Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays

Abstract

This study aimed at quantitatively comparing the occurrence/formation of DNA adducts with the carcinogenicity induced by a selection of DNA-reactive genotoxic carcinogens. Contrary to previous efforts, we used a very uniform set of data, limited to in vivo rat liver studies in order to investigate whether a correlation can be obtained, using a benchmark dose (BMD) approach. Dose-response data on both carcinogenicity and in vivo DNA adduct formation were available for six compounds, i.e. 2-acetylaminofluorene, aflatoxin B1, methyleugenol, safrole, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and tamoxifen. BMD(10) values for liver carcinogenicity were calculated using the US Environmental Protection Agency BMD software. DNA adduct levels at this dose were extrapolated assuming linearity of the DNA adduct dose response. In addition, the levels of DNA adducts at the BMD(10) were compared to available data on endogenous background DNA damage in the target organ. Although for an individual carcinogen the tumour response increases when adduct levels increase, our results demonstrate that when comparing different carcinogens, no quantitative correlation exists between the level of DNA adduct formation and carcinogenicity. These data confirm that the quantity of DNA adducts formed by a DNA-reactive compound is not a carcinogenicity predictor but that other factors such as type of adduct and mutagenic potential may be equally relevant. Moreover, comparison to background DNA damage supports the notion that the mere occurrence of DNA adducts above or below the level of endogenous DNA damage is neither correlated to development of cancer. These data strongly emphasise the need to apply the mode of action framework to understand the contribution of other biological effect markers playing a role in carcinogenicity.

DNA Adducts of the Tobacco Carcinogens 2-Amino-9H-pyrido[2,3-b]indole and 4-Aminobiphenyl Are Formed at Environmental Exposure Levels and Persist in Human Hepatocytes

“…37,38 The carcinogenic potential of genotoxic chemicals in rodents has been assessed by the carcinogen DNA binding index and bench mark dose values. 39–41 The doses of chemicals and the levels of their DNA adducts required at the steady-state to induce liver tumors in rodents vary greatly. 39–41 The steady-state levels of some types of DNA adducts in rats chronically exposed to a single carcinogen, including HAAs or arylamines, generally must be greater than 100 adducts per 10 8 DNA bases to increase the frequencies of tumors by 10% or greater than the spontaneous background levels.…”

“…37,38 In vivo animal models have been employed to measure DNA adduct formation and the level of covalent binding of genotoxicants to DNA has been correlated to cancer risk. 39–41 …”

Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach

“…The BMDL 10 values were calculated from data on the induction of kidney tumours by AAs in rats (Mengs et al 1982) using all models for dichotomous data using the Environmental Protection Agency's (EPA) Benchmark Dose Software (BMDS) version 2.5. The doses and the duration of treatment were adjusted to the standard lifespan (104 weeks), as discussed by Paini et al (2011). Only models that met the requirements for acceptance of the model fit were considered for the determination of BMDL 10 values.…”

Novel Aspects of the Liver Microenvironment in Hepatocellular Carcinoma Pathogenesis and Development

“…Chemical exposure and dietary ingestion of carcinogens are known to directly alter DNA sequences and cause DNA mutation [175,176,177]. For example, the chemical carcinogen 2-acetylaminofluorene (2-AAF) causes DNA adducts in mice [175].…”

“…Chemical exposure and dietary ingestion of carcinogens are known to directly alter DNA sequences and cause DNA mutation [175,176,177]. For example, the chemical carcinogen 2-acetylaminofluorene (2-AAF) causes DNA adducts in mice [175]. AFB1, a mycotoxin present in a wide range of foods, is also a direct carcinogen that causes DNA adducts and mutations via DNA base conversion from G to T [177].…”