k86 Trimellitic anhydride, TMA

A chemical, which may result in allergy symptoms in sensitised individuals. 

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 (1).

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 (2-3).

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 (4).

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 (5).

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 (6). 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 (7). 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 (8).

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 (9).

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 (10).

Total antibodies for TM-HAS have been found to be associated with measured ambient exposure to the chemical in the workplace (11). 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 (12). 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 (1)

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) (9).

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 (6).

Pulmonary hemorrhage due to inhalation of fumes or powders containing Trimellitic anhydride (TMA) is well known (12).

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 (14). 

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 (15).

Acid anhydride ligands are unique in that they form imide linkages with amino groups and also form neoantigens on autologous proteins (14). 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 (12). 

Last reviewed: May 2022