EFSA provides guidance on possible use of the Threshold of Toxicological Concern approach in chemical risk assessment

The European Food Safety Authority (EFSA) has published a new scientific opinion on the potential use of the threshold of toxicological concern (TTC) approach for estimating possible human health risks from low level exposure to chemical substances found in food or feed, for which there are limited or no toxicity data available. Where there are insufficient data to carry out a risk assessment, the TTC approach is a scientific tool that can be used to support policy-makers to protect consumers.

Following a thorough evaluation of the science underpinning this methodology, an extensive public consultation was undertaken both online and through meetings with the Authority’s European and national partners and stakeholders, including the European Chemicals Agency, the European Medicines Agency and the non-food scientific committees of the European Commission. Following this, EFSA’s Scientific Committee recommends the use of the TTC approach as a useful screening tool in chemical risk assessment. In particular, it could be used both for priority setting and for deciding whether or not exposure to a substance is so low that the probability of adverse health effects is low and no further data are necessary. As well as enabling advice to be given when toxicity testing data are not available, the TTC approach would enable more focused and thus efficient use of available resources to protect consumers and possible reductions in unnecessary animal testing. However, the TTC approach is not to be used as an alternative to conventional risk assessment for substances such as food additives and pesticides, for which EU legislation requires the submission of toxicological data.

Increasing numbers of chemicals present at low and very low concentrations in food and feed are now detectable due to improved analytical methods. There is a need to assess the potential health significance of these previously undetectable trace substances. However, for many such substances found in such small quantities in the diet it is not always possible to generate toxicological data.

Where could it be used? – The TTC approach can only be used where the chemical structure of the substance is known and the exposure is anticipated to be very low. It is already used in EFSA’s work on the safety evaluation of flavouring substances, as outlined in the relevant EU legislation. The EFSA opinion clarifies the applicability of the TTC approach (developed by Munro et al. and first published in 1996) to other areas of the Authority’s work: it can potentially be used in relation to low-level exposure to impurities, breakdown and reaction products, metabolites (for example of pesticides) and other contaminants in food/feed. Wider use of the TTC approach could, on a case-by-case basis, include tiered approaches in which toxicity testing requirements are linked to the level of human exposure. It is not to be used for the following types of substances: high potency carcinogens, inorganic substances, metals and organometallics, proteins, steroids, substances that are known or predicted to bioaccumulate, nanomaterials, radioactive substances and mixtures of substances with unknown chemical structures.

How does it work? – The TTC approach is founded on the principle that the likelihood of toxicity is related to the extent and duration of exposure to a substance. For many types of toxic effects a dose threshold can be identified in experimental studies below which adverse effects are not observed. Based on extensive published data on the toxicity of chemicals that have been tested, generic human thresholds of exposure for chemicals (called ‘TTC values’) have been established for groups of substances of similar chemical structure and likelihood of toxicity. Taking a cautious approach, chemical structures have been grouped into three broad categories defined as of low, moderate or high toxicity (known as Cramer classes I, II and III respectively). TTC values have been derived for each Cramer class. Untested substances can be conservatively assessed by comparing the appropriate TTC value with reliable human exposure data. If human exposure to a substance is below the relevant threshold of concern for its structural class, the likelihood of adverse effects is considered to be very low.

Prior to finalising its opinion, the Scientific Committee considered all comments received during an extensive public consultation. A report on the outcome of this process has been published together with the opinion.

Notes to editors
  • In 1996, Munro et al. published a paper on “Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern”. This paper included a dataset comprised of 613 organic chemicals with associated NOEL (No-Observed-Effect Level) values derived from a variety of non-cancer endpoints from toxicity studies carried out in rodents and rabbits. Each substance in the database was classified into one of three structural classes using a decision tree approach with the purpose of deriving human exposure levels (TTC values) for toxicity endpoints other than carcinogenicity. See Munro IC, Ford RA, Kennepohl E & Sprenger JG (1996). Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern. Food and Chemical Toxicology 34, 829-867.
  • As part of its evaluation of the TTC approach, EFSA commissioned a project which demonstrated that the range of structures in the two main datasets (Carcinogenic Potency Database and Munro et al.) underpinning the TTC values, are broadly representative of the world of chemicals. This provides further confidence in the general utility of the TTC approach.
  • EFSA’s safety evaluation of flavouring substances follows a tiered approach whereby the predicted effects of a flavouring substance can either trigger the need for additional data or lead to a conclusion that there is no safety concern. This is a modification of an approach used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). It was incorporated into EU legislation on flavouring evaluations in 2000 upon the advice of the European Commission’s former Scientific Committee on Food (SCF).
  • EFSA’s Scientific Committee supports the work of EFSA’s Scientific Panels on scientific matters of a horizontal nature and is responsible for general co-ordination to ensure consistency in the scientific opinions prepared by the Scientific Panels. The Scientific Committee focuses on developing harmonised risk assessment methodologies suitable for food and feed and in fields where EU-wide approaches are not already defined.
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