The effects of dose and duration of administration on the promotion index of phenobarbital in multistage hepatocarcinogenesis in the rat

The relative potency of chemicals as promoting agents in multistage hepatocarcinogenesis has been previously defined as the Promotion Index through calculations of quantitative stereology. The Promotion Index is a function of the total cell population of altered hepatic foci in the liver at any given time and dose of promoting agent. When the Promotion Index was determined as a function of the dose of phenobarbital given in the diet for varying periods of time, a value of 394 was obtained for doses less than 0.01%; at doses between 0.01% and 0.1%, the Promotion Index was found to be 47. These values were obtained by the extrapolation of slopes of the Promotion Indices at various doses and durations of administration of phenobarbital. The volume percentages of the liver occupied by seven possible phenotypes using three different markers (gamma-glutamyltranspeptidase, canalicular ATPase and glucose-6-phosphatase) were relatively constant in distribution for up to one year of phenobarbital administration except at the two highest doses employed, 0.5% and 0.1%, at which a maximal effect of the promoting agent has been obtained. Possible mechanisms for the biphasic relationship of the Promotion Index of phenobarbital with the dose and time of administration are discussed.