Trimellitic anhydride, TMA

Code: k86
Other sensitising acid anhydrides
  • Phthalic anhydride - PA
  • Maleic anhydride - MA
  • Hexahydrophtalic anhydride - HHPA
  • Methyl hexahydrophthalic anhydride - MHHPA
  • Methyl tetrahydrophthalic anhydride - MTHPA
  • Tetrachlorophthalic anhydride - TCPA
  • Himic anhydride - HA
  • Pyromellitic dianhydride - PMDA
  • Chlorendic anhydride - CA
Occupational Allergen
A chemical, which may result in allergy symptoms in sensitised individuals. 

Allergen Exposure

Geographical distribution
Acid anhydrides are a group of highly reactive chemicals used widely in the formulation of paints and plastics. These chemicals are used in the synthesis of plasticisers and for producing epoxy and alkyd resins as well as a variety of other products including dyes, insecticides, polyester resins and pharmaceuticals. In turn, epoxy and alkyd resins are used as constituents of paints, varnishes, surface coatings, adhesives, encapsulated materials and sealants (1). Trimellitic anhydride (TMA) has a variety of industrial uses.
 
Environment
Phthalic anhydride (PA) and Trimellitic anhydride are two of the most widely used acid anhydrides in industry. Inhalation and dermal contact are the two most common routes of exposure to acid anhydrides in the workplace (2).
 
Trimellitic anhydride is used mainly in the synthesis of trimellitate esters. These esters are used as plasticisers for polyvinyl chloride, especially when temperature stability is required, e.g., in wire and cable coatings. Since Trimellitic anhydride esters are less volatile and less water-soluble than corresponding phthalates, the former have begun to replace the latter in some applications, e.g., car interior linings, the wire enamels used to coat magnetic wire, and for other applications where high thermal resistance is required. Trimellitic anhydride is also often used as a binder for glass fibres, sand, and other aggregates.
 
Exposure to TMA occurs mainly by inhalation of dust or fumes. Since Trimellitic anhydride has a very low vapour pressure at room temperature, extensive exposure occurs mainly when dust is generated from the powder, by mixing or spraying, or by inhalation of the fumes generated during processes requiring high temperature, e.g., oven curing. Exposure to very high levels of Trimellitic anhydride fumes occurs when heated metal surfaces are sprayed with anticorrosive materials containing Trimellitic anhydride-based compounds. High levels of Trimellitic anhydride dust are found in bagging areas.
 
Exposure of the general population to Trimellitic anhydride is possible, for example, around industrial plants, through its use in food storage and protection materials, from car interior linings, and during transportation of the compound. However, the likelihood of exposure from these sources is very low. When trimellitate plasticisers are used, Trimellitic anhydride itself is not present, but rather its ester derivatives; these are stable and do not migrate. There are no reports of populations being affected in the vicinity of industrial sites.
 
Allergens
No allergenic epitopes from this substance have yet been characterised. But it is known that acid anhydride ligands are unique in that they form imide linkages with amino groups and also form neoantigens on autologous proteins (3). 

Potential Cross-Reactivity

The purpose of one study was to determine whether workers sensitised by one acid anhydride, Trimellitic anhydride (TMA), would possibly react immunologically to two other acid anhydrides, Phthalic anhydride (PA) and Maleic anhydride (MA). The researchers concluded that cross-inhibition studies might not be the best method for determining whether an individual sensitised to one antigen will react to a related antigen. However, the determination of biologic reactivity in a rhesus monkey model of passive cutaneous transfer makes it likely that some biologic reactivity would also occur in a human sensitised to TMA and then exposed to another anhydride such as PA (4).
 
Acid anhydride ligands are unique in that they form imide linkages with amino groups and also form neoantigens on autologous proteins (3). Structurally these agents share a common anhydride ring: But IgE antibodies directed against neoantigens formed by anhydride ligands often exhibit a high degree of hapten specificity and thus in some cases do not recognise heterologous acid anhydride antigens (5). 

Clinical Experience

IgE-mediated reactions
Acid anhydrides are strong respiratory irritants known to produce hypersensitivity pulmonary disease, often beginning as hypersensitivity pneumonitis, which can be known as Epoxy Resin Lung. Hypersensitivity pneumonitis can be precipitated either by acute or chronic exposure to acid anhydrides. Acute hypersensitivity pneumonitis may be characterised by fever, chills, nonproductive cough, chest pains, and dyspnea. Symptoms associated with chronic hypersensitivity include fever, cough, fatigue, weight loss, and shortness of breath (6).
 
Four clinical syndromes have been identified. Three of these syndromes are associated with immunological reactions. The 1st is an immediate-type airway response characterised by asthma or rhinitis, or both. These symptoms occur only when individuals are sensitised following a latent period of exposure, which may be weeks or years. Once sensitisation is acquired, symptoms occur within seconds or minutes of exposure. The syndrome is associated with an increase in antibody levels (7-8).
 
The 2nd form, late respiratory systemic syndrome, often termed "TMA-flu", also requires a latent period of exposure for sensitisation. But it is characterised by a delayed onset of symptoms after exposure; typically, coughing and wheezing occur 4-12 hours after exposure to Trimellitic anhydride; however, the syndrome also includes muscle and joint pains, and fever. High levels of antibodies are also associated with this syndrome.
 
The most severe and rare reaction is the pulmonary-disease-anaemia syndrome, which may lead to respiratory failure.  But no fatal cases have been reported. This illness has appeared only after exposures to high concentrations of Trimellitic anhydride fumes, from the heating of materials containing Trimellitic anhydride, for relatively short periods. The symptoms vary in severity and may include cough with blood-stained sputum, as well as breathlessness, resulting in severe pathological changes in the lung. The disease also requires a latent period of exposure before the onset of symptoms and is characterised by high serum antibody levels. These symptoms are, however, reversible after Trimellitic anhydride exposure has ceased.
 
The 4th respiratory syndrome is a non-immunological irritant reaction to Trimellitic anhydride, characterised by a transient irritation in the upper airways, with lacrimation and rhinorrhoea. The irritant symptoms are related to exposure level and can occur in any worker after a single high-level exposure to Trimellitic anhydride powder or fumes (8).
 
A case report concerning allergic alveolitis caused by polyester powder paint has been published. The aim of this study was to determine whether Phthalic anhydride or Trimellitic anhydride (TMA) was the alveolitis-causing agent in such paint. A 61-year-old woman showed recurrent symptoms of chills, cough, and fever while at work. She was working in a plant where epoxy polyester powder paints were used to paint metal. The paint was found to contain low (<1%) amounts of TMA and PA. The symptoms, exposure, reduction in transfer factor, findings on chest radiographs and bronchoalveolar lavage were consistent with allergic alveolitis. The polyester powder paint used in the plant appeared to cause allergic alveolitis in this patient. Of the constituents in the paint, Trimellitic anhydride and Phthalic anhydride were the possible causative agents (9).
 
TMA is a potent respiratory sensitiser. TMA has caused immunologically mediated respiratory illness in 29% of relevant workers, exposed prior to 1979 to levels considerably above the present threshold limit value. The period from 1979 to 1985 was characterised by implementation of control measures to reduce exposure to TMA in the workplace. These measures clearly resulted in a marked decrease in both clinical symptoms and levels of TMA antibody formation.
 
TMA-induced asthma has been reported (10). Individuals with occupational asthma may also report symptoms of rhinitis or conjunctivitis. In a group of 25 of asthmatics studied, 22 (88%) reported rhinitis symptoms, whereas 17 of the 25 (68%) reported conjunctivitis symptoms. In 17 of the 22 (77%) individuals with rhinitis and asthma, the rhinitis symptoms preceded the asthma symptoms. In 14 of the 17 (82%) individuals with conjunctivitis, those symptoms preceded the asthma symptoms (11). A syndrome of immediate-onset work-related asthma and rhinoconjunctivitis associated with exposure to TMA chemical powder was described; specific IgE and/or prick test responses were demonstrated (12).
 
In 196 workers involved in the manufacture of Trimellitic anhydride (TMA), 17 workers had IgE-mediated asthma/rhinitis with a positive skin prick test to TM-HAS and IgE antibody of 0.8-57 ng of TM-HSA bound/ml. Seven workers had a late respiratory systemic syndrome with TA from 760 to 56,000 ng of TM-HSA bound/ml. Four had both syndromes. Three had late onset asthma with TA of 3,700-10,000 and trace levels of IgE to TM-HSA. One had marked arthralgia and myalgia occurring hours after TMA exposure, without respiratory symptoms, with an elevated TA level of 24,000. Of 46 workers reporting no symptoms, 8% had low TA levels, while 16% of 113 with irritant symptoms had low TA levels (13).
 
In addition to allergic reactions, acid anhydrides are potent irritants (including to the skin), a property that could enhance epithelial penetration of chemical and subsequent local sensitisation (14).
 
Total antibodies for TM-HAS have been found to be associated with measured ambient exposure to the chemical in the workplace (15). The detection of TMA-specific IgG or IgE antibodies has been reported to be predictive of subsequent development of clinical disease, whereas the absence of specific antibodies is associated with a very low risk of development of TMA-induced respiratory disorders (16). It has been suggested that antibody titres should be determined in workers exposed to Trimellitic anhydride every 6 months. Quantitative allergen-specific IgE testing offers the capability of monitoring workplace exposure to acid anhydrides through the measurement of acid anhydride-specific IgE levels. Increases in acid anhydride-specific IgE levels are correlated with elevations in exposure to acid anhydrides (6).
 
Other reactions
In addition to allergic reactions, acid anhydrides are potent irritants, including to the skin, (a property that could enhance epithelial penetration of chemical and subsequent local sensitisation) (14).
 
Trimellitic anhydride dust and fumes are highly irritating to the eyes and respiratory system. The dust may cause corrosive eye damage. Trimellitic anhydride can produce skin irritation following prolonged or repeated exposure. One respiratory syndrome is a non-immunological irritant reaction to Trimellitic anhydride, characterised by a transient irritation in the upper airways, with lacrimation and rhinorrhoea. The irritant symptoms are related to exposure level and can occur in any worker after a single high-level exposure to Trimellitic anhydride powder or fumes (8).
 
Pulmonary hemorrhage due to inhalation of fumes or powders containing Trimellitic anhydride (TMA) is well known (17).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

  1. Zeiss CR, Patterson R, Venables K. Acid anhydrides, in Asthma in the Workplace, C.-YM. Bernstein IL, Malo J-L, Bernstein DI, eds., Editor. Marcel Dekker. New York. 1999:479-500
  2. Montanaro A, "Asthma Secondary to Acid Anhydrides," Occupational Asthma, Bardana EJ, Montanaro A, and O'Hollaren MT, eds, Philadelphia, PA: Hanley & Belfus Inc, 1992, 145-7.
  3. Patterson R, Zeiss CR, Pruzansky JJ. Immunology and immunopathology of trimellitic anhydride pulmonary reactions. J Allergy Clin Immunol 1982;70(1):19-23
  4. Lowenthal M, Shaughnessy MA, Harris KE, Grammer LC. Immunologic cross-reactivity of acid anhydrides with immunoglobulin E against trimellityl-human serum albumin. J Lab Clin Med. 1994;123(6):869-73
  5. Bernstein DI, Gallgher JS, D'Souza L, Bernstein IL. Heterogeneity of specific-IgE responses in workers sensitized to acid anhydride compounts. J Allergy Clin Immunol 1984;74(6):794-801
  6. Brooks BO and Sullivan JB, "Immunotoxicology," Hazardous Material Toxicology: Clinical Principles of Environmental Health, Sullivan JB and Krieger GR, eds, Baltimore, MD: Williams & Wilkins, 1992, 209-10.
  7. Zeiss CR, Wolkonsky P, Pruzansky, JJ, Patterson R. Clinical and immunologic evaluation of trimellitic anhydride workers in multiple industrial settings.  J. Allergy Clin Immunol 1982;70(1):15-18
  8. Grammer LC, Shaughnessy MA, Zeiss CR, Greenberger PA, Patterson R. Review of trimellitic anhydride (TMA) induced respiratory response. Allergy Asthma Proc. 1997;18(4):235-7
  9. Piirila P, Keskinen H, Anttila S, Hyvonen M, Pfaffli P, Tuomi T, Tupasela O, Tuppurainen M, Nordman H. Allergic alveolitis following exposure to epoxy polyester powder paint containing low amounts (<1%) of acid anhydrides. Eur Respir J. 1997;10(4):948-51.
  10. Bernstein DI, Zeiss CR, Wolkonsky P, Levitz D, Roberts M, Patterson R. The relationship of total serum IgE and blocking antibody in trimellitic anhydride--induced occupational asthma. J Allergy Clin Immunol. 1983;72(6):714-9
  11. Grammer LC, Ditto AM, Tripathi A, Harris KE. Prevalence and onset of rhinitis and conjunctivitis in subjects with occupational asthma caused by trimellitic anhydride (TMA). J Occup Environ Med. 2002;44(12):1179-81
  12. Zeiss CR, Patterson R, Pruzansky JJ, Miller MM, Rosenberg M, Levitz D. Trimellitic anhydride-induced airway syndromes: clinical and immunologic studies. J Allergy Clin Immunol 1977;60(2):96-103
  13. Zeiss CR, Mitchell JH, Van Peenen PF, Harris J, Levitz D. A twelve-year clinical and immunologic evaluation of workers involved in the manufacture of trimellitic anhydride (TMA). Allergy Proc. 1990;11(2):71-7
  14. Bernstein DI, Wanner MA, Lummus ZL. Pathogenisis of occupational asthma due to chemical sensitizers. ACI International 2002;14(6):257-265
  15. Bernstein DI, Roach DE, McGrath KG, Larsen RS, Zeiss CR, Patterson R. The relationship of airborne trimellitic anhydride concentrations to trimellitic anhydride--induced symptoms and immune responses.  J Allergy Clin Immunol 1983;72(6):709-13
  16. Grammer L, Shaughnessy M, Kenamore B. Utility of antibody in identifying individuals who have or will develop anhydride-induced respiratory disease. Chest 1998;114(4):1199-202.
  17. Kaplan V, Baur X, Czuppon A, Ruegger M, Russi E, Speich R. Pulmonary hemorrhage due to inhalation of vapor containing pyromellitic dianhydride. Chest. 1993;104(2):644-5

 

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.