STATISTICAL MODELS IN TOXICOLOGY AND BIOCHEMISTRY

毒理学和生物化学的统计模型

• 批准号: 3841087
• 负责人: C T PORTIER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3841087
• 关键词: DNA repair; cancer risk; carcinogenesis; chemical carcinogenesis; chemical structure function; dioxins; environment related neoplasm /cancer; environmental toxicology; hematopoietic stem cells; immunotoxicity; liver neoplasms; mathematical model; model design /development; molecular oncology; mutagens; neoplasm /cancer classification /staging; neuropharmacology; oncogenes; skin neoplasms; statistics /biometry; toxin

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 new 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 and immunology. In carcinogenesis; (1) an estimate of carcinogenic potency which adjusts for chemically related changes in survival was evaluated and a modification allowing for nonlinear dose-response was developed; (2) mathematical model of carcinogenesis which explicity incorporates DNA repair into the multistage process was applied to initiation-promotion experiments in the skin and liver models; (3) health risks from exposure to 2,3,7,8-TCDD are being explored via several mechanistically-based mathematical models; (4) mechanistic models for ligand-receptor binding were developed and their implications for risk assessment were explored; (5) the shape of the carcinogenesis dose-response curve using information on biological activity of the chemical has been studied and suggests that chemical structure correlates well with dose response shape; (6) a multistage model of carcinogenesis incorporating an explicit component for stem cells was developed and applied to an initiation-promotion study in mouse skin; (7) alternatives to the two- stage model of carcinogenesis utilizing multiple pathways to better incorporate the role of oncogenes are underway; (8) extra-Poisson variability in two-stage models of carcinogenesis is being explored. In teratology, it was found that resampling techniques and quasi-likelihood methods can be used to account for interlitter correlations when analyzing teratological data. In immunotoxicology, it was found that there is little or no relationship between immunotoxicity and mutagenicity but that carcinogenicity and immunotoxicity are related with immunotoxic compounds having a high probability of being carcinogenic. In neurology, a research effort is underway with NINDS to apply multivariate smoothing techniques to characterize the relationship between areas of the brain and different parts of the body. Also, the application of smoothing spline methods to the estimation of rate functions in pharmacology and biochemistry is underway. Finally, a graph theoretical modeling technique for qualitative determination of the regulatory properties of biochemical networks was developed.

该项目旨在增加我们对使用的理解， 数学和统计模型在毒理学中的应用 生物化学和实施新的数学模型，以帮助 解释目前的研究成果。 研究工作探索了一个 包括致癌作用在内的多种生物学领域， 药理学、发育生物学、神经学和免疫学。 在 致癌作用;（1）调整致癌效力的估计 化学相关的生存变化进行了评估， 开发了允许非线性剂量反应的修改;（2） 显式结合DNA的致癌作用数学模型 采用多阶段修复法进行引发-促进 皮肤和肝脏模型实验;（3）接触的健康风险 到2，3，7，8-TCDD正在通过几种基于机械的 配体-受体结合的机理模型 并探讨了其对风险评估的影响; (5)致癌剂量-反应曲线的形状， 研究了化学品的生物活性信息， 表明化学结构与剂量反应相关 （6）多阶段致癌模型， 开发了干细胞的显式组件，并将其应用于 在小鼠皮肤中的引发-促进研究;（7）两种的替代物- 利用多种途径更好地实现致癌作用的阶段模型 纳入癌基因的作用正在进行中;（8）额外的泊松 正在探索两阶段致癌模型的可变性。 在 畸胎学，它被发现，resception技术和准似然 方法可用于解释窝间相关性， 分析畸形学数据 在免疫毒理学中，发现 免疫毒性与 致突变性，但致癌性和免疫毒性相关 具有免疫毒性的化合物， 致癌的 在神经病学方面，NINDS正在进行一项研究， 应用多元平滑技术来表征关系 大脑区域和身体不同部位之间的联系 还 光滑样条方法在速率估计中的应用 药理学和生物化学的功能正在进行中。 最后 定性测定的图论建模技术 开发了生物化学网络的调节特性。