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CORESTA Congress, New Orleans, 2002, ST 09

The relative toxicity of substituted phenols reported in cigarette mainstream smoke

SMITH C.J.; PERFETTI T.A.; MORTON M.J.; RODGMAN A.; GARG R.; SELASSIE C.D.; HANSCH C.
R.J. Reynolds Tobacco Company, R&D, Winston-Salem, NC, USA

Cigarette mainstream smoke (MS) contains a number of structurally diverse substituted phenols. Recent quantitative structure activity relationship (QSAR) studies of phenols show that substituted phenols with electron-releasing groups can form potentially toxic phenoxyl free radicals. In contrast, substituted phenols with electron-withdrawing groups do not form phenoxyl free radicals but may be toxic due to their lipophilicity. The chemical structures of 253 different substituted phenols reported in MS have been described in sufficient detail to allow identification of the individual compounds. From a laterally validated equation based on published data on the toxic effects of phenols on cultured cells, the relative toxicity, on a molar basis, of the 253 MS phenols has been estimated. Based on this approach, the most toxic phenols in MS are estimated to include in descending order of toxicity: 2-(dimethylamino)-phenol, 2-ethyl-6-methyl-1,4-benzenediol, 2-methoxy-1,4-benzenediol and 4-ethyl-2-methoxy-6-methylphenol. The least toxic phenols in ascending order of toxicity are 4-hydroxybenzoic acid and 3-hydroxybenzenepropanoic acid. In the human exposure situation, the toxicity of MS phenols is a complex interaction with contributions made by the following factors: toxicity per mole; MS concentration; synergistic, additive or antagonistic interactions with other MS components; host susceptibility; metabolism; and individual smoking behavior and inhalation patterns. Since reducing the number and concentration of toxic MS components is widely considered to be desirable, studies of this type can play an important role in helping to identify specific MS components for reduction or removal.