Can carcinogenic potency be predicted from in vivo genotoxicity data? a meta‐analysis of historical data

Abstract

Genotoxicity is generally a parameter used for hazard identification, however, the applicability of using in vivo genotoxicity tests for hazard characterization has never been thoroughly investigated in a quantitative manner. Genotoxicity assays could be useful for the determination of cancer potency parameters given that genotoxicty tests measure mutations and/or chromosomal aberrations which are strongly associated with carcinogenesis. A detailed literature survey was performed in search for dose-response data in various in vivo genotoxicity and carcinogenicity studies. The benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST. Dose-response data were available from 18 compounds in the micronucleus assay (MN), the in vivo transgenic rodent mutation assay (TG) and the comet assay, and their BMD(10) values were compared to the BMD(10) from carcinogenicity studies in mice. Of the 18 compounds, 15 had acceptable dose-response data from the MN and the TG, but only 4 from the comet assay. A major limitation in our analysis was the lack of proper dose-response studies using the recommended protocols. Nevertheless, our findings are promising because even with these suboptimal studies, a positive correlation was observed when the lowest BMD(10) from the genotoxicity tests (MN and TG) was compared to the tissue-matched carcinogenicity BMD(10) . It is evident that more compounds need to be analyzed with proper dose-response schemes to further validate our initial findings. Experimental designs of genotoxicity assays need to shift from focusing only on hazard identification where positive and negative results are reported, to a more quantitative, dose-response assessment.

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

“…Thus, considering both the Hernandez et al, 2011 and 2012 reports [65,66], there is a general quantitative correlation between carcinogenic and mutagenic or clastogenic potency for a wide range of agents believed to have a genotoxic mode of cancer induction, but metabolic, toxicokinetic, and distributional properties limit the precision of these potency correlations when comparisons are made between studies that differ in tissue target site, species, strain, sex, dosage route, etc., unless these factors are taken into account. Nonetheless, these results suggest that, in the absence of carcinogenicity data, an estimate of probable cancer potency can be derived from in vivo genotoxicity studies.…”

“…The quantitative relationship between gene mutation in transgenic rodent models and micronucleus induction (an index of chromosomal aberrations) in bone marrow (or peripheral blood erythrocytes) with carcinogenic potency has been examined by Hernandez et al [65,66], using quantitative dose-response analysis of the genotoxicity data. Although these data were, in general, not tissue or strain matched, a remarkably good quantitative correlation with carcinogenic potency was observed.…”

“…The comparison of BMDL values calculated using data from micronucleus and transgenic rodent studies vs. the carcinogenic BMDL 10 was examined for 18 compounds [65]. The correlation of carcinogenic with mutagenic/clastogenic potency over five orders of magnitude showed a high degree of correlation on a log-log scale even though genotoxicity data were in most cases from tissues other than the cancer target site (i.e., genotoxicity data were from the tissue in which the tumor arose for only 4 of the compounds used in this analysis, and the route of exposure was different for half of the compounds).…”

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

“…A dose-dependent increase in mutant Pig-a phenotypes was also observed in these mice. A meta-analysis of published in vivo dose–response genotoxicity studies used the BMD approach to calculate the dose representing a specified 10% change in effect in exposed animals versus controls (BMD 10 ) (Hernandez et al, 2011). BMDs represent a more appropriate and advanced measure than NOAELs (described in Section 2.6).…”

Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: Alternative approaches

“…The median of the ratio LED/T 25 was 1.05% and for 90% of the substances this ratio fell in the range of 0.21-9.2, which shows that the numerical value of the LED is similar to the numerical value of the T 25 within 1.5 orders of magnitude. Hernandez et al (2011) performed a literature search for doseresponse data in various in vivo genotoxicity and carcinogenicity studies. They applied the benchmark dose (BMD) approach using the dose-response modeling program PROAST on dose-response data from 18 compounds in the micronucleus assay (MN) and the in vivo transgenic rodent mutation assay (TGM).…”