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Research Highlights BIRTH DEFECTS Introduction This section taken from Chapter 9 of the full report summarizes published scientific literature on exposure to herbicides and birth defects. A complete discussion of the evidence is presented for these adverse reproductive/develop- mental outcomes because the committee has changed its assessment of this litera- ture since the release of VAO. In VAO, the committee concluded that the evi- dence at that time was inadequate or insufficient to determine whether an association existed between exposure to herbicides and 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 viabil- ity or physical well-being. Major birth defects are seen in approximately 2 to 3 percent of live births (Kalter and Warkany, 1983~. 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 15

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6 VETERANS AND AGENT ORANGE: UPDATE 1996 men who served in Vietnam (2.6 million), and assuming 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). Epidemiologic Studies of Birth Defects Because the publication of new data from the Ranch Hand study has caused the committee to change its conclusion about the strength of the evidence regard- ing the association between exposure to herbicides used in Vietnam and birth defects, the following material was included from VAO to present a complete picture about the evidence for the committee's conclusions. The section entitled "Ranch Hand Study," however, is based on the new information. Chapter 6 of the full report discusses in greater detail the characteristics of each study. Occupational Studies Four occupational epidemiology studies have examined the potential asso- ciation between herbicide exposure of male workers and birth defects. The Townsend study (Townsend et al., 1982) of workers with potential dioxin expo- sure at a Dow Chemical plant did not find an increased risk of birth defects among dioxin-exposed workers (30 births with anomalies; 47/1,000 births) com- pared to unexposed workers (87 births with anomalies; 49/1,000 births; OR = 0.9, CI 0.5-1.4~. A major limitation of this study is its limited statistical power to detect an elevated odds ratio for specific defects. The authors noted that the study had 26 percent power to detect a doubling of risk due to exposure for a group of indicator malformations (anomalies thought to be easily recognized and reported by the mother, such as an oral cleft, spine bifida, and Down's syndrome). An additional problem is that despite the use of these "indicator malformations," without medical records, validation of the accuracy of maternal self-report of birth defects is questionable for many conditions. Two studies of workers from a 2,4,5-T plant in Nitro, West Virginia, did not report an association with birth defects among offspring (Moses et al., 1984; Suskind and Hertzberg, 1984~. The relative risk estimates for any birth defect were 1.3 (CI 0.5-3.4) for Moses et al. and 1.1 (CI 0.5-2.2) from the Suskind and Hertzberg study. Both studies had limited statistical power, given the small number of subjects (204 exposed workers in the Suskind and Hertzberg study; 117 exposed workers in the Moses study). This is especially problematic for the evaluation of most specific birth defects. Both studies also relied on self-reports for the ascertainment of birth defects. A study of 2,4,5-T sprayers found only a slightly elevated odds ratio for congenital anomalies (OR = 1.2, CI 0.5-3.0) associated with the spraying group (Smith et al., 1982~. The study used self-administered questionnaires to deter

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RESEARCH HIGHLIGHTS 17 mine outcomes. Like the other studies, it had limited power for the analysis of individual birth defects. Environmental Studies A variety of environmental studies have examined the relationship between herbicide exposure and prevalence of birth defects (Nelson et al., 1979; Gordon and Shy, 1981; Hanify et al., 1981; Mastroiacovo et al., 1988; Stockbauer et al., 1988; White et al.,1988; Fitzgerald et al., 1989; Jansson and Voog,1989~. Some studies reported a statistical association with specific birth defects (clubfoot, Fitzgerald et al., 1989; cleft lip with or without cleft palate, Gordon and Shy, 1981; heart, hypospadias, clubfoot, Hanify et al., 1981; oral clefts, Nelson et al., 1979), although others have not reported an association (Stockbauer et al., 1988; Fitzgerald et al., 1989; Jansson and Voog, 1989), including the Seveso study (Mastroiacovo et al., 1988~. Interpretation of the results of these environmental studies is difficult, because most of the studies were inconsistent, were based on ecologic correlations, had inadequate statistical power, did not validate birth defects recorded from vital statistics or self-reports, and included both male and female exposures. A recently published study from Vietnam evaluated the risk of birth defects among the offspring of mothers who resided in a village in the southern part of the country that had been sprayed during the conflict (Phuong et al., 1989~; 81 cases of birth defects (diagnosis not specified) were identified. No differences were reported between cases and controls for the potentially confounding factors investigated. Strong associations were found for birth defects (calculated from data presented; OR = 3.8, CI 1.1-13.1~. The paper is difficult to evaluate given the sparse details presented. Study design factors such as how birth defects were diagnosed and what types were detected, the size of the original case and control groups from which the final groups were sampled, the pattern of patient accrual for this hospital, the method of data collection, and how the potential herbicide spraying histories were determined were not specified. Finally, to put the study in the context of this review, the potential exposure 17 to 22 years earlier pertains to both the mother and the father. Results from a number of other studies from Vietnam, both of sprayed vil- lages in the southern part of the country and of veterans returning to the unsprayed northern regions, have been reported, mostly in a review by Constable and Hatch (1985~. These studies indicate an increased risk of birth defects, including anen- cephaly, oral clefts, and a variety of other anomalies. Nonetheless, these studies generally suffer from poor reporting and a variety of methodologic problems such as limited control of confounding factors, use of a referral hospital, lack of comparison groups, uncertainty of exposure classification, and no validation of reported birth defects. Although the findings are suggestive of an association

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8 VETERANS AND AGENT ORANGE: UPDATE 1996 between herbicide spraying and birth defects, the available studies are insuffi- cient to draw firm conclusions. Vietnam Veterans Studies As part of the CDC Vietnam Experience Study (1989), the reproductive outcomes and the health of children of male veterans were examined. The VES assessment included a telephone interview, a review of hospital birth defect records for a subsample of veterans who underwent a medical examination, and a review of the medical records of selected birth defects for all study subjects. The interview data revealed that Vietnam veterans reported more birth de- fects (64.6 per 1,000 total births) among offspring than did non-Vietnam veterans (49.5 per 1,000 total births). The adjusted odds ratio estimate for congenital anomalies as a group was 1.3 (CI 1.2-1.4~. When examined by specific defect category, elevated adjusted odds ratios were found for defects of the nervous system (OR = 2.3, CI 1.2-4.5~; ear, face, neck (OR = 1.6, CI 0.9-2.8~; and integument (OR = 2.2, CI 1.2-4.0~. A small but statistically significant odds ratio of 1.2 (CI 1.1-1.5) was found for musculoskeletal defects. An analysis of specific defects considered by the investigators to be relatively common and reliably diagnosed was also conducted. Elevated (crude) odds ratios were reported for hydrocephalus (OR = 5.1, CI 1.1-23.1), spine bifida (OR = 1.7, CI 0.6-5.0), and hypospadias (OR = 3.1, CI 0.9-11.3~. Vietnam veterans also reported having more children with multiple defects (OR = 1.6, CI 1.1-2.5) than non-Vietnam veterans. An analysis of Vietnam veterans' self-reported herbicide exposure found a dose-response gradient, with an adjusted odds ratio for birth defects of 1.7 (CI 1.2-2.4) at the highest level of exposure. The VES also examined serious health problems in the veterans' children; that is, the veterans were asked to report physician-diagnosed major health prob- lems or impairments during the first five years of their children's lives. About half of the health conditions reported were respiratory disease (mostly asthma and pneumonia) and otitis media. For most of the conditions, the veterans re- ported more health conditions than non-Vietnam veterans (all conditions, OR = 1.3, CI 1.2-1.4~. After excluding children with a serious health condition or either a birth defect or cancer, the overall crude OR was 1.2 (CI 1.1-1.3~. E1- evated crude odds ratios were found for anemias (OR = 2.0, CI 1.2-3.3), diseases of the skin (OR = 1.5, CI 1.1-1.9), rash (OR = 2.3, CI 1.1-4.9), and allergies (OR = 1.6, CI 1.2-2.1~. Without medical records that validate for many of these types of common conditions and health problems, recall bias may be an explanation for many of these findings. The CDC (1989) did conduct two substudies using hospital records to iden- tify birth defects among the veterans' offspring. The first, the General Birth Defects Study (GBDS), compared the occurrence of birth defects recorded on hospital records for the children of Vietnam and of non-Vietnam veterans (130

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RESEARCH HIGHLIGHTS 19 cases and 112 cases, respectively) who participated in the medical examination component of the VES. For a variety of characteristics, there were no apparent differences between the group of men who participated in the exam and the total interview group. There was no difference in the prevalence of birth defects be- tween the two groups of children (crude OR = 1.0, CI 0.8-1.3~. There was a slight but nonsignificant excess for major birth defects (OR = 1.2, CI 0.8-1.9~. When analyzed by organ system, only digestive system defects appeared to be elevated (OR = 2.0, CI 0.9-4.6), although the small number of defects precluded the analysis of several broad categories. The number of defects was also too small for the analysis of specific individual defects. An analysis by race did indicate an elevated odds ratio (3.4, CI 1.5-7.6) for black Vietnam veterans. An examination of the specific defects listed on hospital records for children of black veterans did not reveal any particular pattern. A comparison of interview and hospital records was also conducted to evaluate the extent of potential misclassification of veteran responses. In general, interview responses were not predictive of the presence of a defect for either veteran group. The agreement between interview and hospital records was slightly poorer for Vietnam veterans. For example, the positive predictive value of the interview response for the presence of a defect in the hospital record was 24.8 percent among Vietnam veterans and 32.9 percent among non-Vietnam veterans. Sensitivity was 27.1 percent among Vietnam veterans and 30.3 percent among non-Vietnam veterans. The kappa measure of agreement was also lower (20.9 percent versus 27.6 percent) among Vietnam veterans. The second substudy, the Cerebrospinal Malformation (CSM) Study, in- volved the analysis of medical records for all cases of cerebrospinal malforma- tions (spine bifida, anencephalus, hydrocephalus) and stillbirths reported by vet- erans in the interview study. The substudy found 26 cerebrospinal malformations (live and stillbirths) among children of Vietnam veterans and 12 among children of non-Vietnam veterans. No formal analysis of the difference in malformations between the veteran groups was conducted, because negative responses (i.e., children without a reported malformation) were not verified and the participation rates differed between groups (7.8 percent of Vietnam veterans and 22.1 percent of non-Vietnam veterans refused to participate). The VES did find suggestive associations for birth defects. It is interesting to note that some potential associations were found for birth defects considered by the investigators to be "relatively common, easily diagnosed, and observable at birth" (CDC, 1989~. These include hydrocephalus (OR = 5.1, CI 1.1-23.1) and hypospadias (OR = 3.1, CI 0.9-11.3~. The GBDS did not replicate these findings, but this sample had limited power for the analysis of specific defects. Although associations were not found for all conditions, there was clearly a general pattern of a greater prevalence of birth defects in the offspring of Vietnam veterans, according to self-reports. The authors properly note the potential for recall bias as an explanation for the pattern of excess risk. As an attempt to evaluate recall bias, two record validation studies of birth defects were conducted. Overall, the

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20 VETERANS AND AGENT ORANGE: UPDATE 1996 GBDS did not find any association with an increased risk of birth defects among offspring of Vietnam veterans. However, this validation study had limited power to detect an increased risk for specific birth defects. The second validation substudy, the CSM review, was flawed by the differentially poor response rate among the non-Vietnam veteran group. This result and the fact that negative responses were not pursued discouraged the investigators from estimating the relative risk for cerebrospinal malformations. Another important study of Vietnam veterans was the CDC Birth Defects Study (Erickson et al., 1984a,b). In this study, children with birth defects among 428 fathers who were reported to have been Vietnam veterans were compared to children with birth defects among 268 control fathers who were non-Vietnam veterans. The odds ratio for Vietnam veteran status in relation to any major birth defect among offspring was 1.0 (CI 0.8-1.1~. Analysis of the Agent Orange exposure opportunity index (EOI; see VAO Chapter 6 for details) based on both military records and self-reports did not indicate a statistically significant trend of increasing risk of all types of birth defects (combined) with increasing levels of Agent Orange exposure. No association was noted between Vietnam veteran status or self-reported Agent Orange exposure and risk of fathering a child with multiple birth defects (OR = 1.1, CI 0.7-1.7~. The odds ratios for Vietnam veteran status, self-reported Agent Orange exposure, and logistic regression coef- ficients for EOI based on self-report and military records for most of the 95 birth defect groups were not significantly elevated. Although the odds ratio for spine bifida was not elevated with Vietnam veteran status (OR = 1.1), the EOI indices showed a pattern of increasing risk. For example, the odds ratios for the EOI based on information obtained during the interview for low to high levels of exposure (levels 1 to 5) were 1.2 (CI 1.0-1.4), 1.5 (CI 1.1-2.1), 1.8 (CI 1.1-3.0), 2.2 (CI 1.2-4.3), 2.7 (CI 1.2-6.2~. A similar pattern was found for cleft lip with/ without cleft palate namely, EOI-1 (OR = 1.2, CI 1.0-1.4), EOI-2 (OR = 1.4, CI 1.0-1.9), EOI-3 (OR = 1.6, CI 1.0-2.6), EOI-4 (OR = 1.9, CI 1.0-3.6), and EOI-5 (OR = 2.2, CI 1.0-4.9~. The category "specified anomalies of nails" had an increased odds ratio for Vietnam veteran status and elevated coefficients (not statistically significant) for the two exposure indices. The category "other neo- plasms" was related to the EOI based on the father's self-reported Agent Orange exposure. This group included a variety of congenital neoplasms such as cysts, teratomas, and benign tumors. In an attempt to search for a Vietnam veteran birth defect "syndrome," pairs and triplets of defects were examined for combinations that yielded significant differences in the distribution among Vietnam veterans and controls. According to the authors, these analyses did not produce any important associations or patterns among defect combinations. The results of this study were generally negative; that is, there was not a general pattern of increased risk for birth defects among the offspring of Vietnam veterans. However, the analysis of the Agent Orange EOIs based on military records found a significant trend for increased risk for spine bifida with increased

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RESEARCH HIGHLIGHTS 21 exposure. As the authors note, this finding must be viewed with caution, because a related defect, anencephalus, was not found to be associated with a significant EOI trend. Another positive association was noted for cleft lip without cleft palate, where a significant regression coefficient was found for the EOI index based on the father's interview. No association was found for the EOI from military records. The CDC Birth Defects Study has many strengths, including the use of a population-based registry system with careful classification of birth defects for analysis. The statistical power of the study was excellent for many major birth defects. Use of the Agent Orange EOIs is an attempt to refine exposure assess- ment procedures compared to measures used in most other studies. The study did have several important limitations. First, the response rates among cases and controls were problematic, with approximately 56 percent of eligible case and control fathers interviewed. Examination of the nonparticipation group revealed lower participation among persons classified as "nonwhite." The analyses by race did not find important differences, but the potential for bias should not be overlooked. Another problem relates to the fact that case births occurred from 1968 through 1980, but interviews took place during 1982 and 1983, up to 14 years after the birth. To minimize the potential recall bias induced by this long lag period, controls were matched on year of birth. Aschengrau and Monson (1990) studied late adverse pregnancy outcomes among 14,130 obstetric patients who delivered at Boston Hospital for Women from August 1977 to March 1980. History of the fathers' military service in Vietnam was determined from Massachusetts and national military records by using the husbands' names and Social Security numbers. The likelihood of combat experience, based on branch of service and military occupation, was used to estimate potential herbicide exposure. The analyses compared the risk of malformations among children of 107 Vietnam veterans to that for children of 1,432 men without known military service; the risk in 313 non-Vietnam veterans compared to the men without military service; and the risk in the Vietnam veter- ans compared with the non-Vietnam veterans. There was a slight, nonsignificant increase in the odds ratio for all congenital anomalies for Vietnam veterans compared to men without known military service (OR = 1.3, CI 0.9-1.9) and for Vietnam veterans compared with non-Vietnam veterans (OR = 1.2, CI 0.8-1.9~. For major malformations, the odds ratio was elevated for Vietnam veterans com- pared with men without military service (OR = 1.8, CI 1.0-3.1), but the ratio decreased for Vietnam veterans compared with non-Vietnam veterans (OR = 1.3, CI 0.7-2.4~. Only slight increases were found for the analysis of minor malfor- mations and "only normal variants." Although based on small numbers, the analyses of 12 malformation groups found that children of Vietnam veterans, compared to children of men with no known military service, had an increased risk of malformations of the nervous system, cardiovascular system, genital or- gans, urinary tract, and musculoskeletal system. Confidence intervals were not

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22 VETERANS AND AGENT ORANGE: UPDATE 1996 presented with the odds ratio estimates, but it was noted that they included 1.0, so elevated risks were not significantly increased. Further examination of specific anomaly diagnoses for the 18 infants of Vietnam veterans with major malforma- tions did not reveal any pattern of association with potential herbicide exposure. Although the study did find a positive association between paternal military service in Vietnam and the risk of major malformations in offspring, the authors suggest cautious interpretation of their findings, given the small number of sub- jects in many of the comparisons involving specific groups of birth defects. Additionally, it was noted that some of the malformations observed can also be due to maternal and delivery factors (endocrine condition and fetal presentation). An important problem relates to misclassification of herbicide exposure due to equating exposure to service in Vietnam. Two state health surveys of veterans (Iowa and Hawaii) did not indicate an increased prevalence of birth defects (Rellahan, 1985; Wendt, 1985), but a survey in Maine did report an increased risk of birth defects among veterans (Deprez et al., 1991~. The limitations of these general survey studies affect their usefulness in this evaluation. As part of the National Vietnam Veterans Birth Defects/Learning Disabili- ties Registry and database, a joint project of the Association of Birth Defect Children and the New Jersey Agent Orange Commission, a self-administered questionnaire was sent to Vietnam veterans to inquire about birth defects and a variety of conditions and disabilities in the children of Vietnam veterans and non- Vietnam veterans (Lewis and Mekdeci, 1993~. A preliminary analysis indicated no differences in birth defects between the two groups; however, for a variety of conditions, including allergies, frequent infections, benign tumors, cysts, and chronic skin disorders, the veterans showed a higher frequency. The possibility of recall bias and the self-selected nature of the registry are of concern. Nonethe- less, a carefully designed and comprehensive epidemiologic study with review of medical records could address the possibility of an association with some of these childhood health conditions. A study of birth defects among offspring of Australian Vietnam veterans was conducted using a total of 8,517 matched case-control pairs, with 127 infant cases and 123 infant controls having a father who served in Vietnam (Donovan et al., 1984~. There were 202 cases and 205 controls whose fathers were in the Army but did not serve in Vietnam. The adjusted odds ratio for birth defects among children of Vietnam veterans versus all other men was 1.02 (CI 0.8-1.3~. Analy- sis of subgroups based on the type of Army veteran (Australian Regular Army enlisters, National Service draftees) did not detect any increased odds ratios for these comparisons. There was a slight, statistically nonsignificant increase in the odds ratio for National Service Vietnam veterans versus those who did not serve in Vietnam (OR = 1.3, CI 0.9-2.0~. The risk was independent of the length of Vietnam service and the time between service and conception. Analyses by diagnostic group (central nervous system, cardiovascular, oral clefts, hypospadias,

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RESEARCH HIGHLIGHTS 23 musculoskeletal, dislocation of hip, chromosomal anomalies) did not show an excess risk for Vietnam veterans. However, two defects had odds ratios above 1.5 (statistically nonsignificant) ventricular septal defects (OR = 1.8) and Down's syndrome (OR = 1.7~. Overall, this study was negative; that is, there was no evidence of an in- creased risk of fathering a child with a congenital anomaly for Australian Army veterans who served in Vietnam. As indicated by the upper confidence limit (1.3), this study had adequate power to rule out an odds ratio greater than 1.3 for congenital anomalies. Assessment of potential Agent Orange exposure in this study is limited, because "history of service" in Vietnam was used as the primary "exposure" variable. This uncertainty is further compounded by potential differ- ences in the location and nature of service of Australian veterans in Vietnam and their resultant herbicide exposure. The Australian study of veterans living in Tasmania reported more congeni- tal anomalies among the 357 Vietnam veterans than among the comparison fami- lies (Field and Kerr, 1988~. The authors suggested that the results indicated a pattern of association with congenital heart disease and anomalies of the central nervous system. As described earlier in the section on spontaneous abortion, there are several notable problems with this study, including inadequate presenta- tion of results, potential selection bias, self-reported health outcomes, and using service in Vietnam as a surrogate for herbicide exposure. Ranch Hand Study The latest report from the Air Force Health Study (AFHS) of Operation Ranch Hand veterans ("Ranch Hands") and their children was pub- lished in 1995 (Wolfe et al., 1995~. The Air Force released a first report on the analysis of reproductive effects in 1982, and this report was reviewed in VAO (AFHS, 1992~. The original study cohort comprised 1,098 Ranch Hands who regularly handled and sprayed herbicides in Southeast Asia from 1962 to 1971 ("exposed cohort") and a comparison group of 1,549 Air Force veterans who were in Southeast Asia at the same time but presumably were not exposed to herbicides. In 1987, 995 Ranch Hands (91 percent of original study group) and 1,299 comparison veterans (84 percent of original group) participated in a physi- cal exam and agreed to provide serum samples for the dioxin assay. A total of 872 Ranch Hands (79 percent of original cohort, 88 percent of 1987 cohort) and 1,036 comparison subjects (67 percent of original group, 80 percent of 1987 cohort) were available for analysis, after exclusion of samples that were unreli- able because of laboratory error or that had dioxin levels below the level of detection or above an upper threshold for background (10 parts per trillion [ppti) for comparison subjects. Of the 872 Ranch Hands, 454 had 1,006 self-reported conceptions and 419 fathered 792 liveborn infants during their service in Viet- nam or until January 1990. Of the 1,036 comparison veterans, 570 had 1,235 conceptions and 531 fathered 981 liveborn infants during this period. The initial dioxin level was estimated from the current level using a first

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24 VETERANS AND AGENT ORANGE: UPDATE 1996 order decay rate model with a fixed 7.1-year half-life estimate. The referent group for the Ranch Hands included the conceptions and offspring of comparison men with "background" levels (<10 ppt, N= 570, mean = 3.9 ppt). Ranch Hands with levels at background were analyzed as a separate stratum (N= 179), since the authors felt this group included a mixture of exposed and unexposed veterans, given their mean level of 6.1 ppt and uncertainties in dioxin elimination. The other strata used in the analysis included Ranch Hand "low" (current <10 ppt and initial < 1 10 ppt, N = 1 19) and Ranch Hand "high" ~ current <10 ppt and initial >110 ppt, N= 156~. The 110 ppt level was chosen because it is the median estimated initial dioxin level at the time of conception of the Ranch Hands with levels greater than 10 ppt. As the authors point out, this cutoff is arbitrary, with no assumed biologic meaning. Reproductive outcomes of comparison veterans with a current dioxin levels of greater than 10 ppt were not analyzed, because the investigators suspected that these may reflect dioxin exposure after service in Vietnam. The reproductive and developmental outcomes included in the analyses in- cluded spontaneous abortion (miscarriage, fetal death less than 20 weeks gesta- tion), stillbirth (fetal death 20 weeks or greater gestation), and birth defects. All conceptions reported by the men, their wives, or their partners were verified through medical records and vital statistics review. The proportion of adverse outcomes verified by specific sources was not stated. This may be important, given the known limitations of vital statistics records for the identification and classification of certain pregnancy outcomes. Stratified analyses were performed, adjusting for six covariates, including father's race, mother's smoking and drinking during pregnancy, mother's and father's age at birth or conception, and father's military occupation (officer, enlisted flyer, enlisted nonflyer). In addition, adjustment was made for history of spontaneous abortion prior to service in Southeast Asia. The authors noted that the adjustment of father's military occupation was performed because it may serve as a proxy for education and occupation is associated with dioxin level. Adjustment for occupation may, in fact, lead to some degree of "overadjustment" owing to the high correlation between occupation and exposure potential. Com- parison of the adjusted estimates with the unadjusted risk ratio estimates derived from the data provided in the paper showed little difference, indicating that the adjustment for military occupation did not materially affect the results. The validation of self-reported birth defects in this study was systematic and of high quality. Although the etiology of most birth defects remains unknown, the study accounted for an array of factors controlled for in most previous studies of birth defects. Considering all birth defects combined, there was a slightly higher proportion of defects among Ranch Hand children than among compari- son children (22.3 percent versus 20.8 percent). No general pattern of increasing risk with increasing dioxin levels was found. A small increased RR of 1.3 (CI 1.0-1.6) was found for the low-dioxin category. There was a slightly higher

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RESEARCH HIGHLIGHTS 25 prevalence or major birth defects among Ranch Hand children compared to com- parison children (7.4 percent versus 5.7 percent). There was an elevated risk ratio for the low-level category (RR = 1.7; CI 1.1-2.7), although a dose-response gradient was not evident, with an RR of 1.1 for background (0.6-1.8) and 1.2 (CI 0.8-2.1) for the high-level category. The analysis of birth defect groups yielded a total of 11 increased and five decreased risk ratios for the low- and high-level comparisons with the referent category. For example, the analysis of circulatory system and heart defects found risk ratios of 2.3 for low and 0.9 for high levels. Genital defects had risk ratios of 1.8 for low and 1.2 for high; urinary system defects had risk ratios of 2.0 for low and 2.1 for high. Examination of specific defects included in this larger defect grouping did not show any specific associa- tions or patterns. Interestingly, neural tube defects (spine bifida, anencephaly) were in excess among offspring of Ranch Hands, with four total (rate of five per 1,000), in contrast to none among the comparison infants (exact p = .04~. The four cases were distributed as two spine bifida in the high-level category, one anencephaly and one spine bifida in the low-dioxin category. There was no clear pattern of association with developmental disabilities in terms of specific delays in development or hyperkinetic syndrome, although the low-level stratum for specific delays in development had a risk ratio of 1.5 (CI 1.0-2.3~. Summary The recently published results of the analysis of birth defects among the offspring of Ranch Hands suggest the possibility of an association between di- oxin exposure and risk of neural tube defects. These findings require a consider- ation of the current evidence for an association between herbicides and neural tube defects and an increased risk among Vietnam veterans exposed to herbi- cides. Table 2.1 includes a summary of the studies that have reported results specifically for neural tube defects (typically anencephaly and/or spine bifida), including studies in VAO and more recent publications. Unfortunately, some studies (e.g., Seveso), particularly the occupational and environmental studies, do not have results specific for individual birth defects, usually because of the small number of cases. A number of studies of veterans appear to show an elevated relative risk for either service in Vietnam or estimated exposure to herbicides or dioxin and neural tube defects (anencephaly and/or spine bifida) in their offspring. Many of the estimates are imprecise, and chance cannot be ruled out. Nonetheless, the pattern of association warrants further evaluation. The CDC Birth Defects Study (Centers for Disease Control, 1988), the CDC Vietnam Experience Study (Centers for Disease Control, 1989), and the Ranch Hand Study (Wolfe et al., 1992) are of the highest overall quality. The CDC VES cohort study found that more Vietnam veterans reported that their children had a central nervous system anomaly (OR = 2.3; 95 percent CI 1.2-4.5) than did non- Vietnam veterans (Centers for Disease Control, 1989~. The odds ratio for spine

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26 VETERANS AND AGENT ORANGE: UPDATE 1996 bifida was 1.7 (CI 0.6-5.0~. A substudy was conducted in an attempt to validate the reported cerebrospinal defects (spine bifida, anencephaly, hydrocephalus) by examination of hospital records. A difference was detected, but its interpretation was limited by differential participation between the veteran groups and failure to validate negative reported that is, the veterans not reporting their children hav- ing a birth defect. Thus, the issue of a recall bias remains a major concern with this study. The CDC Birth Defects Study utilized the population-based birth defects registry system in the metropolitan Atlanta area (Centers for Disease Control, 1988~. There was no association between overall Vietnam veteran status and the risk of spine bifida (OR = 1.1, CI 0.6-1.7) or anencephaly (OR = 0.9, CI 0.5-1.7~. However, the exposure opportunity index based on interview data was associated with an increased risk of spine bifida; for the highest estimated level of exposure (EOI-5), 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 the case and control subjects (approximately 56 percent) and the lag between birth and interview for some cases and controls. Thus, all three epidemiologic studies (Ranch Hand, VES, CDC Birth Defects Study) suggest an association between herbicide exposure and an increased risk of spine 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 embryo- logically related defect, is of concern. Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and spine bifida. There is inadequate or insufficient evidence to determine whether an association exists between expo- sure to the herbicides and all other birth defects. The evidence regarding associa- tion is drawn from occupation and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Biologic Plausibility Laboratory studies of the potential developmental toxicity, specifically birth defects, of TCDD and herbicides as a result of exposure to adult male animals are too limited to permit conclusions. Chapter 3 of the full report examines these

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RESEARCH HIGHLIGHTS TABLE 2-1 Epidemiologic Studies Neural Tube Defects 27 OR/RR Reference Description N (95% CI) Occupational No specific results for neural tube defects Environmental Hanify et al., 1981 Anencephaly Spina bifida Stockbauer et al., 1988 TCDD soil contamination in Missouri Central nervous system defects Vietnam veterans Erickson, 1984a,b CDC, 1989 10 1.4 (0.6-3.3) 13 1.1 (0.6-2.3) 3 3.0 (0.3-35.9) Birth Defects Study Vietnam veteran: spine bifida Vietnam veteran: anencephaly EOI-5: spine bifida EOI-5: anencephaly Vietnam Experience Study Interview study Spina bifida Anencephaly 19 1.1 (0.6-1.7) 12 0.9 (0.5-1.7) ga 2.7 (1.2-6.2) 7a 0.7 (0.2-2.8) 9 1.7 (0.6-5.0) among Vietnam veterans 5 among non Vietnam veterans 3 among Vietnam veterans among non Vietnam veterans Australian veterans Birth defects and father's Vietnam service (Australia) Health Studies, 1983 Neural tube defects 16 0.9 AFHS, 1995 Follow-up of Air Force Ranch Hands Neural tube defects 4 among Ranch Handb 0 among comparison NOTE: N= number of exposed cases; OR/RR = Odds Ratio/Relative Risk; CI = Confidence Interval; SIR = Standardized Incidence Ratio. aNumber of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index score. bFour neural tube defects among Ranch Hand offspring include 2 spine bifida (high dioxin level), 1 spine bifida (low dioxin), and 1 anencephaly (low dioxin). Denominator for Ranch Hand group is 792 liveborn infants.

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28 VETERANS AND AGENT ORANGE: UPDATE 1996 experimental studies at greater length, as well as others focusing on developmen- tal toxicity. Risk in Vietnam Veterans Since the strongest associations are from studies of Vietnam veterans and there are some data suggesting that the highest risks were for 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 in Vietnam veterans of spine bifida in offspring. PERIPHERAL NEUROPATHY Introduction This section taken from Chapter 10 of the full report summarizes published scientific literature on exposure to herbicides and acute and subacute transient peripheral neuropathy. At the specific request of the Department of Veterans Affairs (DVA), earlier data in VAO relating to chronic persistent and transient acute or subacute peripheral neuropathy were reclassified and reexamined in the Update 1996 report. Although some of the case reports reviewed in VAO suggested that an acute or subacute peripheral neuropathy can develop with exposure to TCDD and related products, other reports with comparison groups did not offer clear evi- dence that TCDD exposure is associated with chronic peripheral neuropathy. The most rigorously conducted studies argued against a relationship between TCDD or herbicides and chronic persistent neuropathy. The current report places chronic persistent peripheral neuropathies and acute or subacute peripheral neuropathies into distinct disease categories. The commit- tee found there is inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and chronic persistent periph- eral neuropathy. The methodology used to establish associations between putative causal agents and persistent chronic neurological deficits relies heavily on epidemio- logical studies with adequate control or comparison populations. Such methodol- ogy can rarely be set in motion with sufficient speed to assess relationships between unexpected chemical exposure and the development of acute or subacute transient neurological disturbance. Because of the very transient nature of the conditions, documenting signs and symptoms in association with documented exposures can be difficult to accomplish in a systematic manner. In such in- stances, greater reliance must be placed on isolated case histories and less well controlled studies. This section reviews the data from such sources regarding occupational, environmental, and Vietnam herbicide exposure. Because this

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RESEARCH HIGHLIGHTS 29 disorder is of special interest to the DVA, this discussion integrates the studies reviewed in VAO with those published more recently. The following text reviews the data from such sources regarding occupa- tional, environmental, and Vietnam herbicide exposure and acute and subacute transient peripheral neuropathy. Because this disorder is of special interest to the DVA, this discussion integrates the studies reviewed in VAO with those pub- lished more recently. Chapter 6 of the full report expounds on many of these studies. Review of the Scientific Literature on Acute and Subacute Transient Peripheral Neuropathy Occupational Studies A number of reports have suggested that acute or sub- acute peripheral neuropathies can be associated with occupational exposure to herbicides (Ashe and Suskind, 1950; Baader and Bauer, 1951; Goldstein et al., 1959; Todd, 1962; Berkley and Magee, 1963; Poland et al., 1971; Jirasek et al., 1974~. However, only a very limited number of studies on the PNS provide any control or comparison group data. Since peripheral neuropathies can be induced by such common medical and environmental conditions as diabetes and poor nutrition, especially in alcoholics, the presence of neuropathy in an herbicide- exposed population cannot be attributed necessarily to the herbicide without consideration of these other factors. Rigorously defined and examined compari- son groups, although especially important in the analysis of peripheral neuro- pathies, are not available for the topic of acute and subacute neuropathies. The studies cited below provide suggestive but limited evidence of the concept that acute or subacute peripheral neuropathy can develop after exposure to dioxin or related compounds. Todd (1962) reported a sprayer of 2,4-D weedkiller who developed a gas- trointestinal disturbance and, within days, a severe sensory/motor polyneuropathy after contact with the chemical. Recovery occurred gradually over the ensuing months. Berkley and Magee (1963) reported another patient who developed a polyneuropathy four days after exposure to a liquid solution of 2,4-D, which was being sprayed in a cornfield. The neuropathy was purely sensory in type. His symptoms gradually resolved over months. Goldstein et al. (1959) described three patients who had sensory/motor polyneuropathies that developed over sev- eral days and progressed over several weeks after exposure to 2,4-D. All had incomplete recovery after several years. Although these patients were not exam- ined neurologically before their exposure, the temporal relationship between the development of their clinical problem and the herbicide exposure was clearly documented. Nonetheless, the possibility that their occurrence was unrelated to the herbicide exposure and represented examples of other disorders, such as idiopathic Guillain-Barre syndrome, cannot be entirely excluded.

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30 VETERANS AND AGENT ORANGE: UPDATE 1996 Environmental Studies After the Seveso, Italy, chemical explosion, inhabitants from the high-exposure zone were evaluated for signs and symptoms of periph- eral nerve disease and compared with inhabitants of a lower-exposure zone. No information is available on acute transient neuropathic effects, since the first reports documented findings in patients evaluated more than six months after the disaster. Boeri et al. (1978) conducted clinical and neurophysiological examina- tion of the peripheral nerves 7 to 11 months after the explosion and reported descriptive differences between 470 volunteer subjects in Zone A (high-exposure group) and 152 volunteer residents of Zone R (low-exposure group). Peripheral nerve problems were frequent in both groups, suggesting to the authors that undefined neuropathic factors predating the explosion may well have been re- sponsible for their findings. Although cranial and peripheral nerve problems were generally more prevalent among the highly exposed group, no statistical analyses were performed on the prevalence data. The electrophysiological studies failed to show any significant abnormalities in either group. As a complement to the above screening in the first year after exposure, Pocchiari et al. (1979) echoed the observation that neuropathic symptoms were more prevalent in the high-exposure group. No new data were provided. Report- ing on symptoms and signs in patients examined eight or more months after the accident, Filippini et al. (1981) compared 308 Seveso residents with 305 non- exposed residents from nearby towns. They examined patients clinically and electrophysiologically, using strict physiological criteria for defining peripheral neuropathy. The authors found no increased risk of "acute" peripheral neuropathy among the exposed residents. However, within the subgroup of exposed subjects who showed clinical signs of significant exposure (chloracne or elevated hepatic enzymes), the risk ratio was 2.8 (CI = 1.2-6.5~. Similarly, for Seveso residents with other risk factors for peripheral neuropathy (alcoholism, diabetes, and in- flammatory diseases), an elevated risk ratio was also observed (2.6, CI = 1.2-5.6~. The authors argued that heavy exposure to dioxin was associated with mild peripheral neuropathy in this two-year follow-up report. Subsequent follow-up studies suggested that there was no increased prevalence of peripheral neuropathy several years after the accident among the high-risk Seveso group (Barbieri et al., 1988; Assennato et al., 1989~. Vietnam Veterans Studies The committee has identified no data on acute or subacute neuropathies related to herbicide exposure in Vietnam. All published data concern chronic effects. Summary of Acute and Subacute Transient Peripheral Neuropathy There is some evidence to suggest that neuropathy of acute or subacute onset may be associated with herbicide exposure. This is based primarily on case

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RESEARCH HIGHLIGHTS 31 histories from occupational exposure and the descriptive reports following the Seveso accident. The trend to recovery in the individual cases reported and the negative findings of many long-term follow-up studies of peripheral neuropathy (see section on Chronic Persistent Peripheral Neuropathy in the full report) sug- gest that if a neuropathy indeed develops, it resolves with time. Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and acute and subacute transient periph- eral neuropathy. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. New data from animals (Grehl et al., 1993; Grahmann et al., 1993) suggest biological plausibility for an association between TCDD and peripheral neuropathy. Chapter 3 of the full report discusses the toxicologic studies in greater detail. Increased Risk of Disease among Vietnam Veterans If TCDD is associated with the development of transient acute and subacute peripheral neuropathy, the disorder would become evident shortly after exposure; therefore, there is no evidence that new cases that develop long after service in Vietnam are associated with herbicide exposure that occurred there.

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