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 EPAIPCS (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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