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HPRU Research Forward Business Plan 2017-19 Application Ref No: 1 NIHR HEALTH PROTECTION RESEARCH UNITS Forward Business Plan 2017-2019 Please use this form to provide details of your specific Forward Business Plan to be conducted with the funding provided through this scheme. Please note this should be completed in a font no smaller than 10-point Arial. Please insert your unique Application Reference Number into the footer space provided. HPRU Details HPRU name: Health Impact of Environmental Hazards Director: Professor Frank Kelly Address: Room 4.116B, 4 th floor, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH Email: [email protected] Tel: 020 7848 4004 PHE Lead: Professor Tim Gant Address: Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon, OX11 0RQ Email: [email protected] Tel: 01235 825139 The Forward Business Plan must be developed and agreed in partnership with PHE. NIHR HPRU Forward Business Plan (max 10 pages) In no more than 10 pages please provide detailed description addressing the following: 1. Proposed projects that will be pursued in the next two years; 2. The project lead; 3. Cost allocation for each project; 4. How these projects meet or contribute to the overall aims and objectives of the Theme or HPRU; 5. Key milestones for the two years (2017-19). Introduction: The research priorities for the Health Impact of Environmental Hazards HPRU continue to focus on the identification, quantification and advice provision of environmental hazards to minimise the impact on morbidity and mortality. Our Objectives during years four and five are to build upon the

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Page 1: NIHR HEALTH PROTECTION RESEARCH UNITS Forward Business …hieh.hpru.nihr.ac.uk/sites/default/files/private/secure/4... · 2018-02-28 · PHE is contributing to the COST Action IS1408

HPRU Research Forward Business Plan 2017-19 Application Ref No: 1

NIHR HEALTH PROTECTION RESEARCH UNITS

Forward Business Plan 2017-2019

Please use this form to provide details of your specific Forward Business Plan to be conducted with the funding provided through this scheme. Please note this should be completed in a font no smaller than 10-point Arial. Please insert your unique Application Reference Number into the footer space provided.

HPRU Details

HPRU name: Health Impact of Environmental Hazards Director: Professor Frank Kelly Address: Room 4.116B, 4th floor, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH Email: [email protected] Tel: 020 7848 4004

PHE Lead: Professor Tim Gant Address: Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon, OX11 0RQ Email: [email protected] Tel: 01235 825139

The Forward Business Plan must be developed and agreed in partnership with PHE.

NIHR HPRU Forward Business Plan (max 10 pages)

In no more than 10 pages please provide detailed description addressing the following:

1. Proposed projects that will be pursued in the next two years; 2. The project lead; 3. Cost allocation for each project; 4. How these projects meet or contribute to the overall aims and objectives of the Theme

or HPRU; 5. Key milestones for the two years (2017-19).

Introduction: The research priorities for the Health Impact of Environmental Hazards HPRU continue to focus on the identification, quantification and advice provision of environmental hazards to minimise the impact on morbidity and mortality. Our Objectives during years four and five are to build upon the

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 2

work/outcomes achieved in years 1-3 by completing those remaining projects and initiating a number of new ones identified in our forward planning. Details of these are provided under the relevant Themes. Where outputs have direct policy relevance we will continue to dialogue through meetings/interactions with relevant PHE and DH staff. Budget plans:

King’s: (2017/18)

£283,107 (2018/19) £246,383

TOTAL

£ 529,489

Imperial (2017/18) £217,297 (2018/19) £222,519 TOTAL £ 439,817 PHE: (2017/18) £236,876 (2018/19) £237,008 TOTAL £ 473,884

Theme 0 - Management and coordination costs – (2017/18 and 2018/19)

King's staff Imperial staff PHE staff

Frank Kelly 10% Paul Elliott 5% Tim Gant 2.5%

Angela Lewis 50%

King’s: Research Salaries £85,902 Non pay research costs £ 20,000 Indirect costs £25,771 Imperial: Research Salaries £15,800 Non pay research costs £ 0 Indirect costs £ 4,740 PHE: Research Salaries £ 7,288 Non pay research costs £ 4,500 Indirect costs £ 1,458

Theme I: Epidemiological assessment of low level environmental exposures Lead: Anna Hansell (Imperial); Deputy lead: Tony Fletcher (PHE) Overall aim of this theme: To use epidemiological methods to show association between disease and exposure to environmental hazards. Work in this theme comprises epidemiology and surveillance methodology development, involving substantive exposures where there is uncertainty or lack of data on population impacts such as carbon monoxide and bioaerosols and development of methodology to facilitate epidemiological assessments relating to a range of possible environmental exposures. Theme I/Project 1 - Carbon monoxide Lead: Giovanni Leonardi (PHE) and Fred Piel (Imperial) Initial work has highlighted the likely extent of low-level exposure to CO to a much larger proportion of the English population than previously thought. Following our analyses of hospital admissions and initial work on A&E attendances 2007-10, epidemiological analyses of will be extended to the development of methodologies to link across A&E, hospital admissions, coroners’ data and mortality datasets (a novel exercise which has benefits for other research) and to the estimation of spatial uncertainty in CO patterns or trends. This work will be linked with information on exposure and exposure markers (such as housing quality) to enable a better estimate of “low-level” exposures. This information on population exposure and health effects will support an overall estimate of disease burden from CO to the national population. Deliverables and milestones

• Milestone 2 - Follow-on work on assessment of A&E presentations 2007-15 of those subsequently

diagnosed with CO poisoning on hospital admission. Within year 4 (by March 2018), dependent on

recruitment of replacement for RA. (Imperial led, PHE input)

• Milestone 3 - Submit a paper on the assessment of CO A&E presentations. Within year 5 (2018-19)

dependent on work in previous bullet point. (Imperial led, PHE input)

• Milestone 5 - Funders identified. Apply for funding for the international comparison of CO. By Au-

gust 2017

• Milestone 6 - Identify the elements required for an improved CO global burden of disease. By end

March 2018

King's staff Imperial staff PHE staff

Anna Hansell No cost Tony Fletcher 10%

Fred Piel No cost

RA TBA No cost

Database/IT sup-port TBA 5%

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 3

Theme I/Project 1 costs King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 7,800 Non pay research costs £ 2,625 Indirect costs £ 2,340

PHE: Research Salaries £ 7,196 Non pay research costs £ 1,000 Indirect costs £ 1,439

Theme I/Project 2 – Health impacts from bioaerosols from waste composting facilities and intensive farming Lead: Anna Hansell (Imperial) and Tim Gant (PHE) This project links with the bioaerosols project in Theme II/Project 5.Bioaerosols from waste composting and intensive farming are of particular concern to Defra and the Environment Agency (EA) as the evidence base on which to regulate composting on health grounds is lacking. In discussion with two NERC funded consortia assessing emissions, further work on exposure assessment is required before a dispersion model of population exposure can be developed. Deliverables and milestones

• Milestone 1 - Systematic review paper on bioaerosols from intensive farming by end Dec 2017

(PHE lead).

• Milestone 3 - Quantification of the temperature of bioaerosol emissions from compost windrows

(shown to be an important dispersion model input from the sensitivity analysis paper published in

2016) and comparison with core windrow temperatures. Paper submission by Dec 2017 (Imperial

lead)

• Milestone 4 - Epidemiological study on respiratory admissions taking into account wind direction

and seasonality and with extended years of coverage. Analyses continuing, further report by March

2018

• Milestone 5 - Continued linkage with the Human and Environmental Microbiome project in Theme II

in respect of development and application of molecular methods for fungal species.(17/18)

King's staff Imperial staff PHE staff

Anna Hansell 5% Tim Gant No cost

Pippa Douglas No cost Emma Marczylo No cost

Database/IT support TBA 20%

Theme I/Project 2 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 20,315 Non pay research costs £ 3,625 Indirect costs £ 6,095 PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme I/Project 3 – Cluster guidelines/Rapid Inquiry Facility Lead: Tony Fletcher (PHE) and Anna Hansell (Imperial) We aim to complete and make available guidelines on investigation of clusters of non-infectious disease; involving developing case studies, completing draft guidance, consulting widely in the public health community (including PHECs & FES) on these guidelines, and finalising them in the light of the consultation. In addition a journal article will be prepared reflecting this policy and public health teaching materials developed. There will be close cooperation with the Rapid Inquiry Facility (RIF) and the RIF will be modified as needed to permit the use of its disease mapping and cluster analysis statistical software in the cluster guidelines and for environmental public health tracking. Deliverables and milestones

• Milestone 1 - Evaluate draft cluster guidance completed in year 2 in PHE centres PHECs. Comple-

tion by December 2017.(PHE lead)

• Milestone 2 - Prepare paper on the evaluation results. Completion in year 4. (PHE lead)

• Milestone 3 - Revise and update draft guidance in light of Evaluation and review of new WHO guid-

ance document. Completion in year 4. (PHE lead)

• Milestone 4 - Enhanced Rapid Inquiry Facility (RIF) - development of software on cluster analysis

and disease mapping, available as freeware. A beta working version in field testing by end 2017.

(Imperial lead)

King's staff Imperial staff PHE staff

Anna Hansell No cost Tony Fletcher 10%

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 4

Database/IT support TBA 75%

RA TBA No cost

Theme I/Project 3 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 86,209 Non pay research costs £ 1,000 Indirect costs £25,863

PHE: Research Salaries £ 7,196 Non pay research costs £ 1,000 Indirect costs £ 1,439

Theme I/Project 4 - Assessing environmental epidemiology evidence for health effects of low level exposures Lead: Tony Fletcher (PHE) and Anna Hansell (Imperial) There is uncertainty in how best to characterize exposure and uptake at low exposure levels, Anna Hansell has led on the ‘Synthesising Environmental Epidemiology Subgroup of the COT and COC’ looking at methods available for risk assessment and to ensure evidence based public health policy. The report will be turned into a paper in Year 4, also working with Heather Walton in Theme 4 on this topic. Research on some environmental chemicals have identified the power of the use of biomarkers for guidance on setting no effect levels, but these also have limitations. We will continue this work on perfluorinated compounds, with two main aims – one is to illustrate in this case study the role of epidemiology in validating dose-response relationships by assessing both internal and external exposure contrasts, the second is using these data in support of standard setting by benchmark dose modelling. Deliverables and milestones

• Milestone 1 - Completion of publication on PFAS serum biomarkers as exposure indicators in the

epidemiology of perfluorinated compounds: Thyroid hormones. Second paper on benchmark dose

modelling for PFAS Further paper on associations between PFAS and thyroid disease outcomes.

Both papers to be submitted by March 2018.

King's staff Imperial staff PHE staff

Anna Hansell No cost Tony Fletcher 5%

Theme I/Project 4 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 3,522 Non pay research costs £ 0 Indirect costs £ 704

Theme I/Project 5 – Low level population heavy metal exposure Lead: Anna Hansell (Imperial) and Giovanni Leonardi (PHE) “Contaminated land” is a recognised problem for areas of the UK with some previous industrial and brown field sites having persistent high levels of metals and other contaminants. The potential importance of population exposures for health, particularly infant health, has recently been highlighted in work by the Committee on Toxicity but there are uncertainties relating to current population exposure levels. Imperial College have recently obtained a comprehensive data set from the British Geological Society with extensive sampling of soil concentrations of metals, but these are at different resolutions. PHE is contributing to the COST Action IS1408 “Industrially Contaminated Sites and Health Network” (ICSHNet), which is assembling Europe-wide data on health risks potentially associated with industrially contaminated land. This work will update UK population exposure assessment for use in risk assessment. . Deliverables and milestones.

• Milestone 1 - A series of maps of small-area level soil concentrations of important heavy metals to be completed by end of 2017

• Milestone 2 - A review of studies that have measured heavy metals in human breast milk, to be completed in year 4.

King's staff Imperial staff PHE staff

Anna Hansell No cost Tony Fletcher 5%

RA TBA No cost

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 5

Theme I/Project 5 costs King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 3,522 Non pay research costs £ 0 Indirect costs £ 704

Theme I/Project 6 – Exposure to emissions from incinerators Lead: Anna Hansell (Imperial) and Ovnair Sepai (PHE) Staff experienced in the specialised environmental exposure modelling skills being employed for the bioaerosols project (project 2) have also been participating in emissions modelling for UK municipal waste incinerators. Exposure modelling of particulates has been completed, but it proved impossible to conduct modelling for dioxins or metals as measurements were too sparse. Exposure modelling by HPRU staff has informed the chemical analysis plan for a study led by Mireille Toledano, the Incinerators Biomonitoring Study (IBMS), collecting human breast milk near three incinerators. Chemical analyses of the breast milk will inform whether there are significant differences in persistent organic pollutant (POP) concentrations, including dioxins, metals and metabolic profiling, informed by modelled PM10 exposure tertiles. Results are contributing towards substantive PHE funded epidemiological studies to assess if there are any associations between incinerator emissions and adverse birth outcomes. These health studies are not part of the HPRU. Deliverables and milestones

• Milestone 1 - Submission of paper modelling population exposure to emissions from municipal

waste incinerators in year 4.

• Milestone 3 - Epidemiological analysis interpreting chemical analysis of POPs in breast milk includ-

ing QA samples completed in year 4.

King's staff Imperial staff PHE staff

Gary Fuller No cost Anna Hansell No cost Ovnair Sepai No cost

Pippa Douglas No cost

Mireille Toledano No cost

Theme I/Project 6 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme I total costs – (2017/18 & 2018/19):

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 114,324 Non pay research costs £ 7,250 Indirect costs £ 34,297 PHE: Research Salaries £ 42,572 Non pay research costs £ 4,500 Indirect costs £ 8,514

Theme II – Modes of toxicity Lead: Tim Gant (PHE); Deputy lead: David Phillips (King’s) The concept of a mode of toxicity is an understanding of the interaction of a chemical with cellular biochemistry from the level of exposure though to outcome, and therefore includes internal exposure, mechanisms of toxicity and disease pathways. With the exception of disease pathways these aspects are captured in this theme. This activity has a particular, but not exclusive focus, on early life effects because this is recognised as a susceptible stage of life of particular public health concern and addresses one of PHE’s seven Big Ambitions ‘Every Child ready to learn’. Overall aim of this theme: To use molecular methods to show causation association between disease and exposure to environmental hazards and better assess risk by reference to mechanism of action. Theme II/Project 1 – Early life exposures and effect Lead: Tim Marczylo (PHE) and Mireille Toledano (Imperial) The foetus represents one of the most vulnerable stages of life for susceptibility to the effects of chemical exposure. This has been highlighted in several publications and remains of public concern as demonstrated by the interest that surrounded the publication in 2013 of a report from the Royal College of Obstetricians and Gynaecologists that made several recommendations for pregnant women in respect of reducing their potential chemical exposure (http://www.rcog.org.uk/news/rcog-release-mothers-be-should-be-aware-unintentional-chemical-exposures-say-experts). This report highlights the information void that exists in the understanding of the actual levels of chemical exposure that occur in the foetus. Here we are first seeking to better understand the qualitative and quantitative nature of foetal environmental exposures

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 6

to chemicals using neonatal blood spots with an assessment of effect on one recognised biochemical susceptibility of fertilisation and embryonic development – DNA epigenetic modification. Epigenetic modifications are vital to life and passed from the mother and father onto the progeny through their gametes where they influence the phenotype of the offspring. Furthermore epigenetic modifications are known to alter throughout life in response to changes in the environment and chemical exposure. The consequence of environmentally induced epigenetic change for public health, if any, is unknown. Hypothesis: that exposure to environmental chemicals to the gamete and in utero occurs and can lead to specific alteration of the epigenome in target cell types that may have an adverse effect in early life that can persist throughout life. Deliverables and milestones

• This work has started well in 2014/15 continued through 2015/17 and will proceed further in 2017/19. A number of significant unexpected challenges have occurred and largely resolved though there are some technical aspects that are still being addressed. As reported in 14/15 ethical approval for the project took longer than expected. This was granted in Q1 2015/16 that allowed sampling of the bloodspot cards without having to contact the parents of each child, provided only anonymous samples are used. Therefore, as the blood spot cards have patient identifiable data on them, the cards have to be initially sampled by the NHS heath care team, who we are collaborating with and they will provide us with the anonymous sample. This condition led to delays in getting blood spots from the John Radcliffe Hospital, but samples were obtained in 2015/16 Q3. We are now finding the sensitivity of the analysis challenging. We have had most success with the analysis of metals using ICPMS and a small volume autosampler obtained in 2016 and for these reasons metals will be the predominant focus of this work for this year with carbon monoxide analysis that is separately funded. This project also had challenges in staff recruitment on the limited funds available. The services of an experienced mass spectrometrist were obtained for two days a week in q3 of 15/16 until March 31, 2016 initially. This contract has been extended to March 31, 2019 and will thus be available to the end of the project. This resource has been use in 2016/17 to develop the analysis methods for carbon monoxide on a separate project funded by the Gas Safety Trust and additionally to support work in project 2 due to the sudden death of the project leader in 2016. Analysis methods have been developed and are now waiting for patient recruitment to start; currently awaiting ethical approval. For 2017-19 the services of a new SEO position will be added to the project to provide more human resource. Methylation work in the primordial germ cells is complete and we are now validating changes of interest and investigating their potential functional consequences. An extensive review of epigenetics and early life/transgenerational toxicology was published in Critical Reviews in Toxicology.

Deliverables and milestones

• Milestone 1- To have completed method development and validation for metals in blood spots. (17/18)

• Deliverable 2 – Application of the developed GC/MS methods in CO exposure to co-hort samples and further development of the method for application to blood spots (17/18).

• Deliverable 1- To apply the methods of foetal blood spot metals analysis on up to 500 blood spots to assess foetal exposure by the end of the project in March 2019 (18/19)

• Deliverable 3 -Completion of ongoing studies in DNA methylation and closure of this as a specific project. Technical ability maintained to apply to other projects in relation to early life effects as the need arises particularly in collaboration with the University of Newcastle based HPRU Chemical and Radiation Threats and Hazards. Paper to be published. (18/19).

• Deliverable 4 – Analysis of 5000 samples for CO under the separately funded Gas Safety Trust Project. (18/19)

King's staff Imperial staff PHE staff

Mireille Toledano No cost Karen Exley No cost

Tim Marczylo 10%

Emma Marczylo No Cost Tim Gant No cost Gwyn Lord 40%

Theme II/Project 1 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 18304 Non pay research costs £6000 Indirect costs £ 3660

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 7

Theme II/Project 2 – Toxicokinetics Lead: Tim Gant (PHE) and Tim Ebbels (Imperial) The majority of epidemiological studies are carried out using an assessment of external/blood or urine exposure measures. These are most often though not the target organ or cell of interest that is usually not available for analysis. To overcome this deficiency modelling approaches are used to assess the exposure level at the target site of interest. A project will be carried out over three years to build mathematical models to assess internal exposure using data from concentrations measured in accessible body fluids. This project will utilise expertise in radiation models and data from human exposure studies to further develop and characterise mathematical modules of internal chemical exposures. Alexander Cooper, a student on this project, has presented his work at several meetings this year. He has had regular meetings with Dow chemicals who have been impressed by achievements and he passes his second year PhD transition point with an Excellent ranking from the advisory panel. Matthew Puncher who led on this project died suddenly in 2016. This has delayed the completion of the Cadmium work. For these reasons the work being undertaken in the project will be completed in 2017 and the project suspended after completion. Toxicokinetic work though is often cited as essential by those involved in risk assessment and the DH expert committees and there is a lack of expertise in the UK. Loss of this work is therefore unfortunate for the NIHR. The major resource that was attributed to this project is shifting to projects 1 and 3 and Theme IV. Aim: To develop toxicokinetic models that permit the evaluation of internal exposure at the target site from measures taken in accessible body fluids such as urine and blood. Deliverables and milestones

• Milestone 1- Models be further refined for use with metals and organic molecules and tested using data from Dow agrochemicals. (17/18)

• Milestone 2 – Further model testing (17/18)

• Deliverable 1- Paper for the work with Dow Chemicals. (17/18)

• Deliverable 2 – Submission of a student thesis. (17/18)

King's staff Imperial staff PHE staff

Tim Ebbels No cost Tim Gant 5% Tim Marczylo 0% Gwyn Lord 0%

Theme II/Project 2 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 5529 Non pay research costs £ 2000 Indirect costs £ 1105

Theme II/Project 3 – Environmental and Human Microbiome Lead: Emma Marczylo (PHE) and Anna Hansell (Imperial) Exposure to environmental microbiomes occurs though bioaerosols. This project focusses particularly on the application of molecular methods to the analysis of fungal species in molecular epidemiology. It links both with Theme I and also to the bioaerosol work in the Environmental Change and Health HPRU. This work will be carried out with members of theme 1 with the purpose of better associating specific fungal exposure with health outcomes. This is difficult because fungal spores vary in size, have segmental duplications over the genome region of interest for speciation and diversity of cell number. There is a lack of understanding of the effects of fungal species on health. Fungal species also form part of the human microbiome and the significance of environmental effects on both the environmental and human microbiome and link to health will form part of the work of this project. We have further developed an assay for analysing the fungal composition of different samples, successfully identifying fungi present within different environmental and human samples. During this year will be looking to further explore potential collaborations with the Respiratory Infections HPRU and an international consortium on urban green space to perform some small scale studies to both develop our experience and establish a recognised expertise in this emerging field. We have had one meeting with RIVM in the Netherlands to discuss co-operation and have another meeting of experts planned for May 2017. A small review papers has not been completed as planned in 16/17 and will be carried forward to 17/18. Likewise the PhD project with the university of Keele is ongoing.

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 8

Aim: to better characterise the Environmental and human microbiomes and relationship to health. Deliverables and milestones

• Milestone 1 – Application of the fungal bioassay to samples from ongoing and new small projects (in collaboration) to further establish the resilience and application of the system and the association of fungal exposure with health outcomes (17/18, 18/19)

• Milestone 2 – Linkage to Cranfield ongoing. Workshop in May to explore further opportunities (17/18)

• Deliverable 1 – A paper detailing environmental fungal exposure using the genomic analysis methods (18/19).

• Deliverable 2- Small review paper on the role of the human microbiome in public health. (17/18)

• Deliverable 3 – In a joint PhD project with Keele University (Dr Dan Tonge) - Analysis bacterial DNA fragments in serum as a biomarker of the individual microbiome. (17/18)

King's staff Imperial staff PHE staff Paul Elliott No cost Emma Marczylo 40% Anna Hansell No cost Tim Gant 5%

Theme II/Project 3 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 21611 Non pay research costs £ 19500 Indirect costs £ 4322

Theme II/Project 4 – Genotoxicity of air pollutants Lead: David Phillips (King’s) and Tim Gant (PHE) Human exposure to airborne particulate matter (PM) and associated chemicals, including polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs, has been associated with a number of adverse health effects including respiratory diseases and cancer. One of the most important aspects of studying human toxicity in an in vitro system is selecting appropriate models that are able to predict toxicity in vivo. The primary route of exposure to airborne PM is the respiratory system; pollutants are inhaled and deposit in the airways. Larger size PM (> 10 µm) typically penetrates the uppermost regions (nasal cavity and trachea). Smaller PM particles (< 10 µm) can penetrate the bronchiole regions and very fine particles (< 2.5 µm) can penetrate the alveolar regions where gas exchange occurs. In this study we investigated the genotoxic response of the established alveolar tumour-derived A549 cell line with the more recently described non tumour-derived TT1 cell line; we hypothesised that the TT1 cell line would be a more suitable in vitro model for studying the genotoxic effects of airborne PM and associated chemicals. This study showed that coarse PM and 3-nitrobenzanthrone, a nitro-PAH associated with diesel emissions, induce a genotoxic response in alveolar cell models. A paper describing this work was submitted for publication and is currently undergoing revision, with additional analyses, pending resubmission.

• Deliverable 1: Publish first report of effects of PAHs and mixtures in immortalised alveolar cells as a precursor to future studies (17/18).

• Milestone 1: Expand analysis of the effects of PAHs and mixtures in air/liquid cultures of primary human lung cells as a more relevant replacement for immortalised mono cultures (17/18).

• Milestone 2: Establish co-culture conditions for lung epithelial cells and macrophages to investi-gate the contribution of immune cells in response to PAHs and PM (17/18).

• Milestone 3: Obtain new PM samples from existing filters collected in London and based around a number of parameters including seasonal variation, demographic location and traffic load (17/18)

King's staff Imperial staff PHE staff David Phillips 3% Martin Leonard No cost Volker Arlt No cost Ian Jarvis 100%

Theme II/Project 4 costs

King’s: Research Salaries £ 81,032 Non pay research costs £ 17,650 Indirect costs £24,310

Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 9

Theme II/Project 5 - Analysis of the serum and urinary metabolome in relation to air pollutants Lead: Paul Elliott (Imperial) and Frank Kelly (King’s) As part of our work on the exposome, and linking to Theme IV, we will investigate the serum and urinary human metabolome in relation to air pollution exposures, using various population resources, eg the US MESA study and the Airwave study (Theme III). Both these studies have a rich dataset on the serum metabolome from untargeted analysis of 4,000 samples in each of the cohorts using both Nuclear Magnetic Resonance (NMR) and Ultra Performance Liquid Chromatography Mass Spectrometry (UPLC-MS). Air pollution exposures based at place of residence are already available from the MESA study. We aim to discover potential markers of air pollutants in MESA and investigate to what extent these are related to cardiovascular risk factors and inflammatory markers in MESA and Airwave. Deliverables and milestones

• Milestone 4 – Analysis of cohort data in relation to metabolomics signatures of air pollution exposures (17/18)

• Milestone 5 – Analysis of metabolic features associated with air pollutants in relation to cardiovascular risk factors (18/19)

King's staff Imperial staff PHE staff Frank Kelly No cost Paul Elliott No cost TBA 35%

Theme II/Project 5 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ 39,166 Non pay research costs £ 0 Indirect costs £11,750 PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme II Project 6 Lead: Tim Gant (PHE)

One of the most challenging areas in regulatory toxicology is assessment of the UVCBs (Unknown or Variable composition, Complex reaction products and Biological materials). UVCBs are substances with few solutions for science-informed regulatory decisions. Regulators and registrants have a common interest to understand how to evaluate UVCBs under current chemical regulatory policy and ensure that there is no underestimation of hazard. The CAT-APP project tackles the challenge of UVCBs and will provide regulators and registrants with a cost-effective integrative approach to solving the similarity challenges of UVCBs and will define the best practical strategies for the read-across and grouping approaches. This project is conducted entirely in vitro and is funded by CONCAWE the European Association of Oil refiners. Its output contributes to a direct need of regulators in Europe and has further application for the regulatory assessment of other UVCB products. The project is a collaboration with Texas A&M University (TAMU), North Carolina State University and the University of Ulster.

Aim To develop a workflow for category read-across for UVCBs consisting of an intelligent integrated testing strategy, using experimental, computational, integrative analysis, and transparent outcome communication elements to meet the regulatory information requirements. Deliverables and milestones

• Milestone 1 – Establishment of 10 cell lines for treatment with UVCB products and reference materials (17/18)

• Milestone 2 - In house analysis of toxicity and of Temp-O-Seq data (18/19)

• Deliverable 1- UVCB treated cells dispatched to TAMU for sequencing analysis (17/18).

King's staff Imperial staff PHE staff Abigali Dalzell No cost Tim Gant No cost

Theme II/Project 6 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ Non pay research costs £ 0 Indirect costs £ PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 10

Theme II total costs – (2017/18 & 2018/19): King’s: Research Salaries £ 81,032 Non pay research costs £ 17,650 Indirect costs £ 24,310 Imperial: Research Salaries £ 39,166 Non pay research costs £ 0 Indirect costs £ 11,750 PHE: Research Salaries £ 79,832 Non pay research costs £ 54,000 Indirect costs £ 15,966

Theme III - Health impact of low dose non-ionising and ionising radiation. Lead: Simon Bouffler (PHE); Deputy lead: Mireille Toledano (Imperial) Overall aim of this theme: To quantify the health risks and benefits associated with exposures to low-level non-ionising and ionising radiation, including the effects of light, UV and radiofrequency exposures. There were no changes to strategy, all short-term objectives were or will be met. Theme III/Project1: Novel human cell model of atherogenesis Lead: Ken Raj (PHE) Our work thus far has demonstrated that ionising radiation causes (A) the apical surface of endothelial cells become highly adhesive and (B) disruption to the bonds holding adjacent endothelial cells tightly together. The former is due to the increased production and display of an adhesive protein called CD44, on the surface of the endothelial cells. The latter is due to the reduced availability of junction proteins that normally hold adjacent cells together to form a membrane of cells with highly regulated permeability. Collectively, these two features, which are induced by ionising radiation, enhances the likelihood that monocytes in the blood stream would attach themselves onto the surface of the blood vessel wall and burrow their way into the wall of the blood vessel. At the same time, the loss of permeability control allows cholesterol, in the form of LDL, to also lodge in the wall of the blood vessel. Together, the interaction between monocytes and LDL constitute the major pre-requisite for the initiation of atherosclerotic plaques. While we have elucidated the mechanism of how radiation causes adhesiveness of endothelial cell, the mechanism by which radiation causes the disruption of cell junction proteins requires further analyses. Hence our objectives for the next two years are as follows: Deliverables and milestones

• Milestone 3: Elucidate the mechanism by which radiation reduces the availability of junction proteins (18/19)

• Milestone 4: Determine if radiation induces pro-atherosclerotic properties is dependent on the age of the cell population (18/19)

Collectively, the results of these experiments together with those we have already obtained will reveal the mechanisms by which ionising radiation impact on blood vessel wall, raising the risk of atherosclerotic plaque development. Secondly, through milestone 2, we will also learn whether radiation would have ef-fects of similar magnitudes on people of different ages. These information are undoubtedly relevant in the area of health protection in regards to exposure to ionising radiation in clinical, occupational and environ-mental settings.

King's staff Imperial staff PHE staff Donna Lowe 40% Sylwia Kabacik 40%

Theme III/Project 1 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 31,673 Non pay research costs £ 21,000 Indirect costs £ 6,335

Theme III/Project 2 – Electromagnetic fields Lead: Mireille Toledano (Imperial) and Simon Bouffler (PHE) The SCAMP cohort study is investigating whether children’s use of mobile phones and/or other wireless technologies that use radio waves (e.g. tablets, laptops) might affect their neurocognitive or behavioural development (e.g. attention and memory). We plan biomarker validation study in a sub-set (50-100) of SCAMP children. We will also collect personal RF-EMF exposure measurements over a 48-hour study period. In the validation study data will include Information on phone usage via mobile phone network operators, data from smartphone apps, personal RF exposimeter data, and school environment RF-EMF measurements. These data will be used to validate and calibrate models estimating brain and whole-body RF-EMF exposure. PHE has extensive experience of EMF exposure assessment and this expertise will be used to evaluate available personal exposure monitors through functionality testing in terms of isotropic response at the middle frequency of the main environmental bands. PHE will conduct exposure assessments in a limited number of school environments of SCAMP cohort participants. Urinary analysis (in collaboration with Theme 4, project 2) will include, in the first instance, quantification of biomarkers e.g.

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environmental tobacco smoke (cotinine), as important potential confounders/risk factors of neurocognitive development. Longer term, urinary analysis will aim to generate new knowledge on potential biological effects to gain mechanistic insights via urinary metabolomic profiling. We are also investigating the potential health effects of the TETRA radiocommunication system on health in the UK police force (Airwave study) and use of mobile phones and health in the international COSMOS study. Deliverables and milestones

• Milestone 1 - Recruitment of SCAMP children with specific consent/assent for the biomarker validation study (see Theme 4). (17/18)

• Milestone 2 - Exposure monitoring of noise and air pollution and urine sampling for 50-100 SCAMP children in validation study. (17/18)

• Milestone 4 – EMF, noise and air pollution exposure assessment in additional schools. (17/18)

• Milestone5 - Report on exposure assessment at 5 additional school locations. (18/19)

• Milestone 6 - Publication of paper on baseline patterns of mobile phone usage amongst the SCAMP children. (17/18)

• Milestone 7 - Investigation of urinary biomarkers in a sub-set of the validation study group (see Theme 4) (17/18,-18/19)

• Milestone 8 – Continue the rollout of Airwave follow up screening across the country. Recommence April 2018. Proposal to follow up Scottish participants under review. Welsh participant follow up proposal in preparation.

• Milestone 9- Secure Airwave biosample collection, principally by outsourcing (17/18)

• Milestone 10 - Prepare to make available a relevant subset of the Airwave dataset on the Dementia Platform UK platform as a member cohort. (17/18)

• Milestone 11- Develop methods to adjust for bias in self-reported personal radio usage via a calibration model. Investigate change of personal radio usage during follow-up and combine usage for all radio types in order to estimate total TETRA radio usage. These data will be necessary in order to investigate reliably the association between TETRA use and health outcomes. (17/18)

• Milestone 12 – Contribute to initial analyses of the COSMOS international cohort investigating use of mobile phones and i) symptoms, ii) cancer risk. Lead on analyses of cardiovascular outcomes.(17/18, 18/19)

• Milestone 13 – Draft of SCAMP cohort profile paper for submission to IJE (17/18)

King's staff Imperial staff PHE staff Mireille Toledano 5% Simon Bouffler No cost Rachel B. Smith 100% Simon Mann No cost Myron Maslanyj 5% Darren Addison 5%

Theme III/Project 2 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 100,709 Non pay research costs £ 40,000 Indirect costs £30,213

PHE: Research Salaries £ 6,720 Non pay research costs £ 500 Indirect costs £ 1,344

Theme III/Project 3: UV radiation effects on vitamin D sufficiency and blood pressure Lead: Antony Young (King’s) & Ken Raj (PHE) In addition to the synthesis of vitamin D, it has been proposed that another potential positive effect of UV radiation is the reduction of blood pressure. This project explores both vitamin D sufficiency and blood pressure aspects of UV effects. The blood pressure study extends a few early stage reports that show UV to increase the production of nitric oxide (NO), which is a very potent vasodilator. Our work has thus far revealed that while UVB (which is very much more damaging to DNA) has no appreciable effect on NO production from skin cells, UVA, which is much less DNA-damaging, induces skin cells to produce NO. We have collected over 30 donor foreskins from which primary cells were isolated. We observed that keratinocytes and endothelial cells are very responsive to UVA while fibroblasts and melanocytes are refractive. There are several possible routes by which UVA can induce NO production and this will be one of the objectives for the coming year. At the same time, we also plan to determine the dynamics of this process. This is particularly important if exposure to UVA is to be eventually considered as a potential means to control hypertension especially in winter. Deliverables and milestones

• Milestone 3 – Determine the radiation dose that is effective for inducing NO production in cells. (17/18)

• Milestone 4 - Determine the route by which UVA induces NO production (17/18, 18/19)

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• Milestone 5 - Determine the dynamics of NO production by UVA on keratinocytes and endothelial cells. (17/18, 18/19)

• Milestone 6 – Q-PCR validation of gene expression changes identified in microarray analysis of dendritic cell sub populations. (17/18, 18/19)

• Milestone7 - Completion of immune-phenotyping of major cell populations as analysed by FACS (17/18, 18/19)

King's staff Imperial staff PHE staff

Antony Young No cost Ken Raj No cost

Kasia Hawrylowicz No cost Graham Holliman No cost

Kylie Morgan Stipend/fees Simon Bouffler No cost

Theme III/Project 3 costs

King’s: Research Salaries £ 0 Non pay research costs £ 25,500 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 0 Non pay research costs £ 1,000 Indirect costs £ 0

Theme III total costs – (2017/18 & 2018/19):

King’s: Research Salaries £ 0 Non pay research costs £ 25,500 Indirect costs £ 0 Imperial: Research Salaries £ 100,706 Non pay research costs £ 40,000 Indirect costs £ 30,212 PHE: Research Salaries £ 76,791 Non pay research costs £ 46,000 Indirect costs £ 15,358

Theme IV- Health effects of noise and air pollution including nanoparticles Lead: Heather Walton (King’s); Deputy lead: Rachel Smith (PHE) Overall aim of this theme: to advance the scientific evidence base to support public health protection with respect to ambient air pollution (including nanoparticles) and transport related noise. Some funding finishes in year 4 and external funding will be sought to cover some of the work. Theme IV/Project 1 – Optimising assessment of health impacts of air pollution Lead: Heather Walton (King’s) and Karen Exley (PHE) Estimate the health burden of total air pollution, and health impacts of feasible reductions in air pollution, selected in consultation with stakeholders in London, and more widely, using WHO and COMEAP recommendations, DH-funded meta-analyses on effects of short-term exposure and on long-term exposure and asthma prevalence, outputs from key air pollution and health projects and other areas of literature sufficient for a consensus position. Set out a strategy for development of health impact assessment (HIA) methods considering use of simulations, data from studies in the unit and consideration of the literature to investigate the importance of matching the geographical scale of exposure estimates in epidemiological studies underlying the coefficients and exposure estimates used in HIA, relationships between average and personal exposure, and use of coefficients from multipollutant models. Deliverables and milestones

• Milestone 2 – Continue to develop processes for fast and convenient calculations of health impacts, including incorporating COMEAP recommendations on PM10 and chronic bronchitis. Commence cal-culations of burden and impact of typical reductions for the UK at a fine spatial scale. (17/18, 18/19)

• Milestone 3 – Continue preparation of a strategy paper for publication on the future development of health impact assessment methodologies to guide proposals for further work, expanding coverage to ultrafine particles and noise, and on how to reflect biomarker evidence. (17/18).

• Milestone 4 - Consult stakeholders on potential air pollution reduction scenarios. Selection of a few key illustrative scenarios and calculation of health impacts. Paper preparation. (17/18, 18/19)

• Milestone 5 - Finalise a review to inform simulation inputs, finalise simulation protocol, gather more input data. Meta-analyse the data, partition personal exposure from outdoor sources, apply correction formulas and simulate multiple scenarios for publication (17/18, 18/19). Seek funding to extend work beyond Sept 18. Organise a workshop on interpretation of multi-pollutant models with international ex-perts (17/18).

• Milestone 6 – Analyse differences between measured personal exposure and measured central site ambient concentrations using six-month personal monitoring deployments in a London-based COPD cohort (17/18). Develop a methodology for extending snapshot personal exposure monitoring to repre-sentative annual mean personal exposure estimates using the previous analysis and outputs from M4 (18/19)

King's staff Imperial staff PHE staff

Heather Walton 15/50 Karen Exley No cost

Klea Katsouyanni No cost

Dimitris Evangelopoulos No cost

Hanbin Zhang No cost

Benjamin Barratt No cost

Ana Oliete 25/100

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 13

Theme IV/Project 1 costs King’s: Research Salaries £ 120,310 Non pay research costs £17,650 Indirect costs £36,092 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £

Theme IV/Project 2 – Neurocognitive & behavioural impacts of traffic derived pollutants in children Lead: Ian Mudway (King’s) and Mireille Toledano (Imperial) An emerging literature demonstrates impaired neuropsychological development (motor skills, language development, intelligence quotient) in children exposed to elevated air pollutant concentrations and indicators of high traffic exposure, such as proximity to busy roads, or the proportion of diesel traffic. Aims: To test the hypothesis that exposure to traffic derived pollutants, especially those from diesel vehicles, is associated with impaired neurocognitive and behavioural development, employing secondary-school aged children living within the Greater London area. This will make use of the cohort established in Project 3, Theme 2 examining the impact of exposure to radio-frequency (RF) fields from mobile phones. We will augment this by examining the association between neurocognitive and behavioural functioning, assessed by web-based standardized neuropsychological tests and validated questionnaire scales, with long term (annual and 3-year cumulative) exposures to a panel of pollutants (NO2, NOx, PM10 and PM2.5), modelled at the residential address level. In addition, we will examine the association with these behavioural endpoints with traffic indicators, including distance to the nearest busy road, traffic density and composition within pre-set buffer zones. Deliverables and milestones

• Milestone 1 - Continue to investigate markers of traffic exposure, following up on the preliminary work using urinary metals and expanding the work to a consideration of PAH metabolites in collaboration with Theme 3/project 2. (17/18)

• Milestone 2 - To investigate the determination of markers of neuroinflammation and injury (neuron specific enolase and S100B) in saliva samples, as well as systemic markers of oxidative stress (urinary 8-hydroxy-2’-deoxyguanisine and 8-isoprostane) and examine their relationship to traffic exposure, assessed using modelled attributions or exposure biomarkers. (17/18)

• Milestone 3 - Establish annual and short term (NOWCAST corrected) exposures to air pollutants (NO2, NOx, PM10 and PM2.5), modelled at the child’s residential address, for the children undergoing cognitive assessments as part of the SCAMP study (aligned with Theme 3/project 2). (17/18, 18/19)

• Milestone 4 - To expand the pollutant attributions at residential address to consider more direct measures of traffic proximity: distance to the nearest busy road, traffic density and composition.

• (17/18, 18/19)

King's staff Imperial staff PHE staff

Ian Mudway No cost Mireille Toledano No cost Karen Exley No cost

Ben Barratt No cost

Frank Kelly No cost

Rosamund Dove 100%

Theme IV/Project 2 costs

King’s: Research Salaries £ 49,440 Non pay research costs £ 11,000 Indirect costs £14,832 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme IV/Project 3 – Nanoparticle Exposure Assessment Lead: Rachel Smith (PHE), Terry Tetley (Imperial) The public health risks associated with exposure to many engineered nanoparticles remain uncertain. Recent studies illustrating similarities between the pulmonary effects of some carbon nanotubes and asbestos, and the well-documented effects of fine particulate air pollution on cardiorespiratory health, add to these concerns. This project aims to characterise the inhalation exposures of members of the public from nanoparticles in consumer products, in terms of nanomaterial types and the levels and characteristics of the exposure (e.g. particle size and other physico-chemical properties), focussing on a key panel (5 – 10) of representative products. This project provides input to project 4 and more to the currently scarce information in this area required to support appropriate risk assessments. Deliverables and milestones

• Milestone 1 – The bulk characterisation of the representative products using standard techniques (e.g. DLS, TEM, ICP-MS) and single particle ICP-MS will be completed (17/18).

• Milestone 2 - Experimental systems will be set-up and protocols developed to mimic the expected airborne emissions produced using such products in various realistic exposure scenarios and sample the resulting airborne aerosol (17/18). Exposures from products will be characterised and quantified (18/19).

• Milestone 3 – The review of relevant NP aerosol exposure models will be completed (18/19).

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 14

• Milestone 4 - Completion of paper for publication (18/19).

King's staff Imperial staff PHE staff

Terry Tetley No cost Rachel Smith 5 %

Alison/Matt 20%

Theme IV/Project 3 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 7,921 Non pay research costs £ 4,000 Indirect costs £ 1,364

Theme IV/Project 4 - Health Impacts; nanoparticles Lead: Terry Tetley (Imperial), Rachel Smith (PHE) The health risks associated with exposure to engineered nanoparticles remain uncertain. Recent studies illustrating similarities between the pulmonary effects of some carbon nanotubes and asbestos, and the well-documented effects of fine particulate air pollution on cardiorespiratory health, add to these concerns. This subtheme is concerned with understanding the potential health effects of nanoparticle exposures. Deliverables and milestones

• Milestone 1 – Our studies using A549 cells and organotypic reconstituted 3D human primary small air-way epithelial (HPSAE) cell cultures exposed to spark generated silver nanoparticle aerosols in an aerosol exposure Air-Liquid Interface system (AE-ALI), in which adverse effects were characterised using lactate levels, LDH release and alterations in mRNA and miRNA expression, indicated that mod-est toxicological effects were paralleled by significant regulation in gene expression reflective mainly of specific inflammatory events. A paper on this study will be submitted for publication (17/18). A fur-ther study using the AE-ALI system will be undertaken using another nanomaterial identified as being potentially significant for public exposures (17/18).

• Milestone 2 – Progress to demonstrate an in vitro airway model developed to explore the toxicological impact of nanoparticles relevant for inflammatory respiratory conditions including asthma has been good. Exposure of HPBE cells in an ALI system to diesel exhaust particles (DEPs), cerium dioxide nanoparticles (CeO2NPs) and DEP+CeO2NPs for 24hours showed differences in selected cytokines (ELISA analysis) in the apical and basal compartments after 24hours of exposure and also differences in gene expression of selected markers after 24hours of exposure. These studies will be finalised (17/18) to also include inflammatory and allergen co-exposures and a manuscript submitted for publication (18/19).

• Milestone 3 - Extend studies completed in years 1-3 to other nanomaterials in everyday use, e.g. sil-ver, zinc and ceria and others identified by PHE. These studies will use a number of cell lines, includ-ing the 3D co-culture model of the human alveolar unit established and fully characterised at Imperial during year 1. The endpoints considered will include: cell viability, oxidative stress, inflammatory re-sponses and release of pro-thrombotic mediators. A number of publications are anticipated within year 4. (17/18)

• Milestone 4 - Undertake preliminary exposures using AE-ALI exposure system developed at PHE, towards the end of the second year to test the feasibility of using this system with the alveolar model (18/19).

King's staff Imperial staff PHE staff

Terry Tetley No cost Rachel Smith 5 %

Andrew Thorley No cost Martin Leonard No cost

Lareb Dean Stipend/fees Chang Guo 20%

Theme IV/Project 4 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 23,437 Non pay research costs £ 11,100 Indirect costs £ 7,031

PHE: Research Salaries £ 14,659 Non pay research costs £ 13,500 Indirect costs £ 2,932

Theme IV/Project 5 - Improved in vitro systems for evaluating and comparing toxicity of air pollutants Lead: Terry Tetley (Imperial), Rachel Smith (PHE) To build on established networks within the current HPRU, capitalising on the novel systems developed in the toxicological assessment of nanomaterials and other in vitro cell systems in the HPRU, we aim to investigate the mechanistic basis of the adverse health effects of combustion derived nanoparticles (traffic and biomass derived) and their co-pollutant gases, currently ill-understood and difficult to separate in epidemiological studies. These novel systems have many advantages in terms of achieving more realistic exposure modalities (eg ALI aerosol exposure) and

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HPRU Research Forward Business Plan 2017-19 Application Ref No: 15

biological relevance (eg co-culture models). Comparative toxicology using these approaches will allow measured/considered judgement on the plausibility and likely size of possible mechanistic effects, to include lung inflammation, oxidative stress, carcinogenic, neurological and cardiovascular effects. Deliverables and milestones

• Milestone 2 – Commence pilot studies examining the toxicity of particle samples from different com-bustion sources (the samples will reflect those currently, or previously employed in human challenge studies in collaboration with the University of Northern Sweden, Umea). (17/18, 18/19)

• Milestone 3 – Develop a research proposal for submission to the Wellcome Collaborative Award for a programme of experimental work comparing contrasting pollutants (via exposure to respiratory tract lining fluids or relevant reaction products), across cell systems representing respiratory zones and gas-blood compartments of the lung (bronchial/alveolar/endothelial), and more complex models, in-cluding ex vivo models of human lung sensory nerves and translational research with human chamber exposures providing materials/biological samples for metabolomics and similar –omics approaches. (17/18)

• Milestone 4 – Consider a proposal developing systems for examining effects of air pollutants on aged cells (important in COPD and possibly other conditions) as an aspect of the milestone 2 proposal or for separate Royal Society blue skies funding, or funding of ageing research. (17/18)

• Milestone 5 – Commence work proposed in milestones 2/3, subject to obtaining funding. (18/19) King's staff Imperial staff PHE staff Heather Walton No cost Andrew Thorley No cost Alison/Matt 10 % Ian Mudway No cost Terry Tetley No cost Martin Leonard No cost Ian Jarvis No cost Lareb Dean No cost Volker Arlt No cost

Theme IV/Project 5 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 2258 Non pay research costs £ 11,500 Indirect costs £ 451

Theme IV/Project 6 - Adherence to preventative recommendations during public health emergencies (Air pollution). Lead: Heather Walton (King’s) and John Weinman (Emergency Preparedness & Response HPRU) During many public health crises, members of the public are advised to follow official recommendations to prevent them from becoming ill. Adherence to these health risk communications, which can also involve advice to use preventative medications, is often poor. Adherence to air quality advice to modify behaviours during pollution episodes may be suboptimal, and the traditional strategy of simply informing people about high pollution episodes may not be effective. The aim of this project is to improve the behavioural impact of air quality alerts. A literature review will be followed by use of the COM-B model to develop specific communication strategies. After piloting, improved messages will be tested with the users of an existing air alert App developed by the KCL ERG group. Implications of this study include the potential to reduce the health burden of air pollution, through the development of more effective communication strategies provided via existent air quality alert systems. This project is led and primarily resourced by the Emergency Preparedness and Response HPRU who have expertise on the psychology of behavioural responses. Theme IV is contributing the air pollution expertise. Deliverables and milestones

• Milestone 2 – Provide first submission of a paper on the systematic review of predictors of adherence and non-adherence to health advice accompanying air quality warning systems, by Apr 2017;

• Milestone 3 - PPI workshops to improve the research materials for the air quality alert study are scheduled for Apr-May 2017.

• Milestone 4 - Carry out the intervention study evaluating the effects of different types of health messages accompanying existing air quality alerts on adherence to respiratory protection behaviour between Jun-Aug 2017

• Milestone 5 - Write up PhD by Apr 2018.

• Milestone 6 - Submit a paper on the air quality alerts study (by Apr 2018)

King's staff Imperial staff PHE staff

Heather Walton No cost

Robert Hepburn No cost

Gary Fuller No cost

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Theme IV/Project 6 costs King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme IV/Project 7 - Methods for assessing the public health benefits of local transport interventions. Lead: Heather Walton (King’s) and Sani Dimitroulopoulou (Environmental Change & Health HPRU). Given the contribution of transport emissions to air pollution concentrations, transport interventions have an important role in reducing air pollution concentrations. Transport interventions within cities are also important for the Environmental Change HPRU, Theme 2 on healthy, sustainable cities. This joint project plans to take advantage of synergies between the two HPRUs using the HIA methodological expertise in this HPRU and the link to co-benefits assessment (air pollution, physical activity and traffic accidents) in the Environmental Change HPRU. School travel plans have been selected as meeting 2 PHE objectives, air pollution and early life. There are particular challenges in assessing the air pollution health impacts of local transport interventions: (i) the studies used for concentration-response functions may not be at the fine spatial scale needed to assess the impact of concentration changes at roadsides; (ii) the population affected may be very small; (iii) health impact assessment of some other risk factors for co-benefits may be less well developed than for air pollution; (iv) changes in transport behaviour affect personal exposure to air pollution and (v) the links between the broader exposure metrics used in epidemiological studies and personal exposure are poorly understood. Preparatory work is needed to continue developing a project on school travel plans in 17/18, but external funding needs to be sought for later work in 18/19. Deliverables and milestones

• Milestone 1- Develop a protocol for a project addressing health impacts of school travel plans (17/18)

• Milestone 2 - Commence defined project, adapted according to available funding. (17/18, 18/19)

King's staff Imperial staff PHE staff

Heather Walton No cost Anna Hansell No cost Karen Exley No cost

Dimitris Evangelopoulos No cost

Klea Katsouyanni No cost

Ben Barratt No cost

Theme IV/Project 7 costs

King’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0 PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme IV total costs – (2016/17 & 2017/18):

King’s: Research Salaries £ 169,750 Non pay research costs £ 28,650 Indirect costs £ 50,925 Imperial: Research Salaries £ 23,438 Non pay research costs £ 11,100 Indirect costs £ 7,031 PHE: Research Salaries £ 47,170 Non pay research costs £ 60,500 Indirect costs £ 9,434

Finances

Please also complete financial break down and cost allocation amongst partners and collaborators (attached financial plan sheet). Please ensure totals are in line with the contract payment schedule

This form, together with other requested supporting information, must be submitted electronically by 1:00pm on 3 May 2017 to Dr Joanna Topping at the email below. Any questions about the completion of this form should be directed to Dr Joanna Topping ([email protected]). The email should be copied to both the HPRU director and PHE lead. The HPRU director should confirm that the PHE are content with both the narrative and financial Forward Business Plan.