期刊
ENVIRONMENTAL HEALTH PERSPECTIVES
卷 117, 期 8, 页码 1257-1264出版社
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.0800471
关键词
acute toxicity; computational toxicology; IC50; LD50; LOAEL; NOAEL; QSAR
资金
- National Institutes of Health [GM076059, ES005948]
- U.S. EPA [RD83272001, RD83382501]
BACKGROUND: Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public-private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. OBJECTIVE: A wealth of available biological data requires new computational approaches to link chemical structure, in vitro data, and potential adverse health effects. METHODS AND RESULTS: A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments). The application of conventional quantitative structure-activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models to predict the group affiliation based on chemical descriptors only. Third, we developed k-nearest neighbor continuous QSAR models for each subclass to predict LD50 values from chemical descriptors. All models were extensively validated using special protocols. CONCLUSIONS: The novelty of this modeling approach is that it uses the relationships between in vivo and in vitro data only to inform the initial construction of the hierarchical two-step QSAR models. Models resulting from this approach employ chemical descriptors only for external prediction of acute rodent toxicity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据