ABSTRACT
Since the administration of PPs to rodents generally results in hepatic tumours in the absence of a genotoxic effect, including the lack of any hepatic tumour initiating effect, the primary mechanism of carcinogenicity of these agents most probably involves promotional activity. Therefore, recent research effort has addressed the hepatic proliferative effect of PPs. This research began by characterizing the proliferative effect in the normal hepatocytes. It has been a well known fact for many years that PPs cause substantial increase in liver size within a few days of the onset of administration of chemical (Reddy and Lalwani, 1983). This increase in size is associated with a burst of hepatocyte DNA synthesis that peaks within a few days and then rapidly decreases toward control rates. Using more sensitive techniques to detect low rates of hepatocyte proliferation, Marsman et al. (1988) noted that the livers in rats chronically administered Wy-14,643 had an initial burst of hepatocyte proliferation that rapidly decreased but remained elevated at 10 times the control level (as defined by labelling indices) throughout 1 year of treatment. In contrast, DEHP resulted in a similar initial burst of hepatocyte proliferation that returned to control levels within a few days and remained at control levels for up to 1 year. This result suggested that chronic proliferation in the liver may contribute to the tumour response since Wy-14,643 administration results in a 100% incidence of hepatocellular carcinomas after 1 year compared to a 10% incidence in the livers of rats fed DEHP for 2 years. While implicating chronic enhancement of cell proliferation in the normal hepatocyte population in increasing the tumour response, these data also indicate that chronic enhancement of hepatocyte proliferation may not be essential for tumorigenicity since DEHP, which produced a tumorigenic response after 2 years, did not produce consistent increases in replication for up to 1 year. Further studies have evaluated the correlation of liver tumorigenicity with chronic enhancement of hepatocyte proliferation using a number of other PPs (Price et al., 1991; Eacho et al., 1991). Methylclofenapate is the only other agent that caused a sustained enhancement of hepatocyte proliferation under the conditions of the original bioassay. These results substantiate the early findings noted in the comparison study evaluating Wy-14,643 and DEHP (Marsman et al., 1988). Collectively, the results indicated that chronic enhancement of hepatocyte proliferation is not necessary for tumour formation; however, the compounds and regimens that caused the highest incidence of tumours correlated with the chronic enhancement of cell proliferation. The collective interpretation of these results require caution, because the studies were designed to evaluate hepatocyte replication using one or two doses as previously used in bioassays. Except for Wy-14,643 (Wada et al., 1992) and ciprofibrate (Budroe et al., 1992), no detailed dose response studies have been performed in which cell proliferation has been compared to tumour response over a wide dose range. Therefore, statements made regarding the effect of a chemical may only represent the effect at the dose studied and
apparent differences between compounds may disappear when the various compounds are evaluated at various doses.
