Handling


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


Figure 1: Cyclophosphamide penetration in oral mucosa and keratinised skin


individual fate outside and inside the human body. For example, our laboratory experiments have focused on the kinetics of tissue penetration and demonstrated fairly rapid and quantitative (100%) transfer of cyclophosphamide through mucous membranes, whereas keratinised skin layers seemed to significantly reduce drug uptake (Figure 1). These findings, along with others such as highly variable polymorphism in drug metabolism,16 demonstrate that there are still many unknowns that ultimately require further research and attention of risk assessors.


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 published by the International Society of Oncology Pharmacy Practitioners (ISOPP).17


In Europe, widely accepted 4


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.18 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 International Colloquium on


www.hospitalpharmacyeurope.com


Antineoplastic Drug Monitoring in Hennef, Germany.19


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.19


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)20


, and voltammetry or


inductively coupled plasma mass spectrometry (ICP-MS) for platinum- based cytostatics. A large-scale study in Germany (MEWIP)15


up ‘safe limits’ is fairly complicated for a number of reasons. For example, platinum is a metal widely used in electronics, and it is also naturally present and (heterogeneously) 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. Furthermore, 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.


Conclusions 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?


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 for radiopharmacological applications. 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. ●


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