New Ways of Reducing Uncertainty
When EPA lacks data, the Agency may be compelled to make highly precautionary decisions to account for uncertainties in their assumptions. In some cases, the conservatism can be magnified from one assumption to the next until the regulatory model no longer resembles real world events.
With chlorpyrifos, however, the database is data-rich from many years of extensive study, including availability of new data. This allows EPA to use more refined methods and techniques, including the following:
Benchmark Dose Modeling
New statistical modeling techniques are available to evaluate data across all available studies and identify with greater accuracy the internal dose required to produce a biological response (regulatory endpoint for safety evaluations). The Benchmark Dose Modeling approach results in more accurate determination of the “point of departure” or dose below which no biological effect is anticipated. In the past, data had to be analyzed on a study-by-study basis using the old “No Observable Effect Level” approach and as a result many of the available studies were not fully utilized.
Age-Related Sensitivity Assessment
EPA is required as per the Food Quality Protection Act to determine potential differences in sensitivity to exposures between immature and mature individuals. Evaluation of findings from the recently completed comparative cholinesterase assay (CCA) study will now provide the Agency with specific information on biological responses to chlorpyrifos exposure to immature and mature organisms, and allow estimation of the appropriate uncertainty factor for consideration of age-related differences in sensitivity. In the past, a standard FQPA uncertainty factor of 10X was applied to assessments in the absence of such data, but it may now be appropriate to reduce this factor based on the availability of new data.
Source-to-Outcome Modeling
Based on availability of chlorpyrifos metabolism data from animal studies as well as human tissue and human volunteer studies, a state-of-the-art model following disposition and effects of chlorpyrifos following dietary exposures has been developed. The model simulates processes such as absorption, enzymatic detoxification, excretion, and blood cholinesterase inhibition so as to better characterize person-to-person variability across the human population. In the past, a standard uncertainty factor of 10X was applied to assessments as a default to account for individual differences, but the source-to-outcome modeling approach allows a more specific determination of this variability to be made. The source-to-outcome model for chlorpyrifos was reviewed by EPA’s Scientific Advisory Panel during February of 2011.
