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A Biologically-Based Dose—Response Model for Developmental Toxicology

Authors

  • Brian G. Leroux,

    1. Department of Biostatistics, University of Washington, Seattle, Washington 98195.
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  • Wendy M. Leisenring,

    1. Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
    2. Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
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  • Suresh H. Moolgavkar,

    1. Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
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  • Elaine M. Faustman

    Corresponding author
    1. Department of Environmental Health, Box 357234, University of Washington, Seattle, Washington 98195.
    2. Child Development and Mental Retardation Center, University of Washington, Seattle, Washington 98195.
      6 To whom all correspondence should be addressed.
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6 To whom all correspondence should be addressed.

Abstract

The methods currently used to evaluate the risk of developmental defects in humans from exposure to potential toxic agents do not reflect biological processes in extrapolating estimated risks to low doses and from test species to humans. We develop a mathematical model to describe aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can be incorporated into the model includes timing and rates of dynamic cell processes such as differentiation, migration, growth, and replication. The dose-response models produced can explain patterns of malformation rates as a function of both dose and time of exposure, resulting in improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain development in rats.

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