36--Chemical Degradation of Wastes of Anti Neoplastic Agents Amsacrine Azathioprine Asparaginase and Thiotepa

8/4/2019 36--Chemical Degradation of Wastes of Anti Neoplastic Agents Amsacrine Azathioprine Asparaginase and Thiotepa

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PergamonPI I: S0003-4878(98)0 0023-^

Ann. occup. Hyg.. Vol. 42. No. 4. pp. 259-266. 1998r 1998 British Occup ational H ygiene SocietyPublished by Elsevier Science Ltd. All rights reservedPrinted in Great Britain0003^)878-98 S19.00+0.00

Chemical Degradation of Wastes of AntineoplasticAgents Amsacrine, Azathioprine, Asparaginase andThiotepaJ. BAREK*, J. CVACKA*, J. Z IMA *, M. rDE MEOt, M. LAGETt,J. MICHELON+ and M. CASTEGNAROtfDegartment of Analytical Chemistry, Charles UniversiJj>J\28 43 /Prague, Czech Republic^ FaculteaePharmacie, Marseille, France; \lnternational Agency for Research on Cancer, Lyon, France

/ A s a part of a program devoted to the destruction of an tineoplastic agen ts, three chemical methodsreadily available in the hospital environment, viz. oxidation with sodium hypochlorite (NaCIO,5%), hydrogen peroxide (H 2O 2, 30%), and Fenton reagent (FeCl2 2H 2O; 0.3 g in 10 ml H 2O 2,30%), were tested for the degradation of four anticancer drugs: Amsacrine, Azathioprine, Aspa-raginase and Thiotepa. The efficiency of the degradation was monitored by high-performanceliquid chromatography. The mutagenicity of the degradation residues were tested by Ames testusing tester strains Salmonella typhimurium TA 97 a, TA 9 8, TA 100 and TA 102 with and withoutan exogenous metabolic activation system. Using sodium hypochlorite, 98.5% of Amsacrine,99.0% of Azathioprine, 99.5% of Asparaginase and 98.7% of Thiotepa were destroyed after 1 hr.The hydrogen peroxide treatment destroyed 99% of Asparaginase and 98.7% of Thiotepa in 1 hr.However, this procedure was not efficient for the treatment of Amsacrine (28% after 16hr) andof Azathioprine (53% degradation in 4 hr). The action of Fenton reagent resulted in the destructionof 98 % of Amsacrine, and 99.5% of Azathioprine, 98.5% of Asparaginase and 98.7% of Thiotepain 1 hr. In all cases where a high degree of degradation was achieved, the residues obtained werenon mutagenicJ 1998 British Occupational Hygiene Society. Published by Elsevier ScienceLtd. All rigTitsreserved.

INTRODUCTIONSeveral cytostatic drugs have been shown to be muta-genic, leratogenic and carcinogenic in experimentalsystems (Sorsa et al., 1985). A number of cytostaticdrugs have been classified by the International Agencyfor Research on Cancer (IARC, 1994) as human car-cinogens (group I) , probable human carcinogens(group 2A) or possible human carcinogens (group2B). Among the four compounds considered in thisstudy Thiotepa has been classified in group I whilethe others have not yet been evaluated by the IARCworking group. Thus, hospital personnel handlingthese drugs may have an occupational risk. Inhalationand skin absorption are the main routes of con-tamination in unprotected individuals. Inhalationmay occur by formation of aerosols during drug prep-arations. Skin absorption occurs by direct contactwith the compounds, after spillage and during the

Author to whom correspondence should be addressedJTel.:+ 420-2-2195 2295, Fax: +420-2-24913538. E-mail^Sjrek(a . prfdec.natur.cuni.S7Received 3 October 1997; in final form 6 February 1998

handling of biological fluids of patients undergoingchem otherapy (see De Meo et al. (1995) and referencestherein). Numerous references reporting the risks ofexposure of pharmacy, nursing and other hospitalpersonnel to these mutagenic drugs can be found inour previous paper (Hansel et al., 1997). Possibleadverse health effects caused by the handling of thesedrugs have been reviewed (Rousselin and Stucker,1990). Hospital staff or family members handling theexcreta from patients treated with antineoplasticdrugs or equipment contaminated by these excreta,such as urinals and chamber pots, may be moreheavily exposed to the drugs or their metabolites thantrained hospital nurses or pharmacists (Guinee et al.,1991; Cass and Mu sgra ve, 1992; Sessink el al., 1992).The handling of these drugs, in pure form or in solu-tion, generates residual amounts of cytotoxic solu-t ions, which should not be discarded in the domesticsewage system w ithout prior inactivation. In 1979, aprogram for the development of chemical methods forthe treatment of wastes contaminated with chemicalcarcinogens was initiated by the International Agencyfor Research on Cancer, with the support of the Office

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26 0 J. Barek el al.of Safety of the National Institutes of Health (IARC,1979). In 1985, antineoplastic drugs were considered,in this program (Castegnaro et al., 1985). Since then,several publications have been issued (Barek et al..1987; Monteith et al., 1987; Lunn et al., 1989;Benvenuto et al., 1993; Allwood and W righ t, 1993)describing the destruction of antineoplastic drugsusing acids or strong oxidising agents, such as pot-assium permanganate, which are not consideredacceptable by hospital staff. A new program was thusinitiated by IARC with the support of the FrenchMinistry of the Environment and of the NationalInstitutes of Health to systematically investigate theefficiency of 5% sodium hypochlorite and 30% hydro-gen peroxide in the degradation of 36 antineoplasticagents. (These two reagents were indicated acceptablein a survey conducted among the nurses, pharmacistsand members of the Hygiene and Safety Committeeof the Hospitals of Montpellier (France)). Five lab-oratories from France, the Czech Republic and theUnited States were involved in the testing of theefficiency of degradation of these compounds and ofthe residues for mutagenic activity. So far, the resultsof destruction of cyclophosphamide, ifosfamide andmelphalan (Hansel el al., 1997) and of six anthra-cyclines (Castegnaro et al. (1997) submitted for pub-lication) using sodium hypochlorite, hydrogen per-oxide and Fenton reagent were reported. This paper isdevoted to the degradation of residual pharmaceuticalsolutions contaminated by Amsacrine, Azathioprine,Asparaginase and Thiotepa. As in the previous IARCinvestigations, the effectiveness of the degradation orinactivation methods was determined by HPLC formonitoring the disappearance of the parentcompound. Mutagenicity was then chosen as an indi-cator of potential toxic or genotoxic effects of thedegradation products .

Amsacrine is an acridine-like intercalating agent[see Fig. l(a)] currently used as a chemotherapeuticagent for the treatment of acute leukaemia and solidtumours. Therapeutic activity was seen in Hodgkin'sdisease, hepatoma and epidermoid carcinoma of theoesoph agus. Azathioprine is an im munosu ppressantand antineoplastic agent [see Fig. l(b)] with similaraction to those of mercap topurine to which it is slowlyconv erted in the body . Its main use involves the im mu-nosup pressing properties. Asparaginase is a thera-peutic enzyme mainly used in combination with otheragents in the treatment of acute lymphatic leukaemia.Thiotepa is a polyfunctional alkylating agent [see Fig.l(c)] mainly used in the treatment of adenocarcinomaof the breast and of the ovary, and of superficial pap-illary carcinoma of the bladder. It is also used forcontrolling intracavity efTusions secondary to diffuseor localised neoplastic diseases of various serosal cavi-ties and has been found effective against lympho-sarcoma and Hodgkin's disease.The three above mentioned methods, based ontreatment with sodium hypochlorite, hydrogen per-oxide and Fenton reagent were investigated on: (1)

a)

NHSO2CH3

N O r

NCH NH

c)C H , - C H -

CH--W N ^ C H -IN P

CH

Fig. I. Structures of Amsacrine (a). Azathioprine (b) andThiotepa (c)

aqueous solutions of Amsacrine formulation(0.15mg/ml) in 5% [>glucose; (2) aqueous solutionsof Azathioprine formulation (2mg/ml) in 5% n-glucose; (3) aqueous solutions of Asparaginase for-mulation containing 200 I.U. of Aspara ginase . 1.6 mgof mann itol an d 45 mg of D-glucose per 1 ml and (4)aqueous solutions of the Thiotepa formulation(0.016mg/ml) in 5% D-glucose.

MATERIALS AND METHODSWarningSeveral antineoplastic agents are carcinogenic tohumans (Thiotepa has been classified in group I byIARC) and must be handled with great care. Appro-priate precautions must be taken and protective cloth-ing such as latex gloves, eye goggles and laboratorycoat must be worn.ReagentsReference compounds. Amsacrine (as a solution inanhydrous N.N -dimethylacetam ide containing 50 mgof Amsacrine per I ml) was obtained from Nation alCancer Institute (Bethesda, Maryland, U.S.A.). Thereconstitution solution conta ining 5 mg ml of Amsa-crine in 10% v v of N.N-dimethylacetamide and 0.318

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Chemical degradation of wastes of antineoplastic agents 261mol/1 L-lactic acid was prepared according to a pre-scribed p roc edu re, i.e. by injecting 1.5 ml of the sup-plied solution of Amsacrine (50mg/ml in anhydrousN.N -dim ethylac etam ide) into the 13.5 ml of suppliedsterile diluent (0.0353 mol/1 L-lactic acid). Stock solu-tion of Amsacrine (0.15mg/ml of Amsacrine in 5% D-glucose) was prepared by diluting 3 ml of recon-stitution solution with 5% a queo us solution of D-glucose to 100 ml. The stock solution was kept at 4 C.All destructions were carried out within 4 hours afterthe preparation of the stock solution.

Azathioprine formu lation (as the disodium salt) wasobtained from Burroughs Wellcome Co. (ResearchTriangle Park, NC, U.S.A.). Stock solution (2mg/mlof Azathioprine in 5% D-glucose was prepared bydissolving 100 mg of A zathiop rine in 50 ml of 5%solution of D-glucose in deionised water. The stocksolution w as kept at 4C. All destructions were carriedout within 24 hours after the preparation of the stocksolution.Asparaginase (as a white powder containing10000 l.U. of Asparagin ase and 80m g of mannito lper vial) was obtained from Merck, Sharp Dome(West Point, PA, U.S.A.). Asparaginase was dissolvedby injecting 5 ml of deionised wate r into the vial, giv-ing rise to solution containing 2 000 l.U. and 16 mg ofmannitol per 1 ml. Stock solution containing 200 l.U.of Asparag inase, 1.6 mg of man nitol and 45 mg of D -glucose per 1 ml was prepared by exact 1/10 dilutionof the initial solution with solution of 5% D-glucosein deionised water. All destructions were carried outwithin 4 hours after the preparation of the stock solu-

tion.Thiotepa as a lyophilised powder was supplied byLederle Laboratories Ltd. Stock solution containing0.06mg/ml in 5% D-glucose was prepared by dis-solving 3m g of T hiotep a in 50 ml of 5% solutionof glucose in deionised water. All destructions werecarried out within 24 hours after the preparation ofthe stock solution.Reagents for degradation. Sodium hypochlorite (5 %aqueous solution) and hydrogen peroxide (30% aque-ous solution) were obtained as commercial products.FeCl , 2H 2O was purchased from Merck (Darmstadt,Ger ma ny). Fenton reagent (0.3 g of FeC I2-2H 2O per10 ml of 30% H 2O 2) was prepared in situ. Solutionsof sodium hypochlorite and hydrogen peroxide werestored in well-filled airtight containers at a tem-perature not exceeding 20'C and were protected fromlight. Their activity was tested prior to use as describedby Castegnaro et al. (1991) for the sodium hypo-chlorite and in Pharmacopee Francaise (1992) forhydrogen peroxide.Other reagents. Methanol, acetonitrile. triethyl-

amine phosphate, potassium dihydrogenphosphate,glacial acetic acid, sodium hydroxide, disodium saltof ethylenediamine tetraacetic acid (used in HPLCmonitoring of the efficiency of the degradation) werepurchased from Merck (Darmstadt, Germany).

Apparatus and HPLC conditionsHPLC system. LKB 2150 HPLC pump (Bromma,Sweden) equipped with LKB 2151 Variable Wave-length Monitor, LCI 30 injection valve with a 20^1loop (Laboratorni pfistroje, Prague, Czech Republic),and PC integrator INCOM (Labio, Prague, CzechRepublic) sup ported with Xerius DX 386 33 M Hzcomputer (CS2I, Prague, Czech Republic).HPLC conditions. Amsacrine: The HPLC procedurewas a modified version of the technique of Jurlina andPaxton (1983). Briefly, the analyses were performedon a reversed-phase C18 analytical columns (Tessek,Pragu e, Czech Repub lic, particle size 5//m; 150 mmlong x 3 mm i.d.) using isocratic conditions. Degra-dation with sodium hypochlorite and hydrogen per-oxide were monitored using the mobile phase ace-tonitr ile-water-aqueous 1M triethylamine pho sphate

(60 + 4 0 + 1). The pH of this mobile phase was 3.5 andthe flow rate w as maintained at 0.5 ml/m in. Degra -dation with Fenton reagent was monitored usingmobile phase methanol0.025M KH 2PO 4glacialacetic acid (20 + 79.5 + 0.5). The pH of this m obilephase was 4.5 and the flow rate was maintained at0.4 ml/m in. UV detection at 270 nm was used t hro ugh -out. Under these conditions. Amsacrine had a reten-tion time of 5.5 minutes.

Azathioprine: The HPLC procedure was a modifiedversion of the method of Fell et al. (1979). Briefly,the analyses were performed on a reversed-phase C18analytical columns (Tessek, Prague, Czech Republic,partic le size 5/


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262 J. Barek el al.cratic condit ions with 0.1M KH,PO 4 solution indeionised water adjusted with 2 M sodium hydroxide(NaOH) to pH 6.9 as a mobile phase. The flow rate of0.8m l/min and UV photom etr ic detection at 210 nmwas used throughout. Under these condit ions. Aspa-raginase had a retention time of 2.1 minutes.

Thiotepa: HPLC procedure was a modified versionof the technique of Tinsley el al. (1889). Briefly, theanalyses were performed on a reversed-phase C18 ana-lytical columns (Tessek, Prague, Czech Republic, par-ticle size 5/


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Chemical degradation of wastes of antineoplastic agents 263RESULTS AND DISCUSSION

HPLC analysisUnder the above mentioned analytical conditions,the limits of detec tion based on a 3 fold signal to

noise ratio were: Amsac rine, 0.1 /(g/ml; Aspara ginase,0.5I.U./ml; Thiotepa, 0.5/ 9 8 . 7 % .

mV a "j200 I'e.

I 1 /1 0 0 I ' '

0 2 4 6 min 10 20 minm V200 .

2 4 mir 10 minFig. 2. Ch rom atog ram s of degradation with sodium hypoch lorite. [2a] Am sacrine solution degraded for 2h before (1) andafter (2) addition of stand ard so lution of Amsacrine correspon ding to 1 % of the originally present am ount ; [2b] Azathio prinesolution degraded for 16 h before (I) and after (2) addition of standard solution of Azathio prine correspon ding to 0.5 % ofthe originally present amount. [2c] Asparaginase solution degraded for 1 h before (I) and after (2) addition of standardsolution of Asparaginase co rrespondin g to 0.5% of the originally present amou nt. [2d] Thiotepa solution deg raded for 1 hbefore (1) and after (2) addition of standard solution of Thiotepa corresponding to 5% of the originally present amount. Anarrow indicates the position of the peak of the tested substance.

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264 J. Barek el al.Degrad ation with hydrogen peroxide

Amsacrine: From the comparison of the area of thetreated and spiked solutions, it was calculated thatonly 15% of Amsacrine was destroyed after 4hr and28 % after 16 hr. Therefore, the method was notefficient for practical purposes and mutation assayswere not performed.

Azathioprine: From the comparison of the area ofthe peaks of the treated and spiked solutions it wasdetermined that only 53% of Azathiop rine wasdestroyed af ter 4hr and 65% after 16 hr. Therefore,the method is not efficient enough for practical pur-poses and mutation assays were not performed.Asparaginase: No peak of Asparaginase at retentiontime 2.1 min could be detected in the solution after 1 hrdegradation with hydrogen peroxide [see Fig. 3(a)]. Inthe solution after the standard addition of Aspa-raginase corresponding to I % of the original amountof this substance this peak could be detected [see Fig.

3(a)]. It can be calculated from the signal to noiserati o at the re ten tion time 2.1 min tha t the limit ofdetection of Asparaginase un der these condit ions cor-responds to 1% of the amount of Asparaginase orig-inally present in the solution prior to degradation.Therefore, it can be concluded that the efficiency ofthe deg rada tion is at least 99.0% . (The real value ofthe degree of degradation is probably even higher,the above given value being affected by the limit ofdetection of our analytical method). It was againnecessary to adjust the pH to 7 after the d egrad ationfor the above explained reasons.

Thiotepa: Again, no peak of Thiotepa can be

10 0

4 minmV200100o

b--

nII1

10 mirFig. 3. Cn rom atog ram s oi degradation wun nyarogenperoxide. [3a] Asparaginase solution degraded for I h before(I) and after (2) addition of standard solution of Aspa-raginase corresponding to 1% of the originally presentamount. [3b] Thiotepa solution degraded for 1 h before (I)and after (2) add ition of stand ard so lution of Thi otep acorresponding to 10% of the originally present amount.An arrow indicates the position of the peak of the testedsubstance.

detected in the solution after destruction without theadjustment of pH to 7. However, the peak of Thiotepaafter the standard addit ion corresponding to 50% ofthe originally present amount of Thiotepa could noteither be detected. Possible explanation is again thelack of stability of Thiotepa in the solution afterdestruction. When the pH of the solution afterdestruction was adjusted to 7, we were able to detectthe standard addit ion corresponding to 10% of theoriginally present amount of Thiotepa [see Fig. 3(b)].Because the peak of Thiotepa in the solution afterdestructio n was not detectable an d in view of the limitof detectability of Thiotepa it was concluded that atleast 98.7% was degraded by this procedure.

Degradation bv Fenlon reagent. Amsacrine: Fromthe comparison of the area of the peak of the solutionafter destruction and after addition of the spike itwas calculated that ca 98% of the Amsacrine wasdestroyed after 30 minutes and 99.5% after 16 hr [seeFig. 4(a)].Azathioprine: No peak at retention time cor-responding to Azathioprine. The spike correspon dingto 0.5% of the original amounts resulted in a peakeasily discernible from the noise [see Fig. 4(b)]. There-

fore, it can be concluded that at least 99.5% of theoriginally present Azathioprine was destroyed.Asparaginase: No peak was detectable at retentiontime of Asparaginase after degradation with Fentonreagent [see Fig. 4(c)]. In the solution after the stan-dard addit ion of Asparaginase corresponding to 2%of the original amount of this substance this peakcould be detected [see Fig. 4(c)]. It was therefore cal-

culated from the signal to noise ratio at the retentiontime that the limit of detection of Asparaginase underthese condit ions corresponds to 2% of the amount ofAsparaginase originally present in the solution priorto degradation. Therefore, it can be concluded thatthe efficiency of the degradation is at least 98%>. (Thereal value of the degree of degradation is probablyeven higher, the above given value being affected bythe limit of detection of our analytical method). Itwas again necessary to adjust th e pH to 7 after thedegradation for the above explained reasons.Although the adsorption of Asparaginase on freshlyprecipitated ferric hydroxide cannot be completelyruled out, the results of mutagenicity testing (see fur-ther) confirm the absence of Asparaginase in the solu-tion after destruction.

Thiotepa: No peak of Thiotepa was detectable inthe solution after destruction at retention time cor-responding to Thiotepa [see Fig. 4(d)]. The standardaddit ion corresponding to 50% of the originally pre-sent amount of the substance does not give any peak,either. As in the previous cases, instability of Th iotepain the solution after destruction is a possible expla-nation. The method is probably very efficient.However, the efficiency ca nn ot b e checked by the stan-dard addition method. The pH of the solution afterdestruction cannot be adjusted to 7 because of ironoxides precipitation.

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Chemical HeoraHnHnn nf wastes of antineoplastic agents 265mV200

100I i

0 ^ 2.5 5 minmV150

0

150

b-

-

1

10 20 minm V300

200100

c

t4 min

mV dr~l200 -

100 -

10 minFig. 4. Chromatograms of degradation with the Fentonreagent. [4a] Amsacrine solution degraded for 16 h before (I)and after (2) addition of standard solution of Amsacrinecorresponding to l% of the originally present amount; [4b]degraded Azathioprine solution before (I) and after (2)addition of standard solution of Azathioprine correspondingto 0.5% of the originally present amou nt. [4c] Asparaginasesolution d egrade d for I h before (I) and after (2) additio n ofstandard solution of Asparaginase corresponding to 2% ofthe originally present am oun t. [4d] Thiotepa solutiondegraded for 1 h before (I) and after (2) addition of standardsolution of Thiotepa correspo nding to 10% of the originallypresent amou nt. An arrow indicates the position of the peakof the tested substance.

Mulagenicity test performanceFor each compound an initial reaction time of onehour was adopted to measure the efficiency of the

degradation. When incomplete destruction wasnoticed the reaction time was lengthened. When com-plete degradation was achieved, samples were pre-pared for mutagenicity testing by the removal of the

oxidant using addition of solid sodium bisulphite andneutralisation with concentrated hydrochloric acid.These reactions were performed on ice to avoid anexothermic reaction.Throughout this s tudy, the background of spon-taneous revertants/plate were: (i) TA 97a ( S9,

189 + 28 ; + S9 , 190 2 4 ) , ( i i ) TA 98 ( -S9, 26 8 ;+ S9 , 33 + 7) , ( ii i) TA 100 ( - S 9 , 122+1 9; +S 9,1232 0) ,( iv)TA 102 ( - S 9 , 337 + 37; + S9,364 + 44).

The response to the positive controls were: TA 97a(20 ng IC R 191) 2625 + 304 reverta nts per p late; T A98 (20 ng 2,4,7-TNFone) 725 +14 3 revertants perplate; TA 100 (0.5/(g sodium azide) 564 + 63 revert-ants per plate; TA 102 (20 ng m itomycine C)3315 + 321 revertants per plate. The positive controlsfor S9 mix included (TA 97 + 0.5/(g benzo[a]pyrene)1170 + 241 reve rtant s per plate , (TA 98 + 0.5/


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26 6 J. Barek et al.

The results obtained indicate that Thiotepa andAsparaginase quickly decompose under acidic con-ditions which offers another possibility for theirdestru ction. This possibility will be further studied.This investigation is being extended to decon-tamination of faeces and blood plasma and to furtherantineop lastic agents used in cancer treatment and thenew results will be published as soon as the exper-imental data are available.Acknowledgements T his work was performed w ith the sup-port of the French Ministry of the Environment under con-tract N" 93038. The authors would also like to thank theU.S. Natio nal Insti tutes of Health and all the pha rmace uticalcompanies which participated by providing the necessarydrugs and formula tions for this investigation. JB. JC and JZthan ks the G ran t Agency of Charles University for financialsupport (grant no. 150/94).

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36--Chemical Degradation of Wastes of Anti Neoplastic Agents Amsacrine Azathioprine Asparaginase and Thiotepa