Genotoxicity nonlinearity

W. K. Lutz, S. Vamvakas, A. Kopp-Schneider, J. Schlatter and H. Stopper, Deviation from additivity in mixture toxicity relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and g-radiation. Environmental Health Perspectives Supplements, 2002,110(6), 915-918. 

Once a chemical s mode(s) of action has been identified, the risk assessor can proceed with the evaluation of carcinogenic potential, including consideration of the relevance of the mode of action to humans. Further consideration of mode of action distinguishes between a genotoxic (or sometimes more rigorously described as DNA-reactive) mode of action, for which there may be some risk at every nonzero dose, and nongenotoxic (or nonmutagenic) modes of action, for which threshold or nonlinear dose-response curves may apply. 

Supporting data from studies in isolated rodent tissues and the standard geno-toxicity assays in Salmonella and other species can help inform the mechanistic interpretations. However, a risk assessor must evaluate these data with caution. Are the results from liver (where regenerative hyperplasia is most often observed) relevant to tumors that may be observed in other organs If a chemical caused tumors in liver, bladder, and lung, for example, but correlative cytotoxicity was only documented in liver, what should be concluded from the liver cytotoxicity data The data may seem solid for a cytotoxic threshold for liver tumors in rats, while kidney tumors are observed without notable renal cytotoxicity in mice, and a genotoxic metabolite is detected. In this case, a cautious risk assessor would not likely conclude that a nonlinear extrapolation is appropriate for determination of a regulatory standard, based on the mouse data. 

The potential for a nonhnear extrapolation from human data should also be considered. Some risk assessors have argued that benzene-induced leukemia and lymphoma is a threshold phenomenon, based on mechanistic considerations, and that the human data demonstrate such a threshold (Cox and Ricci 1992 Cox 1996 Yokley et al. 2006). However, regulatory risk assessors have not yet accepted these arguments for benzene (Bailer and Hoel 1989 ERA 1998 OEHHA 2001). Considerations include the multiple genotoxic metabolites of benzene, a nonlinear production of protein and DNA adducts in humans (saturated at higher benzene doses), and the difficulty of establishing dose-response relationships at lower doses with the available animal and human data (Bailer and Hoel 1989 Henderson et al. 1992 Turteltaub and Mani 2003 Rappaport et al. 2005 Lin et al. 2007). 

Once a dose metric is selected and estimated, a dose extrapolation model can be applied to estimate cancer risk. The choice of the model will be driven by the likely mechanism of action of the chemical or agent. For example, if the substance is a genotoxic material, such as radiation, a linear model would be used. A threshold model or nonlinear model might be used if the chemical or agent is not genotoxic (Paustenbach 2002 Williams and Paustenbach 2002). The general theory behind both models is discussed below. 

Oesch F, Hengstler JG, Arand M (2004) Detoxification strategy of epoxide hydrolase—the basis for a novel threshold for definable genotoxic carcinogens. Nonlinearity Biol Toxicol... 

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