Chlorpyrifos Protects

Although EPA determined at the start of registration review in 2009 that the database of information on chlorpyrifos was largely complete, new testing was required in several areas to meet evolving regulatory guidelines and to supplement regulatory requirements. Chlorpyrifos registrants have conducted new toxicology studies, providing new data for the Agency’s consideration and its estimates of potential effect levels. Initial consideration of these studies has been incorporated into the EPA’s preliminary human health assessment for chlorpyrifos registration review, and a summary of proposed revisions in EPA’s health standards is available.

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 (known as the 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 the NOEL was selected based on the single study showing the most sensitive results. As a result, data from other available studies was not fully utilized. The Benchmark Dose Modeling approach for chlorpyrifos has been effectively applied to make better use of all available studies supporting EPA’s registration review.

Age-Related Sensitivity

EPA is required as per the Food Quality Protection Act (FPQA) to determine potential differences in sensitivity to exposures between immature and mature individuals. Evaluation of findings from a recently-completed comparative cholinesterase assay (CCA) study has provided the Agency with specific information on biological responses to chlorpyrifos exposure to immature and mature organisms, and allowed 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; EPA believes 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.

Further Resources

Marty, M.S. et al. “Cholinesterase inhibition and toxicokinetics in immature and adult rats after acute or repeated exposures to chlorpyrifos or chlorpyrifos-oxon.” Regulatory Toxicology and Pharmacology, 2012, Volume 63(2): 209-224
http://www.sciencedirect.com/science/article/pii/S0273230012000621

Reiss, R. et al. “Acetylcholinesterase inhibition dose-response modeling for chlorpyrifos and chlorpyrifos-oxon.”Regulatory Toxicology and Pharmacology, 2012, Volume 63(1):124-131.
http://www.sciencedirect.com/science/article/pii/S0273230012000554

Price, P.S. et al. “Application of a source-to-outcome model for the assessment of health impacts from dietary exposures to insecticide residues.”, Regulatory Toxicology and Pharmacology, 2011, Volume 61(1): 23-31.
http://www.sciencedirect.com/science/article/pii/S027323001100105X