title: Inhalation TTC values: A new integrative grouping approach considering structural, toxicological and mechanistic features.
abstract: The present publication describes an integrative grouping concept to derive threshold values for inhalation exposure. The classification scheme starts with differences in toxicological potency and develops criteria to group compounds into two potency classes, namely toxic (T-group) or low toxic (L-group). The TTC concept for inhalation exposure is based on the TTC RepDose data set, consisting of 296 organic compounds with 608 repeated-dose inhalation studies. Initially, 21 structural features (SFs) were identified as being characteristic for compounds of either high or low NOEC values (Schüürmann et al., 2016). In subsequent analyses these SF groups were further refined by taking into account structural homogeneity, type of toxicological effect observed, differences in absorption, metabolism and mechanism of action (MoA), to better define their structural and toxicological boundaries. Differentiation of a local or systemic mode of action did not improve the classification scheme. Finally, 28 groups were discriminated: 19 T-groups and 9 L-groups. Clearly distinct thresholds were derived for the T- and L-toxicity groups, being 2 × 10(-5) ppm (2 μg/person/day) and 0.05 ppm (4260 μg/person/day), respectively. The derived thresholds and the classification are compared to the initial mainly structure driven grouping (Schüürmann et al., 2016) and to the Cramer classification.
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany; Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany. Electronic address: inga.tluczkiewicz@item.fraunhofer.de.
authors.forename: I
authors.initials: I
authors.lastname: Tluczkiewicz
authors.affiliation: Helmholtz Centre for Environmental Research - UFZ, Permoserstr. 15, 04318 Leipzig, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kühne
authors.affiliation: Helmholtz Centre for Environmental Research - UFZ, Permoserstr. 15, 04318 Leipzig, Germany.
authors.forename: R-U
authors.initials: RU
authors.lastname: Ebert
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Batke
authors.affiliation: Helmholtz Centre for Environmental Research - UFZ, Permoserstr. 15, 04318 Leipzig, Germany; Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schüürmann
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Mangelsdorf
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
authors.forename: S E
authors.initials: SE
authors.lastname: Escher
mesh_terms: D065567:Absorption, Physiological; D000818:Animals; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D015386:Hazardous Substances / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008958:Models, Molecular; D015394:Molecular Structure; D019055:No-Observed-Adverse-Effect Level; D009930:Organic Chemicals / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D010363:Pattern Recognition, Automated; D018570:Risk Assessment; D013329:Structure-Activity Relationship; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015386:Hazardous Substances; D009930:Organic Chemicals
keywords: Grouping; Inhalation exposure; Local effects; Repeated dose; TTC; Threshold of toxicological concern; Toxicity