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7 Reproductive and Developmental Effects
Pages 517-565

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From page 517...
... The literature discussed includes papers that describe environmental, occupational, and Vietnam-veteran studies that evaluate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirth, neonatal and infant mortality, low birth weight and preterm birth, and childhood cancer. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
From page 518...
... , TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that finding.
From page 519...
... Intermenstrual bleeding 1.1 (0.9–1.4) Studies Reviewed in Update 2000 Abell et al., 2000 Female greenhouse workers in Denmark (maternal exposure)
From page 520...
... Studies Reviewed in Update 2002 Staessen et al., Adolescents in communities close to industrial 2001 sources of heavy metals, PCBs, VOCs, and PAHs -- delays in sexual maturity In Hoboken, Belgium 8 4.0 (*
From page 521...
... Studies Reviewed in VAO CDC, 1989b Vietnam Experience Study Lower sperm concentration 42 2.3 (1.2–4.3) Proportion of abnormal sperm 51 1.6 (0.9–2.8)
From page 522...
... (2004) reported on the menstrual-cycle characteristics of 3,103 premenopausal women in the Agricultural Health Study (AHS)
From page 523...
... and earlier onset of natural menopause but also suggested that women with the highest serum TCDD did not have the earliest onset of menopause. Age at which the subjects of this study were exposed represents an appropriate match for the experience of female Vietnam veterans.
From page 524...
... In contrast with the lack of evidence on 2,4-D and 2,4,5-T, many diverse laboratory studies provide evidence that TCDD can affect reproductive organ function and reduce fertility in both men and women. TCDD exposure can reduce fertility in male rats and is associated with histologic changes in the testis (Chahoud et al., 1989)
From page 525...
... Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion. Information available to the committee responsible for Update 2002, however, led to the conclusion that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion, but that there was insufficient information to determine whether an association exists between maternal exposure to TCDD and the risk of spontaneous abortion or between maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion.
From page 526...
... No new occupational or Vietnam-veteran studies concerning exposure to the compounds of interest and spontaneous abortion were published since Update 2004. Biologic Plausibility Laboratory animal studies demonstrate that TCDD exposure during pregnancy can alter circulating steroid hormone concentrations (Simanainen et al., 2004)
From page 527...
... 1,120 ppt 8 1.0 (0.4–2.2) Studies Reviewed in Update 2000 Driscoll et al., Women employed by the US Forest 1998 Service -- miscarriages (maternal exposure)
From page 528...
... ) Studies Reviewed in Update 2000 Schwartz, 1998 Female Vietnam veterans (maternal exposure)
From page 529...
... Conclusions The present committee concurs with the overall conclusion of the previous committees that paternal exposure to TCDD is not associated with risk of spontaneous abortion and that insufficient information is available to determine whether an association exists between the risk of spontaneous abortion and maternal exposure to TCDD or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid. STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH Stillbirth or late fetal death typically refers to the delivery at or after 20 weeks of gestation of a fetus that shows no signs of life, including fetuses that
From page 530...
... Biologic Plausibility Laboratory studies of maternal TCDD exposure during pregnancy have demonstrated the induction of fetal death; neonatal death, however, is only rarely
From page 531...
... Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest and stillbirth, neonatal death, or infant death. BIRTH WEIGHT AND PRETERM DELIVERY The World Health Organization recommends 2,500 g as the threshold for designation of low birth weight (Alberman, 1984)
From page 532...
... Such an alteration would, however, be indicative of some impact on reproductive function, as mentioned in the section on biologic plausibility at the end of this chapter. Of the new articles reporting reproductive effects, two environmental studies that presented findings on birth weight and gestational age also assessed possible changes in the sex ratio at birth; their findings for this additional endpoint are included below.
From page 533...
... was not available. Categorical comparisons of the predicted high and low exposed districts with the reference districts found no associations for low birth weight (under 2,500 g)
From page 534...
... Synthesis The three studies reviewed here (two environmental and one based on an occupational cohort) did not find an association between exposure to the compounds of interest and the risk of low birth weight or prematurity.
From page 535...
... Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest and low birth weight or preterm delivery. BIRTH DEFECTS The March of Dimes defines a birth defect as "an abnormality of structure, function or metabolism, whether genetically determined or as the result of an environmental influence during embryonic or fetal life" (Bloom, 1981)
From page 536...
... The committee for Update 2002, which reviewed the study of female Vietnam veterans (Kang et al., 2000) reporting significant increases in the occurrence of birth defects among their offspring, did not find those results adequate to modify prior conclusions.
From page 537...
... Studies Reviewed in VAO Moses et al., 1984 Follow-up of 2,4,5-T male production workers 11 1.3 (0.5–3.4) Suskind and Follow-up of 2,4,5-T male production workers 18 1.1 (0.5–2.2)
From page 538...
... index 14 3.1(0.6–16.9) Studies Reviewed in VAO Fitzgerald et al., Persons exposed to an electrical transformer 1989 fire -- total birth defects (maternal or paternal exposure)
From page 539...
... e Isolated cleft palate 7 1.4 (0.6–3.2) e VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., 2000 Female Vietnam-era veterans -- deployed vs non deployed (maternal exposure)
From page 540...
... Donovan et al., Australian Vietnam veterans 1984 Vietnam veterans vs all other men 127 1.02 (0.8–1.3) National Service veterans -- Vietnam service vs no Vietnam service 69 1.3 (0.9–2.0)
From page 541...
... TABLE 7-4 Selected Epidemiologic Studies -- Neural Tube Defects in the Offspring of Subjects Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI) a OCCUPATIONAL Studies Reviewed in Update 1998 Blatter et al., Dutch farmers 1997 Spina bifida -- moderate/heavy exposure Pesticide use 8 1.7 (0.7–4.0)
From page 542...
... ) Studies Reviewed in VAO CDC, 1989b Vietnam Experience Study Spina bifida Vietnam veterans' children 9 1.7 (0.6–5.0)
From page 543...
... 454 post-service births were studied in Ranch Hand veterans; 570 in comparison cohort. f Number of Vietnam veterans fathering a child with a neural tube defect given any exposure op portunity index.
From page 544...
... and 9 of Vietnam veterans (2 unpublished)
From page 545...
... . The non-Vietnamese study populations consisted of Vietnam veterans, who were almost exclusively men, whereas the Vietnamese populations had a much greater likelihood of maternal exposure.
From page 546...
... Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion.
From page 547...
... It reclassified AML from "limited/suggestive evidence of an association" to "inadequate evidence to determine whether an association exists." Table 7-5 summarizes the results of the relevant studies. The committees responsible for Update 2000, Update 2002, and Update 2004 reviewed the material in earlier VAO reports and in newly available published literature and agreed that there remained inadequate or insufficient evidence of an association between exposure and childhood cancers.
From page 548...
... Central nervous system tumors 31 0.9 (0.5–1.4) Studies Reviewed in Update 2004 Flower Offspring of male pesticide applicators in Iowa from et al., 2004 AHS Maternal exposure to chlorophenoxy herbicides 7 0.7 (0.3–1.5)
From page 549...
... Studies Reviewed in Update 2000 Meinert Childhood cancer -- population-based case–control study et al., 2000 Leukemia Paternal exposure; year before pregnancy 62 1.5 (1.1–2.2) Paternal exposure; during pregnancy 57 1.6 (1.1–2.3)
From page 550...
... VIETNAM VETERANS Studies Reviewed in Herbicide/Dioxin Exposure and AML in the Children of Veterans AIHW, Australian Vietnam veterans' children -- Revised 2001 Validation Study -- AML 12d 1.3 (0.8–4.0) Studies Reviewed in Update 2000 AIHW, 2000 Australian Vietnam veterans' children -- Validation Study–AML This study, which incorrectly calculated the expected number of AML cases, is superseded by AIHW, 2001 above.
From page 551...
... Leukemia 12 1.6 (0.6–4.0) Field and Cancer in children of Australian Vietnam veterans 4 (*
From page 552...
... Vietnam-Veteran Studies No new Vietnam veteran studies concerning exposure to the compounds of interest and childhood cancer were published since Update 2004. Biologic Plausibility Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to developing cancer through multiple mechanisms.
From page 553...
... As with other outcomes in the offspring of Vietnam veterans, the small number of these rare childhood cancers expected among the circumscribed number of Vietnam veterans would seriously hinder detection of any actual increases; meta-analytic methods may be the best approach for assessing the overall significance of the association between exposures to the chemicals of interest and the risk of specific childhood cancers. Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest and childhood cancers.
From page 554...
... In animal studies, TCDD exposure during pregnancy can reduce body weight at birth, but this typically occurs at high doses. Thus, there is little evidence that TCDD exposure is associated with reduction in birth weight.
From page 555...
... It has been hypothesized that concentrations of parental hormones at conception or induction of lethal mutations before birth could affect sex ratio. There has been no work with experimental animals that specifically examined the effects of TCDD on sex ratios of offspring, nor have any alterations in sex ratio been reported in animal studies that examined developmental effects of TCDD on offspring.
From page 556...
... There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of those compounds' reproductive or developmental effects. Considerable uncertainty remains about how to apply toxicologic information to the evaluation of potential health effects of herbicide or TCDD exposure on the offspring of Vietnam veterans.
From page 557...
... The possibility of structural or functional abnormalities in the offspring of exposed people will continue to be of interest. Conclusions There is inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations; semen quality; infertility; spontaneous abortion; late fetal, neonatal, or infant death; low birth weight or preterm delivery; birth defects other than spina bifida; and childhood cancers.
From page 558...
... 1984. Low birth weight.
From page 559...
... 1989a. Health Status of Vietnam Veterans Vols.
From page 560...
... 1984b. Vietnam veterans' risks for fathering babies with birth defects.
From page 561...
... 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leuke mia in the Children of Vietnam Veterans.
From page 562...
... 2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects.
From page 563...
... 2001. Spontaneous abortion, sex ratio, and paternal occu pational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
From page 564...
... 2004. Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan.
From page 565...
... 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.


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