Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet

• Published in: Food and chemical toxicology 2004, Vol.42 (1), p.65-83
• Main Authors: Kroes, R, Renwick, A.G, Cheeseman, M, Kleiner, J, Mangelsdorf, I, Piersma, A, Schilter, B, Schlatter, J, Schothorst, F. van, Vos, J.G
• Format: Article
• Language: English
• Subjects: acceptable daily intake; Animals; Biological and medical sciences; carcinogenicity; Carcinogens - toxicity; chemical substances; Decision Trees; Diet; Endocrine Glands - drug effects; Food - toxicity; Food Hypersensitivity; food intake; food safety; Food toxicology; guidelines; health effects assessments; Humans; Medical sciences; Metabolism; neurotoxicity; No-Observed-Adverse-Effect Level; Pharmacokinetics; Risk Assessment; safety testing; Structure-Activity Relationship; teratogenicity; toxic substances; toxicity testing; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2003.08.006

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related t