PRINCIPLES FOR THE SELECTION OF DOSES IN CHRONIC RODENT BIOASSAYS

Dose selection in chronic rodent bioassays has been one of the most de bated issues in risk assessment. The Committee on Risk Assessment Meth ods of the National Research Council attempted but failed, in 1993 to reach consensus on how to select doses for chronic rodent bioassays. H owever, a more recent effort conducted by the ILSI Risk Science Instit ute has resulted in a consensus set of principles for dose selection, including selection of the highest dose for chronic rodent bioassays. The principles encourage a move away from sole reliance on a maximum t olerated dose (MTD), as it has been traditionally defined (primarily b y body weight and histopathology), and toward the use of sound scienti fic and toxicologic principles for the selection of all doses in the c hronic bioassay. Specifically, the principles recommend that dose sele ction for chronic studies must be based on sound toxicologic principle s; dose selection should consider human exposure; dose selection shoul d be based on a variety of endpoints and effects derived from prechron ic studies; and dose selection should consider physicochemical and oth er factors. Implementation of the principles internationally will have two important benefits: improvement in the quality and consistency of the rodent bioassay and international harmonization of dose selection procedures.