Ethical and Scientific Considerations for Minimizing Animal Species in Pesticide Toxicity Studies: Implications for Acceptable Daily Intake Determination

Background Pesticide residues in agricultural products pose potential human health risks, prompting regulatory agencies to establish acceptable daily intake (ADI) values based on the no-observed (adverse) effect level (NO(A)EL) derived from animal toxicity studies. Current regulatory guidelines mandate toxicity testing in two mammalian species, typically a rodent (rat or mouse) and a non-rodent (usually dog), to assess chemical safety. However, this two-species testing paradigm faces increasing scrutiny from both animal welfare advocates and toxicologists questioning its scientific necessity. This retrospective analysis examined toxicity data from 58 registered pesticides to identify which animal species contributed NO(A)ELs for ADI establishment. Results The analysis revealed that ADIs were predominantly derived from combined chronic toxicity/carcinogenicity studies in rats (typically 2-year studies) and 1-year chronic toxicity studies in dogs. Notably, across 61 toxicity studies reviewed, 90-day subacute toxicity studies in mice contributed no NO(A)ELs for ADI derivation. Our results suggest that 90-day repeated-dose toxicity studies in mice provide no additional safety information beyond that obtained from rat and dog studies for pesticide ADI setting. Conclusion While rats are typically used for 90-day studies to characterize hazards and establish doses for chronic studies, and dogs provide complementary non-rodent data, mice in 90-day studies appear redundant for this regulatory purpose. This evidence supports eliminating 90-day mouse toxicity studies as a mandatory data requirement for pesticide ADI establishment, potentially reducing animal use by several hundred mice per pesticide evaluation while maintaining the scientific rigor necessary for human health protection.