Phthalates in Drugs and Male Genital Malformation

描述（由申请人提供）：最近，科学界和公众对邻苯二甲酸酯潜在生殖毒性的关注大幅增加，邻苯二甲酸酯是一组具有广泛工业和消费品应用的合成化学品。然而，制造商使用低分子量邻苯二甲酸酯（例如，邻苯二甲酸二乙酯[DEP]和邻苯二甲酸二正丁酯[DBP]）来制备用于口服药物的包衣;邻苯二甲酸酯用于靶向药物释放（例如，至大肠）或提供定时释放。其它邻苯二甲酸酯，例如邻苯二甲酸二（2-乙基己基）酯（DEHP），也可用于药物输送系统，例如吸入器。雄性大鼠产前暴露于DBP和DEHP可导致隐睾症和尿道下裂，可能是由于其抗雄激素活性。产前暴露对发育中的人类胎儿的潜在影响尚不清楚。然而，某些药物中存在的邻苯二甲酸酯可能会显著增加人体暴露量，其水平远高于背景一般人群暴露水平。这种情况令人严重关切。因此，我们建议评估母体暴露于药物中作为“非活性”成分的特定类型邻苯二甲酸酯后男性生殖器畸形的风险。这些目标可以有效地实现利用现有的数据，通过一个大的正在进行的多中心病例对照监测计划的出生缺陷，斯隆流行病学中心出生缺陷研究（BDS）。自1976年成立以来，BDS已涉及波士顿、费城、多伦多、圣地亚哥等大都市地区和爱荷华州选定地区的100多家出生和三级医院，以及马萨诸塞州和纽约州的出生缺陷登记处。BDS确定了出生后五个月内患有各种畸形的婴儿和非畸形婴儿的样本，研究护士在分娩后六个月内采访了母亲，了解人口统计学，行为，生殖和医疗因素;以及有关使用各种药物的详细信息，包括所有处方药和非处方药。我们建议增加感兴趣的病例组的累积，并将1,100多名尿道下裂婴儿和675名隐睾婴儿的数据与无畸形的对照婴儿的数据进行比较。我们将计算与子宫内暴露于含邻苯二甲酸酯药物相关的比值比和95%置信区间。邻苯二甲酸酯暴露的环境提供了一个独特的机会：邻苯二甲酸酯通常包含在用于给定适应症的一些（但不是全部）药物中，这种情况类似于随机分配;此外，与其他非活性成分一样，处方医生或研究受试者不太可能知道邻苯二甲酸酯的存在，因此他们在功能上对暴露设盲。因此，拟议的观察性研究在某种程度上模拟了随机试验，最大限度地减少了适应症和回忆偏倚的混杂。这项工作的结果将有助于确定这些暴露在男性生殖器畸形发展中所起的作用，并将协助公共卫生当局向妇女提供有关其风险的建议。公共卫生相关性：药物中被认为是“无活性”的成分可能是邻苯二甲酸酯的主要来源，邻苯二甲酸酯是一组在我们社会中广泛使用的合成化学品。这些 在实验室动物中，这些物质会导致雄性生殖器畸形，但我们不知道它们对人类的影响。我们将确定在怀孕期间服用的药物，包括邻苯二甲酸酯，并确定这些“非活性”成分是否与两种出生缺陷的风险增加有关，这两种出生缺陷只影响男婴（尿道下裂和隐睾症）。

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).