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Published on 23 March 2010

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Exposure risks with cytotoxic drugs

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Chromosomal abnormalities characteristic of chemotherapy-related myelodysplastic syndrome have been detected in healthcare workers who handle cytotoxic drugs

Christine Clark
BSc MSc PhD FRPharmS
FCPP(Hon)

Editor
HPE

Delegates at the American Society of Health- System Pharmacists (ASHP) Midyear Clinical Meeting in Las Vegas in December 2009 heard that patients who have been treated with anticancer drugs are at risk of developing secondary malignancies-often myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)- and these are associated with specific abnormalities on chromosomes 5, 7 and 11. A recent study showed that similar patterns of chromosomal changes occur in health-care workers  who have been handling antineoplastic agents.

A comprehensive exposure assessment study of oncology, pharmacy and nursing personnel funded by the US National Institute for Occupational Safety and Health (NIOSH) provides more evidence for the risks posed by the handling of cytotoxic drugs, according to the principal investigators, Melissa McDiarmid (professor of medicine, epidemiology and preventive medicine, University of Maryland, Baltimore) and Thomas Connor (research biologist, division of applied research and technology, National Institute for Occupational Safety and Health, Cincinnati, Ohio). The study was conducted in three University hospital cancer centres in the USA, all of which claimed to be operating the recommended “safe handling” practices. It included environmental sampling, prospective recording of every drug handling event over a six-week period, biological monitoring for specific anticancer drugs in urine and measures of genotoxic effects. A total of 109 healthcare workers participated in the study, 63 of whom were exposed to cytotoxic drugs in the course of their work and 46 who were not and acted as controls.

“We should have respect for and concern about the use of antineoplastic agents because most of these drugs bind to DNA and act like oncogenes,” said Dr McDiarmid. Developmental genotoxicity is a feature of many common anticancer drugs and genotoxicity has been recorded for all classes of these drugs including alkylating agents, antimetabolites and mitotic
inhibitors.

Historically these drugs emerged from the chemical warfare agents that were developed in the First World War. They were introduced into cancer treatment during the 1960s and secondary malignancies were first reported during the 1970s. In 1979 mutagenicity was noted in healthcare workers. The hazardous drugs in question are the 12 defined by the International Agency for Research on Cancer (IARC; see Resources) as group 1 human carcinogens along with 19 other drugs classified as “probable” and “possible” carcinogens.

Turning to evidence of chromosomal damage, Dr McDiarmid pointed out that there is now clear evidence of the types of specific chromosomal changes that lead to the development of MDS or AML. Damage to chromosomes 5 and 7 is known to occur with alkylating agents and damage to chromosome 11 is
linked to treatment with topoisomerase inhibitors.

One arm of this study looked for specific chromosome changes in healthcare workers while the other arm involved a detailed assessment of the extent and level of exposure. Fluorescent in-situ hybridisation was used to look for changes in chromosomes 5, 7 and 11. This is a technique that detects deletions, explained Dr McDiarmid. Abnormalities in chromosomes 5 and 7 were expected from the outset because of the high use of alkylating agents, she added.

Pharmacy staff had twice as many handling events as nursing staff and alkylating agents were the most common products. The results showed that for every handling event there was an increase in the risk of a change to chromosome 5 or 7. When the handling events involving alkylating agents only were analysed there was a five-fold increase in the effect estimate. Dr McDiarmid concluded that the study had demonstrated the presence of the signature lesions of therapy-related MDS and AML in the healthcare workers who handled cytotoxic agents. Moreover, she added, biological exposure to genotoxic agents was clearly occurring despite the adoption of protection
measures.

Dr McDiarmid commented that people often claim to be operating safe handling procedures but they are not evident on “walkthroughs”.

She acknowledged that the current guidelines need to be revisited. “We must get everybody on the same page with correct guidelines,” she said. She also noted that there was a tendency to assume that this issue had been addressed because guidelines had been published- “we need to demythologise this”, she said.

Dr Connor described how the level of exposure to cytotoxic drugs was determined. The healthcare workers included were pharmacists, pharmacy technicians, nurses and nurse aides, along with matched controls. Exposure was assessed by means of a six week handling diary, surface wipe samples, area air samples, personal air samples, urine drug levels and the comet assay for DNA damage. Handling events for pharmacy personnel included preparation of doses, checking, priming tubing and spills and splashes. Handling events for nurses also included drug administration. Surface wipe samples were tested for five drugs-cyclophosphamide, ifosfamide, paclitaxel, 5- fluorouracil and cytarabine- using a highly sensitive liquid chromatography-mass spectroscopy-mass spectroscopy (LC-MS-MS) technique. Wipe samples were collected from multiple sites in the pharmacy and nursing areas. Area air samples were collected from the working areas and personal air samples were collected from the breathing zones of workers. Urine was collected from workers for paclitaxel and cyclophosphamide determination during the last four hours of each shift and during the four-hour period afterwards. Finally, comet assays were performed to assess DNA damage. This relies on single cell gel electrophoresis; the result looks like a comet and broken DNA forms a visible tail to the comet, explained Dr Connor. The comet assay provides evidence of non-specific chromosome damage.

A total of 9491 handling events were recorded and 145 wipe samples were collected. Sixty per cent of the wipe samples demonstrated at least one of the five drugs at concentrations above the limit of detection. As a rule of thumb, wipe sample results of less than 1ng/cm2 are acceptable, but some “quite substantial” values were detected during this study, said Dr Connor. For example at one site, where the drug preparation area was open to adjoining office space (without a pass-through facility or ante-room), contamination was found in the office area and two members of staff had cyclophosphamide in their urine. A total of 108 spills were recorded during more than 4000 handling events at two of the pharmacies. At the third pharmacy, where a closed system transfer device (CSTD) was routinely used, no spills were recorded during more than 5000 handling events. In general, there was less contamination in the nursing areas although heavy contamination with fluorouracil (910ng/cm2) was found on the lid of a waste container in one ward. This was probably due to a breakdown in work practice, such as dripping tubing, commented Dr Connor. No drugs were detected in the air samples collected and this suggests that dermal exposure is the main route of occupational contamination.

Overall, the results showed that surface contamination continues to occur in pharmacy and nursing areas and that levels tend to be higher in pharmacies. Proper clean room facilities with ante-rooms, pass-through hatches and air handling arrangements should be in place where hazardous drugs are handled to minimise contamination risks, Dr Connor said. He also emphasised that there were no spillages in the high-use, highvolume facility that routinely used a CSTD.

Resources
NIOSH
The National Institute for Occupational Safety and Health (NIOSH) is the federal agency responsible for conducting research and making recommendations for the prevention of work-related injury and illness. www.cdc.gov/niosh

IARC

The mission of the International Agency for Research on Cancer (IARC) is to coordinate and conduct research on the causes of human cancer, the mechanisms of carcinogenesis, and to develop scientific strategies for cancer prevention and control. www.iarc.fr



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