Innovative Designs and Practices for Acute Systemic Toxicity Studies

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Abstract
Over 4 yr, 124 acute systemic toxicity studies (64 oral, 39 dermal and 21 inhalation) were conducted, altering study and program design with the objectives of maximizing information while minimizing animal usage. By employing dose selection strategies, probes, lethality limits instead of LD50, staggered sequential dosing and by conducting studies in batteries, animal usage was reduced by 48% below the average number currently quoted as necessary for an LD50 study. Simultaneously, use of a neurobehavioral screen, adjunct studies and a flexible study design led to a significant upgrading in the information generated by these studies. The use of a decision tree approach for selecting tissues for histopathology was developed. The use of specific indicators (such as organ weights) for selecting organs for microscopic examination was also evaluated. Significantly more information was generated by studies utilizing fewer animals than that in common practice.

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