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1 2015; 57 (6): LC/MS P- 5 ml 2 1 ml LC/MS P % % % % 10 / logp ow 1 P J-STAGE tak-t1924@outlook.jp ; 57(6): doi: /sangyoeisei.B15004 Anti-cancer drugs, Hospital contamination, LC/MS, Smear method I. 1 1) NIOSH 2) IARC 3) Group 1 Group 2A Group 2B Group 3 Falck 4) 1979

3 11% 10 / logp ow 1 P- 9 2015 3 9 2015 7 7 J-STAGE 2015 8 12 487-8501 1200 e-mail:

2 ) ) 9) ) Sessink 11) GC/MS 12) 0.03M JK 13) HPLC 1.5 ng/100 cm 2 14) 10 LC/MS II 1. HPLC Whitehouse Station, NJ. USA Saint Louis, MO. USA 98.0% HPLC Tokyo Japan 79.0% Tokyo, Japan 10 Fig Tokyo, Japan Tokyo, Japan Tokyo, Japan New York, NY. USA Tokyo, Japan Osaka, Japan Indianapolis, IN. USA 5- Osaka, Japan LC/MS 5C, 110 mm, ADVANTEC, Tokyo, Japan Osaka, Japan Osaka, Japan DISMIC-13HP, ADVANTEC LC/MS Alliance2695/Micromass ZQ Waters, Milford, USA LC/MS Table 1 L-Column2 ODS Tokyo, Japan TSK-GEL Amide-80 Tokyo, Japan 8 L-Column2 ODS 2 TSK-GEL Amide-80 HILIC

1 10 9 10 Tokyo, Japan Tokyo, Japan Tokyo, Japan New York, NY. USA Tokyo, Japan Osaka, Japan Indianapolis, IN. USA 5- Osaka, Japan 10 2.

3 277 Fig. 1. Chemical structures, molecular weights and logp ow values of the anti-cancer drugs. ESI SIM 1 ml LC/ MS 3. Fig. 2 P mg/l 10 µl % v/v 5 ml 40 C 10 2 III. 1. P- P- Table 2 Table 2 MDL Carolyn 15) MDL = t (a) σ t (a): 5% t σ : logp ow

4 Table 1. Measurement conditions of LC/MS LC Conditions MS Conditions Equipment : Waters alliance 2695 Equipment : Waters micromass ZQ Column : L-column2 ODS, mm, 3 µm Ionization mode : ESI-Positive (L-column2 ODS) (except fluorouracil and gemcitabine) TSK-gel Amide-80, mm, 3 µm (fluorouracil and gemcitabine) ESI-Positive and Negative (TSK-gel Amide 80) Mobile phase of L-column2 ODS : Capillary voltage : 3 kv A : 0.1% (v/v) formic acid in Water Source temperature : 100 C B : Methanol Desolvation temperature : 300 C C : Acetonitrile Cone gas flow : 60 L/Hr 0 2 min A : 98% B : 1% C : 1% Desolvation gas flow : 600 L/Hr 2 6 min A : 98% 0% B : 1% 80% C : 1% 20% Monitor Ion : (paclitaxel, Positive) 6 20 min A : 0% B : 80% C : 20% (vincristine, Positive) min A : 0% 98% B : 80% 1% C : 20% 1% (docetaxel, Positive) min A : 98% B : 1% C : 1% (vinorelbine, Positive) Mobile phase of TSK-gel Amide-80 : (irinotecan, Positive) A : 0.1% (v/v) formic acid in Water (methotrexate, Positive) B : Acetonitrile (oxaliplatin, Positive) 0 2 min A : 10% 50% B : 90% 50% (gemcitabine, Positive) 2 11 min A : 50% B : 50% (cyclophosphamide, Positive) min A : 50% 10% B : 50% 90% (fluorouracil, Negative) min A : 10% B : 90% Flow : 0.2 ml/min Column oven temperature : 40 C Injection volume : 10 µl Fig. 2. Analysis scheme of the anti-cancer drug residues. 9 P- 50% 10% 40% 10% 45 82% 15% 20% % 9 10% P- 19% 15% 4. 2 P- t 5% Table 3 10%

0 150 mm, 3 µm (fluorouracil and gemcitabine) ESI-Positive and Negative (TSK-gel Amide 80) Mobile phase of L-column2 ODS : Capillary voltage : 3 kv A : 0.

5 279 Table 2. Smear recoveries of the anti-cancer drugs spread on a P-tile with cellulose filter paper and polypropylene nonwoven (n=7) Recovery (%) (SD (%)) MDL* Recovery (%) (SD (%)) with cellulose filter paper (ng) with polypropylene nonwoven MDL* (ng) vincristine** 45 (16) (9.6) 6.7 oxaliplatin** 82 (19) (3.1) 0.8 gemcitabine** 73 (15) (1.5) 0.3 fluorouracil** 18 (2.8) (2.4) 7.8 paclitaxel*** 85 (13) (13) 26 docetaxel*** 38 (10) (5.5) 7.9 vinorelbine*** 15 (2.6) (1.8) 1.4 irinotecan*** 23 (4.0) (2.7) 2.3 methotrexate*** 18 (3.5) (7.5) 5.3 cyclophosphamide*** 42 (9.6) (6.2) 10 *5% error. **by smearing P-tile surface with cellulose filter paper. ***by smearing P-tile surface with polypropylene nonwoven. Table 3. t-test results comapiring anti-cancer drug recoveries from a P-tile between the smearing analysis and the rinsing analysis t value* p value** paclitaxel docetaxel vincristine vinorelbine irinotecan methotrexate oxaliplatin gemcitabine cyclophosphamide fluorouracil *t = {(recovery in the smearing analysis) (recovery in the rinsing analysis)} / [{(population variance in the smearing analysis recovery) ^2 / (number of samples in the smearing analysis)} + {(population variance in the rinsing analysis recovery) ^2 / (number of samples in the rinsing analysis)}] ^0.5. **5% error degree of freedom = (number of samples in the smearing analysis) + (number of samples in the rinsing analysis) 2. Table 4. Smear recoveries of the anti-cancer drugs from a stainless steel plate with cellulose filter paper and polypropylene woven (n=3) Recovery (%) (SD (%)) with cellulose filter paper with polypropylene nonwoven paclitaxel* 75 (5.2) 54 (17) docetaxel* 83 (6.8) 79 (7.8) vincristine* 74 (11) 66 (14) vinorelbine* 35 (2.9) 17 (0.42) irinotecan* 51 (6.6) 23 (0.17) oxaliplatin* 74 (6.1) 59 (8.9) gemcitabine* 111 (9.4) 32 (0.69) cyclophosphamide* 81 (2.8) 71 (6.5) fluorouracil* 47 (1.3) 22 (4.9) methotrexate** 29 (1.6) 61 (4.7) *by smearing stainless steel plate surface with cellulose filter paper. **by smearing stainless steel plate surface with polypropylene nonwoven Table 4 P- IV P- OH OH %

(ng) with polypropylene nonwoven MDL* (ng) vincristine** 45 (16) 14 36 (9.6) 6.7 oxaliplatin** 82 (19) 30 13 (3.1) 0.8 gemcitabine** 73 (15) 21 10 (1.5) 0.3 fluorouracil** 18 (2.8) 1.0 13 (2.4) 7.

6 Fig. 3. Comparison of anti-cancer drug recoveries from a P- tile by rinsing and smearing with cellulose filter paper and polypropylene nonwoven. Fig. 4. Comparison of anti-cancer drug recoveries from a stainless steel plate by rinsing and smearing with cellulose filter paper and polypropylene nonwoven. 3 20% P- logp ow 2 logp ow 10 logp ow logp ow 2. P- P- Fig. 3 P- 40% P- P- P- 4 P- 18% 37% P- Fig. 4 50% % 2

7 281 Fig. 5. Correlations of three elements. Recoveries from P-tile by smearing; π electrons and amine-n, except that in aromatic rings, and low reactivity of lone-pair electrons /molecular weights of anti-cancer drugs. 3. P- P- Fig. 5 P- Fig P- P % - P- N N N 1 P- 101% 83% 98% 102% 80% P- 853 P- 261

aromatic rings, and low reactivity of lone-pair electrons /molecular weights of

8 P- 80% P- 74% 68% Table 3 t Fig. 1 a b 2 P- P- P- 110% P- P- 2 2 P- 2 2 OH P- 3 4 P % P % P- P- 80% 35% P- - P- 4 P- 18% P- 37% 54% 5 P % 5 47% 93% P- P- P- 100% P- P

45% P- 42 50% 454 825 P- P- 80% 35% P- - P- 4 P- 18% P-

9 283 Table 5. Extraction recoveries of the anti-cancer drugs added to cellulose filter paper, polypropylene nonwoven, quartz fiber filter and Kimwipe Recovery (%) (SD (%)) cellulose filter paper polypropylene nonwoven quartz fiber filter nylon filter paper Kimwipe paclitaxel 61 (11) 89 (9.0) 27 (9.1) 64 (3.9) 66 (7.0) docetaxel 60 (5.4) 110 (4.0) 57 (4.4) 90 (6.5) 104 (2.6) vincristine 85 (11) 69 (5.0) 72 (3.4) 67 (8.0) 104 (18) vinorelbine 78 (4.6) 53 (1.4) 38 (3.5) 20 (2.9) 33 (3.0) irinotecan 30 (7.6) 67 (2.5) 61 (5.3) 61 (2.0) 84 (5.6) methotrexate 34 (1.7) 69 (6.0) 27 (4.3) 70 (5.5) 25 (1.0) oxaliplatin 73 (12) 64 (5.5) 44 (9.0) 7.5 (0.70) 79 (1.3) gemcitabine 69 (12) 40 (2.9) 57 (4.6) 5.9 (0.22) 40 (11) cyclophosphamide 66 (6.5) 79 (5.4) 66 (3.8) 70 (3.2) 99 (0.33) fluorouracil 54 (1.2) 36 (5.1) 64 (9.2) 16 (1.2) 33 (1.9) number of experiments n=5 n=5 n=3 n=3 n=3 1 QR-100 ADVANTEC Nylon Membrane Darmstadt Germany 200 Tokyo, Japan mg/l 10 µl 0.01% Table 5 logp ow logp ow logp ow logp ow logp ow 3 logp ow 2 50 C C L- 4- LC/MS 4- V. LC/MS P % % % % UV MS 2 3 MS MDL UV 2 1) ND 5-FU < 20 ng/ml

nonwoven quartz fiber filter nylon filter paper Kimwipe paclitaxel 61 (11) 89 (9.0) 27 (9.1) 64 (3.9) 66 (7.0) docetaxel 60 (5.4) 110 (4.0) 57 (4.4) 90 (6.5) 104 (2.6) vincristine 85 (11) 69 (5.

10 ND 3,200 ng MDL 7.8 ng MDL 3 MS 16) MDL 16 ng GC/MS/MS 10 ng LC/MS/MS 10 MDL 10 ng MDL 9 MDL 1 17) 80% BD Phaseal TM Becton, Dickinson and Company, Franklin Lake, New Jersey 16) BD Phaseal TM 18) 1) 2012; 3: ) Natl. Inst. for Occup. Saf. and Heal. (NIOSH). Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. ALERT DHHS (NIOSH). 2004; No ) Int. Agency for Res. on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC. [Online]. [cited 2014 Oct 23]; Available from: URL: monographs.iarc.fr/eng/classification/index.php 4) Falck K, Gröhn P, Sorsa M, Vainio H, Heinonen E, Holsti LR. Mutagenicity in urine of nurses handling cytostatic drugs. Lancet 1979; 1: ) Sessink PJM, Kroese ED, van Kranen HJ, Bos RP. Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide. Int Arch Occup Environ Health 1995; 67: ) Sorsa M, Anderson D. Monitoring of occupational exposure to cytostatic anticancer agents. Mutat Res 1996; 355: ) Sugiura S, Asano M, Kinoshita K, Tanimura M, Nabeshima T. Risks to health professionals from hazardous drugs in Japan: a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide. J Oncol Pharm Pract 2011; 17: ) 2005; 47: ) 2014; 22: ) ; 5. 11) Sessink PJM, Scholtes MM, Anzion RBM, Bos RP. Determination of cyclophosphamide in urine by gas chromatographymass spectrometry. J Chromatogr 1993; 616: ) 2010; No.40: ) Yakugaku Zasshi 2010; 130: ) 2011; 37: ) Carolyn J. Oblinger Childress, William T. Foreman, Brooke F. Conner and Thomas J. Maloney. New Report. Procedures Based on Long-Term Method Detection Levels and Some Considerations for Interpretations of Water-Quality Data Provided by the U.S. Geological Survey National Water Quality Laboratory. U.S. GEOLOGICAL SURV. Reston, Virginia. Open-file Rep (US Geol Surv) 1999; ) 2013; 28: [Online]. [cited 2009 Mar 31]; Available from: URL: 18) Phaseal system ; 287.

2) Natl. Inst. for Occup. Saf. and Heal. (NIOSH). Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. ALERT DHHS (NIOSH). 2004; No.2004 165. 3) Int.

11 285 A smear method for measuring anti-cancer drugs residues in hospitals Takumi Takano 1, Shigeru Suzuki 1, Ikuto Tsukiyama 2 and Hiroko Saito 3 1 Graduate School of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi , Japan 2 Aichi Medical University Hospital 3 Faculty of Pharmacy Meijo University Objectives: Anti-cancer drugs are harmful to healthy persons. In recent years, occupational exposure to anti-cancer drugs has become a major concern to health care workers. To address this issue, a smear method was developed to measure widely using anti-cancer drugs depositing on the floors, safety cabinet surfaces, and tables in hospital. Methods: Ten kinds of widely used anti-cancer drugs, paclitaxel, vincristine, docetaxel, vinorelbine, irinotecan, methotrexate, oxaliplatin, cyclophosphamide, gemcitabine and fluorouracil were collected by smearing material surfaces with methanol impregnated cellulose filter paper and/or polypropylene nonwoven. The collected anti-cancer drugs are extracted in 5 ml of 0.01% (v/v) hydrazine/methanol solution by sonication. The extracted solution was filtered and concentrated to prepare 1ml of sample solution. Then, the anti-cancer drugs in the sample solution were simultaneously measured by LC/MS. Results: The anti-cancer drugs excepting fluorouracil spread on P-tile surface were measured with recoveries of % and standard deviations (SD) of %. All 10 of the anti-cancer drugs on a stainless steel plate surface were measured with the recoveries of % and SD of %. Conclusions: Using this smear method, 9 or 10 kinds of widely used anti-cancer drug residues in hospital, possibly exposed to health care workers, were grasped. (Sangyo Eiseigaku Zasshi 2015; 57: )

persons. In recent years, occupational exposure to anti-cancer drugs has become a major concern to health care workers.

平成26年度化学物質分析法開発報告書

平成26年度化学物質分析法開発報告書 2,2-2,2 -Iminodiethanol Diethanol amine CAS 111-42-2 C 4 H 11 NO 2 105.1356-105.0790-28 C 1) 1.0881 g/cm 3 1)