Robert P. Streicher

Skin Exposure to Isocyanates: Reasons for Concern

Objective Isocyanates (di- and poly-), important chemicals used worldwide to produce polyurethane products, are a leading cause of occupational asthma. Respiratory exposures have been reduced through improved hygiene controls and the use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in settings with minimal inhalation exposure but opportunity for skin exposure. In this review we evaluate the potential role of skin exposure in the development of isocyanate asthma. Data sources We reviewed the published animal and human literature on isocyanate skin-exposure methods, workplace skin exposure, skin absorption, and the role of skin exposure in isocyanate sensitization and asthma. Data extraction We selected relevant articles from computerized searches on Medline, U.S. Environmental Protection Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, and Google databases using the keywords “isocyanate,” “asthma,” “skin,” “sensitization,” and other synonymous terms, and our own extensive collection of isocyanate publications. Data synthesis Isocyanate production and use continues to increase as the polyurethane industry expands. There is substantial opportunity for isocyanate skin exposure in many work settings, but such exposure is challenging to quantify and continues to be underappreciated. Isocyanate skin exposure can occur at work, even with the use of personal protective equipment, and may also occur with consumer use of certain isocyanate products. In animals, isocyanate skin exposure is an efficient route to induce sensitization, with subsequent inhalation challenge resulting in asthma-like responses. Several lines of evidence support a similar role for human isocyanate skin exposure, namely, that such exposure occurs and can contribute to the development of isocyanate asthma in certain settings, presumably by inducing systemic sensitization. Conclusions Integrated animal and human research is needed to better understand the role of skin exposure in human isocyanate asthma and to improve diagnosis and prevention. In spite of substantial research needs, sufficient evidence already exists to justify greater emphasis on the potential risks of isocyanate skin exposure and the importance of preventing such exposures at work and during consumer use of certain isocyanate products.

Determination of Airborne Isocyanate Exposure: Considerations in Method Selection

To assess worker isocyanate exposures in a variety of processes involving the manufacture and use of surface coatings, polyurethane foams, adhesives, resins, elastomers, binders, and sealants, it is important to be able to measure airborne reactive isocyanate-containing compounds. Choosing the correct methodology can be difficult. Isocyanate species, including monomers, prepolymers, oligomers, and polyisocyanates, are capable of producing irritation to the skin, eyes, mucous membranes, and respiratory tract. The most common adverse health effect is respiratory sensitization, and to a lesser extent dermal sensitization and hypersensitivity pneumonitis. Furthermore, isocyanate species formed during polyurethane production or thermal degradation may also produce adverse health effects. Isocyanate measurement is complicated by the fact that isocyanates may be in the form of vapors or aerosols of various particle size; the species of interest are reactive and therefore unstable; few pure analytical standards exist; and high analytical sensitivity is needed. There are numerous points in the sampling and analytical procedures at which errors can be introduced. The factors to be considered for selecting the most appropriate methodology for a given workplace include collection, derivatization, sample preparation, separation, identification, and quantification. This article discusses these factors in detail and presents a summary of method selection criteria based on the isocyanate species, its physical state, particle size, cure rate, and other factors.

Development of a Novel Derivatization Reagent for the Sampling and Analysis of Total Isocyanate Group in Air and Comparison of its Performance with that of Several Established Reagents

Analytical reference standards generally are not available for non-monomeric isocyanate species, making accurate identification and quantitation by high-performance liquid chromatography (HPLC) difficult. A successful derivatizing reagent must react rapidly with all isocyanate groups, the derivatized isocyanate must be detectable selectively and at very low levels, and the detector used for quantitation must give a response proportional to the number of derivatized isocyanate groups present. A novel derivatizing reagent, 1-(9-anthracenylmethyl)piperazine (MAP), was prepared in an attempt to achieve these goals. Derivatives were prepared by reacting five mono- and difunctional isocyanates with MAP and three other established isocyanate derivatizing reagents. These reagents included 1-(2-methoxyphenyl)piperazine (MOPP),9-(methylaminomethyl)anthracene (MAMA), and tryptamine (TRYP). The relative reactivities of MAP, MOPP, TRYP, and MAMA with phenyl isocyanate were found to be 100, 88, 30, and 25, respectively. Average molar absorptivities at the absorbance maxima +/- compound-to-compound variabilities were, for MAP: 1.47 x 10(5) +/- 3.50%; MAMA: 1.38 x 10(5) +/- 7.07%: and TRYP: 3.98 x 10(4) +/- 13.1%. Average fluorescence responses were, for MAP: 100 +/- 32.6%; MAMA: 41.0 +/- 58.8%; and TRYP: 2.27 +/- 15.6%. A comparison of MAP and MOPP ureas by HPLC/ultraviolet (UV)/electrochemical (EC) gave average responses for UV, EC, and EC/UV for MAP: 117 +/- 7.3%, 52.1 +/- 6.6%, and 0.447 +/- 10.7%, respectively; for MOPP: 24.3 +/- 62.5%, 76.7 +/- 28.5%, and 4.28 +/- 59.1%, respectively. The favorable performance of MAP warrants its further study as a reagent for the determination of total isocyanate group in air.

Evaluation of the NIOSH draft method 5525 for determination of the total reactive isocyanate group (TRIG) for aliphatic isocyanates in autobody repair shops

This paper evaluates the performance of the NIOSH draft method 5525 for analysis of monomeric and TRIG aliphatic isocyanates in autobody repair shops. It was found that an optimized pH gradient enhanced noticeably the resolution and, therefore, identification of aliphatic isocyanates. Samples proved to be very stable for at least a year when stored at -13 degrees C in the freezer, and no major stability problems were found for the MAP reagent. The detector response factor RSD for selected MAP ureas was 40% in the fluorescence (FLD), 3% in the UV at 254 nm (UV254), and 1% in the UV at 370 nm (UV370). The mean FLD/UV254 and UV254/UV370 detector response ratios of standards were 31.7 (RSD = 37.8) and 17.1 (RSD = 5.4), respectively. The FLD/UV254 ratio in bulks varied from 0.41 to 1.97 times the HDI monomer ratio. The mean UV254/UV370 ratio in bulks was 16.1 (range 14.1 to 19.2, N = 38). Mean (range) recovery of 92 (91.2-93.2)% was found for the N3300 (isocyanurate) spiked on 25 mm quartz fiber filters in the range 0.07 to 2.2 microg NCO ml(-1). Mean (range) recovery for impingers was 100.7 (91.7-106.0)% for N3300 in the concentration range of 0.018 to 2.5 microg NCO ml(-1) and 81.0 (76.1-89.1)% for IPDI in the concentration range of 0.016 to 1.87 microg NCO ml(-1). Analytical method precision was 3.4% and mean bias 7.4% (range = 0-25%). The NIOSH draft method 5525 provides flexibility, enhanced sensitivity and specificity, powerful resolution, and very small compound-to-compound variability in the UV254, resulting in a more reliable identification and quantification of aliphatic isocyanates.

An FTIR investigation of isocyanate skin absorption using in vitro guinea pig skin

Isocyanates may cause contact dermatitis, sensitization and asthma. Dermal exposure to aliphatic and aromatic isocyanates can occur in various exposure settings. The fate of isocyanates on skin is an important unanswered question. Do they react and bind to the outer layer of skin or do they penetrate through the epidermis as unreacted compounds? Knowing the kinetics of these processes is important in developing dermal exposure sampling or decontamination strategies, as well as understanding potential health implications such exposure may have. In this paper the residence time of model isocyanates on hairless guinea pig skin was investigated in vitro using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrometry. Model isocyanates tested were octyl isocyanate, polymeric hexamethylene diisocyanate isocyanurate (pHDI), polymeric isophorone diisocyanate isocyanurate (pIPDI) and methylenediphenyl diisocyanate (MDI). Isocyanates in ethyl acetate (30 microL) were spiked directly on the skin to give 0.2-1.8 micromol NCO cm(-2) (NCO = -N=C=O), and absorbance of the isocyanate group and other chemical groups of the molecule were monitored over time. The ATR-FTIR findings showed that polymeric isocyanates pHDI and pIPDI may remain on the skin as unreacted species for many hours, with only 15-20% of the total isocyanate group disappearing in one hour, while smaller compounds octyl isocyanate and MDI rapidly disappear from the skin surface (80+% in 30 min). Isocyanates most likely leave the skin surface by diffusion predominantly, with minimal reaction with surface proteins. The significance of these findings and their implications for dermal exposure sampling and isocyanate skin decontamination are discussed.

Comparison of Sampling Methods for Monomer and Polyisocyanates of 1,6-Hexamethylene Diisocyanate During Spray Finishing Operations

A comparison study of isocyanate sampling methods for 1,6-hexamethylene diisocyanate (HDI) monomer and HDI-based polyisocyanates was conducted in spray painting environments. This study compared the performance of the Iso-chek sampler against existing and proposed National Institute of Occupational Safety and Health (NIOSH) and Occupational Safety and Health Administration (OSHA) monitoring methods for HDI-based isocyanates. Six methods for monitoring HDI monomer and polyisocyanate levels were compared. Fifty-eight sampling sets were collected during spray painting of aircraft and aircraft parts at four U.S. Air Force bases. Impinger and cassette samplers were mounted side-by-side on a mannequin located in paint overspray areas. For HDI monomer sampling results, there were no significant differences between NIOSH 5521, NIOSH 5522, OSHA 42, MAP (the proposed NIOSH method), and the Iso-Chek. For HDI-based polyisocyanates, NIOSH 5522, NIOSH 5521, Iso-Chek, and the Total Aerosol Mass Method (TAMM) were significantly different from one another. There was no significant difference between MAP and the NIOSH 5522 polyisocyanate sampling results. This study suggests the Iso-Chek and MAP sampling methods compare favorably with established methods for monitoring in HDI spray painting environments and the Total Aerosol Mass Method provides a reasonable upper boundary for estimating HDI polyisocyanate concentrations. The results also reemphasize aerosol sampling physics and sampler geometries must be carefully considered and appropriate samplers used when measuring exposures in spray paint environments where particulates are of the inhalable size.

Field Comparison of Impingers and Treated Filters for Sampling of Total Aliphatic Isocyanates with the MAP Reagent

Results of a comparative field study on the performance of 25-mm inhalable samplers (Institute of Occupational Medicine [IOM]) and midget impingers for the collection of total isocyanates in air using the 1-(9-anthracenylmethyl)piperazine (MAP) reagent are presented. Air sampling and analysis was performed according to the National Institute for Occupational Safety and Health MAP draft method 5525. Midget impingers filled with 15 mL of 1 x 10(-4) M MAP in butyl benzoate were operated at 1 L/min. IOM cassettes loaded with 25-mm quartz fiber filters impregnated with 500 microg MAP, were operated at 2 L/min. Filters were field extracted with 10 mL of 1 x 10(-4) M MAP in acetonitrile. Thirty-four impinger-IOM pairs were collected in three autobody shops during spray painting tasks. Regression analysis [Ln (IOM) = 1.0 Ln (impinger), R2 = 0.98] and a paired t-test (Pr > 0.9) demonstrated that impingers and IOMs perform equally in their collection efficiency for the monomer and total oligomeric hexamethylene diisocyanate (HDI). IOM performance did not deteriorate at longer sampling times compared with the impinger performance. Within-sampler variability was calculated from the individual coefficients of variation (CV) of the 17 pairs of like samplers. The mean of CVs (SD)% for the monomer and total oligomeric HDI was approximately 12 (12)% and 15 (13)% for the IOM and the impinger sampler, respectively. Poor correlation (Pearson correlation coefficient < 0.3) and statistically nonsignificant differences (P > 0.74 two-sided) were found for the between-sampler CVs. Factors that might have influenced the observed sampler agreement are also discussed. It is concluded that MAP impregnated filters can be successfully used for sampling of slow curing total aliphatic isocyanates in air.

Isocyanates and human health: multistakeholder information needs and research priorities.

Objectives: To outline the knowledge gaps and research priorities identified by a broad base of stakeholders involved in the planning and participation of an international conference and research agenda workshop on isocyanates and human health held in Potomac, Maryland, in April 2013. Methods: A multimodal iterative approach was used for data collection including preconference surveys, review of a 2001 consensus conference on isocyanates, oral and poster presentations, focused break-out sessions, panel discussions, and postconference research agenda workshop. Results: Participants included representatives of consumer and worker health, health professionals, regulatory agencies, academic and industry scientists, labor, and trade associations. Conclusions: Recommendations were summarized regarding knowledge gaps and research priorities in the following areas: worker and consumer exposures; toxicology, animal models, and biomarkers; human cancer risk; environmental exposure and monitoring; and respiratory epidemiology and disease, and occupational health surveillance.

A laboratory investigation of the effectiveness of various skin and surface decontaminants for aliphatic polyisocyanates

Isocyanates may cause contact dermatitis and respiratory sensitization leading to asthma. Dermal exposure to aliphatic isocyanates in auto body shops is very common. However, little is known about the effectiveness of available commercial products used for decontaminating aliphatic polyisocyanates. This experimental study evaluated the decontamination effectiveness of aliphatic polyisocyanates for several skin and surface decontaminants available for use in the auto body industry. The efficiency of two major decontamination mechanisms, namely (i) consumption of free isocyanate groups via chemical reactions with active hydrogen components of the decontaminant and (ii) physical removal processes such as dissolution were studied separately for each decontaminant. Considerable differences were observed among surface decontaminants in their rate of isocyanate consumption, of which those containing free amine groups performed the best. Overall, Pine-Sol(R) MEA containing monoethanolamine was the most efficient surface decontaminant, operating primarily via chemical reaction with the isocyanate group. Polypropylene glycol (PPG) had the highest physical removal efficiency and the lowest reaction rate with isocyanates. All tested skin decontaminants performed similarly, accomplishing decontamination primarily via physical processes and removing 70-80% of isocyanates in one wiping. Limitations of these skin decontaminants are discussed and alternatives presented. In vitro testing using animal skins and in vivo testing with field workers are being conducted to further assess the efficiency and identify related determinants.

Analytical Performance Criteria: Field Evaluation of Diacetyl Sampling and Analytical Methods

D iacetyl and acetoin are ketones that are used extensively in the flavoring and food production industries. Both compounds are monitored in the workplace to assess exposures, to aid in the selection of respirators, and to evaluate the effectiveness of ventilation and other control procedures. Researchers from the National Institute for Occupational Safety and Health (NIOSH) published methods to sample and analyze airborne concentrations of diacetyl and acetoin in workplaces.(1) Recent laboratory investigations indicate that the diacetyl method is affected by humidity, resulting in an underestimation of true diacetyl concentration.(2) The effects of humidity on the collection and subsequent desorption of organic compounds on solid sorbent media has been investigated previously. McCammon and Woebkenberg(3) describe the effects of humidity on both silica gel and carbon molecular sieve. The polar nature of silica gel causes it to both adsorb water vapor and show a decrease in breakthrough capacity for non-water-soluble substances with increasing humidity. Carbon molecular sieves retain adsorbed species according to molecular size, and small organic compounds with molecular size similar to water must compete for sorption sites in an equilibrium at least partially based on concentration, which favors adsorption of water. In a study more specific to this effect, Karbiwnyk et al.(4) found that water vapor can interfere significantly in the measurement of volatile organic compounds using solid sorbents of varying hydrophobic characteristics. That interference is attributed to a reduction in retention of analyte during sampling. A compound-specific change in minimum detectable level of analyte with increase in humidity was seen using an Environmental Protection Agency Carbotrap/Carboxen 1000 method,(5) although this change produced both increased as well as decreased detection levels. Similarly, a study of dual phase (vapor/particulate) pesticide sampling(6) concluded that a competitive mechanism seems to exist “between water molecules in gas phase and pesticides to adsorb on the receiving sites of the particles.” The effect of humidity on the collection of volatile polar organic compounds using carbon molecular sieve tubes may have a threshold below which humidity is not an issue, although that threshold seems to vary with sorbent material and possibly with analyte.(7) To aid in the evaluation of sampling and analytical methods for diacetyl, a field comparison between new and existing sampling collection methods was conducted. Side-by-side field samples were collected and analyzed according to NIOSH method 2557, OSHA method PV 2118, and a modified version of the Occupational Safety and Health Administration (OSHA) method. Because many of these samples were analyzed for acetoin as well as diacetyl, data are presented for both measurements in this report.