Veterans and Agent Orange Update 2008 (2009) / Chapter Skim
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7 Reproductive Effects and Impacts on Future Generations
7 Reproductive Effects and Impacts on Future Generations
Pages 435-509
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From page 435... ...
, increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant mortality, and other adverse birth outcomes (including low birth weight, preterm birth, and birth defects)
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From page 436... ...
Whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately. 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 a male or female veteran.
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From page 437... ...
Toxicologists often distinguish between reproductive effects, which concern the reproductive process itself, and developmental effects, which involve differentiation of fetal tissues and maturation of the offspring. A connection between TCDD exposure and human reproductive and developmental effects is, in general, biologically plausible.
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From page 438... ...
Conclusions from VAO and Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies, and Update 2004 examined three environmental studies. Two additional environmental studies considered in Update 2006 did not change the conclusion that the evidence was inadequate or insufficient to support an association with herbicide exposure.
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From page 439... ...
examined Tsuchiya 138 infertility patients in Japan; Results for advanced endometriosis et al., laproscopically confirmed case– Total TEQ: OR = 0.5 (95% CI 0.2–1.7) 2007 control status, serum dioxin, PCB Genotype-specific: ORs = 0.3–0.6 TEQ; P450 genetic polymorphism significant interaction between genotype, No dioxin TEQ Studies Reviewed in Update 2006 Heilier Endometriosis in Belgian women 50 exposed cases, risk of increase of 10 pg/p lipid et al., with overnight fasting serum of TEQ compounds: OR = 2.6 (95% CI 1.3–5.3)
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From page 440... ...
, OR = 2.1 (90% CI 0.5–8.0) TCDD concentrations Studies Reviewed in Update 2002 Pauwels Patients undergoing infertility Six exposed cases: OR = 4.6 (95% CI 0.5–43.6)
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From page 441... ...
The study used indirect measures of dioxin exposure that are expected to be less precise than measures of serum dioxin, so the results do not necessarily contradict those of their earlier study. The investigators were unable to identify any likely source of dioxin exposure that differed between cases and controls.
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From page 442... ...
In summary, the study found some evidence of a gene–environment interaction related to the occurrence of endometriosis, but women who had higher concentrations of dioxin were found to be at lower risk for advanced endometriosis. Biologic Plausibility Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis and TCDD exposure provide evidence to support the biologic plausibility of a link between TCDD exposure and endometriosis.
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From page 443... ...
To probe the effect of dioxin exposure and estrogen on expression of those chemokines in endometriosis-associated cells and to explore the pathogenesis of endometriosis, endometrial stromal cells were exposed to a combination of 17β-estradiol and TCDD. The combined treatment increased the secretion of RANTES and MIP-1α, promoted the invasiveness of endometrial stromal cells, and increased the expression of matrix metalloproteins MMP-2 and MMP-9 in endometrial stromal cells, indicating that combined TCDD and estradiol may facilitate the onset of endometriosis and contribute to its development by increasing the invasion of endometrial stromal cells mediated by CC-motif chemokines (Yu et al., 2008)
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From page 444... ...
Overall, the studies linking dioxin exposure with endometriosis are few in number and inconsistent. The association in animal studies is biologically plausible, but it is possible that human exposures are too low to show an association consistently.
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From page 445... ...
An affect on age at menarche would be of concern among the daughters of Vietnam veterans rather than among female veterans themselves, but the occurrence of this effect in other populations would demonstrate the ability of the chemicals in question to perturb functioning of the female reproductive system. Conclusions from VAO and Updates The committee responsible for the original VAO report (IOM, 1994)
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From page 446... ...
nr -0.056 (0.02) Studies Reviewed in Update 1996 Henriksen Effects on specific hormone concentrations or et al., sperm count in Ranch Hands 1996 Low testosterone High dioxin (1992)
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From page 447... ...
23 1.6 (0.8–3.3) Studies Reviewed in Update 2006 Oh et al., Male fertility, dioxin exposure with air 2005 monitoring 31 1.4 (nr)
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From page 448... ...
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; CI, confidence interval; dl, dioxin-like; FSH, follicle-stimulating hormone; IU, international unit; LH, luteinizing hormone; nr, not reported; PAH, polycyclic aromatic hydrocarbon; PCB, polychlorinated biphenyl; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxicity equivalency factor; TEQ, toxicity equivalent quotient; VOC, volatile organic compounds. aGiven when available; results other than estimated risk explained individually.
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From page 449... ...
a OCCUPATIONAL Studies Reviewed in Update 2006 Farr Age of menopause women who self-reported et al., pesticide exposure 2006 8,038 0.9 (0.8–1.0) Farr Menstrual-cycle characteristics of et al., premenopausal women in AHS 21–40 years old 1,754 2004 Short menstrual cycle 0.8 (0.6–1.0)
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From page 450... ...
ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; BMI, body mass index; CI, confidence interval; OR, odds ratio; PCB, polychlorinated biphenyl; SWHS, Seveso Women's Health Study; TCDD, 2,3,7,8tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent quotient. aGiven when available; results other than estimated risk explained individually.
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From page 451... ...
. The study found that TCDD exposure in infancy–prepuberty was associated with lower sperm concentration and motility in adulthood, lower estradiol, and higher FSH.
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From page 452... ...
; this difference remained statistically significant after controlling for age, BMI, smoking, and alcohol consumption. Female Fertility No new Vietnam-veteran or occupational studies addressing female fertility have been published since Update 2006.
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From page 453... ...
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 hypothalamicpituitary-gonadal axis. Interaction of the activated AHR leads to inhibition of estradiol-induced gene expression and to enhancement of estrogen-receptor protein degradation; both activities may contribute to TCDD's antiestrogenic effects.
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From page 454... ...
Ovarian endocrine disruption appears to be the predominant functional change induced by chronic exposure to the low doses of TCDD that are associated with premature reproductive senescence in female rats without depletion of ovarian follicular reserves (Shi et al., 2007)
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From page 455... ...
. In the single report relevant to this outcome in Vietnam veterans, however, the sex ratio was increased in the Ranch Hand group that had the highest serum dioxin concentrations (Michalek et al., 1998b)
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From page 456... ...
exposed Studies Reviewed in Update 2002 Schnorr Workers producing trichlorophenol and No difference on et al., 2001 derivatives, including 2,4,5-T basis of age at Serum TCDD in fathers first exposure Neighborhood controls (< 20 ppt) 0.544 Referent Worker fathers < 20 ppt 0.507 None 20–255 ppt 0.567 significantly 255– < 1,120 ppt 0.568 decreased (or ≥ 1,120 ppt 0.550 increased)
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From page 457... ...
0.490 p = 0.037 Father under 20 years old in 1979 0.458 p = 0.020 Father at least 20 years old in 1979 0.541 p = 0.60 Mother exposed (whether or not father exposed) 0.504 p = 0.45 Mother under 20 years old in 1979 0.501 p = 0.16 Mother at least 20 years old in 1979 0.500 p = 0.40 Studies Reviewed in Update 2002 Karmaus Births after 1963 to Michigan fish-eaters et al., 2002 with serum PCBs in both parents Paternal PCBs > 8.1 µg/L 0.571 p < 0.05 (but for more sons)
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From page 458... ...
to parental TCDD serum Births 1985–1994 0.484 ns (60 boys: 64 girls) ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; dl, dioxin-like; ns, not significant; nr, not reported; 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, toxicity equivalent quotient.
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From page 459... ...
There is little evidence that exposure to dioxin is associated with a reduction in sperm quality or a reduction in fertility. However, the committee notes that the evidence that TCDD exposure reduces serum testosterone in men is consistent among several epidemiologic studies with appropriate consideration of confounders, including one of Vietnam veterans; shows a dose–response relationship; and is biologically plausible on the basis of concomitant increases observed in gonadotropins and biologic plausibility shown by animal studies.
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From page 460... ...
Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion. The committee responsible for Update 2002, however, did conclude that there was enough evidence available concerning paternal exposure to TCDD specifically to conclude that there was suggestive evidence that paternal exposure to TCDD is not associated with the risk of spontaneous abortion.
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From page 461... ...
Biologic Plausibility Laboratory animal studies have demonstrate that TCDD exposure during pregnancy can alter concentrations of circulating steroid hormones and disrupt placental development and function and thus contribute to a reduction in survival of implanted embryos and to fetal death. However, the reproductive significance of those effects and the risk of recognized pregnancy loss before 20 weeks of gestation in humans are not clear.
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278 nr Vietnam-era veterans who did not serve in Vietnam (1,912 pregnancies) 317 nr Studies Reviewed in Update 2000 Schwartz, Female Vietnam veterans (maternal exposure)
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nr, but reported ns 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 464... ...
; PCB, polychlorinated biphenyl; PeCDF, 2,3,4,7,8p entachlorodibenzofuran; SWHS, Seveso Women's Health Study; TCDD, 2,3,7,8-tetrachlorodibenzop-dioxin; TEF, toxic equivalency factor; TEQ, toxicity equivalent quotient. aUnless otherwise indicated, results are for paternal exposure.
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From page 465... ...
. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and stillbirth, neonatal death, or infant death.
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From page 466... ...
, but spontaneous abortions appear to dominate the analyses. 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.
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From page 467... ...
. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence of an association between exposure to the chemicals of interest and low birth weight or PTD.
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From page 468... ...
However, the significance of those animal effects for humans is not clear. Synthesis The four environmental studies reviewed here did not provide compelling evidence of an association between exposure to the chemicals of interest and the risk of low birth weight or prematurity.
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From page 469... ...
Conclusions On the basis 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 compounds of interest and low birth weight or preterm delivery. BIRTH DEFECTS The March of Dimes defines a birth defect as an abnormality of structure, function, or metabolism, whether genetically determined or as the result of an environmental influence during embryonic or fetal life (Bloom, 1981)
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From page 470... ...
The committee for Update 2002, which reviewed the study of female Vietnam veterans (Kang et al., 2000) that reported significant increases in birth defects in their offspring, did not find those results adequate to modify prior conclusions.
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From page 471... ...
Studies Reviewed in Update 2000 AIHW, 1999 Australian Vietnam veterans -- validation study Cases expected (95% CI) Down syndrome 67 92 expected (73–111)
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From page 472... ...
Digestive system defects 18 2.0 (0.9–4.6) Birth defects -- black Vietnam veterans only 21 3.4 (1.5–7.6)
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From page 473... ...
2,4-D 7 1.0 (0.4–2.3) Studies Reviewed in Update 2006 Lawson et al., Wives of workers with measured serum TCDD 2004 in NIOSH cohort 14 nr Studies Reviewed in Update 1998 Kristensen et al., Norwegian farmers (maternal, paternal 1997 exposure)
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From page 474... ...
≥ 0.04 nr 0.9 (0.4–2.1) Studies Reviewed in Update 2006 Cordier et al., Residents of Rhône-Alpes region of France 2004 living near municipal solid-waste incinerators (maternal, paternal exposure)
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From page 475... ...
index 14 3.1 (0.6–16.9) Studies Reviewed in VAO Fitzgerald et al., Persons exposed to an electric-transformer 1989 fire -- total birth defects (maternal, paternal exposure)
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From page 476... ...
Studies Reviewed in Update 1996 Wolfe et al., Air Force Operation Ranch Hand personnel -- 1995 neural-tube defects 4c nr Studies Reviewed in VAO CDC, 1989b Vietnam Experience Study 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 Erickson CDC birth defects case–control study et al., Service in Vietnam 1984a,b Spina bifida 19 1.1 (0.6–1.7)
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From page 477... ...
ENVIRONMENTAL Studies Reviewed in Update 2006 Cordier Residents of Rhône-Alpes region of France et al., 2004 (maternal, paternal exposure)
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Biologic Plausibility Little information is available on the reproductive and developmental effects of exposure to the herbicides discussed in this report. Studies indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities.
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From page 479... ...
Studies in which effects of TCDD on the developing embryo or fetus were investigated after maternal exposure to TCDD; they include an array of animal models and a variety of experimental outcomes. Such laboratory studies have established that maternal exposure to TCDD during pregnancy is associated with a wide variety of birth defects, which depend on the timing of exposure and the species being studied.
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From page 480... ...
. Thus, there is biologic potential for paternal exposure to contribute to TCDD-induced developmental toxicity.
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From page 481... ...
Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion.
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From page 482... ...
Field and Cancer in children of Australian Vietnam veterans 4 nr Kerr, 1988 Erikson CDC Birth Defects Study -- children of Vietnam et al., 1984b veterans "Other" neoplasms 87 1.8 (1.0–3.3) OCCUPATIONAL New Studies Monge Parental occupational exposure to pesticide, et al., 2007 childhood leukemia in Costa Rica Paternal exposure in year before conception to: Herbicides 53 1.2 (0.8–1.7)
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From page 483... ...
Paternal exposure to chlorophenoxy herbicides 28 1.3 (0.6–2.6) Maternal exposure to 2,4-D 7 0.7 (0.3–1.6)
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From page 484... ...
Paternal exposure to dioxin 7 6.9 (1.3–68.4) Studies Reviewed in Herbicide/Dioxin Exposure and AML in the Children of Veterans Kristensen Children of agricultural workers in Norway et al., 1996 Children with AML whose parents purchased pesticides 12 1.4 (0.6–2.9)
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From page 485... ...
Maternal exposure during pregnancy 15 3.6 (1.5–8.8) Lymphomas Paternal exposure year before pregnancy 11 1.5 (0.7–3.1)
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From page 486... ...
, but only paternal exposures before conception and maternal exposure before and during gestation could be of any possible relevance to the circumstances under which Vietnam veterans were exposed. Paternal exposure to herbicides during the year before conception was slightly associated with all types of leukemia (OR = 1.2, 95% CI 0.8–1.7)
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From page 487... ...
However, the pattern of associations with paternal exposure was similar to the pattern of associations between maternal exposure and AL (OR = 1.2, 95% CI 1.0–1.4)
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From page 488... ...
They were limited by definition of exposure on the basis of residence in counties of greater agricultural activity and did not meet the level of exposure specificity required for full review by the committee. Biologic Plausibility Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to cancer through multiple mechanisms.
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From page 489... ...
. Although there is no direct evidence from animal models that TCDD increases 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 490... ...
. Animal studies have repeatedly shown adverse effects of prenatal TCDD exposure on various reproductive characteristics of the offspring.
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From page 491... ...
have indicated that development of the male reproductive system is exceptionally sensitive to in utero and lactational TCDD exposure. Maternal exposure to TCDD impairs prostate growth and seminal vesicle weight and branching and decreases sperm production and caudal epididymal sperm number in offspring.
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From page 492... ...
. Methylation status is genetically determined, but recent work in animal model systems suggests that environmental exposures, particularly during fetal development and early life, also induce epigenetic changes in somatic tissues (Cutfield et al., 2007)
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From page 493... ...
(2004) have demonstrated that TCDD exposure of mouse embryos before implantation in unexposed females resulted in reduced fetal weight in association with reduced expression and increased methylation of imprinted genes.
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From page 494... ...
SUMMARY Synthesis The studies reviewed for this update did not find any significant associations between the relevant exposures and reproductive outcomes. The scientific evidence supports the biologic plausibility of a connection between exposure to the chemicals of interest and reproductive effects, but the epidemiologic studies of occupational cohorts, exposed communities, and Vietnam veterans have not provided conclusive evidence of any additional associations between exposures and an array of reproductive outcomes and conditions in the offspring of exposed parents.
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From page 495... ...
2001. Morbidity of Vietnam veterans.
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From page 496... ...
2007a. The aryl hydrocarbon receptor is required for normal gonadotropin responsiveness in the mouse ovary.
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From page 497... ...
Environmental Health Perspectives 116(4)
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From page 498... ...
Environmental Health Perspectives 115(1)
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From page 499... ...
2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study.
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From page 500... ...
1998. Paternal exposure to pesticides and congenital malformations.
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From page 501... ...
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 502... ...
2002 Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring. Journal of Occupational and Environmental Medicine 44(1)
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From page 503... ...
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 504... ...
2008. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality.
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From page 505... ...
2002. Developmental stage–specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring.
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From page 506... ...
2001. Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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From page 507... ...
2007. Ovarian endocrine disruption underlies premature reproductive senescence following environmentally relevant chronic ex posure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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From page 508... ...
1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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From page 509... ...
gene expression in human endometrial stromal cells. Journal of Clinical Endocrinology and Metabolism 87(6)
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