Relevance of the mouse skin initiation–promotion model for the classification of carcinogenic substances encountered at the workplace

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Highlights

  • The MAK Commission evaluates occupational chemicals for adverse health effects.

  • Amongst these effects, tumor promoting activity in mouse skin is considered.

  • We now suggest that this activity be evaluated on a case by case basis.

  • Mouse skin tumor promoters requiring high doses are not classified as carcinogens.

  • Receptor-mediated effects observed at very low doses require such classification.

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.

Section snippets

Current situation and issue

The “classical” standardized (Schmidt and Hecker, 1989, Filler et al., 2007) two-stage carcinogenesis experiment (synonym: initiation–promotion model) in dorsal mouse skin provides valuable mechanistic information on chemically provoked skin cancer development. In this standardized procedure, a carcinogen such as 7,12-dimethylbenz[a]anthracene (DMBA) is applied for tumor initiation – as a single dose – followed by repeated treatment with a tumor promoter, such as the phorbol ester 12-O

Quantitative aspects of DMBA/TPA tumor promotion in the skin

The dose and time response of TPA promotion was investigated in numerous experimental studies. Lutz et al. (1996) analyzed papilloma development on the dorsal mouse skin at a constant DMBA dose and variable TPA doses. Very low doses of DMBA (2 nmol; twice weekly) were applied in combination with TPA. The authors observed saturation of the papilloma response in the high TPA dose range. A 50% papilloma response was reached after ∼7 weeks at 10 nmol/application and after ∼8 weeks at 3 nmol. A papilloma

Evaluation of other compounds with promoting effects on the dorsal mouse skin in the two-stage initiation–promotion model

A large number of substances have tumor-promoting activity in the two-stage initiation–promotion model in dorsal mouse skin. The chemical structure of various tumor promoters is very heterogeneous, as are the assumed primary mechanism of action and the potency of the different substances. Table 1 shows some of the known active compounds (DiGiovanni, 1992).

Skin irritation is a common characteristic of the listed substances (see below). At certain doses, strong tumor promoters, such as TPA,

Actinic keratoses in humans as compared with chemically induced papillomas in mice

Papillomatous changes of the skin formed by the epidermis are quite common in humans and are sometimes caused by viruses. There is no direct equivalence to papillomas in mice because no malignant courses are known either morphologically or clinically (DiGiovanni, 1992). However, several authors are of the opinion that low-frequency high-risk papillomas might be a small subgroup of papillomas that were induced chemically in animal studies (Hennings et al., 1983, Hennings et al., 1985, Glick et

Evaluation

The experimental results available from model phorbol ester-type promoters indicate considerable species differences and steep dose–response relationships that have almost threshold characteristics. Conversely, the underlying mechanisms of tumor development in the skin of animals and humans are more or less the same, and RAS-mutated stem cells that can be promoted are presumably also latent in human skin. However, humans are probably considerably less susceptible to tumor promoters due to the

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Acknowledgments

We thank Prof. Helmut Greim for very helpful discussions and Ms. Patricia Brozena and Ms. Bettina Teschner for help in preparation of the manuscript.

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