know about the human situation and experimental animal models? Reproductive Toxicol- ogy 20(3):301–322. Erickson J, Mulinare J, Mcclain P, Fitch T, James L, McClearn A, Adams M. 1984a. Vietnam Veter- ans’ Risks for Fathering Babies with Birth Defects. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control.
OCR for page 601
601 REPRODUCTIVE EFFECTS AND IMPACTS 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, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W, Gerthoux PM. 2002a. Serum di- oxin concentrations and endometriosis: A cohort study in Seveso, Italy. Environmental Health Perspectives 110(7):629–634. Eskenazi B, Warner M, Mocarelli P, Samuels S, Needham LL, Patterson DG Jr, Lippman S, Vercellini P, Gerthoux PM, Brambilla P, Olive D. 2002b. Serum dioxin concentrations and menstrual cycle characteristics. American Journal of Epidemiology 156(4):383–392. 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. En- vironmental 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. Environ- mental Health Perspectives 113(7):858–862. Eskenazi B, Warner M, Samuels S, Young J, Gerthoux PM, Needham L, Patterson D, Olive D, Gavoni N, Vercellini P, Mocarelli P. 2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women’s Health Study. American Journal of Epidemiology 166(1):79–87. Eskenazi B, Warner M, Marks AR, Samuels S, Needham L, Brambilla P, Mocarelli P. 2010. Serum dioxin concentrations and time to pregnancy. Epidemiology 21(2):224–231. Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. 2004. Pesticide use and menstrual cycle charac - teristics 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. Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2000. Adverse effects of TCDD on mammary gland development in Long Evans rats: A two generational study. Organohalogen Compounds 48:157–160. Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2002. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8–tetrachlorodibenzo- p-dioxin (TCDD). Toxicological Sciences 67(1):63–74. Field B, Kerr C. 1988. Reproductive behaviour and consistent patterns of abnormality in offspring of Vietnam veterans. Journal of Medical Genetics 25:819–826. Fierens S, Mairesse H, Heilier JF, de Burbure C, Focant JF, Eppe G, de Pauw E, Bernard A. 2003. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: Findings in a pop - ulation-based study in Belgium. Biomarkers 8(6):529–534. 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. Environmen- tal Health Perspectives 112(5):631–635. Foster WG, Maharaj-Briceno S, Cyr DG. 2010. Dioxin–induced changes in epididymal sperm count and spermatogenesis. Environmental Health Perspectives 118(4):458–464. Gan LQ, Fu YX, Liu X, Qiu L, Wu SD, Tian XF, Liu Y, Wei GH. 2009. Transforming growth factor- beta3 expression up-regulates on cleft palates induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin in mice. Toxicology and Industrial Health 25(7):473–478. 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.
OCR for page 602
602 VETERANS AND AGENT ORANGE: UPDATE 2010 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. Giordano F, Abballe A, De Felip E, di Domenico A, Ferro F, Grammatico P, Ingelido AM, Marra V, Marrocco G, Vallasciani S, Figa-Talamanca I. 2010. Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring. Birth Defects Research 88(4):241–250. Gonzalez BS, Lopez ML, Rico MA, Garduno F. 2008. Oral clefts: A retrospective study of prevalence and predisposal factors in the state of Mexico. Journal of Oral Science 50(2):123–129. Greenlee AR, Arbuckle TE, Chyou PH. 2003. Risk factors for female infertility in an agricultural region. Epidemiology 14(4):429–436. Gupta VK, Ali I, Suhas, Saini VK. 2006. Adsorption of 2,4-D and carbofuran pesticides using fertil - izer and steel industry wastes. Journal of Colloid and Interface Science 299(2):556–563. Halldorsson TI, Thorsdottir I, Meltzer HM, Strøm M, Olsen SF. 2009. Dioxin-like activity in plasma among Danish pregnant women: Dietary predictors, birth weight and infant development. En- vironmental Research 109(1):22–28. 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. Harari R, Julvez J, Murata K, Barr D, Bellinger DC, Debes F, Grandjean P. 2010. Neurobehavioral deficits and increased blood pressure in school-age children prenatally exposed to pesticides. Environmental Health Perspectives 118(6):890–896. 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 chloro - phenate fungicides. Epidemiology 9(1):56–60. 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. Heiden TCK, Struble CA, Rise ML, Hessner MJ, Hutz RJ, Carvan IMJ. 2008. Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: Insights into TCDD- induced endocrine disruption and reproductive toxicity. Reproductive Toxicology 25(1):47–57. Heilier JF, Nackers F, Verougstraete V, Tonglet R, Lison D, Donnez J. 2005. Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (ad - enomyotic) nodules. Fertility and Sterility 84(2):305–312. Heilier JF, Donnez J, Defrere S, Van Kerckhove V, Donnez O, Lison D. 2006. Serum dioxin-like compounds and aromatase (CYP19) expression in endometriotic tissues. Toxicology Letters 167(3):238–244. Heilier JF, Donnez J, Nackers F, Rousseau R, Verougstraete V, Rosenkranz K, Donnez O, Grandjean F, Lison D, Tonglet R. 2007. Environmental and host-associated risk factors in endometrio - sis and deep endometriotic nodules: A matched case–control study. Environmental Research 103(1):121–129. Henriksen GL, Michalek JE, Swaby JA, Rahe AJ. 1996. Serum dioxin, testosterone, and gonadotro - pins 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. Hertz-Picciotto I, Jusko TA, Willman EJ, Baker RJ, Keller JA, Teplin SW, Charles MJ. 2008. A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio. Environmental Health: A Global Access Science Source 7:37. Huisman M, Koopman-Esseboom C, Fidler V, Hadders-Algra M, van der Paauw CG, Tuinstra LG, Weisglas-Kuperus N, Sauer PJ, Touwen BC, Boersma ER. 1995. Perinatal exposure to poly - chlorinated biphenyls and dioxins and its effect on neonatal neurological development. Early Human Development 41:111–127.
OCR for page 603
603 REPRODUCTIVE EFFECTS AND IMPACTS Igarashi TM, Bruner-Tran KL, Yeaman GR, Lessey BA, Edwards DP, Eisenberg E, Osteen KG. 2005. Reduced expression of progesterone receptor-B in the endometrium of women with endome - triosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Fertility and Sterility 84(1):67–74. Ilsen A, Briet JM, Koppe JG, Pluim HJ, Oosting J. 1996. Signs of enhanced neuromotor maturation in children due to perinatal load with background levels of dioxins. Follow-up until age 2 years and 7 months. Chemosphere 33(7):1317–1326. Imura H, Yamada T, Mishima K, Fujiwara K, Kawaki H, Hirata A, Sogawa N, Ueno T, Sugahara T. 2010. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin suggests abnormal palate development after palatal fusion. Congenital Anomalies 50(2):77–84. 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 Leuke- mia in the Children of Vietnam Veterans. Washington, DC: National Academy 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. IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. IOM. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. Ishimura R, Kawakami T, Ohsako S, Tohyama C. 2009. Dioxin-induced toxicity on vascular remodel- ing of the placenta. Biochemical Pharmacology 77(4):660–669. James WH. 2006. Offspring sex ratios at birth as markers of paternal endocrine disruption. Environ- mental Research 100:77–85. Jang JY, Shin S, Choi BI, Park D, Jeon JH, Hwang SY, Kim JC, Kim YB, Nahm SS. 2007. Antiteratogenic effects of alpha-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed mice in utero. Reproductive Toxicology 24(3-4):303–309. Jang JY, Park D, Shin S, Jeon JH, Choi Bi, Joo SS, Hwang SY, Nahm SS, Kim YB. 2008. Antiteratogenic effect of resveratrol in mice exposed in utero to 2,3,7,8-tetrachlorodibenzo- p- dioxin. European Journal of Pharmacology 591(1–3):280–283. 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. Karmaus W, Huang S, Cameron L. 2002. Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring. Journal of Oc- cupational and Environmental Medicine 44(1):8–13. Keller JM, Zelditch ML, Huet YM, Leamy LJ. 2008. Genetic differences in sensitivity to alterations of mandible structure caused by the teratogen 2,3,7,8-tetrachlorodibenzo- p-dioxin. Toxicologic Pathology 36(7):1006–1013. Kerr M, Nasca PC, Mundt KA, Michalek AM, Baptiste MS, Mahoney MC. 2000. Parental occu - pational exposures and risk of neuroblastoma: A case–control study (United States). Cancer Causes and Control 11:635–643.
OCR for page 604
604 VETERANS AND AGENT ORANGE: UPDATE 2010 Khorram O, Garthwaite M, Golos T. 2002. Uterine and ovarian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions. Molecular Human Reproduction 8(1):75–80. Kline J, Stein Z, Susser M. 1989. Conception to birth: Epidemiology of prenatal development. New York: Oxford University Press. Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, eds. 1994. The Physiology of Reproduc- tion. New York: Raven Press. Konishi K, Sasaki S, Kato S, Ban S, Washino N, Kajiwara J, Todaka T, Hirakawa H, Hori T, Yasutake D, Kishi R. 2009. Prenatal exposure to PCDDs/PCDFs and dioxin-like PCBs in relation to birth weight. Environmental Research 109(7):906–913. Koopman-Esseboom C, Weisglas-Kuperus N, De Ridder MA, van der Paauw CG, Tuinstra LG, Sauer PJ. 1996. Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants’ mental and psychomotor development. Pediatrics 97(5):700–706. Kransler KM, McGarrigle BP, Swartz DD, Olson JR. 2009. Lung development in the Holtzman rat is adversely affected by gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 107(2):498–511 Kreuzer PE, Csanady GA, Baur C, Kessler W, Papke O, Greim H, Filser JG. 1997. 2,3,7,8-Tetra- chlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Archives of Toxicology 71(6):383–400. 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. Krüger T, Spanò M, Long M, Eleuteri P, Rescia M, Hjelmborg PS, Manicardi G-C, Bizzaro D, Giwercman A, Toft G, Bonde JP, Bonefeld-Jorgensen EC. 2008. Xenobiotic activity in serum and sperm chromatin integrity in European and Inuit populations. Molecular Reproduction and Development 75:669–680. Kuscu OO, Caglar E, Aslan S, Durmusoglu E, Karademir A, Sandalli N. 2009. The prevalence of molar incisor hypomineralization (MIH) in a group of children in a highly polluted urban region and a windfarm–green energy island. International Journal of Paediatric Dentistry 19(3):176–185. Laisi S, Kiviranta H, Lukinmaa PL, Vartiainen T, Alaluusua S. 2008. Molar–incisor–hypomineralisa - tion and dioxins: New findings. European Archives of Paediatric Dentistry: Official Journal of the European Academy of Paediatric Dentistry 9(4):224–227. 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. Lerda D, Rizzi R. 1991. Study of reproductive function in persons occupationally exposed to 2,4-di - chlorophenoxyacetic acid (2,4-D). Mutation Research 262(1):47–50. 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.
OCR for page 605
605 REPRODUCTIVE EFFECTS AND IMPACTS 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 defects in Seveso area after TCDD contamination. Journal of American Medical Associa- tion 259:1668–1672 (published erratum appears in JAMA 1988, 260:792). Mayani A, Barel S, Soback S, Almagor M. 1997. Dioxin concentrations in women with endometriosis. Human Reproduction 12(2):373–375. Meinert R, Schüz J, Kaletsch U, Kaatsch P, Michaelis J. 2000. Leukemia and non-Hodgkin’s lym - phoma in childhood and exposure to pesticides: Results of a register-based case–control study in Germany. American Journal of Epidemiology 151(7):639–646. Meyer KJ, Reif JS, Veeramachaneni DN, Luben TJ, Mosley BS, Nuckols JR. 2006. Agricultural pesticide use and hypospadias in eastern Arkansas. Environmental Health Perspectives 114(10): 1589–1595. Michalek JE, Albanese RA, Wolfe WH. 1998a. Project Ranch Hand II: An Epidemiologic Investiga- tion 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 retarda - tion, and infant death. Epidemiology 9(2):161–167. Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, Fujii-Kuriyama Y. 1997. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2(10):645–654. Mocarelli P, Brambilla P, Gerthoux PM, Patterson DG Jr, Needham LL. 1996. Change in sex ratio with exposure to dioxin. Lancet 348(9024):409. Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak SM, Brambilla P, Vincoli N, Signorini S, Tramacere P, Carreri V, Sampson EJ, Turner WE, Needham LL. 2000. Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355:1858–1863. Mocarelli P, Gerthoux PM, Patterson DG Jr, Milani S, Limonta G, Bertona M, Signorini S, Tramacere P, Colombo L, Crespi C, Brambilla P, Sarto C, Carreri V, Sampson EJ, Turner WE, Needham LL. 2008. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Environmental Health Perspectives 116(1):70–77. Monge P, Wesseling C, Guardado J, Lundberg I, Ahlbom A, Cantor KP, Weiderpass E, Partanen T. 2007. Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica. Scandinavian Journal of Work, Environment and Health 33(4):293–303. 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. Ameri- can Journal of Industrial Medicine 5(3):161–182. Moshammer H, Neuberger M. 2000. Sex ratio in the children of the Austrian chloracne cohort. Lancet 356:1271. Nagayama J, Okamura K, Iida T, Hirakawa H, Matsueda T, Tsuji H, Hasegawa M, Sato K, Ma HY, Yanagawa T, Igarashi H, Fukushige J, Watanabe T. 1998. Postnatal exposure to chlori - nated dioxins and related chemicals on thyroid hormone status in Japanese breast-fed infants. Chemosphere 37(9-12):1789–1793. National Institute of Child Health and Human Development. 2007. Endometriosis. National Institute of Health. http://www.nichd.nih.gov/health/topics/endometriosis.cfm (accessed December 17, 2008). NCI (National Cancer Institute). 2001. Surveillance, Epidemiology, and End Results (SEER) database. http://seer.cancer.gov/ScientificSystems/CanQues (accessed March 19).
OCR for page 606
606 VETERANS AND AGENT ORANGE: UPDATE 2010 Niskar AS, Needham LL, Rubin C, Turner WE, Martin CA, Patterson DG Jr, Hasty L, Wong L-Y, Marcus M. 2009. Serum dioxins, polychlorinated biphenyls, and endometriosis: A case–control study in Atlanta. Chemosphere 74(7):944–949. Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immuno- and reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 210(1):65–80. Oikawa K, Ohbayashi T, Mimura J, Fujii-Kuriyama Y, Teshima S, Rokutan K, Mukai K, Kuroda M. 2002. Dioxin stimulates synthesis and secretion of IgE-dependent histamine-releasing factor. Biochemical and Biophysical Research Communications 290(3):984–987. Oikawa K, Kosugi Y, Ohbayashi T, Kameta A, Isaka K, Takayama M, Kuroda M, Mukai K. 2003. Increased expression of IgE-dependent histamine-releasing factor in endometriotic implants. Journal of Pathology 199(3):318–323. Oikawa K, Yoshida K, Takanashi M, Tanabe H, Kiyuna T, Ogura M, Saito A, Umezawa A, Kuroda M. 2008. Dioxin interferes in chromosomal positioning through the aryl hydrocarbon receptor. Biochemical and Biophysical Research Communications 374(2):361–364. Park JS, Hwang SY, Hwang BY, Han K. 2008. The spermatogenic effect of 50% ethanol extracts of Yacon and its ameliorative effect against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced testicular toxicity in the rat. Natural Product Sciences 14(2):73–80. Pauwels A, Schepens PJC, Hooghe TD, Delbeke L, Dhont M, Brouwer A, Weyler J. 2001. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: A case–control study of infertile women. Human Reproduction 16(10):2050–2055. Pearce MS, Parker L. 2000. Paternal employment in agriculture and childhood kidney cancer. Pedi- atric Hematology and Oncology 17(3):223–230. Peltier MR. 2003. Immunology of term and preterm labor. Reproductive Biology and Endocrinology 1:122–132. Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. 1993. Cancer in a young popu - lation in a dioxin-contaminated area. International Journal of Epidemiology 22(6):1010–1013. Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, Peterson MR, Phillips DL. 1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 27:165–171. Pluim H, de Vijlder J, Olie K, Kok J, Vulsma T, van Tijn D, van der Slikke JW, Koppe JG. 1993. Ef - fects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations. Environmental Health Perspectives 101(6):504–508. Polsky JY, Aronson KJ, Heaton JP, Adams MA. 2007. Pesticides and polychlorinated biphenyls as potential risk factors for erectile dysfunction. Journal of Andrology 28(1):28–37. Porpora MG, Ingelido AM, di Domenico A, Ferro A, Crobu M, Pallante D, Cardelli M, Cosmi EV, De Felip E. 2006. Increased levels of polychlorobiphenyls in Italian women with endometriosis. Chemosphere 63(8):1361–1367. Porpora MG, Medda E, Abballe A, Bolli S, De Angelis I, di Domenico A, Ferro A, Ingelido AM, Maggi A, Panici PB, De Felip E. 2009. Endometriosis and organochlorinated environmental pollutants: A case–control study on Italian women of reproductive age. Environmental Health Perspectives 117(7):1070–1075. 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 pesti - cide use and childhood cancer in California. Epidemiology 16(1):93–100. Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL. 1993. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Funda- mental and Applied Toxicology 21(4):433–441.
OCR for page 607
607 REPRODUCTIVE EFFECTS AND IMPACTS Romo A, Carceller R, Tobajas J. 2009. Intrauterine growth retardation (IUGR): Epidemiology and etiology. Pediatric Endocrinology Reviews 6(Suppl 3):332–336. Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. 2008. A case–control study of childhood brain tumors and fathers’ hobbies: A Children’s Oncology Group Study. Cancer Causes and Control 19(10):1201–1207. Rudant J, Menegaux F, Leverger G, Baruchel A, Nelken B, Bertrand Y, Patte C, Pacquement H, Verite C, Robert A, Michel G, Margueritte G, Gandemer V, Hemon D, Clavel J. 2007. Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE). Environmental Health Perspectives 115(12):1787–1793. Rull RP, Gunier R, Von Behren J, Hertz A, Crouse V, Buffler PA, Reynolds P. 2009. Residential proximity to agricultural pesticide applications and childhood acute lymphoblastic leukemia. Environmental Research 109(7):891–899. Ryan JJ, Amirova Z, Carrier G. 2002. Sex ratios of children of Russian pesticide producers exposed to dioxin. Environmental Health Perspectives 110(11):A699–A701. Savitz DA, Arbuckle A, Kaczor D, Curtis KM. 1997. Male pesticide exposure and pregnancy out - come. American Journal of Epidemiology 146(12):1025–1036. 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 occu - pational 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. Schwartz LS. 1998. Health Problems of Women Veterans of the Vietnam War. Doctoral dissertation, Yale University. Shim YK, Miynarek SP, van Wijngaarden E. 2009. Parental exposure to pesticides and childhood brain cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environmental Health Per- spectives 117(6):1002–1006. Singh MN, Stringfellow HF, Taylor SE, Ashton KM, Ahmad M, Abdo KR, El-Agnaf OMA, Martin- Hirsch PL, Martin FL. 2008. Elevated expression of CYP1A1 and gamma–SYNUCLEIN in human ectopic (ovarian) endometriosis compared with eutopic endometrium. Molecular Human Reproduction 14(11):655–663. Skinner MK, Manikkam M, Guerrero-Bosagna C. 2010. Epigenetic transgenerational actions of envi- ronmental factors in disease etiology. Trends in Endocrinology and Metabolism 21(4):214–222. 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. Spix C, Schulze-Rath R, Kaatsch P, Blettner M. 2009. Case–control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany. Klinische Padiatrie 221(6):362–368. 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 Epidemiol- ogy 128:410–419.
OCR for page 608
608 VETERANS AND AGENT ORANGE: UPDATE 2010 Su P-H, Chen J-Y, Chen J-W, Wang S-L. 2010. Growth and thyroid function in children with in utero exposure to dioxin: A 5-year follow-up study. Pediatric Research 67(2):205–210. 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, 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. Tawara K, Nishijo M, Honda R, Maruzeni S, Seto T, Kido T, Saito S, Nakagawa H. 2009. Effects of maternal dioxin exposure on newborn size at birth among Japanese mother-infant pairs. Envi- ronmental Health and Preventive Medicine 14(2):88–95. Teixeira de Siqueira M, Braga C, Cabral–Filho JE, Augusto LGDS, Figueiroa JN, Souza AI. 2010. Correlation between pesticide use in agriculture and adverse birth outcomes in Brazil: An ecological study. Bulletin of Environmental Contamination and Toxicology 84 (6):647–651. ten Tusscher GW, Stam GA, Koppe JG. 2000. Open chemical combustions resulting in a local in - creased incidence of orofacial clefts. Chemosphere 40(9-11):1263–1270. ten Tusscher GW, Steerenberg P, van Loveren H, Vos JG, von dem Borne AE, Westra M, van der Slikke J, Olie K, Pluim H, Koppe JG. 2003. Persistent hematologic and immunologic distur- bances in 8-year-old Dutch children associated with perinatal dioxin exposure. Environmental Health Perspectives 111(12):1519–1523. ten Tusscher GW, Guchelaar H-J, Koch J, Ilsen A, Vulsma T, Westra M, van der Slikke JW, Olie K, Koppe JG. 2008. Perinatal dioxin exposure, cytochrome p-450 activity, liver functions and thyroid hormones at follow-up after 7–12 years. Chemosphere 70(10):1865–1872. Toft G, Long M, Kruger T, Hjelmborg PS, Bonde JP, Rignell-Hydbom A, Tyrkiel E, Hagmar L, Giwercman A, Spano M, Bizzaro D, Pedersen HS, Lesovoy V, Ludwicki JK, Bonefeld-Jor- gensen EC. 2007. Semen quality in relation to xenohormone and dioxin-like serum activity among Inuits and three European populations. Environmental Health Perspectives 115(Suppl 1):15–20. 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 Epidemiol- ogy 115:695–713. Tsuchiya M, Tsukino H, Iwasaki M, Sasaki H, Tanaka T, Katoh T, Patterson DG Jr, Turner W, Needham L, Tsugane S. 2007. Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis. Molecular Human Reproduction 13(6):399–404. Tsukimori K, Tokunaga S, Shibata S, Uchi H, Nakayama D, Ishimaru T, Nakano H, Wake N, Yoshimura T, Furue M. 2008. Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident. Environmental Health Perspec- tives 116(5):626–630. Tuyet LTN, Johansson A. 2001. Impact of chemical warfare with Agent Orange on women’s reproduc- tive lives in Vietnam: A pilot study. Reproductive Health Matters 9(18):156–164.
OCR for page 609
609 REPRODUCTIVE EFFECTS AND IMPACTS Vreugdenhil HJI, Slijper FME, Mulder PGH, Weisglas-Duperus N. 2002. Effects of perinatal ex - posure to PCBs and dioxins on play behavior in Dutch children at school age. Environmental Health Perspectives 110(10):A593–A598. Waller SA, Paul K, Peterson SE, Hitti JE. 2010. Agricultural–related chemical exposures, season of conception, and risk of gastroschisis in Washington State. American Journal of Obstetrics and Gynecology 202(3):241–246. Wang Y, Yu J, Luo X, Wang X, Li M, Wang L, Li D. 2010. Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells. Cellular and Molecular Im- munology 7(1):51–60. Ward MH, Colt JS, Metayer C, Gunier RB, Lubin J, Crouse V, Nishioka MG, Reynolds P, Buffler PA. 2009. Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia. Environmental Health Perspectives 117(6):1007–1013. 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. Warner M, Eskenazi B, Olive DL, Samuels S, Quick-Miles S, Vercellini P, Gerthoux PM, Needham L, Patterson DG Jr, Mocarelli P. 2007. Serum dioxin concentrations and quality of ovarian function in women of Seveso. Environmental Health Perspectives 115(3):336–340. Weisglas-Kuperus N, Sas T, Koopman-Esseboom C, van der Zwan C, De Ridder M, Beishuizen A, Hooijkaas H, Sauer, P. 1995. Immunologic effects of background prenatal and postna- tal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Pediatric Research 38(3):404–410. Weisglas-Kuperus N, Patandin S, Berbers GAM, Sas TCJ, Mulder PGH, Sauer PJJ, Hooijkaas H. 2000. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environmental Health Perspectives 108(12):1203–1207. 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. Weselak M, Arbuckle TE, Wigle DT, Krewski D. 2007. In utero pesticide exposure and childhood morbidity. Environmental Research 103(1):79–86. Weselak M, Arbuckle TE, Wigle DT, Walker MC, Krewski D. 2008. Pre-and post-conception pesti - cide exposure and the risk of birth defects in an Ontario farm population. Reproductive Toxicol- ogy 25(4):472–480. 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. Winchester PD, Huskins J, Ying J. 2009. Agrichemicals in surface water and birth defects in the United States. Acta Paediatrica, International Journal of Paediatrics 98(4):664–669. 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 em - bryos 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, Asano A, Ohta M, Hirata S, Shoda T, Ohyama K. 2009. Expression of rat sperm flagellum- movement associated protein genes under 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Biosci- ence, Biotechnology and Biochemistry 73(4):946–949. Yen SC, Jaffe RB. 1991. Reproductive Endocrinology. Philadelphia: W.B. Saunders Company. Yoshimura T, Kaneko S, Hayabuchi H. 2001. Sex ratio in offspring of those affected by dioxin and dioxin-like compounds: The Yusho, Seveso, and Yucheng incidents. Occupational and Envi- ronmental Medicine 58(8):540–541.
OCR for page 610
610 VETERANS AND AGENT ORANGE: UPDATE 2010 Yoshizawa K, Brix AE, Sells DM, Jokinen MP, Wyde M, Orzech DP, Kissling GE, Walker NJ, Nyska A. 2009. Reproductive lesions in female Harlan Sprague-Dawley rats following two-year oral treatment with dioxin and dioxin-like compounds. Toxicologic Pathology 37(7):921–937. Yu J, Wang Y, Zhou W-H, Wang L, He Y-Y, Li D-J. 2008. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. Human Reproduction 23(7):1614–1626. Zhao D, Lebovic DI, Taylor RN. 2002. Long-term progestin treatment inhibits RANTES (regulated on activation, normal T cell expressed and secreted) gene expression in human endometrial stromal cells. Journal of Clinical Endocrinology and Metabolism 87(6):2514–2519.