9
Reproductive Effects

INTRODUCTION

This chapter summarizes published scientific literature on exposure to herbicides and adverse reproductive and developmental effects. The literature discussed includes papers published since Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996). Both Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994) and Update 1996 included a number of environmental, occupational, and Vietnam veteran studies that evaluated herbicide and dioxin exposure and the risk of adverse reproductive outcomes, including spontaneous abortion, birth defects, stillbirths, neonatal and infant mortality, low birthweight, and semen quality and infertility. The reports concluded that the evidence at that time was inadequate or insufficient to determine whether an association exists between exposure to herbicides and most of the above reproductive and developmental outcomes. Update 1996 concluded that there was limited/suggestive evidence for an association between herbicides and spina bifida.

The primary emphasis of VAO, Update 1996, and this report is on the potential adverse reproductive and developmental effects of herbicide exposure on males, because the vast majority of Vietnam veterans are men. Nevertheless, a brief discussion of the epidemiologic findings pertaining to female exposure is warranted because of the Department of Veterans Affairs' current study of female Vietnam veterans, their reproductive history, and the health of their children. A number of studies have evaluated the potential association between herbicide exposure in women and the risk of adverse reproductive outcomes,



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Veterans and Agent Orange: Update 1998 9 Reproductive Effects INTRODUCTION This chapter summarizes published scientific literature on exposure to herbicides and adverse reproductive and developmental effects. The literature discussed includes papers published since Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996). Both Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994) and Update 1996 included a number of environmental, occupational, and Vietnam veteran studies that evaluated herbicide and dioxin exposure and the risk of adverse reproductive outcomes, including spontaneous abortion, birth defects, stillbirths, neonatal and infant mortality, low birthweight, and semen quality and infertility. The reports concluded that the evidence at that time was inadequate or insufficient to determine whether an association exists between exposure to herbicides and most of the above reproductive and developmental outcomes. Update 1996 concluded that there was limited/suggestive evidence for an association between herbicides and spina bifida. The primary emphasis of VAO, Update 1996, and this report is on the potential adverse reproductive and developmental effects of herbicide exposure on males, because the vast majority of Vietnam veterans are men. Nevertheless, a brief discussion of the epidemiologic findings pertaining to female exposure is warranted because of the Department of Veterans Affairs' current study of female Vietnam veterans, their reproductive history, and the health of their children. A number of studies have evaluated the potential association between herbicide exposure in women and the risk of adverse reproductive outcomes,

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Veterans and Agent Orange: Update 1998 including spontaneous abortion, stillbirth, preterm delivery, and birth defects (Hemminki et al., 1980; McDonald et al., 1987; Ahlborg et al., 1989; Savitz et al., 1989; Fenster and Coye, 1990; Restrepo et al., 1990; Goulet and Theriault, 1991; Correa-Villasenor et al., 1991; Lin et al., 1994; Nurminen et al., 1995; Blatter and Roeleveld, 1996; Blatter et al., 1996). In addition, recent studies have investigated maternal dioxin exposure and neurological development among offspring (Koopman-Esseboom et al., 1996). Another study found no association between potential Agent Orange exposure and risk of gestational trophoblastic disease among women living in Vietnam (Ha et al., 1996). The quality and results of these studies have been mixed. A major limitation of nearly all the studies is the determination of specific exposures. Many studies have defined exposure based solely on employment in agricultural occupations. Exposure to specific chemicals and other agents in these agricultural settings is usually not ascertained. Further, problems such as incomplete ascertainment of the outcome of interest, selection of inappropriate or no control groups, and failure to account for confounding factors have limited some of this work. Improvements in study design, especially exposure assessment, should allow for a more definitive evaluation of the relationship between herbicide exposure and adverse reproductive outcomes among women. The remainder of this chapter discusses the following specific categories of reproductive effects: birth defects, fertility, stillbirth, neonatal and infant death, and low birthweight and preterm birth. For most outcomes, a brief summary of the scientific evidence in VAO and Update 1996 is presented, followed by a review of the recent scientific literature. BIRTH DEFECTS Background 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 with birth defects are "congenital anomalies" and "congenital malformations." Major birth defects are usually defined as those abnormalities that are present at birth and severe enough to interfere with viability or physical well-being. Major birth defects are seen in approximately 2 to 3 percent of live births. An additional 5 percent of birth defects can be detected with follow-up through the first year of life. Given the general frequency of major birth defects of 2 to 3 percent and the number of men who served in Vietnam (2.6 million), if one assumes that they had at least one child, it has been estimated that 52,000 to 78,000 babies with birth defects have been fathered by Vietnam veterans, even in the absence of an increase due to exposure to herbicides or other toxic substances (Erickson et al., 1984a). The cause of most birth defects is

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Veterans and Agent Orange: Update 1998 unknown. In addition to genetic factors, a number of other factors and exposures including medications, environmental, occupational, and lifestyle have been implicated in the etiology of some birth defects (Kalter and Warkany, 1983). Most of the etiologic research has focused on maternal and fetal exposures. Paternal exposures could exert an effect through direct genetic damage to the male germ cell that is transmitted to the offspring and is expressed as a birth defect; through seminal fluid transfer of chemicals, with subsequent fetal exposure; or via indirect exposure from household contamination. There is limited animal evidence that some chemicals are associated with an increase in birth defects after paternal exposure, although the relative importance of male-mediated developmental toxicity is not established (Olshan and Faustman, 1993). The previous reports and this update have limited their reviews to studies of paternal exposures. Summary of VAO and Update 1996 There have been several occupational and environmental studies of parental herbicide exposure. The results have been inconsistent, with some studies suggesting an increased risk of a variety of specific birth defects and others reporting no association. In addition, some studies conducted in Vietnam have indicated an association between birth defects and herbicide spraying. Several problems have limited these studies for the evaluation of specific birth defects: relatively small sample sizes; failure to document reported birth defects; use of ecologic exposure measures; inability to isolate specific pesticides and exposure of specific parents; and uncontrolled confounding. Because of the importance of conclusions regarding spina bifida in Update 1996, the relevant studies are summarized in this section. Table 9.1 is a summary of the studies that have reported results specifically for neural tube defects (typically anencephaly and/or spina bifida), including studies in VAO, Update 1996, and more recent publications reviewed in this report. Results of the analysis of birth defects among the offspring of Ranch Hands and other Vietnam veterans suggested the possibility of an association between dioxin exposure and risk of neural tube defects. Unfortunately, some studies, particularly the occupational and environmental studies (e.g., Seveso), do not have results specific for individual birth defects, usually because of the small number of cases. Several studies of veterans appear to show an elevated relative risk for neural tube defects such as anencephaly and/or spina bifida in the offspring of veterans which may be related to either service in Vietnam or estimated exposure to herbicides or dioxin. Many of the estimates are imprecise, chance cannot be ruled out, and the specific parent exposed is unclear. Nonetheless, the pattern of association warrants further evaluation. The Centers for Disease Control and Prevention (CDC) Birth Defects Study (Erickson et al., 1984a,b), the CDC Vietnam Experience Study (VES) (CDC, 1989), and the Ranch Hand Study (Wolfe et al., 1995) are of the highest

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Veterans and Agent Orange: Update 1998 TABLE 9-1 Selected Epidemiologic Studies—Neural Tube Defects Reference Study Population Exposed Cases Estimated Risk (95% CI) OCCUPATIONAL New Studies Blatter et al., 1997 Offspring of Dutch farmers—spina bifida       Pesticides use (moderate or heavy exposure) 9 1.7 (0.7-4.0)   Herbicides use (moderate or heavy exposure) 7 1.6 (0.6-4.0) Kristensen et al., 1997 Offspring of Norwegian farmers—spina bifida       Tractor spraying equipment 28 1.6 (0.9-2.7)   Tractor spraying equipment and orchards/greenhouses 5 2.8 (1.1-7.1) Dimich-Ward et al., 1996 Sawmill Workers       Spina bifida or anencephaly 22a 2.4 (1.1-5.3)   Spina bifida 18a 1.8 (0.8-4.1) Garry et al., 1996 Private Pesticide Appliers Central nervous system defects 6 1.1 (0.5-2.4) ENVIRONMENTALb Studies Reviewed in VAO Stockbauer et al., 1988 TCDD soil contamination in Missouri       Central nervous system defects 3 3.0 (0.3-35.9) Hanify et al., 1981 Spraying of 2,4,5-T in New Zealand       Anencephaly 10 1.4 (0.6-3.3)   Spina bifida 13 1.1 (0.6-2.3) VIETNAM VETERANS       Studies Reviewed in Update 1996 Wolfe et al., 1995 Follow-up of Air Force Ranch Hands       Neural tube defects among Ranch Handsc 4     Neural tube defects among comparison 0   Studies Reviewed in VAO CDC, 1989 Vietnam Experience Study       Spina bifida among Vietnam veterans 9 1.7 (0.6-5.0)   Spina bifida among non-Vietnam veterans 5     Anencephaly among Vietnam veterans 3     Anencephaly among non-Vietnam veterans 0   Erickson et al., 1984a,b Birth Defects Study       Vietnam veteran: spina bifida 19 1.1 (0.6-1.7)   Vietnam veteran: anencephaly 12 0.9 (0.5-1.7)   EOI-5: spina bifida 19d 2.7 (1.2-6.2)   EOI-5: anencephaly 7d 0.7 (0.2-2.8)

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Veterans and Agent Orange: Update 1998 Reference Study Population Exposed Cases Estimated Risk (95% CI) Australia Department of Veteran Affairs Health Studies, 1983 Australian Vietnam veterans—Neural tube defects 16 0.9 a Number of workers with maximal index of exposure (upper three quartiles) for any job held up to three months prior to conception. b Either or both parents potentially exposed. c Four neural tube defects among Ranch Hand offspring include 2 spina bifida (high dioxin level), 1 spina bifida (low dioxin), and 1 anencephaly (low dioxin). Denominator for Ranch Hand group is 792 live-born infants and 981 for comparison group. d Number of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index (EOI) score based upon interview. overall quality. The CDC VES cohort study found more Vietnam veterans than non-Vietnam veterans reported that their children had a central nervous system anomaly (odds ratio [OR] = 2.3, 95 percent confidence interval [95% CI] 1.2-4.5) (CDC, 1988). The odds ratio for spina bifida was 1.7 (CI 0.6-5.0). A substudy was conducted as an attempt to validate the reported cerebrospinal defects (spina bifida, anencephaly, hydrocephalus) by examination of hospital records. A difference was detected, but its interpretation was limited by differential participation between veteran groups and failure to validate negative reports (i.e., veterans who did not report children having a birth defect). Thus, the issue of recall bias remains a major concern with this study. The CDC General Birth Defects Study utilized the population-based birth defects registry system in the metropolitan Atlanta area (Erickson et al., 1984a,b). There was no association between overall Vietnam veteran status and the risk of spina bifida (OR = 1.1, CI 0.6-1.7) or anencephaly (OR = 0.9, CI 0.5-1.7). However, the exposure opportunity index (EOI) based on interview data was associated with an increased risk of spina bifida; for the highest estimated level of exposure (EOI-5, based on interview data), the OR was 2.7 (CI 1.2-6.2). There was no similar pattern of association for anencephaly. This study has a number of strengths, including the use of a population-based birth defects registry system and adjustment for a number of potentially confounding factors. Two study limitations include the relatively low response proportions among both case and control subjects (approximately 56 percent) and the lag between birth and interview for some cases and controls. The analysis of birth defects from the Air Force Health Study (AFHS) of Operation Ranch Hand veterans and their children was published in 1995 (Wolfe

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Veterans and Agent Orange: Update 1998 et al., 1995). Of the 872 Ranch Hands, 419 fathered 792 live-born infants during their service in Vietnam or until January 1990. Of the 1,036 comparison veterans, 531 fathered 981 live-born infants during this period. Birth defects were validated by a medical records review. In considering all birth defects combined, there was a slightly higher proportion of defects among Ranch Hand children than among comparison children (22.3 percent versus 20.8 percent). No general pattern of increasing risk with increasing dioxin levels was found. However, neural tube defects (spina bifida, anencephaly) were in excess among offspring of Ranch Hands, with 4 total (rate of 5 per 1,000), in contrast to none among the comparison infants (p = 0.04). The four cases were distributed as two spina bifida in the high-dioxin-level category, one anencephaly and one spina bifida in the low-dioxin category (exact p for spina bifida = 0.09). Thus, all three epidemiologic studies (Ranch Hand, VES, CDC Birth Defects Study) (Wolfe et al., 1995; CDC, 1988; Erickson et al., 1984a,b) suggest an association between herbicide exposure and an increased risk of spina bifida in offspring. Although the studies were judged to be of relatively high quality, they suffer from methodologic limitations, including possible recall bias, nonresponse bias, small sample size, and misclassification of exposure. In addition, the failure to find a similar association with anencephaly, an embryologically related defect, is of concern. Update of Scientific Literature Dimich-Ward et al. (1996) conducted a nested case-control analysis of birth defects among offspring of fathers employed in British Columbia sawmills. The cohort included 9,512 fathers who had worked at least one year in sawmills where chlorophenate wood preservatives (anti-sap stain fungicides) had been used. Teschke et al. (1994) summarized the concentrations of various dioxin congeners in a variety of product formulations used in the British Columbia sawmill industry. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was not detected in the samples. However, varying levels of related congeners, specifically hexachlorodibenzodioxins, heptachlorodibenzodioxins, and octachlorodibenzodioxins were found (2-330 ppm [parts per million], as a proportion of 100 percent active ingredient). Births (1952-1988) to these men were identified by linkage with the British Columbia (BC) live and stillbirth records. Further linkage with the BC Health Surveillance Registry identified cases of birth defects. The registry system is population based and uses multiple sources of identification. A case-control analysis was conducted, matching 5 controls (non-defect births) per case on year of birth and gender. Covariates included mother's and father's age. Exposure to chlorophenates for specific time periods was assessed by a team of industrial hygienists based on job title. Continuous estimates of cumulative hours of chlorophenate exposure were calculated for time windows relative to conception and pregnancy. Estimates of maximal exposure were determined for the most ex-

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Veterans and Agent Orange: Update 1998 posed job in each time period. A total of 19,675 newborns were fathered by the 9,512 workers. There were a total of 942 birth defects among the offspring (4.8 percent). Several birth defects were associated with estimated chlorophenate exposure including cataracts, anencephaly or spina bifida, and anomalies of genital organs. Relative risk measures were calculated using a comparison of the 75th with the 25th percentile of estimated exposure. Exposure measures included MAX1—maximal exposure index in the three months prior to conception, and CUM2—estimated cumulative exposure in the three months prior to conception. Odds ratios were 2.4 (CI 1.1-5.3) for spina bifida or anenecephalus (N = 22; MAX1) and 1.8 (CI 0.8-4.1) for spina bifida alone (N = 18; MAX1). For cataracts, odds ratios of 2.3 (CI 0.7-2.9; N = 11; MAX1) and 5.7 (CI 1.4-22.6; CUM2) were reported. The difference in the odds ratios between the combined analysis of spina bifida and anencephaly (OR = 2.4) and spina bifida only (OR = 1.8) suggests some association with anencephaly alone, although no specific results were presented. Weaker associations were found for genital organ anomalies (OR = 1.3, CI 0.9-1.5 for CUM2). No other defect groups showed an association with the exposure indices. The study has a number of strengths including the use of a well-defined cohort, linkage with a population-based registry system, a careful time period-specific exposure assessment by a team of industrial hygienists, and analysis of exposure by specific time windows relative to conception and pregnancy. Limitations include the lack of direct individual exposure measurements, the inability to separate effects of potential chlorophenates and dioxins, and the use of broad defect groups based on anatomic systems that were of relatively small size. In addition, only the mother's and the father's ages were adjusted for in the analysis. Nonetheless, this unique cohort provides useful information on the relationship between a specific industry and related exposures and the risk of birth defects in offspring. A series of analyses were conducted using data on birth defects among the offspring of male pesticide applicators in Minnesota (Garry et al., 1996). In addition, analyses of the relationship between birth defect rates and county-specific agricultural data were performed. Information on private state-licensed pesticide applicators registered with the Minnesota Department of Agriculture in 1991 (N = 34,772) was linked with live birth data for the state of Minnesota (1989-1992). Birth defect data were contained in these birth files. Pesticide data for units or clusters of Minnesota counties with similar geologic features and crops were employed to obtain use data for 12 specific herbicides (including 2,4-dichlorophenoxyacetic acid [2,4-D]). Overall, the pesticide applicators had a higher prevalence rate of birth defects than the general population (maternal age-adjusted OR = 1.4, CI 1.2-1.7) as well as higher rates of circulatory/respiratory (OR = 1.7, CI 1.04-2.8), gastrointestinal (OR = 1.7; CI 0.8-3.8), urogenital (OR = 1.7, CI 1.1-2.6), musculoskeletal/integumental (maternal age >30 OR = 2.5, CI 1.6-4.0), and other defects (maternal age >35 OR = 2.9, CI 1.6-5.3). No increase was seen for central nervous system defects (OR = 1.1, CI 0.5-2.4). The investi-

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Veterans and Agent Orange: Update 1998 gators also reported higher rates of birth defects among the general population residing in predominantly agricultural regions of Minnesota compared to the rates in forest/urban regions. Higher rates were found for defects of the central nervous system, circulatory/respiratory, gastrointestinal, and urogenital systems. An additional analysis was conducted to evaluate specific pesticide use. Based on pounds of active ingredient per county, data for low-and high-use categories were defined for 12 specific pesticides and comparisons of the birth defect rates were made within each region. The authors reported that the most consistent associations were found for 2,4-D and MCPA (2-methyl-4-chlorophenoxyacetic acid). The overall rates were presented after combining the data for both herbicides and combining all defects into a "major" defects category (central nervous system, circulatory/respiratory, urogenital, musculoskeletal/integumental). The overall rate ratio, comparing high-and low-use regions, was 1.9 (CI 1.7-2.1) for major defects and 1.5 (CI 1.4-1.6) for all defects. No results for specific defect groups were presented. It was also noted that six of the seven counties with the greatest use of chlorophenoxy herbicides also used fungicides most frequently. The results of the study suggest a higher rate of birth defects among offspring of pesticide applicators than among the general population and a higher rate in regions with a greater use of chlorophenoxy herbicides. The study had the advantage of evaluating the risk of birth defects among the offspring of a unique occupational group—pesticide applicators—with a high potential for exposure to a variety of pesticides. County pesticide use data also provided interesting information for a regional ecologic analysis. The study had several limitations including the use of birth vital statistics to ascertain birth defects, use of a small number of confounders, lumping of birth defects into broad system groups, ecologic rather than individual-level pesticide data, and inability to separate the possible effects of multiple pesticides. Blatter et al. (1997) conducted a multicenter case-control study of paternal occupation and risk of spina bifida in offspring. Live-born cases of spina bifida were identified by medical records review at seven hospitals and two rehabilitation centers in the Netherlands (1980-1992). Controls were children who were born healthy but developed trauma capitis or meningitis during early childhood and were diagnosed at three of the hospitals where cases were identified (N = 456). Birth registries were used to identify another group of controls (N = 1,894). Case and control parents were initially mailed a questionnaire to collect data on occupational histories and potentially confounding factors. A follow-up telephone interview was conducted for fathers that had an occupation with potential chemical or physical exposure. This second interview included items on the frequency of tasks and exposures and the use of protective gear. Agricultural workers were included in this second interview. Estimation of exposure level was based on responses to a questionnaire, a detailed follow-up phone interview, and the judgment of industrial hygienists. Exposure was analyzed for the period from three months prior to the estimated conception date to one month after. Re-

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Veterans and Agent Orange: Update 1998 sponses to the initial questionnaire included 77 percent of cases and 68 percent of controls. The final analysis sample, including the second interview, totaled 222 cases and 764 controls. Data were collected on a number of potentially confounding factors including medication use, maternal diabetes, parity, family history of neural tube defects, and parental smoking and alcohol consumption. Overall, the prevalence of paternal pesticide use did not differ between cases and controls (11 case fathers, 35 control fathers; OR = 0.9, CI 0.4-1.9). However, an association was found for estimated moderate or high exposure to pesticides (73 percent of cases, 35 percent of controls; OR = 1.7, CI 0.7-4.0). The association was slightly reduced after adjustment for maternal agricultural employment (OR = 1.6). It was also noted that more case fathers used a backpack sprayer than control fathers (45 percent versus 21 percent). Calculation of the unadjusted odds ratio from data presented in the paper (Blatter et al., 1997, Table III) shows moderate association with moderate or heavy exposure to herbicides specifically (OR = 1.6, CI 0.6-4.0; 7 exposed cases and 15 exposed controls). The study had a number of strengths such as a relatively large number of cases, a two-stage interview to elicit more specific information on occupational exposures and work practices, and adjustment for multiple confounders, including maternal employment in agriculture. Study limitations included the use of only live-born cases, the lag between exposure and interview (2 to 15 years), response proportions, the lack of data on folic acid use, and the absence of separate analyses for each type of control group (hospital, population) to evaluate potential selection bias. In addition, although exposure determination and assessment were better than in some other earlier studies, they were still incomplete. For example, no consideration was given to potential pesticide exposure in workers outside of the agricultural industry. Further, no analyses were presented on specific pesticides, especially herbicides of interest such as 2,4-D, probably because of the small number of exposed subjects. A recent study of birth defects among the offspring of Norwegian farmers noted several associations, including spina bifida (Kristensen et al., 1997). The investigators created a cohort of farming families by linking several Norwegian national registries. Farm holders born after 1924 were identified from the computerized files of national agricultural censuses held in 1969, 1979, and 1989, and horticultural censuses in 1974 and 1985. Linkages with the Central Population Register and Medical Birth Registry identified a total of 192,417 births in 1967-1991 to farm holders. A comparison group consisted of 61,351 births to mothers residing in agricultural municipalities who were known to not be farm holders. Birth defects were identified from the Medical Birth Registry, a national registry of all births of 16 completed weeks' gestation with up to three birth defects recorded. In addition, data were available on potential confounding factors including maternal age, birth order, parental consanguinity, geographic location, and maternal chronic disease. Exposure information for each farm was obtained from the agricultural censuses. Exposure variables used in the analysis were

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Veterans and Agent Orange: Update 1998 based on type of farming (animal husbandry, grain farming, and orchard and greenhouse farming) and indicators of use (amount of money spent on pesticides, tractor pesticide-spraying equipment, and amount of phosphorus and nitrogen in fertilizers). Exposure information was derived from the census closest to the time of birth. The sensitive period for exposure was considered to be three months before the estimated date of conception. Overall, the prevalence rate of all birth defects among farmers was 217.7 per 10,000 births compared to 231.1 among non-farmer births (adjusted OR = 1.0, CI 0.9-1.1). Except for a few birth defects, there was no general association with farming. However, when specific exposure variables were evaluated, several associations were noted, including spina bifida and tractor spraying equipment (28 exposed cases; OR = 1.6, CI 0.9-2.7) and the combination of tractor spraying equipment and orchards/greenhouses (5 exposed cases; OR = 2.8, CI 1.1-7.1); hydrocephaly (tractor spraying equipment and orchards/greenhouses; 5 exposed cases; OR = 3.5, CI 1.3-9.1); cryptorchism (pesticide purchase and field vegetables; 19 exposed cases; OR = 2.3, CI 1.3-4.0); hypospadias (tractor spraying equipment and grain; 40 exposed cases; OR = 1.5 CI, 1.0-2.3); and limb reduction defects (pesticide purchase and grain; 16 exposed cases; OR = 2.5, CI 1.1-5.9). There was no positive association found with anencephaly (tractor spraying equipment; OR = 0.7, CI 0.4-1.2). No results were presented for spina bifida and other exposure combinations. The authors note that the finding for spina bifida is supported by the fact that more extensive use of pesticides at higher levels occurs in orchards/greenhouses in Norway and that higher ORs were found for births conceived in April-June. The study was truly population based (all of Norway), and some data on potential exposures and confounders were available. Nonetheless, exposure indices were indirect and based on an agricultural or horticultural census taken by the government at approximately 10-year intervals, hence not usually in the same year as conception and pregnancy, and exposure level of specific parents is uncertain. With respect to neural tube defects, the association appeared to be limited to spina bifida, not anencephaly. Synthesis The previous literature was generally inconsistent with regard to paternal occupational and environmental herbicide exposure and risk of birth defects in offspring. Several previous studies of veterans showed a suggestive association with spina bifida, although a number of methodologic issues limit interpretation. The occupational studies of Dimich-Ward et al. (1996), Blatter et al. (1997), and Kristensen et al. (1997) provide some additional support for the association of herbicide exposure with this specific birth defect, although concerns remain, including the control of confounding, exposure determination, statistical imprecision, and isolation of exposure to specific herbicides and TCDD. Association with other birth defects in the studies of veterans and agricultural occupations is inconsistent.

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Veterans and Agent Orange: Update 1998 Conclusions Strength of Evidence in Epidemiologic Studies There are no changes from Update 1996. In Update 1996, there was limited/ suggestive evidence of an association between exposure to the herbicides considered in this report and spina bifida. There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and other birth defects. Biologic Plausibility Laboratory studies, using adult male animals, of the potential male-mediated developmental toxicity of TCDD and herbicides, specifically with regard to birth defects, are too limited to permit conclusions. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and reproductive and developmental disorders is contained in Chapter 3; a summary is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans Since there are some data suggesting that the highest risks occur in those veterans estimated to have had exposure to Agent Orange (e.g., Ranch Hands), it therefore follows that there is limited/suggestive evidence for an increased risk of spina bifida among offspring of Vietnam veterans. A more thorough discussion of the issue of increased risk of disease among Vietnam veterans is contained in Chapter 1. FERTILITY Background Male reproductive function is a complex system under the control of several components whose proper coordination is important for normal fertility. There are several components or end points related to male fertility, including reproductive hormones and sperm parameters. Only a brief description of male reproductive hormones is given here; more detailed reviews can be found elsewhere (Yen and Jaffe, 1991; Knobil et al., 1994). The reproductive neuroendocrine axis involves the central nervous system, the anterior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates gonadotropins (luteinizing hormone and follicle-stimulating hormone). Both of these hormones are necessary for normal spermatogenesis. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are secreted in episodic bursts by the anterior pituitary gland into the circulation. LH interacts

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Veterans and Agent Orange: Update 1998 TABLE 9-4 Selected Epidemiologic Studies—Neonatal Death Reference Study Population Exposed Cases Estimated Risk (95% CI) OCCUPATIONAL Studies Reviewed in VAO Suskind and Hertzberg, 1990 Follow-up of 2,4,5-T production workers 17 1.8 (0.7-4.5) May, 1982 Follow-up of 2,4,5-T production workers—perinatal death 1   ENVIRONMENTAL       Studies Reviewed in VAO Stockbauer et al., 1988 TCDD soil contamination in Missouri Perinatal deaths (includes stillbirths) 1.3 (0.4-4.2)   VIETNAM VETERANS       Studies Reviewed in VAO Aschengrau and Monson, 1990 Neonatal death and paternal Vietnam service       Vietnam veterans compared to men with no known military service 3 1.2 (0.2-4.2)   Vietnam veterans compared to non-Vietnam veterans 3 1.1 (0.2-4.5) CDC, 1989 Vietnam Experience Study       GBDS study—early neonatal death 16 2.0 (0.8-4.9) Field and Kerr, 1988 Follow-up of Australian Vietnam veterans 12 18.1 (2.4-134.4) (Alberman, 1984). Although often treated as a single entity, the concept of low birthweight actually encompasses two different causal pathways: (1) low birth-weight secondary to intrauterine growth retardation (IUGR) or small for gestational age, which is more related to neonatal morbidity, and (2) low birthweight secondary to preterm delivery, which is more strongly associated with neonatal mortality (Alberman, 1984; Kallen, 1988). The concept of IUGR represents birthweight adjusted for gestational age. The currently used definition of preterm delivery (PTD) is delivery at less than 259 days, or 37 completed weeks of gestation, calculated on the basis of the date of the last menstrual period (Bryce, 1991). Approximately 7 percent of live births have low birthweight. The incidence of IUGR is much more difficult to quantify since there are no universally applied standards for dividing the distribution of birthweight for gestational age. When no distinction is made between the causes of low birthweight (i.e., IUGR versus PTD), the factors most strongly associated with reduced birthweight are maternal smoking during pregnancy, multiple births, and race or ethnicity. Other potential risk factors for low birthweight include socioeconomic status (SES), maternal size, birth order, maternal complications during pregnancy (e.g., severe

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Veterans and Agent Orange: Update 1998 TABLE 9-5 Selected Epidemiologic Studies—Infant Death Reference Study Population Exposed Cases Estimated Risk (95% CI) OCCUPATIONAL New Studies Dimich-Ward et al., 1996 British Columbia sawmill workers       Maximal index of exposure for any job held up to three months prior to conception 300 1.0 (0.9-1.0) Studies Reviewed in VAO Townsend et al., 1982 Follow-up of Dow chemical plant workers 9 0.6 (0.3-1.4) ENVIRONMENTAL Studies Reviewed in VAO Stockbauer et al., 1988 TCDD soil contamination in Missouri 5 2.0 (0.5-8.7) VIETNAM VETERANS New Studies Michalek et al., 1998 Ranch Hand—infant death post-service in southeast Asia       Background 5 3.2 (1.0-10.3)   Low 2 1.5 (0.3-7.5)   High 6 4.5 (1.5-14.0) Studies Reviewed in VAO CDC, 1989 Vietnam Experience Study       Interview study 152 1.0 (0.8-1.3)   Low exposure 58 1.9 (1.2-2.9)   Medium exposure 38 2.0 (1.2-3.1)   High exposure 11 2.7 (1.4-5.4) Field and Kerr, 1988 Follow-up of Australian Vietnam Veterans—deaths between ages 1 month and 1 year 4 0.9 (0.2-3.5) preeclampsia) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Kallen, 1988). Established risk factors for preterm birth include race, marital status, socioeconomic status, previous low birthweight or preterm birth, multiple gestations, cigarette smoking, and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993). Summary of VAO and Update 1996 Given the lack of available occupational and environmental studies, the evidence on low infant birthweight was considered inadequate. Its inadequacy is due to the paucity of occupational studies and lack of consistent findings. One avail-

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Veterans and Agent Orange: Update 1998 able epidemiologic study (Stockbauer et al., 1988) of dioxin exposure (soil contamination) reported a weak association (statistically nonsignificant) with low birthweight. Studies of veterans were inconsistent (AFHS, 1992; CDC, 1989; Field and Kerr, 1988); some indicated no increased risk, whereas others suggested an increased risk among certain subgroups. Update of Scientific Literature The study of sawmill workers in British Columbia also evaluated the association between chlorophenates and risk of low birthweight (Dimich-Ward et al., 1996). The sawmill worker cohort was linked with birth records maintained by the British Columbia Division of Vital Statistics. Low birthweight was defined as less than 2,500 grams, and small for gestational age as less than the 10th percentile based on the distribution of birthweight for gestational age in British Columbia. In addition, the investigators examined preterm birth (<37 weeks gestation). Adjustment was made for gender and, in the case of low birthweight, gestational age as well. No association was found for either low birthweight, small for gestational age, or PTD and any of the chlorophenate exposure measures. For the maximal index of exposure for any sawmill job held up to three months prior to conception, the odds ratios were close to 1.0 (low birthweight OR = 0.99, CI 0.97-1.0; small for gestational age OR = 1.0, CI 0.9-1.0; preterm birth OR = 0.9, CI 0.9-1.0). The recent Ranch Hand analysis described in the previous section also evaluated PTD and IUGR (Michalek et al., 1998). Preterm delivery (<37 weeks gestation) was determined using the mother' s record of labor and delivery. IUGR was defined as birthweight less than the 10th percentile of birthweight for gestational week. The post-SEA analysis did not find a pattern of increased risk relative to dioxin exposure (background RR = 1.4, CI 0.9-2.3; low RR = 0.5, CI 0.2-1.5; high RR = 1.3, CI 0.8-2.3). With respect to IUGR, the relative risks were close to 1.0 for all exposure categories (background RR = 0.9, CI 0.6-1.4; low RR = 0.9, CI 0.6-1.3; high RR = 0.9, CI 0.6-1.3). As discussed previously, the Ranch Hand study is a valuable cohort because of exposure and outcome assessment, although again some of the analyses are limited by a small number of subjects. Synthesis Previous studies of Vietnam veterans (AFHS, 1992; CDC, 1989; Field and Kerr, 1988) did not consistently find an association between herbicide and dioxin exposure and an increased risk of low birthweight and preterm birth. The British Columbia study (Dimich-Ward et al., 1996) of chlorophenate-exposed sawmill workers did not find any association with low birthweight, small for gestational age, or preterm birth. The new Ranch Hand report (Michalek et al., 1998) did not find an association between dioxin exposure and an increased risk of preterm

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Veterans and Agent Orange: Update 1998 birth or small for gestational age. The evidence remains inadequate because some studies were limited by small sample sizes for higher-exposure categories, failure to account for potential confounding factors, and exposure misclassification. Studies are summarized in Table 9-6. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in the report and low birthweight and preterm birth. Biologic Plausibility Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are too limited to permit conclusions. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and reproductive and developmental disorders is contained in Chapter 3; a summary is presented in the conclusion to this chapter. CONCLUSIONS FOR REPRODUCTIVE EFFECTS Strength of Evidence in Epidemiologic Studies In Update 1996 there was limited/suggestive evidence of an association between exposure to the herbicides considered in this report and spina bifida. The occupational studies of Dimich-Ward et al. (1996), Blatter et al. (1997), and Kristensen et al. (1997) provide some additional support for the association with this specific birth defect, although concerns remain including control of confounding, exposure determination, statistical imprecision, and isolation of exposure to specific herbicides and TCDD. There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides and fertility, stillbirth, neonatal and infant death, birth defects (other than spina bifida), and low birthweight and preterm birth. Biologic Plausibility Chapter 3 details the committee's evaluation of data from animals and studies with cells regarding the biological plausibility of a connection between exposure to dioxin or herbicides and various reproductive and developmental effects.

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Veterans and Agent Orange: Update 1998 TABLE 9-6 Selected Epidemiologic Studies—Low Birthweight and Preterm Birth Reference Study Population Exposed Cases Estimated Risk (95% CI) OCCUPATIONAL New Studies Dimich-Ward et al., 1996 Sawmill workers—Maximal index of exposure for any job held up to three months prior to conception Low birthweight 848 0.9 (0.9-1.0)   Preterm birth 867 0.9 (0.6-1.3) Studies Reviewed in VAO Fitzgerald et al., 1989 Follow-up of an electrical transformer fire 3 81 (16.7-236.4)* ENVIRONMENTAL       Studies Reviewed in VAO Stockbauer et al., 1988 TCDD soil contamination in Missouri       Intrauterine growth retardation 14 1.1 (0.5-2.3)   Low birthweight 27 1.5 (0.9-2.6) VIETNAM VETERANS New Studies Michalek et al., 1998 Ranch Hand preterm birth       Background 20 1.4 (0.9-2.3)   Low 6 0.5 (0.2-1.2)   High 16 1.3 (0.8-2.3)   Intrauterine growth retardation—post-service in southeast Asia       Background 29 0.9 (0.6-1.4)   Low 22 0.9 (0.6-1.3)   High 22 0.9 (0.6-1.3) Studies Reviewed in VAO AFHS, 1992 Follow-up of Air Force Ranch Hands conceptions during or after Southeast Asian service with high current dioxin levels 20 2.3 (1.3-4.0) CDC, 1989 Vietnam Experience Study (GBDS) 99 1.0 (0.8-1.4) Field and Kerr, 1988 Follow-up of Australian Vietnam veterans 48 1.6 (1.0-2.5) Stellman et al., 1988 Offspring of American Legion Vietnam veterans — — * Standard incidence rate (SIR).

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Veterans and Agent Orange: Update 1998 This section summarizes that evidence. Some of the preceeding discussions of reproductive and developmental outcomes include references to specific relevant papers. TCDD is reported to cause a number of reproductive and developmental effects in laboratory animals. 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. TCDD has also been found to decrease the levels of hormones such as testosterone in rats. The reproductive systems of adult male laboratory animals are considered to be relatively insensitive to TCDD, because high doses are required to elicit effects. Limited research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed varying concentrations of simulated Agent Orange mixtures concluded there were no adverse effects in offspring. A statistically significant excess of fused sternebra in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of the defect in the controls. Another study reported an increase in the incidence of malformed offspring of male mice exposed to subacute levels of a mixture of 2,4-D and picloram in drinking water. However, the paternal toxicity observed in the high dosage levels used and inconsistent dose-response pattern are of concern. Studies in male rats and hamsters show that decreased daily sperm production and cauda epididymal sperm number result from in utero and lactational TCDD exposure. Research suggests that in utero and lactational TCDD exposure selectively impairs rat prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate DHT concentrations. Studies in female animals are limited but demonstrate in utero and lactational exposure reduced fertility, decreased ability to remain pregnant throughout gestation, decreased litter size, increased fetal death, impaired ovary function, and decreased levels of hormones such as estradiol and progesterone. Most of these 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. Recent studies on female rats show that a single dose of TCDD administered on gestational day 15 results in malformations of the external genitalia in Long-Evans and Holtzman rats. There was complete to partial clefting of the phallus. Exposure on gestation day 8 was more effective in inducing functional reproductive alterations in female progeny (e.g., decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, and increased incidences of constant estrus). TCDD also induced changes in serum hormone levels in immature female rats administered TCDD by gastric intubation, increasing LH, FSH, and gonadotropin levels. This effect is partially due to the action of TCDD on the pituitary and is calcium dependent.

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Veterans and Agent Orange: Update 1998 TCDD exposure did not increase egg mortality nor did it affect time-to-hatching of newly fertilized zebrafish eggs. However, pericardial edema and craniofacial malformations were observed in zebrafish larvae. In ovo TCDD exposure adversely affected the body and skeletal growth and hatchibility of the domestic pigeon but had no effect on the domestic chicken or great blue heron. TCDD is teratogenic in mice, inducing cleft palate and hydronephrosis. Research indicates that co-exposure with either of two other chemicals, hydrocortisone or retinoic acid, synergistically enhances expression of cleft palate. This synergy suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. Several reports published during the reference period describe developmental deficits in the cardiovascular system of TCDD-treated animals. For example, the cardiotoxicity induced by TCDD was examined in the chick embryo. The spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed following TCDD exposure. Evidence suggests that the endothelium lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. CYP1A1 induction in the endothelium may be linked to early lesions that result in TCDD-induced vascular derangements. CYP1A1 is induced in mammalian endothelial cells in culture in the vascular endothelium in lake trout of developing animals and in adult quail aortic smooth muscle cells. DNA damage and consequent cell death in the embryonic vasculature are key physiological mediators of TCDD-induced embryotoxicity in Medaka, a type of fish often used in laboratory studies. Treatment of TCDD-exposed Medaka embryos with an anti-oxidant provides significant protection against TCDD-induced embryotoxicity and suggests that reactive oxygen species may participate in the teratogenic effects of TCDD. Little information is available on the cellular and molecular mechanisms of action that mediate TCDD's reproductive and developmental effects in laboratory animals. Evidence from mice indicates that the Ah receptor may play a role. However, other, as-yet-unidentified factors also play a role, and it is possible that these effects occur only secondarily to TCDD-induced general toxicity. Extrapolating these results to humans is not straightforward because of the many factors that determine susceptibility to reproductive and developmental effects vary among species. More generally, TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. These effects may in turn influence reproductive and developmental outcomes. Limited information is available on reproductive/developmental effects of the herbicides discussed in the report. Studies indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities, but when preg-

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Veterans and Agent Orange: Update 1998 nant rats or mice are exposed it does reduce the rate of growth of offspring and increase their rate of mortality. Very high doses were required to elicit these effects. 2,4,5-T was toxic to fetuses when administered to pregnant rats, mice, and hamsters. The ability of 2,4,5-T to interfere with calcium homeostasis in vitro was documented and linked to the teratogenic effects of 2,4,5-T 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. Limited data suggested that picloram may produce fetal abnormalities in rabbits at doses that are also toxic to the pregnant animals. The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human reproductive and developmental disorders, is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains and species, lack of strong evidence of organ-specific effects across species, and differences in route, dose, duration and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for induction of specific reproductive and developmental disorders by TCDD and herbicides. Considerable uncertainty remains over how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes, and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee's general findings regarding this charge. Where more specific information about particular health outcomes is available, this information is related in the preceding discussions of those health outcomes. REFERENCES Ahlborg G, Hogstedt C, Bodin L, Barany S. 1989. Pregnancy outcome among working women. Scandinavian Journal of Work, Environment, and Health 15:227-233. Air Force Health Study (AHFS). 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1992-0090.

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