Air pollutants, a possible factor in gastrointestinal cancer

During incomplete combustion of organic matter there is formation of polycyclic aromatic hydrocarbons (PAH), which can react with oxides of nitrogen, with the generation of nitro-PAH's as a result, a reaction which is catalyzed by a low pH. 2-Nitrofluorene (NF), a marker for nitro-PAH, is metabolized in vivo via two different routes. After inhalation there is a formation of potent mutagenic metabolites, ON-NF's, which are distributed in the body. After oral administration, NF is reduced to the amine, a reaction mediated by the intestinal microflora, and further acetylated to 2-acetylaminofluorene (AAF), a potent carcinogen. Further ring-hydroxylation of AAF leads to detoxification and excretion. Induction of cytochrome P450c, d affects the metabolism in that more OH-NF's are formed. As a consequence, more mutagenic metabolites are found in the circulation. The liver excretes OH-NF's as, in terms of mutagenicity, glucuronide conjugates. When these conjugates are excreted via the bile, intestinal beta-glucuronidase can liberate direct-acting mutagens in the intestine. Thus, inhalation of NF can lead to formation of potent mutagens in the intestine. NF induces DNA-repair, in vivo, and is an initiator and a weak promotor, measured as formation of preneoplastic lesions in the liver. Risk estimates, by two different methods, indicate that nitro-PAH's extrapolated from the marker NF, can expose humans to a cancer risk at a nonneglectable level.