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Occupational Medicine 2007 57(6):391-393; doi:10.1093/occmed/kql148
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorials

Biological monitoring for isocyanates

Organic diisocyanates are a significant occupational health problem. They are respiratory and skin sensitizers and a major cause of occupational asthma in the UK [1]. The most common are hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), isopherone diisocyanate (IPDI) and methylene-diphenyl diisocyanate (MDI) in decreasing order of volatility. HDI and IPDI are used for varnishes, coatings and two-pack spray paints used in motor vehicle repair. TDI and MDI are used for flexible and rigid polyurethane foams, floor coverings and adhesives. This wide range of uses means that there are thousands of workers potentially exposed to isocyanates.

In the UK, a management control system is required for workers exposed to isocyanates and for this to be successful workers should not become sensitized. Apart from occupational asthma, airway irritation and asthma-like symptoms such as cough, wheezing and dyspnoea are commonly reported. Other respiratory effects are hypersensitivity pneumonitis, rhinitis and accelerated rate of decline in lung function. Diisocyanates can also cause both irritant and allergic contact dermatitis as well as skin and conjunctival irritation. Health surveillance that detects occupational asthma is recording failure—there needs to be intervention earlier in the exposure-to-disease paradigm. Although there is evidence that detecting respiratory symptoms early and removing workers from exposure improves prognosis, the goal should be to control exposure to prevent any symptoms.

In an attempt to reduce the risks posed by isocyanates, airborne exposure limits are low. The UK workplace exposure limit is 0.02 mg m–3 for an 8-h time-weighted average (TWA) and 0.07 mg m–3 for a 15-min short-term exposure limit (STEL). The American Conference of Governmental Industrial Hygienists have recently proposed lowering the threshold limit value for TDI to 0.007 mg m–3 8 h TWA and 0.021 mg m–3 STEL and added a ‘skin’ notation to signify that dermal absorption of TDI can contribute significantly to the systemic dose [2]. This reduction in airborne limit may lead to increased use of respiratory protective equipment and together with the skin notation it points to a need for biological monitoring of isocyanate exposure to help assess the efficacy of the controls.

Biological monitoring of isocyanate exposure by the analysis of isocyanate-derived diamines released from protein adducts in urine or plasma has been available for many years [3,4]. The most recent study by Austin [5] is in this issue (pages 444–448).

Several volunteer and occupational studies show good correlations between isocyanate-derived diamines in urine and airborne concentrations of TDI, HDI and IPDI [4,6–12]. Peak excretion occurs at the end of exposure and the initial elimination half-life is ~2 h for TDI and for HDI and IPDI suggesting end of exposure urine sample collection for biological monitoring of exposure [6,12,13].

These studies involved exposure to the isocyanate monomer but in many workplaces exposure is to polymeric isocyanates. This is particularly important for exposures to HDI in two-pack paints used for motor vehicle repair where free monomeric HDI is much <1% and the remainder is polymeric HDI. However, occupational studies show that hexamethylene diamine (HDA) can be detected in urine of spray painters after brief exposures to high concentrations or where exposure controls were not working correctly [3,14]. It is still not clear whether the HDA in these cases is released from conjugates of HDI monomer only or from conjugates of polymeric HDI or both. Nevertheless, measurement of isocyanate-derived diamines has been widely used to assess occupational exposure and last year the Health & Safety Executive (HSE) proposed a biological monitoring guidance value for isocyanates of 1 µmol isocyanate-derived diamine mol–1 creatinine. The guidance value is not health-based but was derived from the 90th percentile of biological monitoring data from workplaces with exposure to HDI, TDI, IPDI and MDI [15]. Exceeding the guidance value should trigger an investigation into the exposure controls.

The most recent paper on biological monitoring for isocyanates in this journal raises the issue reported by others of dermal absorption of isocyanates [4,5,7,16,17]. Austin [5] found higher values of urinary toluenediamine (TDA) in handlers of uncured TDI-based foam than non-handlers and speculated that this may be due to dermal absorption. The paper is careful to note that the metabolism and toxicokinetics of TDI, particularly dermal absorption of TDI, are not well understood. However, the 20-fold difference in urinary TDA levels is such that even with an increased ventilation rate for handlers, inhalation of TDI alone is unlikely to account for the difference in urinary levels and dermal absorption is a possibility. The paper does not mention the possibility of hydrolysis of TDI to yield TDA prior to exposure or the possibility of coexposure to TDA in the TDI mixture. However, the higher reactivity of diisocyanates to thiols and primary amines (present in the side chain of some amino acids) than towards water suggests that diisocyanates are preferentially conjugated to various macromolecules either at the site of contact or after systemic absorption, rather than hydrolyzed to their corresponding amines. So the protein conjugates of isocyanates found in urine are most likely to be derived from systemic absorption and reaction of the intact diisocyanate. This hypothesis is supported by an inhalation and dermal exposure study of polymeric MDI and methylenedianiline (MDA) in rats which showed MDI can react at the site of contact to form adducts but hydrolysis of MDI to MDA before absorption was not significant [16]. However, on an equimolar basis, MDA is better absorbed and contributes more to urinary metabolites than MDI so if there was any MDA present in the MDI mixture measurement of urinary MDA would tend to overestimate exposure to MDI. This study also showed that on an equimolar basis, inhalation exposure to MDI will yield higher levels of MDA in urine than after dermal exposure to MDI. Interpretation of urinary diamine results can be difficult if there is mixed dermal an inhalation exposure to isocyanates and diamines.

The consequences of dermal absorption of diisocyanates are a subject of debate. There is some evidence from animal studies that dermal absorption can lead to respiratory sensitization but whether this applies in humans is not clear [18–20]. Volunteer studies to look at the possibility of dermal exposure to diisocyanates leading to respiratory sensitization are unethical. Studies of workplaces are likely to have both inhalation as well as dermal exposure. An HSE sponsored workshop involving clinicians and scientists found there was insufficient data to determine the importance of dermal absorption both mechanistically and occupationally but 73% of the participants felt that the skin could act as a route for respiratory allergy [21].

The good correlation between urinary metabolites in inhalation exposures in field studies suggests that the major route of absorption of isocyanates into the body, particularly for HDI, IPDI and TDI is by inhalation. The lower volatility of MDI means that dermal absorption may be more significant for this substance. Most isocyanates are skin sensitizers so dermal exposure should be avoided, if possible, regardless of whether it can lead to respiratory sensitization.

Work still needs to be done to evaluate the metabolism and mechanism of sensitization of isocyanates and whether the dermal route can contribute to respiratory sensitization. In the mean time, biological monitoring clearly has a role in assessing occupational exposure to isocyanates and the adequacy of control measures, especially efficacy of respiratory protection in use and human behavioural aspects which are difficult to measure by other means.

Occupational health professionals should be aware that HSE is conducting a series of safety and health awareness days for workers potentially exposed to isocyanates in motor vehicle repair and has produced new guidance documents that emphasize the need to control exposures to isocyanates and to use biological monitoring to check that the controls work [22–24].

John Cocker

e-mail: John.Cocker{at}hsl.gov.uk

References

  1. McDonald JC, Chen Y, Zekveld C, Cherry NM. Incidence by occupation and industry of acute work related respiratory diseases in the UK, 1992 –2001. Occup Environ Med (2005) 62:836–842.[Abstract/Free Full Text]

  2. ACGIH. TLVs and BEIs. In: Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indicies (2006) Cincinnati, OH: ACGIH Worldwide.

  3. Rosenberg C, Saviolainen H. Determination in urine of diisocyanate-derived amines from occupational exposure by gas chromatography-mass spectrometry. Analyst (1986) 111:1069–1071.[CrossRef][Medline]

  4. Rosenberg C, Saviolainen H. Determination of occupational exposure to toluenediisocyanate by biological monitoring. J Chromatogr (1986) 367:385–392.[CrossRef][Web of Science][Medline]

  5. Austin S. Biological monitoring of TDI-derived amines in polyurethane foam production. Occup Med (Lond) (2007) 57:444–448.

  6. Brorson T, Skarping G, Sango C. Biological monitoring of isocyanates and related amines IV. 2,4 and 2,6 toluenediamine in hydrolysed plasma and urine after test chamber exposure of humans to 2,4 and 2,6 toluene diisocyanate. Int Arch Occup Environ Health (1991) 63:253–259.[CrossRef][Web of Science][Medline]

  7. Maitre A, Berode M, Perdix A, Romazini S, Savolainen H. Biological monitoring of occupational exposure to toluene diisocyanate. Int Arch Occup Environ Health (1993) 65:97–100.[CrossRef][Web of Science][Medline]

  8. Persson P, Dalene M, Skarping G, Adamsson M, Hagmar L. Biological monitoring of occupational exposure to toluene diisocyanate: measurement of toluenediamine in hydrolysed urine and plasma by gas chromatography-mass spectrometry. Br J Ind Med (1993) 50:1111–1118.[Web of Science][Medline]

  9. Kaaria K, Hirvonen A, Norppa H, Piirila P, Vainio H, Rosneberg C. 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 (2001) 126:1025–1031.[CrossRef][Medline]

  10. Sennbro CJ, Lindh CH, Tinnerberg H, Welinder H, Littorin M, Jonsson BA. Biological monitoring of exposure to toluene diisocyanate. Scand J Work Environ Health (2004) 30:371–378.[Web of Science][Medline]

  11. Maitre A, Berode M, Perdix A, Stoklov M, Mallion JM, Saviolainen H. Urinary hexane diamine as an indicator of occupational exposure to hexamethylenediisocyanate. Int Arch Occup Environ Health (1996) 69:65–68.[CrossRef][Web of Science][Medline]

  12. Tinnerberg H, Skarping G, Dalene M, Hagmar L. Test chamber exposure of humans to 1,6 hexamethylene diisocyanate and isophorone diisocyanate. Int Arch Occup Environ Health (1995) 67:367–374.[CrossRef][Web of Science][Medline]

  13. Skarping G, Brorson T, Sango C. Biological monitoring of isocyanates and related amines III. Test chamber exposures of humans to toluene diisocyanate. Int Arch Occup Environ Health (1991) 63:83–88.[CrossRef][Web of Science][Medline]

  14. Williams NR, Jones K, Cocker J. Biological monitoring to assess exposure from use of isocyanates in motor vehicle repair. Occup Environ Med (1999) 56:598–601.[Abstract/Free Full Text]

  15. HSE. WATCH Committee Biological Monitoring for Isocyanates. http://www.hse.gov.uk/aboutus/hsc/iacs/acts/watch/051005/13.pdf (10 November 2006, date last accessed).

  16. Pauluhn J, Lewalter J. Analysis of markers of exposure to polymeric methylene-diphenyl diisocyanate (pMDI) in rats: a comparison of dermal and inhalation routes of exposure. Exp Toxicol Pathol (2004) 54:135–146.[CrossRef]

  17. Creely KS, Hughson GW, Cocker J, Jones K. Assessing isocyanate exposures in polyurethane industry sectors using biological and air monitoring methods. Ann Occup Hyg (2006) 50:609–621.[Abstract/Free Full Text]

  18. Kimber I. The role of skin in the development of chemical respiratory hypersensitivity. Toxicol Lett (1996) 86:89–92.[CrossRef][Web of Science][Medline]

  19. Rattray NJ, Botham PA, Hext PM, et al. Induction of respiratory hypersensitivity to diphenylmethane-4,4'-diisocyanate (MDI) in guinea pigs. Influence of route of exposure. Toxicology (1994) 88:15–30.[CrossRef][Web of Science][Medline]

  20. Karol MH, Hauth BA, Riley EJ, Magreni CM. Dermal contact with toluene diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea pigs. Toxicol Appl Pharmacol (1981) 58:221–230.[CrossRef][Web of Science][Medline]

  21. Curran A. Does the Skin Act as a Route for Respiratory Allergy. Report Froman HSE Workshop Held at the Radisson SAS Hotel Manchester 18–19 November 1999 (2002) Buxton: Health & Safety Laboratory. Internal Report HEF/002/02.

  22. HSE. Isocyanates and Printing. http://www.hse.gov.uk/pubns/guidance/p47.pdf (10 November 2006, date last accessed).

  23. HSE. Safe Working with 2 Pack Isocyanate Paints. http://www.hse.gov.uk/pubns/indg388.pdf (10 November 2006, date last accessed).

  24. HSE. COSHH Essentials Urine Sampling for Isocyanate Exposure Measurement. http://www.hse.gov.uk/pubns/guidance/g408.pdf (10 November 2006, date last accessed).


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