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Veterans and Agent Orange: Update 2010 (2012)

Chapter: 8 Reproductive Effects and Impacts on Future Generations

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Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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8

Reproductive Effects and Impacts on Future Generations

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2008, hereafter referred to as Update 2008 (IOM, 2009), on the association between exposure to herbicides and adverse reproductive or developmental effects. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, 2004, and 2006 [IOM, 1996, 1999, 2001, 2003, 2005, 2007] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to 2,3,7,8-tetrachlorodibenzo-p-dioxin (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).

As in previous updates, the adverse outcomes evaluated include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant mortality, and such other adverse birth outcomes as low birth weight, preterm birth, and birth defects. In addition to the more delayed problem of childhood cancer in their offspring, this update also addresses the concern of Vietnam veterans that their military exposures may contribute to other problems that their children experience later in life or that are manifested in later generations. Finally, as suggested in Update 2008, endometriosis and pregnancy loss will no

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

longer be fully evaluated after this update. It is unlikely, given the age of the Vietnam veteran cohort, that any newly published data on those two outcomes will provide additional information that would be directly relevant to that cohort. However, if new research suggests that the two outcomes may be influenced by epigenetic changes, their relevance to transgenerational effects will be assessed in future updates.

To reduce repetition throughout the report, Chapter 5 presented design information on new studies that report findings on multiple health outcomes. To provide context for publications that present new results on study populations that were addressed in publications reviewed in earlier updates, Chapter 5 also discussed the overall characteristics of those populations with details about design and analysis relevant to individual publications. Design information on new studies that report only reproductive health outcomes and are not revisiting previously studied populations is summarized in this chapter with results.

This chapter’s primary emphasis is on the potential adverse reproductive effects of herbicide exposure of men because the vast majority of Vietnam veterans are men. 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 are also included. Whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately. Exposure scenarios in human populations and experimental animals studied differ in their applicability to our population of concern according to whether the exposed parent was a male or female veteran. In addition, for published epidemiologic or experimental results to be fully relevant to evaluation of the plausibility of reproductive effects in Vietnam veterans, whether female or male, the timing of exposure needs to correspond to the veterans’ experience (that is, it must have occurred only before conception). With the possible exception of female veterans who became pregnant while serving in Vietnam, pregnancies that might have been affected occurred after deployment, when primary exposure had ceased.

BIOLOGIC PLAUSIBILITY OF REPRODUCTIVE EFFECTS

This chapter opens with a general discussion of factors that influence the plausibility that TCDD and the four herbicides used in Vietnam could have adverse reproductive effects. 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 outside of controlled experimental circumstances usually occurred in a mixture of dioxins (dioxin congeners in addition to TCDD).

Because TCDD is stored in fat tissue and has a long biologic half-life, internal exposure at generally constant concentrations may continue after episodic,

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

high-level exposure to external sources has ceased. If a person had high exposure, there may still be high amounts of dioxins stored in fat tissue, which may be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid.

A father’s contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg and any damage to the embryo or offspring would result from either genetic or epigenetic changes of the sperm DNA. Epigenetic effects are ones that result in permanent (heritable) changes in gene expression without a change in DNA sequence. Dioxins have not been shown to mutate DNA sequence, so any damage to an embryo or offspring from a dioxin-exposed father would be limited to epigenetic effects.

A mother’s contribution to a pregnancy is obviously more extensive, and any damage to an embryo or offspring can result from epigenetic changes of the egg DNA or from direct effects of exposure on the fetus during gestation and on the neonate during lactation. Dioxin in the mother’s bloodstream can cross the placenta and expose the developing embryo and fetus. Furthermore, mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus or nursing infant. In humans, TCDD has been measured in circulating maternal blood, cord blood, placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as that in an infant not breastfed (Lorber and Phillips, 2002).

On the basis of laboratory animal studies, TCDD can affect reproduction and development, so a connection between TCDD exposure and human reproductive and developmental effects is biologically plausible. However, definitive conclusions based on animal studies about the potential for TCDD to cause reproductive and developmental toxicity in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that they have subcellular effects that could constitute a biologically plausible mechanism for reproductive and developmental effects. Evidence from animals, however, indicates that they do not have reproductive effects and that they have developmental effects only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their reproductive or developmental effects.

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

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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 given time (National Institute of Child Health and Human Development, 2007). The endometrium is the tissue that lines the inside of the uterus and 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 lining the uterus, 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 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 with immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometrio-sis, 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, and Update 2004 examined three environmental studies. Three additional environmental studies considered in Update 2008 did not change the conclusion that the evidence was inadequate or insufficient to support an association with herbicide exposure. Table 8-1 provides a summary of relevant studies that have been reviewed.

Update of the Epidemiologic Literature

No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and endometriosis have been published since Update 2008.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-1 Selected Epidemiologic Studies—Endometriosis


Reference Study Population Study Results

ENVIRONMENTAL
Studies Conducted In the Lnlted States
Niskar et al.. 2009 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 = 01.00 (95% CI 0.930-1.07)
Studies Conducted In Belgium
Heilier et al.. 2007 88 matched triads (264 total); patients with deep endometrioid 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.. 2006 Serum DEC and aromatase activity in endometrioid tissue from 47 patients in Belgium No association between TEQs (determined by GC/MS) of DECs in serum and aromatase activity by regression analyses. p-values = 0.37-O.90 for different endometriosis subgroups
Heilier et al.. 2005 Endometriosis in Belgian women with overnight fasting serum levels of 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) PCDD, PCDF. PCB
Fierens et al.. 2003 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
Pauwels et al.. 2001 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)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Study Results

Studies Conducted In Italy
Porpora et al., 2009 Case-control study of Italian women with endometriosis; 80 cases and 78 controls (TEQs determined by CALUX bioassay) Results for endometriosis vs controls: dl-PCB 118 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) Tola! 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 fal: OR = 0.73 (95% CI 0.26-2.01)
Porpora et al., 2006 Case-control study of Italian women with endometriosis, measured serum PCBs Mean total PCBs (ng/g)Cases, 410 ng/gControl, 250 ng/gAll PCB congeners: OR = 4.0 (95% CI 1.3-13)
Do Felip et al., 2004 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), 1.6Cases (two sets of 6 pooled samples), 2.1, 1.3Belgium:Controls (7 pooled samples), 2.5Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 2.3, 2.3Mean 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 ± 1.5Belgium: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
Eskenazi et al., 2002a Residents of Seveso Zones A and B up to 30 years 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)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Study Results

Studies Conducted in Israel
Mayani et al., 1997 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)
Studies Conducted in Japan
Tsuchiya et al., 2007 138 infertility patients in Japan; laproscopically confirmed case-tontrol 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 = 0.3-0.6No significant interaction between genotype, dioxin TEQ

ABBREVIATIONS: 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 dibenzodioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent.

Environmental Studies

Niskar et al. (2009) recruited 144 women who lived in Atlanta, Georgia, during 1998–1999 for a case–control study of endometriosis. TCDD TEQs were calculated on the basis of the serum concentration of each of the dioxin-like PCDDs, PCDFs, and PCBs; total PCBs were calculated on the basis of the sum of 36 PCB congeners measured in serum. Persons who had endometriosis (n = 60) and controls who did not (n = 64) were selected from patients seeking consultation at a reproductive-medicine clinic. At the time of enrollment, cases had been recently diagnosed, confirmed with biopsy, and staged as minimal, mild, moderate, or severe. No difference was observed between cases and controls with regard to TEQ or total PCBs on the basis of either lipid-adjusted or non–lipid-adjusted values.

A second case–control study of endometriosis was completed in Rome, Italy (Porpora et al., 2009). Women scheduled for laparoscopy were recruited from a reproductive-medicine clinic. Cases (n = 80) were confirmed and staged with

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

histologic analyses. Controls (n = 78) were women who had no known infertility and underwent laparoscopy for unrelated gynecologic conditions. An increased risk of endometriosis was observed with increasing serum concentrations of the dioxin-like PCB 118. When they were compared with women who had the lowest concentrations of PCB 118 (≥ 13.3 ng/g serum lipid), the adjusted odds ratios (ORs) for endometriosis were 3.14 (95% confidence interval [CI] 1.36–7.37) and 3.79 (95% CI 1.61–8.91) for women who had serum PCB 118 concentrations of 13.3–24.2 ng/g lipid and more than 24.2 ng/g lipid, respectively. However, no association was observed with total TEQs: an OR of 0.73 (95% CI 0.26–2.01) in women who had the highest concentration of total TEQ (> 29.6 pg TEQ/g lipid).

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. 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 (Rier et al., 1993). Ten years after the exposure ended, the investigators documented an increased incidence of endometriosis in the monkeys that correlated with the TCDD exposure concentration. The small sample prevented a definitive conclusion that TCDD was a causal agent of endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of pre-existing endometriotic lesions.

A number of proposed mechanisms by which TCDD may promote endometrial lesions provide additional biologic plausibility of the link between TCDD and endometriosis. Human endometrial tissue expresses the aryl hydrocarbon receptor (AHR) and its dimerization partner, the aryl hydrocarbon nuclear translocator (ARNT) (Khorram et al., 2002), and three AHR target genes: CYP1A1, 1A2, and 1B1 (Bulun et al., 2000); this suggests that endometrial tissue is responsive to TCDD. Recently, it was shown that CYP1A1 expression increases in ectopic endometrial tissue from women, compared with eutopic uterine tissue, in the absence of TCDD exposure, and this suggests that CYP1A1 may play a role in disease etiology (Singh et al., 2008). Other mechanisms by which TCDD may promote endometriosis include altering the ratio of progesterone receptor A to B and blocking the ability of progesterone to suppress matrix metalloproteinase (MMP) 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 histaminereleasing factor, which is increased in endometrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). Similarly, TCDD stimulates expression of RANTES (regulated on activation, normal

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

T-cell–expressed, and secreted) 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 showed that the combination of 17α-estradiol and TCDD increased 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 increased expression of the chemokine C receptor 9 (CCR9) and the secretion of its ligand, thymus-expressed chemokine (TECK), in endometriosis-associated cells (Wang et al., 2010). Those results support the idea that TCDD in combination with estradiol may contribute to the development of endometriosis by increasing invasive-ness of endometrial cells. Despite that compelling evidence, chronic exposure of rats to TCDD, a dioxin-like PCB, or PCDF or a mixture of the three fails to alter endometrial histology in a consistent manner (Yoshizawa et al., 2009). Differences between the rodent uterus and human endometrium could account for that lack of observed effects in rats.

In summary, experimental studies, particularly those using human eutopic and ectopic endometrial tissue provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis.

Synthesis

The new epidemiologic studies described above were contradictory in their findings and did not assess dioxin directly. Overall, the studies linking dioxin exposure with endometriosis are few and inconsistent. The association in animal studies is biologically plausible, but it is possible that human exposures are too low to show an association consistently.

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 chemicals of interest and human endometriosis.

FERTILITY

Male reproductive function is under the control of several components whose proper coordination is important for normal fertility. Several of the 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 an-

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

terior 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. More detailed reviews of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde and Giwercman, 1995; Tas et al., 1996).

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 altered sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Reviews of the relevant studies are presented in the earlier reports. Tables 8-2 and 8-3 summarize the studies related to male and female fertility, respectively.

Update of the Epidemiologic Literature

Male Fertility

No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and male fertility have been published since Update 2008.

Environmental Studies Since Update 2008, two studies published on semen quality and exposure to organochlorine compounds have been published. The first, by Cok et al. (2010), explored associations between PCBs measured in adipose tissue and fertility status in 25 infertile men and 21 healthy men. Infertile

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility)


Reference Study Population Exposed Casesa Exposure of Interest/
Estimated Risk
(95% CI)a

VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans n SEA veterans All COIs
Gupta et al.. 2006 Coefficient tp-value) for In(Testosterone) vs
AFHS (964 Ranch Hands. 1,259 comparison) In(TCDD) in 1987
Comparison TCDD quartile I (mean. 2.14 ppl) nr 0(referent)
Comparison TCDD quartile II (mean. 3.54 ppl) nr -0.063 (0.004)
Ranch Hand TCDD quartile I (mean. 4.14 ppl) nr 0.002 (0.94)
Comparison TCDD quartile III (mean. 4.74 ppl) nr -0.048 (0.03)
Comparison TCDD quartile IV (mean. 7.87 ppl) nr -0.079 (< 0.001)
Ranch Hand TCDD quartilc II (mean. 8.95 ppl) nr -0.052 (0.03)
Ranch Hand TCDD quartile III (mean. 18.40 ppl) nr -0.029 (0.22)
Ranch Hand TCDD quartile IV (mean. 76.16 ppl) nr -0.056 (0.02)
Henriksen et al.. 1996 Effects on specific hormone concentrations or sperm count in Ranch Hands Low testosterone
High dioxin (1992) 18 1.610.9-2.7)
High dioxin (1987) 3 0.7 (0.2-2.3)
Lowdioxin(l992) 10 0.9(0.5-1.8)
Low dioxin (1987) 10 13(1.1-4.5)
Background (1992) 9 0.5(0.3-1.1)
High FSH
High dioxin (1992) 8 1.0(0.5-2.1)
Lowdioxin(l992) 12 1.6(0.8-3.0)
Background (1992) 16 1.3(0.7-2.4)
High I.H
High dioxin (1992) 5 0.8(0.3-1.9)
Lowdioxin(l992) 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)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesa Exposure of Interest/
Estimated Risk
(95% CI)a

US CDC Vietnam Experience Study All COIs
CDC, 1989a Vietnam Experience Study
Lower sperm concentration
Proportion of abnormal sperm
Reduced sperm motility
 
42
51
83
 
2.3 (1.2-4.3)
1.6 (0.9-2.8)
1.2 (0.8-1.8)
American Legion Cohort   All COIs
Stellman et al., 1988 American Legionnaires who served in SEA
Difficulty in having children
 
349
 
1.3 (p < 0.01)
OCCUPATIONAL
US Chemical Workers Dioxin
Oh et al., 2005 Male waste incinerator workers (n = 6) vs controls (n = 8), dioxin measured by air monitoring    
  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
Egeland et al., 1994 Male chemical workers exposed to dioxin vs neighborhood controls in New Jersey, Missouri measured in 1987   Risk of extreme hormone concentration
  Testosterone (< 10.4 nmol/L)    
  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)
Agricultural Workers Herbicides
Larsen et al., 1998 Danish farmers who used any potentially spermatotoxic pesticides, including 2,4-D    
  Farmers using pesticides vs organic farmers 523 1.0 (0.8-1.4)b
  Used three or more pesticides nr 0.9 (0.7-1.2)b
  Used manual sprayer for pesticides nr 0.8 (0.6-1.1)b
Lerda and Rizzi, 1991 Argentinean farmers exposed to 2,4-D
Sperm count (millions/mL)
Motility (%)
Sperm death (%)
Anomalies (%)
32
exposed: 49.0 vs control: 101.6
exposed: 24.8 vs control: 70.4
exposed: 82.9 vs control: 37.1d
exposed: 72.9 vs control: 33.4
Forestry Workers   Herbicides
Heacock et al., 1998 Workers at sawmills using chlorophenates    
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesa Exposure of Interest/
Estimated Risk
(95% CI)a

  Standardized fertility ratio 18,016
(births)
0.7 (0.7-0.8)c
  Mantel-Haenszel rate-ratio estimator 18,016
(births)
0.9 (0.8-0.9)c
  Cumulative exposure (hours)    
  120-1,999 7,139 0.8 (0.8-0.9)c
  2,000-3,999 4,582 0.9 (0.8-1.0)c
  4,000-9,999 4,145 1.0 (0.9-1.1)c
  ≥ 10,000 1,300 1.1 (1.0-1.2)c
(p < 0.01 overall)
ENVIRONMENTAL
Seveso, Italy Residential Cohort Dioxin
Mocarelli et al., 2008 Men exposed in Seveso, Zone A vs age-matched men residing outside the contamination zone, measured semen characteristics, estradiol, FSH, testosterone, LH, inhibin B   Authors' evaluation (data not shown)
  Age at 1976 exposure:   Sensitive
  Infant/prepuberty (1-9 years), n = 71 vs 176   Intermediate response
  Puberty (10-17 years), n = 44 vs 136   No associations
  Adult (18-26 years), n = 20 vs 60    
Ankara, Turkey Case-Control Study of Infertile Men DLCs
Cok et al., 2010 Adipose-tissue samples assayed for PCB-118 21 fertile
25 infertile
68.6 ng/g lipid
21.7 ng/g lipid (p = 0.003)
Cok et al., 2008 Adipose-tissue samples assayed for dioxins, furans, dl PCBs 22 fertile
23 infertile
9.4 TEQ pg/g lipid
12.5 TEQ pg/g lipid
(p = 0.065)
US Environmental Study 2,4-D
Swan et al., 2003 Men in Missouri, US with or without low sperm quality    
  Increased urinary metabolite marker for 2,4-D 5 0.8 (0.2-3.0)
International Environmental Studies
Krüger et al., 2008 DNA sperm integrity among Inuit men from Greenland (n = 53) and European men (n = 247)   POPs
  Median % DNA fragmentation index    
  Inuits   6.8
  Europeans   12
  Median % DNA stainability    
  Inuits   11
  Europeans   8.9
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesa Exposure of Interest/
Estimated Risk
(95% CI)a

Polsky Case-control study of erectile dysfunction in PCBs/Highest vs
el al., 2007 urology patients patients in Ontario, Canada lowest PCB groups
PCB-118 (TEF = 0.000l) 1.0(0.5-2.1)
PCB-156 (TEF = 0.0005) 0.9(0.5-1.6)
PCB-170 0.6(0.3-1.2)
PCB-180 0.7(0.4-1.4)
Toft el al.. 2007 Men in general population of Poland, Greenland, Ukraine, Sweden; AHR binding measured with CALUX assay Dioxin-like activity
Measurements of semen quality No consistent
(concentration, motility, percentage normal) associations
Dhooge el al., 2006 Men in general population of Belgium PCBs, dioxin
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)
Slaessen el al., 2001 Adolescents in communities close to industrial sources of heavy metals, PCBs, VOCs, and PAHs—delays in sexual maturity PCBs. DLCs
In Hoboken, Belgium 8 4.0 (nr)
In Wilrik, Belgium 15 1.7 (nr)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHR, aryl hydrocarbon receptor; CALUX, assay for determination of dioxin-like activity; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; DLC, dioxin-like chemical; FSH, follicle-stimulating hormone; IU, international unit; LH, luteinizing hormone; 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 fecundability ratio, for which value less than 1.0 indicates adverse effect.

cFor this study, relative risk has been replaced with standardized fertility 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:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-3 Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility)


Reference Study Population Exposed Cases Exposure of Interest/
Estimated Risk
(95% CI)a

OCCUPATIONAL
Agricultural Health Study
Herbicides
Farr et al., 2006 8,038 premenopausal women aged 35–55 at enrollment Laier menopause
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)
Farr et al., 2004 Menstrual-cycle characteristics of 3,103 premenopausal women aged 21-40 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 Women's Health Sludv TCDD
Eskenazi et al..2010 Time to pregnancy and infertility in women from Zones A and B who attempted pregnancy after 1976 Time to pregnancy (adjusted fecundability OR)
Log10TCDD 278 0.8 (0.6-1.0)
Categorical TCDD (ppt)
≤20 52 1.0 (reference)
20.1-444 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)
Log10TCDD 49 1.9(1.1-3.2)
Categorical TCDD (ppt)
≤20 6 1.0 (reference)
20.1-444 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)
Eskenazi et al., 2007 Fibroids among women from Zones A and B who were newborn to age 40 in 1976 Uterine fibroids (age-adjusted HR)
Log10 TCDD (ppt) 251 0.8(0.7-1.1)
Categorical TCDD (ppt)
≤20.0 62 1.0 (reference)
20.1-75.0 110 0.6 (0.4-0.8)
>75.0 79 0.6 (0.4-0.9)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Cases Exposure of Interest/
Estimated Risk
(95% CI)a

Warner et al., 2007 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
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 B) 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 B) in luteal phase 87 -0.7 (-2.4-1.0)
in midluteal phase 55 -0.8 (-3.7-2.0)
Eskenazi et al., 2005 Age at menopause in women from Zones A and B who were newborn to age 40 in 1976 616
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)
Peri menopause 33 36.5 (0.2-0.9)
Other 58 39.6 (0.2-0.9)
Warner Age at menarche in women from Zones A and B 282 1.0(0.8-1.1)
el al., who were premenarcheal in 1976
2004 All premenarcheal women in 1976 (unadjusted HR)
Log10TCDD 282 1.0(0.8-1.1)
Women<8 years in 1976 (unadjusted HR)
Log10TCDD 158 1.1 (0.9-1.3)
Eskenazi et al., 2002b 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 Menstrual cycle lenath (adjusted B)
Log10TCDD 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)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Cases Exposure of Interest/
Estimated Risk
(95% CI)a

Days of menstrual flow (adjusted B)
Log10TCDD 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)
Log10TCDD 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) Log10TCDD 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 Environmental Studies
Chao et al., 2007 Pregnant women in Taiwan: measured placentaldioxin TEQ, PCB TEQ Older of "regular menstrual cycle" Dioxin/Regression adjusted for maternal age, BMI, parity
Dioxin TEQ p = 0.032
PCB TEQ p = 0.077
Longer "longest menstrual cycle"
Dioxin TEQ p = 0.269
PCB TEQ p = 0.006
Greenlee et al., 2003 Women in Wisconsin, US with or without infertility (maternal exposure) Mixed or applied herbicides 21 Phenoxy herbicides

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%)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BMI, body mass index; CI, confidence interval; HR, hazard ratio; IQR, inter-quartile range; OR, odds ratio; PCB, polychlorinated biphenyl; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent.

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

men had higher adipose-tissue concentrations of PCB 52 and PCB 180 but lower concentrations of the one dioxin-like PCB congener measured, PCB 118.

The second study included 53 men in Greenland (Inuits) and 247 Europeans (in Sweden, Poland, and Ukraine) whose sperm DNA integrity was measured using flow cytometry to assess the integrity of sperm chromatin structure (Krüger et al., 2008). Total TCDD TEQs were calculated from serum samples analyzed with the AHR-CALUX assay; analogous CALUX assays were used to determine

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

estrogenic and androgenic activity in the samples. Results for none of the three measured outcomes showed a coherent pattern across sub-populations. The fraction of sperm showing DNA breaks was negatively associated with serum TEQs for Greenland Inuits, while it was positively associated for the groups of European men. Thus, neither study provides convincing evidence of an association between dioxin exposure and reduced semen quality.

Female Fertility

No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and female fertility have been published since Update 2008.

Environmental Studies Since Update 2008, Eskenazi et al. (2010) examined the relationship between serum TCDD level around the time of the Seveso accident and time to pregnancy (TTP) in 472 Seveso Women’s Health Study (SWHS) participants who attempted pregnancy since the accident. Participants were eligible for this study if they were newborn to 40 years old at the time of the accident, lived in the contaminated area at the time of the accident, and had adequate stored sera available for analyses. Nine women were excluded due to fertility-related problems, leaving 463 eligible women in the analysis sample. The main analysis was restricted to women whose pregnancies were not the result of contraceptive failure and resulted in a live birth (n = 278). Additional analyses of subgroups included women who conceived after contraceptive failure and pregnancies not resulting in a live birth. TTP for the first post-accident pregnancy was determined from interviews conducted between 1996 and 1998 using the question “How many months did it take to become pregnant? In other words, for how many months had you been having sexual intercourse without doing anything to prevent pregnancy?” Women whose TTP was 12 months or more were classified as infertile.

Initial serum TCDD levels at the time of the accident were measured using stored samples for 444 participants (431 collected in 1976 or 1977, 13 collected between 1978 and 1981). For 19 participants with insufficient stored samples, new samples were collected in 1996 or 1997. For women with detectable post-1977 TCDD measurements (n = 27), the TCDD level was back-extrapolated to 1976, using the Filser Model (Kreuzer et al., 1997). Initial serum TCDD levels were extrapolated to the time each woman initiated her attempt to become pregnant using a toxicokinetic model (Kreuzer et al., 1997) for women 16 years old or younger at the time of the accident, and a first-order kinetic model assuming a 9-year half-life (Pirkle et al., 1989).

The association between serum TCDD and TTP was assessed using a Cox proportional hazards model to estimate the fecundability odds ratios (fOR) and 95% confidence intervals. The association between serum TCDD and infertility was assessed using multiple logistic regression. Both models were adjusted for

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

maternal age, maternal smoking in the year before conception, parity, menstrual cycle irregularity, oral contraceptive use in the year before attempt, paternal age near the time of conception, and history of reproductive and endocrine conditions including pelvic infection, or thyroid or urogenital problems. A variety of sensitivity analyses were conducted to investigate the consistency of study findings and to check for possible bias.

Serum TCDD was specified both as a continuous variable on the logarithmic scale, and as categorical variables. The fOR was calculated to evaluate the odds of conceiving in a given cycle for each 10-fold increase in TCDD (on the continuous scale) or each exposure category. A fOR less than 1 represents increased TTP for those designated as exposed. In these analyses, TTP increased with increasing exposure on both the continuous and categorical scales. For example, for every 10-fold increase in TCDD, a 25% decrease in fecundability was observed (fOR = 0.75, 95% CI 0.60–0.95). Seventeen percent of the women in this study were classified as infertile (a TTP of longer than 12 months). As with TTP, the odds of infertility increased with every 10-fold increase in exposure (adjusted OR 1.92, 95% CI 1.14–3.22). The results did not substantively change when different eligibility criteria and exposure models were considered.

Biologic Plausibility

There is little evidence that 2,4-D or 2,4,5-T has substantial effects on reproductive organs or fertility. 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, and seminal vesicle weight and function and by decreasing the rate of sperm production. The mechanisms of those effects are not known, but a primary hypothesis is that they are mediated through dysregulation of testicular steroidogenesis. Studies published since Update 2008 have reinforced those findings. Single intraperitoneal injections of TCDD induced marked histologic changes in the testis, impaired spermatogenesis, increased serum estradiol, decreased testosterone in male rats (Choi et al., 2008; Park et al., 2008), and impaired epididymal function (Foster et al., 2010). The effects of TCDD on the reproductive system of the male rat depend heavily on the developmental time of exposure.

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 cross-talk of the AHR with the estrogen receptor and dysregulation of the hypothalamic– pituitary–gonadal axis. In addition, oocytes are directly responsive to TCDD. Thus, TCDD’s effects on hormone concentrations, hormone-receptor signaling, and ovarian responsiveness to hormones all probably contribute to TCDD- induced

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

female reproductive toxicity. Since Update 2008, additional work addressing TCDD’s effects on female reproduction in animal models has been published. The data of Heiden et al. (2008) on zebrafish suggest that TCDD inhibits follicle maturation via attenuated gonadotropin responsiveness or depression of estradiol biosynthesis and that interference of estrogen-regulated signal transduction may also contribute to TCDD’s effects on follicular development, possibly by disrupting signaling pathways, such as glucose and lipid metabolism, and disrupting regulation of transcription.

Since the Update 2008, studies with TCDD in rodents have suggested that dioxin has a pharmacologic effect on sperm flagellum movement (Yamano et al., 2009) and that TCDD has a greater effect on epididymal function and sperm analysis than on spermatogenesis (Foster et al., 2010). Studies of female reproduction in rats involved the demonstration that a number of PCBs and dioxin compounds have numerous effects on reproductive physiology after 2-year oral treatment, including infertility, and the different actions of the various chemicals suggested that more than one signaling mechanism was involved (Yoshizawa et al., 2009). Another study suggested direct effects on human trophoblast formation in vitro and thus the capacity to influence the developing fetus (Chen et al., 2010). The more recent literature continues to support the biologic plausibility of effects of TCDD on male and female reproduction.

Although it would not constitute an adverse health outcome in an individual veteran, there is fairly strong evidence (see Table 8-4) that paternal exposure to dioxin may result in a lower sex ratio (that is, a smaller than expected proportion of male infants at birth). Pronounced reductions in sex ratio have been observed in the offspring of men exposed to dioxin after the Seveso accident, especially those under 19 years old at the time of the dioxin release (Mocarelli et al., 2000); this phenomenon was not observed in the offspring of young women exposed by the Seveso accident (Baccarelli et al., 2008). Similar results of a depression in the sex ratio concentrated among fathers who were under 20 years old at the time of the incident were following the Yucheng poisoning with oil contaminated with PCBs, PCDFs, and PCDDs (del Rio Gomez et al., 2002). Reductions in the expected number of male offspring have also been reported in several cohorts of men 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., 1998b).

Chao et al. (2007) mention that they did not find an association between sex ratio of the offspring and the TEQ concentrations of dioxins, furans, or PCBs in the placentas from 119 Taiwanese women. Crude sex ratios for all births in 1994–2005 to women who were less than 18 years old at the time of the Seveso accident are reported in Baccarelli et al. (2008), and the proportion of male births

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-4 Selected Epidemiologic Studies—Sex Ratioa


Reference Study Population Sex Ratio of Offspring (boys/total )b Comments

VIETNAM VETERANS
US Air Force Health Study
Michalck et al., 1998b Births from service through 1993 in AFHS    
  Comparison group 0.504 Not formally
  Dioxin level in Ranch Hand personnel   analyzed
  Background 0.502  
  Low 0.487  
  High 0.535  
OCCUPATIONAL
NIOSH Cross-Sectional Study
Schnorr el al., 2001 Workers producing trichlorophenol and derivatives, including 2,4,5-T   No difference on basis of age at first
  Serum TCDD in fathers   exposure
  Neighborhood controls (< 20 ppt) 0.544 Referent
  Worker fathers    
  < 20 ppt
20-255 ppt
255- < 1,120 ppt
≥ 1,120 ppt
0.507
0.567
0.568
0.550
None significantly decreased (or increased)
International Occupational Studies
Ryan et al., 2002 Russian workers manufacturing
2,4,5,-irichlorophenol (1961-1988) or 2,4,5-T (1964-1967)
   
  Either parent exposed 0.401
(91 boys: 136 girls)
p < 0.001
  Only father exposed 0.378
(71 boys: 117 girls)
p < 0.001
  Only mother exposed 0.513
(20 boys: 19 girls)
ns
Moshammer and Neuberger, 2000 Austrian chloracne cohort—157 men, 2 women; exposed to TCDD during 2,4,5-T production   Fewer sons, especially if father was under 20 years old when exposed: SR = 0.20 (1 boy: 4 girls)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Sex Ratio of Offspring (boys/total )b Comments

Heacock et al., 1998 Sawmill workers in British Columbia    
  Chlorophenate-exposed workers 0.515  
  Nonexposed workers 0.519  
  Province overall 0.512  
Savitz et al., 1997 OFFHS fathers’ exposure during 3 mo before conception:    
  No chemical activity 0.503 Referent
  Crop herbicides (some phenoxy herbicides) 0.500 ns
  Protective equipment used 0.510 ns
  No protective equipment 0.450 ns
ENVIRONMENTAL
Seveso, Italy Residential Cohort
Baccarelli et al., 2008 Births 1994-2005 in women 0-28 yrs of age at time of Seveso accident    
  Zone A 0.571  
  Zone B 0.508  
  Zone R 0.495  
Mocarelli et al., 2000 Births 1977-1996 in people from Zones A, B, R, 3-45 yrs of age at time of 1976 Seveso accident 0.514 Referent
  Neither parent exposed 0.608 ns
  Father exposed (whether or not mother exposed) 0.440 p = 0.03
  Father under 19 yrs of age in 1976 0.382 p = 0.002
  Father at least 19 yrs of age in 1976 0.469 ns
  Only mother exposed 0.545 ns
Mocarelli et al., 1996 Parent (either sex) from Seveso Zone A    
  Births 1977-1984 0.351
(26 boys: 48 girls)
p < 0.001, related to parental TCDD serum
  Births 1985-1994 0.484
(60 boys: 64 girls)
ns
Chapaevsk, Russia Residential Cohort
Revich et al., 2001 Residents near chemical plant in operation 1967-1987 in Chapaevsk, Russia    
  1983-1997 0.507 No clear pattern
  Minimum in 1989 0.401  
  Maximum in 1987 0.564  
  Maximum in 1995 0.559  
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Sex Ratio of Offspring (boys/total )b Comments

US Environmental Studies
Hertz-Ptcciotto et al., 2008 San Francisco Bay area—serum concentrations in pregnant women during 1960s OR for male birth (not SR)  
  90th percentile vs 10th percentile   SRs all < 0.5
  Total PCBs
d1 PCBs
0.4 (0.3-0.8) p = 0.007
  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
Karmaus et al., 2002 Births after 1963 to Michigan fish-eaters with serum PCBs in both parents   ns
  Paternal PCBs > 8.1 μg/L 0.571 p < 0.05
  Maternal PCBs > 8.1 μg/L 0.494 (but for more sons)
ns
International Environmental Studies
Chao et al., 2007 Taiwan—placental TEQ concentrations of TCDDs, TCDFs, PCBs nr No association
del Rio Gomez et al., 2002 Births in individuals exposed to PCBs, PCDFs, PCDDs in 1979 Yucheng incident   vs unexposed with same demographics
  Father exposed (whether or not mother exposed) 0.490 p = 0.037
  Father under 20 yrs of age in 1979 0.458 p = 0.020
  Father at least 20 yrs of age in 1979 0.541 p = 0.60
  Mother exposed (whether or not father exposed) 0.504 p = 0.45
  Mother under 20 yrs of age in 1979 0.501 p = 0.16
  Mother at least 20 yrs of age in 1979 0.500 p = 0.40
Yoshimura et al., 2001 Parents (one or both) exposed to PCBs, PCDFs in Yusho, Japan    
  All Japan in 1967 0.513 Referent
  Births 1967 (before poisoning incident) 0.516 ns
  Births 1968-1971 (after incident) 0.574 ns

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; dl, dioxin-like; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; SR, sex ratio; TCDD, 2,3,7,8–tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (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.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

exceeds that of female births in Zones A and B. The only new evidence of an effect on sex ratio came from Hertz-Picciotto et al. (2008), who reported on serum concentrations of nine PCB congeners (four of which were dioxin-like: PCB 105, 118, 170, and 180) in blood gathered during the 1960s from 399 pregnant women in the San Francisco Bay area. The adjusted odds of a 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). The proportion of male births was significantly reduced for two of the dioxin-like PCBs analyzed separately, and the decrease in the proportion of male babies was not significant for any of the five non–dioxin-like PCBs.

A population-level finding of a paternally mediated effect would be a strong indicator that dioxin exposure can interfere with the male reproductive process. To date, however, the results for a reduced number of sons for exposed fathers are mixed. James (2006) has interpreted perturbation of sex ratios by dioxins and other agents as being an indicator of parental endocrine disruption. If James’ hypothesis were demonstrated to hold, it would be concordant with observing a reduction in testosterone levels among exposed men. Another pathway to an altered sex ratio might involve male embryos experiencing more lethality with induction of mutations due to their unmatched X chromosome. A genotoxic mechanism has not been expected to apply to TCDD, but gender-specific adverse consequences of modified imprinting of gametes might be a possible mechanism leading to observation of altered sex ratios at birth.

There has been no work with experimental animals that specifically examines the effects of TCDD on sex ratios of offspring, nor have any alterations in sex ratio been reported in animal studies that examined developmental effects of TCDD on offspring.

Synthesis

Reproduction is a sensitive toxic endpoint of TCDD and dioxin-like compounds (DLCs) in rodents. It is clear that the fetal rodent is more sensitive to adverse effects of TCDD than the adult rodent. 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 notes that the evidence that TCDD exposure reduces serum testosterone in men is consistent across several epidemiologic studies with appropriate consideration of confounders, including one of Vietnam veterans, shows a dose–response relationship and is biologically plausible based on concomitant increases observed in gonadotropins and biologic plausibility from animal studies. Human populations showing evidence of reduced testosterone with exposure to dioxin-like chemicals include a general population sample (Dhooge et al., 2006),

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

occupationally exposed individuals (Egeland et al., 1994), and Vietnam veterans studies in the AFHS (Gupta et al., 2006). The evidence that dioxin-like chemicals may modify the sex ratio lends credence to the hypothesis that these chemicals do have an impact on male reproductive functioning.

Despite the relative consistency of the findings of a reduction in testosterone level, the testosterone levels observed even in the highest exposed 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 physiological mechanisms coming into play. The occupational study of Egeland et al. (1994) found elevated gonadotropins in addition to reduced testosterone. The gonadotropins stimulate the production of testosterone in men.

The first published study to examine dioxin exposure in women and association with TTP and infertility was reviewed in this update. A dose–response relationship with increasing TCDD exposure and increased TTP and infertility was observed, which is consistent with published observations in the rat model. However, given that this is the first study to observe these associations in women, the continued review of the epidemiology literature will be needed to more fully assess any relationship between dioxin exposure and female-mediated infertility.

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 compounds of interest and decreased sperm counts or sperm quality, subfertility, or infertility.

SPONTANEOUS ABORTION

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 7–15% (Hertz-Picciotto and Samuels, 1988), but it is established that many more pregnancies terminate before women become aware of them (Wilcox et al., 1988); 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 loss of memory, particularly of spontaneous abortions that took place 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

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

pregnancy. Enrollment of women before pregnancy provides the theoretically most valid estimate of risk, but it can attract nonrepresentative study groups because the study protocols are demanding for the women.

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. 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 to TCDD specifically to conclude that there was suggestive evidence that paternal exposure to TCDD is not associated with 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 of higher). Indications of positive association were seen in studies of Vietnam veterans (CDC, 1989a,b; Field and Kerr, 1988; Stellman et al., 1988), but the committee for Update 2002 asserted that they might be due to 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, and Update 2008 did not change that conclusion. The relevant studies are reviewed in the earlier reports. Table 8-5 summarizes their findings.

Update of the Epidemiologic Literature

No studies of exposure to the chemicals of interest and spontaneous abortion have been published since Update 2008.

Biologic Plausibility

Laboratory animal studies have demonstrated that TCDD exposure during pregnancy can alter concentrations of circulating steroid hormones and disrupt placental development and function and thus contribute to a reduction in survival of implanted embryos and to fetal death (Ishimura et al., 2009). There is

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-5 Selected Epidemiologic Studies—Spontaneous Abortiona


Reference Study Population Exposed Casesb Exposure of Interest/Estimated Risk(95% CI)b

VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
Wolfe et al., 1995 Air Force Ranch Hand veterans
Background
Low exposure
High exposure
157
57
56
44
 
1.1 (0.8-1.5)
1.3 (1.0-1.7)
1.0 (0.7-1.3)
US CDC Cohort of Army Chemical Corps All COIs
CDC, 1989a Vietnam Experience Study    
  Overall 1,566 1.3 (1.2-1.4)
  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
Kang et al., 2000 Female Vietnam-era veterans (maternal exposure)   1.0 (0.82-1.21)
  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
Schwartz, 1998 Female Vietnam veterans (maternal exposure)    
  Women who served in Vietnam 113 nr
  Women who did not serve in the war zone 124 nr
  Civilian women 86 nr
American Legion Cohort All COIs
Stellman et al., 1988 American Legionnaires with service 1961-1975
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 9 1.6 (0.7-3.3)
  Vietnam veterans    
  Low exposure 72 1.0
  Medium exposure 53 1.2 (0.8-1.7)
  High exposure 58 1.4 (0.9-1.9)
State Studies of US Vietnam Veterans (wives) All COIs
Aschengrau and Monson, 1989 Wives of Vietnam veterans presenting at Boston
Hospital for Women
27 weeks of gestation
13 weeks of gestation
 

10
nr
 

0.9 (0.4-1.9)
1.2 (0.6-2.8)
Tasmanian Veterans with Service in Vietnam All COIs
Field and Kerr, 1988 Follow-up of Australian Vietnam veterans 199 1.6 (1.3-2.0)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/Estimated Risk(95% CI)b

OCCUPATIONAL
NIOSH Cohorl (12 US plants, production 1942-1984) (included in IARC cohort) Dioxin, phenoxy herbicides
Schnorr et al., 2001 Wives and partners of men in NIOSH cohort
Estimated paternal TCDD scrum 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 Chemical Company—Midland, MI (included in IARC and NIOSH cohorts) Dioxin, 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)
Other Production Workers Dioxin, phenoxy herbicides
Moses et al., 1984 Follow-up of 2,4,5-T production workers 14 0.9 (0.4-1.8)
Sukind and Henzberg, 1984 Follow-up of 2,4,5-T production workers 69 0.9 (0.6-1.2)
Agricultural Exposures Herbicides
Carmelli et al., 1981 Wives of men occupationally exposed to 2,4-D    
  All reported work exposure to herbicides (high and medium) 63 0.8 (0.6-1.1)c
  Farm exposure 32 0.7 (0.4-1.5)c
  Forest and commercial exposure 31 0.9 (0.6-1.4)c
  Exposure during conception period    
  Farm exposure 15 1.0 (0.5-1.8)c
  Forest and commercial exposure 16 1.6 (0.9-1.8)c
  Fathers 18-25 yrs of age    
  Farm exposure 1 0.7 (nr)
  Forest and commercial exposure 3 4.3 (nr)
  Fathers 26-30 yrs of age    
  Farm exposure 4 0.4 (nr)
  Forest and commercial exposure 8 1.6 (nr)
  Fathers 31-35 yrs of age    
  Farm exposure 10 2.9 (nr)
  Forest and commercial exposure 5 1.0 (nr)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Smith et al., 1982 Follow-up of 2,4,5-T sprayers vs nonsprayers 43 0.9 (0.6-1.3)c
US Forest Service Herbicides
Driscoll et al., 1998 Women employed by US Forest Service—miscarriages (maternal exposure) 141 2.0 (1.1-3.5)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/Estimated Risk(95% CI)b

ENVIRONMENTAL
Seveso Women’s Health Study TCDD
Eskenazi et al., 2003 SWHS participants living in exposure Zones A, B in 1976 (maternal exposure)    
  Pregnancies 1976-1998 97 0.8 (0.6-1.2)
  Pregnancies 1976-1984 44 1.0 (0.6-1.6)
Other Environmental Studies
Tsukimori et al., 2008 Spontaneous abortions among pregnancies (excluding induced abortions) of women in 1968 Yusho incident (maternal exposure)   PCBs, PCDFs
  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)
Chao et al., 2007 Pregnant Taiwanese women, placental TEQ of dioxins, PCBs (maternal exposure)   Dioxin, PCBs/
nr, but reported ns
Arbuckle et al., 2001 Ontario farm families (maternal and paternal exposure)   Phenoxy herbicides
  Phenoxyacetic acid herbicide exposure in preconception period, spontaneous-abortion risk 48 1.5 (1.1-2.1)
Revich et al., 2001 Residents of Samara Region, Russia (maternal and paternal exposure)   TCDD
  Chapaevsk nr 24.4% (20.0-29.5%)d
  Samara nr 15.2% (14.3-16.1%)d
  Toliatti nr 10.6% (9.8-11.5%)d
  Syzran nr 15.6% (13.4-18.1%)d
  Novokuibyshevsk nr 16.9% (14.0-20.3%)d
  Other small towns nr 11.3% (9.4-13.8%)d
Tuyet and Johansson, 2001 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

ABBREVIATIONS: 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; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant (usually refers to p < 0.05); PCB, polychlorinated biphenyl; PCDF, polychlorinated dibenzofuran; PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; 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.

c90% CI.

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

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Synthesis

No new epidemiologic evidence concerning the chemicals of interest and spontaneous abortion have been published since Update 2008, and toxicologic studies do not provide clear evidence of biologic plausibility of an association between these chemicals and spontaneous abortion. Furthermore, given the ages of the Vietnam-veteran cohort, publication of additional information on this outcome in the target population of the VAO series is not likely.

Conclusions

On the basis of the evidence reviewed to date, the committee concludes 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.

STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Stillbirth or late fetal death typically refers to the delivery at or after 20 weeks of gestation of a fetus that shows no signs of life, including fetuses that weigh more than 500 g regardless of gestational age (Kline et al., 1989). Neonatal death refers to the death of a liveborn infant within 28 days of birth, and infant death to a death that occurs before the first birthday.

Because the causes of stillbirth and early neonatal death overlap considerably, they are commonly analyzed together in a category referred to as perinatal mortality (Kallen, 1988). Stillbirths make up less than 1% of all births (CDC, 2000). The most common causes of perinatal mortality (Kallen, 1988) in low-birth-weight (500–2,500 g) liveborn and stillborn infants are placental and delivery complications—abruptio placenta, placenta previa, malpresentation, and umbilical-cord conditions. The most common causes of perinatal death of infants weighing more than 2,500 g at birth are complications of the cord, placenta, and membranes and congenital malformations (Kallen, 1988).

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and stillbirth, neonatal death, or infant death. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Reviews of the relevant studies are presented in the earlier reports.

Update of the Epidemiologic Literature

One study published since Update 2008 examined pesticide use and infant death in Brazil (Teixeira de Siqueira et al., 2010). However, given that the study defined exposure at the ecologic level (as pesticide-use intensity in agricultural-crop areas) and did not examine specific pesticides separately, it did not meet the level of exposure specificity required for review by the committee. No additional studies of exposure to the chemicals of interest and perinatal death have been published since Update 2008.

Biologic Plausibility

Laboratory studies of maternal TCDD exposure during pregnancy have demonstrated the induction of fetal death; neonatal death, however, is only rarely observed and is usually the result of cleft palate, which leads to an inability to nurse. Studies addressing the potential for perinatal death as a result of paternal exposure to TCDD or herbicides are inadequate to support conclusions. One new study demonstrated that TCDD alters vascular remodeling of the placenta in rats leading to an increase in the incidence of fetal death under hypoxic conditions (Ishimura et al., 2009).

Synthesis

No new epidemiologic evidence concerning exposure to the chemicals of interest and stillbirth, neonatal death, and infant death have been published since Update 2008, and toxicologic studies do not provide clear evidence of biologic plausibility of an association.

Conclusions

On the basis of the evidence reviewed in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

whether there is an association between exposure to the chemicals of interest and stillbirth, neonatal death, or infant death. Given the ages of the Vietnam-veteran cohort, publication of additional information on this outcome in the target population of the VAO series is highly unlikely.

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 subsequent health over the life-span. Defined by the World Health Organization as birth weights under 2,500 g (Alberman, 1984), low birth weight has two distinct causes. Intrauterine growth retardation (IUGR) occurs when fetal growth is diminished and a fetus or baby fails to attain a normal weight or is small for gestational age. The concept of IUGR represents birth weight, adjusted for gestational age, that is lower than average according to local or national fetal-growth graphs (Romo et al., 2009). Low birth weight can also be secondary to preterm delivery (PTD), which is delivery at less than 259 days, or 37 completed weeks, of gestation, calculated on the basis of the date of the first day of the last menstrual period (Bryce, 1991). Low birth weight of either causes occurs in about 7% of live births. When no distinction is made between the causes of low birth weight (IUGR or PTD), the factors most strongly associated with it are maternal tobacco use during pregnancy, multiple births, and race or ethnicity. Other potential risk factors are low socioeconomic status (SES), 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; Kallen, 1988; Peltier, 2003). Established risk factors for PTD include race (black), marital status (single), low SES, previous low birth weight or PTD, multiple gestations, tobacco use, and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993).

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 chemicals of interest and low birth weight or PTD. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Reviews of the relevant studies are presented in the earlier reports.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Update of the Epidemiologic Literature

No occupational or Vietnam-veteran studies of exposure to the chemicals of interest and low birth weight or PTD have been published since Update 2008.

Environmental Studies

Two studies in Japan examined prenatal exposure to dioxin-like PCDDs, PCDFs, and PCBs, calculated as total TEQs, and birth weight. In a prospective cohort study of 514 women in Sapporo, Japan (Konishi et al., 2009), a significant reduction in birth weight was observed in connection with total TEQs (–220.5 g per 10-fold increase in TEQ; 95% CI –399.2 to –41.9). A significant reduction in birth weight was also observed in connection separately with dioxin-like PCDD TEQs and PCDF TEQs and marginally with PCB TEQs. When stratified on infant sex, the association remained statistically significant for male but not female infants. The second study, in a coastal area of Japan (where consumption of seafood is common), measured dioxin-like PCDD and PCDF congeners in maternal breast milk and markers of fetal growth (Tawara et al., 2009). The concentration of several individual dioxin-like PCDD and PCDF congeners was inversely related to newborn length as was total TEQs, but none was related to birth weight. In the Danish National Birth Cohort (Halldorsson et al., 2009), 100 women were enrolled in a nested study on the basis of their reported intake of fatty fish; about one-third of the women were in each of three fish-intake categories (high, medium, and low). Total TEQs were calculated from serum samples analyzed with the AhR-CALUX assay. No association with birth weight was observed.

One study published since Update 2008 examined pesticide use and birth weight in Brazil (Teixeira de Siqueira et al., 2010). However, given that the study defined exposure at the ecologic level (as pesticide-use intensity in agricultural-crop areas) and did not examine specific pesticides separately, it did not meet the level of exposure specificity required for review by the committee.

Biologic Plausibility

The available experimental evidence on animals indicates that TCDD exposure during pregnancy can reduce body weight at birth but only at high doses. Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are inadequate to permit conclusions. TCDD and herbicides are known to cross the placenta, and this leads to 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.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Synthesis

The three environmental studies reviewed here did not provide evidence of an association between exposure to the chemicals of interest and the risk of low birth weight or prematurity.

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 chemicals of interest and low birth weight or preterm delivery.

BIRTH DEFECTS

The March of Dimes defines a birth defect as an abnormality of structure, function, or metabolism, whether genetically determined or resulting from an environmental influence during embryonic or fetal life (Bloom, 1981). Other terms, often used interchangeably, are congenital anomaly and congenital malformation. Major birth defects, which occur in 2–3% of live births, are abnormalities that are present at birth and are severe enough to interfere with viability or physical well-being. Birth defects are detected in another 5% of babies through the first year of life. The causes of most birth defects are unknown. Genetic factors, exposure to some medications, exposure to environmental contaminants, occupational exposures, and lifestyle factors have been implicated in the etiology of birth defects (Kalter and Warkany, 1983). Most etiologic research has focused on the effects of maternal and fetal exposures, but some work has addressed paternal exposures. Paternally mediated exposures might occur by several routes and exert effects in various ways. One way is through direct genetic damage to the male germ cell transmitted to the offspring and dominantly expressed as a birth defect. A hypothesized route is the transfer of toxic chemicals through a man’s body into his seminal fluid that results in intermittent fetal exposure throughout gestation (Chia and Shi, 2002). Another, even more indirect route of paternally mediated exposure could be contact of family members with contamination brought into the home from the workplace, but this would not be applicable to offspring of Vietnam veterans conceived after deployment.

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 2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid and birth defects in offspring. Additional information available to the committee re-

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

sponsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association between at least one of the chemicals of interest and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. The committee for Update 2002, which reviewed the study of female Vietnam veterans (Kang et al., 2000) that reported significant increases in birth defects in their offspring, did not find those results adequate to modify prior conclusions. Later VAO committees have not encountered additional data to merit changing the conclusion that the evidence is inadequate to support an association between exposure to the chemicals of interest and birth defects (aside from spina bifida) in the offspring of either male or female veterans.

Summaries of the results of studies of birth defects and specifically neural-tube defects that were reviewed in the current report and in earlier VAO reports are in Tables 8-6 and 8-7, respectively.

Update of the Epidemiologic Literature

No Vietnam-veteran or occupational studies of exposure to the chemicals of interest and birth defects have been published since Update 2008.

Environmental Studies

In a retrospective case–control study of births in Washington state, Waller et al. (2010) assessed agricultural exposure and season of conception possible association with gastroschisis, a defect in the abdominal wall usually near the umbilicus. The Washington State Department of Agriculture database was used to classify exposure to surface-water concentrations of atrazine, nitrates, nitrites, and 2,4-D by season. Residential proximity to areas of increased exposure to those chemicals was estimated by using the latitude and longitude of ZIP code for each maternal residence. Although an increased OR was observed for high atrazine exposure, this is not a chemical of interest to the committee; no associations with the remaining chemicals examined were observed.

Cordier et al. (2010) evaluated residence near municipal-waste incinerators and urinary tract birth defects. Infants born with renal defects in 2001–2003 were eligible for a population-based case–control study in southeastern France. Controls were randomly selected from the same region. The mothers of 187 of the located 304 case infants agreed to participate and completed interviews. With stratification on the infant’s sex, year of birth, and family address at birth, 226 mothers of qualifying controls were identified, agreed to enroll, and completed telephone interviews. For each of the 21 incinerators in the region, emissions of dioxins were measured for the period of study; on the basis of residential proximity to the incinerators, exposure to emissions for the period from 1 month before conception to the end of the first trimester was modeled for all infants. Women were classified as exposed or not exposed, and the exposed were dichotomized

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-6 Selected Epidemiologic Studies—Birth Defects in Offspring of Subjectsa

Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans
All COIs
Michalek et al., 1998a Air Force Ranch Hand veterans
Before service in SEA nr 0.7 (nr)
After service in SEA nr 1.5 (nr)
Wolfe et al., 1995 High-exposure Ranch Hands relative to comparisons
All anomalies 57 1.0(0.8-1.3)
Nervous system 3 nr
Eye 3 1.6(0.4-6.0)
Ear, face, neck 5 1.7(0.6-4.7)
Circulatory system, heart 4 0.9 (0.3-2.7)
Respiratory system 2 nr
Digestive system 5 0.8 (0.3-2.0)
Genital system 6 1.2 (0.5-3.0)
Urinary system 7 2.1 (0.8-5.4)
Musculoskeletal 31 0.9(0.6-1.2)
Skin 3 0.5(0.2-1.7)
Chromosomal anomalies 1 nr
AMIS, 1992 Air Force Operation Ranch Hand veterans—birth defects in conceptions after service in SEA
Congenital anomalies 229 1.3(1.1-1.6)
Nervous system 5 1.9(0.5-7.2)
Respiratory system 5 2.6(0.6-10.7)
Circulatory system, heart 19 1.4(0.7-2.6)
Urinary system 21 2.5(1.3-5.0)
Chromosomal 6 1.8(0.6-6.1)
Other 5 2.6(0.6-10.7)
US CDC Vietnam Experience Study All COIs
CDC, 1989a Vietnam Experience Study—interview data
Total anomalies 826 1.3(1.2-1.4)
Nervous system defects 33 2.3(1.2-4.5)
Ear, face, neck defects 37 1.6(0.9-2.8)
Integument 41 2.2(1.2-4.0)
Musculoskeletal defects 426 1.2(1.1-1.5)
Hydrocephalus 11 5.1 (1.1-23.1)
Spina bifida 9 1.7(0.6-5.0)
Hypospadias 10 3.1 (0.9-11.3)
Multiple defects 71 1.6(1.1-2.5)
Children of veterans reporting high exposure 46 1.7(1.2-2.4)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
US VA Cohort of Female Vietnam Veterans All COIs
Kang et al., 2000 Female Vietnam-era veterans—deployed vs nondeployed (maternal exposure)
“Likely” birth defects nr 1.7(1.2-2.2)
“Moderale-to-severe” birth defects nr 1.5(1.1-2.0)
CDC—General Birth Defects Study All COIs
CDC, 1989b GBDS—hospital records
Birth defects 130 1.0(0.8-1.3)
Major birth defects 51 1.2(0.8-1.9)
Digestive system defects 18 2.0 (0.9-4.6)
Birth defects—black Vietnam veterans only 21 3.4(1.5-7.6)
CDC—Metropolitan Atlanta Congenital Defects Program All COIs
Erikson et al., 1984a Vietnam veterans identified through CDC
Metropolitan Atlanta Congenital Defects Program
Any major birth defects 428 1.0(0.8-1.1)
Multiple birth defects with reported exposure 25 1.1 (0.7-1.7)
EOI-5: spina bifida 1 2.7(1.2-6.2)
EOI-5: cleft lip with or without cleft palate 5 2.2(1.0-4.9)
State Studies of US Vietnam Veterans All COIs
Aschengrau and Monson, 1990 Vietnam veterans whose children were borm at Boston Hospital for Women All congenital anomalies (crude OR)
vs men without known military service 55 1.3(0.9-1.9)
vs non-Vietnam veterans 55 1.2(0.8-1.9)
One or more major malformations (crude OR)
vs men without known military service 18 1.8(1.0-3.1)
vs non-Vietnam veterans 18 1.3(0.7-2.4)
Australian Vietnam Veterans vs Australian Population All COIs
AIHW, 1999 Australian Vietnam veterans—validation study Cases expected (95% CI)
Down syndrome 67 92 expected (73-111)
Tracheo-esophageal fistula 10 23 expected (14-32)
Anencephaly 13 16 expected (8-24)
Cleft lip or palate 94 64 expected (48-80)
Absent external body part 22 34 expected (23-45)
Extra body part 74 74 expected (nr)
Donovan el al., 1984 Australian Vietnam veterans
Vietnam veterans vs all other men 127 1.0(0.8-1.3)
National Service veterans—Vietnam 69 1.3(0.9-2.0)
service vs no Vietnam service
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
OCCUPATIONAL
NIOSH Cohort (12 US plants, production 1942-1984)
(included in IARC cohort)
Dioxin, phenoxy herbicides
Lawson et al., 2004 Wives of workers with measured serum TCDD in NIOSH cohort 14 nr
Dow Chemical Company—Midland, MI (included in IARC and NIOSH cohorts) Dioxin, phenoxy herbicides
Townsend et al., 1982 Follow-up of Dow Chemical plant workers 30 0.9(0.5-1.4)
Production Workers Dioxin, phenoxy herbicides
Moses el al., 1984 Follow-up of 2.4,5-T male production workers 11 1.3 (0.5-3.4)
Suskind and Hertzberg. 1984 Follow-up of 2,4,5-T male production workers 18 1.1 (0.5-2.2)
Herbicide and Pesticide Applicators Herbicides
Smith et al., Follow-up of 2,4,5-T sprayers—sprayers vs 13 90% CI
1982 non-sprayers 1.2(0.6-2.5)
Agricultural Workers Herbicides
Weselak et al.,2008 Pregnancies with one or more birth defects in OFFHS 108
Use on farm, during 3 months before conception, of:
Herbicides 24 0.7(0.4-1.1)
Male offspring 19 0.9(0.5-1.6)
Direct paternal use 19 0.5(0.3-1.0)
Phcnoxy herbicides 12 0.6(0.3-1.1)
Male offspring 9 0.8(0.4-1.7)
Direct paternal use 8 0.4 (0.2-0.9)
2,4-D 10 1.1 (0.6-2.1)
Male offspring 7 1.3(0.6-2.8)
Direct paternal use 6 0.6(0.3-1.5)
Dicamba 8 1.7(0.8-3.5)
Male offspring 7 2.4(1.1-5.5)
Use on farm, during 3 months after
conception, of:
Herbicides 7 0.5 (0.2-1.2)
Phenoxy herbicides 9 0.8(0.4-1.5)
2,4-D 7 1.0(0.4-2.3)
Kristensen et al., 1997 Norwegian farmers (maternal, paternal exposure) 4,189 1.0(1.0-1.1)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Ganyelal., 1996 Private pesticide appliers
All births with anomalies 125 1.4(1.2-1.7)
Circulatory, respiratory 17 1.7(1.0-2.8)
Gastrointestinal 6 1.7(0.8-3.8)
Urogenital 20 1.7(1.1-2.6)
Musculoskeletal, integumental 30
Maternal age under 30 yrs 19 0.9(0.5-1.7)
Maternal age over 30 yrs 19 2.5(1.6-4.0)
Chromosomal 8 1.1 (0.5-2.1)
Other 48
Maternal age under 35 yrs 36 1.1 (0.8-1.6)
Maternal age over 35 yrs 12 3.0(1.6-5.3)
Forestry Workers Herbicides
Dimich-Ward Sawmill workers with exposure in upper
et al., 1996 three quartiles for any job held up to 3 months before conception
Cataracts 11 5.7(1.4-22.6)
Genital organs 105 1.3(0.9-1.5)
ENVIRONMENTAL
Seveso, Italy Residential Cohort
TCDD
Mastroiacovo et al., 1988 Seveso residents (maternal, paternal, in utero exposure) 90% CI
Zones A, B, R—total defects 137 1.0(0.8-1.1)
Zones A and B—total defects 27 1.2(0.9-1.6)
Zones A and B—mild defects 14 1.4(0.9-2.2)
US Environmental Studies
Meyer et al., 2006 Case-control study in eastern Arkansas of hypospadias as function of mother's residence within 500 m of agricultural pesticide use during gestation weeks 6-16 Dicamba (lb) Dicamba
0 nr 1.0
>0-<0.04 nr 0.5(0.3-1.0)
≥0.04 nr 0.9(0.4-2.1)
Schreinemachers, 2003 Rural or farm residents of Minnesota, Montana, North Dakota, South Dakota (maternal, paternal exposure) Herbicides
Any birth anomaly 213 I.I (0.9-1.3)
Central nervous system anomalies 12 0.8(0.5-1.4)
Circulatory, respiratory anomalies 39 1.7(1.1-2.6)
Digestive system anomalies 24 0.9(0.6-1.5)
Urogenital anomalies 44 1.0(0.7-1.5)
Musculoskeletal, integumental anomalies 70 1-5(1.1-2.1)
Chromosomal anomalies 17 0.9(0.6-1.6)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Loffredo et al., 2001 Mothers in the BWIS exposed to herbicides during first trimester (maternal exposure) 8 Herbicides
2.8 (1.2-6.9)
Fitzgerald et al., 1989 Persons exposed to an electric-transformer fire—total birth defects (maternal, paternal exposure) 1 Chlorophenols
2.1 (0.1-11.9)
Stockbauer et al., 1988 Persons in Missouri with documented TCDD soil contamination near residence (maternal, paternal, in utero exposure)   TCDD
  Total birth defects 17 0.8 (0.4-1.5)
  Major defects 15 0.8 (0.4-1.7)
  Midline defects 4 0.7 (0.2-2.3)
French Studies of Birth Defects Registry in Rhône-Alpes Region Dioxin
Cordier et al., 2010 Case-control study (2001-2003 births) of urinary tract defects (n = 304) vs regional controls (n = 226)    
  Maternal exposure to:    
  Atmospheric dioxin 63 2.0 (1.2–3.4)
  Above median 33 2.8 (1.3–6.1)
  Below median 30 1.4 (0.7–2.9)
  Dioxin deposits 75 1.8 (1.1–3.0)
  Above median 41 3.0 (1.5–5.9)
  Below median 34 1.2 (0.6–2.2).
Cordier et al., 2004 Births (1988–1997): maternal residence in municipality with solid-waste incinerator vs not    
  Minor anomalies 518 0.9 (0.8–1.1)
  Chromosomal anomalies 204 1.0 (0.9–1.2)
  Monogenic anomalies 83 1.1 (0.8-1.4)
  Unknown or multifactoral etiology 964 1.1 (1.0–1.2)
  Specific major anomalies with significant increases reported (of 23 categories reported)    
  Facial clefts 152 1.3 (1.1–1.6)
  Renal dysplasia 60 1.6 (1.1–2.2)
Other International Environmental Studies
Kuscu et al., 2009 Cross-sectional study of MIH in Turkey; n = 109 from industrialized community with high levels of PCDDs and n = 44 from low industrialized community   PCDDs
Prevalence of MIH 4/44 and 10/109, no difference
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Population Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Lai si cl al.. 2008 Follow-up of participants from previous PCDDs, PCDFs
case—control study of cleft lip and palate, n 24/167 with MIH
= 167 placenta tissue analyzed for PCDD/ TFQ of PCDDs not
Fs and children assessed for Mill association with Mill; duration of breast feeding not association with Mill
Tango cl al.. Investigated multiple pregnancy outcomes Dioxin
2004 in Japan-infant deaths from congenital defects 42 nr, but ns
Rcvich cl al.. Residents of Chapacvsk. Russia— Dioxin
2001 congenital malformations nr nr, but ns
ten Tusschcr Infants bom in Zccburg, Amsterdam, clinics Dioxin
et al.. 2000 1963-1965 with orofacial cleft (maternal exposure)
Binds in 1963 5 nr, but said to be significant
Binds in 1964 7 nr, but said to be significant Herbicides
Garcia cl al.. Residents of agricultural areas in Spain—at 14 3.1 (0.6-16.9)
1998 least median score on chlorophcnoxy-herbicide exposure duration (months) index
Hanify cl al., Residents of areas of northland New 2,4,5-T
1981 Zealand subject to aerial 2,4.5-T spraying 90% Cl
All birth malformations excluding 164 1.7(1.4-2.1)
dislocated or dislocatablc hip
All heart malformations 20 3.9(2.1-7.4)
Hypospadias, epispadias 18 5.6(2.7-11.7)
Talipes 52 1.7(1.2-2.3)
Cleft lip 6 0.6(0.3-1.3)
Isolated cleft palate 7 1.4(0.6-3.2)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BWIS, Baltimore–Washington Infant Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, exposure opportunity index; GBDS, General Birth Defects Study; IARC, International Agency for Research on Cancer; MI, Michigan; MIH, molar incisor hypomineralization; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OFFHS, Ontario Farm Family Health Study; OR, odds ratio; PCDD, polychlorinated dibenzodioxins; PCDF, polychlorinated dibenzofurans; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

aUnless otherwise indicated, studies show paternal exposure.

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

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-7 Selected Epidemiologic Studies—Neural-Tube Defects in Offspring of Subjectsa


Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

VIETNAM VETERANS
US Air Firce Health Study—Ranch Hand veterans vs SEA veterans All COIs
Wolfe et al., 1995 Air Force Operation Ranch Hand personnel—neural-tube defects 4c nr
US CDC Vietnam Experience Study All COIs
CDC, 1989a VES cohortSpina bifida    
  Vietnam veterans’ children 9 1.7 (0.6-5.0)
  Non-Vietnam veterans’ children 5 1.0
  Anencephaly    
  Vietnam Veterans’ children 3 nr
  Non-Vietnam veterans’ children 0 1.0
US CDC Birth Defects Study All COIs
Erickson et al., 1984a,b CDC birth defects case-control studyService in Vietnam    
  Spina bifida 19 1.1 (0.6-1.7)
  Anencephaly 12 0.9 (0.5-1.7)
  Military records indicate opportunity for exposure    
  Spina bifida 20 2.7 (1.2-6.2)
  Anencephaly 7 0.7 (0.2-2.8)
Australian Vietnam Veterans vs Australian Population All COIs
AIHW, 1999     Cases expected (95% CI)
  Australian Vietnam veterans—validation study    
  Spina bifida—maximums 50 33 expected (22-44)
  Anencephaly 13 16 expected (8-24)
ADVA, 1983 Australian Vietnam veterans—neural-tube defects 16 0.9 (nr)
OCCUPATIONAL
Agricultural Workers    
Blatter et al., 1997 Dutch farmersSpina bifida—moderate, heavy exposure    
  Pesticide use 8 1.7 (0.7-4.0)
  Herbicide use 7 1.6 (0.6-4.0)d
Kristensen et al., 1997 Norwegian farmers—spina bifida (maternal, paternal exposure)    
  Tractor spraying equipment 28 1.6 (0.9-2.7)
  Tractor spraying equipment, orchards, greenhousese 5 2.8 (1.1-7.1)
Pesticide Applicators Pesticides
Garry et al., 1996 Private pesticide appliers—central nervous system defects 6 1.1 (0.5-2.4)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

Forestry Workers Herbicides
Dimich- Sawmill workers with exposure in upper three
Ward cl al.. quartiles for any job held up to 3 months before
1996 conception
Spina bifida, anencephaly 22 2.4(1.1-5.3)
Spina bifida only 18 1.8(0.8-4.1)
ENVIRONMENTAL
US Environmental Studies TCDD
Stockbaucr Persons in Missouri with documented TCDD 3 3.0 (0.3-35.9)
ct al.. 1988 soil contamination—central nervous system
defects (maternal, paternal, in utcro exposure)
Internationa] Environmental Studies
Cordicr Population-based birth defects registry in Dioxin
ct al.. 2004 Rhonc-Alpcs region of France (1988-1997):
Residence in municipality with solid-waste
incinerator (maternal, paternal exposure) vs not
near—neural tube defects
49 0.9 (0.6-1.2)
Hanify Spraying of 2,4,5-T in New Zealand (all
ctal.. I98I exposures) 2,4,5-T/90% CI
Anenccphaly 10 1.4(0.7-2.9)
Spina bifida 13 1.1 (0.6-2.1)

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; nr, not reported; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VES, Vietnam Experience Study.

aUnless otherwise indicated, studies show paternal exposure.

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

cOf four neural-tube defects reported in Ranch Hand offspring, two were spina bifida (high dioxin exposure), one spina bifida (low dioxin), one anencephaly (low dioxin); no neural-tube defects reported in comparison cohort; 454 postservice births studied in Ranch Hand veterans; 570 in comparison cohort.

dCalculated from data presented in the paper.

eGreenhouse workers would not have been exposed to chemicals of interest.

at the median exposure: 3.8 × 10–3 pg/m3 for atmospheric dioxins and 1.7 × 10–5 pg/m2-s for soil deposits of dioxins. The presence of additional industries (such as the cement industry) with potential dioxin emissions was also considered in the analyses. If there was at least one additional industry in the municipality of the study participant, the participant was considered potentially exposed to other sources of dioxin. Pollutant concentrations more than 10 km away were considered negligible, and such residences were considered not exposed. The procedures for recruitment were not identical, but the response rates did differ by case status, with 62% of eligible cases and more than 85% of eligible controls

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

participating. Residential addresses were available for the nonparticipating cases but not for the noninterviewed controls; the primary results reported contrasted all 304 located cases, whether or not the mother had been interviewed, with the interviewed control subjects. A higher incidence of urinary tract birth defects was observed in infants of mothers who were exposed to atmospheric dioxin above median concentrations than in infants of women who had no exposure (OR = 2.84, 95% CI 1.32–6.09). A smaller risk was observed for infants of women classified as exposed below the median but not unexposed (OR = 1.44, 95% CI 0.72–2.87). Atmospheric dioxin levels and dioxin soil deposits were highly correlated across the study area (p < 0.0001), so the largely parallel results for exposure to dioxin soil deposits (for which some results excluding the noninter-viewed case mothers were reported) cannot be considered independent. Proximity to dioxin deposits above the median was also associated with the outcome (OR = 2.95, 95% CI 1.47–5.92; OR = 2.25, 95% CI 1.04–4.87, without noninterviewed cases; OR 2.05, 95% CI 0.92–4.57, with adjustment for geographical origin of parents, family history of urinary tract birth defects, parity, and maternal alcohol consumption), but exposure to deposits below the median was only marginally associated with urinary tract defects (OR = 1.18, 95% CI 0.63–2.19). A similar diminution in significance was said to occur in the analyses of exposure to atmospheric dioxins when only the interviewed case mothers were included and when confounders were considered. Other sources of dioxin emissions were not associated with urinary tract defects. A higher proportion of the noninterviewed case mothers were exposed to atmospheric and dioxin deposits than of those who were interviewed, and they were more likely to live in low-SES areas. It is possible, but not known, that the nonparticipating cases differed in the distribution of additional key confounding variables. If the proportion of exposed controls remained the same, then excluding the noninterviewed cases would have resulted in an underestimate of effect. However, the disparity in participation rates between cases and controls suggests the potential for selection bias, which may explain some of the observed excess risk.

Two studies examined dioxin exposure and molar-incisor hypomineralization (MIH) in children, the enamel hypomineralization of the molars. Kuscu et al. (2009) assessed the prevalence of MIH in children living in two regions in Turkey, one with dense industrialization and the other an agricultural area known for its use of organic techniques and its use of wind farms for energy. Soil PCDD and PCDF concentrations were higher in the urbanized region, but there was no difference in MIH prevalence between the two regions. Laisi et al. (2008) conducted a case–control study of children born in 1995–1999 in Finland. Placenta samples were collected and analyzed for PCDDs, PCDFs, and PCBs. Total exposure to PCDDs and PCDFs and total PCBs was not associated with MIH.

Five other studies of birth defects did not meet the level of exposure specificity required for review by the committee. One study examined pesticide use at the state level and all congenital abnormalities combined (Teixeira de Siqueira

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

et al., 2010). A second examined maternal exposure to pesticides and neural-tube defects in Mexican Americans (Brender et al., 2010). A third examined parental occupational exposure in agriculture (not the application of pesticides of interest) and oral clefts (Gonzalez et al., 2008), and a fourth evaluated birth defects in pregnancies conceived during months of high surface-water agrichemical concentration (Winchester et al., 2009). Exposure assessments in those studies did not specify individual herbicides and therefore did not present results on the chemicals of interest to the committee. In the fifth study, Giordano et al. (2010) examined hypospadias and maternal exposure to endocrine-disrupting chemicals as defined by parental job title and maternal diet, but the chemicals of interest to this committee were not assessed individually.

Biologic Plausibility

Studies indicate that 2,4-D does not produce fetal abnormalities. Other herbicides of interest can induce fetal malformations but typically only at high doses that are toxic to pregnant women. It is well established that TCDD is a potent teratogen in all laboratory species that have been studied although the pattern of birth defects that are produced is often species-specific. Since Update 2008, studies have investigated the mechanism underlying various TCDD- induced birth defects in mice, including hydronephrosis, cleft palate, altered jaw structure, and delayed lung development (Dong et al., 2010; Gan et al., 2009; Imura et al., 2010; Jang et al., 2008; Keller et al., 2008; Kransler et al., 2009). Those mechanisms have not been fully elucidated, but it has been demonstrated that TCDD-induced birth defects require the AHR but do not require induction of cytochrome P4501A1 (Dragin et al., 2006; Jang et al., 2007; Mimura et al., 1997). When pregnant AHR-null mice are exposed to TCDD, the fetuses do not exhibit any of the typical developmental malformations associated with TCDD exposure, but fetuses of TCDD-exposed pregnant CYP1A1 null mice do. In addition, an AHR antagonist can significantly attenuate TCDD-induced birth defects in mice. Thus, activation of the AHR by TCDD during development appears to be a key first step in mediating TCDD’s developmental toxicity. Although structural differences in the AHR have been identified among species, it functions similarly in animals and humans. Therefore, a common mechanism mediated by the AHR in which tissue growth and differentiation processes are affected probably underlies the developmental toxicity of TCDD in humans and animals. It has been shown that antioxidant treatment provides protection against some TCDD-induced teratogenicity; this suggests that reactive oxygen species might be involved in the pathways that lead to these structural changes (Jang et al., 2008). Few laboratory studies of potential male-mediated developmental toxicity (and birth defects specifically) attributable to exposure to TCDD and herbicides have been conducted. Feeding of simulated Agent Orange mixtures to male mice produced no adverse effects in offspring; a statistically significant excess of fused

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

sternebrae in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of this defect in the controls (Lamb et al., 1981).

Synthesis

Embryonic and fetal development is a sensitive toxic outcome of exposure to TCDD and dioxin-like chemicals in rodents. It is clear that the fetal rodent is more sensitive to adverse effects of TCDD than the adult rodent; human data are generally lacking, however, and the sensitivity of this outcome in humans is less apparent.

Overall, one study (Cordier et al., 2010) observed an association between dioxin exposure and urinary tract defects, but the influence of selection bias on the observed results could not be fully assessed. Therefore, the results of the study are insufficient to determine whether there is an association between maternal exposure to dioxin and urinary tract defects.

Conclusions

There were no new relevant studies of the association between parental exposure to 2,4-D, 2,4,5-T, TCDD, cacodylic acid, or picloram and spina bifida in offspring. The committee concludes that the evidence of an association between exposure to the chemicals of interest and spina bifida is still limited or suggestive. The evidence of an association between exposure to the chemicals of interest and other birth defects is inadequate or insufficient.

CHILDHOOD CANCER

The American Cancer Society estimated that 10,700 children under 15 years old would receive a diagnosis of cancer in the United States in 2010 (ACS, 2010). Treatment and supportive care of children with cancer have improved greatly, and mortality has declined by 55% over the past 35 years. Despite those advances, cancer remains the leading cause of death from disease in children under 15 years old, and 1,340 deaths were projected for 2010 (ACS, 2010).

Leukemia is the most common cancer in children. It accounts for about one-third of all childhood cancer cases; leukemia was expected to be diagnosed in nearly 3,317 children in 2010 (ACS, 2010). Of those, nearly 2,000 will have acute lymphocytic leukemia (ALL); most of the rest will have acute myeloid leukemia (AML). AML (ICD-9 205) is also referred to as acute myelogenous leukemia or acute nonlymphocytic leukemia. For consistency, this report uses acute myeloid leukemia, or AML, regardless of usage in the source materials. ALL is most common in early childhood, peaking at the ages of 2–3 years, and AML is most common during the first 2 years of life. ALL incidence is consistently higher in boys than in girls; AML incidence is similar in boys and girls (NCI, 2001). Through

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

early adulthood, ALL rates are about twice as high in whites as in blacks; AML exhibits no consistent pattern in this respect. Chapter 7 contains additional information on leukemia as part of the discussion of adult cancer.

The second-most common group of cancers in children are those of the central nervous system—the brain and the spinal cord. Other cancers in children include lymphomas, bone cancers, soft-tissue sarcomas, renal cancers, eye cancers, and adrenal gland cancers. In contrast with adult cancers, relatively little is known about the etiology of most childhood cancers, especially about potential environmental risk factors and the effects of parental exposures.

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 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion. The committee responsible for Update 2000 reviewed the material in earlier VAO reports and newly available published literature and concluded that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest and AML. After the release of Update 2000, investigators involved in one study discovered an error in their published data. The Update 2000 committee reconvened to evaluate the previously reviewed and new literature regarding AML, and it produced Acute Myelogenous Leukemia (IOM, 2002). It reclassified AML from “limited/suggestive evidence of an association” to “inadequate evidence to determine whether an association exists.” Table 8-8 summarizes the results of the relevant studies. The committees responsible for Update 2002, Update 2004, Update 2006, and Update 2008 reviewed the material in earlier VAO reports and in newly available published literature and agreed that there remained inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and childhood cancers.

Update of Epidemiologic Literature

No occupational or Vietnam-veteran studies of exposure to the chemicals of interest and childhood cancer have been published since Update 2008.

Environmental Studies

Two studies were published on the basis of information gathered in the Northern California Childhood Leukemia Study, a case–control study of acute lymphoblastic leukemia in 35 counties. Rull et al. (2009) examined 213 cases and 268 controls (matched on birth date, sex, race, and Hispanic ethnicity) for

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 8-8 Selected Epidemiologic Studies—Childhood Cancersa


Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

VIETNAM VETERANS US CDC Vietnam Experience Study All COIs
CDC, VES—outcomes in offspring of veterans
1989a Cancer 25 1.5(0.7-2.8)
Leukoma 12 1.6(0.6-4.0)
US CDC Birth Defects Study All COIs
Erikson et aL, 1984b Children of Vietnam veterans “Other” neoplasms 87 1.8 (1.0–3.3)
Australian Vietnam Veterans All COIs
A1HW,2001 Australian Vietnam veterans' children—revised validation study—AML 12c 1.3(0.8-4.0)
AIHW,2000 Australian Vietnam veterans' children—revised validation study—AML
This study, which incorrectly calculated expected number of AML cases, is updated by AIHW, 2001 above.
Tasmanian Male Veterans with Service in Vietnam All COIs
Field and Kerr, 1988 Cancer in children of Australian Vietnam veterans 4 nr
Other Studies of Vietnam Veterans All COIs
Wen et al., 2000 Case–control study of children’s leukemia AML, ALL
Father ever served in Vietnam, Cambodia 117 1.2(0.9-1.6)
<1 yr in Vietnam or Cambodia 61 1.4(0.9-2.0)
> 1 yr in Vietnam or Cambodia 44 1.2(0.8-1.7)
AML only
Father ever served in Vietnam, Cambodia 40 1.7 (1.0-2.9)
< 1 yr in Vietnam, Cambodia 13 2.4(1.1-5.4)
> 1 yr in Vietnam, Cambodia 16 1.5(0.7-3.2)
OCCUPATIONAL Agricultural Health Study Herbicides
Flower et al., 2004 Offspring of male pesticide applicators in Iowa from AHS
Maternal exposure to chlorophenoxy herbicides 7 0.7(0.3-1.5)
Paternal exposure to chlorophenoxy herbicides 28 1.3(0.6-2.6)
Maternal exposure to 2,4-D 7 0.7(0.3-1.6)
Paternal exposure to 2,4-D 26 1.3(0.7-2.4)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

Other Parental Agricultural Exposures Herbicides
Monge et al., 2007 Parental occupational exposure to pesticide.childhood leukemia in Costa Rica Paternal exposure in year before conception to:
Herbicides 53 1.2(0.8-1.7)
Phenoxyacetic acids 28 1.0(0.6-1.6)
Picloram (all ALL) 11 1.6(0.7-3.4)
High vs low 8 6.3(1.0-38.6)
Maternal exposure to:
Herbicides
In year before conception 9 2.0 (0.8-5.0)
In 1st trimester 8 5.3(1.4-20.0)
In 2nd trimester 8 5.3(1.4-20.0)
In 3rd trimester 7 2.3 (0.8-6.8)
Phenoxyacetic acids in year before conception 4 1.3(0.4-4.8)
Chen et al., 2005 Parental occupational exposure to pesticide.childhood GCTs
Maternal 32 1.1(0.7-1.6)
Paternal 39 0.9(0.6-1.3)
Reynolds et al..2005b Maternal exposure to agricultural pesticide in class of “probable human carcinogens” (including cacodylic acid) during 9 months before delivery
All sites 223 1.0(0.9-1.2)
Leukomas 179 1.2(0.9-1.5)
Central nervous system tumors 31 0.9(0.5-1.4)
Buckley etal.. 1989 Children's Cancer Study Group—exposure to pesticides, weed killers—AML
Any paternal exposure 27 2.3 p = 0.5)
Paternal exposure over 1,000 days 17 2.7 1.0-7.0)
Maternal exposure over 1,000 days 7 undefined
Forestry Workers Herbicides
Heacock et al.. 2000 Offspring of sawmill workers exposed to fungicides contaminated with PCDDs, PCDPs Leukoma
All workers offspring—incidence 11 1.0(0.5-1.8)
Chlorophenate exposure: high- vs low- 5 0.8 (0.2-3.6)
exposure subjects
Brain cancer
All workers offspring—incidence 9 1.3(0.6-2.5)
Chlorophenate exposure: high- vs low- 5 1.5(0.4-6.9)
exposure subjects
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

ENVIRONMENTAL Seveso, Italy Residential Cohort TCDD
Pesalori etal.. 1993 Seveso residents 0-19 yrs of age—10-yr follow-up, morbidity, all exposure zones
All cancers 17 1.2(0.7-2.1)
Ovary, uterine adnexa 2 nr (0 cases expected)
Brain 3 1.1(0.3-4.1)
Thyroid 2 4.6 (0.6-32.7)
HL 3 2.0(0.5-7.6)
Lymphatic leukemia 2 1.3(0.3-6.2)
Myeloid leukemia 3 2.7(0.7-11.4)
Bertazzi etal.. 1992 Seveso residents 0-19 yrs of age—10-yr follow-up, mortality, all exposure zones
All cancers 10 7.9(3.8-13.6)
Leukomas 5 3.9(1.2-1.8)
Lymphatic leukemia 2 1.6(0.1-4.5)
Myeloid leukemia 1 0.8(0.0-3.1)
Leukemia, others 2 l.6(0.M.6)
Central nervous system tumors 2 l.6(0.M.6)
US Environmental Studies Herbicides
Cooney et al.. 2007 Case—control study of Wilms' tumor in the United States and Canada
Maternal report of household use of herbicides from month before conception through child’s diagnosis 112 1.0(0.7-1.4)
Chen et al.. 2006 Childhood GCTs residential exposure to herbicides 6 months before conception, during gestation, through breastfeeding period
Maternal exposure 47 1.3(0.9-1.7)
Daughters 36 1.4(1.0-2.0)
Sons 11 1.0(0.5-1.8)
Paternal exposure 90 1.0(0.7-1.3)
Daughters 32 1.2(0.7-2.0)
Sons 58 (0.7-L4)
Kerr et al..2000 Neuroblastoma risk in children
Maternal occupational exposure to insecticides 40 2.3(1.4-3.7)
Paternal exposure to dioxin 7 6.9(1.3-68.4)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

International Environmental Studies Herbicides
Rudant et al.. 2007 Case-control study of childhood hematopoietic malignancies in France Maternal household herbicide use during pregnancy
Acute leukemia 53 1.5(1.0-2.2)
Without paternal exposure 4 5.0(1.3-19.0)
All ALL nr 1.7(1.2-2.5)
Common B-cell ALL nr 1.9(1.3-2.9)
Mature B-cell ALL nr 1.5(0.3-6.4)
T-cell ALL nr 0.5(0.1-2.0)
AMI. nr 1.2(0.5-2.8)
HL 9 1.1(0.5-2.4)
Without paternal exposure 0 nr
Nodular sclerosis nr 1.3(0.5-3.1)
Mixed cell nr 0.8(0.1-6.6)
NHL 14 1.5(0.8-2.7)
Without paternal exposure 0 nr
Burkitt's lymphoma nr 1.7(0.7-4.0)
B-cell lymphoblastic nr 0.7 (0.2-3.0)
T-cell lymphoblastic nr 2.6 (0.7-9.0)
Anaplastic large cell nr 1.4(0.3-2.8)
Daniels et al., 2001 (United States and Canada) Neuroblastoma risk in children (538 cases, 504 controls) from 139 hospitals in United States and Canada (exposures as reported by both parents)
Pesticides in home (used ever) nr 1.6(1.0-2.3)
Herbicides in garden nr 1.9(1.1-3.2)
Pesticides in garden nr 2.2(1.3-3.6)
Meinert et al., 2000 Childhood cancer—population-based case–control study in Germany
Paternal exposure year before pregnancy 62 1.5(1.1-2.2)
Paternal exposure during pregnancy 57 1.6(1.1-2.3)
Maternal exposure year before pregnancy 19 2.1(1.1-4.2)
Maternal exposure during pregnancy 15 3.6(1.5-8.8)
Lymphomas
Paternal exposure year before pregnancy 11 1.5(0.7-3.1)
Paternal exposure during pregnancy 10 1.6(0.7-3.6)
Maternal exposure year before pregnancy 3 2.9(0.7-13)
Maternal exposure during pregnancy 4 11.8(2.2-64)
Pearce and Parker, 2000 Renal cancer in subjects (1–15 years old) with paternal occupation in agriculture 21 0.9 (0.2-3.8)
Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Reference Study Population Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b

Infante-Rivard et al., 1999 Childhood ALL in households using herbicides—populalion-based case—control study
Exposure during pregnancy 118 1.8 (1.3–2.6)
Exposure during childhood 178 1.4 (1.1–1.9)
Kristensen et al., 1996 Children of agricultural workers in Norway Children with AML whose parents purchased pesticides 12 1.4(0.6-2.9)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; AIHW, Australian Institute for Health and Welfare; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; GCT, germ-cell tumor; HL, Hodgkin lymphoma; nr, not reported; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofuran; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VES, Vietnam Experience Study.

aUnless otherwise indicated, studies show paternal exposure.

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

cOf the 12, 9 were observed, 3 additional cases estimated to have occurred in portion of cohort whose data were not validated.

residential proximity to specific pesticide applications accumulated over the life of the child, and they evaluated 191 cases and 244 matched controls for risk associated with applications limited to the first year of life. Residential history was obtained from parental interviews and linked to the comprehensive statewide pesticide-use reporting system to identify potential exposure to specific pesticides during the periods of interest. However, analyses were limited to categories of pesticides; results were not reported for the chemicals of interest to the committee. In the second study (Ward et al., 2009), dust samples collected from carpets in the homes of 184 cases and 212 controls were analyzed for PCBs and organochlorines. No association between DDT or DDE and leukemia was observed. An increased risk in connection with several PCB congeners was observed, but analyses that considered dioxin-like activity were not available. For relevance to the offspring of Vietnam veterans, however, only analyses of parental exposures (prenatal to be applicable for female veterans or preconception for male veterans).

Three other studies of childhood cancer did not meet the level of exposure specificity required for review by the committee. One examined paternal exposures that occurred in working on hobbies during or a month before pregnancy, but exposure was limited to “lawn care using insecticides, bug or weed killer” (Rosso et al., 2008). The two other studies examined maternal exposures during pregnancy, but exposure was limited to any herbicide or pesticide and was not specific to the chemicals of interest (Shim et al., 2009; Spix et al., 2009).

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Biologic Plausibility

Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to cancer through multiple mechanisms. Susceptibility could be increased by inheriting a genetic predisposition, which by itself could increase the development of cancer or the likelihood of developing cancer after future exposure to a carcinogen; the mother or father would transmit either an acquired genetic defect or an epigenetic alteration that predisposed the child to cancer. Alternatively, a maternally mediated increase in susceptibility to childhood cancer could result from direct exposure of a child in utero or via lactation to a xenobiotic that induces epigenetic alterations that increase cancer susceptibility or is itself carcinogenic.

It has been shown that prenatal TCDD exposure of rats is associated with altered mammary gland differentiation and an increase in the number of mammary adenocarcinomas (Brown et al., 1998). A recent study’s demonstration that early postnatal TCDD exposure does not increase mammary-cancer risk (Desaulniers et al., 2004) is consistent with the finding that TCDD-induced changes in utero mediate the increase in cancer susceptibility (Fenton et al., 2000, 2002). Developmental epigenetic alterations may be involved in those prenatal effects. TCDD has been shown to suppress the expression of two tumor-suppressor genes, p16Ink4a and p53, via an epigenetic mechanism that appears to involve DNA methylation (Ray and Swanson, 2004). Similarly, it was reported that prenatal TCDD exposure increases methylation of two growth-related imprinted genes, H19 and Igf2, in the developing fetus (Wu et al., 2004).

Although there is no direct evidence from animal models that TCDD increases the risk of childhood cancers, such as acute leukemia or germ-cell tumors, emerging research suggests that prenatal TCDD exposure can disrupt epigenetic imprinting patterns and alter organ differentiation, which could contribute to an increased susceptibility to cancer later in life. A recent study has shown that chromosomal rearrangements associated with childhood ALL are evident in the neonatal blood spots; this suggests that childhood leukemias begin before birth and that maternal and perinatal exposures to xenobiotics may contribute to genetic mutations (Smith et al., 2005).

Synthesis

No new epidemiologic evidence concerning the chemicals of interest and childhood cancers has been published since Update 2008.

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

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

determine whether there is an association between exposure to the chemicals of interest and childhood cancers.

EFFECTS OCCURRING LATER IN OFFSPRING’S LIFE OR IN LATER GENERATIONS

In response to a special request from the Department of Veterans Affairs, continuing inquiries from the veterans themselves and their families, and increasing attention in research efforts, the present update addresses whether it is feasible to assess associations between exposure to the herbicides sprayed in Vietnam and health effects in the children and grandchildren of Vietnam veterans that have not been formally reviewed in previous VAO updates. The additional outcomes may include effects (other than cancer) in children that become apparent after the first year of life and that are related to maternal or paternal exposures. In addition, the committee explored the possibility of transgenerational effects resulting from exposure-related epigenetic changes, either in the parents or exposed fetuses, that would lead to adverse health effects in later generations, such as grandchildren.

Conclusions from VAO and Previous Updates

The potential impact of maternal and paternal exposure of Vietnam veterans to herbicides on the development of disease in their children after the first year of life or in later generations has not been considered in previous updates for any health outcomes other than cancer. Therefore, no conclusions have been made previously.

Changes Detected in Children after Parental Exposure

Epidemiologic studies that evaluated the potential for effects in offspring as a result of maternal or paternal exposure to the chemicals of interest were identified. Those found did not, however, deal with specific diseases in the offspring, but rather measured physiologic biomarkers that might indicate a potential for disease development later in life. Thus, despite support for measurable changes after maternal exposure as described below, the committee strongly cautions that the clinical consequences of the observed changes are highly uncertain. In order to review the studies, the committee broadly categorized them by the physiologic biomarkers that were assessed, including measurements of thyroid hormones, cognitive and motor development, and immune-cell populations. The committee also maintained its standard requirement for exposure specific to components of the herbicides sprayed in Vietnam. Finally, although it may be physiologically possible for paternal exposure to cause changes in offspring that are manifested later in life, as discussed in Chapter 4 and at the beginning of this chapter, none of the published epidemiologic studies assessed the potential for paternal exposure to contribute to outcomes that would be manifested later in their offspring’s

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

lives. Thus, any of the observed changes reported in the studies discussed below would be applicable only to children born to female Vietnam veterans during or after their deployment in Vietnam.

A number of studies have evaluated thyroid hormone concentrations in infants and children after exposure to TCDD and dioxin-like chemicals prenatally and during lactation and had mixed outcomes. For example, Baccarelli et al. (2008) evaluated neonatal thyroid-stimulating hormone (TSH) concentrations in children born to women in the Seveso cohort up to 25 years after the accident. Compared with the reference population, the risk of increased blood TSH was increased in Zone A (OR = 6.60, 95% CI 2.45–17.8) and Zone B (OR = 1.79, 95% CI 0.92–3.50). Neonatal TSH correlated with current maternal plasma TCDD concentration and dioxin-like PCB TEQs. Nagayama et al. (1998) assessed neonatal T3 and T4 concentrations and compared them with the concentrations of PCDDs, PCDFs, and PCBs, expressed as total TCDD-like TEQs, in the breast milk of their mothers. They found that both neonatal T3 and T4 were correlated negatively with total TEQs (p = 0.037 and 0.018, respectively). Physiologically, a decrease in T3 and T4 production by the thyroid would stimulate the pituitary to increase the secretion of TSH. Thus, the increase in TSH observed by Baccarelli et al. (2008) is consistent with the reductions in T3 and T4 observed by Nagayama et al. (1998). In studying newborns in Amsterdam, Pluim et al. (1993) found that total T4 levels at 1 and 11 weeks after birth were correlated with dioxin concentrations in maternal serum and breast milk, but the pattern was less clear for TSH, In contrast with those results, Darnerud et al. (2010) failed to find any relationship between neonatal (3 weeks) or infant (3 months) blood TSH and maternal plasma dioxin-like TEQs after adjusting for important confounders, including mother’s age, smoking, and alcohol consumption during pregnancy. Those important confounders were not considered by Baccarelli et al. (2008) or Nagayama et al. (1998). Furthermore, changes in thyroid hormone concentrations observed early after birth do not appear to be sustained in the offspring later in life. Su et al. (2010) found a slight increase in T3 in 2-year-old girls after in utero exposure to dioxin-like PCDDs and PCDFs, but this was not evident in either boys or girls at the age of 5 years. Similarly, following the same cohort of Dutch children, neither Ilsen et al. (1996) nor ten Tusscher et al. (2008) found any association between thyroid hormone concentrations and prenatal or lactational exposure to TCDD in children 2 or 7–12 years old, respectively, and none of the children exhibited any clinically pathologic changes in TSH or T4.

A number of studies evaluated cognitive and motor development, using such standard testing methods as the Bayley Scales of Infant Development and self-reporting questionnaires. The results of those studies, like the results of the studies that evaluated thyroid hormone concentrations, reported mixed outcomes relative to an association with prenatal or lactational exposure to TCDD and dioxin-like compounds. For example, Halldorsson et al. (2009) evaluated the attainment of specific milestones by infants, on the basis of maternal reporting,

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

in relation to maternal plasma dioxin-like activity, assessed as CALUX-TEQs. They found a significant inverse correlation between maternal CALUX-TEQs and a total developmental score (Spearman r = –0.23, p = 0.046), but only one specific outcome, crawling, showed a significant delay (OR = 3.0, 95% CI 1.0–8.6). In another study, Koopman-Esseboom et al. (1996) found a significant negative association between PCB-dioxin TEQs in breast milk and a psychomotor development index at 7 months, but not at 18 months, and neither prenatal nor postnatal PCB-dioxin TEQs were associated with a mental-developmental index at any age. Similarly, Huisman et al. (1995) reported no association between PCB-dioxin TEQs in breast milk and neurologic optimality score, and Ilsen et al. (1996) reported that all psychomotor and neurologic indexes were within normal ranges, although there was an association between PCB-dioxin TEQs in breast milk and enhanced neuromotor maturation. Analyses in other epidemiologic studies reviewed (Boersma and Lanting, 2000; Harari et al., 2010; Vreugdenhil et al., 2002) were based on inadequately specific exposures (such as exposure to pesticides or total PCB concentrations).

Finally, a number of studies have measured immune-cell populations and the prevalence of allergies in children after prenatal and postnatal exposure to TCDD and dioxin-like chemicals; outcomes varied with children’s ages. Three studies followed the same cohort of Dutch children as they aged (ten Tusscher et al., 2003; Weisglas-Kuperus et al., 1995, 2000). They found that postnatal exposure to breast-milk PCB-dioxin TEQs was associated with significant decreases in white blood cell counts at 3 months and significant increases in T-cell markers at 18 months, but had no effect on respiratory tract symptoms or antibody production at either age. At 3.5 years, they found that postnatal exposure to breast-milk PCB-dioxin TEQs was associated with a significant increase in recurrent middle ear infections and a slight increase in coughing, chest congestion, and phlegm, but no longer with changes in white blood cell counts or T-cell markers. By 8 years, postnatal exposure to breast-milk PCB-dioxin TEQs was associated with significant increases in T-cell markers and a decrease in allergy. A separate study of offspring of farm families found an association between 2,4-D use and the incidence of allergy in children (Weselak et al., 2007).

Developmental Effects in Later Generations

Epidemiologic studies designed to investigate associations of occupational or environmental exposures with adverse developmental effects manifested in later generations have not been reported in connection with the chemicals of interest or any other chemicals; they will be even more challenging to conduct than research on adverse effects on the first generation. However, recently recognized epigenetic mechanisms that are the focus of intensive research could constitute a mechanism by which such outcomes might occur (Baccarelli and Bollati, 2009; Skinner et al., 2010).

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Biological Plausibility

It has been proposed that TCDD could produce adverse effects via epigenetic mechanisms. Research into dioxin’s potential as an epigenetic agent is in its early stages, but a few studies have suggested that dioxin has such properties. For instance, Wu et al. (2004) demonstrated that TCDD exposure of mouse embryos before implantation in unexposed females resulted in epigenetic changes, including increased methylation and reduced expression of imprinted genes. Another mode of epigenetic change is modification of the spatial arrangement of chromosomes, which can influence gene expression and cell differentiation. Oikawa et al. (2008) have found that TCDD, through the AHR, modifies the position of chromosomes in the interphase nuclei of human preadipocytes. Those studies suggest that TCDD has the potential to influence the epigenome and therefore could promote changes in offspring that lead to disease later in life. The mechanisms are presented in more detail in Chapter 4.

Synthesis

The epidemiologic studies designed to examine effects of the chemicals of interest in more mature offspring have evaluated a variety of biomarkers pertaining to the neurologic, immunologic, and endocrine systems. However, they have not examined defined clinical health conditions in those or other systems. The animal literature does provide evidence that environmental agents mediated by maternal affect later generations through fetal and germ-line modifications. However, in the case of adult male exposures before conception of the next generation, there is insufficient evidence of generational affects.

Conclusions

There is inadequate or insufficient evidence to determine whether there is an association between exposure of men and women to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid before conception or during pregnancy and disease in their children as they mature or in later generations. Although laboratory research supports the plausibility of transgenerational clinical conditions, no completed epidemiologic studies have provided data to support an association between the chemicals of interest and such disease states in human offspring.

SUMMARY

Synthesis

The studies reviewed for this update did not find any new significant associations between the relevant exposures and reproductive outcomes. The scientific

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

evidence supports the biologic plausibility of a connection between exposure to the chemicals of interest and reproductive effects, but the epidemiologic studies of occupational cohorts, exposed communities, and Vietnam veterans have not provided conclusive evidence of any additional associations between exposures and an array of reproductive outcomes and conditions in the offspring of exposed parents beyond neural tube defects. The mechanisms by which the chemicals exert their biologic effects are still subjects of scientific investigation. With the aging of the Vietnam-veteran population, additional studies of endometriosis and pregnancy loss cannot be expected, although there may be additional studies of reproductive outcomes in other populations after exposure to the chemicals of interest. The possibility that structural or functional abnormalities will be manifested in the maturing offspring of exposed people will continue to be of interest. In addition, the committee strongly recommends that careful consideration be given to systematically evaluating whether recently recognized mechanisms of epigenetic modification imply that there could be long-term consequences of herbicide exposure for the health of the progeny of Vietnam veterans in future generations.

Conclusions

There is inadequate or insufficient evidence to determine whether there is an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and endometriosis; semen quality; infertility; spontaneous abortion; stillbirth; late fetal, neonatal, or infant death; low birth weight or preterm delivery; birth defects other than spina bifida; childhood cancers; or diseases in more mature offspring or later generations.

There is limited or suggestive evidence of an association between exposure to the chemicals of interest and spina bifida. There is some evidence of altered hormone concentrations, but the degree to which testosterone concentration may be modified is not great enough for clinical consequences to be expected.

There is limited or suggestive evidence of no association between paternal exposure to TCDD and spontaneous abortion.

REFERENCES1

ACS (American Cancer Society). 2010. Cancer Facts and Figures 2010. http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc–024113.pdf (accessed May 16, 2011).

ADVA (Australia Department of Veterans Affairs). 1983. Case–Control Study of Congenital Anomalies and Vietnam Service. Canberra, Australia.

_____________________

1 Throughout the report the same alphabetic indicator following year of publication is used consistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

AFHS (Air Force Health Study). 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB, TX: USAF School of Aerospace Medicine. AL-TR-1992-0090. 602 pp.

AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community: Volume 3: Validation Study. Canberra, Australia.

AIHW. 2000. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and non-Hodgkin’s Lymphoma: Supplementary Report No. 2 (AIHW cat. no. PHE 28). Canberra, Australia: AIHW.

AIHW. 2001. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and non-Hodgkin’s Lymphoma: Supplementary Report No. 2. Revised edition (AIHW cat. No. PHE 34). Canberra, Australia: AIHW.

Alberman E. 1984. Low birth weight. In: Bracken MB, ed. Perinatal Epidemiology. New York: Oxford University Press. Pp. 86–98.

Alexander GR, Slay M. 2002. Prematurity at birth: Trends, racial disparities, and epidemiology. Mental Retardation and Developmental Disabilities Research Reviews 8(4):215–220.

Alexander GR, Kogan M, Bader D, Carlo W, Allen M, Mor J. 2003. US birth weight/gestational age-specific neonatal mortality: 1995–1997 rates for whites, Hispanics, and blacks. Pediatrics 111(1):e61–e66.

Arbuckle TE, Lin Z, Mery LS. 2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspectives 109(8):851–857.

Aschengrau A, Monson RR. 1989. Paternal military service in Vietnam and risk of spontaneous abortion. Journal of Occupational Medicine 31(7):618–623.

Aschengrau A, Monson RR. 1990. Paternal military service in Vietnam and the risk of late adverse pregnancy outcomes. American Journal of Public Health 80(10):1218–1224.

Baccarelli A, Bollati V. 2009. Epigenetics and environmental chemicals. Current Opinion in Pediatrics 21(2):243–251.

Baccarelli A, Giacomini SM, Corbetta C, Landi MT, Bonzini M, Consonni D, Grillo P, Patterson DG Jr, Pesatori AC, Bertazzi PA. 2008. Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. PLoS Medicine 5(7):1133–1142.

Berkowitz GS, Papiernik E. 1993. Epidemiology of preterm delivery. Epidemiologic Reviews 15:414–443.

Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Consonni D, Tironi A, Landi MT. 1992. Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin. International Journal of Epidemiology 21(1):118–123.

Blatter BM, Hermens R, Bakker M, Roeleveld N, Verbeek AL, Zielhuis GA. 1997. Paternal occupational exposure around conception and spina bifida in offspring. American Journal of Industrial Medicine 32(3):283–291.

Bloom AD, ed. 1981. Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. White Plains, NY: March of Dimes Foundation.

Boersma ER, Lanting CI. 2000. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins: Consequences for longterm neurological and cognitive development of the child lactation. Advances in Experimental Medicine and Biology 478:271–287.

Bonde JP, Giwercman A. 1995. Occupational hazards to male fecundity. Reproductive Medicine Review 4:59–73.

Brender JD, Felkner M, Suarez L, Canfield MA, Henry JP. 2010. Maternal pesticide exposure and neural tube defects in Mexican Americans. Annals of Epidemiology 20(1):16–22.

Bretveld RW, Thomas CMG, Scheepers PTJ, Zielhuis GA, Roeleveld N. 2006a. Pesticide exposure: The hormonal function of the female reproductive system disrupted? Reproductive Biology and Endocrinology 4:20.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Bretveld RW, Zielhuis GA, Roeleveld N. 2006b. Time to pregnancy among female greenhouse workers. Scandinavian Journal of Work, Environment and Health 32(5):359–367.

Brown NM, Manzolillo PA, Zhang JX, Wang J, Lamartiniere CA. 1998. Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19(9):1623–1629.

Bryce R. 1991. The epidemiology of preterm birth. In: Kiely M, ed. Reproductive and Perinatal Epidemiology. Boca Raton, FL: CRC Press. Pp. 437–444.

Buckley JD, Robison LL, Swotinsky R, Garabrant DH, LeBeau M, Manchester P, Nesbit ME, Odom L, Peters JM, Woods WG, Hammond GD. 1989. Occupational exposures of parents of children with acute nonlymphocytic leukemia: A report from the Childrens’ Cancer Study Group. Cancer Research 49(14):4030–4037.

Bulun SE, Zeitoun KM, Kilic G. 2000. Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. American Journal of Obstetrics and Gynecology 182(4):767–775.

Carmelli D, Hofherr L, Tomsic J, Morgan RW. 1981. A Case–Control Study of the Relationship Between Exposure to 2,4-D and Spontaneous Abortions in Humans. SRI International. Prepared for the National Forest Products Association and the US Department of Agriculture, Forest Service.

CDC (Centers for Disease Control and Prevention). 1989a. Health Status of Vietnam Veterans. Vietnam Experience Study, Vol. V, Reproductive Outcomes and Child Health. Atlanta, GA: US Department of Health and Human Services.

CDC. 1989b. Health Status of Vietnam Veterans. Vietnam Experience Study, Vol. V, Reproductive Outcomes and Child Health. Atlanta, GA: US Department of Health and Human Services.

CDC. 2000. National Center for Health Statistics. National Vital Statistics System. Vital Statistics of the United States, Vol. II, Mortality, Part A, for Data Years 1950–1993. Washington, DC: US Government Printing Office. Data for 1994 to 1998, data are available on the NCHS Web site at http://www.cdc.gov/nchs/datawh/statab/unpubd/mortabs.htm.

Chao HR, Wang YF, Chen HT, Ko YC, Chang EE, Huang YJ, Tsai FY, Tsai CH, Wu CH, Tsou TC. 2007. Differential effect of arecoline on the endogenous dioxin-responsive cytochrome P450 1A1 and on a stably transfected dioxin-responsive element-driven reporter in human hepatoma cells. Journal of Hazardous Materials 149(1):234–237.

Chen SC, Liao TL, Wei YH, Tzeng CR, Kao SH. 2010. Endocrine disruptor, dioxin (TCDD)-induced mitochondrial dysfunction and apoptosis in human trophoblast-like jar cells. Molecular Human Reproduction 16(5):361–372.

Chen Z, Stewart PA, Davies S, Giller R, Krailo M, Davis M, Robison L, Shu XO. 2005. Parental occupational exposure to pesticides and childhood germ-cell tumors. American Journal of Epidemiology 162(9):858–867.

Chen Z, Robison L, Giller R, Krailo M, Davis M, Davies S, Shu XO. 2006. Environmental exposure to residential pesticides, chemicals, dusts, fumes, and metals, and risk of childhood germ cell tumors. International Journal of Hygiene and Environmental Health 209(1):31–40.

Chia SE, Shi LM. 2002. Review of recent epidemiological studies on paternal occupations and birth defects. Occupational and Environmental Medicine 59(3):149–155.

Choi JS, Kim IW, Hwang SY, Shin BJ, Kim SK. 2008. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on testicular spermatogenesisrelated panels and serum sex hormone levels in rats. BJU International 101(2):250–255.

Cok I, Donmez MK, Satiroglu MH, Aydinuraz B, Henkelmann B, Shen H, Kotalik J, Schramm KW. 2008. Concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs in adipose tissue of infertile men. Archives of Environmental Contamination and Toxicology 55(1):143–152.

Cok I, Durmaz TC, Durmaz E, Satiroglu MH, Kabukcu C. 2010. Determination of organochlorine pesticide and polychlorinated biphenyl levels in adipose tissue of infertile men. Environmental Monitoring and Assessment 162(1-4):301–309.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Cooney MA, Daniels JL, Ross JA, Breslow NE, Pollock BH, Olshan AF. 2007. Household pesticides and the risk of Wilms tumor. Environmental Health Perspectives 115(1):134–137.

Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. 2004. Risk of congenital anomalies in the vicinity of municipal solid waste incinerators. Occupational and Environmental Medicine 61(1):8–15.

Cordier S, Lehebel A, Amar E, Anzivino-Viricel L, Hours M, Monfort C, Chevrier C, Chiron M, Robert-Gnansia E. 2010. Maternal residence near municipal waste incinerators and the risk of urinary tract birth defects. Occupational and Environmental Medicine 67(7):493–499.

Daniels JL, Olshan AF, Teschke K, Herz-Picciotto I, Savitz DA, Blatt J, Bondy ML, Neglia JP, Pollock BH, Cohn SL, Look AT, Seeger RC, Castleberry RP. 2001. Residential pesticide exposure and neuroblastoma. Epidemiology 12:20–27.

Darnerud PO, Lignell S, Glynn A, Aune M, Tornkvist A, Stridsberg M. 2010. POP levels in breast milk and maternal serum and thyroid hormone levels in mother-child pairs from Uppsala, Sweden. Environment International 36(2):180–187.

De Felip E, Porpora MG, di Domenico A, Ingelido AM, Cardelli M, Cosmi EV, Donnez J. 2004. Dioxin-like compounds and endometriosis: A study on Italian and Belgian women of reproductive age. Toxicology Letters 150(2):203–209.

del Rio Gomez I, Marshall T, Tsai P, Shao Y-S, Guo YL. 2002. Number of boys born to men exposed to polychlorinated byphenlys [sic]. The Lancet 360:143–144.

Desaulniers D, Leingartner K, Musicki B, Cole J, Li M, Charboneau M, Tsang BK. 2004. Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the development of methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Journal of Toxicology and Environmental Health Part A 67(18):1457–1475.

Dhooge W, van Larebeke N, Koppen G, Nelen V, Schoeters G, Vlietinck R, Kaufman JM, Comhaire F, Flemish E, Health Study Group. 2006. Serum dioxin-like activity is associated with reproductive parameters in young men from the general Flemish population. Environmental Health Perspectives 114(11):1670–1676.

Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproductive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinavian Journal of Work, Environment and Health 22(4):267–273.

Dong B, Nishimura N, Vogel CF, Tohyama C, Matsumura F. 2010. TCDD-induced cyclooxygenase-2 expression is mediated by the nongenomic pathway in mouse MMDD1 macula densa cells and kidneys. Biochemical Pharmacology 79(3):487–497.

Donovan JW, MacLennan R, Adena M. 1984. Vietnam service and the risk of cogenital anomalies: A case–control study. Medical Journal of Australia 140(7):394–397.

Dragin N, Dalton TP, Miller ML, Shertzer HG, Nebert DW. 2006. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1b1 are inconsequential. Journal of Biological Chemistry 281(27):18591–18600.

Driscoll R, Donovan B, Esswein E, Mattorano D. 1998. Health hazard evaluation report. US Department of Agriculture 1–72.

Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE. 1994. Total serum testosterone and gonadotropins in workers exposed to dioxin. American Journal of Epidemiology 139:272–281.

Ergaz Z, Avgil M, Ornoy A. 2005. Intrauterine growth restriction—etiology and consequences: What do we know about the human situation and experimental animal models? Reproductive Toxicology 20(3):301–322.

Erickson J, Mulinare J, Mcclain P, Fitch T, James L, McClearn A, Adams M. 1984a. Vietnam Veterans’ Risks for Fathering Babies with Birth Defects. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Vietnam veterans’ risks for fathering babies with birth defects. Journal of the American Medical Association 252(7):903–912.

Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W, Gerthoux PM. 2002a. Serum dioxin concentrations and endometriosis: A cohort study in Seveso, Italy. Environmental Health Perspectives 110(7):629–634.

Eskenazi B, Warner M, Mocarelli P, Samuels S, Needham LL, Patterson DG Jr, Lippman S, Vercellini P, Gerthoux PM, Brambilla P, Olive D. 2002b. Serum dioxin concentrations and menstrual cycle characteristics. American Journal of Epidemiology 156(4):383–392.

Eskenazi B, Mocarelli P, Warner M, Chee WY, Gerthoux PM, Samuels S, Needham LL, Patterson DG Jr. 2003. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. Environmental Health Perspectives 111(7):947–953.

Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, Mocarelli P. 2005. Serum dioxin concentrations and age at menopause. Environmental Health Perspectives 113(7):858–862.

Eskenazi B, Warner M, Samuels S, Young J, Gerthoux PM, Needham L, Patterson D, Olive D, Gavoni N, Vercellini P, Mocarelli P. 2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women’s Health Study. American Journal of Epidemiology 166(1):79–87.

Eskenazi B, Warner M, Marks AR, Samuels S, Needham L, Brambilla P, Mocarelli P. 2010. Serum dioxin concentrations and time to pregnancy. Epidemiology 21(2):224–231.

Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. 2004. Pesticide use and menstrual cycle characteristics among premenopausal women in the Agricultural Health Study. American Journal of Epidemiology 160(12):1194–1204.

Farr SL, Cai J, Savitz DA, Sandler DP, Hoppin JA, Cooper GS. 2006. Pesticide exposure and timing of menopause: The Agricultural Health Study. American Journal of Epidemiology 163(8):731–742.

Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2000. Adverse effects of TCDD on mammary gland development in Long Evans rats: A two generational study. Organohalogen Compounds 48:157–160.

Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2002. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8–tetrachlorodibenzo-p-dioxin (TCDD). Toxicological Sciences 67(1):63–74.

Field B, Kerr C. 1988. Reproductive behaviour and consistent patterns of abnormality in offspring of Vietnam veterans. Journal of Medical Genetics 25:819–826.

Fierens S, Mairesse H, Heilier JF, de Burbure C, Focant JF, Eppe G, de Pauw E, Bernard A. 2003. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: Findings in a population-based study in Belgium. Biomarkers 8(6):529–534.

Fitzgerald EF, Weinstein AL, Youngblood LG, Standfast SJ, Melius JM. 1989. Health effects three years after potential exposure to the toxic contaminants of an electrical transformer fire. Archives of Environmental Health 44:214–221.

Flower KB, Hoppin JA, Lynch CF, Blair A, Knott C, Shore DL, Sandler DP. 2004. Cancer risk and parental pesticide application in children of Agricultural Health Study participants. Environmental Health Perspectives 112(5):631–635.

Foster WG, Maharaj-Briceno S, Cyr DG. 2010. Dioxin–induced changes in epididymal sperm count and spermatogenesis. Environmental Health Perspectives 118(4):458–464.

Gan LQ, Fu YX, Liu X, Qiu L, Wu SD, Tian XF, Liu Y, Wei GH. 2009. Transforming growth factor-beta3 expression up-regulates on cleft palates induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. Toxicology and Industrial Health 25(7):473–478.

García AM, Benavides FG, Fletcher T, Orts E. 1998. Paternal exposure to pesticides and congenital malformations. Scandinavian Journal of Work, Environment and Health 24(6):473–480.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Garry VF, Schreinemachers D, Harkins ME, Griffith J. 1996. Pesticide appliers, biocides, and birth defects in rural Minnesota. Environmental Health Perspectives 104(4):394–399.

Giordano F, Abballe A, De Felip E, di Domenico A, Ferro F, Grammatico P, Ingelido AM, Marra V, Marrocco G, Vallasciani S, Figa-Talamanca I. 2010. Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring. Birth Defects Research 88(4):241–250.

Gonzalez BS, Lopez ML, Rico MA, Garduno F. 2008. Oral clefts: A retrospective study of prevalence and predisposal factors in the state of Mexico. Journal of Oral Science 50(2):123–129.

Greenlee AR, Arbuckle TE, Chyou PH. 2003. Risk factors for female infertility in an agricultural region. Epidemiology 14(4):429–436.

Gupta VK, Ali I, Suhas, Saini VK. 2006. Adsorption of 2,4-D and carbofuran pesticides using fertilizer and steel industry wastes. Journal of Colloid and Interface Science 299(2):556–563.

Halldorsson TI, Thorsdottir I, Meltzer HM, Strøm M, Olsen SF. 2009. Dioxin-like activity in plasma among Danish pregnant women: Dietary predictors, birth weight and infant development. Environmental Research 109(1):22–28.

Hanify JA, Metcalf P, Nobbs CL, Worsley KJ. 1981. Aerial spraying of 2,4,5-T and human birth malformations: An epidemiological investigation. Science 212:349–351.

Harari R, Julvez J, Murata K, Barr D, Bellinger DC, Debes F, Grandjean P. 2010. Neurobehavioral deficits and increased blood pressure in school-age children prenatally exposed to pesticides. Environmental Health Perspectives 118(6):890–896.

Heacock H, Hogg R, Marion SA, Hershler R, Teschke K, Dimich-Ward H, Demers P, Kelly S, Ostry A, Hertzman C. 1998. Fertility among a cohort of male sawmill workers exposed to chlorophenate fungicides. Epidemiology 9(1):56–60.

Heacock H, Hertzman C, Demers PA, Gallagher R, Hogg RS, Teschke K, Hershler R, Bajdik CD, Dimich-Ward H, Marion SA, Ostry A, Kelly S. 2000. Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides. Environmental Health Perspectives 108(6):499–503.

Heiden TCK, Struble CA, Rise ML, Hessner MJ, Hutz RJ, Carvan IMJ. 2008. Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: Insights into TCDD-induced endocrine disruption and reproductive toxicity. Reproductive Toxicology 25(1):47–57.

Heilier JF, Nackers F, Verougstraete V, Tonglet R, Lison D, Donnez J. 2005. Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (adenomyotic) nodules. Fertility and Sterility 84(2):305–312.

Heilier JF, Donnez J, Defrere S, Van Kerckhove V, Donnez O, Lison D. 2006. Serum dioxin-like compounds and aromatase (CYP19) expression in endometriotic tissues. Toxicology Letters 167(3):238–244.

Heilier JF, Donnez J, Nackers F, Rousseau R, Verougstraete V, Rosenkranz K, Donnez O, Grandjean F, Lison D, Tonglet R. 2007. Environmental and host-associated risk factors in endometriosis and deep endometriotic nodules: A matched case–control study. Environmental Research 103(1):121–129.

Henriksen GL, Michalek JE, Swaby JA, Rahe AJ. 1996. Serum dioxin, testosterone, and gonadotropins in veterans of Operation Ranch Hand. Epidemiology 7(4):352–357.

Hertz-Picciotto I, Samuels SJ. 1988. Incidence of early loss of pregnancy. New England Journal of Medicine 319(22):483–484.

Hertz-Picciotto I, Jusko TA, Willman EJ, Baker RJ, Keller JA, Teplin SW, Charles MJ. 2008. A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio. Environmental Health: A Global Access Science Source 7:37.

Huisman M, Koopman-Esseboom C, Fidler V, Hadders-Algra M, van der Paauw CG, Tuinstra LG, Weisglas-Kuperus N, Sauer PJ, Touwen BC, Boersma ER. 1995. Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development. Early Human Development 41:111–127.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Igarashi TM, Bruner-Tran KL, Yeaman GR, Lessey BA, Edwards DP, Eisenberg E, Osteen KG. 2005. Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertility and Sterility 84(1):67–74.

Ilsen A, Briet JM, Koppe JG, Pluim HJ, Oosting J. 1996. Signs of enhanced neuromotor maturation in children due to perinatal load with background levels of dioxins. Follow-up until age 2 years and 7 months. Chemosphere 33(7):1317–1326.

Imura H, Yamada T, Mishima K, Fujiwara K, Kawaki H, Hirata A, Sogawa N, Ueno T, Sugahara T. 2010. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin suggests abnormal palate development after palatal fusion. Congenital Anomalies 50(2):77–84.

Infante-Rivard C, Labuda D, Krajinovic M, Sinnett D. 1999. Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 10:481–487.

IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington DC: National Academy Press.

IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.

IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press.

IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press.

IOM. 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans. Washington, DC: National Academy Press.

IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press.

IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press.

IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press.

IOM. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press.

Ishimura R, Kawakami T, Ohsako S, Tohyama C. 2009. Dioxininduced toxicity on vascular remodeling of the placenta. Biochemical Pharmacology 77(4):660–669.

James WH. 2006. Offspring sex ratios at birth as markers of paternal endocrine disruption. Environmental Research 100:77–85.

Jang JY, Shin S, Choi BI, Park D, Jeon JH, Hwang SY, Kim JC, Kim YB, Nahm SS. 2007. Antiteratogenic effects of alpha-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed mice in utero. Reproductive Toxicology 24(3-4):303–309.

Jang JY, Park D, Shin S, Jeon JH, Choi Bi, Joo SS, Hwang SY, Nahm SS, Kim YB. 2008. Antiteratogenic effect of resveratrol in mice exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin. European Journal of Pharmacology 591(1–3):280–283.

Kallen B. 1988. Epidemiology of Human Reproduction. Boca Raton, FL: CRC Press.

Kalter H, Warkany J. 1983. Congenital malformations. Etiologic factors and their role in prevention (first of two parts). New England Journal of Medicine 308:424–431.

Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy outcomes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4):447–454.

Karmaus W, Huang S, Cameron L. 2002. Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring. Journal of Occupational and Environmental Medicine 44(1):8–13.

Keller JM, Zelditch ML, Huet YM, Leamy LJ. 2008. Genetic differences in sensitivity to alterations of mandible structure caused by the teratogen 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicologic Pathology 36(7):1006–1013.

Kerr M, Nasca PC, Mundt KA, Michalek AM, Baptiste MS, Mahoney MC. 2000. Parental occupational exposures and risk of neuroblastoma: A case–control study (United States). Cancer Causes and Control 11:635–643.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Khorram O, Garthwaite M, Golos T. 2002. Uterine and ovarian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions. Molecular Human Reproduction 8(1):75–80.

Kline J, Stein Z, Susser M. 1989. Conception to birth: Epidemiology of prenatal development. New York: Oxford University Press.

Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, eds. 1994. The Physiology of Reproduction. New York: Raven Press.

Konishi K, Sasaki S, Kato S, Ban S, Washino N, Kajiwara J, Todaka T, Hirakawa H, Hori T, Yasutake D, Kishi R. 2009. Prenatal exposure to PCDDs/PCDFs and dioxin-like PCBs in relation to birth weight. Environmental Research 109(7):906–913.

Koopman-Esseboom C, Weisglas-Kuperus N, De Ridder MA, van der Paauw CG, Tuinstra LG, Sauer PJ. 1996. Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants’ mental and psychomotor development. Pediatrics 97(5):700–706.

Kransler KM, McGarrigle BP, Swartz DD, Olson JR. 2009. Lung development in the Holtzman rat is adversely affected by gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 107(2):498–511

Kreuzer PE, Csanady GA, Baur C, Kessler W, Papke O, Greim H, Filser JG. 1997. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Archives of Toxicology 71(6):383–400.

Kristensen P, Andersen A, Irgens LM, Bye AS, Sundheim L. 1996. Cancer in offspring of parents engaged in agricultural activities in Norway: Incidence and risk factors in the farm environment. International Journal of Cancer 65(1):39–50.

Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. 1997. Birth defects among offspring of Norwegian farmers, 1967–1991. Epidemiology 8(5):537–544.

Krüger T, Spanò M, Long M, Eleuteri P, Rescia M, Hjelmborg PS, Manicardi G-C, Bizzaro D, Giwercman A, Toft G, Bonde JP, Bonefeld-Jorgensen EC. 2008. Xenobiotic activity in serum and sperm chromatin integrity in European and Inuit populations. Molecular Reproduction and Development 75:669–680.

Kuscu OO, Caglar E, Aslan S, Durmusoglu E, Karademir A, Sandalli N. 2009. The prevalence of molar incisor hypomineralization (MIH) in a group of children in a highly polluted urban region and a windfarm–green energy island. International Journal of Paediatric Dentistry 19(3):176–185.

Laisi S, Kiviranta H, Lukinmaa PL, Vartiainen T, Alaluusua S. 2008. Molar–incisor–hypomineralisation and dioxins: New findings. European Archives of Paediatric Dentistry: Official Journal of the European Academy of Paediatric Dentistry 9(4):224–227.

Lamb JC 4th, Moore JA, Marks TA, Haseman JK. 1981. Development and viability of offspring of male mice treated with chlorinated phenoxy acids and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Toxicology and Environmental Health 8(5-6):835–844.

Larsen SB, Joffe M, Bonde JP. 1998. Time to pregnancy and exposure to pesticides in Danish farmers. Occupational and Environmental Medicine 55(4):278–283.

Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, Piacitelli LA, Sweeney MH, Connally LB. 2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects. Environmental Health Perspectives 112(14):1403–1408.

Lerda D, Rizzi R. 1991. Study of reproductive function in persons occupationally exposed to 2,4-dichlorophenoxyacetic acid (2,4-D). Mutation Research 262(1):47–50.

Loffredo CA, Silbergeld EK, Ferencz C, Zhang J. 2001. Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides. American Journal of Epidemiology 153(6):529–536.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Lorber M, Phillips L. 2002. Infant exposure to dioxin-like compounds in breast milk. Environmental Health Perspectives 110(6):A325–A332.

Mastroiacovo P, Spagnolo A, Marni E, Meazza L, Betrollini R, Segni G, Brogna-Pignatti C. 1988. Birth defects in Seveso area after TCDD contamination. Journal of American Medical Association 259:1668–1672 (published erratum appears in JAMA 1988, 260:792).

Mayani A, Barel S, Soback S, Almagor M. 1997. Dioxin concentrations in women with endometriosis. Human Reproduction 12(2):373–375.

Meinert R, Schüz J, Kaletsch U, Kaatsch P, Michaelis J. 2000. Leukemia and non-Hodgkin’s lymphoma in childhood and exposure to pesticides: Results of a register-based case–control study in Germany. American Journal of Epidemiology 151(7):639–646.

Meyer KJ, Reif JS, Veeramachaneni DN, Luben TJ, Mosley BS, Nuckols JR. 2006. Agricultural pesticide use and hypospadias in eastern Arkansas. Environmental Health Perspectives 114(10): 1589–1595.

Michalek JE, Albanese RA, Wolfe WH. 1998a. Project Ranch Hand II: An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides—Reproductive Outcome Update. US Department of Commerce, National Technical Information Service. Report number AFRL-HE-BR-TR-1998-0073.

Michalek JE, Rahe AJ, Boyle CA. 1998b. Paternal dioxin, preterm birth, intrauterine growth retardation, and infant death. Epidemiology 9(2):161–167.

Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, Fujii-Kuriyama Y. 1997. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2(10):645–654.

Mocarelli P, Brambilla P, Gerthoux PM, Patterson DG Jr, Needham LL. 1996. Change in sex ratio with exposure to dioxin. Lancet 348(9024):409.

Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak SM, Brambilla P, Vincoli N, Signorini S, Tramacere P, Carreri V, Sampson EJ, Turner WE, Needham LL. 2000. Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355:1858–1863.

Mocarelli P, Gerthoux PM, Patterson DG Jr, Milani S, Limonta G, Bertona M, Signorini S, Tramacere P, Colombo L, Crespi C, Brambilla P, Sarto C, Carreri V, Sampson EJ, Turner WE, Needham LL. 2008. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Environmental Health Perspectives 116(1):70–77.

Monge P, Wesseling C, Guardado J, Lundberg I, Ahlbom A, Cantor KP, Weiderpass E, Partanen T. 2007. Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica. Scandinavian Journal of Work, Environment and Health 33(4):293–303.

Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: Comparison of findings with and without chloracne. American Journal of Industrial Medicine 5(3):161–182.

Moshammer H, Neuberger M. 2000. Sex ratio in the children of the Austrian chloracne cohort. Lancet 356:1271.

Nagayama J, Okamura K, Iida T, Hirakawa H, Matsueda T, Tsuji H, Hasegawa M, Sato K, Ma HY, Yanagawa T, Igarashi H, Fukushige J, Watanabe T. 1998. Postnatal exposure to chlorinated dioxins and related chemicals on thyroid hormone status in Japanese breast-fed infants. Chemosphere 37(9-12):1789–1793.

National Institute of Child Health and Human Development. 2007. Endometriosis. National Institute of Health. http://www.nichd.nih.gov/health/topics/endometriosis.cfm (accessed December 17, 2008).

NCI (National Cancer Institute). 2001. Surveillance, Epidemiology, and End Results (SEER) database. http://seer.cancer.gov/ScientificSystems/CanQues (accessed March 19).

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Niskar AS, Needham LL, Rubin C, Turner WE, Martin CA, Patterson DG Jr, Hasty L, Wong L-Y, Marcus M. 2009. Serum dioxins, polychlorinated biphenyls, and endometriosis: A case–control study in Atlanta. Chemosphere 74(7):944–949.

Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immuno-and reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 210(1):65–80.

Oikawa K, Ohbayashi T, Mimura J, Fujii-Kuriyama Y, Teshima S, Rokutan K, Mukai K, Kuroda M. 2002. Dioxin stimulates synthesis and secretion of IgE-dependent histamine-releasing factor. Biochemical and Biophysical Research Communications 290(3):984–987.

Oikawa K, Kosugi Y, Ohbayashi T, Kameta A, Isaka K, Takayama M, Kuroda M, Mukai K. 2003. Increased expression of IgE-dependent histamine-releasing factor in endometriotic implants. Journal of Pathology 199(3):318–323.

Oikawa K, Yoshida K, Takanashi M, Tanabe H, Kiyuna T, Ogura M, Saito A, Umezawa A, Kuroda M. 2008. Dioxin interferes in chromosomal positioning through the aryl hydrocarbon receptor. Biochemical and Biophysical Research Communications 374(2):361–364.

Park JS, Hwang SY, Hwang BY, Han K. 2008. The spermatogenic effect of 50% ethanol extracts of Yacon and its ameliorative effect against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced testicular toxicity in the rat. Natural Product Sciences 14(2):73–80.

Pauwels A, Schepens PJC, Hooghe TD, Delbeke L, Dhont M, Brouwer A, Weyler J. 2001. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: A case–control study of infertile women. Human Reproduction 16(10):2050–2055.

Pearce MS, Parker L. 2000. Paternal employment in agriculture and childhood kidney cancer. Pediatric Hematology and Oncology 17(3):223–230.

Peltier MR. 2003. Immunology of term and preterm labor. Reproductive Biology and Endocrinology 1:122–132.

Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. 1993. Cancer in a young population in a dioxincontaminated area. International Journal of Epidemiology 22(6):1010–1013.

Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, Peterson MR, Phillips DL. 1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 27:165–171.

Pluim H, de Vijlder J, Olie K, Kok J, Vulsma T, van Tijn D, van der Slikke JW, Koppe JG. 1993. Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations. Environmental Health Perspectives 101(6):504–508.

Polsky JY, Aronson KJ, Heaton JP, Adams MA. 2007. Pesticides and polychlorinated biphenyls as potential risk factors for erectile dysfunction. Journal of Andrology 28(1):28–37.

Porpora MG, Ingelido AM, di Domenico A, Ferro A, Crobu M, Pallante D, Cardelli M, Cosmi EV, De Felip E. 2006. Increased levels of polychlorobiphenyls in Italian women with endometriosis. Chemosphere 63(8):1361–1367.

Porpora MG, Medda E, Abballe A, Bolli S, De Angelis I, di Domenico A, Ferro A, Ingelido AM, Maggi A, Panici PB, De Felip E. 2009. Endometriosis and organochlorinated environmental pollutants: A case–control study on Italian women of reproductive age. Environmental Health Perspectives 117(7):1070–1075.

Ray SS, Swanson HI. 2004. Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a. Journal of Biological Chemistry 279(26):27187–27193.

Revich B, Aksel E, Ushakova T, Ivanova I, Zuchenko N, Lyuev N, Brodsky B, Sotsov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43(4-7):951–966.

Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. 2005b. Agricultural pesticide use and childhood cancer in California. Epidemiology 16(1):93–100.

Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL. 1993. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundamental and Applied Toxicology 21(4):433–441.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Romo A, Carceller R, Tobajas J. 2009. Intrauterine growth retardation (IUGR): Epidemiology and etiology. Pediatric Endocrinology Reviews 6(Suppl 3):332–336.

Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. 2008. A case–control study of childhood brain tumors and fathers’ hobbies: A Children’s Oncology Group Study. Cancer Causes and Control 19(10):1201–1207.

Rudant J, Menegaux F, Leverger G, Baruchel A, Nelken B, Bertrand Y, Patte C, Pacquement H, Verite C, Robert A, Michel G, Margueritte G, Gandemer V, Hemon D, Clavel J. 2007. Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE). Environmental Health Perspectives 115(12):1787–1793.

Rull RP, Gunier R, Von Behren J, Hertz A, Crouse V, Buffler PA, Reynolds P. 2009. Residential proximity to agricultural pesticide applications and childhood acute lymphoblastic leukemia. Environmental Research 109(7):891–899.

Ryan JJ, Amirova Z, Carrier G. 2002. Sex ratios of children of Russian pesticide producers exposed to dioxin. Environmental Health Perspectives 110(11):A699–A701.

Savitz DA, Arbuckle A, Kaczor D, Curtis KM. 1997. Male pesticide exposure and pregnancy outcome. American Journal of Epidemiology 146(12):1025–1036.

Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally LB, Fingerhut MA. 2001. Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109(11):1127–1132.

Schreinemachers DM. 2003. Birth malformations and other adverse perinatal outcomes in four US wheat-producing states. Environmental Health Perspectives 111(9):1259–1264.

Schwartz LS. 1998. Health Problems of Women Veterans of the Vietnam War. Doctoral dissertation, Yale University.

Shim YK, Miynarek SP, van Wijngaarden E. 2009. Parental exposure to pesticides and childhood brain cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environmental Health Perspectives 117(6):1002–1006.

Singh MN, Stringfellow HF, Taylor SE, Ashton KM, Ahmad M, Abdo KR, El-Agnaf OMA, Martin-Hirsch PL, Martin FL. 2008. Elevated expression of CYP1A1 and gamma–SYNUCLEIN in human ectopic (ovarian) endometriosis compared with eutopic endometrium. Molecular Human Reproduction 14(11):655–663.

Skinner MK, Manikkam M, Guerrero-Bosagna C. 2010. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends in Endocrinology and Metabolism 21(4):214–222.

Smith AH, Fisher DO, Pearce N, Chapman CJ. 1982. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Archives of Environmental Health 37:197–200.

Smith MT, McHale CM, Wiemels JL, Zhang L, Wiencke JK, Zheng S, Gunn L, Skibola CF, Ma X, Buffler PA. 2005. Molecular biomarkers for the study of childhood leukemia. Toxicology and Applied Pharmacology 206(2):237–245.

Spix C, Schulze-Rath R, Kaatsch P, Blettner M. 2009. Case–control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany. Klinische Padiatrie 221(6):362–368.

Staessen JA, Nawrot T, Hond ED, Thijs L, Fagard R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, Van Hecke E, Verschaeve L, Vlietinck R, Roels HA. 2001. Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: A feasibility study of biomarkers. Lancet 357(9269):1660–1669. [Comment in Lancet 2001. 358(9295):1816–1817.]

Stellman SD, Stellman JM, Sommer JF Jr. 1988. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam. Environmental Research 47:150–174.

Stockbauer JW, Hoffman RE, Schramm WF, Edmonds LD. 1988. Reproductive outcomes of mothers with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Epidemiology 128:410–419.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Su P-H, Chen J-Y, Chen J-W, Wang S-L. 2010. Growth and thyroid function in children with in utero exposure to dioxin: A 5-year follow-up study. Pediatric Research 67(2):205–210.

Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372–2380.

Suzuki G, Nakano M, Nakano S. 2005. Distribution of PCDDs/PCDFs and co-PCBs in human maternal blood, cord blood, placenta, milk, and adipose tissue: Dioxins showing high toxic equivalency factor accumulate in the placenta. Bioscience, Biotechnology and Biochemistry 69(10):1836–1847.

Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, Wang C, Brazil C, Overstreet JW; Study for Future Families Research Group. 2003. Semen quality in relation to biomarkers of pesticide exposure. Environmental Health Perspectives 111(12):1478–1484.

Tango T, Fujita T, Tanihata T, Minowa M, Doi Y, Kato N, Kunikane S, Uchiyama I, Tanaka M, Uehata T. 2004. Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan. Journal of Epidemiology 14(3):83–93.

Tas S, Lauwerys R, Lison D. 1996. Occupational hazards for the male reproductive system. Critical Reviews in Toxicology 26(3):261–307.

Tawara K, Nishijo M, Honda R, Maruzeni S, Seto T, Kido T, Saito S, Nakagawa H. 2009. Effects of maternal dioxin exposure on newborn size at birth among Japanese mother-infant pairs. Environmental Health and Preventive Medicine 14(2):88–95.

Teixeira de Siqueira M, Braga C, Cabral–Filho JE, Augusto LGDS, Figueiroa JN, Souza AI. 2010. Correlation between pesticide use in agriculture and adverse birth outcomes in Brazil: An ecological study. Bulletin of Environmental Contamination and Toxicology 84 (6):647–651.

ten Tusscher GW, Stam GA, Koppe JG. 2000. Open chemical combustions resulting in a local increased incidence of orofacial clefts. Chemosphere 40(9-11):1263–1270.

ten Tusscher GW, Steerenberg P, van Loveren H, Vos JG, von dem Borne AE, Westra M, van der Slikke J, Olie K, Pluim H, Koppe JG. 2003. Persistent hematologic and immunologic disturbances in 8-year-old Dutch children associated with perinatal dioxin exposure. Environmental Health Perspectives 111(12):1519–1523.

ten Tusscher GW, Guchelaar H-J, Koch J, Ilsen A, Vulsma T, Westra M, van der Slikke JW, Olie K, Koppe JG. 2008. Perinatal dioxin exposure, cytochrome p-450 activity, liver functions and thyroid hormones at follow-up after 7–12 years. Chemosphere 70(10):1865–1872.

Toft G, Long M, Kruger T, Hjelmborg PS, Bonde JP, Rignell-Hydbom A, Tyrkiel E, Hagmar L, Giwercman A, Spano M, Bizzaro D, Pedersen HS, Lesovoy V, Ludwicki JK, Bonefeld-Jorgensen EC. 2007. Semen quality in relation to xenohormone and dioxin-like serum activity among Inuits and three European populations. Environmental Health Perspectives 115(Suppl 1):15–20.

Townsend JC, Bodner KM, Van Peenen PFD, Olson RD, Cook RR. 1982. Survey of reproductive events of wives of employees exposed to chlorinated dioxins. American Journal of Epidemiology 115:695–713.

Tsuchiya M, Tsukino H, Iwasaki M, Sasaki H, Tanaka T, Katoh T, Patterson DG Jr, Turner W, Needham L, Tsugane S. 2007. Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis. Molecular Human Reproduction 13(6):399–404.

Tsukimori K, Tokunaga S, Shibata S, Uchi H, Nakayama D, Ishimaru T, Nakano H, Wake N, Yoshimura T, Furue M. 2008. Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident. Environmental Health Perspectives 116(5):626–630.

Tuyet LTN, Johansson A. 2001. Impact of chemical warfare with Agent Orange on women’s reproductive lives in Vietnam: A pilot study. Reproductive Health Matters 9(18):156–164.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Vreugdenhil HJI, Slijper FME, Mulder PGH, Weisglas-Duperus N. 2002. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environmental Health Perspectives 110(10):A593–A598.

Waller SA, Paul K, Peterson SE, Hitti JE. 2010. Agricultural–related chemical exposures, season of conception, and risk of gastroschisis in Washington State. American Journal of Obstetrics and Gynecology 202(3):241–246.

Wang Y, Yu J, Luo X, Wang X, Li M, Wang L, Li D. 2010. Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells. Cellular and Molecular Immunology 7(1):51–60.

Ward MH, Colt JS, Metayer C, Gunier RB, Lubin J, Crouse V, Nishioka MG, Reynolds P, Buffler PA. 2009. Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia. Environmental Health Perspectives 117(6):1007–1013.

Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, Eskenazi B. 2004. Serum dioxin concentrations and age at menarche. Environmental Health Perspectives 112(13):1289–1292.

Warner M, Eskenazi B, Olive DL, Samuels S, Quick-Miles S, Vercellini P, Gerthoux PM, Needham L, Patterson DG Jr, Mocarelli P. 2007. Serum dioxin concentrations and quality of ovarian function in women of Seveso. Environmental Health Perspectives 115(3):336–340.

Weisglas-Kuperus N, Sas T, Koopman-Esseboom C, van der Zwan C, De Ridder M, Beishuizen A, Hooijkaas H, Sauer, P. 1995. Immunologic effects of background prenatal and postnatal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Pediatric Research 38(3):404–410.

Weisglas-Kuperus N, Patandin S, Berbers GAM, Sas TCJ, Mulder PGH, Sauer PJJ, Hooijkaas H. 2000. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environmental Health Perspectives 108(12):1203–1207.

Wen WQ, Shu XO, Steinbuch M, Severson RK, Reaman GH, Buckley JD, Robison LL. 2000. Paternal military service and risk for childhood leukemia in offspring. American Journal of Epidemiology 151(3):231–240.

Weselak M, Arbuckle TE, Wigle DT, Krewski D. 2007. In utero pesticide exposure and childhood morbidity. Environmental Research 103(1):79–86.

Weselak M, Arbuckle TE, Wigle DT, Walker MC, Krewski D. 2008. Pre-and post-conception pesticide exposure and the risk of birth defects in an Ontario farm population. Reproductive Toxicology 25(4):472–480.

Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. 1988. Incidence of early pregnancy loss. New England Journal of Medicine 319:189–194.

Winchester PD, Huskins J, Ying J. 2009. Agrichemicals in surface water and birth defects in the United States. Acta Paediatrica, International Journal of Paediatrics 98(4):664–669.

Wolfe WH, Michalek JE, Miner JC, Rahe AJ, Moore CA, Needham LL, Patterson DG Jr. 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6:17–22.

Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C. 2004. Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2. Biological Reproduction 70(6):1790–1797.

Yamano Y, Asano A, Ohta M, Hirata S, Shoda T, Ohyama K. 2009. Expression of rat sperm flagellum-movement associated protein genes under 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Bioscience, Biotechnology and Biochemistry 73(4):946–949.

Yen SC, Jaffe RB. 1991. Reproductive Endocrinology. Philadelphia: W.B. Saunders Company.

Yoshimura T, Kaneko S, Hayabuchi H. 2001. Sex ratio in offspring of those affected by dioxin and dioxin-like compounds: The Yusho, Seveso, and Yucheng incidents. Occupational and Environmental Medicine 58(8):540–541.

Suggested Citation:"8 Reproductive Effects and Impacts on Future Generations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Yoshizawa K, Brix AE, Sells DM, Jokinen MP, Wyde M, Orzech DP, Kissling GE, Walker NJ, Nyska A. 2009. Reproductive lesions in female Harlan Sprague-Dawley rats following two-year oral treatment with dioxin and dioxin-like compounds. Toxicologic Pathology 37(7):921–937.

Yu J, Wang Y, Zhou W-H, Wang L, He Y-Y, Li D-J. 2008. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. Human Reproduction 23(7):1614–1626.

Zhao D, Lebovic DI, Taylor RN. 2002. Long-term progestin treatment inhibits RANTES (regulated on activation, normal T cell expressed and secreted) gene expression in human endometrial stromal cells. Journal of Clinical Endocrinology and Metabolism 87(6):2514–2519.

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Because of continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Congress passed the Agent Orange Act of 1991. The legislation directed the Secretary of Veterans Affairs (VA) to request the Institite of Medicine to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam to be followed by biennial updates. The 2010 update recommends further research of links between Vietnam service and specific health outcomes, most importantly COPD, tonsil cancer, melanoma, brain cancer, Alzheimer's disease, and paternally transmitted effects to offspring.

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