Phthalates and baby boys: potential disruption of human genital development.

Epidemiologic research has revealed widespread human exposure to phthalates, a class of chemicals that appear in products as diverse as flexible plastics, industrial solvents, and personal care products. Rodent studies indicate that prenatal exposure to some phthalates can disrupt normal male reproductive tract development, causing effects such as reduced anogenital (anus-to-penis) distance, undescended testicles, and testicular abnormalities affecting function. Although the phthalate concentrations that cause these effects are quite high, changes in gene expression have been seen at much lower levels, and concern exists that human males might be similarly affected. The current study, the first to investigate an association between prenatal phthalate exposure and altered genital formation in humans, finds that these chemicals may indeed contribute to such changes in boys exposed in utero [EHP 113:1056-1061].

The research team gathered physical data on 134 boys aged 2-36 months who were enrolled with their parents in the Study for Future Families II, a multicenter study to investigate pre- and postnatal phthalate exposure and potential related effects on development. The researchers examined each boy's testes and scrotum, placement and size of each testis, penis size, and anogenital distance; none of the boys had obvious disease or malformation. Urine samples collected during pregnancy were available for 85 of the boys' mothers. Sample analysis quantified concentrations of nine phthalate metabolites, which served as biomarkers of prenatal phthalate exposure.

To investigate correlation between prenatal phthalate exposure and genital development, the researchers calculated an anogenital index (AGI) by dividing each boy's anogenital distance by his weight. After considering how AGI varied as a function of age, they calculated expected values and 25th and 75th percentiles. Each boy's AGI was categorized as either smaller than expected or at least as large as expected. Based on the age-adjusted percentiles for AGI, the boys were further categorized as having a short, intermediate, or long AGI. The researchers also determined the proportion of boys in these three groups who had normal testicular descent, scrotal size, and scrotal appearance.

More than 90% of the mothers had evidence of some phthalate exposure. Urinary metabolite concentrations were categorized as indicating low, intermediate, or high phthalate exposure. The researchers tested whether a boy's exposure level correlated with his odds of having a short AGI while controlling for various confounding factors such as maternal smoking and timing of urine sample collection.

They found that four metabolites--monoethyl phthalate, mono-n-butyl phthalate, monobenzyl phthalate, and monoisobutyl phthalate--were significantly associated with short AGI. The association was stronger when high levels of all four metabolites were seen. Phthalate metabolite levels among the mothers of boys classified as having a short AGI were comparable to those measured in one-quarter of the U.S. female population based on data from the National Health and Nutrition Examination Survey published in 2004. The researchers also found that short AGI was associated with incomplete descent of one or both testicles.

Although this study was small, the researchers conclude that, consistent with animal studies, these data provide support for a link between prenatal phthalate exposure and health effects in humans. The researchers suggest that commonly used phthalates may adversely affect male reproductive development, and indicate that this possibility needs to be investigated more thoroughly in a larger, more diverse population.