ENDOTOXIN EXPOSURE AND ENDOTOXIN EXPOSURE AND RESPIRATORY OUTCOMES - - PowerPoint PPT Presentation

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ENDOTOXIN EXPOSURE AND ENDOTOXIN EXPOSURE AND RESPIRATORY OUTCOMES RESPIRATORY OUTCOMES AMONG DAIRY, FEEDLOT, AND AMONG DAIRY, FEEDLOT, AND GRAIN ELEVATOR WORKERS IN GRAIN ELEVATOR WORKERS IN COLORADO COLORADO Reynolds SJ, Cranmer B, Keefe

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SLIDE 1

ENDOTOXIN EXPOSURE AND ENDOTOXIN EXPOSURE AND RESPIRATORY OUTCOMES RESPIRATORY OUTCOMES AMONG DAIRY, FEEDLOT, AND AMONG DAIRY, FEEDLOT, AND GRAIN ELEVATOR WORKERS IN GRAIN ELEVATOR WORKERS IN COLORADO COLORADO

Reynolds SJ, Cranmer B, Keefe T, Reynolds SJ, Cranmer B, Keefe T, Mehaffy J, Serrano Martinez A, Saito Mehaffy J, Serrano Martinez A, Saito R, Tessari J, Burch J, Koehncke N, R, Tessari J, Burch J, Koehncke N, Wood E, Burch L, Siegel P. Wood E, Burch L, Siegel P.

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SLIDE 2

Scope of Problem Scope of Problem

More than 1,000,000 men, women, and More than 1,000,000 men, women, and children are at risk for occupational lung children are at risk for occupational lung disease related to organic dust exposure in disease related to organic dust exposure in the U.S. the U.S. Components of organic dust include fecal Components of organic dust include fecal matter, animal skin, feathers, feed and matter, animal skin, feathers, feed and bedding components, insects, fungi, bacteria bedding components, insects, fungi, bacteria and microbial products. and microbial products.

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SLIDE 3

Clinical and Epidemiological Studies Clinical and Epidemiological Studies

Wilkins et al: cash grain farmers, chronic cough 9%, Wilkins et al: cash grain farmers, chronic cough 9%, phlegm 11%, phlegm 11%, dysphnea dysphnea 16%, wheeze 8% 16%, wheeze 8% Schenker et al 1998 Schenker et al 1998 – – asthma, ODTS, chronic bronchitis asthma, ODTS, chronic bronchitis NIOSH: fatalities from hypersensitivity NIOSH: fatalities from hypersensitivity pneumonitis pneumonitis

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SLIDE 4

Clinical and Epidemiological Studies Clinical and Epidemiological Studies

Reynolds et al: exposure and Reynolds et al: exposure and respiratory symptoms in respiratory symptoms in turkey barn workers turkey barn workers – – Reynolds, Donham, Thorne, Reynolds, Donham, Thorne, Merchant, et al: Merchant, et al: occup

  • ccup.

. asthma 20%, chronic asthma 20%, chronic bronchitis 25%, ODTS 33% bronchitis 25%, ODTS 33% (Swine, Poultry, Dairy) (Swine, Poultry, Dairy) Suggested Suggested OELs OELs for Swine, for Swine, Poultry environments Poultry environments

  • Dust 2.5 mg/m

Dust 2.5 mg/m3

3,

,

  • Endotoxin

Endotoxin 1,000 EU/m 1,000 EU/m3

3,

,

  • Ammonia 7

Ammonia 7 ppm ppm) )

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SLIDE 5

Endotoxins Endotoxins

Lipid A portion Lipid A portion – – Pathogen Associated Molecular Pathogen Associated Molecular Pattern (germ line encoded receptors) Pattern (germ line encoded receptors) Role in immune system modulation and asthma Role in immune system modulation and asthma – –

  • Adaptation or down

Adaptation or down-

  • regulation of response

regulation of response

  • Hygiene Hypothesis

Hygiene Hypothesis – – Merchant et al (2004) Merchant et al (2004)

Genetic risk factors (CD14, TLR4) Genetic risk factors (CD14, TLR4)

  • LeVan

LeVan and Von Essen (2005) CD14 and PFT decrements and Von Essen (2005) CD14 and PFT decrements

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SLIDE 6

Objectives Objectives

1) Characterize worker exposure to endotoxin 1) Characterize worker exposure to endotoxin-

  • containing

containing corn dust aerosols; corn dust aerosols; 2) Evaluate respiratory outcomes including symptoms, 2) Evaluate respiratory outcomes including symptoms, cross shift changes in pulmonary function, (PFT) and cross shift changes in pulmonary function, (PFT) and cellular/immune markers (cytokines); cellular/immune markers (cytokines); 3) Survey genetic markers related to lung disease and 3) Survey genetic markers related to lung disease and endotoxin etiology (TLR4 gene mutations, and endotoxin etiology (TLR4 gene mutations, and polymorphisms of IL1 polymorphisms of IL1-

  • RN, and TNF

RN, and TNF-

  • alpha);

alpha); 4) Explore whether endotoxin assay or GC/MS is best 4) Explore whether endotoxin assay or GC/MS is best predictor of biomarkers, predictor of biomarkers, PFTs PFTs, , Sx Sx; ; 5) Explore whether cellular/immune responses and PFT 5) Explore whether cellular/immune responses and PFT differ among those with different genetic status. differ among those with different genetic status.

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SLIDE 7

Research Team Research Team

Colorado State University Colorado State University Stephen Reynolds, Stephen Reynolds, PhD,CIH PhD,CIH PI (Exposure/ PI (Exposure/Epi Epi) ) James Burch, Ph.D. James Burch, Ph.D. Epidemiology Epidemiology Thomas Keefe, Ph.D. Thomas Keefe, Ph.D. Biostatistics Biostatistics John Tessari, Ph.D. John Tessari, Ph.D. Analytical Chemistry Analytical Chemistry John Mehaffy, M.S. John Mehaffy, M.S. Industrial Hygiene Industrial Hygiene Angelica Serrano Martinez, M..D Angelica Serrano Martinez, M..D Occ Occ Medicine/ Medicine/Epi Epi Rena Saito, B.S. Rena Saito, B.S. IH/Chemistry IH/Chemistry University of Saskatchewan University of Saskatchewan Niels Koehncke, M.D. Niels Koehncke, M.D. Occ

  • Occ. Medicine

. Medicine University of Nebraska University of Nebraska Susanna Von Essen Susanna Von Essen Pulmonary Medicine Pulmonary Medicine NIEHS NIEHS David Schwartz, M.D. David Schwartz, M.D. Genetics Genetics Nell Burch, Ph.D. Nell Burch, Ph.D. NIOSH NIOSH Paul Siegel, Ph.D. Paul Siegel, Ph.D. Biomarkers Biomarkers

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SLIDE 8

Population Population

N = 250 Workers, N = 250 Workers, > 18 years > 18 years Corn Growers Corn Growers Association Association Grain Handlers Grain Handlers Association Association Colorado Livestock Colorado Livestock Association Association Nebraska Nebraska – – Grain Grain Handlers and Farmers Handlers and Farmers

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SLIDE 9

Methods Methods

Pre Pre-

  • Work Shift

Work Shift

  • Exposure/Respiratory Health

Exposure/Respiratory Health Questionnaire Questionnaire

Based on ATS and Organic Dust Based on ATS and Organic Dust ( (Rylander Rylander, Donham) , Donham)

  • Pulmonary Function Test (

Pulmonary Function Test (Spirometrics

Spirometrics 2500) 2500)

  • Blood Sample

Blood Sample – – Genetics ( Genetics (TLR4 gene mutations TLR4 gene mutations Puregene Puregene ) )

Exposure Measurement Exposure Measurement

  • IOM Personal Dust Sample

IOM Personal Dust Sample

Post Post – – Work Shift Work Shift

  • Respiratory Questionnaire

Respiratory Questionnaire

  • Pulmonary Function Test

Pulmonary Function Test

  • Nasal

Nasal Lavage Lavage

(Cytokines IL (Cytokines IL-

  • 4, IL

4, IL-

  • 8, TNF

8, TNF-

  • α

α, , ECP, ECP, myloperoxidase myloperoxidase) )

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SLIDE 10

Organic Dust/Endotoxin Sampling Organic Dust/Endotoxin Sampling

IOM Personal IOM Personal Sampler Sampler Gravimetric Analysis Gravimetric Analysis rFC rFC Endotoxin Assay Endotoxin Assay GC/MS Endotoxin GC/MS Endotoxin Analysis Analysis

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SLIDE 11

Demographics Demographics

N = 81 N = 81 Mean age = 33 yrs (19 Mean age = 33 yrs (19 – – 57) 57) 98.8% Male 98.8% Male 51.9% Hispanic/Latino 51.9% Hispanic/Latino 53% White 53% White 35.8% Other 35.8% Other 1.2 % Asian 1.2 % Asian 3.7% American Indian 3.7% American Indian

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SLIDE 12

Characteristics Characteristics

Smoking Smoking

  • 26% cigarettes

26% cigarettes

  • 1% cigars

1% cigars

  • 8% chewing tobacco

8% chewing tobacco

  • 3.5% snuff

3.5% snuff

Respiratory Protection Respiratory Protection

  • 10.6% used dust mask

10.6% used dust mask

  • 1.2% used respirator with cartridge

1.2% used respirator with cartridge

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SLIDE 13

Exposure Results Exposure Results -

  • Overall

Overall N = 81 N = 81

50,100 50,100 13,500 13,500 75.9 75.9

Maximum Maximum

29.5 29.5 34.7 34.7 0.36 0.36

Minimum Minimum

5.8 5.8 4.2 4.2 2.8 2.8

GSD GSD 1,288 1,288 393 393 3.13 3.13 Geometric Geometric Mean Mean EU/m EU/m3

3

EU/mg EU/mg Mg/m Mg/m3

3

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SLIDE 14

Personal Dust Exposures By Facility Personal Dust Exposures By Facility Geometric Means (ANOVA p = 0.017) Geometric Means (ANOVA p = 0.017)

1 2 3 4 5 6

Farms (n=7) Grain (n=22) Feedlots (n= 34) Dairy (n=17)

Mg/m3

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SLIDE 15

Personal Personal Endotoxin Endotoxin Exposures By Facility Exposures By Facility

Geometric Means (ANOVA p = 0.001 EU/mg) Geometric Means (ANOVA p = 0.001 EU/mg)

500 1000 1500 2000 2500

Farms (n=7) Grain (n=22) Feedlots (n= 34) Dairy (n=17)

EU/m3 EU/mg

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SLIDE 16

Exposure Results Exposure Results – – Overall Overall Pearson Correlations Pearson Correlations N = 81 N = 81

1.0 1.0

EU/m EU/m3

3

0.80 0.80 P <0.01 P <0.01 1.0 1.0

EU/mg EU/mg 0.55 0.55

P <0.01 P <0.01

NS NS 1.0 1.0 Mg/m Mg/m3

3

EU/m EU/m3

3

EU/mg EU/mg Mg/m Mg/m3

3

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SLIDE 17

Multiple Linear Regressions Multiple Linear Regressions GC/MS 3 GC/MS 3-

  • OHFA with

OHFA with rFC rFC

Combinations of 3-OH FA R2 OVERALL 14, 17 0.6177 Grain elevator 13, 14 0.4047 Feedlot 13, 14, 18 0.9604 Dairy 18 0.2969

with 90% significance level

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SLIDE 18

Cross Cross – – Shift Change in Shift Change in Pulmonary Function Results Pulmonary Function Results Overall N = 81 Overall N = 81 Mean(SD Mean(SD) )

  • 1.4 (3.0)

1.4 (3.0)

  • 2.0 (6.0)

2.0 (6.0)

  • 3.1 (5.6)

3.1 (5.6)

FEV1/FVC% FEV1/FVC% FVC% FVC% FEV1% FEV1%

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SLIDE 19

Cross Cross – – Shift Change in Shift Change in Pulmonary Function Results Pulmonary Function Results Mean (SD) Mean (SD)

P = 0.088 P = 0.088 P = 0.006 P = 0.006 P = 0.039 P = 0.039 ANOVA ANOVA

  • 1.3 (3.2)

1.3 (3.2)

  • 2.8 (5.7)

2.8 (5.7)

  • 4.2 (5.3)

4.2 (5.3) Dairy Dairy N = 17 N = 17

  • 1.3 (2.1)

1.3 (2.1)

  • 0.6 (5.8)

0.6 (5.8)

  • 1.8 (5.0)

1.8 (5.0) Feedlots Feedlots N = 34 N = 34

  • 2.4 (4.1)

2.4 (4.1)

  • 1.6 (6.0)

1.6 (6.0)

  • 3.0 (6.6)

3.0 (6.6) Grain Grain N = 22 N = 22 0.97 (2.0) 0.97 (2.0)

  • 9.1 (3.2)

9.1 (3.2)

  • 8.1 (2.9)

8.1 (2.9) Farms Farms N = 7 N = 7

FEV1/FVC% FEV1/FVC% FVC% FVC% FEV1% FEV1%

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SLIDE 20

Pearson Correlations Pearson Correlations PFTs PFTs N = 81 N = 81

1.0 1.0

FEV1/ FEV1/ FVC FVC

NS NS 1.0 1.0

FVC FVC 0.26 0.26

P = 0.02 P = 0.02

0.82 0.82

P < 0.1 P < 0.1

1.0 1.0 FEV1 FEV1 FEV1/ FEV1/ FVC FVC FVC FVC

FEV1 FEV1

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SLIDE 21

Prevalence of Symptoms (n = 81) Prevalence of Symptoms (n = 81)

{ANOVA {ANOVA – – shortbreath shortbreath > grain p = 0.015} > grain p = 0.015}

5 10 15 20 25 30 35 40 45

E y e I r r t . N

  • s

e I r r t . M u c u s S h

  • r

t B r . W h e e z e T h r

  • a

t I r r t . C

  • u

g h

PreShift % PostShift %

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SLIDE 22

Immune Markers Immune Markers

{ANOVA {ANOVA – – IL8 > farmers (1099) p = 0.014, IL8 > farmers (1099) p = 0.014, ECP > farmers (17.9 p = 0.039} ECP > farmers (17.9 p = 0.039}

0.01 0.1 1 10 100 1000

I L 8 ( n = 7 8 ) I L 4 ( n = 1 8 ) T N F a ( n = 1 8 ) A l b u m i n ( n = 7 1 ) E C P ( n = 5 6 ) M P O ( n = 7 2 )

Conc.

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SLIDE 23

Pearson Correlations (all p < 0.05) Pearson Correlations (all p < 0.05)

56 56

  • 0.30

0.30 dFVC dFVC ECP ECP 18 18 0.54 0.54 Log Log mg/m3 mg/m3 IL4 IL4 18 18 0.54 0.54 dFVC dFVC IL4 IL4 18 18 0.74 0.74 IL4 IL4 IL8 IL8

n n r r Immune Immune

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SLIDE 24

Pearson Correlations (all p < 0.05) Pearson Correlations (all p < 0.05)

81 81

  • 0.37

0.37 EU/m3 EU/m3 Throat Throat irrit irrit. . 80 80

  • 0.31

0.31 EU/mg EU/mg Throat Throat irrit irrit. . 79 79

  • 0.22

0.22 Log Log mg/m3 mg/m3 Wheeze Wheeze 80 80

  • 0.25

0.25 EU/m3 EU/m3 Cough Cough 18 18 0.48 0.48 TNF TNFα α Cough Cough

n n r r

Pre Pre Symptoms Symptoms

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SLIDE 25

Pearson Correlations (all p < 0.05) Pearson Correlations (all p < 0.05)

18 18 0.56 0.56 TNF TNFα α Nose Nose irrit irrit. . 18 18 0.50 0.50 IL4 IL4 Eye Eye irrit irrit. . 79 79

  • 0.23

0.23 Log Log EU/mg EU/mg Short Short breath breath

n n r r

Pre Pre Symptoms Symptoms

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SLIDE 26

Pearson Correlations (all p < 0.05) Pearson Correlations (all p < 0.05)

55 55 0.40 0.40 TLR4 TLR4-

  • 399

399 Short Short breath breath 55 55 0.46 0.46 TLR4 TLR4-

  • 299

299 Short Short breath breath 18 18 0.48 0.48 TNF TNFα α Nose Nose irrit irrit. . 80 80 0.22 0.22 Smoking Smoking Mucus Mucus

n n r r

Post Post Symptoms Symptoms

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SLIDE 27

Pearson Correlations (all p < 0.05) Pearson Correlations (all p < 0.05)

80 80 0.40 0.40 Log Log mg/m3 mg/m3 dFEV1/FVC dFEV1/FVC 80 80

  • 0.29

0.29 MPO MPO dFEV1/FVC dFEV1/FVC 56 56 0.30 0.30 ECP ECP dFEV1 dFEV1 56 56 0.30 0.30 ECP ECP dFVC dFVC 18 18 0.54 0.54 IL4 IL4 dFVC dFVC

n n r r

PFT PFT

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SLIDE 28

Regression (stepwise) Regression (stepwise)

FEV1/FVC FEV1/FVC

  • logmg/m3, R

logmg/m3, R2

2 = 0.183

= 0.183

Post Cough Post Cough

  • smoking, R

smoking, R2

2 = 0.091

= 0.091

Post Short Breath Post Short Breath

  • TLR4 299, log EU/m

TLR4 299, log EU/m3

3, R

, R2

2 = 0.269

= 0.269

Post Mucus Post Mucus

  • smoking, R

smoking, R2

2 = 0.0.82

= 0.0.82

IL4 IL4

  • Log mg/m3, R

Log mg/m3, R2

2 = 0.29

= 0.29

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SLIDE 29

Interpretation Interpretation

Personal exposures to dust and endotoxin Personal exposures to dust and endotoxin quite variable. quite variable. Some endotoxin and dust levels very high. Some endotoxin and dust levels very high. Means exceed current recommended Means exceed current recommended OELs OELs Dust (grain>farm > feedlot>dairy) Dust (grain>farm > feedlot>dairy) Endotoxin Endotoxin (feedlot>farm>dairy>grain) (feedlot>farm>dairy>grain)

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SLIDE 30

Interpretation Interpretation

Respiratory Outcomes Respiratory Outcomes– –

  • Irritation

Irritation Sx Sx increased over shift, increased over shift, resp resp Sx Sx decreased decreased

  • FEV1(flow) and FVC (capacity) decrease

FEV1(flow) and FVC (capacity) decrease

  • Change in FEV1 (farm>>dairy>grain>feedlot)

Change in FEV1 (farm>>dairy>grain>feedlot)

  • Change in FVC (farm>>dairy>grain>feedlots)

Change in FVC (farm>>dairy>grain>feedlots)

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SLIDE 31

Interpretation Interpretation

Cross Cross-

  • shift change in FEV1/FVC and IL4

shift change in FEV1/FVC and IL4 associated with log mg/m associated with log mg/m3

3.

. Pre Pre-

  • shift cough, wheeze associated with

shift cough, wheeze associated with dust and dust and endotoxin endotoxin levels. levels. Post Post-

  • shift cough and mucus associated

shift cough and mucus associated with smoking. with smoking. TLR4 299 and TLR4 299 and endotoxin endotoxin associated with associated with shortness of breath. shortness of breath.

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SLIDE 32

Future Future

Data collection Data collection Genetic markers Genetic markers Cytokines Cytokines GC GC-

  • MS

MS Na Naï ïve Dairy Workers ve Dairy Workers Study Study CA Dairy Worker Study CA Dairy Worker Study Collaboration with IAREH Collaboration with IAREH comparing populations comparing populations

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SLIDE 33

Acknowledgements Acknowledgements

CDC NIOSH 5U50 OH008085 CDC NIOSH 5U50 OH008085 High Plains Center for Agricultural Health High Plains Center for Agricultural Health and Safety and Safety R01 OH007841 R01 OH007841

Dr.

  • Dr. Lenart

Lenart Larsson, Lund, Sweden Larsson, Lund, Sweden

  • Dr. Don Milton, HSPH and
  • Dr. Don Milton, HSPH and UMass

UMass Lowell Lowell