Information needed to support hazard identification and risk assessment of toxic substances

Today pharmacokinetic data are not routinely required for food safety evaluation. The new Red Book, the Center's outline of animal testing protocols, does suggest some pharmacokinetic studies, but their use is still limited. Primarily this is because of our current reliance on animal studies only and the use of safety factors (SFs) to bridge the human to animal response. But the situation is changing and the role of pharmacokinetics and physiologically based pharmacokinetic modeling will probably increase for several reasons. (1) The increasing role of quantitative risk assessment and regulations acknowledging and permitting some level of risk. This places a demand of greater quantitation of risk and emphasizes the need for better measurement of effective dose. We made need to consider more carefully the possible nonlinear pharmacokinetic effects in high-to-low dose extrapolation. (2) The increasing need to understand more about a chemical's mechanism of action prior to a major corporate commitment. The increasing cost of mistakes in judgement regarding a chemical's prospects in the commercial and regulatory arena are demanding a better and deeper understanding of possible toxic effects. (3) The increasing desire to expand the use of a successful additive beyond the spectrum of the uses covered in the original approval. This usually means the request for a higher ADI. This must be based on more refined toxicity testing and better estimate of effective dose in order to permit the reduction of the SF. (4) The advent of novel foods for which conventional toxicological methods are inappropriate. For example, noncaloric fat substitutes that may comprise a large portion of the daily diet cannot adequately be tested in conventional animal studies. The doses cannot be exaggerated enough to permit a large enough SF. These substances may well require human clinical investigations similar to those used for drugs.