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Qualitative and Quantitative Variability of Repeat Dose Animal Toxicity Studies (Health Canada 2024)
Citation:
Friedman, K. Qualitative and Quantitative Variability of Repeat Dose Animal Toxicity Studies (Health Canada 2024). Webinar for Health Canada Modernized Approaches to Risk Sciences Working Group, online, CANADA, January 17, 2024. https://doi.org/10.23645/epacomptox.24937140
Impact/Purpose:
This presentation will be given to the Health Canada Modernized Approaches to Risk Sciences Working Group. The slides detail work that has been published in its entirety. The slides were also previously cleared in their exact form in advance of presentation to the 2023 Society of Toxicology meeting. The work herein provides additional data-informed benchmarks for new approach method (NAM) performance related to the qualitative and quantitative reproducibility of organ-level effects in vivo in studies used for regulatory toxicology. Organ-level effects were examined as a means of grouping biological findings in the absence of mechanistic information that would enable mapping to specific adverse outcome pathways. The understanding that a prediction of an in vivo systemic effect level, for an organ or for a study, within approximately ± 1 log10-mg/kg/day would demonstrate a very good NAM is important for the acceptance of NAMs for chemical safety assessment. Further, qualitative concordance of biological effects between NAMs and animal studies may range widely, not only due to the variable concordance among animal studies but also because animal studies may demonstrate greater negative predictive value for human effects. In terms of modeling approaches, and alternatives to repeat dose toxicity testing, it is likely that subchronic and chronic study data for existing chemicals can be combined to develop repeat-dose point of departure (POD) predictions, which could be adjusted to be more or less conservative in the POD prediction. Finally, this work provides an important contribution to the field in terms of understanding how construction of NAM-based POD estimates may offer equivalent levels of public health protection as the PODs produced by animal methods.
Description:
This work estimates benchmarks for new approach method (NAM) performance in predicting organ-level effects in repeat dose studies of adult animals based on variability in replicate animal studies. Treatment-related effect values from the Toxicity Reference database (v2.1) for weight, gross, or histopathological changes in the adrenal gland, liver, kidney, spleen, stomach, and thyroid were used. Please see our recent publication: https://doi.org/10.1016/j.comtox.2023.100287. In brief, our findings suggest the following: (1) variance explained by study metadata was similar for organ and study findings (52-69%); (2) the odds of a chronic study organ effect were <1 if no organ findings were observed in a subchronic study; (3) mean differences in lowest effect level by exposure duration were similar in size to replicate study variance (approaching 0.5 log10-mg/kg/day); and (4) mean differences in organ lowest effect levels and extrapolated administered equivalent doses approached 0.5 log10-mg/kg/day with larger differences observed for some chemicals. This abstract does not reflect U.S. EPA policy.
URLs/Downloads:
DOI: Qualitative and Quantitative Variability of Repeat Dose Animal Toxicity Studies (Health Canada 2024)
PAULFRIEDMAN_QUALQUANT_VAR_REPEAT_DOSE_WEBINAR_HC_MARS_17JAN2024.PDF (PDF, NA pp, 1839.114 KB, about PDF)