Assessment of mechanisms driving non-linear dose–response relationships in genotoxicity testing

Guérard, Melanie; Baum, Matthias; Bitsch, Annette; Eisenbrand, Gerhard; Elhajouji, Azeddine; Epe, Bernd; Habermeyer, Michael; Kaina, Bernd; Martus, Hans‐Jörg; Pfuhler, Stefan; Schmitz, C.; Sutter, Andreas; Thomas, Alex; Ziemann, Christina; Frötschl, Roland

doi:10.1016/j.mrrev.2014.11.001

Cited by 56 publications

(29 citation statements)

References 189 publications

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“…One common element across these cases is generation of data to support a hypothesized or demonstrated MOA, a framework with less detailed description than that required for establishing mechanism, based on identification of key events responsible for the observed effects [36]. There are many well-understood biological processes that could underpin a non-linear/bilinear dose-response for genotoxic effects that include DNA repair processes, redundancy in the genetic code, non-coding regions of DNA, processes associated with DNA replication and damage tolerance, DNA damage response networks, and apoptosis/cell death [11, 13, 30]. For DNA alkylating agents, the involvement of certain DNA repair systems, such as BER, HR, Direct Repair, and MMR, shifts the dose-response curve for genotoxic endpoints.…”

Section: New Methods To Investigate Responses At Low-dose Exposuresmentioning

confidence: 99%

“…Under normal conditions, the steady state level of endogenous DNA damage was recently estimated at ≥50,000 lesions per cell; the non-instructional and pro-mutagenic abasic sites are the most common DNA lesions, present daily at ~30,000 nucleoside sites in DNA per cell [18, 22, 24]. DNA repair influences the outcome and dose-response of mutation and chromosome damage following exposure to DNA damaging agents at all exposure levels [11-15]. DNA repair is usually error-free, but there may be rare events where the mis-repair will result in genotoxic outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

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Section: New Methods To Investigate Responses At Low-dose Exposuresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

View full text Add to dashboard Cite

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“…As a result, persistent lung injury and inflammation can trigger secondary genotoxicity due to oxidative stress and frustrated phagocytosis of long, rigid fibers or nanotubes. Cell proliferation is triggered in response to lung cell injury as well as by cytokines and growth factors released from inflammatory cells (Colotta et al 2009; Guerard et al 2015). Persistent inflammation, oxidative stress, and epithelial or mesothelial injury and cell proliferation are considered to play important roles in the development of lung cancer and mesothelioma.…”

Section: Hypotheses On the Mechanistic Events Related To Genotoxicitymentioning

confidence: 99%

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

Kuempel

Jaurand

Møller

et al. 2016

Critical Reviews in Toxicology

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In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose–response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

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“…Degradation of ONs by nucleases to mononucleotides could result in a genotoxic event, due to the incorporation of mononucleotides into a newly synthesized DNA strand, which could lead to DNA strand breaks due to chain termination during replication or mis‐pairing and mutation. Such genotoxic mechanisms have been described for nucleoside analogues used as antiviral drugs (Wutzler and Thust, ; Guérard et al, ) and are well detected by the standard genotoxicity tests (S2(R1) June 2011). In the case of current‐generation ONs, due to the (I) slow degradation rate of the parent molecules to mononucleotides, (II) the generally balanced mix of monomers within therapeutic ONs and (III) the fact that most modified nucleotides, resulting from nuclease cleavage of ONs, are poor substrates for endogenous kinases or polymerases, this type of genotoxic event is deemed to be of low toxicological concern in this class (Berman et al, ).…”

Section: Discussionmentioning

confidence: 77%

Locked nucleic acid (LNA): Based single‐stranded oligonucleotides are not genotoxic

Guérard

Zeller

Koller

et al. 2017

Environ and Mol Mutagen

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Over the last decade, single stranded oligonucleotides (ON) have gained increased attention as a new drug modality. Because the assessment of genotoxicity risk during early development of pharmaceuticals is essential, we evaluated the potential of locked nucleic acids (LNA)-ONs to induce DNA damage in L5178Y tk cells both with the mouse lymphoma assay (MLA) and the micronucleus test (MNT). Further, the MLA was performed to assess gene and chromosome mutation over 3 and 24h (± metabolic activation). In addition, the MNT was performed to assess, in addition, a potential aneugenic liability. None of the experiments demonstrated a genotoxic effect for the five tested LNA-ONs. We further show data from four proprietary LNA-ONs tested in standard genotoxicity assays in vitro and partially in vivo, which were all negative. In addition, cellular and nuclear uptake of LNA-ONs in L5178Y tk cells was demonstrated. Based on the results presented here as well as in the literature about other representatives of this class, we consider LNA-ONs as generally not DNA reactive and question whether genotoxicity testing of this class of ONs should be required. This is in line with recent recommendation made by the OSWG that extensively assessed the genotoxicity of oligonucleotides. Environ. Mol. Mutagen. 58:112-121, 2017. © 2017 Wiley Periodicals, Inc.

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Assessment of mechanisms driving non-linear dose–response relationships in genotoxicity testing

Cited by 56 publications

References 189 publications

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

Locked nucleic acid (LNA): Based single‐stranded oligonucleotides are not genotoxic

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