Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

Abstract

The determination of whether a chemical induces cancer through a mutagenic or genotoxic mechanism frequently plays an important role in evaluating the risks associated with low dose exposure. Although various approaches are employed for making mode of action decisions, a systematic investigation to identify the major factors that influence these determinations has not been performed. To accomplish this, over 40 chemical risk assessments conducted by U.S. or international regulatory agencies and organizations were reviewed to identify components that had played a significant role, either directly or indirectly, in the decision-making process. The major factors identified included the chemical properties of the agent, its metabolites and degradation products; its metabolism and toxicokinetics; genotoxic effects seen in vivo, particularly in the target organ; structural or metabolic similarities to known mutagenic or nonmutagenic chemicals; characteristics of the tumors induced in the animal bioassays; and the origin of the observed effects. The quality of the data, the specific genotoxic endpoint and its sensitivity to assay conditions and toxicity were also important considerations. In all cases, the authoritative groups used a weight-of-evidence approach and, in most cases where evaluations were conducted by more than one authoritative body, similar conclusions were reached. In summary, a critical evaluation of the data as well as expert judgment is necessary in reaching mechanism of action conclusions. These determinations should be made within the broader context of evaluating the chemical's overall toxicity and carcinogenicity.

Recommendations for the evaluation of complex genetic toxicity data sets when assessing carcinogenic risks to humans

“…In addition to genotoxicity test results, other factors should be considered in making a determination of whether or not a chemical acts through a mutagenic mode of action. As described in Eastmond [], these include “the chemical properties of the agent, its metabolites and degradation products; its metabolism and toxicokinetics;… structural or metabolic similarities to known mutagenic or nonmutagenic chemicals; characteristics of the tumors induced in the animal bioassays; and the origin of the observed effects. The quality of the data, the specific genotoxic endpoint and its sensitivity to assay conditions and toxicity were also important considerations….…”

“…In addition to genotoxicity test results, other factors should be considered in making a determination of whether or not a chemical acts through a mutagenic mode of action. As described in Eastmond [2012], these include "the chemical properties of the agent, its metabolites and degradation products; its metabolism and toxicokinetics;. .…”

Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium

“…Some regulatory authorities have concluded that captan, folpet, and Cr(VI) induce intestinal tumors in mice via chronic mucosal toxicity and regenerative hyperplasia ( U.S. EPA 2004 ; Eastmond 2012 ; IPCS 1995 ; HealthCanada 2015 ; TCEQ 2016 ). These MOA determinations were based on multifaceted research efforts conducted for each agent ( Cohen et al 2010 ; Gordon 2007 ; Thompson et al 2013 ).…”

“…Like Cr(VI), neither captan nor folpet induces intestinal tumors in rats ( Cohen et al 2010 ; Gordon 2007 ). Despite evidence for in vitro genotoxicity, both captan and folpet are not genotoxic in vivo and appear to increase tumor risk in mice due to chronic mucosal wounding and regenerative hyperplasia ( Cohen et al 2010 ; Gordon 2007 ; Arce et al 2010 ), and regulators have determined that these organochloride compounds induce intestinal tumors via nonmutagenic (i.e., threshold) mechanisms ( United States Environmental Protection Agency [U.S. EPA] 2004 ; Eastmond 2012 ; International Programme for Chemical Safety (IPCS) 1995 ), in which chemically induced villous cytotoxicity and resulting crypt regenerative hyperplasia are nonneoplastic precursors that increase the chance of intestinal carcinogenesis. More recently, some scientists have concluded that Cr(VI) induces intestinal tumors through similar mechanisms ( Haney 2015 ; HealthCanada 2015 ; TCEQ 2016 ; Thompson et al 2013 , 2014 , 2017 ).…”

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

“…Critical involvement of non-DNA targets Aneuploidy: benomyl; carbendazim [9][10][11] [14,19] Species and tumor-specific non-genotoxic mode of action Induction of thyroid follicular cell tumors by inorganic chlorates [20] In order to establish exposure limits that minimize human risk of organ toxicity or carcinogenicity, PoD values from animal models in conjunction with uncertainty factors are used (e.g. [33][34][35][36][37][38]).…”