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 cancer modeling, major accomplishments include (1) two new models of carcinogenesis were studied in detail (a model with true stem cells for skin carcinogenesis and a multipathway, multistage model for studying colon and liver cancer); (2) development of new methods for utilizing data on malignant and premalignant states when building a mechanistic model; (3) applying mechanistic models to data on premalignant lesions and tumors simultaneously; (4) the development of a general algorithm for estimating tumor incidence from arbitrarily complicated multistage models and (5) developed methods to link PBPK models to tumor incidence models. In physiologically-based pharmacokinetic modeling, this group has (1) substantially improved a PBPK model for TCDD and applied it to study TCDDs effects on thyroid hormone metabolism; and (2)developed rules for using mechanistic models in risk assessment. In risk assessment, this group has (1) collaborated with EPA on the reasessment of TCDD; (2) developed code for estimating benchmarks doses using a profile likelihood.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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Portier, C (2009) 4 Toxicological decision-making on hazards and risks - status quo and way forward: 4.1 current concepts and schemes of science-driven toxicological decision-making - an overview. Hum Exp Toxicol 28:123-5
Prause, Andrea S; Stoffel, Michael H; Portier, Christopher J et al. (2009) Expression and function of 5-HT7 receptors in smooth muscle preparations from equine duodenum, ileum, and pelvic flexure. Res Vet Sci 87:292-9
Schmitz, A; Portier, C J; Thormann, W et al. (2008) Stereoselective biotransformation of ketamine in equine liver and lung microsomes. J Vet Pharmacol Ther 31:446-55
Gohlke, Julia M; Griffith, William C; Faustman, Elaine M (2008) Computational models of ethanol-induced neurodevelopmental toxicity across species: Implications for risk assessment. Birth Defects Res B Dev Reprod Toxicol 83:1-11
Pfeiffer, Julia B R; Mevissen, Meike; Steiner, Adrian et al. (2007) In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows. Am J Vet Res 68:313-22
Barton, Hugh A; Chiu, Weihsueh A; Woodrow Setzer, R et al. (2007) Characterizing uncertainty and variability in physiologically based pharmacokinetic models: state of the science and needs for research and implementation. Toxicol Sci 99:395-402
Gohlke, Julia M; Portier, Christopher J (2007) The forest for the trees: a systems approach to human health research. Environ Health Perspect 115:1261-3
Smith, Marjo V; Miller, Chris R; Kohn, Michael et al. (2007) Absolute estimation of initial concentrations of amplicon in a real-time RT-PCR process. BMC Bioinformatics 8:409
Knobloch, M; Portier, C J; Levionnois, O L et al. (2006) Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion. Toxicol Appl Pharmacol 216:373-86
Becker, Richard A; Borgert, Christopher J; Webb, Simon et al. (2006) Report of an ISRTP workshop: progress and barriers to incorporating alternative toxicological methods in the U.S. Regul Toxicol Pharmacol 46:18-22

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