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Gulf War and Health: Volume 2: Insecticides and Solvents (2003)

Chapter: 8. Reproductive and Developmental Effects

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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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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

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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).

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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,

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 8.3 Selected Epidemiologic Studies: Time-to-Pregnancy and Exposure to Organic Solvents

Reference

Population

Number of Pregnancies

Fecundability Ratio (95% CI)

Toluene

Plenge-Bonig and Karmaus, 1999

Printing-industry workers in Germany

 

Female employees

89

0.52 (0.28–0.99)

Male employees

16

1.05 (0.93–1.19)

Solvents

Sallmen et al., 1995

Female workers in Finland

197

 

High exposure

46

0.41a (0.27–0.62)

 

Low exposure

59

0.69a (0.48–0.99)

Sallmen et al., 1998

Male workers in Finland

282b

 

Low or intermediate exposure

80c

0.74 (0.51–1.06)

 

High or frequent exposure

141c

0.80 (0.57–1.11)

Ethylene glycol ethers, work in semiconductor manufacturing

Samuels et al., 1995

Male semiconductor workers

688b

 

Fabrication

118d

0.98 (0.80–1.19)

 

Masking

23d

1.03 (0.70–1.51)

Eskenazi et al., 1995a

Female semiconductor workers

 

Fabrication

19

0.69 (0.38–1.25)

 

Exposure to ethylene glycol ethers

3

0.37 (0.11–1.19)

aIDR.

bNumber of couples participating. Paternal exposure was reported.

cNumber of men reporting exposure to solvents during pregnancies of their spouses.

dNumber of births.

PREGNANCY

A number of adverse outcomes of pregnancy have been studied for possible associations with exposure to insecticides or solvents. Many of the studies have focused on the risk of fetal loss prior to normal gestation of 40 weeks. Spontaneous abortion (miscarriage) refers to the loss of a fetus prior to 20 weeks of development; after 20 weeks gestation, fetal loss is termed a stillbirth. A birth at less than 37 weeks is referred to as a preterm delivery or premature birth. The overall incidence of spontaneous abortion is estimated to be as high as 43%, with the majority occurring in the 14 days after conception when most pregnancies would not have been detected (Bennett, 1992; Smith and Suess, 1998). About 10% of clinically recognized pregnancies end in spontaneous abortion, usually between 7 and 12 weeks of gestation (NLM, 2002). Completeness of ascertainment is thus a great challenge in epidemiology studies of spontaneous abortion.

The most common identified cause of spontaneous abortion is a genetic abnormality of the embryo. Risk factors for spontaneous abortion include age, maternal illness, cigarette smoking, alcohol use, taking of medications, and having a previous spontaneous abortion. The risk of pregnancy loss is known to increase with increasing maternal age, especially after the age of 30 or 35, and is also high for women under the age of 18. In women who have had one previous spontaneous abortion, the probability of a second is estimated to be 13–26%, and the probability of another increases with successive spontaneous abortions (Smith and Suess, 1998). Several maternal occupational exposures have been associated with the risk of spontaneous

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

abortion, including exposure to ethylene oxide, antineoplastic agents, and possibly anesthetic gases.

The committee sought information on whether exposure to insecticides or solvents could result in adverse effects on pregnancies that were conceived after cessation of exposure, but there is a paucity of data on that issue. Several studies provided some information on preconception exposures (generally in the 3 months before conception) and the outcomes of those pregnancies. Most studies, however, examined the results of exposure during pregnancy.

Epidemiologic Studies of Pregnancy Outcomes and Exposure to Insecticides

Maternal Exposure

A nested case-control study by Thomas and colleagues (1992) examined malathion spraying in the San Francisco Bay area to control a Mediterranean fruit fly infestation. The study evaluated spontaneous abortion (n=559) or stillbirth (n=37), using 1000 normal live births as the referent group. An exposure index was developed incorporating residential proximity to “spray corridors” and the number and dates of malathion applications. The relative risks of spontaneous abortion ranged from 0.99 to 1.20 for direct exposure to malathion during various periods of gestation. For stillbirth, the strongest association was observed for exposures occurring 1 month before the stillbirth (relative risk [RR]=1.95, 95% CI=0.88–4.35). Analysis of intrauterine growth did not show an association between malathion exposure and low birth weight. The investigators noted that exposure misclassification would most likely be nondifferential, thus biasing estimated associations toward the null.

Willis and colleagues (1993) examined a cohort of 535 women enrolled in a perinatal program during 1987–1989 in San Diego County, California, a heavy agricultural-production area where carbaryl and lindane were among the pesticides applied. Maternal interviews were prospective, once during each trimester of pregnancy, and plasma cholinesterase activity was measured at each point. Spontaneous abortion or preterm delivery occurred only in the unexposed group, and there was also a greater incidence of low-birthweight infants in the unexposed population. Those results are difficult to interpret, however, because the number of exposed women in the cohort was not presented. The authors did not report on the correlation between maternal reports of insecticide exposure and plasma cholinesterase activity. The investigators discussed the study’s limitations, including the likelihood of exposure misclassification, inability to control for important confounders, and differing degrees of followup among the study participants.

Bell and colleagues (2001a) examined the association between residential proximity to areas of pesticide application and risk of fetal death. They compared the possible maternal exposure for 319 cases (explicitly not due to congenital malformations) with that of the mothers of 611 live births during the same period. They did not find statistically precise elevations regarding this outcome and potential exposure to carbamates, pyrethroids, or phosphates in analyses for each of the three trimesters of gestation.

In 10 agricultural counties of California, Bell and colleagues (2001b) evaluated the relationship between maternal residential proximity to agricultural pesticide applications and the risk of fetal death due to congenital anomalies. They compared the gestational exposure of the mothers of 73 such cases and of 611 live normal births. When several critical periods for exposure during gestation were compared, the largest risks were seen for exposure during the 3rd to 8th week of pregnancy for each of five types of pesticide considered (carbamates, phosphates,

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

pyrethroids, halogenated hydrocarbons, and endocrine disruptors). Interestingly, for each of these pesticide types the risks increased when the application area defining exposure was made more specific to a mother’s residence (reduced from a 9- to a 1-square-mile area around her home). A followup note (Bell et al., 2001c) presented results from a reanalysis of corrected pyrethroid exposure data, which demonstrated an even more pronounced increase in risk of fetal death following exposure during this high-risk period to that type of pesticide (OR=3.8, 95% CI =1.6–9.1 for the 9-square-mile exposure definition); with the revised data there were insufficient cases to perform the 1-square-mile analysis. The 1-square-mile ORs were 2.3 (95% CI=0.9–6.4) for carbamates and 3.0 (95% CI=1.4–6.5) for phosphates. As for the previous study (Bell et al. 2001a), the analyses were exclusively restricted to gestation exposures, so the results do not illuminate the consequences of preconceptional exposure.

When maternal occupational exposure to pesticides in general was examined by using job title or recall of exposure, employment in agriculture-related jobs appeared to be related to spontaneous abortion or stillbirth (Goulet and Theriault, 1991; Pastore et al., 1997; Restrepo et al., 1990), but not consistently so (Heidam, 1984; Roan et al., 1984). An ecologic study conducted in 1971–1981 in New Brunswick supported an association with stillbirth, although the exposure was during the second trimester of pregnancy (White et al., 1988). There was little evidence of an association with perinatal death (Kristensen et al., 1997a; Zhang et al., 1992), but an ecologic study in Sudan (Taha and Gray, 1993) did suggest an association.

Paternal Exposure

The relationship between paternal insecticide exposure and pregnancy outcome was examined in a small study of the wives of 32 pesticide applicators in Rome (Petrelli et al., 2000). Lindane and carbamates were among the commonly applied pesticides. The occurrence of spontaneous abortion was compared with that in 51 spouses of food retailers in 1970–1995. The study showed an increased risk of spontaneous abortion among the wives of pesticide applicators (OR=3.8, 95% CI=1.2–12.0), but was severely limited by lack of details on selection and recruitment of study subjects, and crude exposure measurement.

Data from the Ontario Farm Family Health Study were used in two epidemiologic studies regarding pregnancy outcomes. The study by Savitz and colleagues (1997) focused on paternal insecticide exposure and pregnancy outcome. Detailed questionnaires regarding pregnancy outcomes and exposures were mailed to eligible farm couples, and telephone interviews were sought for those who did not respond by mail. Investigators examined 3984 pregnancies among 1898 farm couples who participated in the study. The men were interviewed to obtain extensive information on their farming activities over the preceding 5 years, with exposure defined as the mixing or applying of insecticides, pesticides, or fungicides in the 3-month window before conception. Men who had not engaged in farm activities or who reported no chemical exposures during that interval served as the referent group. There were approximately two-fold increases in the risk of spontaneous abortion for couples in which the man reported simultaneous application of carbaryl with herbicides or with insecticides or fungicides (OR=1.9, 95% CI=1.1–3.1 and OR=2.1, 95% CI=1.1–4.1, respectively). Use of organophosphates on the farm did not result in an increased risk (adjusted OR=0.9, 95% CI=0.3–2.4). The risks of small-for-gestational-age deliveries or for preterm births were not increased in workers exposed to any of the specific insecticides or groups of insecticides. The investigators also determined that there was no association between any of the chemical exposures and altered sex ratios (proportion of male births) in this cohort, although a reduced proportion of male births was seen for the fathers who

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

did not wear protective gear when applying crop insecticides or fungicides (OR=0.8). The study did not consider the influence of maternal exposure. Moreover, inclusion of multiple pregnancies per couple might be expected to overstate the significance by inflating the number of events treated as independent, but additional analyses indicated only a modest effect on confidence intervals. The authors state that the lengthy time (often as much as 10–15 years) between pregnancy and recall of chemical exposures may have an effect on the quality of the exposure information.

Parental Exposure

A companion study using data from the Ontario Farm Family Health Study assessed the couple as the unit of analysis in examining the relationship between specific groups of pesticides and spontaneous abortion (Arbuckle et al., 2001). Again, multiple pregnancies per couple were included; 2110 women reported 3936 pregnancies, 395 of which ended in spontaneous abortion. The spontaneous abortions were dichotomized into early (less than 12 weeks of gestation) and late (12–19 weeks). Exposure information was obtained from both husband and wife, and pesticides were divided into four major classes: insecticides, herbicides, fungicides, and “other.” Exposures were examined during preconception (3 months before and the calendar month of conception) and postconception (the 3 months corresponding to the first trimester). Neither carbaryl, organophosphates, nor insecticides in general were related to overall, early, or late spontaneous abortion. The analysis of preconception exposure to carbaryl found an OR of 1.2 for spontaneous abortion (95% CI=0.9–1.7, 41 exposed cases). Postconception exposures, however, were associated with a slight decrease in the occurrence of spontaneous abortion (OR=0.8, 95% CI=0.5–1.2, 21 exposed cases). Consideration of the couple as the unit of exposure improved the analysis over that of only paternal exposures in the same cohort (Savitz et al., 1997).

A study using the National Natality and Fetal Mortality Surveys, which included both maternal and paternal recall of exposure to “pesticides, herbicides, and fungicides,” reported an association of maternal and paternal exposure with stillbirth, but not with preterm delivery (Savitz et al., 1989a). The nonspecific nature of the exposure measurements makes it difficult to use the results of this study in weighing the evidence of an association between insecticides and pregnancy outcomes.

Summary and Conclusion

The body of literature on insecticide exposure and pregnancy outcomes during the preconception period is limited mainly by the nonspecific nature of the exposure assessments. Among studies that describe an ecologic measure of exposure to the insecticides under review, the evidence of an association with spontaneous abortion or stillbirth is weak. Two studies examined the same cohort of farm couples and found some evidence of a relationship between exposure to carbaryl and spontaneous abortion; however, their usefulness is limited by the length of time between when the events of interest occurred and when the information was gathered for the study.

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 spontaneous abortion or other adverse pregnancy outcomes.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Epidemiologic Studies of Pregnancy Outcomes and Exposure to Organic Solvents

Maternal Exposure

The possible association between maternal solvent exposure and adverse pregnancy outcomes have been investigated in studies in a number of industries, including dry cleaning, semiconductor and electronics manufacturing, and pharmaceutical and petrochemical research. Most of the studies have focused on the effects of occupational exposure during pregnancy. Studies that asked women about their occupational histories were generally not designed to separate potential effects of exposure during pregnancy from the effects of exposure before pregnancy.

A number of epidemiologic studies have examined pregnancy and birth outcomes among female semiconductor workers exposed to ethylene glycol ethers (particularly in the fabrication process) and other chemicals. However, no studies were identified that focused on preconception exposure of the mother and birth outcomes. A set of retrospective cohort studies in the semiconductor industry examined spontaneous abortion among fabrication and nonfabrication workers (Beaumont et al., 1995) and analyzed exposure to specific agents in this cohort (Swan et al., 1995). A prospective cohort study in the industry (Eskenazi et al., 1995b) monitored spontaneous abortion and early fetal loss as detected by urinary human chorionic gonadotropin. A later study found positive associations between high potential exposure to ethylene glycol ethers and spontaneous abortion in female employees in two semiconductor manufacturing plants with an indication of a trend of increased risk of spontaneous abortion with higher potential exposure (Correa et al., 1996). Several other studies of workers in the semiconductor or electronics manufacturing industries have produced inconsistent results. The earliest study by Pastides and colleagues (1988) found an elevated increase in spontaneous abortion among women working in the photolithography process in the industry, in which exposure to solvents was likely (RR=1.75, 95% CI=0.77–3.25). No association between semiconductor fabrication and spontaneous abortion was reported by Shusterman and colleagues (1993), but the number of pregnancies in women exposed to semiconductor chemicals was small (n=15). Another study of a small number of spontaneous abortions included extensive exposure-assessment efforts in the British semiconductor industry; the number of cases was too small for a detailed analysis of specific exposures (Elliott et al., 1999).

Several studies have investigated the effects on pregnancy of employment in the dry-cleaning industry (a likely source of occupational exposure to solvents). Kyyronen and colleagues (1989) conducted a case-control study of spontaneous abortion and congenital malformations in dry-cleaning and laundry workers in Finland and reported an increased risk in those with “high” exposure.

Olsen and colleagues (1990) studied low birthweight, congenital malformations, and spontaneous abortion among dry-cleaning and laundry workers in Sweden, Norway, Denmark, and Finland, by linking company records to their corresponding national medical and hospital records. When the data from Sweden, Denmark, and Finland were combined, a slight increase in the risk of spontaneous abortion was seen for women with potential low exposure, defined as work in a dry-cleaning facility but not engaging in work known to produce high exposure (OR=1.17, 95% CI=0.74–1.85); the increase was more marked for women in jobs with potential high exposure, defined as performing dry-cleaning work or spot removal for at least one hour per workday (OR=2.88, 95% CI=0.98–8.44).

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

In the United Kingdom, Doyle and colleagues (1997) compared a cohort of dry-cleaning workers potentially exposed to tetrachloroethylene to laundry workers. They found a small increase in the risk of spontaneous abortion (OR=1.03, 95% CI=0.48–2.21), when analysis was restricted to first pregnancies and adjusted for maternal age and year of birth.

Using a combined-outcome measure (spontaneous abortion, perinatal death, congenital malformations, and low birthweight), Ahlborg (1990) studied two cohorts of women working in laundry or dry-cleaning facilities in Sweden. He found an elevated but imprecise estimate of risk adverse pregnancy outcome associated with exposure to tetrachloroethylene during the first trimester.

Lindbohm and colleagues (1990) conducted a study of Finnish women occupationally exposed to organic solvents. Each woman’s level of exposure was categorized based on occupation, work description, self-reports of solvent exposure, and biologically monitored data when available. Five percent of the workers had their exposure to solvents biologically monitored during the first trimester of their pregnancy. After adjusting for potential confounders, they found an association between solvent exposure and spontaneous abortion (OR=2.2, 95% CI=1.2–4.1). The odds ratios increased with the magnitude of exposure to aliphatic hydrocarbons as a group or to trichloroethylene specifically.

Windham and colleagues (1991) conducted a case-control study of spontaneous abortions in California. Exposure to solvents was ascertained by telephone interview. Among women who were employed (n=1361) there was a slightly increased risk of spontaneous abortion associated with exposure to solvents. There was an increased risk of spontaneous abortion in women exposed to aliphatic solvents specifically (OR=1.8, 95% CI=1.1–3.0), but no trend of increasing risk with higher exposure. The study also looked at fetal-growth measures, but did not find associations between solvent exposure and intrauterine growth retardation.

A case-control study in the shoe industry (Agnesi et al., 1997) used crudely defined exposure categories. The authors reported an association between “high” solvent exposure and spontaneous abortion (OR=3.85, 95% CI=1.24–11.9), adjusting for coffee consumption and previous spontaneous abortion. A retrospective cohort study in the petrochemical industry in China (Xu et al., 1998) reported an association between benzene and spontaneous abortion (RR=2.5, 95% CI=1.7–3.7).

Taskinen and colleagues (1994) conducted a case-control study of female laboratory workers potentially exposed to solvents and spontaneous abortion (206 cases and 329 controls). They reported increased risks with exposure to toluene (OR=4.7, 95% CI=1.4–15.9) and xylene (OR=3.1, 95% CI=1.3–7.5). Another study by the same authors of women working in pharmaceutical factories found an association between exposure to methylene chloride and spontaneous abortion (OR=2.3, p=0.06) (Taskinen et al., 1986).

Lipscomb and colleagues (1991) examined maternal occupational solvent exposure among the residents of Santa Clara County, California, an area where possible effects of contaminated drinking water on pregnancy outcomes had been of concern. An increased risk of spontaneous abortion was associated with first-trimester solvent exposure (OR=3.34, 95% CI=1.42–7.81) when confounders, including previous miscarriage, were controlled for in the analysis.

In a study of maternal occupational exposure to a number of chemicals, Seidler and colleagues (1999) reported a slightly increased risk for associations between exposure to solvents and small-for-gestational-age infants.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
Paternal Exposure

A study in Finland used a nationwide database of pregnancy outcomes, data from clinics and hospitals, and census data to examine the effect of paternal occupational exposure to solvents and other chemicals on the occurrence of spontaneous abortion (Lindbohm et al., 1991). A job-exposure matrix based on occupation and industry was used to classify exposures. The study used the time of spermatogenesis (80 days before conception) as the relevant time for exposure. Increased risks of spontaneous abortion were associated with exposure to solvents used in petroleum refineries (OR=2.2, 95% CI=1.3–3.8) and solvents used in the manufacture of rubber products (OR=1.9, 95% CI=1.2–2.8). Examination of the relationship between spontaneous abortion and exposure to specific solvents or to solvents used in other manufacturing processes, however, found mixed results (imprecise ORs ranging from 0.3 to 1.5). The study did not rely on recall of exposure and thus had less bias than many other studies of spontaneous abortion, but it did not control for other occupational exposures and so left open the possibility of confounding by other hazards in these industries.

Another study in Finland examined spontaneous abortion and congenital malformations for a group of 120 male workers, many of whom had been biologically monitored for organic-solvent exposure by the Finnish Institute of Occupational Health (Taskinen et al., 1989). Information on spontaneous abortion was obtained from the Hospital Discharge Register. Three controls were identified for each case, matching to the mother’s age within 30 months. Questionnaires sent to both partners asked the man to record his occupational and medical history and frequency of solvent exposure during the year of conception, and asked the woman to provide information on her occupational and lifestyle exposures in the first trimester of the pregnancy. Exposure was defined as high or frequent if the worker had biological monitoring measurements above the general population levels or had handled solvents daily. The study controlled for a number of potential confounders, including maternal heavy lifting, history of previous spontaneous abortion, exposure to other organic solvents and dusts, and maternal exposure to solvents. Consistent increases in risk were seen in association with high or frequent paternal exposure to toluene (OR=2.3, 95% CI=1.1–4.7), high or frequent use of organic solvents (OR=2.6, 95% CI=1.2–5.9), and high or frequent use of miscellaneous organic solvents (OR=2.1, 95% CI=1.1–3.9). The analysis did not, however, find any noteworthy dose-responses for paternal exposure to solvents or categories of solvents. An analysis by paternal occupation found associations with employment as a painter (OR=3.3, 95% CI=1.6–6.8) or woodworker (OR=3.8, 95% CI=1.2–11.9).

The effect of paternal exposure to benzene on the risk of spontaneous abortion was examined in a study of male workers at two chemical plants in France (Stucker et al., 1994). Occupational histories were provided by the companies and were categorized according to benzene exposure (none; low, <5 ppm; and moderate, ≥5 ppm). Wives of 823 male workers filled in a questionnaire regarding their pregnancies. The study did not find pronounced increases in the incidence of spontaneous abortion when the fathers were exposed to benzene during the 3 months before conception (RR=1.1, 95% CI=0.6–2.0) or when all past exposures to benzene were considered (RR=1.3, 95% CI=0.9–2.0).

A small study found approximately equivalent rates of spontaneous abortion between the wives of 17 dry-cleaning workers (11.1%) and the wives of 32 laundry workers (15.2%) (Eskenazi et al., 1991).

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
Parental Exposure

Several studies have examined potential associations between maternal and paternal exposure to solvents and pregnancy outcomes other than spontaneous abortion, including low birthweight and stillbirth. The results have been inconsistent. Ahlborg and colleagues (1989) reported that solvent exposure was not associated with any late-pregnancy outcomes. In a prospective study, Chen and colleagues (2000) found an association between low birthweight and benzene exposure, which was intensified when benzene was combined with work stress.

Goulet and Theriault (1991) conducted a study of stillbirth (n=227) that included detailed exposure assessment. They reported no association between stillbirth and solvent exposure.

A study of parental occupational exposure reported a weak association between paternal solvent exposure and small-for-gestational-age infants (Savitz et al., 1989b).

Summary and Conclusion

Only a few studies have examined the potential for an association between preconception exposure to solvents among males and spontaneous abortion, and their results have been inconsistent (Table 8.4). Although there were many studies of the effects of maternal solvent exposure during pregnancy, no studies were found that specifically assessed preconception exposure among females and spontaneous abortion. The question of the potential for persistent effects of solvent exposure (after cessation of that exposure) on subsequent pregnancies has not been adequately examined. The body of evidence on other pregnancy outcomes (such as small-for-gestational-age infants and stillbirth) is also inconsistent.

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 specific organic solvents under review or solvent mixtures and spontaneous abortion or other adverse pregnancy outcomes.

TABLE 8.4 Selected Epidemiologic Studies: Spontaneous Abortion and Paternal Exposure to Organic Solvents

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Lindbohm et al., 1991

Men in Finland

 

Solvents, petroleum refineries

16

2.2 (1.3–3.8)

 

Solvents, manufacture of rubber products

26

1.9 (1.2–2.8)

 

1,1,1-Trichloroethane

3

1.5 (0.4–5.0)

 

Benzene (low level exposure)

55

1.0 (0.7–1.3)

 

Trichloroethylene

5

0.9 (0.3–2.1)

 

Tetrachloroethylene

3

0.7 (0.2–2.4)

Taskinen et al., 1989

Men in Finland

 

Organic solvents

 

 

Low or rare exposure

14

2.8 (1.0–7.9)

 

Intermediate exposure

17

1.8 (0.7–4.6)

 

High or frequent exposure

72

2.6 (1.2–5.9)

 

Toluene

 

 

Low or rare exposure

11

0.9 (0.4–2.2)

 

Intermediate exposure

9

0.7 (0.3–1.7)

 

High or frequent exposure

28

2.3 (1.1–4.7)

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

 

Xylene—high or frequent exposure

19

1.6 (0.8–3.2)

 

Halogenated hydrocarbons

 

 

Low or rare exposure

14

1.1 (0.5–2.6)

 

High or frequent exposure

6

0.8 (0.3–2.2)

Stucker et al., 1994

Male workers at chemical plants exposed to benzene

 

 

Exposed to benzene during the 3 months before conception

NA

1.1 (0.6–2.0)

 

Any past exposure to benzene

NA

1.3 (0.9–2.0)

NOTE: NA=not available.

CONGENITAL MALFORMATIONS

Congenital malformations involve major or minor abnormalities of structure or function that are present at birth. Major congenital malformations are seen in about 2–3% of newborns (Holmes, 1999); some anomalies and developmental defects (such as aneuploidy and mental retardation) can go undetected until after the first year of life. As infant mortality has declined in the United States, the proportion of infant deaths attributable to birth defects has increased. Birth defects are now the leading cause of death in infants in the United States and accounted for 19.6% of the 27,937 infant deaths in 1999 (Hoyert et al., 2001).

The etiology of many congenital malformations is yet to be discovered (Holmes, 1999). About 25% of congenital malformations have primarily genetic causes (including chromosomal abnormalities and single gene mutations); but most involve varying combinations of genetic and environmental factors. Uterine factors (such as crowding, breech presentation, and vascular disruption) are involved in a small percentage of cases. Other risk factors are maternal infections (such as rubella and syphilis), maternal diabetes, high maternal age (associated with Down syndrome), and folate deficiency (associated with neural tube defect). An estimated 3% of congenital malformations are caused by teratogenic exposures, but even in the case of well-known teratogens (such as thalidomide, diethylstilbestrol, androgenic hormones, coumarin anticoagulants, lithium, and tetracycline) manifestation is influenced by the genetic constitution of the mother and fetus.

The evaluation of the etiology of specific congenital malformations is difficult because of the rarity of each type; for example, the prevalence of spina bifida is generally reported to be 4.6 cases per 10,000 births (Lary and Edmonds, 1996). Anomalies are often grouped with the intention of increasing the study’s power to detect potential associations with suspected exposure, but that approach can compromise power rather than enhance it. It is increasingly apparent that specific congenital malformations can differ in their etiology, and the circumstances of an exposure (such as timing and route) can differ between anomalies (Selevan et al., 2000). Other methodologic issues include the fact that there are few suspected or known risk factors to take into account when adjusting for potential confounders. Further, analysis can be complicated by multiple pregnancies (and multiple fetuses per pregnancy), which cannot be considered independent events. Since only embryos and fetuses that survive are included in an analysis, it may be difficult to detect an association with malformations for an agent that also decreases survival.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Epidemiologic Studies of Congenital Malformations and Exposure to Insecticides

Neural-Tube Defects and Other Central Nervous System Anomalies

A neural-tube defect (NTD) occurs early in gestation (prior to the 28th day) and involves damage to the tissue that will become the brain or spinal cord. Spina bifida (involving protrusion of the spinal cord) and anencephaly (involving the absence of parts of the skull or the cerebral hemispheres of the brain) comprise the majority of NTDs. Due to the developmental stage when they occur, exposures occurring at the beginning of gestation or exposure to compounds with long half-lives are potentially relevant to studies of NTDs.

Shaw and colleagues (1999a) compared maternal pesticide exposure in cases of selected congenital anomalies (662 orofacial clefts, 207 conotruncal defects, 165 limb defects, and 265 NTDs) ascertained by the California Birth Defects Monitoring Program and 734 randomly selected controls born in the same geographic area and period (1987–1989). The mothers were interviewed about exposure to pesticides from several sources for the period from 1 month before to 3 months after conception. In general, the women were unable to identify the specific pesticide chemicals to which they were exposed. Positive associations with NTDs were reported for professionally applied pesticides in the home (OR=1.6, 95% CI=1.1–2.5), but a weaker association was found when the mother applied pesticides in the home (OR=1.1, 95% CI=0.8–1.7). A slightly elevated risk was seen with the use of insect foggers (OR=1.1, 95% CI=0.6–2.0), but positive associations were not seen between NTDs and maternal use of insect repellent or use of flea collars on pets. The ORs for NTDs in the children of mothers categorized as “maybe” and “likely” exposed to pesticides occupationally were 1.3 (95% CI=0.6–2.7) and 0.9 (95% CI=0.2–3.8), respectively. The study examined several congenital anomalies and multiple sources of exposure, but the exposure measures were nonspecific with regard to particular insecticides. The study did not independently assess preconception exposures.

In anther study, Shaw and colleagues (1999b) focused solely on NTDs and maternal exposure to occupation- and hobby-related chemicals, including several classes of insecticides. Cases were ascertained through review of medical records of infants and fetuses in whom NTDs were diagnosed in California from June 1989 to May 1991. Control infants were randomly selected from a population-based cohort of California births during the same period. For 538 cases and 539 controls, mothers were interviewed to obtain detailed work histories and information on specific hobbies, including gardening. The primary period of interest was from 3 months before conception through the first trimester of pregnancy (periconception). An industrial hygienist, blinded to case-control status, classified the women as likely to have been, maybe, or not exposed to 74 chemical-agent groups. Potential association with NTDs was evaluated for periconceptional maternal exposure to 48 chemical groups. The authors reported elevations in risk associated with exposure to carbamate insecticides (OR=1.2, 95% CI=0.38–3.7) or to organophosphates (OR=1.2, 95% CI=0.60–2.5). When the insecticides were grouped, the risk of NTDs increased (OR=1.3, 95% CI=0.81–2.1). Analyses comparing the 3-month preconception period with the 3-month postconception period suggested the effect might be somewhat greater for exposure during the postconception period (carbamates: preconception OR=1.5, 95% CI=0.41–5.1; postconception OR=2.1, 95% CI=0.51–7.6 and organophosphates: preconception OR=1.2, 95% CI=0.56–2.5; postconception OR=1.6, 95% CI=0.71–3.7). The period between the birth (or NTD diagnosis) and the maternal interview was not stated, and recall bias was possible. Exposure misclassification remains a possibility, but is likely to be nondifferential, thus biasing associations toward the null. Adjustment for

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

maternal education, race or ethnicity, and multivitamin use did not produce substantially different results.

Other studies have used broad exposure categories without specific measures of insecticide use. A case-control study in Finland reported an adjusted OR of 1.2 (95% CI=0.6–2.4) between maternal agricultural work and CNS defects (Nurminen et al., 1995). Blatter and colleagues (1997) reported on a multicenter study in the Netherlands that found an OR for spina bifida of 1.7 (95% CI=0.7–4.0) for moderate or high paternal exposure to pesticides. The level of exposure was categorized by the investigators based on interview responses regarding the nature of the exposures, exposure frequency, and use of protective equipment. A study of births to licensed pesticide applicators in Minnesota found six cases of CNS anomalies compared with 242 in the general population (age-adjusted OR=1.10, 95% CI=0.50–2.40) (Garry et al., 1996). The focus of the study was chlorophenoxy herbicide and fungicide use. Kristensen and colleagues (1997b) conducted a study of birth defects reported to the Medical Birth Registry of Norway and pesticide use in farmers and found an adjusted OR for CNS defects of 2.30 (95% CI =1.31–4.04). As noted, the major limitation of those studies for the purposes of this review was the characterization of pesticide exposure without an analysis of specific types of pesticides.

Congenital Heart Malformations

Loffredo and colleagues (2001) conducted a case-control study of congenital heart defects, including transposition of the great arteries (TGA), as part of the Baltimore-Washington Infant Study. Maternal pesticide exposure for 180 cases (including 66 cases of TGA) born in 1987–1989 was compared with 771 randomly selected infants born in the same period. The critical exposure period was the first trimester of pregnancy and the preceding 3 months. Questions were asked about a wide range of potential confounders, including family history of heart defects, cigarette smoking, alcohol drinking, and socioeconomic status. For the 21 TGA cases and 179 controls with insecticide exposure during the critical period, the study found an increased OR of 1.5 (95% CI=0.9–2.6), with similar results for insecticide exposure in the 4–6 months before pregnancy (OR=1.6, 95% CI=0.9–2.9). This study was population-based, and pediatric cardiologists confirmed all diagnoses. The authors tried to reduce exposure misclassification by conducting interviews within a year after the birth of the infants. The authors stated that there might have been confounding by factors related to socioeconomic status, such as poor housing. There could also have been confounding by exposure to other pesticides—rodenticides and herbicides—that showed stronger associations.

The study by Shaw and colleagues (1999a) described above examined conotruncal heart defects and maternal pesticide exposure during the period from 1 month before to 3 months after conception. The study found positive associations with several categories of exposure, including maternal application of pesticides during gardening (OR=3.1, 95% CI=1.3–7.3), use of insect repellent (OR=2.2, 95% CI=1.3–3.9), and use of more than one pet-flea product (OR=1.2, 95% CI=0.8–1.8). Positive associations were not found with use of insect foggers or use of pet-flea collars.

Other studies of cardiac anomalies have information only on the broader category of pesticides. In a related publication of the Baltimore-Washington Infant Study, Wilson and colleagues (1998) reported an attributable fraction2 of 5.5% (95% CI=0.8–10.1%) for maternal or paternal periconception pesticide exposure and a specific congenital heart defect,

2  

Attributable fraction is the fraction of cases in the population that might have been prevented if the risk factor had been absent.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

isolated/simplex membranous ventricular septal defect. In a study comparing exposure of the mothers of children with Down syndrome, Fixler and Threlkeld (1998) found an OR of 0.79 (95% CI=0.44–1.44) for children’s congenital heart defects and maternal prenatal exposure to pesticides.

Multiple and Other Malformations

Thomas and colleagues (1992) reported a nested case-control study of reproductive outcomes and potential exposure to malathion during pregnancy; the exposure resulted from spraying to control a Mediterranean fruit fly infestation in the San Francisco Bay area. The investigators found a slightly increased risk for reportable anomalies in offspring of women who resided in an active spraying corridor during their first trimester (adjusted RR=1.20, 95% CI=0.83–1.73). Limb (n=38) and orofacial (n=8) anomalies were positively associated with potential malathion exposure in the first trimester (adjusted RR=1.73, 95% CI=0.87–3.46 and adjusted RR=3.35, 95% CI=0.61–18.5, respectively).

Grether and colleagues (1987) conducted a study of exposure during 1981–1982 to aerially applied malathion, in the same counties as Thomas and colleagues (1992). For 1981, they found strong positive associations for anomalies of the ear, bowing of the long bones of the leg, varus deformities, grouped clubfoot diagnoses, and tracheoesophageal fistula. In 1982, however, the incidences of all these anomalies were not associated with malathion spraying.

Schwartz and LoGerfo (1988) employed county pesticide-use data to estimated exposure in a study of limb reduction defects. Comparing maternal residence in California counties with high versus minimal pesticide use, they found an OR of 1.9 (95% CI=1.2–3.1).

Garcia and colleagues (1998) reported a case-referent study of 261 matched pairs of infants in eight hospitals in agricultural areas of Spain and paternal pesticide exposure. Following interviews with the fathers, 28 chemical classes of pesticides and 78 active ingredients were identified as having been used during the period from 3 months before conception through the first trimester of pregnancy. After control for common confounders, there was no evidence of increased risk of congenital anomalies posed by OP or carbamate use. Malathion use also did not increase the risk of congenital anomalies (OR=0.30, 95% CI=0.06–1.43). A limitation of the study was that congenital anomalies were treated as a group rather than as specific defects, which would tend to bias associations toward the null.

Paternal exposure to pesticides was also examined by Lin and colleagues (1994) in a study of limb reduction defects. Cases were identified from the New York State Congenital Malformation Register, and birth-certificate data were used to provide demographic and occupational information on the parents. Pesticide- and insecticide-exposure information was determined from place of residence and type of occupation. Limb reduction defects were not found to be associated with paternal or maternal exposure to insecticides (OR=1.0, 95% CI=0.5–1.7 and OR=0.7, 95% CI=0.4–1.5, respectively).

Summary and Conclusion

Although there have been numerous studies on the relationship between congenital malformations and various sources of parental pesticide exposure, few have looked at the relationship between congenital malformations and insecticides, particularly the specific insecticides examined in this report (Table 8.5). Various approaches were used to estimate exposures, ranging from self-reports to linkages with aerial spraying records. The rarity of the malformations means the numbers of exposed cases is limited, and so constrains the studies’

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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)

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
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,

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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)

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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"8. Reproductive and Developmental Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Next: 9. Additional Health Effects »
Gulf War and Health: Volume 2: Insecticides and Solvents Get This Book
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Gulf War and Health, Volume 2, is the second in a series of congressionally-mandated studies by the Institute of Medicine that provides a comprehensive assessment of the available scientific literature on potential health effects of exposure to certain biological, chemical, and environmental agents associated with the Gulf War. In this second study, the committee evaluated the published, peer-reviewed literature on exposure to insecticides and solvents thought to have been present during the 1990-1991 war.

Because little information exists on actual exposure levels – a critical factor when assessing health effects – the committee could not draw specific conclusions about the health problems of Gulf War veterans. However, the study found some evidence, although usually limited, to link specific long-term health outcomes with exposure to certain insecticides and solvents.

The next phase of the series will examine the literature on potential health effects associated with exposure to selected environmental pollutants and particulates, such as oil-well fires and jet fuels.

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