Nongenotoxic or Epigenetic Carcinogenesis

Abstract

Carcinogens are considered nongenotoxic where they cannot be shown to interact directly with DNA in a number of short-term screening assays, but which are capable of producing tumours in laboratory rodents in bioassays. Epigenetic events, either acting alone or in concert with genetically determined events, may produce tumours. A key feature is that dose-threshold effects may be identifiable. In both the rat and the mouse, the liver is the most common site of nongenotoxic carcinogenesis. A special sort of hepatic carcinogenesis is that produced in rodents by peroxisome proliferators; this is of questionable significance for humans. Other important sites of non-genotoxic carcinogenesis include endocrine glands notably the thyroid, bladder and, in the rat, the forestomach. Carcinoid tumours are tumours of the diffuse neuroendocrine cell populations, found particularly in the gastrointestinal tract. Their incidence is increased with certain drugs, notably the histamine H2 antagonists. Haemangiosarcoma, which may occur at a variety of sites, clearly arises by a number of mechanisms, some of which may be genotoxic. Mesothelioma, most often of the pleura, as a human response to asbestos, may be considered a form of non-genotoxic carcinogenesis. Keywords: carcinogens; nongenotoxic; DNA; tumours; liver; peroxisome; thyroid; bladder; forestomach; carcinoid; haemangiosarcoma; mesothelioma