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

Abstract

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 to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxi...

Emerging contaminants in surface waters and their relevance for the production of drinking water in Europe

“…These benchmarks are derived from toxicity data. Examples of such benchmarks are the acceptable daily intake (ADI), provided by the World Health Organisation (World Health Organisation 2006), and the Threshold of Toxicological Concern (TTC) as proposed by an International Life Sciences Institute expert group (Kroes et al 2000(Kroes et al , 2004. Whether or not drinking water exposure exceeds these benchmarks indicates whether the exposure may be associated with adverse health risks.…”

Thresholds of Toxicological Concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space

“…1) and further developed into a COSMOS TTC dataset in this project. The oral TTC values relevant to cosmetics have been derived and can be compared with the previously established generic human exposure thresholds (Kroes et al, 2004;Munro et al, 1996).…”

“…Tetra sodium ethylenediaminetetraacetate (EDTA) (Chemical Abstract Services Registry Number [CAS RN]: 64-02-8) was the first chemical to which TOR was applied in 1996 at US FDA Center for Food Safety and Nutrition (CFSAN). 2 It was subsequently expanded into the TTC concept to include non-cancer endpoints by Munro et al (1996) and further elaborated by Kroes et al (2004), who proposed the addition of another tier intended to be protective for DNA-reactive carcinogens.…”

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

“…14 Some high potency genotoxic carcinogens like aflatoxin-like-, N-nitroso-, and azoxy-compounds have to be excluded from the TTC approach. 19 Compound-specific toxicity data is needed for the risk assessment of such compounds. A TTC value higher than 1.5 μg/day may be acceptable for short term-exposure drugs, for treatment of life-threatening conditions, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources, e.g.…”

“…14,15 The limit was set based on the analysis of 343 carcinogens, 16 expanded to more than 700 carcinogens from a carcinogenic potency database. [17][18][19] A simple linear extrapolation from 50 % tumor incidence (TD50) data for the most sensitive species and most sensitive site to a 1 in 10 6 incidence was used, which makes the principle very conservative. 14 Some high potency genotoxic carcinogens like aflatoxin-like-, N-nitroso-, and azoxy-compounds have to be excluded from the TTC approach.…”