Traditional toxicological procedures have only limited application to the safety assessment of macronutrient substitutes. Experience indicates that spurious effects are often encountered when macronutrients or their replacements are fed to rodents at high dietary levels. These effects may result in nutritional imbalances that lead secondarily to adverse physiological consequences including cancer, renal disease, or reproductive effects. In approaching the safety assessment of macronutrient substitutes, consideration needs to be given to designing and implementing a safety assessment program which acknowledges the physical, chemical, and biological properties of the substance. Factors such as molecular size, physical state, solvent properties, hydrolysis potential, digestibility, absorption potential, and metabolic fate must be well established prior to selection of appropriate test models. Armed with this information, many potential undesirable physiological effects of the substances can be predicted, thus precluding the need for a full spectrum of animal testing. Predicted physiological and metabolic effects, however, should be characterized using in vitro methods and confirmed with in vivo models. Initial short-term toxicity screening tests with rodents should be carried out to identify unanticipated systemic toxicity. Testing in laboratory animals and trials in humans should then proceed with more appropriate models that are specially selected to assess the significance of predicted outcomes, to characterize dose-response relationships, and to identify possible needs to modify the product to mitigate adverse physiological consequences. These might include physical changes to alter particle size, chemical changes to modify digestibility, or nutrient supplementation to overcome impacts on nutrient availability. Thoughtful selection of appropriate and relevant models based on the physical, chemical, and biological properties of test substances will provide more rational approaches to safety assessments and avoid the pitfalls of routine application of traditional tests. (C) 1996 Academic Press, Inc.
