Colt Foundation Day 2012

Colt Foundation Day 2012 was held on Wednesday 24th October 2012 at the Royal Society of Medicine in Wimpole Street with over 80 delegates attending. The presenters have all been recipients of grants from the Colt Foundation.

Professor Sir Anthony Newman Taylor CBE FRCP FFOM FMedSci
Imperial College

Professor Sir Anthony Newman Taylor, Chairman of the Colt Foundation, opened the meeting. He spoke about how the Foundation was initially set up by the O’Hea family with a gift of shares in the family-owned business, Colt International Limited, to promote and encourage research into social, medical and environmental problems created by commerce and industry. The current fund, which is made up of listed investments as well as the Colt shares, is valued at close to £17 million. Since 1978 the Foundation has awarded grants of almost £14 million to over 200 different projects, with support for more than 220 students studying some aspect of occupational or environmental health.

Tony also spoke about the Foundation’s support for a number of relevant meetings, including the British Occupational Hygiene Society (BOHS), British Association for Lung Research (BALR), Epidemiology in Occupational Health (EPICOH), Royal Society of Medicine United Services Section – Research in the Military, UK & Ireland Occupational and Environmental Epidemiology Meetings, Nanotoxicology 2010, and most recently Workplace Health 2012 in Birmingham in November 2012.

He described grants awarded for capacity building in Universities as centres of excellence through research programmes, staff and laboratory refurbishment, and explained that up to ¼ of the annual sums awarded are for the benefit of students. The Foundation will continue to address important health challenges of workplace and environmental health in the UK, and on occasion abroad, through project grants, programme grants and PhD studentships, with strategic consideration as income allows.

Presentations

Presentations were then heard from the following:

Professor Raymond Agius from the University of Manchester
Professor John Barbur from City University London
Professor David Coggon from the MRC Lifecourse Epidemiology Unit in Southampton
Professor Paul Cullinan from the NHLI at Imperial College London
Professor Ken Donaldson from the University of Edinburgh
Professor Keith Palmer from the MRC Lifecourse Epidemiology Unit in Southampton
Dr Craig Poland from the Institute of Occupational Medicine in Edinburgh
Professor Peter Robbins from Oxford University 
Dr Pam Sonnenberg from University College London

Professor Raymond Agius MD DM FRCP FRCPE FFOM
Centre for Occupational and Environmental Health, Faculty of Medical and Human Sciences, University of Manchester
Quantitative structure activity relationships (QSAR) in occupational asthma

Raymond Agius, Martin Seed, James Jarvis, Nazia Zarin
 
Raymond Agius is Professor of Occupational Medicine and Director of the Centre for Occupational and Environmental Health, as well as Leader of the Centre for Epidemiology in the Institute of Population Health at the University of Manchester’ s Faculty of Medical and Human Sciences.

Study of the relationship between the structure of a chemical and its propensity to cause asthma is important for three reasons: it could help screen thousands of chemicals, rapidly, reliably and economically to determine respiratory sensitisation potential; it may assist in the investigation of possible cases of respiratory sensitisation where there may be many potential causal chemicals in the workplace; finally, it may help as a ‘model’ to help medical science understand better the causation of asthma.

By collecting data on low molecular weight (LMW) chemicals which cause asthma as well as ‘controls’ which probably do not cause this disease, a database of hundreds of detailed chemical structures has been built up. Through statistical analyses (mainly calculation of odds ratios, and logistic regressions) it has been possible both to determine what chemical structures are more likely to be associated with an asthma hazard, as well as to generate a predictive ‘asthma hazard index’ for a LMW chemical whose structure is known.

The research has shown that the high negative predictive value of the QSAR means that it can be used at least for the initial screen for asthmagenicity of Low Molecular Weight (<1000) organic chemicals by excluding those unlikely to be asthmagens. Where there is a high prior probability of asthma (as in cases presenting clinically) the QSAR exhibits good positive and negative predictive values and therefore can be clinically useful. The QSAR has been made freely available on line and has been evaluated both with external data sets, and through feedback from several users.
 
http://www.medicine.manchester.ac.uk/oeh/research/workrelatedillhealth/asthma/

Professor John Barbur BSc ARCS MSc DIC PhD
Applied Vision Research Centre, The Henry Wellcome Laboraties for Vision Sciences, School of Health Sciences, City University London
Variability within human colour vision with consequences for occupational environments

John Barbur is Professor of Optics & Visual Science and Director of the Applied Vision Research Centre at City University London.

Colour assessment has become of great interest in recent years because of the need to quantify severity of loss in congenital deficiency with relevance to occupational environments, and also for its increased use in the very early detection and monitoring of retinal disease in older people. Many jobs require applicants to have normal colour vision, which prevents anyone, often with even mild, inherited loss of colour vision from entering the profession. The talk focused on recent, significant advances in the isolation and measurement of colour signals and the improved understanding and description of the inherent variability in both “normal” trichromacy and in congenital deficiency. The outcome of this research was to develop a new approach to colour assessment and to establish objective colour vision requirements within selected occupations which ensure that all applicants that can carry out the most demanding, colour-related tasks with the same accuracy as people with normal colour vision pass and are therefore not discriminated against on the basis of their congenital colour vision deficiency. 

Professor David Coggon OBE MA PhD DM FRCP FFOM FFPH FMedSci 
MRC Lifecourse Epidemiology Unit, University of Southampton
How can we best prevent common musculoskeletal illness and disability in people of working age?
 
David Coggon is Professor of Occupational and Environmental Medicine at the MRC Lifecourse Epidemiology Unit, University of Southampton. His main research interests are the relation of work to musculoskeletal disorders and the health risks from chemical hazards in the workplace. In addition, he has a major interest in the translation of research into policy.

Speaking at Colt Foundation Day, David talked about common musculoskeletal illness and the scale of the problem, pointing out that this is the single biggest cause of incapacity for work in Europe, with direct costs amounting to up to 2% of gross domestic product. He described studies on carpal tunnel syndrome and the CUPID study - cross cultural study of musculo-skeletal and other somatic symptoms and associated disability.

His conclusions from this work were that non-specific musculoskeletal symptoms should be distinguished from those which arise from specific pathology: that occupational physical activities are only one of many influences, whose effects are importantly modified by other circumstances: that socio-economic factors contribute, but the variables examined in the CUPID study still leave much variation unexplained: and that it is prudent not to exaggerate the dangers of occupational activities.

Professor Paul Cullinan MB MSc MD FRCP FFOM
National Heart and Lung Institute at Imperial College
Atopy in Polish villages and the Common Agricultural Policy

Paul Cullinan has a chair in Occupational and Environmental Respiratory Disease at the Department of Occupational and Environmental Medicine at Imperial College London (National Heart & Lung Institute) and is consultant in Respiratory Medicine at the Royal Brompton Hospital.

About ten years ago, while I was minding my own business running the COLT Foundation ‘Asthma in Ashford’ study, I had an unexpected telephone call from a young doctor in Poland. Barbara Sozanska, a paediatric allergist in Wroc?aw, had learned of our work in Ashford (and a number of spin-off studies in other parts of Europe) and, she told me, wanted to do some similar research herself.
Wroc?aw is in lower Silesia, currently the south western corner of Poland. It is a very beautiful city and I have a soft spot for Poland so I agreed to meet Barbara there and discuss a joint project. As a result, in 2003 and on a shoe-string, she and I organised a comparative survey of the prevalence of allergy in the inhabitants of a small town (Sobotka) some 50km south of the city and in a number of very small, nearby villages. The findings were remarkable. Among the villagers, the prevalence of atopy (‘allergy’) was just 5%, the lowest figure ever recorded and invariant across all ages. In contrast, among the townspeople of Sobotka, atopy was as prevalent as it is in the UK which itself has one of the highest rates in the world; as in Britain the prevalence was especially high (35%) in young.
Why was atopy up to seven times less common in the villages than in Sobotka? The contrast cannot be explained by differences in the gene pool and nor, easily, by differences in say exposures to ‘pollution’ of which there isn’t any. We postulated that there was something protective about a village life and that this probably derived from a farm-related exposure most likely, by analogy with studies of Alpine farm children, related to the keeping of dairy cows. We wrote up the findings in the journal Allergy (http://www.ncbi.nlm.nih.gov/pubmed?term=sozanska+B%5Bfirst+author%5D&cmd=detailssearch) and suggested that here in rural Silesia was a snapshot of a contrast and process that had been evident across Europe for decades and possibly longer.

This was 2003. At that time most of the village families lived off smallholdings, each with a couple of cows, a pig or two and a handful of chickens and rabbits; most families drank unpasteurised milk. In many respects this was a way of life enjoyed or endured by millions of central Europeans for a thousand years.

The following year everything changed. In 2004 Poland acceded to the European Union and adopted the Common Agricultural Policy. Among other things, this latter enforced standards of animal husbandry designed to protect the health of consumers which effectively made Silesian smallholding impossible to sustain. Within just 18 months almost all of the villagers we had studied stopped rearing and tending large farm animals; the number of cows in the seven study villages, for example, fell from 295 to just 58, a reduction of 80%. Very few people now drank unpasteurised milk. As a local farmer put it, wryly “We had survived Communist efforts to collectivise us so we thought we would survive this. We didn’t realize that the European Union would be even harder”.

In 2012 Barbara and I decided to repeat the survey using exactly the same methods as before and with a small grant from the Polish government. Allowing for the nine year interval, we found exactly the same prevalence of atopy in the people of Sobotka. Remarkably, this time the figures for the village population were indistinguishable from those of the town. In a very short period, it seemed, all had changed.

What do these findings mean? First, they demonstrate that the institution of a well-meaning agricultural policy can wipe out a centuries-old way of rural life almost overnight. Second, they indicate that the trait of (non-)atopy is plastic and that it is plastic at all ages, a concept that many will find surprising. Third, they suggest that the removal of a protective factor, if that is what has happened, can have a detrimental effect in a remarkably short period of time.

Whether all of this can be tied together remains speculative still but it is surely intriguing to consider whether we witnessed an example of rapid ‘westernisation’ and of the ‘hygiene hypothesis’ almost in real time.

Poland, Wroclaw, Sobotka and surrounding villages
Milking the family cow in 2003. Practices such as this are virtually impossible under EU regulations.

Professor Ken Donaldson BSc PhD DSc FIBiol FRCPath FFOM
University of Edinburgh
The structure:toxicity relationship; the magnum opus of particle toxicology

Ken Donaldson is the Scientific Director of the ELEGI Colt Laboratory in the Queens Medical Research Institute at the University of Edinburgh where he is Professor of Respiratory Toxicology.

Alchemists undertook the search for the philosopher’s stone that would turn base metal into gold, as their magnum opus, or great work. Knowledge of the relationship between the structure of a toxin and its toxic potency and action is, in one sense, the ‘philosopher’s stone’ of toxicology that would unlock a number of insights into particle effects and their amelioration. Particles are no different from other toxins in this sense but the fact that they are structurally more complex, diverse and heterogeneous than chemical toxins makes elucidation of the structure:toxicity relationship (STR) more difficult. STR has a number of applications including the selection of metrics, the design of safe particles and the determination of when a particle can be considered to be ‘new’ for regulatory purposes. The Biologically Effective Dose (BED) is a useful concept in STR being defined in particle toxicology as the entity within any dose of particles in tissue that drives a critical pathophysiogically-relevant form of toxicity (e.g. oxidative stress, inflammation, genotoxicity or proliferation) or a process that leads to it.

In conventional chemical toxicology, researchers generally use the mass as the metric to describe dose (such as mass per unit tissue or cells in culture) because of its convenience. Concentration, calculated from mass, may also figure in any description of dose. In the case of a particle dose, mass is the metric generally used although an exception exists in fibres, which are counted by number; however mass is not a BED. BEDs of particles include the following:-

1) The surface area of insoluble particles, which is the only part of an insoluble particles that interacts with the biological systems

2) Soluble and partially soluble particles can release factors that interact with biological systems e.g. copper or zinc ions. Rapid dissolution of these NPs into toxic ions in the acidic environment of the macrophage phagolysosome causes these ions to accumulate, which leads to lysosome destabilization and inflammation. In contrast, soluble NPs that release low toxicity ions, such as magnesium oxide NPs, are not toxic.

3) For insoluble NPs their charge, measured by zeta potential can serve as a BED because the exposure of the particle surface to the acidic milieu of the phagolysosome can compromise the integrity of cell through charge interactions with the lysosomal membrane.

4) Oxidative potential of NP has been extensively explored as an indicator of the BED: the ability of an NP to cause oxidative stress in cells is a key factor in determining cell toxicity, inflammogenicity and oxidative DNA adduct formation.

5) High aspect ratio nanoparticles such as long fibres or extended platelets can cause problems as a consequence of their paradoxically small aerodynamic diameter but large size. As a result, these NPs can deposit beyond the ciliated airways, where their extended dimensions prevents them being fully phagocytosed by macrophages, leading to frustrated phagocytosis.

Many questions and challenges remain in understanding the BEDs and STRs for particles but a sound understanding will yield great benefits in understanding and controlling adverse health effects mediated by particle exposure.

Professor Keith Palmer DM MA MSc BM BCh FFOM FRCP MRCGP DRCOG
MRC Lifecourse Epidemiology Unit, University of Southampton
Metal fume and infectious pneumonia

Professor Palmer is an occupational epidemiologist and is Professor of Occupational Medicine at the University of Southampton, and consultant occupational physician based at the University Hospital Southampton Foundation NHS Trust.

At Colt Foundation Day 2012, Keith spoke about metal fume and infectious pneumonia and the strong association between welding and pneumococcal disease. Research in Southampton has established that welders and other workers exposed to metal fumes die more often from certain types of pneumonia, in particular lobar and pneumococcal pneumonia and are also more likely to develop pneumonia serious enough to need hospital in-patient care [1-3]. The risk is reversible once metal fume exposure stops. Attention has now shifted to potential mechanisms and establishing a biomarker of the hazard which can be used to define safer exposure levels and monitor risk controls. Keith noted that although fatal cases are rare, they are potentially preventable if exposed workers are vaccinated. Mainly on the strength of this research, the Department of Health recommended in 2011 that exposed workers should receive the PPV vaccine. Companies are advised therefore to ensure that workers who undertake welding or are exposed to metal fumes are offered the vaccination [4].

References

Coggon D, Inskip H, Winter P, Pannett B. Lobar pneumonia: an occupational disease in welders. Lancet 1994;344:41-44.
Palmer KT, Poole J, Ayres JG, Mann J, Sherwood Burge P, Coggon D. Exposure to metal fume and infectious pneumonia, Am J Epidemiol 2003;157: 227-233
Palmer KT, Cullinan P, Rice S, Brown T, Coggon D. Mortality from infectious pneumonia in metal workers: a comparison with deaths from asthma in occupations exposed to respiratory sensitizers. Thorax 2009; 64: 983-6.
Palmer KT, Cosgrove M. Vaccinating welders against pneumonia. Occup Med 2012; 62: 325-330.

Dr Craig A. Poland BSc (Hons) MSc PhD MSB
Institute of Occupational Medicine, Edinburgh
Maximising the impact of Toxicological research: Good Science is not Enough

Craig Poland is a research toxicologist within the SAFENANO section at the Institute of Occupational Medicine based in Edinburgh.

The aim of this talk was to show, using a case study of own experience, how the impact of basic research can be increased by maximising the coverage it receives. Our research was looking at the link between carbon nanotubes and other fibres but specifically asbestos fibres. We obtained very interesting results and were looking to publish our findings in the conventional way in Nature Nanotechnology, i.e. submit to a journal, hopefully get it accepted and into print – job done. However we were encouraged by a Colt trustee (Prof David Coggon) after presenting our findings at a Colt Student day to speak to a few people about our findings. This led us to informing various bodies about our work and giving presentations to the HSE, DEFRA and the Working Group on Action to Control Chemicals as well as the Nanotechnologies Industry Association (NIA).

As the publication of our article approached, we spoke to the Science Media Centre (http://www.sciencemediacentre.org) and with them we organised a press event to discuss our findings and answer any questions to give a balanced, non-alarmist overview of our work. This resulted in relatively high press coverage around the world but the important long term effect was to get our work discussed which did happen at high levels such as the House of Lords enquiry, the International Organization for Standardization (ISO) TC 229 (Nanotechnologies) as well as HSE publishing a guidance document on the safe handling of nanofibres – something which was of immediate benefit to workers and UK industry. This impact did not occur because we were the first to make the link between carbon nanotubes and asbestos or report findings of toxicity (we weren’t); it was simply because we tried a different way of putting our work out there to maximise its impact on worker health. Within the talk, we gave the following points on what we learned:

Good science is crucial – But so is getting the message across
Work with your press office 
Work with people outside your field to get the message to the right ears (i.e. those who can affect a difference) such as those governmental departments etc. 
Overall we wanted to show that good science and publishing that science is incredibly important, but as part of that, interaction with a University press office and/ or bodies such as the Science Media Centre can help reach a far wider audience. The implications of this are simple – the more people who read about it, the more people who can potentially take that work further or use that work to help people either through more fundamental research, providing funding for other research or, as in our case, providing guidance and discussing safety implications of exposure.

Professor Peter Robbins MA DPhil BBM BCh
Department of Physiology, Anatomy and Genetics, University of Oxford
The potential importance of iron status to working at high altitude

Professor Robbins is Professor of Physiology and Head of the Department of Physiology, Anatomy and Genetics at the University of Oxford.

Minerals form a very significant part of a number of South American countries, and for Peru and Chile comprise over half of their exports. Mining is relatively high risk occupation, and as much of the mineral extraction for these countries occurs high in Andes, exposure to high altitude adds a further complication. In particular, high-altitude exposure disrupts proper sleep, generates fatigue and malaise, it is associated with headaches, it causes dehydration and anorexia and it is associated with marked breathlessness and limited ability to undertake manual tasks. Relatively recent work searching for signals of selection within the genomes of high-altitude adapted populations – particularly Tibetans – has uncovered significant selection within the hypoxia-inducible factor transcriptional pathway. The selected variants appear to down-regulate the pathway, as if to compensate for the presence of environmental hypoxia. An intriguing feature of the hypoxia-inducible pathway is that it is very iron sensitive, such that iron deficiency mimics the effects of hypoxia. This raises the possibility that the mal-adaptive effects of environmental hypoxia could be, at least to some degree, offset by modest increases in iron availability so as to mimic the down-regulated pathway of the Tibetans. In support of this proposition, physiological experimentation on humans has shown that iron infusion significantly reduces the pulmonary hypertension associated with exposure to hypoxia. Our on-going work with the Colt foundation is first to explore the relationship between iron loading and the commonly used indices of iron status, and, secondly, to explore whether the reduction in hepcidin with hypoxia – hepcidin is the major hormone regulating iron homeostasis – could make oral iron administration a viable route for modulating iron status in high-altitude workers.

Dr Pam Sonnenberg MBBCh DTM&H DPH MSc PhD FFPH
University College London
Making a difference as an academic: experience from working on TB and HIV in South African miners

Pam Sonnenberg trained in medicine, clinical infectious diseases and public health in South Africa before coming to the UK, and is now Reader in STI/HIV epidemiology in the Research Department of Infection and Population Health at UCL.

Speaking at the Colt Foundation Day, Pam explained how research on HIV and pulmonary tuberculosis (TB) in South African gold and platinum miners is making an impact across the mining community and beyond. Pam presented data from several Colt Foundation funded cohort studies on HIV and TB prevalence among miners before and after the widespread introduction of antiretroviral therapy (ART) in 2003. The results have been extensively published in leading academic journals https://iris.ucl.ac.uk/research/personal?upi=PSONN00

The focus of her presentation, however, was on the challenge for any academic – how to make a difference in the real world. ‘For research to have a higher chance of making a difference it has to answer an important question and needs to follow rigorous science,’ she said. The approach should be multidisciplinary and be ‘translational – from bench, to bedside to behaviour’. But, as the HIV and TB studies demonstrate, it can take many years of sustained intervention to tackle these huge problems. ‘Making a difference is a marathon not a sprint!’.