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.
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.
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%, dysphnea dysphnea 16%, wheeze 8% 16%, wheeze 8% phlegm 11%, Schenker et al 1998 – Schenker et al 1998 – asthma, ODTS, chronic bronchitis asthma, ODTS, chronic bronchitis NIOSH: fatalities from hypersensitivity pneumonitis pneumonitis NIOSH: fatalities from hypersensitivity
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: occup occup. . Merchant, et al: asthma 20%, chronic asthma 20%, chronic bronchitis 25%, ODTS 33% bronchitis 25%, ODTS 33% (Swine, Poultry, Dairy) (Swine, Poultry, Dairy) Suggested OELs OELs for Swine, for Swine, Suggested Poultry environments Poultry environments Dust 2.5 mg/m 3 , Dust 2.5 mg/m 3 , � � Endotoxin 1,000 EU/m 1,000 EU/m 3 3 , , Endotoxin � � Ammonia 7 ppm ppm) ) Ammonia 7 � �
Endotoxins Endotoxins Lipid A portion – – Pathogen Associated Molecular Pathogen Associated Molecular Lipid A portion 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 �
Objectives Objectives 1) Characterize worker exposure to endotoxin- -containing containing 1) Characterize worker exposure to endotoxin 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- -RN, and TNF RN, and TNF- -alpha); alpha); polymorphisms of IL1 4) Explore whether endotoxin assay or GC/MS is best 4) Explore whether endotoxin assay or GC/MS is best predictor of biomarkers, PFTs predictor of biomarkers, 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.
Research Team Research Team Colorado State University Colorado State University Stephen Reynolds, PhD,CIH PhD,CIH PI (Exposure/Epi Epi) ) Stephen Reynolds, PI (Exposure/ James Burch, Ph.D. James Burch, Ph.D. Epidemiology Epidemiology Thomas Keefe, Ph.D. Biostatistics Thomas Keefe, Ph.D. Biostatistics John Tessari, Ph.D. Analytical Chemistry John Tessari, Ph.D. Analytical Chemistry John Mehaffy, M.S. Industrial Hygiene John Mehaffy, M.S. Industrial Hygiene Angelica Serrano Martinez, M..D Angelica Serrano Martinez, M..D Occ Occ Medicine/ Medicine/Epi Epi Rena Saito, B.S. IH/Chemistry Rena Saito, B.S. IH/Chemistry University of Saskatchewan University of Saskatchewan Niels Koehncke, M.D. Occ. Medicine . Medicine Niels Koehncke, M.D. Occ University of Nebraska University of Nebraska Susanna Von Essen Pulmonary Medicine Susanna Von Essen 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. Biomarkers Paul Siegel, Ph.D. Biomarkers
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 – – Grain Grain Nebraska Handlers and Farmers Handlers and Farmers
Methods Methods Pre- - Work Shift Work Shift Pre 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 ( Spirometrics Pulmonary Function Test ( Spirometrics 2500) 2500) � � Blood Sample – Blood Sample – Genetics ( Genetics ( TLR4 gene mutations Puregene ) ) TLR4 gene mutations Puregene � � Exposure Measurement Exposure Measurement IOM Personal Dust Sample IOM Personal Dust Sample � � Post – – Work Shift Work Shift Post Respiratory Questionnaire Respiratory Questionnaire � � Pulmonary Function Test Pulmonary Function Test � � Nasal Lavage Lavage Nasal � � (Cytokines IL (Cytokines IL- -4, IL 4, IL- -8, TNF 8, TNF- - α α , , ECP, ECP, myloperoxidase myloperoxidase) )
Organic Dust/Endotoxin Sampling Organic Dust/Endotoxin Sampling IOM Personal IOM Personal Sampler Sampler Gravimetric Analysis Gravimetric Analysis rFC Endotoxin Assay Endotoxin Assay rFC GC/MS Endotoxin GC/MS Endotoxin Analysis Analysis
Demographics Demographics N = 81 N = 81 Mean age = 33 yrs (19 – – 57) 57) Mean age = 33 yrs (19 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
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 �
Exposure Results - - Overall Overall Exposure Results N = 81 N = 81 Mg/m 3 3 EU/mg EU/m 3 3 Mg/m EU/mg EU/m Geometric 3.13 393 1,288 Geometric 3.13 393 1,288 Mean Mean 2.8 4.2 5.8 GSD 2.8 4.2 5.8 GSD Minimum 0.36 34.7 29.5 Minimum 0.36 34.7 29.5 Maximum 75.9 13,500 50,100 75.9 13,500 50,100 Maximum
Personal Dust Exposures By Facility Personal Dust Exposures By Facility Geometric Means (ANOVA p = 0.017) Geometric Means (ANOVA p = 0.017) Mg/m3 6 5 4 3 2 1 0 Farms Grain Feedlots Dairy (n=7) (n=22) (n= 34) (n=17)
Personal Endotoxin Endotoxin Exposures By Facility Exposures By Facility Personal Geometric Means (ANOVA p = 0.001 EU/mg) Geometric Means (ANOVA p = 0.001 EU/mg) EU/m3 2500 EU/mg 2000 1500 1000 500 0 Farms Grain Feedlots Dairy (n=7) (n=22) (n= 34) (n=17)
Exposure Results – – Overall Overall Exposure Results Pearson Correlations Pearson Correlations N = 81 N = 81 Mg/m 3 3 EU/mg EU/m 3 3 Mg/m EU/mg EU/m Mg/m 3 1.0 NS 0.55 3 Mg/m 1.0 NS 0.55 P <0.01 P <0.01 1.0 0.80 EU/mg 1.0 0.80 EU/mg P <0.01 P <0.01 EU/m 3 3 1.0 EU/m 1.0
Multiple Linear Regressions Multiple Linear Regressions GC/MS 3- -OHFA with OHFA with rFC rFC GC/MS 3 R 2 Combinations of 3-OH FA 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
Cross – – Shift Change in Shift Change in Cross Pulmonary Function Results Pulmonary Function Results Overall N = 81 Overall N = 81 Mean(SD) ) Mean(SD FEV1% FVC% FEV1/FVC% FEV1% FVC% FEV1/FVC% -3.1 (5.6) 3.1 (5.6) -2.0 (6.0) 2.0 (6.0) -1.4 (3.0) 1.4 (3.0) - - -
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