Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Abstract

It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though individual chemicals might not be toxic at low doses. Chemical mixtures may also cause additive or less than additive toxicity. From the perspective of public health, highly exaggerated toxicity is of significant concern. Assessment of risk from exposure to chemical mixtures requires knowledge of the underlying mechanisms. Previous studies from this laboratory have shown that nontoxic doses of chlordecone (10 ppm, 15 days) and carbon tetrachloride (CCl4) (100 microliters/kg) interact at the biologic interface, resulting in potentiated liver injury and 67-fold amplification of CCl4 lethality. In contrast, although interaction between phenobarbital and CCl4 leads to even higher injury, animal survival is unaffected because of highly stimulated compensatory tissue repair. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by hepatotoxicants. These findings led us to propose a two-stage model of toxicity. In this model, tissue injury is inflicted in stage one by the well-described mechanisms of toxicity, whereas in stage two the ultimate toxic outcome is determined by whether timely and sufficient tissue repair response accompanies this injury. In an attempt to validate this model, dose-response relationships for injury and tissue repair as opposing responses have been developed for model hepatotoxicants. Results of these studies suggest that tissue repair increases in a dose-dependent manner, restraining injury up to a threshold dose, whereupon it is inhibited, allowing an unrestrained progression of injury. These findings indicate that tissue repair is a quantifiable response to toxic injury and that inclusion of this response in risk assessment may help in fine-tuning prediction of toxicity outcomes. Images Figure 3 Figure 4 Figure 6

The Effects of Combined Treatment of Antioxidants on the Liver Injury in STZ Diabetic Rats

“…Shankar et al [55] determined that number of G 2 phase hepatocytes are significantly higher 10 days after STZ treatment (1.26%). These data support that, in addition to the mechanism of initiate toxicity, the dynamics of the compensatory tissue repair response influence the ultimate outcome of toxicity (survival or death) [56]. As a result, hepatocyte proliferation may peak at day 10, then decline at days 30 or 60 after STZ injection.…”

The Effects of Combined Treatment of Antioxidants on the Liver Injury in STZ Diabetic Rats

“…Shankar et al [55] determined that number of G 2 phase hepatocytes are significantly higher 10 days after STZ treatment (1.26%). These data support that, in addition to the mechanism of initiate toxicity, the dynamics of the compensatory tissue repair response influence the ultimate outcome of toxicity (survival or death) [56]. As a result, hepatocyte proliferation may peak at day 10, then decline at days 30 or 60 after STZ injection.…”

Acetaminophen-Induced Forestomach Lesion in Normal Rats Following Intravenous Exposure

“…For example, it has been shown that a low, non-necrogenic dose of carbon tetrachloride (CCl 4 ) administered to rats produced a rapid proliferation in hepatocytes, which was thought to be instrumental in the prevention of necrosis. When the early proliferative response to CCl 4 was blocked with chlordecone, the non-necrogenic dose of CCl 4 caused significant necrosis (Soni and Mehendale 1998).…”

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

“…Body weight was significantly decreased in the 154 kcal group, suggesting an overall decrease in total body water and volume of distribution; this could be a cause of the increased UECs in that group. Compensatory tissue repair is known to influence the final outcome of hepatotoxicity (8,31,44), and it is known that nutritional factors may modulate the tissue repair response in addition to altering the metabolic activation of hepatotoxicants (32). Timely onset of cell division and sustained continuation of the cell proliferative response are of pivotal importance for survival in the face of liver injury; however, such a sustained increase in the hepatocyte proliferative rate will also increase the risk of carcinogenesis (15).…”

The Effects of Combined Treatment of Antioxidants on the Liver Injury in STZ Diabetic Rats

“…Shankar et al [55] determined that number of G 2 phase hepatocytes are significantly higher 10 days after STZ treatment (1.26%). These data support that, in addition to the mechanism of initiate toxicity, the dynamics of the compensatory tissue repair response influence the ultimate outcome of toxicity (survival or death) [56]. As a result, hepatocyte proliferation may peak at day 10, then decline at days 30 or 60 after STZ injection.…”

Acetaminophen-Induced Forestomach Lesion in Normal Rats Following Intravenous Exposure

“…For example, it has been shown that a low, non-necrogenic dose of carbon tetrachloride (CCl 4 ) administered to rats produced a rapid proliferation in hepatocytes, which was thought to be instrumental in the prevention of necrosis. When the early proliferative response to CCl 4 was blocked with chlordecone, the non-necrogenic dose of CCl 4 caused significant necrosis (Soni and Mehendale 1998).…”

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

“…Body weight was significantly decreased in the 154 kcal group, suggesting an overall decrease in total body water and volume of distribution; this could be a cause of the increased UECs in that group. Compensatory tissue repair is known to influence the final outcome of hepatotoxicity (8,31,44), and it is known that nutritional factors may modulate the tissue repair response in addition to altering the metabolic activation of hepatotoxicants (32). Timely onset of cell division and sustained continuation of the cell proliferative response are of pivotal importance for survival in the face of liver injury; however, such a sustained increase in the hepatocyte proliferative rate will also increase the risk of carcinogenesis (15).…”

The Effects of Combined Treatment of Antioxidants on the Liver Injury in STZ Diabetic Rats

“…Shankar et al [55] determined that number of G 2 phase hepatocytes are significantly higher 10 days after STZ treatment (1.26%). These data support that, in addition to the mechanism of initiate toxicity, the dynamics of the compensatory tissue repair response influence the ultimate outcome of toxicity (survival or death) [56]. As a result, hepatocyte proliferation may peak at day 10, then decline at days 30 or 60 after STZ injection.…”

Acetaminophen-Induced Forestomach Lesion in Normal Rats Following Intravenous Exposure

“…For example, it has been shown that a low, non-necrogenic dose of carbon tetrachloride (CCl 4 ) administered to rats produced a rapid proliferation in hepatocytes, which was thought to be instrumental in the prevention of necrosis. When the early proliferative response to CCl 4 was blocked with chlordecone, the non-necrogenic dose of CCl 4 caused significant necrosis (Soni and Mehendale 1998).…”

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

“…Body weight was significantly decreased in the 154 kcal group, suggesting an overall decrease in total body water and volume of distribution; this could be a cause of the increased UECs in that group. Compensatory tissue repair is known to influence the final outcome of hepatotoxicity (8,31,44), and it is known that nutritional factors may modulate the tissue repair response in addition to altering the metabolic activation of hepatotoxicants (32). Timely onset of cell division and sustained continuation of the cell proliferative response are of pivotal importance for survival in the face of liver injury; however, such a sustained increase in the hepatocyte proliferative rate will also increase the risk of carcinogenesis (15).…”