Food ingredient safety evaluation: Utility and relevance of toxicokinetic methods

The use of toxicokinetic (TK) data is becoming more prevalent in the evaluation of food ingredient safety as more TK information is being incorporated in safety data packages. Data demonstrating 1) the extent of absorption, 2) tissue distribution, 3) pathways and rates of metabolism, and 4) rate(s) of elimination of food ingredients and their metabolites of intermediate and high toxicological potential may be useful for planning and designing toxicity studies, selecting doses for toxicity studies, addressing species differences, and understanding the potential modes of action to evaluate their safety. TIC data reported in the literature or generated from mechanistic TK studies can be analyzed using mathematical methods, including compartment and noncompartment TK methods, whose predictions can enhance interpretation of observed effects. Because of recent advancements, several approaches have been developed to improve sensitivity of analyses of available TK data and reduce uncertainty for evaluating safety of food ingredients. An example of advanced TK methods is physiologically-based TIC (PBTK) modeling that incorporates physiological/biochemical parameters into a TIC framework to predict internal exposure. In this review, we discuss the utility of some TIC methods and explore their relevance and potential value for food ingredient safety evaluation. We also describe the strengths and limitations of these TIC methods and discuss current challenges and opportunities for expanding their application for evaluating safety of food ingredients. This review represents a state of science report, and not a guidance document, on the utility and relevance of TK methods for the safety evaluation of food ingredients.