Common names: Hexahydrophthalic anhydride, HHPA
Other sensitising acid anhydrides:
- Maleic anhydride - MA
- Methylhexahydrophthalic anhydride - MHHPA
- Methyltetrahydrophthalic anhydride - MTHPA
- Tetrachlorophthalic anhydride - TCPA
- Himic anhydride - HA
- Pyromellitic dianhydride - PMDA
- Chlorendic anhydride - CA
An occupational allergen, which may result in allergy symptoms in sensitised individuals.
Hexahydrophthalic anhydride (HHPA) belongs to a group of organic compounds called acid anhydrides. In component epoxy resins, they serve as hardeners, which bind covalently to 2 molecules, allowing polymerisation. They are widely used in the production and processing of plastics, paints and fine chemicals, and in the manufacture of electrical machines (1).
Above are listed other important members of this class of substances. These potent low-molecular-weight allergens induce predominantly Type 1 allergies, by forming haptens through the binding of lysine to endogenous proteins (2).
Epoxy resins have good adhesive strength, electrical insulation, and chemical resistance and are thus widely used in adhesives, coatings, materials for molds and composites, and encapsulation. In the electronic components industry, Methyltetrahydrophthalic anhydride (MTHPA), a mixture of HHPA and methylhexahydrophthalic anhydride (MHHPA), is used as a hardener in an epoxy resin system for electrical insulation and typically requires a high curing temperature (100-150 degrees C), which facilitates the escape of anhydride vapours (3).
See under Geographical distribution and Environment.
No allergenic epitopes have yet been characterised.
Specific IgG against phthalic anhydride-rabbit serum albumin was produced, and in ELISA studies, specific IgG to phthalic anhydride-human serum albumin revealed cross-reactivity to 3 other phthalyl anhydride conjugates: Hexahydrophthalic anhydride (HHPA)-human serum albumin, methylhexahydrophthalic anhydride (MHHPA)-human serum albumin, and methyltetrahydrophthalic anhydride (MTHPA)-human serum albumin (4).
Although there is immunological cross-reactivity between various acid anhydride derivatives, RAST inhibition studies have indicated hapten-specific IgE antibodies (2).
Hexahydrophthalic anhydride may commonly induce symptoms of occupational allergy in sensitised individuals. Adverse health effects of occupational exposure to acid anhydrides are mucosal and skin irritation, and sensitisation of the respiratory tract (3, 10). HHPA, MTHPA, and MHHPA have been reported to induce occupational IgE-mediated respiratory allergy, including asthma (5-8).
Occupational rhinitis or rhinitis and contact urticaria caused by airborne methylhexahydrophthalic anhydride and HHPA have been described (1, 9).
The risk of sensitisation to acid anhydrides appears to be dependant upon the ambient air concentration (10). Safety precautions will result in a decrease in the prevalence of occupational allergy to these substances. However, a researcher has stated that in cross-sectional studies there appears to be a selection bias, with a risk of underestimating the incidence of allergic disease (11).
Organic acid anhydrides can cause rhinoconjunctivitis and asthma associated with specific IgE against hapten-carrier protein conjugate. Only a proportion of exposed workers develop IgE-associated allergy to acid anhydrides (12), and hence there is considerable debate about the mechanisms through which this chemical may cause respiratory sensitisation, and particularly whether there is a universal requirement for specific IgE antibodies. Despite this controversy, there is a growing consensus that chemical respiratory hypersensitivity is associated with the selective development of T lymphocytes with a type 2 (Th2) phenotype (13).
Furthermore, in a study of 52 workers exposed to HHPA, MHHPA and MTHPA who had confirmed specific IgE, the DQB1(*)05 gene was shown to confer susceptibility to the development of specific IgE antibodies against HHPA, MHHPA and, to a lesser degree, MTHPA (12). Symptoms in workers may be caused by an IgE-mediated mast cell degranulation and followed by an inflammatory reaction, engaging eosinophil and neutrophil cells (14).
Early studies reported frequent sensitisation and allergic symptoms following exposure to this allergen. For example, in a study of 27 workers with occupational exposure to HHPA from an epoxy resin molding system, 7 reported symptoms of asthma and rhinitis, and 4 had symptoms consistent with occupational asthma. Fourteen of the remaining 20 workers reported nasal or ocular symptoms while they were at work. Twelve workers had significant levels of specific IgE to HHPA-HAS (human serum albumin); 11 had elevated levels of specific IgG to HHPA-HSA. A group of workers estimated to have higher exposures to HHPA had a significantly higher mean total IgE level and significant titers of HHPA-HSA-specific IgE or IgG, or both, as compared to a group with lower exposure to the anhydride. All 4 workers with occupational asthma/rhinitis had significant levels of specific IgE to HHPA-HSA; 3 workers did not work directly in the HHPA area but were located in nearby sections of the plant and had lower exposures to HHPA; this led to the conclusion that HHPA is a potent industrial sensitiser, readily capable of inducing IgE-mediated disease (8).
In a study of 33 employees with respiratory symptoms associated with HHPA, 20 had no immunologically mediated disease. Seven had both immunoglobulin E-mediated and immunoglobulin G-mediated disease, 5 had immunoglobulin E-mediated disease only, and 1 had immunoglobulin G-mediated disease only. The study concluded that in HHPA-exposed employees with respiratory symptoms, development of immunologically mediated respiratory disease is most closely associated with the presence of specific immunoglobulin E or immunoglobulin G antibodies. Neither race, age, smoking status, atopy, nor exposure levels emerged as significant risk factors in this symptomatic study population (7).
Hemorrhagic rhinitis was described in 6 men who had been occupationally exposed to heated epoxy resin containing HHPA. They presented with rhinitis, nasal mucosal erosions, and significant epistaxis; 3 also had asthma. When they were removed from exposure to HHPA, the rhinitis symptoms, nasal erosions, and epistaxis resolved spontaneously. All 6 had high titers of IgG and IgE against HHP-HSA. Other asymptomatic workers with similar HHPA exposure had very low or negative titers of IgG and IgE against HHP-HAS (15).
In a cross-sectional study of 32 workers from a plant using epoxy resin with a mixture of HHPA and MHHPA as a hardener, the main component in the hardener was HHPA, and the geometric mean concentrations of HHPA in the workstations were extremely low (<40 microg/m3). However, specific IgE antibody to HHPA was detected in serum from 25% of the workers: of those, 5 workers experienced symptoms of the eyes and nose during work, and 3 workers did not. The authors suggested that short, peak exposures may have a great impact on the development of specific IgE or work-related symptoms (3). A similar conclusion was reached in a study that reported that the development of immunologically mediated respiratory disease due to HHPA was most closely associated with exposure level and development of specific IgE or IgG antibodies (16). HHPA is a sensitising compound even at low exposure levels, and peak exposures of short duration may have an impact on immunoglobulin E sensitisation (17).
Among 110 employees exposed to HHPA and MTHPA, a serum-specific IgE investigation was conducted with commercially available conjugates of phthalic anhydride and skin-specific IgE determination with 1% and 5% acetonic solutions of phthalic anhydride. In 109 of these employees, serum-specific IgE determination was performed. Specific IgE against acid anhydrides was detected in a total of 17 (15.4%). In a subsequent challenge test, 6 (5.4%) of those sensitised were shown to be clinically relevant. Skin-specific IgE determination, in comparison with serum-specific IgE tests, resulted in 3 false positive and 3 false negative results (2).
Occupational rhinitis or rhinitis and contact urticaria caused by airborne MTHPA and HHPA was described in 3 subjects. Specific IgE antibody was detected in serum from 1 of the 3 workers. One unsensitised worker displayed nasal pain and rhinorrhea only when loading liquid epoxy resins into the pouring machine, and this was thought to probably be an irritant reaction. Two workers had work-related symptoms at relatively low levels of exposure; 1 complained of only rhinitis, and the other was sensitised against HHPA and displayed both rhinitis and contact urticaria of the face and neck. The worker's skin symptoms were thought to be due to airborne contact, since she had not had any skin contact with liquid epoxy resin or mixtures of MHHPA and HHPA. Urticarial symptoms were confirmed by a patch test for MHHPA, but not by one for HHPA. The causative agent was considered to be MHHPA, although specific IgE determination for MHHPA was not performed (1).
In a cross-sectional study of 139 workers in a plant manufacturing electrical capacitors, long-term exposure to HHPA and MHHPA was assessed. The mean level of the total plasma protein adducts (TPPA) of HHPA was 840 fmol/ml, and that of the TPPA of MHHPA was 1700 fmol/ml. Of all the workers, 19% were found to be positive for specific IgE, and 17-19% for IgG. A positive association was observed between HHPA exposure and specific IgE and IgG, and between MHHPA exposure and specific IgG. Twenty-seven percent of the workers had nasal symptoms, 21% had symptoms of the eyes, 11% had symptoms of the lower airways, and 8% had nose bleeding. A significant exposure-response relationship for symptoms of the eyes and nose for HHPA exposure was shown (18).
In an epoxy resin-using factory, air levels of organic acid anhydrides (OAA) were low (HHPA < 1 to 94, MHHPA < 3 to 77 microg/m3) and associated with the concentrations of the OAA metabolites in urine. A high prevalence of sensitisation (IgE 22%, IgG 21%) was demonstrated in the study of 154 exposed workers, and prevalence correlated with the exposure. The study concluded that in spite of the very low levels of OAA in the air and of OAA metabolites in the urine, there were high and exposure-related risks of specific IgE and IgG sensitisation and of work-related symptoms in the eyes, nose (especially bleeding), and lower airways (19).
To determine whether immunologic anhydride-induced respiratory disease could be predicted on the basis of the level of specific immunoglobulin E (IgE) or immunoglobulin G (IgG) antibody, 81 anhydride-exposed employees in a plant were studied. Fourteen had such a disease. When optimal discriminant analysis was used, IgE < 1:5 and IgG < or = 1:10 were found to be the optimal titers for separating employees with and without immunologic respiratory disease caused by anhydrides. When IgG < or = 1:10 was used, 62 of 81 workers were correctly classified; the sensitivity was 100%, the positive predictive value was 45%, the specificity was 75%, and the negative predictive value was 100%. When IgE < 1:5 was used, 73 of 81 workers were correctly classified; the sensitivity was 86%, the positive predictive value was 67%, the specificity was 91%, and the negative predictive value was 97%. The authors concluded that anhydride disease status can be predicted on the basis of specific IgG or IgE antibody level (20).
In a surveillance study spanning 4 years, 28 employees with HHPA-induced immunologic respiratory disease who had been removed from exposure for at least 1 year were evaluated. Seven had asthma, 9 had hemorrhagic rhinitis, 4 had both, and 8 had allergic rhinitis alone. Antibody against HHPA conjugated to human serum albumin (HHP-HSA) was measured using ELISA testing. Symptoms, signs, and spirometry normalised in all but 1 employee. There had been a decline in antibody titers for both immunoglobulin E and G against HHP-HSA. In this group of 28 employees, there was only 1 employee with mild asthma after removal from exposure for at least I year. Although specific antibody was still present in many, the titers were generally lower at follow-up than at presentation (21).
Total plasma protein adducts levels of HHPA and MHHPA have been reported to be excellent biomarkers of long-term exposure to anhydrides (22).
- Yokota K, Johyama Y, Miyaue H, Matsumoto N, Yamaguchi K. Occupational contact urticaria caused by airborne methylhexahydrophthalic anhydride. Ind Health 2001 Oct;39(4):347-52.
- Drexler H, Weber A, Letzel S, Kraus G, Schaller KH, Lenhert G. Detection and clinical relevance of a type I allergy with occupational exposure to hexahydrophthalic anhydride and methyltetrahydrophthalic anhydride. Int Arch Occup Environ Health 1994;65(5):279-83
- Yokota K, Johyama Y, Yamaguchi K. A cross-sectional survey of 32 workers exposed to hexahydrophthalic and methylhexahydrophthalic anhydrides. Ind Health 2002;40(1):36-41
- Hatanaka S, Imamura I, Terazawa Y, Kuroda K, Endo G. The characteristics of specific IgG to phthalic anhydride (PA)-albumin conjugate. Ind Health 1997 Oct;35(4):508-14.
- Kanerva L, Hyry H, et al. Delayed and immediate allergy caused by methylhexahydrophthalic anhydride. Contact Dermatitis 1997;36(1):34-8
- Chee CB, Lee HS, Cheong TH, Wang YT, Poh SC. Occupational asthma due to hexahydrophthalic anhydride: a case report. Br J Ind Med 1991 Sep;48(9):643-5.
- Grammer LC, Shaughnessy MA, Yarnold PR. Risk factors for immunologically mediated disease in workers with respiratory symptoms when exposed to hexahydrophthalic anhydride. J Lab Clin Med 1996;127(5):443-7
- Moller DR, Gallagher JS, Bernstein DI, Wilcox TG, Burroughs HE, Bernstein IL. Detection of IgE-mediated respiratory sensitization in workers exposed to hexahydrophthalic anhydride. J Allergy Clin Immunol 1985 Jun;75(6):663-72.
- Kanerva L, Alanko K, Jolanki R, Estlander T. Airborne allergic contact urticaria from methylhexahydrophthalic anhydride and hexahydrophthalic anhydride. Contact Dermatitis 1999 Dec;41(6):339-41.
- Venables KM. Low molecular weight chemicals, hypersensitivity, and direct toxicity: the acid anhydrides. Br J Ind Med 1989 Apr;46(4):222-32.
- Drexler H, Schaller KH, Nielsen J, Weber A, Weihrauch M, Welinder H, Skerfving S. Efficacy of measures of hygiene in workers sensitised to acid anhydrides and the influence of selection bias on the results. Occup Environ Med. 1999 Mar;56(3):202-5.
- Jones MG, Nielsen J, Welch J, Harris J, Welinder H, Bensryd I, Skerfving S, Welsh K, Venables KM, Taylor AN. Association of HLA-DQ5 and HLA-DR1 with sensitization to organic acid anhydrides. Clin Exp Allergy 2004 May;34(5):812-6.
- Dearman RJ, Warbrick EV, Humphreys IR, Kimber I. Characterization in mice of the immunological properties of five allergenic acid anhydrides. J Appl Toxicol 2000;20(3):221-30.
- Nielsen J, Welinder H, Ottosson H, Bensryd I, Venge P, Skerfving S. Nasal challenge shows pathogenetic relevance of specific IgE serum antibodies for nasal symptoms caused by hexahydrophthalic anhydride. Clin Exp Allergy 1994 May;24(5):440-9.
- Grammer LC, Shaughnessy MA, Lowenthal M. Hemorrhagic rhinitis. An immunologic disease due to hexahydrophthalic anhydride. Chest 1993;104(6):1792-4
- Grammer LC, Shaughnessy MA, Lowenthal M, Yarnold PR. Risk factors for immunologically mediated respiratory disease from hexahydrophthalic anhydride. J Occup Med 1994;36(6):642-6
- Welinder HE, Jonsson BA, Nielsen JE, Ottosson HE, Gustavsson CA. Exposure-response relationships in the formation of specific antibodies to hexahydrophthalic anhydride in exposed workers. Scand J Work Environ Health 1994 Dec;20(6):459-65.
- Rosqvist S, Nielsen J, Welinder H, Rylander L, Lindh CH, Jonsson BA. Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers. Scand J Work Environ Health 2003 Aug;29(4):297-303.
- Nielsen J, Welinder H, Jonsson B, Axmon A, Rylander L, Skerfving S. Exposure to hexahydrophthalic and methylhexahydrophthalic anhydrides--dose-response for sensitization and airway effects. Scand J Work Environ Health 2001 Oct;27(5):327-34.
- Grammer LC, Shaughnessy MA, Hogan MB, Berggruen SM, Watkins DM, Yarnold PR. Value of antibody level in diagnosing anhydride-induced immunologic respiratory disease. J Lab Clin Med 1995;125(5):650-3
- Grammer LC, Shaughnessy MA. Study of employees with anhydride-induced respiratory disease after removal from exposure. J Occup Environ Med 1996;38(8):771-4
- Rosqvist S, Johannesson G, Lindh CH, Jonsson BA. Total plasma protein adducts of allergenic hexahydrophthalic and methylhexahydrophthalic anhydrides as biomarkers of long-term exposure. Scand J Work Environ Health 2001 Apr;27(2):133-9.