Castano, Roberto MD, PhD; Johnson, Victor J. PhD; Cartier, Andre MD
Isocyanates are chemical compounds containing the highly reactive isocyanate group; they are widely used in different industrial settings as the hardening agents in urethane paints and plastics. Nowadays, exposure to isocyanates at the workplace is one of the most frequent causes of occupational asthma (OA) in developed countries, imposing a significant burden on health care systems and affected workers.1,2 The isocyanates most commonly used are hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), and isophorone diisocyanate. A common setting for exposure to these chemicals is in autobody repair shops where HDI-containing paints are used as a spray paint hardener.
Although isocyanate exposure is a widely recognized cause of OA, few data are available on the effect of these chemicals on the upper airways. Although there is evidence from cross-sectional studies of an increased prevalence of work-related upper airway symptoms in exposed workers,3–8 the prevalence of occupational rhinitis related to isocyanate exposure is unknown; however, estimates range from 36% to 42%.9 Also, rhinitis symptoms are often associated with OA to isocyanates.10 Considering that the nasal mucosa is the primary site of entry for inhaled isocyanates in the respiratory system, it is likely that isocyanate-induced occupational rhinitis may be highly prevalent and possibly more frequent than OA.
The objective of this prospective case series study was to assess the utility of specific inhalation challenge (SIC) to evaluate the objective and subjective nasal congestive response to isocyanate exposure in workers complaining of work-related upper and lower respiratory symptoms. The study was designed to evaluate whether a short-duration (4-minute) and long-duration (120-minute) exposure to isocyanate by SIC was able to induce changes in nasal patency measured by acoustic rhinometry and self-reported nasal congestion measured by a visual analogue scale (VAS). Besides, we examined changes in nasal inflammation by quantifying inflammatory cells in nasal lavage (NAL) fluid in some of our study subjects.
Nine subjects, all males, aged 26 to 49 years participated in this study. All subjects were referred for investigation of possible isocyanate-induced OA by SIC, and they also complained of work-related nasal symptoms. The following were exclusion criteria at the time of SIC: (1) a history of recent common cold, rhinosinusitis, or allergic rhinitis exacerbation; (2) regular use of medications for relief of nasal symptoms; (3) antecedent of recent nasal or sinus surgery; and (4) evidence of significant structural abnormalities such as nasal septum deviations, nasal septum perforations, or nasal polyposis. Eight subjects worked in autobody repair and car painting and one subject in aircraft painting. At the time of SIC, subjects had been exposed to isocyanates for a median of 10 years (interquartile range: 14 years). Seven subjects were atopic (ie, showed at least one immediate reaction to a battery of 12 common aeroallergens by the skin-prick method). Most subjects were nonsmokers (six of nine). The study was approved by the Hôpital du Sacré-Coeur de Montréal research ethics committee, and all subjects gave written informed consent.
Specific Inhalation Challenge
The investigation of isocyanate-induced OA by SIC is a standardized procedure in our hospital.11 SICs were performed as previously described following international recommendations.12 Briefly, after a control challenge day intended to assess asthma stability through forced expiratory volume in 1 second (FEV1) monitoring for 7 to 8 hours, subjects are gradually exposed to isocyanates on subsequent days.13 They are gradually exposed for up to 4 minutes on the first day, 30 minutes on the second day, and 2 hours on the third day, unless a fall in FEV1 of 20% or more is observed after each exposure. During these days, lung function is assessed by monitoring FEV1 before the challenge and serially for 7 to 8 hours after the challenge.
During the first day, all subjects were exposed for 30 minutes to a nonspecific irritant (n-butyl acetate), commonly used as a solvent in the production of lacquers and other products. During the active challenge days, seven subjects were exposed to HDI and two subjects to MDI. All subjects were exposed on 3 consecutive days for up to 2 hours. In this study, we assessed nasal responses before and after exposure to the nonspecific irritant and during the first and third active challenge days in which subjects were exposed to isocyanates for 4 and 120 minutes, respectively, to reflect the effect of a short-duration and a long-duration exposure. We assessed objective nasal congestion by measuring nasal volume by acoustic rhinometry before the challenge and at 15 minutes, 30 minutes, 1 hour, and 6 hours after challenge. Subjective nasal congestion was assessed on a VAS at the same time and always before acoustic rhinometry measurements. Nasal inflammation was monitored by collecting nasal fluid before the challenge and at 30 minutes and 6 hours after challenge for quantification of inflammatory cells. In addition, subjects completed a questionnaire with questions about upper airway symptoms and their temporal relationship with their work and a VAS to grade the severity of rhinitis symptoms “at work” and “out of work.”
Nasal Patency Assessment
Acoustic rhinometry (Hoods Laboratories, Pembroke, MA) was performed following the guidelines of the Standardization Committee on Acoustic Rhinometry.14 Each set of measurements comprised three measurements with a coefficient of variation equal to or less than 6% that were used to calculate the volume of the nasal cavity between 2 and 5 cm (Vol2–5) from the tip of the device nosepiece. This distance was selected as endpoint to better represent the nasal congestive response induced by the challenge.14
For the interpretation of results, a decrease in Vol2–5 20% or more from baseline values was meant to represent a clinically significant response to challenge according to published studies and recommended guidelines for performing nasal challenge test.15,16
Subjective Nasal Congestion and Rhinitis Severity Assessment
During SIC, the changes in nasal congestion were monitored and quantified using a VAS of 0 to 10 cm for both nasal cavities. The extremes were labeled “no congestion” (0 cm) and “nose completely congested” (10 cm). Another VAS ranging from 0 (symptoms not at all bothersome) to 10 cm (symptoms, extremely bothersome) was administered before the challenge investigation to assess the severity of combined rhinitis symptoms (congestion, rhinorrhea, sneezing, and itching) “at work” and “out of work.” Rhinitis symptom severity was classified as mild when the VAS score was less than 5 cm and as moderate or severe when it was 5 cm or more.17
Nasal Inflammation Assessment
Nasal fluid was collected by NAL before and after control and active challenge as previously described18 in six of nine subjects who agreed to provide nasal fluid samples for analysis. The analysis consisted in the quantification of cells (neutrophils, eosinophils, macrophages, lymphocytes, and epithelial cells). Lymphocytes were not considered for analysis because of the very low number observed in all samples. Specimens were taken from Hôpital du Sacré-Coeur de Montréal site of the Respiratory Health Network Tissue Bank of the FRQS (www.tissuebank.ca).
Analysis of Results
Normally distributed data were expressed as mean and standard deviation, whereas nonnormally distributed data were expressed as median and interquartile range. Related-samples Friedman's two-way analysis of variance by rank test was used to compare changes in nasal volume, VAS and NAL at different challenge times. Whenever statistically significant differences were observed, the Friedman test was supplemented with the Wilcoxon signed rank test. The Spearman rank test for nonparametric data was used to examine the correlation between study outcomes. The analysis was performed using the SPSS 18.0 statistical package (SPSS, Inc, Chicago, IL).
Upper Airway Symptoms and Rhinitis Severity
At the time of investigation, all subjects reported work-related nasal symptoms: nasal obstruction (six of nine), rhinorrhea (six of nine), sneezing (six of nine), nasal itching (five of nine), nasal crusting (seven of nine), nasal bleeding (four of nine), and impaired olfaction (four of nine). They also reported other work-related upper airway symptoms: burning throat (four of nine), throat clearing (eight of nine), postnasal drip (four of nine), and hoarseness (three of nine).
Rhinitis symptom severity was reported as mild (VAS <5 cm) by all subjects when “out of work” whereas four subjects considered it as mild and five as moderate/severe (VAS >6 cm) when “at work.”
Bronchial Response to Challenge
Table 1 shows the maximum percentage decrease in FEV1 from prechallenge values for each subject after challenge with the nonspecific irritant and after exposure to isocyanates for 4 and 120 minutes. None of the subjects showed a clinically significant bronchoconstriction defined as a fall in FEV1 20% or more compared with the prechallenge value.
The observed changes in nasal patency after SIC were analyzed in different ways. First, we examined changes in nasal volume as compared with prechallenge levels occurring after exposure to the nonspecific irritant and after exposure to isocyanates. Figure 1 (upper panel) shows boxplots of values of Vol2–5 for the whole group of subjects after nonspecific challenge and after exposure to isocyanates for 4 and 120 minutes. The exposure to the nonspecific irritant induced a nonsignificant fall in Vol2–5 at 30 minutes postchallenge with a gradual recovery to prechallenge levels at the end of the monitoring period. The 4-minute isocyanate SIC induced a nonsignificant fall in Vol2–5 at 30 and 60 minutes (Fig. 1) that did not reach baseline levels at 6 hours postchallenge. In contrast, the 120-minute isocyanate SIC induced a gradual and sustained significant fall (P = 0.01) in Vol2–5 over the first hour postchallenge (at 15 minutes, P = 0.02; at 30 minutes, P = 0.02; at 60 minutes, P = 0.05) that persisted at 6 hours after challenge although without reaching statistical significance (P = 0.26) (Fig. 1).
Then we analyzed the results for the whole group of subjects accounting for baseline between-day variability by looking at the proportional change in nasal volume from prechallenge levels to compare measurements at each time point after exposure to the nonspecific irritant and to isocyanates for 4 and 120 minutes. Figure 2 (upper panel) shows the median percentage fall in Vol2–5 from baseline values. Overall, the changes in Vol2–5 after short- and long-duration challenge with isocyanate were of slightly greater magnitude than those observed after challenge with the nonspecific irritant substance. Nevertheless, the observed differences in the extent of the nasal congestive response at each time point postchallenge were not statistically different. Besides, we examined individual differences in the nasal congestive response to nonspecific and isocyanate challenges. A cutoff point of 20% fall in nasal volume from baseline values was selected to designate a clinically significant reaction to challenge. Figure 2 (lower panel) shows that at each postchallenge time point there were a higher number of subjects showing a clinically significant reaction during the days they were exposed to isocyanates than the nonspecific exposure day.
Finally, we looked at the maximum percentage fall in Vol2–5 from each individual after nonspecific challenge and after exposure to isocyanates for 4 and 120 minutes (Table 1). A fall in Vol2–5 20% or more was noted in two subjects (cases 6 and 9) after nonspecific challenge; in four subjects (cases 2, 5, 7, and 8) after 4-minute isocyanate SIC; and in five subjects (cases 2, 3, 5, 7, and 9) after 120-minute isocyanate SIC. The correlation analysis showed significant correlations between the observed maximum percentage fall in Vol2–5 and the maximum percentage fall in FEV1 for each subject after 4-minute isocyanate SIC (r = −0.65; P = 0.05) and 120-minute isocyanate SIC (r = 0.76; P = 0.01).
Subjective Nasal Congestion
Figure 1 shows (lower panel) boxplots of the VAS score for nasal congestion (0 to 10 cm) for the whole group of subjects after nonspecific challenge and after exposure to isocyanates for 4 and 120 minutes. After challenge with the nonspecific irritant, only a nonsignificant (P = 0.15) increase in subjective nasal congestion at 30 minutes after challenge was observed. The 4-minute isocyanate challenge was not associated with increased subjective nasal congestion (P = 0.39). In contrast, the 120-minute isocyanate challenge induced a significant increase (P = 0.01) in subjective nasal congestion as compared with baseline levels over the first 30 minutes postchallenge (at 15 minutes, P = 0.02; at 30 minutes, P = 0.01; at 1 hour, P = 0.16; at 6 hours, P = 0.74). Table 1 shows the observed maximum VAS score for each subject after nonspecific challenge and after short- and long-duration challenge with isocyanates.
No correlation between subjective nasal congestion (VAS) and acoustic rhinometry measurements (Vol2–5) during nonspecific and isocyanate challenge days was observed (data not shown).
Neutrophils were the predominant inflammatory cells observed in nasal fluid under baseline conditions and after challenge with isocyanates. The analysis for the whole group of subjects showed nonsignificant changes in the number of inflammatory cells after exposure to the nonspecific irritant and to isocyanate for 4 and 120 minutes (see the Supplementary Digital Content Table 1 available at http://links.lww.com/JOM/A124). Individual results are shown in the Supplementary Digital Content Table 2 available at http://links.lww.com/JOM/A124.
Nasal congestion is often reported by workers exposed to isocyanates in diverse industries.7 Our group of subjects reported not only common symptoms of rhinitis (congestion, runny nose, sneezing, and itching) but also other less common nasal symptoms (nasal bleeding, nasal crusting, and impaired olfaction) as well as pharyngeal and laryngeal symptoms. To our knowledge, no study has ever experimentally assessed the effect of isocyanate exposure on nasal patency using objective means. This study has objectively demonstrated for the first time that the exposure to isocyanates by SIC induces changes in nasal patency in patients complaining of work-related respiratory symptoms.
Overall, the limited evidence on the role of isocyanates in work-related rhinitis comes from questionnaire surveys conducted in industries with high risk of isocyanate exposure. Thus, the vast majority of previous attempts to examine the nasal effects of this exposure have been mainly limited to document self-reported nasal symptoms. In a cross-sectional survey conducted in a plant that uses a foam injection process with MDI, 33% of workers reported work-related nasal symptoms.4 The prevalence of work-related rhinitis symptoms was 19.8% among 241 Dutch spray painters.19 In another survey, the prevalence of work-related stuffy or runny nose among workers exposed to isocyanates was 16.2%.7 Workers exposed to sprayed and heated polyurethane glue based on MDI and HDI reported frequent work-related nasal symptoms.6 More than once a month episode of nasal congestion was much higher among pipelayers exposed to thermal degradation products from MDI-based polyurethane than controls.5 There is also evidence of the association between isocyanate exposure and rhinitis symptoms from a prospective study of 385 apprentice car painters, in which 19 subjects potentially exposed to isocyanates experienced one or more new work-related nasal symptom after 18 months of training.20 Also, the potential of isocyanates to induce an inflammatory response in the nasal mucosa was examined in a survey that showed that workers exposed to isocyanates and also complaining of work-related nasal symptoms had higher levels of inflammatory markers in nasal fluid than asymptomatic workers.21
This study has demonstrated the utility of the SIC methodology to objectively assess the nasal congestive response after isocyanate exposure.12 Our subjects comprised a selected group of workers complaining of work-related upper and lower airways symptoms who underwent SIC with gradual increase in exposure to investigate possible isocyanate-induced asthma. We used this well-controlled laboratory setting to monitor changes in nasal patency with acoustic rhinometry, which is a validated technique14 often used in nasal challenge testing.16,22
In this study, subjects were first exposed to a nonspecific irritant. After this exposure, we observed a nonsignificant decrease in nasal volume with a gradual return to prechallenge values at the end of the observation period. Besides, nasal symptoms were not reported by subjects. A similar nasal response was observed after 4-minute isocyanate challenge, but the observed decrease was more sustained and no recovery to prechallenge conditions was noted at the end of the observation period. By contrast, the 120-minute isocyanate SIC induced a significant decrease in nasal volume from prechallenge levels that persisted over the entire postchallenge observation period; this change was found also associated to an increase in nasal symptoms. Nevertheless, the analysis showed a very weak and nonsignificant correlation between subjective and objective nasal congestion measurements, which is a finding consistent with the published literature. The lack of correlation between subjective and objective measurements of nasal congestion is often reported in the literature,23,24 and there is still a lot of controversy on this subject.25 These findings should be viewed with caution considering that it is well known that there is considerable interindividual variability in the nasal response under baseline conditions as well as after exposure to irritant substances.26 Nevertheless, the analysis accounting for baseline between-day variability also showed changes in nasal patency of greater magnitude after exposure to isocyanates.
The pattern of nasal reaction elicited by repeated exposure to isocyanates has not been characterized. Interestingly, we expected a greater nasal congestive response after long-duration isocyanate exposure, but the observed changes in nasal volume did not differ significantly compared with results after short-duration exposure. Nevertheless, this is not surprising because different patterns of bronchial reactions have been observed after repeated exposures to isocyanates by SIC including (1) a minimal effect after a brisk change; (2) a significant change after a plateau; and (3) a change after a decrease in effect and change on the last day of exposure.11 Although our observation may allow us to speculate that the exposure to isocyanates for even a short period may exert an irritant effect capable of inducing nasal congestion in sensitized individuals, further research is needed to establish whether the exposure of the nose to isocyanates elicits varied patterns of reactions comparable to those observed in the bronchi.
Isocyanate-induced asthma has been associated with neutrophilic airway inflammation.27,28 To our knowledge, only one published study has assessed nasal inflammation in NAL fluid in workers exposed to isocyanates.21 The study showed no increase in myeloperoxidase and an unexpected decrease in the number of neutrophils cells in nasal fluid after work shift in workers exposed to isocyanates by heating polyurethane. Also, animal studies have shown contradictory results as to the type of nasal inflammation occurring after isocyanate inhalation. Neutrophils counts increased significantly in nasal fluid of rats compared with control values after TDI inhalation although eosinophils were not prominent in the NAL fluid.29 Another study in mice exposed to TDI vapor showed significant inflammatory changes of the nasal mucosa, with a predominant eosinophilic infiltration that corresponded with increased IgE and TDI-specific IgGAbs in the serum. In this study, neutrophils were the predominant inflammatory cells in NAL fluid under baseline conditions as compared with macrophages and eosinophils that were present in lower numbers. This study does not permit to speculate about the predominant type of nasal inflammatory response after isocyanate SIC. A major limitation was the lack of samples for analysis from three of nine subjects as well as the limited number of nasal fluid samples collected to characterize the late-phase reaction after isocyanate challenge. We observed that the exposure to isocyanates did not induce significant changes in the number of inflammatory cells in NAL fluid in the whole group of subjects. Nevertheless, it is worth noting that an increase in the number of eosinophils was observed in some subjects after isocyanate exposure. Further larger studies are needed to determine the predominant type and kinetics of nasal inflammatory response in reaction to isocyanate exposure.
The main strength of this study is that it was conducted in a controlled laboratory environment to avoid potential influences from other irritant exposures found in the subjects' workplace. Also, the study involved a real-life clinical scenario in which patients were referred to our hospital by the provincial workers' compensation board to confirm a diagnosis of isocyanate-induced asthma. The adverse respiratory effects of isocyanate exposure on the lower airways have been well documented.1 Regarding the upper airways, we believe that our results showed a nasal congestive effect of isocyanate exposure. Consequently, we believe that the SIC methodology seems to be a useful tool to evaluate workers with a potential diagnosis of isocyanate-induced rhinitis. Nevertheless, more SIC studies are needed intended to differentiate an irritant effect from a clinically significant effect in a potentially sensitized individual that could contribute to establish a diagnosis of occupational rhinitis because of isocyanate exposure. Also, further human studies involving a larger number of subjects are necessary to investigate the type of nasal inflammatory response induced by exposure to isocyanates.
The authors thank the staff at the Respiratory Health Network Tissue Bank for their valuable assistance.
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