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7 Reproductive and Developmental Effects
Pages 354-403

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From page 354...
... This chapter's primary emphasis is the potential adverse reproductive effects of herbicide exposure in men, because the vast majority of Vietnam veterans are men. Because about 8,000 women served in Vietnam (H.
From page 355...
... Additional information available to the committee responsible for Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996) led it to conclude that there was limited or suggestive evidence of an association between at least one of the compounds of interest and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects.
From page 356...
... Studies Reviewed in VAO Moses et al., 1984 Follow-up of 2,4,5-T production workers (paternal exposure)
From page 357...
... ) SS Studies Reviewed in Update 2000 García et al., 1998 Residents of agricultural areas in Spain- median score on chlorophenoxy herbicides exposure duration (months)
From page 358...
... e Isolated cleft palate 7 1.4 (0.6­3.2) e VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., 2000 Female Vietnam veterans 4,140 "Likely" birth defects 1.7 (1.2­2.2)
From page 359...
... Vietnam veterans compared to men without known military service 18 1.8 (1.0­3.1) Vietnam veterans compared to non-Vietnam veterans 18 1.3 (0.7­2.4)
From page 360...
... Birth defects 130 1.0 (0.8­1.3) Birth defects -- black Vietnam veterans only 21 3.4 (1.5­7.6)
From page 361...
... d VIETNAM VETERANS Studies Reviewed in Update 2000 AIHW, 1999 Australian Vietnam veterans -- Validation Study (paternal exposure) Spina bifida -- maxima 50 33 expected (22­44)
From page 362...
... 454 post-service births were studied in Ranch Hand veterans; 570 in comparison cohort. fNumber of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index.
From page 363...
... . After covariate adjustment, increased risk for musculoskeletal and integumental anomalies was observed (OR, 1.5; 95% CI, 1.1­2.1)
From page 364...
... Its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports leads the committee to conclude that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and all other birth defects. Although there were reports of increased risks of transposition of the great arteries, non-syndromal orofacial clefts, and congenital morphogenetic condi
From page 365...
... A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and birth defects among offspring, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in the risk of this outcome in their children.
From page 366...
... . Summary of VAO, Update 1996, Update 1998 Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility.
From page 367...
... a OCCUPATIONAL Studies Reviewed in Update 2000 Abell et al., 2000 Female greenhouse workers in Denmark -- fecundibility ratio (maternal exposure) >20 hours manual contact per week 220 0.7 (0.5­1.0)
From page 368...
... ) VIETNAM VETERANS Studies Reviewed in Update 1996 Henriksen et al., 1996 Effects on specific hormone levels or sperm count in Ranch Hands (paternal exposure)
From page 369...
... Studies Reviewed in VAO CDC, 1989 Vietnam Experience Study (paternal exposure) Lower sperm concentration 42 2.3 (1.2­4.3)
From page 370...
... (2002a) studied the association between TCDD exposures, as measured first from serum samples collected immediately after an industrial explosion in 1976 at Seveso, Italy, and then in menstrual-cycle characteristics 20 years after the explosion.
From page 371...
... Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations; decreased sperm counts; or sperm quality, subfertility, or infertility.
From page 372...
... Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and altered sperm characteristics or infertility, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. SPONTANEOUS ABORTION Spontaneous abortion is the expulsion of a nonviable fetus, generally before 20 weeks of gestation, that is not induced through physical or pharmacologic means.
From page 373...
... . Those women had slightly lower TCDD concentrations than were found in women who had live births.
From page 374...
... 1120 ppt 8 1.0 (0.4­2.2) Studies Reviewed in Update 2000 Driscoll, 1998 Women employed by the US Forest Service -- pregnancies ending in miscarriage 141 2.0 (1.1­3.5)
From page 375...
... VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., 2000 Female Vietnam-era veterans- spontaneous abortions or stillbirths Vietnam veterans (1,665 pregnancies)
From page 376...
... Studies Reviewed in VAO Aschengrau and Monson, Wives of Vietnam veterans presenting 1989 at Boston Hospital for Women Spontaneous abortions through 27 weeks gestation 10 0.9 (0.4­1.9) First-trimester (through 13 weeks gestation)
From page 377...
... Conclusions Strength of Evidence from Epidemiologic Studies Additional information available to committee responsible for Update 2002 led that committee to note that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion, but that the information remained insufficient 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. On the basis of its evaluation of the epidemiologic literature examining spontaneous abortion reviewed here and in previous VAO reports, the current committee concurs with the overall conclusion of the previous committees that the data are inadequate or insufficient to determine whether an association exists between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and the risk of spontaneous abortion.
From page 378...
... A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and spontaneous abortion, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
From page 379...
... A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and stillbirth, neonatal death, or infant death, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
From page 380...
... , the factors most strongly associated with reduced birthweight are maternal tobacco use during pregnancy, multiple births, and race or ethnicity. Other potential risk factors are socioeconomic status (SES)
From page 381...
... (2003) examined the association of TCDD exposure with reproductive outcomes among 510 SWHS participants.
From page 382...
... Thus, no conclusion is possible with respect to a connection between dioxin exposures in the SWHS cohort and decreased birthweight or increased prematurity. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and low birthweight or PTD.
From page 383...
... A discussion of the biologic plausibility of reproductive effects in general arising from exposure to the chemicals of interest is presented at the end of this chapter. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and low birthweight, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
From page 384...
... 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 and Update 2002 reviewed the material in earlier VAO reports and in newly available published literature and agreed that there remained inadequate or insufficient evidence to determine an association between exposure and childhood cancers.
From page 385...
... Paternal exposure to 2,4-D 6 1.3 (0.7­2.4) Studies Reviewed in Update 2000 Heacock et al., 2000 Offspring of sawmill workers exposured to fungicides contaminated with PCDDs and PCDFs (paternal exposure)
From page 386...
... Studies Reviewed in Update 2000 Meinert et al., 2000 Childhood cancer -- population-based case-control study Leukemias Paternal exposure; year before pregnancy 62 1.5 (1.1­2.2) Paternal exposure; during pregnancy 57 1.6 (1.1­2.3)
From page 387...
... VIETNAM VETERANS Studies Reviewed in Herbicide/Dioxin Exposure and AML in the Children of Veterans AIHW, 2001 Australian Vietnam veterans' children -- Revised Validation Study AML 12d 1.3 (0.8­4.0) 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 superceded by AIHW, 2001 above.
From page 388...
... The lack of significance could be attributable to the very small number of cases and the attendant lack of statistical power. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or
From page 389...
... Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and childhood cancers, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. SEX RATIO Sex ratio (males to females at birth)
From page 390...
... 390 VETERANS AND AGENT ORANGE: UPDATE 2004 an altered sex ratio are uncertain, but parental age, social class, illness, race, tobacco use, and stress have been considered. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The potential association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered sex ratio was not explored in the VAO and Update 1996 reports.
From page 391...
... exposed Studies Reviewed in Update 2002 Schnorr et al., 2001 Workers producing 0.53 vs NS overall; trichlorophenol and derivatives, 0.54 no difference including 2,4,5-T: exposed on basis of age fathers vs unexposed at first exposure Okubo et al., 2000 Japanese workers exposed to 0.25 p < 0.01 dicyclopentadiene, (6 boys: cyclopentadiene, epoxy resin, 18 girls) bisphenol A epichlorohydrin vs Japanese population Moshammer and Austrian chloracne cohort 0.46 Fewer sons, Neuberger, 2000 (children born after start TCDD (26 boys: especially if exposure in 1971 vs children 30 girls)
From page 392...
... (26 boys: 48 girls) VIETNAM VETERANS Studies Reviewed in Update 2000 Michalek et al., 1998b Sex ratio of births to Ranch Hand SR higher for personnel (high, low, or higher dioxin background dioxin level)
From page 393...
... . Biologic Plausibility 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 for animal studies that have examined developmental effects of TCDD on offspring.
From page 394...
... That would not, however, correspond to the tendency for any suggestive observed effects to be associated with paternal exposure. SUMMARY Strength of the Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations, semen quality, or infertility; spontaneous abortion; late-fetal, neonatal, or infant death; low birthweight or preterm delivery; birth defects other than spina bifida; altered sex ratio; and childhood cancers.
From page 395...
... Little research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed various concentrations of simulated Agent Orange mixtures produced no adverse effects in offspring.
From page 396...
... However, biologic plausibility for effects of TCDD on development in humans is also supported by several studies reporting effects on children exposed in utero to PCBs containing dioxin-like compounds. Furthermore, some of these effects were reported to occur at near background levels of exposure.
From page 397...
... Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicide or TCDD exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animal and cellular studies can be used to predict human health outcomes and about the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure.
From page 398...
... 2000. Morbidity of Vietnam Veterans.
From page 399...
... 1989. Health Status of Vietnam Veterans.
From page 400...
... 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leu kemia in the Children of Vietnam Veterans.
From page 401...
... 2000. Pregnancy outcomes among US women Vietnam veterans.
From page 402...
... American Journal of Epidemiology 146:1025­1036. Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally LB, Fingerhut MA.
From page 403...
... 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.


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