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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
National Institute of Environmental Health Sciences
CLOSED - FOR REFERENCES PURPOSES ONLY
COMPLEX CHEMICAL MIXTURES
Opening Date: April 10, 2000
Closing Date: July 10, 2000
The U.S. Environmental Protection Agency, the National Institute for Occupational Safety and Health, and the National Institute of Environmental Health Sciences share the common goal of promoting research that will reduce adverse human health impacts from exposure to hazardous materials in the environment and in the workplace. The object of this Request for Applications (RFA), the second in a series on this subject, is to encourage innovative experimental approaches and computational, statistical, or predictive strategies for assessing the impact of chemical mixtures that focus on the mechanistic basis for chemical interactions and related health effects.
Historically, the focus of toxicity testing and mechanistic research on environmental chemicals has been on single chemicals. Over the years this approach has been critical in providing information which has led to a better understanding of the interactions of exposure and susceptibility in relation to time and has improved risk assessment. However, it is increasingly recognized that humans are generally not exposed to single chemicals and therefore knowledge of individual chemical toxicity is often inadequate for risk assessment.
Our inability to predict whether agents will act in an additive, synergistic, or antagonistic fashion at concentrations encountered in the environment and the workplace creates real problems for human health risk assessment. Many examples exist where the interactions of chemicals with each other or other physical or biological agents affect health to a greater extent than would have been predicted based on toxicity of the individual components.
The magnitude of the problem is immense. In our daily living, mixtures of chemicals are ubiquitous in the air we breathe, the food we eat, and the water we drink. There are over 80,000 existing chemicals on the Toxic Substances Control Act inventory. Each year an additional 2,000 chemicals are added. Humans are exposed to thousands of agents in various combinations every day in the home, the ambient environment, and the workplace. Many of those chemicals are members of chemical classes that have similar or intersecting modes of action. Furthermore, chemicals with different modes of action may still affect the same organ or tissue and thus interact with each other
The task of testing these chemicals is formidable. Chemical mixtures vary significantly in their composition; some contain two or three chemicals of a similar class, whereas more complex mixtures can be composed of hundreds of chemicals representing a variety of organic and inorganic classes of chemicals, with varying degrees of toxicity and different modes of action. Changes in the toxicokinetics and/or toxicodynamics of one chemical by another may alter the resultant toxicity from predicted values. Though changes in toxicity have been described for simple binary mixtures, unraveling the effects of complex mixtures has not been achieved.
Increasingly, regulatory agencies such as EPA face the formidable task of assessing risk to mixtures of chemicals when information is available on only the component chemicals in isolation. The task is to move beyond the simplistic assessment of single chemicals to consideration of aggregate and cumulative risk, as required by the Food Quality Protection Act of 1996. In addition, standards for limits on air and water pollutants must also consider the impact of mixtures of chemicals.
Toxicity studies of mixtures have been ongoing
for some decades. In earlier years, most of the studies concerned
binary mixtures. Later, studies with defined mixtures of more than
two compounds and studies with natural complex mixtures were also
reported. However, to design a full factorial study to examine the
interaction(s) of three chemicals at five different dose levels
requires 125 treatment groups and 750 animals if six animals are
included in each treatment group. The end result of such a large
expenditure of time and money would be information on only one temporal
sequence of exposures at one time point post-exposure. Clearly,
the information gained would be of limited value. Therefore, it
would seem prudent to develop a rational approach to studying mixtures
by devising innovative experimental, mechanistic, and statistical
strategies and to prioritize chemical mixtures for study based on
known human exposures.
Since individual testing of the many binary, tertiary, and higher combinations of mixtures of chemicals would be impossible, the approach of this RFA is to support research to develop innovative and credible statistical, computational, and predictive approaches for assessing risks from mixtures of chemicals either within one of the three subsections listed below or that integrates across two or more of the subsections. A better understanding of the mechanistic basis of interactions both in the environment and in biological systems will be necessary before confidence can be gained in risk assessments for chemical mixtures. The mechanistic basis for chemical-initiated cellular and/or molecular perturbations and associated health effects also needs to be better understood. In addition, research on chemical interactions that affect movement through the environment should be considered. Information on the effects of mixtures must be obtained for long-term and short-term exposures of the general population, as well as for effects on particularly susceptible subgroups, such as children, and groups exposed at higher levels than the general population, such as those occupationally exposed.
The goal and scope of this request for applications (RFA) is to advance our knowledge of the behavior of chemical mixtures: their potential for harm to plants and animals, including humans, and their behavior in biological systems and the environment. In most situations there is a scarcity of scientific knowledge to make informed decisions about associated health risks. However, specific testing of mixtures of chemicals will not be supported in this program except in cases where the testing is used as an example or model of approaches or methodologies to be developed.
Making meaningful scientific advances in knowledge about chemical mixtures will necessitate taking advantage of the latest advances in computational, engineering, and information technologies as well as molecular biology techniques. Not only should the consideration of adverse health effects caused by exposures to mixtures be an integral part of our next generation of human health risk assessment techniques, but a holistic approach needs to be developed that encompasses environmental transport and fate, bioavailability, and both exposure and effects research.
Environmental Transport and FateThe physical behavior of chemicals is affected by interactions with other chemicals in the matrix or medium in which they are found. Thus, their solubility in water or sorption to soils and sediments may be altered from what would be predicted for a single chemical. Also, under some conditions chemicals may react with each other in the environment to form new chemicals, an added complication for an evaluation of their environmental behavior. Research on the chemical mixtures created by human activities, as in Superfund sites, naturally occurring mixtures, such as petroleum, and in the workplace should include a focus on the transport phenomena and ultimate fate of chemicals when they are inadvertently spilled or intentionally emitted into the environment or workplace. This should include methods to quantify the chemical, physical, and biological processes that govern the bioavailability of mixture components.
Exposure AssessmentA major, long-term challenge for regulatory agencies is to develop defensible means of combining exposure assessments in a manner that provides meaningful ways of determining potential health risks from total exposures to many chemicals. Lacking are methods to characterize potential toxicological risk. Rapid and inexpensive exposure monitoring methods that are capable of identifying exposure and its relative significance need to be developed. Application of such tests, in combination with chemical analysis, could provide a total exposure assessment, that is, an assessment of the toxic potential of an environmental or occupational exposure and the chemical components contributing to that toxic potential.
Given the large number of possible combinations for exposures to multiple chemicals, it will be necessary to use exposure information to better identify those which actually occur for human populations and to set priorities for more intensive study. This could be done initially using current hazard identification techniques to determine the highest priority mixtures for consideration in health effects and exposure research and risk assessments.
Pharmacokinetic interactions must be investigated so that toxicologically relevant doses for mixtures can be quantified. This point is complicated by the fact that in some cases non-toxic chemical relatives of toxic compounds contribute to toxicity, not by direct action but rather by interactions, such as those that affect metabolism and absorption. For example, how might the liver metabolism of one group of compounds be affected by exposure to other compounds, including pharmacological agents? Interpretation of results and better models for predictive toxicology will require the development of novel statistical and mathematical strategies. Some promising approaches include quantitative structure activity relationships, physiologically based pharmacokinetic and pharmacodynamic modeling, and fractional factorial designs.
Effects AssessmentMechanisms of action should be elucidated so compounds can be grouped according to similar toxic endpoints. Investigations of the health effects of exposure to chemical mixtures for enhanced or diminished risk of developing cancer, respiratory diseases, multiple chemical sensitivity, immunological, endocrine, reproductive, developmental, and neurological conditions are needed.
Strategies should be developed to elucidate
the mechanism for non-additive effects of chemical mixtures using
animal models, in vitro cell systems, and gene expression
systems. High-priority chemical mixtures should be considered for
these mechanistic studies. Dose-response, temporal effects, and
multiple target endpoints should be taken into consideration. Epidemiological
tools also need to be developed to interpret chemical interactions
in population and molecular epidemiology studies. Research should
also consider the potential risk from mixtures of toxic and nontoxic
chemicals. For example, the neurotoxicity risk of exposure to metals
such as mercury and lead might be complicated by deficiencies in
other metals such as calcium, magnesium, and potassium.
EPA's National Center for Environmental Research
The U.S. Environmental Protection Agency's National Center for Environmental Research (NCER) promotes and advances environmental science in the United States by competitively awarding grants for research focusing on reduction of risks to human health and ecosystems and on reduction of uncertainty associated with risk assessment. This is done through the Science to Achieve Results (STAR) Program. Requests for Applications (RFAs) are derived from the Strategic Plan of EPA's Office of Research and Development (ORD) and from specific topical research plans developed by ORD. The most recent plans and strategies can be found on the ORD web site: http://www.epa.gov/ORD/. The RFAs are prepared in cooperation with other parts of the Agency and focus research on areas of particular importance to the Agency and/or on areas that complement the ORD intramural research programs and the programs of research partners in other Agencies. From time to time, NCER will also establish larger research centers and programs competitively in specific areas of national concern.
The latest information about STAR programs and
the latest announcements can be found on the NCER web site: http://www.epa.gov/ncer/.
NIOSH National Occupational Research Agenda
The research needs identified in this announcement relevant to NIOSH are consistent with the National Occupational Research Agenda (NORA) developed by NIOSH and partners in the public and private sectors to provide a framework to guide occupational safety and health research into the next decade. This attempt to guide and coordinate research nationally is responsive to a broadly perceived need to address systematically those topics that are most pressing and most likely to yield gains to the worker and the nation. There are 21 research priority areas identified in NORA; however, the area with specific relevance to this announcement is "Mixed Exposures."
Exposures to combinations of chemical or physical agents is common in many occupations, but knowledge about the potential health effects of such exposures is limited. Thus, NIOSH is interested in studies that identify synergistic effects of multiple exposure, improve characterization of worker exposures to mixtures, or improve laboratory and statistical analysis methods. Information about NORA is available through the NIOSH Home Page; http://www.cdc.gov/niosh/norhmpg.html.
Healthy People 2000
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Health People 2000," a PHS-led national activity for setting priority areas. This RFA, "Complex Chemical Mixtures," is related to the priority area of environmental health. Potential applicants may obtain a copy of "Healthy People 2000:" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800).
Up to $5 million is expected to be available for awards in this program area. The projected award range is up to $250,000/year total costs for up to 3 years. Awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Applicants should include in their budgets funds for one trip/year for an annual meeting of grantees to be held either in Research Triangle Park, NC, or Washington, DC.
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 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 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. 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.
Potential applicants who are uncertain of their eligibility should contact Dr. Robert E. Menzer, phone (202) 564-6849, email: email@example.com.
Mechanism of Support
The funding mechanisms to be used to assist the scientific community in participating in this grant program will be those of: (1) the Environmental Protection Agency's Office of Research and Development, administered in accordance with 40 CFR Parts 30 and 40 or (2) the National Institutes of Health (NIH) Investigator Initiated Award (R01) mechanism. Policies that govern grant award programs of each agency will prevail for respective sources of support. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant.
This RFA is a joint announcement by EPA, NIOSH, and NIEHS and reflects our common research interests. The program will be managed by the three agencies to ensure complementary balance of the research portfolio.
Inclusion of Women and Minorities in Research Involving Human Subjects
The NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) requires that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. Grantees, regardless of funding source, will be expected to adhere to this policy.
All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register or March 28, 1994 (FR 59, 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, and is available at the following URL address: http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html. Investigators also may obtain copies of the policy from the program staff listed under "Contacts." Program staff may also provide further discussion concerning the policy.
Inclusion of Children as Participants in Research Involving Human Subjects
It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under "Contacts." Program staff may also provide additional relevant information concerning the policy.
A set of special instructions on how applicants should apply for a grant in this program is found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/, Standard Instructions for Submitting a STAR Application. The necessary forms for submitting an application will also be found on this web site.
Sorting CodesThe 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 codes for applications submitted in response to this solicitation are
Environmental Transport and Fate 2000-STAR-P1.
Exposure Assessment 2000-STAR-P2
The deadline for receipt of the application by NCERQA is no later than 4:00 p.m. ET, July 10, 2000.
Authority and Regulations
This program is described in the Catalog of Federal Domestic Assistance Nos. 93.114, 93.115, 93.262, and 66.500. NIEHS and NIOSH awards are made under authorization of the Public Health Service Act, Title IV, Part a (Public Law 78-410, as amended by Public Law 99-158, 43 USC 241 and 285) and administered under PHS Grants Policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. EPA Awards are made under authority of 40 CFR Part 30 and 40. This program is not subject to the intergovernmental review requirements of executive order 12372 or Health Systems Agency review.
The Public Health Service, EPA, and NIOSH strongly encourage all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children.
Further information, if needed, may be obtained from the Agency officials indicated below. Email inquiries are preferred.
Chris Saint, Ph.D.
Michael Galvin, Ph.D.
(for fiscal matters)
Claudia Thompson, Ph.D.
(for fiscal matters)