U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program


Issues in Human Health Risk Assessment: Novel Mechanistic Approaches in Human Health Risk Assessment

Opening Date: June 01, 2001
Closing Date: September 12, 2001

*** NOTICE ***

    Closing Date has been extended:

  • Issues in Human Health Risk Assessment: Novel Mechanistic Approaches in Human Health Risk Assessment Open: June 01, 2001 - Closing: September 12, 2001 - Extended to September 19, 2001

Specific Areas of Interest
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The U.S. Environmental Protection Agency’s (EPA) Office of Research and Development solicits grant applications for the development of novel mechanistic approaches in human health risk assessment. Risk assessment is an essential tool for setting environmental and occupational standards aimed at protecting human health. However, risk assessment is a relatively new discipline and currently available methods and relevant information on the exposure to, and the toxicity of, a given agent are frequently inadequate to fully satisfy the demands for high quality characterizations of risk. Quantitative risk assessment methods for both cancer and non-cancer endpoints have been and continue to be developed. However, the underlying bases and approaches used to assess human health risk tend to differ, depending on whether the response is a cancer or non-cancer health effect.

In 1997, the Commission on Risk Assessment and Risk Management of the National Research Council concluded that the simple dichotomy between cancer and non-cancer risk assessment is not fully supported by current scientific evidence (NRC, 1997). They also stated that one outcome of this dichotomy is expressions of risk that are not directly comparable and that differ significantly in defining maximal exposures considered to have negligible risk. In addition, the National Research Council’s report on Science and Judgment in Risk Assessment (NRC, 1994) noted the importance of a risk assessment approach that is less fragmented, more consistent in application of similar concepts, and more holistic than endpoint-specific guidelines.

It is now believed that some chemically-induced carcinogenic and non-carcinogenic effects share common biological pathways or precursor events. Identification of such common steps and their mechanistic bases could lead to a more consistent approach in risk assessments. A framework for how such mechanistic or mode of action information could be used in risk assessments is lacking. The EPA recognizes the need to develop a consistent, yet flexible set of principles and guidelines for using and drawing inferences from scientific information in risk assessment. This requires improved methods for more effectively using toxicological information from both animals and humans for predicting risk for both cancer and non-cancer outcomes.

Regulatory agencies use a variety of methods to estimate the risks to humans from environmental and occupational exposures to toxic agents. Many of these methods are based on toxicological data derived from animal models, particularly rodents, and have limitations in their ability to predict human risk. Animal bioassay data are based on late or terminal stages of complex sequences of events and processes that are determined by both genotype and phenotype which differ considerably between rodents and humans. Also, animal bioassays are generally carried out at doses that exceed relevant human exposures. Based on these and other criticisms, it is argued that risk estimations based strictly on animal bioassay data may be unnecessarily high in some cases and, in others, deceptively low and not protective of human health.

In order to improve the estimation of risks to humans from exposures to toxic agents, it is important to continually evaluate all risk assessment methods and practices in light of new scientific information so that better risk assessment methodologies can be developed. A pivotal and emerging source of information that has significant consequences for developing these new methodologies comes from the fields of molecular and cellular biology. Over the last decade, these disciplines have increased our understanding of biological mechanisms, including the basic pathways and processes that control cell growth, differentiation, and death, and have provided new insights into how these pathways and processes are subverted by toxic agents. While it is clear that some pathways and processes are common to all eukaryotic cells, there are also clear phenotypic and genotypic differences that cause responses at other levels of organization to be cell type- and species-specific. These differences can profoundly affect how animals and humans respond to the same toxic agent.


This Request for Applications (RFA) solicits studies that focus on the development and characterization of new risk assessment methods, approaches, and practices that take into account current understanding of the commonalities and differences in the basic mechanisms through which animals and humans respond to toxic agents. This includes studies that identify and characterize the key mechanisms, pathways, and processes that control the effects of toxic environmental chemicals on cell proliferation, differentiation, and death in both humans and animal models. Major emphasis should be on defining those aspects that are the same or different from both qualitative and quantitative aspects between animals and humans. Studies that correlate comparisons between human and rodent primary tissue-specific cells in vitro and the corresponding rodent tissue in vivo and which focus on agents or metabolites that have previously tested positive in animal models are encouraged. Successful proposals will demonstrate an improved understanding of a toxic response and use of that knowledge in improving human health risk assessments.

EPA is also interested in research on the use of mechanistic information in risk assessments from the aspect of the types of information necessary to:

  • demonstrate that a substance acts via a particular mode or mechanism,

  • demonstrate that two toxic manifestations caused by the same substance are produced by different modes of action, and

  • justify the approach for dose-response assessment for chemicals that produce multiple toxic manifestations, but through similar or different mode(s) of action.
The purpose of this research is eventually to allow the derivation of a commonly accepted set of principles defining how mechanistic or mode of action information can be used in risk assessments, particularly as it relates to extrapolation issues across and within species, across time, and from high-to-low doses. Information derived from these studies will help establish commonalities in the rationale for interspecies default methods for cancer and non-cancer endpoints. It will also be important to determine how differing exposure durations and subsequent toxicity processes may indicate that different measures of dose for a particular toxic agent, such as peak concentrations of a particular metabolite, may be more appropriate than the integrated value of the concentration of an unmetabolized parent compound. Therefore, comparative studies of chemicals having different metabolic routes and the conditions influencing those different routes, such as species, gender, and physiological status, will have a high priority. The EPA is particularly interested in proposals that address the following areas:
1. Differences and commonalities between rodents and humans in the pathways, processes, and mechanisms that control the effects of toxic chemicals in the environment on cell proliferation including cell senescence and programmed cell death, cell cycle control mechanisms, aspects of telomere/telomerase function, and mechanisms of apoptosis;

2. Differences and commonalities in homologous gene function, expression, and genomic organization between rodents and humans that affect the pathways, processes, and mechanisms associated with the effects of toxic chemicals in the environment;

3. Biological markers (biomarkers) that provide direct human dose-response data that will reduce the assumptions and uncertainties that arise from interspecies and high-dose to low-dose extrapolations, thereby making health risk assessments more reliable, meaningful, realistic, and cost effective;

4. Studies to determine if mode of action information can be used in a more consistent way to improve dose-response assessment across types of adverse health effects. This is true for both chemicals producing different toxicities by a similar mode of action and chemicals that produce multiple toxicities by different modes of action; and

5. Case studies that assess the human health endpoints by evaluating currently available information on cellular and molecular mechanisms and modes of action, including studies that attempt to integrate cancer and non-cancer risk assessment via statistical or computational techniques. These case studies should demonstrate the relevance and application of the proposed approaches to improving human health risk


National Research Council (NRC). 1997. Building a Foundation for Sound Environmental Decisions, Washington D.C., National Academy Press.

National Research Council (NRC). 1994. Science and Judgement in Risk Assessment, Washington D.C., National Academy Press.


Subject to the availability of funds, up to $6 million is expected to be awarded in fiscal year 2002 in this program area. The projected award range is $200,000 to $300,000 per year total costs for up to 3 years.


Academic and not-for-profit institutions located in the U.S., and state or local governments, are eligible under all existing authorizations. Profit-making firms are not eligible to receive grants from EPA under this program. Federal agencies and national laboratories funded by federal agencies (Federally-funded Research and Development Centers, FFRDCs) may not apply.

Federal employees are not eligible to serve in a principal leadership role on a grant. FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations. They may participate in planning, conducting, and analyzing the research directed by the principal investigator, but may not direct projects on behalf of the applicant organization or principal investigator. The principal investigator's institution may provide funds through its grant from EPA to a FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research. However, salaries for permanent FFRDC employees may not be provided through this mechanism.

Federal employees may not receive salaries or in other ways augment their agency's appropriations through grants made by this program. However, federal employees may interact with grantees so long as their involvement is not essential to achieving the basic goals of the grant.1 The principal investigator’s institution may also enter into an agreement with a federal agency to purchase or utilize unique supplies or services unavailable in the private sector. Examples are purchase of satellite data, census data tapes, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere, etc. A written justification for federal involvement must be included in the application, along with an assurance from the federal agency involved which commits it to supply the specified service.

1EPA encourages interaction between its own laboratory scientists and grant principal investigators for the purpose of exchanging information in research areas of common interest that may add value to their respective research activities. However, this interaction must be incidental to achieving the goals of the research under a grant. Interaction that is “incidental” is not reflected in a research proposal and involves no resource commitments.

Potential applicants who are uncertain of their eligibility should contact Jack Puzak in NCER, phone (202) 564-6825, E-mail: puzak.jack@epa.gov.


A set of special instructions on how applicants should apply for an NCER grant is found on the NCER web site, https://www.epa.gov/ncer/rfa/forms/, Standard Instructions for Submitting a STAR Application. The necessary forms for submitting an application will be found on this web site.

Sorting Codes

The need for a sorting code to be used in the application and for mailing is described in the Standard Instructions for Submitting a STAR Application. The sorting code for applications submitted in response to this solicitation is 2001-STAR-T1. The deadline for receipt of the application by NCER is no later than 4:00 p.m. ET, September 12, 2001. DEADLINE EXTENDED TO SEPTEMBER 19, 2001.


Further information, if needed, may be obtained from one of the EPA officials indicated below.
E-mail inquiries are preferred.

Chris Saint 202-564-9839

or Nigel Field 228-688-1981