HEALTH PROTECTION RESEARCH UNIT ANNUAL REPORT 2017/18 Financial Year
Note: The accompanying ‘NIHR Health Protection Research Unit – Guidance on Completion of Annual Reports’ for 2017/18 Financial Year contains essential guidance on the information you need to provide when completing this form. Please note that the overview of activities (and other sections of the Progress Report) should reflect activities which fall within the remit of the NIHR HPRU funding scheme. Please complete the form using a font size no smaller than 10 point (Arial).
1. UNIT DETAILS
Name of the NIHR Health Protection Research Unit:
Contact details of the individual to whom any queries on this Annual Report will be referred. Feedback on this report will be provided to the Director, copied to the manager.
Name: Angela Lewis
Job Title: Programme Manager
Address: King’s College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH
Email: [email protected]
Tel: 020 7848 3765
2. DECLARATIONS AND SIGNATURES
Contact details of the University administering the NIHR Health Protection Research Unit award:
Name: King’s College London
Address: Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH
Name of the Director: Professor Frank J. Kelly
I hereby confirm, as Director of the NIHR Health Protection Research Unit award, that this Annual Report has been completed in accordance with the guidance issued by the Department of Health and provides an accurate representation of the activities of the NIHR Health Protection Research Unit:
Signature …… ………….. Date: 8th May 2018…… (Director)
NIHR Health Protection Research Unit– Progress Report 201718 1
3. SUMMARY OF ACTIVITIES FOR THE COLLECTIVE NIHR HPRU PUBLIC REPORT
The NIHR HPRU in the Health Impact of Environment Hazards (HIEH) provides high quality scientific evidence to support PHE’s roles in implementing effective public health interventions to prevent and reduce the burden of ill health associated with environmental hazards. During 2017/18 the HIEH HPRU progressed its leading environmental effects on health research to advance understanding of the causes and effects of key environmental issues affecting public health on a number of fronts.
In Theme 1 we progressed work on the health impacts of bioaerosols from waste composting facilities and intensive farming. Intensive farming sites require permits to operate from the English Environment Agency and current guidance requires that a site specific risk assessment be carried out for sensitive receptors living within 100m of the site. This differs from the requirement for composting which applies to large scale composting sites. The primary purpose of this work was therefore to provide evidence about whether these limits should be aligned. This work revealed that most occupational studies that had considered this issue reported a negative impact on worker health outcomes, particularly respiratory symptoms. The findings from studies investigating the health of communities living near intensive farms were more mixed indicating further work is required. There is a clear need for the new studies to include better exposure data in terms of the qualification and quantification of different bioaerosols, and variation due to farming type or practice under consideration. Ideally long-term continuous measurements using molecular analysis methods to determine the type of bioaerosol exposure are required. These would take into account the effectiveness of measures of air filtering at sites. Additionally, greater understanding of bioaerosol dispersal patterns downwind of farms is required as this would assist in determining suitable distances for residences from the site. On the basis of the limited current evidence it was felt there was no compelling evidence to align the limit values for risk assessment at the current time.
In Theme 2 we addressed a fundamental issue in testing for hazard in complex mixtures as UVCB products are a challenge for regulators and producers alike for assessing hazard. Currently read across is seen as the best way forward to avoid large amounts of new animal based testing but the complexity and variability of these products is proving challenging for defining read-across groups acceptable to the regulators. In this project we sought to establish biologically based, rather than chemically based groupings to which new products can be added for the purposes of read-across as required. With our partners we designed a multi cell assay that uses 10 cell lines and 6 iPESC derived lineages to test the effects of these mixtures using both apical end point assays and partial transcriptome gene expression analysis in response to UVCB. Measurable end points of response to exposure to 161 distillation oil products and reference chemicals across four concentrations have been derived. This research will contribute to the greater understanding and assessment of these complex mixtures, allowing potential reduction in hazard and therefore risk for products that are extensively used by most people. Further work understanding chemical exposures was progressed for both chemical and biological exposures.
In Theme 3 we addressed the validity of self-reported mobile phone use as a better understanding of this issue is essential to any future evaluation and interpretation of the associations between exposure to radio- frequency electromagnetic fields and long-term health. In COSMOS, we found fair to moderate agreement between self-reported and operator-derived data on mobile phone use. The sensitivity of self-report was generally high for correctly identifying those adults with the smallest amount of mobile phone use, but lower for identifying heavy mobile phone use. This is in line with our observation that respondents were more likely to underestimate than overestimate their mobile phone use. In the SCAMP study, agreement between self- reported mobile phone use and mobile operator traffic data was highest for the duration spent talking on mobile phones per day compared to frequency of calls and number of text messages sent. Adolescents overestimated their mobile phone use during weekends compared to weekdays.
In Theme 4 a successful cross-collaboration with the Emergency Preparedness and Response HPRU was undertaken which investigated how to increase the behavioural impact of health communications in various public health threat contexts. Crucial for this work was the acknowledgement that protecting public health must involve the development of more effective communications strategies aiming at encouraging people to take protective measures against the health impact of air pollution. The work informed the design of a study that investigated how to improve the behavioural impact of existing air quality alert messages through a systematic manipulation of key communication variables found by systematic review. Both intended and actual adherence behaviours were investigated. Although the sample size was small, we had encouraging results. Compared to the usual air quality alert messages sent by an existing air alert smartphone App, our newly developed messages seemed able to increase intentions to make permanent behavioural changes
NIHR Health Protection Research Unit– Progress Report 201718 2
and actual use of preventative medication.
During 2017/18 the work we are undertaking in the HPRU has continued to contribute to our success in securing £13,385,884 of external funding. Tim Gant received funding from CONCAWE to establish new toxicological screening assays (£271K). Paul Elliott received funding via Imperial BRC award for biobanking and health informatics development (£5M) and a UK DRI award (£1.5M). Mireille Toledano received MRC funding to add a cognitive development arm to the ongoing SCAMP study (£618K). Terry Tetley’s nanotoxicology research was supported by AstraZeneca (£2M). David Green received NERC/Defra funding to establish a new air quality monitoring supersite in London (£397K & £150K, respectively). Frank Kelly received funding via the new Wellcome Trust Centre investigating Pathways to Equitable Health Cities (£325K).
We continue to be actively involved in public engagement activities. Researchers from Themes I, II and IV took part in the New Scientist Live event in July 2017 with posters, leaflets and interactive games on topics including bioaerosols, the microbiome, air quality and health and a compendium of other chemical hazards. At this event, HPRU researchers spoke to approximately 4000 people (1000 per day), with the Unit Director Professor Frank Kelly delivering one of the key podium presentations on the risks associated with air pollution. A new initiative has led to the establishment of a joint Community Advisory Board (CAB) between the HPRU and the MRC-PHE Centre for Environment and Health. New members from the British Lung Foundation, the British Heart Foundation and the Patient’s Association, as well as a director of public health (Lewisham), have joined the CAB. CAB members meet 2-3 times per year and provide comment and feedback on research strategy and programmes, input ideas, and provide opinion on ethical issues.
NIHR Health Protection Research Unit– Progress Report 201718 3
4. OVERVIEW OF ACTIVITIES
The Health Impact of Environmental Hazards HPRU undertakes cutting edge research to advance understanding of the causes and effects of key environmental issues affecting public health and thereby influence policy for improving health locally, nationally, and globally. The focus of our research addresses four key areas of need which will improve understanding of the impact of exposure to low level environmental (a) chemicals, (b) biologicals (c) non ionising and ionising radiation and (d) air pollution and nanoparticle toxicity. The Unit promotes novel cross disciplinary approaches and provides high quality training to attract, motivate, and develop the next generation of environmental and health research leaders.
Unit strategy
As we approach the end of year 4 activity for the Health Impact of Environmental Hazards HPRU it is pleasing to see that a number of our projects have led to key publications. As planned, many of these papers include authors from both academic partners alongside staff from Public Health England meeting a primary requirement of the NIHR funding. Indeed as we move forward to year 5 we plan to further make best use of the complementary capabilities of the three partners. Examples of strategic developments include:
Theme I A much larger proportion of the English population is exposed to low-level CO than previously thought. Following analyses of hospital admissions and A&E attendances, epidemiological analyses will be extended to the development of methodologies to link across A&E, hospital admissions, coroners’ data and mortality datasets and to the estimation of spatial uncertainty in CO patterns or trends.
Theme II Biodiesel is becoming a viable alternative to diesel as an engine fuel, although still currently blended with conventional diesel fuel. Whilst biodiesel is considered a more environmentally friendly fuel source, the health effects are much less understood. We are examining the genotoxic and inflammatory effects of low-sulphur diesel exhaust (LSDE) and a rapeseed methyl ester (RME) biodiesel blend in primary human airway epithelial cells (hAEC) and immortalised human bronchial cells (BEAS-2B).
Theme III The studies carried out in year 4 on the development of atherosclerotic plaques has yielded novel insights into how ionising radiation may contribute to circulatory disease risk. Novel mechanisms of action of ionising radiation have been established that are distinct from the mutational mode of action that is generally thought to underpin the effects of radiation at low doses and dose rates. Further investigations using this, and related models will have a role in the re-assessment of radiation risk by international bodies such as UNSCEAR and ICRP.
Theme IV New developments including the adoption of standardised models and focused in vitro and in silico approaches have been shown to have the potential to more reliably identify properties of concern of nanomaterials through comparative analysis across robust and select testing systems. The adoption of in vitro testing systems has many advantages including the ability to greatly increase the number of different nanomaterials that can be tested as well as reducing the uncertainties surrounding species specific effects. Importantly, key to refinement and choice of the most appropriate testing systems is a more complete mechanistic understanding of how these materials may influence disease at the cellular and molecular level. Such approaches have the potential to more clearly extrapolate relevant toxicological information, which can be used to identify properties of concern and improve nanomaterial safety assessment for human disease susceptibility in asthma and allergic airway disease.
Progress against short, medium and long term objectives
Theme I /Projects 1-6 - all milestones surpassed or on-track except for the following: Project 3, milestones 1&3 delayed due to staff maternity leave. Project 5 milestone 2 has been revised to completion in year 5 due to staff leaving. Theme II /Projects 1-6 - all milestones surpassed or on-track. Note: Project 2 finishes at end of year 4. Theme III/ Projects 1-3 - all have a mixture of completed and ongoing milestones. Theme IV/Projects 1-7 - milestones completed or ongoing.
NIHR Health Protection Research Unit– Progress Report 201718 4
Leadership, governance and management arrangements
As we complete the 4th year of activity our governance and management arrangements continue to work well. The leadership team (Kelly – King’s; Elliott – Imperial; Gant – PHE) meet formally three times/year and informally as required. Two of these meeting include the Theme leaders who report and review progress. The individual Themes meet on a regular (usually bimonthly) basis to review progress in their portfolio of projects. Dr Anna Hansell, PI on Theme I left Imperial College for a new post at the University of Leicester at end of April 2018 and she has been replaced by Dr Fred Piel, also of imperial College. Our PPI/PPE team meet on an ad hoc basis to ensure preparations are in place for planned activities (see later).
Governance is via our External Advisory Board (EAB) chaired by Prof Roy Harrison (University of Birmingham) which contains relevant external experts and a lay member (Mr Simon Birkett). Following positive feedback from the EAB from our annual meeting in April 2018 which was held at PHE, CRCE - Chilton, no changes to our programmes of work have been necessary. It was recognised that the format of our annual meeting attained a better balance as now more discussion time was available. The annual Unit lecture, (presented this year by Prof Gant), presentations from younger staff and the poster session across the lunch break were all successful items. All members of the EAB attended our annual HPRU meeting to review progress made during 2017/18 and provide comment on the annual report. One final area identified for further improvement was our strategy for establishing better links and projects with other HPRU’s.
Major grant awards received
Value Funder Project PI
Theme I - Epidemiological assessment of low level environmental exposures
£ 730,145 MRC Aircraft noise and cardiovascular outcomes Anna Hansell
£ 9,000 Wellcome Mapping survival in sickle-cell disease in Nigeria Fred Piel £ 314,609 NIHR Respite Impacts on Short-Term Aircraft Noise Anna Hansell and Cardiovascular Outcomes (RISTANCO) £ 99,643 Wellcome Trust Seed Award in Science Fred Piel
Theme II - Modes of toxicity (Biochemical Pathways from toxin to disease) £ 271,000 CONCAWE Cat-App Tim Gant
£ 172,776 Horizon 2020 Smoke free brain Tim Marczylo
£ 224,000 Ramathibodi Environmental Health in Children Emma Marczylo Hosp. Thailand £ 23,427 ECETOC Deriving guideline methods for using genomics Tim Gant data in regulatory testing. £ 173,900 CRUK Mutographs of cancer – Year 2 David Phillips
£5,038,385 BRC BRC - Biobank & Health Informatics Theme Paul Elliott £ 155,591 BRC ITMAT SP3 Paul Elliott £1,500,000 UK DRI UK DRI Programme Grant (2017-22) Paul Elliott
£ 331,574 MRC Application of deep learning to heterogeneous Paul Elliott open data for measuring environment and health
£ 331,486 MRC Identification of Metabolic Phenotypes and Paul Elliott Systemic Biochemical Reaction Networks
NIHR Health Protection Research Unit– Progress Report 201718 5
Theme III - Health impact of low dose non-ionising and ionising radiation
£ 119,000 Home Office Airwave Paul Elliott
£ 618,055 MRC Cognitive Development in the Urban Mireille Toledano Environment (The CLUE study)
Theme IV - Health effects of noise and air pollution including nanoparticles
£ 59,000 KC Wong Effects of air pollution on cardiopulmonary Frank Kelly Fellowship disease in urban Beijing residents
£ 227,000 NIHR Investigating the impact of London’s Ian Mudway ULEZ on children’s respiratory health
£2,016,575 AstraZeneca Investigate drivers of respiratory disease Terry Tetley
£ 325,000 Wellcome Pathways to Equitable Healthy Cities Frank Kelly
£ 98,600 Defra Delivering a pilot study for researching Ben Barratt personal air quality exposure
£ 397,118 NERC Advanced UK observing network for air quality, Dave Green public health and greenhouse gas research
£ 150,000 Defra Air Quality Supersites Dave Green
Top three achievements
Public health risks of bioaerosols from intensive farming: Intensive farming sites require permits to operate and current guidance requires that a risk assessment be carried out for those living within 100m. This differs from the requirement for large scale composting sites were a risk assessment is required for those beyond 300m. We conducted an analysis of the effects of living near intensive farming sites and respiratory health. The work indicated a potential impact of intensive farming on childhood respiratory health, based on a small number of studies using self-reported outcomes, but supported by findings from available occupational studies. For studies are warranted to clarify this situation.
Incinerators exposure research: Emission concentrations for 2003-10 were modelled for all UK municipal waste incinerators, confirming that particulate exposures from incinerators operating to EU standards are extremely low. This is the first country-wide exposure assessment and we received and responded to detailed comments from two key community groups opposed to incinerators (UKWIN and plumeplotter), with a useful dialogue about assumptions used in the model. In particular, one of the community groups flagged that parameters used (supplied by Environment Agency) were different from the planning application; this was queried with EA who provided new input parameters and emissions were remodelled for that incinerator.
Radiation and atherogenesis: Our studies on the development of atherosclerotic plaques has yielded novel insights into how ionising radiation may contribute to circulatory disease risk. Novel mechanisms of action of ionising radiation have been established that are distinct from the mutational mode of action that is generally thought to underpin the effects of radiation at low doses and dose rates.
NIHR Health Protection Research Unit– Progress Report 201718 6
5. PROGRESS MADE IN EACH RESEARCH THEME 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 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 1 - Completed 2016/17 • 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). Completed. Abstract submitted ISEE Young conference (19-20 March) and to UK Occupational & Environmental Epidemiology meeting (April 2018). • 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). On track. English analyses completed, planned paper to include discussion of situation in other countries. • Milestone 4 – Completed 2016/17 • Milestone 5 - Identify funders and apply for funding for the international comparison of CO. By August 2017. Gas Safety Trust or the Colt Foundation are identified – specific funding has not been applied for yet as, as a first step, a paper is in preparation (see milestone 3). Funding to be applied for (18/19). • Milestone 6 - Identify the elements required for an improved CO global burden of disease. By end March 2018. The aim was to write a short paper to describe the inclusion of CO poisoning as a new sub- type in the Global Burden of Disease data, but it looks likely that the GBD will now have a “gas poisoning” category rather than a specific one on CO. However, a short general paper on the challenges of assessing the burden of CO poisoning is planned for year 5. (18/19)
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). Published (Philippa Douglas, Sarah Robertson, Rebecca Gay, Anna L Hansell, Timothy W Gant. A systematic review of the public health risks of bioaerosols from intensive farming. https://doi.org/10.1016/j.ijheh.2017.10.019.) • Milestone 2 – Completed 2016/17
NIHR Health Protection Research Unit– Progress Report 201718 7
• 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). This has been delayed due to the staff member relocating to a new post and working part time due to health issues. Due for completion 18/19. • Milestone 4 - Epidemiological study on respiratory admissions taking into account wind direction and seasonality and with extended years of coverage. Analyses complete by March 2018. We have conducted an updated distance based analyses. Awaiting verification results on the exposure modelling before deciding whether to move to an epidemiological case-crossover study (for which plans have been drawn up). • 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. A joint (Imperial-PHE) application was made for a PhD studentship at PHE that wasn’t successful.
Note: Dr Anna Hansell leaves Imperial College London for a new post at the end of April 2018. This project links with the bioaerosols project in Theme II/Project 3 and therefore all work will continue under the Theme II project except the epidemiology study. This will be revisited when the suitable expertise is identified.
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. Completion by December 2017. (PHE lead) Delayed due to maternity leave/sick leave. Alternative staff member now recruited so work is progressing. (18/19). • Milestone 2 - Prepare paper on the evaluation results. Completion in year 4. (PHE lead). Delayed as mentioned above. Completion 18/19. • Milestone 3 - Revise and update draft guidance in light of Evaluation and review of new WHO guidance document. Completion in year 4. (PHE lead). Delayed as mentioned above. Completion 18/19. • 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). Delayed due to staff recruitment issues. A new software programmer started 5 March 2018. Revised completion date September 2018.
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. 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.
NIHR Health Protection Research Unit– Progress Report 201718 8
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 submitted in 2017. This work was presented in papers to scientific conferences: a) “Consistency is the evidence for PFAS affecting thyroid function in adults – results from the mid Ohio Valley”, 9th Copenhagen Workshop on Endocrine Disrupters, COW2017, May 2017 , Copenhagen; b) “Using biomarker data to establish a benchmark dose limit for perfluoro‐ octanoic acid (PFOA)”, 10th International Symposium on Biological Monitoring (ISBM-10), October 2017, Naples. Papers are in 1st draft and will be submitted in 18/19.
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. Maps of concentration surfaces for lead, cadmium and arsenic were completed and an estimate made of uncertainty. These will be used in forthcoming epidemiological studies. An abstract was submitted to the UK & Ireland Exposure Science meeting (held April 2018). • Milestone 2 - A review of studies that have measured heavy metals in human breast milk, to be completed in year 4. Staff turnover has held up progress on this (lead author has moved back to Australia, co-author who took over has had to reduce hours to half-time). New target date in year 5. (18/19)
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. Completed. Published in ES&T. Douglas P, Freni-Sterrantino A, Leal Sanchez M, Ashworth DC, Ghosh RE, Fecht D, Font A, Blangiardo M, Gulliver J, Toledano MB, Elliott P, de Hoogh K, Fuller GW, Hansell AL. Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain. Environ Sci Technol. 2017 Jul 5;51(13):7511-7519. doi: 10.1021/acs.est.6b06478. Epub 2017 Jun 16. • Milestone 2 – Completed 2016/17 • Milestone 3 - Epidemiological analysis interpreting chemical analysis of POPs in breast milk including QA samples completed in year 4. Analysis completed and included in discussion section of draft incinerators epidemiological paper (work not funded through HPRU). Following advice received
NIHR Health Protection Research Unit– Progress Report 201718 9
from study advisory board this will be moved into a separate paper, with additional sample analysis planned in year 5. (18/19)
Theme II – Modes of toxicity (Biochemical pathways to disease) Lead: Tim Gant (PHE); Deputy lead: David Phillips (King’s) 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.
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’.
Theme II/Project 1 – Early life exposures and effect Lead: Tim Marczylo (PHE) and Mireille Toledano (Imperial) This work has started well in 2014/15 continued through 2015/18 and will proceed further in 2018/19. A number of significant unexpected challenges have occurred and are 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. 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 but likely not into the project extension of 2019/20 and how to use this 0.4 FTE HEO resource to most advantage in 2019/20 is something we will have to consider through this year. At the midpoint of 2017/18 we obtained the full time service of another mass spectrometrist and he is now advancing the project at a much accelerated rate which is gratifying. We will formally review progress at the end of the 2018/19 year.
Deliverables and milestones • Milestone 1- To have completed method development and validation for metals in blood spots. (17/18). This is mainly completed and is undergoing final validation. The work was presented at our 2018 annual meeting. • 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) On going and delivery is anticipated. • 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). Completed. We are now waiting (still) for ethical approval of the study so recruitment can begin (Deliverable 4). • 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). Completed and the capability is being used as required. There is still a great deal of interest in this area from regulatory agencies ((Presented by Prof Gant to a joint meeting of COT, COC & COM 9 October 2017) and application will be on a targeted basis when appropriate. • Deliverable 4 – Analysis of 5000 samples for CO under the separately funded Gas Safety Trust Project using the assay developed in Deliverable 2 (18/19). Likely delayed. Project partners have changed and the ethical submission is about to be submitted but the delays on this project are still a serious concern. This project is directly linked to the recently launched International Carbon Monoxide Research Network (ICORN) launched May 2 2018 at the House of Lords by Baroness Finlay and Mr Alex Cunningham MP and is therefore highly relevant and pertinent and will be pursued.
Theme II/Project 2 – Toxicokinetics Lead: Tim Gant (PHE) and Tim Ebbels (Imperial) Alexander Cooper, a student on this project is in the process of finalising his thesis with an intention to submit towards the end of June. His work has presented his work at several meetings this year. He has had regular meetings with Dow chemicals who have been impressed by achievements Due to there being a lack of any further resource that could be committed to this project it closed in 2018 which is a loss to the UK as skills in this area are in great demand.
NIHR Health Protection Research Unit– Progress Report 201718 10
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). Completed. This is being incorporated into the thesis of A. Cooper • Milestone 2 – Further model testing (17/18). Completed. This is being incorporated into the thesis of A. Cooper • Deliverable 1- Paper for the work with Dow Chemicals. (17/18). This is currently under review and revision with Dow Chemical prior to submission. Discussions are ongoing in respect of the exposure level calculated of one individual in the cohort that is causing some concern to Dow Chemical. (18/19) • Deliverable 2 – Submission of a student thesis. (17/18). Anticipated completion June 2018.
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.
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). This has been completed and samples from a number of locations have been analysed that have indicated the potential wide application of this method in assessing the possible effect of bioaerosols on health. • Milestone 2 – Linkage to Cranfield ongoing. Workshop in May to explore further opportunities (17/18). This was completed and there was further input into an RIVM workshop that took place in June. • Deliverable 1 – A paper detailing environmental fungal exposure using the genomic analysis methods (18/19). This is ongoing as indicated and results are being gathered. (18/19) • Deliverable 2- Small review paper on the role of the human microbiome in public health. (17/18). This is slightly delayed but is ongoing. (18/19) • 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). This is ongoing and bacterial fragments have been detected in serum but not in the lung. (18/19)
Theme II/Project 4 – Genotoxicity of air pollutants Lead: David Phillips (King’s) and Tim Gant (PHE) 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.
Deliverables and milestones • Deliverable 1 - Publish first report of effects of PAHs and mixtures in immortalised alveolar cells as a precursor to future studies (17/18). Published. Genotoxicity of fine and coarse fraction ambient particulate matter in immortalised normal (TT1) and cancer‐derived (A549) alveolar epithelial cells. Ian W.H. Jarvis Zachary Enlo‐Scott Eszter Nagy Ian S. Mudway Teresa D. Tetley Volker M. Arlt David H. Phillips. https://doi.org/10.1002/em.22166. Environmental and Molecular Mutagenesis 59:290-301 (2018). • 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). Work on these models showed very little DNA damage or inflammatory response to mixtures of PM. Given the cost of the commercial models, and the lack of a reliable reproduction of the airway in in-house models, this aspect hasn’t been pursued. There is growing work in the field looking at ALI models in non-differentiated cultures; this could be an acceptable compromise for future studies. • Milestone 2 - Establish co-culture conditions for lung epithelial cells and macrophages to investigate the contribution of immune cells in response to PAHs and PM (17/18). Conditions for growth of immortalised bronchial cells and monocytes-derived macrophages have been established; these involve using culture medium that contain serum so are not applicable for primary lung cells.
NIHR Health Protection Research Unit– Progress Report 201718 11
Preliminary evidence suggests that the cultures show comparable toxicity profiles, and co- cultures show elevated release of some cytokines, though this is likely due to their release from the macrophages and not the exposures. Further work to identify to the best ratio of epithelial cells and macrophages would be warranted. • 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). London PM samples haven’t been easy to obtain as the archived samples cover a small time period and hence limited in extractable material. New diesel and biodiesel samples from Umeå University, in collaboration with Ian Mudway (Theme IV), have been studied for genotoxicity and inflammatory effects. Data from this work was presented at the 2017 Nanoparticle conference at ETH in Zurich. These studies are ongoing with a prediction to publish this work in summer/autumn 2018.
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). An MRC project grant application has been submitted to accommodate this research. Revised completion is 18/19 • Milestone 5 – Analysis of metabolic features associated with air pollutants in relation to cardiovascular risk factors (18/19). An MRC project grant application has been submitted to accommodate this research. Revised completion is 19/20.
Theme II Project 6 - UVCBs 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).
Deliverables and milestones • Milestone 1 – Establishment of 10 cell lines for treatment with UVCB products and reference materials (17/18). Eight cell lines are complete and the remaining two are ongoing. (18/19) • Milestone 2 - In house analysis of toxicity and of Temp-O-Seq data (18/19). Completed. • Deliverable 1- UVCB treated cells dispatched to TAMU for sequencing analysis (17/18). Completed.
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 will 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 NIHR Health Protection Research Unit– Progress Report 201718 12
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 below:
Deliverables and milestones • Milestone 3: Elucidate the mechanism by which radiation reduces the availability of junction proteins (18/19) - Work is going very well and on track to deliver on time. (18/19) • Milestone 4: Determine if radiation induces pro-atherosclerotic properties is dependent on the age of the cell population - (18/19) Work is going very well and on track to deliver on time. (18/19)
Theme III/Project 2 – Electromagnetic fields Lead: Mireille Toledano (Imperial) and Simon Bouffler (PHE) Ongoing EMF work will provide key information on risk of cancer, cardiovascular disease and reproductive effects associated with exposure to mobile phone EMFs. An increasing integration of biomarker assays into the study cohorts is expected and this will help the development of prognostic markers. Future plans for 2018-20 aim to leverage more from our existing cohorts by further exposure assessment, evaluation of the effects of shift working on circadian clock function and integration of epigenetic ageing biomarkers. An information booklet aimed at schools participating in one study (SCAMP) will be developed to provide accessible information on exposures and potential health risks.
Deliverables and milestones • Milestone 1 - Recruitment of SCAMP children with specific consent/assent for the biomarker validation study (see Theme 4). (17/18). Ongoing, due for completion 07.2018. (18/19) • Milestone 2 - Exposure monitoring of noise and air pollution and urine sampling for 50-100 SCAMP children in validation study. (17/18). Ongoing, due for completion 08.2018. (18/19) • Milestone 4 – EMF, noise and air pollution exposure assessment in additional schools. (17/18). Ongoing, due for completion 07.2018. (18/19) • Milestone5 - Report on exposure assessment at 5 additional school locations. (18/19). Data collection ongoing, report to be completed in 18/19. • Milestone 6 - Publication of paper on baseline patterns of mobile phone usage amongst the SCAMP children. (17/18). Completed. • Milestone 7 - Investigation of urinary biomarkers in a sub-set of the validation study group (see Theme 4) (17/18-18/19). Data collection ongoing, analysis to be completed in 2019. (18/19) • Milestone 8 – Continue the rollout of Airwave follow up screening across the country. Proposal to follow up Scottish and Welsh participants accepted by MRC. Follow-up ongoing. Planned completion date 2022. (21/22) • Milestone 9- Secure Airwave biosample collection, principally by outsourcing (17/18). In progress, final configuration pending grant application to Home Office. (18/19) • 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). First dataset uploaded. • 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). Manuscript submitted and currently under revision. • 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). Ongoing: symptoms analysis due for completion in 2018, other analyses will be undertaken during 18/19. • Milestone 13 – Draft of SCAMP cohort profile paper for submission to IJE (17/18). Completed, publication under review.
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 NIHR Health Protection Research Unit– Progress Report 201718 13
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 was one of the objectives for 2017/18. At the same time, we also planned 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). Completed on time and results published. Holliman G, Lowe D, Cohen H, Felton S, Raj K. Ultraviolet Radiation-Induced Production of Nitric Oxide:A multi-cell and multi-donor analysis. Sci Rep. 2017 Sep 11;7(1):11105. doi: 10.1038/s41598-017-11567-5. • Milestone 4 - Determine the route by which UVA induces NO production (17/18, 18/19). Completed on time and results published. See publication above • Milestone 5 - Determine the dynamics of NO production by UVA on keratinocytes and endothelial cells. (17/18, 18/19). Despite a break due to recruitment delays work is still on course to be completed on time. (18/19) • Milestone 6 – Q-PCR validation of gene expression changes identified in microarray analysis of dendritic cell sub populations. (17/18, 18/19). Completed. UVR and vitamin D supplementation treatments induced distinct gene signatures within myeloid and plasmacytoid cells. Differentially regulated pathways pathways predominantly involved regulation of protein translation, folding and degradation. These are intrinsically linked to cell survival, function and proliferation, the regulation of which appears modulated to an extent by metabolic pathways. Notably, Interferon signalling was significantly upregulated by vitamin D supplementation but not UVR treatment concurrent with the literature. And, UVR treatment increased anti-microbial gene expression more significantly than vitamin D, indicating an additional UVR mediated response. • Milestone7 - Completion of immune-phenotyping of major cell populations as analysed by FACS (17/18, 18/19). Completed. Vitamin D and solar-simulated UVR treatments significantly increased the frequency of FoxP3+ T regulatory cells within the periphery of healthy individuals and that serum25(OH)D positively associates with FoxP3 levels. The frequency of other major peripheral immune cell types were not affected by either treatment. PhD thesis encompassing the results of the 'UV radiation effects on vitamin D sufficiency' project is in its final stages. Submission anticipated June 2018. (18/19)
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 1 – Completed 2016/17. • Milestone 2 – Continue to develop processes for fast and convenient calculations of health impacts, including incorporating COMEAP recommendations on PM10 and chronic bronchitis. Commence NIHR Health Protection Research Unit– Progress Report 201718 14
calculations of burden and impact of typical reductions for the UK at a fine spatial scale. (17/18, 18/19). The development of fast/convenient calculations of health impacts continues, with systems set up for hospital admission calculations almost complete for mortality burden calculations across Great Britain rather than just London. Inputs for chronic bronchitis calculations under investigation. (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). Preparation of a strategy paper continues with publication of work on spatial scale of mortality rates published within a report to the European Commission. More meetings on HIA strategy document planned/drafting started. (18/19) • 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). Policy scenarios discussed by HPRU’s Community Advisory Board in October. Further stakeholder discussions deferred as scenario analysis resources to be diverted to responsive work for 2018/19. • Milestone 5 - Finalise a review to inform simulation inputs, finalise simulation protocol, gather more input data. Completed. Meta-analyse the data, partition personal exposure from outdoor sources, (completed, paper in preparation) apply correction formulas and simulate multiple scenarios for publication (Initial results generated, now investigating how different types of errors bias the health estimates. Organise a workshop on interpretation of multi-pollutant models. Successful, report in preparation. (2018/19) • 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). Initial model development using this cohort has been extended to integrating personal, residential and ambient exposures from a field study in Beijing into a database ready for testing the methodology. Develop a methodology for extending snapshot personal exposure monitoring to representative annual mean personal exposure estimates using the previous analysis and outputs from M4 (18/19) Exposure characterisation work is currently being undertaken to facilitate further extension of personal exposure snapshots. (18/19)
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.
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) Have developed a GC/MS based method for detecting low levels of PAH metabolites in low volume urine samples following solid phase extraction and TBDMS derivatization. Ongoing work improving sensitivity using LC-MS. Bio-sampling and air pollution monitoring of children taking part in SCAMP sub-study ongoing. (18/19) • 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). Examined the relationship between long and short-term air pollutant exposures with urinary metals/metalloids, 8- isoprostane and 8-hydroxy-2’-deoxyguanisine in samples obtained from the ACAP study. Work presented at European Respiratory Society meeting 2017. Investigated the use of blood markers of neuroinflammation in subjects exposed experimentally to diesel exhaust. Focus on Glial fibrillary acidic protein. This work will be continued using urine and saliva samples from the SCAMP sub-study once this activity has been completed, with funding obtained as part of the MRC funded CLUE study. (18/19)
NIHR Health Protection Research Unit– Progress Report 201718 15
• 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). See below. • 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) Exposure models, to allow pollutant attributions for the SCAMP cohort are now available (KCL urban). This modelling has now been superseded through work to develop a CMAQ-urban model, which has been funded as part of the the MRC funded CLUE study . Theme IV/Project 3 – Nanoparticle Exposure Assessment Lead: Rachel Smith (PHE), Terry Tetley (Imperial) 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). Analysis completed and results presented at 12th International Conference on the Environmental Effects of Nanoparticles and Nanomaterials, Sept 2017. • 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). Experimental system set-up and airborne aerosol characterised for a number of products. • Milestone 3 – The review of relevant NP aerosol exposure models will be completed (18/19). Review is underway. (18/19) • Milestone 4 - Completion of paper for publication (18/19). Not started. (18/19)
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 – Studies using A549 cells and organotypic reconstituted 3D human primary small airway epithelial (HPSAE) cell cultures exposed to silver nanoparticle aerosols in an aerosol exposure Air-Liquid Interface system (AE-ALI). A paper on this study will be submitted for publication (17/18). Paper published. Genotoxicity of fine and coarse fraction ambient particulate matter in immortalised normal (TT1) and cancer‐derived (A549) alveolar epithelial cells. Ian W.H. Jarvis Zachary Enlo‐ Scott Eszter Nagy Ian S. Mudway Teresa D. Tetley Volker M. Arlt David H. Phillips. https://doi.org/10.1002/em.22166. Environmental and Molecular Mutagenesis 59:290-301 (2018) • A further study using the AE-ALI system will be undertaken using another nanomaterial identified as being potentially significant for public exposures (17/18). Issues with equipment and material availability mean that the further study has not been completed and will continue into 2018/19. • Milestone 2 – In vitro airway model development to explore the toxicological impact of nanoparticles relevant for inflammatory respiratory conditions including asthma. Studies on modifying effects of cerium dioxide nanoparticles (CeO2NPs) on the toxicity of diesel particles (DEP) in HPBE cells in an ALI system. The in vitro airway model has been developed, to include alveolar macrophages, and is being used to explore the toxicological impact of nanoparticles relevant for inflammatory respiratory conditions including asthma. Paper on CeO2NP exposure in model system submitted, paper on DEP+CeO2NPs under development (18/19). • Milestone 3 - Extend studies completed in years 1-3 to other nanomaterials in everyday use. These studies will include use of the 3D co-culture model of the human alveolar unit established at Imperial during year 1. A number of publications are anticipated within year 4. (17/18). Studies have been undertaken using DEPs, carbon black and carbon nanotubes in the co-culture model, including
NIHR Health Protection Research Unit– Progress Report 201718 16
on the effect of surface charge on toxicity. Minor submission delay. Publications are in preparation. (18/19) • Milestone 4 - Undertake preliminary exposures using AE-ALI exposure system developed at PHE to test the feasibility of using this system with the alveolar model (18/19). Discussions underway. May ultimately be limited by availability of effort as PhD student finishes this year. (18/19)
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 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. The mechanistic aspects of this project will link with mechanistic work in Theme II.
Deliverables and milestones • Milestone 1 – Completed 2016/17. • Milestone 2 – Commence pilot studies examining the toxicity of particle samples from different combustion 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). Preliminary work started on biodiesel (in two cell systems) and on diesel in one system. Ongoing. • 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, including 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). After some staff availability obstacles, a recent meeting discussed plans to submit an expression of interest to the Wellcome Trust, May deadline, for a collaborative award, to include PIs from Themes II, III and IV, across Imperial College, Kings College and the University of Northern Sweden, Umea, using the biodiesel work to support our case. Ongoing (18/19) • 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) Meeting held to discuss. Ongoing. (18/19) • Milestone 5 – Commence work proposed in milestones 2/3, subject to obtaining funding. (18/19). Ongoing.
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) 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 1 – Completed 2016/17. • 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. Published. Psychosocial and demographic predictors of adherence and non-adherence to health advice accompanying air quality warning systems: a systematic review. Donatella D’Antoni, Louise Smith, Vivian Auyeung and John Weinman. Environmental Health. 201716:100 • https://doi.org/10.1186/s12940-017-0307-4. NIHR Health Protection Research Unit– Progress Report 201718 17
• Milestone 3 - PPI workshops to improve the research materials for the air quality alert study are scheduled for Apr-May 2017. Completed as programmed. • 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: All data collection for this project has been completed. • Milestone 5 - Write up PhD by April 2018. Slight delay. Completion expected June 2018. • Milestone 6 - Submit a paper on the air quality alerts study (by April 2018). Slightly delayed. Completion expected June 2018.
Theme IV/Project 7 - Methods for assessing the public health benefits of local transport interventions. Lead: Heather Walton (King’s) and Christina Mitsakou (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.
Deliverables and milestones • Milestone 1- Develop a protocol for a project addressing health impacts of school travel plans (17/18). In progress. Links made with another project at King’s funded by Waltham Forest local authority to (i) model air pollution concentration changes if a realistic percentage of school trips were switched from cars to walking and cycling and (ii) incorporate physical activity benefits into lifetable analyses. (18/19) • Milestone 2 - Commence defined project, adapted according to available funding. (17/18, 18/19) Linked project above started March 2018. A PhD studentship will be sought through PHE. (18/19).
NIHR Health Protection Research Unit– Progress Report 201718 18
6. PATIENT AND PUBLIC INVOLVEMENT, ENGAGEMENT AND PARTICIPATION (PPI/E/P)
As stated in our Patient and Public Involvement & Engagement Strategy document our Patient and Public Involvement & Engagement (PPI/E) objectives are:
(1) embedding PPI/E activities across each thematic area within the HPRU; (2) to build PPI/E capacity through training; (3) to provide support to patient/public representatives through educational resources to enable them to engage with scientists on public-directed research; (4) to present work directly to the public through science events; (5) to undertake research into the effectiveness of our communication strategies; (6) to develop PPI networks/forums to ensure a common approach to PPI/E, sharing of resources and best practice; and (7) to evolve the evidence base for the effectiveness of PPI/E in directing public understanding of environmental health issues.
Our PPI/E Strategic Oversight Group includes lay member(s) and PPI/E Leads from across each theme, under the overall leadership of Mireille Toledano: Theme I - Tony Fletcher (PHE) and Anna Hansell* (Imperial); Theme II - Tim Gant (PHE) and David Phillips (KCL); Theme III - Mireille Toledano (Imperial) and Antony Young (PHE); and Theme IV - Ian Mudway (KCL) and Rachel Smith (PHE).
*Susan Hodgson will replace Anna Hansell from 1st April 2018.
Patient and Public Involvement: A new initiative has led to the establishment of a joint Community Advisory Board (CAB) between the HPRU and the MRC-PHE Centre for Environment and Health. New members from the British Lung Foundation, the British Heart Foundation and the Patient’s Association, as well as a director of public health (Lewisham), have recently joined the CAB. The CAB seeks to bridge the gap between the HPRU/MRC-PHE Centre and their stakeholder communities and provides a permanent consultation forum for the exchange of opinions and ideas. CAB members meet 2-3 times per year and provide comment and feedback on research strategy and programmes, input ideas, and provide opinion on ethical issues.
Topics discussed by the CAB in the last year include: health impacts of air pollution and associated costs to NHS and social care (Theme IV), HPRU workstreams including incinerators (Theme I) and nanoparticles (Theme IV) and a consultation on the fair processing notice for personal data (across themes). This demonstrates our ongoing commitment to developing PPI networks/forums to ensure a common approach to PPI/E, sharing of resources and best practice (objective 6). This is a recent initiative that has been highly successful.
Public Engagement: The HPRU has demonstrated an ongoing commitment to engaging the public with its research across themes. For example, HPRU researchers hosted a Healthy Environments exhibit at the Imperial Festival in May 2017, with activities designed to help members of the public understand how small changes that they make can create a big change in their health and environment. This engaged the public on air and noise pollution (Theme IV) at an event attended by approximately 20,000 visitors. Additionally, researchers from all themes took part in the New Scientist Live event in July 2017 with posters, leaflets and interactive games on topics including bioaerosols, the microbiome, air quality and health and a compendium of other chemical hazards. At this event, HPRU researchers spoke to approximately 4000 people (1000 per day), with the Unit Director Professor Frank Kelly delivering one of the key podium presentations on the risks associated with air pollution.
Also, in June 2017, members of the HPRU (All Themes) organised an evening MRC Festival of Medical Research event in Deptford, South London. Deptford was identified as an area of low social and scientific capital for the event, as part of our wider strategy to engage with difficult to reach groups with environmental health related topics. The event which was attended by over 200 individuals, including representatives from the local council and schools, included interactive activities, talks and expert advice concerning air quality and health (Theme IV) and bioaerosols (Theme I). Elizabeth Hayes produced an evaluation report for this event, and the MRC surveyed those taking part. These evaluations will help feed-back and inform practice at future public engagement events. Moreover, HPRU members were involved in the production by Camden NIHR Health Protection Research Unit– Progress Report 201718 19
People's Theatre ‘FOG Everywhere’ - (31st October - 11th November 2017) which aimed to stimulate discussions around air quality with teenagers in disadvantaged communities. Additionally, in December 2017, Imperial Fringe hosted a live discussion with members of the public on ways to reduce air pollution, simultaneously allowing members of the public to learn about the invisible gasses encountered in everyday life and consider individual mitigation strategies (Theme IV). For the project aimed at improving the behavioural impact of air quality alerts (Theme IV collaboration with HPRU in Emergency Preparedness and Response) two workshops were conducted aimed at improving the research materials for the study: the first was conducted with five patients from St Thomas’ Hospital, London, with severe respiratory conditions. The second workshop was conducted with seven members of the public.
All the above events demonstrate an ongoing commitment across the themes to present work directly to the public through science events (objective 4). In Theme III, the SCAMP study also runs a variety of PPE activities, including doing science/ careers/ research talks at schools and offering work experience placements. For example, they recently presented a SCAMP progress update at a school conference on “The Adolescent and the Mobile Phone”, which also involved taking part in a discussion panel on specific issues relating to pupils’ use of mobile phones. Furthermore, the Annual Report of the Chief Medical Officer in 2017 (“Health Impacts of All Pollution – what do we know?”) had chapters that were co-authored by HPRU co-investigators: Professor Timothy Gant (Theme II), Dr Heather Walton (Theme IV) and Professor Paul Elliot (HPRU Deputy Director). The CMO’s report also referenced some HPRU incinerator work (Theme I), and chapter 9 also discussed communication of health risks. Additionally, chapter 4 (“New Horizons”) contained perspectives from Giovanni Leonardi and Tony Fletcher (Theme I) and David Phillips (Theme II).
All of the above demonstrates the achievement of objective 1 (embedding PPI/E activities across each thematic area within the HPRU).
Case Study
Researchers in Theme III are currently undertaking a PPI project (ESRC IAA Award ES/M500562/1) which aims to identify barriers to study participation and provision of consent for data linkage in difficult to reach groups. This project is a collaboration between the SCAMP study and the NIHR Patient Experience Research Centre (PERC) at Imperial College London. This project involves two focus groups in community centres, containing a mixture of people from the local community and SCAMP study parents (March 2018). The objectives of these focus groups are to a) establish barriers to consent provision for data linkage and participation in the exposure validation assessment and bio-sampling in seldom-heard individuals/ communities, b) to co-produce specific, actionable solutions to increase consent for bio-sampling and exposure validation participation in the SCAMP cohort and c) discuss more widely how to address barriers to participation in similar population based research studies. A range of parents of different ethnicities and economic backgrounds attended these focus groups. While the team have not yet analysed the results of these focus groups, several common barriers have emerged, particularly regarding data sharing and the concept of trust (both institution-parent and parent-child).
There is also a further focus group for consented SCAMP parents and some telephone interviews have been conducted (March/April 2018), to discuss why these parents provided consent and why other parents do not do so. In the focus group for consented parents, we will also consider SCAMP’s communication materials and strategy, thus achieving our HPRU PPI/E objective 5. In addition to this, the SCAMP/PERC team also ran a stall at the QPR Community Day, where they held the scoping version of the focus groups with members of the public, concentrating on the barriers and solutions to participation in research on mobile phones. Thus, as a whole, this project will fulfil HPRU PPI/E objective 7, as these focus groups will evolve the evidence base for the effectiveness of PPI/E in directing public understanding of environmental health issues.
The results from the focus groups, will be fed back into the SCAMP study in order to engage seldom-heard groups, which will create real impact in the SCAMP study. We also aim to feed back our results both to other researchers who need to engage with groups that are known to be difficult to reach and focus group participants. One way we aim to do this is to host a symposium for other researchers who aim to engage difficult to reach groups. This symposium will help us to address HPRU PPI/E objectives 2 and 6.
NIHR Health Protection Research Unit– Progress Report 201718 20
7. CONTRIBUTION TO THE GROWTH AGENDA (including links with industry) (if applicable)
7.1 Please describe up to three examples of outputs from the Unit which demonstrate the potential to contribute to the growth agenda.
Theme II
Project 1 has links with the NHS through both the blood spots project that utilises the resources of the NHS and CO exposure that also utilises NHS resources levering industrial monies.
Project 2 has been completed in collaboration with Dow Chemical working on some of their active herbicides and also using data generated internally by Dow.
Project 3 has contributed towards the better risk assessment and regulation of industrial composting sites and intensive farming sites and furthermore is using sampling methods in collaboration with a working composting site to better understand how these methods can be applied to risk assessment.
Project 6 is entirely funded by the European refining industry and is contributing towards the better hazard assessment of UVCB products that included all refined oil products. This is a substantial issue in the EU at the present time and this project contributes directly to the growth agenda of these industries.
Links with Industry - Please note that this section may not apply to your Unit. However, if applicable, please answer the following questions to describe your Units engagement with industry
7.2 Please outline your Unit’s engagement with industry (if applicable), separately as appropriate in the following sectors: with i) pharma, ii) biotech, iii) medtech/devices, iv) diagnostics, v) CRO’s, vi) non-life sciences companies. For each sector please describe any significant successes or any challenges faced during financial year 2017/18. Please also outline any strategic plans for increasing engagement with industry (if applicable).
See answers in 7.1 for active collaboration with the biotech sector.
7.3 Please indicate the total number of UK Small and Medium Enterprises (SMEs) you have worked with during financial year 2017/18 and provide brief details of key examples. None
7.4 Please provide details of; i) any new strategic partnerships between your Unit and industry during financial year 2017/18 ii) the progress of ongoing strategic partnerships between your Unit and industry during financial year 2017/18. None
7.5 Please provide brief details of key examples of studies active in financial year 2017/18, as follows: ● Contract commercial trials ● Industry collaborative research studies ● Other academic commercial research
Theme II
Project 2 was completed in collaboration with Dow Chemical working on some of their active herbicides and also using data generated internally by Dow.
Project 6 is entirely funded by the European refining industry and is contributing towards the better hazard assessment of UVCB products that included all refined oil products. This is a substantial issue in the EU at the present time and this project contributes directly to the growth agenda of these industries.
7.6 Please provide the number and key examples (including names of funder/grant schemes) of any partnerships or studies with industry which have led to further industry, public or charity research funding, including as part of consortia. None
NIHR Health Protection Research Unit– Progress Report 201718 21
8. LINKS AND COLLABORATIONS WITH OTHER NIHR HPRUs AND INFRASTRUCTURE
During year four we have continued to focus on strengthening our collaboration with other HPRUs and we are pleased to report the progress made in the following projects:
HPRU in Emergency Preparedness and Response
The project on behavioural responses to air pollution alerts joint with the Emergency Preparedness and Response HPRU has been a very successful project and is presented as a case study elsewhere in the report. The HPRU in Health Impact of Environmental Hazards provided the expertise on the air pollution and health evidence, with the behavioural response expertise coming from the Emergency Preparedness and Response HPRU. While the HPRU funding aspect of this project has finished (a PhD studentship), further collaborations with the same Unit members on other projects is under discussion.
HPRU in Environmental Change and Health
The project with the Environmental Change and Health HPRU on local transport interventions with a focus on school travel plans is ongoing. King’s staff in the Health Impact of Environmental Hazards HPRU have secured external funding from the London Borough of Waltham Forest to undertake some work, including modelling of the potential benefits of switching a proportion of car trips to school with walking or cycling. PHE staff from the Environmental Change and Health HPRU plan to apply for a PHE PhD studentship on this subject. School audits of air pollution concentrations outside schools were recently highlighted in the CMO report. This may increase the likelihood of being able to obtain further external funding in this area.
A new PhD award secured this year has allowed for new work to be developed with the Environmental Change and Health HPRU that will particularly focus on understanding the exposures to bioaerosols in different indoor environments.
HPRU in Chemical and Radiation Threats and Hazards
Work has also continued with the Chemical and Radiation Threats and Hazards (CRTH) HPRU on understanding the effects of radiation on cardiovascular disease. This specifically relates to the work investigating the potential impact of solar UV exposure on blood pressure reduction, mediated by nitric oxide (NO). The studies in the Health Impact of Environmental Hazards HPRU are focussed on a better definition of the components of the UV spectrum most active in upregulating NO levels in relevant cell types. The CRTH HPRU studies are looking into the negative impacts on DNA damage response and cell killing induced by the optimal exposures for prompting NO production. Together these studies will help inform the risk- benefit judgements on UV exposure. Additionally, the CRTH HPRU examines the effects of chemicals from toxic waste sites on causing primary biliary cholestasis, which has had input from Theme II of this HPRU.
NIHR Health Protection Research Unit– Progress Report 201718 22
9. IMPACT IN HEALTHCARE AND PUBLIC HEALTH PROVISION
Please list any significant new work showing how your Unit is translating its work into practice for the benefit of the public and/or patients; you may also summarise on significant developments in examples reported previously.
Our staff serve on a number of expert committees of relevance to the activity of the Health Impact of Environmental Hazards HPRU. Professor Kelly chairs COMEAP, Dr Walton chairs QUARK, a subgroup of COMEAP.
Our research activity in the HPRU will be of benefit to these committee duties. Dimitris Evangelopoulos has assisted COMEAP with some statistical issues relating to multi-pollutant models – a particular challenge for determining health impacts of specific pollutants.
An NIHR funded project on the air pollution health impacts of policies to meet the greenhouse gas targets in 2050, to which Dr Walton and Dr Toledano contributed has been published and has been presented to staff at PHE, Defra and the Committee on Climate Change
Please also describe examples of work which have significant potential to improve patient outcomes or public benefits in the future, setting out how the Unit plans to ensure that these potential benefits are achieved.
There will be public benefit from projects 3 and 6 in Theme II in terms of improving the risk assessment of intensive farming and composting sites (project 3) and the regulation of the extensively used UVCB material type (project 6) that affects close, or at, 100% of the European population.
10. RESPONSIVE STUDIES (no more than one page)
Please provide details of any responsive work that you have done in the last year.
None
This form, together with the completed Added Value examples, must be submitted, by email, no later than 5pm on 08 May 2018 to Aoife Keohane ([email protected]).
A signed copy of this report should be sent no later than 31 May 2018 to:
Dr Aoife Keohane NIHR Central Commissioning Facility Grange House 15 Church Street Twickenham, Middlesex TW1 3NL
NIHR Health Protection Research Unit– Progress Report 201718 23