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Biological (Mechanistic) Research
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- Accountability - Assessing Risk Management Decisions
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The Issue | Science Objectives | Research Highlights | Impact and Outcome
The Issue
Understanding risk from an environmental pollutant requires knowledge of more than the symptoms or diseases that occur after chemical exposure. In addition to what may occur in the entire individual, scientists must explore the cellular and molecular universe to identify underlying causes of disease. These underlying causes frequently form a biological chain of events. By understanding the biological causes or mode of action (MOA), accurate science-based human health risk assessments are possible.
By understanding and describing a MOA, one will be able to determine if the biological responses that occur in laboratory animals are different from those in humans. Describing the key biological steps in a MOA will improve the understanding of the dose or amount of a contaminant that is necessary to cause disease. Understanding the biological processes that make up a MOA will improve the ability to develop data-based risk assessments, rather than depend on ones based on assumptions.
Science Objectives
The goal of biologically based or mechanistic research is to eliminate or decrease uncertainties in the risk assessment process. This is done by conducting MOA research on chemicals of interest to risk assessors. These chemicals include pesticides, arsenic, air pollutants, water contaminants, and chemicals that appear to act by increasing oxidative stress.
The objective of this research is to identify key biological events that may be common for similar chemicals in each representative chemical class. The goal is to develop MOA information for extrapolation to humans.
Research Goals:
- Identify key biological events for representative MOAs that can be used to reduce uncertainty in extrapolation for risk assessment
- Cell culture to whole animal
- From high doses used in experiments to low doses in the environment
- From animal studies to humans
- Determine a common MOA for similar chemicals
- Use MOA data to help decide what methods would provide the most accurate risk assessment
- Use of MOA information to develop uniform approaches for risk assessments to protect against cancer and toxicity
- Use MOA data to develop new testing approaches that will reduce, refine, or replace current methods for testing environmental agents
Research Highlights
- Conazoles. This integrated research effort uses the new technologies of genomics in combination with traditional testing methods to describe MOAs for a class of fungicides called conazoles. This work should develop a model approach utilizing the new science of toxicogenomics for reducing uncertainties in interspecies extrapolation, identifying MOAs, and developing a harmonized approach for individual chemical and cumulative risk assessment.
- Neuroendocrine mechanisms. This research will develop animal models that will provide the means to identify the cellular mechanisms altered by endocrine-disrupting chemicals. Once established, these models can be used for extrapolation from animals to humans.
- Arsenic and related compounds. Research is being conducted to understand the MOAs to reduce uncertainties in the risk assessments for arsenicals by clarifying the process underlying cellular injury and its relationship to the development of cancer in humans.
- Oxidative stress. Oxidative stress (OS) is associated with many normal biological events, such as aging, exercise, diseases, and exposure to environmental pollutants. OS may contribute to the development of many adverse health effects from exposure to environmental pollutants. Researchers are investigating the role of OS in developing diseases of the respiratory tract and cardiovascular system.
- Brominated drinking water contaminants. Disinfection of water so that it is safe to drink can result in the production of potentially toxic chemicals grouped together as disinfection by-products (DBPs). Previous EPA research has suggested the possibility that many of these DBPs can cause reproductive and developmental toxicity and colon cancer. Research is being conducted to determine the biology involved in the development of these effects and to reduce uncertainties in risk assessments of particular classes of DBPs.
Impact and Outcomes
- Arsenical research. This program has made several important contributions to understanding the mechanistic basis for the actions of arsenicals as toxicants and carcinogens. Contributions include the elucidation of the role for methylation of arsenicals in their activity, the identification of the generation of reactive oxygen species as a key biological event in a potential MOA, the role of DNA damage as a key event in the cancer MOA, and the collection of data to derive a biologically based dose-response model for arsenic-induced toxicity and cancer in humans.
- Oxidative stress research. Research has described the contribution that OS plays in the respiratory toxicity associated with exposure to particulate matter (PM) and ozone. In addition, research has described the role of OS in arsenic-induced toxicity. This research provides a strong foundation for the hypothesis that OS may be a generic key biological step in the MOA for many toxicities.
- Dioxin research. Dioxins are environmental contaminants that can cause many health effects, including cancer. EPA research has contributed to the development of a common MOA for dioxin-induced health effects. The initiating event is when dioxin binds to a protein in a cell called the aryl hydrocarbon (Ah) receptor. ORD research has been instrumental in demonstrating that interaction with the Ah receptor occurs at very low doses, which results in similar responses across many species, including humans. EPA used the dioxin MOA information for its risk assessments, as did the World Health Organization and the Japanese Ministry of the Environment.
- Other mechanistic research. ORD research has played an important role in reducing reliance on default assumptions in risk assessments for several chemicals over the past several years, including chlorpyrifos, methamidophos, bromate, dichloroacetic acid, diesel exhaust, PM, and ozone.
- Benchmark Dose Software was developed and made publicly available with an on-line training program to evaluate dose-response relationships for chemicals.
- Research contributed to the delisting of ethylene glycol monobutyl ether and retention of methanol as a hazardous pollutant.
- Research contributed to revised guidelines for carcinogen risk assessment.
- Research contributed to a document evaluating the Reference Dose/Reference Concentration process in the risk assessment process.
- Research contributed to drafting of a framework for computational research at ORD.