Annals of Occupational Hygiene Advance Access originally published online on June 17, 2005
Annals of Occupational Hygiene 2005 49(7):611-618; doi:10.1093/annhyg/mei029
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© 2005 British Occupational Hygiene Society Published by Oxford University Press
Original Article |
A Case Study: Surface Contamination of Cyclophosphamide due to Working Practices and Cleaning Procedures in Two Italian Hospitals
1 Dipartimento di Medicina Pubblica e della Sicurezza Sociale,Università degli Studi di Napoli, Naples, Italy; 2 Dipartimento di Medicina Sperimentale—Sezione di Medicina del Lavoro—Igiene e Tossicologia Industriale, Seconda Università degli Studi di Napoli, Naples, Italy; 3 Servizio di Prevenzione e Protezione—Azienda Ospedaliera di Verona presso Istituti Biologici II, Università degli Studi di Verona, Verona, Italy
* Author to whom correspondence should be addressed. Tel: +39 081 7463413; fax: +39 081 5469185; e-mail: acampora{at}unina.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The efficacy of preventive and organisational measures implemented in Italy to prevent the contamination of cytotoxic drug preparation rooms has been investigated, and oncologic wards of two Italian hospitals were examined. The sampling strategy was based not only on potential sources of contamination but also on responses to detailed questionnaires on workplace practices and work organisation. Wipe samples were taken from different surfaces of preparation rooms, before and after the work shift, over a span of a month. Cyclophosphamide was taken as the marker drug that reflects exposure to cytotoxic drugs, being measurable by GC/MS. In one of the two hospitals (Hospital A), a large amount of cyclophosphamide was found, both before and after shift, on the workbench (median value, 2.55 µg dm–2, before shift), on the floor between the operator working position and the waste bin (>10 µg dm–2, after shift), as also on door handles and storage shelves. No quantifiable levels of cytotoxic drug were detected in the second hospital investigated (Hospital B). These results could be attributed to the efficacy of cleaning procedures and working practices. In fact, both hospitals were provided with vertical-laminar airflow hoods and the (male) nurses had attended special training courses; but in Hospital A, cleaning procedures were carried out without substances used specifically for the cleaning of surfaces contaminated by cytotoxic drugs such as sodium hypochlorite. Working practices did not include Luer Lock devices. Cyclophosphamide concentrations found in both hospitals, compared with the quantities of drug handled, gave evidence of the importance of the correct handling of cytotoxic agents as a major tool in reducing contamination levels. The results reveal the insufficiency of the risk management measures which do not take into account working practices that are prevailing, and stress the necessity for periodic environmental monitoring, indispensable for evolving effective procedures to prevent antineoplastic drug exposure.
Keywords: cyclophosphamide • environmental monitoring • wipe test • working conditions
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Despite their therapeutic effect, many of the antineoplastic drugs have mutagenic, teratogenic, or carcinogenic properties (Black and Livingston, 1990a
,b; Otto and Rubben, 2004), where a no-effect threshold dose cannot be identified (Stahlmann et al., 1985; Rogers, 1987; Baxter, 1991). As a consequence, there has been concern over potential exposure to and its after effects on healthcare workers who handle cytotoxic or antineoplastic drugs; and in the past 10 years numerous guidelines have been issued for the management of antineoplastic drugs (Canadian Society of Hospital Pharmacists, 1984; American Society of Hospital Pharmacists, 1990; Allwood et al. 1997; Goodman, 1998). There is a large number of published studies that have been carried out both in Europe and in the USA, examining exposure of hospital staff to cytotoxic drug. These studies include measurements of environmental and surface contamination and the amount of drugs detectable in the urine of staff involved both in the preparation of cytotoxic drugs and in their administration to patients (Hirst et al., 1984; Sessink et al., 1992, 1995, 1997; Ziegler et al., 2002).
In Italy, labour legislation relating to the healthcare of workers exposed to chemical agents includes both Legislative Decrees and Guidelines issued by National Agencies for workers protection (I.S.P.E.S.L., Istituto Superiore per la Prevenzione e la Sicurezza sul Lavoro, Institute for Labour Safety and Prevention). Legislative Decrees, such as 626/1994, 66/2000 and 25/2002 (D. Lgs. 626/1994; D.Lgs 66/2000; D.Lgs. 25/2002), incorporating European Directives (89/391/CE, 89/654/CE, 89/655/CE, 89/656/CE, 90/269/CE, 90/270/CE, 90/394/CE, 90/679/CE, 93/88/CE, 95/63/CE, 97/42/CE, 98/24/CE, 99/38/CE); and, in the particular case of antineoplastic agents, specific Guidelines have been issued in 1999 and 2000 (G.U. 236/1999; I.S.P.E.S.L., 1999). Nevertheless, only a few studies (Minoia et al., 1999a,b; Perico et al., 2003) are reported in the literature on the monitoring of Italian hospitals; and although strict health and safety rules have been established and implemented, the potential health hazard for persons handling these drugs is still a matter of concern for hospital staff members.
The aim of the present study was to verify if, and how, Italian Guidelines were actually implemented, i.e. if they were efficacious in lowering contamination levels, and if the exposure risk on wards where antineoplastic drugs were handled was appropriately controlled. To achieve this, the hospitals for study had to be chosen randomly, suitable questionnaires framed and responses obtained, and contamination levels measured. In particular, two Italian hospitals were examined by analysing data obtained from detailed questionnaires about preventive measures, working practices and cleaning procedures; and an environmental monitoring of surfaces of drug preparation rooms that was carried out. Since cyclophosphamide has been identified to be the most suitable of indicators of potential exposure to antineoplastic drugs mixtures (G.U. 236/1999, Italy), the environmental monitoring was carried out by measuring cyclophosphamide levels in wipe samples.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study design
Sampling procedures were instituted in two Italian hospitals, referred to as Hospitals A and B. The two hospitals were asked to provide detailed plans of the arrangement of rooms and from which twelve sampling surfaces were selected, based on potential sources of contamination. Figure 1 shows a schematic representation of drug preparation rooms. Sampling spots from 1 to 8 were intended to investigate contamination arising from possible spillage of cyclophosphamide during vial handling: sampling spots 1–5 were located on the workbench and on the internal and external fore planes of the laminar flow hood used during the drug preparations; sampling spots 6–8 were on the floor near the operator work location. The contamination of objects such as door handles, transport box surfaces and drug-safety cabinets (sampling spots 9–12) would indicate that either the gloves, used as a protective measure, are not immediately removed after drug preparation, or that the outer surfaces of vials are contaminated, as recently reported in literature (Mason et al., 2003).
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Environmental monitoring was carried out by collecting wipe samples over the span of a month, at three different times: before and after work shifts on the same day in positions of close proximity, and 15 times after one single drug preparation that included cyclophosphamide, without cleaning the workbench. Samples collected before a shift were intended to verify the efficacy of cleaning procedures followed by the hospital cleaning staff. Since the tasks of (male) nurses included both drug preparation and cleaning of workbenches after each single preparation, the working method as a whole was investigated by collecting after-work samples, although the samples collected after one single preparation (without workbench cleaning) are related exclusively to the drug handling procedure.
The working organisation was investigated using a questionnaire on the following aspects: (i) exposure: the number of nurses involved in drug preparation and administration; weekly and/or daily shifts; the average amount of drugs handled weekly and/or daily; (ii) drug storage, preparation, waste disposal; work practices, such as utilisation of the laboratory for any work other than the preparation of cytostatic drugs; use of the different rooms dedicated to their storage and preparation; restriction of access to personnel only; the amount of cyclophosphamide handled each day; to where the waste is removed from the workbench and mode of removal; (iii) cleaning: frequency of cleaning of laboratory work-surfaces and floors; methods of cleaning, and chemical agent used (sodium hypochlorite, alcohol, generic detergent). Additional information about protective measures and safety occupational training courses was also collected.
Wipe samples
Wipe-tests were carried out by using a 9 x 20 cm gauze (TNT, Farmac-Zabban, Italy) dampened in 2 ml of a 0.03 M sodium hydroxide solution, wiped on surfaces and placed in a 50 ml polypropylene tube. In the case of plane areas, sampling surfaces were defined by placing on them a plastic object with an open surface of 15 x 15 cm (2.25 dm2); when handles were sampled, the surface area was measured by approximating the handle to a rectangle.
To avoid sample decay (Schmaus et al., 2002), each sample was stored at 4°C up to the end of the whole sampling period (8 h) whereafter it was frozen at –20°C. Frozen samples were transported to the laboratory and analyzed within 10 days.
After defrosting, 18 ml of the sodium hydroxide solution was added to each test-tube and the sample divided into two aliquots. To one aliquot was added 100 µl of a freshly prepared aqueous solution of 50 ng µl–1 iphosphamide (from Baxter, Germany; purity, 95%), and used as internal standard. Samples were shaken for 10 min, mixed in a vortex mixer, and centrifuged (15 min, 3000 r.p.m.). The second aliquot was used for the detection of iphosphamide: aliquots of five samples were combined and purified by the following procedure without addition of the internal standard: samples containing iphosphamide were discarded as far as the quantitative determination was concerned; the analytes were purified from matrix by liquid–liquid extraction with 30 ml of diethyl ether (twice) and the organic layers combined; residual water was removed with anhydrous sodium sulfate; samples were dried, dissolved in 100 µl of ethyl acetate and derivatized by adding 100 µl of heptafluorobutyric anhydride (Sannolo et al., 1999); after 20 min at 70°C, the solvent was evaporated under a stream of nitrogen and the residue stored at 4°C. Samples were dissolved in 100 µl of isooctane and analysed by Gas Chromatography/Mass Spectrometry (TraceGC/PolarisQ, ThermoFinnigan, San Jose', CA, USA); chromatographic and instrument conditions are described elsewhere (Sannolo et al., 1999). Data were elaborated by Xcalibur software, version 1.2 (ThermoFinnigan). Quantitative analyses were based on standard curves from 0.25 to 250 ng µl–1 (corresponding to 0.01–10.0 µg dm–2). Wipe samples with higher drug concentrations were diluted 1:10. When, despite the dilution, the amount of cyclophosphamide was >10.0 µg dm–2, the result was reported as >10.
Standard curves were obtained by analyzing calibration standards samples, prepared as follows: known amounts of aqueous solutions of cyclophosphamide (from Baxter, Germany; purity, 95%) were added to clean surfaces of a chemical hood, previously cleaned with sodium hypochlorite 5%, in order to have five cyclophosphamide concentrations in the range 0.01–10.0 µg dm–2, surfaces were then wiped and samples processed as described above. Quality control samples were also prepared with concentrations of 0.1, 1 and 5 µg dm–2. Blank wipe samples (with neither cyclophosphamide nor iphosphamide added) and zero-point samples were prepared (by adding only iphosphamide) were used to evaluate the specificity of the method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Working conditions
Table 1 summarizes information about working conditions (cyclophosphamide amounts usually handled with respect to the total antineoplastic drugs used, the number of drug preparations carried out, cleaning procedures and working practices) collected by means of a questionnaire in Hospitals A and B.
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The percentage ratios between the amount of cyclophosphamide and the total antineoplastic agents prepared in a day ranged from 76.2 to 89.2% and from 61.3 to 89.2%, respectively, for Hospitals A and B.
The absolute amount of cyclophosphamide handled in a day ranged from 10 800 to 21 600 mg (Hospital A) and from 33 750 to 71 550 mg (Hospital B).
The total number of daily preparations of antineoplastic drugs ranges from 9 to 15 and from 38 to 60 for Hospitals A and B, respectively. The number of daily cyclophosphamide preparations accounts for 66.7–88.9% and 50.0–93.0% of the total number of antineoplastic drugs preparations (Hospitals A and B, respectively).
The number of (male) nurses deployed on drug preparations was 13 for the Hospital A and 30 for the Hospital B, with a turn shift of 8 h day–1.
In both the hospitals examined the nurses involved in drug preparations had attended a special training course and were provided with written guidelines on working practices to be adopted when handling antineoplastic drugs. They prepare drugs in a vertical laminar flow hood on 5 successive days. Work shifts are organised so that one subject is employed in drug preparation for a whole week in Hospital B, although in Hospital A one subject prepares antineoplastic drugs for 3 days a week for a maximum of 2 consecutive days. For each subject, the number of daily preparations of cyclophosphamide ranged from 1 to 5 in Hospital A, and from 5 to 12 in Hospital B.
Potential causes of contamination, such as unsuitable cleaning procedures and working practices were investigated. The cleaning of working surfaces (workbenches, storage shelves and transport boxes) is mainly assigned to the nursing staff itself, but only the workbench planes of the hood are cleaned after each preparation. The analytical procedure introduced by Guidelines, concerning the cleaning of surfaces potentially contaminated by antineoplastic drugs (G.U. 236/1999, Italy), involves the use of sodium hypochlorite as specific detergent. Hospital A does not use sodium hypochlorite for workbench cleaning; in both hospitals floors and furniture are cleaned by the cleaning staff, with detergents non-specific for antineoplastic drugs. While Hospital B adopts the Luer Lock device during drug preparation (as suggested by Guidelines), nurses of Hospital A prepare the drugs that are to be administered to patients using two needles: one to inject the physiological solution into the lyophilized drug vial, and the other to avoid the phenomenon of overpressure.
For personal protection, the (male) nurses wear latex gloves, hairnets and special clothing. As for general protective measures, Hospital A is not provided with a centralized air system; in both hospitals, the rooms are assigned to the exclusive use of drug preparation where the only indispensable article is the furniture.
Wipe samples
The detection limit for cyclophosphamide was measured by analysing wipe samples from clean surfaces (2.25 dm2 each) previously spread with decreasing known amounts of cyclophosphamide. A ratio of signal to noise of 3:1 corresponded to 0.00135 µg per sample, hence the detection limit was fixed at 0.0006 µg dm–2. The detection limit for ifosphamide was 0.003 µg dm–2. The quantification limit for cyclophosphamide was established as 10 times the detection limit (0.006 µg dm–2). Experiments were repeated in triplicate.
Even though the literature reports many studies on the quantification of cyclophosphamide by wipe tests, there is no standardized and validated procedure. Hence the specificity of the method was evaluated by analysing blank and zero-point samples. In both cases, no peaks at the cyclophosphamide retention time were detectable. The calibration curves used for cyclophosphamide quantification reflected the latest FDA guidelines (US FDA: Bioanalytical Method Validation, 2001), which state that precision and accuracy should not deviate by >20%, with which the results obtained were in line. In fact, both within-batch and between-batch accuracy and precision were <14%, and from 5 to 15%, respectively. Moreover, the calibration curves had correlation coefficients 
0.9949, showing good linearity in the dynamic range evaluated.
The quantification of cyclophosphamide in unknown samples implied a calibration curve for every 20 unknown samples; i.e. for every 20 unknown samples, five calibration standard samples were analysed and a calibration curve plotted. In addition, quality control samples were analysed for every 5 unknown samples. Wipe samples from 1 to 8 were collected from the two hospitals on analogous surfaces (Fig. 1). Each examined surface was monitored at three different work times. First: every day after the room was cleaned, before the work shift, over the period of a month (30 samples for each location). Second: on 15 chosen days, (male) nurses were asked not to clean working surfaces after a single preparation, and wipe samples were taken after the preparation. Third: after the shift; in this case, the (male) nurses were aware of the monitoring process but this knowledge was expected to have no effect on the study because they were asked to work as usual. Altogether, 400 wipe samples were taken. The number of samples tested positive for cyclophosphamide contamination (without ifosphamide) was 65%, 16% of samples were discarded because they contained both drugs, the others were all negative.
Surface monitoring was carried out on those days when iphosphamide was not administered, since it was used here as internal standard. Moreover, wipe samples were first analysed after mixing together 5 samples without the addition of the internal standard, in order to identify samples eventually containing iphosphamide. In some cases (5 samples) data relating to quantitative determination were discarded because of the presence of iphosphamide; the other samples were independently analysed and the cyclophosphamide amount was determined as previously described. The results obtained, for both hospitals, are as reported in Table 2. Cyclophosphamide was below the quantification limit in many samples from Hospital B, except for the amount found on the floor between the waste bin and the operator working position soon after drug preparation (Table 2, sample 6, columns 3 and 5). On the contrary, Hospital A presented high average levels of contamination—often beyond the upper limit of the quantification range (>10 µg dm–2)—and the floor showed contamination even after the room was cleaned (Table 2, samples 6–8, first column).
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Wipe samples from 9 to 12 (Table 3), corresponding to door handles, transport boxes and cabinet (the cabinet was absent in the preparation room of Hospital B), were taken after the work shift. They also showed, in this case, high contamination levels in Hospital A, ranging from 0.45 (drug cabinet) to >10 µg dm–2 (upper plane of the transport box; Table 3, samples 12 and 10, respectively). In the case of Hospital B, detectable amounts of cyclophosphamide, greater than the detection limit and below the quantification limit, were found on the transport box (Table 3, sample 10).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study was intended to evaluate if organisational measures and working practices guidelines issued in Italy to prevent health hazard are adequate and/or actually implemented in order to reduce the exposure to antineoplastic agents. Two Italian hospitals were considered. From questionnaires submitted, we observed that both hospitals conformed to Italian guidelines; in fact they were provided with vertical laminar airflow hoods, personal equipment such as gloves tested for antiblastic drugs (or latex double gloves for use when preparing the drugs), hairnets and disposable coats. Nurses involved in drug preparation tasks attended special training courses and were provided with written procedures regarding drugs handling and workbench surface cleaning. The organisation of work imposes a restriction on the number of (male) nurses involved in the preparations, a weekly shift rotation and an anteroom for drug storage. These findings show that the Guidelines for the safe handling of cytotoxic drugs issued up to now are implemented both as regards protective equipment and organisational measures. Nevertheless, we found detectable levels of cyclophosphamide on many surfaces, in both hospitals. Vertical laminar flow hoods may decrease cyclophosphamide air concentrations, but the release of aerosols could not be wholly prevented, as was largely reported in the literature, and as indicated by the antineoplastic drugs detected on different surfaces. The contamination levels of floors and storage shelves show that there is a real possibility of these compounds being spread throughout the facilities even when vertical laminar flow hoods are present in the preparation room (Schmaus et al., 2002
). Working practices and cleaning procedures could be improved in order to reduce contamination levels, so we monitored surfaces in different locations to establish a possible correlation between cyclophosphamide contamination and working practices. Working methods were investigated by taking wipe samples soon after a shift without cleaning the surfaces. The operators are to handle the drug on the central part of the workbench and they should wrap the waste up, before depositing it from the workbench into the waste bin. However we found high contamination levels on both sides (above all on the right side) of the workbench plane, suggesting that potentially contaminated objects (flacons, gauze used for avoiding spillage, syringes etc.) are probably placed on the work surface. Also, the contamination level of the floor between the hood and the waste bin showed that wastes are discarded in the waste bin without exercising adequate care. Working practices were also investigated by sampling door handles and transport box surfaces and, in Hospital A, high contamination levels were found on such surfaces too. The presence of cyclophosphamide on handles, both of the room door and of the drug storage cabinet, should be attributed to wrong use of the gloves (not removed immediately) or to inadequate cleaning procedures. Contamination of the transport box surfaces could be on account of the wrong use of the gloves and/or to the absence of disposable papers. Normally, it would be reasonable to assume a positive correlation between use and exposure. According to our investigation, the two hospitals examined deal with different quantities of cyclophosphamide in a month (Table 1). In Hospital B, where a higher amount of cyclophosphamide was handled daily, we found only traces of the drug. Furthermore, the comparison of the results of contamination reveals that Hospital B had lower contamination levels than Hospital A at most locations. This could be explained if it is assumed that the correct handling of cytotoxic agents rather than the quantity prepared is the more important in minimizing contamination. Nevertheless, drug contamination was also found in particular locations, such as internal and external vertical panels of the hood, in the case of Hospital B, too. This supports the hypothesis that contamination is related not only to correct working practices but also to the adoption of Luer Lock device, that can avoid the spillage of the drug, and to the frequency of cleaning up with adequate detergents. The importance of the cleaning frequency in environmental contamination was shown by the fact that, in some cases, we found detectable amounts of iphosphamide even if this substance had not often been used during the sampling month, and had not been used at all on the days we took wipe samples. We investigated cleaning methods by sampling each surface before and after the shift performed under normal working conditions, i.e. without instructing the (male) nurses not to clean the workbench. Data relating to samples taken before the shift correspond to contamination levels that can be found after cleaning of the drug preparation room by the hospital cleaning staff; while the samples taken after the shift reflect the efficacy of cleaning procedures carried out by the (male) nurses. Figure 2 shows the trend of cyclophosphamide contamination levels in each location of Hospital A reflecting the different steps in working and cleaning up. The cleaning staff do not have to clean workbench surfaces; consequently there is no difference between contamination levels before and after cleaning (Fig. 2, samples 1–3, white and black bars, respectively). On the contrary, as expected, high levels of contamination were found after a single preparation when (male) nurses were instructed not to clean any surface (Fig. 2, samples 1–3, central bars). On the other hand, in the same three locations the amount of cyclophosphamide found in Hospital B was below the analytical detection limit. These results show that the use of the Luer Lock device actually prevent the contamination of working surfaces; moreover, when Luer Lock devices are not used and cyclophosphamide lies on workbench surface, the use of common detergents is not suitable, because they are not capable of molecular degradation. Samples 6–8 correspond to the floor below the hood. Soon after the shift, large amounts of drug are to be expected (Fig. 2, samples 6–8, grey and black bars) because cleaning of the floor is assigned to specific cleaning staff, who work early in the morning. The effect of this cleaning, which is before the beginning of the shift, is shown in Fig. 2, samples 6–8, white bars. Nevertheless, contamination levels should be reduced as much as possible, and this could be achieved if sodium hypochlorite solutions, instead of polyphenols or generic detergents, are used for floor cleaning, as they are for the workbenches. Locations numbered as 4 and 5 indicate the internal and the external panels of the hood, respectively. The cleaning of these surfaces is not assigned either to the (male) nurses or to the cleaning staff. The latter consider the external parts of the hood to be common furniture, which is why they are cleaned only periodically, and not adequately (Fig. 2, sample 5, white bar). On the other hand, the contamination levels of the internal panel hood before and after the shift are lower than those found after a single drug preparation (>10 µg dm–2), when we specifically instructed the nurses not to clean. This suggests that the nurses do normally clean this surface after a preparation (Fig. 2, sample 4). The generally high levels of contamination found in Hospital A after a single drug preparation when (male) nurses were asked not to clean (Fig. 2, grey bars) clearly indicate inadequate case in drug handling by the (male) nurses themselves.
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The results obtained from this study suggest that several improvements could be effected in working practices, leading to a considerable reduction of contamination levels. As suggested by guidelines on the handling of antineoplastic drugs, any surface in the drug preparation room should be covered with disposable papers, Luer Lock devices are highly recomended and workbenches and transport boxes should be cleaned with sodium hypochlorite on a daily basis. The inside of the hood, including not merely the work plane but also the vertical panels, should be cleaned most frequently.
Finally, environmental as well as biological monitoring analyses should be periodically carried out to verify the efficacy of the preventive and protective measures adopted and to provide a statistical base for assessment of risk and its management, aimed at preventing health hazards arising from exposure to cytotoxic drugs.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This work was supported by I.S.P.E.S.L., Institute for Safety and Prevention, grant no. 66-A/00.
Received November 30, 2004; in final form March 16, 2005
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Allwood M, Stanley A, Wright P. (2002) The cytotoxics handbook, 4th edn. Rodcliffe Medical Press Ud, Abingdon, Oxon.
American Society of Hospital Pharmacists. (1990) ASHP Technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm; 47: 1033–9.[Medline]
Baxter PJ. (1991) Research in occupational health. The UK National Health Service. J Soc Occup Med; 41: 7–9.[Web of Science][Medline]
Black DJ, Livingston RB. (1990a) Antineoplastic drugs in 1990. A review. Drugs; 39: 489–501.[Web of Science][Medline]
Black DJ, Livingston RB. (1990b) Antineoplastic drugs in 1990. A review. Drugs; 39: 652–73.[Web of Science][Medline]
Canadian Society of Hospital Pharmacists. (1981) Guidelines for the handling of hazardous pharmaceuticals. Can J Hosp Pharm; 34: 126–8.[Medline]
D.Lgs. 19 September 1994, n.626 [Legislative Decree] (Italian). Available from: http://www.amblav.it.
D.Lgs. 25 February 2000, n. 66 [Legislative Decree. Workers protection about risks from the exposure to carcinogenic or mutagenic agents] (Italian). Protezione dei lavoratori circa i rischi derivanti dall'esposizione ad agenti cancerogeni o mutageni. Available from: http://www.amblav.it.
D.Lgs. 2 February 2002, n.25 [Legislative Decree. Updating of D.Lgs. 626/94: protective measures about carcinogenic and mutagenic agents] (Italian). Aggiornamento 2002 del Titolo VII del D. Lgs. 626/94: protezione ad agenti cancerogeni e/o mutageni. Available from: http://www.amblav.it.
Goodman I. (1998) Clinical practice guidelines: the administration of cytotoxic chemotherapy. Technical report. Oxford: Royal College of Nursing.
G.U. n. 236, 07/10/1999 [Safety and Hygiene. National Document] (Italian) Sicurezza e Igiene del Lavoro. Documento di Origine Nazionale.
Hirst M, Tse S, Mills DG et al. (1984) Occupational exposure to cyclophosphamide. Lancet; 1: 186–8.[CrossRef][Web of Science][Medline]
I.S.P.E.S.L., Istituto Superiore per la Prevenzione e la Sicurezza sul Lavoro (Institute for Labour Safety and Prevention). Guidelines for the safety and the healthcare of workers exposed to antineoplastic drugs in hospitals (Italian) 5 August 1999.
Minoia C, Turci R, Sottani C. (1999a) Risk assessment concerning hospital personnel participating in the preparation and administration of antineoplastic drugs. (Article in Italian) G Ital Med Lav Ergon; 21: 93–107.[Medline]
Minoia C, Turci R, Sottani C et al. (1999b) 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 Spectrom; 12: 1485–93.
Otto T, Rubben H. (2004) Prevention of bladder cancer. Urologe A; 43: 56–4.
Perico A, Lorini C, Biliotti T et al. (2003) Evaluation of professional exposure to antiblastic chemotherapeutic agents in a Tuscan hospital environment. Ann Ig; 15: 363–71.[Medline]
Rogers B. (1987) Health hazards to personnel handling antineoplastic agents. Occup Med; 2: 513–24.[Medline]
Sannolo N, Miraglia N, Biglietto M et al. (1999) Determination of cyclophosphamide and ifosphamide in urine at trace levels by gas chromatography/tandem mass spectrometry. J Mass Spectrom; 34: 845–9.[CrossRef][Web of Science][Medline]
Schmaus G, Schierl R, Funck S. (2002) Monitoring surface contamination by antineoplastic drugs using gas chromatography-mass spectrometry and voltammetry. Am J Health Syst Pharm; 59: 956–61.
Sessink PJ, Boer KA, Scheefhals AP et al. (1992) 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; 64: 105–12.[CrossRef][Web of Science][Medline]
Sessink PJ, Kroese ED, van Kranen HJ et al. (1995) Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide. Int Arch Occup Environ Health; 67: 317–23.[CrossRef][Web of Science][Medline]
Sessink PJ, Wittenhorst BC, Anzion RB et al. (1997) Exposure of pharmacy technicians to antineoplastic agents: revaluation after additional protective measures. Arch Environ Health; 52: 240–4.[Web of Science][Medline]
Stahlmann R, Bluth U, Neubert D. (1985) Effects of the cyclophosphamide metabolite acrolein in mammalian limb bud cultures. Arch Toxicol; 57: 163–7.[CrossRef][Web of Science][Medline]
US Food and Drug Administration: Center for Drug Evaluation and Research. (2001) Guidance for industry: bioanalytical method validation. Available from: www.fda.gov/cder/guidance/4252fnl.htm.
Ziegler E, Mason HJ, Baxter PJ. (2002) Occupational exposure to cytotoxic drugs in two UK oncology wards. Occup Environ Med; 59: 608–12.
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