Relevance of carcinogenicity bioassays in mice in assessing potential health risks associated with exposure to methylene chloride

Abstract

Considerable research has been conducted to identify possible mechanisms of the carcinogenicity of methylene chloride in rodents, and to ascertain whether the observed increased incidences of liver and lung tumours in mice exposed to this substance, are relevant in assessing the potential hazards and risks to human health. On the basis of a study that purported to show qualitative differences between murine and human tissues, in the subcellular localization of the Theta-class glutathione S-transferase enzyme responsible for converting methylene chloride to a putative highly unstable, but reactive genotoxic metabolite, it was suggested that the mouse is an inappropriate model for human health risk assessment. However, other studies conducted in vitro with intact cells do not support the hypothesis that a putatively reactive metabolite of methylene chloride must be generated only within the nucleus in order to be able to interact with genomic DNA. Moreover, investigations employing semi-quantitative methods of mRNA hybridization are not convincing in identifying the subcellular localization of active Theta class glutathione S-transferase, and do not support the hypothesis of the differential subcellular localization of this enzyme within the nucleus of mouse, but not human cells. There is therefore, insufficient evidence to support the view that qualitative differences between humans and mice in the subcellular distribution of Theta-class glutathione S-transferase, renders carcinogenicity studies conducted with mice irrelevant in human hazard identi-fication and risk assessment.