Back
Full-text
Journal article

Mode of action-based risk assessment of genotoxic carcinogens.

  • Hartwig A Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany. andrea.hartwig@kit.edu.
  • Arand M Institute of Pharmacology and Toxicology, University of Zurich, 8057, Zurich, Switzerland.
  • Epe B Institute of Pharmacy and Biochemistry, University of Mainz, 55099, Mainz, Germany.
  • Guth S Department of Toxicology, IfADo-Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, Ardeystr. 67, 44139, Dortmund, Germany.
  • Jahnke G Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
  • Lampen A Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany.
  • Martus HJ Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland.
  • Monien B Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany.
  • Rietjens IMCM Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
  • Schmitz-Spanke S Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Henkestr. 9-11, 91054, Erlangen, Germany.
  • Schriever-Schwemmer G Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
  • Steinberg P Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany.
  • Eisenbrand G Retired Senior Professor for Food Chemistry and Toxicology, Kühler Grund 48/1, 69126, Heidelberg, Germany. eisenbra@rhrk.uni-kl.de.
Show more…
  • 2020-06-17
Published in:
  • Archives of toxicology. - 2020
Biomarker dosimetry
Carcinogens
Endogenous exposure
Exogenous exposure
Genotoxicity
Mode of action
Mutagens
Risk assessment
Toxicogenomics
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/33023
Statistics
Document views: 87 File downloads:
  • Full-text: 0