Threshold of Toxicological Concern (TTC)

Does the current TTC approach adequately cover non-genotoxic tumorigenic substances?

Genotoxic substances are currently regulated according to the TTC1 concept and are thus subject to a very low daily limit of 0.15 µg per person, because it is assumed that even tiny amounts of these substances can potentially cause mutations and thereby lead to tumor formation. But does this also hold true for carcinogenic substances that do not directly damage DNA? Or should such carcinogens be subject to other regulatory limits, e.g. according to the Cramer classes in the TTC concept? 

These questions were addressed in a recently completed Cefic LRI project. The researchers initially identified 137 non-genotoxic tumorigenic substances whose threshold limits could be derived from studies in the Cancer Potency Database and from peer-reviewed publications. To distinguish the most sensitive point of departure for risk assessment, they plotted the study NOAELs against the effective tumor dose (ETD10) and the benchmark dose level (BMDL10) calculated by model averaging using the Proast software. The comparative analysis of NOAEL/EDT10 and BMDL10 values revealed that bioaccumulating substances and steroids were among the 5 percent most toxic compounds. Exclusion of these compounds led to comparable 5th percentiles for chronic NOAEL/BMDL10 values, whereas the 5th percentile EDT10 value was about three times higher. A statistically significant difference, however, was not detected. These results were evaluated with regard to the current TTC, supporting the application of Cramer Class thresholds to non-genotoxic tumorigenic substances.


Sylvia Escher

Contact Press / Media

Dr. Sylvia Escher

Head of Department of In-silico Toxicology

Phone +49 511 5350-330