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Evaluation of Variability Across Rat Acute Oral Systemic Toxicity Studies
Citation:
Karmaus, A., K. Mansouri, K. To, B. Blake, J. Fitzpatrick, J. Strickland, G. Patlewicz, D. Allen, W. Casey, AND N. Kleinstreuer. Evaluation of Variability Across Rat Acute Oral Systemic Toxicity Studies. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 188(1):34-47, (2022). https://doi.org/10.1093/toxsci/kfac042
Impact/Purpose:
As the field of toxicology moves toward the development of new approach methodologies (NAMs) that do not require the use of laboratory animals, there is an inherent need for fully characterized reference test data against which NAMs can be compared. For acute oral toxicity, rodent LD50 values serve as the primary reference comparator, and therefore it is important to compile a resource of in vivo reference data and to characterize the variability of these values based on independently conducted studies for the same test substances. Simply put, a solid understanding of the reproducibility and inherent variability of the rat in vivo acute oral toxicity assays will provide a foundation to contextualize results and set expectations regarding NAM performance.
Description:
Regulatory agencies rely upon rodent in vivo acute oral toxicity data to determine hazard categorization, require appropriate precautionary labeling, and perform quantitative risk assessments. As the field of toxicology moves toward animal-free new approach methodologies (NAMs), there is a pressing need to develop a reliable, robust reference data set to characterize the reproducibility and inherent variability in the in vivo acute oral toxicity test method, which would serve to contextualize results and set expectations regarding NAM performance. Such a data set is also needed for training and evaluating computational models. To meet these needs, rat acute oral LD50 data from multiple databases were compiled, curated, and analyzed to characterize variability and reproducibility of results across a set of up to 2,441 chemicals with multiple independent study records. Conditional probability analyses reveal that replicate studies only result in the same hazard categorization on average at 60% likelihood. Although we did not have sufficient study metadata to evaluate the impact of specific protocol components (e.g., strain, age, or sex of rat, feed used, treatment vehicle, etc.), studies were assumed to follow standard test guidelines. We investigated, but could not attribute, various chemical properties as the sources of variability (i.e., chemical structure, physiochemical properties, functional use). Thus, we conclude that inherent biological or protocol variability likely underlies the variance in the results. Based on the observed variability, we were able to quantify a margin of uncertainty of ± 0.24 log10 (mg/kg) associated with discrete in vivo rat acute oral LD50 values.
URLs/Downloads:
DOI: Evaluation of Variability Across Rat Acute Oral Systemic Toxicity Studies
https://pubmed.ncbi.nlm.nih.gov/35426934/