Veterans and Agent Orange Update 2014 (2016) / Chapter Skim
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10 Effects on Veterans' Descendants
10 Effects on Veterans' Descendants
Pages 699-742
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From page 699... ...
and spina bifida from limited suggestive to inadequate or insufficient, consistent with all other birth defects and parental exposures to the COIs. Current evidence supports the findings of earlier studies that • No adverse outcomes in future generations had sufficient evidence of an association with the COIs.
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From page 700... ...
This chapter summarizes the scientific literature published since Update 2012 that investigated associations between parental exposure to herbicides and adverse effects on offspring, including future generations, throughout their lifespans. The epidemiologic literature considered in this chapter includes studies of a broad spectrum of effects in the children of Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
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From page 701... ...
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 male or female, and it is necessary to evaluate the effects of maternal and paternal exposure separately. As will be noted repeatedly, however, almost all Vietnam veterans were men, but the amount of research providing reliable information on the consequences of paternal exposure is extremely sparse for the COIs in the VAO report series and also for the full array of environmental agents that may pose threats to the health of future generations.
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From page 702... ...
However, because dioxins are not genotoxic skepticism persisted concerning whether adverse outcomes in offspring could arise from paternal exposure to the COIs. Recent investigation of DOHaD and epigenetics in particular, however, have raised the possibility that epigenetic mechanisms might constitute a plausible mechanism by which parental exposures to the COIs might contribute to adverse outcomes in offspring.
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From page 703... ...
Paternal Preconception and Postconception Exposure There is particular interest in the possibility of paternally mediated effects on offspring and later generations because the vast majority of Vietnam veterans are male. Paternal exposures to TCDD or the other COIs could lead to developmental and later-life effects in offspring and potentially future generations by three feasible pathways.
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From page 704... ...
. The mature sperm cell has less global methylation than somatic cells, particularly at gene promoters, and unique DNA methylation marks (particularly on paternally imprinted genes)
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From page 705... ...
; thus, this transmission route is theoretically possible. In the Schecter study, serum TCDD was measured in 50 Vietnam veterans from Michigan who had a confirmed or self-reported potential for herbicide exposure and had blood drawn an average of 26 years after the possible exposure.
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From page 706... ...
. Epidemiologic studies have reported occasional findings of paternally transmitted adverse outcomes associated with paternal exposures to certain agents, but none has been replicated convincingly.
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From page 707... ...
. Nonetheless, a recent study showed that odor fear conditioning in the father could be paternally transmitted to the F1 and F2 generations and implicated reduced DNA methylation in the responsible odor receptor gene (Dias and Ressler, 2013)
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From page 708... ...
Therefore, the hypothesis that paternal preconception exposure to toxic agents may result in harm to their children remains unresolved in significant part because of the sparseness of epidemiologic research on the subject. Maternal Exposure A mother's exposures can affect a pregnancy and the resulting offspring far more extensively than can paternal exposures.
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From page 709... ...
, and a variety of adult diseases including kidney, prostate, ovarian primordial follicle loss, and polycystic ovarian disease (Manikkam et al., 2012a)
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From page 710... ...
Nonetheless, Congress did mandate that a number of birth defects in the children of female Vietnam veterans be assigned service-related status. Later VAO committees have not encountered enough additional data to merit changing the conclusion that the evidence is inadequate to support an association between exposure to the COIs and birth defects (aside from spina bifida)
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From page 711... ...
b Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study -- Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) Verified birth defects in children born to Michalek et al., AFHS veterans 1998a Before service in SEA nr 0.7 (nr)
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Children of veterans reporting high 46 1.7 (1.2–2.4) exposure US VA Cohort of Female Vietnam Veterans All COIs Female Vietnam-era veterans -- deployed Kang et al., vs non-deployed (maternal exposure)
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From page 713... ...
Vietnam veterans vs all other men 127 1.0 (0.8–1.3) Donovan et al., National Service veterans -- Vietnam 69 1.3 (0.9–2.0)
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From page 714... ...
Phenoxy herbicides 9 0.8 (0.4–1.5)
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From page 715... ...
(Same population as Cordier et al., 2004) Maternal exposure to: Atmospheric dioxin 63 2.0 (1.2–3.4)
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1989 NY -- total birth defects (maternal, paternal exposure) CASE-CONTROL STUDIES US Case-Control Studies Arkansas -- hypospadias as function Dicamba Meyer et al., of mother's residence within 500 m of 2006 agricultural pesticide use during gestation weeks 6–16 Dicamba (lb)
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From page 717... ...
2001 (maternal exposure) International Case-Control Studies Denmark/Finland -- Relationship between Dioxin, PCBs Krysiak-Baltyn congenital cryptorchidism and PCBs and ns et al., 2012 dioxins in breast milk (130 samples)
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From page 718... ...
1998 herbicide exposure duration (months) index The Netherlands -- Infants born in Zeeburg, Dioxin ten Tusscher Amsterdam, clinics 1963–1965 with orofacial et al., 2000 cleft (maternal exposure)
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From page 719... ...
b Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study -- Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) Air Force Operation Ranch Hand Wolfe et al., personnel -- neural-tube defects 4c nr 1995 CDC Birth Defects Study -- Hospital All COIs records reviewed for offspring of 7,924 Vietnam veterans and 7,364 non-Vietnam veterans Vietnam veterans identified through CDC Erickson et al., Metropolitan Atlanta Congenital Defects 1984a,b Program Service in Vietnam Spina bifida 19 1.1 (0.6–1.7)
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From page 720... ...
ADVA, 1983 defects OCCUPATIONAL -- HERBICIDE-USING WORKERS Norwegian farmers -- spina bifida (maternal, Herbicides Kristensen et al., paternal exposures) 1997 Tractor spraying equipment 28 1.6 (0.9–2.7)
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From page 721... ...
4 nr NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; nr, not reported; SEA, Southeast Asia; 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 722... ...
. In sum, studies with maternal exposure in animal models suggest that a role for TCDD and related chemicals in causing birth defects is plausible and also that the AHR plays a causal role.
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From page 723... ...
Given the long-standing concern of the Vietnam veterans about the potential of the COIs to adversely affect the health of their children, birth defects and childhood cancers have been among the outcomes considered by VAO committees since the first comprehensive review published in 1994. As indicated in the section above summarizing the findings of prior VAO committees, the committee for the second VAO report (Update 1996)
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From page 724... ...
As with studies of paternal exposure, additional confirmatory epidemiologic evidence has not become available to support an association of spina bifida with maternal exposure to the components of the herbicides sprayed in Vietnam. In fact, an increase in birth defects following adult exposure of only the male parent has not (as yet)
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From page 725... ...
There are, however, no epidemiologic results supporting an association between maternal exposure to the COIs and spina bifida specifically, so spina bifida in association with exposure of either parent has been moved to the inadequate and insufficient category of association. CANCERS IN OFFSPRING The American Cancer Society (ACS)
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From page 726... ...
After adjustment for confounders among the 327 cases with paternal exposure information, 8 reported exposure to phenoxy herbicides. Only 2 of the 378 cases with maternal information reported exposure to phenoxy herbicides.
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From page 727... ...
b Reference VIETNAM VETERANS US Vietnam Veterans CDC Birth Defects Study -- Hospital records All COIs reviewed for offspring of 7,924 Vietnam veterans and 7,364 non-Vietnam veterans Vietnam veterans identified through CDC Erickson Metropolitan Atlanta Congenital Defects et al., 1984b Program "Other" neoplasms 87 1.8 (1.0–3.3) US CDC Vietnam Experience Study -- Cross- All COIs sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed VES cohort -- reproductive outcomes CDC, 1988a Cancer 25 1.5 (0.7–2.8)
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From page 728... ...
, enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010 Offspring of male pesticide applicators in Flower et al., Iowa from AHS 2004 Maternal exposure to chlorophenoxy 7 0.7 (0.3–1.5) herbicides Paternal exposure to chlorophenoxy 28 1.3 (0.6–2.6)
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From page 729... ...
pesticides CASE-CONTROL STUDIES US Case-Control Studies Children's Oncology Group -- Studies Herbicides Slater et al., association between infant leukemia and ns 2011 maternal herbicide exposure (443 cases vs 324 population controls) Children's Oncology Group -- Childhood Pesticides Chen Z et al., GCTs residential exposure to herbicides 6 2006 mos before conception, during gestation, through breastfeeding period Maternal exposure 47 1.3 (0.9–1.7)
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From page 730... ...
Paternal exposure over 1,000 days 17 2.7 (1.0–7.0) Maternal exposure over 1,000 days 7 undefined California (Northern California Childhood Herbicides Leukemia Study)
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High vs low 8 6.3 (1.0–38.6) Maternal exposures to: Herbicides In yr before conception 9 2.0 (0.8–5.0)
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. Biologic Plausibility Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to cancer through multiple mechanisms.
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. Perhaps related, prenatal TCDD exposure led to increased DNA methylation at the BRCA1 (breast cancer)
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Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and childhood cancers. EFFECTS OCCURRING LATER IN OFFSPRING'S LIFE OR IN LATER GENERATIONS In response to a special request from the Department of Veterans Affairs, continuing inquiries from veterans and their families, and increasing attention in research efforts, the committee for Update 2010 addressed whether it was feasible to assess associations between exposure to the herbicides sprayed in Vietnam and health effects that occur later in the lives of children of Vietnam veterans and even in their grandchildren; such associations had not been formally reviewed in prior VAO updates.
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From page 735... ...
Thus, the observation of any changes reported in studies discussed in this section should be applicable only to children born to female Vietnam veterans during or after their deployment in Vietnam. Thus, no transgenerational studies have been reported to date.
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From page 736... ...
Dioxin was measured in both maternal blood collected in the period 28–42 weeks after conception and breast-milk samples. While most comparisons were not statistically significant, a doubling of maternal blood levels of PCDD/F and PCDD/F+PCB
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From page 737... ...
Two studies on subcohorts of the collaborative European NewGeneris study of mother–child pairs examined anogenital distance and maternal exposure to dioxin and dioxin-like compounds. Anogenital distance has historically been used as a marker of androgen function in toxicology studies involving animals.
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From page 738... ...
, increased DNA methylation of the BRCA1 tumor suppressor gene in mammary tissue (Papoutsis et al., 2013) , altered uterine response to estradiol (Burns et al., 2013)
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From page 739... ...
Research into dioxin's potential as an epigenetic agent is in its early stages, but a few studies have suggested that dioxin has such properties that are, in significant part, linked to the AHR. Direct evidence, however, is limited to maternal exposures of the developing embryo or fetus during in utero growth, and no reports exist showing paternal TCDD exposure and later-life effects in offspring or paternally mediated transgenerational effects.
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From page 740... ...
The latter appear to be transmitted through the sperm originally exposed to maternal dioxin in utero inasmuch as sperm DNA methylation changes were observed at 50 chromosomal sites in generations F1–F3. Testicular inflammation from TCDD exposure has also been reported to manifest in multiple generations (Bruner-Tran et al., 2014)
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From page 741... ...
Although the results of laboratory research support the plausibility of transgenerational clinical conditions, human data are currently lacking to support an association between the COIs and such disease states in human offspring.
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