Urine Biomonitoring for TDI Exposure

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1 1. Introduction Diisocyanates Panel Scientific Information Statement (with references) Urine Biomonitoring for TDI Exposure Toluene diisocyanate (TDI) has been used for decades, primarily in the production of flexible polyurethane foams by reacting TDI with polyols and amines under controlled conditions in dedicated production lines. It is also used to manufacture polyurethane plastics, coatings, and elastomers. TDI has been well-studied and a variety of safety precautions and engineering controls are available to protect workers and the public. A When TDI industrial products are sold through distributors, a number of measures exist to help ensure the products are only used for industrial purposes. Due to its vapor pressure, inhalation is the primary exposure route of concern in the workplace. Inhalation exposures may result from emissions associated with accidental spills, sample collection, residue removal, and equipment maintenance. Worker exposure to TDI is usually evaluated by ambient air monitoring, which can be reliably measured with appropriate expertise and equipment. 8 Occasionally, biological monitoring has been used. The American Conference of Governmental Industrial Hygienists (ACGIH) has established a Threshold Limit Value (TLV) of ppm (time weighted average) and 0.02 ppm (15-minute average) 2 for worker exposure to TDI in air. ACGIH has not developed a Biological Exposure Index (BEI) for TDI. A Biological Monitoring Guidance Value (BMGV) of 1 µmol urinary diamines/mol creatinine has been established for workers exposed to TDI in the United Kingdom by the WATCH Committee of the Health and Safety Executive TDI Exposure Assessment as Hydrolyzed Toluene Diamine in Urine Samples Biological monitoring for TDI may serve as a useful supplement to air monitoring particularly for workplaces where individuals are involved in a variety of activities, each presenting possibly different exposure levels and durations and where routes of exposure other than inhalation may potentially occur. The advantage of biomonitoring is that, in principle, the "total dose" may be estimated for each individual. 5 However, due to inter-individual variation in absorption, metabolism and excretion, and compounded by the use of a variety of analytical methods at different laboratories, biological monitoring data tend to vary greatly, consequently limiting their wide-spread use for estimation of TDI exposures. 2.1 Methodology Biomonitoring assays attempt to estimate TDI exposure by measuring a relevant biomarker in urine. A commonly used procedure is to convert the urinary metabolites of TDI to toluene diamine (TDA) by hydrolysis. 15 Virtually all subsequently published analysis of human urine of TDI exposed individuals use some variation of the same principle of applying vigorous acid or base hydrolysis prior to derivatization and A Material Safety Data Sheets, available from TDI suppliers, provide additional health and safety information regarding this chemical. Page 1 of American Chemistry Council October 2008

2 1, 4, 6, 7, chromatographic analysis for the measurement of compounds hydrolyzed to TDA Although various analytical methods determine the amount of TDA generated in the laboratory by hydrolysis, these protocols do not provide information on the relative contribution of any free (unconjugated) TDA to total hydrolysable TDA, unless the hydrolysis step is omitted. In addition to sample processing and selecting the analytical method, another variable that influences the interpretation of the data is the urine sampling regimen. Urine sampling has been conducted either at a single time point, 6, 7, 13, 20 over multiple times within one day 22 or extending over several days. 4, 11, 14, 23 Ideally, multiple samples collected over a 24-hour period are likely to provide the most useful information. However, due to practical constraints of an occupational environment, investigators have typically collected samples at a single point during the work shift. Variability in sampling regimen can be expected to result in under- or over-estimation of the actual daily dose of TDI, depending on the proximity to time and magnitude of past exposure. 2.2 Interpretation It should be noted that no studies were found in a review of the scientific literature to indicate a correlation between levels of TDA found after hydrolysis of urine from TDIexposed workers and adverse health effects. Data generated by such urine biomonitoring assays must be evaluated with caution for the following reasons: 1. Levels of TDA detected in hydrolyzed urine of TDI-exposed workers show 4, 13, 16, 20 some degree of association to TDI air concentrations whereas 1, 24 other investigators have not found a correlation. 2. Measurement of TDA in hydrolyzed urine samples cannot distinguish the relative contributions of prior exposures to TDI and TDA because metabolites of both compounds are measured as TDA. Therefore, this analytical procedure has limited value and reliability in estimating TDI exposures, if the potential for TDA exposure also exists. 3. Detection of TDA in laboratory assays on hydrolyzed urine samples does not necessarily indicate the presence of free TDA in the body. Free TDA was not detected in the non-hydrolyzed urine of workers exposed to TDI 19, It is not clear whether urine biomonitoring based on measurement of TDA following hydrolysis of urine from TDI-exposed workers can detect shortterm, intermittent spikes in exposures. Peak exposures are important because they are believed to be involved in the development of airway sensitization Quantitative inter-laboratory comparison of data is limited by the variability in sample processing and analytical methodology. For example, variations in hydrolysis agent (acid or base), temperature and duration are 2008 American Chemistry Council Page 2 of 6 October 2008

3 3. Conclusions 9, 16, 19, 23 reported. Furthermore, evidence supports the conclusion that despite efforts at improving sample processing and the analytical procedure, the true amount of hydrolysable TDA in urine cannot be determined 19, 23, thus adding further emphasis on the importance of all investigators to validate and use a single standardized method. 6. Background levels of TDA in hydrolyzed urine from individuals not known to be exposed to TDI or TDA have been found. 21 Thus, not all analytical findings of TDA in processed urine samples reflect prior occupational exposure to TDI. Biomonitoring to estimate exposure to TDI by converting TDI-derived urinary metabolites to TDA using vigorous acid or base hydrolysis, and measuring the hydrolyzed TDA have been conducted in the occupational setting. Theoretically, such procedures integrate exposure via multiple routes and consequently are expected to lead to more accurate estimation of total TDI dose. However, there are some limitations for quantitative use of these data. At present, the multiplicity of analytical methods employed for quantitative analysis of TDI-derived urinary metabolites precludes reliable inter-laboratory comparisons. This limits the application of TDA biomarker-based exposure indices to control TDI exposures in the workplace. It is recognized that reliable data can be produced within a given laboratory if that laboratory has standardized and validated a specific analytical method and, by extension, a similar effort could, in the future, lead to inter-laboratory consistency of biomarker data. Another important consideration is the non-specificity of the hydrolysis method when individuals are exposed to both TDI and TDA. Under such co-exposure conditions, the resulting inability to distinguish the relative contribution of TDI to the total hydrolyzed urinary TDA level precludes drawing particularized conclusions about TDI exposure. It is important to recognize that levels of urinary TDA in TDI-exposed workers have not been correlated to the existence of adverse health effects. In this regard, it is important to note that free TDA has not been found in the non-hydrolyzed urine of workers exposed to TDI. Based on the current methods discussed herein, biomonitoring for hydrolyzed urinary TDI metabolites may provide some qualitative guidance for workplace practices and industrial hygiene, and serve as an adjunct to air monitoring for TDI for worker health and safety. However, at present, biomonitoring does not offer a reliable mechanism for serving as the sole determinant of exposure to TDI. Mere detection of a substance in a human biomonitoring study does not mean there s a health risk. In a review of the scientific literature, no studies were found that correlated the levels of putative TDI-derived metabolites in urine to adverse health effects in humans. As CDC has indicated, Just because people have an environmental chemical in their blood or urine does not mean that the chemical causes disease. The toxicity of a chemical is related to its dose or concentration in addition to a person s individual susceptibility. Small amounts may be of no health consequence, whereas larger amounts may cause adverse health effects. Research studies are required to determine which levels of a chemical may cause health effects and which levels are not a significant health concern American Chemistry Council Page 3 of 6 October 2008

4 References * * * This document summarizes information from the technical, scientific literature and is intended for reference by medical, scientific and regulatory personnel. The Diisocyanates Panel of the American Chemistry Council and its member companies believe that this document is, as of the date of its publication, a technically accurate summary of available scientific information. However, the Panel and its member companies do not make any warranties, express or implied, regarding the completeness or accuracy of the information presented and assume no responsibility or liability for its use. New information may be developed subsequent to the publication of this summary, which may render the summary incomplete or inaccurate. The Panel and its member companies assume no responsibility to amend, revise or update the summary to reflect any such information that may become available after its publication. For additional information regarding Urine Biomonitoring for TDI Exposure, please contact Sahar Osman-Sypher, Manager of the Diisocyanates Panel of the American Chemistry Council, at (703) Austin, S. (2007) Biological monitoring of TDI-derived amines in polyurethane foam production. Occupational Medicine 57: ACGIH (2008) TLVs and BEIs, Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices. American Conference of Governmental Industrial Hygenists, Cincinnati, Ohio. 3. Bernstein, D.I., Korbee, L., Stauder, T., Bernstein, J.A., Scinto, J., Herd, Z.L., and Bernstein, I.L. (1993) The low prevalence of occupational asthma and antibody-dependent sensitization to diphenylmethane diisocyanate in a plant engineered for minimal exposure isocyanates. J. Allergy Clin. Immunol. 92: Brorson T, Skarping G and Sango C (1991). Biological monitoring of isocyanates and related amines. IV. 2,4- and 2,6-toluenediamine in hydrolysed plasma and urine after testchamber exposure of humans to 2,4- and 2,6-toluene diisocyanate. Int. Arch. Occup. Environ. Health 63: Chappelle, A. H., Shiotsuka, R.N. and Bartels, M.J. (2002). Some limitations in the use of urine biomonitoring for measuring TDI exposure, in Isocyanates: Sampling, Analysis, and Health Effects, ASTM STP 1408, J. Lesage, I. D. DeGraff and R. S. Danchik, Eds., American Society for Testing and Materials, West Conshohocken, PA. 6. Dahlke, W., E. Schriever, G. Skarping, J. Lewalter, D. Dahmann, X. Baur and D. Berger (2001). Exposure to isocyanate after thermal degradation from coated parts. Arbeitsmed. Sozielmed. Umweltmed. 36: Kaaria, K., A. Hirvonen, H. Norppa, P. Piirila, H. Vainio and C. Rosenberg (2001) Exposure to 2,4- and 2,6-toluene diisocyanate (TDI) during production of flexible foam: determination of airborne TDI and urinary 2,4- and 2,6-toluenediamine (TDA). Analyst 126: American Chemistry Council Page 4 of 6 October 2008

5 8. Levine SP, Hillig, K.J.D., Dharmarajan,,V. Spence, M.W. and Baker, M.D. (1995). Critical review of methods of sampling, analysis and monitoring for TDI and MDI. Am. Ind. Hyg. Assoc. J. 56: Lewalter J and Biedermann P (1994). Aromatic Amines (aniline, o-toluidine, m-toluidine, p-toluidine, 4-chloro-o-toluidine, 2,4-toluylenediamine, 2,6-toluylenediamine, 4- aminodiphenyl, 4,4 -diaminodiphenylmethane. Analyses of Hazardous Substances in Biological Materials, Vol. 4. Angerer J and Schauer KH (eds.), pp Verlagsgesellschaft mbh, Weinheim, FDR 10. Lind, P., Dalene, M., skarping, G., and Hagmar, L. (1996) Toxicokinetics of 2,4- and 2,6- toluenediamine hydrolysed urine and plasma after occupational exposure to 2,4- and 2,6- toluene diisocyanate. Occup. Environ. Med. 53: Lind, P., Dalene, M., Tinnerberg, H. and Skarping, G. (1997). Biomarkers in hydrolysed urine, plasma and erythrocytes among workers exposed to thermal degradation products from toluene diisocyanate foam. Analyst 122: Lind, P., Skarping, G. and Dalene, M. (1996) Biomarkers of toluene diisocyanate and thermal degradation products of polyurethane, with special reference to the sample preparation. Analytica Chimca Acta 333: Maitre A, Berode M, Perdrix A, Romazini S, and Savolainen (1993). Biological monitoring of occupational exposure to toluene diisocyanate. Int. Arch. Occup. Environ. Health 65: Persson P, Dalene M, Skarping G, Adamsson M and Hagmar L (1993). Biological monitoring of occupational exposure to toluene diisocyanate: measurement of toluenediamine in hydrolysed urine and plasma by gas chromatography-mass spectrometry. Brit. J. Indus. Med. 50: Rosenberg, C. and Savolainen, H. (1985). Detection of urinary amine metabolites in toluene diisocyanate exposed rats. J. Chromatogr. 323: Sakai, T., Morita, Y., Roh, J., Kim, H. and Kim, Y. (2005) Improvement in the GC-MS method for determining urinary toluene-diamine and its application to the biological monitoring of workers exposed to toluene-diisocyanate. Int. Arch. Occup. Environ. Health 78: Sakai, T., Morita, Y. Kim, Y. and Tao, Y.X. (2002). LC-MS determination of urinary toluenediamine in workers exposed to toluenediisocyanate, Tox. Letters, 134: Sandstrom, J.F., Skarping, G. and Dalene, M. (1989) Chromatographic determination of amines in biological fluids with special reference to the biological monitoring of isocyanates and amines: II. Determination of 2,4- and 2,6-toluenediamine in human urine using capillary gas chromatography and selected ion monitoring with special reference to the biological monitoring of exposure to toluene diisocyanates. J. Chromatogr. 479: American Chemistry Council Page 5 of 6 October 2008

6 19. Sennbro, C. J., Lindh, C.H., Tinnerberg,, H. Gustavsson, C., Littorin, M., Welinder, H. and Jonsson, B.A.G. (2003). Development, validation and characterization of an analytical method for the quantification of hydrolysable urinary metabolites and plasma protein adducts of 2,4- and 2,6-toluene diisocyanate, 1,5-naphthalene diisocyanate and 4,4 - methylenediphenyl diisocyanate, Biomarkers, 8 (3-4): Sennbro, C. Lindh, C., Tinnerberg, H., Welinder, H., Littorin, M., Jonsson, B. (2004). Biological monitoring of exposure to toluene diisocyante. Scand J Work Environ Health, 30: Sennbro C.J., Littorin, M., Tinnerberg, H., and Jőnsson, A.G. (2005) Upper reference limits for biomarkers of exposure to aromatic diisocyanates. Int Arch Occup Environ Health. On line publication, July. 22. Skarping G, Brorson T and Sango C (1991). Biological monitoring of isocyanates and related amines. III. Test chamber exposure of humans to toluene diisocyanate. Int. Arch. Occup. Environ. Health 63: Skarping G, Dalene M and Lind P (1994). Determination of toluenediamine isomers by capillary gas chromatography and chemical ionization mass spectrometry with special reference to the biological monitoring of 2,4- and 2,6-toluene diisocyanate. J. of Chromotography 663: Tinnerberg H, Dalene M and Skarping G (1997). Air and biological monitoring of toluene diisocyanate in a flexible foam plant. Am. Ind. Hyg. Assoc. J. 58: Tinnerberg, H. and Mattsson, C. (2008) Usage of air monitoring and biomarkers of isocyanate exposure to assess the effect of a control intervention. Ann. Occup. Hyg. 52: WATCH Committee, Health and Safety Executive, WATCH meeting October 2005 [ 27. Centers for Disease Control and Prevention. Third National Report on Human Exposure to Environmental Chemicals. Atlanta (GA: CDC, American Chemistry Council Page 6 of 6 October 2008

exposure to 2,4- and 2,6- toluene diisocyanate

exposure to 2,4- and 2,6- toluene diisocyanate 94 Department of Occupational and nvironmental Medicine, University Hospital, S-221 85 Lund, Sweden P Lind M Dalene G Skarping L Hagmar Correspondence to: Dr Pernilla Lind, Department of Occupational and