TTC: A new concept for inhalation exposure

The TTC concept derives thresholds to structural groups of compounds below which a risk for human health is not assumed for a life-time exposure. Thresholds were derived by analyzing datasets of oral in vivo studies to which the Cramer decision tree was applied. Inhalation is, however, an important route in human risk assessment e.g. for workers and consumers. The application of the Cramer decision tree to datasets of repeated-dose studies with inhalation exposure resulted in very low thresholds compared to oral TTC values. Reasons might be route specific differences e.g. an observed high sensitivity of the respiratory tract to local effects (Carthew et al. 2009, Escher et al. 2010). We present an integrative approach to derive inhalation specific threshold values, which are based on a dataset of 296 chemicals with repeated-dose toxicity studies (www.fraunhofer-repdose.de). Systemic and local NOEC values were discriminated. Groups of compounds with specific structural features (SF) were identified based on atom centered fragments (Kühne et al. 2009). Few SF were explicit for local or systemic activity indicating that this mode of action is not a determining factor. The structural and toxicological boundaries of the initial SFs were further evaluated considering differences in absorption, published data on mechanism/ metabolism and sensitive targets/effects observed in the in vivo studies. 28 SF groups resulted, 9 low (L) and 19 toxic (T) groups. About 20% of the compounds are, however, not yet grouped. Compared to the Cramer classes the T and L-groups better discriminate low toxic and toxic compounds. Two clearly distinguished TTC values are proposed