environmental exposures and health – nihr - best...

NIHR HEALTH PROTECTION RESEARCH UNITS

Forward Business Plan 2018-2020

1. 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

2. Details of the Research Team (max 1 page)

The Health Impact of Environmental Hazards HPRU consists of staff and students from King's College London, Environmental Research Group (ERG), Imperial College London, Department of Epidemiology and Biostatistics (EBS) and Public Health England, Centre for Radiation, Chemical and Environmental Hazards.

As we complete the 4th year of activity our governance and management arrangements remain unchanged and continues to work well. The leadership team (Kelly – King’s; Elliott – Imperial; Gant – PHE) will continue to work closely, meeting on four occasions in both years 5 and 6 to discuss progress and new funding opportunities. Theme leaders will meet formally twice/year to report and review progress and individual Themes will meet/teleconference on a bimonthly basis to review progress in their portfolio of projects. In addition, the PPE/PPI team meet on an ad hoc basis to ensure preparations are in place for planned activities. Dr Anna Hansell, Theme I Lead, leaves Imperial at the end of April 2018. Dr Susan Hodgson will replace Anna as Theme I Lead. Dr Fred Piel will be the Imperial Lead on Theme I Projects 3 and 4 and Dr Mireille Toledano will be the Imperial Lead on Project 6.

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). The EAB play an essential 'sounding board' role providing intellectual input to study planning and interpretation of results obtained. They also consider how our work programme aligns with PHE policy needs. All members of the EAB have confirmed their attendance at our annual meeting scheduled to held on April 12 th & 13th 2018.

We are pleased that two of our Research Associates, Drs Becky Ghosh and Pippa Douglas have progressed to new roles – Dr Ghosh is now working with the CPRD GP database. Dr Douglas was successful in securing a MRC-PHE Centre for Environment & Health Early Career Research Fellowship and is still at Imperial, but now based at the National Heart and Lung Institute.

HPRU Research Forward Business Plan 2018-2020 Application Ref No:1

Dr Aina Roca Barcelo (funded by the MRC-PHE Centre for Environment & Health) will complete Dr Ghosh’s work on carbon monoxide in Theme I/Project 1 and Dr Douglas’s bioaerosols work in Theme I/Project 2 which was funded in the past year as part of the NERC Bioaerosols grant (a successful outcome from the HPRU). Dr Brandon Parkes (currently funded by the MRC-PHE Centre for Environment & Health – to be funded 25% by the HPRU in Y5) will take over some of Dr Ghosh’s work on Theme I/Project 5.

Four additional members of staff will join the HPRU during years 5 and 6 to work on Themes I, II & III – Dr Jinkang Zhang, 1 RA funded by MRC-PHE Centre for Environment & Health; 1.5 FTE RA’s and 1 Database/IT Manager funded by the HPRU.

We are also very pleased that three of our PhD students (Alexander Cooper, PHE; Kirsty Meldrum, PHE and Kylie Morgan, King’s) will be completing their programmes prior to the start of Year 5. We have been successful in obtaining funding from EPSRC to appoint one new PhD student (Dylan Wood, King’s) who started his project in October 2017.

3. Theme Summary and Translational Output (max 3 pages)

Introduction: The research priorities for the Health Impact of Environmental Hazards HPRU focus on the identification, quantification and advice provision of environmental hazards to minimise the impact on morbidity and mortality. We focus on four major environmental challenge areas which are of importance to PHE. These include: air pollution, low level chemical/biological exposures, non-ionising radiation and nanoparticles.

Our objectives during years five and six are to build upon the work/outcomes achieved in years 1-4 by com-pleting those remaining projects and initiating several new ones identified in recent discussions with PHE and DH colleagues and through our forward planning process. Details of these activities are provided under the relevant themes. Where outputs have direct policy relevance we will continue to dialogue through meet-ings/interactions with relevant PHE and DH staff. In year 5 we will also undertake responsive work to invest-igate 'Air pollution and adverse birth outcomes' for the Department of Health and Social Care.

Theme I: Epidemiological assessment of low level environmental exposuresLead: Susan Hodgson (Imperial); Deputy lead: Tony Fletcher (PHE)

Overall aim of Theme I: 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; development of methodology to facilitate epidemiological assessments for cluster detection and reported excesses of non-communicable disease that may be due to environmental exposures; facilitation of methods relating to a range of possible low-level environmental exposures; assessment of hazards from specific industries, using the example of waste incineration.

Project 1 - Carbon monoxide (CO)Following our analyses of hospital admissions and initial work on A&E attendances 2007-10, epidemiological analyses will be extended to inpatient and A&E admissions in recent years (2010-2016) to confirm temporal trends and spatial patterns previously identified, and to the development of methodologies to link across A&E, hospital admissions, coroners’ data and mortality datasets. This work will be linked with information on exposure and exposure markers 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 carbon monoxide to the national population.

Project 2 - Health impacts from bioaerosols from waste composting facilities and intensive farmingDr 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.

Project 3 - Cluster guidelines/Rapid Inquiry FacilityWe 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 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.

Project 4 - Assessing environmental epidemiology evidence for health effects of low level expo-suresA new activity for years 5 & 6 arises from PHE’s tracking work assessing the potential health risk and benefits of fluoridation schemes. This work will utilise multi-level models of small area rates of relatively rare outcomes, adjusting for strong socio-economic determinants.

Project 5 - Low level population heavy metal exposureWe recently obtained a comprehensive data set from the British Geological Society with extensive sampling of soil concentrations of metals. As these data are currently at different resolutions work is required to standardise these before they can be assembled into a Europe-wide database on exposure and health risks potentially associated with industrially contaminated land. This work will update UK population exposure assessment for use in risk assessment.

Project 6 - Exposure to emissions from incineratorsA human breast milk collection has been conducted near three incinerators in the BEED study and chemical analyses of these samples will inform whether there are significant differences in breast milk contaminants, informed by modelled PM10 exposure tertiles.

Theme II – Modes of toxicity (Biochemical Pathways from toxin to disease)Lead: Tim Gant (PHE); Deputy lead: David Phillips (King’s)

Overall aim of Theme II: To use molecular methods to demonstrate causation pathways and associations between disease and exposure to environmental chemical and biological hazards and better assess risk by reference to mechanism of action. Causation pathways provide the conclusive underpinning to associations and permit targeted policies for interventions and improved public health. The concept of a mode of toxicity is an understanding of the interaction of a chemical with cellular biochemistry from the level of exposure through 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 focus on early life effects, though not exclusively, because this is recognised as a susceptible stage of life of particular public health concern and addresses one of the PHE strategy objectives (2016 to 2020), to ensure children have the best start in life'. The activities on Thailand cohorts also contribute to the PHE objectives in Global Public Health (2016-20).

Project 1 - Early life exposures and effect, has suffered from many delays but is finally getting off the ground. Support from the NIHR and PHE has been vital in achieving gestation of this project. Continuation into the 2019/20 period is proposed to build on the work already completed, coupled with a review point at the end of 2018/19. This project is considered essential to understanding early life exposure levels and epigenetic effects at this sensitive life stage. The project will benefit from additional funding and samples from Thailand under a project sponsored by the Mahidol University through the Mahidol Oxford Research Unit (MORU). This also contributes to the PHE Global Health strategic plan.

Project 2 – Toxicokinetics, will be complete at the end of the 2017/18 period and the PhD student involved will submit his thesis and two papers for publication.

Project 3 - Environmental and Human Microbiome, will be a major component of the theme in the 2018/20 period. Building on the two papers with high public health and policy relevance dealing with the health effects of composting and intensive farming the major aim will be to develop the evidence base through novel research dealing with 1) the environmental microbiome and health effects and 2) the effect of air pollution on the lung microbiome. This project will link with a new initiative in the microbiome by the Health and Environmental Sciences Institute of Washington DC (Gant). This project also has a close interaction with the project with MORU (Project 1) that will also consider the microbiome.

These first three projects are extensively about exposure while Project 4 - Genotoxicity of air pollutants, (closed in 2018 having achieved its objectives) and the remaining projects in the theme deal with interactions of chemicals with cellular biochemistry and physiology.

Project 5 - Analysis of the serum and urinary metabolome in relation to air pollutants, continues to examine chemical interactions following exposure by looking at effects on the metabolome of air pollutants


and will start to quantify those air pollutants that have the major effect on biochemistry and physiology.

Project 6 - UVCB Grouping, deals with an important aspect of chemical regulation in assessing the hazards of complex chemical mixtures, in this case oil products. The project is highly policy focussed dealing with chemical regulation and is being monitored closely by many European Regulatory agencies.

Project 7 - E-cigarette risk, is new for 2019/20 and builds on work started in a Horizon 2020 project. E-cigarettes are being heavily promoted in the UK, particularly by PHE, for smoking cessation. In other countries however, they are differentially regulated and in some cases such as Thailand banned from sale. These differing policy approaches reflect the lack of understanding of risk which is in part due to the lack of available toxicological information. This project examines risk and has a direct link to public health messaging and policy.

Theme III - Health impact of low dose non-ionising and ionising radiation.Lead: Simon Bouffler (PHE); Deputy lead: Mireille Toledano (Imperial)

Overall aim of Theme III: Theme III will continue to explore the effects of different radiations, environmental exposure to which, is essentially unavoidable – ionising radiation (IR), present as natural background and artificial sources, electromagnetic fields (EMF), widely used in communications technologies and ultra-violet (UV), present in sunlight. Projects will now move to a more translational phase. By the end of the current funding period we will have generated evidence for translation into public health practice/guidance relating to all three types of radiation. The evidence will provide valuable input to PHE’s views and advice on risk-benefit balance to ensure adequate and appropriate public health measures for radiation health protection.

Project 1 - Novel human cell model of atherogenesis, having established a plausible link between IR and atherogenesis we will now address the non-mutational mechanisms that underlie the observed effects. This work is critical for developing a sound risk extrapolation model and the age-dependency of the effects which will inform on the distribution of risk amongst the population.

Project 2 - Electromagnetic fields, 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.

Project 3 - UV radiation effects on vitamin D sufficiency and blood pressure, will seek insights into the optimal exposures that elicit blood pressure reduction and investigate prospects for use of simulated solar radiation for blood pressure reduction. Longer term we are looking to develop a protocol for a human volunteer study to validate findings in humans and confirm the link between UV stimulated NO production and blood pressure reduction.

Theme IV - Health effects of noise and air pollution including nanoparticles Lead: Heather Walton (King’s); Deputy lead: Rachel Smith (PHE)

Overall aim of Theme IV: In recent years, air pollution has received increased emphasis within PHE as an environmental risk of key public health concern. PHE note as an achievement the establishment of a long term ‘air pollution and health’ work programme and undertake to provide scientific and technical advice on reducing the health impacts of air pollution at a local level, along with providing advice on environmental risks to local government as part of their strategic plan for the next 4 years1. Their action plan includes developing a PHE Environmental Health approach, strengthening the operation of the Centre for Radiation, Chemicals and Environmental Hazards (CRCE) with whom this HPRU is linked. The work of Theme IV on air pollution, including nanoparticles, supports these priorities.

Project 1 - Optimising assessment of health impacts of air pollution, continues to develop methodology for estimation of health benefits of policies in support of PHE’s role in advising Defra. We have extended the work on understanding the effect of measurement error on multi-pollutant models (new milestone 7), as separating the effects of nitrogen dioxide from those of particles is a key issue for PHE, DH and Defra.


Project 2 - Neurocognitive & behavioural impacts of traffic derived pollutants in children, will continue and has now obtained increased external funding (as the original SCAMP cohort has expanded in size).

Project 3 - Nanoparticle Exposure Assessment, will finish in 2018/19 as originally planned to allow more emphasis on health aspects of nanoparticle exposures in projects 4 and 5. Nanoparticles continue to be an important area for PHE e.g. to assist in responding to forthcoming formal proposals on changes to REACH annexes to better address nanomaterial assessment. Results from this research will be disseminated through discussion within fora such as the cross-Government nanomaterial group meetings.

Project 4 - Health Impacts; nanoparticles, will extend studies completed in previous years to other nanomaterials in everyday use, e.g. silver, zinc and ceria and others identified by PHE.

Project 5 - Improved in vitro systems for evaluating and comparing toxicity of air pollutants,will continue, subject to external funding, applying nanoparticle toxicology experience to assessment of air pollution particles (as suggested by our External Advisory Board) and comparing and contrasting particulate and gaseous pollutants to assist with interpretation of the causality of epidemiological associations.

Project 6 - Adherence to preventative recommendations during public health emergencies, will be completed in 2017/18, the culmination of a successful project across two HPRUs to support PHE responsibilities to provide information to the public on environmental threats. Thus, no future costs requested.

Project 7 - Methods for assessing the public health benefits of local transport interventions, supports PHE plans for action on sustainable travel and air pollution advice to local government.

Project 8 - Association between primary mental health outcomes with air pollution in urban populations, will be new work linking King’s CRIS database of mental health outcomes and air pollution exposure to support PHE objectives on awareness of risk factors for mental health.

Project 9 - Review of air pollution and adverse birth outcomes, will be responsive work to investigate 'Air pollution and adverse birth outcomes'.

1 - Public Health England Strategic plan for the next four years: Better outcomes by 2020https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/516985/PHE_Strategic_plan_2016.pdf

4. NIHR HPRU Forward Business Plan (max 10 pages)

Budget plans:

King’s: (2018/19)£234,900

(2019/20) £257,400

TOTAL £ 492,300

Imperial (2018/19)£262,947

(2019/20) £205,490

TOTAL £ 468,437

PHE: (2018/19)£237,008

(2019/20) £245,917

TOTAL £ 482,925

Theme 0 - Management and coordination costs – (2018/19 and 2019/20)King's staff Imperial staff PHE staff

Frank Kelly Paul Elliott Tim Gant

Angela Lewis Natalie Blowfield

King’s: Research Salaries £94,496 Non pay research costs £13,897 Indirect costs £28,349


https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/516985/PHE_Strategic_plan_2016.pdf

Imperial: Research Salaries £19,737 Non pay research costs £0 Indirect costs £ 5,921PHE: Research Salaries £ 7,941 Non pay research costs £ 4,942 Indirect costs £ 1,588

Theme I: Epidemiological assessment of low level environmental exposuresLead: Susan Hodgson (Imperial); Deputy lead: Tony Fletcher (PHE)

Theme I/Project 1 - Carbon monoxide (CO)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 inpatient and A&E admissions in recent years (2010-2016) to confirm temporal trends and spatial patterns previously identified, and 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). 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. (18/19) Milestone 3 - Submit a paper on the assessment of CO A&E presentations. (18/19) Milestone 7 - Submission of short manuscript on estimating global burden of disease related to CO

poisoning joint with US Centers for Disease Control and Prevention. (18/19) Milestone 8 - Funding application to Gas Safety Trust to work with CO Gas Safety to analyse indi-

vidual risk factors for CO poisoning, using their CO poisoning database. (18/19) (for work in year 6 if successful)

Milestone 9 - Creation of a risk map of CO poisoning for England. (19/20)

King's staff Imperial staff PHE staffTony Fletcher

Fred Piel No cost Giovanni Leonardi No costAina Roca Barceló No costDatabase/IT support No cost

Theme I/Project 1 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £10,794 Non pay research costs £1,000 Indirect costs £2,159

Theme I/Project 2 – Health impacts from bioaerosols from waste composting facilities and intensive farmingLead: Emma Marczylo (PHE)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.

Deliverables and milestones Milestone 4 - Epidemiological study on respiratory admissions using modelled exposure and a case-

crossover design. On hold. Will be revisited when suitable expertise is identified.

King's staff Imperial staff PHE staffTim Gant No cost

Pippa Douglas No cost Emma Marczylo No costJeanette Spear No costAina Roca Barcelo No costDatabase/IT Support No cost

Theme I/Project 2 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0


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

Theme I/Project 3 – Cluster guidelines/Rapid Inquiry FacilityLead: Tony Fletcher (PHE) and Fred Piel (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 3 - Revise and update draft guidance in light of evaluation and review of new WHO guid-

ance document. (18/19) (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 of all elements available for field testing. (18/19) (Imperial lead)

Milestone 6 - A publication submission on use of the RIF in cluster detection and disease mapping. (18/19)

Milestone 7 - Extensive in-field testing of the RIF with test cases, which will inevitably need modific-ations and result in improved usability and new features for cluster detection. (19/20)

King's staff Imperial staff PHE staffFred Piel Tony FletcherDatabase/IT support

Theme I/Project 3 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £121,171 Non pay research costs £6,664 Indirect costs £36,351PHE: Research Salaries £ 10,567 Non pay research costs £ 500 Indirect costs £ 2,113

Theme I/Project 4 - Assessing environmental epidemiology evidence for health effects of low level exposuresLead: Tony Fletcher (PHE) and Fred Piel (Imperial)This project addresses uncertainties in assessing dose-response effects of low level exposures, with initial work focussing on systematic reviews and work on dose response assessment from perfluorinated compounds. A new activity for years 5 & 6 arises from PHE’s tracking work assessing the potential health risk and benefits of fluoridation schemes, using multi-level models of small area rates of relatively rare outcomes, adjusting for strong socio-economic determinants. We will continue this work on perfluorinated substances (PFAS), now in collaboration with the Horizon2020 HBM4EU project. Pooling various existing cohorts with biomarker assessments of PFAS will allow more precise characterisations of dose response relationships and assessment of thresholds of effect, as up to now most studies have been exclusively of either very high or very low exposure. A publication arising from this work is anticipated in 2019.

Deliverables and milestones Milestone 2 – Completion of publication “Multi-level methods for improved adjusted for geographic

confounders in assessing risk and benefits of fluoride levels in drinking water” following publication of the PHE report in March 2018. (18/19)

Deliverable 1 - Completion of publication on PFAS serum biomarkers contrasting high and low ex-posure populations to improve dose response characterisations across a wide exposure range. (19/20)

King's staff Imperial staff PHE staff

Fred Piel No cost Tony Fletcher


Theme I/Project 4 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £7,045 Non pay research costs £0 Indirect costs £1,409

Theme I/Project 5 – Low level population heavy metal exposureLead: Susan Hodgson (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 partner in the COST Action IS1408 “Industrially Contaminated Sites and Health Network” (ICSHNet), which is assembling Europe-wide data on exposure and 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 3 - Development of current HPRU lead, cadmium and arsenic mapping work into a

publication submission on soil exposure patterns, routes of exposure and evidence on health effects. (18/19)

Milestone 4 - Development of PHE-Imperial risk map for lead risk (taking into account exposure from various sources, not just soil) to be worked up into a paper and online atlas page. (18/19)

Milestone 5 - Heavy metal analyses in breast milk from the BEED study are in progress and this will be written up into a paper submission. (19/20)

King's staff Imperial staff PHE staffTony Fletcher

Susan Hodgson No cost Giovanni Leonardi No costBrandon Parkes

Theme I/Project 5 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £14,275 Non pay research costs £0 Indirect costs £4,283PHE: Research Salaries £ 7,045 Non pay research costs £0 Indirect costs £1,409

Theme I/Project 6 – Exposure to emissions from incineratorsLead: Mireille Toledano (Imperial) and Ovnair Sepai (PHE)Exposure modelling of particulates has been completed, but it proved impossible to conduct modelling for dioxins or metals as measurements were too sparse. A human breast milk collection has been conducted near three incinerators in the BEED study and chemical analyses of the breast milk will inform whether there are significant differences in breast milk contaminants, informed by modelled PM10 exposure tertiles.

Deliverables and milestones Milestone 3 - Epidemiological analysis interpreting chemical analysis of POPs in breast milk includ-

ing QA samples will be completed in year 4 and included in main epidemiological incinerators paper – may require further analysis in response to reviewers in year 5. (18/19)

Milestone 4 - Further analyses of POPs in breast milk. (18/19) (dependent on current funding ap-plication to Committee on Toxicity)

Milestone 5 - Paper submission on determinants of POPs in breastmilk, including analysing mother questionnaires. (19/20)

King's staff Imperial staff PHE staffOvnair Sepai No cost

Mireille Toledano No costRA TBC No cost

Theme I/Project 6 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0


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

Theme I total costs – (2018/19 & 2019/20):King’s: Research Salaries £ 0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £ 135,446 Non pay research costs £6,664 Indirect costs £40,634PHE: Research Salaries £ 35,451 Non pay research costs £2,500 Indirect costs £ 7,090

Theme II: Modes of toxicity (Biochemical Pathways from toxin to disease)Lead: Tim Gant (PHE); Deputy lead: David Phillips (King’s)

Theme II/Project 1 – Early life exposures and effectLead: 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 to chemicals using neonatal blood spots and will then use these in in vitro models to assess effects on early life stages such as epigenetic modification.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.

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 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. 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 with whom we are collaborating, 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. For 2020 the resource will transfer to partially fund another experienced full time member of staff (Jinkang Zhang). This project has also benefitted from the addition of a project supported by the Mahidol University Thailand that has provided a clinical DPhil student (University of Oxford) as well as an additional biobank of about 1500 samples with associated clinical information.

Deliverables and milestones Milestone 2 - setting up of ethics and sample collection for a mother child cohort in Thailand.

(18/19). Deliverable 1 - To apply the methods of foetal blood spot metals analysis on up to 500 UK blood

spots to assess foetal exposure. (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 subject to this project obtaining support for the sample collection. (18/19, 19/20)

Deliverable 5 - Analysis of 150 blood and urine samples from mothers in the first trimester and neonates after birth from Thailand for early life exposures to metals and organic. Comparison with the UK samples. (19/20)

Deliverable 6 - If deliverable 1 proceeds well then more samples and some organic analytes will be


http://www.rcog.org.uk/news/rcog-release-mothers-be-should-be-aware-unintentional-chemical-exposures-say-experts

http://www.rcog.org.uk/news/rcog-release-mothers-be-should-be-aware-unintentional-chemical-exposures-say-experts

added for 2019/20. An assessment of progress will be made in 2019 before proceeding to this deliverable. (19/20)

King's staff Imperial staff PHE staffMireille Toledano No cost Tim Marczylo

Jinkang Zhang

Tim Gant No cost

Gwyn Lord

Theme II/Project 1 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £32,677 Non pay research costs £19,400 Indirect costs £6,535

Theme II/Project 2 – ToxicokineticsLead: Tim Gant (PHE) and Tim Ebbels (Imperial)

Project completed 31st March 2018

Theme II/Project 3 – Environmental and Human MicrobiomeLead: 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 I 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 we 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.

A review paper has not been completed as planned in 17/18 and will be carried forward to 18/19. Likewise, the PhD project with Keele University is ongoing.

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. (18/19, 19/20)

Milestone 3 - Obtain two sets of samples from HSE of workers exposed to bioaerosols to analyse for changes in fungal composition and align with the meta data on exposure from air samples from two composting sites. (18/19)

Milestone 4 - Set up and evaluate the feasibility of using an in vitro exposure of bronchial alveolar cells to environmental fungal allergen for modelling allergenic outcomes. (19/20)

Deliverable 1 - A paper detailing environmental fungal exposure and respiratory health using the genomic analysis methods. (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. (18/19)

Deliverable 4 - Evaluation of an in vitro system as a model for allergenic fungal exposures using fungal species identified in deliverable 2. (18/19, 19/20)

Deliverable 5 - Analysis of fungal early-life exposures in a Thailand co-hort and linkage to atopic health outcomes in the children in collaboration with Mahidol Oxford Research Unit. (19/20)


Deliverable 6 - Analysis of a set of human and air samples from HSE for changes to the fungal microbiome and alignment with the meta data on workplace exposure. (19/20)

Deliverable 7 - Paper of analysis of environmental samples from relevant sites such as composing and soil indicating potential human relevant fungal exposures that could lead to disease outcomes. (19/20)

King's staff Imperial staff PHE staffPaul Elliott No cost Emma Marczylo

Anna Hansell No cost Tim Gant No costSameirah Macchiarulo

Theme II/Project 3 costs

King’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £59,243 Non pay research costs £35,000 Indirect costs £11,849

Theme II/Project 4 – Genotoxicity of air pollutantsLead: David Phillips (King’s) and Tim Gant (PHE)

Project completed 31st March 2018.

Theme II/Project 5 - Analysis of the serum and urinary metabolome in relation to air pollutantsLead: Paul Elliott (Imperial) and Frank Kelly (King’s)As part of our work on the exposome, and linking to Theme IV, we are investigating the serum and urinary human metabolome in relation to air pollution. We are using various short-term exposure chamber studies and a population cohort, the US MESA study, which has a rich dataset on the serum metabolome from untargeted analysis of 4,000 samples 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-Air. A MRC project grant has been submitted to accommodate this research.

Deliverables and milestones Milestone 4 - Analysis of cohort data in relation to metabolomics signatures of air pollution expos-

ures. (18/19) Milestone 5 - Analysis of metabolic features associated with air pollutants in relation to cardiovascu-

lar risk factors. (19/20)

King's staff Imperial staff PHE staffFrank Kelly No cost Paul Elliott No cost

Theme II/Project 5 costsKing’s: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0Imperial: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0PHE: Research Salaries £ 0 Non pay research costs £ 0 Indirect costs £ 0

Theme II Project 6 - UVCB GroupingLead: 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. (18/19) 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. (18/19) Deliverable 2 - Consolidation of the phenotype cell data in to a reference paper for publication.

(18/19) Deliverable 3 - Analysis of Temp-O-Seq data and pattern matching with the consortium. (18/19)

King's staff Imperial staff PHE staffAbigail Dalzell No cost

Tim Gant No cost

Theme II/Project 6 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme II/Project 7 – E-cigarette riskLead: Tim Marczylo (PHE) and Tim Gant (PHE)E-cigarettes first appeared in the UK as an import from China in 2006. These were relatively low power and now called first generation devices. Since that time battery and other technological developments have led to the second and third generation devices that are more controllable, have higher power and longer battery life. Furthermore, a large array of different products has appeared to generate nicotine-containing aerosol and cross over products have appeared that use tobacco either as a flavouring or by directly heating the tobacco to release the nicotine and flavours without causing combustion. Those products that contain tobacco have to be notified to PHE as the UK competent authority under the tobacco directive whereas e-cigarettes are notified to the MHRA. These products contain a bewildering array of chemicals as solvents, flavourings sweeteners etc. in addition to nicotine. Some of these flavourings are used by the food industry and will have been tested for oral exposure but not for exposure by the inhalational route. In addition, secondary materials from the e-cigarette need to be considered such as particles and other products formed by thermal degradation of constituents. Despite all of this, e-cigarettes are considered to be a much safer alternative to smoking tobacco. However, a risk potentially remains and this project will contribute to the further assessment of that risk using in vitro methods.

Deliverables and milestones Milestone 1 - Setting up of an analytical system to quantify and characterise particles present in e-

cigarette aerosols. (18/19) Milestone 2 - Exposure of cells in an air liquid interface system to e-cigarette aerosols from various

commercial product sources. (18/19) Milestone 3 - Collection of urine, saliva and blood from human subjects who are users of e-

cigarettes for the analysis of nicotine, nicotine metabolites and other biomarkers of tobacco-use. (18/19, 19/20)

Deliverable 1 - A quantification of the effects of e-cigarette aerosol on cells in vitro using a variety of end point toxicity analyses. (19/20)

Deliverable 3 - An analysis of nicotine, nicotine metabolites and other biomarkers of tobacco-use in human users of these products and assessment of carcinogenic risk. (19/20)

King's staff Imperial staff PHE staffTim Gant No Cost

Tim MarczyloMatthew WrightEmma Marczylo


Theme II/Project 7 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £13,329 Non pay research costs £9,511 Indirect costs £2,666

Theme II total costs – (2018/19 & 2019/20):King’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £105,249 Non pay research costs £62,911 Indirect costs £21,050

Theme III: Health impact of low dose non-ionising and ionising radiation.Lead: Simon Bouffler (PHE); Deputy lead: Mireille Toledano (Imperial)

Theme III/Project1 - Novel human cell model of atherogenesisLead: Ken Raj (PHE)We have demonstrated that ionising radiation (A) causes the apical surface of endothelial cells to become highly adhesive and (B) disrupts the production of junction proteins that hold adjacent endothelial cells together. These features increase the risk of atherosclerotic plaque formation because they facilitate the entrapment and passage of monocytes and LDL across the endothelium into the arterial wall. These findings explain at least in part, the curious epidemiological association between exposure of the heart to ionising radiation and subsequent increased risk of cardiovascular disease. The underlying molecular mechanisms have been elucidated and published: Lowe and Raj (2014) Ageing Cell and Kabacik and Raj (2017) Oncotarget. The next phase of this research programme is predicated on two identified features: (1) pro-atherosclerotic properties are only exhibited by irradiated cells that have become senescent and (2) these properties are not acquired through mutations generated by ionising radiation. The former would suggest that radiation may be particularly detrimental to young tissues, which naturally have very few senescent cells, but it is questionable whether exposure of older tissues, which naturally already have many senescent cells bear equal risk. This is an important health protection question especially in the context of rising use of scans in medical procedures in general and the increasing need for scans among the elderly. Hence, from April 1 2018 to March 31 2020, we will address the question of age effect on radiation risk. Secondly, as the radiation effects described above are not mediated by mutations, we will characterise non-mutational effects of ionising radiation that can potentially affect cell physiology and function. This will inform on whether there may be other non-cancer diseases that could be induced by ionising radiation that are presently not known or appreciated.

Deliverables and milestonesAim (1): To ascertain the influence of age on radiation effectsStrategy: Generate isogenic primary cell banks of different ages

Ascertain ages of cell banks (Measurement of epigenetic clock with multi-tissue age predictor)Irradiation of isogenic cells of different agesMeasure effects of radiation on different age isogenic cells

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

Aim (2): To uncover and characterise non-mutational effects of ionising radiationStrategy: Subject primary cells to ionising radiation

Collect RNA and protein for RNA seq analysis and SILAC analysis respectively Confirm and follow up detected changes and ascertain consistency of changes Elucidate the molecular pathways and mechanisms that underlie the changes

Milestone 5 - Determine and characterise non-mutational effects of ionising radiation. (19/20)

King's staff Imperial staff PHE staffDonna LoweSylwia Kabacik

Theme III/Project 1 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £64,216 Non pay research costs £41,500 Indirect costs £12,843

Theme III/Project 2 - Electromagnetic fields


Lead: Mireille ToledanoThe 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). A biomarker validation study is being conducted in a sub-set (50-100) of SCAMP children. Moreover, personal RF-EMF exposure measurements over a 48-hour study period are taken. In the validation study data include information on phone usage via mobile phone network operators, data from smartphones, 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 is being 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 also conducts exposure assessments in a limited number of school environments of SCAMP cohort participants. Urinary analysis (in collaboration with Theme IV/Project 2) will include, in the first instance, quantification of biomarkers e.g. 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 - Continue recruitment of SCAMP children with specific consent/assent for the

biomarker validation study (see Theme IV). (18/19) Milestone 2 - Exposure monitoring of noise and air pollution and urine sampling for 50-100 SCAMP

children in validation study. (18/19) Milestone 5 - Report on exposure assessment at 5 additional school locations. (18/19) Milestone 7 - Investigation of urinary metabonomics and biomarkers in a sub-set of the validation

study group (see Theme IV). (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. (18/19)

Milestone 9 - Secure Airwave biosample collection, principally by outsourcing. (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. (18/19) 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. (18/19)

Milestone 14 - Contribute to initial analyses of the COSMOS international cohort investigating use of mobile phones and reproductive health outcomes: birth outcomes and time to pregnancy. Lead on analyses for the latter of cardiovascular outcomes. (18/19)

Milestone 15 - Continuation with COSMOS study to provide bridging funding as COSMOS funding from DH finishes in March 2019. (18/19, 19/20)

Milestone 16 - Prepare a manuscript on the effects of TETRA use on long-term and excessive sickness absence in the UK police population using data from Airwave. (18/19)

Milestone 17 - Analysis to evaluate the impact of TETRA use on cancer outcomes using data from Airwave. (18/19)

Milestone 18 - DNA methylation array analysis for ~1200 samples in Airwave. (18/19, 19/20) Milestone 19 - Sending another ~900 Airwave samples for new genotyping (18/19, 19/20). Milestone 20 - Development of an information booklet for schools participating in SCAMP to provide

information on levels of EMF exposure and their origin plus comparison to international guideline levels. (18/19)

King's staff Imperial staff PHE staffMireille Toledano Simon Bouffler No costResearch Asst TBC Simon Mann No costDatabase Manager Myron MaslanyjTBC Darren Addison

Theme III/Project 2 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £159,109 Non pay research costs £40,000 Indirect costs £47,733PHE: Research Salaries £ 13,442 Non pay research costs £ 1,000 Indirect costs £ 2,688

Theme III/Project3 - UV radiation effects on vitamin D sufficiency and blood pressure


Lead: Ken Raj (PHE)The blood pressure study was initiated to test the claims that UV can decrease blood pressure; a claim that is potentially very relevant in health protection. Our own investigations revealed that while UVB (which is very much more damaging to DNA) has no appreciable effect on nitric oxide (NO) production from skin cells, UVA, which is much less DNA-damaging, induces skin cells to produce NO, the most potent vasodilator that is purported to mediate the effect of sunlight on blood pressure. We observed that in addition to keratino-cytes, dermal endothelial cells are highly responsive to UVA in this regard and their location which is adja-cent to smooth muscle cells suggest that they may be primarily responsible for the reported dilation of blood vessel. The route by which this occurs has been elucidated and published (Holliman et al., (2017) Scientific Reports). In the coming period (April 1 2018 to March 31 2020) we will determine the optimal UV dose that is effective for inducing NO production in cells and the dynamics of the process of NO production. This is par-ticularly important if exposure to UVA is to be considered when defining a ‘healthy dose’ of sunlight and if ec-topic exposure to UVA could offer a potential means to mitigate the seasonal increase in hypertension during winter.

Deliverables and milestonesAim (1): To determine the optimal dose of UVA in generating NO productionStrategy: Using filter set specific to different wavelengths within the UVA spectrum, determine the optimal

wavelength that stimulate NO productionEmployment of UVA alone and solar simulator to ascertain the effective dose necessary for NO production

Milestone 3 - Determine the radiation dose that is effective for inducing NO production in cells. (18/19)

Aim (2): To determine the pattern of NO production after UVA / solar simulator exposureStrategy: Using UVA alone (through specific filters) or solar simulator, ascertain the persistence of NO

production and the dose effect on persistence Milestone 5 - Determine the dynamics of NO production by UVA on keratinocytes and endothelial

cells. (19/20)

King's staff Imperial staff PHE staffKen Raj No cost

Graham Holliman No cost

Simon Bouffler No cost

Theme III/Project 3 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme III total costs – (2018/19 & 2019/20):King’s: Research Salaries £0 Non pay research costs £ Indirect costs £0Imperial: Research Salaries £159,109 Non pay research costs £40,000 Indirect costs £47,733PHE: Research Salaries £ 77,658 Non pay research costs £42,500 Indirect costs £15,532

Theme IV: Health effects of noise and air pollution including nanoparticles Lead: Heather Walton (King’s); Deputy lead: Rachel Smith (PHE)

Theme IV/Project 1 – Optimising assessment of health impacts of air pollutionLead: 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. (18/19, 19/20)

Milestone 3 – Finalise 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. (18/19)

Milestone 4 – Resources for calculations for policy scenarios have been reallocated to the responsive work to review air pollution and adverse birth outcomes (Theme IV/Project 9). Alternative funding sources for this work will be investigated.

Milestone 5 - Publish a review and meta-analysis on differences between ambient concentrations and personal exposure only from outdoor sources. Create multiple scenarios for the quantification of bias due to measurement error in multi-pollutant models. (18/19) Publish a report of the workshop on interpretation of multi-pollutant models. (18/19)

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. Develop a methodology for extending snapshot personal exposure monitoring to representat-ive annual mean personal exposure estimates using the previous analysis and outputs from M4. (18/19)

Milestone 7 - Use method in M5 to partition exposure into personal exposure from outdoor and in-door sources utilising a large COPD cohort personal exposure database gathered in 16/17, allowing quantification of measurement error for each pollutant. Correlation between errors and variances of errors, essential for correcting the health effect estimates but currently unavailable in the literature, will also be derived. Regression models of exposure predictors, such as season, participant age, time spent outdoors etc on the errors will be created. (18/19) Extend simulations to the cohort study context using results from M6 on using snapshot personal exposure measurements to represent an-nual mean personal exposure measurements. (18/19,19/20) Extension to personal exposure data-sets in Sweden and China, with contrasting pollution climates, will also be explored. (19/20)

King's staff Imperial staff PHE staffHeather Walton Karen Exley No cost

Klea Katsouyanni No cost

Dimitris EvangelopoulosHanbin Zhang No costBenjamin Barratt No cost

Theme IV/Project 1 costsKing’s: Research Salaries £205,262 Non pay research costs £8,000 Indirect costs £61,579Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme IV/Project 2 – Neurocognitive & behavioural impacts of traffic derived pollutants in childrenLead: Ian Mudway (King’s) and Mireille Toledano (Imperial)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 Theme III/Project 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 via external MRC CLUE funding 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 III/Project 2. (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. (18/19)


Milestone 3 - Enhanced attribution of short term pollutant exposures pollutants (NO2, NOx, PM10 and PM2.5), to the residential address for children undergoing cognitive assessment as part of the SCAMP study will be delivered as part of the CLUE project. This supersedes the previous NOWCAST corrections (18/19). 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 III/Project 2). (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.(18/19)

King's staff Imperial staff PHE staffIan Mudway No cost Mireille Toledano No cost Karen Exley No costBen Barratt No costAna Oliete

Frank Kelly No cost

Theme IV/Project 2 costsKing’s: Research Salaries £32,860 Non pay research costs £6,800 Indirect costs £9,858Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme IV/Project 3 – Nanoparticle Exposure AssessmentLead: Rachel Smith (PHE) and 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. Project finishes end of 18/19.

Deliverables & milestones Milestone 2 – The experimental systems and protocols previously developed in the project will be

used to characterise the airborne aerosol exposures from representative products. (18/19) Milestone 3 – The review of relevant NP aerosol exposure models will be completed. (18/19) Milestone 4 - Completion of paper for publication. (18/19)


Terry Tetley No cost Rachel Smith

Mathew Wright

Theme IV/Project 3 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £9,079 Non pay research costs £4,000 Indirect costs £1,816

Theme IV/Project 4 - Health Impacts; nanoparticles Lead: Terry Tetley (Imperial) and Rachel Smith (PHE)The health risks associated with exposure to engineered nanoparticles (NPs) 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 & milestones Milestone 1 – Studies using A549 cells and organotypic reconstituted 3D human primary small air-


way epithelial (HPSAE) cell cultures exposed to nanoparticle aerosols in an aerosol exposure Air-Li-quid Interface system (AE-ALI), with adverse effects characterised using gene expression and cyto-toxicity assays (lactate levels, LDH): (a) Silver nanoparticle study completed and published; (b) CeO2 NP study completed and paper to be submitted (18/19); (c) Study on SiO2 NPs to be com-pleted and paper submitted (19/20), (d) Comparison of results from earlier studies to identify trends etc. (19/20)

Milestone 2 – The in vitro airway model developed earlier in the project to explore the toxicological impact of nanoparticles relevant for inflammatory respiratory conditions including asthma (HPBE cells in an ALI system) was exposed to diesel exhaust particles (DEPs), CeO2NPs and DEP+CeO2NPs and differences were identified in selected cytokines and gene expression of selected markers after 24hours of exposure. These studies have also included inflammatory and allergen co-exposures. A manuscript will be submitted for publication. (18/19)

Milestone 3 - Extend studies completed in previous years to other nanomaterials in everyday use, e.g. silver, zinc and ceria and others identified by PHE. These studies will use a number of cell lines, including 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, inflam-matory responses and release of pro-thrombotic mediators. Submit papers. (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)

King's staff Imperial staff PHE staffTerry Tetley No cost Rachel SmithAndrew Thorley No cost Martin LeonardLareb Dean Stipend/fees Chang Guo

Theme IV/Project 4 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £ 7,841 Non pay research costs £ 3,000 Indirect costs £2,352PHE: Research Salaries £44,151 Non pay research costs £22,327 Indirect costs £8,830

Theme IV/Project 5 - Improved in vitro systems for evaluating and comparing toxicity of air pollutantsLead: Terry Tetley (Imperial) and 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 (e.g. ALI aerosol exposure) and biological relevance (e.g. 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 & milestones Milestone 2 – Continue pilot studies (commenced in 17/18) examining the toxicity of particle sam-

ples from different combustion sources (initial samples will reflect those currently, or previously em-ployed in human challenge studies in collaboration with the University of Northern Sweden, Umea) This will include characterization of metals in the particle samples. (18/19, 19/20)

Milestone 3 – Develop a research proposal for submission to the Wellcome Collaborative Award in April 2018 for a programme of experimental work comparing contrasting pollutants (via exposure to respiratory tract lining fluids or relevant reaction products), across cell systems representing respirat-ory zones and gas-blood compartments of the lung (bronchial/alveolar/endothelial), and more com-plex 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. (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 pro-posal or for separate Royal Society blue skies funding, or funding of ageing research. (18/19)

Milestone 5 – Commence work proposed in milestones 2/3, subject to obtaining funding. (18/19, 19/20)

Milestone 6 – Develop other funding proposals. (18/19, 19/20)



Heather Walton No cost Andrew Thorley No cost Rachel Smith No costIan Mudway No cost Terry Tetley No cost Martin Leonard No cost

Lareb Dean No cost Chang Guo No cost

Theme IV/Project 5 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £8,310 Indirect costs £0

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)

Project completed 31st March 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)Transport interventions have an important role in reducing air pollution concentrations. Transport interventions within cities are also important for the Environmental Change HPRU, Theme II 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, land use 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 and external funding needs to be sought for later work in 18/19. Some external funding for HW may be available for estimating the proportion of air pollution emissions and concentrations from car trips taking children to school in a London local authority (confirmation end January).

Deliverables and milestones Milestone 1- Develop a protocol for a project addressing health impacts of school travel plans.

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

studentship in 18/19. (18/19, 19/20)

King's staff Imperial staff PHE staffHeather Walton No cost Anna Hansell No cost Karen Exley No cost

Dimitris Evangelopoulos No cost Sarah Robertson No costKlea Katsouyanni No cost

Ben Barratt No cost

Theme IV/Project 7 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme IV/Project 8 – Association between primary mental health outcomes with air pollution in urban populations. Lead: Ian Mudway (King’s) and Ioannis Bakolis (King’s)The Clinical Record Interactive Search (CRIS) system has been developed for use by the NIHR Maudsley Biomedical Research Centre and Dementia Biomedical Research Unit at the South London and Maudsley (SLaM) NHS Foundation Trust. CRIS provides authorised researchers with regulated access to a wide range of pseudonymised information extracted from the SLaM electronic clinical records system 2008 onwards –


250,000 cases. Mental health outcomes included in the CRIS database are antipsychotic and antidepressant usage, first episode or diagnoses of anxiety, dementia, depression, schizophrenia, schizotypal and delusional disorders, as well as linked mortality and hospital outcomes. In this project we will employ an open cohort approach including all individuals with a first diagnosis on a mental health outcome. We will define an event as a dispensed medication or adverse mental health episode at least once during follow-up. Each cohort member will be followed up until an event occurs, loss-to-follow-up (meaning that they had no longer a registered address in the study area), death, whichever came first. Cox regression models assuming proportional hazards, with time as an underlying variable will be employed and Hazard Ratios and their 95% CIs will be provided. Exposures (PM10, PM2.5, NO2, NOx) will be analysed as continuous variables, as ratios associated with interquartile range pollutant increases. All models will be adjusted for age at the start of follow-up, sex, education level, body mass index, smoking and socio-economic indicators (e.g. Index of Multiple Deprivation).

Deliverables and milestones Milestone 1 – Complete linkage with patient records for the period 2008-2012, with quarterly

estimates for each year. (18/19) Milestone 2 – Examine the association between air pollution and cognitive decline in dementia.

(19/20) Milestone 3 – Examine the association between air pollution of schizotypal and delusional disorders.

(19/20) Milestone 4 – Examine associations between historic air pollution exposures and incidence of ASD.

(19/20)

King's staff Imperial staff PHE staffIan Mudway No cost

Ioannis Bakolis No cost

Klea Katsouyanni No costSean Beevers No costDylan Wood No cost

Theme IV/Project 8 costsKing’s: Research Salaries £0 Non pay research costs £0 Indirect costs £0Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme IV/Project 9 – Responsive Work - Review of air pollution and adverse birth outcomesLead: Julia Fussell (King’s) and Heather Walton (King’s)

The fundamental causes of adverse birth outcomes are not well understood, despite growing evidence that environmental factors may play an important role. Air pollution is one of the most likely environmental factors and evidence of adverse health effects of ambient air pollution has risen dramatically in recent years. An increasing number of studies have shown that maternal exposure to air pollution can affect the developing foetus, resulting in adverse birth outcomes such as infant death, still birth, term low birth weight, preterm birth, and small for gestational age.

To further understanding of the association between air pollution and birth outcomes, we will collect all data presently available and conduct a quantitative meta-analysis on the relationship between PM2.5 exposure and term low birth weight or preterm birth (and other birth outcomes if the evidence base is sufficient).

Deliverables and milestones Deliverable 1 – Produce report of findings (October 2018)

Theme IV/Project 9 costsKing’s: Research Salaries £24,000 Non pay research costs £0 Indirect costs £7,200Imperial: Research Salaries £0 Non pay research costs £0 Indirect costs £0PHE: Research Salaries £0 Non pay research costs £0 Indirect costs £0

Theme IV total costs – (2018/19 & 2019/20):King’s: Research Salaries £262,122 Non pay research costs £14,800 Indirect costs £ 78,637


Imperial: Research Salaries £ 7,841 Non pay research costs £ 3,000 Indirect costs £ 2,352PHE: Research Salaries £ 53,230 Non pay research costs £34,635 Indirect costs £ 10,646


environmental exposures and health – nihr - best...

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