New research exposing mice to a chemical used to make polyurethane foam and paints provides the first experimental confirmation that the compound causes respiratory tract disease. The findings corroborate epidemiological studies showing links between on-the-job exposure to toluene diisocyanate and both nasal inflammations and occupational asthma. These work-induced diseases affect at least half the industrial workers in the US. These results help understand how breathing even small amounts of a chemical can lead to debilitating respiratory diseases.

One common occupational source of exposure to TDI is painting cars.

Context: Allergic rhinitis, or hay fever, is a very common disease of the upper respiratory tract that affects about 20% of Americans. Allergens and chemicals trigger the nasal inflammation -- rhinitis -- that causes symptoms such as sneezing; itchy, watery eyes; runny nose and congestion. The disease also occurs in nearly 90% of patients diagnosed with asthma from an exposure in the workplace. Allergic rhinitis, induced by chronic exposure to environmental sensitizing agents--chemicals that spark an immune response-- can be a first step toward asthma. Thus early diagnosis of rhinitis in workers is an opportunity to intervene and prevent the escalation of symptoms that may lead to asthma, which affects between 5-65% of US workers depending on the occupation. Every year, about 3 billion pounds of isocyanates are produced globally and some 280,000 US workers are exposed to the chemicals through their jobs, according to the National Institute for Occupational Safety and Health (NIOSH 1996). Breathing the compounds irritates the nose, throat and lungs and sensitizes the immune system, which can lead to severe respiratory illnesses and sometimes death. Epidemiology studies of workers show that very low levels, even those below government workplace standards, or a one-time exposure can adversely affect human health. Toluene diisocyanate (TDI) is one of the most prevalent types of isocyanates in the workplace. TDI is an organic solvent widely used in industry. Mouse studies show the chemical can cause asthma in sensitive individuals. The chemical is an intermediate in the production of polyurethane coatings, flexible and rigid foams, rubber, paints, varnishes, wire enamels, sealants, adhesives, binders and nylon fibers. These products are used in many items, including furniture; construction and appliance insulation; and auto seats, body panels and bumpers. The vast majority of TDI exposure occurs in the workplace. As such, isocyanate-induced asthma is the most frequently reported job-linked airway disease affecting at least 42% of percent of exposed workers. The actual percentage is probably higher because occupationally induced airway diseases, including rhinitis, are most likely underreported. Medical staff are not trained to ask -- and usually do not record -- where a patient who complains about a breathing disorder works, so the link back to job exposure may not be made. More...

About isocyanates: Isocyanates are a group of related compounds known to cause asthma in workers exposed to the solvents. Each chemical contains an isocyanate group made up of a nitrogen, a carbon and an oxygen atom. Molecules with two isocyanate groups are called diisocyanate. The groups can be attached to other molecules to form different isocyanate types, such as toluene diisocyanate.     While occupational exposure to TDI is very common, workers are not the only people at risk. People living near factories where the chemicals are used and/or produced are also vulnerable. For example, residents in Randolph County, NC, complained for nearly 16 years of eye irritation, difficult breathing and other health maladies. They blamed the strong odors coming from the nearby Trinity Foam manufacturing facility. A 1997 investigation by the CDC's Agency for Toxic Substances and Disease Registry found that 10% of the residents in the community had a positive IgG antibody response for TDI, proving exposure to the chemical. Interviews and medical case histories suggested that individuals with this very specific immune marker had been exposed to TDI through emissions from the industrial plant. Concentrations of the chemical 100 feet outside the plant’s fence line during the summer of 1996 were as high as 29 ppb. Moreover, TDI odors (if indeed the residents were smelling TDI) can only be detected at levels at or above 2.1 parts per million (ppm), a level considerably higher than the level allowed for occupational exposure, 20 ppb. The Randolph County Trinity Foam plant eventually shut down after federal and state investigations. Other US industrial facilities that use TDI still operate and nearby residents report odor and health problems. Industry groups dispute health claims of chronic environmental exposure to TDI and defend the safety of current manufacturers using state-of-the-art emission and engineering controls, which was not the case at the Trinity Foam plant. Because of health concerns, the US Occupational Safety and Health Agency (OSHA) set a permissible exposure limit (PEL) of TDI for workers at 20 ppb per 8-hour day. The agency reduced the PEL to 5 ppb during a 1989 reevaluation, but a court order reversed the PEL to its previous level. Exposures in excess of the PEL by at least 50 fold have been documented during spills and accidents. Such significant acute exposures are decreasing, but still occur. Controversies about appropriate exposure limits continue, both in the work place and in residential areas near industrial plants that use or produce isocyanates. The disagreements stem from scientific uncertainties surrounding health effects and safe exposure levels of the compounds. Causal links between TDI exposure and respiratory disease are difficult to establish because workers are exposed to a mix of compounds and the disease mechanisms are complex and poorly understood. Genetic or other environmental factors could also contribute to the deleterious health effects of isocyanates as not everyone who is exposed develops symptoms or illness. Results from previous studies looking at TDI-induced asthma found that mice exposed to relevant doses of TDI had increased allergic responses, including more airway inflammation and hyper-responsiveness and higher levels of specific TDI antibodies in the blood. Asthmatic symptoms are reported after exposure to TDI at levels as low as 1 ppb.

What did they do? Johnson et al. exposed mice to the industrial chemical, dividing them into three treatment groups and two control groups. Treatment mice were exposed to 50 ppb TDI vapor for 4 hours per day, 5 days a week (for 12 consecutive business days) to simulate occupational exposure. The exposure used is only 2.5 times higher than the permitted level for occupational exposure, similar to that outside the North Carolina foam plant (above), and well within the range measured during spills and accidents.

After the two week exposure, mice were either 1) analyzed immediately (sensitized group); 2) given a two-week rest then examined (recovery group); or 3) given a two-week rest then exposed to TDI for an additional 3 days (challenged group). Control groups were exposed to air or air followed by a three day TDI exposure (challenge control).

After the conclusion of all control and TDI exposures, researchers evaluated the mice for breathing ability, tested lung and nasal cavity tissues for disease, measured cytokine gene expression in tissues and measured IgE and TDI-specific IgG type antibodies in blood. Cytokines are immunoregulatory proteins that facilitate the type and strength of an immune response. The types of cytokines present following exposure to an allergen or chemical irritant yields important information about how the immune system is responding to the irritant and may offer potential pharmacological targets for ameliorating the condition.

What did they find? TDI exposure for two weeks (12 work days) in a manner consistent with occupational exposure caused nasal inflammation and allergic rhinitis in the mice.

They found a nearly 250-fold increase in the density of eosinophils found in the nasal passages of group 1 sensitized mice exposed to TDI for two weeks. Eosinophils are specialized cells of the immune system and critical mediators of airway diseases (both rhinitis and asthma). In the nasal cavity following TDI exposure, the number of eosinophils increased from approximately 8 per square millimeter (mm²) in control animals to 280 eosinophils per mm² in exposed animals.

Importantly, there was no difference in eosinophil cell density in the lining of the lung using this TDI exposure protocol. The authors' previous work demonstrated considerable eosinophil infiltration into the lung leading to asthma following a 6-week exposure to TDI. These earlier data, along with the new data on allergic rhinitis, show similar symptoms between allergic rhinitis and asthma induced by TDI. Furthermore, these data provide additional evidence of how rhinitis precedes asthma following TDI exposure.

In addition, there was evidence of respiratory tract obstruction associated with TDI exposures that altered breathing capacity (graph to right). The PenH test, a measurement of the time taken between breaths, was increased. Breathing rate, a measurement of breaths per minute, decreased from 520 to 460 in the TDI exposed group. Inspiratory time, the duration of time required for each breath, in the TDI group increased to 0.052 seconds/breath compared with 0.046 seconds/breath in the control group.

The eosinophil and breathing changes were accompanied by a significant increase in total blood IgE levels and elevated concentrations of TDI specific IgG antibodies in mice breathing the TDI vapor. Elevated serum IgE and TDI-specific IgG levels are consistent with the symptoms and characteristics of allergic rhinitis observed in humans exposed to TDI occupationally.

Many of the rhinitis symptoms were alleviated in mice that were allowed to recover for two weeks after breathing TDI vapors for half a month (the 'recovery' group; see above). However, all the signs of inflammation and allergic rhinitis -- increased eosinophils, elevated IgE and TDI-specific IgG antibodies and modulated breathing patterns -- returned in the third group of mice (the 'challenged' group; see above), which were challenged with more TDI after a 2-week break from breathing the chemical.

Finally, TDI vapor exposure caused a considerable induction of both TH1 and TH2 cytokine subtypes. The balance of TH1 and TH2 cytokines regulates the type of immune response for a particular agent or infection. A mixed response of both TH1 and TH2 is very common for allergy of the respiratory tract including rhinitis.

What does it mean? This study is the first to demonstrate experimentally that breathing TDI can cause nasal allergies. Mice exposed to TDI vapor in a manner similar to human job-related exposure developed symptoms and disease progression consistent with the type of allergic rhinitis seen in workers. The results agree with prior epidemiology studies that indicate an association between the chemical exposure and the disease.

This study is also important because it identifies a novel and useful animal model for studying how exposure to occupationally relevant levels of TDI vapor alters the immune response to cause respiratory diseases. It confirms that a mouse model can mimic human disease responses to chemical exposure. Animal models of human diseases offer better estimates of health risks. They can be used to identify stages where appropriate education and intervention -- such as better ventilation, protective clothing and respiratory equipment -- can be developed to improve safety and lower personal exposures.

Allergic rhinitis induced by TDI affects the upper respiratory tract and is a strong predictor for more serious asthmatic conditions. Cases of occupationally induced allergic rhinitis are thought to be largely underestimated due to misunderstanding and misdiagnosis by the medical community and attending physicians. Cost estimates of occupationally induced allergic rhinitis due to lost productivity are around $600 per year per employee, compared with $90 per year for asthma patients.

Researching how TDI-induced airway disease forms is important to understanding the basic health effects occupational and environmentally exposure. The mouse model will be a useful way for researchers to dissect the early stages of disease and follow its progression. The next step will be to identify biomarkers for early detection of chemical sensitivities so controls can begin when the markers are found in workers or residents.

Preventing progression of nasal allergies to asthma and more debilitating respiratory diseases is important for employers, workers and others who breathe the chemicals. Such chronic illnesses affect personal and work life, leading to chronically sick people who are less productive at work, take more sick days and have higher health care costs.

The data presented by Johnson et al indicate that exposure to TDI vapor causes allergic rhinitis. The disease is a serious condition that warrants additional research to better characterize its etiology and dose range of TDI sensitivity. Because TDI-induced allergic rhinitis is a precursor and predictor of asthma, it represents an important first opportunity for intervention and prevention strategies to reduce the health risk associated with TDI exposure both in and out of the workplace.

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