5.1.4 Antineoplastic Drugs

Nurses and pharmacists face a variety of potential hazards from contact with pharmaceuticals. The drugs of greatest concern are those associated with cytotoxicity and fetotoxicity (e.g. folate antagonists, 6-mercaptopurine, and some alkylating agents), and teratogenicity (e.g. actinomycin-D, mitomycin-C, nitrogen mustard, prednisone, procarbazine, streptomycin, and vincristine). Many chemotherapeutic agents have been reported to cause cancer in animals and thus can be considered to be potential human carcinogens (e.g. cyclophosphamide and chlorambucil) (Sorsa et al 1985).

Antineoplastic drugs derive their name from the fact that they interfere with or prevent the growth and development of malignant cells and neoplasms. They may also be called cytotoxic or cytostatic because they have the ability to prevent the growth and proliferation of cells. Approximately 30 antineoplastic drugs are currently available commercially. Each year some 200,000 to 400,000 cancer patients are treated with antineoplastic drugs (Sorsa et al. 1985; Devita 1982).

5.1.4.1 Effects of antineoplastic drugs

Many antineoplastic drugs are reported to cause mutations in test systems and are carcinogenic and teratogenic in experimental animals (See table 5-1). Evidence indicated that cyclophosphadmide, chlorambucil, 1,4-butanediol dimethylsulfonate, and melphalan are human carcinogens (Sorsa et al 1985). When given to patients in therapeutic doses, many antineoplastic drugs (e.g. cyclophosphamide) have been associated with an increased incidence of malignant tumors that develop at a later date (IARC 1981). Available human evidence suggest that cyclophosphamide is also a teratogen.

Toxic effects have been observed in patients treated with antineoplastic drugs. These effects include lack of sperm production, reduced sperm counts, amenorrhea, and adverse effects on the bone marrow, heart, central nervous system, liver, skin, ears and pancreas, lungs, kidneys, and endocrine glands (Stellman and Zoloth 1986). Treatment with antineoplastic drugs has also resulted in depression of the hematopoietic system (LaFond 1978; Caro 1980).

The acute effects of accidental exposure to these drugs can be severs. For example, an accidental needle prick of a patient’s finger with mitomycin-C has been reported to cause the eventual loss of function of that hand (Duvall and Baumann 1980). Some antineoplastic drugs e.g. mustine hydrochloride and doxorubicin are strong vesicants that can cause varying degrees of local tissue necrosis upon direct contact Knowles and Virden 1980.

Little is known about the potential health hazards of chronic exposure to antineoplastic drugs, but Selevan et al. (1985) observed a statistically significant association between fetal loss and the occupational exposure of nurses to these drugs. Sotaniemi et al (1983) documents liver damage in three oncology nurses who hand handled antineoplastic drugs for a number of years. Light-headedness, dizziness, nausea, headaches, skin and mucous membrane reactions, hair loss, cough, and possible allergic reactions have been reported by nurses handling antineoplastic drugs Crudi (1980) These side effects observed in nurses are the same as those noted by patients receiving antineoplastic drugs Crooke and Prestayko (1981).

Several other antineoplastic drugs (e.g. methotrexate and vincristine) are skin and mucous membrane irritants Knowles and Virden 1980. Bleomycin and cisplatin may cause allergic reactions following skin contact Knowles and Virden (1980).

5.1.4.2 Methods for estimating exposure to antineoplastic drugs

At present, few economically feasible tests are available for monitoring the exposures of nurses and pharmacy technicians who work with a variety of antineoplastic drugs. Primary routes of worker exposure to antineoplastic drugs are inhalation and dermal absorption.

Exposures by inhalation can occur during drug preparation or administration. Aerosols can be generated when inserting needles into or withdrawing them from vials, and when expelling air from syringes before injection Hirst et al. 1984 Stellman et al. 1984. In one study, for example, low levels of the antineoplastic drugs cyclophosphamide and fluorouracil were measured in workroom air deWerk et al. (1983).

Skin absorption may occur when antineoplastic drugs are spilled during their preparation or administration Jardine et al. (1978). Skin exposure may also occur as a result of contact with the urine of patients being treated with antineoplastic drugs Hirst et al. (1984). Because of the relatively large number of antineoplastic drugs in use and the variety of metabolites formed, it is not economically feasible for the hospital laboratory to conduct biological monitoring for each drug in use. However, methods have been developed for detecting platinum (from cisplatin exposure) and cyclophosphamide in the urine of exposed workers Venitt et al. (1984).

Mutagenicity assays using urine can detect excreted mutagenic parent compounds or their mutagenic metabolites. Several studies have analyzed mutagenic constituents in the urine as a measure of exposure to antineoplastic drugs. Five studies reported that nurses or pharmacy technicians handling antineoplastic drugs have increased urine mutagenicity compared with a control population (Nguyen et al 1982; Falck et al. 1979; Kolmodin-Hedman 1983; Bos et al. 1982; Anderson et al. 1982). However, negative results were reported in five other studies of similar groups of nurses or pharmacy technicians (Venitt et al. 1984; Staiano et al. 1981; Rorth et al. 1983; Ratcliffe 1983; Gibson et al. 1984). Evidence is still insufficient to recommend routine urine mutagenicity testing for estimating exposure to antineoplastic drugs.

Sister chromatid exchange (SCE) analysis using human peripheral blood lymphocytes is thought to provide an estimate of DNA damage produced by mutagens and carcinogens. Increased frequencies of SCE and chromosome aberrations were found in hospital personnel handling antineoplastic drugs (Norppa et al. 1980; Waksvik et al. 1981; Nikula et al. 1983). However, these observations were not confirmed by other investigators (Barale et al. 1985; Kolmodin-Hedman et al. 1983). Thus evidence is still insufficient to recommend routine SCE analysis for estimating exposure to antineoplastic drugs.

5.1.4.3 Methods for preventing exposure to antineoplastic drugs

Methods for preventing exposure to antineoplastic drugs are detailed in the OSHA work practice guidelines attached to this document as Appendix 7 OSHA 1986. These guidelines address drug preparation, drug administration, waste disposal, spills, medical surveillance, storage and transport, training, and information dissemination. Recommendations have lso been issued by the National Institutes of Health NIH, the Society of Hospital Pharmacists, the American Society of Hospital Pharmacists, the National Study Commission on Cytotoxic Exposure, and Individual directors of hospital pharmacies (Knowles and Virden 1980; Waksvik et al. 1981; Crudi 1980; Crooke and Prestayko 1981; Caro 1980; Vaughn and Christensen 1985).

5.1.4.4 Medical monitoring

Workers exposed to antineoplastic drugs should receive preplacement and periodic medical evaluations that include at least the following:

• A complete work history and medical history

• An examination that emphasizes the skin, the liver, and the hematopoietic, reproductive, and nervous systems

Other tests may be performed at the discretion of the examining physician, who should be particularly alert for symptoms of liver disease, skin and mucous membrane irritation, central nervous system depression, teratogenic effects, and cancer.

5.1.5 Ethylene Oxide

Ethylene oxide, which is a colorless gas with a distinctive sweet, ether-like odor (NIOSH 1981j), is used to sterilize medical instruments, particularly those made of heat-labile materials (Gross et al. 1979). This compound is regulated by OSHA as a carcinogen 29 CFR 1910.1047. Ethylene oxide is typically supplied to US hospitals in compressed gas cylinders that contain 88% Freon (see Section 5.1.7) and 12% ethylene oxide, or in single-dose cartridges of 100% ethylene oxide (NIOSH 1977d).

5.1.5.1 Hazard Location

Workers in central supply, dental operatories, and surgical suites who use ethylene oxide are at risk of potential exposure. In 1983, OSHA estimated that approximately 62,370 workers were directly exposed to ethylene oxide and that 25,000 others may have been incidentally exposed in US hospitals (Federal Register 1983). An estimated 7,700 ethylene oxide sterilizers are in operation in 6,300 hospitals in the United States (Federal Register 1983).

The typical source of ethylene oxide exposure in the hospital environment is through the operation of sterilizing equipment. Unless good engineering controls and good work practices area used, workers may encounter relatively high concentrations of ethylene oxide over relatively brief periods. A study by Yager et al. (1983) highlights the need to control short-term peak exposures to ethylene oxide.

5.1.5.2 Potential Health Effects

Exposure to ethylene oxide occurs primarily through inhalation, but exposure of moist skin to the vapors can also cause irritation.

5.1.5.2.1 Acute effects

Although ethylene oxide has an odor threshold of about 700 ppm Jay et al. (1982), exposure at 200 ppm may cause irritation of the eyes and upper respiratory system. High concentrations can cause severe skin burns, rashes, sores, headache, nausea, and hemolysis (the destruction of red blood cell). Very high exposures may cause vomiting, shortness of breath, weakness, drowsiness, lack of coordination, cyanosis, bluish skin color resulting from oxygen insufficiency, and pulmonary edema (NIOSH 1977d).

Contact with ethylene-oxide-sterilized equipment or wrappings that have not been adequately aerated to remove residual ethylene oxide may cause severe skin burns with large blisters and peeling skin. Healing may leave hyperpigmentation (brown discoloration of skin).

Ethylene oxide may also pose a fire hazard, depending on his it is stored and used (see Section 3).

5.1.5.2.2 Chronic effects

Ethylene oxide is a mutagen in many assay systems and causes reproductive damage in both male and female experimental animals. Some data also suggest that ethylene oxide may adversely affect human reproduction (Hemminki et al. 1982). Thiess et al. (1981) found chromosomal abnormalities in workers exposed to alkylene oxides including ethylene oxide, and Garry et al. (1979) found a dose-response relationship between ethylene oxide concentrations and chromosomal abnormalities. The significance of these chromosomal abnormalities is not known, but concern exists over a possible link between them and the ability to cause cancer and adverse reproductive effects (Hogstedt et al 1979b). An increased incidence of spontaneous abortion has also been associated with ethylene oxide exposure (Hemminki et al. 1982).

In 1981 NIOSH published a Current Intelligence Bulletin stating that ethylene oxide should be considered a potential occupational carcinogen (NIOSH 1981j). An increased rate of leukemia has been found in workers exposed to levels below the former OSHA PEL of 50 ppm as an 8-hr TWA, but this result has not been confirmed by other studies (Hogstedt et al. 1979a).

The neurotoxicity of ethylene oxide has been documented in four exposed workers (Gross et al. 1979). Findings included acute encephalopathy and peripheral neuropathy. Nerve conduction velocity was abnormal in most patients. Decreasing the amount of exposure relieved symptoms, but only total removal from exposure caused nerve conduction velocities to return to normal.

Chronic exposure to ethylene oxide increases the risk of sensitization and cataract development (Jay et al. 1982).

5.1.5.3 Standards and Recommendations

The OSHA PEL for ethylene oxide is an 8-hr TWA of 1 ppm with an excursion limit of 5 ppm for any 15-min period (29 CFR 1910.1047). The NIOSH REL for ethylene oxide is a ceiling of 5 ppm for no more than 10 min in any working day, and an 8-hr TWA less than 0.1 ppm (NIOSH 1983e).

5.1.5.4 Environmental Monitoring

A comprehensive monitoring program is an important part of the overall ethylene oxide control strategy. A detailed discussion of hospital sampling procedures and methods appears in the Technical Industrial Processes Sourcebook (Wood 1984).

Three types of monitoring are generally used for ethylene oxide; direct-reading instruments (e.g. infrared analyzers) samples collected on activated charcoal for subsequent analysis, and passive dosimeters. Portable infrared analyzers are direct-reading instruments that may be used for area monitoring of ethylene oxide concentrations. Note, however, that these instruments may not be accurate at ethylene oxide concentrations below 1 ppm (1.8 mg/m³) because they are sensitive to high humidity and may produce false readings. Activated charcoal tubes are used to determine exposure for the entire sampling period (an 8-hr day, for example). Passive dosimeters are generally worn on a worker’s lapel; after chemical analyses, they can provide a semi-quantitative indication of exposure.

5.1.5.5 Exposure Control Methods

A NIOSH study of hospitals with good engineering controls has shown that ethylene oxide exposures can be kept below 0.1 ppm (0.18 mg/m³) for an 8-hr TWA and below 5 ppm (9mg/m³) for short-term exposures of less than 2 min (Kercher and Mortimer 1987).

5.1.5.5.1 Substitution

In most cases, no acceptable substitute exists for ethylene oxide in the sterilization of heat-sensitive equipment.

5.1.5.5.2 Engineering controls

The following engineering controls are recommended:

• The sterilizer should be enclosed either in a mechanical access room or a cabinet, and the enclosure should be exhausted to a dedicated ventilation system.*

  *A dedicated exhaust system is one that serves the sterilizer area only and routes ethylene oxide directly to the outside of the building at a location where prevailing winds will not carry the exhaust into populated areas or into the air intakes of other buildings.

• Sterilizing operations should be centralized and access to sterilizer rooms should be restricted.

• The sterilizer should be checked with the infrared analyzer at least once every 3 months.

• Floor drains should have a cover with an anti-siphon air gap. The air gap, at the junction of the vacuum pump discharge line with the floor drain, should be enclosed. Dedicated exhaust ventilation should be provided for the enclosures.

• Local exhaust ventilation sufficient to effectively remove ethylene oxide should be as close as possible to the top of the sterilizer door.

• The number of exhaust cycles recommended by the sterilizer manufacturer should be completed before the door is opened; the door should remain only slightly open for at least 15 min.

• Supply cylinders should be located in a ventilated enclosure (either a ventilated cabinet or a hood that covers the point where the cylinder is connected to the sterilizer supply line).

• Aerators and the overpressure relief valves (if present) should be vented to a dedicated exhaust system.

• Sensors should be provided to identify a ventilation failure and to detect ethylene oxide. Both audible and visual alarms should be activated by the sensors.

• Ventilation air from the sterilizing room should not be recirculated.

• Exhaust gases should preferably be vented directly to the outside of the building (away from intake vents); this procedure is strongly recommended for all sterilizers.

• Sterilized material and its packaging should be aerated in aeration cabinets, since approximately 5% of the ethylene oxide in the sterilizer remains in these items. Aeration times depend on the composition, form, and weight of the material. Refer to the recommendations from the Association for the Advancement of Medical Instrumentation (AAMI 1982), and follow the manufacturer’s recommendations for each type of equipment sterilized. Materials that do not absorb ethylene oxide (metal and glass) need no aeration unless they are wrapped.

• Sterilizers that use glass ampules in a plastic bag (flash bag) have a high potential for worker exposure to ethylene oxide. If they are used, all sterilization procedures should be conducted in a ventilated enclosure.

A worker should use protective gloves (see Section 2.3.5) and splash-proof goggles and/or a face shield when changing ethylene oxide supply cylinders. If good engineering controls are used, i.e. if the cylinder is located in a ventilated hood, a respirator should not be necessary. If a respirator is necessary or desired, the worker should use a chemical cartridge respirator with an end-of-service-life indicator that has been approved by NIOSH/MSHA. The end-of-service-life indicator is needed because the odor threshold for ethylene oxide is about 700 ppm (Jay et al. 1982), and failure of the adsorbent material will not be detected by the user.

Protective gloves and long-sleeved garments should be worn when removing items from the sterilizer or transferring them to the aerator.

When cleaning up liquid spills that contain ethylene oxide, workers should wear protective outer clothing and dispose of or launder it immediately afterward. If leather shoes become contaminated with ethylene oxide, they should be discarded.

A positive-pressure, self-contained breathing apparatus should be available for emergency situations and should be stored in an area away from the sterilizer and the ethylene oxide supply location.

5.1.5.5.4 Work practices

Sterilizers should be operated only by personnel trained in sterilization procedures and in the health and safety hazards of ethylene oxide. If local exhaust ventilation has been provided above the sterilizer door, a worker should open the door slightly and step away for an established time period. The time period should be determined by monitoring and should be at least 15 min. The door opening should be smaller than the capture distance of the hood.

To clean the sterilizer, especially the back surfaces, a worker must often reach inside the chamber with the whole upper body. Ethylene oxide exposure during this cleaning can be controlled by (1) scheduling the cleaning activity as long as possible after processing a load, (2) leaving the sterilizer door fully open for at least 30 min before cleaning, and (3) wearing a respirator.

5.1.5.6 Medical Monitoring

Employers should obtain pre-employment baseline data on workers who will be handling ethylene oxide. This information should include data on the eyes, skin, blood, and respiratory tract. Periodic examinations thereafter should include the following organs and systems:

5.1.6 Formaldehyde

NIOSH regards formaldehyde as a potential occupational carcinogen (NIOSH 1981; NIOSH 1986c). Formaldehyde is used for cold sterilization of some instruments, but it is not used as a general disinfectant because it is very caustic.

5.1.6.1 Hazard location

Formaldehyde may be encountered in the laboratory as a tissue preservative, in central supply as a sterilant, and in the dialysis unit as a sterilant. Formaldehyde is often combined with methanol and water to make formalin.

5.1.6.2 Potential Health Effects

5.1.6.2.1 Acute effects

The odor of formaldehyde can be detected in air at about 0.8 ppm (Amoore and Hautala 1983). Formalin solutions splashed in the eyes may cause severe injury and corneal damage. Low ambient concentrations of formaldehyde 0.1 to 5 ppm, may cause burning and tearing of the eyes and irritation of the upper respiratory tract. Higher concentrations, 10 to 20 ppm, may cause coughing, chest tightness, increased heart rate, and a sensation of pressure in the head. Exposures of 50 to 100 ppm may cause pulmonary edema, pneumonitis, and death (NIOSH 1981i).

5.1.6.2.2 Chronic effects

Repeated exposure to formaldehyde may cause some persons to become sensitized. Sensitization may occur days, weeks or months after the first exposure. Sensitized individuals will experience eye or upper respiratory irritation or an asthmatic reaction at levels of exposure that are too low to cause symptoms in most people. Reactions may be quite severe with swelling itching, wheezing, and chest tightness (NIOSH 1976f).

One study (Hendrick et al. 1982) reported that two nurses working in a renal dialysis unit developed asthmatic symptoms associated with their work with formaldehyde. The symptoms completely resolved for the nurse who spent 5 to 7 years without further exposure to formaldehyde, but the other nurse, who continued the exposure, continued to have symptoms. Dermatitis, including red, sore, cracking, and blistered skin, is also a common problem with formaldehyde exposure. Repeated exposure may make the fingernails soft and brown (NIOSH 1976f). A NIOSH health hazard evaluation of a hospital hemodialysis unit (NIOSH 1983a) indicated that respiratory irritation, eye irritation, and dermatological problems were the primary health problems associated with formaldehyde exposure.

Formaldehyde is a mutagen in many assay systems and has caused nasal and other cancers in experimental animals. In 1981, NIOSH published the Current Intelligence Bulletin 34 (NIOSH 1981I) which recommended that formaldehyde be handled as a suspect carcinogen in the workplace.

5.1.6.3 Standards and Recommendations

The OSHA standard for formaldehyde is 1 ppm as an 8-hr TWA with a ceiling concentration of 2 ppm as a 15-min short-term exposure limit (29 CFR 1910.1048).

The NIOSH REL for formaldehyde is 0.1 ppm as determined in any 15-min air sample and 0.016 ppm as an 8-hr TWA (NIOSH 1986d). In the Current Intelligence Bulletin 34, NIOSH recommended that engineering controls and stringent work practices be used to reduce occupational exposure to the lowest feasible limit (NIOSH 1981i).

The ACGIH has designated formaldehyde a suspected human carcinogen and has recommended a TLV of 1 ppm (1.5 mg/m³) as an 8-hour TWA with a short term exposure limit, STEL, of 2 ppm (3 mg/m³) (ACGIH 1987).

The odor of formaldehyde can be detected at about 0.8 ppm (Amoore and Hautala, 1983), but even a short period of exposure will decrease the worker’s ability to smell it Thus odor is not a reliable warning for the presence of formaldehyde (NIOSH 1976f).

5.1.6.4 Environmental Monitoring

NIOSH industrial hygiene surveys have found formaldehyde concentrations ranging from 2.2 to 7.9 ppm in hospital autopsy rooms (NIOSH 1981i). Passive dosimeters, direct-reading colorimetric detector tubes, and the personal sampling pump may be used to monitor exposures. Although some colorimetric detector tubes can detect as little as 0.05 ppm formaldehyde, personal sampling pumps and charcoal tubes are preferred for measuring low-level exposures. For a more detailed description of sampling procedures for formaldehyde, refer to the Technical Industrial Processes Sourcebook (Wood 1984), or Air Sampling Instruments for Evaluation of Atmospheric Contaminants (ACGIH 1983).

5.1.6.5 Exposure Control Methods

Phenols may be substituted for formaldehyde in some cases, and dilute bleach solutions can be used to disinfect the exteriors of dialyzers. Other cold sterilants such as glutaraldehyde are also available. These substitutes should be used with caution.

5.1.6.5.1 Engineering controls

The following engineering controls are recommended to minimize formaldehyde exposure:

• Local exhaust ventilation should be installed over work stations using formalin or specimens preserved in formalin.

• Small quantities of formaldehyde should be purchased in plastic containers for ease of handling and safety.

• Traps should be placed in floor drains.

• Spill-absorbent bags should be available for emergencies.

• Engineering controls in hemodialysis units should include (1) isolating the main system from personnel and patients in case of inadvertent spills of (2) disconnecting the dialyzers before the sterilization process is completed. Also, formaldehyde vapors should be prevented from entering the room from the drains serving the main system and the dialysis consoles. The air should be regularly monitored for formaldehyde, and in-service education should be conducted periodically on the effects of formaldehyde.

5.1.6.5.2 Protective equipment

Skin and eye contact with formaldehyde should be avoided. Goggles, face shields, aprons, NIOSH certified positive-pressure air-supplied respirators, and boots should be used in situation where formaldehyde spills and splashes are likely. Appropriate protective gloves should be used whenever hand contact is possible; latex examination gloves are too fragile.

5.1.6.6 Medical monitoring

Pre-employment baseline data should be recorded for the respiratory tract, liver, and skin condition of any worker who will be exposed to formaldehyde. Thereafter, periodic monitoring should be conducted to detect symptoms of pulmonary or skin sensitization or effects on the liver.