Pharmacokinetic and Pharmacodynamic Modeling

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The Issue | Science Objectives | Research Highlights | Impact and Outcome

The Issue

When a new disease appears on the horizon, medical researchers want to know as much as possible about what happens when the disease attacks. They want to know the potential strength of the invading disease, which organs it affects, and the biological processes to uncover its dangerous properties. Toxicologists have a similar mission when they investigate what happens in humans after exposure to a chemical. Tools used to explore how a chemical moves through the body and results in a possible toxic response include pharmacokinetic (PK) models and pharmacodynamic (PD) models. The development and use of these models are important for assessing risk from environmental toxicants.

PK models enable a more rational understanding and prediction of toxic effects by accounting for the time-dependent processes of absorption, distribution, metabolism, and excretion of a chemical. The application of pharmacodynamics has been employed to further elucidate critical events that occur at the target site (i.e., receptor binding; post-receptor events, such as signal transduction). Core or basic research that integrates PK-PD modeling provides real-time coordination of kinetic and dynamic processes and provides data and analyses needed to make risk management decisions.

Science Objectives

The objective of this research effort is to develop PK-PD models to describe effects for several modes of action (MOAs) and classes of compounds of high regulatory interest to EPA. Research is addressing the PK-PD modeling needs in four areas: (1) impaired nerve cell function from pyrethroid insecticides; (2) multiple cellular responses to arsenic; (3) cellular consequences of altered chemical reactions; and (4) activation of nuclear receptors by a wide range of chemicals, including conazole fungicides.

Research Goals:

Elucidate critical methodological issues and approaches for linking PK-PD models
Determine the utility of PK-PD models for high to low dose, interspecies, and in vitro to in vivo extrapolations in risk assessment
Provide models applicable to broad classes of MOAs from several chemical classes, expanding the options available for risk assessments based on MOA
Provide biological plausibility for substituting data for the uncertainty factors for interspecies and intrapopulation extrapolation in risk assessment

Research Highlights

Nerve cell function impairment by pyrethroids. The signals used by the nervous system to process and transmit information are electrical in nature. Pyrethroid insecticides have been found to disrupt nerve function, causing nerves to be hyperexcitable. Researchers are attempting to use PK and PD models to understand how insecticides, such as pyrethroids, affect the nervous system. This information is important to develop approaches for conducting cumulative risk of pyrethroids based on a common MOA.
Cellular responses to arsenic. Epidemiologic studies have established that relatively high-level inorganic arsenic (As) exposures cause cancer in multiple organs (skin, bladder, and lung). However, the risk associated with the lower exposure levels common in the United States is uncertain. Low dose extrapolation for As is confounded by limited understanding of the relationship between the accurate measure of a dose of As to the targeted tissue and subsequent development of adverse effects. Research is underway to develop pharmacodynamic representations of key events in specific target organs (e.g., bladder, skin, lung) and to develop PK-PD linkages to existing models of arsenical metabolism in both specific cell types and the whole organism. PK information on As and related chemicals will be crucial to develop MOA information for risk assessment.
Role of receptors in toxicity assessment. Nuclear receptors are transcription factors activated by endogenous and exogenous chemicals. A wide range of environmental chemicals, including toxics; pesticides, such as conazole fungicides; and air toxics, may have similar MOAs in that they bind or otherwise activate these transcription factors. Activation results in changes in the expression of genes regulating growth and differentiation in the liver and genes involved in metabolism of xenobiotics and endogenous substances. Researchers are developing PD models of certain receptor systems. A better understanding of the role of these receptors in toxicity could have broad implications for screening and testing of chemicals, as well as for the development of quantitative pharmacodynamic models.

Impact and Outcomes

Human Health Research Contributions: