Methyl methacrylate and respiratory sensitisation: a comprehensive review

Figures & data

Figure 1. Diagnosis of occupational asthma as proposed by the World Allergy Organisation (WAO) RADS: reactive airways dysfunction syndrome. https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-centre/professionals/diagnosis-of-occupational-asthma.

Table 1. Keywords combined to produce the search query.

Set of terms relating to the chemical under study

AND Set of terms relating to the effect in question

"ACR-PA 20" OR "ACRIFIX 1S0116" OR "ACRYESTER M" OR "ACRYESTER MMA" OR "ACRYLOID HT 100" OR "DEGACRYL M 547" OR "DL 101" OR "LIGHT ESTER M" OR "METHACRYLIC ACID METHYL ESTER" OR "METHYL ISOBUTENOATE" OR "METHYL METHACRYLATE" OR "METHYL 2-METHACRYLATE" OR "METHYL 2-METHYL-2-PROPENOATE" OR "METHYL 2-METHYLACRYLATE" OR MMA OR "NSC 4769" OR "PARALOID HT 100" OR PEGALANOR "TEB 3 K" OR "THREE BOND 3057 J" OR "VISIOMER MMA" OR 1196968-39-4 OR 1227277-87-3 OR 1451188-71-8 OR 1453489-95-6 OR 162221-54-7 OR "2-(METHOXYCARBONYL)-1-PROPENE" OR "2-METHYL-2-PROPENOIC ACID METHYL ESTER" OR 211862-43-0 OR 220713-32-6 OR 80-62-6 OR 874217-13-7)

ASTHMA OR OCCUPATIONAL(W)ASTHMA OR RESPIRATORY(W)SENSITISATION OR RESPIRATORY(W)HYPERSENSITIVI OR SPECIFIC(W)INHALATION(W)CHALLENGE OR RESPIRATORY(W)ALLERG OR RESPIRATORY(W)IRRITATION OR PULMONARY(W)IRRITATION OR RESPIRATORY(W)TOXICITY OR PULMONARY(W)TOXICITY "IGE" OR SKIN(W)PRICK(W)TEST

Table 2. Description of adapted Klimisch categories for clinical studies on OA.

Code	Category	Category definitions
1	Reliable without restriction	This includes studies or data from the literature/reports which were carried out or generated according to generally valid and/or internationally accepted or specific(national) testing guideline and which address all applicable parameters by ECHA R.7a guidance (section R7.3.10.2 Human data on respiratory sensitisation).^a
2	Reliable with restriction	This includes studies or data from the literature/reports, in which the test parameters documented do not totally comply with generally valid and/or internationally accepted or specific(national) testing guideline, but which are nevertheless well documented and scientifically acceptable and sufficient to address all applicable parameters by ECHA R.7a guidance (section R7.3.10.2 Human data on respiratory sensitisation).^a
3	Not reliable	This includes studies or data from the literature/reports in which there are interferences between the measuring system and/or effects observed, or the causal relationship between cannot be established with sufficient confidence, or the study was carried out or generated according to a method which is not acceptable, the documentation of which is not sufficient for an assessment and which is not convincing for an expert judgement
4	Not assignable	This includes studies or data from the literature literature/reports, which do not give sufficient experimental details and which are only listed in short abstracts or secondary literature (books, reviews, etc.)

^aECHA R.7a guidance (section R7.3.10.2 Human data on respiratory sensitisation) state that “For evaluation purposes, existing human experience data for respiratory sensitisation should contain sufficient information about:”

Table 3. Description of modified Bradford Hill criteria.

Bradford Hill criteria	Adapted Bradford Hill criteria
Strength (Strength of the association between suspected cause and observation)	The level of confidence that the effect was due to exposure to the agent and not due to other agents suspected or known to cause the effect
Consistency (Repeatability of an association by different persons, in different places, circumstances and times)	The prevalence of the effect on the population of similar individuals of the same and/or comparable sectors
Specificity (The association is limited to a specific population and to particular sites and types of disease)	The effect observed is due to the hypothesised MOA for the claimed disease and alternative hypotheses can be excluded with confidence
Temporality (The exposure occurs before the effect)	The temporal relationship between development and occurrence of the effect and exposure history
Biological gradient (Risk of disease increases with increasing exposure)	Incidence or severity of effects across sector and industries in relation to exposure within these sectors/industries
Plausibility (Biological knowledge supports suspected causation)	Not adapted
Coherence (The association agrees with the generally known facts of the history and biology of the disease)	Not adapted
Experiment (Experimental evidence alters the frequency of associated events)	Incidence and severity of effect corresponds with changes in exposure to agent
Analogy (Information for a similar but different association supports causation)	Consistency with structure activity relationships and information on structural analogues

Table 4. Four-point scoring system as described in the OHAT handbook.

Level of confidence in the association between exposure to the substance and the outcome	Criteria
High confidence (++++)	The true effect is highly likely to be reflected in the apparent relationship.
Moderate confidence (+++)	The true effect may be reflected in the apparent relationship.
Low confidence (++)	The true effect may be different from the apparent relationship.
Very low confidence (+)	The true effect is highly likely to be different from the apparent relationship

Figure 2. Assessing confidence in the body of evidence taken from Figure 1 in Rooney et al. (2014).

Figure 3. Categorisation of the 368 records identified from the literature search.

Table 5. Confidence score in adapted Bradford Hill criteria for worker health studies.

Adapted BH criteria	Confidence score	Justification
Strength	++++	There is no increased risk of asthma in the K2 rated worker-health studies with no consistent contradictory evidence from the K3 rated studies
Consistency	++++	The health effects being observed are in workforces with high exposures to predominantly MMA and that the only indication for an increased risk of asthma come from 2 studies with low reliability and mixed exposures
Specificity	++++	These associations are likely to be due to the known irritant property of MMA vapour
Temporality	++++	The health effects being observed follow, in the majority of cases, many years of employment in the same industry and thereby discount any healthy worker affect
Biological gradient	+++	The health effects reported are being observed in workers with the highest exposures to MMA
Plausibility	+++	The health effects observed are typically associated with irritation, a known property of MMA
Coherence	+++	Primary chemical irritation is known to cause these health effects
Experiment		N/A
Analogy		N/A

MMA: methyl methacrylate; N/A: not applicable.

Table 6. Confidence score in adapted Bradford Hill criteria for case studies.

Adapted BH criteria	Confidence score	Justification
Strength	+	There were no K1 or K2 studies identified. All studies lacked essential details on workplace exposure to assert with confidence that MMA and not other chemicals used was the causative agent.
Consistency	+	The prevalence in orthopaedic and dental sectors is extremely low and inconsistent with other recognised respiratory sensitisers.
Specificity	++	These associations are more likely to be due to the known irritant property of MMA vapour triggering asthma-like symptoms in an asthmatic.
Temporality	++	It is claimed that the OA developed after exposure to MMA but this is not substantiated with evidence. Insufficient data upon which to score.
Biological gradient	+	Insufficient data upon which to score.
Plausibility	+	The causal link between MMA and development of OA is not established neither is an immunological MOA. Observed effects could equally be due to irritation.
Coherence	+	Irritation is known to trigger asthma in asthmatics and could be equally responsible for the pattern of disease.
Experiment		N/A
Analogy	++	There is some evidence that HEMA may be linked with OA in dentists. However, the numbers are small and exposures are mixed so it is uncertain whether this is causally related or coincidental elicitation due to irritation.

MMA: methyl methacrylate; N/A: not applicable; OA: occupational asthma; HEMA: hydroxyethyl methacrylate.

Table 7. Confidence score in adapted Bradford Hill criteria for QSARs.

Adapted BH criteria	Confidence score	Justification
Strength	++	The identified QSARs are K3.
Consistency	+	The prediction of from the two QSAR is inconsistent and overstated.
Specificity	++	QSARs based upon being an asthmagen (Jarvis et al.) covers sensitisation and irritation induced and provoked asthma so is no specific. Whereas, the QSAR of Enoch et al. is MOA based, but has no quantitative level of confidence in the prediction.
Temporality	N/A	N/A
Biological gradient	+	Biological gradient is not taken inti account in the QSAR of Jarvis et al. Potential for chemical reactivity is considered in the QSAR of Enoch et al. but other than low reactivity being mentioned it is not clear if reaction rates are used as a measure of biological gradient
Plausibility	++	QSARs based upon an underlying MOA of sensitisation is recognised. QSARs based upon being an asthmagen covers sensitisation and irritation induced OA but does not necessarily distinguish irritant provoked asthma.
Coherence	+	Neither QSAR gave a reliable prediction of MMA being a respiratory sensitiser.
Experiment	N/A	N/A
Analogy	N/A	N/A

MMA: methyl methacrylate; N/A: not applicable; OA: occupational asthma; QSAR: quantitative structure–activity relationship.

Table 8. Confidence score in adapted Bradford Hill Criteria for exposure data.

Adapted BH criteria	Confidence score	Justification
Strength	+++	The exposure data contained in the EU RAR (EC 2002) is comprehensive and is both supporting and consistent with the published data for the same sectors.
Consistency	+++	The available exposure data is broadly consistent if the impact of effective LEV and different work tasks within a sector are taken into account. In absence of LEV mean exposures into the tens of mg/m³ and short duration peaks into the hundreds and thousands of mg/m³ are achievable
Specificity	++++	The methods used for workplace measurements would have high specificity for MMA.
Temporality	N/A	N/A
Biological gradient	N/A	N/A
Plausibility	N/A	N/A
Coherence	+++	The occupational use of liquid MMA containing products would be expected to generate a heavy MMA vapour that would give rise to high concentrations in the breathing zone of workers in the absence of effective LEV.
Experiment	N/A	N/A
Analogy	N/A	N/A

MMA: methyl methacrylate; N/A: not applicable; LEV: local exhaust ventilation.

Table 9. Confidence score in adapted Bradford Hill criteria for national surveillance data.

Adapted BH criteria	Confidence score	Justification
Strength	+	The clinical and exposure evidence is limited or absent in all cases. Co-exposure and likely other causative agents cannot be excluded and in some cases are more likely explanations
Consistency	+	The cases come from a wide range of sectors indicating a low prevalence. Evidence for dental and orthopaedic sectors under Case Studies would suggest a very low prevalence exists but no comprehensive analysis is available.
Specificity	+	No data on workplace exposure levels upon which to exclude irritation exists for any case
Temporality	+	No clinical history is given for any case study
Biological gradient	+	No data on workplace exposure levels upon which to make this determination. However, no case studies exist for sectors with high exposures such as cast sheet manufacture or reactive floor coating resins.
Plausibility	+	It is not discernible if exposure to MMA occurred and if so whether this caused the development of OA or acted as an irritant trigger of symptoms.
Coherence	+	Irritant provocation of pre-existing asthma cannot be excluded.
Experiment	N/A	N/A
Analogy	N/A	N/A

MMA: methyl methacrylate; N/A: not applicable; OA: occupational asthma.

Table 10. Confidence score in adapted Bradford Hill criteria for SIC data.

Adapted BH criteria	Confidence score	Justification
Strength	+	There is insufficient detail as to workplace exposure to chemicals other than MMA and the products tested in the positive SIC to make causal inference. The lack of exposure measurements during the + ve SIC with the weak read across to other − ve SIC combined with the use of an insensitive method for measurements of peak exposures introduces a high degree of uncertainty.
Consistency	++	Ten + ve SIC with MMA were reported. Other − ve SIC were performed with patients also claimed to have OA due to MMA, but were not reported. This incidence is extremely low compared with the high numbers involved in dentistry within the EU.
Specificity	+	The evidence supporting low exposure during + ve SIC is insufficient and therefore an alternative hypothesis of irritation is more likely.
Temporality	++	The claimed development of OA after an unknown period of working in the dental industry is consistent. However, no clinical histories are available and the causal inference to MMA is not established with sufficient confidence.
Biological gradient	+	No data on workplace exposure levels upon which to make this determination. However, no case studies exist for sectors with high exposures such as cast sheet manufacture or reactive floor coating resins.
Plausibility	++	MMA is a weak Michael addition reactor capable of causing contact allergy so it is plausible that it could cause OA. However, it is also a respiratory irritant so could be provoking a non-specific response.
Coherence	+	Irritant provocation of pre-existing asthma cannot be excluded.
Experiment	N/A	N/A
Analogy	++	QSARs have a low predictive value for MMA and methacrylates. There is some evidence that HEMA may be linked to OA in dentists.

MMA: methyl methacrylate; N/A: not applicable; OA: occupational asthma; HEMA: hydroxyethyl methacrylate; QSAR: quantitative structure–activity relationship; SIC: Specific Inhalation Challenge.

Table 11. Overall level of confidence in the six lines of evidence.

Adapted BH criteria	Worker health studies	Case studies	QSARs	Exposure	National surveillance data	SIC test data
Strength	++++	+	++	+++	+	+
Consistency	++++	+	+	+++	+	++
Specificity	++++	++	++	++++	+	+
Temporality	++++	++	N/A	N/A	+	++
Biological gradient	+++	+	N/A	N/A	+	+
Plausibility	+++	+	++	N/A	+	++
Coherence	+++	+	+	+++	+	+
Experiment	N/A	N/A	N/A	N/A	N/A	N/A
Analogy	N/A	++	N/A	N/A	N/A	++
Overall level of confidence	++++	+	+	+++	+	+

QSAR: quantitative structure–activity relationship; SIC: Specific Inhalation Challenge.

Rooney AA, Boyles AL, Wolfe MS, Bucher JR, Thayer KA. 2014. Systematic review and evidence integration for literature-based environmental health science assessments. Environ Health Perspect. 122(7):711–718.

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[EC] European Chemicals Bureau. 2002. European Union - risk assessment report on methyl methacrylate. Eur Union Risk Assess Rep. 22:1–194

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