Phthalates in Drugs and Male Genital Malformation

药物中的邻苯二甲酸盐与男性生殖器畸形

基本信息

批准号：
8307241
负责人：
Sonia Hernandez-Diaz
金额：
$ 64.81万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307241
关键词：
Adult Affect Age Area Attention Behavioral Biological Availability Birth Blinded Boston Caring Case Study Chemicals Confidence Intervals Congenital Abnormality Cryptorchidism Data Defect Development Dibutyl Phthalate Didanosine Diet Dose Drug usage Ecology Ejaculation Endocrine Disruptors Enteral Environment Environmental Health Epidemiologic Studies Epidemiology Esthetics Exposure to Fetus Folate General Population Genital system Genitourinary system Goals Gold Health Hospitals Human Hypospadias Industrial Product Infant Infection Infertility Inhalators Interest Group Interview Iowa Knowledge Laboratory Animals Large Intestine Lead Male Genital Organs Malignant neoplasm of testis Manufacturer Name Massachusetts Maternal Exposure Medical Mesalamine Molecular Weight Morbidity - disease rate Mothers National Health and Nutrition Examination Survey Natural experiment New York Non-Prescription Drugs North America Nurses Observational Study Occupations Odds Ratio Omeprazole Operative Surgical Procedures Oral Patients Perinatal Exposure Pharmaceutical Preparations Pharmacoepidemiology Pharmacology Philadelphia Play Population Positioning Attribute Pregnancy Pregnant Women Provider Public Health Random Allocation Randomized Randomized Clinical Trials Rattus Registries Reporting Research Infrastructure Risk Rodent Role Sampling Savings Seminal fluid Smoking Societies Source Study Subject Surface Surveillance Program Syndrome System Teratology Theophylline Time Toxic effect Toxicology Ulcerative Colitis Urethra Urinary system Woman administrative database authority case control child bearing consumer product diethylphthalate environmental agent estrogenic activity experience exposed human population human data male malformation metropolitan monobutyl phthalate mortality operation penis phthalates prenatal exposure psychologic randomized trial reproductive research study urinary urologic xenoestrogen

项目摘要

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).

描述（由申请人提供）：最近，科学界和公众对邻苯二甲酸盐潜在生殖毒性的关注日益增加，邻苯二甲酸盐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]）来制造口腔药物包衣这一点并未得到广泛认可；邻苯二甲酸盐用于靶向药物释放（例如，释放到大肠）或提供定时释放。其他邻苯二甲酸酯，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。雄性大鼠产前接触 DBP 和 DEHP 已被证明会产生隐睾和尿道下裂，可能是由于它们的抗雄激素活性。产前暴露对发育中的人类胎儿的潜在影响尚不清楚。然而，某些药物中邻苯二甲酸盐的存在可能会明显导致人类暴露，其水平远高于背景一般人群暴露水平。这种情况引起严重关切。因此，我们建议评估母亲接触药物中作为“非活性”成分的特定类型邻苯二甲酸盐后发生男性生殖器畸形的风险。通过利用正在进行的大型出生缺陷多中心病例对照监测项目——斯隆流行病学中心出生缺陷研究 (BDS) 提供的数据，可以有效地实现这些目标。自 1976 年成立以来，BDS 已涉及波士顿、费城、多伦多、圣地亚哥等大都市区和爱荷华州部分地区的 100 多家出生医院和三级医院，以及马萨诸塞州和纽约州的出生缺陷登记处。 BDS 在出生后 5 个月内识别出患有多种畸形的婴儿和非畸形婴儿样本，研究护士在分娩后 6 个月内采访母亲，了解人口、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。我们建议加强感兴趣病例组的统计，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对照婴儿的数据进行比较。我们将计算与子宫内接触含邻苯二甲酸盐药物相关的比值比和 95% 置信区间。邻苯二甲酸盐暴露的环境提供了一个独特的机会：邻苯二甲酸盐通常包含在某些（但不是全部）用于特定适应症的药物中，这种情况类似于随机分配；此外，与其他非活性成分一样，处方者或研究对象不太可能知道邻苯二甲酸盐的存在，因此他们在功能上对接触情况视而不见。因此，所提出的观察性研究在某些方面模仿了随机试验，最大限度地减少了指示和回忆偏差的混淆。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就其风险向妇女提供建议。公共卫生相关性：药物中被认为“无活性”的成分可能是邻苯二甲酸盐的主要暴露源，邻苯二甲酸盐是我们社会广泛使用的一组合成化学品。这些这些物质会导致实验动物的雄性生殖器畸形，但我们不知道它们对人类的影响。我们将鉴定怀孕期间服用的含有邻苯二甲酸盐的药物，并确定这些“非活性”成分是否与男性婴儿特有的两种出生缺陷（尿道下裂和隐睾）风险增加有关。