EFFECT OF VARYING EXPOSURE REGIMENS ON METHYLENE CHLORIDE-INDUCED LUNG AND LIVER-TUMORS IN FEMALE B6C3F1 MICE

Methylene chloride is a high production chemical used in a variety of applications resulting in estimated occupational and consumer exposure s of at least one million people per day. Results of previously report ed chronic evaluations of inhaled methylene chloride indicated that it caused mammary tumors in Fischer 344 rats and neoplasia in the lungs and liver of B6C3F1 mice. Mechanism(s) for methylene chloride-induced carcinogenesis have not been adequately elucidated. In this paper we d escribe the histologic evaluation of animals at a number of intermitte nt times for the purposes of assessing the progressive development of liver and lung neoplasia. Additionally, a series of stop-exposure trea tments was conducted to evaluate the role of different methylene chlor ide exposure durations on the induction of hepatic and pulmonary neopl asia in female mice. Inhalation exposure to 2000 p.p.m. methylene chlo ride for 6 h per day, 5 days per week, for 104 weeks resulted in an 8- fold increase in the incidence of exposed animals having a lung adenom a or carcinoma (63 versus 7.5%; P < 0.01) and a 13-fold increase in th e total number of pulmonary adenomas and carcinomas per animal at risk (0.97 versus 0.075; P < 0.01). This exposure also caused a 2.5-fold i ncrease in the incidence of mice having liver tumors (69 versus 27%; P < 0.01) and a 3-fold increase in the total number of hepatic adenomas and carcinomas per animal at risk (1.34 versus 0.46; P < 0.01). Methy lene chloride exposure hastened the first appearance of lung tumors (b y 1 year) compared to that observed in control animals; chemical-induc ed and spontaneous liver tumors first occurred simultaneously. A short er exposure duration was sufficient to attain maximal numbers of lung tumors than that needed for a maximal liver tumor burden. Lung tumor m ultiplicity was substantially increased by having additional time afte r cessation of the chemical treatment. This contrasts with the finding s in liver, where additional post-exposure latency time did not effect tumor multiplicity compared to that of mice evaluated immediately aft er cessation of exposure. The incidence of lung alveolar hyperplasia i n methylene chloride exposed animals was very low, even in tumor-beari ng animals and the hyperplasias were not seen until at least 13 weeks after appearance of adenomas and carcinomas. Thus, the genesis of meth ylene chloride induced lung tumors in B6C3F1 mice is not preceeded by overt cytotoxicity, enhanced cell proliferation nor observed hyperplas ia. The differential behavior of the target organs to varying exposure regimens, suggests to us that the mechanisms responsible for its tumo rigenicity are different in the lung and the liver.