Comparison of in vivo genotoxic and carcinogenic potency to augment mode of action analysis: Case study with hexavalent chromium

Abstract

Recent analyses-highlighted by the International Workshops on Genotoxicity Testing Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment-have identified a correlation between (log) estimates of a carcinogen's in vivo genotoxic potency and in vivo carcinogenic potency in typical laboratory animal models, even when the underlying data have not been matched for tissue, species, or strain. Such a correlation could have important implications for risk assessment, including informing the mode of action (MOA) of specific carcinogens. When in vivo genotoxic potency is weak relative to carcinogenic potency, MOAs other than genotoxicity (e.g., endocrine disruption or regenerative hyperplasia) may be operational. Herein, we review recent in vivo genotoxicity and carcinogenicity data for hexavalent chromium (Cr(VI)), following oral ingestion, in relevant tissues and species in the context of the aforementioned correlation. Potency estimates were generated using benchmark doses, or no-observable-adverse-effect-levels when data were not amenable to dose-response modeling. While the ratio between log values for carcinogenic and genotoxic potency was ≥1 for many compounds, the ratios for several Cr(VI) datasets (including in target tissue) were less than unity. In fact, the ratios for Cr(VI) clustered closely with ratios for chloroform and diethanolamine, two chemicals posited to have non-genotoxic MOAs. These findings suggest that genotoxicity may not play a major role in the cancers observed in rodents following exposure to high concentrations of Cr(VI) in drinking water-a finding consistent with recent MOA and adverse outcome pathway (AOP) analyses concerning Cr(VI). This semi-quantitative analysis, therefore, may be useful to augment traditional MOA and AOP analyses. More case examples will be needed to further explore the general applicability and validity of this approach for human health risk assessment.

Letter to “Chepelev et al. Establishing a quantitative framework for regulatory interpretation of genetic toxicity dose–response data: Margin of exposure case study of 48 compounds with both in vivo mutagenicity and carcinogenicity dose–response data”

“…Notably, several regulatory bodies have developed threshold-based oral toxicity values and/or water standards for Cr(VI) using data described in the review articles cited herein (FSCJ, 2019;Health Canada, 2016;TCEQ, 2016;WHO, 2020). Thompson et al (2016) previously raised issues related to the inclusion of Cr(VI) in analyses by Soeteman-Hernandez et al (2016), and do so again regarding the important analyses in Chepelev et al (2023).…”

“…The study expands upon previous important work investigating the relationship between carcinogenic and genotoxic potency of several carcinogens (Soeteman-Hernandez et al, 2016). We were surprised to find sodium dichromate (i.e., hexavalent chromium [Cr(VI)]) among the 48 chemicals investigated by Chepelev et al despite our previous publication highlighting issues with the inclusion of Cr(VI) in Soeteman-Hernandez et al (2016), including the choice of genotoxic endpoint and data indicating that the genotoxic potency of Cr(VI) is likely lower (i.e., higher benchmark dose) than the carcinogenic potency (Thompson et al, 2016). Cr(VI) is a site of contact carcinogen in rodents following oral exposure, inducing tumors in the oral cavity of rats and small intestine of mice (NTP, 2008).…”

A Review of the Role of Curcumin in Metal Induced Toxicity

“…Chromium compounds are highly toxic to humans, primarily hexavalent chromium (Cr +6 ). The main manifestations of excess Cr are inflammatory diseases with a tendency to ulceration of the mucous membranes, an allergic effect, dermatitis and eczema, bronchial asthma, and risk of cancer [178,179].…”

Comparative analysis of the Lindane and sodium dichromate's effect on myocard blood vessels' density.

“…Олар өз кезегінде жүрек камераларының және тамырлар қабырғаларының қайта құрылуына әкелуі мүмкін екендігі болжанады [8,9,10,11]. Осы сипатталған өзгерістерге ұқсас ерекшеліктер, тәжірибелік жағдайда хром қосындыларының әсерінде көрініс табатындығы бірқатар зерттеулерде анықталған [12,13]. Мүшелердің функционалдық қабілеті жоғарылау жағдайында, зат алмасу үдерісінің артуы қызметтік капиллярлар санының көбеюіне әкеледі.…”