Modulation of toxicity by diet and dietary macronutrient restriction.
Restriction of diet and macronutrients has been reported to modulate the toxicity of numerous chemical agents. Of the various forms of restriction studied, using nutritionally adequate diets, food restriction (FR) appears to be most effective, but protein restriction (PR), fat restriction (FtR), carbohydrate restriction (CbR), and excess of dietary fiber (FE) also affect toxicity and the spontaneous diseases that define the background incidence in toxicity tests. The heterogeneity of the dietary macronutrients complicates simple analysis of their effects. Additionally, the interrelationships between these various components in the complex dietary mixture often make experiments difficult to interpret. Despite these complexities, a simple model is presented, which considers the effects of dietary manipulations on the individual steps in the interaction of organism and agent, and puts the varied effects that can occur within an organism into context. Ultimately, many of the effects of dietary modulation on these steps in toxicogenesis can be considered as changing agent exposure and the biologically available dose. The effects of macronutrient restriction are discussed in terms of effects on agent at the interface of organism and toxicant, agent disposition, agent metabolism, and repair of toxicant-induced damage at the level of the genome. After illustrating the influence of these nutritional effects on the chronic bioassay, using mouse liver tumors as an example, the significance of these effects for chronic and short-term testing is discussed. Additionally, methods to address the impact of nutritional factors on toxicity testing are suggested.