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Review
. 2020 Jun;94(6):1787-1877.
doi: 10.1007/s00204-020-02733-2. Epub 2020 Jun 15.

Mode of action-based risk assessment of genotoxic carcinogens

Andrea Hartwig  1 , Michael Arand  2 , Bernd Epe  3 , Sabine Guth  4 , Gunnar Jahnke  5 , Alfonso Lampen  6 , Hans-Jörg Martus  7 , Bernhard Monien  6 , Ivonne M C M Rietjens  8 , Simone Schmitz-Spanke  9 , Gerlinde Schriever-Schwemmer  5 , Pablo Steinberg  10 , Gerhard Eisenbrand  11
Affiliations
Review

Mode of action-based risk assessment of genotoxic carcinogens

Andrea Hartwig et al. Arch Toxicol. 2020 Jun.

Erratum in

Abstract

The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as "omics" approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.

Keywords: Biomarker dosimetry; Carcinogens; Endogenous exposure; Exogenous exposure; Genotoxicity; Mode of action; Mutagens; Risk assessment; Toxicogenomics.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic graph of an apparently non-linear dose–response as observed in many cancer risk studies. In a low dose range (“A”), in which promotional effects are absent and detoxification and repair mechanisms fully active, the cancer risk of genotoxic carcinogens is often too low to be quantified directly. A measurable (often steep) increase of the cancer incidence is observed in the high dose range (“B”) due to the onset of tumour promotion and/or saturation effects. If the slope of this range is used for risk assessment by (linear) extrapolation, the cancer risk in range “A” is likely to be overestimated.
Fig. 2
Fig. 2
Schematic outline of causes and consequences of DNA damage (partly proposed previously by Thomas et al. 2015) Left Endogenous and exogenous factors and cellular processes leading to DNA damage and increasing the risk of tumour development. Right Processes decreasing the extent of DNA damage, mutation induction and tumour development
Fig. 3
Fig. 3
Major causes of DNA damage and DNA repair pathways (adapted from de Laat et al. 1999); BER base excision repair, NER nucleotide excision repair, CPD cyclobutane-pyrimidine dimer cis-Pt cisplatin, MMC mitomycin C
Fig. 4
Fig. 4
Structures of N2-ethyl-2′-deoxyguanosine (N2-ethyl-dG) and α-methyl-γ-hydroxy-1,N2-propano-2′-deoxyguanosine (α-Me-γ-OH-PdG; 1,N2-PdG) (according to Brooks and Theruvathu 2005)
Fig. 5
Fig. 5
Metabolic pathway of AA in the rat. Reprinted (adapted) with permission from (Watzek et al. 2012). Copyright (2012) American Chemical Society
Fig. 6
Fig. 6
Dose–response relation of N7-GA-Gua adducts in rat kidney orally exposed to 0.1–10,000 μg AA/kg bw (R2 = 0.99) (only kidney shown in the linear-log plot for graphic clarity). Insert, linear–linear plot of the low dose range (0.1–1000 μg AA/kg bw); shaded, range of DNA background of N7-carboxyethyl-dGua in human liver (see also part A "Fundamental considerations", chapter “background DNA lesions”). Values represent mean values ± SDs (n = 8 or n = 3). Reprinted with permission from (Watzek et al. 2012), Copyright (2012) American Chemical Society
Fig. 7
Fig. 7
Formation of hydroxymethyl DNA adducts induced by formaldehyde (Swenberg et al. 2011)
Fig. 8
Fig. 8
Hydrolysis of DNA–protein cross-links (Yu et al. 2015)
Fig. 9
Fig. 9
Metabolic activation of aflatoxin B1 (AFB1) to AFB1-8,9-epoxide and subsequent formation of the primary AFB1-DNA adduct 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua), which can give rise to two secondary lesions, an apurinic site or the ring-opened AFB1-formamidopyrimidine (FAPY) adduct. CYP, cytochrome P450; dR, deoxyribose
Fig. 10
Fig. 10
Structures of the related allylalkoxybenzenes
Fig. 11
Fig. 11
Bioactivation of estragole and formation of the different DNA adducts. N2-(trans-isoestragol-3′-yl)-deoxyguanosine (E-3′-N2-dG), N2-(estragol-1′-yl)-deoxyguanosine (E-1′-N2-dG), 7-(trans-isoestragol-3′-yl)-deoxyguanosine (E-3′-7-dG), 8-(trans-isoestragol-3′-yl)-deoxyguanosine (E-3′-8-dG), and N6-(trans-isoestragol-3′-yl)-deoxyadenosine (E-3′-N6-dA)
Fig. 12
Fig. 12
PBK model-predicted dose-dependent formation of 1′-sulfooxyestragole in the liver of rat (─) and human (- -), also indicating the Benchmark dose 10 (BMD10) representing the dose level resulting in a tumour incidence of 10% above background level and the Virtual Safe Dose (VSD), calculated by linear extrapolation to represent a dose level causing one in a million tumour incidence above background level. Reproduced with permission from Rietjens et al. (2010). Copyright (2009) WILEY–VCH Verlag GmbH & Co. KGaA, Weinheim
Fig. 13
Fig. 13
Metabolic activation and detoxification of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx). Reprinted from Turesky et al. (2002), Copyright (2002), with permission from Elsevier.
Fig. 14
Fig. 14
Structures of N-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (dG-C8-MeIQx) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (dG-N2-MeIQx) (reproduced from Paehler et al. 2002)
Fig. 15
Fig. 15
Metabolism of Benzo[a]pyrene (Harvey et al. 2005), reprinted by permission of the publisher (Taylor & Francis Ltd, https://www.tandfonline.com)
Fig. 16
Fig. 16
BPDE-induced DNA adduct levels determined via HPLC/Fluorescence detection (a), mutation frequencies determined by PIG-A assay (b), and the correlation between DNA adducts and mutation frequencies (c). For details see Piberger et al. (2017)
Fig. 17
Fig. 17
Structures of the representative necine bases, retronecine, heliotridine, otonecine and platynecine, that form the basis of a variety of pyrrolizidine alkaloids
Fig. 18
Fig. 18
Generic structure required for pyrrolizidine alkaloids to cause toxicity (reproduced from COT 2008)
Fig. 19
Fig. 19
Metabolic activation and detoxification of pyrrolizidine alkaloids (Chen et al. 2010b). Reprinted by permission of the publisher (John Wiley & Sons, Ltd)
Fig. 20
Fig. 20
A Strategy for the assessment of the carcinogenic risk associated with an exposure to examples of genotoxic compounds. For details see text
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