Potentiation of carbon tetrachloride hepatotoxicity by inhaled methanol: Time course of injury and recovery

Abstract

Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. Because oral exposure to MeOH potentiates the hepatotoxicity of carbon tetrachloride (CCI₄), we examined the ability of inhaled MeOH to potentiate CCI₄ hepatotoxicity and the time course of injury and recovery. Adult male F‐344 rats were exposed to 0 or to 10,000 ppm MeOH by inhalation lor 6 h and gavaged with 0.075 ml CCI₄/kg 24 h later. Hepatotoxicity was assessed 0.5, 1, 1.5, 2, 3, 7, 15, 30, and 61 d after CCI₄ exposure. For CCI₄ alone, hepatotoxicity was most severe at 0.5 and 1 d, when minimal centrilobular hepatoceltular necrosis and predominately mild centrilobular hepato‐cellular vacuolar degeneration occurred. By d 3, the livers from the CCI₄ rats were histo‐logically normal. For MeOH + CCI₄, peak seventy of hepatic injury was at 1 and 1.5 d, when moderate centrilobular necrosis and moderate/marked centrilobular degeneration occurred. MeOH + CCI₄ resulted in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that were increased, relative to CCI₄ alone, 171‐ and 113‐fold, respectively, on d 1, and 166‐ and 140‐fold, respectively, on d 1.5. Significant serum elevations in MeOH + CCI₄ rats, relative to CCI₄ alone rats, were present until d 7 and d 15 for AST and ALT, respectively. By d 3 and d 7, degeneration and necrosis, respectively.