Respiratory effects of toluene diisocyanate in the workplace: a discussion of exposure-response relationships.

Toluene diisocyanate (TDI) is an important industrial intermediate used in manufacturing flexible polyurethane (PUR) foams, surface coatings, cast elastomers, sealants, and adhesives. In this review long-term trends in workplace exposures to TDI are assessed in both the producing and using industries, and respiratory health effects of TDI are evaluated in relation to workplace TDI concentrations. The key respiratory health effects associated with repeated or long-term TDI exposure are bronchial asthma and an accelerated rate of decline in lung function. In the early years of the industry, annual incidence rates of occupational asthma (OA) due to TDI ranged from 1% to as high as 5 to 6%, depending on the extent of engineering and work practice controls in the various workplaces. Since the mid-1970s, annual OA incidence rates have been <1%, where 8 h TDI concentrations have been maintained below 5 ppb as determined by personal monitoring, even where short-termTDI concentrations above 20 ppb and less frequently above 40 ppb were routinely detected. In these latter settings, there is evidence that the majority of OA cases may be attributable to TDI concentrations well above 20 ppb associated with overexposure incidents. Further study is needed regarding the role of such incidents in inducing respiratory sensitization. Cross-sectional and longitudinal studies of lung function have indicated that continued exposure after development of work-related respiratory symptoms can lead to transient or accelerated fixed declines in forced expiratory volume in 1 sec (FEV1). These findings are congruent with the FEV1 declines demonstrated in general population studies of persons with persistent bronchial hyperresponsiveness or nonoccupational asthma. More recent longitudinal studies in settings with ongoing medical surveillance have provided no consistent evidence of accelerated FEV1 loss among employees exposed up to 5 ppb TDI on an 8 h time-weighted average basis.

Phosgene exposure: mechanisms of injury and treatment strategies.

Phosgene (carbonyl chloride, CAS 75-44-5) is a highly reactive gas of historical interest and current industrial importance. Phosgene has also proved to be a useful model for the study of those biochemical mechanisms that lead to permeability-type pulmonary edema (adult respiratory distress syndrome). In turn, the study of phosgene-induced adult respiratory distress syndrome has provided insights leading to revised treatment strategies for exposure victims. We summarized recent findings on the mechanisms of phosgene-induced pulmonary edema and their implications for victim management. In light of that research, we also provide a comprehensive approach to the management and treatment of phosgene exposure victims.

Facts and fallacies involved in the epidemiology of isocyanate asthma.

Personal experience and analysis of the medical literature on isocyanate asthma shows, that the reported incidence of this disease varies between 0 and 25%. Reasons for differences in observed incidence are intensity of isocyanate exposure, criteria for diagnosis, mode of calculation, sensitizing capacity of different isocyanates, individual predisposition and confounding factors (adjuvants). There is no geographical or ethnical prevalence. Work places at risk are those with isocyanate concentrations above 20 ppb (ceiling).

Therapeutic strategy in phosgene poisoning.

For the treatment of phosgene poisoning, glucocorticoids and positive pressure ventilation can be recommended as well as supporting measures such as physical rest, antitussives, buffers, sedatives, antibiotics, antispasmodics and possibly diuretics. Roentgenological evaluation of the lungs is advisable. A therapeutic strategy is presented which is based on the phosgene exposure intensity.

Late sequelae after phosgene poisoning: a literature review.

The vast majority of phosgene intoxications (including cases with pulmonary edema) have a good prognosis. However, nearly all patients complain of exertional dyspnea and reduced physical fitness for several months to years after the accident; normalization of lung function values, too, may require several years. Occasional impairment of pulmonary function appears to be dependent more on smoking habits than on the severity of the original intoxication. Pre-existing chronic bronchitis may undergo severe and progressive deterioration after toxic pulmonary edema due to phosgene. Occupational health check-ups (including pulmonary function tests) are recommended for all persons handling irritant gases. Every patient having undergone the inhalation of phosgene or other irritants will ask the question of possible late sequelae. Due to new forms of treatment (glucocorticoids, positive pressure ventilation) the prognosis of severe cases has considerably improved during the last decades. The paper tries to summarize the present state of our knowledge.

A literature review: therapy for phosgene poisoning.

A literature search designed to collect information on therapy for phosgene poisoning has been conducted for the period 1920-1982. To achieve this goal, literature services were consulted, cross references were carefully followed and, whenever possible, unpublished reports (e.g., from Edgewood Arsenal and Porton Research Station) were evaluated. The various therapeutic agents and measures described in the literature are presented in alphabetical order. When available, detailed data are given for the phosgene dose, interval of time between exposure and institution of therapy, therapeutic effect and parameters used to assess efficacy. A final summary presents general recommendations for therapy and for further research.

Pathogenesis of phosgene poisoning.

Phosgene inhalation in concentrations greater than 1 ppm may produce a transient bioprotective vagus reflex with rapid shallow breathing in some individuals. Phosgene concentrations greater than 3 ppm are moderately irritating to eyes and upper airways. Toxic phosgene doses (greater than or equal to 30 ppm X min) inhaled into the terminal respiratory passages render the blood-air-barrier more permeable to blood plasma, which gradually collects in the lung. Some time passes, however, until the collection of fluid provokes signs and symptoms. This period in which the patient experiences relative well-being is known as the clinical latent phase. The clinical symptoms which follow and the pathological changes underlying them are discussed in detail; dose-effect relationships are demonstrated. The regression phase after poisoning has been overcome is briefly sketched.

Early diagnosis of phosgene overexposure.

At the present time, the following parameters can be recommended for "early diagnosis" of phosgene overexposure: Phosgene indicator paper badges, to be worn by all persons involved in handling phosgene (these badges permit immediate estimation of the exposure dose in each individual case); Observation of the initial irritative symptoms of the eye and the upper respiratory tract after phosgene inhalation can provide a rough indication of the inhalation concentration and dose; X-ray photographs of the lungs make it possible to detect incipient toxic pulmonary edema at an early stage, during the clinical latent period. A number of additional parameters require further critical investigation.

Pulmonary changes in the rat following low phosgene exposure.

Minimal inhalation doses (or concentrations) of phosgene necessary for the production of changes within the blood-air barrier were determined in rats. At least 50 ppm.min (5 ppm X 10 min) was necessary for the production of alveolar oedema (the minimal effective phosgene concentration being 5 ppm). While the smallest phosgene dose to produce an increase in pulmonary lavage protein content was also 50 ppm.min and while the smallest phosgene dose to produce widening of pulmonary interstices was 25 ppm.min, there was no phosgene threshold concentration (down to 0.1 ppm) for these two latter parameters, which are assumed to be indicators of physiological compensatory mechanisms within the blood-air barrier. The primary localisation of pulmonary damage seemed to depend on the concentration of phosgene used: at low concentrations (0.1-2.5 ppm) the changes were primarily located at the transition from terminal bronchioles to the alveolar ducts; at higher concentrations (5 ppm) damage to the alveolar pneumocytes (type I) was more conspicuous.

Re: "Mutagenic action of isocyanates used in the production of polyurethanes" by M. Anderson, M-L Binderup, P. Kiel, H. Larson, J. Maxild. Scand J Work Environ Health 6 (1980) 221-226.

The Ames test results published in Andersen et al's article can, at most, serve as encouragement to engage in more-detailed studies, for example, long-term animal experiments with MDI or epidemiologic studies on man. (Such studies are already in progress or are in the planning stage.) At the moment, it is absolutely unjustifiable to suggest that isocyanates--provided that the customary TLV values are observed--represent a serious health hazard to man in the form of cancer or genetic damage.