Occupational Asthma Reference

Walters GI, Moore VC, Robertson AS, McGrath EE, Parkes E, Burge PS, Occupational asthma from sensitization to 4, 4-methlyene bismorpholine in clean metalworking fluid, Eur Respir J, 2013;42:1137-1139,

Keywords: occupational asthma, new cause, metal-working fluid, biocide, challenge, peak flow, FeNO, NSBR, case report, 4, 4-methylenebis-morpholine

Known Authors

Sherwood Burge, Oasys Sherwood Burge

Vicky Moore, Oasys Vicky Moore

Alastair Robertson, Selly Oak Hospital Alastair Robertson

Emmet McGrath, Oasys Emmet McGrath

Edward Parkes, Birmingham Heartlands Hospital Edward Parkes

Gareth Walters, Heartlands Gareth Walters

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Abstract

European Respiratory Society guidelines on the management of work-related asthma recommend that occupational asthma (OA) with an allergic mechanism should be diagnosed by both identifying the workplace as the cause, and confirming sensitization to the asthmagen by specific inhalational challenge (SIC), in the absence of any available specific IgE tests [1, 2]. Used (contaminated) metal working fluid is the usual cause of occupational asthma in exposed workers. We present the first case of OA due to the biocide additive 4,4-methylene-bismorpholine present in clean MWF.
A 54-year old Kenyan man presented with a 2-year history of rhinitis, wheeze, dry cough and chest tightness, which were worse at night and whilst at work and improved away from work on holiday. He had had rhinitis from grass pollen, perfumes and cleaning agents intermittently for 15 years,and acne due to MWF 5 years previously. There was no childhood or family history of asthma and he had never smoked cigarettes. He had been employed as a machine tool setter-operator for 22 years manufacturing car axles. For the last 6 years he had worked on an enclosed computer numerical controlled (CNC) milling, drilling and boring machine, with its own oil sump, using carbide-tipped tools. It was loaded by a robot but there was no delay between the end of machining and door opening, which produced a visible mist about 3 meters from his work station. The machines used Fuchs Ecocool Ultralife A, a semi-synthetic MWF for aluminium alloys. Clinical examination and chest radiograph were unremarkable. Skin-prick allergy testing (SPT) revealed a 0mm reaction to 0.9% saline and a 7mm reaction to histamine hydrochloride 10mg/ml. There were positive reactions to grass pollen (8mm), dog dander (5mm), cladosporium (4mm) and 4, 4-methylenebis-morpholine (3mm),with borderline reactions to 5mg/ml cobalt chloride (2.5mm) and clean MWF (2.5mm). Total IgE was 2048kU/L, white blood cell count 7.81x109/L and eosinophil count was raised at 0.75x109/L. 2-hourly peak flow measurements made at home and work over 4 weeks were analysed using OASYS [1, 2]. The OASYS score was 3.4 and ABC score 23.4 litres/min/hour confirming a significant work effect (Figure 1). Spirometry revealed a borderline obstructive ventilatory defect (FEV1/FVC=70%) with normal indices (FEV1=2.75L (86% predicted); FVC=3.95L (100% predicted). While work-exposed, his fractional exhaled nitric oxide (FENO) was raised at 71ppb [3, 3] and non-specific bronchial responsiveness (NSBR) to methacholine was normal (>4800mcg by the Yan method [4]).
He underwent specific inhalational challenge (SIC) after 3 weeks away from work. He was challenged with 7% clean Ecocool Ultralife A MWF in water for a total of 50 minutes via aTurboneb II and Maxineb 90 nebulizer. Initial FEV1 was 2.63L, which fell immediately by 20%, recovering after 15 minutes, and fell again at 3-11 hours by 29.7%, accompanied by asthmatic symptoms. Subsequent SIC to 0.7% 4, 4-methylene-bismorpholine in water (Chemical Abstract Service (CAS) registry number 5625-90-1; OA Hazard Index=0.98) for a total of 50 minutes resulted in immediate sustained rhinitis symptoms, then a late fall in FEV1 of 16.5% from 2.36L, at 9-11 hours after challenge (Figure 2). He had a >4-fold increase in NSBR to methacholine (pre-SIC PD20>4800mcg; 24-hour post-SIC PD20=587mcg), but no clinically significant change in FENO (FENO pre-SIC=77ppb; post-SIC=70ppb). He had negative SICs to the solvent 2, 2-aminoethoxyethanol (CAS registry number 929-06-6; OA Hazard Index=0.41), pH stabilizer 2-di-butylaminoethanol (CAS registry number 102-81-8; OA Hazard Index=0.95) and cobalt chloride 5mg/ml. A suitable unexposed workplace could not be found; nine months later he remained unemployed withongoing asthma symptoms that required treatment with 200micrograms of inhaled beclometasone b.d., with an FEV1 of 2.59L (82% predicted) and FVC of 4.45L (113% predicted) and FeNO 56ppb.
The positive SIC and greater than 4-fold increase in NSBR to methacholine supports the diagnosis of OA from sensitization due to 4, 4-methylene-bismorpholine. Geier et al. have previously demonstrated dermatological sensitization to a number of structurally related biocide additives, including 1% 4,4-methylene bismorpholine by skin patch testing [4]. However, a number of features need to be accounted for. The baseline FENO was measured during work-exposure and was high, as was the pre-SIC FENO after 3 weeks away from work but was lower after 9 months without exposure. These values may have been confounded by atopy and rhinitis [Dweik, 5]. Some have found a significant increase in FENOfollowing a late asthmatic reaction; however asignificant proportion of low molecular weight (LMW) occupational asthmagensproduce a non-eosinophilic asthma variant [6] and although we did not obtain sputum cell counts, this may explain the lack of FENO change.. All measurements were carried out according to ERS/ATS guidelines [7] using the NioxMino handheld machine (Aerocrine AB, Solna, Sweden). A 3mm SPT to 4,4-methylene bismorpholine does not provide conclusive evidence of an IgE-mediated mechanism; indeed the absence of demonstrable specific IgE antibodies in subjects with OA caused by LMW agents has made many suspect non-IgE medicated mechanisms [8].

MWFs are used to reduce heat and friction in industrial metalworking operations, and are complex mixtures of oils, emulsifiers, alkaline pH buffers, biocides and other additives. Once used, MWFs may be contaminated with bacterial and fungal microbes, hydraulic fluid, added biocides,dissolved metals and other manufacturing by-products, all of which are potential sensitizers for OA, as well as causing extrinsic allergic alveolitis, humidifier fever and occupational bronchitis [5, 6]. SIC testing to MWF has been undertaken safely, though positive tests are much more common to used- than clean MWF [7, 8]. 4,4-methylene-bismorpholine has a high asthma hazard index (maximum 1.0) using the Manchester Occupational Asthma Hazard Programme, which has a high sensitivity in identifying novel asthmagens[9].

References
[1] Baur X, Sigsgaard T. The new guidelines for management of work-related asthma.EurRespir J 2012;39:518-9.
[2] Baur X, Sigsgaard T, Aasen TB et al. on behalf of the ERS Task Force on the management of work-related asthma. Guidelines for the management of work-related asthma.EurRespir J 2012;39:529-45. Erratum in: EurRespir J 2012;39:1553.
[1] Gannon PF, Newton DT, Belcher J, Pantin CF, Burge PS.Development of OASYS-2: a system for the analysis of serial measurement of peak expiratory flow in workers with suspected occupational asthma. Thorax 1996;51:484-9.
[2] Moore VC, Jaakkola MS, Burge CBSG et al.A New Diagnostic Score for Occupational Asthma.Chest 2009;135:307-14.
[3] Dweik RA, Boggs PB, Erzurum SC et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J RespirCrit Care Med 2011;184:602-15.
[3] See KC and Christiano DC. Normal values and thresholds for the clinical interpretation of exhaled nitric oxide levels in the general U.S. population: results from the National Health and Nutrition Examination Survey 2007-2010. Chest2013;143:107-16.
[4] Yan K, Salome C, Woolcock AJ.Rapid method for measurement of bronchial responsiveness.Thorax 1983;38:760-5.
[4] Geier J, Lessmann H, Becker D et al. Patch testing with components of water-based metalworking fluids: results of a multicentre study with a second series. Contact Dermatitis 2006;55(6):322-9.
[5] Scott M, Razal A, Karmaus W et al. Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study. Thorax 2010;65:258-62.
[6] Anees W, Huggins V, Pavord ID, Robertson AS, Burge PS. Occupational asthma due to low molecular weight agents: eosinophilic and non-eosinophilic variants. Thorax 2002;57:231-6.
[7] Task force of the European Respiratory Society (ERS) and American Thoracic Society (ATS). ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J RespirCrit Care Med. 2005;171:912–30.
[8] Sastre J, Vandenplas O, Park HS. Pathogenesis of occupational asthma.EurRespir J 2003;22:364-73.
[5] Robertson W, Robertson A, Burge CBSG et al. Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant.Thorax 2007;62:981-90.
[6] Zacharisen MC, Kadambi AR, Schlueter DP et al. The spectrum of respiratory disease associated with exposure to metal working fluids.J Occup Environ Med 1998;40:640-7.
[7] Hendy MS, Beattie BE, Burge PS. Occupational asthma due to an emulsified oil mist. Br J Industr Med 1985;42:51-54.
[8] Vellore AD, Moore VC, Robertson AS, Robertson W, Jaakkola MS, Burge PS.Specific bronchial challenge testing to metal working fluid.EurRespir J Suppl 2006;28:245s.
[9] Jarvis J, Seed MJ, Elton R, Sawyer L, Agius R.Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds.Occup Environ Med 2005;62:243-50.

Plain text: European Respiratory Society guidelines on the management of work-related asthma recommend that occupational asthma (OA) with an allergic mechanism should be diagnosed by both identifying the workplace as the cause, and confirming sensitization to the asthmagen by specific inhalational challenge (SIC), in the absence of any available specific IgE tests [1, 2]. Used (contaminated) metal working fluid is the usual cause of occupational asthma in exposed workers. We present the first case of OA due to the biocide additive 4,4-methylene-bismorpholine present in clean MWF. A 54-year old Kenyan man presented with a 2-year history of rhinitis, wheeze, dry cough and chest tightness, which were worse at night and whilst at work and improved away from work on holiday. He had had rhinitis from grass pollen, perfumes and cleaning agents intermittently for 15 years,and acne due to MWF 5 years previously. There was no childhood or family history of asthma and he had never smoked cigarettes. He had been employed as a machine tool setter-operator for 22 years manufacturing car axles. For the last 6 years he had worked on an enclosed computer numerical controlled (CNC) milling, drilling and boring machine, with its own oil sump, using carbide-tipped tools. It was loaded by a robot but there was no delay between the end of machining and door opening, which produced a visible mist about 3 meters from his work station. The machines used Fuchs Ecocool Ultralife A, a semi-synthetic MWF for aluminium alloys. Clinical examination and chest radiograph were unremarkable. Skin-prick allergy testing (SPT) revealed a 0mm reaction to 0.9% saline and a 7mm reaction to histamine hydrochloride 10mg/ml. There were positive reactions to grass pollen (8mm), dog dander (5mm), cladosporium (4mm) and 4, 4-methylenebis-morpholine (3mm),with borderline reactions to 5mg/ml cobalt chloride (2.5mm) and clean MWF (2.5mm). Total IgE was 2048kU/L, white blood cell count 7.81x109/L and eosinophil count was raised at 0.75x109/L. 2-hourly peak flow measurements made at home and work over 4 weeks were analysed using OASYS [1, 2]. The OASYS score was 3.4 and ABC score 23.4 litres/min/hour confirming a significant work effect (Figure 1). Spirometry revealed a borderline obstructive ventilatory defect (FEV1/FVC=70%) with normal indices (FEV1=2.75L (86% predicted); FVC=3.95L (100% predicted). While work-exposed, his fractional exhaled nitric oxide (FENO) was raised at 71ppb [3, 3] and non-specific bronchial responsiveness (NSBR) to methacholine was normal (>4800mcg by the Yan method [4]). He underwent specific inhalational challenge (SIC) after 3 weeks away from work. He was challenged with 7% clean Ecocool Ultralife A MWF in water for a total of 50 minutes via aTurboneb II and Maxineb 90 nebulizer. Initial FEV1 was 2.63L, which fell immediately by 20%, recovering after 15 minutes, and fell again at 3-11 hours by 29.7%, accompanied by asthmatic symptoms. Subsequent SIC to 0.7% 4, 4-methylene-bismorpholine in water (Chemical Abstract Service (CAS) registry number 5625-90-1; OA Hazard Index=0.98) for a total of 50 minutes resulted in immediate sustained rhinitis symptoms, then a late fall in FEV1 of 16.5% from 2.36L, at 9-11 hours after challenge (Figure 2). He had a >4-fold increase in NSBR to methacholine (pre-SIC PD20>4800mcg; 24-hour post-SIC PD20=587mcg), but no clinically significant change in FENO (FENO pre-SIC=77ppb; post-SIC=70ppb). He had negative SICs to the solvent 2, 2-aminoethoxyethanol (CAS registry number 929-06-6; OA Hazard Index=0.41), pH stabilizer 2-di-butylaminoethanol (CAS registry number 102-81-8; OA Hazard Index=0.95) and cobalt chloride 5mg/ml. A suitable unexposed workplace could not be found; nine months later he remained unemployed withongoing asthma symptoms that required treatment with 200micrograms of inhaled beclometasone b.d., with an FEV1 of 2.59L (82% predicted) and FVC of 4.45L (113% predicted) and FeNO 56ppb. The positive SIC and greater than 4-fold increase in NSBR to methacholine supports the diagnosis of OA from sensitization due to 4, 4-methylene-bismorpholine. Geier et al. have previously demonstrated dermatological sensitization to a number of structurally related biocide additives, including 1% 4,4-methylene bismorpholine by skin patch testing [4]. However, a number of features need to be accounted for. The baseline FENO was measured during work-exposure and was high, as was the pre-SIC FENO after 3 weeks away from work but was lower after 9 months without exposure. These values may have been confounded by atopy and rhinitis [Dweik, 5]. Some have found a significant increase in FENOfollowing a late asthmatic reaction; however asignificant proportion of low molecular weight (LMW) occupational asthmagensproduce a non-eosinophilic asthma variant [6] and although we did not obtain sputum cell counts, this may explain the lack of FENO change.. All measurements were carried out according to ERS/ATS guidelines [7] using the NioxMino handheld machine (Aerocrine AB, Solna, Sweden). A 3mm SPT to 4,4-methylene bismorpholine does not provide conclusive evidence of an IgE-mediated mechanism; indeed the absence of demonstrable specific IgE antibodies in subjects with OA caused by LMW agents has made many suspect non-IgE medicated mechanisms [8]. MWFs are used to reduce heat and friction in industrial metalworking operations, and are complex mixtures of oils, emulsifiers, alkaline pH buffers, biocides and other additives. Once used, MWFs may be contaminated with bacterial and fungal microbes, hydraulic fluid, added biocides,dissolved metals and other manufacturing by-products, all of which are potential sensitizers for OA, as well as causing extrinsic allergic alveolitis, humidifier fever and occupational bronchitis [5, 6]. SIC testing to MWF has been undertaken safely, though positive tests are much more common to used- than clean MWF [7, 8]. 4,4-methylene-bismorpholine has a high asthma hazard index (maximum 1.0) using the Manchester Occupational Asthma Hazard Programme, which has a high sensitivity in identifying novel asthmagens[9]. References [1] Baur X, Sigsgaard T. The new guidelines for management of work-related asthma.EurRespir J 2012;39:518-9. [2] Baur X, Sigsgaard T, Aasen TB et al. on behalf of the ERS Task Force on the management of work-related asthma. Guidelines for the management of work-related asthma.EurRespir J 2012;39:529-45. Erratum in: EurRespir J 2012;39:1553. [1] Gannon PF, Newton DT, Belcher J, Pantin CF, Burge PS.Development of OASYS-2: a system for the analysis of serial measurement of peak expiratory flow in workers with suspected occupational asthma. Thorax 1996;51:484-9. [2] Moore VC, Jaakkola MS, Burge CBSG et al.A New Diagnostic Score for Occupational Asthma.Chest 2009;135:307-14. [3] Dweik RA, Boggs PB, Erzurum SC et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J RespirCrit Care Med 2011;184:602-15. [3] See KC and Christiano DC. Normal values and thresholds for the clinical interpretation of exhaled nitric oxide levels in the general U.S. population: results from the National Health and Nutrition Examination Survey 2007-2010. Chest2013;143:107-16. [4] Yan K, Salome C, Woolcock AJ.Rapid method for measurement of bronchial responsiveness.Thorax 1983;38:760-5. [4] Geier J, Lessmann H, Becker D et al. Patch testing with components of water-based metalworking fluids: results of a multicentre study with a second series. Contact Dermatitis 2006;55(6):322-9. [5] Scott M, Razal A, Karmaus W et al. Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study. Thorax 2010;65:258-62. [6] Anees W, Huggins V, Pavord ID, Robertson AS, Burge PS. Occupational asthma due to low molecular weight agents: eosinophilic and non-eosinophilic variants. Thorax 2002;57:231-6. [7] Task force of the European Respiratory Society (ERS) and American Thoracic Society (ATS). ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J RespirCrit Care Med. 2005;171:912-30. [8] Sastre J, Vandenplas O, Park HS. Pathogenesis of occupational asthma.EurRespir J 2003;22:364-73. [5] Robertson W, Robertson A, Burge CBSG et al. Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant.Thorax 2007;62:981-90. [6] Zacharisen MC, Kadambi AR, Schlueter DP et al. The spectrum of respiratory disease associated with exposure to metal working fluids.J Occup Environ Med 1998;40:640-7. [7] Hendy MS, Beattie BE, Burge PS. Occupational asthma due to an emulsified oil mist. Br J Industr Med 1985;42:51-54. [8] Vellore AD, Moore VC, Robertson AS, Robertson W, Jaakkola MS, Burge PS.Specific bronchial challenge testing to metal working fluid.EurRespir J Suppl 2006;28:245s. [9] Jarvis J, Seed MJ, Elton R, Sawyer L, Agius R.Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds.Occup Environ Med 2005;62:243-50.

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