Asthma Technical Summary:

Asthma associated with the workplace (work-related asthma) consists of asthma caused by work (occupational asthma, or OA), and asthma exacerbated by work (work-exacerbated asthma, or WEA). OA can be further broadly divided into 2 main categories, these being asthma that is allergic in nature and associated with sensitisation of the respiratory tract (allergic OA or sensitiser-induced OA; SIOA), and non-allergic, irritant-induced OA (IIOA).

As it is usually extremely difficult to distinguish the mechanism(s) involved i.e., allergic or irritation, the term "asthmagen" has been developed to describe substances that are causally related to the development of OA. Although clinical diagnosis of presence of asthma in a patient is well established the identification of the causative agent(s) is more difficult, and often not possible as this often involves the recognition of work industries associated with the development of asthma, or the identification of patterns in exposure to occupational or life-style substances that triggers asthma symptoms, followed by, in some cases by skin or blood testing to identify specific allergens.

This process of identifying causation by association is not precise as the clinical investigation is unavoidably retrospective and it is difficult to distinguish between agent(s)s that provoke asthma responses from the agent(s) that may have caused the onset of the asthma in the first place.

MPA has commissioned two comprehensive reviews of the medical and other scientific literature linking MMA and methacrylates to asthma to date (Borak 2011 and Pemberton and Kimber, 2022) These reviews concluded that MMA is not causally related to the development of asthma.

MMA is a high production volume chemical that has an extensive database of published and unpublished toxicological studies that have been the subject of three in depth, independent reviews by international governmental agencies. These reviews have also concluded that there is no convincing evidence that MMA causes asthma in humans.

In January 2001, the OECD (Organization for Economic Co-operation and Development) completed its Screening Inventory Dataset (SIDS) Initial Assessment Report (SIAR) for MMA concluding that "There is no convincing evidence that methyl methacrylate is a respiratory sensitizer in humans".

The review panel consisted of medical, toxicological and regulatory experts from the Governmental Agencies of the member OECD countries (Australia, Austria, Belgium, Canada, Czech republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Korea, Norway, Poland, Portugal, Slovak Republic, Spain, Sweden, Switzerland, The Netherlands, UK, USA) as well as from the European Commission, UNEP, and WHO.

Soon thereafter, in April 2001, the European Union finalized its Risk Assessment for MMA. This six-year risk assessment reviewed published and unpublished (company confidential) studies/reports on MMA, concluding that "no convincing evidence was found that MMA acts as a respiratory sensitiser in humans" in Chapter (section) 4.1.2.5.

The review panel consisted of the leading medical and toxicological experts of the Competent Authorities in the European Union as well as the World Health Organisation. The report was also reviewed and approved by an independent panel of International Peer Scientists/Professors/clinicians comprising the Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE). The review specifically addressed asthma and concludes: "The literature reports isolated cases of asthma in the context of MMA exposure. Substance-specific bronchoconstriction or delayed asthmatic responses respectively were confirmed only in very few cases. Asthmatic reactions seem to be restricted to exposure levels which primarily result in respiratory tract irritation".

In 2002, Health Canada (HC) actually reversed an earlier decision (1996) to classify MMA as a respiratory sensitizer (which required all products containing MMA, or MMA residues (polymers etc.); to be labelled "Contains a respiratory sensitizer"). This decision was based upon the conclusion that, "on balance, there is insufficient evidence at this time to regard MMA as a respiratory sensitizer". Accordingly HC has removed MMA from their list of known respiratory sensitizers. For more information, see the Health Canada (WHIMIS) website.

More recently, the EU Risk Assessment Committee (RAC) has been reviewing MMA. Over the course of the 5 years and 3 meetings, RAC has determined that all of the clinical evidence originally cited was unreliable and insufficient. However, in the latest meeting RAC were of the opinion that 4 specific inhalation challenge (SIC) tests was sufficient evidence upon which to classify MMA. These 4 tests do not conform to accepted guidelines and do not meet CLP criteria so the opinion of RAC is unsound. See Cefic position paper. Until this is resolved the opinion of RAC will not be ratified within the EU.

In summary, these three international agencies, after thorough scientific reviews concluded that MMA should not be regarded as an asthma causing chemical or "asthmagen" was based upon the fact that:

  1.  Despite MMA's widespread use it had been implicated in only a small number of clinical case histories reported in the literature and, 

  2. that there was (1) inadequate evidence of an allergic mechanism, and (2) the case reports in the literature were more consistent with individuals that had developed asthma for some other reason and this condition had been aggravated by their occupation exposure to an irritant vapor (MMA).

The lack of a clear causal relationship between MMA exposure and development of the asthmatic condition meant that MMA should not be regarded as an "asthmagen." Until the EU RAC opinion is decided at EU Commission level, MMA remains unclassified for Respiratory Sensitization within the EU.

The evidence surrounding 2-hydroxyethylmethacrylate (HEMA) and 2-hydroxypropylmethacrylate (HPMA) is extremely weak and limited to four published papers containing a handful of clinical case studies. These were critically reviewed by Pemberton et al., 2023 and concluded that it is entirely possible that the observed respiratory reactions both in the workplace and in SIC tests were attributable to irritancy rather than sensitisation. Furthermore, the authors recognized the low volatility of both hydroxy esters and the fact that the products tested were complex mixtures, concluding that there was little justification for attributing the causation of asthma to either HEMA or HPMA.

References:

Borak J., Fields C., Andrews L. and Pemberton M. Methyl Methacrylate and Respiratory Sensitization: A Critical Review. Critical Reviews in Toxicology. 2011; 41(3): 230-268.  Publication.

Pemberton MA, Kimber I. Methyl methacrylate and respiratory sensitisation: a comprehensive review. Crit Rev Toxicol. 2022 Feb;52(2):139-166. doi: 10.1080/10408444.2022.2064267. Epub 2022 May 24. PMID: 35607993. Publication.

Pemberton MA, Kreuzer K, Kimber I. Challenges in the classification of chemical respiratory allergens based on human data: Case studies of 2-hydroxyethylmethacrylate (HEMA) and 2-hydroxypropylmethacrylate (HPMA). Regul Toxicol Pharmacol. 2023 Jun;141:105404. Publication.