Knudsen Thomas B, Martin Matthew T, Kavlock Robert J, Judson Richard S, Dix David J, Singh Amar V
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, United States.
Reprod Toxicol. 2009 Sep;28(2):209-19. doi: 10.1016/j.reprotox.2009.03.016. Epub 2009 Apr 10.
As the primary source for regulatory developmental toxicity information, prenatal studies characterize maternal effects and fetal endpoints including malformations, resorptions, and fetal weight reduction. Results from 383 rat and 368 rabbit prenatal studies on 387 chemicals, mostly pesticides, were entered into the U.S. Environmental Protection Agency's (EPA) Toxicity Reference Database (ToxRefDB) using harmonized terminology. An initial assessment of these data was performed with the goal of profiling environmental chemicals based on maternal and fetal endpoints for anchoring in vitro data provided in the EPA's ToxCast research program. Using 30 years worth of standard prenatal studies, maternal and fetal effects were culled from the database and analyzed by target-description fields and lowest effect levels (LELs). Focusing on inter-species comparison, the complexity of fetal target organ response to maternal dosing with environmental chemicals during the period of major organogenesis revealed hierarchical relationships. Of 283 chemicals tested in both species, 53 chemicals (18.7%) had LELs on development (dLEL) that were either specific, with no maternal toxicity (mLEL), or sensitive (dLEL<mLEL) to exposure in one species or another. The primary expressions of developmental toxicity in pregnant rats were fetal weight reduction, skeletal variations and abnormalities, and fetal urogenital defects. General pregnancy/fetal losses were over-represented in the rabbit as were structural malformations to the visceral body wall and CNS. Based upon administered doses, there was a clear hierarchy to the sensitivity and specificity of dLELs in comparing species, with rat development being more sensitive with regards to the number of endpoints affected and the number of active chemicals. Many of these relationships are consistent with previous database studies of developmental toxicology, indicating that they are driven by the biology of the test species. This novel data model provides an important public resource for cross-scale modeling and predictive understanding of developmental processes and toxicities.
作为监管发育毒性信息的主要来源，产前研究对母体效应和胎儿终点进行了表征，包括畸形、吸收和胎儿体重减轻。对387种化学物质（主要是农药）进行的383项大鼠和368项兔子产前研究结果，使用统一术语录入了美国环境保护局（EPA）的毒性参考数据库（ToxRefDB）。对这些数据进行了初步评估，目的是根据母体和胎儿终点对环境化学物质进行剖析，以便为EPA的ToxCast研究计划中提供的体外数据提供支撑。利用30年的标准产前研究数据，从数据库中筛选出母体和胎儿效应，并按目标描述字段和最低效应水平（LEL）进行分析。着眼于种间比较，在主要器官形成期，胎儿靶器官对母体给予环境化学物质的反应复杂性揭示了层级关系。在两个物种中都进行测试的283种化学物质中，有53种化学物质（18.7%）在发育方面具有最低效应水平（dLEL），这些水平要么是特定的，即没有母体毒性（mLEL），要么对一种或另一种物种的暴露敏感（dLEL<mLEL）。孕鼠发育毒性的主要表现为胎儿体重减轻、骨骼变异和异常以及胎儿泌尿生殖系统缺陷。兔子中一般妊娠/胎儿丢失以及内脏体壁和中枢神经系统的结构畸形出现的比例过高。根据给药剂量，在比较物种时，dLEL的敏感性和特异性存在明显的层级关系，就受影响的终点数量和活性化学物质数量而言，大鼠发育更敏感。其中许多关系与先前发育毒理学的数据库研究一致，表明它们是由受试物种的生物学特性驱动的。这种新颖的数据模型为发育过程和毒性的跨尺度建模及预测性理解提供了重要的公共资源。
