Structure-Based, Tiered TTC Concept

Munro et al. (1996) explored the relationship between chemical structure and toxicities through the compilation of a large reference database consisting of 613 chemical substances tested for a variety of noncarcinogenic toxicological endpoints in rodents and rabbits in oral toxicity tests, including subchronic, chronic, reproductive, and developmental toxicity. For many of the substances, more 

Toxicological Risk Assessments of Chemicals A Practical Guide 

The decision tree method of Cramer et al. (1978) was based on the toxicological data then available and used a series of 33 questions, each leading either to another question or to classification into one of three classes of presumptive toxicity. The questions were primarily based on chemical stmcmre, but namral occurrence in body tissues or fluids as well as natural occurrence in traditional foods was also considered. The three classes of substances were defined as follows  

Cumulative distributions of the logarithms of NOELs were plotted separately for each of the stmcmral classes. The 5th percentile NOEL was estimated for each stmctural class and this was in mrn converted to a human exposure threshold by applying the conventional default safety factor of 100 (Section 5.2.1). The stmcmre-based, tiered TTC values established were 1800 p,g/person/ day (Class I), 540 pg/person/day (Class II), and 90 pg/person/day (Class III). Endpoints covered include systemic toxicity except mutagenicity and carcinogenicity. Later work increased the number of chemicals in the database from 613 to 900 without altering the cumulative distributions of NOELs (Barlow 2005). 

The stmcmre-based, tiered TTC approach as outlined by Munro et al. (1996, 1999) is used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in a procedure for the evaluation of flavoring substances in food, including an acceptance of the general TTC of 1.5 pg/person/day, i.e., the US-FDA Threshold of Regulation (Section 4.13.1). The European Food Safety Authority (EFSA) also uses this approach for evaluation of flavoring substances, except that the general TTC of 1.5 pg/person/day is not accepted (Larsen 2006). 

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