Toxicological Sciences, Vol 49, 110-115, Copyright © 1999 by Society of Toxicology
WK Lutz and A Kopp-Schneider
Dose-response relationships for tumor induction in animal bioassays for
carcinogenicity are often postulated to include thresholds, particularly
for nongenotoxic chemicals that increase the rate of cell proliferation at
high doses. In this report, thresholds are postulated also for genotoxic
carcinogens. The hypothesis is based on the idea of a delay of the cell
cycle induced by low-level DNA damage and an acceleration at cytotoxic dose
levels, thus resulting in a J-shaped (or U-shaped) dose response for cell
turnover. Calculations were based on the 2-stage clonal expansion model of
carcinogenesis. The background values chosen for the model parameters
resulted in a 10.5% "spontaneous" 2-year cumulative tumor incidence. Using
this as a starting point, a decrease by 3, 10, and 30% in the rates of cell
turnover resulted in a decrease in the spontaneous tumor incidence to 9.4,
7.1 and 3.0%, respectively. Dose-responses with J-shaped curves for the
rates of cell birth and death were modeled by shifted quadratic functions
reaching the minimum at dose 1. Combinations with linearly increasing
mutation rates also generated, under certain conditions, J- shaped
dose-response curves for tumor incidence. As an example, for a 30% increase
in mutation rates and a 10% decrease in cell turnover rates (both at dose
1), the dose-response curve showed an initial decrease of tumor incidence
below the spontaneous rate, a reversion to the background value at 0.8 dose
units, and an increase thereafter. The 0.8 dose could be considered to
represent the "threshold dose." The approach presented might reconcile
opposing views on thresholds on a biologically plausible mechanistic basis,
and show a way for the quantitative estimation of threshold doses.
ARTICLES
Threshold dose response for tumor induction by genotoxic carcinogens modeled via cell-cycle delay
Department of Toxicology, University of Wuerzburg, Germany. lutz@toxi.uni-wuerzburg.de
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