Isocyanates are extremely reactive substances which can cause several effects to the human body, including skin irritation, eye irritation, and most devastatingly occupational asthma. The polyurethane industry uses isocyanates in their processes, and the CDC estimates over 280,000 employees are exposed to diisocyanates in their occupational environment. The relationship between occupational asthma and diisocyanate exposure is difficult to define. There is not a “test” that determines the existence of this specific asthmatic condition.
A cohort-work study of 100 individuals would bring upon the most accurate results, occurring over a span of five years within five manufacturing facilities. In-house occupational clinics would provide the necessary conditions for accuracy/reliability. The CDC estimates between 5-15% of employees exposed to diisocyanates will encounter occupational asthma as a result.
This particular study will require certain pre-employment conditions to exist, (Examples: asthma free, non-smoker, no family history of asthma.) Putting these controls in place will allow for a more accurate study.
The theoretical results of the study being performed reject the null hypothesis, due to there being a proven relationship between the subjects involved and the outcome of interest. The results show that an individual is seven times more likely to be diagnosed with occupational asthma when there is a known inhalation of vapors. Therefore, the alternative hypothesis “Inhalation of diisocyanate vapors is related to the onset of occupational asthma” would be accepted.
Isocyanates are organic compounds that contain the formula R–N=C=O. They are known to be extremely reactive, and have exceptionally low molecular weight. In the event that the compound contains two of the R–N=C=O formula, they are then referred to as “diisocyanates.” In the general industrial population, members of the isocyanate family are typically used to aid in the event of certain chemical reactions to form other agents.
Two of the most common types of isocyanates are TDI (Toluene diisocyanate) and MDI (Methylene diphenyl diisocyanate). TDI and MDI together comprise approximately 90% of the total diisocyanate market. The major, most dominant use of these agents is to manufacture polyurethanes. This is an example of where the isocyanate is being used to carry out a reaction to form the final product, which is usually a foam or “elastomer” of some degree. The foam or elastomer that is created is then used in multiple different industrial applications, and can be in both “rigid” or “flexible” state. Elastomers are mainly used when manufacturing shoe soles, conveyors, or vehicle body panels. As for the two types of foam, the main applications revolve around furniture manufacturing and the automotive industry, including thermal insulation (buildings, refrigerators, freezers), furniture, flotation equipment, and equipment housings. MDI is more commonly found in the refrigeration and insulation market, whereas TDI is most commonly found in the furniture and automotive industry. (Wiley, 2001) TDI and MDI are reactive to several different chemicals, especially in the presence of heat. They also are highly reactive to water, even to moisture present in the air. Upon the exposure of isocyanates to a form of water, carbon dioxide is quickly generated. One of the main concerns upon this event is the excess pressure built up in closed containers. In standard factory temperatures both TDI and MDI are in liquid state, unless it is “pure” in which MDI would be a solid.
TDI and MDI have several negative health effects associated with accidental exposure. There are several different means of isocyanates entering the body. The most common, and most dangerous is through the respiratory system via the inhalation of a vapor, aerosol or dust. Slight irritation of the nose and throat is common in mild cases, combined with dryness of the throat. However in severe cases, the person will suffer acute bronchial irritation and difficulty breathing. Asthma, wheezing and tightness of the chest are associated with breathing in aerosols and mists of TDI and MDI. Isocyanates are mainly considered extremely harmful in the workplace due to their sensitizing properties and ability to trigger severe respiratory distress. Currently, they are the most common cause of occupational asthma, otherwise known as OA, in Quebec, Ontario, Great Britain, and the United States. There was a recent review in Canada (Ontario) where the worker’s compensation board accounted for 30% of the total claims submitted being isocyanate related, and 58% accepted being related. (Tarlo, 739) It is typical to see other symptoms such as anaphylaxis (severe whole-body allergic reaction) or dermatitis associated with the occupational asthma. Sensitization to TDI and MDI are what would initially cause OA. Sensitization occurs when an individual is overexposed to the agent, and the body progresses through an allergic reaction. Individual’s bodies get overexposed to the vapors and become sensitized. From that point on (latent period), any exposure to even a remote amount of the chemical causes a reaction. An asthmatic response could take place minutes after sensitization, or up to 24 hours. There are other instances where accidental exposure to extremely high doses of TDI or MDI can cause asthma, which still results in sensitization. It is possible for an individual to be sensitized to TDI, but not MDI and vice versa due to the differences in the compound make-up.
Another exposure route is through the skin, especially if there is an open cut or open wound. Just as mentioned in respiratory exposure, the skin can become sensitized to the agent. Irritation of the skin can cause rashes, burns, and sores. Certain chemicals can expedite this absorption, such as acetone, toluene, and chlorinated hydrocarbons. These should never come in contact with isocyanates when skin contact is possible or probable.
Isocyanates can come into contact with the eyes, causing severe irritation and damaging effects. Corneal scarring can occur in severe cases of TDI exposure. Ingestion by swallowing the agent or through the consumption of contaminated food is known to cause stomach bleeding, burning, and vomiting. (Wiley, 34)
Polyurethane usage is distributed throughout several different industries, and are broken down as follows: mattresses (29%), miscellaneous (27%), construction (16%), automotive (15%), other insulation (10%), and furniture shoes (3%). In 2003, U.S. consumption was 1.9 billion pounds of MDI, and 1.1 billion pounds of TDI, with massive growth in consumption of seven percent per year for MDI, and 2.7 percent per year for TDI – (Center for Disease Control, 2007). Asia-Pacific regions lead the polyurethane market taking up over 40% overall, Europe accounts for 35%, and North American regions follow with 19.96%.
The CDC estimates the amount of workers exposed to isocyanates to be roughly 280,000. The exact number of newly diagnosed cases of asthma in adults due to occupational exposure is unknown. Up to 15% of asthma cases in the United States may be job-related. The length of time you are exposed to a substance before it triggers your asthma varies. It can be months or years before symptoms occur. On the other hand, exposure to a high concentration of irritants can cause asthma within 24 hours. (Wiley, 2001) This leads to heavy confusion is the epidemiological aspects of the disease and its diagnosis. Physicians are expected to make an educated decision on whether or not a new case of asthma in an adult is work-related or not. This is a huge gap in the research of the disease, and there are a lot of underlying factors that are not being considered. For example, the patient’s history of smoking, pre-existing conditions, exposure to other hazardous chemicals, chronic bronchitis, or regular adult-onset asthma. The only way to link an asthma case directly to a workplace exposure would be if there was a certain exposure event, and the worker had pre-employment pulmonary function tests done in order for comparison to be made. This is very similar to carpal tunnel, as there is not one way to truly correlate the disease to workplace exposure. Smoking, alcohol usage, and many other personal factors such as hobbies and sleep patterns all coincide with the condition. There are several case studies related to direct diisocyanate exposures and occupational asthma, such as the following:
In 1994 a maintenance worker repairing an MDI foaming system at a plant that manufactured artificial plants with polyurethane foam bases became tragically ill. The worker had an extreme case of respiratory illness which was later diagnosed as isocyanate-induced asthma. Further respiratory symptoms associated with the MDI exposure required the worker to quit his job. He experienced coughing and progressive loss of lung function as time went on. His illness also caused productive coughing, weakness, sweating, muscle aches, and shortness of breath. He eventually died from this condition (NIOSH Case, 1994).
Worksite evaluations were conducted which found detectable air concentrations of MDI and inadequate ventilation systems in the foaming areas. Vapors and aerosols were observed actually rising into the breathing zones of employees who were working with the foam. Skin contact with the foam was also found during the investigation. (NIOSH Case, 1994)
There are obvious signs that the exposure to MDI did have a major contribution to the worker’s death, however for other cases the signs are not so blatant. Physicians have what are called “reporting guidelines” as for when they must report a certain disease in patients. All occupational asthma cases must be reported, which require a physician diagnosis of asthma, as well as an association between symptoms of asthma and work. Different clinical, epidemiologic, and workplace information is required for collection on any reported cases of occupational asthma. This would lead to a formal investigation on the incidence or exposure of hazardous agents causing the respiratory distress. (Yale School of Medicine, 2014)
The prevalence of reported diisocyanate asthma among exposed workers is estimated to range from 5% to 15%. (CDC, 2004) To this day, it is unclear whether asthma associated with diisocyanate exposure is immunological, or non-immunological. The pathogenesis, (or mechanism that caused the disease,) is not able to be uncovered either. Exposures can occur as a mixture of vapor and aerosol, and can even be formed into different “species” of diisocyanates which makes air monitoring extremely challenging. Quantifying the disease itself is not easy, which raises the question of how accurate the statistics really are.
Understanding the actual relationship between isocyanate exposure and occupational asthma is challenging. Different case studies will be analyzed and interpreted to make the connection between the actual exposures of TDI and MDI and the diagnosis of O.A.
Due to the vast amount of research available, I have chosen to focus on the incidence of diisocyanate-induced occupational asthma in the polyurethane industry. Occupational asthma is a reportable disease, which is oftentimes difficult to differentiate from common allergen-related asthma. There are specific tests and criteria that must be followed in order to clinically diagnose diisocyanate-induced occupational asthma. The research gap that seemed to stand out was the lack of evidence showing that inhaling diisocyanates can indeed cause occupational asthma. It has been documented that this occurs on a regular basis, however what scientific proof actually exists that would say it is directly caused by diisocyanate exposure?
An appropriate “null hypothesis” for this paper would be “inhaling diisocyanate vapor is not related to the onset of occupational asthma.” The alternative hypothesis would be that “inhaling diisocyanate vapors is related to the onset of occupational asthma.” Considering the statistics and history available, one would not question the validity of the current statistics out there.
Designing an effective study to provide an understanding to this issue would pose several challenges. The largest challenge would be that it would need to occur over a longer span of time, and have an extremely close eye on the subject’s lifestyle and medical status. The reasoning behind this is that asthma that is believed to be caused by diisocyanates can be either have quick onset (< 2 hours after potential exposure) or take days/months to occur.
Taking all of this into account, the best study that would be set up for this hypothesis testing would be a prospective cohort study. More specifically, a work cohort study. The subjects would be classified according to their occupations (polyurethane industry) and also have potential exposure to MDI or TDI diisocyanate vapors on a daily basis. They would be observed over a period of time (five years) in which documentation of any breathing/pulmonary-related symptoms would be taken. Before the study would begin, each subject must be put through stringent baseline testing to verify they are free from any asthmatic symptoms/history. In this particular study, the outcomes are more useful than studying individual known exposures (or overexposures.) In order for this study to be successful, it would be necessary to create a working relationship with respiratory doctors across the country. Possibly a professional association for pulmonologists would be a great place to start. There would need to be a span of individuals on board with the study to assist in gathering the data/test results. There have been longitudinal studies done in the past on this matter, however they are very vague and have unclear guidelines. One study done by A.R. Tanser stated that a group of 57 people exposed to rigid foam processes had a 7% prevalence of Isocyanate-induced asthma. There is no information available as to who was involved, or how long the study lasted. Another study by Meredith, J Bugler was performed in 2000 involving two manufacturing companies with employees exposed to diisocyanate vapors. These companies had in-house occupational health clinics, which aided massively in conducting the study. There were pre-employment respiratory tests done, and also IgE tests which provide information on allergens affecting the individual. This study did show that the peak flow rates in individuals after being exposed to the material did lessen. This study concluded that you can develop occupational asthma due to inhaling low exposures of isocyanates, but the higher the exposure, the greater the risk. Also, smoking and atopy increase the odds of isocyanate-induced occupational asthma. Other cross-sectional studies have been done which followed individuals over a course of 5 years to determine if the isocyanate asthma progressively worsened or improved.
A few negatives or concerns regarding this particular type of study may be that since it is long-lived, it might be expensive and overall time-consuming. It may be a barrier to the study to keep control of the subjects in the study, and not lose them in the process. Also, certain subjects may leave the polyurethane industry while the study is occurring. In addition there is always the chance that there will not be any subjects in the study directly exposed to diisocyanate vapors. The most important concern is that doctors may misclassify a case to be diisocyanate-related, when in reality it is not. That is the main issue at hand – how do you know that certain cases are directly caused by inhaling diisocyanate vapors? The best case scenario for this study would be to choose either places who already have occupational health clinics inside the facility or to set this up for the study. The medical professionals in these on-site clinics would be part of the network, and understand the purpose of the study. For example, choosing five manufacturing facilities and conducting the study for a length of five years would provide solid findings. Location would not be too important, mainly choosing five different sites that all use isocyanates in their regular processes, (either MDI or TDI), and know that the TWA of the exposure to isocyanates is over the OSHA permissible exposure limit. Being under the PEL would not provide accurate results, unless the study is to prove that levels under the OSHA PEL are still damaging and could cause occupational asthma. This would need to be verified by a certified industrial hygienist, by doing several air sampling measurements.
There is a certain guideline that medical professionals are required to follow in order to accurately pinpoint a certain asthma case to be directly related to the outcome of interest at hand. State health departments encourage providers to report all suspected or diagnosed cases of occupational asthma. These include subjects with both a physician’s diagnosis of asthma, an association between symptoms of asthma and work, and any one of the following:
- Workplace exposure to an agent or process previously associated with occupational asthma
- Significant work-related changes in FEV1 (Forced expiratory volume in 1 second) or PEFR (Peak expiratory flow rate) – These tests would have to be completed before the study commenced.)
- Significant work-related changes in airways responsiveness as measured by nonspecific inhalation challenge
- Positive response to inhalation provocation testing with an agent to which patient is exposed at work. (Wiley, 2003)
The cohort study that was described earlier would allow for actual accurate determination of the outcome of interest compared to current strategy. There have not been any discoverable cases where the subjects were initially tested with pulmonary function tests (specifically FEV1 AND PEFR) and then tracked throughout the course of occupational exposure. There is also “inhalation challenge testing” which uses histamine and metacholine (common allergens.) If the subject’s response to these allergens mimics the reaction to diisocyanate exposure, this is a tell-tale sign it is not work related. Also, prolonged periods of time off of work lessening the symptoms of the bronchial distress is a major sign that it IS work-related. If symptoms develop within minutes of specific activities or exposures at work or delayed symptoms occur several hours after exposure, it is work-related. Similarly, if during the evenings of workdays or days on vacation result in little to no symptoms it can be deemed work-related. (Redlich, Karol, 2002)
For the null hypothesis to be rejected, the following would need to occur: There would need to be at least one subject who was baseline tested for FEV1 and PEFR pulmonary function and was certified to be asthma-free; the subject would have to experience a direct exposure to diisocyanate vapors by the route of inhalation; the subject must be examined by a pulmonologist within 30 minutes of the initial exposure; the subject must experience asthma-related symptoms within the projected latency period; the subject must be monitored closely after initial exposure for subsequent episodes/reactions to the same irritant (diiisocyanate); and the examining pulmonologist must be able to correlate the symptoms directly to diisocyanate exposure due to employment in the polyurethane industry.
Similarly, the null hypothesis would hold true if there were no subjects who were diagnosed with occupational asthma that is directly resulting from their place of work; following the protocol discussed earlier by the physician. Note: The alternative hypothesis is not suggesting it is impossible for a person to get occupational asthma from directly inhaling diisocyanate vapors; it would however provide statistics leaning towards it being unlikely in nature. There are other issues that are important in considering the outcome of this study: Approximately 5 percent of the population, when exposed to isocyanates, will become sensitized to diisocyanates so that subsequent exposures even at extremely low levels will result in a severe and sometimes fatal reaction to it. (Bernstein, 1996) That means that 95% of the subjects could possibly not experience symptoms to diisocyanate vapor inhalation.
For the study to provide useful results, there are several different statistical methods that could be used. This study would have to be conducted for a period of a certain number of years; in this instance we will say five years. In this case, we will say that the study came out to 6 individuals being diagnosed with diisocyanate-induced occupational asthma over the five-year period (exposed & unexposed.) There were a total of 100 subjects in the study, meaning 6 out of 100, or 6% of the subjects were positive for the outcome of interest. For the unexposed group, there was one subject diagnosed with occupational asthma. Calculating the relative risk (RR) for this study would include taking the incidence rate in the exposed/incidence rate in the unexposed. See the following chart for predicted theoretical results of this study:
|Diisocyanate-induced Occupational Asthma|
|Known exposure to Diisocyanate vapors||
Total Subjects: 100
Relative risk (RR) would be calculated as: 5/5+37 / 1/1+57 = .1190/.0172 = 6.919. Analyzing these results, this would mean that since the RR is >2.0, the risk is more than twice as high among the exposed as among the non-exposed. In fact, there is a 7 times greater chance to to have diisocyanate-induced occupational asthma with a direct known exposure to diisocyanate vapors. There is a positive association between exposure of diisocyanate vapors through inhalation and occupational asthma.
With these results, it is safe to say that the null hypothesis would be rejected and the alternative hypothesis would be accepted. Diisocyanate vapor inhalation is related to the onset of occupational asthma. Only under the strict guidelines to diagnose the disease, constant monitoring of all subjects throughout the course of the study, and through pre-pulmonary function testing would this be able to hold true.
The prospective cohort study would provide both useful and accurate results through the use of onsite occupational health clinics. Understanding the risks involved with diisocyanate exposure is critical, considering the long-term health effects. Despite the strict regulations associated with workplace diisocyanate exposures, the number of reported cases still continues to stay near the same. (CDC, 2013) The Occupational Safety & Health Administration has made “Isocyanates” a National Emphasis Program, which allows for the specific targeting of employers known to use isocyanates in their facilities. Monitoring of isocyanate exposures will increase due to this program and related inspections, which will allow for more quantitative analysis in the future.
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