Advancing the TTC concept as a non-animal safety assessment tool for low level exposure

Background

In 1995, the US Food and Drug Administration (FDA) introduced the Threshold of Regulation (ToR) programme, according to which, at sufficiently low 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 us to:

  • Recognise that exposures lower than the TTC levels do not pose safety concerns;
  • Reduce the use of laboratory animals;
  • Make better use of financial and human resources in both industry and public sector;
  • 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 and expand its applicability as an important risk assessment tool for exposures to substances to which humans are exposed at low levels. It allows for better use of resources for compounds with high exposures and / or high toxicity and for reducing 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. 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.
  • Results on the safety assessment of cosmetics chemicals were recently published (F. Williams et al., 2016). These results are the work of a TTC Task Force expert group within the EU-funded project COSMOS, which aimed to apply the current TTC approach to cosmetics-related substances.
  • An overview of the task force work was presented at EUROTOX 2016 (4-7 September 2016, Seville, Spain).

What’s New

  • A new expert group on ‘Uncertainty in Risk Assessment: A Comparison of TTC versus Chemical-Specific Approaches’ will kick-off in May 2017.

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

Task Force Members

Expert Groups

Uncertainty in Risk Assessment: A Comparison of TTC versus Chemical-Specific Approaches  NEW

Objectives

The probabilistic approach with the use of the 5th percentile of the Cramer class No Observed Effect Level (NOEL) distributions to set the TTC non-cancer thresholds is often perceived as accepting a higher risk of making wrong calls in risk assessments. However, scientific activities to describe sources of uncertainty within the TTC approach have not yet been conducted or published. This activity will examine how much uncertainty may be associated with the application of the TTC approach as compared to substance-specific risk assessment, thus developing scientific knowledge about the sources of uncertainty being specific to TTC.

Activity

The expert group will 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 Level (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 (categories / analogue approach);
  • Derivation of thresholds from other alternative approaches such as Quantitative Structure-Activity Relationship (QSAR) and in vitro assays.

Additionally, the protection goals targeted with the TTC approach versus substance-specific risk assessment will be adressed.

Expected Output

The activity will create scientific knowledge and improve the understanding of stakeholders on the type of and on the degree of uncertainty associated with TTC-based assessments, as compared to traditional assessments. It will allow to better define in which cases a TTC-based approach is fully appropriate and in which cases other approaches might be preferable.


Carcinogen Dose-Response Database for Threshold of Toxicological Concern

Objectives

ILSI Europe, together with Liverpool John Moores University (UK), Molecular Networks Gmbh (DE), and Fraunhofer Institute for Toxicology and Experimental Medicine (DE) received funding from the European Chemical Industry Council Long-Range Research Initiative (CEFIC LRI) for a research proposal entitled ‘Carcinogen Dose-Response Database for TTC’.

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 cancer potency data for genotoxic and non-genotoxic carcinogens. The novel database will form the basis of analysis of TTC distributions for cancer thresholds.

Activity

This 18-month project will leverage the work already done by ILSI Europe’s Threshold of Toxicological Concern Task Force (2014-2015) and utilise the expertise of the four partners involved. ILSI Europe will support the management of the project and, through its experts, will advise on the criteria to identify genotoxic / non-genotoxic carcinogens and review a set number of compounds and scientific documents.

Expected Output

The project will advance 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 database). 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?

Objectives

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 developed scientific criteria to examine whether the TTC exposure limit of 0.15 µg / day for DNA-reactive substances was still appropriate when account was taken of the mode of action (e.g. mutagenic or not) and knowledge on human relevance.

Activity

The expert group developed 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.

Output

This project described a science-based and pragmatic approach to strengthen the scientific underpinnings of the cancer-based TTC tier in the form of a publication. Considerations on and a framework for data quality and data relevance criteria and pragmatic weight of evidence guidance on the inclusion of mode of action information into threshold considerations was examined.

Building upon the work of the expert group, the existing cancer database is being extended as part of a project funded by the European Chemical Industry Council Long-Range Research Initiative (CEFIC-LRI).

Expert Group Members

Uncertainty in Risk Assessment: A Comparison of TTC versus Chemical-Specific Approaches NEW

Carcinogen Dose-Response Database for Threshold of Toxicological Concern

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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