Considerations for the Use of Mutation as a Regulatory Endpoint in Risk Assessment

Abstract

Assessment of a chemical's potential to cause permanent changes in the genetic code has been a common practice in the industry and regulatory settings for decades. Furthermore, the genetic toxicity battery of tests has typically been employed during the earliest stages of the research and development programs of new product development. A positive outcome from such battery has a major impact on the chemical's utility, industrial hygiene, product stewardship practices, and product life cycle analysis, among many other decisions that need to be taken by the industry, even before the registration of a chemical is undertaken. Under the prevailing regulatory paradigm, the dichotomous (yes/no) evaluation of the chemical's genotoxic potential leads to a conservative, linear no‐threshold (LNT) risk assessment, unless compelling and undeniable data to the contrary can be provided to satisfy regulators, typically in a number of different global jurisdictions. With the current advent of predictive methods, new testing paradigms, mode‐of‐action/adverse outcome pathways, and quantitative risk assessment approaches, various stakeholders are starting to employ these state‐of‐the‐science methodologies to further the conversation on decision making and advance the regulatory paradigm beyond the dominant LNT status quo. This commentary describes these novel methodologies, relevant biological responses, and how these can affect internal and regulatory risk assessment approaches. Environ. Mol. Mutagen. 61:84–93, 2020. © 2019 Wiley Periodicals, Inc.

EURL ECVAM Genotoxicity and Carcinogenicity Database of Substances Eliciting Negative Results in the Ames Test: Construction of the Database

“…); its requirement specified in national legislation (e.g., EU, Canada, USA, Japan) aims at the protection of human health. Genotoxicants are capable of inducing the genomic alterations that have been mechanistically and empirically linked to cancer and germ cell effects, the latter leading to fertility problems or heritable genetic disorders [ 1 , 2 ].…”

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide

“…The recognition and the emphasis in recent years that genotoxicity data could and should be used on its own merit for human risk assessment (Gollapudi et al ., 2013; Johnson et al ., 2014; Heflich et al ., 2020; Klapacz and Gollapudi, 2020) provided the impetus to examine the available EO dose–response data for the identification of a PoD for the derivation of a PDE. The in vivo genotoxicity of EO has been investigated via various routes of exposure.…”

“…The analysis of dose-response and the identification of no-effect-levels attracted relatively little consideration. In recent years, however, there has been growing interest in using genotoxicity data to inform not only cancer mode of action but also to quantitatively assess risk from exposure to genotoxic agents (Pottenger et al, 2007;Pottenger and Gollapudi, 2009;Gollapudi et al, 2013;Johnson et al, 2014;MacGregor et al, 2015aMacGregor et al, , 2015bDearfield et al, 2017;Heflich et al, 2020;Klapacz and Gollapudi, 2020;White et al, 2020). The precedent came from Müller and Gocke (2009) [TCEQ], 2020).…”

“…The analysis of dose–response and the identification of no‐effect‐levels attracted relatively little consideration. In recent years, however, there has been growing interest in using genotoxicity data to inform not only cancer mode of action but also to quantitatively assess risk from exposure to genotoxic agents (Pottenger et al ., 2007; Pottenger and Gollapudi, 2009; 2010; Gollapudi et al ., 2013; Johnson et al ., 2014; MacGregor et al ., 2015a, 2015b; Dearfield et al ., 2017; Heflich et al ., 2020; Klapacz and Gollapudi, 2020; White et al ., 2020). The precedent came from Müller and Gocke (2009) who used mutagenicity data to derive permitted exposure levels of a human pharmaceutical contaminated with the mutagen ethyl methane sulfonate, which received acceptance from regulatory authorities (e.g., European Medicines Agency [EMEA], 2008).…”

Genotoxic Assessment of the Dry Decoction of Myracrodruon urundeuva Allemão (Anacardiaceae) Leaves in Somatic Cells of Drosophila melanogaster by the Comet and SMART Assays

“…For that reason, it is imperative to investigate the potentially toxic‐genetics effects of plants used in traditional medicine (EMA ; Rashed et al ; Sponchiado et al ). According to Klapacz and Gollapudi (), the genotoxicity refers to deleterious effects to genetic material that cover both transmissible outcomes and endpoints that themselves are not transmissible. On the other hand, the mutagenicity refers to transmissible changes to genetic material.…”