The broad objective of the proposed research is to investigate the metabolism and toxicity of hydrochlorofluorocarbons (HCFCs), including chlorodifluoromethane (HCFC-22), 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123), 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), 1, 1,1,2,2-pentafluoroethane (HCFC-125), 1,2-dichloro-1,1-difluoroethane (HCFC-132b), 1,1,1,2-tetrafluoroethane (HCFC-134a), 1,1-dichloro-1-fluoroethane (HCFC-141b), and 1-chloro-l,l-difluoroethane (HCFC-142b). These HCFCs have been proposed as replacements for chlorofluorocarbons presently in use whose release into the atmosphere may be associated with destruction of stratospheric ozone. Because stratospheric ozone is an important barrier against ultraviolet radiation and serves to reduce the amount of ultraviolet radiation that may otherwise reach the earth, depletion of the ozone layer by chlorofluorocarbons may lead to global, adverse human health effects.
The Specific Aims of the research are (1) to investigate the metabolism of HCFCs in rat hepatocytes and in rat liver subcellular fractions and (2) to investigate the toxicity of HCFCs and their metabolites. The toxicological investigations will include cytotoxicity studies in isolated hepatocytes, studies on the toxicity of putative 2,2,2-trihaloethanol metabolites of HCFCs in intact rats, and studies on the acylation of cellular macromolecules by HCFC metabolites. The metabolism studies will rely on gas chromatography, gas chromatography/mass spectrometry, and (19)F NMR for metabolite identification and quantification and on immunochemical techniques to study protein acylation by HCFC metabolites. These studies are significant because HCFCs will enjoy widespread use, which may be accompanied by global exposure of the human population to HCFCs. It is, therefore, essential to understand fully the biological effects of HCFCs, and studies on their metabolism and toxicity in experimental animals will provide information needed to assess the risk associated with human exposure to HCFCs.
