Combined toxic effects of multiple chemical exposures Vitenskapskomiteen for mattrygghet 1:2008 1:2008 mattrygghet for Vitenskapskomiteen exposures multiple chemical of effects toxic Combined Vitenskapskomiteen for mattrygghet VKM Report 2008: 16 Norwegian Scientific Committee for Food Safety Combined toxic effects of multiple chemical exposures Published by Vitenskapskomiteen for mattrygghet/ Norwegian Scientific Committee for Food Safety 2008. Postboks 4404 Nydalen 0403 Oslo Combined toxic effects of multiple chemical exposures Tel. + 47 21 62 28 00 www.vkm.no ISBN 978-82-8082-232-1 (Printed edition) ISBN 978-82-8082-233-8 (Electronic edition) Combined toxic effects of multiple chemical exposures Published by Vitenskapskomiteen for mattrygghet/ Norwegian Scientific Committee for Food Safety 2008. Postboks 4404 Nydalen 0403 Oslo Tel. + 47 21 62 28 00 www.vkm.no ISBN 978-82-8082-232-1 (Printed edition) ISBN 978-82-8082-233-8 (Electronic edition) VKM Report 2008: 16 Opinion of the Scientific Steering Committee of the Norwegian Scientific Committee for Food Safety Adopted 7 April 2008 Combined toxic effects of multiple chemical exposures 06/404-6 final Combined toxic effects of multiple chemical exposures Jan Alexander Ragna Bogen Hetland Rose Vikse Erik Dybing Gunnar Sundstøl Eriksen Wenche Farstad Bjørn Munro Jenssen Jan Erik Paulsen Janneche Utne Skåre Inger-Lise Steffensen Steinar Øvrebø 2 Combined toxic effects of multiple chemical exposures 06/404-6 final CONTRIBUTORS Persons working for VKM, either as appointed members of the Committee or as ad hoc experts, do this by virtue of their scientific expertise, not as representatives for their employers. The Civil Services Act instructions on legal competence apply for all work prepared by VKM. Acknowledgements The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has appointed an ad hoc group consisting of both VKM members and external experts to answer the request from the Norwegian Food Safety Authority. The members of the ad hoc group are acknowledged for their valuable contribution to this opinion. The members of the ad hoc group are: Members of VKM Scientific Panels: Jan Alexander (Chair), Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panels 4) and Panel on Contaminants (Panel 5) Erik Dybing, Panel on Plant Protection Products (Panel 2) Gunnar Sundstøl Eriksen, Panel on Contaminants (Panel 5) Wenche Farstad, Panel on Animal Health and Welfare (Panel 8) Ragna Bogen Hetland, Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4) Bjørn Munro Jenssen, Panel on Animal Feed (Panel 6) Jan Erik Paulsen, Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panels 4) and Panel on Nutrition, Dietetic Foods, Novel Food and Allergy (Panel 7) Janneche Utne Skåre, Panel on Plant Protection Products (Panels 2) and Panel on Contaminants (Panel 5) Inger-Lise Steffensen, Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4) Steinar Øvrebø, Panel on Plant Protection Products (Panel 2) External expert: Rose Vikse, Norwegian Institute of Public Health VKM wishes to acknowledge Senior Scientist, PhD Ragna Bogen Hetland and Senior Scientist, PhD Rose Vikse from the Norwegian Institute of Public Health, for their work with the draft report that was prepared as a basis for this opinion. Professor Tore Aune is acknowledged for his contribution with the chapter on algal toxins and MD, Phd Ragnhild Halvorsen for her work with the chapter on allergy. A special thanks to the members of the Scientific Panels 2, 4, 5, 6, 7 and 8 of VKM for their valuable contribution to chapter 5. Assessed by Scientific Steering Committee: Åshild Krogdahl (Chair), Bjørn Næss, Espen Rimstad, Erik Dybing, Knut Berdal, Jan Alexander, Janneche Utne Skåre, Marit Aursand, Margaretha Haugen, Wenche Farstad, Leif Sundheim, Øyvind Lie, Ørjan Olsvik, Helle Margrete Meltzer, Helge Klungland Scientific Coordinators from the VKM Secretariat: Tor Øystein Fotland and Marie Louise Wiborg Norwegian Scientific Committee for Food Safety 3 Vitenskapskomiteen for mattrygghet (VKM) 06/404-6 final CONTENTS CONTRIBUTORS.......................................................................................................................... 3 Acknowledgements ........................................................................................................... 3 Assessed by ........................................................................................................................ 3 CONTENTS.................................................................................................................................. 4 SUMMARY................................................................................................................................... 7 SAMMENDRAG.......................................................................................................................... 10 BACKGROUND .......................................................................................................................... 13 TERMS OF REFERENCE............................................................................................................. 14 ASSESSMENT ............................................................................................................................ 15 1 Introduction ................................................................................................................. 15 2 Basic concepts and terminology used to describe the combined actions of chemicals in mixtures............................................................................................... 17 2.1 No interaction ............................................................................................................. 17 2.2 Interactions ................................................................................................................. 18 2.2.1 Mechanisms and causes of interactions........................................................... 19 2.2.2 Complex similar action .................................................................................... 20 2.2.3 Complex dissimilar action................................................................................ 20 2.2.4 Dose-dependent variations in toxic effects of multiple chemical exposures.... 21 2.3 Test strategies to assess combined actions and interactions of chemicals in mixtures .................................................................................................................................. 21 2.3.1 Testing of whole mixtures................................................................................. 21 2.3.2 Physiologically based toxicokinetic (PBTK) modelling................................... 22 2.3.3 Isobole methods................................................................................................ 22 2.3.4 Comparison of individual dose-response curves ............................................. 23 2.3.5 Other methods .................................................................................................. 24 3 Combined actions with different toxicological endpoints........................................ 25 3.1 Local irritation ............................................................................................................ 25 3.1.1 Skin irritation ................................................................................................... 25 3.1.2 Eye irritation .................................................................................................... 26 3.1.3 Irritation to the respiratory tract ..................................................................... 26 3.2 Genotoxicity and carcinogenicity............................................................................... 26 3.2.1 Interactions between genotoxic substances ..................................................... 27 3.2.2 Carcinogenicity................................................................................................ 27 3.3 Reproductive toxicity ................................................................................................. 29 3.3.1 Testing interaction of teratogenic compounds by using in vitro studies.......... 30 3.3.2 Examples of interaction of reproductive toxicants in vivo............................... 30 3.4 Endocrine disrupting chemicals.................................................................................. 30 3.4.1 In vitro studies.................................................................................................. 31 3.4.2 In vivo studies................................................................................................... 31 3.4.3 Fish and wildlife studies................................................................................... 32 3.5 Neurotoxicity.............................................................................................................. 34 3.5.1 Consequences of adverse effects on the nervous system.................................. 34 3.5.2 Examples of mechanisms of interactions ......................................................... 35 3.5.3 Examples of interactions between agents ........................................................ 35 3.6 Immunotoxicity 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