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Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

(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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

the HERBS tapes to estimate herbicide exposure (see Chapter 6). Among pregnancies of wives of Vietnam veterans, 7.6 percent ended in miscarriage compared with 5.8 percent for veterans who did not serve there (OR = 1.4, CI 1.1-1.6). When stratified by estimated herbicide exposure level, the proportions of pregnancies ending in miscarriage increased from 7.3 (low exposure) to 8.5 (medium exposure) to 9.6 percent (high level of exposure). The corresponding odds ratios were 1.3 (CI 1.0-1.7) for low exposure, 1.5 (CI 1.1-2.1) for medium exposure, and 1.7 (CI 1.2-2.4) for high exposure, relative to the risk for men who did not serve in Vietnam. Relative to men with low exposure, the odds ratios were 1.2 for men with medium exposure and 1.4 for those with high exposure. The authors also examined the risk for men who stated that they had handled herbicides. Compared with men who did not serve in Vietnam, they had an odds ratio of 1.6 (CI 0.7-3.3). The investigators further evaluated the association between Agent Orange exposure and risk of miscarriage by performing an analysis of variance. They found that mean levels of Agent Orange exposure were higher in pregnancies that ended in miscarriage, after adjusting for mother's age and smoking during pregnancy. Multivariate logistic regression analysis was also conducted to examine the risk of miscarriage for Agent Orange while adjusting for potentially confounding factors such as mother's smoking during pregnancy, mother's age, father's age, combat, and father's year of birth. The regression coefficients for Agent Orange exposure and mother's smoking were statistically significant. The authors did not present the number of outcomes classified by Agent Orange exposure and maternal smoking or the corresponding odds ratio estimates from the logistic regression model.

A strength of the American Legion study was the use of a more refined measurement of potential Agent Orange exposure based on the HERBS tapes. However, there are several areas of concern. First, the use of a self-administered mail questionnaire does not yield the best response rate and quality of information. There is some evidence of underreporting, given that the reported prevalence of miscarriage is lower than the level found in most studies (5.8 versus 15 percent). The majority of odds ratio estimates were not statistically significant and were under 2.0. Despite these concerns, their results are suggestive of an increased risk for miscarriage with increased estimated levels of Agent Orange exposure.

A case-control study of spontaneous abortion in Massachusetts (Aschengrau and Monson, 1989) did not indicate an overall increased risk among women married to Vietnam veterans (adjusted OR = 0.9, CI 0.4-1.9). When the data were subdivided by trimester there was a slightly increased, nonsignificant relative risk estimate for first trimester abortions among Vietnam veterans' wives (OR = 1.2, CI 0.6-2.8). The analysis included adjustment for potentially confounding factors; however, the possibility of selection bias resulting from the procedure for approaching patients for interview (interviews

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

were attempted for 32 percent of women admitted to the hospital with a spontaneous abortion) should be noted. In addition, there were only 10 Vietnam veterans among the cases and 60 among the controls, leading to rather imprecise relative risk estimates as evidenced by the wide confidence intervals. Most importantly, the use of service in Vietnam as a surrogate for herbicide exposure is problematic, as described in Chapter 6.

State surveys of the health of Vietnam veterans, including reproductive history, have been conducted for veterans living in Iowa, Maine, and Hawaii (Rellahan, 1985; Wendt, 1985; Deprez et al., 1991). These studies have not generally indicated an increased risk of spontaneous abortion, although Deprez and colleagues (1991) did report a higher percentage of miscarriages among wives of Maine Vietnam veterans (15 percent) than was reported among the entire Maine population (1.6 percent) in 1988. Limitations such as low response rate, small sample size, use of mail questionnaires, and lack of comparison groups apply to varying degrees to this group of studies.

The study of a cohort of 357 Tasmanian veterans who had served in Vietnam from 1965 to 1972 reported a significant excess of a variety of adverse reproductive outcomes when compared with a group of matched friend/neighborhood families (Field and Kerr, 1988). Fetal loss was reported to be significantly higher in the veteran group compared to nonveterans, 24 percent and 15 percent, respectively (crude RR = 1.6, CI 1.3-2.0). The report did not provide enough details about the selection of veteran and comparison subjects, and the fact that the final sample was only 31 percent of the original Vietnam veteran cohort may reflect potential selection bias. As with U.S. veteran studies, the simple use of veteran status as a measure of exposure is a problem. The authors reported an association with jungle duty, a better indicator of potential herbicide exposure, but specific results were not reported.

Summary

The studies involving occupational and environmental herbicide exposure generally reported no association with spontaneous abortion; however, these studies were inadequate with respect to sample size, elimination of potential bias, and assessment of exposure. A list of the studies considered in this review appears in Table 9-1.

The available epidemiologic studies of veterans are generally limited by inadequate sample sizes, potential bias, and other methodologic problems. There are some suggestive findings indicating an increased risk for Vietnam veterans, including a possible dose-response gradient of increasing risk with increasing estimated (self-reported or inferred) Agent Orange exposure. Nonetheless, the inconsistency with environmental and occupational

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 9-1 Epidemiologic Studies—Spontaneous Abortion

Reference

Description

N

OR/RR (95% CI)

Occupational

Townsend et al., 1982

Wives of men employed at Dow involved in chlorophenol processing

85

1.0 (0.8-1.4)

Smith et al., 1982

Follow-up of 2,4,5-T sprayers

 

 

 

Sprayers compared to non-sprayers

43

0.9 (0.6-1.5)

Carmelli et al., 1981

Spontaneous abortion among wives of men occupationally exposed to 2,4-D

 

 

 

All reported work exposure to herbicides (high and medium)

63

0.8 (0.5-1.2)

 

Farm exposure

32

0.7 (0.3-1.8)

 

Forest/commercial exposure

31

0.9 (0.5-1.6)

 

Exposure during conception period:

 

 

 

Farm exposure

15

1.0 (0.4-2.1)

 

Forest/commercial exposure

16

1.6 (0.7-3.3)

 

All exposures, father aged 18-25 years: Forest/commercial exposure

8

3.1 (0.9-9.6)

 

Exposure during conception period:

 

 

 

Father aged 31-35 years, farm

10

2.9 (0.8-10.9)

Suskind and Hertzberg, 1984

Follow-up of 2,4,5-T production workers

69

0.9 (0.6-1.2)

Moses et al., 1984

Follow-up of 2,4,5-T production workers

14

0.9 (0.4-1.8)

Vietnam veterans

CDC, 1989

Vietnam Experience Study

1,566

1.3 (1.2-1.4)

 

Self-reported low exposure

489

1.2 (1.0-1.4)

 

Self-reported medium exposure

406

1.4 (1.2-1.6)

 

Self-reported high exposure

113

1.7 (1.3-2.1)

Stellman et al., 1988

Assessment of reproductive effects among American Legionnaires who served in Southeast Asia (1961-1975)

 

 

 

Vietnam veterans compared to:

 

 

 

Vietnam-era veterans

231

1.4 (1.1-1.6)

 

Low exposure

72

1.3 (1.0-1.7)

 

Medium exposure

53

1.5 (1.1-2.1)

 

High exposure

58

1.7 (1.2-2.4)

 

Herbicide handlers

9

1.6 (0.7-3.3)

 

Compared to low exposure:

 

 

 

Medium exposure

53

1.2 (0.8-1.7)

 

High exposure

58

1.4 (0.9-1.9)

Aschengrau and Monson, 1989

Spontaneous abortion and husband's Vietnam service

 

 

 

Spontaneous abortions

10

0.9 (0.4-1.9)

 

First trimester abortions

NA

1.2 (0.6-2.8)

Field and Kerr, 1988

Follow-up of Australian Vietnam veterans

195

1.6 (1.3-2.0)

NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval; NA = not available.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

studies, uncertainty of the methods of exposure determination, marginal magnitude of the increased risk, and failure to exclude chance are of enough concern that the evidence can be considered insufficient. Future analyses of the Ranch Hand data may contribute important evidence regarding an increased risk for spontaneous abortion among exposed Vietnam veterans.

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 spontaneous abortion.

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, the effects of selection, information, and confounding 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.

BIRTH DEFECTS

Introduction

Definition

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

usually defined as those abnormalities that are present at birth and severe enough to interfere with viability or physical well-being. Birth defects are usually recorded and classified according to the organ or anatomic system affected (Bloom, 1981). Ascertainment and correct diagnosis of birth defects can be difficult, and require careful patient evaluation and registration procedures. The proper grouping of birth defects for epidemiologic study is an area of considerable interest and debate (Khoury et al., 1992b).

Descriptive Epidemiology

Major birth defects are seen in approximately 2 to 3 percent of live births (Kalter and Warkany, 1983a). An additional 5 percent of birth defects can be detected with follow-up through the first year of life. Given the general frequency of major birth defects of 2 to 3 percent and the number of men who served in Vietnam (2.6 million), and by 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). Among U.S. whites, the highest rates of major congenital malformations are for hypospadias (32.7/10,000 births), hip dislocation (32.3), clubfoot (27.5), and patent ductus arteriosus (26.5) (Chavez et al., 1988). As infant mortality has declined in the United States, the proportion of infant deaths attributable to birth defects has increased. Birth defects are currently the single greatest underlying cause of infant deaths in the United States, representing more than 20 percent of such deaths in 1990 (CDC, 1993).

Nonetheless, the etiology of most birth defects is difficult to ascertain; approximately 60 percent of all birth defects in humans have no known cause (Kalter and Warkany, 1983a). Another 20 percent may be due to the effects of many genes or to the interaction of genes and the environment (multifactorial). Among birth defects with a known or suspected genetic cause, those due to a single gene or chromosomal abnormality are responsible for approximately 10 percent of all birth defects. Another 10 percent are known to be caused by environmental (or nongenetic) factors such as maternal disease or infection, radiation, or chemical exposure.

Although approximately 800 drugs and chemicals have been identified as teratogenic in animals, only a handful of them are known to produce birth defects in humans as well (Schardein, 1985; Shepard, 1992). Thalidomide, one of the earliest identified human teratogens, is associated with limb, ear, and other defects. Examples of other known or suspected teratogens include methylmercury, diethylstilbestrol, alcohol, cocaine, tetracycline, warfarin, valproic acid, forms of vitamin A (retinoic acid), androgenic hormones, chlorambucil, cyclophosphamide, fluorouracil, methotrexate,

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

norethindrone, para- and trimethadione, phenytoin, and streptomycin. A variety of maternal infections are known to result in birth defects including rubella, cytomegalovirus, herpes simplex, syphilis, toxoplasmosis, and Venezuelan equine encephalitis. Maternal diabetes and phenylketonuria are also known to produce defects and other disorders in offspring. Older maternal age is associated with several birth defects, most notably Down's syndrome. Exposures such as anesthetic gases, smoking, and certain maternal occupations have also been examined as risk factors for birth defects, with inconsistent results (Kalter and Warkany, 1983b). Some paternal occupations have been suggested as being associated with an increased risk of birth defects in offspring (see discussion of plausibility).

Epidemiologic Studies of Birth Defects

Occupational Studies

Four occupational epidemiology studies have examined the potential association between herbicide exposure of male workers and birth defects. The Townsend study (Townsend et al., 1982) of workers with potential dioxin exposure 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) compared 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, spina bifida, 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 Nitro, West Virginia, 2,4,5-T plant did not report an association with birth defects among offspring (Moses et al., 19841; 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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

group (Smith et al., 1982). The study used self-administered questionnaires to determine outcomes. As with 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 South that had been sprayed during the Vietnam war (Phuong et al., 1989b); 81 cases of birth defects (diagnosis not specified) were identified. There were no differences 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 17-22 years earlier pertains to both the mother and the father.

Results from a number of other studies from Vietnam, both of sprayed villages in the South and of veterans returning to the unsprayed North, have been reported, mostly in a review by Constable and Hatch (1985). These studies indicate an increased risk of birth defects including anencephaly, 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,

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

lack of comparison group, uncertainty of exposure classification, and no validation of reported birth defects. Although the findings are suggestive of an association between herbicide spraying and birth defects, the available studies are insufficient to draw firm conclusions.

Vietnam Veterans Studies

As part of the CDC (1989) Vietnam Experience Study, the reproductive outcomes and the health of children of male veterans were examined. The VES assessment of reproductive outcomes and child health included three components: (1) a telephone interview; (2) hospital record review of birth defects for a subsample of veterans who underwent a medical examination; and (3) medical records review of selected birth defects for all study subjects.

Results from analysis of the interview data found that Vietnam veterans reported more birth defects (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), spina 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 problems or impairments during the first five years of life. It was found that about half of the health conditions reported by veterans were respiratory disease (mostly asthma and pneumonia) and otitis media. For most of the conditions, Vietnam veterans reported 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 and either a birth defect or cancer, the overall crude OR was 1.2 (CI 1.1-1.3). Elevated 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 validation for many of these types of

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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 identify 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 cases and 112 cases, respectively) that participated in the medical examination component of the VES. There were no apparent differences between the group of men who participated in the medical examination and the total interview group for a variety of characteristics. The GBDS analysis did not find any difference in the prevalence of birth defects between the two groups of children (crude OR = 1.0, CI 0.8-1.3). There was a slight, 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 for 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% among Vietnam veterans and 32.9% among non-Vietnam veterans. Sensitivity was 27.1% among Vietnam veterans and 30.3% among non-Vietnam veterans. The kappa measure of agreement was also lower (20.9% versus 27.6%) among Vietnam veterans.

The second substudy, the Cerebrospinal Malformation (CSM) Study, involved the acquisition of medical records for all cases of cerebrospinal malformations (spina bifida, anencephalus, hydrocephalus) and stillbirths reported by veterans in the interview study. The CSM record review 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 CSM between the veteran groups was conducted due to the fact that negative responses (i.e., children without a reported CSM) were not verified and the participation rates differed between groups (7.8 percent of Vietnam veterans in contrast to 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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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 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 CSMs.

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 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 coefficients 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 spina bifida with Vietnam veteran status was not elevated (OR = 1.1), the EOI indices showed a pattern of increasing risk. For example, the odds ratios for the EOI based upon 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)

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

for the two exposure indices. The category "other neoplasms" 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 spina bifida with increased exposure. As the authors note, this 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 assessment 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.

The latest Air Force report on the analysis of the Ranch Hand study updates the previous analysis of baseline data (AFHS, 1992). This new evaluation incorporates the verification of self-reported birth defects and analysis by measured serum dioxin levels. The report stated that there were few significant associations between serum dioxin level and the risk of congenital anomalies. Some analyses of all defects combined and musculoskeletal defects found significant associations, but the authors felt that no consistent patterns among defects and dioxin levels were discernible. They concluded that the apparent statistical associations were due to chance and

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

there is no "underlying association" in their data between birth defects and dioxin.

As the authors noted, the total prevalence of birth defects in the Ranch Hand group is greater than in the unexposed comparison group (veterans involved in air cargo missions, presumably with "background" levels of herbicide or dioxin exposure). This finding was also noted in the baseline evaluation of both groups. The odds ratio comparing the Ranch Hand group with the "comparisons" for total congenital anomalies was 1.3 (CI 1.1-1.6). Although the numbers were rather small, elevated odds ratios (for births after service in Southeast Asia) were found for nervous system (OR = 1.9, CI 0.5-7.2), respiratory system (OR = 2.6, CI 0.6-10.7), circulatory and heart (OR = 1.4, CI 0.7-2.6), urinary (OR = 2.5, CI 1.3-5.0), chromosomal (OR = 1.8, CI 0.6-6.1), and other (OR = 2.6, CI 0.6-10.7) defects. These results are only suggestive but do indicate some difference in the risk of birth defects between these two groups. Based on their analyses incorporating serum dioxin levels, the investigators concluded that dioxin levels do not explain the difference. However, the committee is concerned (see Appendix C) about the methods and presentation employed in the analysis of dioxin levels, and it is unclear what the findings from this important study mean, other than some indication that the Ranch Hand subjects seem to be at a higher risk of fathering a child with a birth defect than the comparison group. Attribution of this increase to herbicides or dioxin must await further analysis.

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 1,432 men without military service; and the 107 Vietnam veterans with the 313 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). The odds ratio was elevated for major malformations for the Vietnam veteran—men without known military service comparison (OR = 1.8, CI 1.0-3.1), but decreased for the Vietnam veteran—non-Vietnam veteran comparison (OR = 1.3, CI 0.7-2.4). Only slight increases were found for the analysis of minor malformations and "only normal variants." Although based on small numbers,

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

the analyses of 12 malformation groups found that children of Vietnam veterans relative to children of men with no known military service had an increased (nonsignificant) risk of malformations of the nervous system, cardiovascular system, genital organs, urinary tract, and musculoskeletal system. Confidence intervals were not 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 malformations did not reveal any pattern of association with potential herbicide exposure.

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 subjects 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). A survey in Maine reported 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 Disabilities 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. Nonetheless, a carefully designed and comprehensive epidemiologic study with medical record review 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 by 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). Analysis of subgroups based on type of

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Army veteran (Australian Regular Army enlistees, 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 National Service veterans who did not serve in Vietnam (OR - 1.3, CI 0.9-2.0). It was found that 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, 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), namely, 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 increased 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 of the use of history of service in Vietnam as the primary "exposure" variable. Further, this uncertainty is compounded by potential differences 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 congenital anomalies among the 357 Vietnam veterans than among the comparison families (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 presentation of results, potential selection bias, self-reported health outcomes, and using service in Vietnam as a surrogate for herbicide exposure.

Summary

There is little evidence of a statistical association between father's occupational exposure to herbicides or dioxin and birth defects among offspring. The available epidemiologic studies have been limited by a number of problems, especially inadequate statistical power for the evaluation of specific birth defects. Studies involving environmental exposure have yielded inconsistent results; furthermore, given the ecologic nature of the studies, the limited sample sizes (for specific defects), and the failure to verify reported birth defects, the evidence can be considered inadequate for an association. A list of the studies considered in this review appears in Table 9-2.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 9-2 Epidemiologic Studies—Birth Defects

Reference

Description

N

OR/RR (95% CI)

Occupational

Townsend et al., 1982

Follow-up of Dow chemical plant workers

30

0.9 (0.5-1.4)

Smith et al., 1982

Follow-up of 2,4,5-T sprayers

 

 

 

Sprayers compared to nonsprayers

13

1.2 (0.5-3.0)

Suskind and Hertzberg, 1984

Follow-up of 2,4,5-T production workers

18

1.1 (0.5-2.2)

Moses et al., 1984

Follow-up of 2,4,5-T production workers

11

1.3 (0.5-3.4)

Environmental

Fitzgerald et al., 1989

Follow-up of an electrical transformer fire Total birth defects

1

SIR = 212 (5.4-1,185.1)

Hanify et al., 1981

All malformations

164

1.7 (1.4-2.2)

 

All heart malformations

20

3.9 (1.7-8.9)

 

Hypospadias, epispadias

18

5.6 (2.1-15.1)

 

Talipes

52

1.7 (1.1-2.4)

 

Anencephaly

10

1.4 (0.6-3.3)

 

Spina bifida

13

1.1 (0.6-2.3)

 

Cleft lip

6

0.6 (0.2-1.5)

 

Isolated cleft palate

7

1.4 (0.5-3.8)

Mastroiacovo et al., 1988

Reproductive outcomes of Seveso, Italy, residents

 

 

 

Zones A and B total defects

27

1.2 (0.8-1.8)

 

Zones A, B, R total defects

137

1.0 (0.8-1.2)

 

Zones A and B mild defects

14

1.4 (0.9-2.6)

Stockbauer et al., 1988

TCDD soil contamination in Missouri

 

 

 

Total birth defects

17

0.8 (0.4-1.5)

 

Major defects

15

0.8 (0.4-1.7)

 

Midline defects

4

0.6 (0.2-2.3)

 

Central nervous system defects

3

3.0 (0.3-35.9)

Vietnam veterans

Erikson et al., 1984a

Birth Defects Study

 

 

 

Any major birth defects

428

1.0 (0.8-1.1)

 

Multiple birth defects

25

 

 

with reported exposure

 

1.1 (0.7-1.7)

 

EOI-5: spina bifida

1

2.7 (1.2-6.2)

 

EOI-5: cleft lip with/without cleft palate

5

2.2 (1.0-4.9)

CDC, 1989

Vietnam Experience Study

 

 

 

Interview study

 

 

 

Any congenital anomaly

826

1.3 (1.2-1.4)

 

Nervous system defects

33

2.3 (1.2-4.5)

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Description

N

OR/RR (95% CI)

 

Ear, face, neck defects

37

1.6 (0.9-2.8)

 

Integument

41

2.2 (1.2-4.0)

 

Musculoskeletal defects

426

1.2 (1.1-1.5)

 

Hydrocephalus

11

5.1 (1.1-23.1)

 

Spina bifida

9

1.7 (0.6-5.0)

 

Hypospadias

10

3.1 (0.9-11.3)

 

Multiple defects

71

1.6 (1.1-2.5)

 

Defects with high exposure

46

1.7 (1.2-2.4)

CDC, 1989

GBDS study

 

 

 

Birth defects

130

1.0 (0.8-1.3)

 

Major birth defects

51

1.2 (0.8-1.9)

 

Black Vietnam veterans with children with birth defects

21

3.4 (1.5-7.6)

 

Digestive system defects

18

2.0 (0.9-4.6)

Aschengrau and Monson, 1990

Birth defects and father's Vietnam service

 

 

 

Vietnam veterans compared to men without known military service

55

1.3 (0.9-1.9)

 

Vietnam veterans compared to non-Vietnam veterans

55

1.2 (0.8-1.9)

 

Major malformations

 

 

 

Vietnam veterans compared to men without known military service

18

1.8 (1.0-3.1)

 

Vietnam veterans compared to non-Vietnam veterans

18

1.3 (0.7-2.4)

Donovan et al., 1984

Birth defects and father's Vietnam service (Australia)

 

 

 

Vietnam veterans vs. all other men

127

1.02 (0.8-1.3)

 

National Service veterans Vietnam service vs. no Vietnam service

69

1.3 (0.9-2.0)

AFHS, 1992

Follow-up of Air Force Ranch Hands

 

 

 

Birth defects in conceptions following service in Southeast Asia:

 

 

 

Congenital anomalies

229

1.3 (1.1-1.6)

 

Nervous system

5

1.9 (0.5-7.2)

 

Respiratory system

5

2.6 (0.6-10.7)

 

Circulatory system or heart

19

1.4 (0.7-2.6)

 

Urinary system

21

2.5 (1.3-5.0)

 

Chromosomal

6

1.8 (0.6-6.1)

 

Other

5

2.6 (0.6-10.7)

NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval; SIR = standardized incidence ratio.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

The results of available epidemiologic studies of Vietnam veterans are also inconsistent; some studies suggest a potential association with defects of the central nervous system and other systems, although others find no increased risk. As noted for other end points, the veteran studies were generally limited by inadequate sample size, the marginal magnitude of the increased risk, and the failure to exclude bias and chance. Moreover, uncertainty regarding the assessment of exposure among Vietnam veterans and the limited evidence from other cohorts do not permit one to draw a conclusion about an increased risk of birth defects among the offspring of men exposed to herbicides in Vietnam. Future analyses of the Ranch Hand data may contribute important evidence regarding an increased risk of birth defects among offspring of exposed Vietnam veterans.

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 birth defects among 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 selection and information bias and low statistical power 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.

STILLBIRTH, NEONATAL DEATH, AND INFANT DEATH

Introduction

Definitions

The use of the terms stillbirth and neonatal death can be confusing and

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

has differed in epidemiologic studies. Varying definitional criteria and vital statistics registration problems have lead to difficulties in interpreting national and international rates (Golding, 1991). Stillbirth (or late fetal death) is typically defined as the delivery of a fetus occurring at or after 28 weeks of gestation and showing no signs of life at birth, although a more recent definition includes deaths among all fetuses weighing more than 500 g at birth, regardless of gestational age at delivery (Kline et al., 1989). Neonatal deaths are usually defined as the death of a live-born infant within the first 28 days of life. Early neonatal deaths occur within the first week of life. Because there are no clear biological differences between late fetal deaths (stillbirths) and deaths in the early neonatal period, these are commonly referred to together as perinatal deaths (Kallen, 1988). The perinatal mortality rate of a population is often calculated as the sum of the number of stillbirths plus the number of deaths in the first week of life occurring per 1,000 live and stillbirths. Late neonatal death is usually defined as death of the infant after the first week but within the first 28 days of life, and infant death as death within the first year.

Descriptive Epidemiology

Stillbirths occur in approximately 1 to 2 percent of all births (Kline et al., 1989). Among low birthweight live- and stillborn infants (weighing 500-2,500 grams), placental and delivery complications such as abruptio placentae, placenta previa, malpresentation, and umbilical cord complications are the most common causes of perinatal mortality (Kallen, 1988). Among infants weighing more than 2,500 grams at birth, the most common causes of perinatal death are lethal congenital malformations and placental complications (Kallen, 1988).

Both maternal age and parity appear to be associated with perinatal mortality, although neither relationship is straightforward. In particular, antepartum (before labor or childbirth) stillbirths increase with increasing maternal age, primarily for women aged 35 years or older (Kline et al., 1989). There is disagreement as to whether this maternal age association varies with birth order (Bakketeig et al., 1984). Perinatal mortality risk appears to be higher among nulliparous women and among those with at least three or four previous births. The parity association is especially strong for intrapartum (during labor and delivery or childbirth) stillbirths (Kline et al., 1989).

Maternal smoking during pregnancy also appears to be a risk factor for perinatal death, although not all studies of this topic have reported positive findings (Bakketeig et al., 1984). The association between maternal smoking and perinatal mortality is probably attributable at least in part to an increase in obstetrical complications (especially abruptio placentae) among

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

smokers. Socioeconomic status (SES) and race are two additional factors that have been linked to perinatal death. The rate of perinatal mortality is known to increase with decreasing SES (Bakketeig et al., 1984). Furthermore, in the United States, black infants have a higher rate of perinatal mortality than white infants; this difference in risk is associated with SES differences, although other factors may also be involved (Wilcox and Russell, 1986).

It has been noted earlier in this section that stillbirths and early neonatal deaths are often combined under the rubric "perinatal deaths." Unfortunately, the precise definitions of neonatal death used in the epidemiologic studies being considered has not been provided in the majority of studies. Thus, for this review of the evidence, the studies have been categorized into stillbirths, neonatal deaths (early and late), and infant deaths, using the terms as applied by the studies' authors.

Epidemiologic Studies of Stillbirth

Occupational and Environmental Studies

The five occupational studies that have directly evaluated stillbirth have not reported any association with potential herbicide or dioxin exposure of male workers (May, 1982; Smith et al., 1982; Townsend et al., 1982; Moses et al., 1984; Suskind and Hertzberg, 1984). The largest study investigated the reproductive histories of male workers at the Dow Midland plant and reported 15 stillbirths to workers exposed to any dioxin (OR = 1.1, CI 0.5-2.1) (Townsend et al., 1982). The limitations of most of the occupational studies with respect to exposure assessment and statistical power have been described previously for other outcomes.

Two environmental studies that have analyzed stillbirth have not reported an overall increased risk related to potential herbicide exposure (Stockbauer et al., 1988; White et al., 1988). White and colleagues (1988) in an ecologic study of agricultural chemical use in New Brunswick, Canada, did find, however, a statistically significant risk ratio for second trimester stillbirths, although not for all stillbirths (results not reported in the article). They also noted that a dose-response relationship was present. The potential for exposure misclassification, as well as the ecologic design of this and other environmental studies, limits the interpretation of these data.

Vietnam Veterans Studies

Three studies of stillbirths to veterans have yielded somewhat mixed results. The Massachusetts study of adverse pregnancy outcomes (Aschengrau and Monson, 1990) found two elevated odds ratios for stillbirth, including 1.5 (CI 0.4-3.9) for the comparison of Vietnam veterans with nonveterans

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

and 3.2 (CI 0.7-14.5) for the comparison with non-Vietnam veterans. Although suggestive, these relative risk estimates are unstable, with rather wide confidence intervals. The Field and Kerr (1988) study of Australian Vietnam veterans did not find an association with stillbirth, (crude RR = 1.4, CI 0.5-3.5). Results from the interview portion of the VES (CDC, 1989) did not show an increased odds ratio (OR = 0.9, CI 0.7-1.1); there was also no difference found based upon the GBDS analysis of hospital records (OR = 1.0, CI 0.4-2.4). Self-reported herbicide exposure in the interview data was not related to stillbirths in a dose-response manner (''low" OR = 1.1; "mid" OR = 1.2; "high" OR = 0.5). Problems with inadequate determination of herbicide exposure affect all these studies.

Epidemiologic Studies of Neonatal Death

Occupational and Environmental Studies

Neonatal death was not associated with herbicide exposure in three occupational and environmental studies (May, 1982; Suskind and Hertzberg, 1984; Fitzgerald et al., 1989). The study by Suskind and Hertzberg (1984) of workers at the Nitro, West Virginia, 2,4,5-T plant found a relative risk estimate of 1.8 (CI 0.7-4.5). A Missouri study of exposure to TCDD-contaminated soil found a nonsignificant odds ratio of 1.3 (CI 0.4-4.2) for perinatal death (Stockbauer et al., 1988).

Vietnam Veterans Studies

The Massachusetts veterans study did not report an increased risk of neonatal death for Vietnam veterans (OR = 1.1, CI 0.2-4.5) versus non-Vietnam veterans or men without military service (OR = 1.2, CI 0.2-4.2) (Aschengrau and Monson, 1990). The Australian veterans study by Field and Kerr (1988), reported that a statistically significant association was found based on 12 neonatal deaths among Vietnam veterans and 1 death among nonveterans (RR = 18.1, CI 2.4-134.4). The VES (CDC, 1989) did not evaluate overall neonatal death, but the GBDS analysis (CDC, 1989) showed an elevated odds ratio of 2.0 (CI 0.8-4.9) for early neonatal death for all veterans and an odds ratio of 4.0 (CI 1.2-14.0) among whites. The study of Ranch Hand veterans (AFHS, 1992) was interpreted by the authors as having found no association with the small number of neonatal deaths (nine cases) identified. There seemed to be a pattern of increasing rates of neonatal deaths (postservice) with increasing estimated dioxin levels among the Ranch Hand cohort relative to the comparison cohort. However, the rates also showed a similar pattern for the time period prior to service in Southeast Asia, which potentially minimizes the importance of these results.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Epidemiologic Studies of Infant Death

Occupational and Environmental Studies

The results for infant death are inconsistent with some studies reporting an elevated risk among male workers or veterans. The Dow study (Townsend et al., 1982) found a decreased odds ratio (OR = 0.6, CI 0.3-1.4). The Missouri study of TCDD-contaminated soil (Stockbauer et al., 1988) found a twofold increased odds ratio, but with a wide confidence interval (CI 0.5-8.7).

The Vietnamese studies conducted in the South have generally reported an increased risk of infant death among individuals in villages with presumed exposure to herbicides (Constable and Hatch, 1989; Dai et al., 1990). The problems with interpreting the results of many of these studies have been described by Constable and Hatch (1985) and in an earlier section of this chapter.

Vietnam Veterans Studies

Overall, the studies of Massachusetts veterans (Aschengrau and Monson, 1990), the VES (CDC, 1989), and the study of Ranch Hand veterans (AFHS, 1992) did not report an association with infant death. Self-reports of infant death from the interview study of the CDC's VES did not indicate an increased risk of deaths among children of Vietnam veterans relative to non-Vietnam veterans (OR = 1.0, CI 0.8-1.3), although there was a dose-response gradient with self-reported herbicide exposure. The adjusted odds ratio for the highest level of reported herbicide exposure was 2.7 (CI 1.4-5.4). The Ranch Hand study did not report an association with infant death, although there were a small number of deaths. Similarly, the Field and Kerr study of Australian veterans (1988) did not find an association with infant deaths occurring between the ages of 1 month and 1 year (RR = 0.9, CI 0.2-3.5).

Summary

Stillbirth and Neonatal Death

A statistical association with stillbirth has not been reported in the available occupational and environmental epidemiologic studies. The majority of studies did not have adequate statistical power, and the assessment of exposure was incomplete. Some studies of veterans have reported an increased risk, whereas others have indicated no statistical association. Interpretation of these veteran studies is constrained by limited statistical power, and most importantly, uncertainty of correctly assigning herbicide exposure to study groups. A list of the studies considered in this review appears in Table 9-3.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 9-3 Epidemiologic Studies—Stillbirth and Neonatal Death

Reference

Description

N

OR/RR (95% CI)

Stillbirth

Occupational

Townsend et al., 1982

Follow-up of Dow chemical plant employees

15

1.1 (0.5-2.1)

Suskind and Hertzberg, 1984

Follow-up of 2,4,5-T production workers

11

1.4 (0.5-4.1)

Smith et al., 1982

Follow-up of 2,4,5-T sprayers

3

Environmental

White et al., 1988

Follow-up of agricultural activity in New Brunswick; highest level of potential exposure in second trimester

NA

1.5 (1.0-2.3)

Stockbauer et al., 1988

TCDD soil contamination in Missouri

4

1.6 (0.3-7.4)

Vietnam veterans

CDC, 1989

Vietnam Experience Study

 

 

 

Interview study

126

0.9 (0.7-1.1)

 

Low exposure

41

1.1 (0.7-1.7)

 

Medium exposure

32

1.2 (0.7-1.9)

 

High exposure

3

0.5 (0.2-1.6)

 

Validation study

10

1.0 (0.4-2.4)

Aschengrau and Monson, 1990

Stillbirth and paternal Vietnam service

 

 

 

Vietnam veterans compared to men with no military service

5

1.5 (0.4-3.9)

 

Vietnam veterans compared to non-Vietnam veterans

5

3.2 (0.7-14.5)

Field and Kerr, 1988

Follow-up of Australian Vietnam veterans

11

1.4 (0.5-3.5)

Neonatal death

Occupational

Suskind and Hertzberg 1984

Follow-up of 2,4,5-T production workers

17

1.8 (0.7-4.5)

May, 1982

Follow-up of 2,4,5-T production workers perinatal deaths

1

Environmental

Stockbauer et al., 1988

TCDD soil contamination in Missouri perinatal deaths (includes stillbirths)

6

1.3 (0.4-4.2)

Vietnam veterans

Aschengrau and Monson, 1990

Neonatal death and paternal Vietnam service

 

 

 

Vietnam veterans compared to men with no known military service

3

1.2 (0.2-4.2)

 

Vietnam veterans compared to non-Vietnam veterans

3

1.1 (0.2-4.5)

Field and Kerr, 1988

Follow-up of Australian Vietnam veterans

12

18.1 (2.4-134.4)

CDC, 1989

Vietnam Experience Study

 

 

 

GBDS study—early neonatal death

16

2.0 (0.8-4.9)

NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval; NA = not available.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 9-4 Epidemiologic Studies—Infant Death

Reference

Description

N

OR/RR (95% CI)

Occupational

Townsend et al., 1982

Follow-up of Dow chemical plant workers

9

0.6 (0.3-1.4)

Environmental

Stockbauer et al., 1988

TCDD soil contamination in Missouri

5

2.0 (0.5-8.7)

Vietnam veterans

CDC, 1989

Vietnam Experience Study

 

 

 

Interview study

152

1.0 (0.8-1.3)

 

Low exposure

58

1.9 (1.2-2.9)

 

Medium exposure

38

2.0 (1.2-3.1)

 

High exposure

11

2.7 (1.4-5.4)

Field and Kerr, 1988

Follow-up of Australian Vietnam Veterans deaths between ages 1 month and 1 year

4

0.9 (0.2-3.5)

NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval.

Infant Death

The available occupational and environmental epidemiologic studies (see Table 9-4) were limited by low statistical power, potential selection bias, and inadequate exposure classification. One study of veterans reported an association of infant death with self-reported herbicide exposure. Nonetheless, other studies did not report an increased risk, but as noted for other outcomes, problems with exposure determination, statistical power, and potential bias limit interpretation.

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 stillbirth, neonatal, and infant death among offspring.

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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
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 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.

LOW BIRTHWEIGHT

Introduction

Definition

Reduced infant weight at birth is one of the most important causes of neonatal mortality and morbidity in the United States. The World Health Organization recommends a 2,500-gram cutpoint for the determination of low birthweight (Alberman, 1984). Although often treated as a single entity, the concept of low birthweight actually encompasses two different causal pathways: (1) low birthweight secondary to intrauterine growth retardation (IUGR), which is more related to neonatal morbidity; and (2) low birthweight secondary to preterm delivery, which is more strongly associated with neonatal mortality (Alberman, 1984; Kallen, 1988). The concept of IUGR represents birthweight adjusted for gestational age. The currently used definition of preterm delivery (PTD) is delivery at less than 259 days, or 37 completed weeks of gestation, calculated on the basis of the date of the last menstrual period (Bryce, 1991).

Descriptive Epidemiology

Approximately 7 percent of live births have low birthweight. The incidence of IUGR is much more difficult to quantify since there are no universally applied standards for dividing the distribution of birthweight for gestational age. In 1982, the incidence of prematurity in the United States was 8 percent in whites and more than twice that in blacks (Bryce, 1991).

When no distinction is made between the causes of low birthweight (i.e., IUGR versus PTD), the factors most strongly associated with reduced birthweight are maternal smoking during pregnancy, multiple births, and race/ethnicity. Other potential risk factors for low birthweight include SES, maternal size, birth order, maternal complications during pregnancy (e.g.,

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

severe preeclampsia) and obstetric history, job stress, and cocaine or caffeine use during pregnancy (Kallen, 1988).

Epidemiologic Studies of Low Birthweight

Occupational and Environmental Studies

In a study of individuals potentially exposed to TCDD in an electrical transformer fire in Binghamton, New York, Fitzgerald and colleagues (1989) found 3 cases of low birthweight infants (3.7 expected) resulting in a standardized incidence ratio (SIR) of 81 (CI 16.7-236.4). One environmental study examined birthweight as an outcome (Stockbauer et al., 1988). This study of TCDD exposure via soil contamination in Missouri reported an odds ratio of 1.5 (CI 0.9-2.6) for low birthweight (8 2,500 g). The odds ratio for IUGR was 1.1 (CI 0.5-2.3). There was no association between birthweight and level of potential TCDD exposure, as estimated by comparison of births to high-risk versus low-risk exposures, or by time period of birth.

Vietnam Veterans Studies

The Field and Kerr (1988) study of Australian veterans showed an increased risk ratio (RR = 1.6, CI 1.0-2.5) for low birthweight. Interpretation of results from this study is difficult because the authors failed to present their findings in a manner that allows a full epidemiologic and statistical assessment. The GBDS validation component of the VES (CDC, 1989) found similar rates of low birthweight among the offspring of Vietnam veterans and non-Vietnam veterans (OR = 1.1, CI 0.8-1.4). Analysis by self-reported herbicide exposure did not indicate a pattern of increase with mid to high levels of exposure (CDC, 1989). The American Legion study did not find an association between low birthweight and service in Vietnam or estimated herbicide exposure (Stellman et al., 1988). The Ranch Hand report (AFHS, 1992) did note some associations with low birthweight. Among births after service in Southeast Asia, the unadjusted odds ratio comparing the high dioxin level to the control group was 2.3 (CI 1.3-4.0). Other analyses yielded inconsistent results. This inconsistency and the general problems with the Ranch Hand report limit the interpretation of these results.

Summary

Given the lack of available occupational and environmental studies, the evidence on low infant birthweight is considered inadequate. Its inadequacy

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 9-5 Epidemiologic Studies—Low Birthweight

Reference

Description

N

OR/RR (95% CI)

Occupational

Fitzgerald et al., 1989

Follow-up of an electrical transformer fire

3

SIR = 81 (16.7-236.4)

Environmental

Stockbauer et al., 1988

TCDD soil contamination in Missouri

 

 

 

Intrauterine growth retardation

14

1.1 (0.5-2.3)

 

Low birthweight

27

1.5 (0.9-2.6)

Vietnam veterans

CDC, 1989

Vietnam Experience Study (GBDS)

99

1.1 (0.8-1.4)

Filed and Kerr, 1988

Follow-up of Australian Vietnam veterans

48

1.6 (1.0-2.5)

AFHS, 1992

Follow-up of Air Force Ranch Hands; conceptions during or after Southeast Asian service with high current dioxin levels

20

2.3 (1.3-4.0)

NOTE: OR/RR = Odds ratio/relative risk; CI = confidence interval; SIR = standardized incidence ratio.

is due to the paucity of occupational studies, lack of consistent findings, and concerns about the interpretation of the Ranch Hand analyses. One available epidemiologic study of dioxin exposure (soil contamination) reported a weak association (statistically nonsignificant) with low birthweight. Studies of veterans were inconsistent; some indicated no increased risk, whereas others suggested an increased risk among certain subgroups. Future analyses of the Ranch Hand data may contribute important evidence regarding an increased risk for low birthweight among offspring of exposed Vietnam veterans. A list of the studies considered in this review appears in Table 9-5.

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 low birthweight in offspring.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
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 selection and 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.

CHILDHOOD CANCER

Introduction

Definition and Descriptive Epidemiology

In most epidemiologic studies, childhood cancer usually refers to cancer diagnosed from birth through age 15 years. Childhood cancers are usually classified by primary anatomic site or tumor cell type.

The distribution of childhood cancers by type includes leukemia (23 percent), lymphoma (13 percent), central nervous system (19 percent), neuroblastoma (8 percent), soft tissue sarcoma (7 percent), kidney (6 percent), bone (5 percent), retinoblastoma (3 percent), liver (1 percent), and other (8 percent). There are approximately 6,500 new cases of cancer diagnosed each year in the United States in persons under age 15 (Young et al., 1986). About 2,200 deaths each year result from childhood cancer. The age-adjusted annual incidence of childhood cancers is estimated to be 136 per million in white children and 108 per million in black children. The cumulative incidence is approximately 1 in 600 before age 15. International rates of some childhood cancers have been found to vary geographically (and ethnically) (Parkin et al., 1988).

Compared with adult cancers, relatively little is known about the etiology of most childhood cancers, especially potential environmental risk factors. Important advances have been made in the study of genetic and molecular factors, and certain cancers in children. Acute leukemia, the most common type in children, has been the subject of most epidemiologic studies, although recent analytic epidemiology studies have been completed

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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).

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
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.

Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

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Suggested Citation:"9 Reproductive Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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Have U.S. military personnel experienced health problems from being exposed to Agent Orange, its dioxin contaminants, and other herbicides used in Vietnam? This definitive volume summarizes the strength of the evidence associating exposure during Vietnam service with cancer and other health effects and presents conclusions from an expert panel.

Veterans and Agent Orange provides a historical review of the issue, examines studies of populations, in addition to Vietnam veterans, environmentally and occupationally exposed to herbicides and dioxin, and discusses problems in study methodology. The core of the book presents

  • What is known about the toxicology of the herbicides used in greatest quantities in Vietnam.
  • What is known about assessing exposure to herbicides and dioxin.
  • What can be determined from the wide range of epidemiological studies conducted by different authorities.
  • What is known about the relationship between exposure to herbicides and dioxin, and cancer, reproductive effects, neurobehavioral disorders, and other health effects.

The book describes research areas of continuing concern and offers recommendations for further research on the health effects of Agent Orange exposure among Vietnam veterans.

This volume will be critically important to both policymakers and physicians in the federal government, Vietnam veterans and their families, veterans organizations, researchers, and health professionals.

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