title: Relevance of the mouse skin initiation-promotion model for the classification of carcinogenic substances encountered at the workplace.
abstract: The Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission of the Deutsche Forschungsgemeinschaft) evaluates chemical substances using scientific criteria to prevent adverse effects on health at the work place. As part of this task there is a need to evaluate tumor promoting activity of chemicals (enhancement of formation of squamous cell carcinomas via premalignant papillomas) obtained from two-stage initiation/promotion experiments using the mouse skin model. In the present communication we address this issue by comparing responses seen in mouse skin with those in humans. We conclude that tumor promotional effects seen in such animal models be carefully analyzed on a case by case basis. Substances that elicit a rather non-specific effect that is restricted to the high dose range are considered to be irrelevant to humans and thus do not require classification as carcinogens. In contrast, substances that might have both a mode of action and a potency similar to the specific effects seen with TPA (12-O-tetradecanoylphorbol-13-acetate), the prototype tumor promoter in mouse skin, which triggers receptor-mediated signal cascades in the very low dose range, have to be classified in a category for carcinogens.
authors.affiliation: Eberhard Karls University of Tübingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany. Electronic address: michael.schwarz@uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Heinz W
authors.initials: HW
authors.lastname: Thielmann
authors.affiliation: Scientific Secretariat of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission), Hohenbachernstr. 15-17, D-85354 Freising-Weihenstephan, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Meischner
authors.affiliation: Ruhr University Bochum, Institute for Prevention and Occupational Medicine of the DGUV, Department for Clinical and Experimental Occupational Dermatology, Bürkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany.
authors.forename: Manigé
authors.initials: M
authors.lastname: Fartasch
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016273:Occupational Exposure / Q000009:adverse effects*; D012867:Skin / Q000187:drug effects* / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage; D017132:Workplace
chemical_list: D002273:Carcinogens; D013755:Tetradecanoylphorbol Acetate
keywords: Carcinoma; Mouse skin; Papilloma; Tumor promotion; Workspace