Innovative designs and practices for acute systemic toxicity studies.

Over a four year period our laboratory has conducted 124 acute systemic toxicity studies (64 oral, 39 dermal, and 21 inhalation), altering study and program designs with the objectives of maximizing information while minimizing animal usage. By employing dose selection strategies, probes, lethality limits instead of LD50's, 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 have led to a significant upgrading in the information generated by these studies. Additionally, 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. Our efforts demonstrate that significantly more information can be generated by studies utilizing fewer animals than is now common practice.