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The WHO Euro pean Centre for Environment and Health, Bonn, WHO Regional Office for Europe, coordinated the development of this publication. ABSTRACT This document presents answers to 24 questions relevant t o review ing European policies on air pollution and to addressing health aspects of these policies. The answers were developed by a large group of scient ists engaged in the WHO project Review of e vidence on health aspects of air pollution REVIHAAP . The experts reviewed and discussed the newly accumulated scientific evidence on the adverse effects on health of a ir pollution, formulating science – based answers to the 24 questions . Extensive rationale s for the answers, including the list of key references , are provided . The review concludes that a considerable amount of new scientific information on the adverse effects on health of particulate matter, ozone and nitrogen dioxide , observed at levels commonly present in Europe , has been published in recent years. This new evidence supports the scientific conclusions of the WHO air quality guidelines , last updated in 2005, and indicates that the effects in some cases occur at air pollution concentrations lower than those serving to establish the se guidelines . It also provides scientific arguments for taking decisive actions to improve air quality and reduce the burden of disease associated with air pollution in Europe. Th is publication arises from the project REVIHAAP and has been co – funded by the European Union . Keywords AIR POLLUTANTS AIR POLLUTION ADVERSE EFFECTS ENVIRONMENT AND PUBL IC HEALTH EVIDENCE BASED PRACT ICE GUIDELINES HEALTH POLICY Address requests about publications of the WHO Regional Office for Europe to: Publications WHO Regional Office for Europe Scherfigsvej 8 DK – 2100 Copenhagen Ø, Denmark Alternatively, complete an online request form for documentation, health information, or for permission to quote or translate, on the Regional Office web site (http://www.euro.who.int/pubrequest). © World Health Organization 201 3 All rights reserved. The Regional Office for Europe of the World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning th e legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate borderlines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or r ecommended by the World Health Organization in preference to others of a similar nature that are not

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mentioned . Errors and omissions excepted , the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The views expressed by authors, editors, or expert groups do not necessarily represent the decisions or the stated policy of the World Health Organization. The views expressed herein can in no way be taken to reflect the official opinion of the European Union.

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REVIHAAP Project : Technical Report Page iv CONTENTS Acknowledgements .. .. .. . v Abbreviations .. .. .. . vi Introduction .. .. .. .. 1 A. Health effects of PM .. .. .. .. 6 Question A1 .. .. .. 6 Question A2 .. .. .. . 10 Question A3 .. .. .. . 32 Question A4 .. .. .. . 35 Question A5 .. .. .. . 38 Question A6 .. .. .. . 41 B. Health effects of ozone .. .. .. 47 Question B1 .. .. .. . 47 Question B2 .. .. .. . 59 Question B3 .. .. .. . 62 Question B4 .. .. .. . 64 C. Proximity to roads, NO 2 , other air pollutants and their mixtures .. 67 Question C1 .. .. .. . 67 Question C2 .. .. .. . 73 Question C3 .. .. .. .. 113 Question C4 .. .. .. .. 117 Question C5 .. .. .. .. 127 Question C6 .. .. .. .. 137 Question C7 .. .. .. .. 142 Question C8 .. .. .. .. 155 Questions A7 & C9 .. .. .. . 165 Question C10 .. .. .. 175 D. General questions .. .. .. .. 182 Question D1 .. .. .. .. 182 Question D2 .. .. .. .. 197 Question D4 .. .. .. .. 208 References .. .. .. . 215 List of invited experts participating in REVIHAAP .. 300

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REVIHAAP Project : Technical Report Page vi Abbreviations Organizations, other entities and studies AHSMOG Loma Linda University Adventist Health and Smog study AIRS Aerometric Information Retrieval System APED Air Pollution Epidemiology Database APHEA Air Pollution and Health: a European Approach APHEIS Air Pollution and Health : a European Information System project APHENA Air pollution and health: a European and North American approach study ATS American Thoracic Society ATSDR Agency for Toxic Substances and Disease Registry of the United States Department of Health and Human Services BENMAP Environmental Benefits Mapping and Analysis program CAFE Clean Air for Europe Programme CLRTAP Convention on Long – range Transboundary Air Pollution COMEAP the U nited K ingdom ‘s Committee on the Medical Effects of Air Pollutants CPS – II American Cancer Society Cancer Prevention Study II EC European Commission EEA European Environment Agency EFSA European Food Safety Authority EGEA French Epidemiological study on Genetics and Environment of Asthma EPA United States Environmental Protection Agency EPAQS United Kingdom Expert Panel on Air Quality Standards EU European Union FAO Food and Agriculture Organization of the United Nations HEIMTSA Health and Environment Integrated Methodology and Toolbox for Scenario Assessment project HRAPIE Health Risks of Air Pollution in Europe IARC International Agency for Research on Cancer JECFA Joint WHO/FAO Expert Committee on Food Additives NAS United States N ational A cademy of S ciences NHANES III Third National Health and Nutrition Examination Survey NMMAPS U nited S tates National Morbidity, Mortality and Air Pollution Study PAPA Public Health and Air Pollution in Asia study PEACE Pollution Effects on Asthmatic Children in Europe project REVIHAAP Review of e vidence on health aspects of air pollution WHO World Health Organization Technical terms CI confidence interval CICADs concise international chemical assessment documents COX – 2 cyclooxygenase – 2 EGF epidermal growth factor EGFR epidermal growth factor receptor HAPs hazardous air pollutants Hg mercury Hg 0 mercury vapour

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REVIHAAP Project : Technical Report Page 1 Introduction A ir pollution i s an important determinant of health. A w ide range of adverse effects of ambient air pollution on health has been well documented by studies conducted in various parts of the world. There is significant inequality in exposure to air pollution and related h ealth risk s : air pollution combines with other aspects of the social and physical environment to create a disproportiona te disease burden in less affluent parts of society. WHO periodically reviews the accumulated scientific evidence to update its air quality guidelines . The most recent update was completed in 2005. The guidelines address all regions of the world and provide uniform targets for air quality that would protect the large majority of individuals from the adverse effects on health of air pol lution. The adverse effects on health of particulate matter (PM) are especially well documented. There is no evidence of a safe level of exposure or a threshold below which no adverse health effects occur. More than 80% of the population in the WHO European Region (including the European Union , EU ) live s in cities with levels of PM exceeding WHO Air Quality Guidelines . Only a slightly decreasing trend in average concentrations has been observed in countries in the EU over the last decade. Pollution from PM creates a substantial burden of disease, reducing life expectancy by almost 9 months on average in Europe. Since even at relatively low concentrations the burden of air pollution on health is significant, effective management of air quality that ai m s to achieve WHO Air Quality Guidelines levels is necessary to reduce health risks to a minimum. Exposure to air pollutants is largely beyond the control of individuals and requires action by public authorities at the national, regional and international levels. A multisectoral approach, engaging such relevant sectors as transport, housing, energy production and industry , is needed to develop and effective ly implement long – term policies t hat reduce the risks of air pollution to health. The EU Directive of 2008 on ambient air quality and cleaner air for Europe explicitly states appropriate objectives set for ambient air quality taking into account relevant World Health Organization standards, guidelines and programmes . In that context , and in the framework of the EU in 2013 , t he World Health Organization (WHO) Regional Office for Europe is implementing two projects : (a) e vidence on health aspects of air pollution , to review EU policies REVIHAAP ; and (b) h ealth r isks of a ir p ollution in Europe , with financial support from the European Commission (EC). These projects will provide scientific evidence – based advice on the health aspects of air pollution , to support the comprehensive review of the 2013. The review focuses on pollutants regulated by EU d irectives 2008/50/EC and 2004/107/EC. 1. Scope of the project The advice provided by the REVIHAAP and HRAPIE projects is formulated as responses to 26 key policy – relevant questions asked by the EC . This advice is grounded i n a review of the latest scientific evidence for PM , ground level ozone, nitrogen dioxide (NO 2 ) , sulfur dioxide ( SO 2 ) , and emissions to the air of individual metals (arsenic, cadmium, nickel, lead and

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REVIHAAP Project : Technical Report Page 2 mercury) and polycyclic aromatic hydrocarbons, as regulated by EU d irectives 2008/50/EC and 2004/107/EC. The questions cover general aspects of importance to air quality management, as well as specific topics on health aspects of individual air pollutants. The review wa s conducted by invited experts from top institutions across the world. This WHO technical report f rom the REVIHAAP project includes answers to 24 of the questions. Further work document s emerging issues on health risks from air pollution related to specific source categories ( for example, transport, biomass combustion, the metals industry, refineries and power production ) , specific gaseous pollutants or specific components of PM ( such as size range , like nanoparticles and ultrafine particle s, and rare – earth metals, black carbon ( e lemental c arbon and / or o rganic c arbon )) ( Q uestion D3). Moreover , concentration response functions to be included in cost benefit analysis will be identified in response to Question D5. This work , under the HRAPIE project , will be concluded by September 2013, although preliminary findings will be made available to the EC earlier , to ensure their suitable use in review ing EU air quality policies. 2. Process A s cientific a dvisory c ommittee of eight scientists, experienced in previous reviews conducted by WHO and representing key areas relevant to the projects (epidemiology, toxicology and atmospheric sciences) , was put together to guide and oversee the projects. Two meetings with the s cientific a dvisory c ommittee members were held , in December 2011 and June 2012 , to provide advice and coordinate the work plan . The review was conducted by a group of 29 invited experts from top institutions a round the world, representing various relevant scientific disciplines. These experts, working in small groups, reviewed the scientific literature accumulated , drafted succinct answers to the questions and drafted longer rationales to the answer emerging from the research results. Answers to questions in section D were prepared using conclusions from answers to questions A C. Thirty – two invited external reviewers, as well as members of the s cientific a dvisory c ommittee , provided detailed comments on the completeness of the literature reviewed , the validity of conclusions reached and the clarity of the answers. The authors used the comments to revise the text , subject to furthe r review. A full list of s cientific a dvisory c ommittee members, expert authors, and external reviewers is provided at the end of this document. All submitted a WHO Declaration of Interests form to ensure the review process was unbiased . Besides discussion s conducted electronic ally , direct discussion s o f the answers and evidence in their support was he ld at two WHO expert meetings , which t ook place at the WHO European Centre for Environment and Health office in Bonn, Germany , on 21 23 August 2012 and 15 17 Janu ary 2013 . During the second meeting, the final text of the answers covered under the REVIHAAP project was adopted. The discussion s covered solely scientific arguments, addressing the methodological quality of the influential studies , as well as the completeness and consistency of the evidence generated by studies conducted in various areas of the world, in various populations and with various scientific methods. The conclusions reflect the collective expert judgment of specialists in the field , an d the final text of the a nswers was ad o pted by a consensus of experts present at the meeting.

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REVIHAAP Project : Technical Report Page 3 Al though some of the questions asked directly for the assessment of individual policies or policy instruments, the REVIHAP discussion and answers covered only the scientific evidence underlying the policy and did not address political arguments. 3. Sources of information and methodology Carrying out a r eview of the effects on health of ambient air pollution is a challenging task, since a remarkably large body of evidence has to be assessed. Thousands of new scientific papers have been published on this topic in the last few years, covering various aspects and research disciplines , such as population exposure , observational epidemiology, controlled human exposure, animal toxicology and in vitro mechanistic studies. With that in mind, the review of the literature in support of the answers therefore f ocused on studies that were published after the 2005 global update of the WHO air quality guidelines . However, when appropriate and necessary, the review also included earlier publications. A l s o , the group made use of recent major reviews, with a particular focus on those prepared by relevant international or national organizations. Only publications with a clearly stated methodology , for literature search es and evidence selection , were used. A more systematic approach was used to review and assess recent individual publications. By necessity, the authors focused on the most significant and relevant studies and on meta – analyses , when available. The evidence presented in this re view is based on all available types of information, including conclusions from epidemiological and toxicological research. The main sources of evidence are quoted and the strength of this evidence is explained. Careful wording has been used throughout the document to pro perly present the strength of the evidence and to determin e potential causality related to association s observed between air pollutants and outcomes. This wording is indicative of the state of the evidence on a particular issue. 4. Reconsideration and revision of guidelines Several questions specifically ask whether the scientific conclusions of the 2005 global update of the WHO air quality guidelines require revision, based on the new evidence that has emerged on adverse health effects. The group of experts thoroughly evaluated the scientific literature published since the 2005 global update of the WHO air quality guidelines and explored whether the new evidence justified reconsideration of the current guidelines . A positive answer indicat es a gain in knowledge. While there are formal frameworks to assess gains in knowledge, the group relie d on its collective expert judg ment to determine if there was sufficient new evidence. Issue s taken into consideration when interpreting the strength of th e new evidence included: the identification of new adverse health outcomes ; the consisten cy of findings of associations at exposure levels lower than previously identified ; and the enhanced mechanistic understanding of the observed associations, which could lead to a reduction of uncertainty . It is important to note that a revision of a guideline does not necessarily mean that a change in the existing WHO air quality guideline value is warranted. It rather implies that the whole body of the scientific evidence should be systematically analysed when reconsidering values that protect health. It is important to emphasize that the REVIHAAP project has not

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REVIHAAP Project : Technical Report Page 4 initiati ng a separate process to update the guidelines, according to WHO rules. 5. From guidelines to limit values Several questions ask explicitly about the impact on EU air quality legislation of the new evidence on the health effects of air pollution . It is important to note that there is a fundamental d ifference between the roles and mandates of WHO and the EC. WHO holds a normative role and evaluates the scientific evidence in order to develop guidelines and recommendations, whereas the EC holds a policy ro le, proposing and implementing legally binding decisions within its jurisdiction. Therefore, according to the normative role of WHO, the recommendations that stem from the REVIHAAP project are based solely on scientific conclusions on health aspects of air pollution and do not consider issues relevant to policy formulation, such as technical feasibility, economic considerations and other political and social fa ctors. For the protection of public health, WHO recommend s maintain ing levels of air pollutants below those at which adverse effects on public health have been documented. The WHO air quality guidelines are typically set at such levels. However, WHO recog nize s the heterogeneity in underlying factors influencing air quality management decisions in various countries and has therefore ( in the past ) developed interim target values for some pollutants. These target values should promote a steady process towards meeting WHO guideline values, which are the main recommendations. 6. General issues of relevance to all pollutants This section sets out the views of the authors on core issues embedded within some of the questions. 6.1 Pollution mixture s The request to review the health effects of individual air pollutants separately implicitly suggests that each has adverse effects on health per se . The pollutants currently regulated in the EC directives , and covered in this document, share many common sources and are linked by complex chem ical processes in the atmospher e . The group of experts recognizes that air pollution exists as a complex mixture and that the effects attributed to individual air pollutants may be influenced by the underlying toxicity of the full mixture of all air pollutants. This is also specifically addressed as part of the Answer to Question C8. 6.2 Health impact assessment Questions A6, B3, and C4 ask what metrics, health outcomes and concentration response functions can be used to assess the health impact of PM, ozone, and NO 2 . The calculation of health impacts requires several components: ( a ) an estimate of current concentrations of the pollutant(s) under review; ( b ) a determination of the target concentration or standard , or the expected concentration change from a policy under consideration ; ( c ) the concentration response functions that typically relate a change in pollution to a per cent change in a health outcome; ( d ) a baseline level of the health outcome; and ( e ) a characterization of uncertainty.

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