HEPATIC AND PULMONARY CARCINOGENICITY OF METHYLENE-CHLORIDE IN MICE -A SEARCH FOR MECHANISMS

An inhalation study utilizing over 1400 female B6C3F1 mice was underta ken to study mechanistic factors associated with liver and lung tumor induction following exposure to 2000 ppm of methylene chloride. Mice w ere exposed to methylene chloride (treated) or,chamber air (controls) 6 h per day, for varying durations up to 104 weeks. Several interim sa crifices and 'stop exposures' were included. Exposure to 2000 ppm meth ylene chloride caused an increase in liver and lung neoplasia in the a bsence of overt cytotoxicity. Measurement of replicative DNA synthesis done after 13, 26, 52 and 78 weeks of exposure showed a significant d ecrease in the hepatocyte labeling index at 13 weeks. Replicative DNA synthesis in pulmonary airways after 1 2, 3, 4, 13 and 26 weeks of exp osure to methylene chloride was significantly lower than in air-expose d controls. Likewise, the increase in tumor induction in treated mice was not associated with increased replicative DNA synthesis in liver f oci or in alveolar parenchyma. The frequency and pattern of H-ras gene activation were similar in control and methylene chloride-induced liv er neoplasms. Similarly, the frequency and pattern of K-ras activation in lung neoplasms were not altered by exposure to methylene chloride. Early exposure to methylene chloride for only 26 weeks was sufficient to cause an increase in lung tumors by 2 years, suggesting that methy lene chloride may cause early and persistent loss of growth control in lung cells. This implies that risk management strategies should be ai med at minimizing or eliminating exposure to methylene chloride. Liver neoplasms continued to increase in incidence and multiplicity as expo sure continued, suggesting that methylene chloride-induced hepatocarci nogenesis is facilitated by continuing exposure to methylene chloride. Since methylene chloride is a more potent inducer of lung than liver neoplasia, it is recommended that health risk assessment be based on t he lung data. While no novel molecular lesions have been found to expl ain the induction of lung and liver neoplasia in mice, ongoing studies may identify other molecular changes that are important in the genesi s of these neoplasms. Hence, it may be necessary to revise risk assess ment and management strategies in light of future research findings.