328 VOLUME 115 | NUMBER 3 | March 2007 • Environmental Health Perspectives

Review

Isocyanates, a group of reactive chemicals

[with the functional group N = C = O

(NCO)] used extensively in the production of

numerous polyurethane foams, coatings, and a

wide array of consumer products, are a major

cause of occupational asthma worldwide. The

polyurethane industry has expanded dramatically, along with the number of workers and

consumers at risk for exposure. Inhalation has

long been considered the primary route of

isocyanate exposure, induction of sensitization, and asthma; research, practice, and

regulation have focused almost exclusively on

understanding and preventing inhalation

exposures. Airborne isocyanate exposures

have been reduced through improved controls and use of less-volatile isocyanates. Yet

isocyanate asthma continues to occur, not

uncommonly in work settings where measured isocyanate respiratory exposures are very

low or nondetectable, but where there is

opportunity for skin exposure. 

It has been > 25 years since Karol et al.

(1981) demonstrated in guinea pigs that skin

contact with isocyanates could lead to sensitization and subsequent asthmatic responses following inhalation exposure. However,

knowledge and awareness remain limited

regarding the potential for isocyanate skin

exposure to contribute to the development of

isocyanate asthma. For example, the literature

on occupational asthma rarely mentions isocyanate skin exposure as a potential risk factor

or target for prevention (Nicholson et al. 2005;

Tarlo and Liss 2005). Over the past several

years there has been a growing, but largely

unrecognized, collection of animal, industrial

hygiene, clinical, and epidemiologic data

related to isocyanate skin exposure and its role

in the development of isocyanate sensitization

and asthma. Our primary purpose in this article is to review and synthesize this multidisciplinary literature to address several key

unresolved issues, including the extent of

isocyanate skin exposures in the workplace,

the effectiveness of personal protective equipment, and most importantly, whether human

skin exposure contributes to the development

of isocyanate asthma. The findings may be relevant to the larger issue of the role of skin as

an important underrecognized site of exposure

and sensitization for other environmental

allergens.

Methods

Definition of terms. The terms “skin exposure”

and “dermal exposure” are used interchangeably to indicate exposure to the outermost

layer of the epidermis or epicutaneous exposure, as is commonly done in the occupational

and environmental literature. “Isocyanates”

refers to diisocyanate monomers (two NCO

groups) and their related polyisocyanates,

which have similar health effects (Bello et al.

2004). The term “sensitization” can generate

misunderstanding. “Sensitization” generally

refers to priming of the immune system in

response to a specific non-self antigen, a condition that involves immune memory, typically

antigen-specific T cells and/or antibodies.

Subsequent reexposure to the antigen can

result in an immunopathologic adverse reaction, such as a Th2 (T-helper 2)-type acute

Address correspondence to D. Bello, Department of

Work Environment, KI 200, University of

Massachusetts Lowell, One University Ave., Lowell,

MA 01854 USA. Telephone: (978) 934-3343. Fax:

(978) 452-5711. E-mail: dhimiter_bello@uml.edu

This study was supported by National Institute for

Occupational Safety and Health (NIOSH)/Centers

for Disease Control and Prevention (CDC) grants

R01H3457 and 5 R01OH004246. D.B. was supported by National Research Service Award training

grant T32 ES07069, and C.A.R. was supported by

National Institutes of Health grant K24-ES00355.

Mention of company names and/or products does

not constitute endorsement by the CDC. The findings

and conclusions in this report are those of the

author(s) and do not necessarily represent the views of

NIOSH. 

Under contracts, the Yale Occupational and

Environmental Medicine Program (YOEMP), including M.R.C. and C.A.R, has provided consulting services related to occupational lung diseases, including

isocyanate asthma. The resources from these contracts

have gone to the YOEMP to support research, education, and patient care—all related to occupational diseases.The remaining authors declare they have no

competing financial interests.

Received 27 July 2006; accepted 27 November 2006.

Skin Exposure to Isocyanates: Reasons for Concern

Dhimiter Bello,1,2 Christina A. Herrick,3 Thomas J. Smith,1 Susan R. Woskie,2 Robert P. Streicher,4 Mark R. Cullen,5

Youcheng Liu,5 and Carrie A. Redlich5

1Exposure, Epidemiology and Risk Program, Harvard School of Public Health, Boston, Massachusetts, USA; 2Department of Work

Environment, University of Massachusetts Lowell, Lowell, Massachusetts, USA; 3Department of Dermatology, Yale University School of

Medicine, New Haven, Connecticut, USA; 4Division of Applied Research and Technology, National Institute for Occupational Safety and

Health, Cincinnati, Ohio, USA; 5Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven,

Connecticut, USA

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 skinexposure 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. 

KEY WORDS: asthma, dermal exposure, isocyanates, sensitization, skin. Environ Health Perspect

115:328–335 (2007). doi:10.1289/ehp.9557 available via http://dx.doi.org/ [Online 28 November

2006]
allergic reaction or asthmatic response, or contact hypersensitivity-type reaction, such as

allergic contact dermatitis (Sheaarer and

Fleisher 2003). Others consider sensitization

any immunologic memory of exposure, regardless of its pathogenic potential (i.e., a specific

IgG response) (Abbas et al. 2000). Skin or respiratory sensitization typically refers to the

route of exposure that results in systemic sensitization, rather than localized immune

responses at those sites. 

Literature search. We have been active in

the field of isocyanate research and have collected > 800 published and unpublished articles and documents from 1951 to the present;

these articles and documents are related to isocyanates and span many disciplines. In addition, we performed computerized searches of

the literature on Medline [1966 to the present

(National Library of Medicine, Bethesda,

MD)], National Institute for Occupational

Safety and Health (NIOSH), Occupational

Safety and Health Administration (OSHA)

and U.S. Environmental Protection Agency

(EPA) databases and Google (google.com)

using the key words “isocyanate,” “diisocyanate,” “asthma,” “sensitization,” “exposure,” “dermal,” “skin,” “occupational,”

“methylene diphenyl diisocyanate,” and other

synonymous terms. Additional articles were

identified from the reference lists of the

selected relevant articles. We reviewed primarily English-language articles, as well as selected

articles in German, Danish, and French.

Human and animal articles that addressed isocyanate skin exposure, sensitization, and

health effects were retained for further analysis. We also included clinical, epidemiologic,

and biomarker studies and case reports that

mentioned skin as a potential route of exposure or had low isocyanate air levels based on

exposure data or work processes. 

Results and Discussion

Health effects of isocyanate exposure.

Isocyanates are considered potent respiratory

allergens. Isocyanate asthma is the major health

problem in isocyanate-exposed workers, affecting approximately 1–25% of the exposed population. The most important risk factor is

isocyanate exposure, but the exposure characteristics and host factors involved remain

unclear (Bernstein 1996; Wisnewski et al.

2006). Isocyanates can also cause hypersensitivity pneumonitis, contact dermatitis, and rhinitis, but these outcomes are less commonly

reported (Baur et al. 1994; Musk et al. 1988).

Clinically isocyanate asthma presents similar to other types of allergic Th2-like asthma:

Isocyanate asthma typically develops after

repeated exposure for months to years, during

which time sensitization to isocyanates is presumed to occur. Once sensitized, extremely

low respiratory levels of isocyanate can elicit

asthmatic responses. However, unlike for typical high molecular weight (MW) occupational

allergens or environmental aeroallergens,

research has failed to identify an isocyanatespecific immune response in most isocyanate

asthmatics that indicates isocyanate Th2-like

sensitization, such as a radioallergosorbent test

(RAST) or skin prick test, thus hindering diagnosis. This difference may reflect involvement

of non-IgE mechanisms in isocyanate asthma

pathogenesis, and/or may be related to the

NCO functional group common to all isocyanates that renders them ideal cross-linking

agents (Wisnewski et al. 2006). Unlike highMW allergens, isocyanates can react with

amino (NH2, NH), hydroxyl, and sulfhydryl

groups of various proteins and peptides,

including albumin and keratin, to form a

number of different hapten–protein complexes

or antigens (Wisnewski et al. 1999, 2000).

Human isocyanate skin-patch testing has been

used to confirm sensitization in the uncommon person who develops contact hypersensitivity (allergic contact dermatitis) due to

isocyanate skin exposure, but has not been

helpful for detecting the Th2-like sensitization

presumed to lead to isocyanate asthma

(Kanerva et al. 2001). The mechanisms by

which isocyanates cause asthma remain poorly

defined, and lack of a good immunologic

marker and unclear dose–response relationships have hindered diagnosis and prevention

(Wisnewski et al. 2006). The primary focus

here is on the potential for skin exposure to

contribute to the development of isocyanate

asthma rather than pathogenic mechanisms.

However, a better understanding of the role of

skin exposure may help address these key

problems. 

Several observations suggest that skin may

also be an important site of exposure and sensitization. Isocyanate respiratory exposure alone,

without any skin exposure, seems unlikely in

most work settings. Isocyanate asthma occurs

in settings with minimal documented respiratory exposures but clear potential for skin

exposure, and splashes and spills have been

reported by workers who subsequently develop

isocyanate asthma (Bernstein et al. 1993;

Lenaerts-Langanke 1992; Liss et al. 1988;

Nemery and Lenaerts 1993; Zammit-Tabona

et al. 1983).

Workplace and environmental isocyanate

exposures. The chemical structures and important physicochemical properties of selected

isocyanates are shown in Figure 1 and Table 1.

The major commercial isocyanates are methylene diphenyl diisocyanate (MDI), toluene

diisocyanate (TDI), and their nonvolatile

polymeric forms pMDI and pTDI, followed

by polymeric hexamethylene diisocyanate

(pHDI) and isophorone diisocyanate (pIPDI).

Isocyanates are reactive chemicals used extensively to make numerous polyurethane and

other commercial products, such as polyurethane foams, adhesives, and coatings. They

are found in a wide range of industries, from

construction to medical care. The increasing

use of nonvolatile polyisocyanates has raised

issues related to their measurement, exposure

metrics, and regulation (Bello et al. 2004).

Occupational exposures to isocyanates

occur primarily in the many end-use settings,

as well as in primary production facilities

where exposures are generally better controlled.

The total number of workers currently exposed

to isocyanates is not known. NIOSH’s estimate of 280,000 U.S. workers exposed or

potentially exposed to isocyanates (NIOSH

1996) is undoubtedly higher today, given

industry growth and new applications. Most

commercial isocyanate products are complex

isocyanate mixtures of variable molecular mass,

volatility, and isocyanate content. Workplace

exposures can occur in the form of isocyanate

vapors, aerosols, or both, depending on the isocyanate type as well as the application method

and other factors. Isocyanates are commonly

mixed with various solvents, polyols, and other

substances, such as catalysts and blowing

agents, which may affect isocyanate reactivity,

skin absorption, and health effects.

Although data are limited, environmental

exposures to unreacted isocyanates are also

possible. A number of consumer products

contain unreacted isocyanates, such as glues,

polyurethane coatings, and foam insulation;

domestic use of such products on rare occasion has been reported to trigger asthma

symptoms in individuals previously sensitized

(Carroll et al. 1976; Dietemann-Molard et al.

1991; Peters and Murphy 1971). Based on

patch testing, a few cases of allergic contact

dermatitis have been reported with the use of

consumer products made from isocyanates

and polyurethanes (Alomar 1986; Morgan

and Haworth 2003; Vilaplana et al. 1987).

Certain biomedical products, such as standard

orthopedic casting material, may be a potential source of skin exposure to unreacted isocyanates for patients and cast technicians

(Legris et al. 1995). Polyurethane foams and

packaging have been reported to contain very

small amounts of unreacted isocyanates

(Gagne et al. 2003; Krone et al. 2003), but

it is unclear whether these products have

any potential to result in skin exposure.

Environmental isocyanate exposures can also

potentially occur from the release of isocyanates into the environment from primary

or secondary production facilities (Darcey

et al. 2002; De Zotti et al. 2000; Orloff et al.

1998), during the transport or storage of isocyanates or polyurethanes (Allport et al.

2003), or during the thermal degradation of

overheated polyurethane products (Boutin

et al. 2006), but these exposures are rarely

reported. Isocyanate releases from end-users,

Skin exposure to isocyanates 

Environmental Health Perspectives • VOLUME 115 | NUMBER 3 | March 2007 329
such as auto body shops located in or near residential neighborhoods, are also possible but

rarely reported. It has been hypothesized that

environmental skin exposure to polyurethanes

in childhood has contributed to the increased

prevalence of childhood asthma (Krone and

Klingner 2005), but human isocyanate exposure from such products has not been documented, and there are numerous other likely

causative factors.

The primary isocyanate exposure routes

are through the respiratory tract and the skin.

Historically, the focus has been on inhalation

exposures. Increased use of less-volatile

MDI and polymeric isocyanates, as well as

improved hygiene practices, have resulted in

reductions in inhalation exposures to volatile

monomer (Bello et al. 2004), thus potentially

increasing the relative importance of skin

exposure. Isocyanate skin exposure could

contribute a significant part of the total body

burden. For example, 1% skin absorption of a

small MDI droplet (10 mg) would deliver a

dose approximately 4.5-fold (450%) higher

than the inhalation exposure at the current

short-term UK occupational exposure limit

(15-min, 70 μg NCO/m3) or approximately 50% of the corresponding 8-hr (20 μg

NCO/m3) standard, assuming 100% lung

retention and a ventilation rate of 7 L/min

(Bello et al. 2004). 

Measuring isocyanate skin exposure.

Quantification of isocyanate skin exposure is

important for research, prevention, and control. Assessment of skin exposure, in general, is

much less developed than that of inhalation

exposure. Skin exposure sampling methods

typically are nonstandardized, have undergone

limited validation, and can be technically challenging. Isocyanate skin sampling is further

complicated by several factors, including the

reactivity of NCO groups toward skin proteins, water, or other compounds, and the

complexity of most isocyanate exposures.

Biomarkers such as urinary metabolites, if

available, could potentially be used to assess

internal dose, but would not distinguish

between skin and respiratory exposure.

Techniques that have been used to detect

isocyanate skin exposure include SWYPE pads

(Colormetric Laboratories Inc., Des Plains,

IL) (Liu et al. 2000), wipes (Bello et al., in

press), and tape stripping (Fent et al. 2006).

These methods rely on removal of isocyanates

from the skin—usually a period of time after

initial exposure, and can underestimate exposure as a result of losses due to absorption,

chemical reactions, and/or poor removal efficiency (Bello et al. 2005; Wester et al. 1999).

Techniques that quantitate isocyanate

deposited on the skin, such as reagentimpregnated patches, may overcome some of

these limitations. Recently, extraction of isocyanates from contaminated gloves was used

to measure hand skin exposure to isocyanates

(Pronk et al. 2006). Application of these skin

exposure methods in the workplace has been

limited, and findings have not been compared

or validated. Workplace isocyanate skin exposure assessment is further complicated by the

frequently sporadic nature of such exposures.

Workplace isocyanate skin exposure.

Numerous isocyanate end uses, such as spraying and application of foams and adhesives,

provide opportunity for isocyanate skin exposure from deposition of aerosols and/or absorption of vapors. Typical workplace isocyanate

exposure levels are not irritating and give few

warning signs, and skin protective equipment

may not be worn, even when respiratory protection is used (NIOSH 1999). Skin exposure

may result from direct contact of unprotected

skin or the failure of personal protective equipment, such as gloves. Opportunities for

Bello et al.

330 VOLUME 115 | NUMBER 3 | March 2007 • Environmental Health Perspectives

Table 1. Selected physicochemical properties of commercially important isocyanates.

MW VP 

Isocyanatea (g/mol) (mm Hg)b Volatilityc 1 ppm = x mg/m3

HDI 168.2 0.02 Very high 6.88

TDI 174.2 0.02 Very high 7.13

IPDI 222.3 0.0003 Moderate 9.09

MDI 250.3 0.000005 Very low 10.24

VP, vapor pressure. 

aAll isocyanates are liquids at room temperature, except for MDI. bVP at 20°C, except for MDI (25°C); data from Streicher

et al. (1994). cThe higher the volatility, the shorter the residence time of isocyanates on the skin; most polymeric isocyanates (MW ~ 500) are nonvolatile at room temperature.

Figure 1. Chemical structures of selected isocyanates of commercial importance.

MDI

n = 0 – 4

pMDI

2,4-TDI 2,6-TDI

Isocyanurate of 2,4-TDI

TDI-trimethylolpropane adduct

HDI biuret

IPDI isocyanurate

HDI isocyanurate

n
isocyanate skin exposure, such as spills,

cleanup, and contact with contaminated

equipment, are well known to workers and

field researchers. For example, NIOSH Health

Hazard Evaluations of a variety of work settings have described workers with skin contact

to isocyanates or uncured polyurethane products (NIOSH 1998, 1999). 

Isocyanate products that are not fully cured

are another potential source of isocyanate skin

exposure (Bello et al., in press). It is commonly

believed that isocyanate-containing products

polymerize rapidly, and once the product

appears hardened, no unbound isocyanate

species remain on the surface. However, there

are few published data confirming this. A

recent study demonstrated that curing proceeded more slowly than expected, with

unbound isocyanate species detected on

painted surfaces for prolonged periods of time

(days to weeks) (Bello et al., in press). Thus,

handling recently cured isocyanate products

could be a source of isocyanate skin exposure.

In addition, release of free isocyanates has been

reported after heating of cured isocyanate

products, as can occur when grinding, cutting,

or sanding such products (Alliance for the

Polyurethanes Industry 2005; Boutin et al.

2006; Littorin et al. 2002). Such tasks could

represent another possible source of isocyanate

skin exposure.

In spite of observational documentation of

workplace isocyanate skin exposures, published data documenting such exposure are

surprisingly limited. Isocyanate skin exposure

has been documented qualitatively with colorimetric techniques in several work settings

(Liu et al. 2000; NIOSH 1998). Recent studies have begun to quantitate such exposures.

Fent et al. (2006) detected HDI monomer on

tape strips from an auto-body painter’s unprotected skin. Pronk et al. (2006) recently

reported isocyanate exposure under gloves on

both hands of auto body and industrial spray

painters, with the highest median hand exposure detected during paint mixing (207 and

63 μg NCO, respectively). 

Effectiveness of personal protective equipment. Gloves and protective clothing remain a

primary means of preventing skin exposure in

the workplace, in addition to engineering and

work practice controls. Gloves and protective

clothing are presumed to protect against isocyanate skin exposure, with nitrile gloves considered preferable to latex. However, data on

the workplace performance of protective gloves

and clothing are limited, and there is evidence

that isocyanates (Liu et al. 2000; Pronk et al.

2006) and solvents (Collin-Hansen et al.

2006) can be detected underneath gloves.

Skin absorption of isocyanates. Animal

studies employing radiolabeled 14C-MDI

have demonstrated absorption of MDI after

skin exposure (Leibold et al. 1999; Vock and

Lutz 1997). However, quantitative data are

limited and may have underestimated absorption due to technical issues, such as isocyanate

binding to the dressing and skin. Studies documenting the disappearance of isocyanates

from guinea pig skin with infrared spectroscopy also support isocyanate skin absorption (Bello et al. 2006).

We are not aware of published data directly

confirming isocyanate skin absorption in

humans; however, a number of studies indirectly demonstrate isocyanate skin absorption.

For example, HDI-conjugated keratins have

been identified from human skin biopsies

obtained after epicutaneous application of HDI

(Wisnewski et al. 2000). Patch testing with isocyanate (0.1–1%) can elicit an isocyanatespecific skin contact hypersensitivity reaction

that implies isocyanate skin absorption. 

Studies investigating urinary biomarkers of

isocyanate exposure (the corresponding

diamines) have provided additional indirect

evidence for isocyanate skin uptake (Creely

et al. 2006; Kääriä et al. 2001; Maitre et al.

1996). Elevated levels of these urinary biomarkers have been detected in workers, in spite

of very low or nondetectable documented

inhalation exposures. Greater than 2-fold

higher urinary metabolite concentrations have

been reported for operators with likely skin

contamination compared to those without

(Creely et al. 2006). Maitre et al. (1996) measured urinary hexamethylene diamine (HDA)

of two HDI-exposed coworkers. Both workers

had similar inhalation exposure as confirmed

by air measurements, but one had considerably

greater HDI skin contact and a 10-fold

increase in urinary levels of HDA. The authors

concluded that HDI seemed to be readily

absorbed through the skin.

Human isocyanate skin absorption likely

depends on a number of factors, in addition to

the extent of isocyanate skin exposure, and

may vary between isocyanates because of differences in their physical and chemical properties, including molecular mass, fat solubility,

and chemical reactivity. Skin absorption can

be enhanced if the barrier properties of skin

have been damaged, such as can occur with

eczema, cuts, hand washing, cosmetics applications (shaving, waxing), and other conditions (Moody and Maibach 2006; Smith

Pease et al. 2002). In addition, coexposures

such as solvents used in the production of

polyurethane foams, coatings, and spray applications can be absorbed through the skin

(Boman and Maibach 2000). Such solvents

may enhance isocyanate absorption and also

break through the gloves.

Skin sensitization. Numerous substances—

primarily low-MW haptens, such as metals and

chemicals, and less commonly proteins—are

known to initiate immune responses in the

skin, most commonly hapten-induced contact

hypersensitivity (Kimber and Dearman 2002).

Contact hypersensitivity (allergic contact dermatitis) following skin exposure to isocyanates

is well documented in animals and in the clinical dermatologic literature, with sensitization

confirmed with patch testing (Goossens et al.

2002; Herrick 2002). Allergic contact dermatitis has been reported following skin exposure to

isocyanates and polyurethane products in a

number of different workplace and nonoccupational settings, but has not been considered common, and is rarely reported in workers

with isocyanate asthma (Alomar 1986; Frick

et al. 2003; Goossens et al. 2002; Wilkinson

et al. 1991). However, allergic contact dermatitis may be more common than suspected

because symptoms can be mild, workers being

evaluated for asthma are frequently not asked

about skin problems, and patch testing can be

falsely negative (Frick et al. 2004; Goossens

et al. 2002). 

Much less is known about the role of skin

exposure in inducing Th2-type immune

responses seen in asthma. Recent animal studies have documented that skin exposure to proteins such as ovalbumin or peanuts can induce

systemic Th2-type sensitization and subsequent asthmatic responses (Herrick et al. 2003;

Strid et al. 2005). Limited clinical and epidemiologic studies also support a role for skin

exposure to allergens in the development of

Th2-type sensitization and asthma, or of other

immunologic lung diseases such as chronic

beryllium disease (Cummings et al. 2006; Lack

et al. 2003; Saloga and Knop 2000; Smith

Pease et al. 2002; Tinkle et al. 2003). 

Isocyanate skin exposure, sensitization,

and asthma. Animal models. Animal models

using the three major isocyanates MDI, TDI,

and HDI have all employed skin exposure to

induce sensitization, with subsequent inhalation challenge, to create an asthmatic response

in the lungs (Table 2). Skin sensitization with

other chemicals, such as trimellitic anhydride,

followed by inhalational challenge has also

produced asthmatic responses (Vanoirbeek

et al. 2006; Zhang et al. 2004).

Different sensitization and challenge protocols (variable doses, frequency, timing, formulation, and route of exposure) using

different isocyanates have resulted in variable

pulmonary responses. In spite of these differences, several common themes emerge from

these animal studies. First, skin has been a

very effective route of inducing sensitization,

sometimes more effective than inhalation

(Ban et al. 2006; Rattray et al. 1994). For

example, Ban et al. (2006) recently evaluated

several different TDI sensitization scenarios

(inhalation, subcutaneous, topical) and challenge protocols (vapor, tracheal instillation) in

mice. Topical sensitization followed by tracheal instillation of TDI most closely reproduced the Th2-type lung inflammatory

Skin exposure to isocyanates 

Environmental Health Perspectives • VOLUME 115 | NUMBER 3 | March 2007 331
response seen in human asthma, whereas sensitization with vapor TDI was not effective. 

Of note, these isocyanate animal models

also demonstrate that a single one-time or

two-time skin exposure with relatively low

concentrations of isocyanates can be sufficient

to induce sensitization (Herrick et al. 2002;

Karol et al. 1981; Rattray et al. 1994).

Additionally, several models have shown paradoxical dose–response relationships, such that

a lower skin sensitization dose can result in

greater lung inflammation upon inhalation

challenge than a higher sensitization dose, and

that isocyanate-specific antibody responses

may not correlate with asthmatic responses

(Herrick et al. 2002; Vanoirbeek et al. 2004).

The effective skin sensitizing doses in these

studies, typically in the order of 1–100 μmol

NCO (Table 2) delivered as diluted 1–10%

isocyanate solution, represent a few droplets of

a diluted isocyanate product. Comparable

exposures likely occur in the workplace.

Thus, several different animal models in

more than one species clearly demonstrate

that isocyanate skin exposure can induce systemic sensitization, which with subsequent

inhalation exposure can lead to asthma.

Control experiments in which animals

received only skin exposure demonstrate that

isocyanate skin exposure alone does not cause

asthmatic responses (Herrick et al. 2002;

Karol et al. 1981; Vanoirbeek et al. 2004).

Although issues of comparability with

humans are inevitable, such as differences in

skin permeability, much can be learned from

animal models regarding exposure–response

relationships and the mechanisms that lead to

skin sensitization and asthma.

Human studies. Although patch testing

has confirmed contact hypersensitivity following human isocyanate skin exposure, direct

evidence that skin exposure leads to Th2-type

sensitization and the subsequent development

of asthma is limited. As noted above, there is

no good test to identify isocyanate sensitization in humans. Isocyanate-specific IgE is present in less than half of isocyanate asthmatics

(Mapp et al. 2005; Wisnewski et al. 2006),

and isocyanate-specific IgG appears to be

indicative primarily of exposure (Liss et al.

1988; Welinder et al. 1988; Wisnewski et al.

2006). Isocyanates are considered a potent

respiratory sensitizer in humans, based largely

on circumstantial evidence rather than on

clear demonstration that respiratory exposure

alone (without associated skin exposure) leads

to isocyanate asthma.

Indirect evidence from a growing number

of case reports and clinical and epidemiologic

studies suggests that isocyanate skin exposure

occurs in the workplace and can increase the

risk for sensitization and isocyanate asthma.

Isocyanate asthma and/or sensitization

(MDI-IgE) have been reported in several case

studies of workers who applied MDI-based

orthopedic casts (Donnelly et al. 2004; Legris

et al. 1995; Sommer et al. 2000). Allergic contact urticaria and asthma following direct hand

contact with MDI glue has been documented

based on a positive MDI-IgE, MDI patch test,

and MDI inhalation challenge (Valks et al.

2003). Consistent across these case reports is

the development of MDI asthma in settings

where skin exposure to MDI occurred and

where MDI air levels, if measured, were nondetectable or extremely low and opportunity

for MDI respiratory exposure was very limited.

These cases strongly suggest that skin exposure

was the predominant exposure route and contributed to the development of isocyanate sensitization and asthma. They also demonstrate

that isocyanate asthma can occur in settings

where measured isocyanate respiratory exposures are below the level of detection, even

when sensitive analytical methods are used.

Skin exposure has also been implicated as

a risk factor for isocyanate asthma in several

epidemiologic studies of MDI-exposed workers, in which measured inhalation exposures

were all very low or nondetectable. Petsonk

et al. (2000) investigated a group of new

workers exposed to MDI resins in a facility

designed for minimal airborne exposures and

noted new asthma-like respiratory symptoms

in 27% of the workers with the highest

potential for MDI exposure. These symptoms

were associated with liquid MDI skin exposure, as evaluated by worker questionnaires

and workplace observations. 

Bello et al.

332 VOLUME 115 | NUMBER 3 | March 2007 • Environmental Health Perspectives

Table 2. Selected animal models of isocyanate asthma: sensitization via skin.

End points (inflammation, 

Compound, Sensitization via skin Inhalation challenge airway responsiveness, 

reference Animal Frequency/form Dose (μmol NCO) Frequency/form/route/timing Dose isocyanate antibodies, other)

TDI

Karol et al. Guinea Single; 1/day × 50 μL 1, 10, 25, Various; ~ 7, 70, 174, Once/inhalation/TDI vapor and 5 ppb TDI vapor and ↑ Respiratory rate, ↑ TDI-IgE 

1981 pig 100% in OO 1,390 TDI-GSA conjugate aerosol, 12 μg/L air TDI-GSA antibodies 

2 weeks later

Erjefält and Guinea Twice; days 1 and 8; 1/day × 2 × ~ 278 = 556 Once; tracheal, TDI, day 15 ~ 1.4–4 pmol NCO ↑ Plasma exudation in lungs 

Persson 1992 pig 2 days × 100 μL 20% TDI in EA/OO (

131I-albumin)

Scheerens Mice Short exp: 2/day × 2 days; Short exp: 2 × 55.6 = 111 Once; intranasal, 20 μL 1% TDI Intranasal 2.8 μmol Short: ↑ TDI-IgG, long: ↑ TDI-IgE

et al. 1999 BALB/c long exp: 1/ week × 6 weeks; Long exp: 6 × ~ 28 = 167 in EA/OO and ear 20 μL 0.5% NCO + ear 1.4 μmol and TDI-IgG, ↑ in vivo tracheal 

both: × 200 μL 1% TDI in Ace/OO in Ace; day 8 or day 42 NCO hyperresponsiveness

Vanoirbeek Mice Variable; once (1% TDI) or 1% TDI: 5.6 × (1+1) = 11.2; Once; intranasal, 20 μL 0.1% 0.28 μmol NCO ↑ Airway responsiveness, 

et al. 2004 BALB/c 1/day × 3 days (1, 2, 3); 40 μL 0.3% TDI: ~ 1.7 × (3 + 1) TDI in Ace/OO, day 10 ↑ mixed Th1/Th2 lung 

0.3% or 3% TDI in Ace/OO, = 6.7; 3% TDI: inflammation, ↑ total IgE, 

+ repeat on day 7 16.7 × (3 + 1) = 66.8 greater response with lower 

skin dose; timing and freq 

skin exposure important

Ban et al. Mice Single; 50 μL 1% TDI in Ace/OO on 7 on skin + 1.4 Trachea instillation with 50 μL 3 × 0.7 = 2.1 μmol Lung Th2 inflammation, 

2006 BALB/c day 0, then tracheal instillation tracheal instillation 0.1% TDI in OO, on days 18, NCO ↑ TDI-IgE, only skin sensit 

with 50 μL 0.2% TDI in OO on 28, 31 induced Th2 asthma-like 

day 5 responses

HDI

Herrick et al. Mice Twice; 50 μL 0.01 or 1% HDI in 1.2 and 12.4 Intranasal; 50 μL HDI-MSA 100 μg Lung and BAL Th2 inflammation,

2002 BALB/c 4:1 A:OO on days 0 and 7 (2 μg/μL) on days 14, 15, 18, ↑ IgE, ↑ HDI-IgG, lower sensit 

19 dose, more lung inflammation

MDI

Rattray et al. Guinea Single, variable; 400 μL of 10, 30, 320, 959, 3,195 Once; inhalation of MDI 26–36 mg/m3 ↑ Respiratory rate, ↑ MDI-IgG1,

1994 pig or 100% MDI in CO aerosol on day 21 inhalation failed to induce 

sensit

Abbreviations: ↑, increase; Ace, acetone; Alb, albumin; BAL, bronchoalveolar lavage; CO, corn oil; EA, ethyl acetate; exp, exposure; Freq, frequency; GSA, guinea pig serum albumin;

MSA, mouse serum albumin; OO, olive oil; sensit, sensitization. 
Leanerts-Langanke (1992) described an

investigation of about 500 coal mine workers

who used MDI for rock consolidation.

Quantitative air sampling results were at or

below the detection limit (1 ppb). MDI skin

exposure was reported in about half the workers; MDI-IgE was detected in several workers;

and 2 were diagnosed with isocyanate asthma

based on a positive specific challenge. Elevated

levels of MDI metabolites in urine were found

in 6 of 8 workers seen after “massive skin contamination.” The authors concluded that skin

could be an important route of exposure, leading to sensitization and asthma. 

Bernstein et al. (1993) studied a cohort of

243 workers in a urethane molding plant that

consistently maintained low MDI airborne

exposures (< 5 ppb). Isocyanate asthma and/or

sensitization (MDI-IgE) was diagnosed in several workers, most of whom were reported

likely to have had MDI skin exposure.

Our group has characterized workplace isocyanate exposures in a population of > 200

auto body shop workers with isocyanatespecific immune responses but without documented isocyanate asthma (Redlich et al. 2001;

Woskie et al. 2004). Respiratory and skin

exposures were estimated for each of the workers, based on exposure algorithms. HDIspecific IgG, present in 21% of the workers,

was strongly associated with inhalation exposure, but skin exposure also contributed (Stowe

et al. 2006). We have also detected MDI-specific IgG in > 30% of about 100 workers in a

factory that uses MDI to produce polyurethane

coated fabrics. MDI air monitoring data have

consistently been very low, and MDI skin

exposure has been documented by worker

questionnaires and direct observation (Liss

et al. 2006). In both work settings, isocyanate

skin exposure appeared to contribute to the

development of isocyanate-specific IgG, which

has been associated with isocyanate exposure

(Welinder et al. 1988; Wisnewski et al. 2004;

Ye et al. 2006). 

Studies investigating the respiratory exposure conditions that lead to isocyanate asthma

also suggest a potential role for skin exposure.

Fewer cases of isocyanate asthma have generally

been reported in settings with lower respiratory

exposures, but cases continue to occur in settings with consistently low reported air levels

(Baur 2003; Tarlo et al. 1997). Skin exposure

(Bernstein et al. 1993; Leanerts-Langanke

1992) or intermittent peak exposures, which

could also entail both respiratory and skin

exposure (Tarlo et al. 1997), have been considered important contributing factors in such

cases. Typically, such exposures are unpredictable and frequently accidental, making

them difficult to investigate and quantify. 

For cutaneous allergen exposure in general, the likelihood of sensitization in a susceptible person is thought to depend on several

factors including the total dose and concentration of allergen, skin surface area, and the frequency of repeated contact with the skin, with

determinants of individual susceptibility

remaining poorly defined (Basketter et al.

2006; Boukhman and Maibach 2001). There

are insufficient data to address isocyanate skin

exposure–response relationships in humans;

however, as noted above, in animal models

relatively small skin doses can induce sensitization, and dose–response relationships may

be variable. 

Regulatory standards for isocyanate skin

exposure. The regulatory framework for skin

exposure to chemicals is underdeveloped compared with inhalation exposures. Chemicals

that pose a health hazard through skin exposure

are commonly assigned two qualitative descriptors: a “skin” notation, referring to absorption

of the chemical through the skin, and/or a “sensitizer” notation for an agent with the potential

to produce sensitization regardless of the exposure route (respiratory, skin, or conjunctiva)

[American Conference of Governmental

Industrial Hygienists (ACGIH) 2006].

In the United States, although NIOSH

recommends prevention of isocyanate skin

exposure, skin exposure is not regulated. No

“skin” notation exists for diisocyanates or

polyisocyanates, except for the NIOSH

(2005) recommendation for IPDI.

Although data confirming the risks of

human isocyanate skin exposure remain limited, there is sufficient information to recommend prevention of skin exposure. Such

recommendations are now being made in

material safety data sheets and are beginning

to appear in the medical literature (Bakke

et al. 2006; Baur 2003). Wider dissemination

and improved hazard communication of this

information by occupational and environmental health professionals, as well as better

personal protection among workers, are

needed. Inclusion of “skin” notation may

encourage such protection for all isocyanates

(diisocyanates and polyisocyanates). 

Research needs. In this review we highlight

several important areas for further research

regarding isocyanate skin exposure, ideally

using multidisciplinary approaches involving

animal models and clinical and epidemiologic

investigations. Such approaches should lead to

a better understanding of the mechanistic

pathways that result in isocyanate asthma and

the role of skin exposure in this process. A key

research need not unique to issues regarding

skin exposure is the development of a good

marker of isocyanate sensitization or “pre-clinical” asthma that correlates well with the subsequent development of asthma. Such a

marker would greatly enhance isocyanate

research, including elucidation of exposure–

response relationships, and facilitate diagnosis

and prevention. 

There is a need to better assess isocyanate

skin exposures in the workplace and other

environments and to incorporate these exposure data into epidemiologic and clinical studies. The typically more sporadic nature of such

exposures further complicates real-world exposure assessment and requires algorithms that

employ a combination of daily activities

(diaries), questionnaires, and task-based exposure data. Development of route-specific biomarkers, such as those specific for skin or

lung, would greatly facilitate isocyanate exposure assessment. Skin exposure methodologies

and biomarkers of exposure can be further

developed and validated using integrated

animal models. 

Numerous host and environmental determinants of isocyanate skin exposure have

barely been investigated. Isocyanate skin

absorption likely depends on various factors

including molecular size and coexposures

(e.g., polyols, solvents, and other additives),

which could enhance absorption. The role of

host factors, such as history of eczema and

hand washing, warrant further investigation,

as does the effectiveness of gloves, protective

clothing, and other preventive strategies.

Given the widespread and growing use of

polyurethane consumer products, research is

also needed to investigate potential environmental exposures from these consumer products, as well as exposures that may occur when

isocyanate products are manipulated (ground,

cut, drilled) or undergo thermal degradation

as in fires. Further research investigating the

curing process is also warranted because

incompletely cured products could be a potential and unexpected source of skin exposure

(Bello et al., in press).

Conclusion

Isocyanates, primarily diisocyanate monomers

and polyisocyanates, are a leading cause of

occupational asthma. Human skin exposure

to isocyanates has been underrecognized and

can occur in various workplace and environmental settings. Multiple lines of evidence

from animal studies and clinical, epidemiologic, and biomarker studies, as well as anecdotal evidence, indicate that in certain

exposure settings human skin likely is an

important route of isocyanate exposure and

can contribute to the development of isocyanate asthma. This presumably occurs by

isocyanate skin exposure inducing systemic

sensitization, which then leads to isocyanate

asthma after inhalation exposure; however,

the mechanistic pathways involved remain

poorly defined. Further research is needed to

address issues regarding isocyanate skin exposure in the growing polyurethane industry. In

spite of substantial research needs, sufficient

evidence already exists to justify greater

emphasis on the potential risks of isocyanate

Skin exposure to isocyanates 

Environmental Health Perspectives • VOLUME 115 | NUMBER 3 | March 2007 333
skin exposure and the need to prevent such

exposures. We conclude with the visionary

statement of Munn (1965): 

The more one knows about these fascinating compounds [isocyanates] the more fascinated one

becomes. So diverse are their uses, it is obvious that

they are here to stay, and that their use will increase.

So numerous have been the accounts of their

effects, it is obvious not merely they are hazardous

but that the nature and extent of their hazard has

not always been fully appreciated.

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