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). Where applicable, the use of the TTC principle enables us to:

  • Apply a practical risk assessment tool that is needed to address low level exposures as more and more sensitive analytical techniques become available;
  • Prioritise toxicological testing based on estimated human exposures;
  • Reduce the use of laboratory animals;
  • Make better use of financial and human resources in both industry and public sector.

Upcoming

The task force is considering a new activity on ‘Non-animal testing approaches to combined toxicity assessments using TTC thresholds’. This activity aims to review how co-exposure risk assessments can be done based on information on the structure, TTC thresholds, estimated human exposures and information from QSAR tools.

What’s New

The manuscript on Thresholds of Toxicological Concern for Cosmetics-Related Substances: New Database, Thresholds, and Enrichment of Chemical Space has just been accepted for publication in Food and Chemical Toxicology. This is a major piece of work which was carried out by a TTC Task Force expert group within COSMOS, a European Commission funded project that aimed to apply the current TTC approach to cosmetics ingredients (January 2011-December 2015).
The task force has published a new review on the origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation in Critical Reviews in Toxicology (Boobis et al., 2017). It has already been viewed over 720 times in the first 4 months.

Objectives

The task force aims to strengthen the scientific underpinnings for the TTC and expand its applicability as an important risk assessment tool for substances to which humans are exposed at low levels. We strive to develop the most scientifically robust, yet pragmatic, non-animal, safety assessment tool.

Impact

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

Task Force Members


* Scientific Advisor

Expert Groups

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

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 addressed.

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, in collaboration 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.

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. Further available genotoxicity data will be included to stratify into genotoxic and not-genotoxic compounds. 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? Completed

Objectives
The TTC-based exposure limit of 0.15 µg/person/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/person/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.

Output
A review describing a science-based and pragmatic approach to strengthen the scientific underpinnings of the cancer-based TTC tier was published in May 2017 (Boobis et al., 2017). 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) (see previous activity).

Expert Group Members

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

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? Completed

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.

Read more

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