Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment

Abstract

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the noobserved-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD 10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL 10 and BMDL 1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due toDisclaimer: This manuscript has been reviewed by the agencies and companies of the authors and approved for publication. The views expressed in the manuscript do not necessarily reflect the policy of these agencies and companies.

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

“…For quantitative analysis of dose-response relationships for genotoxicity, approaches have been developed to derive various PoD metrics [27-29]. The visual shape of the plotted dose-response data can under certain circumstances be potentially misleading and uninformative [136].…”

Theoretical considerations for thresholds in chemical carcinogenesis

“…It is 27 worth noting that such cytoprotective mechanisms will be 28 dependent upon the mode of action of the genotoxicant. Recent 29 evidence suggests that a PoD for mutation is influenced by the DNA 30 adduct spectra and DNA repair proficiencies [4][5][6], as well as 31 chemical clearance through detoxification for reactive oxygen 32 species (ROS) [7]. Given that mutagenesis is an early event in the 33 exposure-to-tumor scenario (the critical steps are summarized in 34 Fig.…”

The Applicable Use of the HPRT Gene Mutation Assay as a Practical Tool in Mutagenesis and DNA Repair Studies

“…Other PoD methods include bilinear modeling (two lines with different slopes) such as the hockey stick model, which may be used to determine the "line of best fit" [28], and the segmented package available in R [29,30]. A novel package based on mgcv, which provides generalized additive modeling functions based on a penalized regression spline approach with automatic data smoothness function, can also be defined as a usable PoD metric called a slope transition dose.…”

“…The most well-regarded approach for defining a PoD using HPRT data is the benchmark dose (BMD) approach [30,31]. BMD analysis can be conducted using PROAST, the dose-response modeling software developed at the National Institute for Public Health and the Environment (RIVM) in the Netherlands (www.…”

“…BMD analysis can also be conducted using EPA's Benchmark Dose Software [33]. For continuous datasets such as HPRT mutant frequencies, the BMDL 10 and the BMDL1 SD are recommended [30].…”