Abstract:

A novel approach to the assessment of the toxicity of the chlorinated pesticide hexachlorocyclohexane (lindane) and the organic solvents methanol and w-butanol, employing endothelial cells in culture, is presented. This highly reproducible system involves the simultaneous treatment of [51Cr]. and [3H]arachidonic acid-labeled rat pulmonary endothelial cells with xenobiotics combined with glucose oxidase-generated H2O2, phospholipase c, streptolysin S, diethyldithiocarbamate (DDC), sodium nitroprusside (NP), histone, and trypsin. Such treatment leads to synergistic cell killing and the release of arachidonic acid (Ginsburg and Kohen, 1995b). Thus, subtoxic amounts of xenobiotics that failed to kill the cells became highly cytolytic when combined with the various mixtures of agonists. Cytotoxicity and the release of membrane lipids are strongly inhibited by catalase, by Mn2+, and by soybean trypsin inhibitor. The "synergism" concept of cellular toxicity is relevant, in particular, in infectious and inflammatory sites where phagocyte- and tissue-derived proinflammatory agonists are generated in large amounts as a result of cellular damage induced either by pathogenic microorganisms, by activated phagocytes, or by xenobiotics. This simple and inexpensive in vitro model of cellular cytotoxicity might supplement and even replace the more costly animal experimentations involved in the assessment of the toxicity and safety of newly designed drugs.