Modes of action considerations in threshold expectations for health effects of benzene.

Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.

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Copyright © 2020. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Colin North is employed by ExxonMobil Biomedical Sciences, Inc., which provided services to various companies within ExxonMobil that may use, manufacture, or sell benzene or products containing benzene. He is a shareholder of Exxon Mobil. Martijn Rooseboom is employed by Shell including stock ownership but was totally free to design and conduct the research and express his own scientific opinion without any obligation to either Shell or CEFIC. He is a member of the Dutch Expert Committee on Occupational Safety (DECOS) of the Health Council of the Netherlands (from December 2019-present). Neslihan Aygun Kocabas is former employee of SABIC Europe and is currently an employee of Total RC, Feluy, BE.A. Rob Schnatter currently works in epidemiology consulting as the principal of EpiSolutions, LLC. The LOA REACH Consortium provided financial support for the current paper via a contract with Penman Consulting. He has previously worked for ExxonMobil Biomedical Sciences, Inc. and owns shares in ExxonMobil Corporation. Frank Faulhammer is employed by BASF including stock ownership. Stephen D Williams currently works in toxicology consulting for the petrochemical sector as a contractor with Penman Consulting and as owner of Steve Williams Consulting Limited. The LOA REACH Consortium provided financial support via Penman Consulting. He has previously worked for BP plc and owns shares in BP plc and Royal Dutch Shell plc.