# Charge Questions

FIFRA Scientific Advisory Panel (SAP) on Integrated Approaches to Testing and Assessment Strategies: Use of New Computational and

Molecular Tools

May 24 -26, 2011 1

# OPP’s Strategic Vision

# OPP’s Strategic Vision – Question 1

• Does the Panel believe that OPP’s strategic vision clearly articulates a sound scientific basis to making the risk assessment process more efficient and informative?
• To what extent have we described the critical components ( i.e., knowledge bases and databases of existing information, predictive tools ( e.g., (Q)SAR, in -vitro methods, HTS assays and AOPs) and the progression of events ( i.e., research and the use of research) to support the evolution from the current testing and assessment paradigm to an improved IATA of targeted tiered testing based on an understanding of AOPs ( i.e., the molecular and cellular events leading to adverse effects at the whole organism level)?
• Are there any key science issues that the Agency has not captured that are necessary elements to consider in an IATA approach?

# OPP’s Strategic Vision – Question 2

• Given that there could be hundreds of AOPs and that varying levels of AOP information are needed depending on the decision being made ( i.e., the tier of the risk assessment), please discuss principles for scientific acceptance ( i.e., tools for gauging the reliability and robustness) of AOPs and the use of AOPs to move away from chemical by chemical approaches.

• OPP plans to evaluate new tools and information using available criteria and methods such as the OECD principles for (Q)SAR expert systems and the EPA IPCS (International Programme on Chemical Safety) mode of action framework. Please discuss these and other criteria the Agency can use to reliably integrate predictive tools earlier in the process.

• How can the foundation of knowledge generated through historical and on - going reductionist ( i.e., making use of information from lower levels of biological organization to understand adverse outcomes), hypothesis - driven, biological experimentation be effectively mined and integrated with the capabilities of omics (including toxicogenomics, transcriptomics, proteomics, and metabolomics) and high -throughput screening to speed the discovery and development of AOPs and their subsequent acceptance as a credible foundation for predictive risk assessment?

# OPP’s Strategic Vision – Question 3

• OPP is at the beginning stages of contemplating metrics to demonstrate success in achieving our vision. What is the Panel’s initial thinking regarding the concepts, considerations, and factors OPP should take into account as we evaluate our progress?

• What methodologies are best suited to measure success in achieving our vision? For example, what methods would you recommend to quantify the development of AOPs and the qualitative and quantitative application of AOPs in risk assessment?

# Integration of Toxicogenomic Technology



# to Inform Risk Assessment Propiconazole Case Study

# Toxicogenomic Case Study – Questions

1. Please comment on the use of omic and related technologies employed to develop and link Key Events to create the MOA/AOP of propiconazole. Was the resultant MOA/AOP for propiconazole logical and scientifically sound? 2. Are there other approaches/technologies that could be used to develop and link Key Events to develop MOAs/AOPs for propiconazole and/or chemicals? 3. Please comment on the general utility of AOPs/MOAs or Key events to read across chemicals to provide a more defensible weight of evidence support for the traditional risk assessment approaches that OPP will continue to use in the near- and mid - term? 4. Please comment on the potential use of omic and related technologies to inform AOPs in non - mammalian taxa for use in ecological risk assessment?

# Use of Adverse Outcome Pathway (AOP) to



# Inform Risk Assessment Triclosan Case Study

# AOP Case Study - Questions 1 & 2

• Use of the adverse outcome pathway concept to characterize the impact of triclosan on the thyroid hormone system promotes a research and risk focus on toxicodynamic and kinetic differences in thyroid homeostasis between (1) the study species (e.g.., rats) and the population of interest (e.g., pregnant women/fetus and young children) and (2) potential species similarities and/or differences in the molecular initiating events. Please comment on scientific knowledge and types of data considered to be informative in selecting appropriate factors for interspecies differences.

• Please comment on the factors most responsible for the variability of toxicokinetics and toxicodynamics of compounds affecting thyroid hormone homeostasis among humans (particularly susceptible subpopulations such as pregnant women and children). May 24 -26, 2011 9

# AOP Case Study - Question 3

• Benchmark dose analysis involves selection of a benchmark response (BMR). The consequences of a perturbation of a key event depend on the magnitude, timing, and duration of the perturbation, which in turn depends on dose. Subtle perturbations of key events may be damped out and have little effect on downstream biology due to the operation of homeostatic processes. Please comment on the current understanding of the magnitude of perturbation of thyroid hormone levels in humans that may be required to lead to adverse outcomes.

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