Isocyanate-induced pulmonary diseases: a current perspective

Abstract

Chemicals of the isocyanate family are required for the production of a variety of commercial products, including insulation materials, automobile upholstery, furniture, and surface coatings. They are highly reactive with other chemicals containing hydrogen atoms. Early reports of medical toxicity appeared 25 yr ago and have been confirmed on a worldwide basis. Adverse respiratory symptoms have been the chief concern, and a wide spectrum of work-related lung diseases has been described. Although some of these reactions were undoubtedly due to primary irritation, the majority presented with airways obstructive abnormalities clearly identified as classic asthma. The possibility of an underlying hypersensitivity mechanism was suggested by the insidious onset of symptoms, a latency period of weeks to months, peripheral and tissue eosinophilia, and the elicitation of symptoms after exposure to very small subtoxic levels of these chemicals. Some cases consistent with the unique clinical features of hypersensitivity pneumonitis have also been recognized. Early animal experimental studies had suggested that immunologic factors were important etiologic components of these syndromes. However, when several independent groups of investigators could not confirm these preliminary results, the pathogenesis of these diseases soon became a highly controversial subject. Current experimental and clinical approaches have therefore been redirected to encompass the role of nonimmunologic mechanisms in the pathogenesis of adverse isocyanate reactions. Collectively, these recent investigations suggest that both immunologic and nonimmunologic mechanisms appear to be operative as causes of isocyanate-induced asthma. There is in vitro evidence both for and against possible specific pharmacologic effects of diisocyanate compounds. Parallel bronchoprovocation studies comparing the activities of diisocyanates, methacholine, and histamine suggest that diisocyanates may act either as direct pharmacologic agonists or as inducers of nonspecific bronchial reactivity. Recent evidence of immunoreactivity to both monofunctional and bifunctional isocyanates in several animal models and sensitized workers has also mandated a reassessment of immunologic factors. Hapten-specific, IgE-mediated antibody responses have been observed in both animal and human investigations. However, only a small subset of sensitized workers developed specific IgE antibodies to p-tolyl monoisocyanate and/or hexyl monoisocyanate. Both IgE and precipitating antibodies have been reported in several cases of workers sensitized to methylene diphenyl diisocyanate. Some toluene diisocyanate-sensitive patients also exhibit other types of immunologic responses, including antigen-induced lymphocyte transformation and synthesis of a leukocyte inhibitory factor. Detailed immunologic investigations have not yet been carried out in most of the suspected cases of hypersensitivity pneumonitis. Other possible nonimmunologic sequelae of isocyanate reactions include chronic bronchitis, recurrent pneumonia, pulmonary edema, and pulmonary emphysema. However, the question of chronic pulmonary disability associated with these diseases is poorly understood and requires further long-term investigation. Despite the brisk controversy that still exists about the pathogenesis of isocyanate-induced pulmonary diseases, new data derived from animal models and clinical investigation of sensitized workers suggest that application of several innovative approaches could result in early detection and treatment of clinical reactions. These are considered in the context of pre-employment screening, serial monitoring in the workplace, and postemployment surveillance.