Center for Child Environmental Health Risks Research

University of Washington School of Public Health and Community

Center for Child Environmental Health Risks Research
Elaine Faustman, Ph.D.
faustman@u.washington.edu
http://depts.washington.edu/chc/

Project Description

The theme of the Center for Child Environmental Health Risks Research is: Working to understand the mechanisms (molecular, genetic, age, exposure and social factors) that define children’s susceptibility to pesticides, identifying the implications of this susceptibility for development and learning, and partnering with the communities to translate our findings into risk communication, risk management and prevention strategies. Consistent with the objectives of the RFA, the investigators have designed a multidisciplinary research program including members from multiple institutions, schools, departments, and disciplines to facilitate both basic and applied research aimed at reducing the adverse effects of environmental pesticide exposures in children. This research program includes basic mechanistic studies of toxicity, exposure, assessment, and community intervention. For the Community Intervention Study, they have partnered with the Yakima Valley community, located in the agricultural center of Washington State to jointly sponsor a program aimed at reducing childhood pesticide exposure. The facility cores support this research program and put these projects into a child specific risk assessment context so that the investigators' scientific findings on pesticide toxicity and exposure can be translated to directly improve the risk assessment models they design, making the models protective of children’s health. These projects are responsive to two of the three specific research foci identified in RFA ES-03004, which are particularly related to the Mission Areas of U.S. EPA and NIEHS. These two topics are childhood neurodevelopment and learning, and exposures of interest.

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Project Highlights

Toxicokinetic and toxicodynamic models for neurodevelopmental toxicity

This Center is built around a risk assessment framework which allows Center investigators to link findings on pesticide exposure and kinetics to improve their ability to predict outcomes using innovative toxicokinetic and toxicodynamic modeling techniques. The lab-based projects investigate the mechanisms of susceptibility during three critical stages of brain development, genetic and age dependent variations in susceptibility, and functional assessments of exposure. In order to link these observations with our environmental and community pesticide exposure studies we needed toxicokinetic and toxicodynamic models.

In light of the growing awareness in the risk assessment field that the effects of a chemical at both the whole animal and cellular level need to be considered in assessments of health risk (Faustman et al. 2005), Center investigators have developed a report establishing a framework for linked toxicokinetic-toxicodynamic models to address effects on neurodevelopment of exposure to toxic compounds (Faustman et al. 2006). By addressing both how a substance is distributed, metabolized, and eliminated (toxicokinetics) as well as how the target organ is affected (toxicodynamics) Center investigators provide a comprehensive picture of toxicity, one that both summarizes the state of current knowledge and allows for prediction of health risks. Center investigators have described a framework for developing a physiologically based toxicokinetic (PBTK) model and provide illustrations of applications and guidelines for the type of data needed for a PBTK model.

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Biologically-based dose response models for neurodevelopmental toxicity

Center investigators have developed models and frameworks that illustrate how improved understanding of the biological processes underlying the toxicity of environmental agents can inform risk questions. Mechanistic Biologically-Based Dose Response (BBDR) models were built from “systems-based” approaches and illustrate how exposure information needs to be linked with kinetic and mechanistic information in order to improve our ability to assess health risks. The development of both kinetic and biologically-based dose response models that integrate this new scientific information and describe the potential for toxic impacts in development is especially promising and key to improved developmental risk assessment (Faustman et al. 2000; Faustman et al. 2005).

Center investigators have built upon a generalized BBDR model for developmental toxicology that was previously developed at the Center. This stochastic model used the developmental paradigm that relatively immature, undifferentiated cells can proliferate, differentiate, or apoptosis to form the final cell population, tissue, or organ of interest. The key model parameters include cell cycle rates, differentiation rates, and cell death rates within a critical time period specific to the toxic compound and cell population, organ, or tissue of interest. Center investigators have been using methyl mercury, ethanol, and ionizing radiation as model agents to develop the BBDR models (Faustman et al. 2005). Each of these agents has been extensively studied and has a vast body of existing literature that Center investigators are using to develop and refine the neocortical and cerebellar models. These newly developed models are able to predict normal neuronal output after neocortical and cerebral neuronogenesis, and furthermore can predict cellular deficit after exposure during neuronogenesis (Gohlke et al. 2002; Gohlke et al. 2004; Gohlke et al. 2005). Model compounds are used to assist us in understanding how to construct BBDR models for neurodevelopment and how to interpret results for exposures to organophosphate pesticides (OPs) as detailed data becomes available on neurodevelopmental effects of OPs from the Center’s current studies.

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