Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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10 Effects on Future Generations
10 Effects on Future Generations
Pages 726-772
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From page 726... ...
• There is limited or suggestive evidence of an association between the chemicals of interest and spina bifida. • There is inadequate or insufficient evidence to determine whether there is an association between parental exposure to the chemicals of interest and birth defects other than spina bifida, childhood cancers, or disease in their children as they mature or in later generations.
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From page 727... ...
It is hoped that by devoting a separate chapter to the possible "post-birth" problems of the progeny of Vietnam veterans, we can more clearly present the evidence for maternally and paternally mediated effects separately because the under ying l biology is quite distinct in the two cases. This chapter summarizes the scientific literature published since Update 2010 that investigated associations between parental exposure to herbicides and adverse effects on offspring, including future generations, throughout their life spans.
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From page 728... ...
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 not only for the COIs in the VAO report series but also for the full array of environmental agents that may pose threats to the health of future generations.
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From page 729... ...
. As a result, it was thought that any paternally-derived damage to the embryo or offspring would have to arise from changes in sequence or arrangement of the sperm's DNA; the fact that dioxins have not been shown to be genotoxic fostered skepticism that adverse outcomes in offspring could arise from paternal exposure to the COIs.
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From page 730... ...
. The mature sperm cell has less global methylaion than somatic cells and unique DNA methylation marks (particularly t on paternally imprinted genes)
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From page 731... ...
. TCDD and other persistent organic pollutants have been identified and quantified in seminal plasma of exposed men, including Vietnam veterans (Schecter et al., 1996; Schlebusch et al., 1989; Stachel et al., 1989)
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From page 732... ...
Empirical Epidemiologic Evidence on Paternal Transmission The idea that exposure of either parent to a toxicant before conception could result in an adverse outcome in offspring is not new and remains a topic of much interest. 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 733... ...
Maternal Exposure A mother's exposures can affect a pregnancy and the resulting offspring far more extensively than paternal exposures. Because of the long half-life of TCDD and its bioaccumulation in adipose tissues, women exposed to Agent Orange in Vietnam would have potential to expose their offspring to TCDD directly during later pregnancies.
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From page 734... ...
. Laboratory animal studies have established that TCDD can affect development, so a connection between TCDD exposure and effects on offspring, including developmental disruption and disease onset in later life, is biologically plausible.
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From page 735... ...
Environmental Studies Since Update 2010, three studies have examined maternal exposure to the COIs in relation to congenital cryptorchidism or hypospadias; two based on a Danish–Finnish joint prospective cohort (Krysiak-Baltyn et al., 2012; Virtanen et al., 2012) and one that used the US National Birth Defects Prevention Study (NBDPS)
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From page 736... ...
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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From page 737... ...
International Vietnam-Veteran Studies Australian Vietnam Veterans -- 58,077 All COIs men and 153 women who served on land or in Vietnamese waters during 5/23/1962– 7/1/1973 vs Australian population Validation Study Expected number AIHW, 1999 of exposed cases Down syndrome 67 92 expected (73–111) continued
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From page 738... ...
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 739... ...
Phenoxy herbicides 9 0.8 (0.4–1.5)
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From page 740... ...
(same population as Cordier et al., 2004) Maternal exposure to Atmospheric dioxin 63 2.0 (1.2–3.4)
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From page 741... ...
1989 York -- total birth defects (maternal, paternal exposure) CASE-CONTROL STUDIES US Case-Control Studies US National Birth Defects Prevention Herbicides, Rocheleau et al., Study -- Hypospadias and maternal herbicide pesticides 2011 exposure; JEM to determine exposure from conception through first trimester of pregnancy (647 cases vs 1,496 controls)
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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 743... ...
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, 1989b Spina bifida Vietnam veterans' children 9 1.7 (0.6–5.0) Non–Vietnam veterans' children 5 1.0 Anencephaly Vietnam veterans' children 3 nr Non–Vietnam veterans' children 0 1.0 International Vietnam-Veteran Studies Australian Vietnam Veterans -- 58,077 men and All COIs 153 women who served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population Validation Study Expected number AIHW, of exposed cases 1999 Spina bifida -- maximums 50 33 expected (22–44)
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From page 744... ...
Australian Vietnam veterans -- neural-tube All COIs ADVA, defects 16 0.9 (nr) 1983 OCCUPATIONAL -- HERBICIDE-USING WORKERS Norwegian farmers -- spina bifida (maternal, Herbicides Kristensen paternal exposures)
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From page 745... ...
e 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 746... ...
. Biologic Plausibility 2,4-D has been previously shown to be a teratogen, although at exposures that exceed maternal renal clearance, which are not relevant to Agent Orange exposure.
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From page 747... ...
The four studies since Update 2010 that have assessed exposure to relevant chemicals and congenital malformations all examined only maternal exposure, which is of little relevance to the majority of Agent Orange–exposed veterans. Furthermore, those environmental studies were conducted in populations exposed to contemporary concentrations, which may be too low for adverse fetal effects to be observed.
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From page 748... ...
Other cancers in children include lymphomas, bone cancers, soft-tissue sarcomas, renal cancers, eye cancers, and adrenal cancers. 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.
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From page 749... ...
(2011) examined infant leukemia risk in the Children's Oncology Group study associated with maternal exposure to herbicides at any time during the period from 1 month before conception throughout pregnancy, during only the
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From page 750... ...
International Vietnam-Veteran Studies Australian Vietnam Veterans' children -- All COIs revised validation study AML 12c 1.3 (0.8–4.0) AIHW, 2001 Australian Vietnam veterans' children -- AIHW, 2000 validation study -- AML This study, which incorrectly calculated expected number of AML cases, is updated by AIHW (2001)
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From page 751... ...
, enrolled 1993–1997; followups 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 752... ...
Sons 11 1.0 (0.5–1.8) Paternal exposure 90 1.0 (0.7–1.3)
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From page 753... ...
2000 Maternal occupational exposure to 40 2.3 (1.4–3.7) insecticides Paternal exposure to dioxin 7 6.9 (1.3–68.4)
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From page 754... ...
Maternal exposure during pregnancy 15 3.6 (1.5–8.8) Lymphomas Paternal exposure yr before pregnancy 11 1.5 (0.7–3.1)
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From page 755... ...
(2005) showed that chromosomal rearrangements associated with childhood ALL are evident in the neonatal blood spots; this suggests that childhood leukemias begin before birth, perhaps due to maternal exposures to genotoxic xenobiotics.
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From page 756... ...
In addition, for the first time, the committee for Update 2010 explored the possibility of transgenerational effects resulting from exposure-related epigenetic changes in the parents or exposed fetuses that would lead to adverse health effects in later generations, such as grandchildren. Conclusions from VAO and Previous Updates The potential effect of maternal and paternal exposure of Vietnam veterans to herbicides on the development of disease other than cancer in their children after the first year of life or in later generations had not been considered in updates before Update 2010.
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From page 757... ...
Changes Detected in Children After Parental Exposure Thyroid Hormone Concentrations Since Update 2010, there has been one additional epidemiologic study of childhood thyroid hormone concentrations associated with perinatal exposure to dioxins and dioxin-like PCBs. Leijs et al.
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From page 758... ...
Asthma was expanded to include cases in which the mother gave positive responses to all questions on the modified ISAAC questionnaire. There were no associations between maternal exposure and childhood food allergy, eczema, or asthma, although there was a weak positive trend of increased risk of asthma with increasing exposure to PCDFs (p = 0.059)
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From page 759... ...
(2011) examined the association with maternal dioxin exposure in the highly-contaminated region of Chapaevsk, Russia, which until 2003 was the site of chlorinated-chemical production at the Middle Volga Chemical Plant.
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From page 760... ...
appeared to be substantially modified by whether the man had been breastfed in childhood; the effects were strongest in, and to some degree limited to, men who had been breastfed. This indicates that early-life exposure via breast milk had more of an impact on these fertility-related outcomes in the later lives of the sons than did in utero exposure, but breastfeeding is a relevant mode of maternal exposure for the children of female Vietnam veterans.
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From page 761... ...
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. Direct evidence, however, is limited to maternal exposures of the developing embryo or fetus during in utero growth, and there have been no reports on paternal TCDD exposure and later-life effects in offspring or paternally-mediated transgenerational effects.
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From page 762... ...
In particular, it would be of interest to obtain information on neuropsychiatric conditions in children who were exposed in utero, such as attention-deficit hyperactivity disorder and other clinicallydefined neurodevelopmental outcomes. The animal literature contains evidence that environmental agents mediated by maternal exposure affect later generations through fetal and germ-line modifications, but, in the case of adult male exposures before conception of the next generation, there is insufficient evidence of transgenerational affects.
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From page 763... ...
2001. Morbidity of Vietnam Veterans.
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From page 764... ...
1989b. Health Status of Vietnam Veterans.
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From page 765... ...
1984b. Vietnam veterans' risks for fathering babies with birth defects.
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From page 766... ...
2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leuke mia in the Children of Vietnam Veterans.
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From page 767... ...
2000. Pregnancy outcomes among US women Vietnam veterans.
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From page 768... ...
2001. Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides.
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From page 769... ...
2007. Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica.
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From page 770... ...
1996. Dioxins and dioxin-like chemi cals in blood and semen of American Vietnam veterans from the state of Michigan.
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From page 771... ...
2011. Maternal exposure to household chemicals and risk of infant leukemia: A report from the Children's Oncology Group.
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From page 772... ...
1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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