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Threshold of Toxicological Concern Task Force

Assessment of Benefits and Risks

Background

The basis of the Threshold of Toxicological Concern (TTC) concept is the assumption that a human exposure threshold for most chemicals exists below which there is negligible probability of any risk to human health. The TTC concept aims to define ‘safe exposure levels’ for untested substances based on their chemical structure and conservative assumptions on toxicity data from similar chemicals. Therefore, this concept is of particular interest in promoting the reduction of animal experiments with isolated substances, in prioritising risk assessments and in assessing risks if information is limited.

Objectives

This task force was one of the first groups in Europe to further develop the underlying science of the TTC concept. Historically, the concept was developed for food packaging migrants. Although only oral exposure to low levels of a wide range of chemicals was considered previously, recent activities attempt to apply the TTC concept to other low level human exposures via the skin or inhalation such as that occurring from use of personal care and other consumer products.

Impact

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Food Safety Authority (EFSA) currently apply the TTC concept to assess the safety of flavouring substances for food. EFSA has set up a working group to further investigate the application of the TTC concept. The European Commission has requested the Non-Food Scientific Committees to further investigate the application of the TTC concept. The Committee for Medicinal Products for Human Use (CHMP) has based their ‘Guideline on the Limits of Genotoxic Impurities in Pharmaceuticals’ on the work of this task force.

Activities

Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of Cosmetics to Optimise Safety (COSMOS)

The ILSI Europe Threshold of Toxicological Concern (TTC) Task Force is a partner in the Framework Programme 7 Collaborative Project on Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of Cosmetics to Optimise Safety (COSMOS) (www.cosmostox.eu).
The task force contributes to work package 2 on TTC with the activities of two expert groups focusing on the:

development of criteria to be applied in the extension of the current TTC approach to cosmetics ingredients;
evaluation of oral-to-dermal extrapolation.

It is envisaged to organise a workshop in early 2013 to discuss the work of both expert groups with a broader audience.

For more details on this project, please visit our EC- funded Projects section.

Expert Group on the Application of the TTC Approach to Cosmetic Ingredients

This expert group will contribute to the overall structure of the new database by providing advice on inclusion criteria for chemicals and studies and point out data gaps within the chemical domain. Once the new database is available, the experts will evaluate new proposed structural categories and Cramer classes and recommend thresholds for cosmetics. The final outcome will be published in a scientific journal.

Expert Group on the Evaluation of Oral-to-dermal Extrapolation

This expert group will advise on the database content and structure from an extrapolation point of view. Furthermore, the experts will assess the feasibility of extrapolation and investigate methods to improve extrapolation and, finally, recommend appropriateness for the use of modelled data when dose level extrapolation is not possible due to a lack of experimental (dermal) data. The final outcome will be published in a scientific journal.

It is envisaged to organise a workshop in early 2013 to discuss the work of both expert groups with a broader audience.

Workshop on TTC

A 3-day workshop on ‘The Threshold of Toxicological Concern: Scientific Challenges and Approaches’ was organised on 8–10 June 2011, in Brussels. The workshop participants:

Reviewed examples of the application of TTC across different regulatory evaluation frameworks and decision-making programs;
Identified scientific barriers to broader acceptance of TTC;
Explored potential opportunities for initiating steps to overcome such barriers.

Based on the workshop discussions, the creation of a global database and updating the Cramer decision tree were identified as two important projects. In addition, it is expected that smaller projects will emerge as a result of this workshop.

A workshop summary article will be published in Regulatory Toxicology and Pharmacology.

Application of the TTC Concept to Unexpected Peaks in Food

The expert group investigated how unknown peaks should be handled. Should the peak be entirely analysed or could it be ignored if it is below a specific threshold? This would be of particular interest for the food industry, providing guidance on how to make a decision in such a situation. The manuscript includes as main chapters methods to exclude the cohort of concern, quantification of peaks and the elimination of genotoxins by bioassays as a potential future screening method. The article was published as Koster et al (2011). Application of the TTC concept to unknown substances found in analysis of foods. Food and Chemical Toxicology 49: 1642 – 1660.

Eurotox 2012

Together with ECHA (European Chemicals Agency), the task force will co-sponsor a session on ‘Read-across in risk assessment; problems or possibilities?’ at Eurotox 2012, Stockholm (SE), 17-20 June 2012. The programme includes the following lectures:

An introduction to read-across for chemicals in food
Chemical-specific metabolism and implications for toxicology and read-across
The application of large data sets of toxicological information to enable read-across
Does read-across give enough certainty to ensure human health?
Application of a read-across framework provides high quality safety information.

Task Force Collaborators

Members - 2012

Dr. Susan Felter - Chair -	Procter & Gamble	US
Dr. Heli Hollnagel - Co-chair-	Dow Europe	CH

Mr. James Edwards	DSM	CH
Dr. Pierre-Jacques Ferret	Pierre Fabre Dermo-Cosmétique	FR
Dr. Leonor Garcia	Coca-Cola Europe	BE
Dr. Elena Lo Piparo	Nestlé	CH
Dr. David Mason	Unilever	UK
Prof. em. Andrew Renwick	University of Southampton	UK
Mr. Robert Safford	Consulltant	UK
Dr. Jürgen Schnabel	Givaudan International AG	CH
Dr. Thomas Stroheker	Danone	FR
Dr. Angelika Tritscher*	World Health Organization (WHO)	CH

Mr. Massimo Ambrosio	ILSI Europe	BE
Ms. Belinda Antonio	ILSI Europe	BE

* Observer

Expert Group on the Application of the TTC Approach to Cosmetic Ingredients

Mr. Robert Safford - Chair -	Consultant	UK

Prof. Alan Boobis	Imperial College London	UK
Prof. Mark Cronin	Liverpool John Moores University	UK
Dr. Susan Felter	Procter & Gamble	US
Dr. Heli Hollnagel	Dow Europe	CH
Dr. Kristi Jacobs	US Food and Drug Administration (FDA)	US
Prof. Daniel Krewski	University of Ottawa	CA
Prof. em. Andrew Renwick	University of Southampton	UK
Dr. Josef Schlatter	Swiss Federal Office of Public Health	CH
Dr. Andrew Worth	European Commission – Joint Research Center	IT
Prof. Chihae Yang	Ohio State University	US

Mr. Massimo Ambrosio	ILSI Europe	BE
Dr. Stéphane Vidry	ILSI Europe	BE

Expert Group on the Evaluation of Oral-to-dermal Extrapolation

Prof. Faith Williams - Chair -	University of Newcastle	UK

Dr. Gordon Barrett	Health Canada	CA
Dr. Scott Boyer	AstraZeneca	SE
Prof. Mark Cronin	Liverpool John Moores University	UK
Prof. Richard Guy	University of Bath	UK
Dr. Nancy Monteiro-Riviere	North Carolina State University	US
Dr. James Plautz	DSM	CH
Prof. Vera Rogiers	Vrije Universiteit Brussels	BE
Dr. Clive Roper	Charles River Laboratories	UK
Dr. Helga Rothe	Procter & Gamble	DE
Dr. Diego Rua	Food and Drug Administration	US
Mr. Robert Safford	Consultant	UK
Dr. Miriam Verwei	TNO	NL
Prof. Faith Williams	University of Newcastle	UK
Dr. Chihae Yang	Ohio State University	US
Dr. José Zaldivar Comenges	European Commission - Joint Research Centre	BE

Mr. Massimo Ambrosio	ILSI Europe	BE
Dr. Stéphane Vidry	ILSI Europe	BE