STATISTICAL MODELS IN TOXICOLOGY AND BIOCHEMISTRY

工作总结：该项目旨在增加我们对毒理学和生物化学中数学和统计模型的使用和应用的理解，并实施这些数学模型以帮助解释当前的研究结果。研究工作探索了不同的生物学领域，包括致癌作用，药理学，发育生物学，神经学，免疫学和内分泌学。主要成就包括：（1）为大鼠发情周期开发了一个全面的、基于生物学的数学模型;（2）开发了一个模型，描述了启动肝细胞进入细胞周期G1期的重要因素;（3）开发了职业队列中暴露量的反算方法;（4）围绕PBPK模型设计的NTP研究，转基因动物暴露于2，3，7，采用两阶段和三阶段模型对8-TCDD进行了分析（5）建立了发育毒性的生物学模型（6）分析了东京市1980 - 1994年的发病率数据，以确定每日温度和空气污染物浓度的影响（NO2、O3和PM10）对热应激和相关疾病的影响;（7）探讨了多态性对一般人群风险估计的影响;（8）制定了评估基准剂量是否适当的方法;（9）通过将可靠的科学应用于关键的环境问题，如接触四氯二苯并对二恶英，黄曲霉毒素和内分泌干扰物。

Summary of Work: This project is intended to increase our understanding of the use and application of mathematical and statistical models in toxicology and biochemistry and to implement these mathematical models to aid in explaining current research findings. The research effort explores a diverse range of biological areas, including carcinogenesis, pharmacology, developmental biology, neurology, immunology and endocrinology. Major accomplishments include (1) A comprehensive, biologically based mathematical model was developed for the rat estrus cycle (2) A model was developed which describes the important factors for priming hepatocytes to enter the G1 phase of the cell cycle (3) Methods were developed for the backcalculation of exposures in an occupational cohort (4) An NTP study, designed around a PBPK model, of transgenic animals exposed to 2,3,7,8-TCDD was analyzed using a two-stage and a three-stage model (5) A biologically-based model was developed for developmental toxicity (6) Data on morbidity for the city of Tokyo from 1980 to 1994 were analyzed to determine the effects of daily temperatures and air pollutant concentrations (NO2, O3 and PM10) on heat stress and related diseases (7) The impact of polymorphisms on the estimation of risks in a general population were explored (8) developed methods for evaluating the adequacy of benchmark doses, (9) continued to aid in the scientific improvement of risk assessment methods through the application of sound science to key environmental issues such as exposure to TCDD, aflatoxins and endocrine disruptors.