1. What is the Threshold of Toxicological Concern?
Increasing numbers of substances present at low and very low concentrations in food and feed are now detectable due to improved analytical methods. However, for many such substances there are little or no toxicological data available. There is an increased need to assess the potential health significance of these previously undetectable trace substances and it is not always possible to generate toxicological data on every single substance found in the diet.
The Threshold of Toxicological Concern (TTC) approach has been developed to qualitatively assess the risk of low-level substances in the diet. It can be used for an initial assessment of a substance to determine whether a comprehensive risk assessment is required. It is an important science-based approach for prioritising assessment of those chemicals with low-level exposures that require more data over those that can be presumed to present no appreciable human health risk.
2. How does it work?
If the chemical structure of a substance is known, it is likely health risk can be evaluated on the basis of generic human thresholds of exposure – “TTC values”. TTC values have been established for substances of similar chemical structure and likelihood of toxicity, based on extensive published toxicological data. There are three broad categories of low, moderate or high toxicity. Substances are conservatively assessed by comparing the appropriate TTC value with reliable human exposure data. If human exposure to a substance is below the TTC value, the likelihood of adverse effects is considered to be very low.
3. What are the current and proposed uses of TTC at EFSA?
The TTC approach is currently only used by EFSA on a regular basis for the evaluation of flavouring substances (according to assessment principles laid down in the EU regulation on flavourings) and of pesticide metabolites in groundwater. However, EFSA’s Scientific Committee has evaluated the relevance and reliability of the TTC approach
in assessing possible human health risks from low levels of exposure to a wider range of substances present in food and feed. It has discussed using TTC for areas within EFSA’s remit including: food contact materials; impurities and breakdown/reaction products in food and feed additives; plant metabolites and degradates of pesticides; metabolites of feed additives; technological feed additives; and flavouring substances in feed.
4. Could the TTC approach become a short-cut to the approval of pesticides, food additives and other regulated substances?
The TTC approach is not a replacement for the risk assessment of regulated products such as pesticides or food and feed additives, where there is a legislative requirement for the submission of toxicological data. In addition, use of the TTC approach has been excluded for a number of categories of substances: high potency carcinogens (i.e. aflatoxin-like, azoxy- or N-nitroso-compounds), inorganic substances, metals and organometallics, proteins, steroids, substances that are known or predicted to bioaccumulate, nanomaterials, radioactive substances, and mixtures of substances containing both known and unknown chemical structures.
5. Does TTC have widespread scientific support?
The TTC approach has been developed over the past 25 years by scientists specialising in chemical risk assessment, including many working for regulatory agencies. Some people and organisations feel that any chemical present in food or feed should be subjected to toxicity testing followed by risk assessment based on data from experiments on animals. However, public authorities have an obligation to use the accumulated scientific knowledge on toxicity of chemicals whilst still ensuring that public health is protected. This knowledge can allow scientists to give guidance to risk managers even when there are few toxicity data available. It also allows risk assessors to focus attention on those substances that are likely to pose a risk to health and can reduce the need for animal testing.
6. Is EFSA the only organisation using the TTC approach?
No. The TTC approach has been used by the U.S. Food and Drug Administration, JECFA (the Joint Expert Committee on Food Additives of the U.N.’s Food and Agriculture Organization and the World Health Organization), the former Scientific Committee on Food (SCF) of the European Commission and by the European Medicines Agency, among others.
7. There are some that argue that the TTC approach is not effective when assessing endocrine-active substances, including those that could have so-called low-dose effects. What is EFSA’s view on this?
EFSA’s Scientific Committee has carefully considered the applicability of the TTC approach to endocrine-active substances, including those that could have “low-dose effects”. It concluded that:
- If there are data showing that an endocrine-active substance has adverse effects, then the TTC approach should not be applied and a full risk assessment should be carried out based on these data.
- If there are data showing that a substance has endocrine activity but the relevance to human health is unclear, then a decision should be made by risk assessors on a case-by-case basis whether or not to apply the TTC approach.
- There is currently extensive work going on at an EU-level about how scientists should define and assess endocrine-active substances; once finalised, the impact of this work will need to be considered in relation to the use of the TTC approach.
8. Is the TTC approach adequately protective of infants and children?
EFSA has found that the TTC approach adequately protects infants and children. Broadly speaking, this is because the TTC values are expressed according to body weight and therefore take into account the lower body weights of infants and children.
EFSA also noted that in the first weeks of life young infants are capable of metabolising and eliminating substances, particularly when exposures are low, and that the differences between young infants and children or adults in this respect are small enough not to invalidate the use of the TTC approach.
However, EFSA does recommend that if the estimated exposure is in the range of the TTC value for young infants, additional considerations, such as predicted metabolism, frequency and duration of exposure, need to be made, on a case-by-case basis, to determine whether the TTC approach can be relied on.
9. What happens next?
Since its original development and application to food, further scientific developments have taken place which mean there may be a need to update the TTC approach. EFSA and the World Health Organization (WHO) have therefore embarked on a review of the TTC approach. As part of this project EFSA and the WHO are holding a workshop in December 2014 involving stakeholders and scientific experts.