9
Reproductive Effects

This chapter reviews the evidence for an association between herbicide exposure and reproductive and developmental endpoints including spontaneous abortion, birth defects, perinatal and infant mortality, low birthweight, childhood cancer, and sperm abnormalities and infertility. The evidence for an increased risk among veterans exposed to herbicides in Vietnam and the biologic plausibility of herbicides causing the outcomes of interest are also reviewed. As a reminder, most of the studies of occupational groups and veterans involve exposure of men to the herbicides in question, the exception being a small number of environmental studies that included maternal (and probably paternal) exposure. This introduction reviews two other topics pertinent to this chapter: some specific methodologic issues of relevance when evaluating the reproductive epidemiology studies discussed, and general comments regarding the plausibility of male-mediated developmental effects.

METHODOLOGIC ISSUES

Chapter 5 describes the general methodologic issues pertaining to the evaluation and interpretation of epidemiologic studies. This section will expand on some of these issues as they relate specifically to reproductive epidemiology. Many of these issues are important in the interpretation of the findings of a number of studies of herbicides and reproductive outcomes in which the relative risk estimate is ''weak" or "moderate," that is, between 1 and 2. It is often stated that the closer the relative risk gets to 1, the



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 9 Reproductive Effects This chapter reviews the evidence for an association between herbicide exposure and reproductive and developmental endpoints including spontaneous abortion, birth defects, perinatal and infant mortality, low birthweight, childhood cancer, and sperm abnormalities and infertility. The evidence for an increased risk among veterans exposed to herbicides in Vietnam and the biologic plausibility of herbicides causing the outcomes of interest are also reviewed. As a reminder, most of the studies of occupational groups and veterans involve exposure of men to the herbicides in question, the exception being a small number of environmental studies that included maternal (and probably paternal) exposure. This introduction reviews two other topics pertinent to this chapter: some specific methodologic issues of relevance when evaluating the reproductive epidemiology studies discussed, and general comments regarding the plausibility of male-mediated developmental effects. METHODOLOGIC ISSUES Chapter 5 describes the general methodologic issues pertaining to the evaluation and interpretation of epidemiologic studies. This section will expand on some of these issues as they relate specifically to reproductive epidemiology. Many of these issues are important in the interpretation of the findings of a number of studies of herbicides and reproductive outcomes in which the relative risk estimate is ''weak" or "moderate," that is, between 1 and 2. It is often stated that the closer the relative risk gets to 1, the

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam greater is the likelihood that confounding or recall bias may explain the association (Wynder, 1987; Khoury et al., 1992a). Confounding can result in the estimate of the relative risk being biased either toward or away from the null value of 1.0 (no association). By definition, confounding factors have to be risk factors for the disease under consideration. Confounding with respect to reproductive outcomes is a difficult issue. For some outcomes, such as birth defects, there are few suspected, let alone established, risk factors (e.g., maternal age and Down's syndrome). The possibility of unmeasured confounding could therefore play a role in explaining some of the associations reported. Conversely, it is possible that in some situations, confounding could mask a stronger association. The extent of confounding in the studies examined for this chapter is uncertain. Biased recall of exposure or outcome is another potential problem in reproductive epidemiology studies. Misclassification of exposure to herbicides has been discussed in Chapter 5. Misclassification of outcome can be a problem leading to either an under- or an overestimate of the true relative risk. For certain reproductive outcomes and childhood conditions (e.g., specific birth defects), accurate recall of the outcome may be difficult, especially if the pregnancy or event occurred in the distant past. If both the study and the comparison groups (e.g., veterans versus nonveterans) have similarly flawed recall, the relative estimate will be reduced toward 1.0. If, however, recall differs between the groups, a biased estimate may be obtained. Medical record verification of many reproductive and childhood health conditions is needed to minimize this potential bias. The statistical power of reproductive epidemiology studies to detect an elevated relative risk, if one exists, should also be borne in mind when interpreting the evidence (see Chapter 5). In a cohort study evaluating herbicide exposure (e.g., among occupational groups or Vietnam veterans) and spontaneous abortion, approximately 266 total pregnancies would have to be studied to detect a doubling of risk (relative risk = 2, alpha = .05, beta = .80). For other outcomes, the sample sizes (exposed and unexposed groups combined) required to detect a doubling of risk would be 656 live births for low birthweight; 2,478 live births for all major birth defects; 16,932 live births for the most common major birth defect; 17,902 live births for chromosomal abnormalities; and 1,856 live births for infant death. Some of the studies reviewed had adequate statistical power for assessment of some of the more common reproductive outcomes such as spontaneous abortion, but power may have been lacking for rarer outcomes such as specific birth defects. When evaluating a given study finding, examination of the confidence interval around the point estimate of the relative risk will provide guidance as to the degree of precision and study size.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam PLAUSIBILITY In this evaluation of herbicide exposure, adverse reproductive outcomes, and potentially increased risk among Vietnam veterans, the primary emphasis is on exposure to the male. As noted in the research recommendations (Chapter 12), further study of female veterans is called for; nonetheless, the majority of potentially exposed workers and veterans are men. This situation requires further general discussion, given the fact that the vast majority of animal and human data on adverse reproductive outcomes pertain to maternal preconceptional or in utero exposure not paternal exposure. Further, as noted in Chapter 4, herbicides have not been fully evaluated in male animal test systems for many developmental endpoints. Therefore, a general summary of the animal and human evidence on paternal exposure to chemicals or radiation and adverse reproductive or developmental outcomes can help put the review of herbicides in context. The role of paternal exposures in the etiology of many reproductive and developmental outcomes has not been investigated extensively (Olshan and Faustman, 1993). The effects of chemicals and radiation on sperm parameters and, possibly, infertility have been demonstrated (Wyrobek et al., 1983). On the other hand, the prevailing view is that exposure of the human male to chemicals and radiation is largely unrelated to the occurrence of developmental endpoints such as miscarriage, birth defects, growth retardation, and cancer (Brown, 1985). This view has been held despite the fact that some animal studies have indicated that male exposure can lead to a variety of developmental outcomes. The paucity of human data and definitive mechanistic models has hindered progress in this area. Several potential mechanisms have been proposed to explain possible male-related effects on offspring. A direct effect of an agent on male germ cell DNA is the traditional explanation for the induction of some developmental abnormalities. The majority of the available animal test data involve this mechanism. More indirect mechanisms involving transfer to toxic agents in seminal fluid and maternal exposure to agents brought home by the father have been suggested, although data supporting these routes are lacking at present. As noted above, experimental animal evidence for direct effects of exposure on male germ cell DNA (germ cell mutagenicity assays) has been available for a number of years. In fact, an important animal test for germ cell mutagenicity, the specific locus test, was developed in 1951 with tests involving ionizing radiation (Russell, 1951). The majority of the animal test data include the evaluation of radiation and chemicals in relation to expression of defined visible phenotypes due to mutations at recessive loci (specific locus test), fetal loss (dominant lethal test), inherited chromosomal aberrations (heritable translocation test), and defined congenital anomalies (dominant skeletal and dominant cataract tests). Ionizing radiation and a

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam small number (compared to animal carcinogenicity assays) of chemicals have yielded positive results in these test systems. One pattern that has emerged from the specific locus test data is that for many chemicals the shorter-lived, postmeiotic spermatogenic cells are more sensitive to the induction of mutations (Russell et al., 1990). There are also animal data showing that male exposure to radiation and some chemicals can produce other outcomes in offspring such as congenital anomalies, tumors, growth retardation, and neurobehavioral effects. Animal test data for these endpoints are suggestive but are still limited at the present time (Selby, 1990). Epidemiologic associations between paternal exposures and developmental abnormalities in offspring have been reported, although further replication of the suggestive findings remains to be done. Two general types of exposure have been studied, namely, occupational and life-style exposures such as tobacco and alcohol consumption. Unfortunately, few other categories of exposure have been examined. A summary of the findings from epidemiologic studies is provided here. Paternal occupational exposure to vinyl chloride, anesthetic gases, dibromochloropropane, mercury, lead, other metals, and various solvents has been linked to an increased risk of fetal loss (spontaneous abortion) (Olshan and Faustman, 1993). Use of tobacco and alcohol has not been associated with an elevated relative risk of spontaneous abortion, although there have been few studies directly focusing on paternal exposure to these substances. Paternal employment in the textile, mining, rubber, plastics, and synthetics industries was associated with prematurity and low birthweight in offspring in one study (Savitz et al., 1989). Another study found an association between paternal alcohol consumption and reduced birthweight of offspring, after adjustment for maternal factors (Little and Sing, 1987). A number of epidemiologic studies have examined the relationship between paternal occupation and birth defects. A variety of occupations have yielded positive associations including painters, welders, auto mechanics, firemen, forestry and logging workers, motor vehicle operators, wood workers, farm workers, metal workers, and plywood mill workers (Olshan and Faustman, 1993). Some associations between birth defects and fathers' smoking and alcohol use have been noted (Savitz et al., 1991). Several recent large case-control studies have suggested some paternal occupations and exposures that may be associated with childhood cancer in the offspring (Savitz and Chen, 1990; O'Leary et al., 1991). These associations include painters, mechanics, machinists, and motor vehicle drivers and leukemia; painters, metal workers, electronics-related industries, and motor vehicle-related jobs and childhood brain tumors; auto mechanics and machinists, welders, and painters and Wilms' tumor (childhood kidney tumor); electronics-related occupations and neuroblastoma. Additional study of these occupational exposures is needed to establish the potential importance of

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam previous findings. Paternal cigarette consumption has been related to an increased risk of childhood cancer in some studies, but not in others (Olshan and Faustman, 1993). A recent study of an excess of leukemia and lymphoma among the children of nuclear plant workers in Great Britain has been the subject of much discussion and controversy (Gardner et al., 1990; MacMahon, 1992). The pregnancies and offspring of two groups of uniquely exposed individuals, atomic bomb survivors and survivors of childhood cancer, have been the subject of epidemiologic study. There does not appear to be an increased risk of adverse reproductive and developmental outcomes in these groups, although some concerns regarding statistical power and methodology persist. The animal and human data indicate that the exposure of the male to various toxic agents may increase the risk of the full spectrum of adverse developmental endpoints from fetal loss to cancer. However, the evidence is not firm and requires much more study in both laboratory and epidemiologic settings. SPONTANEOUS ABORTION Introduction Definition Spontaneous abortion (or miscarriage), according to the World Health Organization (1977), is a "nondeliberate fetal death of an intrauterine pregnancy before 22 completed weeks of gestation, corresponding to a fetal weight of approximately 500 grams or more." Pregnancy losses prior to implantation (preimplantation) are not clinically detectable with currently available diagnostic procedures. In contrast to preimplantation losses, all postimplantation losses are, at least in theory, clinically detectable, since measurable human chorionic gonadotropin production begins at implantation (Kline et al., 1989). However, early postimplantation losses occurring prior to the first missed menstrual period (e.g., 25 to 28 days after the last menstrual period) will also tend to go undetected, since they generally occur prior to pregnancy recognition. The rate of these early detectable (but often unrecognized) pregnancy losses has been estimated to be approximately 30 percent (Wilcox et al., 1988). Because preimplantation and early postimplantation losses are difficult to ascertain for epidemiologic studies of pregnancy loss, the appropriate epidemiologic end point for these studies is not all spontaneous abortions but rather all clinically recognized spontaneous abortions—those that come to the attention of a woman or her physician. All subsequent discussions of pregnancy loss, miscarriage, or spontaneous abortion refer to clinically recognized outcomes unless otherwise specified.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Descriptive Epidemiology Approximately 10 to 15 percent of all clinically recognized pregnancies end in a clinically recognized loss. Of these clinically recognized pregnancy losses, 35 to 40 percent are losses of chromosomally abnormal embryos and fetuses (Kline et al., 1989). A wide range of maternal characteristics and exposures has been linked to miscarriage; however two major risk factors have been established—maternal age and history of previous miscarriage (Kline et al., 1989). The risk of pregnancy loss is known to increase with increasing maternal age, especially after age 30 or 35. A woman's risk of having a second loss once she has had a first is elevated about 60 percent over that of women with no history of miscarriage. The risk of losing a pregnancy may also be increased among women with a history of multiple induced abortions. Pregnancy losses also occur more frequently among nonwhite than among white women. Women of lower socioeconomic status (SES) appear to have a higher proportion of chromosomally normal spontaneous abortions relative to their higher-SES counterparts. Other maternal medical conditions and exposures that have been associated, at least in some studies, with an increased risk of miscarriage include diabetes and epilepsy, a history of maternal fever during pregnancy, uterine and hormonal abnormalities, immunologic (e.g., Rh factor) incompatibilities, maternal exposure to ionizing radiation, and maternal contraceptive use (Kallen, 1988; Kline et al., 1989). An increased risk of miscarriage has also been associated with maternal smoking and consumption of alcohol (Kline et al., 1989). Maternal intake of caffeine during pregnancy has been suggested as a possible risk factor for miscarriage; to date, however, study findings on this topic are inconclusive (Dlugosz and Bracken, 1992). A variety of maternal occupational exposures may also be related to the risk of miscarriage, including exposure to ethylene oxide, antineoplastic agents, and possibly anesthetic gases (Hemminki et al., 1982; Selevan et al., 1985; Kline et al., 1989). As noted in the introduction, paternal occupational exposures (including vinyl chloride, lead dibromochloropropane, and anesthetic gases) may be related to increased risk of miscarriage (Olshan and Faustman, 1993). Epidemiologic Studies of Spontaneous Abortion Occupational Studies There have been six studies of miscarriage among wives of workers occupationally exposed to herbicides. These include the studies of May (1982), Suskind and Hertzberg (1984), Moses and colleagues (1984), Smith

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam and colleagues (1982), Carmelli and colleagues (1981), and Townsend and colleagues (1982). At a production facility manufacturing 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), May (1982) conducted a follow-up of 41 workers who developed chloracne after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 31 workers with no exposure, and 54 workers with potential TCDD exposure. No evidence was provided in the workers' histories to suggest an association between workers' exposure and their wives' history of miscarriage. The major limitation of this study was the small number of exposed and unexposed workers, which resulted in inadequate statistical power to detect anything other than a very large relative risk (RR). Suskind and Hertzberg (1984) and Moses et al. (1984) studied workers exposed to dioxin in an explosion that occurred at a 2,4,5-T manufacturing plant in Nitro, West Virginia. No significant difference in the incidence of miscarriage was found between exposed (105/1,000 pregnancies) and unexposed (119/1,000 pregnancies) worker cohorts [relative risk (RR) = 0.9, CI 0.6-1.2] (Suskind and Hertzberg, 1984). Some concerns about this study include limited power (204 exposed and 163 unexposed workers), low response rates (61 percent of eligible exposed workers and 46 percent of eligible unexposed men), and the fact that the events being asked about in the study questionnaire occurred in the distant past (the mean age at time of interview was 57 years for the exposed workers and 46 years for the unexposed workers). Moses and colleagues (1984) investigated self-reported symptoms among 226 workers. A history of chloracne was used as a surrogate measure of dioxin exposure; 117 of the 226 participants reported current or past chloracne. No consistent differences in spontaneous abortion were found between the groups with and without chloracne. For example, among the 717 pregnancies occurring after 1948 (when 2,4,5-T production began), 6 percent ended in miscarriages in the chloracne group compared to 7 percent in the group without chloracne [odds ratio (OR) = 0.9, CI 0.4-1.8]. The potential misclassification from using chloracne as a measure of exposure, the small number of reported pregnancies, and the low study participation (55 percent of workers contacted participated in the survey) limit the interpretation of these results. Carmelli and colleagues (1981) examined husband's occupational exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) in a case-control study of spontaneous abortion among women in Oregon and Washington. In the entire sample, the crude odds ratio for fathers who reported work exposure to herbicides compared to those without work exposure was 0.8 (CI 0.5-1.2). When stratified by industry, the odds ratio estimate was 0.7 (CI 0.3-1.8) for farm exposure and 0.9 (CI 0.5-1.6) for forest/commercial exposure. When exposure only during the period around conception was considered, the odds ratio for forest/commercial workers was 1.6 (CI 0.7-3.3) and 1.0

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (CI 0.4-2.1) for farm workers. Further stratification by father's age revealed some suggestive associations. Among forest/commercial exposed workers in the age group 18-25 years, the odds ratio for spontaneous abortion was 3.1 (CI 0.9-9.6). Within the 31-35 year age group, farm workers with exposure around conception had an elevated relative risk (OR = 2.9, CI 0.8-10.9). The findings for the forest/commercial workers are suggestive, although the increased odds ratio in another age group for farm workers adds uncertainty to the interpretation of the study findings. One of the larger occupational studies evaluated reproductive outcomes among wives of 370 workers involved in the processing of chlorophenol at the Dow Chemical Midland plant (Townsend et al., 1982). The rates of miscarriage were similar in the group exposed to any dioxin (133 per 1,000 live births) and the unexposed workers (119 per 1,000) (adjusted OR = 1.03, CI 0.8-1.4). The study had good statistical power for the evaluation of spontaneous abortion, and various confounding factors were considered. Potential study limitations include the low proportion of eligible subjects that participated in the interview and the possibility of poor recall given that conception may have occurred up to 40 years prior to the interview. Nonetheless, this relatively well-designed study did not indicate an association with spontaneous abortion. The study by Smith and colleagues (1982) of 548 herbicide applicators in New Zealand did not find an increased risk of spontaneous abortion, with an odds ratio of 0.9 (CI 0.6-1.5) for the comparison of 2,4,5-T sprayers to men who were employed as agricultural workers without herbicide exposure. The study included men with a high likelihood of exposure to 2,4,5-T, confounding factors were considered, and the study's statistical power was adequate. Environmental Studies The available studies assessing the effect of environmental exposure to herbicides or dioxin on the risk of miscarriage have been reviewed. The Alsea, Oregon study by the U.S. Environmental Protection Agency (U.S. EPA, 1979) found a significantly higher rate of spontaneous abortion in an area that had been sprayed with 2,4,5-T than in a comparison area. In addition, a correlation between spontaneous abortion rate and spray pattern (pounds applied by month) was reported. Although suggestive, the study was of ecologic design and has been criticized for a number of reasons (Sharp et al., 1986). Spontaneous abortion rates among residents of Seveso, Italy, were not associated with "zone" of exposure (Bisanti et al., 1980). Although actual exposures were unknown, residence in high versus low exposure areas (based on TCDD contamination levels in the soil) was used to differentiate levels

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam of exposure. A cytogenetic analysis of maternal, placental, and aborted (induced) fetal tissue from Seveso (Tenchini et al., 1983) noted a higher frequency of chromosomal aberration in fetal tissue from TCDD-exposed women than from the unexposed comparison group. Potential problems with variability in the cell culture process were noted by the authors. In the context of no increase in the spontaneous abortion rate among exposed women, and without cytogenetic analysis of fetal tissue from exposed spontaneous abortions, the relevance of these findings is uncertain. Vietnamese Studies Several studies of spontaneous abortion have been conducted by Vietnamese researchers. These included both studies of potential exposure to herbicides among residents, male and female, residing in South Vietnam (sprayed versus unsprayed areas) and studies in North Vietnam involving men who were potentially exposed during service in the South. Only a few of the studies have been published in scientific journals, but most of the results were reported at a 1983 conference in Vietnam (Vietnam Courier, 1983). The conference presentations have been summarized and reviewed in several reports (Westing, 1984; Constable and Hatch, 1985; Sterling and Arundel, 1986). The Constable and Hatch report (1985) serves as the primary source for this review. Three studies conducted in the South reported an increase in spontaneous abortion among people living in sprayed areas. Khoa (1983) reported a 10.1 percent rate of miscarriage among the Montagnard people, compared with 6.1 percent for individuals living in an unsprayed area. Trung and Chien (1983) found an increase in miscarriage in an area after spraying and no similar increase in an unsprayed comparison area. Spontaneous abortion increased in the sprayed area from 5.6 percent before the spraying to 13.9 percent after the time of spraying, and in the unsprayed area from 7.3 to 7.4 percent. An analysis of reproductive outcomes from 1952 to 1981 at a referral hospital in Ho Chi Minh City showed an increase in spontaneous abortion starting in 1967 (14.6 percent versus 4.1 percent in 1966) that reached a peak in 1978 (18.1 percent), possibly consistent with times of heaviest spraying (Huong and Phuong, 1983). Another study in the South (Phuong and Huong, 1983) examined spontaneous abortion in a sprayed village (7,327 pregnancies) compared to a group of women in Ho Chi Minh City who were considered unexposed (6,690 pregnancies). Among the exposed group, 8 percent of pregnancies ended in miscarriage compared to 3.6 percent among the unexposed group. Tung (1980) compared obstetrical statistics from two villages—one with veterans who had served in the South and were considered exposed to herbicides, and another village with unexposed veterans who remained in the

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam North. Among the 1,748 pregnancies involving exposed veterans, 14.4 percent ended in spontaneous abortion as opposed to 9 percent of 1,581 unexposed pregnancies. A follow-up to this study (Lang et al., 1983) attempted to classify veterans with potential herbicide exposure into low-, moderate-, and high-exposure subgroups based on the areas in which they lived while in the South. An association between spontaneous abortion and extent of potential herbicide exposure was reported, but only among older mothers. A large survey (40,064 interviews) of reproductive health was conducted in three districts in the North (Can et al., 1983). Pregnancy outcomes were evaluated with respect to the exposure status of the father. The proportion of miscarriages was higher in the exposed group (2,274 of 32,069; 7.1 percent) compared to the unexposed group (7,148 of 121,933; 5.9 percent). Studies from South Vietnam and of veterans returning to the North suggest an increased risk of spontaneous abortion. A major problem with these studies is that, at present, they have not been published extensively in a form that provides all the relevant information needed to evaluate study design and findings. The studies summarized in several papers appear to have problems with respect to the selection of subjects and collection of exposure data. Ascertainment of the reproductive outcomes, usually based on self-report, seems to be incomplete, given the lower than expected rates of miscarriage among the unexposed pregnancies. Further, control of potentially confounding factors also appears inadequate. At present, from available reports, the studies from Vietnam, although suggesting an increased risk of spontaneous abortion, are of insufficient quality to weigh heavily in the final evaluation of an association with herbicides. Several studies conducted in Vietnam have also examined the risk for hydatidiform mole (Constable and Hatch, 1985; Huong et al., 1989; Phuong et al., 1989a). This disorder, associated with the death of a fetus, produces a mass of degenerated placental tissue in the uterus. It is benign, but has been considered a precursor of choriocarcinoma, a malignant tumor of embryonic tissue. It is more common in Asian populations with an incidence of 1 in 120 deliveries in Taiwan compared to 1 in 1,000-2,000 deliveries in the United States (Bracken et al., 1984; Hayashi and Bracken, 1984). Most of the studies have been conducted in the south of Vietnam, and one study (Can et al., 1983) examined the risk of hydatidiform moles in wives of veterans who had returned to the north. The studies in the South have reported an association between exposure to herbicides and the occurrence of moles. For example, Phuong and colleagues (1989a) conducted a case-control study using patients seen at the Ho Chi Minh City Ob-Gyn Hospital during 1982. Exposure was defined as the patient's residence in villages that had been sprayed, mostly in 1965 to 1970. The odds ratio (calculated from the data presented) for hydatidiform mole was 13.1 (CI 5.6-30.9). The study in the North of Vietnam did not report an increased

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam incidence in moles in villages with potentially exposed veterans. As described previously, interpretation of the Vietnamese studies is difficult because of the inadequate reporting of the studies and concerns about potential biases. Separating maternal from paternal exposure is a problem in the Vietnamese studies conducted in the south because both parents were likely to have been exposed in their village of residence. Further, hydatidiform moles are less common in the United States and have not been an endpoint in occupational, environmental, or U.S. veteran studies. Thus, the direct relevance to this review is limited. Vietnam Veterans Studies The latest report on reproductive outcomes from the Air Force Health Study (AFHS, 1992) stated that there was no significant association with miscarriage and paternal serum dioxin levels based on comparisons between 791 Ranch Hand veterans and 942 comparison veterans. Examination of the results showed some analyses that indicated a possible increased risk; however, given the problems with data analysis and presentation of results (see Appendix C), it is difficult to evaluate the Ranch Hand findings. The Centers for Disease Control (CDC) Vietnam Experience Study (VES) of 7,924 Vietnam veterans and 7,364 non-Vietnam veterans detected a significant, slightly increased relative risk estimate for spontaneous abortion (adjusted OR = 1.3, CI 1.2-1.4; CDC, 1989). Veterans' self-reported herbicide exposure showed an apparent dose-response gradient, with an odds ratio of 1.2 (CI 1.0-1.4) for ''low" exposure, 1.4 (CI 1.2-1.6) for "mid" exposure, and 1.7 (CI 1.3-2.1) for the "high" exposure level. A pattern of excess risk for Vietnam veterans was found for many conditions examined in this study. One possible explanation for this pattern is recall bias, that is, the differential recall of past events or exposures among the exposed (Vietnam veterans) compared to unexposed (non-Vietnam veterans). This bias could artificially increase the relative risk estimate. An additional problem with data quality is that the fathers, rather than the mothers, were interviewed, and they are generally a less reliable source of information on reproductive events. Some potentially confounding factors were accounted for, but an important factor—history of previous miscarriage—was not included. The most important limitation of this study is the characterization of Agent Orange exposure primarily by service in Vietnam. The validity of self-reported herbicide exposure, although related to an increased risk of miscarriage, is highly uncertain and, as noted above, may be affected by recall bias. The American Legion study (Stellman et al., 1988) involved the interview of 6,810 veterans (2,858 Vietnam veterans, 3,933 non-Vietnam veterans, and 19 veterans with an undetermined service location) and the use of

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam on many other cancer types. Recently published reviews can be consulted for further details (Greenberg and Shuster, 1986; Robison et al., 1991). Some of the potential risk factors for childhood cancer that have been suggested (sometimes with inconsistent results) include advanced maternal age, prior fetal loss, birthweight of more than 4,000 grams, prenatal diagnostic radiation, postnatal irradiation, electromagnetic fields, parental occupation, pesticides, prenatal viral exposure, maternal use of marijuana during pregnancy, and parental cigarette smoking. In addition, some childhood cancers involve a familial aggregation of cancer (familial cancer syndromes) or defined chromosomal abnormalities; in some cases, their molecular origins have been delineated (Murphee and Benedict, 1984; Malkin et al., 1990). Epidemiologic Studies of Childhood Cancer Occupational and Environmental Studies There were no studies that directly examined occupational or environmental exposure to herbicides or dioxin in relation to childhood cancer in offspring. Vietnam Veterans Studies The Field and Kerr (1988) study of Australian veterans found four cases of childhood cancer among the offspring of Vietnam veterans and none among the offspring of the comparison group. A variety of conditions appeared to be involved including a thalamic tumor, cerebral teratoma, vascular hamartoma, and lipoblastoma. There was a slight excess of childhood cancers among children of Vietnam veterans in the VES (CDC, 1989). Twenty-five cases of childhood cancer were reported among the children of Vietnam veterans and 17 cases among non-Vietnam veterans (adjusted OR = 1.5, CI 0.7-2.8). Leukemia was the predominant diagnostic category, accounting for 12 cases among Vietnam veterans and 7 among non-Vietnam veterans (OR = 1.6, CI 0.6-4.0). The CDC's Birth Defects Study (Erickson et al., 1984b) reported an odds ratio of 1.8 (CI 1.0-3.3) for "other neoplasms." These included dermoid and epidermoid cysts (26 cases), and teratospermia (14 cases), lipomas (9 cases), neuroblastomas (3 cases), hepatoblastomas (1 case), rhabdomyosarcomas (1 case), and miscellaneous benign tumors (24 cases). This diverse group of congenital neoplasms was also associated with the Agent Orange exposure opportunity index based on interview data for service location (EOI level 5: OR = 2.0, CI 0.6-7.0).

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam TABLE 9-6 Epidemiologic Studies—Childhood Cancer Reference Description N OR/RR (95% CI) Vietnam veterans CDC, 1989 Vietnam Experience Study       Childhood cancer 25 1.5 (0.7-2.8)   Leukemia 12 1.6 (0.6-4.0) Erikson et al., 1984a CDC Birth Defects Study,       "other" neoplasms 87 1.8 (1.0-3.3) Field and Kerr, 1988 Follow-up of Australian Vietnam veterans 4 — NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval. Summary There are no available occupational and environmental epidemiologic studies of herbicide exposure that address childhood cancer as an outcome. Two studies of Vietnam veterans found some suggestion of an increased risk of cancer among offspring (see Table 9-6). The evidence is, however, inadequate, given the lack of other studies, failure to exclude chance and bias, and problems with herbicide exposure assessment. Conclusions Strength of the Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and childhood cancer in offspring. Biologic Plausibility Laboratory studies of the potential developmental toxicity of TCDD and herbicides using male animals are too limited to permit conclusions. Increased Risk of Disease in Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, the effects of information bias and low statistical power in these studies, and the lack of information

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. SPERM PARAMETERS AND INFERTILITY Introduction Definition Sperm Parameters There are several biologic markers of physiologic damage to human male reproduction using seminal sperm (Overstreet and Katz, 1987; NRC, 1989). The most common parameters used to evaluate effects due to toxic agents have been sperm number, sperm motility, and sperm structure or morphology. Sperm number is the number of sperm in the ejaculate (total number or per milliliter of semen). Men with sperm counts of less than 20 million/ml appear to be at an increased risk of infertility, although there is some uncertainty about the specific nature of the relationship between sperm number (or concentration) and fertility. Sperm motility refers to the swimming or ''movement" ability of the sperm. Motility scoring has been shown to be subjective and sensitive to time and temperature, although automated approaches have been developed (Boyers et al., 1989). A strong correlation between sperm motility and fertility has been demonstrated. Sperm structure (morphology) refers to the evaluation of sperm size and shape. Classification systems based on sperm head, midpiece, and tail characteristics have been used. A general association has been found between a greater proportion of abnormal sperm and an increased likelihood of infertility. More recent work has found that a morphometric parameter, mean sperm width-to-length ratio, was associated with measures of infertility (Boyle et al., 1992). Infertility Reduced reproductive capacity usually incorporates two concepts: (1) fecundity, the ability to conceive; and (2) fertility, the ability to produce live children. Typically, in epidemiologic studies, "infertility" is evaluated in two ways: (1) the number of children fathered, and (2) whether the couple had tried for a year or longer to conceive a child without success. Other measures of impaired fertility such as time to pregnancy have also been proposed (Baird et al., 1986). The definitions of male infertility are limited because they do not consider the female's role in the ability of the couple to conceive and produce live children. In addition, these measures usually do not take into account the desire for children, contraceptive practices, and other factors.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Descriptive Epidemiology Most studies have reported that 10-15 percent of couples have impaired fertility (NRC, 1989). Accurate population statistics for sperm parameters are difficult to obtain, given the fact that most studies involve a group of selected men who enter infertility clinics for evaluation. A comprehensive literature review of environmental, occupational, and therapeutic chemical exposures and sperm tests found that, of 87 chemicals tested, exposure to 51 significantly reduced sperm count (Wyrobek et al., 1983). Of the 59 chemicals tested with respect to sperm motility, 22 were related to significant decreases in the numbers of motile sperm. Among the 44 chemicals tested for effects on sperm structure, 17 showed significant evidence for a decrease in the number of morphologically normal sperm. Epidemiologic Studies of Sperm Parameters Occupational and Environmental Studies One study of Italian farmers evaluated sperm parameters in relation to 2,4-D exposure (Lerda and Rizzi, 1991). The study involved 32 farmers exposed to herbicides and 25 control farmers not working with herbicides. Urine measurements of 2,4-D confirmed exposure status, at least for that chemical. An association was found with one type of abnormal sperm morphology and reduced sperm motility. No association with decreased sperm count was noted. Vietnam Veterans Studies The Air Force study of 417 Ranch Hand veterans did not report decreased sperm count or increased percentage of abnormal sperm compared to the controls (AFHS, 1992). In fact, the reported relative risks were lower in the groups of exposed men. The VES (CDC, 1989) evaluation of 324 Vietnam veterans found associations between Vietnam service and lower sperm concentration (<20 million cells/ml; OR = 2.3, CI 1.2-4.3), Lower proportion of normal sperm (<40 percent normal; OR = 1.6, CI 0.9-2.8), and to a lesser extent, reduced sperm motility (<40 percent motile cells; OR = 1.2, CI 0.8-1.8). Further analysis did not show any pattern of association between these sperm parameters or the ability to father children, and history of combat experience or self-reported herbicide exposure. Epidemiologic Studies of Infertility Occupational and Environmental Studies No studies of occupational or environmental exposure to herbicides and infertility were available.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Vietnam Veterans Studies Several studies of veterans have examined infertility. Some studies have used other measures including "difficulty conceiving or having children" and number of conceptions or number of children fathered. The Australian veteran's study did not find an association either with difficulty in conceiving or with number of children (Field and Kerr, 1988). The study of American Legionnaires found a slightly increased odds ratio for difficulty in having children (OR = 1.3), but no association with the number of children fathered (Stellman et al., 1988). The Ranch Hand study reported no difference in the total number of conceptions (AFHS, 1992). The VES (CDC, 1988) did not find an association with the number of children fathered. Summary Only one occupational epidemiology study is available for assessing the association between herbicide exposure and altered sperm parameters (sperm count, motility, morphology). This study of sperm parameters and 2,4-D exposure did indicate an association with abnormal sperm morphology; however, given the small sample size and lack of additional studies, the evidence for determination of an association is considered inadequate. No studies were identified that examined occupational or environmental exposure and impaired fertility. One study of veterans reported an association with altered sperm measures (reduced sperm concentration and increased percentage of abnormal sperm), although there was no relationship to the number of children fathered, self-reported herbicide exposure, or the extent of combat experience (see Table 9-7). The paucity of occupational studies, lack of TABLE 9-7 Epidemiologic Studies—Sperm Parameters and Infertility Reference Description N OR/RR (95% CI) Vietnam veterans Stellman et al., 1988 Assessment of reproductive effects among American Legionnaires who served in Southeast Asia       Difficulty having children 349 1.3, p < .01 CDC, 1989 Vietnam Experience Study       Lower sperm concentration 42 2.3 (1.2-4.3)   Proportion of abnormal sperm 51 1.6 (0.9-2.8)   Reduced sperm motility 83 1.2 (0.8-1.8) NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam consistent findings in veteran studies, and methodologic problems in the studies reviewed do not permit a valid assessment of an increased infertility risk. Conclusions Review of the Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and altered sperm parameters or infertility. Biologic Plausibility TCDD has been reported to reduce fertility in male laboratory animals at doses high enough to produce other toxic effects. Studies of the potential reproductive toxicity of the herbicides are too limited to permit conclusions. Increased Risk of Disease in Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, effects of information bias in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. NOTE *   The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. REFERENCES Air Force Health Study (AFHS). 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB: USAF School of Aerospace Medicine. AL-TR-1992-0090. 602 pp. Alberman E. 1984. Low birthweight. In: Bracken MB, ed. Perinatal Epidemiology. New York: Oxford University Press. 86-98. Armenian HK, Gordis L, Kelsey JL, Levine MM, Thacker SB, eds. 1992. Epidemiologic Reviews. 1992. Baltimore: Johns Hopkins Press.

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