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141. Isoflurane, Sevoflurane and Desflurane

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141. Isoflurane, Sevoflurane and Desflurane View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Göteborgs universitets publikationer - e-publicering och e-arkiv nr 2009;43(9) The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 141. Isoflurane, sevoflurane and desflurane Anne Thoustrup Saber Karin Sørig Hougaard arbete och hälsa | vetenskaplig skriftserie isbn 978-91-85971-16-9 issn 0346-7821 Arbete och Hälsa Arbete och Hälsa (Work and Health) is a scientific report series published by Occupational and Environmental Medicine at Sahlgrenska Academy, University of Gothenburg. The series publishes scientific original work, review articles, criteria documents and dissertations. All articles are peer-reviewed. Arbete och Hälsa has a broad target group and welcomes articles in different areas. Instructions and templates for manuscript editing are available at http://www.amm.se/aoh Summaries in Swedish and English as well as the complete original texts from 1997 are also available online. Arbete och Hälsa Editorial Board: Editor-in-chief: Kjell Torén Tor Aasen, Bergen Gunnar Ahlborg, Göteborg Co-editors: Maria Albin, Ewa Wigaeus Kristina Alexanderson, Stockholm Tornqvist, Marianne Törner, Wijnand Berit Bakke, Oslo Eduard, Lotta Dellve och Roger Persson Lars Barregård, Göteborg Managing editor: Cina Holmer Jens Peter Bonde, Köpenhamn Jörgen Eklund, Linköping © University of Gothenburg & authors 2009 Mats Eklöf, Göteborg Mats Hagberg, Göteborg Arbete och Hälsa, University of Gothenburg Kari Heldal, Oslo SE 405 30 Gothenburg, Sweden Kristina Jakobsson, Lund Malin Josephson, Uppsala ISBN 978-91-85971-16-9 Bengt Järvholm, Umeå ISSN 0346–7821 Anette Kærgaard, Herning http://www.amm.se/aoh Ann Kryger, Köpenhamn Printed at Reproservice, Chalmers Carola Lidén, Stockholm Svend Erik Mathiassen, Gävle Gunnar D. Nielsen, Köpenhamn Catarina Nordander, Lund Torben Sigsgaard, Århus Staffan Skerfving, Lund Kristin Svendsen, Trondheim Gerd Sällsten, Göteborg Allan Toomingas, Stockholm Ewa Wikström, Göteborg Eva Vingård, Uppsala Preface The main task of the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals (NEG) is to produce criteria documents to be used by the regulatory authorities as the scientific basis for setting occupational exposure limits for chemical substances. For each document, NEG appoints one or several authors. An evaluation is made of all relevant published, peer-reviewed original literature found. The document aims at establishing dose-response/dose-effect relationships and defining a critical effect. No numerical values for occupational exposure limits are proposed. Whereas NEG adopts the document by consensus procedures, thereby granting the quality and conclusions, the author is responsible for the factual content of the document. The evaluation of the literature and the drafting of this document on Isoflurane, sevoflurane and desflurane were made by Dr Anne Thoustrup Saber and Dr Karin Sørig Hougaard, National Research Centre for the Working Environment, Denmark. The draft document was discussed within the group and the final version was accepted by NEG on January 9, 2009 as its document. The following experts participated in the elaboration of the document: Gunnar Johanson Institute of Environmental Medicine, Karolinska Institutet, Sweden (chairman) Maria Albin Department of Occupational and Environmental Medicine, University Hospital, Lund, Sweden (former NEG expert) Kristina Kjærheim Cancer Registry of Norway (NEG expert) Tiina Santonen Finnish Institute of Occupational Health, Finland (NEG expert) Vidar Skaug National Institute of Occupational Health, Norway (NEG expert) Mattias Öberg Institute of Environmental Medicine, Karolinska Institutet, Sweden (NEG expert) Jill Järnberg and Swedish Work Environment Authority, Sweden (NEG secretariat) Anna-Karin Alexandrie Editorial work and technical editing were performed by the NEG secretariat. This work was financially supported by the Swedish Work Environment Authority and the Norwegian Ministry of Labour and Social Inclusion. All criteria documents produced by the Nordic Expert Group may be down- loaded from www.nordicexpertgroup.org . Gunnar Johanson, Chairman of NEG Contents Preface Abbreviations and acronyms 1. Introduction 1 2. Substance identification 1 3. Physical and chemical properties 3 4. Occurrence, production and use 4 5. Measurements and analysis of workplace exposure 7 5.1 Environmental exposure monitoring 7 5.2 Biological exposure monitoring 7 6. Occupational exposure data 8 7. Toxicokinetics 18 7.1 Uptake 18 7.2 Distribution 18 7.3 Biotransformation 20 7.4 Excretion 21 8. Biological monitoring 21 9. Mechanisms of toxicity 24 10. Effects in animals and in vitro studies 26 10.1 Irritation and sensitisation 26 10.2 Effects of single exposure 27 10.2.1 Lethality 27 10.2.2 Central nervous system effects 28 10.2.3 Nephrotoxicity 31 10.2.4 Cardiovascular effects 31 10.2.5 Hepatotoxicity 32 10.2.6 Lung toxicity 32 10.2.7 Other studies 33 10.3 Effects of short-term exposure (up to 90 days) 35 10.4 Mutagenicity and genotoxicity 37 10.5 Effects of long-term exposure and carcinogenicity 41 10.5.1 Carcinogenicity 41 10.5.2 Other effects of long-term exposure 42 10.6 Reproductive and developmental studies 42 11. Observations in man 53 11.1 Irritation and sensitisation 53 11.1.1 Irritation 53 11.1.2 Sensitisation 55 11.2 Effects of single and short-term exposure 56 11.2.1 Central nervous system 56 11.2.2 Cardiovascular system 60 11.2.3 Liver 61 11.2.4 Kidney 63 11.2.5 Other effects of single and short-term exposure 64 11.3 Effects of long-term exposure 65 11.4 Genotoxic effects 66 11.5 Carcinogenic effects 70 11.6 Reproductive and developmental effects 70 12. Dose-effect and dose-response relationships 73 12.1 Animal and in vitro studies 73 12.2 Human studies 75 13. Previous evaluations by national and international bodies 90 14. Evaluation of human health risks 91 14.1 Assessment of health risks 91 14.2 Groups at extra risk 93 14.3 Scientific basis for an occupational exposure limit 94 15. Research needs 95 16. Summary 96 17. Summary in Danish 97 18. References 98 19. Data bases used in search of literature 111 Appendix 1. Occupational exposure limit values 112 Appendix 2. Side-effects of the fluranes at anaesthetic dose levels 113 Appendix 3. Previous NEG criteria documents 115 Abbreviations and acronyms CI confidence interval EC electron capture detection EEG electroencephalography EPSC excitatory postsynaptic current FA alveolar blood concentration of flurane FDVE fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether (also called compound A) fEPSP field excitatory postsynaptic potential FEV 1 forced expiratory volume in one second FI concentration of inspired flurane GC gas chromatography HFIP hexafluoroisopropanol IL interleukin LC 50 lethal concentration for 50% of the exposed animals at single inhalation exposure LOAEL lowest observed adverse effect level MAC minimum alveolar concentration of anaesthetic that produces immobility in 50% of subjects exposed to a supramaximal painful/noxious stimulus MS mass spectrometry NOAEL no observed adverse effect level OR odds ratio PET positron emission tomography PS population spike SCE sister chromatid exchange SD standard deviation TFA trifluoroacetic acid TNF α tumour necrosis factor alpha TWA time-weighted average 1. Introduction Isoflurane, sevoflurane and desflurane are halogenated ethers and are used as inhalation anaesthetic agents. These agents are either used separately or in combination with nitrous oxide, intravenous anaesthetics, and muscle relaxants. Enflurane is also a member of this family but is no longer sold in the Nordic countries. For that reason enflurane is not included in this criteria document. This document was made on initial request from the Danish Working Environment Authority due to a report indicating exposure of personnel at Danish hospitals to these agents and the lack of occupational exposure limits (16). Until the 1990s, halothane and enflurane together with nitrous oxide were the primary anaesthetic gases. During the last decade, halothane and enflurane have been phased out and gradually replaced by isoflurane, desflurane and sevoflurane which, compared to halothane and enflurane, are less prone to metabolism causing immune hepatitis and other side-effects. As an example from the Nordic countries, isoflurane has been used in Denmark since 1984, while desflurane and sevoflurane are relatively new anaesthetics, introduced in 1994 and 1996, respectively (150- 152). In this document, the term fluranes is used as a common term for isoflurane, sevoflurane and desflurane. Some selection of literature has been performed. As opposed to most chemicals that occur in the work environment, the fluranes are meant to exert effects in humans at high dose levels. Thus, a large body of literature exists on pharmacological and toxicological effects in humans, mostly after a single exposure at anaesthetic dose levels, i.e. at exposure levels far ex- ceeding the levels met in the working environment. Where relevant, effects of such high acute exposures in humans are described as summarised in reviews. Animal studies are generally described in detail for effects where human data are lacking or scarce, or if the studies were conducted at subanaesthetic concentrations or included repeated exposures. 2. Substance identification The three fluranes are all ethers. Isoflurane and desflurane are halogenated methylethyl ethers with a difluoromethyl group and a fluorinated
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