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

Abstract

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.

Keywords::

• Animal testing
• dog toxicity studies
• health-based reference values
• pesticide chemicals
• retrospective analysis

Acknowledgements

We would like to thank Dr. Karl Baetcke who retired from the Office of Pesticide Programs in 2004 and who led the first analysis of the dog toxicity studies. We would like to thank Drs. Whang Phang and Esther Rinde from the Office of Pesticide Programs for their contributions to the paper. We are also grateful to Dr. Douglas Wolf of EPA’s Office of Research and Development for his review of the manuscript.

Declaration of interest

All of the authors are employees of the US EPA, Office of Pesticide Programs. The authors carried out this work as a normal part of their official government duties. This work summarizes a more extensive analysis that was used in support of decisions regarding dog toxicity testing studies by the US EPA in updating its data requirements in part 158 of Title 40 in the Code of Federal Regulations for the registration of conventional pesticide products. The authors have sole responsibility for the writing and content of the paper, which may not necessarily reflect the views of the US EPA.