Grantee Research Project Results
U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program
CLOSED - FOR REFERENCES PURPOSES ONLY
Biomarkers For The Assessment Of Exposure And Toxicity In Children
Opening Date: January 31, 2002
Closing Date: May 8, 2002
Access Standard STAR Forms
and Instructions (http://www.epa.gov/ncer/rfa/forms/index.html)
View NCER Research Capsules (http://www.epa.gov/ncer/publications/topical/)
View research awarded under previous solicitations (http://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/research.search/rpt/abs/type/3)
Biomarkers for the Assessment of Exposure and Toxicity in Children
Synopsis of Program:
The U.S. Environmental Protection Agencys Office of Research and Development (ORD), National Center for Environmental Research (NCER), is seeking applications for research on biomarkers for the assessment of exposure and toxicity in children. Children may be affected by environmental contaminants in ways that adults are not, both because their exposures may be higher and because they may be more vulnerable to the toxic effects of the contaminants. The use of biomarkers may have important implications for the detection, prevention, and treatment of environmentally induced diseases in children. Research on new biomarkers for the assessment of exposure and toxicity in children is needed to improve comprehensive risk assessment in children.
Applicable Catalog of Federal Domestic Assistance (CFDA) Number(s):
Academic and not-for-profit institutions located in the U.S., and state or local governments are eligible to apply for assistance under this program.
Anticipated Type of Award: Grant
Estimated Number of Awards: Approximately 4-7
Anticipated Funding Amount: Approximately $3 million
Potential Funding per Grant per Year: $150,000 to $250,000 per year for a total of up to three years.
The sorting code for applications submitted in response to this solicitation is 2002-STAR-H1.
Letter of Intent Due Date(s): None
Application Proposal Due Date(s): No later than 4:00 P.M., ET, May 8, 2002
Mailing Address for Applications:
This is an EPA RFA. See the How to Apply section of the Standard Instructions for STAR Grants (http://www.epa.gov/ncer/rfa/forms/standinstr.html)
In 1996, two laws were enacted - the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act Amendments (SDWAA) - that require consideration of infants and children in risk assessments used to determine acceptable levels of environmental contaminants in food and drinking water (http://www.epa.gov/children/whowe/history.htm). Regulations and Executive Orders since that time have required similar consideration of childrens special susceptibilities to environmental chemicals. The inclusion of this type of information, however, is hampered by several difficulties, including the assessment of exposure, the long latency of many diseases influenced by the environment, the number of confounding exposures, and the extrapolation from animal models to humans, especially for critical stages of human development. The use of biomarkers in risk assessments for children may have important implications for the detection, prevention, and treatment of environmentally induced diseases in children (Bearer, 1998).
Biological markers, or biomarkers, are useful tools for understanding the nature and extent of human exposure and risk from environmental toxicants (Travis, 1993). They can act as quantitative measures of chemical exposures and biologically effective doses, as well as early warning signals of biologic effect. With respect to the former, they can play a role in validating and improving aggregate and/or cumulative exposure models. Many models used in risk assessment are probabilistic techniques (Monte Carlo) to estimate the exposure distributions across a population. By linking and comparing exposures estimated through the use of biomarkers with those estimated using exposure models, the models can be better assessed. Their critical assumptions and components can be better evaluated, and their utility in evaluating risk mitigation or management options can be better appreciated. Biomarkers may also help to characterize inter-individual susceptibilities as well as to define critical windows of exposure. Biomarkers may be useful in assessing the contribution of toxicants to several health problems, including asthma and other respiratory diseases, developmental neurotoxicity, childhood cancer, and endocrine disruption (Bearer, 1998).
The choice of biomarkers as a topic for a Request for Applications (RFA) supporting FQPA is related to the requirements of the Act. FQPA specifies that aggregate exposures via multiple pathways and cumulative risk from multiple chemicals be considered in assessing risk to children (The Food Quality Protection Act - Public Law 104-170, 1996). Because biomarkers often represent aggregate exposures and/or cumulative effects, they are potentially useful tools for assessments. Therefore, the EPAs Science to Achieve Results (STAR) Program is sponsoring research to develop and evaluate biomarkers for assessing the risks posed to children by exposure to environmental toxicants.
Developing individuals including embryos, fetuses, newborns, infants, children, and adolescents have unique and increased susceptibilities to adverse effects from environmental toxicants. This can result from greater exposure to environmental toxicants, increased exposure of individual organ systems, differences in distribution of toxicants, immaturity of metabolic pathways or excretory pathways, alterations in target organ susceptibility, critical periods of development, and a longer life span in which to express illness (Bearer, 1998).
Although this enhanced susceptibility has been demonstrated in multiple studies, the nature and extent of illness resulting from environmental exposures has not been well characterized (Bearer, 1998). There are several reasons for this:
- Documentation of exposure can be difficult in certain populations, including children. Pregnant women, infants, and children do not generally wear personal monitoring equipment such as one might expect in an occupational setting.
- Modeling of exposure is difficult. There are currently few studies documenting where children spend their time. Even in situations where exposures are known, individual doses to children are difficult to characterize.
- The long latency of environmentally induced diseases complicates the determination of their etiology. As a result, retrospective epidemiology studies are difficult to conduct.
- Individuals are usually exposed to more than one environmental agent at a time, confounding the association of one toxicant to a specific illness.
- Extrapolation from animal models to human children can be difficult.
- Classic epidemiology has limitations in sensitivity, especially when exposures are rare.
Biologic markers, or biomarkers, are observable properties of an organism that indicate variation in cellular or biochemical components, processes, structure, or function, and that can be measured in biologic systems or samples. Biomarkers can be used in four general ways: 1) to identify the presence of an organism, as in microbiology, 2) to estimate the organisms prior exposure, as in risk assessment, 3) to identify changes or effects occurring within the organism, and 4) to assess the underlying susceptibility of an organism, as in genetics and pharmacology. Three specific types of biomarkers will be considered for this RFA:
1. Biomarkers of Exposure
Biomarkers of exposure include exogenous chemicals, metabolites, or products of interactions between environmental toxicants and target molecules or cells that are measured in a compartment within an organism (Travis, 1993). These can be divided into internal dosimeters or markers of biologically effective dose. Internal dosimeters measure the amount of a toxicant or its metabolite present in cells, tissues, or body fluids. An example of this would be urinary nitrophenol concentration used as a marker for methyl parathion exposure. Internal dosimeters account for individual differences in absorption and bioaccumulation of the xenobiotic and are relatively easy to measure. The biologically effective dose is the amount of xenobiotic that has interacted with a molecular site where the biologic effect is initiated. An example of this type of biomarker is the measurement of carcinogen-DNA adducts in white blood cells (Bearer, 1998).Validation of Biomarkers
2. Biomarkers of Effect
Biomarkers of effect are measurable alterations of an organism that can indicate a potential or established health impairment or disease (Travis, 1993). These can include an alteration in a tissue or organ, an early event in a biologic process that is predictive of disease, a health impairment or clinical disease, or a response parallel to the disease process, but correlated with it, and able to predict health impairment. An example of this type of biomarker is the alteration of pulmonary function in children after exposure to environmental tobacco smoke or the change in blood cholinesterase activity after exposure to anti-cholinesterase organophosphorous pesticides. It is important to note that while biomarkers of effect may or may not be chemical or agent specific, they can be affected by other environmental exposures (Bearer, 1998).
3. Biomarkers of Susceptibility
Biomarkers of susceptibility indicate individual factors that can affect response to an environmental toxicant (Bearer, 1998). They are indicators of inherent or acquired properties of an organism that may lead to an increase or decrease in the internal dose of the xenobiotic or an increased or decreased level of the response resulting from the exposure. Genetic polymorphisms fall into this category 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 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).
The STAR program is interested in supporting research to identify and evaluate biomarkers that can be used to estimate and/or predict both exposure and the health effects that may result from exposures, or that can be used for validation of aggregate and/or cumulative exposure models currently in use. Specifically, there is interest in the following:
- Broad spectrum biomarkers that estimate or predict exposure and effect for classes of chemicals rather than for individual chemicals. The use of arrays of markers to perform this task is also of interest. An example is the development of a three-tiered set of markers, used sequentially, to determine the presence of a toxicant, evidence of the physiologic pathway, and evidence of effect.
- Biomarkers of latent effect, used to predict health effects that may occur later in life as a result of an exposure early in life. These biomarkers of possible precursors of effects could be useful in defining the low-dose area of the dose-response curve.
- Establish normal baseline values and distributions for the biomarker in laboratory experimental test species and/or humans. For example, for a genetic biomarker, this would include quantifying the characteristics of normal gene expression at different stages of development, as well as the time-course of gene expression following environmental exposure.
- Evaluate the sensitivity and specificity of the marker in predicting an exposure, dose, effect, and/or health outcome.
- Determine the time course of response of the marker to the environmental toxicant or a class of chemical, with special attention to the recovery process.
- Utilize, whenever possible, assays in less-invasive samples such as hair, saliva, finger nails, sweat, urine, etc.
Bearer, C. F. (1998). Biomarkers in Pediatric Environmental Health: A Cross-Cutting Issue, Environmental Health Perspectives 103 (Supplement 3):813-816.
The Food Quality Protection Act - Public Law 104-170 (1996). [http://www.epa.gov/docs/opppspsl/fqpa/backgrnd.htm]
Travis, C.C. (Ed.). (1993). Use of Biomarkers in Assessing Health and Environmental Impacts of Chemical Pollutants. New York, NY: Plenum Press.
US Environmental Protection Agency, Office of Childrens Health Protection website, Our History, http://www.epa.gov/children/whowe/history.htm
US Health and Human Services, Centers for Disease Control and Prevention, National Report on Human Exposure to Environmental Chemicals (http://www.cdc.gov/nceh/dls/report )
It is anticipated that a total of approximately $3 million, including direct and indirect costs, will be awarded, depending on the availability of funds. EPA anticipates funding approximately 4-7 grants 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 will not be considered.
Academic and not-for-profit institutions located in the U.S., and Tribal, 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/organization/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 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 investigators 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 sole 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, email:firstname.lastname@example.org
A set of instructions on how applicants should apply for a STAR grant is found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/index.html. Standard Instructions for Submitting a STAR Application and the necessary forms for an application will be found on this web site.
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 2002-STAR-H1
Further information, if needed, may be obtained from the EPA official indicated below. Email inquiries are preferred.