Synergistic Interaction Leads to Supra-additive Hepatotoxicity After Chloroform and Allyl Alcohol Binary Mixture, But Not Toxic Outcome: Role of Stimulated Tissue Repair. S. S. Anand,* S. N. Murthy, M. M. Mumtaz, and H. M. Mehendale, The University of Louisiana at Monroe, ATSDR
The objective of this study was to establish dose-response relationship for chloroform (CHCl3) and allyl alcohol (AA) binary mixture (BM) by measuring liver injury and tissue repair in a temporal manner. Male Sprague Dawley rats (250-300 g) were administered with a 5-fold dose range of CHCl3 (74 to 370 mg/kg, ip) and 7-fold dose range of AA (5 to 35 mg/kg, ip) simultaneously. Liver injury was assessed by plasma alanine aminotransferase (ALT) elevations, and histopathology and tissue repair was measured by 3H-thymidine incorporation into hepatonuclear DNA. CHCl3 and AA levels in blood and liver were quantified by gas chromatography during 30 to 360 min and 5 to 60 min, respectively. The blood and liver AA levels after BM were similar to the levels after AA alone. The absorption and metabolism of CHCl3 were higher after highest combination, whereas at lower combination the levels were not different from CHCl3 alone. Liver injury, as assessed by ALT activity peaked at 24 h for highest combination, and at lower doses injury peaked at 48 h and regressed subsequently. This finding was supported by histopathological observations. Interaction of these compounds at highest combination resulted in supra-additive response. At lower combinations the response was no more than additive. Although liver injury was augmented, it was overcome by promptly stimulated robust liver tissue repair. We report here that irrespective of the extent of injury, repair response determines the final outcome of toxic insult and measuring this response might enhance the precision and predictive value of dose-response paradigms in toxicology.
This work was supported by the Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta, GA, U61/ATU681482.
*Student Travel Award and Best Paper Finalist.
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