Toxicological Sciences 69, 265-278 (2002)
Copyright © 2002 by the Society of Toxicology
SAFETY EVALUATION |
The Relative Toxicity of Substituted Phenols Reported in Cigarette Mainstream Smoke
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* R&D, Bowman Gray Technical Center, RJRT Company, Winston-Salem, North Carolina 27102–1487;
Fundamental Research, R&D, RJRT Company, Winston-Salem, North Carolina 27102–1487; and
Department of Chemistry, Pomona College, Claremont, California
Cigarette mainstream smoke (MS) contains a number of structurally diverse substituted phenols. Recent quantitative structure activity relationship (QSAR) studies on 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 exert their toxicity primarily through 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 determined. Based on this scheme, the most toxic phenols in MS 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 include, in ascending order of toxicity, 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. In the absence of data to the contrary, reduction in the number and concentration of toxic MS smoke components may be considered to be advantageous. Studies of this type can play an important role in identifying MS components for reduction or removal.
Key Words: free radicals; toxic smoke components; lung disease.
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