Statistical Models In Toxicology And Biochemistry

本项目的重点是：(1)开发将尖端技术融入其中的方法学。将研究结果纳入未来的风险评估；(2)开发设计研究的方法，以改进风险评估，特别是在涉及机械数据的情况下；(3)开发评估暴露、剂量-反应形状和效力的方法；(4)开发当涉及多种机制时评估混合物的方法；(5)开发协调癌症和非癌症健康风险评估的方法；(6)通过专家组、同行评审和合作研究直接参与监管社区；(7)通过将理论发展与准确和方便的计算方法仔细联系起来，切实改进随机过程；(8)与NIEHS内的研究小组和从事类似工作的研究小组合作，以提高对疾病发病率的生物学理解；(9)通过假设检验和实验室研究过程，反复改进疾病发病率模型的生物学基础；(10)以科学可信的方式将疾病发病率模型与毒物动力学模型联系起来；(11)在模型的开发及其应用中使用最广泛的数据；(12)支持国家毒理学计划。 ？建立了一个全面的、以生物学为基础的大鼠发情周期数学模型。这个模型描述了8种激素参与的内分泌信号和反馈，这些激素驱动发情周期：促性腺激素释放激素、促黄体生成素、卵泡刺激素、雌二醇、多巴胺、催乳素和孕酮。该模型包括控制这些激素的产生、使用和降解的七个器官系统：脑/下丘脑、垂体门系统、垂体、血液、卵巢、肝脏和胃肠道。 ？当有毒物质在小剂量时起刺激剂作用，但在大剂量时起抑制作用时，就会出现非单调的剂量反应(U型)模式。本文介绍了一个基于力学的数学模型，并讨论了该模型描述非单调剂量响应的能力。 ？当毒性等效应因子(TEF；S)以同种物质之间的ED50之比来定义时，其他同种物质特有的剂量-反应参数应相等。如果不是这样，我们就不能在每个反应水平上获得相对效力的一致定义。检测了暴露于几种二恶英同系物后的两种酶活性反应。我们的分析表明，不同的同类药物的剂量-反应曲线有很大的不同。 ？基准剂量方法学已被提议作为健康风险评估中现有方法的替代品。LCBRA的研究人员对基准剂量方法进行了关键评估，着眼于使用该方法相对于其应用中的实际实践所规定的目标。研究发现，选择用于计算基准剂量的反应对分析中包括剂量反应数据的曲率的程度具有关键影响，并且使用下限作为点估计是不合适的。 ？甲基亮酚和蒽醌的PBTK模型已经升级。 ？建立了一个用出生和死亡过程相关联的模型来描述大鼠肝细胞的细胞增殖周期。该模型被应用于小鼠的呋喃暴露实验，包括对有丝分裂细胞、BrdU标记细胞、坏死和凋亡的显式模拟。 ？一个较早的TCDD诱导酶的PBPK模型被扩展，以描述AH受体的药效学、转录激活、多聚腺苷(PolyA)尾巴长度与mRNA稳定性的关系以及翻译成蛋白质。该模型是第一个再现二恶英与TCDD结合能力短期下降和长期暴露后结合能力增加的二恶英模型。 ？建立大鼠暴露于萘的PBPK模型。可以产生两个氧化萘对映体，并且只能通过使用不同的Vmax来产生每个对映体才能实现处理数据的再现。 ？提出了一种以流程图的形式表示和分析生化反应网络的图论方法。？我们还与其他联邦机构合作，评估环境污染物(例如MTBE、1，3-丁二烯、TCDD)的风险，并开发将基础科学纳入风险评估过程的方法(例如TCDD、内分泌干扰物、过氧化物酶增殖剂)。通过NIEHS毒物动力学学院、化学提名学院和致癌物报告(ROC)审查小组-1的成员资格，我们为NTP提名的化学品的审查、新研究的设计以及关于被提名在ROC上市或退市的化学品的证据审查做出了贡献。 ？NASA和NIEHS有一个联合研究项目，评估气候和环境因素联合暴露对健康的影响。 ？建立了一种估算聚合酶链式反应(PCR)中扩增产物初始浓度的方法。

This Project focuses on (1) The development of methodology for incorporating ?cutting-edge? research findings into future risk assessments; (2) The development of methods for designing studies to improve risk estimates, especially when mechanistic data is involved; (3) The development of methods for the evaluation of exposure, dose-response shape and potency; (4) The development of methods for evaluating mixtures when multiple mechanisms are involved; (5) The development of methods which harmonize cancer and non-cancer health risk assessments; (6) Direct engagement of the regulatory community through expert panels, peer review and collaborative research; (7) Practical improvement of stochastic processes through careful linkage of theoretical developments with computational methods that are accurate and convenient; (8) Collaboration with research groups within the NIEHS and research groups doing similar work to improve the biological understanding of disease incidence; (9) Iterative improvement of the biological basis for disease incidence models through a process of hypothesis testing and laboratory research; (10) Linkage of disease incidence models to toxicokinetics models in a scientifically credible manner; (11) Use of the broadest array of data in both the development of the model and its application; (12) Support of the National Toxicology Program. ? A comprehensive, biologically based mathematical model was developed for the rat estrus cycle. This model describes the endocrine signaling and feedback involved in 8 hormones which drive the estrus cycle: GnRH, LH, FSH, estradiol, dopamine, prolactin and progesterone. Seven organ systems controlling the production, use and degradation of these hormones are included in the model: brain/hypothalamus, hypophysial portal system, pituitary, blood, ovaries, liver and gastro-intestinal tract. ? Non-monotonic dose response (U-shaped) patterns occur when a toxic substance acts as a stimulant in small doses, but as an inhibitor in large doses. A mechanistically based mathematical model is introduced in this manuscript, and the ability of the model to demonstrate non-monotonic dose response is discussed. ? When Toxic Equivalkenct Factors (TEF;s) are defined in terms of ratios of ED50s between congeners, the other congener-specific dose-response parameters should be equal. If not, we cannot obtain a consistent definition of relative potency at every response level. Two enzymatic activity responses from exposure to several dioxin-like congeners were examined. Our analysis suggests that dose-response curves are quite different between congeners. ? The benchmark dose methodology has been proposed as a replacement for existing methods in health risk assessments. Researchers in LCBRA performed a critical assessment of the benchmark dose methodology looking at the stated goals for using this method relative to the actual practice in its application. It was found that choice of the response for which to calculate the benchmark dose had a critical impact on the degree to which curvature in the dose-response data is included in the analysis and using the lower bound as a point estimate was inappropriate. ? PBTK models for methyleugenol and anthraquinone have been upgraded. ? A model was developed using linked birth and death processes to describe the cell proliferation cycle for rat hepatocytes. The model was applied to a furan exposure experiment on mice and includes explicit modeling of mitotic cells, BrdU labeled cells, necrosis and apoptosis. ? An earlier PBPK model of enzyme induction by TCDD was expanded to represent pharmacodynamics of the Ah receptor, transcriptional activation, relation between length of the polyadenylate (polyA) tail and mRNA stability, and translation into protein. This model is the first dioxin model that reproduces both the short-term decline in Ah binding capacity on binding TCDD and the increase in binding capacity after long-term exposure. ? A PBPK model was constructed for exposure of rats to naphthalene. Two enantiomers of naphthalene oxide can be produced, and reproduction of the disposition data could only be achieved by using a different Vmax for production of each one. ? A new graph theoretical method for representing (as a form of flowchart) and analyzing networks of biochemical reaction was developed. ? We also work with other Federal agencies to evaluate risks of environmental pollutants (e.g., MTBE, 1,3-butadiene, TCDD) and to develop approaches for incorporating basic science into the risk assessment process (e.g., TCDD, endocrine disruptors, peroxisome proliferators). Through membership on the NIEHS Toxicokinetics Faculty, the Chemical Nominations Faculty, and Review Group-1 of the Report on Carcinogens (RoC), we contribute to the review of chemicals nominated to NTP, the design of new studies, and the review of evidence on chemicals nominated for listing or delisting in the RoC. ? NASA and NIEHS have a joint research project to assess the health effects of combined exposures to climatic and environmental factors. ? A method was developed for estimating the initial concentration of cDNA amplicon in a PCR process.