Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks

Abstract

Summary.-The dose-response relationships from the data described in Paper I were analysed. Among unpromoted animals, only doses sufficient to cause ulceration with subsequent promotion due to wound healing caused a rapid crop of tumours, so the dose-response curve exhibited strong upward curvature. Among promoted animals, the response of the skin to initiation appeared to have been nearly saturated by all DMBA doses tested, so that a 30-fold decrease in dose produced only a 3-fold decrease in effect. The dose-response relationship thus exhibited strong downward curvature.Among promoted animals, estimation of the risks associated with very low doses of carcinogen by linear extrapolation through the origin from the effects of larger doses (which is often assumed to be conservative) would under-estimate the true risks by 10-fold or more. Our results emphasize that whereas linear interpolation from the results of high doses may be reasonable for data on the effects of continuous treatment with non-toxic dose levels of carcinogen, it may be misleading when extrapolating, as here, from the effects of single large doses.The siynificance ofdowvnward curvature.

The relationship between aging and carcinogenesis: a critical appraisal

“…Cross-talk between mesenchyme and epithelium has been described as a known driver of differentiation and development [82,83] [85]. Also, the average diameter of the tumors was larger in the older animals.…”

Polyclonal origin of mouse skin papillomas

“…Evidence that tumour cells may produce both autocrine and paracrine growth-stimulating substances has provided a possible mechanism for such interaction (Sporn & Roberts, 1985). In addition, there is evidence from both in vivo and in vitro experiments that initiation may be a more frequent event than transformation (Mondal & Heidelberger, 1970;Stenback et al, 1981); and that transformation of initiated cells in culture can be inhibited by co-culture with an excess of non-initiated cells (Haber & Thilly, 1978;Mordan et al, 1983). Both of these observations could be explained by mechamnsms involving interactions between initiated cells and their neighbours.…”

Interspecies Dose Extrapolation for Inhaled Dimethyl Sulfate: A PBPK Model-Based Analysis using Nasal Cavity N7-Methylguanine Adducts

“…In the liver, a nonlinear increase in tumor incidence can be observed when doses of genotoxic compounds are greater than or equal to cytotoxic doses (Scherer & Emmelot, 1975;Williams et al, 1999). In mouse skin tumorigenesis, Stenback and coworkers (Stenback et al, 1981) demonstrated that rapid tumor development only occurs at doses of genotoxic compounds that are cytotoxic. Under these conditions, response is related to the amount exceeding some cytotoxic threshold, not total dose or AUC.…”