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

• 批准号: 8120775
• 负责人: Sonia Hernandez-Diaz
• 金额: $ 64.74万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120775
• 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

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，科学和公众对邻苯二甲酸盐潜在的生殖毒性的关注大大提高，邻苯二甲酸酯的生殖毒性是一组具有广泛工业和消费者产品应用的合成化学物质。但是，并非广泛理解制造商使用低分子量邻苯二甲酸盐（例如邻苯二甲酸二乙酯[DEP]和邻苯二甲酸二二乙酯[DBP]）来制作口服药物涂料；邻苯二甲酸盐用于靶向药物释放（例如，大肠）或提供定时释放。其他邻苯二甲酸酯，例如DI（2-乙基己基）邻苯二甲酸酯（DEHP），也可用于药物输送系统，例如吸入器。雄性大鼠在DBP和DEHP中的产前暴露已显示出产生隐式术和降压症，这可能是由于其抗雄激素活性。产前暴露对发展中胎儿的潜在影响尚不清楚。但是，某些药物中邻苯二甲酸酯的存在可能会导致人类暴露，远高于背景人群的水平。这种情况引起了严重的关注。因此，我们建议评估孕产妇接触药物中含有特定类型的邻苯二甲酸酯的风险。通过利用大型持续的多中心病例对照监视计划的出生缺陷计划，Slone Epidemiology Center中心缺陷研究（BDS），可以通过利用可用的数据来有效实现这些目标。自1976年成立以来，BDS涉及波士顿，费城，多伦多，多伦多，圣地亚哥的大都市地区的100多家出生和三级医院，以及爱荷华州的选定地区，以及马萨诸塞州和纽约州的出生缺陷登记处。 BDS在出生后五个月内确定了畸形广泛的婴儿和非损害婴儿的样本，并且在分娩后六个月内，研究护士在人口统计学，行为，生殖和医疗因素上采访了母亲；以及有关使用多种药物的详细信息，包括所有处方药和反药物。我们建议增强感兴趣的病例群体的应计，并比较1,100多名患有Hypospadias的婴儿和675个具有隐态性的儿童的数据，并与没有畸形的对照婴儿有关。我们将计算与子宫内与含有邻苯二甲酸盐的药物相关的赔率和95％置信区间。发生邻苯二甲酸盐暴露的环境带来了一个独特的机会：邻苯二甲酸盐通常包括在某些但不是全部用于给定指示的药物，这种情况模仿了随机分配；此外，像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酯的存在，因此它们在功能上对暴露不明显。因此，提出的观察性研究在某些方面通过通过指示和回忆偏见来最大程度地降低了一项随机试验。这项工作的发现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，并将帮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：被认为是“不活跃”的药物成分可能是暴露于邻苯二甲酸盐的主要来源，邻苯二甲酸盐是一组合成化学物质，在我们的社会中广泛使用。这些 代理在实验动物中引起男性生殖器畸形，但我们不知道它们在人类中的影响。我们将确定在怀孕中服用的药物，包括邻苯二甲酸酯，并确定这些“无活跃”成分是否与对雄性婴儿的两种出生缺陷的风险增加有关（Hypospadias和Cryptorchidism）。