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.
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.
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.
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.
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 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, 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.
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.
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.
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.
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, 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 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.
Jakab MG, Major J, 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.
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, 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.
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, 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.
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, 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.
Burgaz S, Karahal2l B, Bayrak P, TaÕk2n L, Yavuzaslan F, B`kesoy
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.
Deng H, Zhang M, He J, Wu W, Jin L, Zheng W, Lou J, Wang B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005; 20:351-357.
Fucic A, Jazbec A, Mijic A, Seso-Simic 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, 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.
Laffon B, Teixeira JP, Silva S, Loureiro J, Torres J, Pásaro E,
Méndez, 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. 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.
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, 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.
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.
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.
Cavallo D, Ursini CL, Perniconi B, Francesco AD, 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.
Deng H, Zhang M, He J, Wu W, Jin L, Zheng W, Lou J, Wang B. Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis. 2005; 20:351-357.
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.
Jakab MG, Major J, 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, 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.
Laffon B, Teixeira JP, Silva S, Loureiro J, Torres J, Pásaro E,
Méndez, 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.
Mäki-Paakkanen J, Walles S, Osterman-Golkar S and Norppa H. Single-strand
breaks, chromosome aberrations, sister-chromatid exchanges and micronuclei
in blood lymphocytes of workers exposed to styrene during the production
of reinforced plastics. Environ Mol Mutagen. 1991;17:27-31.
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, 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, Fuchs J. Detection of primary DNA damage:
applicability to biomonitoring of genotoxic occupational exposure and
in clinical therapy. Pharmacogenet. 1995; 5:S118-S122.
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.
Yang D, Xu S, 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.
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, 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.
3. 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.
Jagun O, Ryan M and Waldron HA. Urinary thioether excretion in nurses
handling cytotoxic drugs. Lancet. 1982;2:443-444.
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.
Bos RP, Weissenberger BFJ and Anzion RBM. a-Fluoro-8-alanine in urine
of workers occupationally exposed to 4-fluorouracil in a 5-flourouracil-producing
factory. Biomarkers. 1998;3:81-87.
Burgaz S, Karahal2l B, Bayrak P, TaÕk2n L, Yavuzaslan F, B`kesoy
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, Ursini CL, Perniconi B, Francesco AD, 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.
Deschamps F, Marinutti-Liberge and Lamiable D. Biological monitoring
of occupational exposure to cytostatic drugs with platinum. Cancer Detect
Prev Online. Available: http://www.cancerprev.org/Journal/Issues/26/101/1193/4393
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.
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. 1994a; 65:339-342.
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.
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.
Hirst M, Tse S, Mills DG and Levin L. Occupational exposure to cyclophosphamide.
Lancet. 1984;1:186-188.
Hirst M, Tse S, Mills DG and Levine L, Caution on handling antineoplastic
drugs. N Engl J Med. 1983;309:188-189.
Mader RM, Rizovski B, Steger GG, Wachter A, Kotz R and Rainer. Exposure
of oncologic nurses to methotrexate in the treatment of osteosarcoma.
Arch Environ Health. 1996; 51:310-314.
Mason HJ, Blair S, Sams C, Jones K, Garfitt SJ, Cuschieri MJ, 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.
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.
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.
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, 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, 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, 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, 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.
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, 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, Minoia C. Validation protocol and analytical quality in biological monitoring of occupational exposure to antineoplastic drugs. Tox Lett. 2006; 162:256-262.
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.
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.
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