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Published on 6 October 2008

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Safe handling of cytotoxic drugs: the need for monitoring and critical risk assessment

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Workers other than pharmacists may not be fully informed about the risks they face when handling cytotoxic drugs, and safe levels need to be decided that can be monitored to improve staff safety

Ludek Blaha
PhD

Lenka Dolezalova
MSc

Pavel Odraska
MSc

Masaryk Memorial
Cancer Institute
Pharmacy Department
RECETOX
Masaryk University
Brno
Czech Republic

Anticancer chemotherapy, which is still the best treatment for most cancers, is recognised as a health hazard for the staff who handle cytotoxic drugs. In recent decades, numerous experimental and epidemiological studies have been conducted and long articles written on the subject, including several recent papers in Hospital Pharmacy Europe. This has resulted in a good awareness among pharmacists. However, it is still extremely difficult to responsibly estimate or predict the real “risks” associated with exposure (or dose) and resulting health problems. Here, we outline several issues that still need to be addressed and that are currently under debate internationally. We also discuss a national research project, CYTO, which aims to introduce reasonable methods for monitoring and biomonitoring of cytotoxics in pharmacies and hospitals in the Czech Republic.

Hazards of cytotoxic drugs
Cytotoxic compounds (along with other drugs such as immunosuppressants) are termed hazardous pharmaceuticals. Their “hazardous properties”, such as mutagenicity, genotoxicity and other biochemical and molecular toxicity mechanisms independent from DNA damage (epigenetic toxicity), contribute to many adverse side-effects. Non-intentional contact with high doses of cytotoxic drugs may result in acute signs of toxicity, such as nausea and vomiting, headache, dizziness, local skin irritation or hair loss that all have been described in occupationally exposed persons.[1-3]

However, chronic exposures to low doses are the real problem. Controlled laboratory experiments and epidemiological studies have related cytotoxic drugs to immunosuppression, reproduction toxicity in women and men,[4-6] embryotoxicity, teratogenicity or abortion,[7,8] and increased risk of cancer.[9] Paradoxically, compounds that treat cancer in one person may lead to tumour development in another. The International
Agency for Research on Cancer (IARC) classifies some antineoplastics into group 1 (“carcinogenic to humans”, eg, cyclophosphamide) or group 2A (“probably carcinogenic to humans”, eg, cisplatin drugs, doxorubicine).

Patient safety has always been the major issue, and antineoplastic drugs are handled appropriately: therapeutic doses are carefully calculated for each individual patient, while drugs are prepared under sterile conditions. However, while manipulating highly potent and toxic drugs brings benefit to patients, it may represent risks to workers at manufacturers, pharmacies and hospitals. Consequently, the “safe for the patient” rule has been updated to the rather more complex “safe for the patient and safe for the worker as well”.

Exposure and staff at risk
The major routes of exposure during occupational exposure to cytotoxic drugs are:

  • Respiration of contaminated air.
  • Skin penetration during dermal contact.
  • Accidental ingestion after transfer of drugs from hands to food.

Amounts from nanograms up to milligrams have been detected in air particles or aerosol form,[10] on floors, walls, benches, shelves, doors, telephones and other surfaces within pharmacies, including administration areas;[10-13] on protective gloves, cloths and linens, lavatories and sanitary rooms;[13,14] as well as on drug packaging materials coming from manufacturers.[15] Some studies have also analysed wipes from workers’ skin (hands and forehead): significant amounts of various cytotoxics were found.[14]

Educated pharmacists are apparently informed about the hazards of cytotoxics, and rooms where drugs are being diluted and prepared into medications are well equipped to provide protection for both product (ie, medicine) and staff. However, the fate of drugs in hospitals is much more diverse including delivery, storage, transport, administration to patients and waste disposal. There are also other “sources” of contamination such as the release of drugs from patients in their sweat, urine or excrement, and all staff who are in daily contact with drug residues, such as technicians, doctors and nurses, may still be poorly informed and protected.

In spite of the widespread distribution of cytotoxics in working areas, also documented by the recent MEWIO nationwide study in Germany,[16] there are several reasons why straightforward risk assessment is difficult. First, there are dozens of diverse cytotoxic drugs with variable physicochemical and biological
properties. These properties affect their individual “fate” outside and inside the human body. For example, our recent laboratory experiments focused on the kinetics of tissue penetration and demonstrated fairly rapid and quantitative (100%) transfer of cyclophosphamide through mucous membranes, while keratinised skin layers seemed to significantly reduce drug uptake (Figure 1). These new findings, along with others such as highly variable polymorphism in drug metabolism,[17] demonstrate that there are still many unknowns that ultimately require further research and attention of risk assessors.

[[HPE40.62]]

Are pharmacists and other workers safe?
Various safety measures have been adopted at different levels – from standards at individual hospitals (employers) to national laws and international guidelines, such as those recently published by ISOPP.[18] In Europe, widely accepted recommendations have been produced by the European Society of Oncology Pharmacy (ESOP) since 2001. Quality Standards for
the Pharmacy Oncology Service (QUAPOS) are now available in 15 languages and provide details on the situation of preparatory rooms within pharmacies, on equipment such as air conditioning, laminar hoods or isolators (which are required for example in the Czech Republic) (Figure 2), and on the use of protective clothes or appropriate gloves. QUAPOS provides details on drug preparation, storage, manipulation and sanitation, as well as on training workers.[19] Although
QUAPOS could be used as the “gold standard” in Europe, each country has adopted its own system, and there is still poor coordination, as discussed at the recent International Colloquium on Antineoplastic Drug Monitoring in Hennef, Germany.[20]

Although many protective measures have been adopted, their efficiency is fairly difficult to evaluate. Protections serve as “precautionary principles”, and there are often no existing analyses of working spaces (ambient monitoring) or analyses of exposed workers (biomonitoring). Surprisingly, one of the major questions that remains unanswered is “What drugs should be monitored? Should all cytotoxics in use be covered?” Naturally, the latest discussions focus on a few carefully selected hazardous representatives that are used in high quantities. These are carcinogenic cyclophosphamide and ifosfamide, platinum-based drugs and fluorouracil.[20]

Monitor and biomonitor!
For these specific drugs, analytical methods are currently being developed and standardised, using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) for organic compounds (such as cyclophosphamide or ifosfamide[21]), and voltammetry or inductively coupled plasma mass spectrometry (ICP-MS) for platinum-based cytostatics. A recent large-scale study in Germany (MEWIP)[16] clearly demonstrated that monitoring itself was efficient in significantly
lowering contamination in pharmacies that were provided with feedback monitoring data.

However, highly sensitive ultratrace analyses might be quite expensive, and hospital or pharmacy managers should be provided with reasonable and specific guides – but they, unfortunately, do not exist. Current discussions between international experts thus address very specific questions such as: How often should cytotoxic drugs be monitored? What are
the hot spots in pharmacies that should be wiped and analysed? How many samples per campaign? Should workers be biomonitored? And if so, how to biomonitor – urine samples or blood? What can we expect from biomonitoring? Does a certain concentration of cyclophosphamide in urine represent any risk?
And, last but not least, what levels of cytotoxic drugs can be considered safe?

Although it might seem trivial, setting up “safe limits” is fairly complicated for several reasons. For example, platinum is a metal widely used in electronics, and it is also naturally present and (nonhomogeneously) distributed in the environment. Thus, it is necessary to define what might be considered as the natural background, and only then start to discuss safe vs hazardous concentrations. Further, some drugs (such as
cyclophosphamide) are carcinogens, and – according to traditional risk assessment approaches for carcinogens – any concentration (even one molecule) represents risk. However, it is absolutely not possible to reduce the exposure to carcinogens to zero, and traces of drugs will always be present in working areas. Therefore, it is quite difficult to derive a simple “safe concentration” of, for example, cyclophosphamide in workers’ urine or cisplatin on the telephone in the pharmacy.

[[HPE40.63]]

Concluding remarks
The safety of cytotoxic drugs is still a major problem. Although preparatory rooms where drugs are prepared into medications are well equipped to assure safety of both drugs and pharmacists, other aspects of the “drug’s life” are much less controlled.

Workers other than pharmacists, such as nurses, may not be trained appropriately.

Important guidelines, standards and procedures for monitoring the indoor environment or biomonitoring working staff are not available, although the suitability of monitoring has been demonstrated.

Further research should focus on the development and possible application of “dosimeters” for cytotoxic drugs – similar to those of radiopharmacological application.

Last but not least: the missing key in reasonable risk management of cytotoxic drugs is the issue of threshold or safe levels. These need to be decided by international experts and (it is to be hoped) adopted in pharmacy and hospital practice.

References
1. Tortorici M. Hosp Pharm 1980;15:293-301.
2. Ladik CF, et al. Am J Hosp Pharm 1980;37:1184, 1186.
3. Connor TH. [cited 2008 Aug 22]. Available from: www.sph.uth.tmc.edu/library/antineoplastic_agents/acute_effects.htm
4. Selevan SG, et al. New Engl J Med 1985;313:1173-8.
5. Valanis B, et al. J Occup Env Med 1999;41:632-8.
6. Taskinen H, et al. Br J Ind Med 1986;43:199-205.
7. Zemlickis D, et al. Arch Intern Med 992;152:573-6.
8. Cardonick E, et al. Lancet Oncol 2004;5:283-91.
9. Baker GL, et al. Am J Med 1987;83:1-9.
10. Kiffmeyer T, et al. Pharm J 2002;268:331-7.
11. Kromhout H, et al. Ann Occup Hyg 2000;44:551-60.
12. Mason HJ, et al. Ann Occup Hyg 2005;49:603-10.
13. Sessink PJM, et al. Int Arch Occup Env Health 1992;64:105-12.
14. Fransman W, et al. Int Arch Occup Env Health 2005;78:403-12.
15. Connor TH, et al. Am J Health-Syst Pharm 2005;62:475-84.
16. Kiffmayer T, et al. [cited 2008 Aug 22]. Available from: www.pharma-monitor.de/objectfiles/3080/Kiffmeyer_Germany_Int_Colloquium_Hennef_
30.04.2008.pdf
17. Xie H, et al. Eur J Pharm Sciences 2006;27:54-61.
18. International Society of Oncology Pharmacy Practitioners. ISOPP standards of practice. Safe handling of cytotoxics. J Oncol Pharm Pract 2007;13 Suppl:1-81.
19. European Society of Oncology Pharmacy. Standard for the Oncology Pharmacy Service with commentary. Oldenburg, Germany: Onco-Press; 2003.
20. International Colloquium Hennef. Antineoplastic drug
monitoring [in German], 30 Apr 2008 [cited 2008 Aug 22]. Available from: www.pharma-monitor.de/dyn/php/index.php?id=3080
21. Minoia C, et al. Rapid Commun Mass Spectrom
1998;12(20):1485-93.



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