Comparative cytotoxicity of naphthalene and its monomethyl- and mononitro-derivatives in the mouse lung

Male Swiss-Webster mice were exposed to naphthalene, 1-methyl-, 2-methyl-, 1-nitro- and 2-nitronaphthalene by intraperitoneal injection of peanut oil solutions over a dose range of 0.5-3.0 mmol kg-1 body weight. Treated mice were killed at times from 6 hours to 14 days post-treatment. Tissues were analyzed for cytotoxic effects by optical and electron microscopy, and for cell proliferation by autoradiography following in vitro labeling of lung slices with 3H-thymidine. The naphthalene derivatives varied widely in their cytotoxic effects. The most toxic was 1-nitronaphthalene with no mice surviving doses greater than 1 mmol kg-1. Naphthalene and 2-methylnaphthalene were about equally toxic, followed by 2-nitro- and 1-methylnaphthalene, in decreasing order of toxicity. In all cases the first evidence of cytotoxic effects was seen in the Clara cells of the bronchiolar epithelium, and, at the highest doses, toxic effects were found in the adjacent ciliated cells. Changes could be detected at the ultrastructural level at all doses, and within 6 hours after treatment. Only slight effects were seen in other cell types. Increased cell proliferation following chemical treatment was seen only in the bronchiolar epithelium, among cells tentatively identified as Clara cells or their precursors. Cytotoxic effects of naphthalene and its 1- and 2-methyl derivatives were confined to the lung, with minimal evidence of toxicity in the liver and kidney. The mononitronaphthalenes both produce small areas of centrizonal necrosis in the liver, but no discernible effects in the kidney. The experiments demonstrate the effect of small structural differences on the cytotoxicity of this group of environmental pollutants and also illustrate the sensitivity of the Clara cell as a target for xenobiotics.