Methyl methacrylate and respiratory sensitization: A Critical review

Figures & data

Figure 1.  Metabolism of methyl methacrylate (courtesy of Peter Blomgren).

Table 1.  Reactivity of MMA and other representative (meth)acrylates, respiratory sensitizers and irritants, dermal sensitizers, and non-sensitizers.

Chemicals	Mechanistic category	LLNA EC3	Measures of electrophilicity			Log P
			Electrophilic Index, ω	GSH depletion, KGSH (L mol^−1 min^−1)	GSH depletion, RC 50 (mM)
		(↑ value → ↓ reactivity)	(↑ value → ↑ reactivity)	(↑ value → ↑ reactivity)	(↑ value → ↓ reactivity)
Methyl methacrylate and other (meth) acrylates
Methyl methacrylate	Michael addition	60–90	0.85 (9)	0.20 (12)	70 (7)	1.38
		“Weak” (1)		0.33 (13)	74.1 (15)
				6 (14)	76 (17)
Methyl acrylate	Michael addition	19.6	1.02 (9)	11.4 (15)	0.42 (15)	0.8
		“Weak” (2)		52.0 (13)
				61 (14)
Ethyl methacrylate	Michael addition	No data	0.83 (9)	0.058 (15)	NRAS (7, 17)	1.94
				0.139 (13)
				4 (14)
Ethyl acrylate	Michael addition	28	0.99 (9)	10.6 (15)	0.52 (7, 17)	1.32
		“Weak” (3)		11.9 (16)
				26.6 (13)
				39.7 (12)
				57 (14)
Allyl methacrylate	Michael addition	No data	No data	0.51 (12)	No data	2.12
				3 (14)
Allyl acrylate	Michael addition	No data	0.94 (9)	19.5 (9)	3.5 (17)	1.4
2-Hydroxypropyl methacrylate	Michael addition	“Non-sensitizer” (3)	No data	4 (14)	28 (7)	0.97
2-Hydroxyethyl methacrylate	Michael addition	“Non-sensitizer” (4)	No data	33 (8)	No data	0.47
2-Hydroxyethyl acrylate	Michael	1.4	No data	22.2 (16)	0.27 (7)	−0.21
	addition	“Moderate” (3)		50.9 (12)
				102 (14)
Representative respiratory sensitizers
Trimellitic anhydride	Acylation	0.22	2.35 (10)	No data	No data	1.95
		“Strong” (5)
2,4-TDI	Acylation	0.11	1.37 (10)	No data	No data	3.74
(toluene diisocyanate)		“Strong” (5)	1.23 (11)
Phthalic anhydride	Acylation	0.36	2.61 (11)	No data	No data	1.6
		“Strong” (5)
Known or suspected respiratory sensitizers
Formaldehyde	Acylation	0.4	1.46 (11)	No data	No data	0.35
		“Strong” (5)
Hydroquinone	Michael Addition	0.11	No data	No data	4.4 (7)	0.59
		“Strong” (3)
Representative respiratory irritant
Acrolein	Michael addition	0.86	No data	No data	0.086 (17)	−0.01
		“Strong” (8)
Representative contact sensitizer
DNCB	SnAr	0.04	3.32 (11)	No data	No data	2.17
(dinitrochlorobenzene)		“Extreme” (1)
Representative non-irritant, non-sensitizer
Methyl tiglate	Michael addition	No data	1.24 (10)	0.007 (15)	NRAS (15, 17)	1.69
			0.694 (9)
		(1) Betts 2006	(9) Wondrousch 2010	(9) Wondrousch 2010	(7) Schultz 2009	(18) NLM 2010
		(2) Dearman 2007	(10) Enoch 2010	(12) Freidig 1999	(15) Bohme 2009
		(3) Gerberick 2005	(11) Enoch 2009	(13) McCarthy 1994	(17) Yarbrough 2007
		(4) Roberts 2007a		(14) Chan 2008
		(6) Gerberick 2007b		(15) Bohme 2009
		(7) Schultz 2009		(16) Roberts 2009
		(8) Schultz 2007

Key: NRAS: = not reactive at saturation.

Table 2.  Relative skin sensitization potency of contact allergens based on LLNA (ECETOC, 2008).

Potency rating	EC3 concentration (%)
Extreme	<0.1
Strong	≥0.1≤ to ≤1.0
Moderate	≥1.0≤ to ≤10
Weak	≥10

Table 3.  Summary of skin sensitization studies of MMA.

Species	Induction (sensitization) method	Elicitation (challenge) method	Solvent	Results	Reference
Guinea pig maximization test
Guinea pig	Intradermal injections (day 0); occlusion (day 7)	Occlusion (day 21), open application (day 35)	Ind—80% ethanol;, peanut oil, or Aramek Elicit—Peanut oil or aramek	2/10 3/10	(118)
Guinea pig	Intradermal injections (day 0)	Ost (day 14, repeated up to 12 weeks)	Ind—Ethanol, FCA, saline Elicit—Acetone:olive oil (4:1)	0/6	(119)
Guinea pig	Intradermal injections (3 groups), occlusion (1 group)	Day 21 max non-nonirritating conc. (all groups), 24 24-h occlusion	Ind—Propylene glycol; FCA/propylene glycol; FCA; petrolatum Elicit—Non-Nonirritating conc Occlusion	0/5 2/5 2/5 4/5	(120)
Guinea pig	Intradermal injections (3 rounds, all day 0)	Day 21, 24-h occlusion	Ind—Group 1: FCA:distilled water (day 0) Group 2: MMA:saline (day 0) Group 3: MMA/saline:FCA (1:1) (day 0) All groups: 24-h occlusion (day 7) Elicit—Ethanol	0/10 0/10 0/10	(116)
Guinea pig	Occlusion (days 0, day 7)	Occlusion	Ind—(Day 0,, FCA, saline); (day 7, neat MMA) Elicit—Dilute MMA; 1% MMA: Vaseline,; 5% MMA:Vaseline (day, not described)	Negative (10% of animals treated with 1% conc.) Positive (50% of animals treated with 5% conc.)	{(121),(122)
Guinea pig	Intradermal injections (day 0) OST (day 7)Occlusion, 48 hour (day 8)	Occlusion (day 21)	Ind—Day 0, (FCA:Water, MMA: soybean oil, MMA:FCA:Water;) day 7, (MMA:Petrolatum, SDS); day 8, (neat MMA) Elicit—MMA 3%:petrolatum (occlusion)	9/10	(123)
Guinea pig	Intradermal injections (day 0), occlusion (day 7)	24 hr Occlusion, 24 h (day 21)	Ind—Group 1: (Day 0, 5% MMA:Water, 10% MMA:FCA.; day 7, neat MMA.; day 24, 5% MMA) Group 2: (Day 0, 0.15% MMA:water, 0.3% MMA:FCA.; day 7, 0.15% MMA.; day 24, 100% MMA) Group 3: (Day 0, 0.001% MMA:water, 0.002% MMA:FCA.; day 7, 0.001% MMA.; day 24, 100% MMA) Group 4: (Day 0, 0.5% MMA:water, 10% MMA:FCA.; day 7, 100% MMA.; day 24, 100% MMA) Elicit—Group 1: (5% MMA occlusion, 48 h) Groups 2–4: (100% MMA, 5% MMA, acrylic particles occlusion, 48 h)	Group 1 (4/26) Group 2 (0/13) Group 3 (0/12) Group 4 (20/26)	(124)
Guinea pig	Intradermal injections (day 0), occlusion (day 7)	Occlusion, 24 hr (day 14)	Ind—FCA, MMA:dibutylphthalate, MMA:FCA, acetone. Elicit—Acetone	0/10	(125)
Guinea pig	Intradermal injections and topical (day 0)	Occlusion, 24 hr (day 21)	Ind—Olive oil Elicit—Acetone	2/14 (1 M conc.) 0/10 (10^−−1 M conc.) 0/10 (10^−−2 M conc.)	(126)
Guinea pig	Intradermal injections Day 0: six 6 injections, six 6 sites, FCA.Day 7: SLS (24 hr)Day 8: occlusion (48 hr)	Day 21, occlusion (24 hr)	Ind—Olive oil:acetone (7:3) Elicit—neat MMA	6/6	(127)
Guinea pig	Intradermal injections, 3 control groups and 3 test groups, six 6 injections (day 0), SLS (day 6), occlusion (day 7, 48 hr)	Occlusion (days 20, Day 27; 28 hr, 48 hr, 72 hr)	Ind (test groups)—FCA:water (1:1), MMA:FCA (1%, 3%, 10% MMA)	Challenge (day 20): 1/4 (after 24, 48, 72 hr) 2/5 (after 24, 48, 72 hr) 5/5 (after 24, 48, 72 hr) Rechallenge:1/4 (after 24, 48, 72 hr) 1/5 (after 24, 72 hr and 0/5 after 48 hr) 5/5 (after 24, 72 hr and 3/5 after 48 hr)	(128)
Guinea pig	Intradermal injections Day 0: six 6 injectionsDay 7: occlusion (Day 7, 48 hr)	Occlusion (day 14, 24 hr); OST (day 28)	Ind—FCA:Water (1:1), MMA 10%:maize oil, MMA 10%:FCA/water (1:1) Elicit —25% MMA; maize oil or maize oil/DMSO (day 14) then occlusion (24 hr), OST with 25 and 50% MMA in ethanol/40% DMSO (day 28).	5/5 5/5 5/5 5/5	(129)
Beuhler
Guinea pig	Method A: OST (days 0, 2, 4, 7, 9, 11)Method B: OST (days 0, 1, 2, 3, 4, 7, 8, 9, 10, 11)	Method A: OST shaved flank (day 28, repeated up to 12 weeks)Method B: OST shaved neck (day 21, repeated up to 12 weeks)	Method A: Ethanol 95%:2-methoxyethaol: Tween 80 (9:9:2)Method B: Acetone:olive oil (1:1)	Method A: 0/6 Method B: 0/6	(119)
Guinea pig	OST, 6- hour occlusion (days 0, 7, 14)	24- hour occlusion, day 28	Ind—neat MMA Elicit —Ethanol	0/30	(116)
Freund’s complete adjuvant test (FCAT)
Guinea pig	Intradermal injections in shoulder (days 0, 2, 4, 7, 9)	Occlusion (day 21),); OST (Day 35)	Ind—FCA Elicit—Peanut oil or Aramek (occlusion day 21); peanut oil or Aramek (day 35, OST)	2/8	(118)
Guinea pig	Intradermal injections multi-site (day 0)	Occlusion (day 14, 24 hr); OST (day 28)	Ind—1 M MMA:FCA/saline Elicit—2.5 M in maize oil (occlusion); 2.5 M in DMSO/maize oil (occlusion); 2.5 M in ethanol (OST); 5 M in ethanol (OST)	5/5 5/5 4/5 5/5	(129) *
Split adjuvant test
Guinea pig	Multi-Site intradermal injections of dorsal shaved flank (day 0: FCA, day 1: MMA)	OST (day 14, repeated up to 12 weeks)	Ind—Ethanol:saline (1:100) Elicit—Acetone:olive oil (4:1)	0/6	(119)
Guinea pig	Frozen (dry Ice contact, day 0), occlusion (days 0, 3, 4, 7), intradermal injections (day 4)	Day 22, 24-h occlusion	Ind—Dry ice, ethanol, FCA:ethanol:MMA, ethanol Elicit—Ethanol	0/30	(116)
Polak
Guinea pig	Footpad injections and intradermal injections	OST (day 7, repeated up to 12 weeks)	Ind—Ethanol:saline (1:4) Elicit—Acetone:olive oil (4:1)	0/6	(119)
Guinea pig	Footpad injections and intradermal injections (nape of neck)	Group 1: OST (day 0, reactions recorded days 2, 4, 5, 6) Group 2: OST (cross- reactivity) days 7, Day 14	Ind—Ethanol:saline (1:4) in FCA occluded, some also injected. Elicit—Acetone:olive oil (4:1)	0/5 (8 groups)	(130)
Guinea pig	6 groups: 2 hind footpad injections each group (day 0),); group 1 occlusion day 0), groups 2–3 occlusion (day 10), groups 4–5 occlusion (day 25), group 6 intradermal injection (day 25).	Groups 1–3, OST (day 35).); groups 4-6, OST (day 60)	Ind—FCA (groups 1–6) olive oil (groups 1, 3, 5); ethanol (groups 2, 4); saline injection (group 6) Elicit—Olive oil (groups 1–3, day 35); olive oil (groups 4–6, day 60)	Group 1 (0/10) Group 2 (0/5) Group 3 (0/5) Group 4 (0/5) Group 5 (0/5) Group 6 (0/5)	(131)
Guinea pig	Part A:6 groups: Footpad injections in each group (day 0).); OST, (all groups, days 0, 2, 5); group 4, additional intradermal injection (day 0); group 5, OST (day 25); group 6 intradermal injection (day 25).Part B:Group 4, (same as above);group 7, (footpad injection (day 0), intradermal injection (day 0)	OST (groups 1–3, day 35), OST (groups 4–6, day 60)	Ind—FCA (all groups), ethanol (groups 1–5), saline (groups 4 and 6) Elicit—Ethanol (groups 1–4), olive oil (groups 5 and 6)	Part A: Group 1 (0/25, 72 hr) Group 2 (0/24, 72 hr) Group 3 (0/25, 72 hr) Group 4 (0/10, 72 hr) Group 5 (13/13, 72 hr) Group 6 (8/8, 72 hr) Part B: Group 4 (1/10, 48 hr) Group 7 (2/10, 48 hr)	(132)
Draize
Guinea pig	10 intradermal injections over 1 week.	Intradermal injection 14 days after last induction injection (24-hour determination)	Ind—Saline Elicit—Ethanol	2/30	(116)
Mouse ear sensitization test (MEST)
Mouse	Intradermal injection (day 0), topical application (days 0–3)	Topical application to ear (day 10)	Ind—FCA, Ethanol Elicit—Ethanol	44% sensitized, 118% increase in ear thickness	(115)
Mouse	Topical application (days 0, 2)	Topical application (day 9)	Ind—Ethanol Elicit—Ethanol	114% increase in ear thickness (24 hours after challenge, p < 0.01)	(133)

Note. Ind = vehicle used for the “Induction (Sensitization)” procedure.;

Elicit = vehicle used for the “Elicitation (Challenge)” procedure.;

FCA = Freund’s complete adjuvant;

OST = open skin testing;

SLS = sodium lauryl sulfate;

SDS = sodium dodecyl sulfate.

* = Modified FCAT method.

Figure 2.  MMA air levels measured above a mixing bowl during the mixing of MMA-containing orthopedic cement. Measurements were obtained every 45 seconds over 20 minutes using a photo-acoustic spectrophotometer. Cement A = Endurance^® (DePuy); Cement B = Palacos-R^® (Schering-Plough); Cement C = Simplex-P^® (Stryker). (previously unpublished data courtesy of Leslie J. Ungers, MS, CIH; see also Ungers et al., (2007); Ungers & and Vendrely, (2006)).

Table 4.  Summary of 19 case reports.

Author	Year	Occupation/exposure context	Diagnosis or “clinical description”	PFT	PEFR	NSIC	Specific inhalation challenge
Dental exposures
Lozewicz	1985	Dental Assistant: working on dental prosthetic trays	Asthma	NR	(−)	NR	(+) pMMA powder & MMA liquid NR: Placebo
Basker	1990	Denture wearer	Asthma	NR	(−)	NR	NR (see text)
Savonius	1993	Dental Technician	Asthma	NR	NR	NR	(+) Mix 10 g methacrylate powder & 10 ml methacrylate liquid NR: Placebo
Wittczak	1996	Dental Technician	Asthma	(+)	NR	NR	(+) MMA-containing acrylics (Superacryl, Duracryl) (−) Placebo
Piirila	1998	Dental nurse	Asthma	(−)	(+)	(+) H	(+) Paladur dental composite resin (−) “Scotchbond” primerNR: Placebo
Piriila	1998	Dentist	Laryngitis	(−)	(−)	(−) H	(−) Paladur or Forestacryl dental composite resins NR: Placebo
Scherpereel	2004	Dental Technician trainee	Hypersensitivity pneumonitis	(+)	NR	NR	NR
Scherpereel	2004	Dental Technician trainee	Hypersensitivity pneumonitis	(+)	NR	NR	(+) “Aerolized” MMA particles
Thorette	2006	Dental student	Hypersensitivity pneumonitis	NR	NR	NR	NR
Orthopedic exposures
Lee	1984	Operating Room Anesthetist: bone cement	“Tightness in the chest”	NR	NR	NR	NR
Scolnick	1986	Surgical Nurse trainee: near bone cement mixing table	“Difficulty in breathing”	NR	NR	NR	NR
Pickering	1986	Surgical Nurse: mixing bone cement	Asthma	(−)	NR	NR	(+) Palacos bone cement with gentamicin NR: Placebo
Reynaud-Gaubert	1991	Surgical Nurse: mixing bone cement	Asthma	(−)	NR	(+) A	(+) Palacos bone cement with gentamicin
Kirby	2003	Operating Room Radiology Technician: bone cement	Bronchospasm	NR	NR	NR	NR
Other exposures
Kennes	1981	Handyman: Plexiglass cutter	Asthma	(+)	NR	NR	(+) TDI varnish (+) Plexiglass shavings (−) Other (see text)
Lozewicz	1985	Railway cable joiner	“Headache, sweating, and lassitude”	NR	(+)	(−) H	(−) Acrylic cold curing resin system containing MMA (−) Placebo
Savonius	1993	Plate engraver	Asthma	NR	NR	(−) H	(+) MMA-containing glue NR: Placebo
Savonius	1993	Hearing aid assembler	Asthma	NR	NR	(+) H	(−) Ground piece of methacrylate NR: Placebo
Wittczak	2003	Secretary: photocopying	Asthma	NR	NR	(+) H	(+) MMA, heated (+) Photocopy toner (−) Placebo

Key:Note.

PFTs: = pulmonary function tests (spirometry);

PEFR: = peak expiratory flow rates;

NSIC: = non-specific inhalation challenge;

NR: = tests were either not performed or results were not reported;

H: = histamine challenge;

A: = acetylcholine challenge;

(−): = test results were normal;

(+): test results were positive (as reported by authors).

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