Pottenger_et_al-2018-Environmental_and_Molecular_Mutagenesis.pdf (889.94 kB)
Download file

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.

Download (889.94 kB)
journal contribution
posted on 10.09.2019, 09:31 by LH Pottenger, G Boysen, K Brown, J Cadet, RP Fuchs, GE Johnson, JA Swenberg
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.

Funding

Grant sponsor: European Chemical Industry Council. We would like to acknowledge partial support provided by Cefic LOSG as honoraria to several co-authors and to Olin Corporation, and the thoughtful comments provided by Cefic LOSG on early drafts.

History

Citation

Environmental and Molecular Mutagenesis, 2019 ,60(2), pp. 100-121

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

VoR (Version of Record)

Published in

Environmental and Molecular Mutagenesis

Publisher

Wiley for Environmental Mutagen Society

eissn

1098-2280

Acceptance date

23/08/2018

Copyright date

2018

Available date

10/09/2019

Publisher version

https://onlinelibrary.wiley.com/doi/full/10.1002/em.22248

Language

en