The Health and Occupation Research NetworkTHOR ( UK & Republic of Ireland )

Prof Raymond AgiusCentre for Occupational & Environmental Health

The University of Manchester

Methodologies to identify work-related diseases:Review of sentinel and alert approaches

The European Agency for Safety and Health at Work (EU-OSHA) Workshop – Brussels

18th May 2017 v3

To outline and discuss, with reference to THOR:

• The drivers for sentinel approaches / monitoring systems

• An outline description of relevant THOR schemes and methods, with illustrations (limited to chemicals in this presentation) of:

sentinel monitoringalert function

• Consideration of strengths / weaknesses, obstacles, challenges, and potential solutions

• The link with prevention

• Open debate

Objectives and structure of the presentation

• Original drive was to estimate incidence (and trends in incidence) of WRDs (funded by the UK Health and Safety Executive.)

However this evolved to incorporate sentinel approaches to detect new causes of WRDs, with a view to generating alerts, further investigation and prevention.

• Need to keep up with the EU (e.g. for the Republic of Ireland’s Health and Safety Authority)

• Physicians’ motivation and perceived needs are crucial to THOR’s success:– especially occupational physicians, respiratory physicians and dermatologists

Drivers for THOR sentinel approaches/monitoring systems and alerts for new work-related diseases (WRDs)

The Health and Occupation Research Network (THOR)

• Research & surveillance ‘medical observatory’ - originally for measuring the incidence and determinants of occupational disease / WRDs( but later extended e.g. sentinel reporting, sickness absence burden)

• Started in UK with 1st scheme in 1989: SWORD

• Currently >1000 doctors participate in UK & ROI reporting incident cases (either every month or as a sample for 1 random month p.a.) -> Hence estimate of annual cases

• Reports from clinical ‘system’ specialists account for an estimated 5,000 new UK cases of work-related ill-health per annum.

• Reports from OPs and GPs account for a further estimated 10,000 UK cases per year

OPRAOccupational Physicians

Reporting ActivityOccupational PhysiciansMOSS

Musculoskeletal OccupationalSurveillance Scheme

Rheumatologists

THOR-EXTRA*Special reports outside theIncidence Sampling Frame,

&/or extra data

SIDAWSurveillance of Infectious

Diseases At WorkConsultants in Communicable

Disease Control

EPIDERMOccupational Skin Surveillance

Dermatologists

SWORDSurveillance of Work-related &

Occupational Respiratory DiseaseChest Physicians

SOSMISurveillance of Occupational

Stress and Mental-illness

Psychiatrists

The Health and Occupation Reporting (THOR) network

THOR-GPTHOR in General Practice

General Practitioners

Surveillance networks

Example

General Practitioners

The Health and OccupationResearch Network inGeneral Practice

THOR-GP

(Map shows GB onlyBut reporters also in Ireland)

Recognised in primary care

Unrecognised in primary care

Symptomatic health effects

Asymptomatic health effects

Self reported WRI

THOR-GP

THOR

The work-related ill health Sentinel surveillance pyramid

Specialist diagnosis

Incidence rate per 100,000 persons employed for work-related musculoskeletal, mental, skin and respiratory ill-health (2006 to

2009) as reported by clinical specialists, GPs & self-reports

0 200 400 600 800

Self-reports

GPs

Clinical specialists

Incidence rate per 100,000 persons employed per annum

Respiratory

Skin

Mental ill-health

Musculoskeletal

• Generally highly motivated participating physicians nurtured by:– Generic feedback (quarterly report)– Specific feedback (answers to queries)– Consultation (advisory meetings etc)– Continuing Professional Development esp. EELAB(Electronic, Experiential Learning, Audit and Benchmarking)

• Particularly good for respiratory and skin disease– System specialists– Occupational Physicians– ( GPs )

Specific features of THOR that make it work with regard to the identification of new WRDs

Same doctors in THOR schemes which measure incidence but for:• Reporting sentinel cases outside the usual incidence sampling period• Detailed exposure and other data collection (e.g. non-occupational)

THOR-extra

Dermatitis – from trends in incidence to finding new causes

Incidence trends overall

> Trends with specific work practices, or

> Trends for specific classes of agents

> New causes

Relative risk by year (2015=1) (95% CI) of contact dermatitis as reported to EPIDERM (dermatologists) and OPRA (occ. physns.)

Estimated annual change (1996-2015)

EPIDERM: -3.8% (95% CI: -4.3%, -3.3%) OPRA: -7.4% (95% CI: -8.8%, -6.0%)

Estimated annual change (2006-2015)

EPIDERM: -3.9% (95% CIs: -5.3%, -2.4%) OPRA: -2.9% (95% CI: -6.5%, +0.8%)

0

1

2

3

4

5

6

7

8

Rel

ativ

e ra

te

Year

EPIDERM

OPRA

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

2015 incidence rate per 100,000 employed

0

5

10

15

20

25

EPIDERM OPRA

Trends in Irritant Contact Dermatitis attributed to hand hygiene in healthcare workers

Work and Methyl(chloro)isothiazolinones

Group Total number actual cases

Average annual percentage change and 95% confidence intervals

Personal care exposures 136 +3.8% (-0.3 to 8.0)Healthcare workers 63 8.1 % (2.1 to 14.4)Beauty workers (including nail technicians) 25 6.6% (-2.2 to 16.2)Hairdressers 48 1.5% (-4.7 to 8.1)

Detergent exposures 10Cleaners 10 Insufficient numbers

for analysis

Industrial exposures 133Painters (or paint mentioned as a causal agent) 15 Insufficient numbers

for analysisManufacturing 118 6.3% (1.8 to 10.9)

Other (range of occupations) 79 Insufficient numbers for analysis

Total 358 4.1% (1.4 to 6.9)

Contact Dermatitis 2015; 25: doi: 10.1111/cod.12379.

Average annual percentage change in reported incidence in work-related contact dermatitis attributed to MCI/MI and or MI, 1996-2012

Relative rates by year (95% CI) of Allergic Contact Dermatitis reported by dermatologists attributed to fragrance versus

not attributed to fragrances (all occupations)

Group Average annual percentage change and 95% confidence intervals p*Attributed to fragrances Not attributed to fragrances

Health and social care 0.4 (-2.6, 3.6) -8.3 (-9.9, -6.7)

Preliminary analysis of number of actual cases of Allergic Contact Dermatitis by fragrance ‘type’, reported by

dermatologists to EPIDERM, 1996-2015

0 100 200 300 400 500 600

Eugenol

Cinnam*

Lyral

Limonene

Linalool

Perfume

Essential oils/plant oils

Balsam

Fragrance

Number of actual cases

Each case may be attributed to more than one agent*e.g. cinnamyl alcohol, cinnamaldehydeLyral is Hydroxymethylpentylcyclohexenecarboxaldehyde

n = 808

List of cases of possible interest

reviewed by specialist research

occupational physician

Cases reported via report card or

webform

Increasing the signalof THOR reports

Data coded (occupation,

industry, substance etc.) by 2 project

assistants

Each quarter new cases are scanned for

substances of interest (possible novel causes or workplaces, unusual

clusters etc)

Action taken on cases thought

significant

Highlighted in quarterly report

Contact physician who reported the case for further

details Reporters of similar cases put in contact

with each other

((( )))

Coding discrepancies

reconciled by a third party

‘New’ = new causal agents + rare + new{agent+job/task+agent}

Skin:

• Allergic contact dermatitis in veterinary laboratory worker using limonene for histopathology

• Dermatitis caused by isocyanate exposure in vehicle paint sprayers

• Contact urticaria from cannabis exposure in a forensic scientist

Systemic / skin:

• Scleroderma caused by perchlorethylene in a factory worker in the manufacture of chemical and chemical products

Examples of ‘new’ WRD identified in THOR - 1

Cases of occupational asthma attributed to latex exposure reported to SWORD (1991-2014)

DISEASE > Agent > Job / task

ASTHMADiisocyanates

Car spray painterGlueing ***

FlourBaking

Denatonium***

PNEUMOCONIOSISSilica Stone mason

Chemical engineer***

BRONCHIOLITIS ***

*** = Special focus ? new disease or ? new cause

Extracts of example of hierarchy of searching

‘New’ = new causal agents + rare + new{agent+job/task+agent} Lung:• Chemical pneumonitis caused by silicone waterproofing spray in

boat repair• Alveolitis from spraying fabric protector (? silicone) in furniture

manufacturer• Lipoid pneumonia from spray mount glue in a graphic designer• Non-malignant pleural disease in process operator exposed to

marinite (? cryptic asbestos)• Bronchiolitis (? ketone peroxides) in boat laminator• Asthma caused by heated triglycidyl isocyanurate (TGIC), a

hardening agent used in powder paints.• Asthma / Type 1 allergy due to denatonium benzoate in a nurse

testing PPE for bio-protection• Asthma from cyanoacrylates in forensic fingerprint specialists*• Asthma from isocyanates in funeral wreath manufacturers*

(* disproportionality analysis by Prof Bonneterre)

Examples of ‘new’ WRD identified in THOR - 2

QSAR = a statistical analysis of chemical substructures associated with biological activity.

Example of corroborating evidence:Quantitative Structure Activity Relationships (QSARs)

Internal Validation

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Haza

rd

Asthmagens n=78

Controls n=301

Chart4

1.4893607009

1.2953168582

1.1270975962

1.4812692214

1.3948026032

1.3778326872

1.9258978144

1.150908134

1.6156243809

1.5841339764

1.9447570969

1.6967689175

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1.7913759903

1.1908149124

1.6320142458

1.1097162561

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1.6999115982

1.337355165

1.4895131157

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1.5446986172

1.7154877815

1.3572858985

1.0880432982

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1.3677680491

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1.9271222257

1.3806599842

1.8245676486

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1.9646595153

1.7585359449

1.5415192364

1.0317796372

1.7494399369

1.9668427478

1.9344939651

1.6055640649

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1.0187403966

1.6146818039

1.9648607256

1.1624329643

1.2317566986

1.8868818527

1.3846622588

1.3962608768

1.8292619644

1.7525116443

1.9356459486

1.9645262696

1.0216595717

1.5789778333

1.1188781141

1.3911746664

1.596929376

1.9768467358

1.0842247315

1.2336140496

1.6468885784

1.6785285814

1.5615265509

1.9905251404

1.198155941

1.6830316855

1.0896066294

1.3338046132

1.815780596

1.476429698

1.8026049506

1.1637958108

1.0587419102

1.6719291826

1.5816058543

1.1462679598

1.661350132

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1.2088299188

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1.1881083674

1.640693703

1.8358283121

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1.5607908447

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1.4410415227

1.475854471

1.4031294065

1.9303421023

1.4940548675

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1.9413565113

1.2558171408

1.7589527206

1.7076998859

1.7156114866

1.6659230602

1.789391021

1.9876526649

1.4731977327

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1.3236408001

1.6423884429

1.6067879764

1.0853438307

1.2697651012

1.3214469303

1.7259172484

1.9774876082

1.5615266134

1.5269914945

1.2637946002

1.3961315388

1.9302795574

1.1476640055

1.9981204039

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1.8163200281

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1.7945555231

1.549130766

1.2973189473

1.3501347109

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1.6420802002

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1.7030706067

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1.5106666382

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1.3739880273

1.1344628756

1.660082627

1.4215643118

1.3489150354

1.7883573288

1.2349003587

1.8352204599

1.5119266007

1.499570442

1.0273035792

1.9538500688

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1.538201416

1.6206176435

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1.6173625009

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1.8941126899

1.3778635918

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1.1939210993

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1.3484195889

1.5492603039

1.7540491802

1.1391470496

1.0651108889

1.1118931191

1.9348998369

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1.7150726732

1.1471965292

1.025238258

1.3259950417

1.5900505625

1.8826027502

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1.4231409329

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1.1860368573

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1.5426313936

1.889360212

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1.5974594226

1.7136521977

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1.2979899509

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1.1509190841

1.1175100315

1.3599981292

1.6431113687

1.4908361796

1.6843239855

1.5413966234

1.2326814462

1.9824993438

1.1707775634

3.9917919654

3.9839484905

3.9986533441

3.3402703995

3.6873272911

3.1935033624

3.7177524421

3.8556471801

3.2110144684

3.0294538647

3.1388774165

3.5635401113

3.2241216327

3.7094255516

3.6013394042

3.7243254551

3.5058411764

3.4232329511

3.3451629935

3.328232136

3.969453041

3.5136715317

3.2799417933

3.5356693135

3.7347079398

3.0571947191

3.7734481372

3.7921750056

3.6604105437

3.3865380196

3.429753521

3.7024636445

3.2737693735

3.8360278613

3.4321289154

3.0589765717

3.6319306565

3.682258476

3.5869035693

3.1306094044

3.8688825021

3.7950477969

3.7315500374

3.5064284887

3.0929602585

3.9632231032

3.6005095396

3.3372418314

3.1955660617

3.1919218931

3.6298424892

3.718957774

3.0412870202

3.7814739341

3.4524858379

3.4031951386

3.2992758951

3.5188335738

3.8437922686

3.8344776185

3.8082613301

3.5486206412

3.3795449577

3.1801309059

3.4872641625

3.9788763015

3.3601076786

3.3630893722

3.7401867734

3.0006944032

3.7639947045

3.8986967944

3.8636674542

3.1513685684

3.9800782209

3.2096113701

3.3361767362

3.2713111573

3.5224845409

Asthmagens n=78

Controls n=301

Hazard

Internal Validation

0.1653

0.0985

0.041

0.0426

0.1003

0.6096

0.0485

0.2658

0.007

0.0227

0.1157

0.3561

0.2063

0.0426

0.0219

0.0168

0.0158

0

0.0554

0.0405

0.2213

0.0179

0.0825

0.0244

0.0208

0.1716

0.0146

0.038

0.0468

0.002

0.0114

0.125

0.0082

0.0543

0.0575

0.1615

0.0675

0.2648

0.0217

0.0884

0.0566

0.8854

0.0426

0.0219

0.0111

0.0566

0.1306

0.3209

0.1922

0.1088

0.0319

0.327

0.0579

0.1406

0.0163

0.0225

0.0884

0.0733

0.1653

0.0061

0.0196

0.1653

0.0506

0.0103

0.2063

0.1157

0.2063

0.0198

0.0963

0.083

0.0714

0.0082

0.122

0.1849

0.4619

0.0265

0.6935

0.9821

0.0056

0.1624

0.0149

0.0861

0.0133

0.0165

0.0028

0.6357

0.0708

0.0111

0.014

0.2648

0.0045

0.1306

0.0572

0.767

0.1023

0.0022

0.1157

0.0509

0.1157

0.0022

0.1499

0.0982

0.0154

0.1082

0.0341

0.0131

0.2636

0.1967

0.9379

0.973

0.4914

0.0089

0.4063

0.1069

0.0761

0.1303

0.0671

0.1406

0.1257

0.4737

0.0046

0.0974

0.4691

0.9824

0.02

0.6927

0.6606

0.0834

0.0115

0.0007

0.0053

0.2112

0.0216

0.0048

0.0152

0.0204

0.0021

0

0.0752

0.0959

0.4631

0.2394

0.5352

0.0039

0.0039

0.1644

0.1606

0.1741

0.1603

0.0243

0.8125

0.3194

0.0464

0.0566

0.041

0.0629

0.1265

0.6401

0.0187

0.1157

0.0426

0.2595

0.015

0.0304

0

0.0115

0.0088

0.0134

0.7483

0.0065

0.0196

0.0297

0.0765

0.1808

0.0765

0.0765

0.0984

0.0121

0.0167

0.0021

0.0026

0.0485

0.1499

0.1499

0.0253

0.2719

0.0214

0.1121

0.0706

0.016

0.0287

0.0728

0.0137

0.0108

0.138

0.2098

0.125

0.0287

0.0383

0.0239

0.0184

0.0028

0.0004

0.0196

0.0747

0.055

0.022

0.0005

0.0003

0.0262

0.0223

0.0982

0.0728

0.0294

0.0164

0.1274

0

0.022

0.0187

0

0.0292

0

0.006

0.1281

0.0306

0

0

0.0383

0

0

0.0159

0.018

0

0

0

0

0

0.3149

0.1347

0.0089

0.321

0.0068

0.0033

0.2542

0.0383

0.0383

0.0958

0.0157

0.1839

0.1868

0.1632

0.1245

0.0506

0.0409

0

0.7456

0.768

0.0003

0.9954

0.9649

0.9891

0.9891

0.0006

0.9808

0.3176

0.1306

0.1306

0.0067

0.2908

0.0418

0.0369

0.052

0.0227

0.0472

0.0326

0.0277

0.9198

0.033

0.0415

0.0426

0.0219

0.0268

0.0168

0.0566

0.1306

0.1306

0.1306

0.0247

0.125

0.0575

0.2252

0.0721

0.0566

0.0118

0.0485

0.0313

0.0418

0.041

0.1615

0.0418

0.0815

0.1776

0.0068

0.0111

0.7803

1

0.7671

0.9422

0.9329

0.1137

0.1455

0.9972

0.9451

0.9999

0.0246

0.9946

0.999

0.9701

0.9968

0.8949

0.4744

0.007

0.9999

0.3219

0.3101

0.7486

0.5039

0.0859

1

0.8083

0.0062

0.9999

0.1742

0.853

0.8242

0.4785

1

0.9472

0.7945

0.9999

0.6909

0.0057

0.837

0.99

1

0.4767

0.3657

0.9166

0.9884

0.9959

0.0364

0.8478

1

0.9485

0.269

0.9176

0.8569

0.7509

0.9999

0.9998

0.521

1

1

1

0.0415

0.1823

0.9997

1

0.5365

0.9999

0.22

0.9967

1

0.9984

0.2183

0.3624

0.921

0.9425

0.9999

0.007

Sheet1

19260.08

13950.03

19900.01

10670.02

16910.01

10210.01

14440

13880.34

18950.06

10070.02

11370.01

11060.1

13290.02

14130.05

17350.05

17820.21

18190.01

16750

10820.03

12790

13950.03

18410.02

12900.03

15750.22

14640.04

15360.78

14790.04

11020

10730

14880.2

14160.16

15830.02

14270.13

19220

11410.05

18780

19900.03

13330.03

10220.02

15840.12

19220.03

11130.02

11660

11030.1

19750.06

19100.01

10690.07

16080.39

13500

13350.01

11160.25

14920.11

12980.02

18730.04

17340.08

18490.19

10490.16

10680.32

19410

13400

19160

18830

17500.01

18520.02

15100

17990.2

19630.01

18470.19

14290

16810.03

17790.21

18290.07

18760.34

17710.11

11150.01

12890

14500.02

44170.34

40821

43920.91

44181

46021

45390.99

40761

40610.21

48320

48300.03

40270.55

47830.97

42590.01

47330.31

46350.06

49680.73

79071

75331

79051

75420.89

78211

75660.95

72580.98

78281

72230.08

76240.14

71061

70820.98

74060.95

73931

77590.97

72181

75910

70630.86

70510.96

74091

74491

Sheet1

Hazard Index

Sheet2

1.4893607009

1.2953168582

1.1270975962

1.4812692214

1.3948026032

1.3778326872

1.9258978144

1.150908134

1.6156243809

1.5841339764

1.9447570969

1.6967689175

1.8293582883

1.7913759903

1.1908149124

1.6320142458

1.1097162561

1.949376777

1.6999115982

1.337355165

1.4895131157

1.9279832821

1.5446986172

1.7154877815

1.3572858985

1.0880432982

1.9501590529

1.3677680491

1.2859865832

1.9271222257

1.3806599842

1.8245676486

1.824571928

1.9646595153

1.7585359449

1.5415192364

1.0317796372

1.7494399369

1.9668427478

1.9344939651

1.6055640649

1.9289775737

1.0187403966

1.6146818039

1.9648607256

1.1624329643

1.2317566986

1.8868818527

1.3846622588

1.3962608768

1.8292619644

1.7525116443

1.9356459486

1.9645262696

1.0216595717

1.5789778333

1.1188781141

1.3911746664

1.596929376

1.9768467358

1.0842247315

1.2336140496

1.6468885784

1.6785285814

1.5615265509

1.9905251404

1.198155941

1.6830316855

1.0896066294

1.3338046132

1.815780596

1.476429698

1.8026049506

1.1637958108

1.0587419102

1.6719291826

1.5816058543

1.1462679598

1.661350132

1.3099724639

1.9177478636

1.2149320611

1.4726903016

1.6114181666

1.0681702071

1.2645742909

1.1480420758

1.408362264

1.0878234306

1.2361632404

1.9681423709

1.1576819465

1.5648187343

1.7347277765

1.33626825

1.3157350027

1.4927205689

1.3697388382

1.1319789937

1.0839506192

1.5439813751

1.1160505313

1.138754455

1.6866653051

1.6976646677

1.00279189

1.8503352059

1.5226907855

1.7242595391

1.6652302114

1.4239879267

1.9424930751

1.3229678442

1.1307222309

1.691250832

1.0883463443

1.6206713637

1.8227310143

1.9958538143

1.4347904874

1.1288344017

1.8116259831

1.8204481928

1.5451646266

1.9962608954

1.7668812262

1.2088299188

1.8013129987

1.6217977394

1.1881083674

1.640693703

1.8358283121

1.7478902254

1.5607908447

1.8355328039

1.8152812166

1.4410415227

1.475854471

1.4031294065

1.9303421023

1.4940548675

1.2057402364

1.9413565113

1.2558171408

1.7589527206

1.7076998859

1.7156114866

1.6659230602

1.789391021

1.9876526649

1.4731977327

1.7780203683

1.3236408001

1.6423884429

1.6067879764

1.0853438307

1.2697651012

1.3214469303

1.7259172484

1.9774876082

1.5615266134

1.5269914945

1.2637946002

1.3961315388

1.9302795574

1.1476640055

1.9981204039

1.1786830575

1.8163200281

1.754132858

1.7945555231

1.549130766

1.2973189473

1.3501347109

1.2115635973

1.7951154806

1.5093214355

1.6420802002

1.0094174543

1.2845107108

1.5928796335

1.176879472

1.9162397421

1.2138137999

1.7030706067

1.1826760864

1.5106666382

1.1743162729

1.6214070184

1.700257899

1.7292066543

1.2254888421

1.9878033772

1.6969233229

1.2410273801

1.611787185

1.2635665718

1.3739880273

1.1344628756

1.660082627

1.4215643118

1.3489150354

1.7883573288

1.2349003587

1.8352204599

1.5119266007

1.499570442

1.0273035792

1.9538500688

1.7296388465

1.538201416

1.6206176435

1.5860051027

1.6173625009

1.9375684099

1.8941126899

1.3778635918

1.1731177417

1.6430123614

1.5936908273

1.6883236124

1.3173646929

1.7954371447

1.6495812866

1.9398436889

1.2792923133

1.8743725765

1.7860147478

1.1121951259

1.9676969021

1.1162333738

1.54219801

1.5163635001

1.7718299939

1.156316255

1.0917579321

1.2267761435

1.3751823129

1.8929844747

1.998159577

1.461828636

1.2357245566

1.8405952353

1.5522348045

1.5605398188

1.1939210993

1.6875582082

1.4433897763

1.9175631125

1.6104410357

1.3752353166

1.7691500857

1.6052673228

1.147370272

1.2186370107

1.3484195889

1.5492603039

1.7540491802

1.1391470496

1.0651108889

1.1118931191

1.9348998369

1.1701825076

1.7150726732

1.1471965292

1.025238258

1.3259950417

1.5900505625

1.8826027502

1.3041412615

1.2124970949

1.4231409329

1.120203927

1.1860368573

1.2854616942

1.5426313936

1.889360212

1.1786334079

1.4537717528

1.313459686

1.9274792345

1.9039306941

1.772600685

1.9376872351

1.949537052

1.9483141145

1.5974594226

1.7136521977

1.9779816779

1.2979899509

1.848426986

1.1509190841

1.1175100315

1.3599981292

1.6431113687

1.4908361796

1.6843239855

1.5413966234

1.2326814462

1.9824993438

1.1707775634

3.9917919654

3.9839484905

3.9986533441

3.3402703995

3.6873272911

3.1935033624

3.7177524421

3.8556471801

3.2110144684

3.0294538647

3.1388774165

3.5635401113

3.2241216327

3.7094255516

3.6013394042

3.7243254551

3.5058411764

3.4232329511

3.3451629935

3.328232136

3.969453041

3.5136715317

3.2799417933

3.5356693135

3.7347079398

3.0571947191

3.7734481372

3.7921750056

3.6604105437

3.3865380196

3.429753521

3.7024636445

3.2737693735

3.8360278613

3.4321289154

3.0589765717

3.6319306565

3.682258476

3.5869035693

3.1306094044

3.8688825021

3.7950477969

3.7315500374

3.5064284887

3.0929602585

3.9632231032

3.6005095396

3.3372418314

3.1955660617

3.1919218931

3.6298424892

3.718957774

3.0412870202

3.7814739341

3.4524858379

3.4031951386

3.2992758951

3.5188335738

3.8437922686

3.8344776185

3.8082613301

3.5486206412

3.3795449577

3.1801309059

3.4872641625

3.9788763015

3.3601076786

3.3630893722

3.7401867734

3.0006944032

3.7639947045

3.8986967944

3.8636674542

3.1513685684

3.9800782209

3.2096113701

3.3361767362

3.2713111573

3.5224845409

Controls Actives

Hazard

Internal Validation

0.1653

0.0985

0.041

0.0426

0.1003

0.6096

0.0485

0.2658

0.007

0.0227

0.1157

0.3561

0.2063

0.0426

0.0219

0.0168

0.0158

0

0.0554

0.0405

0.2213

0.0179

0.0825

0.0244

0.0208

0.1716

0.0146

0.038

0.0468

0.002

0.0114

0.125

0.0082

0.0543

0.0575

0.1615

0.0675

0.2648

0.0217

0.0884

0.0566

0.8854

0.0426

0.0219

0.0111

0.0566

0.1306

0.3209

0.1922

0.1088

0.0319

0.327

0.0579

0.1406

0.0163

0.0225

0.0884

0.0733

0.1653

0.0061

0.0196

0.1653

0.0506

0.0103

0.2063

0.1157

0.2063

0.0198

0.0963

0.083

0.0714

0.0082

0.122

0.1849

0.4619

0.0265

0.6935

0.9821

0.0056

0.1624

0.0149

0.0861

0.0133

0.0165

0.0028

0.6357

0.0708

0.0111

0.014

0.2648

0.0045

0.1306

0.0572

0.767

0.1023

0.0022

0.1157

0.0509

0.1157

0.0022

0.1499

0.0982

0.0154

0.1082

0.0341

0.0131

0.2636

0.1967

0.9379

0.973

0.4914

0.0089

0.4063

0.1069

0.0761

0.1303

0.0671

0.1406

0.1257

0.4737

0.0046

0.0974

0.4691

0.9824

0.02

0.6927

0.6606

0.0834

0.0115

0.0007

0.0053

0.2112

0.0216

0.0048

0.0152

0.0204

0.0021

0

0.0752

0.0959

0.4631

0.2394

0.5352

0.0039

0.0039

0.1644

0.1606

0.1741

0.1603

0.0243

0.8125

0.3194

0.0464

0.0566

0.041

0.0629

0.1265

0.6401

0.0187

0.1157

0.0426

0.2595

0.015

0.0304

0

0.0115

0.0088

0.0134

0.7483

0.0065

0.0196

0.0297

0.0765

0.1808

0.0765

0.0765

0.0984

0.0121

0.0167

0.0021

0.0026

0.0485

0.1499

0.1499

0.0253

0.2719

0.0214

0.1121

0.0706

0.016

0.0287

0.0728

0.0137

0.0108

0.138

0.2098

0.125

0.0287

0.0383

0.0239

0.0184

0.0028

0.0004

0.0196

0.0747

0.055

0.022

0.0005

0.0003

0.0262

0.0223

0.0982

0.0728

0.0294

0.0164

0.1274

0

0.022

0.0187

0

0.0292

0

0.006

0.1281

0.0306

0

0

0.0383

0

0

0.0159

0.018

0

0

0

0

0

0.3149

0.1347

0.0089

0.321

0.0068

0.0033

0.2542

0.0383

0.0383

0.0958

0.0157

0.1839

0.1868

0.1632

0.1245

0.0506

0.0409

0

0.7456

0.768

0.0003

0.9954

0.9649

0.9891

0.9891

0.0006

0.9808

0.3176

0.1306

0.1306

0.0067

0.2908

0.0418

0.0369

0.052

0.0227

0.0472

0.0326

0.0277

0.9198

0.033

0.0415

0.0426

0.0219

0.0268

0.0168

0.0566

0.1306

0.1306

0.1306

0.0247

0.125

0.0575

0.2252

0.0721

0.0566

0.0118

0.0485

0.0313

0.0418

0.041

0.1615

0.0418

0.0815

0.1776

0.0068

0.0111

0.7803

1

0.7671

0.9422

0.9329

0.1137

0.1455

0.9972

0.9451

0.9999

0.0246

0.9946

0.999

0.9701

0.9968

0.8949

0.4744

0.007

0.9999

0.3219

0.3101

0.7486

0.5039

0.0859

1

0.8083

0.0062

0.9999

0.1742

0.853

0.8242

0.4785

1

0.9472

0.7945

0.9999

0.6909

0.0057

0.837

0.99

1

0.4767

0.3657

0.9166

0.9884

0.9959

0.0364

0.8478

1

0.9485

0.269

0.9176

0.8569

0.7509

0.9999

0.9998

0.521

1

1

1

0.0415

0.1823

0.9997

1

0.5365

0.9999

0.22

0.9967

1

0.9984

0.2183

0.3624

0.921

0.9425

0.9999

0.007

Sheet3

Sheet3

1.4893607009

1.2953168582

1.1270975962

1.4812692214

1.3948026032

1.3778326872

1.9258978144

1.150908134

1.6156243809

1.5841339764

1.9447570969

1.6967689175

1.8293582883

1.7913759903

1.1908149124

1.6320142458

1.1097162561

1.949376777

1.6999115982

1.337355165

1.4895131157

1.9279832821

1.5446986172

1.7154877815

1.3572858985

1.0880432982

1.9501590529

1.3677680491

1.2859865832

1.9271222257

1.3806599842

1.8245676486

1.824571928

1.9646595153

1.7585359449

1.5415192364

1.0317796372

1.7494399369

1.9668427478

1.9344939651

1.6055640649

1.9289775737

1.0187403966

1.6146818039

1.9648607256

1.1624329643

1.2317566986

1.8868818527

1.3846622588

1.3962608768

1.8292619644

1.7525116443

1.9356459486

1.9645262696

1.0216595717

1.5789778333

1.1188781141

1.3911746664

1.596929376

1.9768467358

1.0842247315

1.2336140496

1.6468885784

1.6785285814

1.5615265509

1.9905251404

1.198155941

1.6830316855

1.0896066294

1.3338046132

1.815780596

1.476429698

1.8026049506

1.1637958108

1.0587419102

1.6719291826

1.5816058543

1.1462679598

1.661350132

1.3099724639

1.9177478636

1.2149320611

1.4726903016

1.6114181666

1.0681702071

1.2645742909

1.1480420758

1.408362264

1.0878234306

1.2361632404

1.9681423709

1.1576819465

1.5648187343

1.7347277765

1.33626825

1.3157350027

1.4927205689

1.3697388382

1.1319789937

1.0839506192

1.5439813751

1.1160505313

1.138754455

1.6866653051

1.6976646677

1.00279189

1.8503352059

1.5226907855

1.7242595391

1.6652302114

1.4239879267

1.9424930751

1.3229678442

1.1307222309

1.691250832

1.0883463443

1.6206713637

1.8227310143

1.9958538143

1.4347904874

1.1288344017

1.8116259831

1.8204481928

1.5451646266

1.9962608954

1.7668812262

1.2088299188

1.8013129987

1.6217977394

1.1881083674

1.640693703

1.8358283121

1.7478902254

1.5607908447

1.8355328039

1.8152812166

1.4410415227

1.475854471

1.4031294065

1.9303421023

1.4940548675

1.2057402364

1.9413565113

1.2558171408

1.7589527206

1.7076998859

1.7156114866

1.6659230602

1.789391021

1.9876526649

1.4731977327

1.7780203683

1.3236408001

1.6423884429

1.6067879764

1.0853438307

1.2697651012

1.3214469303

1.7259172484

1.9774876082

1.5615266134

1.5269914945

1.2637946002

1.3961315388

1.9302795574

1.1476640055

1.9981204039

1.1786830575

1.8163200281

1.754132858

1.7945555231

1.549130766

1.2973189473

1.3501347109

1.2115635973

1.7951154806

1.5093214355

1.6420802002

1.0094174543

1.2845107108

1.5928796335

1.176879472

1.9162397421

1.2138137999

1.7030706067

1.1826760864

1.5106666382

1.1743162729

1.6214070184

1.700257899

1.7292066543

1.2254888421

1.9878033772

1.6969233229

1.2410273801

1.611787185

1.2635665718

1.3739880273

1.1344628756

1.660082627

1.4215643118

1.3489150354

1.7883573288

1.2349003587

1.8352204599

1.5119266007

1.499570442

1.0273035792

1.9538500688

1.7296388465

1.538201416

1.6206176435

1.5860051027

1.6173625009

1.9375684099

1.8941126899

1.3778635918

1.1731177417

1.6430123614

1.5936908273

1.6883236124

1.3173646929

1.7954371447

1.6495812866

1.9398436889

1.2792923133

1.8743725765

1.7860147478

1.1121951259

1.9676969021

1.1162333738

1.54219801

1.5163635001

1.7718299939

1.156316255

1.0917579321

1.2267761435

1.3751823129

1.8929844747

1.998159577

1.461828636

1.2357245566

1.8405952353

1.5522348045

1.5605398188

1.1939210993

1.6875582082

1.4433897763

1.9175631125

1.6104410357

1.3752353166

1.7691500857

1.6052673228

1.147370272

1.2186370107

1.3484195889

1.5492603039

1.7540491802

1.1391470496

1.0651108889

1.1118931191

1.9348998369

1.1701825076

1.7150726732

1.1471965292

1.025238258

1.3259950417

1.5900505625

1.8826027502

1.3041412615

1.2124970949

1.4231409329

1.120203927

1.1860368573

1.2854616942

1.5426313936

1.889360212

1.1786334079

1.4537717528

1.313459686

1.9274792345

1.9039306941

1.772600685

1.9376872351

1.949537052

1.9483141145

1.5974594226

1.7136521977

1.9779816779

1.2979899509

1.848426986

1.1509190841

1.1175100315

1.3599981292

1.6431113687

1.4908361796

1.6843239855

1.5413966234

1.2326814462

1.9824993438

1.1707775634

3.9917919654

3.9839484905

3.9986533441

3.3402703995

3.6873272911

3.1935033624

3.7177524421

3.8556471801

3.2110144684

3.0294538647

3.1388774165

3.5635401113

3.2241216327

3.7094255516

3.6013394042

3.7243254551

3.5058411764

3.4232329511

3.3451629935

3.328232136

3.969453041

3.5136715317

3.2799417933

3.5356693135

3.7347079398

3.0571947191

3.7734481372

3.7921750056

3.6604105437

3.3865380196

3.429753521

3.7024636445

3.2737693735

3.8360278613

3.4321289154

3.0589765717

3.6319306565

3.682258476

3.5869035693

3.1306094044

3.8688825021

3.7950477969

3.7315500374

3.5064284887

3.0929602585

3.9632231032

3.6005095396

3.3372418314

3.1955660617

3.1919218931

3.6298424892

3.718957774

3.0412870202

3.7814739341

3.4524858379

3.4031951386

3.2992758951

3.5188335738

3.8437922686

3.8344776185

3.8082613301

3.5486206412

3.3795449577

3.1801309059

3.4872641625

3.9788763015

3.3601076786

3.3630893722

3.7401867734

3.0006944032

3.7639947045

3.8986967944

3.8636674542

3.1513685684

3.9800782209

3.2096113701

3.3361767362

3.2713111573

3.5224845409

Hazard

Internal Validation

0.1653

0.0985

0.041

0.0426

0.1003

0.6096

0.0485

0.2658

0.007

0.0227

0.1157

0.3561

0.2063

0.0426

0.0219

0.0168

0.0158

0

0.0554

0.0405

0.2213

0.0179

0.0825

0.0244

0.0208

0.1716

0.0146

0.038

0.0468

0.002

0.0114

0.125

0.0082

0.0543

0.0575

0.1615

0.0675

0.2648

0.0217

0.0884

0.0566

0.8854

0.0426

0.0219

0.0111

0.0566

0.1306

0.3209

0.1922

0.1088

0.0319

0.327

0.0579

0.1406

0.0163

0.0225

0.0884

0.0733

0.1653

0.0061

0.0196

0.1653

0.0506

0.0103

0.2063

0.1157

0.2063

0.0198

0.0963

0.083

0.0714

0.0082

0.122

0.1849

0.4619

0.0265

0.6935

0.9821

0.0056

0.1624

0.0149

0.0861

0.0133

0.0165

0.0028

0.6357

0.0708

0.0111

0.014

0.2648

0.0045

0.1306

0.0572

0.767

0.1023

0.0022

0.1157

0.0509

0.1157

0.0022

0.1499

0.0982

0.0154

0.1082

0.0341

0.0131

0.2636

0.1967

0.9379

0.973

0.4914

0.0089

0.4063

0.1069

0.0761

0.1303

0.0671

0.1406

0.1257

0.4737

0.0046

0.0974

0.4691

0.9824

0.02

0.6927

0.6606

0.0834

0.0115

0.0007

0.0053

0.2112

0.0216

0.0048

0.0152

0.0204

0.0021

0

0.0752

0.0959

0.4631

0.2394

0.5352

0.0039

0.0039

0.1644

0.1606

0.1741

0.1603

0.0243

0.8125

0.3194

0.0464

0.0566

0.041

0.0629

0.1265

0.6401

0.0187

0.1157

0.0426

0.2595

0.015

0.0304

0

0.0115

0.0088

0.0134

0.7483

0.0065

0.0196

0.0297

0.0765

0.1808

0.0765

0.0765

0.0984

0.0121

0.0167

0.0021

0.0026

0.0485

0.1499

0.1499

0.0253

0.2719

0.0214

0.1121

0.0706

0.016

0.0287

0.0728

0.0137

0.0108

0.138

0.2098

0.125

0.0287

0.0383

0.0239

0.0184

0.0028

0.0004

0.0196

0.0747

0.055

0.022

0.0005

0.0003

0.0262

0.0223

0.0982

0.0728

0.0294

0.0164

0.1274

0

0.022

0.0187

0

0.0292

0

0.006

0.1281

0.0306

0

0

0.0383

0

0

0.0159

0.018

0

0

0

0

0

0.3149

0.1347

0.0089

0.321

0.0068

0.0033

0.2542

0.0383

0.0383

0.0958

0.0157

0.1839

0.1868

0.1632

0.1245

0.0506

0.0409

0

0.7456

0.768

0.0003

0.9954

0.9649

0.9891

0.9891

0.0006

0.9808

0.3176

0.1306

0.1306

0.0067

0.2908

0.0418

0.0369

0.052

0.0227

0.0472

0.0326

0.0277

0.9198

0.033

0.0415

0.0426

0.0219

0.0268

0.0168

0.0566

0.1306

0.1306

0.1306

0.0247

0.125

0.0575

0.2252

0.0721

0.0566

0.0118

0.0485

0.0313

0.0418

0.041

0.1615

0.0418

0.0815

0.1776

0.0068

0.0111

0.7803

1

0.7671

0.9422

0.9329

0.1137

0.1455

0.9972

0.9451

0.9999

0.0246

0.9946

0.999

0.9701

0.9968

0.8949

0.4744

0.007

0.9999

0.3219

0.3101

0.7486

0.5039

0.0859

1

0.8083

0.0062

0.9999

0.1742

0.853

0.8242

0.4785

1

0.9472

0.7945

0.9999

0.6909

0.0057

0.837

0.99

1

0.4767

0.3657

0.9166

0.9884

0.9959

0.0364

0.8478

1

0.9485

0.269

0.9176

0.8569

0.7509

0.9999

0.9998

0.521

1

1

1

0.0415

0.1823

0.9997

1

0.5365

0.9999

0.22

0.9967

1

0.9984

0.2183

0.3624

0.921

0.9425

0.9999

0.007

Corroboration by QSAR of THOR reports of occupational asthma due to novel agents

Denatonium (benzoate) (CAS 86398-53-0)

Hazard Index = 0.92

Thiamine (CAS no.59-43-8)

Hazard Index = 0.95

N+ N

O

THOR information given to HSE e.g. on specific hazards in: • hairdressing, • car manufacture / repair, • metal working fluids, • silica in new contexts

But: debate about the requisite level of proof and legal aspects (we cannot disclose information which could identity the reporting physician, patient or workplace)

Improvements could be achieved by:• Pooling with other systems (EU wide)• Regular use of disproportionality metrics (as per RNV3P) • Assumption by another body e.g. HSE (UK), or EU-OSHA of the

final alert action and any associated legal responsibility

Alert function of the THOR schemes/ systems

• Need to validate / corroborate novel causes: – expert review, – collation of cases / case finding , (national / international)– other approaches e.g. Other data mining, QSARs

• Alerting HSE and other stakeholders – promoting vigilance

• But legal considerations - cautious and slow approach

• Preventive campaigns for employers and employeese.g. In hairdressers (skin), vehicle manufacture / repair (lung)

• Possible recommendation of less risky options e.g. substitutes

The link with prevention

26

Summary: From sentinel surveillance to dissemination of ‘alert’

• Reporting fatigue, time pressure on physicians – need to maintain motivation– Balance against -

• Limits to data collection e.g. detail on exposure, case management

• Works well for respiratory and skin disorders, but not so well for other organ systems / diseases

• Need to undertake further evaluations

• Funding challenges

• Pooling of data and expertise needed – work for more international collaboration (e.g. Modernet), – with systematically applied methods

Obstacles facing alert and sentinel approaches/monitoring systems for the identification of new WRDs

Acknowledgements

• All participating physicians• Funding bodies: UK HSE, ROI HSA, EU-COST etc

• Thank you for your attention

www.coeh.man.ac.uk/thor

www.agius.com/raymond

The Health and Occupation Research Network�THOR ( UK & Republic of Ireland )Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Incidence rate per 100,000 persons employed for work-related musculoskeletal, mental, skin and respiratory ill-health (2006 to 2009) as reported by clinical specialists, GPs & self-reportsSlide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Work and Methyl(chloro)isothiazolinonesRelative rates by year (95% CI) of Allergic Contact Dermatitis reported by dermatologists attributed to fragrance versus �not attributed to fragrances (all occupations)Preliminary analysis of number of actual cases of Allergic Contact Dermatitis by fragrance ‘type’, reported by dermatologists to EPIDERM, 1996-2015 Slide Number 17Slide Number 18Cases of occupational asthma attributed to latex exposure reported to SWORD (1991-2014)Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28