Veterans and Agent Orange Update 2014 (2016) / Chapter Skim
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9 Effects on Veterans' Fertility and Reproductive Success
9 Effects on Veterans' Fertility and Reproductive Success
Pages 655-698
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From page 655... ...
• There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest 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. • There is limited or suggestive evidence of no association between paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
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From page 656... ...
, endometriosis, increased fetal loss (spontaneous abortion and stillbirth) , neonatal and infant mortality, and the adverse gestational outcomes of low birth weight and preterm delivery.
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From page 657... ...
Dioxin exposure has the potential to disrupt male reproductive function by altering gene expression that is pertinent to spermatogenesis and by altering steroidogenesis (Wong and Cheng, 2011) and to disrupt female reproductive function by altering gene expression relevant to ovarian follicle growth and maturation, uterine function, placental development, and fetal morphogenesis and growth.
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From page 658... ...
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 659... ...
Unlike blood released during normal shedding of the endometrium, blood released from endometrial lesions has no way to leave the body and results in inflammation and internal bleeding. The degeneration of blood and tissue can cause scarring, pain, infertility, adhesions, and intestinal problems.
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From page 660... ...
Studies Conducted in Belgium 88 matched triads (264 total) ; Results for pelvic endometriosis vs Heilier patients with deep endometriotic controls: et al., 2007 nodules, pelvic endometriosis, Dietary fat: OR = 1.0 (95% CI 1.0–1.0)
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From page 661... ...
, 1.6 GC/MS) in pooled blood samples Cases (two sets of 6 pooled samples)
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From page 662... ...
; No significant interaction between P450 genetic polymorphism genotype, dioxin TEQ NOTE: BMI, body mass index; CALUX, chemical activated luciferase gene expression; 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 dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent.
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From page 663... ...
(2008) showed that CYP1A1 expression is greater in ectopic endometrial tissue than in eutopic uterine tissue in the absence of TCDD exposure, which suggests that CYP1A1 may play a role in the etiology of the disease or that AHR and its signaling pathway have been activated by an endogenous ligand other than TCDD, such as bilirubin (Seubert et al., 2002)
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From page 664... ...
Although animal studies support the biologic plausibility of an association, contemporary human exposures may be too low to show an association consistently. Conclusion On the basis of the evidence reviewed here, in VAO, and in the previous VAO updates, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and human endometriosis.
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From page 665... ...
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 alterations in sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change the conclusion that exposure to the COIs had not been found to be associated with impaired fertility in either men or women.
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From page 666... ...
Exposure of Interest/ Estimated Exposed Relative Risk Study Population Casesa (95% CI) a Reference VIETNAM VETERANS US Air Force Health Study -- Ranch Hand veterans All COIs vs SEA veterans (unless otherwise noted)
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From page 667... ...
EFFECTS ON VETERANS' FERTILITY AND REPRODUCTIVE SUCCESS 667 TABLE 9-2 Male Fertility, continued Exposure of Interest/ Estimated Exposed Relative Risk Study Population Casesa (95% CI) a Reference Detailed description of cohort CDC, 1989c Lower sperm concentration 42 2.3 (1.2–4.3)
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From page 668... ...
, n = 44 vs 136 Intermediate response Adult (18–26 yrs) , n = 20 vs 60 No associations Other International Environmental Studies Belgian men in general population PCBs, dioxin Dhooge Association with 2-fold increase in Change (p-value)
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From page 669... ...
in Dl-PCBs Ferguson subfertile couples seeking infertility evaluations et al., and treatment in Massachusetts General 2012 Hospital (01/2000–05/2003) PCB 118 with steroid hormone binding globulin (β = –0.13, p < 0.01)
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From page 670... ...
NOTE: 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, chemicals of interest; dl, dioxin-like; DLC, dioxin-like chemical; DNA, deoxyribonucleic acid; FSH, follicle-stimulating hormone; ICD, International Classification of Diseases; IU, international unit; LH, luteinizing hormone; ln, natural logarithm; 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) toxic equivalent; VOC, volatile organic compound.
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From page 671... ...
a Reference OCCUPATIONAL -- HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts) UNITED STATES US Agricultural Health Study -- prospective Phenoxy study of licensed pesticide sprayers in Iowa and herbicides North Carolina: commercial (n = 4,916)
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From page 672... ...
Log10 TCDD 169 1.0 (0.8–1.3) Menopause Category Serum TCDD median (IQR)
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From page 673... ...
; Dioxin/ Chao placental TEQ concentrations of TCDDs, TCDFs, Regression et al., 2007 PCBs adjusted for maternal 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 CASE-CONTROL STUDIES US Case-Control Studies Women in Wisconsin with or without infertility Phenoxy Greenlee (maternal exposure) -- incidence herbicides et al., 2003 continued
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From page 674... ...
NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BMI, body mass index; CATI, computer-assisted telephone interviewing; CI, confidence interval; HR, hazard ratio; IARC, International Agency for Research on Cancer; IQR, inter-quartile range; OR, odds ratio; PCB, polychlorinated biphenyl; ppt, parts per trillion; TCDD, 2,3,7,8–tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total) toxic equivalent.
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From page 675... ...
(2012) found that 1 nM TCDD exposure in vitro did not reduce the rates of growth of murine antral follicles, but did reduce the secretion of progesterone and estradiol by the follicles.
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From page 676... ...
suggested that paternal exposure to dioxin results in a lower sex ratio (i.e., a smaller-than-expected proportion of male infants at birth) , particularly when the father was exposed early in his life (sex ratio [SR]
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From page 677... ...
Other Studies of Industrial Workers (not related to NIOSH phenoxy cohort) Austrian chloracne cohort -- 157 men, 2 women; Moshammer exposed to TCDD during 2,4,5-T production and Neuberger, Children born after starting TCDD exposure in 0.464 Fewer sons, 2000 1971 (26 boys: 30 especially girls)
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From page 678... ...
678 VETERANS AND AGENT ORANGE: UPDATE 2014 TABLE 9-4 Sex Ratio, continued Sex Ratio of Offspring Study Population (boys/total) b Comments Reference Only father exposed 0.378 p < 0.001 (71 boys: 117 girls)
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From page 679... ...
Ecological Study of Residents of Chapaevsk, Russia Residents near chemical plant in operation Revich 1967–1987 in Chapaevsk, Russia et al., 2001 1983–1997 0.507 No clear pattern Minimum in 1989 0.401 Maximum in 1987 0.564 Maximum in 1995 0.559 Other International Environmental Studies JAPAN -- Yusho incident Parents (one or both) exposed to PCBs, PCDFs Yoshimura (not TCDD)
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From page 680... ...
Maternal PCBs > 8.1 µg/L 0.494 ns NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; dl, dioxin-like; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; ns, not significant; nr, not reported; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; ppt, parts per trillion; SEA, Southeast Asia; SR, sex ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total) toxic equivalent.
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From page 681... ...
There is little evidence that exposure to dioxin is associated with a reduction in sperm quality or a reduction in fertility. However, the committee for Update 2008 noted that the evidence that TCDD exposure reduces serum testosterone in men is consistent across several epidemiologic studies with an appropriate consideration of confounders, including one of Vietnam veterans that found a dose–response relationship.
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From page 682... ...
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 insufficient evidence of an association between exposure to the COIs and decreased sperm counts or sperm quality, subfertility, or infertility. SPONTANEOUS ABORTION, STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH 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 683... ...
, but the committee for Update 2002 asserted that they might be due to an 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 684... ...
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 Ranch Hand veterans 157 Wolfe Background 57 1.1 (0.8–1.5)
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From page 685... ...
> 1120 ppt 8 1.0 (0.4–2.2) Dow Workers with Potential TCDD Exposure Dioxins, phenoxy Townsend and reproductive outcomes studied in offspring herbicides et al., 1982 of 930 men working with chlorophenol, 1939–1975 Wives of men employed involved in 85 1.0 (0.8–1.4)
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From page 686... ...
Women's Health Study -- Industrial TCDD accident July 10, 1976; 981 women between infancy and 40 yrs of age at the time of the accident, who resided in Zones A, B SWHS -- 30-yr updated analysis of pregnancy Wesselink outcomes et al., 2014 10-fold increase in TCDD level at time of 160 0.8 (0.6–1.0) accident Effects on first birth after explosion 75 0.8 (0.6–1.2)
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From page 687... ...
c Ontario Farm Family Health Study Phenoxy herbicides Ontario farm families (maternal, paternal Arbuckle exposures) et al., 2001 Phenoxyacetic acid herbicide exposure in 48 1.5 (1.1–2.1)
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From page 688... ...
. Biologic Plausibility Laboratory animal studies have demonstrated that TCDD exposure during pregnancy can alter the concentrations of circulating steroid hormones and disrupt placental development and function and thus contribute to a reduction in the
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From page 689... ...
Furthermore, toxicologic studies do not provide clear evidence for the biologic plausibility of an association. Conclusions 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 690... ...
, extremes of maternal age, low socioeconomic status, previous LBW or PTD, multiple gestations, tobacco use, and low maternal prepregnancy weight or poor pregnancy weight gain (Rubens et al., 2014)
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From page 691... ...
These appear to have all been independent models. Tasmanian Veterans with Service in Vietnam -- Follow-up of Australian Vietnam veterans Military service in ~550 LBW/RR RR calculated by Field and Vietnam 1.6 (1.0–2.5)
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From page 692... ...
Maternal dietary intake of dioxins was estimated using data from food frequency questionnaires and was correlated with the TEQ concentration measured in maternal blood. For mothers in the highest category of dietary intake of dioxin-like compounds, an inverse relationship with birth weight (−121 g, 95% CI −232 to −10)
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From page 693... ...
Military Service 4,140 LBW (OR = 1.06, Maternal age, Kang et al., 95% CI 0.8–1.5) education, 2000a race, marital status, military characteristics, smoking, drinking, average number of hours worked during pregnancy, complications during pregnancy ENVIRONMENTAL International Studies Mother-child pairs 967 BW decreased with Country, gestational Vafeiadi et al., from four European increased dioxin age, gestational 2014a cohorts measured in cord age squared, blood parity, maternal prepregnancy BMI, gender Japan Yusho, Japan -- 190 ~ −200g BW Gestational age, Tsukimori population exposed reduction with PCDD maternal age, parity, et al., 2012a; to PCDDs, PCDFs, TEQ (p = 0.003)
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From page 694... ...
target height, parity Norway NewGeneris 604 BW decreased Maternal educational Papadopoulou cohort -- Maternal with increased dl- level, energy, et al., 2014 dietary intake of compounds in diet; maternal age, predioxins and PCBs only significant in pregnancy BMI, boys parity, smoking during pregnancy country Norwegian Mother 50,651 BW decreased Maternal age, energy Papadopoulou and Child Cohort with increased dl- intake, maternal et al., 2013a Study -- Maternal compounds in diet education, predietary intake of pregnancy BMI, dioxins and PCBs parity, weight gain and smoking during pregnancy, gestational age, child's gender
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From page 695... ...
toxic equivalent; LBW, low birth weight; OR, odds ratio; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofurans; SAB, spontaneous abortion; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.
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From page 696... ...
. Biologic Plausibility The available evidence from experimental animal studies indicates that TCDD exposure during pregnancy can reduce body weight at birth, but only at high doses.
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From page 697... ...
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 low birth weight or preterm delivery.
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