7

Reproductive and Developmental Effects

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2000 (hereafter, Update 2000; IOM, 2001) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed in this chapter 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, stillbirths, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. Besides studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) are also reviewed when relevant, because TCDD is sometimes a contaminant of PCBs.

The primary emphasis of this chapter is on 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 are also included.

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



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Veterans and Agent Orange: Update 2002 7 Reproductive and Developmental Effects This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2000 (hereafter, Update 2000; IOM, 2001) on the association between exposure to herbicides and adverse reproductive or developmental effects. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature discussed in this chapter 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, stillbirths, neonatal and infant mortality, low birthweight and preterm birth, childhood cancer, and alterations in sex ratio. Besides studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), studies of populations exposed to polychlorinated biphenyls (PCBs) are also reviewed when relevant, because TCDD is sometimes a contaminant of PCBs. The primary emphasis of this chapter is on 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 are also included. 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

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Veterans and Agent Orange: Update 2002 terms often used interchangeably with birth defects are congenital anomalies and congenital malformations. Major birth defects are usually defined as abnormalities that are present at birth and are severe enough to interfere with viability or physical well-being. Major birth defects are seen in about 2– 3% of live births. Birth defects can be detected in an additional 5% of babies with follow-up through the first year of life. The causes of most birth defects are unknown. In addition to genetic factors, a number of exposures—including medications and environmental, occupational, and lifestyle factors—have long been implicated in the etiology of birth defects (Kalter and Warkany, 1983). Historically, most etiologic research focused on the effect of maternal and fetal exposures, but some work has addressed paternal exposures. Paternally mediated exposures could occur via several routes, and therefore exert an effect in various ways. One is through direct genetic damage to the male germ cell that is transmitted to the offspring and expressed as a birth defect. A second is through transfer of chemicals from the work, home, or general environment via seminal fluid with subsequent fetal exposure during gestation. A third route is via indirect exposure from household contamination by take-home exposures. Summary of VAO, Update 1996, Update 1998, and Update 2000 The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 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 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 (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and spina bifida in the children of veterans; there was no change in the conclusions regarding other birth defects. There was no change in those findings in Update 1998 or Update 2000. Reviews of the studies underlying the findings may be found in the earlier reports (see Tables 7-1 and 7-2). Update of the Scientific Literature Occupational Studies No relevant occupational studies have been published since Update 2000 (IOM, 2001). Environmental Studies In a pilot study of 30 Vietnamese women who were known or whose spouses were known to be exposed to Agent Orange, Le and Johansson (2001) reported

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Veterans and Agent Orange: Update 2002 TABLE 7-1 Selected Epidemiologic Studies—Birth Defects Reference Study Population Estimated Casesa Exposed Relative Risk (95% CI)a OCCUPATIONAL Studies Reviewed in Update 1998 Dimich-Ward et al., 1996 Sawmill workers (paternal exposure)   Cataracts 11b 5.7 (1.4–22.6)   Genital organs 105b 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 years 11 0.9 (0.5–1.7)   Maternal age > 30 years 19 2.5 (1.6–2.1)   Chromosomal 8 1.1 (0.5–2.1)   Other 48     Maternal age < 35 years 36 1.1 (0.8–1.6)   Maternal age > 35 years 12 3.0 (1.6–5.3)   All births with anomalies 125 1.4 (1.2–1.7) Kristensen et al., 1997 Offspring of Norwegian farmers (maternal and paternal exposure) 4,189c 1.0 (1.0–1.1) Studies Reviewed in VAO Townsend et al., 1982 Follow-up of Dow Chemical plant workers (paternal exposure) 30 0.9 (0.5–1.4) 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) Suskind and Hertzberg, 1984 Follow-up of 2,4,5-T production workers (paternal exposure) 18 1.1 (0.5–2.2) Moses et al., 1984 Follow-up of 2,4,5-T production workers (paternal exposure) 11 1.3 (0.5–3.4) ENVIRONMENTAL New Studies Loffredo et al., 2001 Infants exposed to herbicides during the first trimester (maternal exposure) 66 2.8 (1.3–7.2) Revich et al., 2001 Residents of Chapaevsk, Russia— congenital malformations * (*) NS ten Tusscher et al., 2000 Infants born in Zeeburg, Amsterdam, clinics in 1963–1965 with orofacial cleft (maternal exposure)       Births in 1963 5 (*) SS   Births in 1964 7 (*) SS

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Veterans and Agent Orange: Update 2002 Reference Study Population Estimated Cases Exposed Relative Risk (95% CI) Studies Reviewed in VAO Fitzgerald et al., 1989 Follow-up of an electric transformer fire—total birth defects (maternal and paternal exposure) 1 SIR = 212 (5.4–1,185.1) Hanify et al., 1981 All birth malformationsd 164 1.7 (1.4–2.2)   All heart malformations 20 3.9 (1.7–8.9)   Hypospadias, epispadias 18 5.6 (2.1–15.1)   Talipes 52 1.7 (1.1–2.4)   Anencephaly 10 1.4 (0.6–3.3)   Spina bifida 13 1.1 (0.6–2.3)   Cleft lip 6 0.6 (0.2–1.5)   Isolated cleft palate 7 1.4 (0.5–3.8) Mastroiacovo et al., 1988 Reproductive outcomes of Seveso, Italy, residents (maternal, paternal, and in utero exposure)       Zones A, 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, B mild defects 14 1.4 (0.9–2.6) Stockbauer et al., 1988 TCDD soil contamination in Missouri (all exposures)       Total birth defects 17 0.8 (0.4–1.5)   Major defects 15 0.8 (0.4–1.7)   Midline defects 4 0.6 (0.2–2.3)   Central nervous system defects 3 3.0 (0.3–35.9) Studies Reviewed in Update 2000 Garcia et al., 1998 Infants born with various birth defects in agricultural areas in Spain 21     Index based on months of work in agriculture and intensity of exposure to chlorophenoxy herbicides   3.1 (0.6–16.9) VIETNAM VETERANS New Studies Kang et al., 2000 Female Vietnam veterans 4,140     “Llikely” 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)   Tracheoesophageal fistula 10 23 expected (14–32)   Anencephaly 13 16 expected (8–24)

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Veterans and Agent Orange: Update 2002 Reference Study Population Estimated Cases Exposed Relative Risk (95% CI)   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., 1998 Children with birth defects born to Air Force Ranch Hand veterans (paternal exposures)       Pre-Southeast Asia * 0.7 (*)   Post-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, 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)   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 VAO Erikson et al., 1984a Birth defects study (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) CDC, 1989 Vietnam Experience Study (paternal exposure)   Interview study   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 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)   Defects with high exposure 46 1.7 (1.2–2.4)

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Veterans and Agent Orange: Update 2002 Reference Study Population Estimated Cases Exposed Relative Risk (95% CI) CDC, 1989 General Birth Defects Study (paternal exposure)       Birth defects 130 1.0 (0.8–1.3)   Major birth defects 51 1.2 (0.8–1.9)   Black Vietnam veterans with children with birth defects 21 3.4 (1.5–7.6)   Digestive system defects 18 2.0 (0.9–4.6) Aschengrau and Monson, 1990 Birth defects and father's Vietnam service       Vietnam veterans compared with men without known military service 55 1.3 (0.9–1.9)   Vietnam veterans compared with non-Vietnam veterans 55 1.2 (0.8–1.9)   Major malformations   Vietnam veterans compared with men without known military service 18 1.8 (1.0–3.1)   Vietnam veterans compared with non-Vietnam veterans 18 1.3 (0.7–2.4) Donovan et al., 1984 Birth defects and father's Vietnam service (Australia)       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) AFHS, 1992 Follow-up of Air Force Ranch Hand personnel       Birth defects in conceptions after 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) a Given when available. b Number of workers with maximal index of exposure (upper three quartiles) for any job held up to three months prior to conception. c 95% confidence intervals contained one for all outcomes. Anencephaly and spina bifida included in this calculation. d Excludes stillbirths, neonatal death, or dislocated or dislocatable hip. * 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; SIR, standardized incidence ratio; SS, statistically significant.

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Veterans and Agent Orange: Update 2002 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 Offspring of 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 Offspring of Norwegian farmers—spina bifida (paternal exposure)       Tractor spraying equipment 28 1.6 (0.9–2.7)   Tractor spraying equipment, 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 18b 1.8 (0.8–4.1) Garry et al., 1996 Private pesticide appliers— central nervous system defects 6 1.1 (0.5–2.4) ENVIRONMENTALc Studies Reviewed in VAO Stockbauer et al., 1988 TCDD soil contamination in Missouri— central nervous system defects (all exposures) 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 (0.6–3.3)   Spina bifida 13 1.1 (0.6–2.3) VIETNAM VETERANS Studies Reviewed in Update 2000 AIHW, 1999 Australian Vietnam veterans—validation study, spina bifida (paternal exposure) 50 1.5 (NR) Studies Reviewed in Update 1996 Wolfe et al., 1995 Follow-up of Air Force Ranch Hands (paternal exposure)       Neural tube defects among Ranch Hand personnel childrend 4 (*)   Neural tube defects among comparison children 0 (*) 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 (*)

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Veterans and Agent Orange: Update 2002 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a   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 19e 2.7 (1.2–6.2)   EOI-5: anencephaly 7e 0.7 (0.2–2.8) Australia Department of Veterans 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 before conception. c Either or both parents potentially exposed. d Four neural tube defects among Ranch Hand offspring include two spina bifida (high dioxin), one spina bifida (low dioxin), and one anencephaly (low dioxin). Denominator for Ranch Hand group is 792 and for comparison group 981. e 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; AIWI, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; EOI, exposure opportunity index; NR, not reported. that two-thirds of their children had congenital malformations or developed disabilities within the first few years of life. However, by the authors' own admission, the study subjects were purposely selected to be those who had given birth to at least one disabled child. So, although suggestive for future research, the results may not be amenable to serious interpretation. Loffredo et al. (2001) reported results from the Baltimore-Washington Infant Study. This case–control study of congenital heart defects in liveborn infants, conducted in 1981–1989, included 1,832 cases of congenital heart defects—66 with transdisposition of the great arteries (TGA) and 114 with non-TGA outflow-tract anomalies—and 771 controls. In 1987–1989, information on exposure was obtained by expanding the original questionnaire to include questions on pesticide exposure for the 1987–1989 period. Information was obtained on type, mode, location, frequency, and time of exposure. A mother was said to be exposed to pesticides if exposure occurred during the 3 months preceding pregnancy or the first trimester, a period of pregnancy considered critical for cardiovascular devel-

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Veterans and Agent Orange: Update 2002 opment. The mothers were further classified into four mutually exclusive groups: mothers not exposed to pesticides at any time 6 months before pregnancy or during pregnancy, mothers exposed to any pesticides 4–6 months before pregnancy, mothers exposed to pesticides during the 3 months preceding pregnancy or during the first trimester, and mothers exposed during the last 4–9 months of pregnancy (late gestational exposures). The authors report significant associations between TGA and exposures to any pesticide (odds ratio [OR] = 2.0, 1.2–3.3), herbicides (OR = 2.8, 1.3–7.2), or rodenticidal chemicals (OR = 4.7, 1.4–12.1) but not insecticides (OR = 1.5, 0.9– 2.6). Of those, only the models for herbicides and rodenticidal chemicals were adjusted for race of infant, socioeconomic status, maternal age, maternal smoking and alcohol use, family history of heart defects, maternal diabetes, maternal solvent exposures, and paternal pesticide exposures. Non-TGA cardiac outflow-tract anomalies were significantly associated with pesticide exposure (OR = 3.8, 1.4–10.6). All other associations were not statistically significant, and ORs ranged from 0.8 to 1.5. The effect on TGA was stronger among those who used pellet, powder, or food imitators (OR = 4.0, 0.7– 9.8); and effects generally were also stronger with more frequent use of pesticides. For both herbicides and rodenticides, the effects on TGA were pronounced if they occurred during the critical period of pregnancy for cardiovascular development, i.e., the 3 months preceding pregnancy and the first trimester. No data were collected on specific chemicals used, although the authors specifically mention chlorophenoxy herbicides being sold commercially during the period of interest. A major strength of this study is the high response rate, even among controls. Also notable are the specificity for exposures early but not late in pregnancy and the lack of association of herbicides with other heart defects. ten Tusscher et al. (2000) reported results of a retrospective observational epidemiologic study that compared trends in incidence of nonsyndromal orofacial clefts during 1961–1969 in clinics in the communities of Zeeberg, Amsterdam, and Wilhelmina Gasthuis, Amsterdam. The two locations were different. Zeeberg was highly exposed to potentially toxic chemicals, including dioxins, because of its proximity to open chemical combustion in a nearby incinerator. In fact, the area was still a prohibited terrain as late as 1998 because of the toxic chemical present. Wilhelmina Gasthuis was a clean control location. The authors showed that the trend in incidence of orofacial clefts was consistently higher in the exposed communities than in the control community. There was also a suggestion of a dose–response relationship in that a higher volume of combustion tended to be followed by higher incidence. Note, however, that information on combusted quantities was sketchy. Combusted quantities were generally under-reported (by up to 70%) and unknown for 5 of the 10 years of interest (1960– 1969). In 1961–1969, the incidence in Zeeberg averaged about 2.4 per 1,000 births, with a peak of about 7.1 per 1,000 births in 1963–1965; it later plateaued at 1.7 per 1,000 births (a figure that is still higher than that in the control commu-

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Veterans and Agent Orange: Update 2002 nity in that period). In Wilhelmina, the maximal incidence over the entire 10-year period was 2.3 per 1,000 births. The differences in incidence between the Zeeberg and Wilhelmina Gasthuis clinics were found to be statistically significant for 1963 and 1964. The results are not based on multivariate models that account for confounding, but the authors outline the comparability of the two populations. Both clinics served communities with low socioeconomic status; hence the need for delivery at the clinics instead of at home. In addition to the social indications that were common to the two clinics, the Wilhelmina clinic handled all pathologic pregnancies. That indicates that the Zeeberg clinic handled healthier pregnancies, despite the observed higher incidence of orofacial clefts. The authors argue, but do not present data, that the two populations are comparable with respect to smoking, socioeconomic status, and alcohol consumption. The study is relevant to the charge of the committee in that chemical emissions from incineration are known to contain TCDD and dioxin-like compounds. Moreover, eels and rabbits from the vicinity of the incinerator were found to have very high concentrations of dioxins in their bodies. The combustion processes, however, were likely to produce multiple chemicals with potential adverse health effects. The nonspecific nature of the exposure information and lack of direct information on potential confounders limit the usefulness of the results of this study for the charge of this committee. Revich et al. (2001) studied the relationship between the relatively high dioxin concentrations in the air, soil, drinking water, and cows' milk of Chapaevsk, Russia, due to pollution from a chemical plant in the area and its effects on the reproductive health status of the study population. In 369 children born in 1990–1995, the average number of congenital morphogenetic conditions (CMGCs) per child was higher in Chapaevsk, Russia (4.5 in boys and 4.4 in girls), than reported previously in other comparably polluted industrial towns. The most frequent CMGCs were sandals chack, epicanthus, shawl scrotum (in boys), clinodactyly, and broad first fingers. Fequencies of congenital malformations in Chapaevsk were not statistically significantly different from the data reported for the entire continent in the European register. Vietnam-Veteran Studies In a historical cohort study of 4,140 female Vietnam veterans and 4,140 female non-Vietnam (but contemporary) veterans, Kang et al. (2000) assessed potential associations between various self-reported pregnancy outcomes and the Vietnam experience or lack thereof. Statistically significant associations were detected only with “likely” (OR = 1.7, 1.2 –2.2) and “moderate-to-severe” (OR = 1.5, 1.1–2.0)] birth defects. Here, “likely” birth defects were defined as congenital anomalies—including structural, metabolic, or hereditary defects—based on an initial 11-category grouping of birth defects. “Moderate-to-severe” birth de-

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Veterans and Agent Orange: Update 2002 fects were defined according to the severity of the diagnosis or were conditions that had any history of surgical or medical treatment or functional impairment or were related to death. The “moderate-to-severe ” category was constructed to analyze possibly teratogenic defects. When analysis was restricted to the nonnurse veterans in both groups, the associations between serving in Vietnam and birth defects became stronger for both “likely” (OR = 3.1, 1.8–5.6) and “moderate-to-severe” (OR = 2.6, 1.4–4.9) birth defects. This study has very high relevance to the assessment of effects of Agent Orange and other herbicides used in the Vietnam era, but its usefulness is somewhat limited by the definition of exposure as service in Vietnam. In addition, a serious attempt to validate the self-reported pregnancy outcomes was not generally successful, possibly because of the long gap between the reported events and data collection. However, the rather strong association with birth defects, in the absence of a significant association with any other pregnancy outcome, is rather convincing. Reanalysis of the data in conjunction with forthcoming data from a current study (which is being overseen by the National Academies) characterizing herbicide exposure in Vietnam could yield information valuable for understanding the effects of Agent Orange and other herbicides on birth defects. Synthesis The interpretation of the increased risk of CMGCs due to high concentrations of dioxin that was reported in Revich et al. (2001) suffers from poor study design (it used an ecologic study design) and inadequate control for confounding factors. Similarly, the findings of Le and Johansson (2001) suffer from an admitted bias in selection of study subjects. Of the three relatively well-designed recent studies (Kang et al., 2000; Loffredo et al., 2001; ten Tusscher et al., 2000), Loffredo et al. (2001) and ten Tusscher et al. (2000) do not deal with effects that are directly associated with Vietnam veterans. The positive associations between TGA and use of pesticides and herbicides give some evidence of increased risks that may be relevant to exposure of Vietnam veterans to Agent Orange and other herbicides. However, the stronger results that were associated with exposures during critical periods may not be relevant to Vietnam veterans unless pregnancies occurred during periods of active duty, although the persistence of TCDD implies that direct exposure during pregnancy might not be required. The results of ten Tusscher et al. (2000) provide evidence of increased risk of nonsyndromal orofacial clefts and a possible dose–response relationship with exposures to potentially high concentrations of dioxins. This study suffers from lack of adjustment for confounders, but its two populations appear to be comparable with respect to potential confounders, such as sociodemographic factors. It is also not possible to rule out confounding by the effects of exposures other than

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Veterans and Agent Orange: Update 2002 polychlorinated dibenzofurans (PCDFs) in 1968 in Yusho, Japan. The study focused on two regions of Japan that were affected by the exposure: Fukuoka and a region of Nagasaki. Using a two-sided binomial test and 85 live births to affected parents in the study area in February 1968 to December 1977, they showed that the sex ratio was not statistically different from the ratio of 0.5 in the general Japanese population. That result is different than the findings in Seveso, Italy, and Yucheng, Taiwan. But, as the authors rightly acknowledged, the exposure in this Japanese study and in the Yucheng study was to PCBs and PCDFs, not to TCDD, as in Seveso (Italy). The study seems to have used appropriate statistical methods for testing the main null hypotheses. It also appears that the study period was too brief to allow for possible effects on sex ratio in offspring of victims who were younger than 19 years old at the time of the incident. Revich et al. (2001) studied the relationship between the relatively high dioxin concentrations in Chapaevsk, Russia (as detected in the air, the soil, drinking water, and cows' milk because of pollution from a chemical plant in the area), and its effects on the reproductive health of the study population. The sex ratio of births in Chapaevsk was examined with demographic data. The overall sex ratio for 1983 –1997 was 0.5. The year-specific sex ratio ranged from 0.4 for 1989 to 0.6 for 1987 and 1995. The authors conclude that these results support the decline in sex ratio that has been shown in other industrial countries. However, the pattern is not clear. Moreover, the nonspecific nature of the exposure and the poor study design limit the usefulness of these results. Karmaus et al. (2002) examined the relationship between environmental parental exposure to PCBs and dichlorophenyl dichloroethene (DDE) in Michigan fish-eaters and sex ratio in their offspring. The study was based on a cohort of 1,177 people who were recruited as a result of three surveys (1973–1974, 1979– 1982, and 1989–1991) that assessed total serum PCB concentrations in Michigan anglers. Notably, dioxin-like activity was not assessed in this investigation. A telephone interview was conducted in 2000 to collect data on their children's birth characteristics, such as birth date, sex, birthweight, and gestational age. Exposure data were obtained from analyses of serum PCB and DDE in samples obtained in each of the three surveys. For each birth of a child, the paternal and maternal exposures (dichotomized at the median) that were closest to the birth were used as the most relevant exposures. Logistic-regression models that used the generalized-estimation-equations approach to account for multiple births in a family were fitted to estimate the OR for sex ratio after adjustment for calendar period of the child 's birth, age of the mother at the child's birth, and whether there was an older brother in the family. The models were based on 101 families, which had 208 offspring born after 1963 and paternal measurements of PCB and DDE. The results indicate that a significantly higher OR (with a higher sex ratio) was associated with paternal PCB concentrations over 8.1 µg/L serum (OR = 2.3, 1.1 –4.7). There was no significant association with maternal PCB concentration, but the estimated OR was in the opposite direction (OR = 0.7, 0.4 –1.5). Some of

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Veterans and Agent Orange: Update 2002 the strengths of the study are the attempt to assess the reliability of questionnaire information on a sample of 30 parents (yielding a kappa statistic of 91% and complete agreement on the sex of the children) and the use of appropriate statistical techniques to account for multiple births in a family. But PCB concentrations were determined only at the times of the three surveys, and it was not possible to study the effects of PCB congeners, such as those that display dioxin-like activity. Vietnam-Veteran Studies No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001). Synthesis Of the four occupational studies evaluated in this section, the two larger studies (Savitz et al., 1997; Schnorr et al. 2001) are of sufficient size to yield results that may be reliable and hence amenable to serious interpretation. Savitz et al. (1997) is a well-designed and well-analyzed case-control study. Schnorr et al. (2001) dealt with a study population with high TCDD exposures, and hence this study is relevant to the charge of the committee. In any case, both studies give evidence of no association of the exposures with sex ratio. The intriguing finding of excess number of female births in the relatively small study of Okubo et al. (2000) suffers from the shortcomings of the study, one of which is the results may not be specifically attributed to any of the chemicals involved. Moshammer and Neuberger (2000) reported that excess female births were observed after exposures to TCDD in the 1970s, but the results were significantly linked to TCDD load or the interval between exposure and date of birth. The results from Yoshimura et al. (2001) show lack of association of exposures to sex ratio, contradicting previous results from Seveso, Italy, and Yucheng, Taiwan, but the exposures were to PCBs and PCDFs, not to TCDD. The results from Revich et al. (2001) support previous findings of declining sex ratios in other industrial countries, but this study suffers from poor design. The results from Karmaus et al. (2002) indicate higher sex ORs (more male births) after exposure to PCB and DDE, but exposure data were based on data from three surveys, and it was not possible to study whether the effects were the result of PCB congeners that may have dioxin-like activity. There is not enough data to determine whether an association exists between exposure to the chemicals of interest and altered sex ratio, but regardless the committee does not necessarily consider this an adverse health outcome. Although a large change in the sex ratio would have adverse effects on the population as a whole, a higher-than-expected number of females may not in itself be an

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Veterans and Agent Orange: Update 2002 adverse event in terms of social or personal capacity on an individual veteran basis. Altered sex ratio might indicate an underlying functional abnormality in one or both parents that might be adverse, such as loss of male fetuses, or alteration of motility of sperm, but altered sex ratio is not necessarily associated with functional deficit in affected persons. Therefore, the committee has reviewed the data but does not treat sex ratio as a health outcome but not an adverse one. SUMMARY Strength of the Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant 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; and childhood cancers. Biologic Plausibility This section summarizes the general biologic plausibility of a connection between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) 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 a number of reproductive and developmental effects in laboratory animals. In males, sperm count and production and seminal vesicle weight have been affected by TCDD. Effects on female reproductive organs have also been seen. The mechanisms of these effects are not known, but one hypothesis is that they are mediated through effects on hormones. Effects on male and female reproductive organs are not always accompanied by effects on reproductive outcomes. 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 are suggestive that exposure to TCDD in utero could affect the body weight of newborn humans. Experiments have examined the effects of TCDD on the adult female reproductive system. TCDD exposure did not increase egg mortality or affect time to hatching of newly fertilized zebrafish eggs, but pericardial edema and craniofacial malformations were observed in zebrafish larvae. In ovo TCDD exposure adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron. Immature

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Veterans and Agent Orange: Update 2002 female rats treated with TCDD have been shown to produce significantly fewer ova; the reduction might have a number of pathways, including direct effects on the ovaries and effects on the ovaries that are secondary to effects on other hormone-producing tissues. Administration of TCDD to male rats, mice, guinea pigs, marmosets, monkeys, and chickens elicits reproductive toxicity by affecting testicular function, decreasing fertility, and decreasing the rate of sperm production. Effects on the prostate have been seen after TCDD exposure. TCDD decreased the concentrations of hormones, such as gonadotropin and testosterone, in rats. High doses of TCDD, however, are required to elicit many of those effects. TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that coexposure with either of two other chemicals, hydrocortisone or retinoic acid, synergistically enhances expression of cleft palate. The synergy suggests that the pathways controlled by these 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. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity; cytochrome P450 1A1 induction in the endothelium might mediate the early lesions that result in TCDD-related vascular derangements. That antioxidant treatment provides substantial protection against TCDD-induced embryotoxicity suggests that reactive oxygen species might be involved in the teratogenic effects of TCDD. Studies in female rats show that a single dose of TCDD results in malformations of the external genitalia and in functional reproductive alterations in female progeny, such as decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and increased incidence of constant estrus. 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 concluded that there were 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 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 or consistently decreasing prostatic dihydrotestosterone concentrations. In utero exposure to TCDD also caused decreased seminal vesicle weight and branching and decreased sperm production and increased sperm transit time in male offspring. Studies in female animals are few but demonstrate that in utero and lacta-

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Veterans and Agent Orange: Update 2002 tional exposure reduced fertility, decreased the ability to carry pregnancy to term, decreased litter size, increased fetal death, impaired ovarian function, and decreased concentrations of hormones, such as estradiol and progesterone. Most of those effects may have occurred as a result of TCDD's general toxicity to the pregnant animal, however, and not as a result of a TCDD-specific mechanism that acted directly on the reproductive system. TCDD also induced changes in serum concentrations of reproductive hormones in immature female rats given TCDD by gastric intubation, partially because of the action of TCDD on the pituitary gland. The mechanism by which TCDD could exert reproductive and developmental effects is not established. Extrapolating results to humans is not straightforward, because the factors that determine susceptibility to reproductive and developmental effects vary among species. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; these effects in turn could lead to reproductive or developmental toxicity. Most 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 lead to changes in transcription; that is, genes are differentially regulated. Modulation of those genes may alter cell function. Although structural differences in the AhR have been identified among species, it operates in a similar manner 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 of 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. Little information is available on reproductive and developmental effects of 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 is reduced, and their mortality increased (Charles et al., 1999); very high doses of 2,4-D and 2,4-DB were required to elicit these effects. 2,4-D has also been shown to alter 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. Data have suggested that picloram alone may 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,

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Veterans and Agent Orange: Update 2002 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; the lack of strong evidence of organ-specific effects among species; and differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they can have effects on cells at the subcellular level 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 these 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 predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure can be extrapolated to low-dose exposure. The biologic mechanisms underlying TCDD's toxic effects continues to be an active field of research, and future updates of this report might have more and better information on which to base conclusions, at least for TCDD. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk of reproductive and developmental outcomes associated with exposure to herbicides in the studies that have been reviewed, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. REFERENCES ACS (American Cancer Society). 2001. Childhood Leukemia Resource Center. http://www3.cancer. org/cancerinfo (accessed March 19, 2001). AFHS (Air Force Health Study). 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB: USAF School of Aerospace Medicine. AL-TR-1992-0090. 602 pp.

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