The isocyanates are an important cause of occupational asthma, but descriptions of ACD and ICD due to them are relatively uncommon [24]. In a mouse local lymph node assay examining the dermal sensitization potential of TDI, Woolhiser et al. [34] reported irritation at the TDI application site [34]. Second, Arnold et al. [35] reported that the animal studies are insufficient to characterize the dermal irritation potential of TDI due to the lack of documentation and use of nonstandard methodology; the overall weight of evidence indicates that TDI is irritating to the skin of experimental animals [35].

ACD caused by isocyanates has been reported mainly in connection with occupational exposure in the manufacture of polyurethane products used in the plastics, car and textile industries, flooring, and the manufacture of medical, electronic, and foam products. It has also been reported in sculptors [36] and a molders [37], although there is still limited knowledge about the skin diseases in occupational setting because the fact that most studies to date have been cross-sectional in design, small in size, or based on selected clinical cases or production workers rather than end use workers.

One of the first investigations on the skin effects of polyurethane products is that of Emmet et al.; this study reported skin rashes on exposed skin areas in eight workers of polyurethane molding plant, with positive patch test reactions to dicyclohexylmethane-4,4′-diisocyanate (DMDI, synonymous with hydrogenated methylene-4,4′-diphenyl diisocyanate – HDI) and diaminodiphenylmethane (MDA) in two of them [38]. White et al. showed ACD and ICD due to DMDI in uncured resin in a factory of car badges [39]. Frick et al. demonstrated ACD in workers of a company manufacturing flooring laminate boards, after the introduction of a water-repellent lacquer based on MDI. Five workers, engaged as machine operators where lacquer was sprayed onto the boards, developed eczematous lesions of the forearms, hands, or arms. Patch testing showed positive reactions to MDA in four, to MDI in one, to HDMI in one, and to a lacquer in three of them [40]. Another study of Frick et al. reported severe eczema in 17 workers exposed to glue based on DMDI, at a factory manufacturing medical equipment. Contact allergy to DMDI, other isocyanates, and/or MDA was demonstrated in 13 individuals [27].

Isolated cases of ACD in workers exposed to MDI were also reported in different occupational environment. Hannu et al. demonstrated a case of ACD due to MDI and MDA from accidental occupational exposure in a female worker of a manufacturing plant of electronic components [41]. Schroder reported a case of ACD to MDI, present in polyurethane adhesive, TDI, MDA, and epoxy resin in a female engaged in a plant manufacturing grinding tools [42]. Estlander et al. diagnosed occupational contact dermatitis in three workers exposed to MDI present, respectively, in a hardener of core binder, a hardener of adhesive, and a laboratory mixture of diisocyanates [43]. Lidén reported a case of ACD of the forearms in a molder exposed to MDI-containing product in a hospital [37]. Tait and Delaney reported a case of a maintenance fitter who developed ACD after cleaning filters contaminated with aptane isocyanate based on MDI [44]. Kerre reports a patient who developed an acute allergic contact dermatitis using a DMDI-charged cartridge to create resin-coated “3D labels” within an office environment [45].

According to Aalto-Korte et al. who analyzed 54 cases of ACD due to monomeric isocyanates, motor vehicle industry was among the most significant occupational fields for isocyanate contact allergy. They identified many sources of allergy to MDI such as polyurethane foam used in the production of car insulation material, pistol foam containing MDI, and uncured polyurethane insulation material [46]. A recent study of Kiec-Swierczynska et al. in a vehicle equipment factory revealed work-related contact dermatitis in 12 workers exposed to polyurethane foam containing MDI. Seven of them developed contact allergy to MDA and were diagnosed with occupational ACD. Irritant skin reactions to the antiadhesive agent were also observed, in three cases coexisting with occupational ACD [47].

There are several reports of sensitization to polyurethane products also in domestic setting, such as to a plastic watchstraps [26], spectacle frames [48], a pacemaker lining [49], and do-it-yourself products used for renovating objects [2], though only one of these reports has been specifically identified, sensitization to 1,6-hexamethylene diisocyanate. It is also described a case of allergic contact dermatitis caused by isocyanates, specifically DMDI, in resin jewelry making. Furthermore, this is not occupational related [50].

Isocyanates causing allergy contact dermatitis included MDI [24, 37, 41–43], TDI [24], HDI [24, 51], and DMDI [27, 39, 45, 52, 53]. Allergy contact dermatitis due to MDI was seen more frequently than that related to other isocyanates, which may be a consequence of the fact that MDI represents more than a half of the worldwide isocyanate production [46].

Occupational allergic contact dermatitis usually develops after months or years of exposure. However, strong allergens may sensitize after a single exposure [54]. According to Kanerva et al., one can assume that sensitization from a single exposure has taken place when a patient, with no previous eczema, develops the first skin symptoms soon after accidental exposure and patch testing with the chemical provokes an allergic reaction.

The most common locations of occupational dermatitis are generally the hands and forearms, but the face is also commonly affected. In a report from a general dermatology clinic, facial symptoms were more common among TDI-positive or isophorone diisocyanate (IPDI)-positive cases than among MDA-positive or MDI-positive ones [55]. Although in later investigations no difference was noted when MDI-positive patients were compared with IPDI-positive or TDI-positive cases, facial symptoms resulted not so common in patients reacting only to MDA [46].

Moreover, cases of urticaria due to MDI were demonstrated [56–58]. Particularly, Stingeni et al. reported a case of nonatopic man with breathing difficulties for 3 months and urticaria on his face (mala and mandibular areas) for 2 months who worked in a chemical factory manufacturing adhesives and 1 year previously had been assigned to the mixing of polyurethane glues. The symptoms developed a few minutes after every working exposure to the Isonate M143 glue containing diphenylmethane-4,4′-diisocyanate (MDI). This study is the first report of concomitant type I and type IV sensitivities to MDI, as respectively shown by the immediate urticaria-type patch test reaction to Isonate M143, positive radioallergosorbent test to MDI, and delayed positive patch test to MDI and Isonate M143 serial dilutions. Contact urticaria belongs to the class of immediate skin immune response, as also proved by specific IgE antibodies against MDI detected in the patient.

Limited number of studies suggests potential neurotoxic effects from exposures to isocyanates; acute exposure to high levels of TDI vapor has been associated with lightheadedness, headache, insomnia, mental aberrations, impaired gait, loss of consciousness, and coma, while chronic exposures have been associated with alterations in the central and peripheral nervous systems.

One of the first case reports, conducted in 1987, described the accidental exposure of three wharf workers at TDI during an accidental chemical spill. Compared with 2 months postexposure, at 16 months postexposure, Full Scale Intelligence Quotient (IQ) dropped an average of 23 points. Results from additional neuropsychological testing at 16 months postexposure indicated severe deficits in all three subjects in memory, manual dexterity, visuomotor tracking, mental flexibility, ability to detect figure-ground relationships, and word fluency [59].

Reyde et al. reported results of neuropsychological functioning of five men suffering alleged physical, cognitive, and behavioral changes following exposure to MDI. All workers reported experiencing subjective symptoms consisting of respiratory distress, headaches, depression, irritability, decreased calculating ability, and reduced concentration. Wechsler Adult Intelligence Scale-Revised IQ revealed in four of the five subjects weakness on the digit symbol subtest and in attention-concentration testing. The authors concluded that neuropsychological test data support the presence of behavioral and cognitive correlates of CNS injury following exposure to MDI [60].

Recently, Moshe et al. described a case report of a 60-year-old Israeli painter/artist with central and peripheral neuropathic findings. His work was unusual in that he painted large posters with different mixtures of organic solvents, including toluene, xylene, benzene, methyl ethyl ketone, TDI, acetone, and thinner. He did not use any protective gloves and did not wear a mask. After 30 years as a painter, he developed weakness and paresthesia of the hands and feet, intention tremor, and difficulty concentrating with memory deficits. He had mild atrophy and distal weakness of both upper and lower limbs and demonstrated bradykinesia. He was evaluated with several methods and was diagnosed as having peripheral and central neuropathy, including ototoxic hearing loss because of long exposures to organic solvents [61].

In recent years, a systematic review conducted by Hughes et al. demonstrated a lack of quality epidemiological studies in the literature on neurotoxic health effects and exposure to diisocyanates. The available evidence consists mostly of case reports and case series, some of which are listed above. Using the Hill criteria or considerations for causality, the authors found limited evidence for strength of association and consistency [30].