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..Physiologic and Genetic Determinants of Physiologic and Genetic Determinants of Occupational Lung DysfunctionOccupational Lung Dysfunction
- Experience in the Swine Industry- Experience in the Swine Industry
Occupational and Environmental Medical Occupational and Environmental Medical Association of CanadaAssociation of Canada
Annual Scientific ConferenceAnnual Scientific Conference
October 5, 2010October 5, 2010
James A Dosman MDJames A Dosman MD
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CREDITS CREDITS
A SenthilselvanA Senthilselvan Ernie Barber Ernie Barber Chuck RhodesChuck Rhodes Tom HurstTom Hurst Shelley KirychukShelley Kirychuk Liliane ChLiliane Chéénardnard Yvon CormierYvon Cormier David SchwartzDavid Schwartz Leslie HolfeldLeslie Holfeld
Don CockcroftDon CockcroftFrank FrohFrank FrohLorne BabiukLorne BabiukPhil WilsonPhil WilsonBaljit SinghBaljit SinghAlan RosenbergAlan RosenbergLouise HagelLouise HagelKendra UlmerKendra UlmerVaneeta GroverVaneeta GroverJosh LawsonJosh LawsonMerry-Lynn MacDonaldMerry-Lynn MacDonald
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CREDITSCREDITS
The Medical Research The Medical Research Council of CanadaCouncil of Canada
National Health National Health Research and Research and Development ProgramDevelopment Program
The Canadian Institutes The Canadian Institutes of Health Researchof Health Research
Saskatchewan Health Saskatchewan Health Research FoundationResearch Foundation
Saskatchewan Saskatchewan LabourLabour
Saskatchewan Saskatchewan Agriculture and FoodAgriculture and Food
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OUTLINE OF PRESENTATION OUTLINE OF PRESENTATION 1.1. Characteristics of the industryCharacteristics of the industry
2. Respiratory health effects2. Respiratory health effects3. Mechanisms of dysfunction3. Mechanisms of dysfunction4.4. InterventionsInterventions
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THE SWINE INDUSTRY IN CANADATHE SWINE INDUSTRY IN CANADA
Annual sales: $4 BillionAnnual sales: $4 BillionNumber of pigs/yr: 31 MillionNumber of pigs/yr: 31 MillionNumber of people in industry: 30,000Number of people in industry: 30,000
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AN EVOLVING INDUSTRYAN EVOLVING INDUSTRY From the family farm From the family farm
with outdoor or small with outdoor or small scale production and scale production and a few hours per day a few hours per day exposureexposure
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AN EVOLVING INDUSTRYAN EVOLVING INDUSTRY Large scale indoor Large scale indoor
animal confinement animal confinement involving thousands of involving thousands of pigs and the “eight pigs and the “eight hour per day” hour per day” employed workeremployed worker
Photo: Prairie Swine Centre, Floral, SKPhoto: Prairie Swine Centre, Floral, SK
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AIR QUALITYAIR QUALITY (n=54 – winter)(n=54 – winter)
Total dust (mg/mTotal dust (mg/m3)3) 2.93 2.93 ±± 0.920.92Endotoxin EU/mEndotoxin EU/m33 11,443 11,443 ± 13,492± 13,492NHNH3 3 (ppm) 11.3 (ppm) 11.3 ± 4.2± 4.2COCO2 2 (ppm)(ppm) 2,632 2,632 ± 807± 807
Zejda et al, JOM 36:49-56, 1994Zejda et al, JOM 36:49-56, 1994
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DUSTS – CHARACTERISTICS (1)DUSTS – CHARACTERISTICS (1)
Animal feedAnimal feed Swine fecesSwine feces Swine danderSwine dander MoldMold
Pollen grainsPollen grains Insect partsInsect parts Mineral ashMineral ash
Median aerodynamic diameter, 2.2 um
Donham et al, Am J Ind Med, 10:294-297,1986.
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DUSTS – CHARACTERISTICS (2)DUSTS – CHARACTERISTICS (2)
Mold – 1.9 x 10Mold – 1.9 x 1033 cfu/mg cfu/mg33
Penicillium Alternaria
Aspergillus Fucarium
Verticillium Scopulariopsis
Donham et al, Am J Ind Med, 10:294-297, 1986
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DUSTS – CHARACTERISTICS (3)DUSTS – CHARACTERISTICS (3)
Bacteria 1.7 x 10Bacteria 1.7 x 1044 cfu/m cfu/m33
Predominant type – gram-positivePredominant type – gram-positiveGram-negative count – 8.4 x 10Gram-negative count – 8.4 x 1033
Donham et al, Am J Ind Med, 10:294-297, 1986
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DUST AND ENDOTOXINDUST AND ENDOTOXIN Dust particles are less Dust particles are less
than 5than 5µ in mean µ in mean aerodynamic diameter aerodynamic diameter and can penetrate and can penetrate
terminal bronchioles.terminal bronchioles.
Endotoxin adheres to Endotoxin adheres to dust particlesdust particles
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ENDOTOXINENDOTOXIN
Soluble lipopolysaccharides (LPS)Soluble lipopolysaccharides (LPS) Outer membrane gram negative bacteriaOuter membrane gram negative bacteria Aggregate to form micellesAggregate to form micelles Molecular weight 1,000,000 kdMolecular weight 1,000,000 kd
Reed CE, Milton DK. 2001. Mosby Inc.Reed CE, Milton DK. 2001. Mosby Inc.
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RESPIRATORY HEALTH EFFECTS RESPIRATORY HEALTH EFFECTS
AsthmaAsthma Chronic airflow limitationChronic airflow limitation Acute effects in new workersAcute effects in new workers Healthy worker effectHealthy worker effect
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CASE # 1, CAUCASIAN WOMAN, AGE 29 (1)CASE # 1, CAUCASIAN WOMAN, AGE 29 (1)
6 weeks -severe wheezing6 weeks -severe wheezing 3 months - quit work 3 months - quit work 1.5 months after quitting - 1.5 months after quitting -
seen in clinicseen in clinic Past history - no asthma, Past history - no asthma,
allergyallergy O/E - wheezes on forced O/E - wheezes on forced
expirationexpiration Dosman et al, Euro Resp J, 24:689, 2004Dosman et al, Euro Resp J, 24:689, 2004
• Chest X-ray clearChest X-ray clear• FEVFEV11 3.48; 10% BD 3.48; 10% BD• Allergy test: weeds, Allergy test: weeds,
grass, alfalfagrass, alfalfa• PCPC20 20 1.03 mg/ml1.03 mg/ml• Diagnosis:Diagnosis: asthma asthma• RxRx: fluticasone prop: fluticasone prop
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CASE # 1, CAUCASIAN WOMAN, AGE 29 (2)CASE # 1, CAUCASIAN WOMAN, AGE 29 (2)
Re-entry challenge - 2.5 Re-entry challenge - 2.5 mo after work cessation mo after work cessation
Spent less than 30 Spent less than 30 minutes in barn before minutes in barn before severe coughing and severe coughing and wheezing forced end of wheezing forced end of challengechallenge
Pre-challenge PCPre-challenge PC20 20 1.03 1.03 mg/mlmg/ml
3 hour post-challenge 3 hour post-challenge PCPC20 20 0.74 mg/ml0.74 mg/ml
Dx:Dx: occup asthma occup asthma
RxRx: fluticasone prop: fluticasone prop
Stay off workStay off workDosman et al, Euro Resp J, 24: 698-702, 2004Dosman et al, Euro Resp J, 24: 698-702, 2004
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CASE # 1, CAUCASIAN WOMAN, AGE 29 (3)CASE # 1, CAUCASIAN WOMAN, AGE 29 (3)
4 months after work 4 months after work cessationcessation
Mildly symptomaticMildly symptomatic Off fluticazone propOff fluticazone prop
PCPC20 20 1.23 mg/ml1.23 mg/ml
Dosman et al, Euro Resp J, 24: 698-702, 2004Dosman et al, Euro Resp J, 24: 698-702, 2004
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CASE # 1, CAUCASIAN WOMAN, AGE 29 (4)CASE # 1, CAUCASIAN WOMAN, AGE 29 (4)
7.5 mo after work 7.5 mo after work cessationcessation
No symptomsNo symptoms Not on treatmentNot on treatment Not working in barnNot working in barn
PCPC20 20 5.9 mg/ml 5.9 mg/ml
( nearly normal)( nearly normal) Dx: dischargedDx: discharged
Dosman et al, Euro Resp J, 24: 698-702, 2004Dosman et al, Euro Resp J, 24: 698-702, 2004
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CASE STUDY: Occupational asthma in newly CASE STUDY: Occupational asthma in newly employed workers in intensive swine employed workers in intensive swine confinement facilities”confinement facilities”
CASECASE ONSETONSET QUITQUIT OUTCOMEOUTCOME1.1. 29 yr f 1.5mo 29 yr f 1.5mo 3 mo 3 mo 7mo, no Rx 7mo, no Rx2.2. 38 yr f 1 mo38 yr f 1 mo 4 mo 4 mo 7mo, on Rx 7mo, on Rx3.3. 44 yr f 6 mo 24 mo 5.5mo, on Rx44 yr f 6 mo 24 mo 5.5mo, on Rx4.4. 39 yr f 39 yr f 12 mo 30 mo days no Rx 12 mo 30 mo days no Rx
Dosman et al, Euro Resp J, 24: 698-702, 2004Dosman et al, Euro Resp J, 24: 698-702, 2004
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CHRONIC AIRFLOW LIMITATIONCHRONIC AIRFLOW LIMITATION
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Saskatchewan Farmers SurveySaskatchewan Farmers Survey Organized by Mr. Frank FrohOrganized by Mr. Frank Froh
n=504 swine farmers
n=448 non-exposed Humboldt men
Dosman et al, J Occ Med 30: 715-720, 1988
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Swine farmers in Saskatchewan had more Swine farmers in Saskatchewan had more respiratory symptoms than control menrespiratory symptoms than control men
FarmersFarmers ControlsControls SigSig (n=504) (n=448)(n=504) (n=448)
age (yr) age (yr) 42.2 42.2 39.7` p 39.7` p<.05<.05smoking (pk yr) 13.6smoking (pk yr) 13.6 13.2 13.2 NS NSwheeze (%) wheeze (%) 29.2 29.2 10.3 10.3 p p<.001<.001sob (%)sob (%) 32.1 32.1 19.4 19.4 pp<.001<.001
Dosman et al, J Occ Med 30: 715-720, 1988Dosman et al, J Occ Med 30: 715-720, 1988
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Swine farmers in Saskatchewan had lower Swine farmers in Saskatchewan had lower values for lung function than control menvalues for lung function than control men
FarmersFarmers ControlsControls SigSig
TestTest n=504) (n=448) n=504) (n=448)FEVFEV11 (pred) (pred) 95.5 95.5 103.6 103.6 p p<.001<.001
FVC (pred) 97.3 106.8FVC (pred) 97.3 106.8 pp<.001<.001
Dosman et al, J Occ Med 30: 715-720, 1988Dosman et al, J Occ Med 30: 715-720, 1988
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INCREASED AIRWAY INCREASED AIRWAY RESPONSIVENESSRESPONSIVENESS
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20 Hutterite swine 20 Hutterite swine farmers (age 39.0farmers (age 39.0±11.1 ±11.1 yrs)yrs) had more had more increases in airways increases in airways responsiveness than responsiveness than did 20 blue collar city did 20 blue collar city workers (age 40.1workers (age 40.1±8.5 ±8.5 years)years)
Zhou et al, CHEST, 99:951-944, 1991Zhou et al, CHEST, 99:951-944, 1991
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ACROSS SHIFT CHANGESACROSS SHIFT CHANGES (n=54(n=54):):
Swine farmers had Swine farmers had significant reductions in significant reductions in expiratory flow rates over an expiratory flow rates over an 8-hour work shift8-hour work shift
Zhou, C, PhD Thesis, University of Zhou, C, PhD Thesis, University of Saskatchewan, 1994Saskatchewan, 1994
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Over a four year period there Over a four year period there was significant accelerated was significant accelerated
lung function decline in swine lung function decline in swine farmers vs non-exposed farmers vs non-exposed
control subjectscontrol subjects
Senthilselvan et al, Chest, 111:1733- 41, 1997Senthilselvan et al, Chest, 111:1733- 41, 1997
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Annual Rate Change in FEVAnnual Rate Change in FEV11
1990/91 – 1994/95 (vs 171 controls)1990/91 – 1994/95 (vs 171 controls) ββ SESE SigSig
Grain FarmersGrain Farmers -16.4-16.4 7.337.33 p=0.03 p=0.03 (n=218),16 cc/year excess loss(n=218),16 cc/year excess loss
Swine FarmersSwine Farmers -26.1-26.1 7.447.44 p<0.0005 p<0.0005(n=217), 26 cc/year excess loss(n=217), 26 cc/year excess loss
Senthilselvan et al Chest 111:1733- 41, 1997Senthilselvan et al Chest 111:1733- 41, 1997
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The best predictor ofThe best predictor of annual decline inannual decline in FEVFEV1 1 over a fourover a four year period was 8 hryear period was 8 hr across-shift changeacross-shift change in FEVin FEV1 1 on the initialon the initial observationobservation
Kirychuk et al, Can Resp J, 5: 472-478, 1998Kirychuk et al, Can Resp J, 5: 472-478, 1998
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RESPIRATORY HEALTH STATUS RESPIRATORY HEALTH STATUS IN SWINE PRODUCERS RELATES IN SWINE PRODUCERS RELATES
TO ENDOTOXIN IN THE TO ENDOTOXIN IN THE PRESENCE OF LOW DUST PRESENCE OF LOW DUST
LEVELSLEVELS
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Respiratory Health Status in Swine Producers Respiratory Health Status in Swine Producers Relates to Endotoxin Exposure in the Presence of Relates to Endotoxin Exposure in the Presence of
Low Dust LevelsLow Dust Levels
n=54, Total Dust = 2.93 ± 0.92mg/m3
FVC FEV1
Airborne endotoxin -0.35* 0.17
Airborne endotoxin x hrs/day -0.42* 0.28**
**p<.05 *p=.06
Zejda et al, JOM 36: 49-56, 1994
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Acute exposure of naïve volunteers for 5 Acute exposure of naïve volunteers for 5 hours in a swine barn resulted in evidence hours in a swine barn resulted in evidence for acute inflammatory response at both for acute inflammatory response at both high and low dust levelshigh and low dust levels
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Dust and endotoxin Dust and endotoxin concentrations (concentrations (± SE)± SE)
treatmenttreatment controlcontrolTotal dustTotal dust (mg/m(mg/m33)) 0.15 0.15 ± 0,02 2.41 ± ± 0,02 2.41 ± 0.090.09**
EndotoxinEndotoxin (EU/m(EU/m3)3) 452.3 452.3 ± 65.8± 65.8 3983.5 3983.5 ± 498.3*± 498.3*
NHNH33 (ppm)(ppm) 18.3 ± 0.5 18.3 ± 0.5 26.0 ± 0.6 *26.0 ± 0.6 * *p<.001*p<.001
Senthilselvan et al, ARRCCM 156: 410-417, Senthilselvan et al, ARRCCM 156: 410-417, 19971997
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Summary: Acute exposure to dust, endotoxin Summary: Acute exposure to dust, endotoxin and NHand NH3 3 results in evidence for acute results in evidence for acute inflammatory response:inflammatory response:
Acute, reversible FEVAcute, reversible FEV1 1 declinedecline Elevation in total WBC, neutrophils and Elevation in total WBC, neutrophils and
lymphocyteslymphocytes Increase in cytokines in nasal wash and bloodIncrease in cytokines in nasal wash and blood Effects are reduced but not eliminated by Effects are reduced but not eliminated by
sprinkling canola oilsprinkling canola oil
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Mask StudyMask StudyNaïve subjects Naïve subjects exposed exposed 1. wearing a mask 1. wearing a mask 2. not wearing a 2. not wearing a maskmask
Dosman et al, Chest, 118: 852-860, Dosman et al, Chest, 118: 852-860, 20002000
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““Positive Human Health Effects of Positive Human Health Effects of Wearing a Respirator in a Swine Barn”Wearing a Respirator in a Swine Barn”
FEVFEV11 % change no mask % change no mask 8.12 8.12 ± 1.1± 1.1
FEVFEV11 % change with mask % change with mask 0.32 0.32 ± 0.62± 0.62
p<.001p<.001
Dosman et al, Chest, 118: 852-860, 2000Dosman et al, Chest, 118: 852-860, 2000
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N-95 mask provides N-95 mask provides similar protection similar protection than reducing dusts than reducing dusts and endotoxin 10 and endotoxin 10 foldfold
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Baseline and interim lung function predicts healthy Baseline and interim lung function predicts healthy worker survival in swine farmersworker survival in swine farmers..
RESULTS OF A 14 YEAR FOLLOW UP IN SWINE FARMERSRESULTS OF A 14 YEAR FOLLOW UP IN SWINE FARMERS
Chenard et al, Chest, 131:245-254, 2006Chenard et al, Chest, 131:245-254, 2006
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There is a significant healthy worker effect There is a significant healthy worker effect among farmers who continue to work in among farmers who continue to work in swine confinement facilitiesswine confinement facilities
Survival in the industry may be predicted Survival in the industry may be predicted by baseline and interim lung function.by baseline and interim lung function.
Genetic make-up may be a factor in the Genetic make-up may be a factor in the healthy worker effecthealthy worker effect
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GENETICSGENETICS
Cellular innate recognition of endotoxin Cellular innate recognition of endotoxin depends on membrane bound receptors depends on membrane bound receptors including the Toll like receptorsincluding the Toll like receptors
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LPS
CD14
LBPMD-2
NEMOIKKαIKKβ
NucleusNucleus
NF-B
IκBβor IκBα
NF-B
TLR4
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LPS
CD14
LBPMD-2
NEMOIKKαIKKβ
NucleusNucleus
NF-B
IκBβor IκBα
NF-B
TLR4
TLR4 299 &/or TLR4 399mutation(s)
x
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Arbour et al, Nature Genetics, 25(2): 187-191, 2000
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We tested the hypothesis that We tested the hypothesis that naïve volunteers with TLR4 naïve volunteers with TLR4
mutation will have less mutation will have less respiratory response when respiratory response when
exposed to endotoxin in a swine exposed to endotoxin in a swine barnbarn
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90 with TLR4Mutation
885 Wildtype
29 TLR4 29 Wildtype
Genotyped
DNA Collection from 975 Students
Subgroup SelectedMatching TLR4 GroupScreening for
Allergies
Acute Pig Barn Exposure
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Senthilselvan et al, JACI 2009; 123(5):1034-1040
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CONCLUSIONCONCLUSION
Genetic make up is a significant factor Genetic make up is a significant factor in the acute respiratory response to swine in the acute respiratory response to swine
barn dust.barn dust.
Endotoxin is a major contributor.Endotoxin is a major contributor.
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INTERVENTIONINTERVENTION
Respiratory Health Program for the Swine Respiratory Health Program for the Swine Industry in SaskatchewanIndustry in Saskatchewan
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Goal: Healthy and Goal: Healthy and safe workplace and safe workplace and workersworkers
Thank YouThank You
Slide Courtesy of Dr Shelly KyrichukSlide Courtesy of Dr Shelly Kyrichuk