Objectives 3-(Bromomethyl)−2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser. We detected two cases who presented respiratory and urticaria symptoms related to BCMBA and had positive skin prick tests to the agent. Subsequently, we conducted outbreak investigations at the BCMBA-producing factory and performed clinical examinations to confirm occupational diseases.
Methods The outbreak investigations included observations of work processes, assessment of exposure, a medical survey with a questionnaire and skin prick tests with 0.5% BCMBA water solution on 85 exposed workers and 9 unexposed workers. We used specific inhalation or nasal challenge and open skin application test to investigate BCMBA-related occupational asthma, rhinitis and contact urticaria.
Results We identified nine workers with respiratory and/or skin symptoms and positive skin prick tests to BCMBA in a chemical factory. A survey among chemical factory workers indicated a BCMBA-related sensitisation rate of 8% among all exposed workers; the rate was highest (25%) among production workers in the production hall. Sensitisation was detected only in workers with the estimated highest exposure levels. Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests. Asthma-provoking doses in specific inhalation challenges were very low (0.03% or 0.3% BCMBA in lactose).
Conclusions We identified a new low molecular weight agent causing occupational asthma, rhinitis and contact urticaria. A typical clinical picture of allergic diseases and positive skin prick tests suggest underlying IgE-mediated disease mechanisms. Stringent exposure control measures are needed in order to prevent BCMBA-related diseases.
- cas 120100-05-2
- contact urticaria
- low molecular weight agent
- occupational asthma
- occupational rhinitis
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What is already known about this subject?
3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser.
What are the new findings?
Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests.
A survey in a chemical factory showed an 8% sensitisation rate to BCMBA among all exposed workers and 25% among production workers with the estimated highest exposure levels.
How might this impact on policy or clinical practice in the foreseeable future?
Careful control of exposure is needed to protect workers.
Several low molecular weight (LMW) agents are known to cause occupational asthma via immunological mechanisms.1 The mechanisms are mainly IgE-independent, but specific IgE antibodies to some agents have been detected. IgE-mediated occupational asthma commonly occurs with occupational rhinitis and contact urticaria.2 3 New LMW agents are occasionally identified as causal agents of sensitiser-induced occupational asthma.4 The respiratory sensitisation potency of these agents is seldom identified in animal or in vitro tests before their industrial usage, resulting in the fact that new sensitisers are often first described in clinical case reports.5 Specific inhalation challenge is the most definitive method of identifying these agents.6
3-(Bromomethyl)−2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) (figure 1) is an LMW agent used as an intermediate product in the manufacture of another chemical. The end product of the process was a plant-protective agent. Two index patients with positive skin prick tests (SPTs) with respiratory and skin symptoms to BCMBA were examined at the Finnish Institute of Occupational Health (FIOH) during 2014. Both patients worked in a chemical factory in which BCMBA powder has periodically been produced since 2009. We subsequently visited the factory and investigated the exposed factory workforce as well as a subset of unexposed workers so as to identify additional cases. We determined the exposure levels and evaluated a possible dose–response relationship related to the BCMBA exposure. We report the results of the outbreak investigations and clinical findings of two index cases and four additional cases with occupational disease due to BCMBA exposure confirmed with challenge tests.
Outbreak investigations were carried out in 2015 in collaboration with industrial safety personnel and factory occupational healthcare personnel. They comprised exposure assessment and a medical survey among workers including a questionnaire of health and exposure, a physician’s interview and SPTs. Workers with BCMBA sensitisation were advised to contact their occupational physician, who referred them for diagnostic tests at FIOH. The study flow diagram is presented in figure 2.
The level of exposure in each job was assessed by an occupational hygienist and a physician. The assessment was based on (1) solitary dust measurements in BCMBA processing that were conducted by the employer before and after the outbreak investigations, (2) the observations by the researchers during the outbreak investigation and (3) interviews with the workers and safety personnel during the outbreak investigation. In the physician interviews, the workers were systematically asked about their current and previous work tasks and location in the factory. The safety personnel were asked about the processes and work tasks as well as exposures and control measures in each task. Based on the overall information including measurements and/or the researchers’ estimation, the workers were roughly categorised into four exposure groups: high, intermediate, low and unexposed.
Questionnaire and medical history
All BCMBA-exposed workers (n=92), except the two index cases, and all unexposed office workers were asked to complete a questionnaire covering smoking habits, work history, BCMBA exposure and medical history including respiratory diseases and atopic dermatitis. Questions covering work-related urticaria, dyspnoea, chest tightness, cough, wheezing, sneezing, nasal itching and rhinorrhoea were included. We used modified Tuohilampi questions for respiratory symptoms and diseases.7 A physician took a medical history regarding previous asthma and allergic rhinitis as well as respiratory and urticaria symptoms related to BCMBA exposure at a face-to-face interview. History of allergic rhinitis was defined as rhinorrhoea, sneezing, nasal obstruction and/or pruritus related to common environmental aeroallergens. History of asthma and atopic dermatitis was defined as previous physician-diagnosed asthma and atopic dermatitis.
Skin tests and IgE
The SPT panel for common environmental allergens included a negative control, a positive control (histamine) and standardised antigens of birch, alder, timothy grass, meadow fescue and mugwort pollen, Alternaria alternata, Cladosporium herbarum, cat and dog epithelium and house-dust mite Dermatophagoides pteronyssinus (ALK-Abello, Hørsholm Denmark). SPT with BCMBA was performed in 0.5% dilution in water. A positive SPT reaction was defined as a weal with a mean diameter of at least 3 mm and equal to or greater than half of the diameter of the histamine weal according to the methods described in our previous reports.8 9
An open skin application test was only carried out if the patient had experienced urticaria in skin contact with BCMBA and had a positive SPT. The test was to confirm the diagnosis of contact urticaria due to BCMBA in accordance with the methods described in our previous reports.8 9 BCMBA in 0.5% dilution in water was spread on a 5×5 cm area of the skin on the forearm and left uncovered. The test was read at 20, 40 and 60 min by a dermatologist. In visual grading, a reaction with urticarial weals in the application area without a simultaneous reaction in the control area was considered positive. The reaction was followed after washing where relevant.
Serum total IgE was measured using the Phadia UniCAP System (Phadia, Uppsala, Sweden). A total IgE level <110 kU/L was regarded as normal.
Lung function and fractional exhaled nitric oxide
Flow-volume spirometry was performed with a standard spirometer (Spirostar USB Medikro, Finland) using the predicted values assessed for the Finnish population. Non-specific airway hyperresponsiveness was measured with a histamine challenge.10 Fractional exhaled nitric oxide (FeNO) was measured using an online chemiluminescence analyser (NIOX, Aerocrine AB, Solna, Sweden) in compliance with ATS/ERS recommendations.11
Specific inhalation challenge and nasal provocation tests
Specific inhalation challenge was performed in a 6 m3 challenge chamber on subsequent days, each day with 24 hours of follow-up. The control challenge was dusting lactose powder. Active challenges with BCMBA in lactose for 30–60 min followed with increasing concentration each day (0.03%, 0.3%, 3% and 10% w/w). Bronchial reaction was monitored with FEV1, FeNO and histamine challenge.6 A positive test was defined as a sustained fall in FEV1 of ≥15% from prechallenge value, when fluctuations of FEV1 were <10% on a control day. A twofold reduction in provocative dose in histamine challenge and a 10 ppb increase in FeNO (at the baseline level below 50 ppb) were considered significant.6 12
A nasal provocation test was carried out by dropping 0.1 mL of control agent (NaCl 0.9%) and subsequently BCMBA 0.5% water solution into both inferior conchae. The nasal reaction was evaluated in a similar way during a specific inhalation challenge and a nasal provocation test: the degree of rhinorrhoea and nasal blockage was scored using anterior rhinoscopy before and 30 min after the test. Nasal secretion during the test was weighted and acoustic rhinometry and anterior rhinomanometry were performed in order to support the scoring. A significant score change in nasal secretion or congestion after BCMBA without significant changes following the control challenge was considered to be a positive nasal reaction.13 To exclude a positive nasal reaction due to irritant effects, a nasal BCMBA provocation test was performed on a healthy unexposed person. The test showed a negative result.
We used SPSS V.20.0 for data analysis. We expressed continuous variables as means and categorical values as percentages. We analysed differences between the groups using Student’s t-test or the Mann-Whitney U test. A P value of <0.05 was considered statistically significant.
The chemical factory had produced BCMBA powder during a period of a few months each year since 2009. BCMBA was an intermediate in the production of a plant protective agent; it was unloaded and stored in sacks and used in the same factory in the next stage of production. BCMBA was produced and used in a closed system of several reaction tanks. Dust release points were unloading and packing BCMBA into sacks from preceding reaction tank where it had been synthesised, and loading it from the sacks into the reactor at the next stage of the process. Dust levels in BCMBA were measured by the employer in 2012–2014 showing mean levels of 3.3 mg/m3 (range 0.0–13.4; six measurements) in unloading/packing and 8.3 mg/m3 (range 0.8–33.3; eight measurements) in loading. BCMBA release was also possible from other points during process failures and maintenance work (no dust measurements).
During the first production years, respirators were used intermittently, but later on the workers regularly wore powered air respirators and protective clothing while loading BCMBA in the process. In 2015, workplace hygiene improvements were applied because of the outbreak, and BCMBA loading to the reactor was transferred from the production hall to an enclosed, ventilated room where formerly unexposed workers took care of this task. Dust levels in BCMBA handling fell significantly after the improvements to mean 1.0 mg/m3 (range 0.0–3.9; six measurements) in unloading/packing and mean 0.24 mg/m3 (range 0.0–0.6; six measurements) in loading.
We categorised exposure after the outbreak investigations. Exposure was estimated to be (1) highest in the maintenance and packing and in production before the improvements, (2) intermediate in the enclosed loading process after the improvements and (3) low in the quality control work in the laboratory. Office workers were regarded as unexposed. There was no air measurement data for quantifying the exposure levels in the two lowest categories, and thus the categorisation was based on observations and other information.
Altogether 94 workers (85 exposed and 9 unexposed office workers) participated in the medical survey including a questionnaire, interview and SPT to BCMBA in 2015 (figure 2). Five exposed workers who declined to participate or were not available during SPTs, and two index cases already diagnosed with BCMBA-related disease and transferred to other locations in the factory, did not participate. Most of the workers were male, working in production and maintenance jobs (online supplementary table S1). Of the exposed workers (excluding two index cases), 11 (12%) reported rhinitis, 11 (12%) asthma and 5 (5%) urticaria symptoms related to BCMBA (table 1). We detected positive SPT to BCMBA in seven (8%) exposed workers; all were male and they belonged to the highest exposure group (production before the improvements, maintenance) and reported respiratory and/or urticaria symptoms. The sensitisation rate based on positive SPTs to BCMBA was highest among production workers (25%) and maintenance workers (13%) working in the production hall (table 1). These groups also had the highest rates of BCMBA-related respiratory and urticaria symptoms.
Supplementary file 1
BCMBA-sensitised workers more commonly had a history of allergic rhinitis to environmental aeroallergens and BCMBA-related asthma, rhinitis and urticaria symptoms than non-sensitised workers (table 2). However, there were no significant differences in their history of preceding asthma and atopic dermatitis, smoking habits or duration of exposure between these groups.
Six BCMBA-sensitised workers were examined at FIOH: two index cases and four cases detected in the survey (table 3). Three BCMBA-sensitised cases detected in the survey declined to participate in clinical examinations at FIOH. Duration of BCMBA exposure before symptom onset was at least 6 months. All patients with respiratory symptoms reported symptom onset within minutes in BCMBA exposure and improvement of symptoms after removal of exposure. Open skin test to BCMBA was positive in three patients; online supplementary figure S2 illustrates the positive skin test reactions of case 1. Specific inhalation challenge to BCMBA was performed on four workers. Two of them (cases 2 and 3) had positive early FEV1 reactions in low exposure levels (0.03% and 0.3% w/w BCMBA in 100 g lactose) combined with increase in FeNO or hyperresponsiveness. Case 5 had an isolated increase in hyperresponsiveness. Three patients tested with the inhalation challenge and one with a nasal provocation test had an immediate rhinorrhoea reaction; significant nasal congestion was not detected.
Supplementary file 2
All patients examined at FIOH (table 3) were removed from BCMBA exposure. Six months after the examinations, case 2 occasionally experienced rhinitis when coming in contact with a worker whose clothes were contaminated with BCMBA dust. Other patients did not have work-related respiratory or skin symptoms.
We identified nine workers with respiratory or skin symptoms and positive SPT to BCMBA in a chemical factory. Six cases of occupational asthma, rhinitis and/or urticaria caused by this agent were confirmed with challenge tests. A medical survey among chemical factory workers indicated a high sensitisation rate of 25% among production workers.
The participation rate in the survey was high, but it is possible that we missed some sensitised workers who did not participate in the survey or who no longer worked in the factory due to healthy worker effect.14 Also, two index cases were excluded from the survey. The sensitisation rate of the highest exposure groups, 25% in production workers and 13% in maintenance, was comparable to some studies among enzyme-exposed and platinum-exposed workers.15 16 BCMBA-sensitised workers reported more allergic rhinitis symptoms to common aeroallergens than the non-sensitised workers suggesting that atopy was associated with BCMBA-sensitisation. Atopy has been associated with increased risk of IgE-mediated sensitisation to occupational agents including enzymes and acid anhydrides.17
Some LMW agents including platinum salts, acid anhydride compounds and reactive dyes have been considered to cause asthma and rhinitis via IgE-mediated mechanisms.18–20 SPTs with acid anhydrides and platinum salts have shown good diagnostic sensitivity.9 16 Workers exhibited positive SPTs to very dilute concentrations of BCMBA, a reaction similar to that to platinum salts. All unexposed workers had negative SPT, whereas workers with positive SPTs had a typical clinical picture of IgE-mediated diseases, suggesting that the positive reactions were caused by sensitisation rather than irritation.18 They had coexistent asthma, rhinitis and/or contact urticaria and a latency period before the onset of symptoms. After sensitisation, very low exposures induced asthma, rhinitis and urticaria. The symptoms improved after removal from exposure. Positive specific inhalation and nasal challenge, SPTs and open skin application tests further supported the suspicion of IgE-dependent mechanisms.
BCMBA, namely 3-(Bromomethyl)−2-chloro-4-(methylsulfonyl)-Benzoic acid (CAS 120100-05-2), represents a new LMW agent causing occupational diseases. According to the European Chemicals Agency (ECHA), it is used in the European Economic Area only as an intermediate in manufacture of other substances.21 In the present workplace, it was an intermediate in the production of a plant protective agent. We are not aware of other uses of BCMBA. It is a benzoic acid derivate composed of a chlorinated benzene ring attached with bromomethyl, carboxylic acid and methylsulfonyl side groups (figure 1), but the chemical structure is nevertheless quite different from benzoic acid, which is a known non-immunological contact urticaria-eliciting compound. Interestingly, occupational asthma and rhinitis due to related benzoic acid derivative have been reported.22 LMW agents causing respiratory sensitisation and occupational asthma are typically reactive electrophilic compounds.23 They are non-immunogenic in their native state, and are thought to react with airway proteins, permitting presentation of these agents to the immune system.24 Non-electrophilic mechanisms for protein binding may occur through disulphide exchange or coordination bonds.25 BCMBA has several functional sites, which has been suggested as a critical characteristic for reactivity with proteins.26 BCMBA in our case was a reactive intermediate in a chemical synthesis consisting of several steps; it differed from its precursor only by the bromium atom in the bromomethyl structure. BCMBA showed a low hazard index (0.0148) in a quantitative structure–activity relationship model developed to predict chemical asthma hazard.27 However, as it is a highly reactive compound with several reactive sites, it may indeed react with human proteins leading to a sensitising conjugate. BCMBA could thus provide valuable input into the asthma hazard model. According to ECHA, BCMBA does not have a harmonised hazard classification, but is classified as a skin sensitiser by two of the notifying companies.28 BCMBA showed some skin sensitising potential in one study based on a local lymph node assay (LLNA) in mice.21 LLNA is an indicator of skin sensitisation potency, but most LMW respiratory allergens also test positive in LLNA or other assays for skin sensitisation.29
The available dust measurements represented the points where BCMBA exposure was estimated to be considerable and they provided basic information on the dust exposure in BCMBA operations before and after the improvements. Measurements from maintenance work would have improved the exposure assessment. Due to the limited amount of dust measurement data, we do not know the airborne BCMBA concentrations at which these diseases develop. However, BCMBA-related sensitisation occurred in workers estimated to have the highest exposure levels, while none of the workers in the quality control were sensitised. This suggests that sensitisation and related diseases were determined mainly by the level of exposure. In specific inhalation challenges, some sensitised persons had asthma and rhinitis reactions in very low concentrations of 0.03% or 0.3% BCMBA in lactose. These lowest asthma-provoking doses are similar to those seen in patients sensitised to enzymes.30 Exposure control in factories using enzymes has been challenging,31 and our data suggest that similar difficulties may be confronted with BCMBA that spreads easily to the breathing zone and skin. Preventing exposure to BCMBA and other sensitisers in fine powder form requires stringent control measures such as careful working habits, closed and ventilated processes and respiratory and skin protection. In this factory, workers have not contacted occupational healthcare due to BCMBA-related symptoms after work-hygienic improvements (personal communication). Workplace surveillance, including evaluation of symptoms and SPT to BCMBA, might be useful in following up on the effect of control measures and the detection of new affected workers.
We identified a new LMW agent causing occupational asthma, rhinitis and contact urticaria. Our findings suggest IgE-dependent mechanisms of BCMBA-related respiratory and skin diseases. Further studies are needed to clarify the underlying disease mechanisms.
We thank Maria Pesonen for the clinical photos and nurse Suvi-Päivikki Salo for performing SPTs.
Contributors All authors participated in conception, design and interpretation of data and approved the final version. HS, KY, LA, SS and IL acquired data, HS and SA analysed data and HS drafted the article, which all authors reviewed.
Funding The study was entirely funded by the unit performing the study.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study was approved by the ethics committee of Helsinki University Central Hospital (approval number 403/13/03/00/15). All the participants signed an informed consentform.
Provenance and peer review Not commissioned; externally peer reviewed.
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