STATISTICAL MODELS IN TOXICOLOGY AND BIOCHEMISTRY

这个项目旨在增加我们对使用和 数学和统计模型在毒理学和生物医学中的应用 生物化学和实施新的数学模型来帮助 解释当前的研究发现。这项研究工作探索了一种 不同的生物学领域，包括致癌， 药理学、发育生物学、神经学和免疫学。在……里面 致癌；(1)可调节的致癌能力的估计 对存活率的化学变化进行了评估，并进行了 发展了允许非线性剂量响应的修正；(2) 显性整合DNA致癌的数学模型 修复进入多阶段过程应用于启蒙-促进 皮肤和肝脏模型的实验；(3)暴露的健康风险 到2，3，7，8-TCDD的研究正在通过几个基于机械的 数学模型；(4)配体-受体结合的机理模型 并探讨了它们对风险评估的影响； (5)致癌剂量-效应曲线的形状 关于该化学物质生物活性的信息已被研究并 表明化学结构与剂量反应有很好的相关性 形状；(6)一个多阶段的致癌模型，包括一个 干细胞的显性组件被开发出来并应用于 在小鼠皮肤中的启动-促进研究；(7)两者的替代品-- 利用多途径改善癌变的分期模型 整合癌基因的作用正在进行中；(8)额外的泊松 癌症发生的两阶段模型的可变性正在探索中。在……里面 畸形学，人们发现重采样技术和准似然 在以下情况下，可以使用方法来解释下层间的相关性 分析畸形学数据。在免疫毒理学中，人们发现 免疫毒性和免疫毒性之间几乎没有关系。 诱变性，但致癌性和免疫毒性是相关的 免疫毒性化合物很有可能是 致癌物质。在神经学方面，NINDS正在进行一项研究，以 应用多变量平滑技术来表征这种关系 在大脑和身体的不同部位之间。另外， 光滑样条方法在速率估计中的应用 在药理学和生物化学方面的功能正在进行中。最后，一个 定性分析的图论建模技术 开发了生化网络的调节特性。

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.