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Raja S. Mangipudy, Sanjay Chanda, and Harihara M. Mehendale

Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, LA 71209-0470 USA

Abstract

The purpose of the present study was to establish a dose-response relationship for thioacetamide (TA) , where tissue regeneration as well as liver injury were two simultaneous but opposing responses. Male Sprague-Dawley rats were injected intraperitioneally with a 12-fold dose range of TA, and both liver injury and tissue repair were measured. Liver injury was assessed by serum enzyme elevations. Serum alanine aminotransferase (ALT) elevation did not show any dose response over a 12-fold dose range up to 24 hr. A dramatic ALT elevation was evident after 24 hr and only for the highest dose (600 mg/kg) . Tissue regeneration response was measured by ³H-thymidine (³H-T) incorporation into hepatocellular DNA and by proliferating cell nuclear antigen (PCNA) procedure during a time course (6, 12, 24, 36, 48, 72, and 96 hr) . Tissue regeneration, as indicated by ³H-T incorporation, peaked at 36 hr after administration of a low dose of TA (50 mg/kg) . With increasing doses, a greater but delayed stimulation of cell division was observed until a threshold was reached (300 mg/kg) . Above the tissue repair threshold (600 mg/kg) , because stimulated tissue repair as revealed by ³H-T incorporation in hepatonuclear DNA was significantly delayed and attenuated, injury assessed by serum enzyme elevations was remarkably accelerated, indicating unrestrained progression of injury leading to animal death. These findings suggest that, in addition to the magnitude of tissue repair response, the time at which this occurs is critical in restraining the progression of injury, thereby determining the ultimate outcome of toxicity. Whereas dose-related stimulation of tissue repair leads to recovery, delayed and diminished tissue repair response at the high dose leads to progression of liver injury, leading to hepatic failure and animal death. These findings impact on the concept of employing maximally tolerated doses in cancer bioassays. Maximum tolerated doses might represent maximal stimulation of cell proliferation, thereby enhancing the likelihood of errors in DNA replication. Measuring tissue repair and injury as simultaneous biological responses to toxic agents might increase the usefulness of dose-response paradigms in predictive toxicology and in risk assessment. Key words: dose response, maximally tolerated dose, mitosis, necrosis, proliferating cell nuclear antigen, thioacetamide, tissue repair. Environ Health Perspect 103:260-267 (1995)

Address correspondence to Harihara M. Mehendale, Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, LA 71209-0470 USA.

Preliminary results of this study were presented at the fall meeting of the American Society for Pharmacology and Experimental Therapeutics, San Francisco and published in Pharmacologist [35:149 (1993) ].

This work was supported by a starter grant from The Burroughs Wellcome Fund. We thank Harvey J. Clewell, senior project officer, ICF Kaiser International, Ruston, Louisiana, for helpful discussion and suggestions concerning the modeling approach.

Received 26 September 1994 ; accepted 7 December 1994.