Using transcriptomics to evaluate thresholds in genotoxicity dose-response

Several genotoxic chemicals have been reported to produce threshold-shaped dose-response curves for mutation and genotoxicity assays, both in vivo and in vitro. These data challenge the current default practice for risk assessment of genotoxic chemicals, which assumes a linear dose-response below the lowest tested dose. Due to the inherent challenges in data collection and analysis, statistical methods cannot determine whether a biological threshold exists with sufficient confidence to overturn this assumption of linearity. Indeed, to truly define the shape of the dose-response curves, we must look to the underlying biology and develop targeted experiments to identify and measure the key processes governing cellular response at low doses. This chapter describes a series of studies aimed at defining the transcriptional responses to DNA damage in an effort to identify the key processes regulating low-dose DNA damage response. HT1080 cells were treated with multiple prototype compounds at a single chemical dose that led to a similar activation of p53-DNA damage pathway (1.5 fold increase in total p53)