7
Reproductive and Developmental Effects

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2002 (hereafter, Update 2002; IOM, 2003) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed includes papers that describe environmental, occupational, and Vietnam-veteran studies that evaluate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirth, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) were reviewed when relevant, because TCDD is sometimes a contaminant of PCBs. For studies new to this update that report only a single reproductive health outcome and that are not revisiting a previously studied population, their design information is summarized here with their results; the design information for all other new studies can be found in Chapter 4.

This chapter’s primary emphasis is the potential adverse reproductive effects of herbicide exposure in men, because the vast majority of Vietnam veterans are men. Because about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), findings relevant to female reproductive health also were included. Studies investigating the potential reproductive consequences of exposure by either parent were considered; whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately.



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Veterans and Agent Orange: Update 2004 7 Reproductive and Developmental Effects This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2002 (hereafter, Update 2002; IOM, 2003) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed includes papers that describe environmental, occupational, and Vietnam-veteran studies that evaluate herbicide exposure and the risk of birth defects, declines in sperm quality and fertility, spontaneous abortion, stillbirth, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. In addition to studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) were reviewed when relevant, because TCDD is sometimes a contaminant of PCBs. For studies new to this update that report only a single reproductive health outcome and that are not revisiting a previously studied population, their design information is summarized here with their results; the design information for all other new studies can be found in Chapter 4. This chapter’s primary emphasis is the potential adverse reproductive effects of herbicide exposure in men, because the vast majority of Vietnam veterans are men. Because about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), findings relevant to female reproductive health also were included. Studies investigating the potential reproductive consequences of exposure by either parent were considered; whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately.

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Veterans and Agent Orange: Update 2004 BIRTH DEFECTS The March of Dimes defines a birth defect as “an abnormality of structure, function or metabolism, whether genetically determined or as the result of an environmental influence during embryonic or fetal life” (Bloom, 1981). 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 that are severe enough to interfere with viability or physical well-being. Birth defects are detected in another 5% of babies during follow-up 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 effect 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 compounds through a man’s body into his seminal fluid, resulting in fetal exposure during gestation (Chia and Shi, 2002). Another more indirect route of paternally mediated exposure could arise from contact of family members with contamination brought into the home from the workplace. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter, VAO; IOM, 1994) determined that there was inadequate or insufficient information to determine an association between exposure to 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or its contaminant TCDD, picloram, or cacodylic acid and birth defects among offspring. Additional information available to the committee responsible for Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996) led it to conclude that there was limited or suggestive evidence of an association between at least one of the compounds of interest and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. Those findings were not modified further in Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999), Veterans and Agent Orange: Update 2000 (hereafter, Update 2000; IOM, 2001), or Veterans and Agent Orange: Update 2002 (hereafter, Update 2002; IOM, 2003). Summaries of the studies of birth defects and neural tube defect specifically that were reviewed here and in earlier reports can be found in the Tables 7-1 and 7-2, respectively.

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Veterans and Agent Orange: Update 2004 TABLE 7-1 Selected Epidemiologic Studies—Birth Defects Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 1998 Kristensen et al., 1997 Norwegian farmers (maternal and paternal exposure) 4,189 1.0 (1.0–1.1)b Dimich-Ward et al., 1996 Sawmill workers (paternal exposure)     Cataracts 11c 5.7 (1.4–22.6)   Genital organs 105c 1.3 (0.9–1.5) Garry et al., 1996 Private pesticide appliers (paternal exposure)       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 < 30 11 0.9 (0.5–1.7)   Maternal age > 30 19 2.5 (1.6–2.1)   Chromosomal 8 1.1 (0.5–2.1)   Other 48     Maternal age < 35 36 1.1 (0.8–1.6)   Maternal age > 35 12 3.0 (1.6–5.3)   All births with anomalies 125 1.4 (1.2–1.7) Studies Reviewed in VAO Moses et al., 1984 Follow-up of 2,4,5-T production workers (paternal exposure) 11 1.3 (0.5–3.4) Suskind and Hertzberg, 1984 Follow-up of 2,4,5-T production workers (paternal exposure) 18 1.1 (0.5–2.2) Smith et al., 1982 Follow-up of 2,4,5-T sprayers (paternal exposure)—sprayers compared with nonsprayers 13 1.2 (0.5–3.0) Townsend et al., 1982 Follow-up of Dow Chemical plant workers (paternal exposure) 30 0.9 (0.5–1.4) ENVIRONMENTAL New Studies Cordier et al. 2004 Residents of the Rhône-Alpes region of France living near municipal solid waste incinerators (maternal and paternal exposure)       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)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Schreinemachers, 2003 Rural or farm residents of Minnesota, Montana, and North and South Dakota (maternal and paternal exposure)       Any birth anomaly 213 1.1 (0.9–1.3)   Central nervous system anomalies 12 0.8 (0.5–1.4)   Circulatory or 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 or integumental anomalies 70 1.5 (1.1–2.1)   Chromosomal anomalies 17 0.9 (0.6–1.6) Studies Reviewed in Update 2002 Loffredo et al., 2001 Mothers in the Baltimore-Washington Infant Study exposed to herbicides during the first trimester (maternal exposures) 66 2.8 (1.3–6.9) Revich et al., 2001 Residents of Chapaevsk, Russia—congenital malformations * (*) NS ten Tusscher et al., 2000 Infants born in Zeeburg, Amsterdam clinics 1963–1965 with orofacial cleft (maternal exposures)       Births in 1963 5 (*) SS   Births in 1964 7 (*) SS Studies Reviewed in Update 2000 García et al., 1998 Residents of agricultural areas in Spain—≥median score on chlorophenoxy herbicides exposure duration (months) index (paternal) 14 3.1(0.6–16.9) Studies Reviewed in VAO Fitzgerald et al., 1989 Persons exposed to an electrical transformer fire—total birth defects (maternal or paternal exposure)—incidence 1 2.1 (0.05–11.85) Mastroiacovo et al., 1988 Seveso residents (maternal, paternal, and in utero exposure)       Zones A and B total defects 27 1.2 (0.8–1.8)   Zones A, B, R total defects 137 1.0 (0.8–1.2)   Zones A and B mild defects 14 1.4 (0.9–2.6) Stockbauer et al., 1988 Persons in Missouri with documented TCDD soil contamination near residence (maternal; paternal; in utero exposure)       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)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Hanify et al., 1981 Residents of areas of Northland New Zealand subject to aerial 2,4,5-T sprayingd       All birth malformations 164 1.7 (1.4–2.1)e   All heart malformations 20 3.9 (2.1–7.4)e   Hypospadias, epispadias 18 5.6 (2.7–11.7)e   Talipes 52 1.7 (1.2–2.3)e   Cleft lip 6 0.6 (0.3–1.3)e   Isolated cleft palate 7 1.4 (0.6–3.2) e VIETNAM VETERANS Studies Reviewed in Update 2002 Kang et al., 2000 Female Vietnam veterans 4,140     “Likely” birth defects   1.7 (1.2–2.2)   “Moderate-to-severe” birth defects   1.5 (1.1–2.0) Studies Reviewed in Update 2000 AIHW, 1999 Australian Vietnam veterans—Validation Study (paternal exposures)       Down syndrome 67 92 expected (73–111)   Tracheo-oesophageal 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 (*) Michalek et al., 1998a Air Force Ranch Hand veterans (paternal exposures)       Before service in Southeast Asia * 0.7 (*)   After service in Southeast Asia * 1.5 (*) Studies Reviewed in Update 1996 Wolfe et al., 1995 High exposure Ranch Hands relative to comparisons (paternal exposure)       Nervous system 3 (*)   Eye 3 1.6 (0.4–6.0)   Ear, face, and neck 5 1.7 (0.6–4.7)   Circulatory system and heart 4 0.9 (0.3–2.7)   Respiratory system 2 (*)   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)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Cases Estimated Relative Risk (95% CI)   Musculoskeletal 31 0.9 (0.6–1.2)   Skin 3 0.5 (0.2–1.7)   Chromosomal anomalies 1 (*)   All anomalies 57 1.0 (0.8–1.3) Studies Reviewed in Update VAO AFHS, 1992 Air Force Operation Ranch Hand veterans—birth defects in conceptions following service in Southeast Asia       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 or 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) Aschengrau and Monson, 1990 Vietnam veterans whose children were born at Boston Hospital for Women (paternal exposure)       All congenital anomalies (crude OR)       Vietnam veterans compared to men without known military service 55 1.3 (0.9–1.9)   Vietnam veterans compared to non-Vietnam veterans 55 1.2 (0.8–1.9)   One or more major malformations (crude OR)       Vietnam veterans compared to men without known military service 18 1.8 (1.0–3.1)   Vietnam veterans compared to non-Vietnam veterans 18 1.3 (0.7–2.4) CDC, 1989 Vietnam Experience Study—interview data (paternal exposure)       Any congenital anomaly 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)   Birth defects in childrens of veterans reporting high exposure 46 1.7 (1.2–2.4)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) CDC, 1989 General Birth Defects Study—hospital records (paternal exposure)       Birth defects 130 1.0 (0.8–1.3)   Birth defects—black Vietnam veterans only 21 3.4 (1.5–7.6)   Major birth defects 51 1.2 (0.8–1.9)   Digestive system defects 18 2.0 (0.9–4.6) Donovan et al., 1984 Australian Vietnam veterans (paternal exposure)       Vietnam veterans vs all other men 127 1.02 (0.8–1.3)   National Service veterans—Vietnam service vs no Vietnam service 69 1.3 (0.9–2.0) Erikson et al., 1984a Vietnam veterans identified through the CDC Metropolitan Atlanta Congenital Defects Program (paternal exposure)       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) a Given when available. b 95% confidence intervals contained one for all outcomes. Anencephaly and spina bifida included in this calculation. c Number of workers with maximal index of exposure (upper three quartiles) for any job held up to three months prior to conception. d Excludes stillbirths, neonatal death, or dislocated or dislocatable hip. e 90% confidence interval * Information not provided by study authors. ABBREVIATIONS: AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; NS, not significant; OR, oddds ratio; SIR, standardized incidence ratio; SS, statistically significant.

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Veterans and Agent Orange: Update 2004 TABLE 7-2 Selected Epidemiologic Studies—Neural Tube Defects Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 1998 Blatter et al., 1997 Dutch farmers—spina bifida (paternal exposure)       Pesticide use (moderate or heavy exposure) 9 1.7 (0.7–4.0)   Herbicide use (moderate or heavy exposure) 7 1.6 (0.6–4.0) Kristensen et al., 1997 Norwegian farmers—spina bifida (parental exposure)       Tractor spraying equipment 28 1.6 (0.9–2.7)   Tractor spraying equipment and orchards or greenhouses 5 2.8 (1.1–7.1) Dimich-Ward et al., 1996 Sawmill workers (paternal exposure)       Spina bifida or anencephaly 22b 2.4 (1.1–5.3)   Spina bifida only 18b 1.8 (0.8–4.1) Garry et al., 1996 Private pesticide appliers—central nervous system defects (paternal exposure) 6 1.1 (0.5–2.4) ENVIRONMENTALc New Studies Cordier et al. 2004 Residents of the Rhône-Alpes region of France living near municipal solid-waste incinerators (maternal and paternal exposure) 49 0.9 (0.6–1.2) Studies Reviewed in VAO Stockbauer et al., 1988 Persons in Missouri with documented TCDD soil contamination near residence—central nervous system defects (maternal; paternal; in utero exposure) 3 3.0 (0.3–35.9) Hanify et al., 1981 Spraying of 2,4,5-T in New Zealand (all exposures)       Anencephaly 10 1.4 (0.7–2.9)d   Spina bifida 13 1.1 (0.6–2.1)d VIETNAM VETERANS Studies Reviewed in Update 2000 AIHW, 1999 Australian Vietnam veterans—Validation Study (paternal exposure)       Spina bifida—maxima 50 33 expected (22–44)   Anencephaly 13 16 expected (8–24) Studies Reviewed in Update 1996 Wolfe et al., 1995 Air Force Operation Ranch Hand personnel—neural tube defectse (paternal exposure) 4 (*)

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Veterans and Agent Orange: Update 2004 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a Studies Reviewed in VAO CDC, 1989 Vietnam Experience Study (paternal exposure)       Spina bifida among Vietnam veterans’ children 9 1.7 (0.6–5.0)   Spina bifida among non-Vietnam veterans’ children 5 (*)   Anencephaly among Vietnam veterans’ children 3 (*)   Anencephaly among non-Vietnam veterans’ children 0 (*) Erickson et al., 1984a,b Birth Defects Study (paternal exposure)       Vietnam veterans: spina bifida 19 1.1 (0.6–1.7)   Vietnam veterans: anencephaly 12 0.9 (0.5–1.7)   EOI-5: spina bifida 19f 2.7 (1.2–6.2)   EOI-5: anencephaly 7f 0.7 (0.2–2.8) Australia Department of Veteran Affairs, 1983 Australian Vietnam veterans—neural tube defects (paternal exposure) 16 0.9 a Given when available. b Number of workers with maximal index of exposure (upper three quartiles) for any job held up to 3 months prior to conception. c Either or both parents potentially exposed. d 90% confidence interval. e Of the four neural tube defects reported among Ranch Hand offspring there were two spina bifida (high dioxin level), one spina bifida (low dioxin), and one anencephaly (low dioxin). No neural tube defects were reported in the comparison cohort. 454 post-service births were studied in Ranch Hand veterans; 570 in comparison cohort. f Number of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index. * Information not provided by study authors. ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; NR, not reported. Update of the Scientific Literature Occupational Studies No relevant occupational studies have been published since Update 2002 (IOM, 2003).

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Veterans and Agent Orange: Update 2004 Enviromental Studies Cordier et al. (2004) studied the impact of exposure to emissions from municipal solid-waste incinerators on birth defects in a region of southeast France for a 10-year period (1988–1997), under the assumption that such emissions increase the environmental load of dioxin and other hazardous compounds. Data on congenital malformations obtained from a regional registry were categorized into four groups: minor, chromosomal, monogenic, and other major anomalies. Communities with more than 50,000 residents were categorized by a detailed scoring system into 194 exposed and 2,678 unexposed. The rates of congenital malformations were compared in analyses adjusted for year of birth, maternal age, department of birth, population density, average family income, and local road traffic (when available). Congenital anomalies were not significantly associated with exposure overall (relative ratio [RR], 1.04; 95% confidence interval [CI], 0.97–1.11), but some specific anomalies (facial clefts, renal dysplasia, obstructive uropathies, cardiac anomalies) showed significant dose–response relationships. The defined exposure indicator could not, however, differentiate exposure to dioxins from exposure to metals in this ecologic study. Schreinemachers (2003) conducted an ecologic study that compared rates of adverse birth outcomes in US agricultural states: Minnesota, Montana, North Dakota, and South Dakota. Counties, the unit of analysis, were included in the study if at least half of the population in the county was rural and if more than 20% of the land was dedicated to raising crops. The 147 counties were then classified according to their acreage of wheat fields, as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D) as high-wheat (N = 74) and low-wheat (N = 73). National birth and infant death data for 1995–1997 were used to derive gender-specific rates of malformations at birth for white singleton births, adjusting for several covariates, including maternal age, parity, maternal education, prenatal care, previous preterm or small-for-gestational-age (SGA) birth, tobacco use during pregnancy, alcohol use during pregnancy, sex of child, and season of conception. A strong association was observed for circulatory and respiratory anomalies (odds ratio [OR], 1.7; 95% CI, 1.1–2.6), which became even stronger after excluding heart malformations (OR, 2.0; 95% CI, 1.1–3.6). Conception during the season of heavy herbicide application (April–June) was the only significant adjustment covariate (OR, 1.7; 95% CI, 1.1–2.8). After covariate adjustment, increased risk for musculoskeletal and integumental anomalies was observed (OR, 1.5; 95% CI, 1.1–2.1). Boys appeared to be more susceptible to congenital anomalies than girls (male-to-female ratios of births with any congenital anomaly were 1.67 and 1.60 in the low- and high-wheat counties, respectively). The authors noted that the use of herbicides other than the chlorophenoxy herbicides should also be considered as a possible cause. Moreover, since acreage was used as an exposure surrogate, lack of directly measured herbicide exposure is a major limitation.

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Veterans and Agent Orange: Update 2004 Vietnam-Veteran Studies Correa-Villasenor et al. (2003) documented the methodology, use, and related results of the Metropolitan Atlanta Congenital Defects Program, in which 35 years of birth defects surveillance was done at the Centers for Disease Control and Prevention. Data from the registry were used by Erickson et al. (1984b), who showed that there was no greater risk among Vietnam veterans for fathering babies with serious birth defects. No health effects analysis was conducted by Correa-Villasenor et al. (2003). Synthesis Cordier et al. (2004) found significant associations with exposure to emissions from municipal solid-waste incinerators only for some facial cleft, renal dysplasia, and “other renal anomalies.” The validity of this ecologic study is limited considerably by the possibility of exposure misclassification and residual confounding. Furthermore, the researchers did not have actual dioxin measurements and the subjects were probably exposed to other toxic substances, particularly metals, in the incinerator emissions. Schreinemachers (2003) reported increased incidences of circulatory or respiratory anomalies (possibly more pronounced among male children) in association with agricultural activity. Because of the study’s ecological design, its results are valid only for regional differences and might not translate to individual comparisons. The use of a county’s wheat-producing acreage as a surrogate for parental exposure to agricultural chemicals and, even more indirectly, for dioxin exposure severely limits the value of these findings in evaluating the exposure experience of Vietnam veterans. Conclusions Strength of Evidence from Epidemiologic Studies There were no new relevant studies on 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 is still limited or suggestive of an association between exposure to the compounds of interest and spina bifida. Its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports leads the committee to conclude that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and all other birth defects. Although there were reports of increased risks of transposition of the great arteries, non-syndromal orofacial clefts, and congenital morphogenetic condi-

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Veterans and Agent Orange: Update 2004 Synthesis Despite some strengths, including the use of blood samples, and its obvious relevance to the charge of this committee, the study by Ryan et al. (2002) had several limitations. Samples were obtained many years after initial exposure, and no attempt was made to extrapolate concentrations at the time of employment. TCDD might be a strong candidate for explaining the altered sex ratios, but other compounds (perhaps with a shorter half-life) cannot be ruled out. The authors’ assertion that the hypothesis that youth at the time of exposure is an important factor could not be tested because “the mean age of the parents at the birth of their children was about 29 (range 20–43) years,” but the parents’ ages at the time of first exposure would be critical information for assessing the hypothesis. The nature of the analysis in the study did not allow for covariate adjustments for confounders or for effect modification. The results are similar to those observed for the Seveso population (Mocarelli et al., 1996, 2000, as reviewed in Update 1998 and Update 2000), but different from those reported for the US chlorophenol cohort (Schnorr et al., 2001, as reviewed in Update 2002). Biologic Plausibility There has been no work with experimental animals that specifically examined the effects of TCDD on sex ratios of offspring, nor have any alterations in sex ratio been reported for animal studies that have examined developmental effects of TCDD on offspring. However, several publications have suggested mechanisms by which an altered sex ratio might occur. James (2002), argued that paternal exposure to organochlorines could have different effects on sex ratios than does maternal exposure; because paternal and maternal exposures can lead to opposite effects on sex ratios, there could be confounding; and the effects of some organochlorines should be examined more closely because some could exhibit estrogenic behavior, whereas others could show antiestrogenic or antiandrogenic behavior. He also suggests that mammalian sex ratios depend partly on hormone concentrations in both parents around the time of conception: Low parental testosterone and high gonadotropin is associated with a higher prevalence of daughters. Numerous animal studies have shown that dioxin disrupts the production of several hormones and that it modulates hormone-dependent pathways, including those involved in reproduction (see Chapter 3). It is plausible that similar effects could disrupt the hormones that affect sex ratio. Jongbloet et al. (2002) pointed out that experimental data are consistent with the possibility that the antiandrogenic effects of dioxin on male sperm (after paternal exposure) alter sperm transit time and mating behavior, causing fertilization of an “over-ripe” oocyte and leading to a reduced number of male progeny. Furthermore, the antiestrogenic properties of dioxin at the midcycle (after mater-

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Veterans and Agent Orange: Update 2004 nal exposure) could result in preferential fertilization of non-optimally matured oocytes by Y-bearing sperm, thus resulting in more male offspring. To have a better understanding of the issues involved, James (2002) suggested several lines of research focusing on closer examination of specific contaminants or congeners that could be associated with different exposure; endocrinologic assays of exposed women with different exposures, to study the hormonal profiles; and animal studies to obtain more decisive data on the effects of dioxin exposure on sex ratios under defined experimental conditions. The above mechanisms are based on sex as determined by the chromosomal constitution of the fetus. The hormonal environment of the mother during gestation also might modify expression of developing genitalia, which are the likely basis of assignment of sex to children at birth. That would not, however, correspond to the tendency for any suggestive observed effects to be associated with paternal exposure. SUMMARY Strength of the Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered hormone concentrations, semen quality, or infertility; spontaneous abortion; late-fetal, neonatal, or infant death; low birthweight or preterm delivery; birth defects other than spina bifida; altered sex ratio; and childhood cancers. There is limited or suggestive evidence for an association between spina bifida and exposure to the compounds of interest. Overall Biologic Plausibility for Reproductive and Hormonal Effects This section summarizes the general biologic plausibility of a connection between exposure to the compounds of interest and reproductive and developmental effects on the basis of data from animal and cellular studies. Details of the committee’s evaluation of data from the recent studies are presented in Chapter 3. TCDD is reported to cause reproductive and developmental effects in laboratory animals. Effects on male and female reproductive organs are not always accompanied by adverse reproductive outcomes. The administration of TCDD to male animals elicits reproductive toxicity by affecting testicular 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 effects on hormones. Exposure to TCDD has been accompanied by decreased concentrations of hormones such as gonadotropin and testosterone, which regulate sperm production. However, high doses of TCDD are required to elicit many of those effects. Furthermore, TCDD-exposed male rats

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Veterans and Agent Orange: Update 2004 were able to sire viable fetuses. Many studies have examined the effects of TCDD on the female reproductive system. Abnormal follicle development and decreased numbers of ova have been observed. Although oocytes appear to be directly responsive to TCDD, effects on hormones, their metabolism, and the ability of hormones to act within the ovaries also are likely contributors to those effects. A recent study indicates that exposure of mice to TCDD during pregnancy disrupts mammary gland differentiation and lactation. On the basis of animal data, there is a biologically plausible mechanism of male and female reproductive effects in humans. In animal studies, offspring of female hamsters given TCDD orally on gestation day 15 had reduced body weight. Although body weight is not consistently reduced in mice and rats exposed to TCDD in utero, those data suggest that exposure to TCDD in utero could affect the body weight of newborn humans. TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that coexposure with either of two other compounds, hydro-cortisone or retinoic acid, synergistically enhances expression of cleft palate. The synergy suggests that the pathways controlled by those agents converge at one or more points in cells of the developing palate. Several reports describe developmental deficits in the cardiovascular system of TCDD-treated animals. Some evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. Cytochrome P450 1A1 induction or alterations in pathways controlled by vascular endothelial growth factor might mediate the early lesions that result in TCDD-related vascular derangements. That antioxidant treatment provides protection against TCDD-induced embryo-toxicity in some systems suggests that reactive oxygen species might be involved in the teratogenic effects of exposure to TCDD. Several reports of studies in exposed animals and humans suggest that low perinatal exposure to TCDD and 2,4-D could impair brain development. Outcomes can be subtle, ranging from altered learning and memory to modified sex-related behavior. The mechanisms of those effects are unclear. Studies in several rodent species show that administration of a single maternal dose of TCDD produces malformations of the external genitalia and functional reproductive alterations in female progeny, including decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and disrupted estrus cycles. Those effects depend on the timing of exposure. Little research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed various concentrations of simulated Agent Orange mixtures produced no adverse effects in offspring. A statistically significant excess of fused sternebrae in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of this defect in the controls. The effects of in utero and lactational exposure on the male reproductive system have been investigated. In utero and lactational exposure to TCDD led to

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Veterans and Agent Orange: Update 2004 decreased daily sperm production and cauda epididymal sperm number in male rat and hamster offspring. Research suggests that in utero and lactational TCDD exposure selectively impairs rat prostatic growth and development without inhibiting testicular androgen production, decreasing prostatic dihydrotestosterone concentrations, or interfering with androgen-signaling pathways. In utero exposure to TCDD also caused decreased seminal vesicle weight and branching, and it decreased sperm production and increased sperm transit time in male offspring. Studies in female offspring of TCDD-exposed dams are few but demonstrate that in utero and lactational exposure can reduce fertility, decrease the ability to carry pregnancy to term, decrease litter size, increase fetal death, impair ovarian function, and decrease concentrations of estradiol and progesterone. Most of those effects could occur as a result of TCDD’s general toxicity to the pregnant dam, however, and not as the result of any TCDD-specific mechanism. TCDD also induces changes in serum concentrations of reproductive hormones in immature female rats given TCDD by gastric intubation, partly because of the action of TCDD on the pituitary gland. As indicated above, some effects observed in the fetuses or offspring from TCDD-treated dams may be due to toxicity to the dams. However, it is clear that many effects of TCDD on development also occur at doses where there is no overt maternal toxicity. The mechanism by which TCDD could exert reproductive and developmental effects is not established. Although the types of developmental effects reported in numerous toxicology experiments have been observed in highly exposed human populations, extrapolating results from animals to humans is difficult, because the factors that determine susceptibility to reproductive and developmental effects vary among species. TCDD has a variety of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; those effects in turn could lead to reproductive or developmental toxicity. Studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex has been shown to bind DNA and to lead to changes in transcription; that is, to genes that are differentially regulated. Modulation of those genes could alter cell function. Although structural differences in the AhR have been identified among species, it operates similarly in animals and humans. Therefore, a common mechanism is likely to underlie the toxic effects of TCDD in humans and animals, and data in animals support a biologic basis for TCDD’s toxic effects. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the TCDD exposure that causes reproductive or developmental effects. However, biologic plausibility for effects of TCDD on development in humans is also supported by several studies reporting effects on children exposed in utero to PCBs containing dioxin-like compounds. Furthermore, some of these effects were reported to occur at near background levels of exposure.

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Veterans and Agent Orange: Update 2004 Little information is available on the reproductive and developmental effects of exposure to the herbicides discussed in this report. Studies indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities. However, when pregnant rats or mice are exposed to 4-(2,4-dichlorophenoxy)butyric acid (2,4-DB), of which 2,4-D is a major metabolite, the rate of growth of offspring was reduced, and their mortality increased (Charles et al., 1999); very high doses of 2,4-D and 2,4-DB were required to elicit those effects. Exposure to 2,4-D also alters the concentration and function of reproductive hormones and prostaglandins. One study reported an increased incidence of malformed offspring of male mice exposed to a mixture of 2,4-D and picloram in drinking water. However, paternal toxicity was observed in the high-dose group, and there was no clear dose–response relationship; both findings were a concern in that study. Picloram alone could produce fetal abnormalities in rabbits at doses that are also toxic to the pregnant animals, but that effect has not been seen in many studies. 2,4,5-T was toxic to fetuses when administered to pregnant rats, mice, and hamsters. Its ability to interfere with calcium homeostasis in vitro has been documented and linked to its teratogenic effects on the early development of sea urchin eggs. Cacodylic acid is toxic to rat, mouse, and hamster fetuses at high doses that are also toxic to the pregnant mother. The foregoing suggests that a connection between TCDD exposure and human reproductive and developmental effects is, in general, biologically plausible. However, more definitive conclusions about the presence or absence of a mechanism for the induction of such toxicity by TCDD in humans is complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; and by differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they have subcellular effects that could provide a biologically plausible mechanism for reproductive and developmental effects. Evidence in 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 those compounds’ reproductive or developmental effects. Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicide or TCDD exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animal and cellular studies can be used to predict human health outcomes and about the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure. The investigation of the biologic mechanisms that underlie TCDD’s toxic effects continues to be an active field of research, and updates of this report could have more and better information on which to base conclusions, at least for TCDD.

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