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. Major accomplishments include (1) used available modeling constructs ranging from simple to highly complex to determine if data needs to be obtained on the toxicokinetics of compounds being considered for NTP chronic bioassays and, when necessary, aided in the design of these toxicokinetic studies (2) methods were derived for the analysis of data on premalignant lesions and carcinomas simultaneously (3) a stochastic model of carcinogenesis which account for intercellular communication was developed and is currently being studied (4) methods were developed for linking PBPK models, premalignant lesion data, cell labelling data and tumor incidence data simultaneously and then were applied to two chemicals (5) used the models and methods developed in the laboratory to give direction to improvements in environmental risk assessment (6) an earlier physiological model of dioxin disposition was modified by including distribution of blood among major vessels and capillary spaces and by adding representation of the complex biochemical mechanisms responsible for TCDD's effects on thyroid hormones in the blood (7) a complete mechanistic model for liver carcinogenesis in female rats following TCDD exposure was developed using all available biochemical, premalignant lesion, malignancy and cell labeling data (8) built and experimentally validated a mathematical model describing the specific phases of the cell cycle.

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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