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Veterans and Agent Orange: Update 2014 (2016)

Chapter: 9 Effects on Veterans' Fertility and Reproductive Success

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Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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9

Effects on Veterans’ Fertility and Reproductive Success

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2014 did not find any new significant associations between the relevant exposures and fertility or gestational outcomes. The current evidence supports the findings of earlier studies that

  • None of the fertility or gestational outcomes had sufficient evidence of an association with the chemicals of interest.
  • 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; spontaneous 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) and spontaneous abortion.

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2012,1 hereafter referred to as Update 2012 (IOM,

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1Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

2014), on the association between exposure to herbicides and adverse effects on fertility and during gestation. (The analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, 2004, 2006, 2008, and 2010 [IOM, 1996, 1999, 2001, 2003, 2005, 2007, 2009, 2011] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans and in other populations exposed occupationally or environmentally to the herbicides sprayed in Vietnam or to TCDD. Because some polychlorinated biphenyls (PCBs), some polychlorinated dibenzofurans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs). Although all studies reporting TEQs based on PCBs were reviewed, those studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10 percent to total TEQs, based on the World Health Organization’s (WHO’s) revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006).

The adverse outcomes evaluated in this chapter include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth), neonatal and infant mortality, and the adverse gestational outcomes of low birth weight and preterm delivery. In this update, consideration of the possibility of adverse health outcomes at any time during the lives of all progeny of Vietnam veterans has been moved to a separate chapter: Chapter 10, “Effects on Veterans Descendants.”

Because the vast majority of Vietnam veterans are men, the primary focus of the VAO series has been on potential adverse effects of herbicide exposure on men, and the etiologic importance of the exposed party’s sex does not play the same dominant role in nonreproductive outcomes that it does in reproductive outcomes. However, about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so findings relevant to female reproductive health, such as those concerning endometriosis, are also included in the present chapter. Whenever the information was available, an attempt has been made to evaluate the effects of exposure on adult men and women separately.

The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. To reduce repetition throughout the report, Chapter 6 characterizes study populations and presents design information related to new publications that report findings on multiple health outcomes or that revisit study populations considered in earlier updates.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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BIOLOGIC PLAUSIBILITY OF EFFECTS ON
FERTILITY AND REPRODUCTION

This chapter opens with a general discussion of the plausibility of the various suggested adverse reproductive effects of TCDD and the four herbicides used in Vietnam. There have been few reproductive studies of the four herbicides in question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the preponderance of the following discussion concerns TCDD, which other than in controlled experimental circumstances, usually occurs in a mixture of dioxins (dioxin congeners in addition to TCDD).

TCDD is stored in fat tissue and has a long biologic half-life, so internal exposure at generally constant concentrations may continue after an episodic, high-level exposure to an external sources ceases. If a person had a high exposure, then high amounts of dioxins may still be stored in fat tissue and be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid.

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.

A father’s direct contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg; those contents had long been thought to consist of greatly condensed, transcriptionally inert deoxyribonucleic acid (DNA) constituting half the paternal genome (a haploid set of chromosomes). Consequently, it was believed that paternally derived damage to the embryo or offspring could only result from changes in sperm DNA, and dioxins have not been shown to mutate DNA sequence. However, as discussed in Chapter 4, TCDD can have epigenetic effects that modify expression of a cell’s genetic material that persist in the daughter cells following cell division, whether the division involves an individual’s own somatic tissues or production of his (or her) gametes. This provides an alternative pathway to creating permanent (heritable) changes in gene expression without altering the DNA sequence. Epigenetic changes include chemical modifications made to DNA (usually involving methylation) or to other cellular components such as histones and RNAs (Jirtle and Skinner, 2007). As a sperm matures, most of its histones are replaced by protamines, which renders it transcriptionally quiescent and permits extensive DNA compaction. The core histones that are retained in human sperm carry epigenetic modifications to maintain open nucleosomes, which permits transcription of genes that are important during embryo development (Casas and Vavouri, 2014). Sperm also carry a considerable collection of ribonucleic acid (RNA) fragments (Kramer and Krawetz, 1997; Krawetz et al., 2011) including ribosomal RNAs (rRNAs), messenger

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

RNAs (mRNAs), and small noncoding RNAs (miRNAs and piRNAs) (Casas and Vavouri, 2014; Lane et al., 2014). Small RNAs have been found to play critical roles in fertilization (Amanai et al., 2006), early embryonic development (Hamatani, 2012; Suh and Blelloch, 2011), and epigenetic modifications (Gapp et al., 2014; Kawano et al., 2012). Therefore, male infertility or fetal loss associated with exposure to the chemicals of interest (COIs) might be mediated by epigenetic modifications to components of sperm other than their DNA (Krawetz, 2005).

A mother’s contribution to a pregnancy is obviously more extensive, and damage to an embryo or offspring can result from epigenetic changes in the egg DNA or from the direct effects of exposure on placenta formation and the fetus during gestation. The mobilization of dioxin during pregnancy may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus. TCDD has been measured in human circulating maternal blood, cord blood, and placenta. Thus, dioxin in the mother’s bloodstream could cross the placenta and expose the developing embryo and fetus. Data indicate that dioxin can accumulate in placental tissue, but the amount of TCDD that can transfer to the fetus appears to be very limited—TCDD’s transfer index was the lowest of 13 environmental toxicants evaluated in perfusion studies of human placentas (Mose et al., 2012).

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. However, making definitive conclusions based on animal studies about the potential for TCDD to cause reproductive and gestational toxicity in humans is complicated by differences in sensitivity and susceptibility among different species including strain-specific differences; by the lack of strong evidence of organ-specific effects across species; by differences in the route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences between laboratory animals and humans in the toxicokinetics of TCDD. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that these chemicals have subcellular effects that could constitute a biologically plausible mechanism for reproductive and gestational effects. 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.

The sections on the biologic plausibility of the specific outcomes considered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed.

ENDOMETRIOSIS

Endometriosis (International Classification of Diseases, 9th revision [ICD-9], code 617) affects 5.5 million women in the United States and Canada at any

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

given time (NICHD, 2007). The endometrium, the tissue that lines the inside of the uterus, is built up and shed each month during menstruation. In endometriosis, endometrial cells are found outside the uterus—usually in other parts of the reproductive system, in the abdomen, or on surfaces near the reproductive organs. The ectopic tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with the menstrual cycle. 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.

There are several theories of the etiology of endometriosis, including one that posits a genetic contribution, but the cause remains unknown. Estrogen dependence and immune modulation are established features of endometriosis but do not adequately explain its cause. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those who have immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis, diagnosis is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure.

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. Table 9-1 provides a summary of relevant studies that have been reviewed.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and endometriosis have been published since Update 2012.

Environmental Studies

Upson et al. (2013) measured persistent organic pollutants in a subset of women enrolled in the Women’s Risk of Endometriosis Study. An increased risk of endometriosis was observed for exposure to β-hexachlorocylohexane (HCH), which is a component of the insecticide lindane, and mirex, but the authors did not measure the COIs.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 9-1 Selected Epidemiologic Studies—Endometriosis

Study Population Study Results Reference
ENVIRONMENTAL
Studies Conducted in the United States
Case-control study of women in Atlanta, GA, with endometriosis; 60 cases and 64 controls

Results for cases vs controls:

Total TEQ (determined by GC/MS): OR = 01.0 (95% CI 0.9–1.1)

Niskar et al., 2009
Studies Conducted in Belgium
88 matched triads (264 total); patients with deep endometriotic nodules, pelvic endometriosis, controls matched for age, gynecologic practice in Belgium; routes of exposure to DLCs examined

Results for pelvic endometriosis vs controls:

Dietary fat: OR = 1.0 (95% CI 1.0–1.0)

BMI: OR = 1.0 (95% CI 0.9–1.0)

Occupation: OR = 0.5 (95% CI 0.2–1.1)

Traffic: OR = 1.0 (95% CI 0.3–2.8)

Incinerator: OR = 1.0 (95% CI 1.0–1.1)

Heilier et al., 2007
Serum DLC and aromatase activity in endometriotic tissue from 47 patients in Belgium

No association between TEQs (determined by GC/MS) of DLCs in serum and aromatase activity by regression analyses

p-values = 0.37–0.90 for different endometriosis subgroups

Heilier et al., 2006
Endometriosis in Belgian women with overnight fasting serum levels of PCDD, PCDF, PCB 50 exposed cases, risk of increase of 10 pg/g lipid of TEQ compounds (determined by GC/MS); OR = 2.6 (95% CI 1.3–5.3) Heilier et al., 2005
Belgian women with environmental exposure to PCDDs, PCDFs; compared analyte concentrations in cases vs controls

Mean concentration of TEQ (determined by GC/MS)

Cases (n = 10), 26.2 (95% CI 18.2–37.7)

Controls (n = 132), 25.6 (95% CI 24.3–28.9)

No significant difference

Fierens et al., 2003a
Patients undergoing infertility treatment in Belgium; compared number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay) Six exposed cases: OR = 4.6 (95% CI 0.5–43.6) Pauwels et al., 2001
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Study Results Reference
Studies Conducted in Italy
Case-control study of Italian women with endometriosis; 80 cases and 78 controls (TEQs determined by CALUX bioassay)

Results for endometriosis vs controls: dl PCB118 compared to ≤ 13.2 ng/g: 13.3–24.2 ng/g; OR = 3.17 (95% CI 1.36–7.37)

≥ 24.3 ng/g; OR = 3.79 (95% CI 1.61–8.91)

Total TEQ compared to ≤ 15.6 pgC-TEQ/g fat:

15.7–29.5 pgC-TEQs/g fat; OR = 0.52 (95% CI 0.18–1.48)

≥ 29.6 pgC-TEQ/g fat; OR = 0.73 (95% CI 0.26–2.01)

Porpora et al., 2009
Case-control study of Italian women with endometriosis, measured serum PCBs

Mean total PCBs (ng/g)

Cases, 410 ng/g

Control, 250 ng/g

All PCB congeners: OR = 4.0 (95% CI 1.3–13)

Porpora et al., 2006
Pilot study of Italian, Belgian women of reproductive age; compared concentrations of TCDD, total TEQ (determined by GC/MS) in pooled blood samples from women who had diagnosis endometriosis with controls

Mean concentration of TCDD (ppt of lipid):

Italy:

Controls (10 pooled samples), 1.6

Cases (two sets of 6 pooled samples), 2.1, 1.3

Controls (7 pooled samples), 2.5

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 2.3, 2.3

Mean concentration of TEQ (ppt of lipid):

Italy:

Controls (10 pooled samples), 8.9 ± 1.3 (99% CI 7.2–11.0)

Cases (two sets of 6 pooled samples), 10.7 ± 1.6; 10.1 ± 1.5

Belgium:

Controls (7 pooled samples), 24.7 ± 3.7 (99% CI 20–29)

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 18.1 ± 2.7; 27.1 ± 4.0

De Felip et al., 2004
Residents of Seveso Zones A and B up to 30 yrs old in 1976; population-based historical cohort comparing incidence of endometriosis across serum TCDD concentrations

Serum TCDD (ppt):

≤ 20 (n = 2 cases), RR = 1.0 (reference) 20.1–100, (n = 8), RR = 1.2 (90% CI 0.3–4.5)

> 100, (n = 9), RR = 2.1 (90% CI 0.5–8.0)

Eskenazi et al., 2002b
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Study Results Reference
Studies Conducted in Israel
Residents of Jerusalem being evaluated for infertility; compared number of women with high TCDD who had (n = 44), did not have (n = 35) diagnosis of endometriosis 8 exposed cases: OR = 7.6 (95% CI 0.9–169.7) Mayani et al., 1997
Studies Conducted in Japan
17 women undergoing diagnostic laparoscopy for infertility, 10 were found to have endometriosis and 7 did not TEQ calculated for each person based on PCDDs, PCDFs, and 12 dl-PCBs. No difference in lipid-adjusted exposure levels between those with and without endometriosis. Association was seen with endometriosis and women with high PCDD and PCDF (OR = 2.5, 95% CI 1.2–5.3) Cai et al., 2011
138 infertility patients in Japan; laparoscopically confirmed case-control status, serum dioxin, PCB TEQ (determined by GC/MS); P450 genetic polymorphism Results for advanced endometriosis: Total TEQ: OR = 0.5 (95% CI 0.2–1.7) Genotype-specific: ORs = 0.3–0.6 No significant interaction between genotype, dioxin TEQ Tsuchiya et al., 2007

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.

Biologic Plausibility

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. Genetic polymorphisms in the aryl hydrocarbon receptor (AHR) signaling complex have recently been associated with a susceptibility to advanced endometriosis in humans (Li Y et al., 2013; Wu et al., 2012), although another recently published study found no association in Japanese women (Matsuzaka et al., 2012). The first suggestion that TCDD exposure may be linked to endometriosis came as a secondary finding of a study that exposed female rhesus monkeys (Macaca mulatta) chronically to low concentrations of dietary TCDD for 4 years (Bowman et al., 1989). Ten and 13 years after the exposure ended, the investigators documented an increased incidence of endometriosis in the monkeys that correlated with the TCDD exposure concentration (Rier et al., 1993, 2001). The sample was too small to,

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

yield a definitive conclusion that TCDD was a causal agent of endometriosis, but this study led to additional studies of the ability of TCDD to promote the growth of pre-existing endometriotic lesions (Bruner-Tran et al., 1999; Johnson et al. 1997; Yang et al., 2000).

There are a number of mechanisms by which TCDD may promote endometrial lesions, which provide additional support of the biologic plausibility of a link between TCDD and endometriosis. 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). These findings suggest that endometrial tissue is responsive to TCDD. MN Singh et al. (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). Other mechanisms by which TCDD may promote endometriosis include altering the ratio of progesterone receptor A to progesterone receptor B and blocking the ability of progesterone to suppress matrix metalloproteinase expression—actions that promote endometrial-tissue invasion and that are observed in women who have endometriosis (Igarashi et al., 2005).

TCDD also induces changes in gene expression that mirror those observed in endometrial lesions. In addition to the induction of CYP1A1 noted above, TCDD can induce expression of histamine-releasing factor, which is increased in endometrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). TCDD disrupts cannabinoid signaling in endometrial stromal cells by inhibiting progesterone-induced expression of cannabinoid receptor type 1 (CB1-R), which is also observed in women with endometriosis (Resuehr et al., 2012). TCDD also stimulates the expression of RANTES (regulated on activation, normal Tcell–expressed, and secreted protein) in endometrial stromal cells, and RANTES concentration and bioactivity are increased in women who have endometriosis (Zhao et al., 2002). The two CC-motif chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory protein 1α (MIP-1α), have been identified as potential contributors to the pathogenesis and progression of endometriosis. Previous studies have shown that the combination of 17β-estradiol and TCDD increases the secretion of RANTES and MIP-1α in endometrial stromal cells (Yu et al., 2008), and a more recent study showed that the same combination suppresses the expression of tetraspanin CD82, a tumor-metastasis suppressor, and thus promotes the invasion of endometrial stromal cells (Li MQ, 2011). Those results support the idea that TCDD in combination with estradiol may contribute to the development of endometriosis by increasing the invasiveness of endometrial cells. Despite that evidence, chronic exposure of rats to TCDD, PCB 153, dioxin-like PCB 118 or PCB 126, or 2,3,4,7,8-PeCDF (the furan congener,

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

with the highest TEF), either individually or in various combinations, fails to alter endometrial histology in a consistent manner (Yoshizawa et al., 2009). The differences between rodent and human endometrium could account for the lack of observed effects in rats.

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. 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.

FERTILITY

Male reproductive function is under the control of a variety of components whose proper coordination is important for normal fertility. Several of these components and some health outcomes related to male fertility, including reproductive hormones and sperm characteristics, can be studied as indicators of fertility. The reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both are secreted into the circulation in episodic bursts by the anterior pituitary gland and are necessary for normal spermatogenesis. In the testis, LH interacts with receptors on Leydig cells, where it stimulates increased testosterone synthesis. FSH and the testosterone from the Leydig cells interact with Sertoli cells in the seminiferous tubule epithelium to regulate spermatogenesis. A more detailed review of the male reproductive hormones can be found elsewhere (Strauss and Barbieri, 2013). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Schrader and Marlow, 2014; Sengupta, 2013). Reviews on the effects of various environmental toxicants, including TCDD, on testicular steroidogenesis and spermatogenesis provide insights into potential underlying mechanisms, including reducing

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

testosterone production in Leydig cells and inhibiting the formation of cAMP (Mathur and D’Cruz, 2011; Svechnikov et al., 2010).

Studies of the relationship between chemicals and fertility are less common in women than in men. Some chemicals may disrupt the female hormonal balance necessary for proper functioning. Normal menstrual-cycle functioning is also important in the risk of hormonally related diseases, such as osteopenia, breast cancer, and cardiovascular disease. Chemicals can have multiple effects on the female system, including modulation of hormone concentrations that result in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and menopause, and impairment of fertility (Bretveld et al., 2006a,b).

Conclusions from VAO and Previous Updates

The committee responsible for the original VAO report (IOM, 1994) 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. Reviews of the relevant studies are presented in the earlier reports. Tables 9-2 and 9-3 summarize the studies related to male and female fertility, respectively.

Update of the Epidemiologic Literature

Male Fertility

Ferguson et al. (2012) reported on a number of male fertility markers in a study of 358 men seeking infertility treatment with their partners. Of the four PCB congeners reported on individually, only the common, mono-ortho PCB 118 has dioxin-like activity, but results were reported for a group of PCBs (95/66, 74, 77/110, 105/141, 118, 156, 167, 128, 138, 170) characterized by Wolff et al. (1997) as having antiestrogenic and dioxin-like activity (although only the four congeners bolded in the preceding list are recognized by WHO as having dioxin-like activity). After adjusting for age, BMI, and serum lipids, inverse relationships were observed for PCB 118 with steroid hormone binding globulin (SHBG) (β = −0.13, p < 0.01) and with total testosterone (β = −22.1, p = 0.08). A similar, but weaker pattern was seen for the group including dioxin-like PCBs with SHBG (β = −0.08, p = 0.08) and with total testosterone (β = −25.9, p = 0.09); it is not clear what impact on fertility might arise from these at-best marginally significant changes in a PCB grouping of questionable relevance with respect to dioxin-like activity.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 9-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility) (Shaded entry is new to this update)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
AFHS (964 Ranch Hands, 1,259 comparisons)   Coefficient (p-value) for ln(Testosterone) vs ln(TCDD) in 1987 Gupta et al., 2006b
Comparison TCDD quartile I (mean, 2.14 ppt) nr 0 (referent)  
Comparison TCDD quartile II (mean, 3.54 ppt) nr –0.063 (0.004)  
Ranch Hand TCDD quartile I (mean, 4.14 ppt) nr 0.002 (0.94)  
Comparison TCDD quartile III (mean, 4.74 ppt) nr –0.048 (0.03)  
Comparison TCDD quartile IV (mean, 7.87 ppt) nr –0.079 (< 0.001)  
Ranch Hand TCDD quartile II (mean, 8.95 ppt) nr –0.052 (0.03)  
Ranch Hand TCDD quartile III (mean, 18.40 ppt) nr –0.029 (0.22)  
Ranch Hand TCDD quartile IV (mean, 76.16 ppt) nr –0.056 (0.02)  
Effects on specific hormone concentrations or sperm count in Ranch Hands     Henriksen et al., 1996
Low testosterone      
High dioxin (1992) 18 1.6 (0.9–2.7)  
High dioxin (1987) 3 0.7 (0.2–2.3)  
Low dioxin (1992) 10 0.9 (0.5–1.8)  
Low dioxin (1987) 10 2.3 (1.1–4..9)  
Background (1992) 9 0.5 (0.3–1.1)  
High FSH      
High dioxin (1992) 8 1.0 (0.5–2.1)  
Low dioxin (1992) 12 1.6 (0.8–3.0)  
Background (1992) 16 1.3 (0.7–2.4)  
High LH      
High dioxin (1992) 5 0.8 (0.3–1.9)  
Low dioxin (1992) 5 0.8 (0.5–3.3)  
Background (1992) 8 0.8 (0.4–1.8)  
Low sperm count      
High dioxin 49 0.9 (0.7–1.2)  
Low dioxin 43 0.8 (0.6–1.0)  
Background 66 0.9 (0.7–1.2)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Detailed description of cohort     CDC, 1989c
Lower sperm concentration 42 2.3 (1.2–4.3)  
Proportion of abnormal sperm 51 1.6 (0.9–2.8)  
Reduced sperm motility 83 1.2 (0.8–1.8)  
US American Legion Cohort   All COIs  
American Legionnaires who served in SEA     Stellman SD et al., 1988b
Difficulty in having children 349 1.3 (p < 0.01)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
NIOSH Cross-sectional Medical Study—248 Chemical workers employed at plants in Newark, NJ (1951–1969) and Verona, MI (1968–1972) vs 231 unexposed neighborhood referents, measured in 1987   Dioxins, phenoxy herbicides  
Testosterone (< 10.4 nmol/L)     Egeland et al., 1994
Referents (TCDD < 20 ppt) 11 1.0  
Workers 25 2.1 (1.0–4.6)  
Quartile I (TCDD < 20 ppt) 2 0.9 (0.2–4.5)  
Quartile II (TCDD 20–75 ppt) 7 3.9 (1.3–11.3)  
Quartile III (TCDD 76–240 ppt) 6 2.7 (0.9–8.2)  
Quartile IV (TCDD 241–3,400 ppt) 10 2.1 (0.8–5.8)  
FSH (> 31 IU/L) 20 1.5 (0.7–3.3)  
LH (> 28 IU/L) 23 1.6 (0.8–3.3)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
Canada—Sawmill Workers in British Columbia: 26,487 workers for ≥ 1 yr at 14 mills using chlorophenates 1950–1985   Chlorophenates, not TCDD  
Workers having a live-birth within 1 yr after the initiation of employment     Heacock et al., 1998
Standard fertility ratio 18,016 (births) 0.7 (0.7–0.8)b  
Mantel-Haenszel rate-ratio estimator 18,016 (births) 0.9 (0.8–0.9)b  
Cumulative exposure (hours)      
120–1,999 7,139 0.8 (0.8–0.9)b  
2,000–3,999 4,582 0.9 (0.8–1.0)b  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
4,000–9,999 4,145 1.0 (0.9–1.1)b  
≥ 10,000 1,300 1.1 (1.0–1.2)b (p < 0.01 overall)  
Denmark—Danish farmers (n = 1,146), 18–50 yrs of age, who used any potentially spermatotoxic pesticides, including 2,4-D   Herbicides Larsen et al., 1998
Farmers using pesticides vs organic farmers 523 1.0 (0.8–1.4)c  
Used three or more pesticides nr 0.9 (0.7–1.2)c  
Used manual sprayer for pesticides nr 0.8 (0.6–1.1)c  
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) (ICD-9 171)   TCDD  
Men exposed in Seveso, Zone A vs age-matched men residing outside the contamination zone, measured semen characteristics, estradiol, FSH, testosterone, LH, inhibin B   Author’s evaluation Mocarelli et al., 2008
Age at 1976 exposure:   (data not shown)  
Infant/prepuberty (1–9 yrs), n = 71 vs 176   Sensitive  
Puberty (10–17 yrs), 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 al., 2006
Association with 2-fold increase in CALUX-TEQ   Change (p-value)  
Sperm concentration   25.2% (p = 0.07)  
Semen volume   –16.0% (p = 0.03)  
Total testosterone   –7.1% (p = 0.04)  
Free testosterone   –6.8% (p = 0.04)  
Belgium—Adolescent girls (17 yrs of age) in communities close to industrial sources of heavy metals, PCBs, VOCs, and PAHs—delays in sexual maturity 200 PCBs, DLCs Staessen et al., 2001
In Hoboken, Belgium 8 4.0 (nr)  
In Wilrik, Belgium 15 1.7 (nr)  
Poland, Greenland, Ukraine, Sweden men in general population; AHR binding measured with CALUX assay   dl activity Toft et al., 2007
Measurement of semen quality (concentration, motility, percentage normal)   No consistent associations  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
United States—Male partners (aged 18–51) in subfertile couples seeking infertility evaluations and treatment in Massachusetts General Hospital (01/2000–05/2003)   Dl-PCBs Ferguson et al., 2012
PCB 118 with steroid hormone binding globulin   (β = –0.13, p < 0.01)  
CASE-CONTROL STUDIES      
US Case-Control Studies      
Missouri—men with or without low sperm quality (21–40 yrs of age)   2,4-D Swan et al., 2003
Increased urinary metabolite markers for 2,4-D 5 0.8 (0.2–3.0)  
International Case-Control Studies      
Argentinean farmers exposed to 2,4-D (n = 32) vs 25 unexposed controls, March–July 1989   2,4-D Lerda and Rizzi, 1991
Sperm count (millions/mL) exposed: 49.0 vs control: 101.6  
Motility (%) exposed: 24.8 vs control: 70.4  
Sperm death (%) exposed: 82.9 vs control: 37.1d  
Anomalies (%) exposed: 72.9 vs control: 33.4  
Canada—study of erectile dysfunction in urology patients in Ontario   PCBs/Highest vs lowest PCB groups Polsky et al., 2007
PCB 118 (TEF = 0.0001)   1.0 (0.5–2.1)  
PCB 118 (TEF = 0.0001)   0.9 (0.5–1.6)  
PCB 170   0.6 (0.3–1.2)  
PCB 180   0.7 (0.4–1.4)  
Greenland Inuit men (n = 53) and European men (n = 247), DNA sperm integrity among Inuit men   POPs Krüger et al., 2008
Median % DNA fragmentation index      
Inuits   6.8  
Europeans   12  
Median % DNA stainability      
Inuits   11  
Europeans   8.9  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Korean male waste incinerator workers (n = 6) vs controls (n = 8), dioxin measured by air monitoring   Phenoxy herbicides Oh et al., 2005
Reduced number of sperm (106/ml)   (p = 0.050)  
Workers   42.9 ± 18.0  
Controls   56.1 ± 44.5  
DNA damaged sperm (%)   (p = 0.001)  
Workers   1.40 ± 0.08  
Controls   1.26 ± 0.03  
Turkey (Ankara)—Adipose-tissue samples from fertile and infertile men (21–46 yrs of age) assayed for PCB 118, April 2002–June 2007 21 fertile DLCs
68.8 ng/g lipid
Cok et al., 2010
  25 infertile 21.7 ng/g lipid (p = 0.003)  
Turkey (Ankara)—Adipose-tissue samples from fertile and infertile men (21–45 yrs of age) assayed for dioxin, furans, dl PCBs, June 2003–September 2005 22 fertile DLCs
9.4 TEQ pg/g lipid
(p = 0.003)
Cok et al., 2008
  23 infertile 12.5 TEQ pg/g lipid
(p = 0.065)
 

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.

aGiven when available; results other than estimated risk explained individually.

bFor this study, relative risk has been replaced with standardized fertility ratio, for which value less than 1.0 indicates adverse effect.

cFor this study, relative risk has been replaced with fecundability ratio, for which value less than 1.0 indicates adverse effect.

dTable 1 in reference reverses these figures—control, 82.9%; exposed, 37.1%—but text (“The percentages of asthenospermia, mobility, necrosperma and teratospermia were greater in the exposed group than in controls…”) suggests that this is a typographical error.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 9-3 Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
UNITED STATES      
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
8,038 premenopausal women aged 30–55 at enrollment     Farr et al., 2006
Pesticide exposure 5,013 0.9 (0.8–1.0)  
Herbicide exposure 3,725 0.9 (0.7–1.1)  
Phenoxy herbicide exposure 1,379 0.9 (0.7–1.1)  
Menstrual-cycle characteristics of 3,103 premenopausal women aged 21–40     Farr et al., 2004
Reported at enrollment had used herbicides 1,291    
Short menstrual cycle   0.6 (0.4–1.0)  
Long menstrual cycle   1.0 (0.5–2.0)  
Irregular   0.6 (0.3–0.9)  
Missed period   1.4 (1.0–2.0)  
Intermenstrual bleeding   1.1 (0.8–1.7)  
ENVIRONMENTAL      
Seveso (Italy) Women’s Health Study—Industrial 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   TCDD  
Time to pregnancy and infertility in women from Zones A and B who attempted pregnancy after 1976     Eskenazi et al., 2010
20-yr follow-up to 1996—men and women      
Time to pregnancy (adjusted fecundability OR)
Log10 TCDD 278 0.8 (0.6–1.0)  
Categorical TCDD (ppt)
≤ 20 52 1.0 (reference)  
20.1–44.4 76 0.8 (0.5–1.3)  
44.5–100 75 0.7 (0.5–1.1)  
> 100 75 0.6 (0.4–1.0)  
Infertility (adjusted OR)
Log10 TCDD 49 1.9 (1.1–3.2)  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Categorical TCDD (ppt)
≤ 20 6 1.0 (reference)  
20.1–44.4 9 1.1 (0.4–3.6)  
44.5–100 16 2.5 (0.8–7.3)  
> 100 18 2.8 (1.0–8.1)  
Fibroids among women from Zones A and B who were newborn to age 40 in 1976     Eskenazi et al., 2007
Uterine fibroids (age-adjusted HR)
Log10 TCDD (ppt) 251 0.8 (0.7–1.1)  
Categorical TCDD (ppt)
≤ 20 62 1.0 (reference)  
20.1–75.0 110 0.6 (0.4–0.8)  
> 75 79 0.6 (0.4–0.9)  
Ovarian function in women from Zones A and B who were newborn to age 40 in 1976; results are for a 10-fold increase in serum TCDD     Warner at al., 2007
Ovarian follicles (age-adjusted OR):
in follicular phase 65 1.0 (0.4–2.2)  
Ovulation (age-adjusted OR):
in luteal phase 87 1.0 (0.5–1.9)  
in midluteal phase 55 1.0 (0.4–2.7)  
Estradiol (age-adjusted ß):   slopes for log TCDD  
in luteal phase 87 −1.8 (−10.4–6.8)  
in midluteal phase 55 −3.1 (−14.1–7.8)  
Progesterone (age-adjusted ß):
in luteal phase 87 −0.7 (−2.4–1.0)  
in midluteal phase 55 −0.8 (−3.7–2.0)  
Age at menopause in women from Zones A and B who were newborn to age 40 in 1976     Eskenazi et al., 2005
Onset of natural menopause (unadjusted HR)
Log10 TCDD 169 1.0 (0.8–1.3)  
Menopause Category   Serum TCDD median (IQR)  
Premenopause 260 43.6 (0.2–0.9)  
Natural menopause 169 45.8 (0.3–1.0)  
Surgical menopause 83 43.4 (0.3–1.0)  
Impending menopause 13 43.8 (0.2–1.1)  
Perimenopause 33 36.5 (0.2–0.9)  
Other 58 39.6 (0.2–0.9)  
Age at menarche in women from Zones A and B who were premenarcheal in 1976 282 1.0 (0.8–1.1) Warner et al., 2004
All premenarcheal women in 1976 (unadjusted HR)
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Log10 TCDD 282 1.0 (0.8–1.1)  
Women < 8 years in 1976 (unadjusted HR)
Log10 TCDD 158 1.1 (0.9–1.3)  
Menstrual-cycle characteristics in women from Zones A and B who were premenopausal, less than age 44, and not recently pregnant, breastfeeding, or using hormonal medications     Eskenazi et al., 2002a
Menstrual-cycle length (adjusted ß)
Log10 TCDD 277 0.4 (−0.1–0.9)  
Premenarcheal at explosion 0.9 (0.0–1.9)  
Postmenarcheal at explosion 0.0 (−0.6–0.5)  
Days of menstrual flow (adjusted ß)
Log10 TCDD 301 0.2 (−0.1–0.4)  
Premenarcheal at explosion   0.2 (−0.2–0.5)  
Postmenarcheal at explosion   0.2 (−0.2–0.5)  
Heaviness of flow (scanty vs moderate/heavy; adjusted OR)
Log10 TCDD 30 0.8 (0.4–1.6)  
Premenarcheal at explosion   0.3 (0.1–1.1)  
Postmenarcheal at explosion   1.4 (0.7–2.6)  
Irregular cycle (vs regular; adjusted OR)
Log10 TCDD 24 0.5 (0.2–1.0)  
Premenarcheal at explosion   0.5 (0.2–1.4)  
Postmenarcheal at explosion   0.4 (0.2–1.2)  
Other International Environmental Studies
Taiwanese pregnant women (18–40 yrs of age); placental TEQ concentrations of TCDDs, TCDFs, PCBs   Dioxin/ Regression adjusted for maternal age, BMI, parity Chao et al., 2007
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 (maternal exposure)—incidence   Phenoxy herbicides Greenlee et al., 2003
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Mixed or applied herbicides 21 2.3 (0.9–6.1)  
Used 2,4,5-T 9 9 cases (2.7%) 11 controls (3.4%)  
Used 2,4-D 4 4 cases (1.2%) 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) toxic equivalent.

aGiven when available; results other than estimated risk explained individually.

Female Fertility

No Vietnam-veteran, occupational, environmental, or case-control studies of exposure to the COIs and female fertility have been published since Update 2012.

Biologic Plausibility

Although a recent study reported that doses of 2,4-D greater than 50 mg/kg/day produce acute testicular toxicity in male rats (Joshi et al., 2012), there is little evidence that lower doses of either 2,4-D or 2,4,5-T (when free of TCDD contamination) given chronically have substantial effects on reproductive organs or fertility (Charles et al., 2001; Munro et al., 1992). The no-observed-adverse-effect level [NOAEL] for 2,4-D is recognized as 15 mg/kg/day (Gervais et al., 2008). In contrast, many diverse laboratory studies have provided evidence that TCDD can affect reproductive-organ function and reduce fertility in both males and females.

The administration of TCDD to male animals elicits reproductive toxicity by affecting testicular, epididymal, prostate, and seminal vesicle weight and function and by decreasing the rate of sperm production (Foster et al., 2010; Rider et al., 2010; Schneider et al., 2014). The mechanisms underlying those effects are not known, but the primary hypotheses are that they are mediated through the dysregulation of testicular steroidogenesis, altered Sertoli cell function, and increased oxidative stress. The exposure of cultured testicular Leydig cells to 25 nM TCDD markedly alters gene expression (Naville et al., 2011), and the exposure of cultured Sertoli cells to 5 nM TCDD decreases viability and increases markers

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

of oxidative stress (Aly and Khafagy, 2011). The exposure of adult rats or mice to TCDD (2–7 μg/kg/week for 45–60 days) reduces testicular and reproductive function, and these effects can be attenuated by co-treatment with various antioxidants (Beytur et al., 2012; Ciftci et al., 2012; Sönmez et al., 2011; Yin et al., 2012). The results of those studies are supported by the transgenic mouse model that harbors a constitutively active AHR in which testicular and ventral prostate weights and sperm number are reduced (Brunnberg et al., 2011).

Many studies have examined the effects of TCDD on the female reproductive system. Two primary mechanisms that probably 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, 2003). 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 female reproductive toxicity. The data of Jung et al. (2010) in rats show that a single gavage treatment of 32 μg/kg TCDD reduces the proliferation of granulosa cells and thus attenuates cell-cycle progression and potentially contributes to the reduction in ovulation rates observed in other studies. In contrast, Karman et al. (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. The concentrations of those hormones could be restored by the addition of the precursor pregnenolone, which suggests that TCDD acts upstream of pregnenolone formation. This would be consistent with previous observations in zebrafish that 10, 40, and 100 ppb TCDD in food depressed estradiol biosynthesis (Heiden et al., 2008).

The effects on early embryo development and the effects on placenta formation attributable to dioxin are well documented (Chen et al., 2010; Ishimura et al., 2009; Tsang et al., 2012). Petroff et al. (2011) used a rat in vitro fertilization model to demonstrate that 100 nM TCDD perturbs chromatin and cytoskeletal remodeling at the earliest stages of embryo development, but these changes failed to result in any apparent morphologic changes at later stages of development. The long-term potential effects of these early changes on pregnancy outcome are unknown. It has previously been shown that TCDD may have direct effects on human trophoblast formation at 0.2–2.0 nM in vitro and thus may have the capacity to influence the developing fetus (Chen et al., 2010). That idea is supported by a study showing the ability of 5 nM TCDD to activate the AHR signaling pathway in both rat and human placental trophoblasts (Stejskalova et al., 2011). Finally, a study has demonstrated that TCDD at 0.1, 1.0, and 10.0 nM reduces in a dose-dependent fashion the ability of trophoblastic spheroids (which constitute an embryo surrogate) to attach to endometrial epithelial cells (Tsang et al., 2012). The more recent literature continues to support the biologic plausibility of TCDD having effects on male and female reproduction.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Sex Ratio

Although it would not constitute an adverse health outcome in an individual veteran, perturbations in the sex ratio of children born to an exposed population would suggest that the exposure had an impact on the reproductive process. As shown in Table 9-4, studies of the sex ratios observed among children born to people exposed during the 1976 Seveso accident (Mocarelli et al., 1996, 2000) 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] = 0.382). However, a consideration of all 481 singleton births in 1994–2005 to women who resided in Zones A and B and were less than 28 years old at the time of the Seveso accident (ages 18–46 years at the beginning of period when births were identified) generated crude sex ratios showing that male births slightly exceeded female births in Zones A and B (SR = 0.516) and that the increase (SR = 0.571) was more pronounced for the 56 births in Zone A (Baccarelli et al., 2008).

A similar depression in the sex ratio concentrated in fathers who were under 20 years old at the time of the Yucheng poisoning with oil contaminated with PCBs, PCDFs, and PCDDs was reported by del Rio Gomez et al. (2002). On the other hand, Yoshimura et al. (2001) found a nonsignificant increase in the sex ratio (SR = 0.574) of children born in the 4 years following the similar 1967 Yusho poisoning by rice oil contaminated with PCBs and PCDFs (but not TCDD) when at least one parent was exposed. Following up on the Yusho cohort, however, Tsukimori et al. (2012b) noted modest nonsignificant decreases in the sex ratio when either the mother (SR = 0.450) or the father (SR = 0.465) was less than 20 years old at the time of the poisoning. In considering the second generation of Yusho offspring, Tsukimori et al. (2012b) found no effect on the sex ratio in the grandchildren of the exposed men, but the daughters of exposed women showed a tendency toward decreased sex ratios, especially if the grandmother had been young when exposed (results not tabled).

Chao et al. (2007) mentioned that they did not find an association between the sex ratio of offspring and the TEQ concentrations of dioxins, furans, or PCBs in the placentas from 119 Taiwanese women. Hertz-Picciotto et al. (2008) found evidence of an effect on sex ratio in an analysis of the serum concentrations of nine PCB congeners (of which the two dioxin-like congeners were the mono-ortho PCBs 105 and 118) in blood gathered during the 1960s from 399 pregnant women in the San Francisco Bay area. The adjusted odds of male birth were significantly decreased when the 90th percentile of the total concentration of all nine PCBs was compared with the 10th percentile (OR = 0.45, 95% CI 0.26–0.80, p = 0.007). The proportion of male births was significantly reduced for only two of the PCBs when analyzed separately: Dioxin-like, mono-ortho PCB 105 and non–dioxin-like PCB 170 (p = 0.02 for each).

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 9-4 Selected Epidemiologic Studies—Sex Ratioa

Study Population Sex Ratio of Offspring (boys/total)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 al., 1998a
Comparison group 0.504 Not formally analyzed  
Dioxin level in Ranch Hand personnel
Background 0.502    
Low 0.487    
High 0.535    
OCCUPATIONAL—INDUSTRIAL NIOSH Cross-Sectional Study
Workers producing trichlorophenol and derivatives, including 2,4,5-T   No difference on basis of age at first exposure Schnorr et al., 2001
Serum TCDD in fathers
Neighborhood controls (< 20 ppt) 0.544 Referent  
Working fathers
< 20 ppt 0.507 None significantly decreased (or increased)  
20–255 ppt 0.567    
255– < 1,120 ppt 0.568    
≥ 1,120 ppt 0.550    
Other Studies of Industrial Workers (not related to NIOSH phenoxy cohort)
Austrian chloracne cohort—157 men, 2 women; exposed to TCDD during 2,4,5-T production     Moshammer and Neuberger, 2000
Children born after starting TCDD exposure in 1971 0.464 (26 boys: 30 girls) Fewer sons, especially if father  
Children born before 1971 0.613 (19 boys: 12 girls) was under 20 years old when exposed: SR = 0.20 (1 boy: 4 girls)  
Russian workers manufacturing 2,4,5,-trichlorophenol (1961–1988) or 2,4,5-T (1964–1967)     Ryan et al., 2002
Either parent exposed 0.401 (91 boys: 136 girls) p < 0.001  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Sex Ratio of Offspring (boys/total)b Comments Reference
Only father exposed 0.378 (71 boys: 117 girls) p < 0.001  
Only mother exposed 0.513 (20 boys: 19 girls) ns  
OCCUPATIONAL—PAPER AND PULP WORKERS
Canada—British Columbian sawmill workers (n = 26,487)     Heacock et al., 1998
Chlorophenate-exposed workers 0.515    
Unexposed workers 0.519    
Province overall 0.512    
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)
Canadian OFFHS fathers’ exposure during 3 mo before conception:     Savitz et al., 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)
Births 1994–2005 in women 0–28 yrs old at time of Seveso accident     Baccarelli et al., 2008
Zone A 0.571    
Zone B 0.508    
Zone R 0.495    
Births 1977–1996 in people from Zones A, B, R, 3–45 yrs old at time of 1976 Seveso accident 0.514 Referent Mocarelli et al., 2000
Neither parent exposed 0.608 ns  
Father exposed (whether or not mother exposed) 0.440 p = 0.03  
Father under 19 yrs old in 1976 0.382 p = 0.002  
Father at least 19 yrs old in 1976 0.469 ns  
Only mother exposed 0.545 ns  
Parent (either sex) from Seveso Zone A     Mocarelli et al., 1996
Births 1977–1984 0.351 (26 boys: 48 girls) p < 0.001, related to parental TCDD serum  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Sex Ratio of Offspring (boys/total)b Comments Reference
Births 1985–1994 0.484 (60 boys: 64 girls) ns  
Ecological Study of Residents of Chapaevsk, Russia
Residents near chemical plant in operation 1967–1987 in Chapaevsk, Russia     Revich 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 (not TCDD) in 1968     Yoshimura et al., 2001
All Japan in 1967 0.513 Referent  
Births 1967 (before poisoning incident) 0.516 ns  
Births 1968–1971 (after incident) 0.574 ns  
Births 1968–2009     Tsukimori et al., 2012b
Father exposed (whether or not mother exposed) 0.505 p = 0.74  
Father under 20 yrs old in 1967 0.465 p = 0.15  
Mother exposed (whether or not father exposed) 0.501 p = 0.62  
Mother under 20 yrs old in 1967 0.450 p = 0.06  
TAIWAN
Taiwanese pregnant women (18–40 yrs old);   No association Chao et al., 2007
placental TEQ concentrations of TCDDs, nr
TCDFs, PCBs
Births in individuals exposed to PCBs, PCDFs,   vs unexposed with same demographics del Rio Gomez et al., 2002
PCDDs in 1979 Yucheng incident
Father exposed (whether or not mother exposed) 0.490 p = 0.037  
Father under 20 yrs old in 1979 0.458 p = 0.020  
Father at least 20 yrs old in 1979 0.541 p = 0.60  
Mother exposed (whether or not father exposed) 0.504 p = 0.45  
Mother under 20 yrs old in 1979 0.501 p = 0.16  
Mother at least 20 yrs old in 1979 0.500 p = 0.40  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Sex Ratio of Offspring (boys/total)b Comments Reference
UNITED STATES
San Francisco Bay area—serum concentrations in pregnant women during 1960s OR for male birth (not SR)   Hertz-Picciotto et al., 2008
90th percentile vs 10th percentile   SRs all < 0.5  
Total PCBs 0.4 (0.3–0.8) p = 0.007  
dl PCBs
PCB 105 0.6 (0.4–0.9) p = 0.02  
PCB 118 0.7 (0.5–1.2) p = 0.17  
PCB 170 0.6 (0.4–0.9) p = 0.02  
PCB 180 0.8 (0.5–1.2) p = 0.32  
Births after 1963 to Michigan fish-eaters with serum PCBs in both parents     Karmaus et al., 2002
Paternal PCBs > 8.1 μg/L 0.571 p < 0.05 (but for more sons)  
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.

aVAO reports before Update 1998 did not address association between perturbations in sex ratio of offspring and exposure to chemicals of interest.

bGiven when available.

Reductions in the expected number of male offspring have also been reported in cohorts of men who were occupationally exposed to dioxin (Moshammer and Neuberger, 2000; Ryan et al., 2002), but other such cohorts did not manifest this relationship (Heacock et al., 1998; Savitz et al., 1997; Schnorr et al., 2001). 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., 1998a), but no formal analysis of this outcome was reported.

A population-level finding of a paternally mediated effect would be a strong indicator that dioxin exposure can interfere with the male reproductive process. James (2006) has interpreted the perturbation of sex ratios by dioxins and other agents as being an indicator of parental endocrine disruption. If James’s hypothesis were demonstrated to be true, then it would be concordant with a reduction

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

in testosterone in exposed men. Another pathway to an altered sex ratio might involve male embryos’ experiencing more lethality from induction of mutations due to their unmatched X chromosome. A genotoxic mechanism has not been expected to apply to TCDD, but sex-specific adverse consequences of the modified imprinting of gametes might be a possible mechanism leading to the observation of altered sex ratios at birth. To date, however, results regarding the proportion of sons among the children of fathers exposed to dioxin-like chemicals do not present a clear pattern of reduction.

No experimental animal studies have specifically examined the effects of TCDD on the sex ratios of offspring, nor have any alterations in sex ratio been reported in animal studies that examined the developmental effects of TCDD on offspring.

Synthesis

Reproduction is a sensitive toxic endpoint of TCDD and dioxin-like compounds (DLCs) in rodents, and the fetal rodent is more sensitive than the adult rodent to the adverse effects of TCDD. The sensitivity of these endpoints in humans is less apparent. 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. The biologic plausibility of such a relationship is supported by concomitant increases observed in gonadotropins and the results of animal studies. Human populations showing evidence of reduced testosterone with exposure to DLCs include a general population sample (Dhooge et al., 2006), occupationally exposed people (Egeland et al., 1994), and Vietnam veterans in the Air Force Health Study (AFHS) (Gupta et al., 2006b). The evidence that DLCs may modify the sex ratio lends credence to the hypothesis that these chemicals have an effect on male reproductive functioning.

Despite the relative consistency of the finding of a reduction in testosterone, the testosterone concentrations observed even in the highest-exposure groups studied are well within the normal range. The small reduction in testosterone is not expected to have adverse clinical consequences. There is evidence of compensatory physiologic mechanisms. The occupational study by Egeland et al. (1994) found increased gonadotropins in addition to reduced testosterone. Gonadotropins stimulate the production of testosterone in men.

Eskenazi et al. (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) and infertility (more than 12 contraceptive-free months to pregnancy). Dose–response relationships between TCDD serum levels in women who were less than 40 years of age at the time of

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

the Seveso accident and both time to pregnancy and infertility were observed, which is consistent with published observations in the rat model. Epidemiologic studies have not provided sufficient data to interpret the effects of dioxin specifically on menstrual-cycle function in humans.

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. The background risk of recognized spontaneous abortion is generally 11 to 22 percent (Avalos et al., 2012, but it is established that many more pregnancies terminate before women become aware of them (Wilcox, 2010). Such terminations are known as subclinical pregnancy losses and generally are not included in studies of spontaneous abortion. Estimates of the risk of recognized spontaneous abortion vary with the design and method of analysis. Studies have included cohorts of women asked retrospectively about pregnancy history, cohorts of pregnant women (usually those receiving prenatal care), and cohorts of women who are monitored for future pregnancies. The value of retrospective reports can be limited by differential recall of details (e.g., exposure history) specific to pregnancies that occurred long before the interview. Studies that enroll women who appear for prenatal care require the use of life tables and specialized statistical techniques to account for differences in the times at which women seek medical care during pregnancy. The enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it can attract non-representative study groups because the study protocols are demanding for the women.

Countries and US states have different legal definitions of the age of fetal viability and apply these terms differently, but typically “stillbirth” or “late fetal death” refers to the delivery at or after 20 weeks of gestation of a fetus that shows no signs of life, including a fetus that weighs more than 400 g regardless of gestational age (Lamont et al., 2015); “neonatal death” refers to the death of a liveborn infant within 28 days of birth (Whitworth et al., 2015); and “postnatal death” refers to a death that occurs before the first birthday (Andrews et al., 2008).

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

The causes of stillbirth and early neonatal death overlap considerably, so they are commonly analyzed together in a category referred to as “perinatal mortality” (Andrews et al., 2008). Stillbirths make up less than 1 percent of all births (CDC, 2000). The most common causes of mortality during the neonatal period are low birth weight (< 2.5 kg at birth), preterm delivery, congenital malformations, pregnancy or delivery complications, and placenta or cord conditions. The most common causes of postnatal death of infants is SIDs (sudden infant death syndrome) (Andrews et al., 2008).

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. 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, found that there was enough evidence available concerning paternal exposure specifically to TCDD to conclude that there was “limited or suggestive evidence” of no association between that paternal exposure to TCDD and the risk of spontaneous abortion. That conclusion was based primarily on the National Institute for Occupational Safety and Health study (Schnorr et al., 2001), which investigated a large number of pregnancies fathered by workers whose serum TCDD concentrations were extrapolated back to the time of conception; no association was observed up to the highest exposure group (1,120 ppt or higher). Indications of a positive association were seen in studies of Vietnam veterans (CDC, 1989c; Field and Kerr, 1988; Stellman SD et al., 1988b), 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) reviewed by the committees responsible for Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change these conclusions.

The relevant studies concerning perinatal death are reviewed in the earlier reports, and Table 9-5 summarizes the findings of studies concerning spontaneous abortion.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 9-5 Selected Epidemiologic Studies—Spontaneous Abortiona (Shaded entry is new to this update)

Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Air Force Ranch Hand veterans 157   Wolfe et al., 1995
Background 57 1.1 (0.8–1.5)  
Low exposure 56 1.3 (1.0–1.7)  
High exposure 44 1.0 (0.7–1.3)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Overall 1,566 1.3 (1.2–1.4) CDC, 1989c
Self-reported low exposure 489 1.2 (1.0–1.4)  
Self-reported medium exposure 406 1.4 (1.2–1.6)  
Self-reported high exposure 113 1.7 (1.3–2.1)  
US VA Cohort of Female Vietnam Veterans   All COIs  
Female Vietnam-era veterans (maternal exposure)   1.0 (0.82–1.21) Kang et al., 2000a
Vietnam veterans (1,665 pregnancies) 278 nr  
Vietnam-era veterans who did not serve in Vietnam (1,912 pregnancies) 317 nr  
US National Vietnam Veterans   All COIs  
Female Vietnam veterans (maternal exposure)     Schwartz, 1998
Women who served in Vietnam 113 nr  
Women who did not serve in the war zone 124 nr  
Civilian women 86 nr  
US American Legion Cohort   All COIs  
American Legionnaires with service 1961–1975     Stellman SD et al., 1988b
Vietnam veterans vs Vietnam-era veterans
All Vietnam veterans 231 1.4 (1.1–1.6)  
Low exposure 72 1.3 (1.0–1.7)  
Medium exposure 53 1.5 (1.1–2.1)  
High exposure 58 1.7 (1.2–2.4)  
Vietnam-era veterans vs herbicide handlers Vietnam veterans 9 1.6 (0.7–3.3)  
Low exposure 72 1.0  
Medium exposure 53 1.2 (0.8–1.7)  
High exposure 58 1.4 (0.9–1.9)  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
State Studies of US Vietnam Veterans
Massachusetts—Wives of Vietnam veterans presenting at Boston Hospital for Women     Aschengrau and Monson, 1989
27 weeks of gestation 10 0.9 (0.4–1.9)  
13 weeks of gestation nr 1.2 (0.6–2.8)  
International Vietnam Veterans Studies
Tasmanian Veterans with Service in Vietnam   All COIs  
Follow-up of Australian Vietnam veterans 199 1.6 (1.3–2.0) Field and Kerr, 1988
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxins, phenoxy herbicides  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Wives and partners of men in NIOSH cohort     Schnorr et al., 2001
Estimated paternal TCDD serum at time of conception
< 20 ppt 29 0.8 (0.5–1.2)  
20 to < 255 ppt 11 0.8 (0.4–1.6)  
255 to < 1120 11 0.7 (0.3–1.6)  
> 1120 ppt 8 1.0 (0.4–2.2)  
Dow Workers with Potential TCDD Exposure and reproductive outcomes studied in offspring of 930 men working with chlorophenol, 1939–1975   Dioxins, phenoxy herbicides Townsend et al., 1982
Wives of men employed involved in chlorophenol processing at Dow Chemical Co. 85 1.0 (0.8–1.4)  
Monsanto workers in Nitro, WV occupationally exposed and potentially exposed after 1949 explosion (1948–1969)   Dioxins, phenoxy herbicides  
Follow-up of current and retired 2,4,5-T production workers (n = 235; 117 with chloracne exposure), 1948–1969 14 0.9 (0.4–1.8) Moses et al., 1984
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Follow-up of 2,4,5-T production workers (204 exposed, 163 unexposed), 1948–1969 69 0.9 (0.6–1.2) Suskind and Hertzberg, 1984
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)
New Zealand—Follow-up of 2,4,5-T sprayers vs nonsprayers (n = 989) 43 Herbicides 90% CI Smith et al., 1982
    0.9 (0.6–1.3)  
US Forest Service   Herbicides  
Women employed by US Forest Service—miscarriages (maternal exposure) 141 2.0 (1.1–3.5) Driscoll et al., 1998
ENVIRONMENTAL
Seveso (Italy) Women’s Health Study—Industrial 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   TCDD  
SWHS—30-yr updated analysis of pregnancy outcomes     Wesselink et al., 2014
10-fold increase in TCDD level at time of accident 160 0.8 (0.6–1.0)  
Effects on first birth after explosion 75 0.8 (0.6–1.2)  
SWHS participants living in zones A, B in 1976 (maternal exposure)     Eskenazi et al., 2003a
Pregnancies 1976–1998 97 0.8 (0.6–1.2)  
Pregnancies 1976–1984 44 1.0 (0.6–1.6)  
Ecological Study of Residents of Chapaevsk, Russia   TCDD  
Residents of Samara Region, Russia (maternal and paternal exposure)     Revich et al., 2001
Chapaevsk nr 24.4% (20.0–29.5%)c  
Samara nr 15.2% (14.3–16.1%)c  
Toliatti nr 10.6% (9.8–11.5%)c  
Syzran nr 15.6% (13.4–18.1%)c  
Novokuibyshevsk nr 16.9% (14.0–20.3%)c  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Other small towns nr 11.3% (9.4–13.8%)c  
Ontario Farm Family Health Study   Phenoxy herbicides  
Ontario farm families (maternal, paternal exposures)     Arbuckle et al., 2001
Phenoxyacetic acid herbicide exposure in preconception period, spontaneous-abortion risk 48 1.5 (1.1–2.1)  
Other International Environmental Studies
Japan—Spontaneous abortions among pregnancies (excluding induced abortions) of women in 1968 Yusho incident (maternal exposure)   PCBs, PCDFs Tsukimori et al., 2008
10 yrs after vs 10 yrs before nr 2.1 (0.8–5.2)  
10-fold increase in maternal blood concentration (drawn 2001–2005) of:
PeCDF nr 1.6 (1.1–2.3)  
PCB 126 (TEF = 0.1) nr 2.5 (0.9–6.9)  
PCB 169 (TEF = 0.01) nr 2.3 (1.1–4.8)  
Taiwanese pregnant women (18–40 yrs old; placental TEQ concentrations of PCDDs, PCDFs, PCBs   PCDD, PCBs nr, but reported ns Chao et al., 2007
Vietnamese women who were or whose husbands were exposed to herbicides sprayed during Vietnam War nr COIs/nr, anecdotal reports of miscarriage in pilot study Tuyet and Johansson, 2001
CASE-CONTROL STUDIES
US Case-Control Studies
Washington, Oregon—wives of men occupationally exposed to 2,4-D; all reported work exposure to herbicides (high and medium) 63 2,4-D 90% CI 0.8 (0.6–1.1) Carmelli et al., 1981
Farm exposure 32 0.7 (0.4–1.5)  
Forest and commercial exposure 31 0.9 (0.6–1.4)  
Exposure during conception period
Farm exposure 15 1.0 (0.5–1.8)  
Forest and commercial exposure 16 1.6 (0.9–1.8)  
Fathers 18–25 yrs old
Farm exposure 1 0.7 (nr)  
Forest and commercial exposure 3 4.3 (nr)  
Fathers 26–30 yrs old
Farm exposure 4 0.4 (nr)  
Forest and commercial exposure 8 1.6 (nr)  
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Fathers 31–35 yrs old
Farm exposure 10 2.9 (nr)  
Forest and commercial exposure 5 1.0 (nr)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant (usually refers to p < 0.05); PeCDF, 2,3,4,7,8-pentachlo-rodibenzofuran; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; ppt, parts per trillion; SEA, Southeast Asia; 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.

aUnless otherwise indicated, results are for paternal exposure.

bGiven when available; results other than estimated risk explained individually.

aSpontaneous abortion rate per 100 full-term pregnancies for 1991–1997.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and spontaneous abortion or perinatal death have been published since Update 2012.

Environmental Studies

Wesselink et al. (2014) reported the results of a 30-year updated analysis of pregnancy outcomes in the Seveso Women’s Health Study (described in Chapter 6). Overall, the lack of association between TCDD and spontaneous abortion, fetal growth, and gestational length observed in the 20-year follow-up (Eskenazi et al., 2003a) was confirmed in this updated analysis. No effect of note was observed between a 10-fold increase in TCDD levels at the time of the accident and the risk of spontaneous abortion (OR = 0.78, 95% CI 0.59–1.02, n = 160) or when only the first births after the explosion were considered (OR = 0.81, 95% CI 0.55–1.18, n = 75).

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

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

survival of implanted embryos and to fetal death (Huang et al., 2011; Ishimura et al., 2009; Wang J et al., 2011; Wu Y et al., 2013, 2014). There is no evidence of a relationship between paternal or maternal exposure to TCDD and spontaneous abortion. Exposure to 2,4-D or 2,4,5-T causes fetal toxicity and death after maternal exposure in experimental animals. However, that effect occurs only at high doses and in the presence of maternal toxicity. No fetal toxicity or death has been reported to occur after paternal exposure to 2,4-D.

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. Studies addressing the potential for perinatal death as a result of paternal exposure to TCDD or herbicides are inadequate to support conclusions.

Synthesis

A single study concerning the COIs and spontaneous abortion, stillbirth, neonatal death, or infant death has been published since Update 2012, but it did not provide supporting evidence of an association with the COIs and these outcomes. 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. 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. Typically, low birth weight (LBW) is defined as a birth weight under 2,500 g (UNICEF, 2004). In the absence of congenital malformations or chromosomal anomalies, LBW is the consequence of either preterm delivery (PTD) or intrauterine growth-restriction (IUGR). PTSD is delivery at less than 259 days or 37 weeks gestation from the date of the first day of the last menstrual period (Jones and Lopez, 2013), and IUGR is birth weight that is lower than average according to local or national fetal-growth graphs (Romo et al., 2009). LBW occurs in about

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

7 percent of live births. When no distinction is made between IUGR and PTD, the factors most strongly associated with LBW are maternal tobacco use during pregnancy, multiple births, and race or ethnicity. Other potential risk factors are low socioeconomic status, malnutrition, maternal weight, birth order, maternal complications during pregnancy (such as severe pre-eclampsia or intrauterine infection) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Alexander and Slay, 2002; Alexander et al., 2003; Ergaz et al., 2005; Jones and Lopez, 2013; Peltier, 2003). Established risk factors for PTD include race (black), 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).

The importance and interpretation of associations with birth weight are often unclear and a subject of controversy among researchers (Barker et al., 2012; Wilcox, 2010). Across populations, the frequency distribution of birth weight is Gaussian, with an extended lower tail, or “residual distribution,” that includes preterm and LBW infants. The predominant, normal distribution corresponds largely to term births. In general, shifts in the predominant distribution do not tend to correspond to notable shifts in infant mortality (Wilcox, 2001). A number of factors may result in shifts in the predominant distribution; altitude, race or ethnicity, and maternal smoking are among the better studied, producing a larger (or smaller) percentage of LBW babies. However, populations that have a larger percentage of LBW infants do not always have higher infant mortality (Wilcox, 2001, 2010). While birth weight is tracked internationally as a public health indicator to identify opportunities for intervention and to understand country-specific infant mortality (UNICEF, 2004), strategies to increase birth weight have not been effective in reducing mortality.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and LBW or PTD.

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 that conclusion. Reviews of the relevant studies are presented in the earlier reports. The most relevant findings on birth weight after paternal and maternal exposure to the COIs are summarized in Tables 9-6 and 9-7, respectively.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and LBW or PTD have been published since Update 2012.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 9-6 Selected Epidemiologic Studies—Birth Weight Following Paternal Exposure

Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates Reference
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans; births from service through 1993 in AFHS
Ranch Hands 2,082 births No association with IUGR Adjusted by stratification for father’s race, mother smoking during pregnancy, mother’s alcohol use, mother’s age, father’s age, father’s military occupation Michalek et al., 1998d
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed
Military service in VA 1,771 Vietnam; 1,561 non-Vietnam LBW/RR 1.1 (0.8–1.4) Maternal age and gravidity. Also model with smoking history, alcohol use, educational attainment, marital status, illicit drug use in military CDC, 1989b,c
US American Legion Cohort—American Legionnaires with service 1961–1975
US men deployed to SEA during Vietnam War, and other deployed men during same time period 2,858 in SEA 3,933 deployed elsewhere (n = 6,081) “no difference between the birth weight of boys born to servicemen stationed in SEA compared to those born to controls, nor did girls’ birth weight differs between two groups” Sex, age of father at time of child’s birth, age of mother, mother smoking during pregnancy, military service in SEA and exposure to combat and AO—these were not multivariate adjusted models, so strong smoking effect might have had an influence. These appear to have all been independent models. Stellman SD et al., 1988b
Tasmanian Veterans with Service in Vietnam—Follow-up of Australian Vietnam veterans
Military service in Vietnam ~550 LBW/RR 1.6 (1.0–2.5) RR calculated by committee member Field and Kerr, 1988
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates Reference
OCCUPATIONAL—INDUSTRIAL
Wives of chemical workers highly exposed to TCDD-contaminated chemicals ~500 exposed 600 referents No association with birth weight overall Adjusted for sex, education, parity, smoking, length of gestation, no stratification by sex Lawson et al., 2004
OCCUPATIONAL—HERBICIDE-USING WORKERS
Chlorophenate, wood preservative in sawmill industry 19,675 births No association (ORs for SGA ~1) Sex, maternal and paternal age, birth yr, matching Dimich-Ward et al., 1996

NOTE: AFHS, Air Force Health Study; AO, Agent Orange; CDC, Centers for Disease Control and Prevention; IUGR, intrauterine growth restriction; LBW, low birth weight; OR, odds ratio; RR, relative risk; SEA, Southeast Asia; SGA, small for gestational age; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

Environmental Studies

Since Update 2012, several studies have examined potential relationships between the COIs and birth weight. Papadopoulou et al. (2013a) analyzed infant weight, length, and head circumference at birth using estimated maternal dietary intake of dioxins during pregnancy. They considered the entire Norwegian Mother and Child (MoBa) cohort enrolled from 2002 to 2008, of which the births occurring in 2007–2008 form a subcohort of the NewGeneris cohort discussed below. The estimated dietary intakes of dioxin-like activity for the 50,651 eligible mothers were partitioned into quartiles inversely associated with birth weight (−62.1 g, 95% CI −73.8 to −50.5). A similar association was observed when the sexes were looked at separately; boys (−68.9 g, 95% CI −85.2 to −52.2) and girls (−55.2 g, 95% CI −71.7 to −38.6). Two other measures of infant growth (length and head circumference at birth) showed similar patterns.

Papadopoulou et al. (2014) used the CALUX assay to measure dioxin-like activity in maternal blood samples collected at delivery from the 604 mothers in the NewGeneris cohort. 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) was observed after adjustment for maternal education, energy intake, age, prepregnancy BMI, parity, smoking, and country of

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 9-7 Selected Epidemiologic Studies—Birth Weight Following Maternal Exposure (Shaded entries are new information for this update)

Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates Reference
VIETNAM VETERANS
US VA Cohort of Female Vietnam Veterans
Military Service 2,689 BW girls = + 0.5 oz BW boys = −0.8 oz (Difference in boys comes to −22.7 g) Unadjusted differences and major uncontrolled confounders (smoking, parity, race) H. Kang, personal correspondence, February 27, 2013
Military Service 4,140 LBW (OR = 1.06, 95% CI 0.8–1.5) Maternal age, education, race, marital status, military characteristics, smoking, drinking, average number of hours worked during pregnancy, complications during pregnancy Kang et al., 2000a
ENVIRONMENTAL
International Studies
Mother-child pairs from four European cohorts 967 BW decreased with increased dioxin measured in cord blood Country, gestational age, gestational age squared, parity, maternal prepregnancy BMI, gender Vafeiadi et al., 2014a
Japan
Yusho, Japan—population exposed to PCDDs, PCDFs, and PCBs in contaminated cooking oil 190 ~ 200g BW reduction with PCDD TEQ (p = 0.003) in males, also overall effect but driven by effect in boys Gestational age, maternal age, parity, smoking, duration breastfeeding, seafood consumption Tsukimori et al., 2012a; Kuratsune et al., 1972
Sapporo, Japan; contemporary cohort 514 BW (−220.5 g per 10-fold increase in TEQ, 95% CI 399.2 to 41.9); effect driven by males Gestational age, maternal age, maternal height, maternal weight before pregnancy, parity, smoking, inshore fish intake, blood sampling period, infant sex Konishi et al., 2009
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates Reference
Coastal Japan; contemporary cohort 75 Some weak negative correlations Unadjusted; Spearman correlations Tawara et al., 2009
Breast milk dioxin levels 42 Negative correlation for TEQ-PCDD and TEQ, PCDF, but not “significant” Spearman correlations Nishijo et al., 2008
Finland
Random sampling of mother/infant pairs from urban/rural Finland 167 BW decreased with increasing concentrations of I-TEQ, especially among boys Unadjusted; effect goes away when restricted to primiparas Vartiainin et al., 1998
Italy
Seveso Women’s Health Study—30-yr updated analysis 807 Small inverse relationship with LBW Gestational age, maternal height, pre-explosion histor of LBW, yr of pregnancy, parity, maternal age Wesselink et al., 2014; Eskenazi et al., 2003a
Seveso Residential Cohort 51 No association with LBW None Baccarelli et al., 2008
Netherlands
Dutch children—PCB 118 exposure (only total) 207 BW = 119 (53.7); p = 0.03 Smoking, alcohol, gestational age, target height, parity Patandin et al., 1998
Norway
NewGeneris cohort—Maternal dietary intake of dioxins and PCBs 604 BW decreased with increased dl-compounds in diet; only significant in boys Maternal educational level, energy, maternal age, prepregnancy BMI, parity, smoking during pregnancy country Papadopoulou et al., 2014
Norwegian Mother and Child Cohort Study—Maternal dietary intake of dioxins and PCBs 50,651 BW decreased with increased dl-compounds in diet Maternal age, energ intake, maternal education, prepregnancy BMI, parity, weight gain and smoking during pregnancy, gestational age, child’s gender Papadopoulou et al., 2013a
Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Primary Exposure Sample Size Outcome/Main Findings Adjustment Covariates Reference
United States
California Child Health and Human Development Study 600 No association with BW Race, age, smoking status, BMI, sex, length of gestation, lipids Kezios et al., 2012
Cord blood in Massachusetts infants (1993–1998)—PCB 118 722 Negative BW effects with increasing exposure quartile, non-significant—0, −18.0, −72.0, −69.5 Gestational age, infant size, birth year, maternal age, race parity, height, prepregnancy BMI, smoking, local fish consumption Sagiv et al., 2007
Times Beach and Quail Run cohorts—TCDD soil contamination in Missouri Matched sets, ~400 (2:1) LBW: 1.5 (95% CI 0.2–2.3) Sex, maternal education, parity, marital status, prepregnancy weight, smoking, history of previous SAB and fetal deaths Stockbauer et al., 1988
Vietnamese Studies
Vietnam—people living around contaminated airbase 210 At birth no effect, but BW discrepancy grows with months from delivery. Significant at 4 months. Effect only seen in boys Parity, maternal age, weight, educational period, alcohol use, family income, family smoking, gestational weeks, infant age on the day of examination Nishijo et al., 2012

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; TCDD, 2,3,7,8-trichlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

cohort, plus infant’s gestational age and gender. When the sexes were examined separately, the inverse relationship was maintained, but it only achieved statistical significance for boys (−170 g, 95% CI −332 to −8). Similarly, when the highest dietary intake group was compared with the lowest, a small, inverse relationship with gestational age was observed (−1.4 days, 95% CI −3.8–1.0 days). The estimate of gestational exposure employed in these two studies (Papadopoulou et al., 2013a; 2014) is a more indirect and presumably less precise metric than the CALUX results used in the next article.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Vafeiadi et al. (2014) examined dioxin-like activity measured by CALUX in maternal and cord blood samples and birth outcomes in 967 mother–child pairs enrolled in four European cohorts. When the highest tertile of TEQs values measured in cord blood was compared with the lowest exposure category, inverse associations were observed for birth weight (−82 g, 95% CI −216–53; p-trend = 0.225) and gestational age (−0.4 weeks, 95% CI −0.8 to −0.1; p-trend = 0.029). In analyses performed on the two sexes independently, nonsignificant inverse relationships with dioxin-like activity in cord blood and birth weight were observed in both boys (−124 g, 95% CI −391–144) and girls (−57 g, 95% CI −300–185). No indication of association was observed for dioxin-like activity measured in maternal plasma and birth outcomes.

Wesselink et al. (2014) reported the results of an updated analysis of pregnancy outcomes in the Seveso Women’s Health Study (described in Chapter 6). Overall, the lack of association between TCDD and spontaneous abortion, fetal growth, and gestational length observed in the first 20-year follow-up (Eskenazi et al., 2003a) was confirmed in this updated analysis. A small inverse association (−22.8 g, 95% CI −80.1–34.6) between a 10-fold increase in serum TCDD levels estimated at pregnancy and birth weight was observed, with the strongest reduction observed for the first births after the explosion (−47.7g, 95% CI −107.3–11.9).

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. A recent study in human placental explants suggests that TCDD exposure may enhance placental inflammation and may influence pre-term births associated with infection (Peltier et al., 2013). 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. TCDD and herbicides are known to cross the placenta, which leads to the direct exposure of the fetus. Data from studies of experimental animals also suggest that the preimplantation embryo and developing fetus are sensitive to the toxic effects of 2,4-D and TCDD after maternal exposure.

Synthesis

Two analyses from European birth cohorts observed a small decrease in birth weight in relation to maternal dietary intake of DLCs (Papadopoulou et al., 2013, 2014). A small decrement in gestational age (1.4 days) was also observed when comparing the highest to lowest dietary intake categories. A similar reduction in birth weight was observed in an analysis of mother–infant pairs enrolled in four European birth cohorts, with an inverse association with birth weight observed

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

when comparing cord blood measurements of the highest to lowest categories. In all three analyses, the reduction in birth weight was less than 200 grams and not likely to be of clinical relevance. In a final study, an update of the Seveso cohort observed no association between TCDD and fetal growth, confirming an earlier analysis of this cohort.

There are a number of challenges in conducting these types of epidemiologic studies in a rigorous way. First, the prenatal and immediate postpartum period is not a stable pharmacokinetic state, because it involves substantial changes in body volume and fat mobilization. Biomarker measures during pregnancy may be substantially affected by weight change during pregnancy. Moreover, the extrapolation of a more recent biomarker measure back many years to a more relevant period is complicated by intervening pregnancy and breastfeeding events, which result in a substantial uncertainty in the index exposure level. Overall, although the committee notes that the animal literature does support an effect of TCDD exposure at high doses on birth weight, the epidemiologic literature is insufficiently robust to allow a final determination.

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.

Suggested Citation:"9 Effects on Veterans' Fertility and Reproductive Success." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 2014 is a cumulative report of the series thus far.

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