Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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9 Fertility and Gestational Outcomes
9 Fertility and Gestational Outcomes
Pages 673-725
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From page 673... ...
• None of the fertility or gestational outcomes had limited or suggestive evidence of an association between the chemicals of interest. • 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.
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From page 674... ...
, endometriosis, increased fetal loss (spontaneous abortion and stillbirth) , neonatal and infant mortality, and the adverse gestational outcomes of low birth weight or preterm delivery.
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From page 675... ...
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 pertinent to ovarian follicle growth and maturation, uterine function, placental development, and fetal morphogenesis and growth.
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From page 676... ...
However, the preponderance of evidence from animal studies indicates that they do not have reproductive effects. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their reproductive or gestational effects.
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From page 677... ...
Conclusions from VAO and Previous Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies. Additional studies considered in later updates have not changed the conclusion that the evidence is inadequate or insufficient to support an association with herbicide exposure.
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From page 678... ...
al., 2001 number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay)
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From page 679... ...
: al., 2004 compared concentrations of TCDD, Italy: total TEQ (determined by GC/ Controls (10 pooled samples)
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From page 680... ...
al., 2007 control status, serum dioxin, PCB Genotype-specific: ORs = 0.3–0.6 TEQ (determined by GC/MS) ; P450 No significant interaction between 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; GC/MS, gas chromatography/mass spectrometry; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-pdioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetra chlorodibenzo-p-dioxin; TEQ, (total)
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From page 681... ...
Human endometrial tissue and cultured human endometrial epithelial cells both express the AHR; its dimerization partner, the aryl hydrocarbon nuclear translocator (Khorram et al., 2002) ; and three AHR target genes -- CYP1A1, 1A2, and 1B1 (Bulun et al., 2000; Willing et al., 2011)
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From page 682... ...
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 studies linking dioxin exposure with endometriosis are few and inconsistent.
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From page 683... ...
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, and Update 2010 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 684... ...
a Reference VIETNAM VETERANS US Air Force Health Study -- Ranch Hand veterans All COIs vs SEA veterans (unless otherwise noted) AFHS (964 Ranch Hands, 1,259 comparisons)
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From page 685... ...
a Reference US CDC Vietnam Experience Study -- Cross- All COIs sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed Detailed description of cohort CDC, 1989a Lower sperm concentration 42 2.3 (1.2–4.3) Proportion of abnormal sperm 51 1.6 (0.9–2.8)
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From page 686... ...
, 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 et Association with 2-fold increase in Change (p-value)
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From page 687... ...
FERTILITY AND GESTATIONAL OUTCOMES 687 TABLE 9-2 Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility) , continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)
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From page 688... ...
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; IARC, International Agency for Research in Cancer; ICD-9, International Classification of Diseases, 9th Revision; IU, international unit; LH, luteinizing hormone; nr, not reported; NIOSH, National Institute for Occupational Safety and Health; PAH, polycyclic aromatic hydrocarbon; PCB, polychlorinated biphenyl; POP, persistent organic pollutants; ppt, parts per trillion; 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 689... ...
ENVIRONMENTAL Seveso (Italy) 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 and B Time to pregnancy and infertility in women from Eskenazi et Zones A and B who attempted pregnancy after al., 2010 1976 20-yr followup to 1996 -- men and women Time to pregnancy (adjusted fecundability OR)
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From page 690... ...
> 75 79 0.6 (0.4–0.9) Ovarian function in women from Zones A and B Warner at who were newborn to age 40 in 1976; results are al., 2007 for a 10-fold increase in serum TCDD Ovarian follicles (age-adjusted OR)
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From page 691... ...
; Dioxin/ Chao et al., placental TEQ concentrations of TCDDs, TCDFs, Regression 2007 PCBs adjusted for maternal age, BMI, parity ≥ 18 yrs old, "regular menstrual cycle" Dioxin TEQ p = 0.032 PCB TEQ p = 0.077 Women with "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 et (maternal exposure) -- incidence herbicides al., 2003 continued
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From page 692... ...
4 controls (1.2%) 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)
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From page 693... ...
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 hypothalamic–pituitary–gonadal axis. Oocytes are directly responsive to TCDD, so TCDD's effects on hormone concentrations, hormone-receptor signaling, and ovarian responsiveness to hormones all probably contribute to TCDD-induced
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From page 694... ...
suggested that paternal exposure to dioxin may result in a lower sex ratio (that is, 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 695... ...
b Comments Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study -- Ranch Hand veterans vs SEA veterans (unless otherwise noted) Births from service through 1993 in AFHS Michalek et Comparison group 0.504 Not formally al., 1998b Dioxin level in Ranch Hand personnel analyzed Background 0.502 Low 0.487 High 0.535 OCCUPATIONAL -- INDUSTRIAL NIOSH Cross-Sectional Study Workers producing trichlorophenol and derivatives, No difference Schnorr et including 2,4,5-T on basis of al., 2001 Serum TCDD in fathers age at first exposure Neighborhood controls (< 20 ppt)
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From page 696... ...
Canadian OFFHS fathers' exposure during 3 mo Savitz et al., before conception: 1997 No chemical activity 0.503 Referent Crop herbicides (some phenoxy herbicides) 0.500 ns Protective equipment used, not used 0.510 ns No protective equipment 0.450 ns ENVIRONMENTAL Seveso, Italy, Residential Cohort -- Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)
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From page 697... ...
Father < 20 yrs old in 1967 0.465 p = 0.15 Mother exposed (whether or not father 0.501 p = 0.62 exposed) Mother < 20 yrs old in 1967 0.450 p = 0.06 TAIWAN Taiwanese pregnant women (18–40 yrs of age)
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From page 698... ...
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; 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 699... ...
. In the single report relevant to this outcome in Vietnam veterans, however, the SR was increased in the Operation Ranch Hand group that had the highest serum dioxin concentrations (Michalek et al., 1998b)
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From page 700... ...
, and Vietnam veterans in the Air Force Health Study (Gupta et al., 2006)
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From page 701... ...
. Conclusions from VAO and Previous Updates The committee responsible for the original VAO report 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 spontaneous abortion or perinatal death.
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From page 702... ...
Studies addressing the potential for perinatal death as a result of paternal exposure to TCDD or herbicides are inadequate to support conclusions. Synthesis No epidemiologic evidence concerning the COIs and spontaneous abortion, stillbirth, neonatal death, or infant death has been published since Update 2010, and toxicologic studies do not provide clear evidence of biologic plausibility of an association.
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From page 703... ...
278 nr Vietnam-era veterans who did not serve in 317 nr Vietnam (1,912 pregnancies) US National Vietnam Veterans All COIs Female Vietnam veterans (maternal exposure)
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From page 704... ...
Monson, 13 weeks of gestation nr 1.2 (0.6–2.8) 1990 International Vietnam-Veteran Studies Tasmanian Veterans with Service in Vietnam All COIs Followup of Australian Vietnam veterans 199 1.6 (1.3–2.0)
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From page 705... ...
preconception period, spontaneous-abortion risk Other International Environmental Studies Japan -- Spontaneous abortions among PCBs, PCDFs Tsukimori et pregnancies (excluding induced abortions) al., 2008 of women in 1968 Yusho incident (maternal exposure)
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From page 706... ...
; PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; PCB, polychlorinated biphenyl; PCDF, polychlorinated dibenzofuran; ppt, parts per trillion; SWHS, Seveso Women's Health Study; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.
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From page 707... ...
The committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and stillbirth, neonatal death, or infant death. BIRTH WEIGHT AND PRETERM DELIVERY Birth weight and the length of the gestation period can have important effects on neonatal morbidity and mortality and on health over the life span.
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From page 708... ...
(2009) found that the concentrations of several individual dioxin-like PCDD and PCDF congeners and of total TEQs in maternal breast milk were inversely related to newborn length, but none was related to birth weight.
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From page 709... ...
(2012b) examined the association of maternal exposure to PCDDs, PCDFs, and PCBs in relation to birth weight among women who were accidentally exposed to rice oil contaminated with PCBs, PCDDs, or PCDFs in western Japan (in the Yusho incident of 1968)
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From page 710... ...
These appear to have all been independent models Tasmanian Veterans with Service in Vietnam -- Followup of Australian Vietnam veterans Field Military service ~550 LBW/RR RR calculated by and Kerr, in Vietnam 1.6 (1.0–2.5) committee member 1988 OCCUPATIONAL -- INDUSTRIAL Lawson Wives of ~500 No association with Adjusted for sex, et al., chemical workers exposed birth weight overall education, parity, 2004 highly exposed 600 smoking, length of to TCDD- referents gestation, no stratification contaminated by sex chemicals
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From page 711... ...
Models were adjusted for important predictors of fetal growth, including gestational age at delivery. Increased maternal exposure to PCDDs and PCDFs was strongly associated with reduced birth weight overall, which appeared to be driven by strong effects in male infants.
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From page 712... ...
education, race, marital status, military characteristics, smoking, drinking, average number of hours worked during pregnancy, complications during pregnancy ENVIRONMENTAL Seveso, Italy, Women's Health Study -- Industrial accident July 10, 1976 (981 women who were between infancy and 40 yrs old, who resided in Zones A or B) Baccarelli et al., Seveso 51 No association None 2008 with LBW Eskenazi et al., Seveso 608 overall Birth weight Gestational age, 2003 (nonsignificant sex, parity, history (B.
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From page 713... ...
in breastfeeding, males, also overall seafood consumption effect but driven by effect in boys Kuratsune et Yusho 11 None calculated -- al., 1972 Other Environmental Studies Japan Konishi et al., Sapporo, Japan; 514 BW (–220.5 g per Gestational age, 2009 contemporary 10-fold increase maternal age, cohort in TEQ, 95% CI maternal height, –399.2 to –41.9) ; maternal weight effect driven by before pregnancy, males parity, smoking, inshore fish intake, blood sampling period, infant sex continued
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From page 714... ...
United States Kezios et al., California 600 No association Race, age, smoking 2012 Child Health with birth weight status, BMI, sex, and Human length of gestation, Development lipids Study Sagiv et al., PCB 118 722 Negative birth- Gestational age, 2007 weight effects infant size, birth with increasing year, maternal age, exposure quartile, race parity, height, nonsignificant -- 0, prepregnancy BMI, –18, –72, –69.5 smoking, local fish consumption NOTE: BMI, body mass index; BW, birth weight; CI, confidence interval; I-TEQ, international (total) toxic equivalent; LBW, low birth weight; OR, odds ratio; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofurans; SAB, spontaneous abortion; SGA, small for gestational age; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; TEQ, (total)
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From page 715... ...
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. Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are inadequate to support conclusions.
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From page 716... ...
However, the committee is concerned about a potential association of maternal exposure with birth weight. 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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From page 717... ...
1989b. Health Status of Vietnam Veterans.
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From page 718... ...
2002b. Serum dioxin concentrations and menstrual cycle characteristics.
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From page 719... ...
2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study.
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From page 720... ...
2000. Pregnancy outcomes among US women Vietnam veterans.
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From page 721... ...
Molecular Human Reproduction 3(6)
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From page 722... ...
2009. Serum dioxins, polychlorinated biphenyls, and endometriosis: A case-control study in Atlanta.
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From page 723... ...
2001. Spontaneous abortion, sex ratio, and paternal occu pational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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From page 724... ...
2008. Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident.
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From page 725... ...
1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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