DESCRIPTION (provided by applicant): Recently, there has been an enormous increase in both scientific and public concern about the potential reproductive toxicity of phthalates, a group of synthetic chemicals with a wide spectrum of industrial and consumer product applications. However, it is not widely appreciated that manufacturers use low molecular weight phthalates (e.g., diethyl phthalate [DEP] and di-n-butyl phthalate [DBP]) to make coatings for oral medications; phthalates are used to target medication release (e.g., to the large bowel) or to provide timed release. Other phthalates, such as di(2-ethylhexyl) phthalate (DEHP), may also be used in medication delivery systems, such as inhalers. Prenatal exposure of male rats to DBP and DEHP has been shown to produce cryptorchidism and hypospadias, presumably due to their anti-androgenic activity. The potential effects of prenatal exposure on the developing human fetus are not yet known. However, the presence of phthalates in some medications may contribute appreciably to human exposure, at levels well above background general population exposure level. This situation raises serious concern. We therefore propose to evaluate the risks of male genital malformations after maternal exposure to specific types of phthalates contained in medications as "inactive" ingredients. These goals can be efficiently achieved by taking advantage of data available through a large ongoing multicenter case-control surveillance program of birth defects, the Slone Epidemiology Center Birth Defects Study (BDS). Since its inception in 1976, the BDS has involved over 100 birth and tertiary hospitals in the greater metropolitan areas of Boston, Philadelphia, Toronto, San Diego, and selected regions in Iowa, as well as birth defects registries in Massachusetts and New York State. The BDS identifies infants with a wide range of malformations and a sample of non-malformed infants within five months after birth, and study nurses interview mothers within six months of delivery about demographic, behavioral, reproductive, and medical factors; and details about use of a wide range of medications, including all prescription and over-the- counter drugs. We propose to enhance accrual of the case groups of interest and compare data for more than 1,100 infants with hypospadias and 675 with cryptorchidism with data on control infants without malformations. We will calculate odds ratios and 95% confidence intervals related to in utero exposure to medications containing phthalates. The setting in which phthalate exposure occurs presents a unique opportunity: Phthalates are often included in some, but not all, drugs used for a given indication, a situation that mimics random allocation; further, like other inactive ingredients, the presence of phthalates is unlikely to be known to either prescribers or study subjects, so they are functionally blinded to exposure. Thus, the proposed observational study in some ways mimics a randomized trial by minimizing both confounding by indication and recall bias. Findings from this effort will help determine the role played by these exposures in the development of male genital malformations, and will assist public health authorities in advising women about their risks. PUBLIC HEALTH RELEVANCE: Ingredients in medications that are assumed to be "inactive" might be a major source of exposure to phthalates, a group of synthetic chemicals with widespread use in our society. These agents cause male genital malformations in laboratory animals, but we don't know their effects in humans. We will identify medications taken in pregnancy that include phthalates and determine whether these "inactive" ingredients are associated with an increased risk of two birth defects that uniquely affect male infants (hypospadias and cryptorchidism).

Lay summary: Ingredients in medications that are assumed to be "inactive" might be a major source of exposure to phthalates, a group of synthetic chemicals with widespread use in our society. These agents cause male genital malformations in laboratory animals, but we don't know their effects in humans. We will identify medications taken in pregnancy that include phthalates and determine whether these "inactive" ingredients are associated with an increased risk of two birth defects that uniquely affect male infants (hypospadias and cryptorchidism).