- Open Access
Bronchial asthma and COPD due to irritants in the workplace - an evidence-based approach
Journal of Occupational Medicine and Toxicology volume 7, Article number: 19 (2012)
Respiratory irritants represent a major cause of occupational obstructive airway diseases. We provide an overview of the evidence related to irritative agents causing occupational asthma or occupational COPD.
We searched MEDLINE via PubMed. Reference lists of relevant reviews were also screened. The SIGN grading system was used to rate the quality of each study. The modified RCGP three-star system was used to grade the body of evidence for each irritant agent regarding its causative role in either occupational asthma or occupational COPD.
A total of 474 relevant papers were identified, covering 188 individual agents, professions or work-sites. The focus of most of the studies and the predominant diagnosis was occupational asthma, whereas occupational COPD arose only incidentally.
The highest level assigned using the SIGN grading was 2+ (well-conducted systematic review, cohort or case–control study with a low risk of confounding or bias). According to the modified RCGP three-star grading, the strongest evidence of association with an individual agent, profession or work-site (“**”) was found for 17 agents or work-sites, including benzene-1,2,4-tricarboxylicacid-1,2-anhydride, chlorine, platinum salt, isocyanates, cement dust, grain dust, animal farming, environmental tobacco smoke, welding fumes or construction work. Phthalic anhydride, glutaraldehyde, sulphur dioxide, cotton dust, cleaning agents, potrooms, farming (various), foundries were found to be moderately associated with occupational asthma or occupational COPD (“*[+]”).
This study let us assume that irritant-induced occupational asthma and especially occupational COPD are considerably underreported. Defining the evidence of the many additional occupational irritants for causing airway disorders will be the subject of continued studies with implications for diagnostics and preventive measures.
Bronchial asthma and chronic obstructive pulmonary disease (COPD) are common conditions and are the dominating obstructive airway diseases in the general population.
Work-related asthma (WRA) including irritant-induced occupational asthma (OA)
Occupational asthma is defined as a chronic inflammatory disorder of the airways with recurrent episodes of coughing, wheezing, chest tightness, dyspnea, shortness of breath at rest, and reversible airflow limitations caused by a particular occupational environment [1–3].
The available epidemiological and comparative studies and reviews provide evidence that occupational agents cause 5 – 25% of all asthma cases [1, 4–23]. Besides these evident occupational asthma (OA) cases, there is probably an even larger population of sufferers of work-aggravated asthma [24–26]. The latter population shows an objective worsening of pre-existing asthma or non-occupational asthma that develops in parallel with causative conditions encountered in the workplace (Figure 1).
Occupational agents eliciting bronchial asthma, i.e. OA, comprise occupational allergens, with their well-defined etiological role and IgE-mediated pathomechanism, as well as occupational agents with unknown pathomechanisms and occupational respiratory irritants, mainly representing low molecular weight chemicals (LMW; <5000 Daltons) causing irritant-induced OA (Figure 2). The latter agents may also elicit occupational COPD (see chapter 1.2) and include chlorine, acids, welding fumes, as well as isocyanates. The etiological role of such low molecular chemicals has not yet been completely clarified, primarily because of the lack of specific diagnostic tests.
There is sparse data available on causes and frequencies of irritant-induced COPD and work-aggravated asthma. Therefore, this work focuses on irritant-induced OA.
Many case reports, case series and a few cross-sectional studies demonstrate that a single short-term accidental massive exposure or several short-term high-level exposures to a respiratory irritant can cause asthma within 24 hours without a latency period. Brooks et al.  defined this disorder as “reactive airways dysfunction syndrome” (RADS). This term was later extended to irritant-induced OA from multiple, somewhat lower, exposure incidents with a less sudden onset that were also shown to cause this disorder [27, 31–36].
Furthermore, there is evidence that a susceptible subgroup of subjects mainly atopics with non-specific bronchial hyperresponsiveness (NSBHR) suffering from irritant-induced OA, is also affected by chronic exposures to relatively low concentrations of irritant gases, fumes or aerosols [27, 37, 38]. This disorder has been called “low-dose irritant asthma” (or “low-dose RADS”). Corresponding studies indicate respiratory effects including asthma from mainly chronic or repeated exposure to a single irritant or a mixture. Demonstrably causative concentrations of a particular irritant are often below their occupational exposure limits (OELs) or permissible exposure limits (PELs). Such irritant examples include swine confinement facilities [39, 40], exposures to cleaning agents [12, 41], solvents, ozone, endotoxin, formaldehyde, quaternary ammonium compounds, chlorine, bisulfite and SO2, or acid mist [36, 37, 42–44], diesel exhaust [10, 45, 46], fumigant residues , dusts in the textile paper, mineral fiber or construction industries or in mines [48–51], as well as a proportion of cases of potroom asthma  and meatwrappers' asthma . Asthma in cold-air athletes may also be relevant [54, 55]. A previous summary of the literature on respiratory effects from asthma due to irritants below their OELs/PELs is available . Many of the earlier exposure limits have been lowered repeatedly in the light of subsequent clinical or epidemiological findings on their respiratory effects. Other limits remain obstinately high given their known irritative effects and/or that they are based on sparse data . Accordingly, adherence to OELs/PELs does not preclude the onset of WRA in susceptible subjects.
The broader definition of these disorders (as used in the legal definition in Germany) includes all irritant-induced obstructive airway diseases irrespective of their causative concentrations and reversibility, i.e. irritant-induced occupational asthma as well as COPD.
Frequency of OA
OA has become the most prevalent occupational lung disease in developed countries [57, 58] and it is one of the most frequent diagnosis among occupational diseases in general . The annual incidence of OA is in the range of 50 per million with extremes up to 250 per million workers and more than 1,300 per million in specific workplaces [57, 60]. As already mentioned there is evidence that occupational agents cause 5 - 25% of of all asthma cases. However, complete registries of OA do not exist and therefore the true frequency of the disease is unknown. Ameille et al.  and Fernández-Nieto et al.  stated that OA is underestimated among occupational diseases, because many OA cases are not subjected to appropriate diagnostic tests.
Chronic obstructive pulmonary disease (COPD) due to occupational exposure
The diagnosis of COPD is based on chronic productive cough, airflow limitation that is usually not fully reversible, and a progressive, abnormal inflammative response of the lungs mostly caused by long-term smoking and by other noxious particles or gases .
During ongoing causative exposures (e.g. smoking particles, droplets and/or gases), airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs. Patients with COPD have greater number of neutrophils and alveolar macrophages in bronchoalveolar lavage fluid than healthy non-smokers . Sites of emphysema, which are frequently found in COPD patients, contain large numbers of lymphocytes, and the extent of lymphocyte accumulation correlates with reduction of FEV1.
Occupational COPD is identified on epidemiological basis, by observing increased frequencies of COPD among certain working groups , e.g. in construction workers . Some occupational exposures (e.g. welding fumes, aluminium, potroom fumes, and cadmium) may cause COPD associated with emphysema [67, 68].
At later stages of OA, the condition of some subjects does not improve over weekends or during holidays and coincides with symptoms of COPD patients. This observation also applies to non-occupational obstructive airways diseases [69, 70] and indicates that a group with changing diagnoses as well as with some overlap between OA and occupational COPD, does exist [66, 71–73].
Background and objective
WRA and occupational COPD are serious and sometimes fatal diseases, which can lead to ill health, inability to work and lost productivity [1, 25, 74–76]. They represent a huge economic burden to the society. For details see Additional file 1: Online Supplement “Economic burden”.
The objective of this study is to summarize present knowledge on respiratory irritants causing obstructive airway diseases in humans in the occupational setting and to provide a rating of the strength of evidence for each irritant which has not been previously available.
A systematic review of the literature on occupational irritant-induced OA and occupational COPD due to occupational irritants was conducted. We considered asthma-inducing irritating agents as well as those reported to cause occupational COPD and related disorders, where obstructive ventilation patterns were demonstrated in clinical investigations, cross-sectional studies, cross-shift and/or in long-term exposure studies. Irritating gases mainly occurring in the general environment, such as ozone, and inorganic dusts, including silica, talcum, silicates and other fibers known to cause pneumoconioses, were not considered even though exposure to them is frequently associated with mixed ventilation patterns.
Occupational COPD: chronic bronchitis symptoms and non-reversible airflow limitation due to particular occupational environment (if lung function data was available; otherwise, clinical diagnosis as given by the authors is cited).
Occupational asthma: episodes of shorteness of breath due to particular occupational environment and reversible airflow limitation (if lung function data was available; otherwise, clinical diagnosis as given by the authors is cited).
Obstructive ventilation pattern: we applied reference values of FEV1/FVC from Brändli, Schindler et al. 2000 .
Information sources and selection criteria
Occupational respiratory irritants
To identify the evidence of irritants of the respiratory tract, all agents denoted as “may cause respiratory irritation” by the phrase H335 (previous code R37) and “may cause allergy or asthma symptoms or breathing difficulties if inhaled” H334 (previous code R42)  and/or as “irritants” by American Conference of Governmental Industrial Hygienists  were initially listed ; later this list was compared with results of our database search (see below).
We searched for publications reporting investigations exclusively in humans (i.e. animal or in-vitro research was excluded). To be included, the publications had to deal with subjects occupationally exposed to airway irritants.
MEDLINE®-Database was searched with PubMed® from its inception up to December 2007 with the following medical subject headings (MeSH) combinations for each single agent:
“Agent”[MeSH] AND “Humans”[MeSH] AND ((“Asthma”[MeSH] OR “Asthma/chemically induced”[MeSH] OR “Asthma/immunology”[MeSH]) OR “Pulmonary Disease, Chronic Obstructive”[MeSH] OR “Lung Diseases, Obstructive/*chemically induced”[MeSH] OR “Respiratory Function Tests”[MeSH]) AND (“Accidents, Occupational”[MeSH] OR “Occupational Exposure”[MeSH] OR “Occupational Diseases”[MeSH] OR “Occupational Diseases/chemically induced”[MeSH])).
If more than 20 publications per agent were found, the search was more specified:
“Agent”[MeSH] AND “Humans”[MeSH] AND (“Cohort Studies”[MeSH] OR “Case–control Studies”[MeSH] OR “Case–control Studies”[All Fields] OR “Longitudinal Studies”[MeSH] OR “Longitudinal Studies”[All Fields] OR “Cross-Sectional Studies”[MeSH] OR “Cross-Sectional Studies”[All Fields] OR “Epidemiologic Studies”[MeSH] OR “Epidemiologic Studies”[All Fields] OR “Case Reports”[Publication Type] OR “Meta-Analysis”[MeSH] OR “Meta-Analysis”[All Fields]) AND “adverse effects”[Subheading] AND ((“Asthma”[MeSH] OR “Asthma/chemically induced”[MeSH] OR “Asthma/immunology”[MeSH]) OR “Pulmonary Disease, Chronic Obstructive”[MeSH] OR “Lung Diseases, Obstructive/*chemically induced”[MeSH] OR “Respiratory Function Tests”[MeSH]) AND (“Accidents, Occupational”[MeSH] OR “Occupational Exposure”[MeSH] OR “Occupational Diseases”[MeSH] OR “Occupational Diseases/chemically induced”[MeSH])).
Reference list screening
We also considered references in the identified already existing 13 systematic reviews or overviews of causes of work-related asthma or COPD and tried to combine results of both approaches.
Occupational diseases statistics
Further, we considered the following occupational diseases statistics based either on statutory surveillance or registration systems: SWORD 1994–1997 [81–83]; SHIELD 1993 ; SORDSA 2001 ; SENSOR 2003 ; Dokumentation der Berufskrankheiten 2007 (BK-DOK) .
Four different conditions were accepted for inclusion:
Irritant-induced OA including RADS. Asthma caused by single or multiple occupational exposures to airway irritants; de novo irritant-induced OA. Asthma within 24 hours without a latency period caused by short-term high-level exposures to a respiratory irritant known as acute irritant-induced asthma, or as RADS .
Work-aggravated (exacerbated) irritant-induced OA. Pre-existing or concurrent asthma worsened by work factors . Subjects with work-related asthmatic symptoms, if not differentiated whether new-onset or work-aggravated.
Occupational COPD. On epidemiological basis, identified by observing increased frequencies of COPD among certain working groups .
Obstructive ventilation pattern. Studies about irritant agents, where obstructive ventilation patterns in occupational settings were reported.
Methodological selection criteria
Publications with one of the following study designs were included: Systematic reviews of cohorts, case–control or cross-sectional studies, cohort studies (prospective/retrospective), case–control studies, cross-sectional studies, surveys.
Non-analytic1a studies (i.e. case series, follow-up of cases or case reports) were only included when for an agent no studies with one of the above mentioned designs had been identified.
Publications were included when they met any of the following criteria: examining the frequency of irritant-induced OA or asthmatic work-related symptoms in occupationally exposed groups or individuals, reporting the causative role of the specific agent or mixture of agents for irritant-inducing WRA or COPD.
Studies were included when they applied any of the following diagnostic tools: description of work-related asthmatic symptoms (questionnaire), lung function test (LFT), testing for non-specific bronchial hyperresponsiveness (NSBHR) by means of methacholine, histamine or other pharmacological agents, serial spirometry or expiratory peak flow (PEF) monitoring or supervised exposure testing in the workplace, challenge with the help of lung function measurements (SFT), specific inhalation challenge testing (SIC), clinical diagnosis of OA by an expert (occupational or pulmonary physician), and exposure to an irritant agent.
Publication period: No restriction for publication dates were made, last updates were between 5th and 15th June 2012.
Language: English, German, Spanish, Italian or French.
Methodological studies, e.g. on effects of study design and subsequent procedures, and studies with non-occupational disorders were excluded. Publications about occupational agents which do not have an irritant effect on the respiratory tract (e.g. about IgE-sensitizing agents) or with unrelated issues (e.g. studies on immunological questions) were also excluded.
Assessment of study quality
The principal study characteristics and study results were systematically extracted using an extraction sheet (see Additional file 2: Table S1A of online supplement “Methodology”).
We assessed study quality with the help of a check list (see Additional file 2: Table S1B of online supplement “Methodology”). The evidence level of each study was graded according to the revised Scottish Intercollegiate Guidelines Network (SIGN) grading system . Since population-based randomized assignment to different levels of irritant exposure are unethical, no randomised controlled trials (RCTs) could be expected on this topic and, thus, no level 1 evidence (as defined by the revised SIGN grading system)  would be available. In order to achieve more differentiation among lower evidence grades, we modified the SIGN grading system and added an additional grade (3+) (see Additional file 2: Table S1C of online supplement “Methodology”).
Overview on publications retrieved
The database search (MEDLINE/ PubMed) yielded 383 potentially relevant publications. 480 additional potentially relevant publications were retrieved from the reference lists of 13 systematic reviews or overviews [2, 30, 36, 80, 89–97], from occupational diseases routine statistics (SWORD 1994–1997 [47, 81–83]; SHIELD 1993 ; SORDSA 2001 ; SENSOR 2003 ; BK-DOK 2007 , and from the library of the Institute of Occupational Medicine, Hamburg. Alltogether, the different search approaches yielded a total of 474 relevant studies, including an extreme early study from the year 1932 . (See selection flow diagram, Figure 3).
Most (n = 337) of the 474 relevant publications were identified through hand searching (i.e. reference list checking of systematic reviews and from our library database).
The 474 publications refer to 131 individual agents, 46 to “mixed” agents and 11 to work-sites or professions reported to cause OA and/ or occupational COPD.
Many different ways of confirming irritant-induced OA were used, with specific inhalation challenge (SIC) and lung function tests (LFT) being the most reliable diagnostic aids.
SIC was used as the “gold standard” in confirming OA mainly in non-analytical studies (n = 189 studies, i.e. 72% of non-analytical studies). Only few (n = 16, i.e. 7.5% of analytical studies) cohort or case–control reported diagnostic confirmation with SIC.
Another frequently used (n = 191) diagnostic method for OA or occupational COPD was lung function testing (LFT); showing an obstructive ventilation pattern and/or NSBHR related to occupational exposures, mostly in combination with WRA symptoms.
Exclusively self-reported asthma symptoms or physician reported asthma as documented in questionnaires as an alternative diagnosis for OA was used in 36 studies.
Other studies (n = 44) had not clear diagnosis of OA or occupational COPD but reported obstructive ventilation pattern. The number of subjects with asthma symptoms and frequencies of obstructive ventilation patterns and/or NSBHR are provided for each study (see Additional file 3: Table S2E of online supplement “Results”).
Irritant-induced OA as outcome
Irritant-induced OA was the focus of most studies and was the predominant diagnosis.
RADS, as a subgroup of irritant-induced OA, was reported to be due to 47 different agents, with the most prevalent being the World Trade Center disaster in 2001 (n = 7 studies), chlorine (n = 11), cleaning agents (n = 18) and isocyanates (n = 46). These were followed by disorders, caused by metam sodium (n = 17), ammonia (n = 11), diesel exhaust (n = 10), acids (n = 9), solvents (n = 8), sulfur dioxide (n = 7), dinitrogen tetraoxide (n = 6), hydrogen chloride (n = 4), smoke (fires, pyrolysis products) (n = 4), chlorofluorocarbons (n = 4), spray paint (n = 3), tear gas (n = 3), bromine (n = 2), dichlorvos (n = 2), sodium azide (n = 2), acrylates (n = 1), amprolium hydrochloride (n = 1), phthalic anhydride (n = 1), bromochlorodifluoromethane (n = 1), bromotrifluoromethane (n = 1), chloramine T (n = 1), chromate (n = 1), hydrazine (n = 1), hydrogen fluoride (n = 1), methylmercaptan (n = 1), phosgene (n = 1), uranium hexafluoride (n = 1), airbag content (n = 1), bleaching agent (n = 1), floor sealant (n = 1), fumigant (n = 1), metal coat remover (n = 1), metal oxide fume (n = 1), pesticides (n = 1), refractory ceramic fibers (n = 1), swine confinement (n = 1).
The majority of asthma-inducing agents elicited OA after prolonged exposure and rarely after a single exposure.
Occupational COPD as outcome
Ten agents and five professions or work-sites were reported to cause occupational COPD, as shown in Table 2.
As already mentioned, occupational COPD was not specifically addressed in most of the studies. Some describe respiratory symptoms, such as chronic bronchitis (n = 21), which may be indicative of COPD. One of the few studies which specifically focused on COPD, was a large retrospective cohort study on diesel exhaust which caused a significantly increased COPD mortality in railroad workers after the introduction of diesel engines in 1945 [105, 106]. Construction work was identified as a cause of occupational COPD in 2 publications [8, 107].
Evidence level of the literature
Some publications investigated more than one irritant agent and thus have been considered several times in our study.
of the 474 publications were non-analytic studies and were rated according to SIGN as 4, 3 or 3+ and consisted of case reports (n = 228), case series (n = 63), and occupational diseases statistics (n = 33) and reviews of that kind of studies (n = 7). The other publications reported analytical studies and were rated according to SIGN as 2+ (n = 15), 2- (n = 103), or 3+ (n = 83).
The highest level was 2+, indicating a well conducted analytical study (case control or cohort studies) with a low risk of confounding or bias (n = 15 studies). Other studies with a similar design had a higher risk of confounding or bias and were individually rated lower by SIGN grading of 2- (n = 30 studies). Most of the other analytical studies were rated with a SIGN grade of 2-, because their design (cross-sectional or longitudinal study) was limiting (n = 82 studies). Cross-sectional studies or longitudinal studies, e.g. those with high risk of confounding or bias, were rated even lower with 3/ 3+ (n = 35 studies). A couple of study designs were difficult to classify epidemiologically, including those which were surveys, mostly with very low analytical evidence, rated 3/ 3+ (n = 53 studies), or larger surveys with a lower risk of confounding or bias, which were graded with 2- (n = 4 studies).
Another assessment of the level of evidence found in individual studies is to consider their OR for irritant-induced OA or occupational COPD; this was done in 39 publications [15, 23, 44, 48, 105–108, 113, 117–120, 122, 126, 128, 134–156].
Strength of evidence per agent, work-site or profession
The outcome for each agent causing OA or occupational COPD was graded according to the modified RCGP three-star system to classify the strength of evidence of its causative role in irritant-induced OA/ occupational COPD. The strongest evidence achieved was two stars “**” (indicating a moderate strength of evidence provided by generally consistent findings in fewer, smaller or lower quality scientific studies) for 17 (mixed) agents, work-sites or professions. For six of them (chlorine, platinum salts, environmental tobacco smoke, welding fumes, construction work, World Trade Center disaster in 2001), this level was based on well- conducted studies with low risk of confounding and/or bias (SIGN 2+). For eleven of these 17 (mixed) agents, SIGN levels of individual studies were lower (benzene-1, 2, 4-tricarboxylic acid-1,2-anhydride [trimellitic anhydride], cobalt, isocyanates, cement dust, grain dust, animal farming (pig, beef/veal, dairy, poultry), or swine confinement.
Low to moderate scientific evidence – provided by generally consistent findings in fewer, smaller or lower quality analytical studies, based on questionnaires or other inadequacies, i.e. “*[*]” – was found for 12 agents (phthalic anhydride, glutaraldehyde [glutaral], sulfur dioxide, cotton (dust, raw) CNT 750, potroom aluminum smelting, farming (various) or foundry), smoke (fires, pyrolysis products), pesticides (not specified), cleaning agents (not specified), ceramic production (dust), health care workers.
Limited or contradictory evidence – provided by only one analytical study or inconsistent findings in multiple scientific studies, i.e.“*” – was identified for 39 agents, and after down-grading because of inadequate methodological aspects, i.e. “[*]” on three occasions. For the majority of agents, only non-analytical studies were reported for ≥ 5 cases, i.e. “(*)” or less than 5 cases, i.e. “-”. When only non-analytical studies were available, the strength of evidence for the agent was raised if at least 5 cases were identified by the case reports/ case series or occupational disease statistics for which proof of irritant-induced OA or occupational COPD existed. The strength of evidence reached when only non-analytical studies were available ranged from “very limited or contradictory evidence” in 29 studies, i.e. “(*)”, to “no scientific evidence” “-” 94 times. (see Tables 3 and 4 and Additional file 3: Table S2E of online supplement “Result”).
The compiled assessment of the individual studies, along with their relevant clinical data and strength of evidence for irritant agents, professions or workplaces causing asthma or COPD, is presented as a summary list (see Additional file 3: Table S2E “Results” for the full information).
The main objective of this study was to give a comprehensive and evidence-based overview of the literature on irritative agents, professions or work-sites causing irritant-induced work-related asthma and occupational COPD. To our knowledge this study is the first attempts to document these respiratory disorders, along with their causative irritant agents in an evidence-based manner.
The 474 publications retrieved (see Table 3 and Additional file 3: Table S2E of online supplement “Results”) in this work mainly refer to individual agents (n = 131), but also to mixed exposure(s) or multicomponent work-sites or professions (n = 57) where heterogeneous exposure to irritating substances is common, e.g. swine confinement, “construction work” or “farming”, giving 188 different causes of irritant-induced OA and/or occupational COPD in total.
Strength and limitations
This work covers a broad range of causative agents of irritant-induced occupational asthma or COPD. We included various study designs.
A strength of our work is that we not only assessed the quality of single investigations but the strength of the body of evidence for each irritant agent.
The paradigm of “evidenced-based medicine” has been criticized by leading scientists [547–550]. Bias in the selection of information may be a problem for generalization of findings in single studies [551, 552]. In spite of these limitations, alternative approaches to evaluation of the literature have not been generally accepted. Evaluation of the evidence depends on the domain, which means the factors to be considered in assessing the extent to which the study results are reliable or valid.
Kunz et al.  stressed the approach of grading scientific studies on basis of additional qualified data, i.e. dose response relationships. This latter was seen in 30/474 individual studies in this current work. Other studies were based on evidence by OR >2 or < 0.5 for irritant-induced OA and occupational COPD which was applied as an approach in 40/474 individual studies (see Additional file 3: Table S2E of online supplement “Results”).
There are numerous procedural methods for rating the strength of scientific evidence. The AHRQ emphasized in 2002: “systems for grading the strength of a body of evidence are much less uniform than those for rating study quality” .
It is possible that not all relevant studies were found in our search of literature. Probably, some studies could not be found by the MeSH term raster applied. Relying solely on MeSH terms might be a problem in the identification of studies of irritant-induced OA or occupational COPD. We restricted the search to the MeSH fields in order to increase the specificity of the search. As for any electronic search strategy, an increase of specificity implies a decrease in sensitivity of the search.
For each single study, we took into consideration possible risks due to confounding, e.g. exposure to multiple agents and selection bias, e.g. healthy worker effect.
Basis and quality of data
Irritant-induced obstructive airways diseases cannot usually be diagnosed in one clinical visit and, instead, follow-up and/or detailed clinical investigations are necessary. The diagnostic “gold standard” for OA is SIC using a specific occupational agent in an exposure chamber. SIC is particularly indicated in the clinical setting where new causative substances with still unknown adverse respiratory sensitization potential are suspected. This “gold standard” is not applicable for large studies; so, it was used mainly in case series or reports.The evidence levels to confirm irritant-induced work-relaated asthma or occupational COPD for the listed irritant agents, professions or worksites (see Additional file 3: Table S2E of online supplement “Results”) are frequently low with the major reasons being that high quality studies were missing and the quality of the available studies was low. Nevertheless, this knowledge is the best available and may help physicians to identify a suspected irritant agent as causative in irritant-induced work-related asthma and / or occupational COPD . As also recently stressed by Quint et al. , “implementing an evidence-based identification and regulatory process for OA will help to ensure primary prevention of OA”. In cases of low evidence level of an agent that does not exclude a causative role, caution should be exercised and a more detailed diagnostic testing of relevant exposure should be performed.
Occupational COPD, an underestimated category
We identified only 20 out of 474 publications that referred to occupational COPD, with most of them implicating inorganic or organic dust or fumes, such as cement dust, construction work and diesel exhaust, as the causative agents.
As an example, the mixed agent cement dust was investigated in 14 studies but only four studies documented cement dust as the causative agent in occupational COPD [111, 418, 419, 422] (see Table 3 and Additional file 3: Table S2E “Results”). The remaining 10 studies described irritant-induced OA cases [235, 423–426, 530] or identified significant asthma symptoms/ obstructive ventilation patterns without a clear diagnosis (5 studies: [178, 417, 420, 556]). It can be assumed that if it had been considered on the other 10 studies then occupational COPD caused by cement dust would have been frequently observed.
The population-attributable fraction for COPD associated with occupational exposure has been estimated between 9% and 31% [1, 64, 65]. However the true population-attributable risk due to occupational exposure is unclear [6, 557] as occupational COPD is rarely clinically diagnosed. Blanc et al.  recently published an ecological analysis using data from three large studies, comprising the Burden of Obstructive Lung Disease study , the Latin American Project for Investigation of Obstructive Lung Disease (PLATINO) and the European Community Respiratory Health Survey follow-up (ECHRS II), where occupational COPD was also not a primary goal. The original publications are mainly concerned with OA or asthma symptoms, but a history of pre-existing OA or RADS cannot be allowed to exclude occupational COPD . Blanc et al.  stressed that the contribution of occupational exposure cannot be ignored, because “the association between adverse working conditions and COPD (…) carries significance as a global finding (…), alongside the (…) critical contribution of cigarette smoking to disease prevalence”.
General acceptance of this statement does not exist [66, 559], although evidence for an association between individual exposure levels and COPD is accumulating in the latest literature [1, 6, 106, 506, 557, 560, 561].
Irritant-induced WRA – a broader definition
Irritant-induced OA includes three subcategories that predominantly differ according to the concentration of irritants in the workplace atmosphere. It can occur without a latency period, such as RADS, as was shown for 46 causative agents in our study, with the highest prevalence after spills of acids or tear gas (see Additional file 3: Table S2E of online supplement“Results”). Other agents, e.g. isocyanates or welding fumes, usually induce a slower onset of low dose irritant-induced asthma with a latency period and mostly without evidence of an IgE-mediated pathomechanism.
The ACCP also stated in its last Consensus Statement in 2008  that cases who do not meet the stringent criteria of RADS  (e.g. where there is a lag of several days before the onset of symptoms or where there is no single massive exposure but rather repeated exposure over days and weeks) should be subsumed into a broader category of irritant-induced OA. As outlined in the section “Introduction” Brooks et al.  and later also others, e.g. Burge  suggested using the term “not so sudden onset of irritant-induced asthma” for those developing the disorder after such exposure within a period of 2 days to 4 months. In an extended definition corresponding to ours, Burge  he used the term “low dose irritant-induced OA” for those developing the disorder after relatively low repeated exposure for more than 4 months.
Bardana  and Vandenplas and Malo  questioned whether such rather low concentrations could actually cause irritant-induced OA. These different opinions about the pathogenetic role of chronic or recurrent exposure(s) to low concentrations of respiratory irritants seem to be due to inadequate considering of the increased susceptibility of a small group of workers. Occupational disease statistics do mostly neither contain such cases nor work-aggravated asthma cases so far.
Another critical issue is the frequent disregarding of work-aggravated asthma due to occupational agents by physicians.
Comparison to occupational guidelines or consensus statements – what is new?
In the current analysis, the focus has been on irritant agents causing irritant-induced occupational asthma and COPD. Both entities have been underestimated or even overlooked in the past. Occupational COPD has not been considered as a subgroup of COPD thus so far [559, 564]; and the definition of irritant-induced OA has been heterogenous at best [24, 552, 565, 566]. Furthermore, the guidelines dealing with respiratory disorders have not even considered causation by individual irritant agents, so far.
The ACCP published a Consensus Statement in 2008  which focuses on the diagnosis and management of WRA after a latency period, i.e. due allergens and “sensitizers” with unknown pathomechanisms, effectively sidelining irritant-induced OA to RADS.
The Agency for Healthcare Research and Quality (AHRQ) in its the Evidence Report “Diagnosis and Management of WRA”  addressed the key question of the best diagnostic approach for a patient with suspected WRA. In respect of irritant-induced OA, they only considered RADS as a non-allergic asthma due to mainly low molecular weight compounds of unknown pathomechanism.
The Canadian Thoracic Society “Guidelines for OA”  was the first evidence-based guideline, although irritant-induced OA was limited to RADS. If criteria were not fulfilled then irritant-induced OA was discussed as a controversial diagnosis. The three evidence levels in the “Guidelines for OA” were based on quality of scientific evidence within analyzed studies . Compared with the modified RCGP three-star grading (see Additional file 2: Table S2D in online supplement “Methodology”), the different levels are defined in a more general way, i.e. not considering the quantitative aspect if only studies with lower scientific evidence exist.
The evidence review and recommendations for OA by the BOHRF [3, 569] were designed to improve the prevention, identification and management of OA. This work mainly deals with asthma after a latency period and considers irritant-induced OA and RADS to be closely related entities. The difference in comparison with our analysis is obvious even though our evidence-based approach was closely related to the BOHRF guidelines and used the same grading systems.
In summary, the existing guidelines or statements mostly define irritant-induced OA as RADS. Work-aggravated asthma, and occupational COPD as a distinct entity, have not been considered in any guideline, although the latter is becoming recognized as such in more recent publications [557, 559, 564].
This evidence-based approach is the first which focuses on especially irritative agents within the broader definition of irritant-induced OA and occupational COPD. For clarification, the grading systems were modified in accordance with BOHRF  when considering the extent and quality of the clinical investigations, with the goal of creating evidence levels for causative irritative agents as precisely as possible.
OA is the most common chronic occupational lung disease in many industrialized countries . COPD is the fourth leading cause of death worldwide with a significant portion of occupational cases . The term occupational COPD does not officially exist. However, it has to be considered as a subcategory of COPD .
Our study shows that reliable, sensitive and specific methods are required in the diagnostic approach for confirming irritant-induced OA, work-aggravated asthma, or occupational COPD. The specific diagnostic work-up in a subject with such a suspected disorder depends on the individual clinical data and on the knowledge of asthma- or COPD-inducing agents in the workplace. On this basis, our review may help in diagnostics especially for agent exposures where we were able to relate irritant-induced work-related asthma or occupational COPD to a high evidence-based level (i.e. two stars according to the RCGP grading).
We have created a list representing the strength of evidence for irritating agents to be causative in irritant-induced work-related asthma or occupational COPD (see Additional file 3: Table S2E of online supplement “Results”).
A low level or absence of evidence for many agents in causing irritant-induced work-related asthma or occupational COPD is sometimes due to contradictory findings in literature, but is mostly due to the absence of rigorous scientific studies, with many gaps remaining in the knowledge of a causative role for individual agents and conditions. Therefore, and because of rarely applied diagnostic approach in the clinical setting, our literature search and evaluation lead us to assume that irritant-induced respiratory disorders are considerably underreported in cross-sectional studies and occupational disease statistics.
Our list needs updating in the light of recent literature, in order to provide a realistic overview of agents and evidence level in their causation of irritant-induced work-related or occupational COPD.
The estimated high population-attributable risk in the range of 5–25% for occupational asthma and COPD from occupational exposure, indicates that more detailed and intensive research, as well as strategies designed to prevent these disorders, should receive high priority in the global efforts to reduce the burden of these diseases. This implies extended evidence-based diagnostic procedures that help to optimize primary and secondary prevention by the physicians dealing with occupational diseases.
Reduction of the exposure to noxious agents by lowering the permissible exposure limits is the best and favoured way for intervention. If this is not possible then other effective primary preventive measures, such as wearing adequate respiratory devices, are required [28, 570–574].
Finally, we would like to mention that the diagnosis of irritant-induced OA should be considered if:
there has been exposure to high concentration of an irritative agent identified in this study and the development of asthma without a latency period (original definition of RADS) or
there has been chronic or repeated exposures to moderate (in the TLV ranges) concentrations of an irritative agent identified in this review and the development of asthma with a latency period, but without evidence of an IgE-mediated pathomechanism and
there is evidence that a highly susceptible subject (e.g. with pre-existing NSBHR) develops new onset asthma upon occupational exposure to an identified irritative agent even at concentrations below the TLV.
Work-aggravated asthma should be considered if:
there have been any of the before-mentioned exposures and
there is a temporally related significant worsening of a pre-existing asthma or of a concomitant non-occupational asthma.
The diagnosis of occupational COPD should be considered if:
there has been exposure to an agent capable of causing occupational COPD, and
not reversible chronic airway disease is demonstrated and
there is a temporal relationship between the period of exposure (mostly cumulative exposures to identified irritants ) and the development of COPD (acute WRA symptoms are frequently missing).
Occupational COPD has to be taken into consideration especially in non-smokers, i.e. when dominating non-occupational causes for COPD are obviously not present.
aEpidemiologic study design which is generally applied to test one or more specific hypotheses, typically whether an exposure is a risk factor for a disease .
Chemical abstracts service
Chronic obstructive pulmonary disease
Reactive airways dysfunction syndrome
Royal college of general practitioners
Scottish intercollegiate guideline network
Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, Milton D, Schwartz D, Toren K, Viegi G: American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003,167(5):787–797.
Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI: Asthma in the workplace and related conditions. 3rd edition. Taylor & Francis, New York; 2006.
Nicholson PJ, Cullinan P, Burge PS, Boyle C: Occupational asthma: Prevention, identification & management: Systematic review & recommendations. British Occupational Health Research Foundation, London; 2010. http://www.bohrf.org.uk/downloads/OccupationalAsthmaEvidenceReview-Mar2010.pdf
Arif AA, Whitehead LW, Delclos GL, Tortolero SR, Lee ES: Prevalence and risk factors of work related asthma by industry among United States workers: data from the third national health and nutrition examination survey (1988–94). Occup Environ Med 2002,59(8):505–511.
Bakke PS, Baste V, Hanoa R, Gulsvik A: Prevalence of obstructive lung disease in a general population: relation to occupational title and exposure to some airborne agents. Thorax 1991,46(12):863–870.
Becklake MR: Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989,140(3 Pt 2):S85-S91.
Becklake MR, Malo J-L, Chan-Yeung MY: Epidemiological approaches in occupational asthma. In Asthma in the workplace. 3rd edition. Edited by: Bernstein IL, Chan-Yeung M, Malo J-L, Bernstein DI. Taylor & Francis Group, New York, London; 2006:37–85.
Bergdahl IA, Toren K, Eriksson K, Hedlund U, Nilsson T, Flodin R, Jarvholm B: Increased mortality in COPD among construction workers exposed to inorganic dust. Eur Respir J 2004,23(3):402–406.
Blanc PD, Toren K: How much adult asthma can be attributed to occupational factors? Am J Med 1999,107(6):580–587.
Henneberger PK, Derk SJ, Davis L, Tumpowsky C, Reilly MJ, Rosenman KD, Schill DP, Valiante D, Flattery J, Harrison R, et al.: Work-related reactive airways dysfunction syndrome cases from surveillance in selected US states. J Occup Environ Med 2003,45(4):360–368.
Karjalainen A, Kurppa K, Martikainen R, Klaukka T, Karjalainen J: Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population. Am J Respir Crit Care Med 2001,164(4):565–568.
Kogevinas M, Anto JM, Sunyer J, Tobias A, Kromhout H, Burney P: Occupational asthma in Europe and other industrialised areas: a population-based study. European Community Respiratory Health Survey Study Group. Lancet 1999,353(9166):1750–1754.
Leuenberger P, Schindler C, Schwartz J, Ackermann-Liebrich U, Tara D, Perruchoud AP, Wuthrich B, Zellweger JP, Blaser K, Bolognini G, et al.: Occupational exposure to inhalative irritants and methacholine responsiveness. Scand J Work Environ Health 2000,26(2):146–152.
Le Moual N, Kennedy SM, Kauffmann F: Occupational exposures and asthma in 14,000 adults from the general population. Am J Epidemiol 2004,160(11):1108–1116.
Medina-Ramon M, Zock JP, Kogevinas M, Sunyer J, Anto JM: Asthma symptoms in women employed in domestic cleaning: a community based study. Thorax 2003,58(11):950–954.
Meldrum M, Rawbone R, Curran AD, Fishwick D: The role of occupation in the development of chronic obstructive pulmonary disease (COPD). Occup Environ Med 2005,62(4):212–214.
Taylor AJ: Respiratory irritants encountered at work. Thorax 1996,51(5):541–545.
Petsonk EL: Work-related asthma and implications for the general public. Environ Health Perspect 2002,110(Suppl 4):569–572.
Viegi G, Di Pede C: Chronic obstructive lung diseases and occupational exposure. Curr Opin Allergy Clin Immunol 2002,2(2):115–121.
WHO: Reducing Risks, Promoting Healthy Life. In The World Health Report 2002. WHO, Geneva; 2002.
Xu X, Christiani DC, Dockery DW, Wang L: Exposure-response relationships between occupational exposures and chronic respiratory illness: a community-based study. Am Rev Respir Dis 1992,146(2):413–418.
Toren K, Blanc PD: Asthma caused by occupational exposures is common - a systematic analysis of estimates of the population-attributable fraction. BMC Pulm Med 2009, 9: 7.
Kogevinas M, Zock JP, Jarvis D, Kromhout H, Lillienberg L, Plana E, Radon K, Toren K, Alliksoo A, Benke G, et al.: Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007,370(9584):336–341.
Tarlo SM, Balmes J, Balkissoon R, Beach J, Beckett W, Bernstein D: Diagnosis and management of work-related asthma: American College of Chest Physicians Consensus Statement. Chest 2008, 134: 1–41.
Henneberger PK, Redlich CA, Callahan DB, Harber P, Lemiere C, Martin J, Tarlo SM, Vandenplas O, Toren K: An official american thoracic society statement: work-exacerbated asthma. Am J Respir Crit Care Med 2011,184(3):368–378.
Lemiere C, Forget A, Dufour MH, Boulet LP, Blais L: Characteristics and medical resource use of asthmatic subjects with and without work-related asthma. J Allergy Clin Immunol 2007,120(6):1354–1359.
Burge SP, Moore VC, Robertson AS: Sensitization and irritant-induced occupational asthma with latency are clinically indistinguishable. Occup Med (Lond) 2012,62(2):129–133.
Baur X, Sigsgaard T, Aasen TB, Burge PS, Heederik D, Henneberger P, Maestrelli P, Rooyackers J, Schlunssen V, Vandenplas O, et al.: Guidelines for the management of work-related asthma. Eur Respir J 2012,39(3):529–545.
Baur X, Aasen TB, Burge PS, Heederik D, Henneberger PK, Maestrelli P, Schlunssen V, Vandenplas O, Wilken D: The management of work-related asthma guidelines: a broader perspective. Eur Respir Rev 2012,21(124):125–139.
Brooks SM, Weiss MA, Bernstein IL: Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 1985,88(3):376–384.
Brooks SM, Hammad Y, Richards I, Giovinco-Barbas J, Jenkins K: The spectrum of irritant-induced asthma: sudden and not-so-sudden onset and the role of allergy. Chest 1998,113(1):42–49.
Chan-Yeung M, Lam S, Kennedy SM, Frew AJ: Persistent asthma after repeated exposure to high concentrations of gases in pulpmills. Am J Respir Crit Care Med 1994,149(6):1676–1680.
Humerfelt S, Gulsvik A, Skjaerven R, Nilssen S, Kvale G, Sulheim O, Ramm E, Eilertsen E, Humerfelt SB: Decline in FEV1 and airflow limitation related to occupational exposures in men of an urban community. Eur Respir J 1993,6(8):1095–1103.
Krzyzanowski M, Jedrychowski W, Wysocki M: Factors associated with the change in ventilatory function and the development of chronic obstructive pulmonary disease in a 13-year follow-up of the Cracow Study. Risk of chronic obstructive pulmonary disease. Am Rev Respir Dis 1986,134(5):1011–1019.
Tarlo SM, Broder I: Irritant-induced occupational asthma. Chest 1989,96(2):297–300.
Gautrin D, Bernstein IL, Brooks SM, Henneberger PK: Reactive airways dysfunction syndrome and irritant-induced asthma. In Asthma in the workplace. Edited by: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI. Taylor & Francis Group, New York, London; 2006:581–629.
Kipen HM, Blume R, Hutt D: Asthma experience in an occupational and environmental medicine clinic. Low-dose reactive airways dysfunction syndrome. J Occup Med 1994,36(10):1133–1137.
Dykewicz MS: Occupational asthma: current concepts in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2009,123(3):519–528. quiz 529–530
Cormier Y, Coll B, Laviolette M, Boulet LP: Reactive airways dysfunction syndrome (RADS) following exposure to toxic gases of a swine confinement building. Eur Respir J 1996,9(5):1090–1091.
Dosman JA, Lawson JA, Kirychuk SP, Cornier Y, Biem J, Koehncke N: Occupational asthma in newly employed workers in intensive swine confinement facilities. Eur Respir J 2004, 24: 698–702.
Reinisch F, Harrison RJ, Cussler S, Athanasoulis M, Balmes J, Blanc P, Cone J: Physician reports of work-related asthma in California, 1993–1996. Am J Ind Med 2001,39(1):72–83.
Liss GM, Tarlo SM, Doherty J, Purdham J, Greene J, McCaskell L, Kerr M: Physician diagnosed asthma, respiratory symptoms, and associations with workplace tasks among radiographers in Ontario, Canada. Occup Environ Med 2003,60(4):254–261.
Smedley J, Coggon D: Health surveillance for hospital employees exposed to respiratory sensitizers. Occup Med (Lond) 1996,46(1):33–36.
Toren K, Jarvholm B, Brisman J, Hagberg S, Hermansson BA, Lillienberg L: Adult-onset asthma and occupational exposures. Scand J Work Environ Health 1999,25(5):430–435.
Makker HK, Ayres JG: Work-related asthma in an aircraft engine mechanic. Respir Med 1999,93(1):69–70.
Wade JF 3rd, Newman LS: Diesel asthma. Reactive airways disease following overexposure to locomotive exhaust. J Occup Med 1993,35(2):149–154.
Baur X: Airborne allergens and irritants in the workplace. In Allergy and allergic diseases. Edited by: Kay AB, Kaplan AP, Bousquet J, Holt PG. Blackwell Publishing, Boston; 2008:1017–1122.
Toren K, Balder B, Brisman J, Lindholm N, Lowhagen O, Palmqvist M, Tunsater A: The risk of asthma in relation to occupational exposures: a case–control study from a Swedish city. Eur Respir J 1999,13(3):496–501.
Hnizdo E, Sullivan PA, Bang KM, Wagner G: Association between chronic obstructive pulmonary disease and employment by industry and occupation in the US population: a study of data from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 2002,156(8):738–746.
Oxman AD, Muir DC, Shannon HS, Stock SR, Hnizdo E, Lange HJ: Occupational dust exposure and chronic obstructive pulmonary disease. A systematic overview of the evidence. Am Rev Respir Dis 1993,148(1):38–48.
Marine WM, Gurr D, Jacobsen M: Clinically important respiratory effects of dust exposure and smoking in British coal miners. Am Rev Respir Dis 1988,137(1):106–112.
Kongerud J, Gronnesby JK, Magnus P: Respiratory symptoms and lung function of aluminum potroom workers. Scand J Work Environ Health 1990,16(4):270–277.
Andrasch RH, Bardana EJ Jr, Koster F, Pirofsky B: Clinical and bronchial provocation studies in patients with meatwrappers' asthma. J Allergy Clin Immunol 1976,58(2):291–298.
Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, Cummiskey J, Delgado L, Del Giacco SR, Drobnic F, et al.: Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: Part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy 2008, 63: 387–403.
Karjalainen A, Kurppa K, Virtanen S, Keskinen H, Nordman H: Incidence of occupational asthma by occupation and industry in Finland. Am J Ind Med 2000,37(5):451–458.
Hansson SO: Critical effects and exposure limits. Risk Anal 1997,17(2):227–236.
Latza U, Baur X: Occupational obstructive airway diseases in Germany: Frequency and causes in an international comparison. Am J Ind Med 2005,48(2):144–152.
Chan-Yeung M, Malo JL: Aetiological agents in occupational asthma. Eur Respir J 1994,7(2):346–371.
Fernandez-Nieto M, Quirce S, Sastre J: Occupational asthma in industry. Allergol Immunopathol (Madr) 2006,34(5):212–223.
Baur X, Latza U: Non-malignant occupational respiratory diseases in Germany in comparison with those of other countries. Int Arch Occup Environ Health 2005,78(7):593–602.
Ameille J, Pauli G, Calastreng-Crinquand A, Vervloet D, Iwatsubo Y, Popin E, Bayeux-Dunglas MC, Kopferschmitt-Kubler MC: Reported incidence of occupational asthma in France, 1996–99: the ONAP programme. Occup Environ Med 2003,60(2):136–141.
Tarlo SM, Liss GM: Occupational asthma: an approach to diagnosis and management. CMAJ 2003,168(7):867–871.
Pesci A, Majori M, Cuomo A, Borciani N, Bertacco S, Cacciani G, Gabrielli M: Neutrophils infiltrating bronchial epithelium in chronic obstructive pulmonary disease. Respir Med 1998,92(6):863–870.
Hnizdo E, Glindmeyer HW, Petsonk EL, Enright P, Buist AS: Case definitions for chronic obstructive pulmonary disease. Copd 2006,3(2):95–100.
Trupin L, Earnest G, San Pedro M, Balmes JR, Eisner MD, Yelin E, Katz PP, Blanc PD: The occupational burden of chronic obstructive pulmonary disease. Eur Respir J 2003,22(3):462–469.
Balmes JR: Occupational airways diseases from chronic low-level exposures to irritants. Clin Chest Med 2002,23(4):727–735. vi
Hendrick DJ: Smoking, cadmium, and emphysema. Thorax 2004,59(3):184–185.
Davison AG, Fayers PM, Taylor AJ, Venables KM, Darbyshire J, Pickering CA, Chettle DR, Franklin D, Guthrie CJ, Scott MC, et al.: Cadmium fume inhalation and emphysema. Lancet 1988,1(8587):663–667.
American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995, 152: 77–121.
Postma DS, Boezen HM: Rationale for the Dutch hypothesis. Allergy and airway hyperresponsiveness as genetic factors and their interaction with environment in the development of asthma and COPD. Chest 2004,126(2 Suppl):96S-104S. discussion 159S-161S
Balmes JR: Work-related COPD. Eur Respir J 1994, 7: 768–778.
Bourdin A, Serre I, Flamme H, Vic P, Neveu D, Aubas P, Godard P, Chanez P: Can endobronchial biopsy analysis be recommended to discriminate between asthma and COPD in routine practice? Thorax 2004,59(6):488–493.
Hargreave FE, Parameswaran K: Asthma, COPD and bronchitis are just components of airway disease. Eur Respir J 2006,28(2):264–267.
Gannon PF, Burge PS: The SHIELD scheme in the West Midlands Region, United Kingdom. Midland Thoracic Society Research Group. Br J Ind Med 1993,50(9):791–796.
Eisner MD, Yelin EH, Katz PP, Lactao G, Iribarren C, Blanc PD: Risk factors for work disability in severe adult asthma. Am J Med 2006,119(10):884–891.
Toren K, Brisman J, Olin AC, Blanc PD: Asthma on the job: work-related factors in new-onset asthma and in exacerbations of pre-existing asthma. Respir Med 2000,94(6):529–535.
Brändli O, Schindler C, Leuenberger PH, Baur X, Degens P, Kunzli N, Keller R, Perruchoud AP: Re-estimated equations for 5th percentiles of lung function variables. Thorax 2000,55(2):173–174.
European Parliament, The Council of EU: Regulation (EC) No 1272/2008 of the European Parliament and on the Council of 16 December 2008 on classification, labelling and packing of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulations (EC) No 1907/2006. Off J EU 2008, L 353: 1–1355. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:0001:en:PDF
American Conference of Governmental Industrial Hygienists: TLVs® and BEIs®. Threshold limit values for chemical substances and physical agents & biological exposure indices. ACGIH, Cincinnaty; 2009.
Baur X: Occupational agents with respiratory effects according to ACGIH 2009 and /or classified with the R42 phrase* (may cause sensitization by inhalation) and /or with the R37 phrase* (irritating to respiratory system) according to the European Union directives 67/548/EEC (1), 2001/59/EC (2), 2004/73/EC (3) or 2009/2/EC (4) (identical to ILO/CIS 2002. 2009,http://www.ilo.org/public/english/protection/safework/cis/products/icsc/dtasht/riskphrs/index.htm) http://www.uke.de/institute/arbeitsmedizin/downloads/universitaetsprofessur-arbeitsmedizin/R42_und_R37A-EU09.pdf and www.eomsociety.org => knowledge center
Meyer JD, Holt DL, Chen Y, Cherry NM, McDonald JC: SWORD '99: surveillance of work-related and occupational respiratory disease in the UK. Occup Med (Lond) 2001,51(3):204–208.
Meyer JD, Holt DL, Cherry NM, McDonald JC: SWORD '98: surveillance of work-related and occupational respiratory disease in the UK. Occup Med (Lond) 1999,49(8):485–489.
Ross DJ, Keynes HL, McDonald JC: SWORD '96: surveillance of work-related and occupational respiratory disease in the UK. Occup Med (Lond) 1997,47(6):377–381.
Esterhuizen TM, Hnizdo E, Rees D: Occurrence and causes of occupational asthma in South Africa–results from SORDSA's Occupational Asthma Registry, 1997–1999. S Afr Med J 2001,91(6):509–513.
Buckley LA, Jiang XZ, James RA, Morgan KT, Barrow CS: Respiratory tract lesions induced by sensory irritants at the RD50 concentration. Toxicol Appl Pharmacol 1984,74(3):417–429.
Haupt B, Drechsel-Schlund C, Guldner K, Rogosky E, Plinske W, Butz M: Dokumentation des Berufskrankheiten-Geschehens in Deutschland. BK-DOK 2005. Deutsche Gesetzliche Unfallversicherung (DGUV), Sankt Augustin; 2007. http://www.dguv.de/inhalt/zahlen/documents/bk_dok_2005.pdf
Harbour R, Miller J: A new system for grading recommendations in evidence based guidelines. BMJ 2001,323(7308):334–336.
The Royal College of General Practitioners RCGP: The development and implementation of clinical guidelines. In Report of the Clinical Guidelines Working Group. RCGP, London; 1995.
Alberts WM, do Pico GA: Reactive airways dysfunction syndrome. Chest 1996,109(6):1618–1626.
American Thoracic Society: Guidelines for assessing and managing asthma risk at work, school, and recreation. Am J Respir Crit Care Med 2004,169(7):873–881.
Baur X, Degens P, Weber K: Occupational obstructive airway diseases in Germany. Am J Ind Med 1998,33(5):454–462.
van Kampen V, Merget R, Baur X: Occupational airway sensitizers: an overview on the respective literature. Am J Ind Med 2000,38(2):164–218.
Malo JL: Irritant-induced asthma and reactive airways dysfunction syndrome. Can Respir J 1998,5(1):66–67.
Malo JL, Chan-Yeung M: Asthma in the workplace: a Canadian contribution and perspective. Can Respir J 2007,14(7):407–413.
McDonald JC, Keynes HL, Meredith SK: Reported incidence of occupational asthma in the United Kingdom, 1989–97. Occup Environ Med 2000,57(12):823–829.
Sastre J, Vandenplas O, Park HS: Pathogenesis of occupational asthma. Eur Respir J 2003,22(2):364–373.
Joules H: Asthma from sensitisation to chromium. Lancet 1932, 2: 182–183.
Boulet LP: Increases in airway responsiveness following acute exposure to respiratory irritants. Reactive airway dysfunction syndrome or occupational asthma? Chest 1988,94(3):476–481.
Simonsson BG, Sjoberg A, Rolf C, Haeger-Aronsen B: Acute and long-term airway hyperreactivity in aluminium-salt exposed workers with nocturnal asthma. Eur J Respir Dis 1985,66(2):105–118.
Matrat M, Laurence MF, Iwatsubo Y, Hubert C, Joly N, Legrand-Cattan K, L'Huillier JP, Villemain C, Pairon JC: Reactive airways dysfunction syndrome caused by bromochlorodifluoromethane from fire extinguishers. Occup Environ Med 2004,61(8):712–714.
Cone JE, Wugofski L, Balmes JR, Das R, Bowler R, Alexeeff G, Shusterman D: Persistent respiratory health effects after a metam sodium pesticide spill. Chest 1994,106(2):500–508.
Valero AL, Bescos M, Amat P, Malet A: Bronchial asthma caused by occupational sulfite exposure. Allergol Immunopathol (Madr) 1993,21(6):221–224.
Cockcroft DW, Hoeppner VH, Dolovich J: Occupational asthma caused by cedar urea formaldehyde particle board. Chest 1982,82(1):49–53.
Hart JE, Laden F, Schenker MB, Garshick E: Chronic obstructive pulmonary disease mortality in diesel-exposed railroad workers. Environ Health Perspect 2006,114(7):1013–1017.
Hart JE, Laden F, Eisen EA, Smith TJ, Garshick E: Chronic obstructive pulmonary disease mortality in railroad workers. Occup Environ Med 2009,66(4):221–226.
Ulvestad B, Lund MB: Increased risk of chronic obstructive pulmonary disease among tunnel construction workers. Tidsskr Nor Laegeforen 2003,123(16):2292–2295.
Kern DG: Outbreak of the reactive airways dysfunction syndrome after a spill of glacial acetic acid. Am Rev Respir Dis 1991,144(5):1058–1064.
Gamble J, Jones W, Hancock J, Meckstroth RL: Epidemiological-environmental study of lead acid battery workers. III. Chronic effects of sulfuric acid on the respiratory system and teeth. Environ Res 1984,35(1):30–52.
Bohadana AB, Massin N, Wild P, Berthiot G: Airflow obstruction in chalkpowder and sugar workers. Int Arch Occup Environ Health 1996,68(4):243–248.
Mwaiselage J, Bratveit M, Moen BE, Mashalla Y: Respiratory symptoms and chronic obstructive pulmonary disease among cement factory workers. Scand J Work Environ Health 2005,31(4):316–323.
Massin N, Hecht G, Ambroise D, Hery M, Toamain JP, Hubert G, Dorotte M, Bianchi B: Respiratory symptoms and bronchial responsiveness among cleaning and disinfecting workers in the food industry. Occup Environ Med 2007,64(2):75–81.
Sprince NL, Oliver LC, Eisen EA, Greene RE, Chamberlin RI: Cobalt exposure and lung disease in tungsten carbide production. A cross-sectional study of current workers. Am Rev Respir Dis 1988,138(5):1220–1226.
Woldeyohannes M, Bergevin Y, Mgeni AY, Theriault G: Respiratory problems among cotton textile mill workers in Ethiopia. Br J Ind Med 1991,48(2):110–115.
Rylander R, Bergstrom R: Bronchial reactivity among cotton workers in relation to dust and endotoxin exposure. Ann Occup Hyg 1993,37(1):57–63.
Rylander R, Haglind P, Lundholm M: Endotoxin in cotton dust and respiratory function decrement among cotton workers in an experimental cardroom. Am Rev Respir Dis 1985,131(2):209–213.
Chen R, Tunstall-Pedoe H, Tavendale R: Environmental tobacco smoke and lung function in employees who never smoked: the Scottish MONICA study. Occup Environ Med 2001,58(9):563–568.
Janson C, Chinn S, Jarvis D, Zock JP, Toren K, Burney P: Effect of passive smoking on respiratory symptoms, bronchial responsiveness, lung function, and total serum IgE in the European Community Respiratory Health Survey: a cross-sectional study. Lancet 2001,358(9299):2103–2109.
Hoppin JA, Umbach DM, London SJ, Alavanja MC, Sandler DP: Diesel exhaust, solvents, and other occupational exposures as risk factors for wheeze among farmers. Am J Respir Crit Care Med 2004,169(12):1308–1313.
Melenka LS, Hessel PA, Yoshida K, Enarson DA: Lung health in Alberta farmers. Int J Tuberc Lung Dis 1999,3(10):913–919.
Ahman M, Alexandersson R, Ekholm U, Bergstrom B, Dahlqvist M, Ulfvarson U: Impeded lung function in moulders and coremakers handling furan resin sand. Int Arch Occup Environ Health 1991,63(3):175–180.
Post W, Heederik D, Houba R: Decline in lung function related to exposure and selection processes among workers in the grain processing and animal feed industry. Occup Environ Med 1998,55(5):349–355.
Schwartz DA, Thorne PS, Yagla SJ, Burmeister LF, Olenchock SA, Watt JL, Quinn TJ: The role of endotoxin in grain dust-induced lung disease. Am J Respir Crit Care Med 1995,152(2):603–608.
Pahwa P, Senthilselvan A, McDuffie HH, Dosman JA: Longitudinal estimates of pulmonary function decline in grain workers. Am J Respir Crit Care Med 1994,150(3):656–662.
Wisnewski AV, Liu Q, Liu J, Redlich CA: Glutathione protects human airway proteins and epithelial cells from isocyanates. Clin Exp Allergy 2005,35(3):352–357.
Zock JP, Rodriguez-Trigo G, Pozo-Rodriguez F, Barbera JA, Bouso L, Torralba Y, Anto JM, Gomez FP, Fuster C, Verea H: Prolonged respiratory symptoms in clean-up workers of the prestige oil spill. Am J Respir Crit Care Med 2007,176(6):610–616.
Wieslander G, Norback D, Edling C: Airway symptoms among house painters in relation to exposure to volatile organic compounds (VOCS)–a longitudinal study. Ann Occup Hyg 1997,41(2):155–166.
Castro-Gutierrez N, McConnell R, Andersson K, Pacheco-Anton F, Hogstedt C: Respiratory symptoms, spirometry and chronic occupational paraquat exposure. Scand J Work Environ Health 1997,23(6):421–427.
Jones SM, Burks AW, Spencer HJ, Lensing S, Roberson PK, Gandy J, Helm RM: Occupational asthma symptoms and respiratory function among aerial pesticide applicators. Am J Ind Med 2003,43(4):407–417.
Hagmar L, Bellander T, Ranstam J, Skerfving S: Piperazine-induced airway symptoms: exposure-response relationships and selection in an occupational setting. Am J Ind Med 1984,6(5):347–357.
Calverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D: Platinum salt sensitivity in refinery workers: incidence and effects of smoking and exposure. Occup Environ Med 1995,52(10):661–666.
Lorimer WV, Lilis R, Nicholson WJ, Anderson H, Fischbein A, Daum S, Rom W, Rice C, Selikoff IJ: Clinical studies of styrene workers: initial findings. Environ Health Perspect 1976, 17: 171–181.
Prezant DJ, Weiden M, Banauch GI, McGuinness G, Rom WN, Aldrich TK, Kelly KJ: Cough and bronchial responsiveness in firefighters at the World Trade Center site. N Engl J Med 2002,347(11):806–815.
Jaakkola MS, Leino T, Tammilehto L, Ylostalo P, Kuosma E, Alanko K: Respiratory effects of exposure to methacrylates among dental assistants. Allergy 2007,62(6):648–654.
Medina-Ramon M, Zock JP, Kogevinas M, Sunyer J, Torralba Y, Borrell A, Burgos F, Anto JM: Asthma, chronic bronchitis, and exposure to irritant agents in occupational domestic cleaning: a nested case–control study. Occup Environ Med 2005,62(9):598–606.
Sauni R, Oksa P, Huikko S, Roto P, Uitti J: Increased risk of asthma among Finnish construction workers. Occup Med (Lond) 2003,53(8):527–531.
Jaakkola MS, Piipari R, Jaakkola N, Jaakkola JJ: Environmental tobacco smoke and adult-onset asthma: a population-based incident case–control study. Am J Public Health 2003,93(12):2055–2060.
Greer JR, Abbey DE, Burchette RJ: Asthma related to occupational and ambient air pollutants in nonsmokers. J Occup Med 1993,35(9):909–915.
Eisner MD, Balmes J, Katz PP, Trupin L, Yelin EH, Blanc PD: Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease. Environ Health 2005,4(1):7.
Fidan F, Cimrin AH, Ergor G, Sevinc C: Airway disease risk from environmental tobacco smoke among coffeehouse workers in Turkey. Tob Control 2004,13(2):161–166.
Radon K, Busching K, Heinrich J, Wichmann HE, Jorres RA, Magnussen H, Nowak D: Passive smoking exposure: a risk factor for chronic bronchitis and asthma in adults? Chest 2002,122(3):1086–1090.
Blanc PD, Ellbjar S, Janson C, Norback D, Norrman E, Plaschke P, Toren K: Asthma-related work disability in Sweden. The impact of workplace exposures. Am J Respir Crit Care Med 1999,160(6):2028–2033.
Flodin U, Jonsson P, Ziegler J, Axelson O: An epidemiologic study of bronchial asthma and smoking. Epidemiology 1995,6(5):503–505.
Eduard W, Douwes J, Omenaas E, Heederik D: Do farming exposures cause or prevent asthma? Results from a study of adult Norwegian farmers. Thorax 2004,59(5):381–386.
Hoppin JA, Umbach DM, London SJ, Alavanja MC, Sandler DP: Animal production and wheeze in the Agricultural Health Study: interactions with atopy, asthma, and smoking. Occup Environ Med 2003,60(8):e3.
Melbostad E, Eduard W, Magnus P: Determinants of asthma in a farming population. Scand J Work Environ Health 1998,24(4):262–269.
Mastrangelo G, Tartari M, Fedeli U, Fadda E, Saia B: Ascertaining the risk of chronic obstructive pulmonary disease in relation to occupation using a case–control design. Occup Med (Lond) 2003,53(3):165–172.
Mastrangelo G, Paruzzolo P, Mapp C: Asthma due to isocyanates: a mail survey in a 1% sample of furniture workers in the Veneto region, Italy. Med Lav 1995,86(6):503–510.
Meredith SK, Bugler J, Clark RL: Isocyanate exposure and occupational asthma: a case-referent study. Occup Environ Med 2000,57(12):830–836.
Jacobs JH, Spaan S, van Rooy GB, Meliefste C, Zaat VA, Rooyackers JM, Heederik D: Exposure to trichloramine and respiratory symptoms in indoor swimming pool workers. Eur Respir J 2007,29(4):690–698.
Schenker MB, Stoecklin M, Lee K, Lupercio R, Zeballos RJ, Enright P, Hennessy T, Beckett LA: Pulmonary function and exercise-associated changes with chronic low-level paraquat exposure. Am J Respir Crit Care Med 2004,170(7):773–779.
Senthilselvan A, McDuffie HH, Dosman JA: Association of asthma with use of pesticides. Results of a cross-sectional survey of farmers. Am Rev Respir Dis 1992,146(4):884–887.
Danuser B, Weber C, Kunzli N, Schindler C, Nowak D: Respiratory symptoms in Swiss farmers: an epidemiological study of risk factors. Am J Ind Med 2001,39(4):410–418.
Andersson E, Nilsson T, Persson B, Wingren G, Toren K: Mortality from asthma and cancer among sulfite mill workers. Scand J Work Environ Health 1998,24(1):12–17.
Preller L, Heederik D, Boleij JS, Vogelzang PF, Tielen MJ: Lung function and chronic respiratory symptoms of pig farmers: focus on exposure to endotoxins and ammonia and use of disinfectants. Occup Environ Med 1995,52(10):654–660.
Wheeler K, McKelvey W, Thorpe L, Perrin M, Cone J, Kass D, Farfel M, Thomas P, Brackbill R: Asthma diagnosed after 11 September 2001 among rescue and recovery workers: findings from the World Trade Center Health Registry. Environ Health Perspect 2007,115(11):1584–1590.
Rajan KG, Davies BH: Reversible airways obstruction and interstitial pneumonitis due to acetic acid. Br J Ind Med 1989,46(1):67–68.
Kivity S, Fireman E, Lerman Y: Late asthmatic response to inhaled glacial acetic acid. Thorax 1994,49(7):727–728.
Moore VC, Manney S, Vellore AD, Burge PS: Occupational asthma to gel flux containing dodecanedioic acid. Allergy 2009,64(7):1099–1100.
Musk AW, Peach S, Ryan G: Occupational asthma in a mineral analysis laboratory. Br J Ind Med 1988,45(6):381–386.
Deschamps D, Soler P, Rosenberg N, Baud F, Gervais P: Persistent asthma after inhalation of a mixture of sodium hypochlorite and hydrochloric acid. Chest 1994,105(6):1895–1896.
Promisloff RA, Lenchner GS, Phan A, Cichelli AV: Reactive airway dysfunction syndrome in three police officers following a roadside chemical spill. Chest 1990,98(4):928–929.
Franzblau A, Sahakian N: Asthma following household exposure to hydrofluoric acid. Am J Ind Med 2003,44(3):321–324.
el-Sadik YM, Osman HA, el-Gazzar RM: Exposure to sulfuric acid in manufacture of storage batteries. J Occup Med 1972,14(3):224–226.
Chatkin JM, Tarlo SM, Liss G, Banks D, Broder I: The outcome of asthma related to workplace irritant exposures: a comparison of irritant-induced asthma and irritant aggravation of asthma. Chest 1999,116(6):1780–1785.
Savonius B, Keskinen H, Tuppurainen M, Kanerva L: Occupational respiratory disease caused by acrylates. Clin Exp Allergy 1993,23(5):416–424.
Yacoub MR, Lemiere C, Malo JL: Asthma caused by cyanoacrylate used in a leisure activity. J Allergy Clin Immunol 2005,116(2):462.
Nakazawa T: Occupational asthma due to alkyl cyanoacrylate. J Occup Med 1990,32(8):709–710.
Lozewicz S, Davison AG, Hopkirk A, Burge PS, Boldy DA, Riordan JF, McGivern DV, Platts BW, Davies D, Newman Taylor AJ: Occupational asthma due to methyl methacrylate and cyanoacrylates. Thorax 1985,40(11):836–839.
Chan CC, Cheong TH, Lee HS, Wang YT, Poh SC: Case of occupational asthma due to glue containing cyanoacrylate. Ann Acad Med Singapore 1994,23(5):731–733.
Quirce S, Baeza ML, Tornero P, Blasco A, Barranco R, Sastre J: Occupational asthma caused by exposure to cyanoacrylate. Allergy 2001,56(5):446–449.
Kopp SK, McKay RT, Moller DR, Cassedy K, Brooks SM: Asthma and rhinitis due to ethylcyanoacrylate instant glue. Ann Intern Med 1985,102(5):613–615.
Weytjens K, Cartier A, Lemiere C, Malo JL: Occupational asthma to diacrylate. Allergy 1999,54(3):289–290.
Pickering CA, Bainbridge D, Birtwistle IH, Griffiths DL: Occupational asthma due to methyl methacrylate in an orthopaedic theatre sister. Br Med J (Clin Res Ed) 1986,292(6532):1362–1363.
Savonius B, Keskinen H, Tuppurainen M, Kanerva L: Occupational asthma caused by ethanolamines. Allergy 1994,49(10):877–881.
Pepys J, Pickering CA: Asthma due to inhaled chemical fumes–amino-ethyl ethanolamine in aluminium soldering flux. Clin Allergy 1972,2(2):197–204.
Hnizdo E, Sylvain D, Lewis DM, Pechter E, Kreiss K: New-onset asthma associated with exposure to 3-amino-5-mercapto-1,2,4-triazole. J Occup Environ Med 2004,46(12):1246–1252.
Ali BA, Ahmed HO, Ballal SG, Albar AA: Pulmonary function of workers exposed to ammonia: a study in the Eastern Province of Saudi Arabia. Int J Occup Environ Health 2001,7(1):19–22.
Bernstein DI: Guidelines for the diagnosis and evaluation of occupational immunologic lung disease. Mosby Co, St. Louis; 1989.
de la Hoz RE, Schlueter DP, Rom WN: Chronic lung disease secondary to ammonia inhalation injury: a report on three cases. Am J Ind Med 1996,29(2):209–214.
Leduc D, Gris P, Lheureux P, Gevenois PA, De Vuyst P, Yernault JC: Acute and long term respiratory damage following inhalation of ammonia. Thorax 1992,47(9):755–757.
Flury KE, Dines DE, Rodarte JR, Rodgers R: Airway obstruction due to inhalation of ammonia. Mayo Clin Proc 1983,58(6):389–393.
Weir DC, Robertson AS, Jones S, Burge PS: Occupational asthma due to soft corrosive soldering fluxes containing zinc chloride and ammonium chloride. Thorax 1989,44(3):220–223.
Gelfand HH: Respiratory Allergy Due to Chemical Compounds Encountered in the Rubber, Lacquer, Shellac, and Beauty Culture Industries. J Allergy Clin Immunol 1963, 34: 374–381.
Greene SA, Freedman S: Asthma due to inhaled chemical agents–amprolium hydrochloride. Clin Allergy 1976,6(2):105–108.
Baur X, Czuppon AB, Rauluk I, Zimmermann FB, Schmitt B, Egen-Korthaus M, Tenkhoff N, Degens PO: A clinical and immunological study on 92 workers occupationally exposed to anhydrides. Int Arch Occup Environ Health 1995,67(6):395–403.
Drexler H, Weber A, Letzel S, Kraus G, Schaller KH, Lenhert G: Detection and clinical relevance of a type I allergy with occupational exposure to hexahydrophthalic anhydride and methyltetrahydrophthalic anhydride. Int Arch Occup Environ Health 1994,65(5):279–283.
Cipolla C, Belisario A, Sassi C, Auletti G, Nobile M, Raffi GB: Occupational asthma caused by dioctyl-phthalate in a bottle cap production worker. Med Lav 1999,90(3):513–518.
Chee CB, Lee HS, Cheong TH, Wang YT, Poh SC: Occupational asthma due to hexahydrophthalic anhydride: a case report. Br J Ind Med 1991,48(9):643–645.
Rosenman KD, Bernstein DI, O'Leary K, Gallagher JS, D'Souza L, Bernstein IL: Occupational asthma caused by himic anhydride. Scand J Work Environ Health 1987,13(2):150–154.
Lee HS, Wang YT, Cheong TH, Tan KT, Chee BE, Narendran K: Occupational asthma due to maleic anhydride. Br J Ind Med 1991,48(4):283–285.
Graneek BJ, Durham SR, Newman Taylor AJ: Late asthmatic reactions and changes in histamine responsiveness provoked by occupational agents. Bull Eur Physiopathol Respir 1987,23(6):577–581.
Nielsen J, Welinder H, Skerfving S: Allergic airway disease caused by methyl tetrahydrophthalic anhydride in epoxy resin. Scand J Work Environ Health 1989,15(2):154–155.
Nielsen J, Welinder H, Schutz A, Skerfving S: Specific serum antibodies against phthalic anhydride in occupationally exposed subjects. J Allergy Clin Immunol 1988,82(1):126–133.
Wernfors M, Nielsen J, Schutz A, Skerfving S: Phthalic anhydride-induced occupational asthma. Int Arch Allergy Appl Immunol 1986,79(1):77–82.
Frans A, Pahulycz C: Transient syndrome of acute irritation of the bronchi induced by single and massive inhalation of phthalic anhydride. Rev Pneumol Clin 1993,49(5):247–251.
Fawcett IW, Taylor AJ, Pepys J: Asthma due to inhaled chemical agents–epoxy resin systems containing phthalic acid anhydride, trimellitic acid anhydride and triethylene tetramine. Clin Allergy 1977,7(1):1–14.
Maccia CA, Bernstein IL, Emmett EA, Brooks SM: In vitro demonstration of specific IgE in phthalic anhydride hypersensitivity. Am Rev Respir Dis 1976,113(5):701–704.
Meadway J: Asthma and atopy in workers with an epoxy adhesive. Br J Dis Chest 1980,74(2):149–154.
Venables KM, Topping MD, Howe W, Luczynska CM, Hawkins R, Taylor AJ: Interaction of smoking and atopy in producing specific IgE antibody against a hapten protein conjugate. Br Med J (Clin Res Ed) 1985,290(6463):201–204.
Venables KM, Topping MD, Nunn AJ, Howe W, Newman Taylor AJ: Immunologic and functional consequences of chemical (tetrachlorophthalic anhydride)-induced asthma after four years of avoidance of exposure. J Allergy Clin Immunol 1987,80(2):212–218.
Howe W, Venables KM, Topping MD, Dally MB, Hawkins R, Law JS, Taylor AJ: Tetrachlorophthalic anhydride asthma: evidence for specific IgE antibody. J Allergy Clin Immunol 1983,71(1 Pt 1):5–11.
Schlueter DP, Banaszak EF, Fink JN, Barboriak J: Occupational asthma due to tetrachlorophthalic anhydride. J Occup Med 1978,20(3):183–188.
Grammer LC, Shaughnessy MA, Kenamore BD: Clinical and immunologic outcome of 42 individuals with trimellitic anhydride-induced immunologic lung disease after transfer to low exposure. Allergy Asthma Proc 2000,21(6):355–359.
Grammer LC, Shaughnessy MA, Kenamore BD, Yarnold PR: A clinical and immunologic study to assess risk of TMA-induced lung disease as related to exposure. J Occup Environ Med 1999,41(12):1048–1051.
Grammer L, Shaughnessy M, Kenamore B: Utility of antibody in identifying individuals who have or will develop anhydride-induced respiratory disease. Chest 1998,114(4):1199–1202.
Zeiss CR, Patterson R, Pruzansky JJ, Miller MM, Rosenberg M, Levitz D: Trimellitic anhydride-induced airway syndromes: clinical and immunologic studies. J Allergy Clin Immunol 1977,60(2):96–103.
Kanerva L, Keskinen H, Autio P, Estlander T, Tuppurainen M, Jolanki R: Occupational respiratory and skin sensitization caused by polyfunctional aziridine hardener. Clin Exp Allergy 1995,25(5):432–439.
Leffler CT, Milton DK: Occupational asthma and contact dermatitis in a spray painter after introduction of an aziridine cross-linker. Environ Health Perspect 1999,107(7):599–601.
Slovak AJ: Occupational asthma caused by a plastics blowing agent, azodicarbonamide. Thorax 1981,36(12):906–909.
Kim CW, Cho JH, Leem JH, Ryu JS, Lee HL, Hong YC: Occupational asthma due to azodicarbonamide. Yonsei Med J 2004,45(2):325–329.
Normand JC, Grange F, Hernandez C, Ganay A, Davezies P, Bergeret A, Prost G: Occupational asthma after exposure to azodicarbonamide: report of four cases. Br J Ind Med 1989,46(1):60–62.
Valentino M, Comai M: Occupational asthma caused by azodicarbonamide: clinical case. G Ital Med Lav 1985,7(2–3):97–99.
Malo JL, Pineau L, Cartier A: Occupational asthma due to azobisformamide. Clin Allergy 1985,15(3):261–264.
Purohit A, Kopferschmitt-Kubler MC, Moreau C, Popin E, Blaumeiser M, Pauli G: Quaternary ammonium compounds and occupational asthma. Int Arch Occup Environ Health 2000,73(6):423–427.
Bernstein JA, Stauder T, Bernstein DI, Bernstein IL: A combined respiratory and cutaneous hypersensitivity syndrome induced by work exposure to quaternary amines. J Allergy Clin Immunol 1994,94(2 Pt 1):257–259.
Moscato G, Omodeo P, Dellabianca A, Colli MC, Pugliese F, Locatelli C, Scibilia J: Occupational asthma and rhinitis caused by 1,2-benzisothiazolin-3-one in a chemical worker. Occup Med (Lond) 1997,47(4):249–251.
Burns MJ, Linden CH: Another hot tub hazard. Toxicity secondary to bromine and hydrobromic acid exposure. Chest 1997,111(3):816–819.
de la Hoz RE: Reactive airways dysfunction syndrome following exposure to a fluorocarbon. Eur Respir J 1999,13(5):1192–1194.
Chan OY, Poh SC, Lee HS, Tan KT, Kwok SF: Respiratory function in cadmium battery workers–a follow-up study. Ann Acad Med Singapore 1988,17(2):283–287.
Leduc D, de Francquen P, Jacobovitz D, Vandeweyer R, Lauwerys R, De Vuyst P: Association of cadmium exposure with rapidly progressive emphysema in a smoker. Thorax 1993,48(5):570–571.
De Silva PE, Donnan MB: Chronic cadmium poisoning in a pigment manufacturing plant. Br J Ind Med 1981,38(1):76–86.
Royce S, Wald P, Sheppard D, Balmes J: Occupational asthma in a pesticides manufacturing worker. Chest 1993,103(1):295–296.
Neghab M, Mohraz MH, Hassanzadeh J: Symptoms of respiratory disease and lung functional impairment associated with occupational inhalation exposure to carbon black dust. J Occup Health 2011,53(6):432–438.
Bourne MS, Flindt ML, Walker JM: Asthma due to industrial use of chloramine. BMJ 1979,2(6181):10–12.
Feinberg SM, Watrons RM: Atopy to simple chemical compounds-sulfonechloramides. J Allergy Clin Immunol 1945,16(5):209–220.
Kujala VM, Reijula KE, Ruotsalainen EM, Heikkinen K: Occupational asthma due to chloramine-T solution. Respir Med 1995,89(10):693–695.
Jouannique V, Pillière F, Pouillard D, Gervais P, Rousselin X, Efthymiou ML: Asthme professionel à la chloramine T. In A propos de deux observations. Société De Médicine et d'Hygiène du Travail, Paris; 1992:654–657.
Dijkman JH, Vooren PH, Kramps JA: Occupational asthma due to inhalation of chloramine-T. I. Clinical observations and inhalation-provocation studies. Int Arch Allergy Appl Immunol 1981,64(4):422–427.
Waclawski ER, McAlpine LG, Thomson NC: Occupational asthma in nurses caused by chlorhexidine and alcohol aerosols. Bmj 1989,298(6678):929–930.
Glindmeyer HW, Lefante JJ, Freyder LM, Friedman M, Weill H, Jones RN: Relationship of asthma to irritant gas exposures in pulp and paper mills. Respir Med 2003,97(5):541–548.
Andersson E, Olin AC, Hagberg S, Nilsson R, Nilsson T, Toren K: Adult-onset asthma and wheeze among irritant-exposed bleachery workers. Am J Ind Med 2003,43(5):532–538.
Gautrin D, Leroyer C, L'Archeveque J, Dufour JG, Girard D, Malo JL: Cross-sectional assessment of workers with repeated exposure to chlorine over a three year period. Eur Respir J 1995,8(12):2046–2054.
Bherer L, Cushman R, Courteau JP, Quevillon M, Cote G, Bourbeau J, L'Archeveque J, Cartier A, Malo JL: Survey of construction workers repeatedly exposed to chlorine over a three to six month period in a pulpmill: II. Follow up of affected workers by questionnaire, spirometry, and assessment of bronchial responsiveness 18 to 24 months after exposure ended. Occup Environ Med 1994,51(4):225–228.
Leroyer C, Dewitte JD, Bassanets A, Boutoux M, Daniel C, Clavier J: Occupational asthma due to chromium. Respiration 1998,65(5):403–405.
Chester EH, Gillespie DG, Krause FD: The prevalence of chronic obstructive pulmonary disease in chlorine gas workers. Am Rev Respir Dis 1969,99(3):365–373.
Ferris BG Jr, Burgess WA, Worcester J: Prevalence of chronic respiratory disease in a pulp mill and a paper mill in the United States. Br J Ind Med 1967,24(1):26–37.
Lemiere C, Malo JL, Boutet M: Reactive airways dysfunction syndrome due to chlorine: sequential bronchial biopsies and functional assessment. Eur Respir J 1997,10(1):241–244.
Schonhofer B, Voshaar T, Kohler D: Long-term lung sequelae following accidental chlorine gas exposure. Respiration 1996,63(3):155–159.
Olaguibel JM, Basomba A: Occupational asthma induced by chromium salts. Allergol Immunopathol (Madr) 1989,17(3):133–136.
Onizuka R, Tanabe K, Nakayama Y, Fukuchi T, Nakata K, Hiki T: A case of chrome asthma induced by exposure to the stone cutter dust. Arerugi 2006,55(12):1556–1561.
Fernandez-Nieto M, Quirce S, Carnes J, Sastre J: Occupational asthma due to chromium and nickel salts. Int Arch Occup Environ Health 2006,79(6):483–486.
Sastre J, Fernandez-Nieto M, Maranon F, Fernandez-Caldas E, Pelta R, Quirce S: Allergenic cross-reactivity between nickel and chromium salts in electroplating-induced asthma. J Allergy Clin Immunol 2001,108(4):650–651.
Nagasaka Y, Nakano N, Tohda Y, Nakajima S: Persistent reactive airway dysfunction syndrome after exposure to chromate]. Nihon Kyobu Shikkan Gakkai Zasshi 1995,33(7):759–764.
Park HS, Yu HJ, Jung KS: Occupational asthma caused by chromium. Clin Exp Allergy 1994,24(7):676–681.
Novey HS, Habib M, Wells ID: Asthma and IgE antibodies induced by chromium and nickel salts. J Allergy Clin Immunol 1983,72(4):407–412.
Bernstein IL, Merget R: Metals. In Asthma in the workplace. 3rd edition. Edited by: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI. Taylor & Francis, New York; 2006:525–554.
Linna A, Oksa P, Palmroos P, Roto P, Laippala P, Uitti J: Respiratory health of cobalt production workers. Am J Ind Med 2003,44(2):124–132.
Kusaka Y, Iki M, Kumagai S, Goto S: Epidemiological study of hard metal asthma. Occup Environ Med 1996,53(3):188–193.
Kennedy SM, Chan-Yeung M, Marion S, Lea J, Teschke K: Maintenance of stellite and tungsten carbide saw tips: respiratory health and exposure-response evaluations. Occup Environ Med 1995,52(3):185–191.
Roto P: Asthma, symptoms of chronic bronchitis and ventilatory capacity among cobalt and zinc production workers. Scand J Work Environ Health 1980,6(Suppl 1):1–49.
Pisati G, Zedda S: Outcome of occupational asthma due to cobalt hypersensitivity. Sci Total Environ 1994,150(1–3):167–171.
Shirakawa T, Kusaka Y, Fujimura N, Goto S, Kato M, Heki S, Morimoto K: Occupational asthma from cobalt sensitivity in workers exposed to hard metal dust. Chest 1989,95(1):29–37.
Shirakawa T, Kusaka Y, Fujimura N, Goto S, Morimoto K: The existence of specific antibodies to cobalt in hard metal asthma. Clin Allergy 1988,18(5):451–460.
Shirakawa T, Kusaka Y, Fujimura N, Kato M, Heki S, Morimoto K: Hard metal asthma: cross immunological and respiratory reactivity between cobalt and nickel? Thorax 1990,45(4):267–271.
Gheysens B, Auwerx J, Van den Eeckhout A, Demedts M: Cobalt-induced bronchial asthma in diamond polishers. Chest 1985,88(5):740–744.
Baik JJ, Yoon YB, Park HS: Cobalt-induced occupational asthma associated with systemic illness. J Korean Med Sci 1995,10(3):200–204.
Wilk-Rivard E, Szeinuk J: Occupational asthma with paroxysmal atrial fibrillation in a diamond polisher. Environ Health Perspect 2001,109(12):1303–1306.
Krakowiak A, Dudek W, Tarkowski M, Swiderska-Kielbik S, Niescierenko E, Palczynski C: Occupational asthma caused by cobalt chloride in a diamond polisher after cessation of occupational exposure: a case report. Int J Occup Med Environ Health 2005,18(2):151–158.
Sargent EV, Brubaker RE, Mitchell CA: Respiratory effects of occupational exposure to an epoxy resin system. Arch Environ Health 1976,31(5):236–240.
Aleva RM, Aalbers R, Koeter GH, De Monchy JG: Occupational asthma caused by a hardener containing an aliphatic and a cycloaliphatic diamine. Am Rev Respir Dis 1992,145(5):1217–1218.
Luczynska CM, Hutchcroft BJ, Harrison MA, Dornan JD, Topping MD: Occupational asthma and specific IgE to a diazonium salt intermediate used in the polymer industry. J Allergy Clin Immunol 1990,85(6):1076–1082.
Graham VA, Coe MJ, Davies RJ: Occupational asthma after exposure to a diazonium salt. Thorax 1981,36(12):950–951.
Emad A, Rezaian GR: The diversity of the effects of sulfur mustard gas inhalation on respiratory system 10 years after a single, heavy exposure: analysis of 197 cases. Chest 1997,112(3):734–738.
Deschamps D, Questel F, Baud FJ, Gervais P, Dally S: Persistent asthma after acute inhalation of organophosphate insecticide. Lancet 1994,344(8938):1712.
Barthel E: Irritative and allergic effects of pesticide aerosols on the respiratory tract and problems of their evaluation. Z Gesamte Hyg 1983,29(11):678–681.
Piipari R, Tuppurainen M, Tuomi T, Mantyla L, Henriks-Eckerman ML, Keskinen H, Nordman H: Diethanolamine-induced occupational asthma, a case report. Clin Exp Allergy 1998,28(3):358–362.
Gadon ME, Melius JM, McDonald GJ, Orgel D: New-onset asthma after exposure to the steam system additive 2-diethylaminoethanol. A descriptive study. J Occup Med 1994,36(6):623–626.
Vallieres M, Cockcroft DW, Taylor DM, Dolovich J, Hargreave FE: Dimethyl ethanolamine-induced asthma. Am Rev Respir Dis 1977,115(5):867–871.
Cockcroft DW, Cotton DJ, Mink JT: Nonspecific bronchial hyperreactivity after exposure to Western Red Cedar. Am Rev Respir Dis 1979,119(3):505–510.
Conrad E, Lo W, de Boisblanc BP, Shellito JE: Reactive airways dysfunction syndrome after exposure to dinitrogen tetroxide. South Med J 1998,91(4):338–341.
Aldrich FD, Stange AW, Geesaman RE: Smoking and ethylene diamine sensitization in an industrial population. J Occup Med 1987,29(4):311–314.
Casas X, Badorrey I, Monso E, Morera J: Occupational asthma due to amines]. Arch Bronconeumol 2002,38(2):93–94.
Hagmar L, Bellander T, Bergoo B, Simonsson BG: Piperazine-induced occupational asthma. J Occup Med 1982,24(3):193–197.
Lam S, Chan-Yeung M: Ethylenediamine-induced asthma. Am Rev Respir Dis 1980,121(1):151–155.
Deschamps D, Rosenberg N, Soler P, Maillard G, Fournier E, Salson D, Gervais P: Persistent asthma after accidental exposure to ethylene oxide. Br J Ind Med 1992,49(7):523–525.
Dugue P, Faraut C, Figueredo M, Bettendorf A, Salvadori JM: Occupational asthma provoked by ethylene oxide in a nurse. Presse Med 1991,20(30):1455.
Nunn AJ, Craigen AA, Darbyshire JH, Venables KM, Newman Taylor AJ: Six year follow up of lung function in men occupationally exposed to formaldehyde. Br J Ind Med 1990,47(11):747–752.
Nordman H, Keskinen H, Tuppurainen M: Formaldehyde asthma–rare or overlooked? J Allergy Clin Immunol 1985,75(1 Pt 1):91–99.
Burge PS, Harries MG, Lam WK, O'Brien IM, Patchett PA: Occupational asthma due to formaldehyde. Thorax 1985,40(4):255–260.
Piipari R, Keskinen H: Agents causing occupational asthma in Finland in 1986–2002: cow epithelium bypassed by moulds from moisture-damaged buildings. Clin Exp Allergy 2005,35(12):1632–1637.
Kim CW, Song JS, Ahn YS, Park SH, Park JW, Noh JH, Hong CS: Occupational asthma due to formaldehyde. Yonsei Med J 2001,42(4):440–445.
Lemiere C, Desjardins A, Cloutier Y, Drolet D, Perrault G, Cartier A, Malo JL: Occupational asthma due to formaldehyde resin dust with and without reaction to formaldehyde gas. Eur Respir J 1995,8(5):861–865.
Porter JA: Letter: Acute respiratory distress following formalin inhalation. Lancet 1975,2(7935):603–604.
Hendrick DJ, Lane DJ: Formalin asthma in hospital staff. BMJ 1975,1(5958):607–608.
Sjogren B, Gunnare S, Sandler H: Inhalation of decomposed chlorodifluoromethane (freon-22) and myocardial infarction. Scand J Work Environ Health 2002,28(3):205–207.
Malo JL, Gagnon G, Cartier A: Occupational asthma due to heated freon. Thorax 1984,39(8):628–629.
Vyas A, Pickering CA, Oldham LA, Francis HC, Fletcher AM, Merrett T, Niven RM: Survey of symptoms, respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff. Occup Environ Med 2000,57(11):752–759.
Curran AD, Burge PS, Wiley K: Clinical and immunologic evaluation of workers exposed to glutaraldehyde. Allergy 1996,51(11):826–832.
Gannon PF, Bright P, Campbell M, O'Hickey SP, Burge PS: Occupational asthma due to glutaraldehyde and formaldehyde in endoscopy and x ray departments. Thorax 1995,50(2):156–159.
Jachuck SJ, Bound CL, Steel J, Blain PG: Occupational hazard in hospital staff exposed to 2 per cent glutaraldehyde in an endoscopy unit. J Soc Occup Med 1989,39(2):69–71.
Ong TH, Tan KL, Lee HS, Eng P: A case report of occupational asthma due to gluteraldehyde exposure. Ann Acad Med Singapore 2004,33(2):275–278.
Cullinan P, Hayes J, Cannon J, Madan I, Heap D, Taylor AN: Occupational asthma in radiographers. Lancet 1992,340(8833):1477.
Corrado OJ, Osman J, Davies RJ: Asthma and rhinitis after exposure to glutaraldehyde in endoscopy units. Hum Toxicol 1986,5(5):325–328.
Nagy L, Orosz M: Occupational asthma due to hexachlorophene. Thorax 1984,39(8):630–631.
Merget R, Topcu M, Friese K, Vormberg R, Fuchs T, Raulf-Heimsoth M, Breitstadt R: A cross-sectional study of workers in the chemical industry with occupational exposure to hexamethylenetetramine. Int Arch Occup Environ Health 1999,72(8):533–538.
Gamble JF, McMichael AJ, Williams T, Battigelli M: Respiratory function and symptoms: an environmental-epidemiological study of rubber workers exposed to a phenolformaldehyde type resin. Am Ind Hyg Assoc J 1976,37(9):499–513.
Bergman A, Svedberg U, Nilsson E: Contact urticaria with anaphylactic reactions caused by occupational exposure to iridium salt. Contact Dermatitis 1995,32(1):14–17.
Baur X, Dewair M, Fruhmann G: Detection of immunologically sensitized isocyanate workers by RAST and intracutaneous skin tests. J Allergy Clin Immunol 1984,73(5 Pt 1):610–618.
Piirila PL, Nordman H, Keskinen HM, Luukkonen R, Salo SP, Tuomi TO, Tuppurainen M: Long-term follow-up of hexamethylene diisocyanate-, diphenylmethane diisocyanate-, and toluene diisocyanate-induced asthma. Am J Respir Crit Care Med 2000,162(2 Pt 1):516–522.
O'Brien IM, Harries MG, Burge PS, Pepys J: Toluene di-isocyanate-induced asthma. I. Reactions to TDI, MDI, HDI and histamine. Clin Allergy 1979,9(1):1–6.
Cartier A, Grammer L, Malo JL, Lagier F, Ghezzo H, Harris K, Patterson R: Specific serum antibodies against isocyanates: association with occupational asthma. J Allergy Clin Immunol 1989,84(4 Pt 1):507–514.
Tarlo SM, Liss GM, Yeung KS: Changes in rates and severity of compensation claims for asthma due to diisocyanates: a possible effect of medical surveillance measures. Occup Environ Med 2002,59(1):58–62.
Bernstein DI, Korbee L, Stauder T, Bernstein JA, Scinto J, Herd ZL, Bernstein IL: The low prevalence of occupational asthma and antibody-dependent sensitization to diphenylmethane diisocyanate in a plant engineered for minimal exposure to diisocyanates. J Allergy Clin Immunol 1993,92(3):387–396.
Liss GM, Bernstein DI, Moller DR, Gallagher JS, Stephenson RL, Bernstein IL: Pulmonary and immunologic evaluation of foundry workers exposed to methylene diphenyldiisocyanate (MDI). J Allergy Clin Immunol 1988,82(1):55–61.
Woellner RC, Hall S, Greaves I, Schoenwetter WF: Epidemic of asthma in a wood products plant using methylene diphenyl diisocyanate. Am J Ind Med 1997,31(1):56–63.
Mapp CE, Corona PC, De Marzo N, Fabbri L: Persistent asthma due to isocyanates. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI). Am Rev Respir Dis 1988,137(6):1326–1329.
Zammit-Tabona M, Sherkin M, Kijek K, Chan H, Chan-Yeung M: Asthma caused by diphenylmethane diisocyanate in foundry workers. Clinical, bronchial provocation, and immunologic studies. Am Rev Respir Dis 1983,128(2):226–230.
Perfetti L, Brame B, Ferrari M, Moscato G: Occupational asthma (OA) with sensitization to diphenylmethane diisocyanate (MDI) presenting at the onset like a reactive airways dysfunction syndrome (RADS). Am J Ind Med 2003,44(3):325–328.
Hur GY, Koh DH, Choi GS, Park HJ, Choi SJ, Ye YM, Kim KS, Park HS: Clinical and immunologic findings of methylene diphenyl diisocyanate-induced occupational asthma in a car upholstery factory. Clin Exp Allergy 2008,38(4):586–593.
Vandenplas O, Malo JL, Dugas M, Cartier A, Desjardins A, Levesque J, Shaughnessy MA, Grammer LC: Hypersensitivity pneumonitis-like reaction among workers exposed to diphenylmethane [correction to piphenylmethane] diisocyanate (MDI). Am Rev Respir Dis 1993,147(2):338–346.
Lemiere C, Malo JL, Boulet LP, Boutet M: Reactive airways dysfunction syndrome induced by exposure to a mixture containing isocyanate: functional and histopathologic behaviour. Allergy 1996,51(4):262–265.
Belin L, Hjortsberg U, Wass U: Life-threatening pulmonary reaction to car paint containing a prepolymerized isocyanate. Scand J Work Environ Health 1981,7(4):310–311.
Vandenplas O, Cartier A, Lesage J, Cloutier Y, Perreault G, Grammer LC, Shaughnessy MA, Malo JL: Prepolymers of hexamethylene diisocyanate as a cause of occupational asthma. J Allergy Clin Immunol 1993,91(4):850–861.
Clarke CW, Aldons PM: Isophorone diisocyanate induced respiratory disease (IPDI). Aust N Z J Med 1981,11(3):290–292.
Kamat SR, Patel MH, Pradhan PV, Taskar SP, Vaidya PR, Kolhatkar VP, Gopalani JP, Chandarana JP, Dalal N, Naik M: Sequential respiratory, psychologic, and immunologic studies in relation to methyl isocyanate exposure over two years with model development. Environ Health Perspect 1992, 97: 241–253.
Baur X, Chen Z, Marczynski B: Respiratory diseases caused by occupational exposure to 1,5-naphthalene-diisocyanate (NDI): Results of workplace-related challenge tests and antibody analyses. Am J Ind Med 2001,39(4):369–372.
Vijayan VK, Sankaran K: Relationship between lung inflammation, changes in lung function and severity of exposure in victims of the Bhopal tragedy. Eur Respir J 1996,9(10):1977–1982.
Kamat SR, Mahashur AA, Tiwari AK, Potdar PV, Gaur M, Kolhatkar VP, Vaidya P, Parmar D, Rupwate R, Chatterjee TS, et al.: Early observations on pulmonary changes and clinical morbidity due to the isocyanate gas leak at Bhopal. J Postgrad Med 1985,31(2):63–72.
Harries MG, Burge PS, Samson M, Taylor AJ, Pepys J: Isocyanate asthma: respiratory symptoms due to 1,5-naphthylene di-isocyanate. Thorax 1979,34(6):762–766.