Reducing the need for animal testing while increasing efficiency in a pesticide regulatory setting: Lessons from the EPA Office of Pesticide Programs' Hazard and Science Policy Council.

As part of EPA's commitment to reducing animal testing, the Office of Pesticide Programs (OPP) created the Hazard and Science Policy Council (HASPOC). This group considers requests for waiving animal study requirements for human health risk assessments and makes recommendations based on a weight-of-the-evidence approach. Since its inception in 2012, the HASPOC has evaluated over one thousand requests to waive animal studies required by default for pesticide evaluation. Here, the number of studies waived, and the types of studies represented were analyzed to determine the impact of the HASPOC decisions in terms of animal and monetary savings. Overall, the waiving of studies by HASPOC resulted in over 200 thousand animals saved. There were also savings of over $300 million in study costs and over $6 million in study review costs as well as less time spent in study processing and review by EPA staff. Thus, the HASPOC has built significant efficiencies into the risk assessment process while continuing to protect human health.

A retrospective analysis of toxicity studies in dogs and impact on the chronic reference dose for conventional pesticide chemicals.

Prior to October 2007, the US Environmental Protection Agency (EPA) required both 13-week and 1-year studies in Beagle dogs be submitted in support of registration for pesticides. Following an extensive retrospective analysis, we (the authors) determined that the 1-year toxicity dog study should be eliminated as a requirement for pesticide registration. The present work presents this retrospective analysis of results from 13-week and 1-year dog studies for 110 conventional pesticide chemicals, representing more than 50 classes of pesticides. The data were evaluated to determine if the 13-week dog study, in addition to the long-term studies in two rodent species (mice and rats), were sufficient for the identification of no observed adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) for the derivation of chronic reference doses (RfD). Only pesticides with adequate 13-week and 1-year duration studies were included in the present evaluation. Toxicity endpoints and dose-response data from 13-week and 1-year studies were compared. The analysis showed that 70 of the 110 pesticides had similar critical effects regardless of duration and had NOAELs and LOAELs within a difference of 1.5-fold of each other. For the remaining 40 pesticides, 31 had lower NOAELs and LOAELs in the 1-year study, primarily due to dose selection and spacing. In only 2% of the cases were additional toxic effects identified in the 1-year study that were not observed in the 13-week study and/or in the rodent studies. In 8% of the cases, the 1-year dog had a lower NOAEL and/or LOAEL than the 13-week study, but there would have been no regulatory impact if the 1-year dog study had not been performed because adequate data were available from the other required studies. A dog toxicity study beyond 13-weeks does not have significant impact on the derivation of a chronic RfD for pesticide risk assessment.

The use of developmental neurotoxicity data in pesticide risk assessments.

Following the passage of the Food Quality Protection Act, which mandated an increased focus on evaluating the potential toxicity of pesticides to children, the number of guideline developmental neurotoxicity (DNT) studies (OPPTS 870.6300) submitted to the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) was greatly increased. To evaluate the impact of available DNT studies on individual chemical risk assessments, the ways in which data from these studies are being used in pesticide risk assessment were investigated. In addition, the neurobehavioral and neuropathological parameters affected at the lowest observed adverse effect level (LOAEL) for each study were evaluated to ascertain whether some types of endpoints were consistently more sensitive than others. As of December 2008, final OPP reviews of DNT studies for 72 pesticide chemicals were available; elimination of studies with major deficiencies resulted in a total of 69 that were included in this analysis. Of those studies, 15 had been used to determine the point of departure for one or more risk assessment scenarios, and an additional 13 were determined to have the potential for use as a point of departure for future risk assessments (selection is dependent upon review of the entire database available at the time of reassessment). Analysis of parameters affected at the study LOAELs indicated that no single parameter was consistently more sensitive than another. Early assessment time points (e.g., postnatal day (PND) 11/21) tended to be more sensitive than later time points (e.g., PND 60). These results demonstrate that data generated using the current guideline DNT study protocol are useful in providing points of departure for risk assessments. The results of these studies also affirm the importance of evaluating a spectrum of behavioral and neuropathological endpoints, in both young and adult animals, to improve the detection of the potential for a chemical to cause developmental neurotoxicity.