Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin.

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumour incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evidence for a non-genotoxic mechanism. Examples of such substances include croton oil, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.