Description:
This FOA solicits Phase I (R43), Phase II, Direct to Phase II (R44) and Fast-track (R44) SBIR grant applications from SBCs to develop resources and approaches that reflect the variability in responses to chemical exposures based on genetic diversity in the human population. These can include panels of human cells or cell lines, rodent panels, including cell lines generated from rodent diversity panels, or lower organism strains with well-characterized genetic backgrounds to enhance the ability to characterize the effects of genetic variation in toxicity testing.
Background
Most laboratory-based toxicology studies rely on the use of a limited number of rodent strains or other models to characterize dose-response relationships for generating hazard information or safe-exposure limits for chemicals. Although the use of a limited number of inbred rodent strains has the advantage of reducing experimental variability due to genetics and can enhance the reproducibility of studies for specific toxicants, these approaches do not capture the potential variability in responses in the human population. The National Academies of Sciences, Engineering, and Medicine held a workshop in 2015 on “Interindividual Variability: New Ways to Study and Implications for Decision Making” that focused on sources of inter-individual responses to chemical exposure, including genetic variability (https://nap.nationalacademies.org/catalog/23413/interindividual-variability-new-ways-to-study-and-implications-for-decision). Developing new methods to capture human genetic variability in response to chemical exposures can help to identify and protect sensitive populations that respond differently to drugs or toxicant exposures and to generate threshold limit values to protect workers from adverse effects of occupational exposures.
Therefore, there is a need for cost-effective approaches to model variation in response to toxicants in human populations for hazard identification, particularly to identify adverse effects that occur in genetically susceptible individuals. Characterizing differences in susceptibility based on genetic variation can further be applied to understanding mechanism or mode of action for toxicity, e.g., through additional molecular, biochemical, or histopathology analyses.
Objectives
Areas of interest and examples of applications that are responsive to this FOA include, but are not limited to development of:
• Panels of genetically diverse human cells, including primary cells and cell lines to characterize a range of potential responses to chemical toxicants. Cell lines should be genetically well-characterized, including karyotypic analyses. Consideration should also be given to characterizing the capacity of xenobiotic metabolism across cell lines for screening a range of chemicals. Panels may include patient-derived cells, such as iPS cells, for characterizing chemical responses with respect to human disease or gene-edited cell lines to characterize toxicity responses with respect to specific disease gene variants. Human cell panels should reflect genetic variation commonly found in human populations.
• Collections of genetically diverse model organisms for toxicology testing that may include, but are not limited to, zebrafish, killifish, Medaka, C. elegans, D. melanogaster, and Daphnia. Strong rationale should be provided on the biological relevance of response pathways in these organisms to response pathways in humans. Panels should have sufficient genetic diversity to assess population dynamics.
• Further development and application of rodent population models for toxicology testing, including the generation of cell lines from these rodent panels for more rapid in vitro testing and characterization of toxicants.
• Approaches to further characterize rodent population models with respect to toxicokinetics, metabolism, and transport functions across multiple tissues.
• Organotypic culture models (OCM) developed from human cells or from cells from experimental animals with diverse genetic backgrounds to assess toxicity responses. Requirements for xenobiotic metabolism should be considered in developing genetically diverse OCM panels.
• Population-based models that measure epigenetic variation in variable response in toxicity studies.
Additional Considerations
The goal of this FOA is to enhance the capability of introducing genetic diversity in toxicity testing. Development of resources and technologies should take into account cost and throughput when applying these approaches to toxicity screening programs, as well as the benefit of identifying adverse responses in susceptible individuals or subpopulations. A combination of in vitro and in vivo approaches may be considered in developing an approach for screening and characterizing chemical responses across diverse genetic backgrounds. Toxicity measures for in vitro assays, including combinations of functional and cytotoxicity assays, should reflect key physiological changes in vivo following chemical exposures. Technologies that lower the cost of screening, particularly for in vivo studies, are encouraged to stimulate the adoption of genetic diversity resources in routine toxicity screening efforts. For approaches using genetically diverse model organisms, applicants should provide a detailed explanation of how results from these models will ultimately inform variability in response to toxicants in human populations.
Applicants should propose test chemicals or compounds that are relevant for developing and applying genetic diversity resources and provide a rationale for the proposed dose ranges in these studies. Applicants should propose to test chemicals or compounds for which relevant toxicity data already exists, and toxicity measures should reflect key physiological changes following chemical exposure. Applicants are expected to include appropriate controls for meaningful interpretation of the results. Proposed panels or resources must include sufficient genetic diversity to assess population dynamics in chemical toxicity testing, and applicants should provide the appropriate power calculations or statistical analyses to demonstrate the ability to detect G x E effects or variation in susceptibility with the proposed number of cell lines or model organisms.
Applicants should provide clear, measurable goals (milestones), particularly for Phase I applications and Phase I components of Fast-track applications.
Responsiveness
Research projects must include chemical testing in the development and application of resources for expanding genetic diversity in screening approaches. Applications that propose small numbers of cell lines or animal models without screening an appropriate set of test chemicals will be considered non-responsive to this FOA.
