IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

Abstract

This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols.

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

“…Model monofunctional alkylating agents have datasets amenable to PoD determination for genotoxic effects in both in vitro and in vivo tests systems; these findings were supported by robust statistical analysis of in vitro and in vivo datasets [27-30]. Such new experimental and computational approaches will help develop mechanistic evidence to support the necessary, biological understanding of the MOA for empirically demonstrated PoDs for DNA-reactive agents.…”

“…The collection and analysis of datasets specifically designed to address the low-dose dose-response for genotoxic chemicals have now accumulated into an impressive body of empirical evidence that allows derivation of the no-observed-genotoxic-effect-level (NOGEL, i.e., highest dose with no statistically significant response) and other useful PoDs for genotoxic effects [27-30]. Indeed several authoritative bodies have accepted non-linear/bilinear dose-response for certain DNA-reactive chemicals based on the extensive empirical evidence and subsequently have applied a margin-of-exposure approach to their assessment [31-35].…”

“…One common element across these cases is generation of data to support a hypothesized or demonstrated MOA, a framework with less detailed description than that required for establishing mechanism, based on identification of key events responsible for the observed effects [36]. There are many well-understood biological processes that could underpin a non-linear/bilinear dose-response for genotoxic effects that include DNA repair processes, redundancy in the genetic code, non-coding regions of DNA, processes associated with DNA replication and damage tolerance, DNA damage response networks, and apoptosis/cell death [11, 13, 30]. For DNA alkylating agents, the involvement of certain DNA repair systems, such as BER, HR, Direct Repair, and MMR, shifts the dose-response curve for genotoxic endpoints.…”

Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations

“…The PoDs from the testing data and the exposure estimates are combined to ascertain the possible risk from any observed genomic damage. The two methods that have been explored to provide an indication of risk from potential genomic damage include the margin of exposure (MOE) approach and the reference dose (RfD) approach [Johnson et al, ; MacGregor et al, ]. If a linear dose‐response relationship is determined from the data, then the estimated risk can be “read” from the curve and associated with the exposure assessment.…”

“…Among the qualitative discussion of the risk characterization, key findings, results, and decisions are highlighted to support whether there is genotoxic risk to humans or not. Key points to highlight would include: the selection of appropriate genetic endpoints and target tissues, the selection of uncertainty factors and extrapolation methods used, the importance and use of information on MOA, toxicokinetics, metabolism, and predicted exposure information, including exposure biomarkers [taken from MacGregor et al, ].…”