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

Recipients List

Understanding the Role of Nonchemical Stressors and Developing Analytic Methods for Cumulative Risk Assessments

This is the initial announcement of this funding opportunity.

Funding Opportunity Number:

• EPA-G2009-STAR-E1: Developing Statistical and Other Analytical Techniques for Cumulative Risk Assessments
  EPA-G2009-STAR-E2: Evaluating the Interaction of Nonchemical and Chemical Stressors

Catalog of Federal Domestic Assistance (CFDA) Number: 66.509

Solicitation Opening Date: February 13, 2009
Solicitation Closing Date: June 17, 2009, 4:00 pm Eastern Time

Eligibility Contact: William Stelz (stelz.william@epa.gov); phone: 202-343-9802
Electronic Submissions: Ron Josephson (josephson.ron@epa.gov); phone: 202-343-9643
Technical Contact: Deborah Segal (segal.deborah@epa.gov); phone: 202-343-9797

Table of Contents:
SUMMARY OF PROGRAM REQUIREMENTS
	Synopsis of Program
	Award Information
	Eligibility Information
	Application Materials
	Agency Contacts
I. FUNDING OPPORTUNITY DESCRIPTION
	A. Introduction
	B. Background
	C. Authority and Regulations
	D. Specific Areas of Interest/Expected Outputs and Outcomes
	E. References
	F. Special Requirements
II. AWARD INFORMATION
III. ELIGIBILITY INFORMATION
	A. Eligible Applicants
	B. Cost Sharing
	C. Other
IV. APPLICATION AND SUBMISSION INFORMATION
	A. Internet Address to Request Application Package
	B. Content and Form of Application Submission
	C. Submission Dates and Times
	D. Funding Restrictions
	E. Submission Instructions and Other Submission Requirements
V. APPLICATION REVIEW INFORMATION
	A. Peer Review
	B. Programmatic Review
	C. Funding Decisions
VI. AWARD ADMINISTRATION INFORMATION
	A. Award Notices
	B. Disputes
	C. Administrative and National Policy Requirements
VII. AGENCY CONTACTS

Access Standard STAR Forms (How to Apply and Required Forms)
View research awarded under previous solicitations (Past Research Funding Opportunities)

SUMMARY OF PROGRAM REQUIREMENTS

Synopsis of Program:
The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications from interdisciplinary teams to address research needs that currently limit the ability to conduct cumulative risk assessments. Exposure to different combinations of environmental stressors can contribute to increased risk for negative health consequences. It has become clear that cumulative risk assessments should include both chemical and nonchemical stressors, exposures from multiple routes, and factors that differentially affect exposure or toxicity to communities. This RFA is focusing on two challenges that exist in conducting cumulative risk assessments: (a) STAR-E1: The development of statistical and other analytical techniques that will enable the analysis of disparate types of data, and (b) STAR-E2: The evaluation of the combined effects of nonchemical and chemical stressors.

Award Information:
Anticipated Type of Award: Grant or cooperative agreement
Estimated Number of Awards: Approximately 9 awards
Anticipated Funding Amount: Approximately $8 million total for all awards
Potential Funding per Award: Up to a total of $750,000 for STAR-E1 and up to a total of $1,250,000 for STAR-E2, including direct and indirect costs, with a maximum duration of 4 years. Cost-sharing is not required. Proposals with budgets exceeding the total award limits will not be considered.

Eligibility Information:
Public nonprofit institutions/organizations (includes public institutions of higher education and hospitals) and private nonprofit institutions/organizations (includes private institutions of higher education and hospitals) located in the U.S., state and local governments, Federally Recognized Indian Tribal Governments, and U.S. territories or possessions are eligible to apply. See full announcement for more details.

Application Materials:
To apply under this solicitation, use the application package available at Grants.gov (for further submission information see Section IV.E. “Submission Instructions and other Submission Requirements”).  The necessary forms for submitting a STAR application will be found on the National Center for Environmental Research (NCER) web site, How to Apply and Required Forms. If your organization is not currently registered with Grants.gov, you need to allow approximately one week to complete the registration process.  This registration, and electronic submission of your application, must be performed by an authorized representative of your organization.

If you do not have the technical capability to utilize the Grants.gov application submission process for this solicitation, call 1-800-490-9194 or send a webmail message to https://www.epa.gov/research-grants/forms/contact-us-about-research-grants at least 15 calendar working days before the submission deadline to assure timely receipt of alternate submission instructions.  In your message  provide the funding opportunity number and title of the program, specify that you are requesting alternate submission instructions, and provide a telephone number, fax number, and an email address, if available.  Alternate instructions will be e-mailed whenever possible.  Any applications submitted through alternate submission methods must comply with all the provisions of this RFA, including Section IV, and be received by the solicitation closing date identified above.

Agency Contacts:
Eligibility Contact: William Stelz (stelz.william@epa.gov); phone: 202-343-9802
Electronic Submissions: Ron Josephson (josephson.ron@epa.gov); phone: 202-343-9643
Technical Contact: Deborah Segal (segal.deborah@epa.gov); phone: 202-343-9797

I. FUNDING OPPORTUNITY DESCRIPTION

A. Introduction
The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) grants program, is seeking applications from interdisciplinary teams to address research needs that currently limit the ability to conduct cumulative risk assessments. Exposure to different combinations of environmental stressors can contribute to increased risk for negative health consequences. It has become clear that cumulative risk assessments should include both chemical and nonchemical stressors, exposures from multiple routes, and factors that differentially affect exposure or toxicity to communities. For this Request for Applications (RFA), environmental stressor is defined as a chemical, physical, biological, or social entity that can cause an adverse response to humans, and community refers to a group of people that share a common characteristic or characteristics, for example, ethnicity, socioeconomic status, or geographic location. Some of these factors may contribute to negative health effects, but others might increase resiliency, which is the ability to overcome stressful conditions. How these factors interact has tremendous public health implications. For example, a pollutant exposure that is benign to children living in a wealthy community may harm children living in a less advantaged environment. In order to protect the most sensitive individuals, an understanding of the complex interactions of various stressors is critical.

Because risk assessments have traditionally focused on the effects of one chemical on one individual via a single route or pathway and have not considered the role of nonchemical stressors and other community-related factors, conducting cumulative risk assessments poses many challenges. This RFA is focusing on two of the challenges: (a) STAR-E1: The development of statistical and other analytical techniques that will enable the analysis of disparate types of data, and (b) STAR-E2: The evaluation of the combined effects of nonchemical and chemical stressors. In order to address these challenges successfully, collaborations will need to be developed among biomedical scientists, public health scientists, mathematical and statistical scientists, social scientists, and community members.

B. Background
Several reports have stressed the need to evaluate risks from multiple stressors, as opposed to a single one. Two such reports are “Science and Judgment in Risk Assessment” (National Research Council, 1994) and “Risk Assessment and Risk Management in Regulatory Decision-Making (Presidential/Congressional Commission on Risk Management, 1997). In addition, the Food Quality Protection Act of 1996 specifically mandates the consideration of cumulative risk to pesticides with a common mechanism of action in the human health risk assessment of pesticides.

One research objective in EPA’s Human Health Research Strategy (www.epa.gov/NHEERL/humanhealth/HHRS_final_web.pdf (67 pp, 1.5 MB)) is to develop “approaches to assess population-based cumulative risk, including those involving exposure to stressors other than pollutants.”  Additionally, EPA’s Framework for Cumulative Risk Assessment defines “cumulative risk” broadly to include nonchemical stressors, such as “current physical and mental health status and past exposure histories…and social factors such as community property values, sources of income, level of income, and standard of living” (EPA’s Framework for Cumulative Risk Assessment, p. 51). The Framework calls for (a) an understanding of the combined effects of more than one stressor, (b) a consideration of nonchemical stressors, (c) a focus on vulnerable populations, and (d) the use of community expertise for place-based or population-based risk assessments.

To help determine the most pressing research needs for cumulative risk assessment and in response to interests of EPA’s Regional risk assessors, Program Offices, Office of Environmental Justice, and Office of Children’s Health Protection and Environmental Education, EPA’s National Center for Environmental Research (NCER) and National Center for Computational Toxicology sponsored a “Workshop on Research Needs for Community-Based Risk Assessment” in October 2007. Workshop participants, who represented EPA, other federal agencies, academia, and private organizations, generated an extensive list of research needs that included data generation, tool and model development, infrastructure improvements, basic research on nonchemical stressors, and training in community-based participatory research (CBPR). As a first step, this RFA will focus on two needs that were repeatedly identified: The development of techniques that will enable the analysis of disparate types of data and the evaluation of the combined effects of nonchemical and chemical stressors. This RFA will also require a CBPR component as discussed in more detail in Section D: Specific Research Areas of Interest/Expected Outputs and Outcomes.

Although representing only one explanation for how nonchemical stressors might modify toxicity resulting from environmental exposures, the framework presented below (Morello-Frosch & Shenassa, 2006) is one example depicting the complexities that exist when considering individual as well as community-level factors.  The authors theorize that an individual’s allostatic load is the cumulative physiologic degradation that results from a lifetime of chronic stress. This influences internal dose, response and resilience, health effect, and the ability to recover. This RFA is seeking research to help elucidate how different (including other chemical and nonchemical) stressors alter the internal dose, resilience, health effects, or ability to recover from exposures to environmental contaminants.

Figure 1. The interplay of community and individual stressors/buffers that shape exposures and susceptibility
to environmental hazards. Thick arrows indicate relationships that have been studied in the epidemiologic
and sociology literature; dashed arrows indicate relationships that have not been extensively explored. 

STAR-E1: Developing Statistical and Other Analytical Techniques for Cumulative Risk Assessments

Several EPA programs have released guidance documents to encourage analytic methods development for cumulative risk assessments. The documents call for consideration of multiple stressors and their interactions with one another.  This could require the analysis of multiple pathways, durations, sources and routes of exposure; analysis of the multiple effects and impacts; inclusion of nonchemical stressors; and a quantification of risks (U.S. EPA, 2003, 2007). In order to foster this more integrated view of environmental risk, the documents acknowledge that traditional analytical techniques—such as estimating reference doses for single chemicals--will increase in complexity.  Refinement of existing methodological approaches or the development of novel ones is required to facilitate a better understanding of the cumulative impacts of multiple chemical and nonchemical stressors on a population. Especially needed are quantitative functions relating health effects to levels of multiple stressors.

Analyzing aggregate measures. The reality that populations are exposed to multiple chemicals through multiple paths of exposure over time has spurred much research on the toxicology of chemical mixtures. EPA staff (2007) reviewed the literature on some of the more recent and innovative approaches in this field.  These approaches include the use of biomarkers (e.g., metabolites in urine and blood samples) and DNA microarrays to collect data on, respectively, the mix of chemical concentrations to which different populations are exposed and the consequent change in gene expression. Techniques that could aid the analysis of these types of measurements, chemical mixtures, and clusters of gene expression patterns include parametric and nonparametric techniques, such as principal component analysis and canonical correlation, and potentially other methods. Ultimately, such work might lead to the development of models that explain mechanisms of toxicity interactions and classification schemes for toxic mixtures. Advanced statistical and analytical methods are needed to determine the overall body burden from the totality of chemicals to which humans are exposed.

Evaluating chemical and nonchemical stressors that contribute to vulnerability. Compounding the complexity of chemical mixtures, the vulnerability of an organism to negative health outcomes is strongly associated with both social environment (Krieger, 2007) and exposure to chemicals (Weiss and Bellinger, 2007), as well as to genetic susceptibility. Weiss and Bellinger argue that social factors—such as parental IQ, family income, marital status, prenatal care, maternal drug use, and family caregiving—are not so much confounders, but rather modifiers of the etiology being investigated. The traditional statistical approach in epidemiological studies for examining whether multiple risk factors modify observed associations between an exposure of interest and health status has been through stratified analyses or the use of interaction terms in regression models. However, the simultaneous consideration of multiple chemical and nonchemical stressors raises several statistical and methodological issues that have not been resolved. Better analytical methods are needed to determine how multiple variables influence an individual’s vulnerability.

Combining information from disparate studies to evaluate risk. Further development is also needed to integrate multiple levels of analysis. In order to better understand the cumulative impact of chemical and nonchemical stressors, it is likely that data and models of exposure and effects will need to be integrated across multiple studies and across multiple scales of time and space. Calder et al. (2008) related ambient particulate matter concentrations to mortality using a Bayesian hierarchical model that incorporated a spatial model and an exposure simulator and modeled the strength of temporally lagged effects. Harris and colleagues (2002) developed regression diagnostic techniques to correlate exposure questionnaires with urine collection data, absorbed dose estimations (from both dermal and inhalation exposures), and equipment variations with multiple pesticides use. Methods involving multilevel analyses are needed to coherently analyze data and to evaluate impacts at both the individual- and community-levels.

STAR E2: Evaluating the Interaction of Nonchemical and Chemical Stressors

As discussed in the National Environmental Justice Advisory Council (NEJAC) 2004 report, “Ensuring Risk Reduction in Communities with Multiple Stressors: Environmental Justice and Cumulative Risks/Impacts,” and mentioned above, a need exists to better characterize risks posed by exposures to multiple chemicals and to incorporate social and nonchemical factors into cumulative risk assessments. Nonchemical stressors are critical to consider in risk assessments because many chemical exposures occur in the context of multiple social disadvantages, which frequently impair human health and well being (Rauh et al., 2004). 

Determining which nonchemical stressors exacerbate chemical exposures. Elevated psychosocial stress has been shown to contribute to several adverse health outcomes, most notably, to cardiovascular disease. The physiological mechanism by which psychosocial stress leads to health effects is due, at least in part, to elevated circulating glucocorticoids, or stress hormones, which are regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Research on the physiologic impacts of nonchemical stressors has focused primarily on the stress experienced by those living in disadvantaged communities. The extent of this stress is often represented by some measure of socioeconomic status (SES), which takes into account income, education, and occupation. SES has consistently been associated with health outcomes, such that people of lower SES generally have poorer health outcomes than those of higher SES (Adler et al., 1994). However, understanding which components of SES have the greatest impact on environmental exposure-related health outcomes is critical. For example, the stress resulting from overcrowding, poverty, and violence in one’s neighborhood or the lack of healthcare, poor nutritional status, or unhealthy behaviors, individually or in combination, may increase vulnerability to toxic effects. Interestingly, researchers have found that the neighborhood in which one resides influences one’s health more than an individual’s SES (Kawachi & Berkman, 2003). 

One example of a chemical-nonchemical interaction is that of lead and psychosocial stress, which both act (through the HPA axis) on the dopamine/glutamate mesocorticolimbic systems of the brain (Virgolini et al., 2006). A body of research on lead toxicity has demonstrated adverse health effects following environmental exposures only when stress is also a factor.  For example, Tong et al. (2000) found that children from socially disadvantaged backgrounds were more sensitive to lead than those of a higher socioeconomic status. Schneider et al. (2001) discovered that lead-exposed rats in an impoverished environment had spatial learning deficits and significantly decreased neurotrophic factor gene expression in the hippocampus, whereas rats reared in an enriched environment were protected against the behavioral and neurochemical toxicity of lead (Guilarte et al., 2003). 

Nonchemical stress exacerbates the toxicity of other chemicals as well. Claugherty and colleagues (2007) found an association between traffic-related air pollution and asthma solely among children exposed to violence, suggesting a synergistic relationship between exposure to air pollution and violence. Others have found an interactive effect of prenatal environmental tobacco smoke and material hardship (Rauh et al., 2004). In addition to psychosocial nonchemical stressors, nutritional status has been demonstrated to affect the toxic response to chemical exposures. For example, iron and calcium deficiencies increase the toxicity resulting from heavy metal exposures.

Understanding the biological role of nonchemical stressors in mediating chemical toxicity. Little is known regarding how nonchemical stressors potentiate the negative health effects resulting from exposure to the vast majority of toxic chemicals. Understanding interactions between chemical and nonchemical stressors will require knowledge of toxicant-specific biological mechanisms of action, as well as stress response mechanisms of action. Additional research is needed to better understand the physiological health impacts, including the neurobiology and immunological effects of nonchemical stressors and how nonchemical stressors can affect health outcomes associated with chemical exposures.

Community-Based Participatory Research (CBPR)

The potential for CBPR to enhance environmental protection has been recognized by EPA. This concept promotes a holistic approach to protecting the environment that involves diverse stakeholders who develop a plan aimed at meeting environmental, economic and social goals in a sustainable manner for a defined geographic area. Community participation enables the identification of variables that might otherwise have been missed. Community and stakeholder involvement is critical to obtaining community knowledge and to understanding complex cumulative exposures (EPA, 2003; NEJAC, 2004). Community members understand community practices that may influence exposures. In addition, because population-based cumulative risk assessments involve community-level stressors and measures of vulnerability, which can help to inform decision making at the local level, earning the trust of community members is necessary.  To understand the key concepts of CBPR, see Israel et al. (2001).

The specific Strategic Goal and Objective from the EPA’s Strategic Plan that relate to this solicitation are:

Goal 4: Healthy Communities and Ecosystems, Objective 4.4: Enhance Science and Research.

The EPA’s Strategic Plan can be found at https://www.epa.gov/ocfo/plan/2006/entire_report.pdf (PDF) (184 pp, 11.56 MB)

C. Authority and Regulations
The authority for this RFA and resulting awards is contained in the Clean Air Act, Section 103, 42 U.S.C. 7403; the Federal Insecticide, Fungicide, and Rodenticide Act, Section 20, 7 U.S.C. 136r; the Safe Drinking Water Act, Section 1442, 42 U.S.C. 300j-1; the Clean Water Act, Section 104, 33 U.S.C. 1254; and the Toxic Substances Control Act, Section 10, 15 U.S.C. 2609.

For research with an international aspect, the above statutes are supplemented, as appropriate, by the National Environmental Policy Act, Section 102(2)(F).

Applicable regulations include: 40 CFR Part 30 (Uniform Administrative Requirements for Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations), 40 CFR Part 31 (Uniform Administrative Requirements for Grants and Cooperative Agreements to State and Local Governments) and 40 CFR Part 40 (Research and Demonstration Grants). Applicable OMB Circulars include: OMB Circular A-21 (Cost Principles for Educational Institutions) relocated to 2 CFR Part 220, OMB Circular A-87 (Cost Principles for State, Local and Indian Tribal Governments) relocated to 2 CFR Part 225, OMB Circular A-102 (Grants and Cooperative Agreements With State and Local Governments), OMB Circular A-110 (Uniform Administrative Requirements for Grants and Other Agreements with Institutions of Higher Education, Hospitals and Other Non-Profit Organizations) relocated to 2 CFR Part 215, and OMB Circular A-122, (Cost Principles for Non-Profit Organizations) relocated to 2 CFR Part 230.

D. Specific Research Areas of Interest/Expected Outputs and Outcomes
Note to applicant:  The term “output” means an environmental activity or effort, and associated work products, related to a specific environmental goal(s), (e.g., testing a new methodology), that will be produced or developed over a period of time under the agreement. The term “outcome” means the result, effect, or consequence that will occur from the above activit(ies) that is related to an environmental, behavioral, or health-related objective.

The Agency is soliciting research that will result in an improved ability to conduct cumulative risk assessments. Anticipated outputs of this research include statistical and computational tools, models and approaches for analyzing disparate types of data required for risk assessments.  It also includes the generation of data evaluating the effects of multiple chemical and nonchemical stressors.  The desired outcome of this research is a better understanding of the combined effects of nonchemical and chemical stressors and the development of statistical and computational tools, models, and approaches for analyzing the disparate types of data required by cumulative risk assessments.  The research will also require involvement by community members in the research process.

There are two distinct areas of research covered by this solicitation. Responsive applications must propose to do one of the following:

• STAR-E1: Develop analytic techniques to characterize effects and health risks at the community and individual levels; synthesize information from multiple datasets; extrapolate data among datasets and/or across communities; develop quantitative functions relating a health outcome to levels of multiple stressors; and characterize the uncertainty and/or limitations associated with these studies.
• STAR-E2: Evaluate the combined effects of nonchemical and chemical stressors.

STAR-E1: Developing Statistical and Other Techniques for Cumulative Risk Assessments.This research should be primarily concerned with the following related questions: (1) How can research be conducted and data from multiple sources be synthesized across space and time to help elucidate the interaction of organisms with multiple stressors in their physical and social environments? (2) How can biological mechanisms be integrated to gain a systems-wide, multi-scale understanding of interactions at the organism and population levels in terms of an individual’s experience of stress and in relation to intrinsic and extrinsic factors contributing to vulnerability or resilience? (3) How can quantitative and qualitative data be integrated to provide some metric of risk?

For STAR-E1, the focus must be on exposures to one of the following: (1) multiple chemicals, (2) a chemical and a nonchemical stressor together, (3) multiple chemicals and a non-chemical stressor, (4) a chemical and multiple nonchemical stressors, or (5) multiple chemicals and multiple nonchemical stressors. In addition, for all developed tools, models or approaches, uncertainties and/or limitations must be characterized. The use of existing datasets is acceptable, but not required.

Research responsive to STAR-E1 must develop tools, models or approaches to accomplish at least one of the following:

• Integrate research results and information from multiple studies, multiple data sources, and across multiple scales of time and/or space to address various components within cumulative risk assessment.
• Determine dose/concentration-response curves when multiple stressors exist.
• Develop metrics or methodologies for assessing and integrating the cumulative effects of multiple sources of stress, including quantitative and qualitative indicators of nonchemical sources of stress.

STAR-E2: Evaluating the Interaction of Nonchemical and Chemical Stressors. This research should be primarily concerned with the following related questions: (1) What is the role of nonchemical stressors in the exacerbation of the health effects resulting from chemical exposures? (2) What is the mechanism of action for nonchemical and chemical stressors? Are they the same, similar, or different? Do they interact and/or intersect? (3) Can dose-response curves and physiologically based pharmacokinetic (PBPK) and physiologically based pharmacodynamic (PBPD) models be developed to incorporate nonchemical stressors? (4) Do different nonchemical stressors modify toxicity responses in a similar way and to the same degree?

For STAR-E2, animal studies are acceptable as are epidemiological investigations focused on humans. Research responsive to STAR-E2 must accomplish at least one of the following:

• Determine the biological impact of psychosocial stress and its interaction with chemical exposures, including mechanisms of action and the resulting health consequences. This may consider exposure influences, such as sequence and timing. It might also consider lifestage.
• Develop dose-response models for combined exposures to chemical and nonchemical stressors. Effects of timing of the exposures may be considered if appropriate.
• Incorporate psychosocial stress into chemical or class-specific PBPK and PBPD models.
• Identify which nonchemical stressors exacerbate negative health outcomes resulting from chemical exposures for particular populations or life stages.

Community-Based Participatory Research (CBPR)

CBPR is defined as a collaborative process of research involving researchers and community representatives. The process of scientific inquiry is such that community members, persons affected by the health condition, disability or issue under study, or other key stakeholders in the community's health, have the opportunity to participate in each phase of the work. Community-based organizations refer to organizations that may be involved in the research process as members or representatives of the community. Although not an exhaustive list, organizations as varied as Tribal governments and colleges, state or local governments, independent living centers, health delivery organizations (e.g., hospitals), health professional associations, non-governmental organizations, and federally qualified health centers are possible community partners.
A CBPR plan will be required for each proposed project. Although a range of levels of community involvement can be considered CBPR, CBPR is characterized by substantial community input in the project. In the application, the applicant will need to justify the level of community involvement that he or she has proposed. For additional information on CBPR, see Minkler and Wallerstein (2008). At a minimum, each applicant must:

• Focus on research issues of significance to a community that is interested in the proposed work.
• Identify the role of community members in the proposed research plan (i.e., the degree of community input or engagement in the conceptualization, design, methods, analyses, or dissemination of research).
• Describe how this research will enhance the capacity of the community.
• Include resources for partnership development (e.g., to hire community liaisons or to provide participant support costs for community involvement).
• If a host organization (any organization/institution other than the applicant) is used to facilitate community participation or partnerships, evaluate the organization’s mission and practices concerning community partnerships (e.g., how the staff has or can develop skills to sustain community participation).
• Determine how to disseminate research findings to the identified community as well as the scientific community.
• Provide evidence of community support.

E. References
Adler, N.E., Boyce, T., Chesney, M.A., Cohen, S., Folkman, S., Kahn, R.L., & Syme, S.L. (1994). “Socioeconomic status and health: The challenge of the gradient.”American Psychologist, 49(1): 15-24.

Bellinger, D.C., Leviton, A., Waternaux, C., Needleman, H., & Rabinowitz, M. (1988) “Low-level lead exposure, social class, and infant development.” Neurotoxicology and Teratology, Vol. 10: 497-503.

Calder, C.A., Holloman, C.H., Bortnick, S.M., Strauss, W., & Morara, M. (2008). “Relating Ambient Particulate Matter Concentration Levels to Mortality Using an Exposure Simulator.” Journal of the American Statistical Association, Vol. 103: 137-148.

Clougherty, J.E., J.I. Levy, L.D. Kubzansky, P.B. Ryan, S.F. Suglia, M.J. Canner, & Wright, R.J. ((2007). “Synergistic Effects of traffic-related air pollution and exposure to violence on urban asthma etiology.” Environmental Health Perspectives 115(8): 1140-1146.

Guilarte, T.R., Toscano, C.D., McGlothan, J.L., & Weaver, S.A. (2003). “Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure.” Annals of Neurology, Jan;53(1):50-6.

Harris, S., Sass-Kortsak, A., Corey, P., & Purdham, J. (2002). “Development of models to predict dose of pesticides in professional turf applicators.”  Journal of Exposure Analysis and Environmental Epidemiology, 12, 130–144.

Israel, B.A., Schulz, J., Parker, E.A., & Becker, A.B. (2001). "Community-Based Participatory Research: Policy Recommendations for Promoting a Partnership Approach in Health Research." Education for Health 14(2): 182-197.
Kawachi, I., & Berkman, L., Eds. (2003). Neighborhoods and Health. Oxford University Press, New York.

Krieger,  N. (2007). “Why epidemiologists cannot afford to ignore poverty.” Epidemiology,18(6):658-63.

Minkler, M. & Wallerstein, N., Eds. (2008). Community-Based Participatory Research for Health: From Process to Outcomes, 2nd Ed. Jossey-Bass Publishers, New York.

Morello-Frosch, R. & Shenassa, E. D. (2006). “The Environmental Riskscape and Social Inequality: Implications for Explaining Maternal and Child Health Disparities.” Environmental Health Perspectives, 114(8): 1150-1153.

Rauh, V.A., Whyatt R.M., Garfinkel, R., Andrews, H., Hoepner L., Reyes, A. Diaz, D., Camann D., & Perera, F.P. (2004). “Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children.” Neurotoxicological Teratology, May-June; 26(3):373-85, 2004.

Schneider, J.S., Lee, M.H., Anderson, D.W., Zuck, L., & Lidsky, T.I. (2001). “Enriched environment during development is protective against lead-induced neurotoxicity.” Brain Research, 896(1-2):48-55.

Virgolini, M.B., Bauter, M.R., Weston, D.D., & Cory-Slechta, D.A. (2006). “Permanent alterations in stress responsivity in female offspring subjected to combined maternal lead exposure and/or stress.” Neurotoxicology, 27(1):11-21.

Weiss, B. & Bellinger, D.C. (2006). “Social ecology of children’s vulnerability to environmental pollutants.” Environmental Health Perspectives, 114(10): 1479-1485.

Reports
National Research Council. Science and Judgment in Risk Assessment. Washington, DC: National Academy Press, 1994.

National Research Council. Models in Environmental Regulatory Decision Making. Committee on Models in the Regulatory Decision Process. Washington, DC: National Academy Press, 2007.

Presidential/Congressional Commission on Risk Assessment and Risk Management. Risk Assessment and Risk Management in Regulatory Decision-Making. Washington, DC, 1997.

U.S. EPA (2003). Framework for Cumulative Risk Assessment, EPA/630/P-02/001F). Risk Assessment Forum. Washington, DC, 2003. Available at https://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=54944.

U.S. EPA. (2004). Ensuring Risk Reduction in Communities with Multiple Stressors: Environmental Justice and Cumulative Risks/Impacts.  National Environmental Justice Advisory Committee. Washington, DC. Available online at www.epa.gov/compliance/resources/publications/ej/nejac/nejac-cum-risk-rpt-122104.pdf.

U.S. EPA. (2007). Concepts, Methods, and Data Sources for Cumulative Health Risk Assessment of Multiple Chemicals, Exposures and Effects: A Resource Document (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-06/013F.

U.S. EPA. (2007). Workshop on Research Needs for Community-Based Risk Assessment: Workshop Proceedings. Office of Research and Development. Washington, DC. Available online at https://www.epa.gov/research-grants/cbra/presentations/11_18_07/proceedings.pdf.

U.S. EPA. (2009). New Approaches and Tools for the Conduct of Community-Based Cumulative Risk Assessments. Human Exposure and Atmospheric Sciences Division. Available online at https://www.epa.gov/heasd/risk/projects/c3a_risk_assessment_tools.htm.

Statutes
U.S. 104th Congress. (1996a) Food Quality Protection Act (FQPA). PL 104-170. Available online at https://www.epa.gov/pesticides/regulating/laws/fqpa/.

F. Special Requirements
Agency policy prevents EPA technical staff and managers from providing individual applicants with information that may create an unfair competitive advantage. Consequently, EPA employees will not review, comment, advise, and/or provide technical assistance to applicants preparing applications in response to EPA RFAs, nor will they endorse an application or discuss in any manner how the Agency will apply the published evaluation criteria for this competition.

Multiple Investigator applications may be submitted as: (1) a single Lead Principal Investigator (PI) application with Co-PI(s) or (2) a Multiple PI application (with a single Contact PI). If you choose to submit a Multiple PI application, you must follow the specific instructions provided in Sections IV. and V. of this RFA. For further information, please see the EPA Implementation Plan for Policy on Multiple Principal Investigators (http://rbm.nih.gov/toolkit.htm).

Groups of two or more eligible applicants may choose to form a consortium and submit a single application for this assistance agreement. The application must identify which organization will be the recipient of the assistance agreement and which organizations(s) will be subawardees of the recipient.

The application must include a plan (see �Data Plan� in section IV.B.5.c.) to make available to the public and community partners all data generated from observations, analyses, or model development (primary data) and any secondary (or existing) data used under an agreement awarded from this RFA. The data must be available in a format and with documentation such that they may be used by others in the scientific community.

These awards may involve the collection of �Geospatial Information,� which includes information that identifies the geographic location and characteristics of natural or constructed features or boundaries on the Earth or applications, tools, and hardware associated with the generation, maintenance, or distribution of such information. This information may be derived from, among other things, a Geographic Positioning System (GPS), remote sensing, mapping, charting, and surveying technologies, or statistical data.

II. AWARD INFORMATION

It is anticipated that a total of approximately $8 million will be awarded under this announcement, depending on the availability of funds and quality of applications received.  The EPA anticipates funding approximately 9 awards under this RFA.  Requests for amounts in excess of a total of $750,000 for STAR-E1 and $1,250,000 for STAR-E2, including direct and indirect costs, will not be considered.  The total project period requested in an application submitted for this RFA may not exceed 4 years.  The EPA reserves the right to reject all applications and make no awards, or make fewer awards than anticipated, under this RFA.  The EPA reserves the right to make additional awards under this announcement, consistent with Agency policy, if additional funding becomes available after the original selections are made.  Any additional selections for awards will be made no later than six months after the original selection decisions.

EPA may award both grants and cooperative agreements under this announcement.

Under a grant, EPA scientists and engineers are not permitted to be substantially involved in the execution of the research.  However, EPA encourages interaction between its own laboratory scientists and grant Principal Investigators after the award of an EPA grant 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.

Where appropriate, based on consideration of the nature of the proposed project relative to the EPA’s intramural research program and available resources, the EPA may award cooperative agreements under this announcement.  When addressing a research question/problem of common interest, collaborations between scientists and the institution’s principal investigators are permitted under a cooperative agreement.  These collaborations may include data and information exchange, providing technical input to experimental design and theoretical development, coordinating extramural research with in-house activities, the refinement of valuation endpoints, and joint authorship of journal articles on these activities.  Proposals may not identify EPA cooperators or interactions; specific interactions between EPA’s investigators and those of the prospective recipient for cooperative agreements will be negotiated at the time of award.

III. ELIGIBILITY INFORMATION

A. Eligible Applicants
Public nonprofit institutions/organizations (includes public institutions of higher education and hospitals) and private nonprofit institutions/organizations (includes private institutions of higher education and hospitals) located in the U.S., state and local governments, Federally Recognized Indian Tribal Governments, and U.S. territories or possessions are eligible to apply. Profit-making firms are not eligible to receive assistance agreements from the EPA under this program.

Eligible nonprofit organizations include any organizations that meet the definition of nonprofit in OMB Circular A-122, located at 2 CFR Part 230. However, nonprofit organizations described in Section 501(c) (4) of the Internal Revenue Code that lobby are not eligible to apply.

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 applicant, but may not direct projects on behalf of the applicant organization. The institution, organization, or governance receiving the award may provide funds through its assistance agreement from the EPA to an 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 an assistance agreement, and may not receive salaries or augment their Agency�s appropriations in other ways through awards made under this program.

The applicant 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. In addition, an appropriate form of assurance that documents the commitment, such as a letter of intent from the Federal Agency involved, should be included.

Potential applicants who are uncertain of their eligibility should contact William Stelz (stelz.william@epa.gov) in NCER, phone (202) 343-9802.

B. Cost-Sharing
Institutional cost-sharing is not required.

C. Other
Applications must substantially comply with the application submission instructions and requirements set forth in Section IV of this announcement or they will be rejected.  In addition, where a page limitation is expressed in Section IV with respect to parts of the application, pages in excess of the page limit will not be reviewed.  Applications must be received by Grants.gov (see Section IV.E. “Submission Instructions and Other Submission Requirements” for further information, or through any authorized alternate submission methods described in Section IV) on or before the solicitation closing date and time in Section IV of this announcement or they will be returned to the sender without further consideration.  Also, applications exceeding the funding limits or project period term described herein will be returned without review.  Further, applications that fail to demonstrate a public purpose of support or stimulation (e.g., by proposing research which primarily benefits a Federal program or provides a service for a Federal agency) will not be funded.

There are two distinct areas of research covered by this solicitation. Responsive applications must propose to do one of the following:

• STAR-E1: Develop analytic techniques to characterize effects and health risks at the community and individual levels; synthesize information from multiple datasets; extrapolate data among datasets and/or across communities; develop quantitative functions relating a health outcome to levels of multiple stressors; and characterize the uncertainty and/or limitations associated with these studies.
• STAR-E2: Evaluate the combined effects of nonchemical and chemical stressors.

For STAR-E1, the focus must be on exposures to one of the following: (1) multiple chemicals, (2) a chemical and a nonchemical stressor together, (3) multiple chemicals and a non-chemical stressor, (4) a chemical and multiple nonchemical stressors, or (5) multiple chemicals and multiple nonchemical stressors. In addition, for all developed tools, models or approaches, uncertainties and/or limitations must be characterized. The use of existing datasets is acceptable, but not required.

Research responsive to STAR-E1 must develop tools, models or approaches to accomplish at least one of the following:

• Integrate research results and information from multiple studies, multiple data sources, and across multiple scales of time and/or space to address various components within cumulative risk assessment.
• Determine dose/concentration-response curves when multiple stressors exist.
• Develop metrics or methodologies for assessing and integrating the cumulative effects of multiple sources of stress, including quantitative and qualitative indicators of nonchemical sources of stress.

 Research responsive to STAR-E2 must accomplish at least one of the following:

• Determine the biological impact of psychosocial stress and its interaction with chemical exposures, including mechanisms of actions and the resulting health consequences. This may consider exposure influences, such as sequence and timing. It might also consider lifestage.
• Develop dose response models for combined exposures to chemical and nonchemical stressors. Effects of timing of the exposures may be considered if appropriate.
• Incorporate psychosocial stress into chemical or class-specific PBPK and PBPD models.
• Identify which nonchemical stressors exacerbate chemical for particular populations or life stages.

A CBPR plan will be required for each proposed project. Although a range of levels of community involvement can be considered CBPR, CBPR is characterized by substantial community input in the project. In the application, the applicant will need to justify the level of community involvement that he or she has proposed. For additional information on CBPR, see Minkler and Wallerstein (2008). At a minimum, each applicant must:

• Focus on research issues of significance to a community that is interested in the proposed work.
• Identify the role of community members in the proposed research plan (i.e., the degree of community input or engagement in the conceptualization, design, methods, analyses, or dissemination of research).
• Describe how this research will enhance the capacity of the community.
• Include resources for partnership development (e.g., to hire community liaisons or to provide participant support costs for community involvement).
• If a host organization (any organization/institution other than the applicant) is used to facilitate community participation or partnerships, evaluate the organization’s mission and practices concerning community partnerships (e.g., how the staff has or can develop skills to sustain community participation).
• Determine how to disseminate research findings to the identified community as well as the scientific community.
• Provide evidence of community support.

In addition, to be eligible for funding consideration, a project’s focus must consist of activities within the statutory terms of EPA’s financial assistance authorities; specifically, the statute(s) listed in I.C. above.  Generally, a project must address the causes, effects, extent, prevention, reduction, and elimination of air pollution, water pollution, solid/hazardous waste pollution, toxic substances control, or pesticide control depending on which statute(s) is listed in I.C. above.  These activities should relate to the gathering or transferring of information or advancing the state of knowledge.  Proposals should emphasize this “learning” concept, as opposed to “fixing” an environmental problem via a well-established method.  Proposals relating to other topics which are sometimes included within the term “environment” such as recreation, conservation, restoration, protection of wildlife habitats, etc., must describe the relationship of these topics to the statutorily required purpose of pollution prevention and/or control.

Applications deemed ineligible for funding consideration will be notified within fifteen calendar days of the ineligibility determination.

IV. APPLICATION AND SUBMISSION INFORMATION

Formal instructions for submission through Grants.gov follow in Section E.

A. Internet Address to Request Application Package
Use the application package available at Grants.gov (see Section E. “Submission Instructions and Other Submission Requirements”).  Note: With the exception of the budget form and the current and pending support form (available at How to Apply and Required Forms), all necessary forms are included in the electronic application package.

An email will be sent by NCER to the Lead/Contact PI and the Administrative Contact (see below) to acknowledge receipt of the application and transmit other important information.  The email will be sent from receipt.application@epa.gov; emails to this address will not be accepted.  If you do not receive an email acknowledgment within 30 days of the submission closing date, immediately inform the Eligibility Contact shown in this solicitation.  Failure to do so may result in your application not being reviewed.  See Section E. “Submission Instructions and Other Submission Requirements” for additional information regarding the application receipt acknowledgment.

B. Content and Form of Application Submission
The application is made by submitting the materials described below. Applications must contain all information requested and be submitted in the formats described.

 

 

 

 

 

 

 

 

1. Standard Form 424

   The applicant must complete Standard Form 424. Instructions for completion of the SF424 are included with the form. (However, note that EPA requires that the entire requested dollar amount appear on the 424, not simply the proposed first year expenses.) The form must contain the electronic signature of an authorized representative of the applying organization.

   Applicants are required to provide a �Dun and Bradstreet Data Universal Numbering System� (DUNS) number when applying for federal grants or cooperative agreements. Organizations may receive a DUNS number by calling 1-866-705-5711 or by visiting the web site at http://www.dnb.com .

   Executive Order 12372, �Intergovernmental Review of Federal Programs,� does not apply to the Office of Research and Development's research and training programs unless EPA has determined that the activities that will be carried out under the applicants' proposal (a) require an Environmental Impact Statement (EIS), or (b) do not require an EIS but will be newly initiated at a particular site and require unusual measures to limit the possibility of adverse exposure or hazard to the general public, or (c) have a unique geographic focus and are directly relevant to the governmental responsibilities of a State or local government within that geographic area.

   If EPA determines that Executive Order 12372 applies to an applicant's proposal, the applicant must follow the procedures in 40 CFR Part 29. The applicant must notify their state's single point of contact (SPOC). To determine whether their state participates in this process, and how to comply, applicants should consult http://www.whitehouse.gov/omb/grants/spoc.html. If an applicant is in a State that does not have a SPOC, or the State has not selected research and development grants for intergovernmental review, the applicant must notify directly affected State, area wide, regional and local entities of its proposal.

   EPA will notify the successful applicant(s) if Executive Order 12372 applies to its proposal prior to award.

2. Key Contacts

   The applicant must complete the �Key Contacts� form found in the Grants.gov application package. An �Additional Key Contacts� form is also available at How to Apply and Required Forms. The Key Contacts form should also be completed for major sub-agreements (i.e., primary investigators). Please make certain that all contact information is accurate.

   For Multiple PI applications: The Additional Key Contacts form must be completed (see Section I.F. for further information). Note: The Contact PI must be affiliated with the institution submitting the application. EPA will direct all communications related to scientific, technical, and budgetary aspects of the project to the Contact PI; however, any information regarding an application will be shared with any PI upon request. The Contact PI is to be listed on the Key Contact Form as the Project Manager/Principal Investigator (the term Project Manager is used on the Grants.gov form, the term Principal Investigator is used on the form located on NCER�s web site). For additional PIs, complete the Major Co-Investigator fields and identify PI status next to the name (e.g., �Name: John Smith, Principal Investigator�).

3. Table of Contents

   Provide a list of the major subdivisions of the application indicating the page number on which each section begins.

4. Abstract (1 page)

   The abstract is a very important document in the review process. Therefore, it is critical that the abstract accurately describes the research being proposed and conveys all the essential elements of the research. Also, the abstracts of applications that receive funding will be posted on the NCER web site.

   The abstract should include the information described below (a-h). Examples of abstracts for current grants may be found on the NCER web site.

   1. Funding Opportunity Title and Number for this proposal.
   2. Project Title: Use the exact title of your project as it appears in the application. The title must be brief yet represent the major thrust of the project. Because the title will be used by those not familiar with the project, strike a balance between highly technical words and phrases and more commonly understood terminology. Do not use general phrases such as �research on.�
   3. Investigators: For applications with multiple investigators, state whether this is a single Lead PI (with co-PIs) or Multiple PI application (see Section I.F.). For Lead PI applications, list the Lead PI, then the name(s) of each co-PI who will significantly contribute to the project. For Multiple PI applications, list the Contact PI, then the name(s) of each additional PI. Provide a web site URL or an email contact address for additional information.
   4. Institution: In the same order as the list of investigators, list the name, city and state of each participating university or other applicant institution. The institution applying for assistance must be clearly identified.
   5. Project Period and Location: Show the proposed project beginning and ending dates and the geographical location(s) where the work will be conducted.
   6. Project Cost: Show the total dollars requested from the EPA (include direct and indirect costs for all years).
   7. Project Summar