Diet: the neglected variable in chemical safety evaluations.

Abstract

The objectives of this review are to alert the community of toxicologic pathologists to the types and significance of various diets fed to experimental animals used in safety evaluations of drugs and other chemicals, to acquaint investigators with dietary nutrients and contaminants of significance to research animals, to review some of the consequences of improper or inadequate diets on results of safety evaluations, and, finally, to offer a brief introduction to a highly promising new digital specimen technology for evaluating histopathology of tissues from animals used in safety evaluations with the aid of computers. Results that form the basis for this review have accumulated for more than 4 decades during research conducted during appointments at the University of Missouri, Columbia; Auburn University; Massachusetts Institute of Technology; and Boston University School of Medicine. The methods used in these studies have generally been state-of-the-art at the time the studies were conducted and involved an integration of techniques and methods used in fundamental nutrition, toxicology, and experimental pathology. Some of these investigations have shown that contaminants, naturally occurring and man-made, intentional and nonintentional, do occur in commercial animal diets; that essential nutrients, including total calories, protein and fat, can be provided in less or more than adequate amounts for the species of animal used in safety evaluations; and that such variables can influence responses to chemicals through effects on xenobiotic metabolism, immunocompetence, secondary diseases, and other factors. Under such conditions, serious differences in final interpretation of human risk for a drug or other chemical can contribute to failure to gain approval for a potentially valuable therapeutic agent. This review discusses the significance of various dietary components with examples of their effects on response of the animal to chemicals and demonstrates why nutrients, new technologies for assessing their effects, and other components in the diet should be accorded greater consideration by investigators and regulators.