Quantitative Modeling in Toxicology

Governments around the world are passing laws requiring industry to assess the toxicity of the chemicals and products they produce, but to do so while reducing, refining, or even replacing testing on animals. To meet these requirements, experimental toxicologists and risk assessors are adopting quantitative approaches and computer simulations to study the biological fate and effects of chemicals and drugs. In Quantitative Modeling in Toxicology leading experts outline the current state of knowledge on the modeling of dose, tissue interactions and tissue responses. Each chapter describes the mathematical foundation, parameter estimation, challenges and perspectives for development, along with the presentation of a modeling template. Additionally, tools and approaches for conducting uncertainty, sensitivity and variability analyses in these models are described. Topics covered include: the quantitative models of pharmacokinetics of individual chemicals and mixtures models for toxicant-target tissue interaction. models for cellular, organ, and organism responses. approaches, tools and challenges for model application and evaluation A website containing computer codes accompanies the book to help the reader reconstruct the models described and discussed in the various chapters. Quantitative Modeling in Toxicology serves as an essential reference source and tool box for risk assessors and researchers and students in toxicology, public health, pharmacology, and human toxicology interested in developing quantitative models for a better understanding of dose-response relationships.

Governments around the world are passing laws requiring industry toassess the toxicity of the chemicals and products they produce, butto do so while reducing, refining, or even replacing testing onanimals. To meet these requirements, experimental toxicologists andrisk assessors are adopting quantitative approaches and computersimulations to study the biological fate and effects of chemicalsand drugs.In Quantitative Modeling in Toxicology leading expertsoutline the current state of knowledge on the modeling of dosetissue interactions and tissue responses. Each chapterdescribes the mathematical foundation, parameter estimationchallenges and perspectives for development, along with thepresentation of a modeling template. Additionally, tools andapproaches for conducting uncertainty, sensitivity and variabilityanalyses in these models are described. Topics coveredinclude:* the quantitative models of pharmacokinetics of individualchemicals and mixtures* models for toxicant-target tissue interaction.* models for cellular, organ, and organism responses.* approaches, tools and challenges for model application andevaluationA website containing computer codes accompanies the book to helpthe reader reconstruct the models described and discussed in thevarious chapters.Quantitative Modeling in Toxicology serves as anessential reference source and tool box for risk assessors andresearchers and students in toxicology, public healthpharmacology, and human toxicology interested in developingquantitative models for a better understanding of dose-responserelationships.

About the Editors.About the Book.List of Contributors.SECTION 1 INTRODUCTION.1 Quantitative Modeling in Toxicology: An Introduction(Melvin E. Andersen and Kannan Krishnan).SECTION 2 PHYSIOLOGICALLY-BASED TOXICOKINETIC ANDPHARMACOKINETIC (PBPK) MODELING.2 PBPK Modeling: A Primer (Kannan Krishnan, George D. LoizouMartin Spendiff, John C. Lipscomb and Melvin E. Andersen).3 Pharmacokinetic Modeling of Manganese - An EssentialElement (Andy Nong, Michael D. Taylor, Miyoung Yoon, and MelvinE. Andersen).4 Physiologically Based Modeling of Pharmacokinetic Interactionsin Chemical Mixtures (Sami Haddad, Robert Tardif, Jonathan Boydand Kannan Krishnan).5 Physiological Parameters and Databases for PBPK Modeling(Douglas O. Johns, Elizabeth Oesterling Owens, Chad M. ThompsonBabasaheb Sonawane, Dale Hattis and Kannan Krishnan).SECTION 3 MODELING TOXICANT-TARGET INTERACTIONS.6 Modeling Cholinesterase Inhibition (Charles Timchalk, PaulM. Hinderliter, and Torka S. Poet).7 Modeling of Protein Induction and Dose-Dependent HepaticSequestration (Andy Nong and Melvin E. Andersen).8 Bistable Signaling Motifs and Cell Fate Decisions (SudinBhattacharya, Qiang Zhang, and Melvin E. Andersen).9 Ultrasensitive Response Motifs in Biochemical Networks(Qiang Zhang, Sudin Bhattacharya, Courtney G. Woods, and MelvinE. Andersen).10 Gene and Protein Expression - Modeling Nested Motifs inCellular and Tissue Response Networks (Melvin E. Andersen, QiangZhang, and Sudin Bhattacharya).11 Modeling Liver and Kidney Cytotoxicity (Kai H. Liao, YeiM. Tan, Harvey J. Clewell III, and Melvin E. Andersen).SECTION 4 MODELING TISSUE AND ORGANISM RESPONSES.12 Computational Model for Iodide Economy and the HPT Axis inthe Adult Rat (Jeffrey W. Fisher and Eva D. McLanahan).13 Two-Stage Clonal Growth Modeling of Cancer (Rory B.Conolly and Melvin E. Andersen).14 Statistical and Physiological Modeling of the Toxicity ofChemicals in Mixtures (Hisham A. El-Masri, Michael A. Lyons, andRaymond S.H. Yang).15 (Q)SAR Models of Adverse Responses: Acute Systemic Toxicity(Mark T.D. Cronin, Yana K. Koleva, and Judith C.Madden).SECTION 5 MODEL APPLICATION AND EVALUATION.16 Modeling Exposures to Chemicals From Multiple Sources andRoutes (Panos G. Georgopoulos, Sastry S. Isukapalli, and KannanKrishnan).17 Probabilistic Reverse Dosimetry Modeling for InterpretingBiomonitoring Data (Yu-Mei Tan and Harvey J. ClewellIII).18 Quantitative Modeling in Noncancer Risk Assessment (Q. JayZhao, Lynne Haber, Melissa Kohrman-Vincent, Patricia Nance, andMichael Dourson).19 Application of Physiologically Based Pharmacokinetic Modelingin Health Risk Assessment (Harvey J. Clewell III).20 Uncertainty, Variability, and Sensitivity Analyses inSimulation Models (Sastry S. Isukapalli, Martin Spendiff, PanosG. Georgopoulos and Kannan Krishnan).21 Evaluation of Quantitative Models in Toxicology: Progress andChallenges (Kannan Krishnan and Melvin E. Andersen).Index.