Phenol and 14 substituted-phenols were tested for their ability to impair e
pithelial cell membrane integrity in WE rat liver cells as determined by an
increase in lactate dehydrogenase release. Two quantitative structure-acti
vity relationship (QSAR) regression equations were developed which showed t
hat separate mechanisms of phenolic cytotoxicity are important - nonspecifi
c toxicity due to hydrophobicity and formation of phenoxyl radicals. The eq
uations most predictive of phenol toxicity are denoted as log 1/C = -0.98 s
igma(+) + 0.77 log P + 0.23 or log 1/C = - 0.11BDE + 0.76 log P + 0.21, res
pectively, where C is the minimum concentration of substituted-phenol requi
red for a toxic response. P is the octanol water partition coefficient, sig
ma(+) is the electronic Hammett parameter and BDE is the OH homolytic bond
dissociation energy. In the literature, phenol toxicity correlated to sigma
(+) is rare, but there is strong evidence that phenols possessing electron-
releasing groups may be converted to toxic phenoxyl radicals. A common feat
ure in a variety of cells is generation of elevated amounts of reactive oxy
gen species (ROS) associated with a rapid growth rate. The slightly elevate
d cancer risk associated with the use of Premarin may be due to phenoxyl-ty
pe radicals derived from one or more of its components. (C) 2000 Elsevier S
cience Ireland Ltd. All rights reserved.