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Safe Handling of Cytotoxic Agents


Marty Polovich, MN, RN, AOCN®
Program Chair
Oncology Clinical Nurse Specialist
Northside Hospital
Atlanta, Georgia
Melissa A. McDiarmid, MD, MPH
Professor of Medicine
University of Maryland
School of Medicine
Occupational Health Project
Baltimore, Maryland
Luci A. Power, MS, RPh
Senior Pharmacist and Manager
IV Additive Service
University of California Medical Center
San Francisco, California
Robert T. Dorr, PhD
Professor of Pharmacology
University of Arizona
Arizona Cancer Center
Tucson, Arizona


Health Effects and Occupational Exposure to Hazardous Drugs  

“Occupational exposure to anticancer drugs has been shown to be associated with both increased incidence of malignancy in male and female healthcare workers, as well as fetal developmental effects in their offspring,” said Melissa A. McDiarmid, MD, MPH, Professor of Medicine at the University of Maryland School of Medicine, Occupational Health Project, in Baltimore. It is therefore essential for oncology nurses to be aware of the potential effects of cytotoxic agents, and diligent in taking the steps needed to minimize exposure.

Potential Toxic Effects
Most antineoplastic agents work by either binding directly to genetic material in the cell nucleus or affecting cellular protein synthesis. In this way, they impair DNA synthesis and replication. These agents are highly effective in killing cancer cells, but can lack specificity of action and damage the growth and reproduction of normal cells. In addition, many anticancer agents are chemical carcinogens and are metabolized to an electrophilic reactant. The binding of drug to cellular macromolecules can result in four outcomes: a normal cell, cell death, cell mutation, or cell transformation (potential malignancy), Dr. McDiarmid explained. Animal and human data have shown the potential for developmental toxicity and genotoxicity, causing insult to offspring and genetic material with several cytotoxic agents (Table 1). In addition, Skov and colleagues found a higher incidence of cancer (particularly Hodgkin’s disease and leukemia) than was statistically expected in physicians (1990) and in nurses (1992) who handle antineoplastic drugs. Valanis and colleagues (1997) showed increased and
significantly increased infertility, respectively, in male and female pharmacists and nurses. In a 1999 study, they also found a significantly increased incidence of fetal loss in female pharmacists and nurses. Finally, Peelen and colleagues (1999) found an increased incidence of low birth weight in infants of nurses who prepare or administer anticancer drugs, with a significantly increased incidence of both birth defects and low birth weight in those who prepare the drugs.

Minimizing Exposure
Dr. McDiarmid noted several resources—such as those of the Occupational Safety & Health Administration, Oncology Nursing Society, and Joint Commission on Accreditation of Healthcare Organizations—that may be used to help minimize healthcare professionals’ exposure to anticancer drugs. In closing, Dr. McDiarmid emphasized the need for an employee surveillance plan to ensure safe handling and to monitor exposure.

Occupational Exposure and Professional Responsibility

Occupational exposure to cytotoxic substances continues to be a hazard in the healthcare setting, according to Luci A. Power, MS, RPh, Senior Pharmacist and Manager, IV Additive Service, University of California Medical Center, San Francisco. “It is therefore highly important for oncology nurses to apply proper drug handling techniques and procedures with great care to prevent such exposure,” said Ms. Power.

Studies of Drug Exposure
According to Ms. Power, several studies have documented the surface contamination that can occur throughout the healthcare setting. Sessink, McDevitt, Rubino, Connor, and Micoli study groups have demonstrated contamination of drug preparation, administration, and other areas with agents such as cyclophosphamide, 5-fluorouracil (5-FU), methotrexate, ifosfamide, and gem-citabine. Sessink, Ensslin, Pethran, and Minoia study groups have also shown evidence of exposure to cytotoxic agents in urine analysis trials.

In one trial, Sessink and colleagues (1992) studied the potential for drug contamination in preparation and administration in both inpatient and outpatient areas. In drug preparation areas, two of 44 drug vials were contaminated before anyone had touched them. Nine of 36 work surface samples (biological safety cabinet [BSC] and BSC area) were contaminated. Seventeen of 24 floor samples near the BSC contained 5-FU. Five of 76 final products were contaminated. The researchers also found contamination in all pairs of gloves used in the inpatient setting and in five of seven pairs and three of four pairs (BSC cleaning) used in the outpatient setting. In the administration area, floor samples were found to be contaminated on all days. Seven tables were found to be contaminated, and contamination was present before administration. Finally, eight of 25 pharmacy and nurse healthcare workers showed urine contamination with cyclophosphamide and ifosfamide. Six of these individuals were not directly involved in the preparation or administration of the drugs. In a more recent trial, Connor and colleagues (1999) studied surface contamination in pharmacy and ambulatory areas in six cancer centers in the United States and Canada. These researchers found that 75% of pharmacy areas and 65% of administration areas were contaminated with cytotoxic agents, and that locations adjacent to drug handling areas were also contaminated.

Professional Responsibility
According to Ms. Power, drug contamination may occur from a variety of sources in the drug preparation, administration, and other areas. In addition, the effectiveness of protective equipment, such as the BSC (class II), is technique dependent and may not prevent all contamination. Contamination may be spread to the outside or to the inside of the BSC through product or gloves. So too, any contamination of gloves, gowns, shoes, or product may lead to spread of contamination to other work areas. Finally, surface contamination may lead to particulate or vaporous air contamination. “Data indicate that exposure is lower than in the past, but also that cleaning techniques remain inefficient, that ineffective surface cleaning can result in spreading contamination, and that surface contamination can and does result in worker contamination,” Ms. Power explained.

Examination of work practices is important to reduce exposure. According to Ms. Power, good technique and appropriate decontamination should reduce the overall contamination that results in spills and vaporization. As the class II BSC has an open front, it is imperative that the BSC blower remain operating at all times to prevent the residual contamination from coming out of the BSC as particulates or vapors. Any time the containment of the BSC is compromised, the entire BSC must be decontaminated (especially under the work tray) and the front opening sealed with plastic and tape.

Traditionally, sealable bags are used to contain the final product for transport. If the BSC surface is contaminated, the outside of the bag also becomes contaminated. Thus, the product should be placed in transport bags outside the BSC using clean gloves.

Priming the intravenous (IV) tubing in the BSC is one recommendation that becomes more problematic if the surface of the BSC is contaminated. This contamination could be transferred to the outside of the tubing and become a source of exposure. A more reasonable approach, especially when using the newer infusion adaptors, is to use a secondary set for chemotherapy infusions and prime this set by allowing non-chemotherapy IV fluid to backflow into the secondary tubing from the primary IV line.

Ms. Power concluded, “It is essential for oncology nurses to understand the risk of hazardous drug exposure in all areas of the healthcare setting, and to ensure careful and proper work practices—such as using appropriate BSC techniques, changing gloves frequently, swabbing final products, and using appropriate drug cleaning and inactivation agents—to reduce the risk of exposure for themselves and their colleagues.”

Cytotoxic Drug Administration: Reducing Exposure

“The risk of contamination with cytotoxic drugs exists both in the preparation and administration of these agents,” said Marty Polovich, MN, RN, AOCN®, Program Chair, Oncology Clinical Nurse Specialist, Northside Hospital, in Atlanta, Georgia. According to Ms. Polovich, it is therefore critical that oncology nurses utilize the various protective measures available to reduce their risk of exposure.

Utilizing ProtectiveEquipment and Techniques
An important first step, said Ms. Polovich, is the appropriate use of personal protective equipment, such as gloves, gowns, eye protection (when splashing is possible), and respirator masks (when cleaning up spills). “While the use of gloves in drug administration areas is generally accepted, the use of gowns is currently not universal,” she said. In terms of other protective equipment, biological safety cabinets (BSCs) are important in protecting the healthcare worker at the site of preparation. “All drug preparation of injectable drugs and crushing of oral tablets, because of risk of inhalation of powder, should take place in the BSC,” Ms. Polovich cautioned.

Oncology nurses should also be aware of possible exposure during injection and intravenous (IV) drug delivery. Needles and syringes should never be recapped. Needle-less systems are beneficial in protecting against needle sticks, but do not completely prevent the release of drug into the environment. Nurses need to be especially careful to avoid exposure with intracavitary administration, because the equipment used here was not meant for the delivery of hazardous drugs.

A main source of exposure for nurses is spiking of the IV bags and priming of the tubing. “One recent study [Vanderbrouke 2001] showed that leakage of drug during spiking of IV bags occurs 25% of the time, and during unspiking 100% of the time. Because of this risk, IV tubing should be attached to IV bags and primed with nondrug solution before adding the cytotoxic drug,” Ms. Polovich said. Either primary or secondary IV tubing sets are appropriate for delivering cytotoxic agents. Locking connections are recommended to prevent accidental dislodgment of IV tubing.

Managing Waste and Spills
Oncology nurses need to use personal protective equipment and adhere to standard precautions when handling body fluids, disposable diapers/pads, and linens. Importantly, said Ms. Polovich, patients and their families should be alerted to the need to allow healthcare professionals to manage bedpans, urinals, and other sources of possible exposure for hospitalized patients. When cytotoxic agents are instilled in the bladder, the urinary catheter and collection bag should be discarded in the hazardous waste container.

For drug spills, Ms. Polovich recommended, “Spill kits should be available wherever cytotoxic drugs are prepared, stored, and administered.” Spill procedures regarding containment, cleaning, and disposal need to be defined and followed carefully.

Finally, any unused drug products should be returned to the pharmacy and any contact material disposed of in a hazardous waste container. Hazardous waste containers should be readily available.

In closing, Ms. Polovich emphasized that “reducing the exposure of oncology professionals to cytotoxic drugs requires maintaining reasonable workloads, proper education and training, and annual competency testing for the safe handling of hazardous drugs.”


Interventions to Ensure Safe Handling

“Because surface contamination throughout the healthcare environment with cytotoxic drugs is evident from recent data, the use of effective methods to clean and inactivate these drugs is essential,” said Robert T. Dorr, PhD, Professor of Pharmacology, University of Arizona, Arizona Cancer Center, Tucson. According to Dr. Dorr, study results on new interventions designed to reduce the risk of exposure, inactivate drug upon surface contamination, and prevent the spreading of contamination appear promising.

Sources and Types of Drug Exposure
According to Dr. Dorr, studies have shown multiple sources of drug contamination, including contaminated vials, leaks or spills in drug preparation or administration, relocation of a drug, and spread by air conditioning units. In addition, contamination of a healthcare professional’s clothing or shoes may in turn lead to contamination of other areas. Several studies have documented antineoplastic drug contamination on work surfaces, on the outsides of vials, on gloves and gowns, and in the air (particulates). Minoia and colleagues (1998), for example, showed significant surface contamination with both cyclophosphamide and ifosfamide at the site of the biological safety cabinet (BSC) tray, floor in front of the BSC, and on gloves. In addition, Connor and colleagues (2000) found that numerous anticancer drugs slowly vaporize at room temperature, and this process is accelerated at body temperature.

Cleaning and Inactivation of Cytotoxic Agents
In addition to careful use of personal protection equipment and techniques, use of effective methods to clean areas exposed to cytotoxic drugs is needed. Indeed, the manufacturers of several anticancer agents recommend inactivation of drug in contaminated areas. The use of isopropyl alcohol does not actually inactivate any of the anticancer agents. Studies indicate that the biogenicity and activity of a number of cytotoxic agents can be significantly decreased by sodium hypochlorite (bleach), including complete loss of activity in cyclophos- phamide, melphalan, and ifosfamide, and partial loss of activity in methotrexate (Benvenuto et al 1993; Hansel et al 1997; Wren et al 1993). However, the direct use of bleach poses several hazards in the healthcare setting: splashing onto skin or eyes, inhalation of vapors, corrosion of surfaces, and bleaching of clothing and surfaces.

Intervention Strategies
One intervention designed to reduce drug contamination and exposure is PhaSeal, a closed system that may be used during chemotherapy preparation and administration. PhaSeal, which features double membranes and an expansion chamber, includes a connector lock to ensure a sealed connection between the injector and the patient’s intravenous line; an infusion set with a built-in connector; and an infusion adaptor with an inline spike to connect the bag to the external intravenous set. In one 11-month intervention study, Connor and colleagues (AHSP 2000) found a significant overall reduction in ifosfamide exposure in preparation and administration areas. Sessink and colleagues (1999) also found that PhaSeal provides a significant reduction in drug exposure. Cost may be a factor with this system, and large direct comparison trials with standard reconstitution are needed.

Surface Safe, a two-step inactivator application, with pad 1 containing hypochlorite and pad 2 containing thiosulfate (inactivates bleach; binds to platinum, other alkylators), has recently been shown to be effective in inactivating several anticancer drugs (Table 1). The hypochlorite/thiosulfate combination neutralizes the potential hazards of the bleach and works to inactivate cytotoxic drugs via two separate mechanisms. Surface Safe can be used to clean spills up to 10 mL (using two sets of pads), and appears to be safe for use on wood, metal, and a variety of hard surfaces. Indeed, Larson and colleagues spiked clean stainless steel sheets with several anticancer agents, treated with either isopropyl alcohol or Surface Safe (two wipes each). Preliminary results show remaining cyclophosphamide and ifosfamide levels to be significantly reduced with Surface Safe (18.9% vs 4.1% cyclophosphamide remaining; 100% vs 3.6% ifosfamide remaining). In a recent Arizona study, a 1-mg/mL solution of doxorubicin was placed into PVC plastic 150-mL bags and the bags were externally wiped with Surface Safe pads. The results showed no loss of drug over a 24-hour period, and no smearing of pre-printed labeling on the bags. “Surface Safe may be useful to wipe bags prior to delivery to units or upon exit from the hood/mixing area,” the speaker said.

Optimal use of Surface Safe would likely include use immediately after drug spills, routinely on work surfaces at least once per shift in low-volume and two to three times per shift in high-volume institutions, and routinely on surfaces adjacent to drug preparation areas (Table 2).

In closing, Dr. Dorr noted, “All oncology professionals need to be aware of the risk for exposure to cytotoxic drugs, and must minimize such exposure with diligent use of protective equipment, techniques, and new cleaning systems.”

Table 2. Proper Use of Surface Safe on Work Surfaces

• Use latex or rubber gloves (gown, mask per institutional guidelines)
• Carefully open pad 1 (hypochlorite) over work surface
• Apply soaked pad to contaminated area
• Carefully dispose of used pad 1 in contaminated waste receptacle
• Open pad 2 (thiosulfate) and apply to areas wiped with pad 1
• Dispose of pad 2 in contaminated waste receptacle



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