Exposure to hazardous drugs

Large numbers of drugs are handled daily in the medical care of patients. In Sweden, for example, 231 million defined daily doses (DDD) were administered in 2005 to patients in closed medical care.(1) These drugs are biologically reactive, and it is well known that most drugs may cause adverse health effects.

There is also concern that the occupational exposure to drugs that occurs among medical staff may give possible negative health effects. When it comes to the reported number of work-related diseases due to drug exposure among medical staff and pharmacists in Sweden,(2) it has varied between five and 25 per annum during the last years. The number of unreported cases is, however, significant when comparing the internal incident reports with official statistics.(3)

Antineoplastic drugs are a heterogeneous group of agents with cytotoxic properties used in the treatment of neoplastic diseases, and also in some non-neoplastic diseases. These compounds are highly toxic, and many are also carcinogenic, according to the International Agency on Cancer Research (IARC).(4)

In many countries, authorities have issued regulations and/or recommendations for handling these drugs in a safe way (eg, Sweden, USA or the UK).(5–8) These regulations and recommendations prescribe various protective measures to be used when handling these drugs.

Many national and international medical and pharmaceutical organisations have also issued recommendations for safe handling of drugs.(9–12) However, Valanis et al,(13) among others, have shown that there could be a significant lack in conforming to the regulations among medical staff.

Several studies(14–20) also show that exposure to antineoplastic drugs does occur despite current regulations. Moreover, most other drugs are handled without any regulation regarding possible exposure among staff. In this article, some of the recent studies on antinenoplastic drug exposure will be summarised and discussed in a wider perspective of drug exposure.

Experiences from studies of exposure to antineoplastic drugs
There has been concern regarding occupational exposure to antineoplastic drugs for many years. The exposure can occur by direct contact with the drugs but also indirectly through contact with contaminated surfaces, equipment, drug packages and with the patients and their excretions, as well as while handling garbage and laundry, or when cleaning or doing technical maintenance.

Uptake of the drugs can occur by inhalation of drug aerosols or vapours and through the skin after dermal exposure. There are several work tasks that can cause exposure, the obvious ones being: handling drug vials; making preparations; and handling them.

It is also possible to become exposed when colleagues handle drugs in the same room and when doing cleaning tasks. Some review articles summarising findings in this area have been published.(21–23)

A number of methods for controlling exposure have been developed, some of them focusing on sampling the actual spill and leakage during a specific preparation using a tracer substance. Technetium m-99 ((99m)Tc), a radioisotope used for contrast X-ray examinations, has been applied in a test method for drug spill onto surfaces.(24) Vials prepared with 99mTc are used in the test, and a number of standardised preparations are carried out. Wipe samples are then collected from surfaces at the preparation place. The activity in the samples is monitored and can be used to calculate the volume of spill onto each wiped surface. Other methods are aimed at sampling actual drug spill during normal activity. These methods either use wipe sampling to collect spill and leakage of drugs from surfaces after drug handling,(15,19,20) or use collection of urine samples from staff to monitor exposure.(16–18) Cyclophosphamide (CP), i-fosfamide (i-F), 5-fluorouracil (5-FU) and cisplatin (c-Pt) are examples of drugs that can be analysed at low concentrations and have been analysed in these samples. Sessink and Bos(25) have also evaluated a number of methods for monitoring occupational exposure to cytotoxic drugs.

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One of the most comprehensive collections of literature on occupational exposure to ­antineoplastic drugs has been compiled by Dr Tom Connor and can be found on the NIOSH website.(26) There are several studies from different countries showing that CP, i-F and 5-FU have been found on surfaces both inside and outside of biological safety cabinets (BSC). CP, i-F and 5-FU have also been found in urine samples from pharmacists and nurses. Elevated platinum (Pt) levels have been found in medical staff handling c-Pt and similar drugs. Several studies have shown that drug vials have been contaminated on the outside, when delivered from the manufacturer. The effectiveness of protective equipment (eg, gloves and clothes) has been evaluated using other methods such as permeation studies.

In a recent Dutch study(27) on CP dermal exposure among pharmacists, it was shown that 46% of pharmacists had contaminated gloves and 4% were contaminated on the hand inside the glove. Moreover, 4% were contaminated on their underarms and 13% on their forehead. It was also found that 46% of the BSC were contaminated on the front side and that 25% of the prepared infusion bags were contaminated.

Experience of studies on exposure to antibiotics
Antibiotics are another heterogeneous group of drugs that are frequently used in medical care. Antibiotics are handled in large volumes (in Sweden, about 4.5 millions DDD) compared with antineoplastic drugs (in Sweden, 32,000 DDD).(1) Many antibiotics can cause various health effects such as skin irritation, skin rash, allergy, irritation of the airways, asthma and reproduction disturbances.(28–30)

These drugs are handled by large groups of staff almost everywhere within closed medical care facilities. Normally there are no specific regulations or provisions on how to handle these drugs safely to avoid spill or leakage. The drugs are normally handled in open systems on normal workbenches.

There are no studies on how large the spill and leakage that arise from handling antibiotics are. Moreover, there are no studies showing the extent of occupational exposure to antibiotics. There are a number of older, mostly Russian, reports on various health effects from exposure to antibiotics during drug manufacture.(31–34) There are only a few examples of recent reports on health effects from occupational exposure to antibiotics in human medical care.(28–30,35) These studies report on contact allergy, extended time to planned pregnancy, asthma and immuno‑genicity. In a Danish study on veterinary surgeons with contact allergy caused by antibiotics, it was shown that 16% could not continue to work as veterinary due to their allergy.(36)

Conclusions
Handling antineoplastic drugs is regulated to avoid staff exposure. A number of methods can be used to monitor spill, leakage and exposure to these drugs. Current studies have shown that spill and leakage of antineoplastic drugs occur during handling and that staff can be exposed to these drugs. By using closed handling systems, spill and leakage can be controlled and exposure significantly decreased. It is desirable to introduce programmes that continuously monitor spill and leakage. This would more efficiently measure the exposure and effects of preventive measures to reduce exposure.

Regarding antibiotics, much less is known, with only a limited number of studies being available. However, based on the experience from studies of antineoplastic drug exposure, at least the same relative spill and leakage will occur during antibiotic handling. Since the used volumes of antibiotics are at least 200 times larger than those of antineoplastic drugs, it is reasonable to assume that 200 times more antibiotic drugs are expelled into facilities with closed medical care, to which staff will be exposed. This spill and leakage may also contribute to the development of resistant bacteria strains. It is necessary to study the effects of antibiotics in the medical work environment in more detail. Methods to control spill and leakage, as well as monitoring exposure, are needed to be able to study how antibiotics are released and spread into medical facilities and how important staff exposure is. Development of more closed and safe handling systems is also desirable.

Author

Olle Nygren
PhD
Associate Professor/Senior Research Scientist
Department of Work and the Physical Environment
National Institute for Working Life
Umeå
Sweden
E:[email protected]

References

1. Swedish Pharmacy. Sale statistics. Available from: http://www2.apoteket.se/om/VadViGor/Forsalj/default.htm (in Swedish).
2. Statistics Sweden. ISA database. Available from: http://www2.apoteket.se/om/VadViGor/Forsalj/Publicerad_statistik/default.htm (in Swedish).
3. Gustavsson Bengt, Östra Hospital, Gothenburg, Sweden, personal ­communication, 2001.
4. International Agency for Research on Cancer. IARC monographs. Available from: http://monographs.iarc.fr
5. Swedish Work Health Authority. ASF 1999:11. Cytostatics and other drugs with enduring toxic effects. Available from: http://www.av.se/inenglish/lawandjustice/provisions
6. OSHA Technical Manual, Section VI, Chapter 2. Controlling occupational exposure to hazardous drugs. Available from: http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
7. NIOSH Alert No 2004-165. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Available from: http://www.cdc.gov/niosh/docs/2004-165/2004-165b.html#j
8. Health and Safety Executive (UK). New guidance on safe handling of cytotoxic drugs. Available from: http://www.hse.gov.uk/press/2003/e03179.htm
9. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990;47:1033-49.
10. Canadian Society of Hospital Pharmacists. Guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs). Ottawa: 1993.
11. Clinical Oncology Society of Australia. Guidelines for safe handling of antineoplastic agents. Med J Australia 1983;1:426-8.
12. Nygren O. Cytotoxic drugs. In: Hasselhorn H, Tomingas A, Lagerkvist M, editors. ICOH Occupational health in medical care. Elsevier: Amsterdam; 1999. p. 115-20.
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26. NIOSH Safety and Health Topic. Occupational exposure to ­antineoplastic agents. Available from: http://www.cdc.gov/niosh/topics/antineoplastic/default.html
27. Fransman W, Vermeulen R, Kromhout H. Ann Occup Hyg 2004;48:237-44.
28. Rudzki E, Rebendel P. Contact Dermatitis 1984;11:41-2.
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31. Samolinski B, Tarchalska B, Zawisza E. Pneumonologia i Alergologia Polska 1992;60 Suppl 2:147-52.
32. Gerasimova MM. Gigiena Truda i Professional’nye Zabolevaniya 1990;8:19-24.
33. Antonyuzhenko VA, Gnesina EA, Gnelitskii GI, et al. Gigiena Truda i Professional’nye Zabolevaniya 1987;2:19-22.
34. Ponomarenko NS. Farmatsevtichnii Zhurnal (Kiev) 1986;1:54-6.
35. Edwards RG, Dewdney JM, Dobrzanski RJ, et al. Int Arch Allergy Appl Immunol 1988;85:184-9.
36. Hjorth N, Roed-Petersen J. Contact Dermatitis 1980;6:27-9.

Resource
NIOSH Database on literature on exposure to antineoplastic drugs.