Approach to risk assessment for genotoxic carcinogens based on data from the mouse skin initiation-promotion model.

Abstract

Tumor induction data in the mouse skin initiation-promotion system were found to be consistent with a quadratic function where the coefficient of the linear term depended on the dose of the promoter. The model implies that the existence of promoters may be more important at low doses of the carcinogen than at high doses where most testing is performed. Experiments are described showing that the initiating effect of carcinogenic chemicals, such as benzo(a)pyrene, 7,12-dimethyl-benz(a)anthracene, nitroquinoline oxide and beta-propiolactone, accumulates in a linear, irreversible manner at low doses. Even when 7,12-dimethylbenz(a)anthracene was applied intragastrically to pregnant females, initiating activity was found in the skins of exposed offspring about in proportion to dose applied and number of cells at risk. The initiated cells essentially represent a potential for cancer that has a high probability for expression in the presence of a promoter. Risk then can be interpreted in terms of the accumulated dose of initiator which alone presents a small risk of cancer. However, a promoter may substantially expand the overall risk, possibly by clonally expanding the initiated cells. Promotion needs to be sustained since there is a reduction of cancer risk if promotion is ended early. Some tissues, such as mouse bladder, may be intrinsically promoted more than others so that comparisons between tissues and between species are best made when the combination of intrinsic promotion and response to extrinsic promotion are comparable.

Macromolecule adducts as biomarkers of exposure to environmental mutagens in human populations.

“…This multiplicative character of the dose response was most convincingly shown by Storer et al (6) in their systematic comparison of radiogenic tumors in mouse strains with different spectra of background tumors, but it is also valid for mutagenic chemicals such as ethylene oxide and butadiene [Ehrenberg et Accordingly, a multiplicative model is now preferred for the description of dose-response relationships (8) P(D)=(1+ D)xP°, [1] where D is the dose, P is a risk coefficient, and P and P0 are the estimated and the background probabilities, respectively. In agreement with this picture, tumors of types that do not occur in a studied strain are not (or are seldom) inducible at low doses (9 (10).…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…Furthermore, the thresholded, S-shaped dose response for skin tumors induced by B[a]P becomes linearized if an effective nonmutagenic promoter, 12-O-tetradecanoylphorbol-13-acetate) (TPA), is added (Burns et al 1983) ( Figure 12A). This general picture is important to the risk estimation for PAHs at low exposure levels.…”

Nonlinearity of dose-response functions for carcinogenicity.

“…Although the basic mechanisms of carcinogenicity are not well understood, it is believed that the process is multistage (2,(8)(9)(10)(11)(12)(13). Ifthis is the case, a dose-response curve for a carcinogen would expectably depend on the transition between particular stages or the clonal expansion of cells in a particular stage that the chemical affects (1,2,4,(11)(12)(13)(14)(15)(16). For example, the first stage is thought to involve mutational changes in the DNA as a result of what is believed to be a linear-in-dose genotoxic effect of the chemical (1,2,4,11,12,15).…”