Review articlePesticides and hypospadias: A meta-analysis
Introduction
Hypospadias is estimated to affect 0.3–1% of live births and is characterized by an abnormal positioning of the meatus, the opening of the urethra, in males [1], [2], [3]. This malformation is most common among non-Hispanic whites and is least common among Hispanics [4], although recent data suggest that birth prevalence is increasing among non-whites [3]. There is substantial unexplained variation in hypospadias rates both within and between countries [2], [7]. Data from the US and several European countries from the 1970s to 1990s showed increases in overall rates which were unlikely to be due to changes in case ascertainment [5], though more recent data seem to indicate that this trend is leveling off or at least not as widespread as was once thought [6].
Because sex hormones play a strong role in fetal genitourinary development [3], [7], it has been hypothesized that in utero exposure to endocrine-disrupting chemicals could contribute to hypospadias [8], [9]. Such chemicals might have an estrogenic or androgen-antagonist effect [8]. In utero exposure to the synthetic estrogen diethylstilbestrol is a known risk factor for hypospadias [10], [11], [12]. Exposure to other synthetic estrogens and progestins, such as those used in oral contraceptives or assisted reproductive techniques, has also been associated with an increased risk of hypospadias in some [4], [13], [14], [15], but not all, studies [16], [17].
Several classes of pesticides have been shown to have endocrine-disrupting potential [18]. Approximately 60% of the herbicides applied in the US, by weight, have demonstrated endocrine-disrupting or reproductive effects in vitro or in animal studies [19], including commercial chlorphenoxy herbicides and glyphosate. The herbicide linuron, which binds weakly to the androgen receptor, was shown to increase rates of hypospadias in rats, as were the dicarboximide fungicides chlozolinate, iprodione, procymidone, vinclozolin and dichlorodiphenyldichloroethylene (DDE) [20], [21], [22].
Despite laboratory evidence of endocrine-disruption by several pesticide classes, few recommendations have been issued by authoritative expert panels or advisory committees. The National Research Council's comprehensive report on pesticides in the diets of infants and children specifically excluded exposure prior to the third trimester of pregnancy, remarking that “the origins of this broader concern with peri- and postnatal toxicology are inextricably rooted in experimental teratology” [23]. Experimental results in animals, they however note, may not be fully applicable to humans.
Animal models may not accurately reflect the typical human experience of pesticide exposure or metabolism of pesticides [24]. Measurement issues, however, have also plagued many human studies. Pesticide exposure might occur in many settings (occupationally, in the home or environmentally) and be mediated by personal behaviors and the use of protective equipment [25], [26], [27]. Even when pesticide exposure has been well measured, the low frequency of hypospadias has resulted in several studies that were underpowered to adequately detect a clinically significant increase in risk [28], [29], [30], [31], [32]. Further, the potential adverse effects of adjuvants used in commercial products—which typically make up 50–60% of the total product weight—have rarely been considered [18].
This meta-analysis was conducted to systematically review the available evidence of an association between pesticide exposure and hypospadias, to provide a quantitative summary of the estimated risk, and to identify areas where further study might be needed. Although a meta-analysis cannot overcome variations in measurement, it might be able to overcome a lack of precision and present a composite estimate of the association between pesticide exposure and hypospadias [33].
Section snippets
Methods
Relevant published studies from January 1966 through March 2008 were identified using Pub Med searches and reviewing references from selected citations. Search terms were included as both keywords and medical subject headings. Exposure terms used were pesticides, fungicides, fumigants, insecticides, herbicides, agriculture, agricultural chemicals, occupation, maternal occupation, paternal occupation, parental occupation, and hypospadias risk factors. Outcome terms used were hypospadias,
Results
Among the nine studies pooled in this meta-analysis, six of the studies evaluated both maternal and paternal exposure, two evaluated paternal exposure only, and one examined maternal exposure only (Table 1). Overall, cases and controls were most often identified from hospital or health care records, and the number of subjects enrolled was reported for most studies. Five studies provided risk ratios adjusted for potential confounders. Only one study attempted to stratify by severity or location
Discussion
This meta-analysis showed that maternal occupational exposure to pesticides or agricultural work was associated with a 36% increased risk of hypospadias overall, and paternal occupational exposure to pesticides or agricultural work was associated with a 19% increased risk of hypospadias. Though modest, these elevated risks may be clinically relevant given the enormous psychological and economic impact of hypospadias on families. The elevated risk observed in this meta-analysis may be an
Conflict of interest statement
The authors of this manuscript do not have any competing financial or personal interests.
Acknowledgements
This work was funded by a grant sponsored by the Centers for Disease Control and Prevention (U50/CCU 713238). Ms. Rocheleau also received fellowship support from a National Institute for Occupational Safety and Health, Occupational Epidemiology Training Grant (T42 OH008491). Study sponsors were not involved in the study design; collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
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