December 10, 2009 by Mark Crane

A forthcoming paper by Mel, me and several other colleagues in January’s
issue of the SETAC journal Integrated Environmental Assessment and Management looks at use of the threshold of toxicological concern. The threshold of toxicological concern (TTC) concept proposes that an exposure threshold value can be derived for chemicals, below which no significant risk to human health or the environment is expected. This concept goes further than setting acceptable exposure levels for individual chemicals, because it attempts to set a de minimis value for chemicals, including those of unknown toxicity, by taking the chemical’s structure or mode of action (MOA) into consideration. Our paper examines the use of the TTC concept for endocrine active substances (EAS) with an estrogenic MOA. A case study formed the basis for a workshop of regulatory, industry and academic scientists held to discuss the use of the TTC in aquatic environmental risk assessment. The feasibility and acceptability, general advantages and disadvantages, and the specific issues that need to be considered when applying the TTC concept for EAS in risk assessment were addressed. Issues surrounding the statistical approaches used to derive TTCs were also discussed. This paper presents discussion points and consensus findings of the workshop.

Overall conclusions were that the TTC approach is used as an effective and proportionate screen for a wide range of substances present at very low concentrations in food for human consumption. In principle, it can be applied to substances likely to be found at very low concentrations in the aquatic environment, including those with an endocrine active MOA, in an approach with some analogies to the use of species sensitivity distributions. Reliable use of a TTC in environmental risk assessment will require understanding of an untested substance’s MOA and potency class, plus a reliable training set of data for long-term demographic effects on sensitive organisms of substances with that specific MOA. These are significant limiting factors for the applicability of this concept for EAS at the present time.

To investigate further the applicability of the TTC concept for EAS, and to help develop the basis for eventual guidance, a number of follow-up activities are recommended. These include: i) further investigation into the combined use of in vitro and structure-activity data in establishing MOAs; ii) establishing criteria for the type, number and acceptability of data when deriving a TTC, and for its subsequent use with a ‘new’ substance with a reliably identified MOA, iii) establishing criteria for estimating reliable exposure concentrations of that substance for comparison with the TTC, and iv) investigation of whether an approach analogous to the use of toxic equivalents could be incorporated into use of the TTC for substances with a similar MOA to address mixture toxicity issues.

Email me if you’d like a copy of the paper.