DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 1 2 PEER REVIEW DRAFT 12 JUNE 2017 3 4 Environmental Health Criteria Document 5 6 Principles and Methods to Assess the Risk of Immunotoxicity Associated 7 with Exposure to Nanomaterials 8 9 10 NOTE TO REVIEWERS 11 The target reader group for the document will be: risk assessors in a regulatory setting, researchers, 12 and industry that needs to provide the data. 13 Peer review comments should pay attention to the technical content of the draft document. The 14 document will be edited following peer review. 15 Should reviewers propose inclusion of additional material, please provide the full citation. In 16 addition, if the material cited is not available free-of-charge, for example via “open access”, please 17 provide a copy of the material. 18 19 Comments should be submitted using the template (provided on the webpage announcing the peer 20 review) to [email protected] by Friday 21 July 2017, along with a completed WHO Declaration of 21 Interests form (also available on the web page). 22 23 24 25 26 27 28 1 DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 29 30 © World Health Organization 2017 31 32 Information on rights, cataloguing-in-publiacation and other matters will be provided in the final document. 33 This is a peer review draft, not for citing, quoting or distribution. 34 35 General disclaimers. The designations employed and the presentation of the material in this publication do not imply the 36 expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or 37 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent 38 approximate border lines for which there may not yet be full agreement. 39 40 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 41 recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, 42 the names of proprietary products are distinguished by initial capital letters. 43 All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the 44 published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the 45 interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. 46 . 47 This publication contains the collective views of an international group of experts and does not necessarily represent the 48 decisions or the policies of WHO. 49 50 51 52 53 54 55 2 DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 56 ACKNOWLEDGMENTS (to be updated upon finalization of the document) 57 This Environmental Health Criteria Document was developed by WHO with the support of the WHO 58 Collaborating Centre for Immunotoxicology and Allergic Hypersensitivity at the National Institute for 59 Public Health and the Environment (RIVM), Bilthoven, the Netherlands. 60 61 A Scoping Meeting held from 8-9 April 2015, at RIVM, Bilthoven, the Netherlands, developed an 62 outline of the document. The meeting was attended by the following: 63 Invited experts: 64 James BONNER, North Carolina State University, USA 65 Yolanda Irasema CHIRINO LOPEZ, Universidad Nacional Autónoma de México, Mexico 66 Bengt FADEEL, Karolinska Institutet, Box 210 67 Sabina HALAPPANAVAR, Health Canada, Canada 68 Jun KANNO, National Institute of Health Sciences, Japan 69 Kee Woei NG, Nanyang Technological University, Singapore 70 Kai SAVOLAINEN, Finnish Institute of Occupational Health, Finland 71 Henk van LOVEREN, RIVM, the Netherlands (Meeting Chair) 72 Il Je YU, Hoseo University, Republic of Korea 73 Representatiaves (Observers); 74 Laura ROSSI, European Chemicals Agency (ECHA), Finland 75 Jihane EL GAOUZI, OECD, France 76 The WHO Secretariat was provided by Carolyn VICKERS, WHO, Switzerland. 77 78 The invited experts contributed to the development of a first draft, which was discussed at a meeting 79 held from 30 March – 1 April 2016, at RIVM, Bilthoven, the Netherlands. The meeting was attended 80 by the following: 81 Invited experts: 82 Harri ALENIUS, Finnish Institute of Occupational Health, Finland 83 James BONNER, North Carolina State University, USA 84 Yolanda Irasema CHIRINO LOPEZ, Universidad Nacional Autónoma de México, Mexico 85 Wim H. DE JONG, RIVM, the Netherlands 86 Janine EZENDAM, RIVM, the Netherlands 87 Bengt FADEEL, Karolinska Institutet, Box 210 88 Sabina HALAPPANAVAR, Health Canada, Canada 89 Kee Woei NG, Nanyang Technological University, Singapore 90 Margriet PARK, RIVM, the Netherlands 91 Barbara ROTHEN-RUTISHAUSER, Université de Fribourg, Switzerland 92 Kai SAVOLAINEN, Finnish Institute of Occupational Health, Finland 93 Susan WIJNHOVEN, RIVM, the Netherlands 94 Henk van LOVEREN, RIVM, the Netherlands (Meeting Chair) 95 Il Je YU, Hoseo University, Republic of Korea 96 Representatiaves (Observers); 97 Laura ROSSI, European Chemicals Agency (ECHA), Finland 98 The WHO Secretariat was provided by Carolyn VICKERS, WHO, Switzerland. 99 100 Revisions to the document were made by the experts following the March 206 meeting, under the 101 Chairmanship of Henk van Loveren, in order to prepare the peer review version. 102 103 WHO intends to convene a final review group meeting to consider the peer review comments 104 received. 105 106 3 DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 107 ABBREVIATIONS AND ACRONYMS (to be provided in the final document). 108 109 110 4 DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 111 EXECUTIVE SUMMARY 112 113 Engeneerd nanomaterials (ENMs) or groups of ENMs may be associated with environmental and 114 human health hazards harmful effects on health [Donaldson et al., 2012]. There are different classes 115 of nanomaterials, such as carbon-based (mainly composed of carbon and examples include carbon 116 nanotubes and fullerenes); metal-based (include nano forms of titanium dioxide, gold, silver, and 117 quantum dots); dendrimers (these are polymers and are mainly used in drug delivery), and 118 composites (combination of nanomaterials; for example, carbon nanotubes coated with nano 119 titanium dioxide). These materials are being readily applied in various nanotechnology products 120 which can be categorized into four generations. 1) The first generation nanoproducts include simple 121 passive nanostructures that are used in various consumer products such as cosmetics, food, etc. The 122 properties or functions of nanomaterials are not expected to change during their use 2) The second 123 generation products include active nanostructures, the properties or function of which are expected 124 to change during their use. These changes can be unintentional in response to their local 125 environment or intentional such as in the case of drug delivery. 3) The products of the third 126 generation nanotechnology involve uses of both passive or active nanostructures to build systems of 127 nanosystems. For example, the development of synthetic organs or engineered microbes; self 128 assembling materials that assemble into new structures in the body upon their release. 4) The forth 129 generation nanostructures, which are not accomplished yet involve molecular nanosystems with a 130 specific function that include molecular devices such as in genetic therapy.. While the technology 131 itself has progressed rapidly and thousands of consumer products containing these materials are 132 beginning to appear on the market, the toxicology of these materials is less understood. Lack of a 133 clear understanding of how is general polulation exposed and the extent of exposure, and potential 134 hazard of these materials has been one of the major impediment. 135 136 Extensive research conducted in the past 20 years shows that size, shape and chemistry are among 137 the important properties that influence the interaction of nanomaterials with biological systems. 138 However, to date, no studies have conclusively shown the unique effects of nanomaterials on 139 biological systems. Considering the rapid development of technology, sheer number of 140 nanomaterials with diverse properties and the constrains associated with the conventional single 141 endpoint based toxicity assessment methods, it will be impossible for toxicologists and risk assessors 142 to keep pace with the rapidly evolving technology. Instead a new science of risk bringing together the 143 physical, chemical, and biological sciences to address the challenges presented by these novel 144 materials is needed. 145 5 DRAFT FOR PEER REVIEW: DO NOT CITE, QUOTE OR DISTRIBUTE 146 The immune system consists of an innate part component that is able to directly respond to foreign 147 agents immediately after exposure regardless of the type of stimulus and an adaptive part 148 component that is targeted and develops over time. needs some time to develop an immune 149 response. Based on the external stimuli or toxic substance, both components may be activated, and 150 the end result could be Both of these may be affected by foreign agents. This interaction may result 151 in immunosuppression, immunostimulation, and/or hypersensitivity and autoimmunity. More 152 recently numerousRecent reports reports have identified ENMs as a potential stimulants of immune 153 response that may culminate in source for eventual immunotoxicity. While there are no validated 154 methodology