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Various endogenous and exogenous compounds exert cytotoxic effects via oxygen reduction. In general, these are reduced by intracellular enzymes (reductases of various kinds) in one-electron transfer reactions, before they in turn reduce O2 to O2, the superoxide anion radical. Thus, a cycle is formed of O2 uptake at the expense of cellular reducing equivalents, notably NADPH, generating further active oxygen species (figs 1,2). Structures capable of 'redox cycling' include catechols and other quinone compounds, iron chelates, and aromatic nitro compounds. Several anticancer agents, and also some mutagens, operate on this principle, and their toxic effects may be explained by redox cycling. The particular importance of hypoxic conditions for deleterious O2 effects is given by the concomitant flux through reductive as well as oxidative pathways. Toxic effects include membrane damage resulting from peroxidative reactions of polyunsaturated fatty acids (lipid peroxidation), as well as the attack of reactive oxygen species on proteins (enzymes) and nucleic acids; thus O2 metabolism is linked to carcinogenicity and mutagenicity. Lipid peroxidation is also induced by various halogenated compounds such as carbon tetrachloride. Again, hypoxic conditions are particularly critical because, on the one hand, metabolic activation leading to the free radical is enhanced and, on the other hand, oxygen required for the maintenance of lipid peroxidation is still available. - Powerful antioxidant systems of the cell maintain low steady state concentrations of oxygen metabolites, and toxic effects may, in part, also be explained by the constant drain of reducing equivalents resulting from redox cycling.

The toxicology of the food preservatives butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT) as well as the naturally occurring vitamin E (alpha-tocopherol) is described. In high dosages all three compounds induce in animals impairment of blood clotting, which can be explained by an antagonism with vitamin K. Specific toxic effects to the lung have only been observed with BHT. The other described toxic effects of BHA and BHT are less characteristic and often occur only after high dosage and long-term treatment. However, BHA induces in animals tumours of the forestomach, which are dose dependent, whereas BHT induces liver tumours in long-term experiments. Because there is no indication of genotoxicity of BHA and BHT, all published findings agree with the fact that BHA and BHT are tumour promoters. In contrast to BHA and BHT, vitamin E is not carcinogenic. On the other hand, all three antioxidants have also anticarcinogenic properties. The intake of the necessary high doses as for these effects are, however, contraindicated with BHA and BHT because of their carcinogenic effects. The present overview concludes that the concentrations of BHA and BHT nowadays used in food, drugs and cosmetics are probably harmless. In addition, vitamin E can also be used in higher doses without the occurrence of adverse effects.

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