Dose-Response Relationships for <i>N</i>7-(2-Hydroxyethyl)Guanine Induced by Low-Dose [14C]Ethylene Oxide: Evidence for a Novel Mechanism of Endogenous Adduct Formation

Marsden, Debbie A.; Jones, Donald J. L.; Britton, Robert G.; Ognibene, Ted; Ubick, Esther A.; Johnson, George E.; Farmer, Peter B.; Brown, Karen

doi:10.1158/0008-5472.can-08-4233

Cited by 35 publications

(23 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, especially lesions derived from lipid peroxidation products such as 7-HEG, M1G and other cyclic adducts have been found to be about one order of magnitude higher in humans than in animals (see Tables2 and 3). For example, 7-HEG adduct levels (supposedly from ethylene oxide) have been reported to be 48-300 adducts/10 8 nucleotides in humans (Farmer and Shuker 1999;Wu et al 1999a) versus 1-9 adducts/10 8 nucleotides in rats (Marsden et al 2009(Marsden et al , 2007Wu et al 1999a;Zhao et al 1999). Likewise, 14-110 M1G adducts/10 8 nucleotides were reported in human liver (De Bont and van Larebeke 2004; Farmer and Shuker 1999) versus 0.8-4.2 adducts/10 8 nucleotides in rat tissues including liver (Jeong et al 2005).…”

Section: Selected Dna Lesions In Rodents and Humansmentioning

confidence: 99%

See 1 more Smart Citation

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Selected Dna Lesions In Rodents and Humansmentioning

confidence: 99%

“…Liver (rats) Lipid peroxidation products 1.3-4.4 Marsden et al (2009); Marsden et al (2007); Swenberg et al (1995) Lymphocytes, liver, kidney (rats)…”

Section: Development Of a Database On Background Dna Lesionsmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The biological responses to alkylating agents are quite complex due to the variety of alkylation adducts produced in DNA, and the variability this imparts to their biological significance [4, 63, 65, 68]. Under certain conditions such as imbalanced DNA excision or abnormally high levels of activity, DNA repair itself can be a cause of mutation [89-92].…”

Section: Alkylating Agentsmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Using the most advanced accelerator mass spectrometry methods, it is now possible to demonstrate that adduct formation is in fact linear over the entire low dose range until the signal vanishes into the background [13, 14]. This level of sensitivity is, of course, the ultimate expression of the vanishing zero dilemma.…”

Section: Introductionmentioning

confidence: 99%

The vanishing zero revisited: Thresholds in the age of genomics

Zarbl

Gallo

Glick

et al. 2010

Chemico-Biological Interactions

View full text Add to dashboard Cite

The concept of the Vanishing Zero, which was first discussed 50 years ago in relation to pesticide residues in foods and food crops, focused on the unintended regulatory consequences created by ever-increasing sensitivity and selectivity of analytical methods, in conjunction with the ambiguous wording of legislation meant to protect public health. In the interim, the ability to detect xenobiotics in most substrates has increased from tens of parts per million to parts per trillion or less, challenging our ability to interpret the biological significance of exposures at the lowest detectable levels. As a result the focus of risk assessment, especially for potential carcinogens, has shifted from defining an acceptable level, to extrapolating from the best available analytical results. Analysis of gene expression profiles in exposed target cells using genomic technologies can identify biological pathways induced or repressed by the exposure as a function of dose and time. This treatise explores how toxicogenomic responses at low doses may inform risk assessment and risk management by defining thresholds for cellular responses linked to modes or mechanisms of toxicity at the molecular level.

show abstract

Dose-Response Relationships for N7-(2-Hydroxyethyl)Guanine Induced by Low-Dose [14C]Ethylene Oxide: Evidence for a Novel Mechanism of Endogenous Adduct Formation

Cited by 35 publications

References 43 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

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

The vanishing zero revisited: Thresholds in the age of genomics

Contact Info

Product

Resources

About