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It cannot be denied that TTC (Threshold of Toxicological Concern) was
originally proposed in the U.S., as Dr Harris states in her commentary on
our article, but her industry-sponsored organisation, the International
Life Sciences Institute (ILSI) played a major role in developing it
further to the form in which it was accepted by European Food Safety
This process took place in an EFSA workin...
This process took place in an EFSA working group, in which ten out of
13 members had previously developed and promoted the tool with ILSI.
While EFSA communicators have attempted damage control in their online
Q&A, the biased work on TTC raised such concerns in the European
Parliament that EFSA was forced to ban ILSI-linked people from being
members of expert panels and working groups. Any link with ILSI now has to
be cut in order to qualify as an EFSA expert.
Apart from this industry infiltration of EFSA, the tool as delivered
by ILSI is far from being "scientifically supported", as Dr Harris
suggests. The database underpinning the TTC for non-genotoxic
substances is entirely made up of (potentially biased) industry
studies. Many of these studies are 40-60 years old and non-retrievable
(cannot be accessed), meaning that their quality cannot be assessed. In
addition, the old protocols used means that current scientific knowledge
will not be taken into account in calculating TTCs. In utero exposure is
generally missing and important risks will be overlooked because of the
limited endpoints considered at that time. The grouping of chemicals for
TTC is artificial and is based on the Cramer classification, which
relies on expert judgement only and is subjective. ILSI has also
manipulated the genotoxin database to get to an apparently desired
outcome. For example, it has removed aflatoxin-like, azo- and N-nitroso-
substances. Another unscientific shortcoming of TTC is its disregard
of cumulative effects.
The TTC is derived by arbitrarily removing from the calculation the
most toxic effects found in the database of NOELs (no adverse effect
levels). The TTC sets the 'level of no concern' at the 5th percentile,
resulting in a 1 in 20 chance that a random substance in any one group of
chemicals is toxic at this exposure level. Thus 5% of the chemicals in the
group are more toxic than the 'level of no concern' that is set for any
one group of chemicals.
TTC is promoted as a screening tool while in practice it is already
being used as a cut-off criterion (safe level) for pesticide
metabolites. Industry is now trying to extend TTC to other fields such
as any chemical found in food, outcomes of developmental testing,
drinking water, and inhaled chemicals. In many cases, and not
coincidentally, advocates of TTC are pursuing these aims through opinions
published in Regulatory Toxicology and Pharmacology, the controversial
chemical/pharmaceutical industry-sponsored journal. The journal was one of
several entities that were investigated by a US Congressional Committee in
2008 over their role in the Food and Drug Administration (FDA) decision
allowing bisphenol A in infant formula and other foods.[11-13]
Analysing the TTC tool and the background of its development can only
lead to the conclusion that industry has invested massively in a tool that
does not safeguard human health, as Dr Harris misleadingly claims, but
exactly the opposite. The tool serves industry's agenda of fast-tracking
chemicals to the market and avoids the costs of testing. The tool
undermines European legislation and policy. It aims to replace the
existing EU policy of 'no safe level' for genotoxic substances with
claimed 'safe levels' arrived at through the TTC. It also aims to replace
the EU policy that health of citizens should be protected by adequate
testing and the precautionary principle with a tool that enables avoidance
of testing for chemicals, metabolites and impurities.
The tool, which serves industry's agenda but places public health at
risk, has been introduced into European agencies by people who have served
as members of expert panels while maintaining conflicts of interest with
industry. Dr Harris's reference to the Danish study as a balanced
review of TTC is a case in point. Its author, John Christian Larsen,
worked in ILSI scientific bodies from 2002 till 2008 and has published
studies with ILSI-affiliated people who have promoted TTC. TTC has
made its way into the regulatory policy of the food safety authority EFSA
because of industry's massive resources and a lack of awareness on the
part of EFSA's staff, not for reasons of sound science.
1. Robinson C, Holland N, Leloup D, et al. Conflicts of interest at
the European Food Safety Authority erode public confidence. J Epidemiol
Community Health Published Online First: 8 March 2013.
2. Muilerman H, Tweedale T. A toxic mixture? Industry bias found in
EFSA working group on risk assessment for toxic chemicals, Pesticide
Action Network Europe 2011.
3. EFSA Scientific Committee. Scientific opinion on exploring options
for providing advice about
possible human health risks based on the concept of Threshold of
Toxicological Concern (TTC). EFSA Journal 2012;10: 2750.
4. Cramer GM, Ford RA, Hall RL. Estimation of toxic hazard - a
decision tree approach. Food Cosmet Toxicol 1978;16: 255-276.
5. Kroes R, Renwick AG, Cheeseman M, et al. Structure-based
thresholds of toxicological concern (TTC): guidance for application to
substances present at low levels in the diet. Food Chem Toxicol 2004; 42:
6. European Commission Health and Consumer Protection Directorate-
General (DG SANCO). Guidance document on the assessment of the relevance
of metabolites in groundwater of substances regulated under Council
Directive 91/414/EEC: Sanco/221/2000-rev.10-final. 25 February 2003.
7. Koster S, Boobis AR, Cubberley R, et al. Application of the TTC
concept to unknown substances found in analysis of foods, Food and
Chemical Toxicology 2011; 49: 1643-1660.
8. Van Ravenzwaay B, Dammann M, Buesen R, et al. The threshold of
toxicological concern for prenatal developmental toxicity. Regulatory
Toxicology and Pharmacology 2011;59: 81-90.
9. Melching-Kollmuss S, Dekant W, Kalberlah F. Application of the
''threshold of toxicological concern" to derive tolerable concentrations
of ''non-relevant metabolites" formed from plant protection products in
ground and drinking water. Regulatory Toxicology and Pharmacology 2010;
10. Escher SE, Tluczkiewicz I, Batke M, et al. Evaluation of
inhalation TTC values with the database RepDose. Regulatory Toxicology and
Pharmacology 2010; 58: 259-274.
11. Michaels, D. Doubt Is Their Product: How Industry's Assault on
Science Threatens Your Health. Oxford University Press. 2008: 53-54.
12. Layton L. Studies on chemical in plastics questioned. Washington
Post 27 April 2008.
13. Dingell JD. Letter to Jack N Gerard, president and CEO, American
Chemistry Council. 2 April 2008.
http://bit.ly/ZWMbi6 (accessed 15 April 2013).
14. Nielsen E, Larsen JC. The Threshold of Toxicological Concern
(TTC) concept: Development and regulatory applications. Danish Ministry of
the Environment, Environmental Protection Agency. Environmental Project
No. 1359. 2011. http://www2.mst.dk/udgiv/publications/2011/03/978-87-92708
-86-1.pdf (accessed 15 April 2013).
15. European Food Safety Authority (EFSA). Declarations of interests
(DoIs). http://www.efsa.europa.eu/en/efsawho/doi.htm (accessed 15 April
16. Pratt I, Barlow S, Kleiner J, et al. The influence of thresholds
on the risk assessment of carcinogens in food. Mutation Research 2009;
Hans Muilerman is employed at Pesticide Action Network Europe, which receives funding from trusts and foundations, including the European Endocrine Health Initiative.