Hathaway, James A. MD, MPH; Molenaar, Donald M. MD, MPH; Cassidy, Laura D. PhD, MS; Feeley, Timothy M. MS; Cummings, Barbara J. MS
Isocyanates are a family of chemicals characterized by the presence of reactive “NCO” groups that include aliphatic diisocyanates, such as 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), and methylene bis(4-cyclohexyl isocyanate) (H12MDI). Diisocyanates are known respiratory sensitizers1,2 and have been reported to cause occupational asthma.3,4 The circumstances that result in respiratory sensitization have not been precisely demonstrated, but accidental exposures above occupational exposure limits have been suggested as one possible mechanism.5
Aliphatic diisocyanates are used in the manufacture of high-performance paints and surface coatings. They also are used in the preparation of adhesives, sealants, elastomers, and other specialized products. Exposures can occur during the production of the basic monomers and during the production of homopolymers (polyisocyanates) from monomers. Even though the polyisocyanates are manufactured to contain less than 1% of the free monomer, exposure can occur to the monomers in the polyisocyanates, for example, during spray painting and curing (heated) operations. During these downstream operations, exposures can also occur to the polyisocyanates, which have been reported to cause respiratory sensitization and occupational asthma.6
There has been increasing concern that direct (unprotected) skin contact with diisocyanates can initiate the process of sensitization where subsequent respiratory exposures may result in occupational asthma.5,7,8 It has not been documented in humans that skin exposure can lead to respiratory sensitization; nevertheless, there are animal studies that support this hypothesis.9,10 Besides the obvious potential for skin exposure to monomers and uncured polyisocyanates, a potential for transfer of isocyanate groups from cured polyisocyanates to the skin has been documented7,11 although the actual amount appears to be very low.12 Concern has also been expressed that there is only limited information on the potential for accidental skin exposures in the workplace.5
This study is a follow-up to a previous retrospective study published in 2010 that included 100 employees with potential exposure to HDI monomer.13 The 2010 study found no accelerated reduction of pulmonary function over a period of up to 19 years (average length was 13 years) in employees working with HDI monomer. Furthermore, no new cases of asthma or occupational asthma were identified from a review of routine medical examination reports. Nevertheless, routine questions on typical medical history questionnaires such as “have you ever had asthma?” or “do you have chronic cough, wheezing, shortness of breath, etc?” may not be specific enough to identify potential cases of occupational asthma. Standardized and more extensive respiratory medical history questionnaires are reported to provide more useful information as well as correlate with respiratory findings.14
Therefore, the objectives of this study were to follow up with a cross-sectional survey to determine whether (1) a more detailed respiratory medical history could identify cases of occupational asthma that might have been missed from a review of routine questions asked during annual medical examinations and (2) accidental unprotected inhalation and skin exposures have occurred. Industrial hygiene monitoring data of exposure to airborne HDI, IPDI, and H12MDI were updated with more recent data and are reported here in more detail.
This cross-sectional survey included employees from two chemical manufacturing facilities (Plants 1 and 2) operated by separate companies, both located in the Southern United States. All current hourly employees in 2011 with potential exposure to HDI, IPDI, H12MDI and their polyisocyanates were eligible to participate. Plant 1 manufactures HDI, IPDI, H12MDI, and their polyisocyanates. At Plant 1, HDI and HDI polyisocyanates were the predominant diisocyanate products. Plant 2 uses HDI as a raw material to manufacture HDI polyisocyanates. Most of the employees involved in these manufacturing processes were included in the previous study13; however, employees hired after 2006 are only reported here in the study.
Questionnaires and Follow-Up to Certain Questions
Questions on detailed respiratory history and symptoms were based on the British Medical Research Council questionnaire.3 Additional questions were also included regarding whether or not an employee had detected the odor of HDI or IPDI and whether they had ever been in the vicinity of an HDI or IPDI leak or spill. Novel questions were included about unprotected skin exposure to HDI monomer or HDI polyisocyanates. The questions also included an approximation of the frequency of such events. The investigators traveled to each plant to present the study, and the participants completed the questionnaires after signing informed consents. Plant medical records (pulmonary function tests and medical respiratory history questions) were reviewed, and if warranted participants were directly contacted to clarify questionnaire responses and to determine whether any of the participants represented a potential case of diisocyanate asthma.
A descriptive analysis was conducted using the statistical program, SAS 9.3 (SAS Institute, Cary, NC). Frequency distributions, means, and cross-tabulations are presented. Responses to the questions on respiratory history and symptoms were compared with other studies with control groups where identical or very similar questions were asked.15–23
Industrial Hygiene Methods
Industrial hygiene personal air monitoring was performed between 2007 and 2012. Historical industrial hygiene air monitoring records (both hard copy and electronic) were reviewed to determine when and whether personal protective equipment was donned. Industrial hygiene results are reported for monitoring events when no respirators were used, as well as for events when they were used. Workers at both plants used respiratory protection whenever exposures were potentially above occupational exposure limits (during spills or leaks) or when such exposures were possible (eg, line breaking). The plants also have automated alarms that alert workers to don air-supplied respirators when airborne concentrations are above the prescribed limits.
For comparison to an 8-hour time-weighted average occupational exposure limit, only sample durations that approximated a full shift (approximately 6 to 9 hours) were included in the evaluation. Two air sampling methods were used for the evaluation of airborne HDI monomer. Occupational Safety and Health Administration (OSHA) Method 42 by which samples were collected by drawing air through glass fiber filters coated with 1-(2-pyridyl) piperazine at a flow rate of 1 L/min24 was used at Plant 2. A modified version of OSHA method 42 was used at Plant 1. Samples collected at Plants 1 and 2 were analyzed by an American Industrial Hygiene Association accredited laboratory. The same modified version of OSHA Method 42 was used for the IPDI and H12MDI samples collected at Plant 1.
Seventy-three employees voluntarily participated, yielding a participation rate of more than 80%. The majority of the participants were male; 63% were employed at Plant 1 and 61.6% reported being nonsmokers as shown in Table 1. The average age of the participants was 45 years.
Responses to Questions on Respiratory Symptoms
If the participants responded positively to any of the following questions, they were prompted to report the frequency of the symptoms: (1) “Does your chest ever sound wheezing or whistling, apart from when you have a cold?” (2) “Have you ever had attacks of shortness of breath with wheezing, whistling, or cough?” (3) “Have you ever had chest tightness associated with difficulty breathing or wheezing?” A total of 15 persons answered one or more of these questions “yes.” Questions on the frequency of symptoms included once, a few times, a couple of days per month, a couple of days per week, or every day. Table 2 presents the results of the 15 positive respondents to the frequency of symptoms as “once or a few times” or as a “couple of days/month or more.” A separate question asked whether a participant had a cough on most days for 3 months or more during the past 12 months. Four of 73 participants answered “yes.” A total of 16 individuals (includes all 15 who answered positively to the previous questions) answered one or more of these questions “yes.” These individuals were identified for further follow-up. There was a section of questions that focused on possible relationships to work. These questions were answered by 15 of the 16 individuals noted previously, and the results are presented in Table 3. Further evaluation was completed on 15 of the 16 participants. One person did not complete the survey. Further evaluation included careful review by the physician conducting the most recent medical examination and/or an interview by one of the investigators. Of the two persons who reported an association with work, one had coronary artery disease and the symptoms disappeared after placement of stents. The physical demands of his work had caused shortness of breath and chest tightness before treatment for coronary artery disease. The other individual reported symptoms related to the use of ammonia when cleaning equipment. Of the three persons who did not answer the question on “associated with work,” one reported symptoms from solvents, and the other two reported that the symptoms were not related to exposure to diisocyanates.
There was a section focused on asthma-related questions. Participants were asked if they had ever had asthma diagnosed by a physician. If they answered “yes” then the following questions were asked: (1) At what age it started and stopped? (2) Whether any asthma medication was used in the past year? [two persons answered yes] (3) Whether asthma was ever treated in an emergency department? [three persons answered yes] (4) Whether they were ever hospitalized? [two persons answered yes]. A total of five persons responded that they had been diagnosed with asthma by a physician (all of these five were included in the earlier 16 identified for further evaluation). Three of these had childhood asthma, which was not a current problem. One had childhood asthma that continued to be a problem in adulthood. One had asthma diagnosed at the age of 54 years along with a diagnosis of chronic obstructive lung disease. He had an 80-pack-year history of cigarette smoking, and he indicated that his respiratory symptoms were due to smoking and not to chemical exposure. He reported that his personal physician concurred with this opinion.
Responses to Questions on Detection of Odor of Diisocyanates, Presence in Vicinity of Leaks/Spills, and Unprotected Skin Contact
Table 4 presents the results of responses to the question: during your work at this plant have you ever detected the odor of HDI or IPDI? Employees at Plant 2 did not work with IPDI, so this is the reason for most blank responses for IPDI. Some Plant 1 employees also did not work with IPDI. A total of 44 reported occasionally or often detecting HDI odor, and 21 reported detecting IPDI odor. During follow-up interviews, some employees indicated that they did not actually detect an odor but rather noted a characteristic irritation (mostly eye irritation). Employees typically would don an air-supplied respirator when an odor of HDI or IPDI was detected. Exposures would be expected to be brief.
Table 4 also presents the results of responses to the question: during your work at this plant have you ever been in the vicinity of an HDI or IPDI leak or spill? A total of 33 reported working in the vicinity of an HDI leak or spill, and 16 reported working in the vicinity of an IPDI leak or spill. Work in the vicinity of a leak or spill would require the donning of an air-supplied respirator. A leak or spill that occurred when work was underway, without the use of a respirator, would result in the worker quickly going to a supplied air connection and donning a respirator; thus, exposures to HDI or IPDI monomer during this period would be expected to be brief.
Responses to Questions on Unprotected Skin Exposure to HDI Monomer or HDI Polyisocyanates
Table 5 presents the responses to the question: have you ever had unprotected skin contact with HDI monomer or with HDI polyisocyanates? A total of 39 respondents reported at least one encounter with HDI monomer and six reported more than 15 times. Because HDI monomer is a skin irritant, skin exposure to HDI monomer would be expected to be brief (probably less than a minute or two) as it is expected that employees would seek to wash it off their skin. No incidents of exposures requiring emergency response had been reported, so it is likely that exposures would have been expected to have been to relatively small amounts of HDI monomer. A total of 27 reported at least one episode of unprotected skin contact with HDI polyisocyanates, and five reported more than 15 encounters. HDI polyisocyanates are not particularly irritating, and exposures might be longer if not noticed. Nevertheless, employees are instructed to immediately wash off any chemicals that contact the skin.
Results of Industrial Hygiene Monitoring for HDI, IPDI, and HMDI
For this study, industrial hygiene monitoring for airborne HDI was performed at Plant 1 between 2007 and 2010 and at Plant 2 between 2010 and 2012. Industrial hygiene monitoring for airborne IPDI and H12MDI was limited to Plant 1 as neither was present at Plant 2. Table 6 presents the combined results of monitoring for airborne HDI monomer at both plants, and includes results stratified by respirator use. Exposures were similar at both plants, and the level reported when respirators were not donned is similar to that reported in the earlier study.13 The previous study did not report results for when respirators were donned.
Industrial hygiene sampling results for IPDI and H12MDI at Plant 1 are presented in Table 7 and stratified by respirator use.
This survey was intended to help shed light on several questions related to aliphatic diisocyanates and occupational asthma. These include the following:
* Can a more detailed respiratory medical history identify potential cases of occupational asthma more effectively than less detailed questions found on typical occupational medicine history forms?
* Were there undiscovered cases of occupational asthma among workers at these plants or were the results similar to previous studies?
* Had accidental inhalation exposures to aliphatic diisocyanates occurred, and if so, how often?
* Had accidental unprotected skin exposures to aliphatic diisocyanates occurred, and if so, how often?
* If there were accidental inhalation and unprotected skin exposures, had these resulted in cases of occupational asthma?
* What insights can these results provide concerning occupational exposure limits and concerns with potential respiratory sensitization after dermal exposure to diisocyanates?
On the basis of the results of the more detailed respiratory medical history, no cases of occupational asthma related to aliphatic diisocyanates were identified in this study. An earlier study that did not use a detailed respiratory history at these two plants also did not find cases of occupational asthma.13 Although no cases of occupational asthma were identified using the more detailed questionnaire, it did result in more focused medical follow-up of several individuals (16 of 73 or 22%).
Comparisons to other studies are limited due to variability in questions used between studies and differing follow-up protocols. It is not possible to extrapolate those data to make statistical comparisons to our data. Also, the age distributions and percentages of smokers varied between studies. Nevertheless, it is possible to compare percentage responses of some specific symptoms such as chronic cough on “most days for 3 months of the past 12 months,” which was reported in previous surveys as 9.4%, 9.7%, 12.0%, 12.3%, 15.3%, and 21%, respectively, in control groups in referenced studies.15,17,18,20,21,23 In this survey of mostly nonsmokers, that percentage was 4 of 73 or 5.5%. The reported percentage of smokers in the other studies was consistently higher than in this survey when reported.
The question on wheezing was also identical to some other studies although reported quantification of the frequency of wheezing varied widely. In this survey there were 13 of 73 workers (17.8%) who reported any wheezing other than with a cold; nevertheless, only 4 of 73 or 5.5% reported wheezing a couple of days a month or more. Percentages of those reporting wheezes among controls in other studies were 0%, 9.2%, 10.3%, 10.8%, and 46%, respectively.17,18,20,26 In the study reporting 0%, it is not clear if this might have been referring to observed wheezing during study observation only. In none of the studies is it clear whether or not a reported one time or infrequent wheeze might have been included. For both chronic cough and wheezing, it seems that the percentage of employees in this survey reporting these symptoms is generally lower than what has been reported in the literature among control groups.
In this survey, five individuals reported being diagnosed with asthma by a physician. Four of these had childhood asthma and only one had continuing problems. An additional individual developed asthma while working. That individual also had a diagnosis of chronic obstructive pulmonary disease and self-reported as a heavy smoker (80-pack-year history). The previous study identified three cases of asthma, all of which were childhood asthma.13 Some, or most of these, probably were the same cases as in this survey. There is likely some selection bias by individuals with preexisting asthma not applying to work in the chemical industry. Also, Plant 1 had a policy of not hiring individuals with active asthma to work with diisocyanates.
Many workers self-reported detection of the odor of HDI or IPDI (the question was not asked for H12MDI). Only 4 of 73 workers reported never having detected the odor of HDI, and 9 of 42 never having detected the odor of IPDI (one reported “don't know” for both). Responses on frequency were not semiquantitated as were subsequent questions on skin exposures; nevertheless, as they appeared on the questionnaires, one might speculate that “rarely” might be similar to once and “occasionally” might be similar to 2 to 5 times (mean approximately 3.5), with “often” being 6 to 15 times or more (mean approximately 10.5). Duration of work with aliphatic diisocyanates was not determined in this survey, but it was in the previous study and it was an average of 12 years. Taking the mean of the ranges approximated here as 1, 3.5, and 10.5, one can estimate the average number of times a person had experienced odors of HDI as 2.9 times and that of IPDI as 2.8 times. If the average duration of work with these materials were 12 years, then these events would have occurred about once every 4 years per employee. A similar question was asked about work in the vicinity of a leak or spill of HDI or IPDI. Leaks or spills in the processing units were likely small such as residual material remaining in a line that had to be opened or during replacement of a valve or pump. The results were slightly less at 2.3 for HDI and 1.9 for IPDI. This would equate to once about every 5 to 6 years per employee. There were no measurements of HDI or IPDI taken during these times when odors were detected. Some employees reported the activation of HDI alarms when odors were detected, but at other times the alarms were silent. Plant 2 has a multistory manufacturing process with one alarm sampling point on each of three floors where the risk of a leak is likely to be greatest. Each sampling point is sampled every 180 seconds, and the alarm is set at 5 parts per billion (ppb). Plant 1 does not have alarms specific to HDI. Rather, there is a general use unit alarm and speaker system that can be activated to clear the unit of personnel when there is a need. It seems likely that exposures were at or above 5 ppb for at least some of the reported instances when odors of HDI were reported.
This survey also inquired about unprotected skin exposures to HDI and HDI polyisocyanates. Using a similar approach to that in the previous paragraph, a typical employee might have experienced such an event to HDI monomer 2.8 times and to HDI polyisocyanates 2.3 times. This might equate to once every 4 to 5 years. As noted in the Results section, these events as well as the detection of odor of HDI or IPDI were not reported to the plants as emergency response incidents. They were also not reported as medical or first-aid incidents. One would therefore expect that exposures were minimal and brief. If a leak or spill occurred, workers in the vicinity would be required to evacuate the area or don an air-supplied respirator. Therefore, any unprotected respirator exposures would have been expected to be brief.
As expected, industrial hygiene air sampling results reported here are very similar to those noted in two previous studies, the latter only involving Plant 2.13,25 The manufacturing processes and process controls were very similar over the past 20 years. More specific data are presented here on air sampling results while respirators were donned. These results were often obtained during procedures such as line breaking, loading/unloading, or sampling where exposure to higher airborne concentrations might occur. As seen in Tables 6 and 7, elevated airborne concentrations were not seen during this period. The two earlier studies reported occasional airborne concentrations that were above the ACGIH 8-hour Threshold Limit Value (TLV®) time-weighted average of 5 ppb for HDI during periods of respirator use as a full shift time-weighted-average exposure as high as 39 and 94 ppb, respectively. Peak exposures could have been higher. As noted previously, these occurred during the use of air-supplied respirators. They could indicate the limited potential exposures that may have occurred when odors of HDI or IPDI were detected when not wearing respirators.
There are a number of limitations to this study, which may limit the generalizability of the findings. The study size is relatively small at 73 participants even though this probably includes the majority of the workers in the United States potentially exposed to HDI, IPDI, or H12MDI during the manufacture of aliphatic diisocyanate monomers and their conversion to their respective polyisocyanates. This study also did not include a control group. Control groups from previously published studies were not always asked identical questions, usually included a higher proportion of cigarette smokers and may not have had similar age distributions. Such differences may limit the usefulness of comparisons to answers in this survey. Questions on detection of odors of HDI or IPDI were self-reported and therefore could not be independently verified. In addition, the use of odor as a means of quantifying potential inhalation exposures is problematic because odor is very subjective and reported odor thresholds for chemicals are often expressed in wide ranges. Questions on unprotected skin exposures to HDI monomer and HDI polyisocyanates were also self-reported and could not be independently verified. There is also concern with a possible “healthy worker effect.” It is certainly possible that there may have been some self-selection by individuals with allergies or respiratory problems to not apply for work at a chemical plant. Also, Plant 1 had a policy of not hiring individuals who had asthma as an adult. Another question is: could workers who developed respiratory problems shortly after being hired have left employment voluntarily? Although this cannot be completely excluded, both plants had low turnover of employees. Also, employees who resigned were interviewed to determine why. Informal discussions with human resources representatives did not reveal any employees leaving for health reasons. The most common reasons for leaving were moving to another area, leaving for a better-paying job, or retirement.
Chemical plants routinely require the reporting of injuries even those only requiring first aid and usually require the reporting of near-misses. The incidents of skin or respiratory exposures self-reported in this study did not result in injuries or first-aid cases and did not require emergency response. Many of these incidents were likely to have been reported as incidents because of alarms that were triggered or as near-misses. Also, some would have been known because leaks would require work orders to have them corrected. The questionnaires did not capture information on how many were actually reported. Nevertheless, on the basis of some interviews with employees, it is possible that some of these may not have been reported as near-misses. Given the nature of potential risks with chemicals such as diisocyanate monomers, rigorous emphasis on incident reporting including near-miss reporting is already required by some plants and is advisable for similar operations elsewhere.26
This study did not include biomonitoring of exposures. The biomonitoring method that has been most widely used for diisocyanates (hydrolysis of urine and measuring the diamine) is inherently nonspecific, such that it cannot distinguish the relative contribution of the diisocyanate and any concurrent exposure to hexamethylene diamine, which is used as a raw material for the manufacture of HDI.27 It may be useful for those employees who do not have this concurrent exposure, which could include Plant 2 employees and some Plant 1 employees. Specific IgG immunoglobulins have been suggested for use as biomarkers of exposure. With respect to using IgG, that immunoglobulin seems to be a better indicator of exposure than is IgE but still falls short of showing a good correlation with exposure.28 Furthermore, this parameter cannot at present provide a quantitative estimate of exposure. For these and other reasons, these procedures have not been widely implemented as part of a routine adjunct to health or exposure surveillance procedures, particularly in the United States. The industry is actively conducting research to try to develop a specific biomarker for diisocyanate exposure that may be useful as a supplement to air monitoring. Biomonitoring such as use of urinary metabolites or specific IgG antibodies could be interesting in a potential future study.
The results of this study do suggest that the use of careful manufacturing procedures including the use of closed systems for manufacture of aliphatic diisocyanate monomers and their polyisocyanates coupled with the use of air-supplied respirators when a closed system is not possible seems sufficient to protect against the development of occupational asthma. Under these conditions, exposures can be kept well under the current TLV® of 5 ppb. Infrequent and very brief accidental exposures to levels sometimes above 5 ppb did not seem to be associated with the development of occupational asthma. Occasional brief unprotected skin exposures to HDI monomer did not seem to contribute to the development of respiratory sensitization and occupational asthma in this study. This does not exclude the possibility that higher exposures might not lead to respiratory sensitization. Also, all exposures to highly toxic and potentially sensitizing chemicals such as HDI, IPDI, or H12MDI monomer should be avoided, and the finding of no cases of occupational asthma in this study does not imply that even brief and/or small exposures might not present a risk of sensitization. Nevertheless, some animal studies suggest that there are thresholds to the development of sensitization either from dermal or respiratory exposures, and that if exposures are kept below these levels, sensitization does not occur.29,30 Although the doses required for sensitization are unknown, they have been suggested to be both a product of duration of exposure and a unit dose per area of the exposed skin. Given the likely very brief skin exposures reported here, it is not surprising that no cases of sensitization were seen. Nevertheless, these results may provide some reassurance that reported skin exposures to nanogram levels of diisocyanate groups found on recently cured coatings5 should not be sufficient to initiate the process of respiratory sensitization. On a concentration (unit dose or amount/area of skin) and duration (time) basis, the exposures reported by workers in this survey are likely significantly higher than those from touching recently painted surfaces where nanogram quantities of diisocyanate groups may be in contact with skin. Thus, contact with even one drop of monomer (which is estimated to involve about 35 mg of material) would equate to several orders of magnitude greater skin exposure than that seen from contact with recently cured coatings.
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