Academic Journal
Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions
| Title: | Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions |
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| Authors: | Pottenger, L. H., Boysen, G., Brown, K., Cadet, J., Fuchs, R. P., Johnson, G. E., Swenberg, J. A. |
| Publisher Information: | John Wiley & Sons, Inc. |
| Publication Year: | 2018 |
| Collection: | PubMed Central (PMC) |
| Subject Terms: | Review |
| Description: | The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N7‐alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus). This review summarizes and evaluates the status of dose–response data for DNA adducts and mutations from recent experimental work with standard mutagenic agents and ethylene oxide and propylene oxide, and the importance for risk assessment. This body of evidence demonstrates that small N7‐alkyl/hydroxyalkylguanine adducts are not pro‐mutagenic and, therefore, adduct formation alone is not adequate evidence to support a mutagenic mode of action. Quantitative methods for dose–response analysis and derivation of thresholds, benchmark dose (BMD), or other points‐of‐departure (POD) for genotoxic events are now available. Integration of such analyses of genetox data is necessary to properly assess any role for DNA adducts in risk assessment. Regulatory acceptance and application of these insights remain key challenges that only the regulatory community can address by applying the many learnings from recent research. The necessary tools, such as BMDs and PODs, and the example datasets, are now available and sufficiently mature for use by the regulatory community. Environ. Mol. Mutagen. 60: 100–121, 2019. © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. |
| Document Type: | text |
| Language: | English |
| Relation: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590209/; http://www.ncbi.nlm.nih.gov/pubmed/30536466; http://dx.doi.org/10.1002/em.22248 |
| DOI: | 10.1002/em.22248 |
| Availability: | https://doi.org/10.1002/em.22248 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590209/ http://www.ncbi.nlm.nih.gov/pubmed/30536466 |
| Rights: | © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. ; This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Accession Number: | edsbas.235A4440 |
| Database: | BASE |
| Description not available. |