Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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8 Reproductive Health Effects and Effects on Descendants
8 Reproductive Health Effects and Effects on Descendants
Pages 365-432
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From page 365... ...
• None of the outcomes met the committee's criteria for determining that there was limited or suggestive evidence of an association with exposure to the COIs. • There is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and endometriosis; decreased sperm counts or sperm quality, subfertility, or infertility; spon taneous abortion, stillbirth, neonatal death, or infant death; and low birth weight or preterm delivery, birth defects, childhood cancers, or other disease in their children as they mature or in later generations.
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From page 366... ...
; neonatal and infant mortality; adverse gestational outcomes of low birth weight and preterm delivery; and the possibility of adverse health outcomes (birth defects, cancer; and changes in growth and physical parameters and in immune, allergic, motor development, cognitive, behavioral and socio-emotional outcomes) at any time during the lives of all progeny of Vietnam veterans.
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From page 367... ...
Dioxin exposure has the potential to disrupt male reproductive function by altering the expression of genes that are pertinent to spermatogenesis and by altering steroidogenesis (Wong and Cheng, 2011) ; it has the potential to disrupt female reproductive function by altering the expression of genes relevant to
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From page 368... ...
. On the basis of laboratory animal studies, it is known that TCDD can affect reproduction, so a connection between TCDD exposure and human reproductive and gestational effects is biologically plausible.
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From page 369... ...
However, the preponderance of evidence from animal studies indicates that these chemicals do not have reproductive effects. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their potential reproductive or gestational effects.
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From page 370... ...
When males with chemical concentrations in the fourth quartile were compared with those in the first quartile, significant associations (at the 0.05 level) were found for several individual POPs and semen quality parameters.
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From page 371... ...
This study was limited by its very small sample size and by a failure to use all of the semen quality markers available. It also had a confusing sampling frame with cases and controls sampled first based on an unsuccessful conception within 12 months status, and then further divided by total motile count.
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From page 372... ...
were: minimum, 0.35; 25th percentile, 1.77; 50th percentile, 2.9; 75th percentile, 4.2; and maximum, 12.1. A general pattern of decreased semen quality (concentration, count, motile sperm)
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From page 373... ...
Other PCBs showed a positive correlation with specific sperm parameters, while parameters such as sperm count and concentration showed no correlation with total PCB levels. The study results suggest an association between exposure to dioxin-like PCBs and semen quality, but it is limited by the small number of participants, and its generalizability is uncertain.
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From page 374... ...
. The discussion of the influence of paternal exposures on outcomes in offspring later in the chapter contains additional information on the biologic plausibility of COI exposure affecting male reproductive health.
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From page 375... ...
The various weaknesses in these studies' methodologies that were noted by the committee, including small sample sizes and difficulty in generalizing the results to the exposure experience of Vietnam veterans, greatly limits their usefulness. Conclusion 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 COIs and alterations in semen quality or other male reproductive health markers.
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From page 376... ...
Endometriosis was first reviewed in Update 2002, which identified two relevant environmental studies. Additional studies considered in later updates did not change the conclusion that the evidence is inadequate or insufficient to support an association with herbicide or dioxin exposure.
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From page 377... ...
A strength of the study was the measurement of dioxins and PCBs in adipose tissue and the calculation of TEQs; its limitations included the small sample size (30 cases; 30 controls) and the selection bias induced by the recruitment of hospital surgery patients as subjects, which limits the generalizability of the results to other populations like female Vietnam veterans.
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From page 378... ...
Soave and colleague's 2015 review contains information on several endometrial studies referenced in Update 2014, plus the Martínez-Zamora paper reviewed above. Biological Plausibility As observed in Update 2014, 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 379... ...
In summary, experimental studies, particularly ones that used human eutopic and ectopic endometrial tissue, provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. Synthesis The human studies linking dioxin exposure with endometriosis are few and inconsistent; information related to exposures to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid is lacking.
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From page 380... ...
(2017) used a cross-sectional/ semi-prospective design to evaluate PCBs and other compounds in first-trimester maternal serum (dioxin-like PCBs 118 and 156 summed)
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From page 381... ...
Biological Plausibility Many studies have examined the effects of TCDD on the female reproductive system. The two primary mechanisms that are believed to contribute to abnormal follicle development and decreased numbers of ova after TCDD exposure are the "cross-talk" of the AHR with the estrogen receptor and the dysregulation of the hypothalamic–pituitary–gonadal axis (Pocar et al., 2005; Safe and Wormke, 1 Androstenedione and dehydroepiandrosterone are so-called "pro-hormones" that are precursors in the production of testosterone and estrogen.
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From page 382... ...
(2010) -- reviewed in Update 2010 -- published the only study to date that has examined dioxin exposure in women with respect to time-to- pregnancy (number of contraceptive-free months before pregnancy)
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From page 383... ...
Information concerning spontaneous abortion, stillbirth, neonatal death, and infant death; sex ratio; birth weight and preterm delivery; and birth defects are discussed below. General Biologic Plausibility Influence of Paternal Exposure James (2006)
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From page 384... ...
. An early experment examining male mice treated with simulated Agent Orange mixtures i prior to breeding with unexposed females failed to find an increase in a variety of different birth defects in progeny compared with the progeny of untreated males (Lamb et al., 1981)
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From page 385... ...
Paternal occupation (characterized by exposure to chemicals via job title or job–exposure matrices) has been linked to an increased risk of selected birth defects (Desrosiers et al., 2012; Fear et al., 2007; Shaw et al., 2002)
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From page 386... ...
(1996) 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 387... ...
Furthermore, the mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developng fetus or nursing infant. TCDD has been measured in circulating human i maternal blood, cord blood, placenta, and breast milk (G.
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From page 388... ...
, and emerging evidence demonstrates that fetal exposures are capable of altering the germ cells epigenetically, resulting in a transmission of adverse effects to future generations (intergenerational and transgenerational inheritance)
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From page 389... ...
. The most common causes of mortality during the neonatal period are low birth weight (< 2.5 kg at birth)
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From page 390... ...
Synthesis No studies concerning the COIs and spontaneous abortion, stillbirth, neonatal death, or infant death have been published since Update 2014, and available toxicologic studies do not provide clear evidence for the biologic plausibility of an association with paternal exposures. Conclusion On the basis of the evidence reviewed to date, the committee concludes that there is limited or suggestive evidence 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 spontaneous abortion.
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From page 391... ...
In brief, studies have found an alteration -- most often, a reduction in -- the expected proportion of male infants at birth, but results are inconsistent and only some reach statistical significance. Update of the Epidemiologic Literature One occupational cohort study on TCDD exposure and sex ratio has been published since Update 2014 was released.
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From page 392... ...
. The lack of an association for maternal exposure is consistent with an endocrine-mediated outcome.
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From page 393... ...
Typically, low birth weight (LBW) is defined as a birth weight under 2,500 g (~5.5 lbs.)
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From page 394... ...
Tables 34 and 35, which can be found at www.nap.edu/catalog/25137, summarize the results of studies related to birth weight after paternal and maternal exposure to the COIs. Update of the Epidemiologic Literature No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and LBW or preterm delivery have been published since Update 2014.
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From page 395... ...
, genes that code for three metabolizing enzymes that had previously been related to dioxin or birth weight.3 Linear regression analyses that were adjusted for confounding factors found that pregnant women with a GSTM1 null genotype -- a genotype previously established to be associated with a high inducibility of cytochrome P450 1A1 gene transcription -- gave birth to infants with a 345 g (95% CI [−584, −105]
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From page 396... ...
Synthesis Studies reviewed in this update continue the pattern observed in earlier research of identifying either no or small decrements in birth weight and size parameters for children born to parents with the highest levels of dioxin exposure. As has been noted by previous committees, there are a number of challenges in conducting these types of epidemiologic studies in a rigorous way.
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From page 397... ...
Additional information from the AFHS available to the committee responsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association between at least one of the COIs and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. The Update 2002 committee, which reviewed a study of female Vietnam veterans that reported significant increases in birth defects in their offspring (Kang et al., 2000a)
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From page 398... ...
The Update 2014 committee concluded that the new evidence it identified concerning the occurrence of birth defects in association with exposure to the COIs, in combination with existing evidence, was inadequate or insufficient to support an association for birth defects overall in the children of Vietnam veterans. In light of the fact that evidence anticipated by the committee responsible for Update 1996 that would support an association between paternal exposure to the COIs and spina bifida had not materialized, that committee concluded that spina ifida should be moved from the category of limited or suggestive evidence b of an association to the default category of inadequate or insufficient evidence of an association.
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From page 399... ...
examined the joint effect of parental occupational exposure to pesticides on the risk of spina bifida in offspring (291 cases)
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From page 400... ...
conducted an ecologic study of hypertrophic pyloric stenosis identified by the Indiana Birth Defects Registry from 2005–2009. Birth defect cases were linked with their birth certificate record to obtain demographic and other infor mation.
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From page 401... ...
. In the multivariable linear regression model, which included an adjustment for the median age of village females, the association between Agent Orange spraying area and infant mortality due to congenital anomalies was statistically significant (standardized regression coefficient β = 2.02; 95% CI 0.08–3.96; p = 0.042)
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From page 402... ...
examined the association between pesticide exposure and the risk of five different types of birth defects ascertained in the San Joaquin Valley of California. The analysis included 367 cases with one of five types of birth efects and 785 controls without any identified malformations born in 1997–2006.
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From page 403... ...
Environmental exposure was estimated by geocoding the residence postal code at the time of pregnancy and factoring in the types of surrounding hazards and their distance from that residence. The odds ratio for maternal exposure to herbicides (otherwise unspecified)
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From page 404... ...
TCDD is a potent teratogen in all laboratory species that have been studied, although the patterns of birth defects that are produced are often species-specific. However, specific mechanisms that link TCDD exposure to specific birth defects have not been fully elucidated.
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From page 405... ...
However, translating these results to human populations has been difficult. Synthesis Given the long-standing concern of Vietnam veterans about the potential of the COIs to adversely affect the health of their children, birth defects have been among the outcomes considered by VAO committees since the first comprehensive review was published in 1994.
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From page 406... ...
and an increased risk of two unrelated birth defects. However, the recent studies did not change the previous conclusion of inadequate or insufficient evidence to support an association for birth defects overall in the children of Vietnam veterans.
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From page 407... ...
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. The committee responsible for VAO concluded that there was 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 childhood cancers.
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From page 408... ...
and 5 controls (3.1%) reported potential Agent Orange exposure during Vietnam War service.
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From page 409... ...
The analysis of paternal Agent Orange exposure was based on a very small number of exposed cases, and the confidence intervals associated with the odds ratios were correspondingly broad. This report found no association between paternal military service in Vietnam or Agent Orange exposure and an increased risk of rhabdomyosarcoma in offspring.
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From page 410... ...
. The study strengths include a population-based design and a comprehensive in-person interview-based collection and assessment of parental occupational exposures, including occupations associated with pesticide use.
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From page 411... ...
. Biologic Plausibility 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 412... ...
There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their developmental or delayed effects in offspring. Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to cancer through multiple mechanisms.
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From page 413... ...
. Similarly, it was reported that prenatal TCDD exposure increases the DNA methylation of two growth-related imprinted genes, H19 and Ig f2, in the developing fetus (Q.
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From page 414... ...
Three European birth cohorts (Belgian, Norwegian, Slovak) that assessed dioxinexposures in cord blood or breast milk were pooled by Iszatt et al.
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From page 415... ...
In this cohort, each mother completed a questionnaire that probed potential occupational, domestic, environmental, and dietary sources of parental exposure to pesticides during her pregnancy. Multivariate regression analyses found that maternal occupational exposure was associated with an elevated risk of low birth weight (OR = 4.2, 95% CI 1.2–15.4)
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From page 416... ...
Perinatal dioxin exposure of infants was estimated by the measurement of dioxin levels in the breast milk of the nursing mothers. Growth parameters -- including weight, height, and head and abdominal circumferences -- were measured at birth, 1 and 4 months, and 1 and 3 years of age.
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From page 417... ...
Many empirical analyses were conducted, with results showing, in general, that prenatal PCB exposures were associated with more optimal devel opment, both before and after adjustment for confounders of birth weight and child's age at assessment. None of the results assessing the association between prenatal exposure to mono-ortho PCBs and non-optimal development were statistically significant: PCB 105 (0.833 per 1 ng/g lipid weight, CI 0.550–1.262)
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From page 418... ...
None of several different metrics estimating the dioxin exposure showed any association with the TDS score in any of the analyses of boys, girls, or different age groups: in linear regression analyses, breast milk TEQ level was not significantly related to the TDS in boys (partial regression coefficient = 2.29; 95% CI [−7.60, 12.18]
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From page 419... ...
base in Vietnam to evaluate potential associations between perinatal dioxin exposure and autism spectrum disorders in the children. Parents completed a full-length Autism Spectrum Rating Scale (ASRS)
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From page 420... ...
, had significantly lower neurodevelopmental scores than lesser-exposed boys without a comparable difference in their ASRS scores. These results suggest that perinatal TCDD exposure has an effect on autistic traits in childhood that is separate from neurotoxic effects of dioxin exposure in general.
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From page 421... ...
, and birth weight of the infants; the age, education, and drinking habit during pregnancy and residential location of the mothers; and the family income and smoking status of family members. Analyses found that the TEQs for three different metrics of exposure (all PCDD/Fs, TCDD, and the daily dioxin intake)
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From page 422... ...
The perinatal dioxin exposure of infants was estimated by the measurement of dioxin levels in breast milk of the nursing mothers. The neurodevelopment of infants and children, including cognitive, language, and motor development, was determined at 4 months, 1 year, and 3 years of age.
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From page 423... ...
-- in a paper published in French -- examined the association between prenatal exposure to PCBs, hexachlorobenzene, and p-p′-DDE and the risk of asthma in children born to women included in a cohort of Danish births in 1988–1989 (the Danish Fetal Origins Cohort)
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From page 424... ...
. Models were adjusted to the child's sex and birth weight as well as to several maternal parameters: age at birth, pre-pregnancy BMI, parity, smoking, alcohol consumption, education level, plasma concentrations of triglycerides, and total cholesterol.
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From page 425... ...
Biologic Plausibility As noted in Update 2014, the results of studies in rodent models provide support for the idea that prenatal exposure to TCDD can result in adverse effects in offspring later in life, including immune disorders, behavioral disturbances, repro ductive impairment, kidney disease, and cancers (Foster et al., 2010; Prescott, 2011; Puga, 2011; Takeda et al., 2012)
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From page 426... ...
. Other studies have focused on neurobehavioral outcomes following perinatal exposure, which is of relevance in understanding the possible consequences in the offspring of Vietnam veterans, particularly the offspring of female veterans.
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From page 427... ...
BIOLOGIC PLAUSIBILITY OF POSSIBLE EFFECTS IN SUBSEQUENT 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 responsible for Update 2010 explored the possibility of intergenerational or 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. Effects in persons exposed in utero are not considered transgenerational because the fetus was likely exposed directly.
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From page 428... ...
Intergenerational Gestational Exposure Transgenerational FIGURE 8-1 The partitioning between intergenerational and transgenerational effects due to the exposure of a parent. SOURCE: Adapted from NASEM, 2018, Figure 3-2.
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From page 429... ...
As part of its response to this directive, VA tasked this committee to "assess the current research available on possible generational health effects that may be the result of exposures to [the COIs] -- including the biologic plausibility or potential for an exposure to lead to an increased risk of birth defects or other adverse conditions in the descendants of male Veterans."10 Epidemiological Studies No relevant studies of potential transgenerational effects of exposure to the COIs in humans have been reported to date.
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From page 430... ...
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 in humans.
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From page 431... ...
Synthesis No epidemiological information exists to evaluate whether paternal or maternal exposure to the COIs results in health effects in grandchildren or subsequent generations of descendants of Vietnam veterans. The animal literature contains evidence that environmental agents mediated by maternal exposure affect later generations through fetal and germline modifications, but in the case of adult male exposures before the conception of the next generation, there is insufficient evidence on which to draw a conclusion regarding transgenerational effects.
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