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.

Diisocyanates are used to produce a wide variety of polyurethane products; they are also recognized as an important cause of occupational asthma. Their chemical reactivity presents challenges to toxicologists and clinicians alike seeking to understand the mechanisms underlying diisocyanate asthma. In this article, we review the literature on immunoassay detection of IgE and IgG binding to diisocyanate-protein conjugates and assess the utility of such testing as a diagnostic tool and exposure indicator. Data from 29 studies of occupational exposure to diisocyanates revealed considerable variability in assay methodology and heterogeneity in the prevalence of positive antibody responses across laboratories. In studies that included both confirmed diisocyanate asthma subjects and exposed nonasthmatics, positive IgE responses identified cases with low sensitivity (18-27%), but high specificity (96-98%). Detection of IgG binding to diisocyanate conjugates is an indirect, qualitative indicator of disease status and past diisocyanate exposure. The utility of these assays is limited, however, due to a lack of (1) method standardization, (2) population norms to guide interpretation of results, and (3) demonstration that the assays improve either on disease prediction or on exposure confirmation beyond that of other indicators. Sources of assay heterogeneity are discussed and suggestions are offered for improving test performance and interpretability.

This position statement reviews several aspects of spirometric testing in the workplace, where spirometry is employed in the primary, secondary, and tertiary prevention of occupational lung disease. Primary prevention includes pre-placement and fitness-for-duty examinations as well as research and monitoring of health status in groups of exposed workers; secondary prevention includes periodic medical screening of individual workers for early effects of exposure to known occupational hazards; and tertiary prevention includes clinical evaluation and impairment/disability assessment. For all of these purposes, valid spirometry measurements are critical, requiring: documented spirometer accuracy and precision, a rigorous and standardized testing technique, standardized measurement of pulmonary function values from the spirogram, adequate initial and refresher training of spirometry technicians, and, ideally, quality assessment of samples of spirograms. Interpretation of spirometric results usually includes comparison with predicted values and should also evaluate changes in lung function over time. Response to inhaled bronchodilators and changes in relation to workplace exposure may also be assessed. Each of these interpretations should begin with an assessment of test quality and, based on the most recent ATS recommendations, should rely on a few reproducible indices of pulmonary function (FEV1, FVC, and FEV1/FVC.) The use of FEF rates (e.g., the FEF25-75%) in interpreting results for individuals is strongly discouraged except when confirming borderline airways obstruction. Finally, the use of serial PEF measurements is emerging as a method for confirming associations between reduced or variable pulmonary function and workplace exposures in the diagnosis of occupational asthma. Throughout this position statement, ACOEM makes detailed recommendations to ensure that each of these areas of test performance and interpretation follow current recommendations/standards in the pulmonary and regulatory fields. Submitted by the Occupational and Environmental Lung Disorder Committee on November 16,1999. Approved by the ACOEM Board of Directors on January 4,2000.

Context Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association.ObjectiveTo perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis.MethodsA comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association.ResultsTwelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or specificity. No plausible mechanism of toxicity was found. Application of a predictive mathematical model for determining probability of causal association for neurotoxicity was calculated to be 21%.ConclusionThere is insufficient evidence for a causal association of neurotoxic effects and diisocyanate exposure based on lack of evidence in all categories of the Hill criteria for causality except for temporal association of reported symptoms and alleged exposure. Future reports should attempt to address more rigorous exposure assessment and control for confounding exposures.

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.