Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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8 Reproductive Effects and Impacts on Future Generations
8 Reproductive Effects and Impacts on Future Generations
Pages 540-610
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From page 540... ...
, 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.
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From page 541... ...
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)
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From page 542... ...
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.
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From page 543... ...
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.
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From page 544... ...
et al., 2001 infertility treatment in Belgium; compared number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay)
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From page 545... ...
, 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)
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From page 546... ...
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)
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From page 547... ...
. 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.
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From page 548... ...
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.
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From page 549... ...
concluded 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.
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From page 550... ...
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)
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From page 551... ...
exposed: 72.9 vs control: 33.4 Forestry Workers Herbicides Heacock Workers at sawmills using chlorophenates et al., 1998 continued
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From page 552... ...
US Environmental Study 2,4-D Swan Men in Missouri, US with or without low et al., 2003 sperm quality Increased urinary metabolite marker for 2,4-D 5 0.8 (0.2–3.0) International Environmental Studies POPs Krüger DNA sperm integrity among Inuit men from et al., 2008 Greenland (n = 53)
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From page 553... ...
In Wilrik, Belgium 15 1.7 (nr) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHR, aryl hydrocarbon receptor; CALUX, assay for determination of dioxin-like activity; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; DLC, dioxin-like chemical; FSH, follicle-stimulating hormone; IU, international unit; LH, luteinizing hormone; nr, not reported; PAH, polycyclic aromatic hydrocarbon; PCB, polychlorinated biphenyl; POP, persistent organic pollutants; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxicity equivalency factor; TEQ, (total)
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From page 554... ...
a Reference Study Population Cases OCCUPATIONAL Agricultural Health Study Herbicides Farr 8,038 premenopausal women aged 35–55 at et al., enrollment 2006 Later menopause Pesticide exposure 5,013 0.9 (0.8–1.0) Herbicide exposure 3,725 0.9 (0.7–1.1)
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From page 555... ...
Log10 TCDD 169 1.0 (0.8–1.3) Menopause category Serum TCDD median (IQR)
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From page 556... ...
Postmenarcheal at explosion 0.4 (0.2–1.2) Other Environmental Studies Dioxin/Regression Chao Pregnant women in Taiwan; measured placental et al., dioxin TEQ, PCB TEQ adjusted for maternal 2007 age, BMI, parity Older of "regular menstrual cycle" Dioxin TEQ p = 0.032 PCB TEQ p = 0.077 Longer "longest menstrual cycle" Dioxin TEQ p = 0.269 PCB TEQ p = 0.006 Phenoxy herbicides Greenlee Women in Wisconsin, US with or without et al., infertility (maternal exposure)
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From page 557... ...
Female Fertility No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and female fertility have been published since Update 2008. Environmental Studies Since Update 2008, Eskenazi et al.
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From page 558... ...
Many studies have examined the effects of TCDD on the female reproductive system. Two primary mechanisms that probably contribute to abnormal follicle development and decreased numbers of ova after TCDD exposure are cross-talk of the AHR with the estrogen receptor and dysregulation of the hypothalamic– pituitary–gonadal axis.
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From page 559... ...
Although it would not constitute an adverse health outcome in an individual veteran, there is fairly strong evidence (see Table 8-4) that paternal exposure to dioxin may result in a lower sex ratio (that is, a smaller than expected proportion of male infants at birth)
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From page 560... ...
Moshammer Austrian chloracne cohort -- 157 men, 2 Fewer sons, and women; exposed to TCDD during 2,4,5-T especially if father Neuberger, production was under 20 years 2000 Children born after starting TCDD 0.464 old when exposed: exposure in 1971 (26 boys: SR = 0.20 (1 boy: 30 girls 4 girls) Children born before 1971 0.613 (19 boys: 12 girls)
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From page 561... ...
0.500 ns Protective equipment used 0.510 ns No protective equipment 0.450 ns ENVIRONMENTAL Seveso, Italy Residential Cohort Baccarelli Births 1994–2005 in women 0–28 yrs of age et al., 2008 at time of Seveso accident Zone A 0.571 Zone B 0.508 Zone R 0.495 Mocarelli Births 1977–1996 in people from Zones A, 0.514 Referent et al., 2000 B, R, 3–45 yrs of age at time of 1976 Seveso accident Neither parent exposed 0.608 ns Father exposed (whether or not mother 0.440 p = 0.03 exposed) Father under 19 yrs of age in 1976 0.382 p = 0.002 Father at least 19 yrs of age in 1976 0.469 ns Only mother exposed 0.545 ns Mocarelli Parent (either sex)
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From page 562... ...
0.516 ns Births 1968–1971 (after incident) 0.574 ns ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; dl, dioxin-like; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; SR, sex ratio; TCDD, 2,3,7,8–tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total)
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From page 563... ...
There is little evidence that exposure to dioxin is associated with a reduction in sperm quality or a reduction in fertility. How ever, the committee notes that the evidence that TCDD exposure reduces serum testosterone in men is consistent across several epidemiologic studies with appropriate consideration of confounders, including one of Vietnam veterans, shows a dose–response relationship and is biologically plausible based on concomitant increases observed in gonadotropins and biologic plausibility from animal studies.
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From page 564... ...
Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the present committee concludes that there is inadequate or insuf ficient evidence of an association between exposure to the compounds of interest and decreased sperm counts or sperm quality, subfertility, or infertility. SPONTANEOUS ABORTION Spontaneous abortion is the expulsion of a nonviable fetus, generally before 20 weeks of gestation, that is not induced by physical or pharmacologic means.
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From page 565... ...
, but the committee for Update 2002 asserted that they might be due to exposure to phenoxy herbicides rather than to TCDD and concluded that there was insufficient information to determine whether there is an association between maternal exposure to TCDD and the risk of spontaneous abortion or between maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontaneous abortion. The additional information (none of which concerned paternal exposure)
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From page 566... ...
US National Vietnam Veterans All COIs Schwartz, Female Vietnam veterans (maternal exposure) 1998 Women who served in Vietnam 113 nr Women who did not serve in the war zone 124 nr Civilian women 86 nr American Legion Cohort All COIs Stellman American Legionnaires with service 1961–1975 et al., 1988 Vietnam veterans vs Vietnam-era veterans All Vietnam veterans 231 1.4 (1.1–1.6)
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et al., 1998 miscarriages (maternal exposure) continued
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Other Environmental Studies PCBs, PCDFs Tsukimori Spontaneous abortions among pregnancies et al., 2008 (excluding induced abortions) of women in 1968 Yusho incident (maternal exposure)
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From page 569... ...
Conclusions On the basis of the evidence reviewed to date, the committee concludes that paternal exposure to TCDD is not associated with risk of spontaneous abortion and that insufficient information is available to determine whether there is an association between maternal exposure to TCDD or either maternal or paternal exposure to 2,4-D, 2,4,5-T, picloram, or cacodylic acid and the risk of spontane ous abortion. 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 weigh more than 500 g regardless of gestational age (Kline et al., 1989)
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From page 570... ...
Biologic Plausibility Laboratory studies of maternal TCDD exposure during pregnancy have demonstrated the induction of fetal death; neonatal death, however, is only rarely observed and is usually the result of cleft palate, which leads to an inability to nurse. Studies addressing the potential for perinatal death as a result of paternal exposure to TCDD or herbicides are inadequate to support conclusions.
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From page 571... ...
. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and low birth weight or PTD.
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From page 572... ...
and did not examine specific pesticides separately, it did not meet the level of exposure specificity required for review by the committee. Biologic Plausibility The available experimental evidence on animals indicates that TCDD exposure during pregnancy can reduce body weight at birth but only at high doses.
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From page 573... ...
Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between expo sure to 2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid and birth defects in offspring. Additional information available to the committee re
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From page 574... ...
Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and birth defects have been published since Update 2008. Environmental Studies In a retrospective case–control study of births in Washington state, Waller et al.
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From page 575... ...
Skin 3 0.5 (0.2–1.7) Chromosomal anomalies 1 nr AFHS, 1992 Air Force Operation Ranch Hand veterans -- birth defects in conceptions after service in SEA Congenital anomalies 229 1.3 (1.1–1.6)
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From page 576... ...
Digestive system defects 18 2.0 (0.9–4.6) Birth defects -- black Vietnam veterans 21 3.4 (1.5–7.6)
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From page 577... ...
Agricultural Workers Herbicides Weselak et al., Pregnancies with one or more birth defects 108 2008 in OFFHS Use on farm, during 3 months before conception, of: Herbicides 24 0.7 (0.4–1.1) Male offspring 19 0.9 (0.5–1.6)
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From page 578... ...
≥ 0.04 nr 0.9 (0.4–2.1) Herbicides Schreinemachers, Rural or farm residents of Minnesota, 2003 Montana, North Dakota, South Dakota (maternal, paternal exposure)
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Maternal exposure to: Atmospheric dioxin 63 2.0 (1.2–3.4) Above median 33 2.8 (1.3–6.1)
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ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BWIS, Baltimore–Washington Infant Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, exposure opportunity index; GBDS, General Birth Defects Study; IARC, International Agency for Research on Cancer; MI, Michigan; MIH, molar incisor hypomineralization; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCDD, polychlorinated dibenzodioxins; PCDF, polychlorinated dibenzofurans; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.
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From page 581... ...
1.6 (0.6–4.0) d Herbicide use 7 Kristensen Norwegian farmers -- spina bifida (maternal, et al., 1997 paternal exposure)
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aUnless otherwise indicated, studies show paternal exposure. bGiven when available; results other than estimated risk explained individually.
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From page 583... ...
A higher incidence of urinary tract birth defects was observed in infants of mothers who were exposed to atmospheric dioxin above median concentrations than in infants of women who had no exposure (OR = 2.84, 95% CI 1.32–6.09)
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. A second examined maternal exposure to pesticides and neural-tube defects in Mexican Americans (Brender et al., 2010)
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From page 585... ...
observed an association between dioxin exposure and urinary tract defects, but the influence of selection bias on the observed results could not be fully assessed. Therefore, the results of the study are insufficient to determine whether there is an association between maternal exposure to dioxin and urinary tract defects.
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From page 586... ...
In contrast with adult cancers, relatively little is known about the etiology of most childhood cancers, especially about potential environmental risk factors and the effects of parental exposures. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between expo sure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and childhood cancers.
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From page 587... ...
OCCUPATIONAL Agricultural Health Study Herbicides Flower Offspring of male pesticide applicators in Iowa et al., 2004 from AHS Maternal exposure to chlorophenoxy herbicides 7 0.7 (0.3–1.5) Paternal exposure to chlorophenoxy herbicides 28 1.3 (0.6–2.6)
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From page 588... ...
Buckley Children's Cancer Study Group -- exposure to et al., 1989 pesticides, weed killers -- AML Any paternal exposure 27 2.3 (p = 0.5) Paternal exposure over 1,000 days 17 2.7 (1.0–7.0)
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From page 589... ...
Sons 11 1.0 (0.5–1.8) Paternal exposure 90 1.0 (0.7–1.3)
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From page 590... ...
Meinert Childhood cancer -- population-based case– et al., 2000 control study in Germany Leukemia Paternal exposure year before pregnancy 62 1.5 (1.1–2.2) Paternal exposure during pregnancy 57 1.6 (1.1–2.3)
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From page 591... ...
pesticides ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; AIHW, Australian Institute for Health and Welfare; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; GCT, germ-cell tumor; HL, Hodgkin lymphoma; nr, not reported; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofuran; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin; VES, Vietnam Experience Study. aUnless otherwise indicated, studies show paternal exposure.
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From page 592... ...
. Although there is no direct evidence from animal models that TCDD in creases the risk of childhood cancers, such as acute leukemia or germ-cell tumors, emerging research suggests that prenatal TCDD exposure can disrupt epigenetic imprinting patterns and alter organ differentiation, which could contribute to an increased susceptibility to cancer later in life.
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From page 593... ...
Finally, although it may be physiologically possible for paternal exposure to cause changes in offspring that are manifested later in life, as discussed in Chapter 4 and at the beginning of this chapter, none of the published epidemiologic studies assessed the potential for paternal expo sure to contribute to outcomes that would be manifested later in their offspring's
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From page 594... ...
A number of studies evaluated cognitive and motor development, using such standard testing methods as the Bayley Scales of Infant Development and self-reporting questionnaires. The results of those studies, like the results of the studies that evaluated thyroid hormone concentrations, reported mixed outcomes relative to an association with prenatal or lactational exposure to TCDD and dioxin-like compounds.
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From page 595... ...
. Developmental Effects in Later Generations Epidemiologic studies designed to investigate associations of occupational or environmental exposures with adverse developmental effects manifested in later generations have not been reported in connection with the chemicals of interest or any other chemicals; they will be even more challenging to conduct than research on adverse effects on the first generation.
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From page 596... ...
Conclusions There is inadequate or insufficient evidence to determine whether there is an association between exposure of men and women to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid before conception or during pregnancy and disease in their children as they mature or in later generations. Although laboratory research supports the plausibility of transgenerational clinical conditions, no completed epidemiologic studies have provided data to support an association between the chemicals of interest and such disease states in human offspring.
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From page 597... ...
In addition, the committee strongly recommends that careful consideration be given to systematically evaluating whether recently recognized mechanisms of epigenetic modification imply that there could be long-term consequences of herbicide exposure for the health of the progeny of Vietnam veterans in future generations. Conclusions There is inadequate or insufficient evidence to determine whether there is an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and endometriosis; semen quality; infertility; spontaneous abortion; still birth; late fetal, neonatal, or infant death; low birth weight or preterm delivery; birth defects other than spina bifida; childhood cancers; or diseases in more mature offspring or later generations.
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From page 598... ...
2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population.
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From page 599... ...
1981. A Case–Control Study of the Relationship Be tween Exposure to 2,4-D and Spontaneous Abortions in Humans.
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From page 600... ...
1996. Reproduc tive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry.
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From page 601... ...
2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study.
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From page 602... ...
Environmental Health Perspectives 104(4)
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From page 603... ...
2002. Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring.
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From page 604... ...
2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects.
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From page 605... ...
Environmental Health Perspectives 116(1)
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From page 606... ...
Environmental Health Perspectives 101(6)
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From page 607... ...
2001. Spontaneous abortion, sex ratio, and paternal occu pational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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From page 608... ...
Environmental Health Perspectives 111(12)
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From page 609... ...
1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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From page 610... ...
gene expression in human endometrial stromal cells. Journal of Clinical Endocrinology and Metabolism 87(6)
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