Biomarkers for the Assessment of Exposure and Toxicity in Children
FY 2000 Science To Achieve Results (STAR) Program
National Center for Environmental Research and Quality Assurance

Opening Date:  November 8, 1999
Closing Date:  March 23, 2000

Specific research areas of interest
Standard instructions for submitting applications


The Food Quality Protection Act (FQPA) of 1996 and several regulations and executive orders have demanded that information concerning the special susceptibility of infants and children be included when assessing risk, setting tolerances, or registering chemicals for use in the environment1.  The inclusion of this type of information 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 of animal models to critical stages of human development.

Biologic markers (biomarkers) can act as quantitative measures of chemical exposures and biologically effective doses, as well as early warning signals of biologic effect.  Biomarkers may help to characterize inter-individual susceptibilities, as well as define critical windows of exposure.  To be useful, biomarkers need to be evaluated in terms of their specificity and sensitivity.  Biomarkers may be useful across all disciplines including asthma and respiratory problems, developmental neurotoxicity, childhood cancer, and endocrine disruption.  Biomarkers have not been developed nor used widely in children's environmental health.  Advances in this field may have important implications for the detection, prevention, and treatment of environmentally induced diseases in children.

The choice of biomarkers as a topic for a Request for Applications (RFA) supporting FQPA is related to the requirements of the Act.  FQPA requires that aggregate exposure via multiple pathways and cumulative risk from multiple chemicals be considered in assessing risk to children2.  Since biomarkers often represent aggregate exposures and/or cumulative effects, they offer potentially useful tools for conducting these kinds of assessments.  Because of this potential, the EPA's Science to Achieve Results (STAR) Program is sponsoring research to develop and evaluate biomarkers for use in assessing the risks posed by exposures to pesticides among children.  Although all classes of pesticides will be considered, the organophosphates, triazine herbicides, and pyrethroids are of particular interest to the STAR Program.


Developing individuals (embryos, fetuses, newborns, infants, children, and adolescents) are uniquely susceptible populations to insults from environmental hazards3.  Their increased susceptibility can arise from increased exposure to environmental toxins, increased exposure of individual organ systems, differences in distribution of toxins, immaturity of metabolic pathways, immaturity of excretory pathways, alterations in target organ susceptibility, and a longer life span in which to express illness.  Although the enhanced susceptibility of infants and children to environmental toxins has been shown in multiple studies, the nature and extent of pediatric illness resulting from environmental exposure have not been well characterized.

There are several reasons for this deficiency.  First, documentation of exposure is difficult in the fetal and pediatric population.  Pregnant women and children do not wear personal monitoring devices such as those worn by workers in an occupational exposure setting.  Modeling of exposure is also difficult.  There are few studies documenting where children spend their time.  Even in situations with known exposures, the individual dose to a child is difficult to document.  The long latency of many environmentally induced diseases makes their etiology difficult to determine.  Thus, retrospective studies are difficult to conduct.  An individual is also exposed to more than one environmental toxicant and probably to other agents, which may confound the association of one toxicant to an illness.  Extrapolation from animal models to human children is also difficult.  Many of the critical stages of development are not well characterized in animals.  For example, an exposure that occurs during puberty in children may be difficult to model in an animal.  Finally, classic epidemiology has limitations in sensitivity.  If thalidomide had caused only mental retardation and not other effects, the rarity of the exposure would never have significantly increased the normal rate of mental retardation above background rates, and hence, thalidomide would not have been recognized as a teratogen4.  Biomarkers have the potential to overcome many of these difficulties.  They may be used to identify the early stages of health impairment and to understand basic mechanisms of exposure and response in research and medical practice.

What Are Biomarkers?

Biomarkers are observable properties of an organism that can be used in four general ways: (1) to identify the presence of an organism, as in microbiology or forensic pathology, (2) to estimate the organism's prior exposure, as in risk assessment, (3) to identify changes or effects occurring in the organism, as in toxicology or diagnostic medicine, and (4) to assess the underlying susceptibility of an organism, as in genetics and pharmacology.  For this solicitation, three specific types of biomarkers will be considered:

? Biomarkers of exposure - exogenous chemicals, metabolite(s) or the products of interactions between a pesticide and target molecules or cells that are measured in a compartment within an organism.  This includes internal dosimeters of pesticide or metabolite concentrations and markers of biologically effective doses.

? Biomarkers of effects - measurable alterations of an organism that, depending on magnitude, can indicate a potential or established health impairment or disease.

? Biomarkers of susceptibility - indicators of inherent or acquired properties of an organism that may lead to an increase in the internal dose of a pesticide or an increased level of the response resulting from exposure to a specific pesticide.

Specific Research Areas of Interest

The STAR Program is interested in supporting research to identify and evaluate biomarkers that can be used to estimate and/or predict both pesticide exposure and the health impacts that may result from pesticide exposure.  Successful proposals will be those that propose research to develop markers applicable to the assessment of pesticide exposure and/or toxicity in  children.  Successful proposals will also address as many of the following factors as possible:

? Establish normal baseline values and distributions for the biomarker in laboratory animals and/or humans.

? Evaluate the sensitivity and specificity of the marker in predicting an exposure, dose, effect, or health outcome.

? Understand the time course of response of the marker to a pesticide, with special attention to the recovery process.

? Utilize, whenever possible, assays in less-invasive samples such as hair, saliva, finger nails, sweat, or urine, rather than more-invasive samples such as tissue or blood.

? Consider a battery of markers that reflect a wide array of physiologic functions and genetic damage and relate a particular marker in question to others in the battery.

? Consider, whenever possible, highly exposed sub-populations of children (e.g., children of agricultural workers).

Evaluation (Validation) of Biomarkers

Each proposal submitted in response to this solicitation should include studies to evaluate the effectiveness of the proposed biomarker in quantifying the event or condition of interest.  To evaluate the use of a biologic measurement as a biomarker, it is necessary to understand the relationship between the marker and the event or condition of interest.  Determining the specificity and sensitivity are critical components of the evaluation process.  Specificity refers to the ability of a measurement to effectively identify negative responses in order to minimize the number of false positives.  Sensitivity refers to the ability of a measurement to detect positive responses.  One of the purposes of biomarkers in environmental health research is to identify highly exposed individuals or groups, so that risk can be predicted and disease prevented.  Therefore, biomarkers must not only be evaluated in terms of their ability to assess the presence or absence of an exposure or disease, but also on their ability to quantify the exposure, dose, or level of disease.

The evaluation of biomarkers includes the "backward" process of associating a biomarker with exposure, and the "forward" process of linking a biomarker with effect.  Appropriate validation for a biomarker depends on its anticipated use.  A biomarker observed well before the onset of disease may have a low predictive value as a biomarker of effect, but be very useful as a biomarker of exposure, enabling long-term surveillance of an exposed population.  In contrast, a biomarker of effect that is expressed long after exposure could be of relatively little use in exposure assessment, but be very useful in predicting progression of disease or in calculating risk.  Animal models are useful for understanding the mechanistic bases of the expression of markers and relationships between exposure, early effects, and disease.  The validity of a specific 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 the pediatric population because of ethical issues involving invasive procedures with little benefit to the pediatric participant.  Of particular interest are studies that incorporate pharmacokinetics.  Pediatric pharmacokinetics are an understudied area of science and this lack of information limits the application of many known biomarkers.


1. National Science and Technology Council.  Investing in Our Future: a National Initiative for Americas's Children for the 21st Century.  Executive Office of the President, Washington, DC (1997).

2. The Food Quality Protection Act - Public Law 104-170 (1996).

3. Bearer, C.F. Biomarkers in Pediatric Environmental Health: a Cross-cutting Issue.  Environ. Health Perspect. 103 (Supplement 3):813-816 (1998).

4. Oakley, G.P.  Frequency of Human Congenital Malformations.  Clin. Perinatol. 13:545-554 (1986).


Approximately $5-6M will be available to support this effort.  The awards are expected to range from $150,000 to $250,000 per year for up to three years.  Awards made through this competition are subject to the availability of funds.


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 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 Dr. Robert E. Menzer in NCER, phone (202) 564-6849, email:

Standard Instructions for Submitting an Application

A set of special instructions on how applicants should apply for an NCER grant is found on the NCER web site, 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 2000-STAR-D1.  The deadline for receipt of the application by NCER is no later than 4:00 p.m. ET,  March 9, 2000.


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

Dr. Chris Saint  202-564-6909

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Last Updated: January 28, 2000