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Scientific Opinion on Exploring options for providing advice about possible human health risks based on the concept of Threshold of Toxicological Concern (TTC)
Synthetic and naturally occurring substances present in food and feed, together with their possible breakdown or reaction products, represent a large number of substances, many of which require risk assessment. EFSA’s Scientific Committee was requested to evaluate the threshold of toxicological concern (TTC) approach as a tool for providing scientific advice about possible human health risks from low level exposures, its applicability to EFSA’s work, and to advise on any additional data that might be needed to strengthen the underlying basis of the TTC approach. The Scientific Committee examined the published literature on the TTC approach, undertook its own analyses and commissioned an in silico investigation of the databases underpinning the TTC approach. The Scientific Committee concluded that the TTC approach can be recommended as a useful screening tool either for priority setting or for deciding whether exposure to a substance is so low that the probability of adverse health effects is low and that no further data are necessary. The following human exposure threshold values are sufficiently conservative to be used in EFSA’s work; 0.15 μg/person per day for substances with a structural alert for genotoxicity, 18 μg/person per day for organophosphate and carbamate substances with anti-cholinesterase activity, 90 μg/person per day for Cramer Class III and Cramer Class II substances, and 1800 μg/person per day for Cramer Class I substances, but for application to all groups in the population, these values should be expressed in terms of body weight, i.e. 0.0025, 0.3, 1.5 and 30 μg/kg body weight per day, respectively. Use of the TTC approach for infants under the age of 6 months, with immature metabolic and excretory systems, should be considered on a case-by-case basis. The Committee defined a number of exclusion categories of substances for which the TTC approach would not be used.
© European Food Safety Authority, 2012
The European Food Safety Authority (EFSA) asked its Scientific Committee to develop an opinion on exploring options for providing advice about possible human health risks based on the concept of Threshold of Toxicological Concern (TTC).
In Europe, substances that are the active or primary ingredients in products added to or occurring as residues in food or feed are assessed, prior to authorisation, on the basis of dossiers that include the results of toxicity tests. A requirement for toxicity testing is appropriate for such substances. However, the use of such substances may also result in the presence in food or feed of low-level impurities, metabolites, breakdown and reaction products, on which there are few toxicological data. The continuing improvements in analytical sensitivity are also resulting in the detection of a growing number of chemical contaminants in food and feed at low concentrations, as well as in the identification of substances on which there are few toxicological data.
In the light of the above considerations, EFSA needs to develop, validate and apply, where possible, practical risk assessment approaches that can be used as priority setting tools and as a means to enable more rapid provision of advice about the possibility of health risks. Such practical approaches should not in any way compromise the high scientific quality of EFSA’s output. Accordingly, as a self task, the Scientific Committee was requested to evaluate the relevance and reliability of the threshold of toxicological concern (TTC) approach as a tool for providing scientific advice about possible human health risks from low level exposures, its applicability to the work of EFSA’s Scientific Committee and Scientific Panels, and to advise on any additional data that might be needed to strengthen the underlying basis of the TTC approach. The TTC approach is currently used by EFSA for evaluation of flavouring substances and for the evaluation of relevant pesticide metabolites in groundwater.
In this opinion, the Scientific Committee has considered a number of published analyses and conducted some analyses itself of both the data originally used to establish human exposure threshold values (TTC values) and data from additional studies that are included in EFSA’s databases on pesticides and in an EU database of substances classified for reproductive toxicity. EFSA also commissioned a project from a contractor to examine the databases underpinning the TTC approach, using in silico chemoinformatic methods to assess the representativeness of the databases and the opportunities for refining the basis for grouping chemicals. Further analyses of oral toxicity data and TTC values have also been conducted and published by others using independent databases. The Scientific Committee’s conclusions from this exploration of the TTC approach are as follows.
- The TTC approach is applicable to substances for which the chemical structure is known but for which there are few or no relevant toxicity data. For the work of EFSA, the TTC approach is recommended as a useful screening tool either for priority setting or for deciding whether exposure to a substance is so low that the probability of adverse health effects is low and that no further data are necessary.
- For application of the TTC approach it is essential to have exposure assessments that take account of high exposure scenarios, and, where possible, take account of exposure from all routes and sources. The EFSA Panels already have in place exposure assessment methodologies for predicting or estimating average and high exposures in relevant sub-populations, and the EFSA Comprehensive European Food Consumption Database is expanding.
- The classification of chemicals according to chemical structure is an essential component of the current TTC approach. The classification scheme most widely used is that described by Cramer et al. (1978). The Scientific Committee is mindful that this scheme is based on the metabolic and toxicological information available at that time. With advances in knowledge over the last three decades, revision and refinement of the scheme is recommended. Nevertheless, the Scientific Committee’s analyses, together with those in several other published studies (referenced elsewhere in this opinion) have demonstrated that the application of the Cramer classification scheme in the TTC approach is conservative and therefore protective of human health.
- The Scientific Committee notes that the TTC value for Cramer Class II substances derived by Munro et al. in 1996 was based on toxicological data on very few substances. Databases compiled subsequently have similarly found few chemicals classifiable as Cramer Class II, apart from flavouring substances. The Scientific Committee considers that the TTC value for Cramer Class II is not well supported by the presently available databases and therefore concludes that consideration should be given to treating substances that would be classified in Cramer Class II under the Cramer decision tree as if they were Cramer Class III substances.
- The Committee’s analysis of the lowest 10th percentiles of the NOELs in the database of Munro et al. (1996) for substances in Cramer Class I and Class III, and confirmation by others of similar NOELs using different datasets (Tluczkiewicz et al., 2011), demonstrate that the respective TTC values of 1800 and 90 μg/person per day derived by Munro et al. are sufficiently conservative to be used.
- Following the Scientific Committee’s analysis of NOELs for organophosphate and carbamate substances, the TTC value of 18 μg/person per day, first proposed by Kroes et al. (2004), is considered sufficiently conservative to cover the anti-cholinesterase activity of substances with organophosphate or carbamate structural features.
- Removing organophosphate and carbamate substances from Cramer Class III (being the most potent substances in that class) would have an impact on the existing TTC value for Cramer Class III. However, pending any future revision of the TTC approach, the Scientific Committee concludes that it would be prudent to maintain the value for Cramer Class III at 90 μg/person per day.
- The Scientific Committee considers that further additions to or subdivisions of existing Cramer Classes are likely to detract from the advantageous features of the current TTC scheme, that is, its ease of use, maintaining consistency in application of the approach, and its in-built conservatism.
- Following the Scientific Committee’s analysis of NOELs for reproductive and developmental toxicity for substances classified as such under EU legislation, the TTC values for Cramer Classes I and III are considered sufficiently protective for adverse effects on reproduction or development.
- Regarding the issue of substances that may have endocrine-mediated toxicity, the Scientific Committee concludes as follows.
- In most situations where the TTC approach might be applied, there would be no a priori knowledge that a substance has endocrine activity.
- If there are data showing that a substance has endocrine activity, but the human relevance is unclear, then these data should be taken into consideration, case-by-case, in deciding whether or not to apply the TTC approach.
- If there are data showing that a substance has endocrine-mediated adverse effects, then, as would be the case for adverse data on any other endpoint, the risk assessment should be based on the data, rather than the TTC approach.
- In view of the extensive work, currently ongoing, to develop an EU-wide approach for defining and assessing endocrine disrupters, once that approach is finalised it will be necessary to consider any impact it may have on the use of TTC approach.
- In the meantime, the Scientific Committee recommends that untested substances, other than steroids, can be evaluated using the TTC approach recommended in this opinion.
- For substances with a structural alert for genotoxicity, the TTC value of 0.15 μg/person per day was derived by Kroes et al. (2004). This value is sufficiently conservative to be used in EFSA’s work, provided the structures already designated as high potency carcinogens are excluded from the TTC approach. The Scientific Committee is aware that further substances have been added to the Carcinogenic Potency Database since this value was derived. However, because a large number of substances were already in the Carcinogenic Potency Database, the Committee does not consider that the TTC value for substances with a structural alert for genotoxicity would change appreciably.
- The Scientific Committee has considered the possibility that a genotoxic metabolite could be produced from a parent substance. If such metabolites were to be predicted and considered relevant, then the TTC value of 0.15 μg/person per day should be applied. The Scientific Committee recognises that there is no general agreement at present on how to interpret the outcome from the currently available tools used to make such predictions, because they have a tendency to generate a large number of potential metabolites.
- The original FDA Threshold of Regulation value of 1.5 μg/person per day is of historical importance, but has little practical application in the overall TTC approach. This is because substances without structural alerts for genotoxicity can proceed down the TTC decision tree to be considered in relation to the higher TTC values for organophosphates and carbamates or Cramer Classes I and III.
- Non-genotoxic carcinogens are considered to have a threshold and, in general, NOELs for these are in the same range or higher than NOELs for other types of toxicity. Thus the TTC values that are higher than the value of 0.15 μg/person per day are appropriate to be used for any substance that does not have a structural alert for genotoxicity.
- The Scientific Committee also notes that the work of the EFSA-commissioned project demonstrated that the range of structures in the two main datasets (Carcinogenic Potency Database and Munro et al.), which underpin the human exposure threshold values, are broadly representative of the world of chemicals, in terms of chemical space, as described by molecular descriptors encompassing both structural features and physicochemical properties. This provides further confidence in the general utility of the TTC approach.
- A number of proposals have been put forward for adjusting the TTC value for substances with a structural alert for genotoxicity for shorter than chronic durations of exposure. The Scientific Committee is not confident about the general applicability of these proposals It therefore recommends that the issue of less than chronic exposure should be addressed case-by-case. This could be done for example by considering the margin between the appropriate TTC value (without any adjustment for duration of exposure) and the estimated dietary exposure. The Scientific Committee also notes that, with the exception of the TTC value for organophosphate and carbamate structures, the current TTC values for non-cancer endpoints are derived from databases that do not address effects from acute exposure. The Scientific Committee is currently unable to recommend a reliable/appropriate general means of adjusting the TTC values for non-cancer endpoints for shorter durations of exposure, and recommends that these too should also be addressed case-by-case for the time being.
- For application of the TTC approach to the whole population including infants and children, all TTC values should be converted to corresponding values that take into account body weight (see Figure 2).
- The Scientific Committee has also considered whether the TTC approach could be applied to young infants under the age of 6 months, in whom not all metabolic and elimination processes are yet mature. The toxicokinetic differences between young infants and children or adults are transient and generally not more than 2- to 5-fold. Thus there is capacity in the first weeks of life to metabolise and eliminate substances, particularly when exposures are low. The Scientific Committee concludes that the TTC approach can be applied to assess exposures in young infants, but in cases where the estimated exposure is in the range of the TTC value, additional consideration needs to be given under which conditions the TTC approach could be used. Additional considerations might include prediction of metabolic routes for the structure concerned and other issues such as frequency and duration of the exposure.
- The Scientific Committee has considered whether TTC approach can be applied in cases where exposures are by dermal or inhalation routes (e.g. for assessment of occupational exposures). It is concluded that more work is needed in this area to establish separate TTC values for routes of exposure other than oral and/or develop systematic schemes for route-to-route extrapolation. It is noted that such work is ongoing elsewhere.
- The Scientific Committee considered whether routinely undertaking metabolic prediction would be helpful for application of the TTC approach other than for prediction of genotoxicity. As the Cramer decision tree and the databases used to derive the TTC values for non-cancer endpoints reflect at least in part the toxicity of metabolites formed in the test species, the Scientific Committee concluded that it is not essential to undertake such metabolic prediction. However, there are situations where this has been helpful, e.g. in the case of flavourings where metabolic data on closely structurally-related substances are available.
- The Scientific Committee considered both previously proposed exclusions and additional exclusions that might be necessary and concludes that the TTC approach should not be used for the following (categories of) substances:
- High potency carcinogens (i.e. aflatoxin-like, azoxy- or N-nitroso-compounds, benzidines, hydrazines).
- Inorganic substances
- Metals and organometallics
- Substances that are known or predicted to bioaccumulate
- Radioactive substances
- Mixtures of substances containing unknown chemical structures
- When the TTC approach is used, it is important for both risk assessors and risk managers to keep in mind that it is a probability-based screening tool and, in common with other risk assessment approaches, it does not offer complete certainty. The derivation of the various TTC values are based on frequency distributions and the TTC values that have been proposed for use are not based on the lowest value in each of the distributions but on a point close to the lowest value. Thus, when using either the cancer or non-cancer TTC values, there is a chance that a substance with an exposure below the relevant TTC value may still pose a potential risk. That probability can be estimated to lie between zero and 5%.
- Lastly, the Scientific Committee has considered where the TTC approach could be applied in EFSA’s work and concludes as follows:
- In principle, the science supports the application of the TTC approach in any area of chemical risk assessment for which human exposures are low, whether exposure is from deliberate addition or due to contamination. However, for substances for which EU legislation requires the submission of toxicity data, the TTC approach would not be used.
- Within EFSA, the Scientific Committee recommends that the TTC approach can be used to assess impurities, breakdown and reaction products, metabolites, and low-level contaminants in food and feed, where an exposure assessment can be conducted, but on which there are few or no toxicological data.
- Wider use of the TTC approach in EFSA’s work, beyond the ones mentioned above, can also be envisaged, for example, as part of tiered approaches in which toxicity testing requirements are linked to the level of human exposure. Such uses in a particular area of EFSA’s work should be considered on a case-by-case basis, in consultation with risk managers. The Scientific Committee further recommends that in such cases, if there is a structural alert for genotoxicity, then genotoxicity testing data on the substance or information (e.g. from read-across) should be sought.
- The Scientific Committee recognises that when the different EFSA Panels apply the TTC approach to their respective areas, specific considerations may apply and the generic scheme shown in Figure 2 may need to be adapted.
Threshold of toxicological concern, TTC, risk assessment, Cramer classification scheme