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

Closed - for reference purposes only

Application of Biomarkers to Environmental Health and Risk Assessment

Opening Date: November 5, 2003
Closing Date: February 11, 2004

Technical Contact: Kacee Deener, 703-347-8514, email: deener.kathleen@epa.gov
Eligibility Contact: Tom Barnwell, 202-343-9862, email: barnwell.thomas@epa.gov

Summary of Program Requirements
Introduction
Specific Areas of Interest
References
Funding
Eligibility
Standard Instructions for Submitting an Application
Sorting Code
Contact

Get Standard STAR Forms and Instructions (http://www.epa.gov/ncer/rfa/forms/)
View NCER Research Capsules (http://www.epa.gov/ncer/publications/topical/)
View research awarded under previous solicitations (http://www.epa.gov/ncer/grants/)
View Frequently Asked Questions on applying for STAR Grants (http://www.epa.gov/ncer/guidance/star_faq.html)

SUMMARY OF PROGRAM REQUIREMENTS
General Information

Program Title: Application Of Biomarkers To Environmental Health And Risk Assessment

Synopsis of Program:

The U.S. Environmental Protection Agency (EPA), Office of Research and Development, National Center for Environmental Research, through its Science to Achieve Results (STAR) program, is seeking applications that provide validation, interpretation and/or application of currently known biomarkers to environmental health and risk assessment. Of special interest is the use of multiple biomarkers that can fill knowledge gaps across different points of the exposure-dose-effect continuum and/or that can be applied in a clinical setting. The proposals should focus on one, or more, of the following investigational areas:

  1. Animal or epidemiology studies that explore the relationship between biomarkers of exposure and measures of subclinical disease (early biological effect or altered structure/function). Additionally, these studies could be expanded to explore the relationship between the subclinical disease measure and the actual clinical disease.
  2. Mechanistic studies (e.g., using genomics or proteomics) of toxicant response linked to clinical disease - for example, the identification of the functional relevance of proteins where genetic polymorphisms have been found to modify the effect of an environmental exposure on a disease endpoint.
  3. Studies to validate the utility of biomarkers for use in large population studies (e.g., reliability, predictive value, sensitivity, specificity, affordability, applicability to the general population and susceptible subpopulations).

Contact Person:

Kacee Deener, phone: 703-347-8514, email: deener.kathleen@epa.gov

Applicable Catalog of Federal Domestic Assistance (CFDA) Number(s): 66.509

Eligibility Information:

Institutions of higher education and not-for-profit institutions located in the U.S., and Tribal, state and local governments, are eligible to apply. See full announcement for more details.

Award Information:

Anticipated Type of Award: Grant.
Estimated Number of Awards: Four to six awards.
Anticipated Funding Amount: Approximately $3 million.
Potential Funding per Grant: $150,000 - 250,000 per year for a duration of up to three years and no more than a total of $750,000, including direct and indirect costs. Proposals with budgets exceeding the total award limits will not be considered.

Sorting Code:

The sorting code for applications submitted in response to this solicitation is:
2004-STAR-D1

Deadline/Target Dates:

Letter of Intent Due Date(s): None
Application Proposal Due Date(s): February 11, 2004

INTRODUCTION

Risk assessment is an essential tool for setting environmental and occupational standards limiting exposure to environmental agents with the aim of protecting human health. However, risk assessment is a relatively new discipline and currently available methods and detailed information on exposure and toxicity are frequently inadequate to fully satisfy the demands for accurate risk characterization. More information is needed regarding the events leading from exposure to dose to effect. Biological markers have significant potential for strengthening current risk assessments by filling in important gaps in the exposure-disease continuum.

WHAT ARE BIOMARKERS?

Biological markers, or biomarkers, are observable properties of an organism that indicate variation in cellular or biochemical components, structure, or function and that can be measured in biologic systems or samples (Bearer, 1998). Biomarkers can be used to estimate prior exposure, to identify changes and effects occurring within an organism, and to assess underlying susceptibility of an organism.

Biomarkers are useful tools for understanding the nature and extent of human exposure and risk from environmental toxicants (Travis, 1993). They can serve as quantitative measures of chemical exposures and biologically effective doses, as well as early warning signals of biologic effect. They can help increase the understanding of the processes by which a chemical is transported and transformed within an organism to produce a dose to a target tissue and the interactions at the cellular and molecular levels leading to a toxic endpoint. Additionally, biological differences or genetic polymorphisms may exist that cause some individuals to be more susceptible to environmentally induced diseases and serve as markers of susceptibility.

It is useful to envision the processes that link exposure, dose, and effect as a continuum, as shown in figure 1.

Figure 1 (Adapted from DeCaprio, 1997)

Events and parameters along the continuum, such as exposure, internal dose, biologically effective dose, early biological effect, altered structure and/or function, and clinical disease can potentially be observed and quantified using biomarkers. Markers of internal dose are direct measures of a toxic chemical or its metabolites in cells, tissues, or body fluids. These markers may integrate multiple portals of entry and fluctuating exposures, and relate time of exposure to internal dose (Strickland, 2002). Markers of biologically effective dose assess the interaction of toxicants with their molecular targets, and markers of early biological effect assess the molecular sequelae of toxicant-cell interactions (Strickland, 2002). Markers of altered structure and/or function are useful for assessing morphological and/or functional changes following toxicant-cell interactions.

Although the field of biomarkers is still relatively new, many different analytical techniques have been developed to quantify such events as exposure to a certain chemical or early biological events resulting from exposures. Problems exist with many current biomarkers in that they have not been validated for use in large population studies and their significance for predicting the risk of clinical disease is unknown. In other words, although a marker may indicate exposure to a certain environmental chemical, it may not be well understood how that marker relates to other events in the toxicological paradigm. For example, does the marker of exposure relate to an exposure dose, an internal dose, a target organ dose, or a biologically effective dose? To what types of effects, such as early biological effects and disease endpoints, can this biomarker be linked? Additionally, what does this mean in terms of quantifying risk of an adverse effect or in identifying susceptible groups, or even in terms of identifying early disease stages?

Ideally, a series of biomarkers can be used to help strengthen the knowledge base about the entire disease continuum, from exposure to effect, or disease outcome. One example where biomarkers have been successfully used in risk assessments involves exposure to aflatoxin. Aflatoxin is a hepatocarcinogen produced by fungi that can contaminate certain types of foods, such as corn and peanuts. People are exposed to aflatoxin when they eat these contaminated foods. Aflatoxin is metabolized in the liver by CYP450 isoforms to form a highly reactive intermediate, AFB1-8,9-epoxide, which can bind covalently to DNA and proteins. Aflatoxin-albumin adducts in serum are considered to be one of the most reliable biomarkers of recent exposure. AFB1-8,9-epoxide can form DNA adducts through covalent binding to the N7 atom of guanine, yielding G-T transversion mutations. Aflatoxin-N7-guanine adducts in urine are a biomarker of biologically effective dose, and aflatoxin-N7-guanine adducts in liver are a biomarker of early biological effect. DNA adduct levels in urine have been associated with measures of exposure and cancer incidence in experimental studies and large population studies (Egner, et al., 2001).

Validation of Biomarkers

It is important that a biomarker be evaluated for effectiveness in quantifying the event or condition of interest. To evaluate the use of a biologic measurement as a biomarker, one must understand the relationship between the marker and the condition/disease of interest. Sensitivity and specificity are both critical components of the evaluation process. Sensitivity refers to the ability of a measurement to detect positive responses, whereas specificity refers to the ability of a measurement to identify negative responses (in order to limit the number of false positives). Since one of the primary purposes of biomarkers in environmental health research is to identify highly exposed groups in order to predict or prevent disease, the biomarkers must not only be evaluated for their ability to assess the presence or absence of an exposure or disease, but also for their ability to quantify the exposure, dose, or level of disease (Bearer, 1998).

The evaluation of biomarkers includes the “backward” process of associating the marker with an exposure, and the “forward” process of linking the biomarker with an effect. The evaluation of a biomarker depends on its anticipated use. A biomarker observed before onset of disease may have a low predictive value as a biomarker of effect, but may be very useful as a marker of exposure, allowing long-term monitoring of an exposed population. On the other hand, a biomarker of effect that is expressed long after the exposure could be of relatively little use in exposure assessment, but be very useful in predicting progression of disease or in assessing risk. Animal models are useful in understanding the mechanistic basis of the expression of markers and the relationship between exposure, early effects, and disease. The validity of a biomarker of effect depends on the reliability of studies that provide the background data, particularly on mechanisms. Estimates of the sensitivity of a biomarker should include its evaluation in an unexposed population or unexposed animals to determine a baseline value for the marker. This evaluation may be difficult in pediatric populations due to ethical issues, such as the use of invasive procedures with little benefit for the participant (Bearer, 1998).

SPECIFIC AREAS OF INTEREST

EPA, through the STAR program, is interested in supporting research that provides validation, interpretation and/or application of currently known biomarkers. Of special interest is the use of multiple biomarkers that can fill knowledge gaps across different points of the exposure-dose-effect continuum and/or that can be applied in a clinical setting. Any of the following areas are of interest:

  1. Animal or epidemiology studies that explore the relationship between biomarkers of exposure and measures of subclinical disease (early biological effect or altered structure/function). Additionally, these studies could be expanded to explore the relationship between the subclinical disease measure and the actual clinical disease.
  2. Mechanistic studies (e.g., using genomics or proteomics) of toxicant response linked to clinical disease. For example, the identification of the functional relevance of proteins where genetic polymorphisms have been found to modify the effect of an environmental exposure on a disease endpoint.
  3. Studies to validate the utility of biomarkers for use in large population studies (e.g., reliability, predictive value, sensitivity, specificity, affordability, applicability to the general population and susceptible subpopulations).

Successful proposals must:

  • Address biomarkers that are measured in biological media. An actual disease endpoint is not considered to be a biomarker of effect.
  • Focus on one of the following emphasis areas: the reproductive system, the brain/nervous system, the immune system, the respiratory system.
  • Link the biomarker(s) to a toxic endpoint through an observation of a statistical relationship between the marker and the endpoint or through a link to a mechanism of action (key precursor event).
  • Be relevant or related to environmental exposures.
  • Consider, as much as possible, issues of validation, robustness, and capacity for high-throughput applications.

REFERENCES

  1. Bearer, C.F. (1998). Biomarkers in Pediatric Environmental Health: A Cross-Cutting Issue. Environmental Health Perspectives, 103 (Supplement 3): 813-816.
  2. DeCaprio, Anthony P. (1997). Biomarkers: Coming of Age for Environmental Health and Risk Assessment. Environmental Science and Technology, 31(7); 1837-1847.
  3. Egner, Patricia A., Jin-Bing Wang, Yuan-Rong Zhu, Bao-Chu Zhang, Yan Wu, Qi-Nan Zhang, Geng-Sun Qian, Shuang-Yuan Kuang, Stephen J. Gange, Lisa P. Jacobson, Kathy J. Helzlsouer, George S. Bailey, John D. Groopman, Thomas W. Kensler. (2001). Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer. Proceedings of the National Academy of Sciences of the United States of America, December 4, 2001; 98(25); 14601-14606.
  4. Strickland, Paul. (2002). Introduction to Molecular Epidemiology and Biomarkers. Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
  5. Travis, C.C. (Ed.). (1993). Use of Biomarkers in Assessing Health and Environmental Impacts of Chemical Pollutants. New York, NY: Plenum Press.

FUNDING

It is anticipated that a total of approximately $3 million will be awarded, depending on the availability of funds. Approximately four to six awards will be made under this RFA. The projected award per grant is $150,000 to $250,000 per year total costs, for up to 3 years. Requests for amounts in excess of a total of $750,000, including direct and indirect costs, will not be considered.

ELIGIBILITY

Institutions of higher education and not-for-profit institutions located in the U.S., and Tribal, state and local governments, are eligible to apply. Profit-making firms are not eligible to receive grants from EPA under this program.

National laboratories funded by federal agencies (Federally-funded Research and Development Centers, “FFRDCs”) may not apply. 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, organization, or governance 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 agencies may not apply. Federal employees are not eligible to serve in a principal leadership role on a grant, and 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. EPA encourages interaction between its own laboratory scientists and grant principal investigators for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities. This interaction must be incidental to achieving the goals of the research under a grant. Interaction that is “incidental” does not involve resource commitments.

The principal investigator’s institution may 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. 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.

Potential applicants who are uncertain of their eligibility should contact Tom Barnwell in NCER, phone 202-343-9862, email:barnwell.thomas@epa.gov

STANDARD INSTRUCTIONS FOR SUBMITTING AN APPLICATION

The Standard Instructions for Submitting a STAR Application including the necessary forms will be found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/.

SORTING CODE

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: 2004-STAR-D1

The deadline for receipt of the applications by NCER is no later than 4:00 p.m. ET, February 11, 2004.

CONTACT

Further information, if needed, may be obtained from the EPA official indicated below. Email inquiries are preferred.

Kacee Deener
703-347-8514
deener.kathleen@epa.gov

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