title: Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals.
abstract: The aims of the study were to clarify potential exposure situations to anticancer agents during industrial processing, drug manufacture and hospital administration, using cyclophosphamide (CP) as the model compound. CP is considered an animal and human carcinogen, and it is shown to be an indirect mutagen in various test systems using several genetic endpoints. Environmental monitoring was performed by collecting ambient air samples during the different processing and handling stages. Both stationary and personal sampling was used. CP was analyzed by liquid chromatography (HPLC) and mass spectrometry (MS). The process materials and intermediates were also analyzed for genotoxic activity using the Ames test and SCE induction in CHO cells as endpoints. Biological monitoring studies were performed on 147 persons representing 5 groups of workers, control subjects and patients. In the experimental part of the project, the intermediates in the CP manufacturing process, CP I (nor-nitrogen mustard) and CP II (phosphoroxydichloride mustard) were found directly active in the 2 genotoxicity tests. These findings led to improvements in work hygiene when handling CP I and CP II in the process. The CP measurements showed that the highest potential-exposure sites occurred during specific operations of the process, e.g., during emptying of the drying drum and during tablet mass preparation (the range of CP concentrations in air was 0.16-0.49 mg/m3). The correlation between indirect genotoxicity and chemical analyses of the ambient air samples was good, revealing the activity to be due to cyclophosphamide. However, the air samples were found mutagenic without metabolic activation also in the beginning of the process; this is obviously due to CP II particles in the ambient air, since no CP was detected chemically. The personal protection of workers in the plant collaborating in the study is efficient and the production unit is equipped with the best available techniques to protect both the personnel and the quality of the drug. Both the urine mutagenicity analyses using strain TA1535 of Salmonella typhimurium as indicator and the cytogenetic analyses of peripheral blood lymphocytes using sister-chromatid exchanges or structural chromosomal aberrations as endpoints were negative. However, a statistically nonsignificant trend in increased number of micronuclei was observed in binucleated lymphocytes of the worker groups as compared with controls. The studies on the hospital use of CP were performed in 3 oncological units and 1 pharmacy unit.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Institute of Occupational Health, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Sorsa
authors.forename: L
authors.initials: L
authors.lastname: Pyy
authors.forename: S
authors.initials: S
authors.lastname: Salomaa
authors.forename: L
authors.initials: L
authors.lastname: Nylund
authors.forename: J W
authors.initials: JW
authors.lastname: Yager
mesh_terms: D000393:Air Pollutants / Q000032:analysis; D002467:Cell Nucleus / Q000648:ultrastructure; D002869:Chromosome Aberrations; D003520:Cyclophosphamide; D004345:Drug Industry; D006761:Hospitals; D006801:Humans; D008214:Lymphocytes / Q000648:ultrastructure; D009152:Mutagenicity Tests; D009784:Occupational Diseases / Q000139:chemically induced / Q000175:diagnosis*; D012854:Sister Chromatid Exchange
chemical_list: D000393:Air Pollutants; D003520:Cyclophosphamide