1. Food Advisory Committee Meeting December 16 and 17, 2014 Questions to the Committee Suzanne C. Fitzpatrick, PhD, DABT Senior Advisory for Toxicology Center for Food Safety & Applied Nutrition

2. Background In administering the pertinent provisions of the Federal Food, Drug, and Cosmetic Act, the Foods Program’s Center for Food Safety and Applied Nutrition and Center for Veterinary Medicine need to ensure that their chemical assessments and any resulting risk management decisions protect all affected human populations to the extent feasible and consistent with the applicable statutory standard. The Foods Program requests guidance from its Food Advisory Committee on how to integrate scientific considerations for susceptible populations into its risk assessment procedures and methodologies, including under what conditions a separate risk assessment should be conducted.

3. 1. When conducting a risk assessment: – What are the most important susceptibility factors to consider when determining whether a certain segment of a population could be considered more (or less) susceptible to the effects of a chemical? – What data and level of confidence in the data are needed to initiate the development of a separate risk assessment for the subpopulation(s) determined to be susceptible? Is an epidemiologic study or animal bioassay that reports quantitative results showing an association between exposure and effects for susceptible individuals sufficient? What additional types of data should be considered? How should data that cannot be quantified be considered and weighted? Should different types of data be weighted differently?

4. 2 a. Are these appropriate questions to be considered in the problem formulation, planning, and scoping phases? Are there specific subpopulations or life stages of particular concern? Are some exposure routes or durations of particular concern to specific populations? How will exposures of the populations of interest be estimated? What are the quality and quantity of data available to identify whether or not subpopulations are disproportionately susceptible? How can the assessment be used to support decisions regarding susceptible populations? What additional questions should be considered?

5. 2 b. What additional areas of expertise should be considered? Examples of expertise needed on a risk assessment team could include: Toxicologists Epidemiologists Physicians Exposure assessors

6. 3. What are the mechanisms to ensure that relevant outcomes are identified, considered, and prioritized for different susceptible populations? For example- NRC (2014b), in its review of EPA’s Integrated Risk Information System, recommends conducting a systematic review to identify, evaluate, and integrate evidence from the literature regarding those outcomes that are of greatest significance, including for susceptible populations.

7. 4.How do differences in outcome latency and outcome development influence consideration of susceptibility factors in assessing whether a particular subpopulation is differentially susceptible? What types of studies are needed to address such differences? For example, there can be latent effects that do not present clinically for years to decades after exposure, such as carcinogenesis, cognitive deficits, and endocrine disruption. Other effects can be transient, such as some peripheral neuropathies.

8. 5. For potential departures from use of the established intraspecies factor of 10 in risk assessments, what criteria need to be considered? There has been considerable debate surrounding the use of this default uncertainty factor and its adequacy in accounting for susceptible populations. Efforts to evaluate the scientific basis of this uncertainty factor have focused on evaluating inter-individual variability in healthy adult populations or by considering the sensitivity of specific subsets of the population thought to be particularly susceptible (Martin et al. 2013).

9. 6.Should FDA consider adopting defined life stages into recommendations it may develop on susceptible subpopulations? If so, what relevant issues should be considered in defining these life stages? What should these stages be?