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Serum Levels of Methyl Methacrylate Following Inhalational Exposure to Polymethylmethacrylate Bone Cement Kelly C. Homlar MD a , Meredith H. Sellers BA a , Jennifer L. Halpern MD a , Erin H. Seeley PhD b , Ginger E. Holt MD a a Vanderbilt Orthopaedic Institute; Medical Center East, Nashville, Tennessee b Vanderbilt Mass Spectrometry Research Center; Medical Research Building III Vanderbilt University, Nashville, Tennessee abstract article info Article history: Received 18 April 2012 Accepted 24 June 2012 Keywords: polymethylmethacrylate PMMA methyl methacrylate serum Teratogenic effects of polymethylmethacrylate cement at levels used during routine orthopaedic procedures have never been reported, however the hypothetical risk remains a major concern among female surgeons. Our aim was to determine if methyl methacrylate is detectible in the serum during routine cement exposure. Methods: Twenty healthy volunteers were exposed during the mixing of polymethylmethacrylate cement in a simulated operating room environment. Forty serum samples were obtained during the expected peak inhalational exposure and levels of methyl methacrylate were assessed utilizing headspace gas chromatog- raphy mass spectrometry. Results: Methyl methacrylate was not detected in any of the forty experimental specimens. Conclusions: With a detection level of 0.5 ppm, methyl methacrylate is undetectable in the serum during routine mixing of polymethylmethacrylate cement. Published by Elsevier Inc. Polymethylmethacrylate (PMMA), commonly known as bone cement, is the synthetic polymer of methyl methacrylate (MMA). It has been commercially used since the 1930's in cast acrylic sheet manufacturing. Its use in arthroplasty was popularized in the 1960's by Sir John Charnley [1,2]. Questions continue to arise as to its carcinogenic and teratogenic effects [3]. The American Conference of Governmental Industrial Hygienists (ACGIH) has established a threshold limit value (TLV) for methyl methacrylate of 100 ppm, meaning the time-weighted-average for a normal 8h workday and a 40 h workweek to which nearly all workers may be repeatedly exposed to methyl methacrylate without adverse effects [4]. Singh et al. in 1972 [5] studied the possible teratogenic effects of methyl methacrylate by exposing pregnant female rats to high levels of methacrylate esters via intraperitoneal injections. Analysis of fetuses showed a dose-related increase in resorptions, gross and skeletal abnormalities, and a reduction in fetal weight. Though the increase in adverse effects was only minor when compared to controls, this landmark article led to the generally accepted practice for pregnant operating room personnel to leave the room during cementation. Even with later animal studies utilizing an inhalational exposure closer to the recommended TLV showing no statistically signicant difference in resorptions, fetal weight, or external/visceral/skeletal malformations [6,7], concerns among pregnant operating room personnel still exist [3]. With an increasing number of female surgeons specializing in arthroplasty, leaving the room during cementation is not possible. This growing dilemma is the impetus for this study. Linehan et al. [8] attempted detection of methacrylic acid (the hydrolyzed form of MMA) in their own serum following routine total joint arthroplasty using headspace gas chromatography. Seven total serum samples were taken from 11 to 23 min from initiation of mixing. No MA was detectable in any of the samples. Based on our review of the literature showing peak concentrations of MMA in the air occurring before two minutes after the initiation of mixing, and peak serum levels of MMA at 30 s following IV administration and 23min in patients following cementation of implants in joint arthroplasty [6,914], it is felt that this study was limited by poor timing of blood draws in addition to small sample size. Thus, we aimed to increase the chances of detecting MMA in the serum following routine mixing of PMMA cement by collecting the samples within this expected early peak and increasing the sample size. Materials and Methods Following IRB approval, healthy volunteers aged 1865 were solicited through an email announcement to medical students and residents at our medical center. Participants were excluded if they had any signicant medical comorbidity (specically, a history of pulmonary disease, to include asthma), were pregnant, or had a history of adverse reaction to PMMA. Twenty healthy volunteers (10 male and 10 female) were divided into ve groups of four. Informed The Journal of Arthroplasty 28 (2013) 406409 The Conict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2012.06.038. Reprint requests: Kelly C. Homlar, MD, Vanderbilt Orthopaedic Institute, Medical Center East, South Tower, Suite 4200, Nashville, TN 37232-8774. 0883-5403/2803-0005$36.00/0 see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arth.2012.06.038 Contents lists available at SciVerse ScienceDirect The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org

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The Journal of Arthroplasty 28 (2013) 406–409

Contents lists available at SciVerse ScienceDirect

The Journal of Arthroplasty

j ourna l homepage: www.ar throp lasty journa l .o rg

Serum Levels of Methyl Methacrylate Following Inhalational Exposure toPolymethylmethacrylate Bone Cement

Kelly C. Homlar MD a, Meredith H. Sellers BA a, Jennifer L. Halpern MD a,Erin H. Seeley PhD b, Ginger E. Holt MD a

a Vanderbilt Orthopaedic Institute; Medical Center East, Nashville, Tennesseeb Vanderbilt Mass Spectrometry Research Center; Medical Research Building III Vanderbilt University, Nashville, Tennessee

The Conflict of Interest statement associated with thidx.doi.org/10.1016/j.arth.2012.06.038.

Reprint requests: Kelly C. Homlar, MD, VanderbiltCenter East, South Tower, Suite 4200, Nashville, TN 372

0883-5403/2803-0005$36.00/0 – see front matter. Pubhttp://dx.doi.org/10.1016/j.arth.2012.06.038

a b s t r a c t

a r t i c l e i n f o

Article history:Received 18 April 2012Accepted 24 June 2012

Keywords:polymethylmethacrylatePMMAmethyl methacrylateserum

Teratogenic effects of polymethylmethacrylate cement at levels used during routine orthopaedic procedureshave never been reported, however the hypothetical risk remains a major concern among female surgeons.Our aim was to determine if methyl methacrylate is detectible in the serum during routine cement exposure.Methods: Twenty healthy volunteers were exposed during themixing of polymethylmethacrylate cement in asimulated operating room environment. Forty serum samples were obtained during the expected peakinhalational exposure and levels of methyl methacrylate were assessed utilizing headspace gas chromatog-raphy mass spectrometry. Results: Methyl methacrylate was not detected in any of the forty experimentalspecimens. Conclusions: With a detection level of 0.5 ppm, methyl methacrylate is undetectable in the serumduring routine mixing of polymethylmethacrylate cement.

s article can be found at http://

Orthopaedic Institute, Medical32-8774.

lished by Elsevier Inc.

Published by Elsevier Inc.

Polymethylmethacrylate (PMMA), commonly known as bonecement, is the synthetic polymer of methyl methacrylate (MMA). Ithas been commercially used since the 1930's in cast acrylic sheetmanufacturing. Its use in arthroplasty was popularized in the 1960'sby Sir John Charnley [1,2]. Questions continue to arise as to itscarcinogenic and teratogenic effects [3]. The American Conference ofGovernmental Industrial Hygienists (ACGIH) has established athreshold limit value (TLV) for methyl methacrylate of 100 ppm,meaning the time-weighted-average for a normal 8h workday and a40 h workweek to which nearly all workers may be repeatedlyexposed to methyl methacrylate without adverse effects [4]. Singhet al. in 1972 [5] studied the possible teratogenic effects of methylmethacrylate by exposing pregnant female rats to high levels ofmethacrylate esters via intraperitoneal injections. Analysis of fetusesshowed a dose-related increase in resorptions, gross and skeletalabnormalities, and a reduction in fetal weight. Though the increasein adverse effects was only minor when compared to controls, thislandmark article led to the generally accepted practice for pregnantoperating room personnel to leave the room during cementation.Even with later animal studies utilizing an inhalational exposurecloser to the recommended TLV showing no statistically significantdifference in resorptions, fetal weight, or external/visceral/skeletalmalformations [6,7], concerns among pregnant operating room

personnel still exist [3]. With an increasing number of femalesurgeons specializing in arthroplasty, leaving the room duringcementation is not possible. This growing dilemma is the impetusfor this study.

Linehan et al. [8] attempted detection of methacrylic acid (thehydrolyzed form of MMA) in their own serum following routine totaljoint arthroplasty using headspace gas chromatography. Seven totalserum samples were taken from 11 to 23min from initiation ofmixing. No MA was detectable in any of the samples. Based on ourreview of the literature showing peak concentrations of MMA in theair occurring before two minutes after the initiation of mixing, andpeak serum levels of MMA at 30s following IV administration and 2–3min in patients following cementation of implants in jointarthroplasty [6,9–14], it is felt that this study was limited by poortiming of blood draws in addition to small sample size. Thus, weaimed to increase the chances of detecting MMA in the serumfollowing routine mixing of PMMA cement by collecting the sampleswithin this expected early peak and increasing the sample size.

Materials and Methods

Following IRB approval, healthy volunteers aged 18–65 weresolicited through an email announcement to medical students andresidents at ourmedical center. Participants were excluded if they hadany significant medical comorbidity (specifically, a history ofpulmonary disease, to include asthma), were pregnant, or had ahistory of adverse reaction to PMMA. Twenty healthy volunteers (10male and 10 female) were divided into five groups of four. Informed

407K.C. Homlar et al. / The Journal of Arthroplasty 28 (2013) 406–409

consent was obtained from each participant. Height and weight wererecorded for each participant. Each female participant completed aurine dipstick pregnancy test.

The experiment was performed in a standard, non-laminar flowoperating room without the use of exhaust hoods and using an openmixing bowl technique. Each volunteer had a 23-gauge butterfly IVplaced by a registered nurse after donning routine universalprecaution operating room attire (mask, hat, gown, gloves). A groupof four participants surrounded a mixing bowl while the studyinvestigators mixed the PMMA cement (two bags of Stryker Simplex Pradiopaque bone cement) and timed blood draws (Fig. 1). Two bloodsamples of 5mL each were obtained from each participant. The firstsample was obtained 30s after the initiation of mixing and a secondsample at the three minute time point. Collecting serum sampleswithin three minutes after the initiation of mixing was chosen basedon our review of the literature showing peak concentrations of MMAin the air occurring before two minutes after the initiation of mixing,and peak serum levels of MMA occurring at 30s following IVadministration and 2–3min in patients following cementation ofimplants in joint arthroplasty [6,9–14]. Because the peak of MMAfollowing an inhalational exposure is unknown, we chose to drawblood samples at two different points within this 3min window,hoping to increase our likelihood of detection.

Blood samples were collected in BD Vacutainer tubes (5mL drawvolume, 13×100mm) and were immediately transported to the labfor processing. The samples were cold centrifuged at 4°C at 3000rpmfor 10min. Two mL of serum was then transferred to glass vialsdesigned to have minimal headspace. Each vial was closed with aTeflon septum and secured by a crimped aluminum cap. Care wastaken to keep the samples at 4°C until the very timing of transfer. Thevials were then immediately placed in a −57°C freezer until beingshipped on dry ice. Analysis of the serum samples was performedusing headspace gas chromatography mass spectrometry by JordiLabs LLC (Bellingham, MA), a lab with special expertise in this area.The analysis was run using a Tekmar 7000 equilibrium headspaceanalyzer, Hewlett Packard 5890 Series II gas chromatograph and a VG70SE magnetic scanning mass spectrometer with electron impactionization. The protocol for the collection, storage, transport andserum analysis via headspace gas chromatography has been previ-ously well described and accepted to detect MMA and MA[8,10,11,15]. To ensure accuracy of detection of MMA by this protocol,two serum samples from the author prior to the experiment and

MixeParticipant A

Participant C

18 in.

Ceme

Fig. 1. Schematic of experimental set up. The cement is mixed in the middle of the table by ainches from the cement. A nurse stands next to each participant to draw blood at 30s and

without any exposure to MMA or other everyday acrylic vapors werecollected, stored, and transported according to the study protocol toJordi Labs LLC, where they were spiked with 1 μg MMA and were re-analyzed, with a detection limit calculated to be 0.5ppm. Additionalcontrols were created using samples of water spiked with 1ppmMMA, again analyzed with detection limits calculated to be 0.5ppm,consistent within ±4%, which is presently considered to be theindustry standard.

Results

Both the serum and water control samples yielded the analytepeak ofMMA as expected, validating the experimental techniques andensuring no interference from the serum itself. No MMAwas detectedin any of the forty samples at the 0.5-ppm detection level. Three of theparticipants, including one of the authors and two registered nursesinvolved with the study, were exposed to fumes over the entire sixhour study period totaling six rounds of cement mixing. Theseparticipants assisted in collecting specimens for the first 5 rounds ofmixing and then became participants during the last round of mixing,having their blood drawn at the same 30s and 3min time points.These six samples thus effectively represented a cumulative exposure.These samples also had no detectable MMA (Fig. 2).

Discussion

Literature evaluating serum levels in patients and air and serumlevels in operating room personnel is limited. MMA has beenconsistently detected in the serum of patients undergoing total jointreplacements with peak levels at 2–3min after initiation of cemen-tation [10,11]. After intravenous administration of MMA in beagles,peak levels were seen at 30s and were nondetectable at 5min [9].Personal air sampling devices have been used to measure exposurelevels of MMA experienced by operating room personnel [6,12,13]with McLaughlin et al. [9] demonstrating concentrations never risingabove 280ppm with levels dropping rapidly to 60ppm two minutesafter mixing and to less than 10ppm six minutes after mixing. Onlyone animal study successfully detected MMA in serum following aninhalational exposure [15]. Linehan et al. [8] attempted detection ofmethacrylic acid (the hydrolyzed form of MMA) in their own serumfollowing routine total joint arthroplasty, but in the seven serum

r

Participant D

Participant B

nt

designated mixer while each participant sits at one corner of the table approximately 183min from the initiation of mixing.

2.6

2.1

1.4

0.7

Min.

m/z 41

Min.

m/z 41

Min.

m/z 41

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11 12 13 14

E3

6.6

2.1

1.4

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8.3

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E3

A

B

C

Fig. 2. Results of headspace gas chromatography/mass spectrometry. Representative example of control specimens (A) shows expected methyl methacrylate peak. A representativesample of a volunteer exposed to one round of mixing (B) and to all six rounds of mixing (C) shows no methyl methacrylate peak.

408 K.C. Homlar et al. / The Journal of Arthroplasty 28 (2013) 406–409

samples taken 11–23min from initiation of mixing, no MA wasdetectable in any of the samples.

Our study did not find evidence of MMA in the sera of twentyparticipants at either 30s or three minutes from the initiation ofmixing of PMMA cement under simulated operating room conditions.Nor was MMA detected in the sera of the three participants exposedthroughout the entire six hour study period. Results of this study aresimilar to findings previously reported in the literature. Though onestudy successfully detected MMA in the serum of rats afterinhalational exposure using headspace gas chromatography [15], nostudy has been able to detect MMA in the serum of humans after aninhalational exposure, despite at least two attempts [8,16]. Thus, thepeak of MMA via this route is unknown. Because of this, we chose thetiming of blood draws based on our review of the literature showing

peak concentrations of MMA in the air following mixing of PMMAcement occurring before two minutes after the initiation of mixing,and peak serum levels of MMA occurring at 30s following IVadministration and 2–3min in patients following cementation ofimplants in joint arthroplasty [6,9–14]. Ideally, the in vivo peakconcentration of MMA via an inhalation route would be established bydrawing samples at regular intervals during the entire exposure toensure the peak is captured. Even more informative would then be tocorrelate this peak concentration with measurement of breathingzone concentrations, however both of these investigations are costprohibitive and not feasible.

It is known that a certain percentage of volatile compounds will belost with each transfer to a new container prior to analysis viaheadspace gas chromatography mass spectrometry [17]. Every

409K.C. Homlar et al. / The Journal of Arthroplasty 28 (2013) 406–409

attempt was made to keep MMA in the liquid form and not in theheadspace to avoid loss with transfer (including keeping samples at4°C except to transfer, minimizing time the tube is open, etc.),however it is possible that this minute amount of loss was enough tokeep the levels below the detectable limits.

In summary, no human study has been able to detect MMA in theserum after an inhalational exposure. We also were unable to detectMMA in forty serum samples from twenty volunteers exposed toMMA vapors at anticipated peak inhalational exposure. These resultssuggest, in accordance with prior conclusions in the literature [18],that MMA in routine operating room exposure is rapidly metabolizedat the portal of entry. While we cannot definitively deem MMAexposure safe during pregnancy, this study confirms that the serumlevels of MMA after an acute exposure are less than 0.5ppm, thusmaking the likelihood of large enough concentration in the blood-stream to have any teratogenic effect on a developing fetus unlikely.This study was purposefully designed using non-laminar flow rooms,open bowl mixing technique (as opposed to vacuum mixing), andwithout the use of personal exhaust hoods to simulate a worst casescenario exposure. An additional margin of safety may be added bywearing a personal exhaust system, which was shown in one study tolower breathing zone concentrations to nearly zero [12]. This studyfocuses only on acute exposure. Though MMAwas not detected in thethree participants who were exposed to vapors the entire six hourstudy period, we cannot make any conclusions about serum levelswith prolonged exposure. It is hoped that this information can guideoperating room personnel; however, it remains the decision of eachindividual whether or not she remains in the operating room duringthe mixing of PMMA cement.

References

1. Charnley J. Anchorage of the femoral head prosthesis to shaft of the femur. J BoneJoint Surg 1960;42B:28.

2. Charnley J. Acrylic cement in orthopaedic surgery. Edinburgh, London: ChurchillLivingstone; 1972. p 1–131.

3. Keen RR, Hillard-Sembell DC, Robinson BS, et al. Occupational hazards to thepregnant orthopaedic surgeon. J Bone Joint Surg Am 2011;93 e141(1–5).

4. American Conference of Governmental Industrial Hygienists. Threshold limitvalues for chemical substances and physical agents. Cincinnati, OH: ACGIHWorldwide; 1996:112.

5. Singh AR, Lawrence WH, Autian J. Embryonic-fetal toxicity and teratogenic effectsof a group of methacrylate esters in rats. J Dent Res 1972;51:1632.

6. McLaughlin RE, Reger SI, Barkalow JA, et al. Methylmethacrylate: a study ofteratogenicity and fetal toxicity of the vapor in the mouse. J Bone Joint Surg Am1978;60:355.

7. Solomon HM, McLaughlin JE, Swenson RE, et al. Methyl methacrylate: inhalationdevelopmental toxicity study in rats. Teratology 1993;48:115.

8. Linehan CM, Gioe TJ. Serum and breast milk levels of methylmethacrylate followingsurgeon exposure during arthroplasty. J Bone Joint Surg Am 2006;88:1957.

9. McLaughlin RE, DiFazio CA, Hakala M, et al. Blood clearance and acute pulmonarytoxicity of methylmethacrylate in dogs after simulated arthroplasty and intrave-nous injection. J Bone Joint Surg Am 1973;55:1621.

10. Gentil B, Paugam C,Wolf C, et al. Methylmethacrylate plasma levels during total hiparthroplasty. Clin Orthop Relat Res 1993;287:112.

11. Svartling N, Pfaffli P, Tarkkanen L. Blood levels and half-life of methylmethacrylateafter tourniquet release during knee arthroplasty. Arch Orthop Trauma Surg1986;105:36.

12. Darre E, Jorgensen LG, Vedel P, et al. Breathing zone concentrations ofmethylmethacrylate monomer during joint replacement operations. PharmacolToxicol 1992;71:198.

13. Darre E, Hölmich P, Jensen JS. The use and handling of acrylic bone cement inDanish orthopaedic departments. Pharmacol Toxicol 1993;72:332.

14. Crout DH, Corkhill JA, James ML, et al. Methylmethacrylate metabolism in man: thehydrolysis of methylmethacrylate to methacrylic acid during total hip replacement.Clin Orthop Relat Res 1979;141:90.

15. Raje RR, Ahmad S, Weisbroth SH. Methylmethacrylate: tissue distribution andpulmonary damage in rats following acute inhalation. Res Commun Chem PatholPharmacol 1985;50:151.

16. Bereznowski Z. In vivo assessment of methyl methacrylate metabolism andtoxicity. Int J Biochem Cell Biol 1995;27(12):1311.

17. Gill R, Hatchett SE, Osselton MD, et al. Sample handling and storage for thequantitative analysis of volatile compounds in blood: the determination of tolueneby headspace gas chromatography. J Anal Toxicol 1988;12:141.

18. US Environmental Protection Agency. Toxicological review of methyl methacrylate.(CAS No. 80-62-6). In support of summary information on the integrated riskinformation system (IRIS). Research Triangle Park, NC; National Center forEnvironmental Assessment, Office of Research and Development, 1998.