8
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS

Evaluating toxicologic impacts upon the reproductive process requires consideration of the mother, father, and fetus/offspring. A toxic insult may be sustained by either the father or mother prior to conception or by the mother and fetus during gestation with results that might not be detected until considerably after the child’s birth. Potential effects may be observed over an extended period of time from before conception to after birth.

In the male, sperm undergo a three-month maturation cycle during which they might receive an acute insult, which could interfere with their successfully fertilizing an ovum to produce a healthy fetus. Of more concern here is that exposures incurred more than a decade ago during the Gulf War may have produced persisting damage that could impair reproduction. Similarly, in the female, exposure of the maturing ovum in a given menstrual cycle or of a developing fetus might cause immediate damage that will be realized within that reproductive cycle. The adverse effect might be a transient event like a spontaneous abortion or, in the case of a congenital malformation, a permanent condition for the offspring. Inasmuch as there were more women serving in the Persian Gulf, the issue of adverse reproductive effects in exposed women is of more concern than it has been in previous conflicts. The occurrence of pregnancy was reason for immediate evacuation from the area. The committee was concerned that toxic exposures during the earliest period of gestation (when pregnancy may have not yet have been recognized) might pose a threat to the developing fetus. The committee considered whether possible exposures might have produced a lasting impact on the reproductive capacity of both male and female Gulf War veterans.

Most research on reproductive toxicity has focused on exposures occurring just prior to conception or during gestation. Animal toxicology studies can be much more specific about timing of exposure with respect to conception than is possible in epidemiology studies. Few epidemiology studies have focused specifically on delayed reproductive effects as was the committee’s main concern, but some studies will span a long enough observation period to include such events. Furthermore, the short-term responsiveness of the male and female reproductive systems to toxic insults provides an indication of whether any effect that might be persistent is plausible. This chapter discusses studies of maternal and paternal exposure to insecticides and solvents that have examined several reproductive end points, grouped below according to whether they occur prior to conception (sperm morphology, infertility, and hormonal changes), during pregnancy (fetal loss), or as congenital malformations (following birth).

PRECONCEPTION

Conception entails the fertilization of a healthy ovum by a functional sperm. Female gametes are not readily observable, but the accessibility of semen provides an indirect means of



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Gulf War and Health: Insecticides and Solvents, Volume 2 8 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Evaluating toxicologic impacts upon the reproductive process requires consideration of the mother, father, and fetus/offspring. A toxic insult may be sustained by either the father or mother prior to conception or by the mother and fetus during gestation with results that might not be detected until considerably after the child’s birth. Potential effects may be observed over an extended period of time from before conception to after birth. In the male, sperm undergo a three-month maturation cycle during which they might receive an acute insult, which could interfere with their successfully fertilizing an ovum to produce a healthy fetus. Of more concern here is that exposures incurred more than a decade ago during the Gulf War may have produced persisting damage that could impair reproduction. Similarly, in the female, exposure of the maturing ovum in a given menstrual cycle or of a developing fetus might cause immediate damage that will be realized within that reproductive cycle. The adverse effect might be a transient event like a spontaneous abortion or, in the case of a congenital malformation, a permanent condition for the offspring. Inasmuch as there were more women serving in the Persian Gulf, the issue of adverse reproductive effects in exposed women is of more concern than it has been in previous conflicts. The occurrence of pregnancy was reason for immediate evacuation from the area. The committee was concerned that toxic exposures during the earliest period of gestation (when pregnancy may have not yet have been recognized) might pose a threat to the developing fetus. The committee considered whether possible exposures might have produced a lasting impact on the reproductive capacity of both male and female Gulf War veterans. Most research on reproductive toxicity has focused on exposures occurring just prior to conception or during gestation. Animal toxicology studies can be much more specific about timing of exposure with respect to conception than is possible in epidemiology studies. Few epidemiology studies have focused specifically on delayed reproductive effects as was the committee’s main concern, but some studies will span a long enough observation period to include such events. Furthermore, the short-term responsiveness of the male and female reproductive systems to toxic insults provides an indication of whether any effect that might be persistent is plausible. This chapter discusses studies of maternal and paternal exposure to insecticides and solvents that have examined several reproductive end points, grouped below according to whether they occur prior to conception (sperm morphology, infertility, and hormonal changes), during pregnancy (fetal loss), or as congenital malformations (following birth). PRECONCEPTION Conception entails the fertilization of a healthy ovum by a functional sperm. Female gametes are not readily observable, but the accessibility of semen provides an indirect means of

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Gulf War and Health: Insecticides and Solvents, Volume 2 evaluating the male reproductive system. Traditionally measured characteristics of semen samples include sperm concentration, motility, and structure. Oligospermia is defined as sperm concentration below the reference value of 20 million sperm/mL, asthenospermia as less than 50% motile sperm with forward progression, and teratospermia as less than 30% sperm with normal head structure (Rowe et al., 1993). A number of factors may adversely influence male fertility, including sexually transmitted and other diseases (such as diabetes, tuberculosis, and mumps), prolonged high fever, some drugs and medications (such as hormone treatments and cimetidine), some injuries, and some occupational exposures (such as to lead and to the pesticide dibromochloropropane) (Rowe et al., 1993). Another means of indirectly evaluating the impact of potentially toxic exposures on reproductive health is to assess hormone levels in either male or female subjects. Infertility is the failure to conceive after at least 12 months of unprotected intercourse (Rowe et al., 1993). It has been estimated that 10–15% of couples of reproductive age experience some form of infertility (Speroff et al., 1999). In the general population, the probability that a couple engaging in unprotected intercourse will conceive in the first month is 30%; about half of all couples will conceive within 2 months, and 80% in 6 months (Joffe, 1997). There are numerous risk factors for infertility, including advanced age and obesity in women; previous reproductive experiences; genetic factors; diseases such as chlamydial infection in women or epididymitis in men; and, to a lesser extent, cigarette smoking, alcohol consumption, and toxic agents in environmental and occupational settings in either sex (Templeton, 2000). A frequently used measure of infertility is time-to-pregnancy (TTP). TTP studies examine the number of months or menstrual cycles that are required to conceive. The results of TTP studies are often expressed as fecundability ratios. Fecundability refers to the probability of conceiving within one menstrual cycle and is a population-based measure that is useful in the quantitative analysis of fertility potential (Speroff et al., 1999). A fecundability ratio (FR) is the ratio of the probability of conception in an exposed group with that in a comparison group. Decreases in the fecundability ratio indicate longer time to pregnancy for the exposed group. Some studies use a conditional fecundability ratio (CFR), which includes only couples that have conceived a child. Epidemiologic Studies of Preconception End Points and Exposure to Insecticides Sperm and Semen Characteristics Only a few studies have examined the relationship between insecticide use and semen characteristics. Two cross-sectional studies were conducted on a small cohort of men who were employed for 1–8 years in a carbaryl production and packaging plant. In the first study, by Whorton and colleagues (1979), 47 current and past carbaryl workers with at least 1 year of work in carbaryl production and packaging were compared with a control group of 90 male chemical-plant workers. The carbaryl-plant workers were divided into three exposure groups (high, medium, and low exposure) on the basis of frequency of exposure and job classification. Each participant was interviewed, provided a semen sample, and underwent a physical examination. The study found a greater proportion of oligospermic men among the carbaryl workers than among the chemical workers (14.9% and 5.5%, respectively, p=0.07). In further analyses by job classification and exposure group, the study found that 16% of the 25 men in the high-exposure group were oligospermic, compared with 13.6% of the 22 men in the low- and medium-exposure

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Gulf War and Health: Insecticides and Solvents, Volume 2 groups. Among the 29 currently exposed workers, 17.2% were oligospermic, compared with 11.1% of the 18 previously exposed workers. The study provides some evidence of an increased risk of oligospermia with carbaryl exposure. The proportion of oligospermic men among the carbaryl workers was nearly three times the proportion among the controls, and there was some evidence of an association with increased exposure. Because 29 of the carbaryl workers were currently exposed to carbaryl, it was not possible to determine whether oligospermia was a long-term outcome that would persist after cessation of exposure. Furthermore, the use of chemical workers as comparison subjects might mask an effect if they were exposed to spermatotoxic chemicals. A second study of the same carbaryl workers (Wyrobek et al., 1981) examined the relationship between sperm shape abnormalities and exposure to carbaryl. When it was possible, the same semen samples were used in both studies. However, instead of using chemical workers as the control population, this study used newly hired workers at the carbaryl plant; those men provided semen samples at their pre-employment medical examination. Workers were assigned to one of three exposure groups on the basis of the type of job held during the preceding year: nonexposed (new hires), low dose, and high dose. For morphologic analyses, 500 sperm for each person were scored, with blinding as to exposure status. As in the study by Whorton and colleagues, the control group of new hires had a lower proportion (two of 34, or 5.9%) of oligospermic men than did the carbaryl production workers (seven of 48, or 14.6%). Morphological analyses showed increases in the proportion of abnormal sperm among the carbaryl workers (52% of 30 currently exposed and 50% of 18 previously exposed) versus the new hires (42% of 34); the results were similar after stratification on potential confounders, such as smoking, medical history, or previous exposure to hazardous agents. The proportion of men classified as teratospermic (defined in this study as having more than 60% abnormal sperm) was higher in the carbaryl workers than in the comparison group (14 of 49, or 28.6%, and four of 34, or 11.8%, respectively). A dose-response relationship was not found, although the measure of exposure was rather crude for such a determination. An inverse association between number of years worked with carbaryl and percentage of abnormal sperm was found; this was opposite the direction that was expected and could not be explained by the authors. Furthermore, it was expected that there would be differences due to age; however, among the carbaryl workers, the relationship between age and percentage of abnormal structure was opposite what was expected, in that younger men had a higher percentage of sperm abnormalities. Several studies have examined the relationship between semen characteristics and exposure to broader categories of pesticides. Larsen and colleagues (1998a, 1999) studied traditional and organic farmers in Denmark and did not find an association between pesticide spraying and adverse effects on sperm concentration, motility, or morphology. The studies were prospective and controlled for several potential confounders including the period of abstinence and the delay from sample collection to analysis. In a cross-sectional study on testicular function in 122 workers in ornamental-flower greenhouses, expert judgment was used to categorize workers into high-, medium-, and low-exposure groups (Abell et al., 2000a). The median sperm concentration and the median proportion of normal sperm were 60% and 14% lower, respectively, in the group with high estimated dermal exposure (n=13) than in the group with low estimated dermal exposure (n=44). Those differences remained after adjustment for potential confounders. However, the relevance of this study for the purposes of this report is limited by the exposure of the workers to more than 60 pesticides, including a number of fungicides.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Two studies examined men in couples seeking infertility treatment at clinics in the Netherlands (Tielemans et al., 1999) and Argentina (Oliva et al., 2001). Tielemans and colleagues found an increased, but imprecise association between abnormal semen characteristics and self-reports of occupational use of insecticides (odds ratio [OR]=1.52, 95% confidence interval [CI]=0.33–7.06). Using a broad exposure category that grouped all pesticide exposures, Oliva and colleagues found associations between pesticide use and several sperm characteristics, including reduced motility and abnormal structure. Because of their broad definitions of pesticide exposure, these two studies do not provide specific insight into the relationship between insecticides under consideration exposure and sperm characteristics. Additional Indirect Studies of Infertility A case-control study of Danish couples undergoing infertility examinations used mailed questionnaires about occupational exposure (Rachootin and Olsen, 1983). Information on occupational exposures was gathered from an original sample of 927 infertile and 3728 control couples (selected from couples who had a healthy child born at the same hospital). Subgroups of couples with at least one year’s infertility were defined on the basis of explanations for the subfecundity: men with sperm abnormalities (n=258), women with hormonal disturbances (n=305, 48 of whom had husbands with sperm abnormalities), or women or men from 129 couples with idiopathic infertility. Pesticide exposure was not more frequent in any of these subgroups as compared to their respective fertile controls. Several studies have examined the effects of insecticide exposure on reproductive hormones. In a lindane-producing factory, Tomczak and colleagues (1981) conducted a cross-sectional study of 54 male workers (85% participation rate) and 20 clerks (unexposed external comparison group). The analysis of blood samples found elevated serum luteinizing hormone (LH) concentrations, somewhat elevated levels of follicle stimulating hormone (FSH), and somewhat depressed testosterone levels in the exposed workers. Straube and colleagues (1999) found similar results in a prospective followup study of 67 professional pesticide applicators (studied before, during, and after applying pesticides) and 125 comparison subjects. Although those studies found minor alterations in serum hormones, the clinical significance, if any, of these hormonal alterations is unclear. Infertility Fertility can be measured directly by determining delays in conception for couples attempting to conceive. Maternal, paternal, or couple-related exposure may be the focus of infertility studies evaluating time-to-pregnancy (TTP). As part of the Ontario Farm Family Health Study, Curtis and colleagues (1999) conducted a retrospective cohort TTP study that examined pesticide use by farm couples in Ontario, Canada. Of 2946 eligible couples, 1898 (64%) completed three mailed questionnaires; of the responders, 1048 couples with 2012 pregnancies were eligible for inclusion in the analysis. Each couple was asked to construct a monthly pesticide-use history for the year 1991 and to provide details on the pesticides used on the farm. Exposure was defined as pesticide use during the month of attempted conception or at any time during the previous 2 months (to allow residual effects of pesticide exposure on spermatogenesis). Information was collected separately for wives and husbands on monthly participation in direct pesticide use (such as mixing and application). Extensive data on potentially confounding variables were also obtained. The study found that there was no strong overall pattern of association between TTP and exposure to insecticides or other pesticides.

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Gulf War and Health: Insecticides and Solvents, Volume 2 There was a suggestion of decreased fecundability (increased TTP) when the women used organophosphates (CFR=0.75, 95% CI=0.51–1.10), carbaryl (CFR=0.97, 95% CI=0.63–1.49), and several herbicides. For insecticides as a group, however, the women’s CFR was 1.02 (95% CI=0.76–1.37). The CFRs were close to unity for the periods in which only the men used insecticides (CFR=1.01, 95% CI=0.87–1.17), carbaryl (CFR=1.03, 95% CI=0.84–1.26), or organophosphates (CFR=1.04, 95% CI=0.89–1.22). A major strength of the study is the detailed information on specific pesticides. The inclusion of all pregnancies for each couple is problematic, although the authors report that an analysis restricted to first pregnancies did not alter the results. The fact that pesticide use was highly correlated between members of a couple makes it difficult to determine whether any observed effect was specifically maternally or paternally mediated. Other studies of TTP examined pesticides in general and did not provide specific information on insecticides. Abell and colleagues (2000b) evaluated a cohort of Danish women who worked in flower greenhouses where there was extensive use of pesticides (primarily insecticides, fungicides, and growth regulators). When overall pesticide exposure was analyzed with control for maternal and paternal smoking, maternal age, parity, and other factors, a slightly increased fecundability ratio (decreased TTP) was observed (FR=1.11, 95% CI=0.90–1.36). However, conception was delayed among the workers who did not use gloves (FR=0.67, 95% CI=0.46–0.98) and among those in the high exposure group (FR=0.64, 95% CI=0.45–0.90). The study did not examine specific pesticides, and it lacked paternal-exposure information, but it is important to note that the exposed group was not exposed to herbicides. Several studies have examined paternally mediated associations between pesticide exposure and TTP. A study by de Cock and colleagues (1994) examined a population of Dutch fruit-growers; 43 couples with 91 pregnancies were eligible for the analysis. There was an association between longer TTP and application of pesticides solely by the farm owner (FR=0.46, 95% CI=0.28–0.77); in addition, delays in time to conception were noted during the spraying season (FR=0.42, 95% CI=0.20–0.92). This study is limited for the purposes of this review by the crude measure of pesticide exposure and the lack of information on the specific insecticides used. Larsen and colleagues (1998b) examined TTP and exposure to pesticides in Danish male farmers. The study did not find differences in TTP when comparing traditional farmers (who sprayed pesticides) with organic farmers (FR=1.03, 95% CI=0.75–1.40). Similarly, none of the specific characteristics of pesticide use (such as cumulative years of spraying and type of equipment used) was associated with TTP. Thonneau and colleagues (1999) investigated TTP in a group of male farmers and agricultural workers in Denmark and France. In France, 142 exposed and 220 nonexposed workers were examined, while in Denmark, the corresponding numbers were 447 and 123. The fecundability ratios did not differ between exposed and unexposed workers. However, the crude nature of the exposure measure and the problems associated with the definition of exposure limit the interpretation of the data. Summary and Conclusion In reviewing the studies on indirect measures of fertility, the committee did not find strong evidence of association with exposure to insecticides (Table 8.1). The studies of semen characteristics by Whorton and Wyrobek and colleagues provide limited evidence of an association between current work in carbaryl production and oligospermia and teratospermia.

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Gulf War and Health: Insecticides and Solvents, Volume 2 However, the studies were cross-sectional and reported on results in workers who, for the most part, were currently exposed to carbaryl, so it is unclear whether the response would persist after cessation of exposure. Two studies found altered hormonal status in individuals with pesticide exposure, but the clinical significance of the findings and whether they persist after exposure were not determined. Only one of the TTP studies provided an analysis of specific insecticide use (Curtis et al., 1999) (Table 8.2). It did not show delayed TTP for either maternal or paternal exposure, although there was a suggestion of delayed time to conception for women who used organophosphates and carbaryl. Other studies considered pesticide exposures that were too broad for the purposes of this review. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the insecticides under review and male or female infertility after cessation of exposure. TABLE 8.1 Selected Epidemiologic Studies: Sperm and Semen Parameters and Exposure to Carbaryl Reference Population N Results (% with Oligospermia or teratospermia) Whorton et al., 1979 Carbaryl production workers   Oligospermia     Carbaryl workers 47 14.9a   Current carbaryl workers 29 17.2   Previous carbaryl workers 18 11.1   Chemical-worker controls 90 5.5a Wyrobek et al., 1981 Carbaryl production workers   Oligospermia     Carbaryl workers 48 14.6   New-hire controls 34 5.9   Teratospermia     Carbaryl workers 49 28.6   New-hire controls 34 11.8 aThe comparison of carbaryl workers with controls resulted in p value of 0.07. No further comparisons were presented. TABLE 8.2 Selected Epidemiologic Studies: Time-to-Pregnancy and Exposure to Insecticides Reference Population Number of Exposure Intervalsa Fecundability Ratio (95% CI) Curtis et al., 1999 Ontario farm couples     Insecticides     Females 111 1.02 (0.76–1.37)   Males 744 1.01 (0.87–1.17)   Organophosphates     Females 89 0.75 (0.51–1.10)   Males 391 1.04 (0.89–1.22)   Carbaryl     Females 51 0.97 (0.63–1.49)   Males 214 1.03 (0.84–1.26) aNumber of 3-month exposure windows in which the man or woman reported pesticide use.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Epidemiologic Studies of Preconception End Points and Exposure to Organic Solvents Sperm and Semen Characteristics Many studies have examined the relationship between occupational exposures and male infertility. Often, work in a specific industry was used as a surrogate for solvent exposure. In some industries (such as dry cleaning), a fairly consistent set of compounds is used, while in other industries (such as leatherwork or shoemaking), workers might be exposed to more ill-defined, heterogeneous groups of compounds. The committee’s review focused on studies with well-characterized solvent exposure and adequate participation rates. A number of other studies were examined, but had limitations for the purposes of this review (e.g., Chia et al., 1994, 1996; De Celis et al., 2000; Eskenazi et al., 1991; Kurinczuk and Clarke, 2001; Rendon et al., 1994; Xiao et al., 2001). Lemasters and colleagues (1999) achieved a high participation rate (79.5%) in a prospective longitudinal study of a group of 50 aircraft-maintenance personnel. Subjects were evaluated before first exposure to solvents and then 15 and 30 weeks after exposure had begun. The study included quantitative measurement of exposure to solvents (for example, breath-sampling and industrial-hygiene monitoring) in the interval prior to sperm collection. The average industrial exposures were less than 10% of the Occupational Safety and Health Administration personal exposure limits. The analysis controlled for risk factors for semen abnormalities (such as medication use). Exposure to solvents, defined by work area and personal measurements, was not associated with any decline below normal limits in the measures of semen quality as defined by WHO reference values (WHO, 1999). Job status correlated with several semen characteristics, but there was not a consistent pattern of association. For example, sheet metal workers had higher levels of exposure to fuels and solvents (measured in expired breath) compared with aircraft painters and had decreased sperm directional movement (p= 0.03); the painters had greater declines in sperm motility (19.5%, p=0.04) as compared with sheet metal workers (3.2%). Given the multiple comparisons and the fact that the semen analysis results were mostly within normal ranges, these conflicting results are even less suggestive of an association between exposure to solvents and semen characteristics. A case-control study in the Netherlands examined the relationship between occupational exposures and semen characteristics in the male partners of couples that had an infertility consultation (Tielemans et al., 1999). The 899 participants were asked to provide a semen sample and to complete detailed questionnaires regarding their occupational history. A job-exposure matrix was used to assess and verify exposures, and subjects who were exposed or nonexposed to the various chemical agent groups were compared. Changes in semen parameters were not found to be associated with exposure to organic solvents as a general category when evaluated in the total population (OR=0.98, 95% CI=0.60–1.59) or in men with primary infertility1 (OR=1.15, 95% CI=0.66–1.99). The results for exposure to aliphatic and halogenated solvents were similar when analyzed in the total population or in men with primary infertility. Exposure to aromatic solvents showed an increased risk of abnormal semen parameters in men with primary infertility, based on 49 exposed cases (OR=1.92, 95% CI=0.88–4.19). 1   Primary infertility describes the fertility status of a couple that has not conceived after a minimum of 1 year of unprotected intercourse. Secondary infertility describes the condition of a couple that has conceived but is not able to conceive again (NLM, 2002).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Cherry and colleagues (2001) reported on two studies in Canada, one using records of couples attending a fertility clinic in Montreal in 1972–1991, and the other using records from other clinics across Canada (1984–1987). For both studies, semen samples were collected from over 80% of participants. For jobs indicating manual work, investigators used self-reported occupational title and a job-exposure matrix to classify job titles by intensity of exposure to organic solvents. In the Montreal study, among 656 males, there was an increased risk of low-active sperm count (less than 12×106/mL) with high exposure to solvents (OR=3.83, 95% CI=1.37–10.65) and moderate exposure (OR=2.07, 95% CI=1.24–3.44), adjusted for confounders, including age and occupational exposure to lead. The second study found a strong association only in the men with high exposure to solvents (OR=2.90, 95% CI=1.01–8.34). The authors acknowledged that the Montreal study spanned a 20-year period and that changes in the type and intensity of exposures over this period might lead to confounding by calendar time. However, for confounding by time to occur, there would need to be a time trend in semen parameters. Oliva and colleagues (2001) examined occupational exposures in relationship to semen characteristics among 177 Argentinean men recruited from 253 couples that were having their first infertility consultation. Occupational history was taken by interview, and semen samples were collected. Of the participants, 22 were classified as exposed to solvents. In a comparison among all study subjects, the study found associations between solvent exposure and several measures of abnormal semen characteristics (based on WHO guidelines), including sperm concentration (OR=2.7, 95% CI=0.9–8.3), sperm structure (OR=3.0, 95% CI=1.0–9.0), and sperm motility (OR=3.1, 95% CI=1.0–9.5). Sperm motility was most impaired in those with primary infertility and solvent exposure (OR=10.6, 95% CI=1.1–105.6). This finding may be confounded because the 10 solvent-exposed cases were mostly mechanics and so might have had other exposures in common. Rasmussen and colleagues (1988) studied metal workers exposed to trichloroethylene and found no association between exposure and semen characteristics. The study had low statistical power inasmuch as it was based on only 15 subjects. Exposure to ethylene glycol ethers has been examined in several studies of semen characteristics. These chemicals are of concern because evidence from animal studies shows that the metabolites of ethylene glycol ethers are associated with impaired fertility characterized by testicular atrophy, abnormal sperm morphology, and decreased sperm motility (Bruckner and Warren, 2001). In a case-control study, Veulemans and colleagues (1993) examined the associations between the presence of the urinary metabolites of ethylene glycol ethers (methoxyacetic acid, or MAA, and ethoxyacetic acid, or EAA) and a diagnosis of infertility or differences in semen characteristics. They also assessed a variety of occupational exposures. The study involved 1019 men who had been clinically diagnosed as infertile or subfertile; controls were 475 male patients of the same clinic for reproductive disorders who were diagnosed as fertile. A comparison of cases and controls found inconsistent results for exposure to degreasers or cleaning products (OR=0.89), paint removers (OR=1.56), and solvents (OR=0.87). Urinary EAA was detected in 45 participants, of whom 29 reported occupational exposure to solvent-related products. The study did not find an association between urinary EAA and abnormal semen characteristics; the authors speculated that might be due to a latent period between exposure and the time when observable effects are seen. Ratcliffe and colleagues (1989) studied semen quality in 37 workers exposed to 2-ethoxyethanol (ethylene glycol monoethyl ether) at a metal-casting company and in 39 nonexposed workers from other locations in the same plant. The study found decreases in mean

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Gulf War and Health: Insecticides and Solvents, Volume 2 sperm count in the exposed workers but no marked changes in sperm motility, structure, or velocity or in testicular volume after adjustments for many potential confounders, including alcohol and tobacco consumption, sexual abstinence, and urogenital or other medical disorders. There was a possibility of selection bias because the participation rate among exposed workers was 50%, and the study had low statistical power. A study of shipyard painters by Welch and colleagues (1988) examined potential exposure to the ethylene glycol ethers, 2-ethoxyethanol, and 2-methoxyethanol. An industrial-hygiene survey of the worksite measured exposures to ethylene glycol ethers and other compounds. The study examined semen samples from 73 painters (a 50% participation rate) and 40 controls and found that the painters had a higher prevalence of oligospermia and azoospermia. An analysis controlling for smoking found a higher risk of decreased sperm count per ejaculate in the exposed group (OR=1.85, 95% CI=0.6–5.6). No important differences were found in sperm structure, motility, or viability. Additional Indirect Studies of Infertility Studies have examined other indirect end points of infertility. Most are cross-sectional, and participants have continuing solvent exposure; those characteristics limit the studies’ ability to inform the discussion of persistent effects. The effect of solvent exposure on women’s menstrual cycles has been examined in several studies, including a cross-sectional study of women working in a factory who were exposed to toluene in the manufacture of audio speakers (Ng et al., 1992). The frequency of dysmenorrhea (painful menstruation) was higher in the high-exposure group (15.6%) and in the low-exposure group (13.8%) than in the community control group (3.2%). A study of 1408 female workers in petroleum and chemical processing plants in Beijing, China, found a consistent association between exposure to aromatic solvents and abnormal menstrual-cycle length, but the exposure and health-outcomes assessments were limited and there was potential for confounding by other chemical exposures (Cho et al., 2001). Other studies of menstrual disorders have had inconsistent results (Georgieva et al., 1998; Gold et al., 1995; Zielhuis et al., 1989). In a case-control study of Danish couples, Rachootin and Olsen (1983) compared the male or female occupational exposures of subfecund subgroups (with sperm- or hormone-related reasons for infertility or idiopathic infertility) with those of fertile control couples. (The derivation of the subgroups was described above where this study was considered with respect to pesticides.) The participants completed a questionnaire asking about occupational exposures, which included degreasers, dry-cleaning chemicals, and other organic solvents. Among the many comparisons, the only suggestive association was for women with idiopathic infertility and exposure to dry-cleaning chemicals (OR=2.7, 95% CI=1.0–7.1), adjusted for age, education, residence, and parity. Several cross-sectional studies have examined the effects of solvents on reproductive hormones. Svensson and colleagues (1992a,b) found that exposure to toluene was associated with lower blood concentrations of FSH, LH, prolactin, and testosterone in young male rotogravure printers when compared with factory workers. The authors state that the effects may be transitory, since a reversal of the decreases in LH and FSH levels was seen in a subset of the printers after a 4-week exposure-free period. Studies of exposure to trichloroethylene among 85 male workers found moderate decreases in FSH and testosterone, and stronger increases in dehydroepiandrosterone sulfate with increasing duration of exposure (Chia et al., 1997; Goh et al., 1998). Those studies were relatively small and had little or no control for important

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Gulf War and Health: Insecticides and Solvents, Volume 2 confounders (such as alcohol use). No adverse clinical consequences were reported. Oliva and colleagues (2001) also found lower LH concentrations in men exposed to solvents who were seeking infertility treatment. Infertility Several studies have examined the effects of solvent exposure on infertility by studying TTP. In a cross-sectional study, Plenge-Bonig and Karmaus (1999) examined infertility in printing-industry workers. The workers (150 men and 90 women) were interviewed about their occupational and reproductive histories, and their exposure to toluene was categorized according to job descriptions and previous measurements by industrial hygienists. The study did not find an effect on TTP in the men who were exposed to toluene (FR=1.05, 95% CI=0.93–1.19); there was no relation to exposure category (none, low, medium, or high). The analysis of exposed female workers found increased TTP (FR=0.52, 95% CI=0.28–0.99). The study controlled for such confounders as age, ethnicity, smoking, parity, and frequency of sexual intercourse. The participation rates were low (50% in men and 39% in women) and may have involved bias by self-selection. Sallmen and colleagues conducted two studies on TTP. The first (Sallmen et al., 1995) examined women who had been biologically monitored for exposure to organic solvents at the Finnish Institute of Occupational Health. The participants were asked about a number of occupational and environmental factors, including work history and possible solvent exposure in the 12 months before pregnancy. Using a fecundability measure termed the incidence density ratio (IDR), this study controlled for a number of confounders and found reductions in fecundability in the groups with high (IDR=0.41, 95% CI=0.27–0.62) and low solvent exposure (IDR=0.69, 95% CI=0.48–0.99). Exposures to high levels of specific solvents were found to reduce fecundability with imprecise risk estimates (trichloroethylene, IDR=0.61, 95% CI=0.28–1.33; tetracholoroethylene, IDR=0.69, 95% CI=0.31–1.52). In the second study, Sallmen and colleagues (1998) looked at TTP among couples in which the man had been monitored for organic solvent exposure at the same Finnish institute. The questionnaire on reproductive history was returned by 316 of the 438 wives of the men (72% participation rate); the final study population consisted of 282 couples after exclusions. Biologic measurements of exposure were available for 69% of those men and were used to supplement self-reported information on occupational exposures. The study found an adjusted fecundability measure (fecundability density ratio [FOR]) of 0.80 (95% CI=0.57–1.11) for high or frequent paternal exposure and a similar result for low or intermediate exposure (FDR=0.74, 95% CI=0.51–1.06). Nor did this study find effects on TTP for specific solvent exposures; for example, for intermediate/high exposure to trichloroethylene the investigators found an FDR of 1.03 (95% CI=0.60–1.76). Several studies have examined the reproductive histories of semiconductor workers with a focus on exposure to ethylene glycol ethers. Samuels and colleagues (1995) conducted a study of fertility among men working in eight semiconductor-manufacturing companies (1984–1989). They used the workers’ current jobs to define exposure status, first dichotomizing among fabrication workers (n=241) and nonfabrication workers (n=447) and then subdividing the fabrication workers by types of work processes. The study did not find increases in TTP when fabrication and nonfabrication workers were compared (adjusted FR=0.98, 95% CI=0.80–1.19). Fecundability was also not reduced in the subanalysis of the workers (adjusted FR=1.03,

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Gulf War and Health: Insecticides and Solvents, Volume 2 95% CI=0.70–1.51) in whom exposure to ethylene glycol ethers was of particular concern (those involved in masking work—etching and photolithography). A prospective study (Eskenazi et al., 1995a) asked female semiconductor workers to complete a daily diary on reproductive history and occupational exposures and to collect a daily urine sample for 6 months. As in the previous study, fabrication and nonfabrication workers and subgroups of fabrication workers were compared. Extensive analysis, adjusting for a number of confounders, found reduced fecundability (increased TTP) in fabrication workers (FR=0.69, 95% CI=0.38–1.25) with adjustments for recent pregnancy or lactation. In workers exposed to ethylene glycol ethers (259 cycles), there was also a longer TTP (FR=0.37, 95% CI=0.11–1.19). Several studies of infertility used measures other than TTP. Correa and colleagues (1996) examined the extent of subfertility (taking more than 1 year to conceive) related to 561 pregnancies of female workers and 589 pregnancies of wives of male workers at two semiconductor manufacturing plants in the eastern United States. Reproductive and occupational histories were obtained through interviews; company records were used to develop matrices of industrial processes and to differentiate potential exposure to ethylene glycol ethers and their acetates. In female employees, of whom only six were exposed, there was a increased risk (OR=4.6, 95% CI=1.6–13.3). Among spouses of male employees with high potential exposure to ethylene glycol ethers the risk of subfertility was elevated (OR=1.7; 95% CI=0.7–4.3). A study of solvent-exposed male workers at an Italian mint (Figa-Talamanca et al., 2000) also found an elevation in the risk of conception delay of more than 6 months (OR=1.69, 95% CI=0.62–4.62); this was based on a small number of cases. Summary and Conclusion Although a number of studies have examined the potential effects of occupational exposure to solvents on semen characteristics, few studies have investigated persistent effects after cessation of solvent exposure. There is evidence from animal studies that exposure to specific solvents, particularly ethylene glycol ethers, is associated with testicular atrophy, decreased sperm motility, and abnormal sperm structure (Bruckner and Warren, 2001). Data on the effects of human exposure to ethylene glycol ethers also show associations with several semen parameters but are insufficient to conclude that the effects would persist after exposure ceases. Studies of TTP and other measures of infertility have found inconsistent associations with exposure to solvents regarding paternal exposures (Table 8.3). Increased TTP was seen in several studies of maternal exposures to solvents. No studies have examined the presence or absence of persistent effects on fertility once exposure ceases. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to specific organic solvents under review or solvent mixtures and male or female infertility after cessation of exposure.

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Gulf War and Health: Insecticides and Solvents, Volume 2 power to detect actual effects. The few studies that examined maternal or paternal preconception exposures did not find clear and consistent evidence of an association with any type of malformation. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between maternal or paternal preconception exposure to the insecticides under review and congenital malformations. TABLE 8.5 Selected Epidemiologic Studies: Congenital Malformations and Exposure to Insecticides Reference Population Exposed Cases Estimated Relative Risk (95% CI) Maternal Exposure NTDs and CNS Anomalies Shaw et al., 1999a Maternal exposure 1 month before to 3 months after conception     Use of insect foggers 20 1.1 (0.6–2.0)   Professionally applied pesticides in the home 53 1.6 (1.1–2.5)   Mothers applying pesticides in the home 54 1.1 (0.8–1.7)   Insect-repellent use 16 1.0 (0.6–1.9)   Maternal occupational exposure likely 3 0.9 (0.2–3.8) Shaw et al., 1999b Occupational and hobby-related exposures 3 months before conception through pregnancy     Carbamates 6 1.2 (0.38–3.7)   Organophosphates 17 1.2 (0.60–2.5)   Pyrethrins 7 1.0 (0.36–2.8)   Insecticides 40 1.3 (0.81–2.1) Heart Malformations Loffredo et al., 2001 Maternal exposure and infants born with transposition of the great arteries     Insecticides—critical period 32 1.5 (0.9–2.6)   Insecticides—4–6 months before pregnancy 28 1.6 (0.9–2.9) Shaw et al., 1999b Maternal exposure 1 month before to 3 months after conception     Mothers applying pesticides during gardening 12 3.1 (1.3–7.3)   Insect-repellent use 25 2.2 (1.3–3.9)   More than one pet-flea collar product used 53 1.2 (0.8–1.8)   Insect-fogger use 12 0.8 (0.4–1.7) Paternal Exposure Multiple or Other Malformations Garcia et al., 1998 Paternal exposure for infants born in agricultural areas of Spain     Malathion 6 0.30 (0.06–1.43)   Carbamates 10 0.81 (0.30–2.22)   Organophosphates 31 0.77 (0.38–1.58) Lin et al., 1994 Parental exposure for infants born with limb reduction defects in New York state     Paternal exposure to insecticides 23 1.0 (0.5–1.7)   Maternal exposure to insecticides 13 0.7 (0.4–1.5)

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Gulf War and Health: Insecticides and Solvents, Volume 2 Epidemiologic Studies of Congenital Malformations and Exposure to Organic Solvents Neural Tube Defects and Other Central Nervous System Anomalies A study by Holmberg and colleagues used the Finnish Register of Congenital Malformations to identify children with CNS anomalies (Holmberg, 1979; Holmberg and Nurminen, 1980). They reported that maternal occupational exposure to solvents was associated with an increased incidence of anomalies. Shaw and colleagues (1999b) studied occupational and hobby-related exposures of mothers of 538 children with NTDs (diagnosed June 1989–May 1991) and 539 controls born in selected California counties. Maternal interviews assessed exposures from 3 months before to 3 months after conception (periconception) and included a detailed work history and questions about hobbies. An industrial hygienist used the data to create exposure classifications for 74 chemical-agent groups, exposure to 48 of which were assessed for NTDs. In the extensive analysis, periconceptional maternal exposure to glycol ethers and derivatives resulted in an OR of 0.93 (95% CI=0.66–1.3), with 75 exposed cases. The study found inconsistent results for associations between NTDs and any of the categories of solvent exposure considered, such as aliphatic chlorinated hydrocarbons (OR=1.1), aliphatic alcohols (OR=0.87), and ketones (OR =0.71). The strengths of this study included a detailed exposure assessment that was based on interviews conducted close to the birth and an analysis that controlled for medical risk factors. The study did not provide a separate analysis of data regarding preconception exposure, but provides some insights into exposure-outcome relationships in the 3 months before and after conception. Two studies by Blatter and colleagues (1996, 1997) examined occupational exposures of mothers and fathers of children born with spina bifida in nine hospitals in the Netherlands. The controls were healthy children born in the same period, selected from several of the hospitals and from the general population. In a two-step data-collection process, questionnaires were mailed to case and control parents to gather information on occupations and potential confounders, followed by personal interviews regarding job- and task-specific information. In the study of maternal exposures (Blatter et al., 1996), the period of interest was from 2 weeks before conception to 6 weeks after conception. Exposures were assessed as none, light, moderate, and heavy. No differences were found in risk of spina bifida with exposure to all organic solvents; the analysis of 29 exposed cases and 35 exposed controls resulted in an OR of 0.9 (95% CI=0.6–1.6). In the companion study (Blatter et al., 1997), paternal occupational exposures were assessed for the period from 3 months before conception to 1 month after conception. Interviews were conducted with 122 fathers of children with spina bifida and 411 fathers of controls. The study controlled for a number of medical risk factors, including maternal diabetes and the use of antiepileptic medications. The investigators did not find an increased risk associated with paternal exposure to solvents at any level (OR=0.7, 95% CI=0.4–1.1), low solvent exposure (OR=0.6), or moderate to high solvent exposure (OR=0.9). Other studies of paternal exposure and CNS anomalies that were examined by the committee used broad exposure categories based on occupational titles (e.g., Brender and Suarez, 1990; Irgens et al., 2000; Olshan et al., 1991). Thus, they did not have specific information on solvent exposure necessary to inform conclusions.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Congenital Heart Malformations As part of the Baltimore-Washington Infant Study, Wilson and colleagues (1998) examined risk factors potentially associated with several major cardiac malformations. They interviewed 1585 parents of children born in 1981–1989 with structural heart defects. The exposure period of interest encompassed the 3 months before and after the mother’s last normal menstrual period. The study found attributable fractions of 4.6% (95% CI=3.2–6.0%) for solvent or degreasing-agent exposure with hypoplastic left heart, 3.0% (95% CI=1.6–4.5%) for solvent exposure with coarctation of the aorta, and 5.1% (95% CI=1.2–8.9%) for painting with atrioventricular septal defect in Down syndrome. Tikkanen and Heinonen published several case-control studies of maternal exposure during early pregnancy and different congenital cardiac malformations. The earliest study found an adjusted RR of 1.3 (95% CI=0.8–2.2) for maternal solvent exposure during the first trimester and all cardiovascular malformations (Tikkanen and Heinonen, 1988). In a study focused on atrial septal defects in 50 cases compared with 756 controls, maternal first-trimester occupational exposure to solvents resulted in an increased RR of 2.6 (95% CI=0.7–9.1) (Tikkanen and Heinonen, 1992a). In a similar analysis for conal malformations of the heart, Tikkanen and Heinonen (1992b) found no association with maternal exposure to solvents during the first trimester (OR=0.6, 95% CI=0.2–1.4). Oral Clefts Holmberg and colleagues (1982) found that more mothers of children with oral clefts had occupational exposure to solvents than did mothers of unaffected children born in the same time period and geographic area. A case-control study in France compared exposure to solvents by mothers whose children were born from 1985 to 1989 with or without oral cleft (Laumon et al., 1996). Interviews with each mother focused on exposures in the first 2 months after conception. Among all the categories of solvents considered, increased risks were found for exposure specifically to halogenated aliphatic solvents (OR=4.40, 95% CI=1.41–16.15) and for exposure to any solvent (OR=1.62, 95% CI=1.04–2.52). The estimates of the risk of oral clefts associated with other categories of solvent exposures were not markedly elevated. Maternal occupational exposures during pregnancy were also the focus of studies by Cordier and colleagues. In a preliminary case-control study in two regions of France, the mothers of 325 children with major malformations and 325 normal referents were interviewed about exposures during pregnancy (Cordier et al., 1992). The study found an increased estimated risk for maternal solvent exposure and children with oral clefts (OR=7.9, 90% CI 1.8–44.9). A later multicenter case-control study by the same investigators (Cordier et al., 1997) focused on maternal exposure to glycol ethers during the first trimester of pregnancy. The overall OR for congenital malformations was 1.44 (95% CI=1.10–1.90) after adjustment for several potential confounders. Positive associations were found between first-trimester exposure to glycol ethers and several specific types of congenital malformations considered in the study: NTD (OR=1.94, 95% CI=1.16–3.24), spina bifida (OR=2.37, 95% CI=1.22–4.62), cleft lip (OR=2.03, 95% CI=1.11–3.73), and multiple anomalies (OR=2.00, 95% CI=1.24–3.23). The most recent study by those investigators also focused on first-trimester maternal occupational exposure (Lorente et al., 2000). An increased risk was seen for exposure to glycol ethers and cleft lip (with or without cleft palate) on the basis of 23 exposed cases (OR=2.10,

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Gulf War and Health: Insecticides and Solvents, Volume 2 95% CI=1.14–3.88), but the risk for cleft palate alone was not as elevated (OR=1.82, 95% CI =0.82–4.03). Other Types of Congenital Malformations Potential risk factors for the congenital malformation gastroschisis were examined in a case-control study by Torfs and colleagues (1996). The registry of the California Birth Defects Monitoring Program was used to ascertain 110 cases of infants born with abdominal wall defects, and a pediatric geneticist reviewed the diagnosis. The 220 controls for the study did not have a congenital malformation and were matched on maternal age and ethnicity. Interviews included questions on hobbies during pregnancy, occupational exposures during the 3 months before conception and the first trimester of pregnancy, and medications and illnesses during the first trimester. An industrial hygienist evaluated the type of exposure associated with the occupations and categorized exposures as low or high intensity based on the working conditions, duration of work, and route of exposure. The study found increased risks associated with high solvent exposure (OR=3.84, 95% CI=1.61–9.17) on the basis of 15 exposed cases; the risk posed by low exposure was also increased (OR=2.28, 95% CI=0.99–5.24). High exposure specifically to aromatic hydrocarbons was associated with abdominal defects (OR=4.74, 95% CI=1.45–15.49). This study’s outcomes were carefully confirmed, but little other research has been directed at this specific malformation. McDonald and colleagues (1988) examined occupational risks of congenital malformations in 47,913 pregnancies of women in Montreal and found no evidence of increased risk of congenital malformations associated with solvent exposure in any of the groups. Khattak and colleagues (1999) reported the results of a prospective study of solvent exposure and congenital malformations in women who were occupationally exposed to solvents. Those women sought counseling (1987–1996) about their exposures at a pregnancy and antenatal counseling service in Toronto. Women who worked with organic solvents during at least their first trimester (n=125) were compared with women who participated in the counseling service but did not work with solvents or other suspected teratogens. The study found that 13 of the solvent-exposed women had children with major malformations compared with one in the control group (RR=13.0, 95% CI=1.8–99.5). The malformations included ventricular septal defect, NTD, and clubfoot. The prospective design reduces the likelihood of differential exposure misclassification and selection bias, because the outcome had not occurred at the time of exposure assessment and subjects had not been recruited retrospectively. In addition, drawing the comparison group (non-solvent exposed women) from the same counseling service as the solvent-exposed women further minimized the possibility of selection bias. Summary and Conclusion Few studies of solvent exposure and congenital malformations focused on preconception exposure of either mothers or fathers (Table 8.6). Paternal preconception exposure to solvents was examined in a study that did not find an increased risk of spina bifida in the children (Blatter et al., 1997). A few studies included preconception exposure and gestational exposure but did not provide a separate analysis of exposures before pregnancy; therefore, these studies are unable to present risks independently for the preconception period. A case-control study on gastroschisis found increased risks posed by solvent exposure in the period from preconception through the first trimester (Torfs et al., 1996). A study of NTDs by Shaw and colleagues (1999a) found inconsistent results of periconception exposure to various classes of solvents.

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Gulf War and Health: Insecticides and Solvents, Volume 2 The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between maternal or paternal preconception exposure to the specific organic solvents under review or solvent mixtures and congenital malformations. TABLE 8.6 Selected Epidemiologic Studies: Congenital Malformations and Exposure to Organic Solvents Reference Population Exposed Cases Estimated Relative Risk (95% CI) Maternal exposure Neural tube defects Shaw et al., 1999 Occupational and hobby-related exposure (3 months before conception to 3 months after conception)       Aliphatic alcohols 143 0.87 (0.67–1.1)   Aliphatic chlorinated hydrocarbons 26 1.1 (0.62–1.9)   Glycol ethers and derivatives 75 0.93 (0.66–1.3)   Glycols 26 1.3 (0.71–2.3)   Ketones 21 0.71 (0.41–1.3) Spina bifida Blatter et al., 1996 Occupational exposure (2 weeks before to 6 weeks after conception)     All organic solvents 29 0.9 (0.6–1.6) Gastroschisis Torfs et al., 1996 Children born with gastroschisis     Maternal exposure from preconception through first trimester     All solvents, low exposure 13 2.28 (0.99–5.24)   All solvents, high exposure 15 3.84 (1.61–9.17)   Aromatic hydrocarbons, high exposure 9 4.74 (1.45–15.49)   Glycols 6 2.00 (0.65–6.20) Paternal exposure Spina bifida Blatter et al., 1997 Paternal occupational exposure (3 months before conception to 1 month after conception)     Solvents 29 0.7 (0.4–1.1)   Low 19 0.6 (0.4–1.1)   Moderate or high 10 0.9 (0.4–2.0) REFERENCES Abell A, Ernst E, Bonde JP. 2000a. Semen quality and sexual hormones in greenhouse workers. Scandinavian Journal of Work, Environment and Health 26(6):492–500. Abell A, Juul S, Bonde JPE. 2000b. Time to pregnancy among female greenhouse workers. Scandinavian Journal of Work, Environment and Health 26(2):131–136. Agnesi R, Valentini F, Mastrangelo G. 1997. Risk of spontaneous abortion and maternal exposure to organic solvents in the shoe industry. International Archives of Occupational and Environmental Health 69(5):311–316. Ahlborg G Jr. 1990. Pregnancy outcome among women working in laundries and dry-cleaning shops using tetrachloroethylene. American Journal of Industrial Medicine 17(5):567–575. Ahlborg G Jr, Hogstedt C, Bodin L, Barany S. 1989. Pregnancy outcome among working women. Scandinavian Journal of Work, Environment and Health 15(3):227–233. Arbuckle TE, Lin Z, Mery LS. 2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspectives 109(8):851–857.

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