Threshold of Toxicological Concern

Supporting science in the advancement of the TTC concept as a non-animal safety assessment tool for low level exposures

Background

In 1995, the US Food and Drug Administration (FDA) introduced the Threshold of Regulation (ToR) programme, according to which, at sufficiently low enough exposure, the associated risk related to the consumption of substances used in food contact articles (food packaging and food processing equipment) may be deemed negligible. Based on the principles of the ToR, the Threshold of Toxicological Concern (TTC) concept is a pragmatic but conservative science-based tool to help regulators and industry assess potential health risk from substances when specific toxicological data are not yet available (R. Kroes, et al. 2000). The use of the TTC principle enables to:

  • Recognise that exposures lower than the TTC levels do not pose safety concerns;
  • Decrease the use of laboratory animals;
  • Make better use of financial and human resources in both industry and governments
  • Apply a practical risk assessment tool that is needed to address low level exposures as more and more sensitive analytical techniques become available.

Objectives

The objectives of the task force are to strengthen the scientific underpinnings for the TTC, expanding its applicability as an important risk assessment tool for exposures to substances to which humans are exposed to at low levels. It allows for better use of resources for compounds with high exposures and/or high toxicity and for decreasing the use of animals in laboratory experiments.

Impact

The task force was one of the first groups in Europe to further develop the underlying science of the TTC concept.

Since 1996, ILSI Europe has played a major role in advancing and promoting a broad application of the TTC concept in Europe. The scientific approach of the TTC concept is now recognised by scientific committees of international authorities that have issued favourable opinions on the use of TTC as a risk assessment tool.

In 2011, the task force organised a workshop on ‘Evaluation of the Threshold of Toxicological Concern (TTC) – Challenges and Approaches’ with support of the European Chemical Industry Council (Cefic-LRI), the European Partnership for Alternatives Approaches to Animal Testing (EPAA) and the International Society of Regulatory Toxicology (ISRTP). Participants reached the general consensus that the TTC approach is a valid first tier approach to risk characterisation (I. Dewhurst and A.G. Renwick, 2013).

The task force presented its current and completed scientific activities on TTC at the EFSA/WHO Stakeholder Meeting on Threshold of Toxicological Concern, held on 2 December 2014.

What's New

The task force developed a new activity proposal on ‘Uncertainty within the TTC Concept in Comparison to Traditional Risk Assessment’. This activity plans to provide a differentiated review and comparison of quantitative and qualitative uncertainties associated with different steps of:

  • Data generation in toxicological studies and No Observed Adverse Effect Level (NOAEL)/ Benchmark Dose, Lower Confidence Limit (BMDL) derivation;
  • Assumptions made in risk assessment based on specific data;
  • Derivation of thresholds from large groups of substances, i.e. TTC;
  • Derivation of thresholds from small groups of substances.

For more detailed information, please contact Mr Cyril Marsaux at cmarsaux@ilsieurope.be

Task Force Members

Expert Groups

Activity funded by CEFIC-LRI Carcinogen Dose-Response Database for Threshold of Toxicological Concern – New

A new activity has been funded by the European Chemical Industry Council Long-range Research Initiative (CEFIC-LRI)

Objective

Building on the evaluation of the Cancer Potency Database (CPDB) by the ILSI Europe CPDB Expert Group, this project aims to generate a fully-curated, quality-controlled and publically-available database on genotoxic and non-genotoxic carcinogens. The novel database will form the basis of analysis of TTC distributions for cancer thresholds.

Activity

This 18-month-long project utilises the expertise of 4 separate partners leveraging the work already done by ILSI Europe Threshold of Toxicological Concern Task Force (2014-2015).

Expected Output

The project will advance on the current state-of-the-art in cancer potency TTC in a number of ways:

  • The cancer database will extend the existing datasets through data harvesting activities and strategic alliances with key stakeholders e.g. US FDA. The database will be expandable and freely available in Microsoft Access, via the CEFIC Toolbox and from a web-based centralised TTC database site (COSMOS TTC db). The decisions will be recorded in a transparent fashion;
  • Current approaches (e.g. Kirkland, WHO Mode of Action) to categorise genotoxic and non-genotoxic carcinogens will be updated and expanded to include further information on genetic toxicity. In addition there will be demonstrable better use of (Quantitative) Structure-Activity Relationships ((Q)SARs) for DNA reactivity;
  • Knowledge of current Points of Departure (PODs) (e.g. TD50, BMDL) will be extended by further data harvesting and analysis the output of which will be captured in the database;
  • The current TTC thresholds for cancer potency will be re-evaluated following potency analysis of the extended cancer database.

Is the 0.15 µG/Day Tier of the Threshold of Toxicological Concern (TTC) still Appropriate?

Objective

The TTC-based exposure limit of 0.15 µg/day is based on an evaluation of the Cancer Potency Database (CPDB) that includes information from carcinogenicity studies of over 700 chemicals. This expert group will examine whether the TTC exposure limit of 0.15 µg/day for DNA-reactive substances is still appropriate when account is taken of the mode of action (e.g. mutagenic or not) and knowledge on human relevance. This will be undertaken on a subset of carcinogenic chemicals, in the first instance.

Activity

The expert group is developing a concept for the re-evaluation of the cancer TTC dataset by providing state-of-the-art scientific background support to the derivation of the threshold for DNA-reactive carcinogens and those probably acting via different modes of action. This work might also provide support for more than one TTC limit based on considerations such as mode of action or chemical class.

  • Study inclusion and data evaluation framework definition;
  • Building and analysing a proof of concept dataset;
  • Publication of the results of the evaluation.

Expected Output

The project is applying current state-of-the-art approaches in cancer risk assessment to the existing database of carcinogens and will provide updated quantitative analyses for a representative subset of chemicals based on current approaches, including considerations of both human relevance and mode of action. This project will describe a science-based and pragmatic approach to strengthening the scientific underpinnings of the cancer-based TTC tier.

The task force presented the project in a poster session at EFSA's 2nd Scientific Conference 'Shaping the Future of Food Safety, Together’ in October 2015, in Milan, Italy.

Building upon the work of the expert group, the existing cancer database will be extended in a project funded by the European Chemical Industry Council Long-range Research Initiative (CEFIC-LRI). This project will be kicked off in April 2016.

Expert Group Members

Activity funded by CEFIC-LRI Carcinogen Dose-Response Database for Threshold of Toxicological Concern – New

This activity has just been launched; the list of expert group members will be available soon.

Is the 0.15 µG/Day Tier of the Threshold of Toxicological Concern (TTC) still Appropriate?

Publications

All Publications

The Role of Hazard- and Risk-Based Approaches in Ensuring Food Safety

Trends in Food Science & Technology. 2015;46(2) Part A:176-188. Supported by the following task forces: Emerging Microbiological Issues, Food Allergy, Food Intake Methodology, Novel Foods and Nanotechnology, Process Related Compounds and Natural Toxins, Risk Analysis in Food Microbiology, and Threshold of Toxicological Concern.

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