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OCCUPATIONAL EXPOSURE TO ANTINEOPLASTIC AGENTS

Occupational Monitoring: Biological Studies

Muti-channel infusion pump for delivery of chemotherapy and needle and syringe

Several biological endpoints have been employed to monitor healthcare workers’ exposure to antineoplastic agents. Most of these endpoints measure various types of genotoxic damage.


Urinary Mutagenicity

Since most antineoplastic agents and/or their metabolites are excreted in the urine and a large percentage of them are mutagenic, the analysis of the urine of workers handling antineoplastic agents is a means to document exposure. However, relatively high doses are needed in order to detect an effect and, because the assays are nonspecific, confounding factors must be controlled for. Concentrated urine from workers is usually tested with a bacterial mutagenicity assay (Ames test) that is sensitive to many of the antineoplastic agents and/or their metabolites and the results compared to a control population.

Anderson RW, Puckett WH, Dana WJ, Nguyen TV, Theiss JC and Matney TS. Risk of handling injectable antineoplastic agents. Am J Hosp Pharm. 1982;39:1881-87.

Barale R, Sozzi G, Toniolo P, Borghi O, Reali D, Loprieno N and Della Porta G. Sister-chromatid exchanges in lymphocytes and mutagenicity in urine of nurses handling cytostatic drugs. Mutat Res. 1985;157:235-40.

Benhamou S, Callais F, Sancho-Garnier H, Min S, Courtois YA and Festy B. Mutagenicity in urine from nurses handling cytostatic agents. Eur J Cancer Clin Oncol. 1986;22:1489-93. 

Bos RP, Leenaars AO, Theuws JLG and Henderson PT. Mutagenicity of urine from nurses handling cytostatic drugs, influence of smoking. Int Arch Occup Environ Health. 1982;50:359-69.

Caudell KA, Vredevoe DL, Dietrich MF, Caudell TP, Hoban MJ and Block JB. Quantification of urinary mutagens in nurses during potential antineoplastic agent exposure:A pilot study with concurrent environmental and dietary control. Cancer Nurs. 1988;11:41-50.

Cloak MM, Connor TH, Stevens KR, Theiss JC, Alt JM, Matney TS and Anderson RW. Occupational exposure of nursing personnel to antineoplastic agents. Oncol Nurs Forum. 1985;12:33-39.

Connor TH, Theiss JC Anderson RW, Puckett WH and Matney TS. Re-evaluation of urine mutagenicity of pharmacy personnel exposed to antineoplastic agents. Am J Hosp Pharm. 1986;43:1236-39.

Courtois YA, Beaubestre C, Benhamou S, Min S, Callais F, Sancho-Carnier HS and Festy B. Determination de la génotoxicité urinaire:Application au dépistage de l'exposition tabagique et/ou professionnelle. Ann Pharmaceutiques Francaises. 1987;45:289-300.

DeMeó MP, Mérono S, DeBaille AD, Botta A, Laget M, Guiraud H and DumJnil G. Monitoring exposure of hospital personnel handling cytostatic drugs and contaminated materials. Int Arch Occup Environ Health. 1995;66:363-68.

Falck K, Gröhn P, Sorsa M, Vainio H, Heinonen E and Holsti LR. Mutagenicity in urine of nurses handling cytostatic drugs. Lancet. 1979;1:1250-51.

Friederich U, Molko F, Hofmann V, Scossa D, Würgler FE and Senn HJ. Limitations of the salmonella/mammalian microsome assay (Ames test) to determine occupational exposure to cytostatic drugs. Eur J Cancer Clin Oncol. 1986;22:567-75.

Gibson JF, Gompertz D and Hedworth-Whitty RB. Mutagenicity of urine from nurses handling cytotoxic drugs. Lancet. 1984;1:100-01.

Hama T, Aoyama T, Shirai T, Higuchi S, Yokokawa T and Sugimoto Y. Environmental Contamination due to preparation of cyclophosphamide and exposure to pharmacists to it. Jpn J Pharm Health Care Sci. 2009; 35: 693-700.

Hoffman DM. Lack of urine mutagenicity of nurses administering pharmacy prepared doses of antineoplastic agents. Am J Intravenous Ther Clin Nutrition. 1983;28-31.

Kolmodin-Hedman B, Hartvig P, Sorsa M and Falck K. Occupational handling of cytostatic drugs. Arch Toxicol. 1983;54:25-33.

Krepinsky A, Bryant DW, Davison L, Heddle J, McCalla DR, Douglas G and Michalko K. Comparison of three assays for genetic effects of antineoplastic drugs on cancer patients and their nurses. Environ Mol Mutagen. 1990;15:83-92.

Labuhn K, Valanis B, Schoeny R, Loveday K and Vollmer WM. Nurses' and pharmacists exposure to antineoplastic drugs:Findings from industrial hygiene scans and urine mutagenicity tests. Cancer Nursing. 1998;21:79-89.

Lovejoy N, Powers L, Flessel P, Lecocq G, Guirguis G and Chang K. Mutagenicity in urine of hospital workers who prepare and administer chemotherapy agents. EMS Abstracts. 1985;7.

Newman MA, Valanis BG, Schoeny RS and Hee SQ. Urinary biological monitoring markers of anticancer drug exposure in oncology nurses. Am J Pub Health. 1994;84:852-55.

Nguyen TV, Theiss JC and Matney TS. Exposure of pharmacy personnel to mutagenic antineoplastic drugs. Cancer Res. 1982;42:4792-96.

Pohlová H, Cerná M and Rössner P. Chromosomal aberrations, SCE and urine mutagenicity in workers occupationally exposed to cytostatic drugs. Mutat Res. 1986;174:213-17.

Poyen D, DeMeó MP, Botta A, Gouvernet J and Duménil G. Handling of cytostatic drugs and urine mutagenesis. Int Arch Occup Environ Health. 1988;61:183-88.

Ratcliffe JM. Occupational exposure to cancer chemotherapeutic agents in pharmacists and nurses. NIOSH (Industry-wide study E:-80-41) Washington, DC, General Printing Office, 1983.

Rogers B and Emmett EA. Handling antineoplastic agents: Urine mutagenicity in nurses. Image: J of Nurs Scholar. 1987;19:108-13.

Rössner P, Cerná M, Pokorána D, Hájek V and Petr J. Effect of ascorbic acid prophylaxis on the frequency of chromosome aberrations, urine mutagenicity and nucleolus test in workers occupationally exposed to cytostatic drugs. Mutat Res. 1988;208:149-53.

Sabatini L, Barbieri A, Lodi V and Violante FS. Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings. Med Lav. 2012;103(5):394-401.

Sorsa M, Pyy L, Salomaa S, Nyland L and Yager JW. Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals. Mutat Res. 1988;204:465-79.

Stiller A, Obe G, Boll I and Pribilla W. No elevation of the frequencies of chromosomal alterations as a consequence of handling cytostatic drugs: Analyses with peripheral blood and urine of hospital personnel. Mutat Res. 1983;121:253-59.

Stücker I, Hirsch A, Doloy T, Bastie-Sigeac, I and Hémon D. Urine mutagenicity, chromosomal abnormalities and sister chromatid exchanges in lymphocytes of nurses handling cytostatic drugs. Int Arch Occup Environ Health. 1986;57:195-205.

Thiringer G, Granung G, Holmén A, Hogstedt B, Jarvhom B, Jonsson D, Persson L, Wahlstrom J and Westin J. Comparison of methods for the biomonitoring of nurses handling antitumor drugs. Scand J Work Environ Health. 1991;17:133-38.

Venitt S, Crofton-Sleigh C, Hunt J, Speechley V and Briggs K. Monitoring exposure of nursing and pharmacy personnel to cytotoxic drugs: Urinary mutation assays and urinary platinum as markers of absorption. Lancet. 1984;1:74-77.


Chromosomal Aberrations

Chromosomal aberrations represent damage to DNA that is visible in stained cells. Usually, lymphocytes are obtained from exposed populations and examined for various types of chromosomal damage. This methodology has been applied to numerous occupational and environmental exposures to chemicals and radiation in addition to extensive animal studies. A number of chromosomal aberration studies have demonstrated an increase in chromosomal damage in the lymphocytes of nurses and pharmacists handling antineoplastic agents.

Anwar WA, Salama SI, Serafy MM, Hermida S and Hafez AS. Chromosomal aberrations and micronucleus frequency in nurses occupationally exposed to cytotoxic drugs. Mutagenesis. 1994;9:315-317.

Boughattas AB, Bouraoui S, Debbabi F, El Ghazel H, Saad A and Mrizak N. Genotoxic risk assessment of nurses handling antineoplastic drugs. Ann Biol Clin (Paris). 2010; 68:545-553.

Bouraoui S, Brahem A, Tabka F, Mrizek N, Saad A and Elghezal H. Assessment of chromosomal aberrations, micronuclei and proliferation rate index in peripheral lymphocytes from Tunisian nurses handling cytotoxic drugs. Environ Toxicol Pharmacol. 2011; 31:250-257.

Brumen V, Horvat D and Trošic I. Potential genotoxic risk related to simultaneous exposure to radionuclides and cytostatics. Am J Ind Med. 1995;27:871-876.

Burgaz S, Karahalil B, Canhi Z, Terzioglu F, Ancel G, Anzion RB, Bos RP and Huttner E. Assessment of genotoxic damage in nurses occupationally exposed to antineoplastics by the analysis of chromosomal aberrations. Hum Exp Tox. 2002; 21:129-135.

Cavallo D, Usini CL, Perniconi B, Di Francesco A, Giglio M, Rubino FM, Marinaccio A, Iavicoli S. Evaluation of genotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat Res. 2005; 587:45-51.

Cavallo D, Ursini CL, Omodeo-Salé E and Iavicoli S. Micronucleus induction and FISH analysis in buccal cells and lymphocytes of nurses administering antineoplastic drugs. Mutat Res. 2007; 628:11-18.

Cooke J, Williams J, Morgan RJ, Cooke P and Calvert RT. Use of cytogenetic methods to determine mutagenic changes in the blood of pharmacy personnel and nurses who handle cytotoxic agents. Am J Hosp Pharm. 1991;48:1199-1205.

Fucic A, Jazbec A, Mijic A, Seso-Simic D and Tomek R. Cytogenetic consequences after occupational exposure to antineoplastic drugs. Mutat Res. 1998;416:59-66.

Goloni-Bertollo EM, Tajara EH, Manzato AJ and Varella-Garcia M. Sister chromatid exchanges and chromosome aberrations in lymphocytes of nurses handling antineoplastic drugs. Int J Cancer. 1992;50:341-344.

Grummt T, Grummt H-J and Schott G. Chromosomal aberrations in peripheral lymphocytes of nurses and physicians handling antineoplastic drugs. Mutat Res. 1993; 302: 19-24.

Harris PE, Connor TH, Stevens KR and Theiss JC. Cytogenetic assessment of occupational exposure of nurses to antineoplastic agents. J Occup Med Toxicol. 1992;1:243-254.

Jakab MG, Major J and Tompa A. Follow-up genotoxicological monitoring of nurses handling antineoplastic drugs. J Tox Environ Health. 2001; 62:307-318.

Karelová J, Jablonická A, Gavora J and Hano Lubomír. Chromosome and sister-chromatid exchange analysis in peripheral lymphocytes and mutagenicity of urine in anesthesiology personnel. Int Arch Occup Environ Health. 1992;64:303-306.

Kopjar N, Garaj-Vrhovac V, Kašuba V, Rozgaj R, Ramić S, Pavlica V and Želježić D. Assessment of genotoxic risks in Croatian health care workers occupationally exposed to cytotoxic drugs: A multi-biomarker approach. Int J Hyg Environ Health. 2009; 212:414-431.

Kopjar N, Graj-Vrhovac V and Milas I. Acute cytogenetic effects of antineoplastic drugs on peripheral blood lymphocytes in cancer patients [sic] chromosome aberrations and micronuclei. Tumori. 2002; 88:300-312.

Krepinsky A, Bryant DW, Davison L, Heddle J, McCalla DR, Douglas G and Michalko K. Comparison of three assays for genetic effects of antineoplastic drugs on cancer patients and their nurses. Environ Mol Mutagen. 1990;15:83-92.

Major J, Jakab MG and Tompa A. The frequency of induced premature centromere division in human populations occupationally exposed to genotoxic chemicals. Mutat Res. 1998; 445:241-249.

McDevitt MA, Condon M, Stamberg J, Karp JE and McDiarmid M. Fluorescent in situ hybridization (FISH) in bone marrow and peripheral blood of leukemia patients: Implications for occupational surveillance. Mutat Res. 2007; 629:24-31.

McDiarmid MA, Oliver MS, Roth TS, Rogers B. and Escalante CP. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med. 2010; 52:1028-1034.

McDiarmid MA, Rogers B and Oliver MS. Chromosomal effects of non-alkylating drug exposure in oncology personnel. Environ Mol Mutagen. 2014 (Epub ahead of print) DOI: 10.1002/em.21852.

Milkovic-Kraus S and Horvat D. Chromosomal abnormalities among nurses occupationally exposed to antineoplastic drugs. Am J Ind Med. 1991;19:771-774.

Milkovic-Kraus S, Kraus O, Kršnjavi H and Kubelka D. Environmental effects on chromosomes in oncology and radiology department personnel. Preventive Med. 1992;21:498-502.

Nikula E, Kiviniitty K, Leisti J and Taskinen PJ. Chromosome aberrations in lymphocytes of nurses handling cytostatic agents. Scand J Work Environ Health. 1984;10:71-74.

Oestreicher U, Stephan G and Glatzel M. Chromosome and SCE analysis in peripheral lymphocytes of persons occupationally exposed to cytostatic drugs handled with and without use of safety covers. Mutat Res. 1990;242:271-277.

Pohlová H, Cerná M and Rössner P. Chromosomal aberrations, SCE and urine mutagenicity in workers occupationally exposed to cytostatic drugs. Mutat Res. 1986;174:213-217.

Rössner P, Cerná M, Pokorána D, Hájek V and Petr J. Effect of ascorbic acid prophylaxis on the frequency of chromosome aberrations, urine mutagenicity and nucleolus test in workers occupationally exposed to cytostatic drugs. Mutat Res. 1988;208:149-153.

Roth S, Norppa H, Järventaus H, Kyyrönen P, Ahonen M, Lehtomäki J, Sainio H and Sorsa M. Analysis of chromosomal aberrations, sister chromatid exchanges and micronuclei in peripheral lymphocytes of pharmacists before and after working with cytostatic drugs. Mutat Res. 1994;325:157-162.

Rubeš J, Kucharová S, Vozdová M, Musilová P and Zudová Z. Cytogenetic analysis of peripheral lymphocytes in medical personnel by means of FISH. Mutat Res. 1998 412:293-298.

Sarto F, Trevisan A, Tomanin R, Canova A and Fiorentino M. Chromosomal aberrations, sister chromatid exchanges and urinary thioethers in nurses handling antineoplastic drugs. Am J Ind Med. 1990;18:689-695.

Sessink PJM, Cerná M, Rössner P, Pastorkova A, Bavarova H, Frankova K, Anzion RB and Bos RP. Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents. Mutat Res. 1994;309:193-199.

Stiller A, Obe G, Boll I and Pribilla W. No elevation of the frequencies of chromosomal alterations as a consequence of handling cytostatic drugs: Analyses with peripheral blood and urine of hospital personnel. Mutat Res. 1983;121:253-259.

Stücker I, Hirsch A, Doloy T, Bastie-Sigeac, I and Hémon D. Urine mutagenicity, chromosomal abnormalities and sister chromatid exchanges in lymphocytes of nurses handling cytostatic drugs. Int Arch Occup Environ Health. 1986;57:195-205.

Testa A, Giachelia M, Palma S, Appolloni M, Padua L, Tranfo G, Spagnoli M, Trindelli D and Cozzi R. Occupational exposure to antineoplastic agents induces a high level of chromosome damage. Lack of an effect of GST polymorphisms. Tox and Appl Pharmacol. 2007; 223:46-55.

Thulin H, Sundberg E, Hansson K, Cole J and Hartley-Asp B. Occupational exposure to nor-nitrogen mustard: Chemical and biological monitoring. Toxicol Ind Health. 1995;11:89-97.

Tompa A, Jakab M, Biro A, Magyar B, Fodor Z, Klupp T and Major J. Chemical safety and health conditions among Hungarian hospital nurses. Ann NY Acad Sci. 2006; 1076:635-648.

Waksvik H, Klepp O and Brøgger A. Chromosome analyses of nurses handling cytostatic agents. Cancer Treat Rep. 1981;65:607-610.

Yang D-P, Xu S-J and Wang J-X. Study on chromosomal damage among nurses occupationnaly exposed to antineoplastic drugs in an oncology department. Biomed Environ Sci. 2002; 15:268-270.


Sister Chromatid Exchanges

Although Sister Chromatid Exchanges (SCEs) are typically measured in lymphocytes, similar to chromosomal aberrations and micronuclei, they are involved with DNA repair. This endpoint has been used extensively in other occupational settings as a marker for agents that may damage DNA, thus resulting in its repair. Several studies of workers exposed to antineoplastic agents have shown an increase in their frequency as compared to control populations.

Barale R, Sozzi G, Toniolo P, Borghi O, Reali D, Loprieno N and Della Porta G. Sister-chromatid exchanges in lymphocytes and mutagenicity in urine of nurses handling cytostatic drugs. Mutat Res. 1985;157:235-240.

Brumen V and Horvat D. Work environment influence on cytostatics-induced genotoxicity in oncologic nurses. Am J Indus Med. 1996;30:67-71.

Brumen V, Horvat D and Trošic I. Potential genotoxic risk related to simultaneous exposure to radionuclides and cytostatics. Am J Ind Med. 1995;27:871-876.

Evelo CTA, Bos RP, Peters JGP and Henderson PT. Urinary cyclophosphamide assay as a method for biological monitoring of occupational exposure to cyclophosphamide. Int Arch Occup Environ Health. 1986;58:151-155.

Fucic A, Jazbec A, Mijic A, Seso-Simic D and Tomek R. Cytogenetic consequences after occupational exposure to antineoplastic drugs. Mutat Res. 1998;416:59-66.

Goloni-Bertollo EM, Tajara EH, Manzato AJ and Varella-Garcia M. Sister chromatid exchanges and chromosome aberrations in lymphocytes of nurses handling antineoplastic drugs. Int J Cancer. 1992;50:341-344.

Gulten T, Evke E, Ercan I, Evrensel T, Kurt E and Manavoglu O. Lack of genotoxicity in medical oncology nurses handling antineoplastic drugs: effect of work environment and protective equipment. Work. 2011; 39:485-489.

Ikeda K, Yagi Y, Tkegami M, Lu Y, Morimoto K and Kurokawa N. Efforts to ensure safety of hospital pharmacy personnel occupationally exposed to antineoplastic drugs during a preparation task. Hosp Pharm. 2007; 42:209-218.

Jakab MG, Major J and Tompa A. Follow-up genotoxicological monitoring of nurses handling antineoplastic drugs. J Tox Environ Health. 2001; 62:307-318.

Jordan DK, Patil SR, Jochimsen PR, Lachenbruch PA and Corder MP. Sister chromatid exchange analysis in nurses handling antineoplastic drugs. Cancer Invest. 1986;4:101-107.

Karelová J, Jablonická A, Gavora J and Hano Lubomír. Chromosome and sister-chromatid exchange analysis in peripheral lymphocytes and mutagenicity of urine in anesthesiology personnel. Int Arch Occup Environ Health. 1992;64:303-306.

Kasuba V, Rozgaj R and Garak-Vrhovac V. Analysis of sister chromatid exchange and micronuclei in peripheral blood lymphocytes of murses handling cytostatic drugs. J Appl Toxicol. 1999;19:401-404.

Kevekordes S, Gebel TW, Hellwig M, Dames W and Dunkelberg H. Human effect monitoring in cases of occupational exposure to antineoplastic drugs: A method comparison. Occup Environ Med. 1998;55:145-149.

Kolmodin-Hedman B, Hartvig P, Sorsa M and Falck K. Occupational handling of cytostatic drugs. Arch Toxicol. 1983;54:25-33.

Kopjar N, Garaj-Vrhovac V, Kašuba V, Rozgaj R, Ramić S, Pavlica V and Želježić D. Assessment of genotoxic risks in Croatian health care workers occupationally exposed to cytotoxic drugs: A multi-biomarker approach. Int J Hyg Environ Health. 2009; 212:414-431.

Krepinsky A, Bryant DW, Davison L, Heddle J, McCalla DR, Douglas G and Michalko K. Comparison of three assays for genetic effects of antineoplastic drugs on cancer patients and their nurses. Environ Mol Mutagen. 1990;15:83-92.

Lambert B, Bredberg A, McKenzie W and Sten M. Sister chromatid exchange in human populations:the effect of smoking, drug treatment and occupational exposure. Cytogenet Cell Genet. 1982;33:62-67.

Lanza A, Robustelli della Cuna FS, Zibera C, Pedrazzoli P and Robustelli della Cuna G. Somatic mutations at the T-cell antigen receptor in antineoplastic drug-exposed populations: comparison with sister chromatid exchange frequency. Int Arch Environ Health. 1999;72:315-322.

McDiarmid MA, Kolodner K, Humphrey F, Putman D and Jacobson-Kram D. Baseline and phosphoramide mustard-induced sister-chromatid exchanges in pharmacists handling anti-cancer drugs. Mutat Res. 1992;279;199-204.

McDiarmid MA, Kolodner K, Humphrey F, Putman D and Jacobson-Kram D. Baseline and mutagen-induced sister chromatid exchanges in lymphocytes of pharmacists handling anticancer drugs. Environ Epidemol Tox. 2000; 2:254-260.

Milkovic-Kraus S and Horvat D. Chromosomal abnormalities among nurses occupationally exposed to antineoplastic drugs. Am J Ind Med. 1991;19:771-774.

Mrđanović J, Jungić S, Šolajić S, Bogdanović V and Jurišić V. Effects of orally administered antioxidants on micronuclei and sister chromatid exchange frequency in workers professionally exposed to antineoplastic agents. Food Chem Toxicol. 2012; 50:2937-2744.

Norppa H, Sorsa M, Vainio H, Grohn P, Heinonen E, Holsti L and Nordman E. Increased sister chromatid exchange frequencies in lymphocytes of nurses handling cytostatic drugs. Scand J Work Environ Health. 1980;6:299-301.

Oestreicher U, Stephan G and Glatzel M. Chromosome and SCE analysis in peripheral lymphocytes of persons occupationally exposed to cytostatic drugs handled with and without use of safety covers. Mutat Res. 1990;242:271-277.

Pilger A, Kohler I, Stettner H, Mader RM, Rizovski B, Terkola R, Diem E, Franz-Hainzl E, Konnaris C, Valic E and Rudiger. Long-term monitoring of sister chromatid ecchanges and micronucleus formation in pharmacy personnel occupationally exposed to cytostatic drugs. Int Arch Occup Environ Health. 2000; 73:442-448.

Pohlová H, Cerná M and Rössner P. Chromosomal aberrations, SCE and urine mutagenicity in workers occupationally exposed to cytostatic drugs. Mutat Res. 1986;174:213-217.

Roth S, Norppa H, Järventaus H, Kyyrönen P, Ahonen M, Lehtomäki J, Sainio H and Sorsa M. Analysis of chromosomal aberrations, sister chromatid exchanges and micronuclei in peripheral lymphocytes of pharmacists before and after working with cytostatic drugs. Mutat Res. 1994;325:157-162.

Sarto F, Trevisan A, Tomanin R, Canova A and Fiorentino M. Chromosomal aberrations, sister chromatid exchanges and urinary thioethers in nurses handling antineoplastic drugs. Am J Ind Med. 1990;18:689-695.

Sorsa M, Pyy L, Salomaa S, Nyland L and Yager JW. Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals. Mutat Res. 1988;204:465-479.

Stücker I, Hirsch A, Doloy T, Bastie-Sigeac, I and Hémon D. Urine mutagenicity, chromosomal abnormalities and sister chromatid exchanges in lymphocytes of nurses handling cytostatic drugs. Int Arch Occup Environ Health. 1986;57:195-205.

Thiringer G, Granung G, Holmén A, Hogstedt B, Jarvhom B, Jonsson D, Persson L, Wahlstrom J and Westin J. Comparison of methods for the biomonitoring of nurses handling antitumor drugs. Scand J Work Environ Health. 1991;17:133-138.

Thulin H, Sundberg E, Hansson K, Cole J and Hartley-Asp B. Occupational exposure to nor-nitrogen mustard: Chemical and biological monitoring. Toxicol Ind Health. 1995;11:89-97.

Tompa A, Jakab M, Biro A, Magyar B, Fodor Z, Klupp T and Major J. Chemical safety and health conditions among Hungarian hospital nurses. Ann NY Acad Sci. 2006; 1076:635-648.

Waksvik H, Klepp O and Brøgger A. Chromosome analyses of nurses handling cytostatic agents. Cancer Treat Rep. 1981;65:607-610.

Yang D-P, Xu S-J and Wang J-X. Study on chromosomal damage among nurses occupationnaly exposed to antineoplastic drugs in an oncology department. Biomed Environ Sci. 2002; 15:268-270.


Micronuclei Induction

Micronuclei induction results from exposure to many chemicals that react with DNA. This assay has been employed extensively in animal studies, and to a lesser extent in occupational studies, to determine the ability of a chemical agent to damage DNA resulting in the formation of small fragments of DNA termed micronuclei. Micronuclei are usually measured in peripheral lymphocytes, but also can be evaluated in other cell types.

Anwar WA, Salama SI, Serafy MM, Hermida S and Hafez AS. Chromosomal aberrations and micronucleus frequency in nurses occupationally exposed to cytotoxic drugs. Mutagenesis. 1994;9:315-317.

Boughattas AB, Bouraoui S, Debbabi F, El Ghazel H, Saad A and Mrizak N. Genotoxic risk assessment of nurses handling antineoplastic drugs. Ann Biol Clin (Paris). 2010; 68:545-553.

Bouraoui S, Brahem A, Tabka F, Mrizek N, Saad A and Elghezal H. Assessment of chromosomal aberrations, micronuclei and proliferation rate index in peripheral lymphocytes from Tunisian nurses handling cytotoxic drugs. Environ Toxicol Pharmacol. 2011; 31:250-257.

Burgaz S, Karahalil B, Bayrak P, Taşin L, Yavuzaslan F, Bökesoy I, Anzion RBM, Bos RP and Platin N. Urinary cyclophosphamide excretion and micronuclei frequencies in periperal lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics. Mutat Res. 1999;439:97-104.

Cavallo D, Usini CL, Perniconi B, Di Francesco A, Giglio M, Rubino FM, Marinaccio A, Iavicoli S. Evaluation of genotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat Res. 2005; 587:45-51.

Cavallo D., Ursini CL, Omodeo-Salé E and Iavicoli S. Micronucleus induction and FISH analysis in buccal cells and lymphocytes of nurses administering antineoplastic drugs. Mutat Res. 2007; 628:11-18.

Cavallo D, Ursini CL, Rondinone B and Iavicoli S. Evaluation of a suitable DNA damage biomarker for human biomonitoring of exposed workers. Environ Mol Mutagen. 2009; 50:781-790.

Cornetta T, Padua L, Testa A, Ievoli E, Festa F, Tranfo G, Baccelliere L and Cozzi R. Molecular biomonitoring of a population of nurses handling antineoplastic drugs. Mutat Res. 2008; 638:75-82.

Deng H, Zhang M, He J, Wu W, Jin L, Zheng W, Lou J and Wang B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005; 20:351-357.

Deng H, Lou, J, Zhang M, Wu W, Jin J, Chen S, Zheng W, Wang B and He J. Detecting the cytogenetic effects in workers occupationally exposed to vincristine with four genetic tests. Mutat Res. 2006; 599:152-159.

Fucic A, Jazbec A, Mijic A, Seso-Simic D and Tomek R. Cytogenetic consequences after occupational exposure to antineoplastic drugs. Mutat Res. 1998;416:59-66.

Garaj-Vrhovac V and Kopjar N. Micronuclei in cytokinesis-blocked lymphocytes as an index of occupational exposure to antineoplastic drugs. Radio Oncol. 1998; 32:385-392.

Harris PE, Connor TH, Stevens KR and Theiss JC. Cytogenetic assessment of occupational exposure of nurses to antineoplastic agents. J Occup Med Toxicol. 1992; 1:243-254.

Hessel H, Radon K, Pethran A, Maisch B, Grobmair S, Sautter I and Fruhmann G. The genotoxic risk of hospital, pharmacy and medical personnel occupationally exposed to cytostatic drugs-evaluation by the micronucleus assay. Mutat Res. 2001; 497:101-109.

Kasuba V, Rozgaj R and Garak-Vrhovac V. Analysis of sister chromatid exchange and micronuclei in peripheral blood lymphocytes of nurses handling cytostatic drugs. J Appl Toxicol. 1999; 19:401-404.

Kopjar N, Garaj-Vrhovac V, Kašuba V, Rozgaj R, Ramić S, Pavlica V and Želježić D. Assessment of genotoxic risks in Croatian health care workers occupationally exposed to cytotoxic drugs: A multi-biomarker approach. Int J Hyg Environ Health. 2009; 212:414-431.

Kopjar N, Graj-Vrhovac V and Milas I. Acute cytogenetic effects of antineoplastic drugs on peripheral blood lymphocytes in cancer patients [sic] chromosome aberrations and micronuclei. Tumori. 2002; 88:300-312.

Laffon B, Teixeira JP, Silva S, Loureiro J, Torres J, Pásaro E, Méndez and Mayan O. Genotoxic effects in a population of nurses handling antineoplastic drugs, and relationship with genetic polymorphisms in DNA repair enzymes. Am J Ind Med. 2005; 48:128-136.

Machado-Santelli GM, Cerqueira EM, Oliveira CT and de Braganca Peira CAA. Biomonitoring of nurses handling antineoplastic drugs. Mutat Res. 1994; 332:203-208.

Maluf SW and Erdtmann B. Evaluation of occupational genotoxic risk in a Brazilian hospital. Genetics Mol Biol. 2000; 23: 485-488.

Maluf SW and Erdtmann B. Follow-up study of the genetic damage in lymphocytes of pharmacists and nurses handling antineoplastic drugs evaluated by cytokinesis-block micronuclei analysis and single cell gel electrophoresis assay. Mutat Res. 2000; 471: 21-27.

Mrđanović J, Jungić S, Šolajić S, Bogdanović V and Jurišić V. Effects of orally administered antioxidants on micronuclei and sister chromatid exchange frequency in workers professionally exposed to antineoplastic agents. Food Chem Toxicol. 2012; 50:2937-2744.

Pethran A, Hauff K and Hessel H. Biological, cytogenetic and ambient monitoring of exposure to antineoplastic drugs. J Oncol Pharm Practice. 1998; 4:57.

Pilger A, Kohler I, Stettner H, Mader RM, Rizovski B, Terkola R, Diem E, Franz-Hainzl E, Konnaris C, Valic E and Rudiger. Long-term monitoring of sister chromatid ecchanges and micronucleus formation in pharmacy personnel occupationally exposed to cytostatic drugs. Int Arch Occup Environ Health. 2000; 73:442-448.

Rekhadevi PV, Sailaja N, Chandrasekhar M, Mahboob M, Rahman MF and Grover P. Genotoxicity assesment in oncology nurses handling anti-neoplastic drugs. Mutagenisis. 2007; 22:395-401.

Rombaldi F, Cassini C, Salvador M, Saffi J and Erdtmann B. Occupational risk assessment of genotoxicyty and oxidative stress in workers handeling anti-neoplastic drugs during a work week. Mutagenesis. 2009; 24:143-148.

Rössner P, Cerná M, Pokorána D, Hájek V and Petr J. Effect of ascorbic acid prophylaxis on the frequency of chromosome aberrations, urine mutagenicity and nucleolus test in workers occupationally exposed to cytostatic drugs. Mutat Res. 1988; 208:149-153.

Roth S, Norppa H, Järventaus H, Kyyrönen P, Ahonen M, Lehtomäki J, Sainio H and Sorsa M. Analysis of chromosomal aberrations, sister chromatid exchanges and micronuclei in peripheral lymphocytes of pharmacists before and after working with cytostatic drugs. Mutat Res. 1994; 325:157-162.

Sorsa M, Pyy L, Salomaa S, Nyland L and Yager JW. Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals. Mutat Res. 1988;204:465-479.

Thiringer G, Granung G, Holmén A, Hogstedt B, Jarvhom B, Jonsson D, Persson L, Wahlstrom J and Westin J. Comparison of methods for the biomonitoring of nurses handling antitumor drugs. Scand J Work Environ Health. 1991; 17:133-138.

Villarini M, Dominici L, Fatigoni C, Muzi G, Monarca S and Moretti M. Biological effect monitoring in peripheral blood lymphocytes from subjects occupationally exposed to antineoplastic drugs: assessment of micronuclei frequency. J Occup Health. 2012; 54:405-415.

Yager JW, Sorsa M and Selvin S. Micronuclei in cytokinesis-blocked lymphocytes as an index of occupational exposure to alkylating cytostatic drugs. 1980. IARC #80; 213-216.


DNA Damage

A number of methods are available to measure DNA damage directly. These include alkaline elution, and more recently, the Comet assay. These assays have been used in vitro and in animal studies, but only sparingly in occupation exposure studies. They usually measure DNA strand breaks. Since most antineoplastic agents target DNA, this is a sensitive and relevant endpoint to study.

Balcarová O, Zavázal V, Seberová E, Kuklová D and Halík J. The risk of work with cytostatics and immunomodulation compounds. Pracov Lék. 1993; 45:195-201. (English abstarct)

Buschini A, Villarini M, Feretti D, Mussi F, Dominici L, Zerbini I, Moretti M, Ceretti E, Bonfiglioli R, Carrieri M, Gelatti U, Rossi C, Monarco S and Poli P. Multicentre study for the evaluation of mutagenic/carcinogenic risk in nurses exposed to antineoplastic drugs: assessment of DNA damage. Occup Environ Med. 2013; 70:789-794.

Cavallo D, Ursini CL, Perniconi B, Francesco AD and Giglio M, Rubino FM, Marinaccio A, Iavicoli S. Evaluation of gentotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat Res. 2005; 587:45-51.

Cavallo D, Ursini CL, Rondinone B and Iavicoli S. Evaluation of a suitable DNA damage biomarker for human biomonitoring of exposed workers. Environ Mol Mutagen. 2009; 50:781-790.

Connor TH, DeBord G, Pretty JR, Oliver MS, Roth TS, Lees PSJ, Krieg EF, Rogers B, Escalante CP, Toennis CA, Clark JC, Johnson B and McDiarmid MA. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010; 52:1019-1027.

Cornetta T, Padua L, Testa A, Ievoli E, Festa F, Tranfo G, Baccelliere L and Cozzi R. Molecular biomonitoring of a population of nurses handling antineoplastic drugs. Mutat Res. 2008; 638:75-82.

Deng H, Zhang M, He J, Wu W, Jin L, Zheng W, Lou J and Wang B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005; 20:351-357.

Deng H, Lou, J, Zhang M, Wu W, Jin J, Chen S, Zheng W, Wang B and He J. Detecting the cytogenetic effects in workers occupationally exposed to vincristine with four genetic tests. Mutat Res. 2006; 599:152-159.

Fuchs J, Hengstler JG, Jung D, Hiltl G, Konietzko J and Oesch F. DNA damage in nurses handling antineoplastic agents. Mutat Res. 1995; 342:17-23.

Huang YW, Jian L, Zhang MB, Zhou Q, Yan XF, Hua XD, Zhou Y and He JL. An investigation of oxidative DNA damage in pharmacy technicians exposed to antineoplastic drugs in two Chinese hospitals using the urinary 8-OHdG assay. Biomed Environ Sci. 2012; 25:109-116.

Izdes S, Sardas S, Kadioglu E, Kaymak C and Ozcagli E. Assessment of genotoxic damage in nurses occupationally exposed to anesthetic gases or antineoplastic drugs by the comet assay. J Occup Health. 2009; 51:283-286.

Jakab MG, Major J and Tompa A. Follow-up genotoxicological monitoring of nurses handling antineoplastic drugs. J Tox Environ Health. 2001; 62:307-318.

Kevekordes S, Gebel TW, Hellwig M, Dames W and Dunkelberg H. Human effect monitoring in cases of occupational exposure to antineoplastic drugs: A method comparison. Occup Environ Med. 1998; 55:145-149.

Kopjar N and Garaj-Vrhovac V. Application of the alkaline comet assay in human biomonitoring for genotoxicity: A study on Croatian medical personnel handling antineoplastic drugs. Mutagenesis. 2001; 16:71-78.

Kopjar N, Garaj-Vrhovac V, Kašuba V, Rozgaj R, Ramić S, Pavlica V and Želježić D. Assessment of genotoxic risks in Croatian health care workers occupationally exposed to cytotoxic drugs: A multi-biomarker approach. Int J Hyg Environ Health. 2009; 212:414-431.

Laffon B, Teixeira JP, Silva S, Loureiro J, Torres J, Pásaro E, Méndez and Mayan O. Genotoxic effects in a population of nurses handling antineoplastic drugs, and relationship with genetic polymorphisms in DNA repair enzymes. Am J Ind Med. 2005; 48:128-136.

Lambert B, Bredberg A, McKenzie W and Sten M. Sister chromatid exchange in human populations:the effect of smoking, drug treatment and occupational exposure. Cytogenet Cell Genet. 1982; 33:62-67.

Maluf SW and Erdtmann B. Follow-up study of the genetic damage in lymphocytes of pharmacists and nurses handling antineoplastic drugs evaluated by cytokinesis-block micronuclei analysis and single cell gel electrophoresis assay. Mutat Res. 2000; 471:21-27.

Mucci, N, Ianni A, Ursini CL, Orsini M, Arzani D and Romano-Spica V. Cytostatic drugs and health risks for exposed personnel: Search for New biomarkers. Anticancer Res. 2000; 20:2995-3000.

Oesch F, Hengstler JG, Arand M and Fuchs J. Detection of primary DNA damage: applicability to biomonitoring of genotoxic occupational exposure and in clinical therapy. Pharmacogenet. 1995; 5:S118-S122.

Rekhadevi PV, Sailaja N, Chandrasekhar M, Mahboob M, Rahman MF and Grover P. Genotoxicity assesment in oncology nurses handling anti-neoplastic drugs. Mutagenisis. 2007; 1-7.

Rombaldi F, Cassini C, Salvador M, Saffi J and Erdtmann B. Occupational risk assessment of genotoxicyty and oxidative stress in workers handeling anti-neoplastic drugs during a work week. Mutagenesis. 2009; 24:143-148.

Sasaki M, Dakeishi M, Hoshi S, Ishii N and Murata K . Assessment of DNA damage in Japanese nurses handeling antineoplastic drugs by the comet assay. J Occup Health. 2008; 50:7-12.

Ündeger Ü, Basaran, Kars A and Güç D. Assessment of DNA damage in nurses handling antineoplastic drugs by the alkaline COMET assay. Mutat Res. 1999; 439:277-285.

Ursini CL, Cavallo D, Colombi A, Giglio M, Marinaccio A and Iavicoli S. Evaluation of early DNA damage in healthcare workers handeling antineoplastic drugs. Int Arch Occup Environ Health. 2006; 80:134-140.

Villarini M, Dominici L, Piccinini R, Fatigoni C, Ambrogi M, Curti G, Morucci P, Muzi G, Monarca S and Moretti M. Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis. 2011; 26:359-369.

Yang D, Xu S and Wang J. Study of DNA damage of peripheral lymphocytes in the nurses occupationally exposed to anticancer drugs. Zhonghua Laodong Weisheng Zhiyebing Zazhi. 2002; 20:197-199.

Yoshida J, Kosaka H, Tomika K and Kumagai S. Genotoxic Risks to nurses from contamination of the work enviroment with antineoplastic drugs in Japan. J Occup Health; 2006; 48:517-522.


HPRT Mutations

HPRT mutations are typically measured in lymphocytes and targets mutations in a specific gene. This method had been employed recently in other occupational setting as a marker for exposure to agents which mutate DNA. A small number of studies of occupational exposure to antineoplastic agents has shown an increase in HPRT mutations.

Chrysostomou A, Seshadri R and Morley AA. Mutation frequency in nurses and pharmacists working with cytotoxic drugs. Aust NZ J Med. 1984; 14;831-834.

Deng H, Zhang M, He J, Wu W, Jin L, Zheng W, Lou J and Wang B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005; 20:351-357.

Dubeau H, Zazi W, Baron C and Messing K. Effects of lymphocyte subpopulations on the clonal assay of HPRT mutants: Occupational exposure to cytostatic drugs. Mutat Res. 1994; 321:147-157.

Thulin H, Sundberg E, Hansson K, Cole J and Hartley-Asp B. Occupational exposure to nor-nitrogen mustard: Chemical and biological monitoring. Toxicol Ind Health. 1995; 11:89-97.


Thioether Excretion

The excretion of thioethers in the urine has been used in a limited number of occupational studies as a marker for exposure. The method is nonspecific and may be seen with other exposures, including smoking.

Bayhan A, Burgaz S and Karakaya AE. Urinary thioether excretion in nurses at an oncologic department. J Clin Pharm Ther. 1987; 12:303-306.

Burgaz S, Özdamar YN and Karakaya AE. A signal assay for the detection of genotoxic compounds:Applications on the urines of cancer patients on chemotherapy and of nurses handling cytotoxic drugs. Hum Toxicol. 1988; 7:557-560.

Deng H, Lou, J, Zhang M, Wu W, Jin J, Chen S, Zheng W, Wang B and He J. Detecting the cytogenetic effects in workers occupationally exposed to vincristine with four genetic tests. Mutat Res. 2006; 599:152-159.

Jagun O, Ryan M and Waldron HA. Urinary thioether excretion in nurses handling cytotoxic drugs. Lancet. 1982; 2:443-444.

Rombaldi F, Cassini C, Salvador M, Saffi J and Erdtmann B. Occupational risk assessment of genotoxicyty and oxidative stress in workers handeling anti-neoplastic drugs during a work week. Mutagenesis. 2009; 24:143-148.

Sarto F, Trevisan A, Tomanin R, Canova A and Fiorentino M. Chromosomal aberrations, sister chromatid exchanges and urinary thioethers in nurses handling antineoplastic drugs. Am J Ind Med. 1990; 18:689-695.

Thiringer G, Granung G, Holmén A, Hogstedt B, Jarvhom B, Jonsson D, Persson L, Wahlstrom J and Westin J. Comparison of methods for the biomonitoring of nurses handling antitumor drugs. Scand J Work Environ Health. 1991; 17:133-138.


Occupational Monitoring: Analytical Studies

Over the past several years, the direct measurement of antineoplastic agents in body fluids of healthcare workers has been employed to assess exposure to these agents. Methods for a number of the more common agents are included in the citations on this page. Currently, these techniques are only used in research settings and not for routine monitoring of healthcare workers.


Urinary Excretion of Antineoplastic Agents

Urinary analysis is the direct measurement of antineoplastic agents and/or their metabolites in the urine of exposed workers by analytical methods. Typically, gas chromatography/mass spectrometry (GC-MS or GC-MS-MS), high performance liquid chromatography (LC-MS or LC-MS-MS) or high performance liquid chromatography with UV detection LC-UV are employed to identify the drugs and/or their metabolites in the urine. For platinum-containing compounds, votammetry or inductively coupled plasma mass spectrometry (ICPMS) are used to determine the presence of platinum in the urine.

Andreasson SN, Anundi H, Thoren SB, Ehrsson H and Mahteme H. Is platinum present in blood and urine from treatment givers during hyperthermic intraperitoneal chemotherapy? J Oncol. 2010; (Epub ahead of printing) DOI: 10.1155/2010/649719.

Bos RP, Weissenberger BFJ and Anzion RBM. α-fluoro-β-alanine in urine of workers occupationally exposed to 4-fluorouracil in a 5-flourouracil-producing factory. Biomarkers. 1998; 3:81-87.

Burgaz S, Karahalil B, Bayrak P, Taşin L, Yavuzaslan F, Bökesoy I, Anzion RBM, Bos RP and Platin N. Urinary cyclophosphamide excretion and micronuclei frequencies in periperal lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics. Mutat Res. 1999; 439:97-104.

Cass Y and Musgrave CF. Guidelines for the safe handling of excreta contaminated by cytotoxic drugs. Am J Hosp Pharm. 1992; 49:1957-1958.

Cavallo D, Ursini CL, Perniconi B, Francesco AD, Giglio M, Rubino FM, Marinaccio A and Iavicoli S. Evaluation of gentotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat Res. 2005; 587:45-51.

Connor TH, DeBord G, Pretty JR, Oliver MS, Roth TS, Lees PSJ, Krieg EF, Rogers B, Escalante CP, Toennis CA, Clark JC, Johnson B and McDiarmid MA. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010; 52:1019-1027.

Deschamps F, Marinutti-Liberge and Lamiable D. Biological monitoring of occupational exposure to cytostatic drugs with platinum. Cancer Detect Prev Online.

Ensslin AS, Stoll Y, Pethran A, Pfaller A, Rommelt H and Fruhmann G. Biological monitoring of cyclophosphamide and ifosfamide in urine of hospital personnel occupationally exposed to cytostatic drugs. Occup Environ Med 1994; 51:229-233.

Ensslin AS, Pethran A, Schierl R and Fruhmann G. Urinary platinum in hospital personnel occupationally exposed to platinum-containing antineoplastic drugs. Int Arch Occup Environ Health. 1994; 65:339-342.

Ensslin AS, Huber R, Pethran A, Pethran A, Rommelt H, Schelerl, Kulka U and Fruhmann G. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health 1997; 70:205-208.

Evelo CTA, Bos RP, Peters JGP and Henderson PT. Urinary cyclophosphamide assay as a method for biological monitoring of occupational exposure to cyclophosphamide. Int Arch Occup Environ Health. 1986; 58:151-155.

Favier B, Gilles L, Gesage M and Latour JF. Analysis of cyclophosphamide in the urine of antineoplastic drug handlers. Bull Cancer. 2003; 90:905-909.

Friese CR, McArdle C, Zhao T, Sun D, Spasojevic I, Polovich M and McCullagh MC. Antineoplastic drug exposure in an ambulatory setting. Cancer Nurs. 2014 (Epub ahead of print).

Hama K, Fukushima K, Hirabatake M, Hashida T and Kataoka K. Verification of surface contamination of Japanese cyclophosphamide vials and an example of exposure by handling. J Oncol Pharm Practice. 2011; 18:201-206.

Hedmer M, Tinnerberg H, Axmon A and Jönsson BAG. Environmental and biological monitoring of antineoplastic drugs in four workplaces in a Swedish hospital. Int Arch Occup Environ Health. 2008; 81:899-911.

Hirst M, Tse S, Mills DG and Levine L. Caution on handling antineoplastic drugs. N Engl J Med. 1983; 309:188-189.

Hirst M, Tse S, Mills DG and Levin L. Occupational exposure to cyclophosphamide. Lancet. 1984; 1:186-188.

Huang YW, Jian L, Zhang MB, Zhou Q, Yan XF, Hua XD, Zhou Y and He JL. An investigation of oxidative DNA damage in pharmacy technicians exposed to antineoplastic drugs in two Chinese hospitals using the urinary 8-OHdG assay. Biomed Environ Sci. 2012; 25:109-116.

Ikeda K, Yagi Y, Tkegami M, Lu Y, Morimoto K and Kurokawa N. Efforts to ensure safety of hospital pharmacy personnel occupationally exposed to antineoplastic drugs during a preparation task. Hosp Pharm. 2007; 42:209-218.

Kopp B, Crauste-Manciet S, Guibert An, Mourier W, Guerrault-Moro MN, Ferrari S, Jomier JY, Brossard D and Schierl R. Environmental and biological monitoring of platinum-containing drugs in two hospital pharmacies using positive air pressure isolators. Ann Occup Hyg. 2013; 57:374-383.

Mader RM, Rizovski B, Steger GG, Wachter A, Kotz R and Rainer H. Exposure of oncologic nurses to methotrexate in the treatment of osteosarcoma. Arch Environ Health. 1996; 51:310-314.

Maeda S, Miyawaki K, Matsumoto S, Oishi M, Miwa Y and Kurokawa N. Evaluation of environmental contaminations and occupational exposures involved in preparation of chemotherapeutic drugs. Yakugaku Zasshi. 2010; 130:903-910.

Mason HJ, Blair S, Sams C, Jones K, Garfitt SJ, Cuschieri MJ and Baxter PJ. Exposure to antineoplastic drugs in two UK hospital pharmacy units. Ann Occup Hyg. 2005; 49:603-610.

Minoia C, Turci R, Sottani C, Schiavi A, Perbellini L, Angeleri S, Draicchio F and Apostoli P. Application of high performance liquid chromatography/tandem mass spectrometry in the environmental and biological monitoring of health care personnel occupationally exposed to cyclophosphamide and ifosfamide. Rapid Commun Mass Spetrom. 1998; 12: 1485-1493.

Minoia C, Turci R, Sottani C, Schiavi A, Perbellini L, Angeleri S, Frigerio F, Draicchio F and Apostoli P. Risk assessment concerning hospital personnel participating in the preparation and administration of antineoplastic drugs. [Italian] Giornale Italiano di Medicina del Lavoro ed Ergonomia. 1999; 21:93-107.

Ndaw S, Denis F, Marsan P, d'Almedia A and Robert A. Biological monitoring of occupational exposure to 5-fluorouracil: urinary α-fluoro-β-alanine assay by high performance liquid chromatography tandem mass spectrometry in health care personnel. J Chromatogr B. 2010; 878:2630-2634.

Nussbaumer S, Bonnabry P, Veuthey JL and Fleury-Souverain S. Analysis of anticancer drugs: a review. Talanta. 2011; 85:2265-2289.

Nygren O and Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health. 1997; 70:209-214.

Nyman H, Jorgenson J and Slawson MH. Workplace contamination with antineoplastic agents in a new cancer hospital using a closed-system drug transfer device. Hosp Pharm. 2007; 42:219-225.

Pethran A, Hauff K and Hessel H . Biological, cytogenetic and ambient monitoring of exposure to antineoplastic drugs. J Oncol Pharm Practice. 1998; 4:57.

Pethran A, Schierl R, Hauff K, Grimm C-H, Boos K-S and Nowak D. Uptake of antineoplastic agents in pharmacy and hospital personnel. Part I: monitoring of urinary concentrations. Int Arch Environ Health. 2003; 76:5-10.

Pieri M, Castiglia L, Basilicata P, Sannolo N, Acampora A and Mirglia N. Biological monitoring of nurses exposed to doxorubicin and epirubicin by a validated liquid chromatography/fluorescence detection method. Ann Occup Hyg. 2010; 54:368-376.

Ramphal R, Bains T, Vaillancourt R, Osmond MH and Barrowman N. Occupational exposure to cyclophosphamide in nurses at a single center. J Occup Environ Med. 2014; 56:304-312.

Rekhadevi PV, Sailaja N, Chandrasekhar M, Mahboob M, Rahman MF and Grover P. Genotoxicity assesment in oncology nurses handling anti-neoplastic drugs. Mutagenisis. 2007; 22:395-401.

Sabatini L, Barbieri A, Lodi V and Violante FS. Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings. Med Lav. 2012;103(5):394-401.

Sessink PJM, Boer KA, Scheefhals APH, Anzion RBM and Bos, RP. Occupational exposure to antineoplastic agents at several departments in a hospital: Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992; 64:105-112.

Sessink PJM, Joost HC, Pierik FH, Anzion RBM and Bos RP. Occupational exposure of animal caretakers to cyclophosphamide. J Occup Med. 1993; 35:47-52.

Sessink PJM, Cerná M, Rössner P, Pastorkova A, Bavarova H, Frankova K Anzion RB and Bos RP. Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents. Mutat Res. 1994; 309:193-199.

Sessink PJM, Friemèl NSS, Anzion RBM and Bos RP. Biological and environmental monitoring of occupational exposure of pharmaceutical plant workers to methotrexate. Int Arch Occup Environ Health. 1994; 65:401-403.

Sessink PJM, Timmersmans JL, Anzion RB and Bos RP. Assessment of occupational exposure of pharmaceutical plant workers to 5-Fluorouracil. J Occup Med. 1994; 36:79-83.

Sessink PJM, Van de Kerkhof MCA, Anzion RB, Noordhoek J and Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: Is skin absorption an important exposure route? Arch Environ Health. 1994; 49:165-169.

Sessink PJM, Wittenhorst BCJ, Anzion RBM and Rob RP. Exposure of pharmacy technicians to antineoplastic agents: Reevaluation after additional protective measures. Arch Environ Health. 1997; 52:240-244.

Sottani C, Tranfo G, Bettinelli M, Farranda P, Spagnoli M and Minoia C. Trace determination of anthracyclines in urine : a new high-performance liquid chromatography/tandem mass spectrometry method for assessing exposure of hospital personnel. Rapid Commun Mass Spectrom. 2004; 18:2426-2436.

Sottani C, Porro B, Cornelli M, Imbriani M and Minoia C. An analysis to study trends in occupational exposure to antineoplastic drugs among health care workers. J Chromatog B. 2010; 878:2593-2605.

Sottani C, Porro B, Imbriani M and Minoia C. Occupational exposure to antineoplastic drugs in four Italian health care settings. Toxicol Lett. 2012; 213:107-115.

Stuart A, Stephens AD, Welch L and Sugarbaker PH. Safety monitoring of the coliseum technique for heated intraoperative intraperitoneal chemotherapy with mitomycin C. Ann Surg Oncol. 2002; 9:186-191.

Sugiura S, Asano M, Kinoshita K, Tanimura M and 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 Practice. 2010; 17:14-19.

Suguira S, Nakanishi H, Asano M, Hashida T, Tanimura M, Hama T and Nabeshima T. Multicenter study for environmental and biological monitoring of occupational exposure to cyclophosphamide in Japan. J Oncol Pharm Practice. 2010; 17:20-28.

Tanimura M, Yamada K, Sugiura S, Mori K, Nagata H, Tadokoro K, Miyake T, Hamaguchi Y, Sessink P, Nabeshima T. An environmental and biological study of occupational exposure to cyclophosphamide in the pharmacy of a Japanese community hospital designated for the treatment of cancer. J Health Sci. 2009; 55: 750-756.

Tuerk J, Reinders M, Dryer M, Kiffmeyer TK, Schmidt KG and Kuss HM. Analysis of antibiotics in urine and wipe samples from environmental and biological monitoring- comparison of HPLC with UV-, single MS- and tandem MS-detection. J Chromatog. 2006; 831:72-80.

Turci R, Sottani C, Ronchi A and Minoia C. Biological monitoring of hospital personnel occupationally exposed to antineoplastic agents. Tox Lett. 2002; 134:57-64.

Turci R, Sottani C, Spagnoli G and Minoia C. Biological and environmental monitoring of hospital personnel exposed to antineoplastic agent: a review of analytical methods. J Chromatog B. 2003; 789:169-209.

Turci R, Sottani C, Schierl R and Minoia C. Validation protocol and analytical quality in biological monitoring of occupational exposure to antineoplastic drugs. Tox Lett. 2006; 162:256-262.

Turci R, Minola C, Sottani C, Coghi R, Severi P, Castriotta C, Del Bianco M and Imbriani M. Occupational exposure to antineoplastic drugs in seven Italian hospitals: the effect of quality assurance ad adherence to guidelines. J Oncol Pharm Practice. 2011; 17:320-332.

Ursini CL, Cavallo D, Colombi A, Giglio M, Marinaccio A and Iavicoli S. Evaluation of early DNA damage in healthcare workers handeling antineoplastic drugs. Int Arch Occup Environ Health. 2006; 80:134-140.

Venitt S, Crofton-Sleigh C, Hunt J, Speechley V and Briggs K. Monitoring exposure of nursing and pharmacy personnel to cytotoxic drugs: Urinary mutation assays and urinary platinum as markers of absorption. Lancet. 1984; 1:74-77.

Villarini M, Dominici L, Piccinini R, Fatigoni C, Ambrogi M, Curti G, Morucci P, Muzi G, Monarca S and Moretti M. Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis. 2011; 26(3):359-369.

Wick C, Slawson MH, Jorgenson JA and Tyler LS. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health-Syst Pharm. 2003; 60:2314-2320.

Yoshida J, Tei G, Mochizuki C, Masu Y, Koda S and Kumagai S. Use of a closed system device to reduce occupational contamination and exposure to antineoplastic drugs in the hospital work environment. Ann Occup Hyg. 2009; 53:153-160.

Yoshida J, Koda S, Nishida S, Yoshida T, Miyajima K and Kumagai S. Association between occupational exposure levels of antineoplastic drugs and work environment in five hospitals in Japan. J Oncol Pharm Practice. 2010; 17:29-38.

Yuki M, Sekine S, Takase K, Ishida T and Sessink PJM. Exposure of family members to antineoplastic drugs via excreta of treated cancer patients. J Oncol Pharm Pract. 2012; 19:208-217.

Ziegler E, Mason HJ and Baxter PJ. Occupational exposure to cytotoxic drugs in two UK onkology wards. Occup Environ Med. 2002; 59:608-612.

 
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