The Threshold of Toxicological Concern (TTC) in risk assessment

Abstract

The Threshold of Toxicological Concern (TTC) is a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data. The TTC approach is a form of risk characterisation in which uncertainties arising from the use of data on other compounds are balanced against the low level of exposure. The approach was initially developed by the FDA for packaging migrants, and used a single threshold value of 1.5 μg/day (called the threshold of regulation). Subsequent analyses of chronic toxicity data resulted in the development of TTC values for three structural classes with different potentials for toxicity (1,800, 540 and 90 μg/day). These TTC values have been incorporated into the procedure that is used internationally for the evaluation of flavouring substances. Further developments included additional TTC values for certain structural alerts for genotoxicity (0.15 μg/day), and for the presence of an organophosphate group (18 μg/day). All of these TTC values were incorporated into an extended decision tree for chemicals, such as contaminants, which might be present in human foods. The TTC approach has been shown to have potential applications to risk assessments of cosmetic ingredients, household products and impurities in therapeutic drugs.

Introduction

Humans are exposed daily to increasing numbers of chemicals from food, cosmetics, household products, medicines and the environment. Extensive safety data exist for some of these chemicals, but for others only limited data are available currently. Nevertheless, risk assessment for all chemicals is necessary to ensure that the health of the population is not adversely affected. Intentional addition of chemicals to food without adequate safety assessment is not acceptable; however, the generation of substance-specific toxicity data on the thousands of chemicals that may be present at low levels in food, due to migration from packaging or the use of flavouring substances, is not feasible in the near future. Thus, a rigorous, scientifically sound, and practical approach is necessary to allow risk characterisation of the myriad of chemicals to which humans are exposed.

For individual chemicals with known toxicological profiles, there are established procedures for determining levels of exposure without significant health risks to humans. For non-genotoxic chemicals a conventional toxicological safety evaluation relies on the identification of the highest dose level, usually derived from animal toxicity studies, at which the most sensitive adverse effect does not occur, and application of an adequate margin of safety to determine a level of exposure that is likely to be safe in humans.

The Threshold of Toxicological Concern (TTC) approach is based on the concept that reasonable assurance of safety can be given, even in the absence of chemical-specific toxicity data, providing that the intake is sufficiently low, i.e. that an exposure level can be defined below which there is no significant risk to human health (JECFA, 2006). The approach is based on the knowledge gained from the general toxicity database that has been developed in the past 50–60 years. The TTC approach is a form of risk characterisation that balances uncertainties inherent in extrapolation of these data to an unstudied substance against the predicted or known low level of exposure.