Table of Contents:
List of Appendices:
In response to numerous inquiries,1 OSHA published guidelines for the management of Cytotoxic (antineoplastic) drugs in the work place in 1986.106 At that time, surveys indicated little standardization in the use of engineering controls and personal protective equipment (P.E.).56, 73 Although practices improved in subsequent years, problems still exist.111 In addition, the occupational management of these chemicals has been further clarified. These trends, in conjunction with many information requests, have prompted OSHA to revise its recommendations for hazardous drug handling. Furthermore, some of these agents are covered under the Hazard Communication Standard (HCS). [29 CFR 1910.1200]107
In order to provide recommendations consistent with current scientific knowledge, this informational guidance document has been expanded to cover hazardous drugs (HD), in addition to the cytotoxic drugs (CD) that were covered in the 1986 guidelines. The recommendations apply to all settings where employees are occupationally exposed to HD's, such as hospitals, physicians' offices and home health care agencies. It is recognized that sections dealing with work areas and prevention of employee exposure refer to workplaces where pharmaceuticals are used in concentrations appropriate for patient therapy. In those settings where employees work with drugs in a more potentially hazardous form, (e.g., a more concentrated form, encountered in certain components of pharmaceutical manufacturing), measures that afford employees a greater degree of protection from exposure are commonly employed and should be used.
This review will:
Anesthetic agents have not been considered in this review. However, exposure to some of these agents is a recognized health hazard,104 and a separate document on this topic is in the planning stage.
The purpose of this Paragraph is to describe the biological effects of those pharmaceuticals that are considered hazardous. A number of pharmaceuticals in the health care setting may pose occupational risk to employees through acute and chronic workplace exposure. Past attention had mainly focused on drugs used to treat cancer. However, it is clear that many other agents also have toxicity profiles of concern. This recognition prompted the American Society of Hospital Pharmacists (ASHP) to define a class of agents as "hazardous drugs".3 That report specified concerns about antineoplastic and non-antineoplastic hazardous drugs in use in most institutions throughout the country. OSHA shares this concern.
The ASHP Technical Assistance Bulletin (TAB) described four drug characteristics, each of which could be considered hazardous:
Appendix VI:2-1 of this review lists some common drugs that are considered hazardous by the above criteria. There is no standardized reference for this information nor is there complete consensus on all agents listed.
Professional judgment by personnel trained in pharmacology/toxicology is essential in designating drugs as hazardous, and reference 65 provides information regarding the development of such a list at one institution. Some drugs, which have a long history of safe use in humans despite in vitro or animal evidence of toxicity, may be excluded by the institution's experts by considerations such as those used to formulate GRAS (Generally Regarded As Safe) lists by the FDA under the Food, Drug, and Cosmetics Act. In contrast, investigational drugs are new chemicals for which there is often little information on potential toxicity. Structure or activity relationships with similar chemicals and in vitro data can be considered in determining potential toxic effects. Investigational drugs should be prudently handled as HD's unless adequate information becomes available to exclude them.
Some major considerations by professionals trained in pharmacology/toxicology65 in designating a drug as hazardous are:
Some of the abbreviations used in this review are listed in Table VI:2-1 below.
|ANSI||American National Standards Institute|
|ASHP||American Society of Hospital Pharmacists|
|BSC||Biological Safety Cabinet|
|EPA||Environmental Protection Agency|
|HCS||Hazard Communication Standard|
|HEPA||High Efficiency Particulate Air|
|IARC||International Agency for Research on Cancer|
|MSDS||Material Safety Data Sheet|
|NIOSH||National Institute for Occupational Safety and Health|
|NTP||National Toxicology Program|
|OSHA||Occupational Safety and Health Administration|
|PPE||Personal Protective Equipment|
Preparation, administration, and disposal of HD's may expose pharmacists, nurses, physicians, and other health care workers to potentially significant workplace levels of these chemicals. The literature establishing these agents as occupational hazards deals primarily with CD's; however, documentation of adverse exposure effects from other HD's is rapidly accumulating.15,40-43,59 The degree of absorption that takes place during work and the significance of secondary early biological effects on each individual encounter are difficult to assess and may vary depending on the HD. As a result, it is difficult to set safe levels of exposure on the basis of current scientific information. However, there are several lines of evidence supporting the toxic potential of these drugs if handled improperly. Therefore, it is essential to minimize exposure to all HD's. Summary tables of much of the data presented below can be found in Sorsa95 and Rogers.84
Most HD's either bind directly to genetic material in the cell nucleus or affect cellular protein synthesis. Cytotoxic drugs may not distinguish between normal and cancerous cells. The growth and reproduction of the normal cells are often affected during treatment of cancerous cells.
Numerous studies document the carcinogenic, mutagenic, and teratogenic effects of HD exposure in animals. They are well summarized in the pertinent IARC publications.37-43 Alkylating agents present the strongest evidence of carcinogenicity (e.g., cyclophosphamide, mechlorethamine hydrochloride [nitrogen mustard]). However, other classes, such as some antibiotics, have been implicated as well. Extensive evidence for mutagenic and reproductive effects can be found in all antineoplastic classes. The antiviral agent ribavirin has additionally been shown to be teratogenic in all rodent species tested.31,49 The ASHP recommends that all pharmaceutical agents that are animal carcinogens be handled as human carcinogens.
Risks to personnel working with HD's are a function of the drugs' inherent toxicity and the extent of exposure. The main routes of exposure are: inhalation of dusts or aerosols, dermal absorption, and ingestion. Contact with contaminated food or cigarettes represents the primary means of ingestion. Opportunity for exposure to HD's may occur at many points in the handling of these drugs.
Examples of manipulations that can cause splattering, spraying, and aerosolization include:
Evaluation of these preparation techniques, using fluorescent dye solutions, has shown contamination of gloves and the sleeves and chest of gowns.97
Contaminated materials used in the preparation and administration of HD's, such as gloves, gowns, syringes and vials, present a hazard to support and housekeeping staff. The use of properly labeled, sealed and covered disposal containers, handled by trained and protected personnel, should be routine, and is required under the Bloodborne Pathogens Standard109 if such items are contaminated with blood or other potentially infectious materials. HD's and contaminated materials should be disposed of in accordance with federal, state, and local laws. Disposal of some of these drugs is regulated by the EPA. Drugs that are unused commercial chemical products and are considered by the EPA to be toxic wastes must be disposed of in accordance with 40 CFR part 261.33,24 Spills can also represent a hazard; the employer should ensure that all employees are familiar with appropriate spill procedures.
Surveys of U.S. cancer centers and oncology clinics reveal wide variation in work practices, equipment or training for personnel preparing CD's.56,73 This lack of standardization results in a high prevalence of potential occupational exposure to CD's. One survey found that 40% of hospital pharmacists reported a skin exposure to CD's at least once a month, and only 28% had medical surveillance programs in their workplaces.16 Nurses, particularly those in outpatient settings, were found to be even less well protected than pharmacists.111 Such findings emphasize current lack of protection for all personnel who risk potential exposure to HD's.
The ASHP further recommends that specific consideration of the following provisions be included where appropriate:
The ASHP recommends that the Hazardous Drug Safety and Health Plan be reviewed and its effectiveness reevaluated at least annually and updated as necessary.
Gloves. Research indicates that the thickness of the gloves used in handling HD's is more important than the type of material, since all materials tested have been found to be permeable to some HD's.3,19,53 The best results are seen with latex gloves. Therefore, latex gloves should be used for the preparation of HD's unless the drug-product manufacturer specifically stipulates that some other glove provides better protection.19,53,72,93,100 Thicker, longer latex gloves that cover the gown cuff are recommended for use with HD's. Gloves with minimal or no powder are preferred since the powder may absorb contamination.3,104
The above referenced sources have noted great variability in permeability within and between glove lots. Therefore, double gloving is recommended if it does not interfere with an individual's technique.3 Because all gloves are permeable to some extent and their permeability increases with time, they should be changed regularly (hourly) or immediately if they are torn, punctured, or contaminated with a spill. Hands should always be washed before gloves are put on and after they are removed. Employees need thorough training in proper methods for contaminated glove removal.
Gowns. A protective disposable gown made of lint-free, low-permeability fabric with a closed front, long sleeves, and elastic or knit closed cuffs should be worn. The cuffs should be tucked under the gloves. If double gloves are worn, the outer glove should be over the gown cuff and the inner glove should be under the gown cuff. When the gown is removed, the inner glove should be removed last. Gowns and gloves in use in the HD preparation area should not be worn outside the HD preparation area.3
As with gloves, there is no ideal material. Research has found nonporous Tyvek and Kaycel to be more permeable than Saranex-laminated Tyvek and polyethylene-coated Tyvek after four hours of exposure to the CD's tested.54 However, little airflow is allowed with the latter materials. As a result, manufacturers have produced gowns with Saranex or polyethylene reinforced sleeves and front in an effort to decrease permeability in the most exposure prone areas, but little data exists on decreasing exposure.
Eye and Face Protection. Whenever splashes, sprays, or aerosols of HD's may be generated that can result in eye, nose, or mouth contamination, chemical-barrier face and eye protection must be provided and used in accordance with 29 CFR 1910.133. Eyeglasses with temporary side shields are inadequate protection.
When a respirator is used to provide temporary protection as described above, and splashes, sprays, or aerosols are possible, employee protection should be:
Eyewash facilities should also be made available.
C. Work Equipment
NIH has recommended that work with HD's be carried out in a BSC on a disposable, plastic-backed paper liner. The liner should be changed after preparation is completed for the day or after a shift, whichever comes first. Liners should also be changed after a spill.103 Syringes and IV sets with Luer-lock fittings should be used for HD's. Syringe size should be large enough so that they are not full when the entire drug dose is present.
A covered disposable container should be used to contain excess solution. A covered sharps container should be in the BSC. The ASHP recommends that HD-labeled plastic bags be available for all contaminated materials (including gloves, gowns, and paper liners), so that contaminated material can be immediately placed in them and disposed of in accordance with ASHP recommendations.3
Work Practices. Correct work practices are essential to worker protection. Aseptic technique is assumed as a standard practice in drug preparation. The general principles of aseptic technique, therefore, will not be detailed here. It should be noted, however, that BSC benches differ from horizontal flow units in several ways that require special precautions. Manipulations should not be performed close to the work surface of a BSC. Unsterilized items, including liners and hands, should be kept downstream from the working area.
Entry and exit of the cabinet should be perpendicular to the front. Rapid lateral hand movements should be avoided. Additional information can be found in the National Sanitation Foundation Standard 49 for Class II (Laminar Flow) Biohazard Cabinetry70 and Avis and Levchuck's paper.6 All operators should be trained in these containment area protocols. All PPE should be donned before work is started in the BSC. All items necessary for drug preparation should be placed within the BSC before work is begun. Extraneous items should be kept out of the work area.
SPECIAL HANDLING/DISPOSAL PRECAUTIONS
Those HD's covered under HCS must also have labels in accordance with section (f) of the standard to warn employees handling the drug(s) of the hazards.
Handling Vials. Extremes of positive and negative pressure in medication vials should be avoided, e.g., attempting to withdraw 10 cc of fluid from a 10-cc vial or placing 10 cc of a fluid into an air-filled 10-cc vial. The use of large-bore needles, #18 or #20, avoids high-pressure syringing of solutions. However, some experienced personnel believe that large-bore needles are more likely to drip. Multiuse dispensing pins are recommended to avoid these problems.
Venting devices such as filter needles or dispensing pins permit outside air to replace the withdrawn liquid. Proper worker education is essential before using these devices.3 Although venting devices are recommended, another technique is to add diluent slowly to the vial by alternately injecting small amounts and allowing displaced air to escape into the syringe. When all diluent has been added, a small amount of additional air may be withdrawn to create a slight negative pressure in the vial. This should not be expelled into room air because it may contain drug residue. It should either be injected into a vacuum vial or remain in the syringe to be discarded.
If any negative pressure must be applied to withdraw a dosage from a stoppered vial and handling safety is compromised, an air-filled syringe should be used to equalize pressure in the stoppered vial. The volume of drug to be withdrawn can be replaced by injecting small amounts of air into the vial and withdrawing equal amounts of liquid until the required volume is withdrawn. The drug should be cleared from the needle and hub (neck) of the syringe before separating to reduce spraying on separation.
Handling Ampules. Prudent practice requires that ampules with dry material should be "gently tapped down" before opening to move any material in the top of the ampule to the bottom quantity. A sterile gauze pad should be wrapped around the ampule neck before breaking the top.3 This can protect against cuts and catch airborne powder or aerosol. If diluent is to be added, it should be injected slowly down the inside wall of the ampule. The ampule should be tilted gently to ensure that all the powder is wet before agitating it to dissolve the contents.
After the solution is withdrawn from the ampule with a syringe, the needle should be cleared of solution by holding it vertically with the point upwards; the syringe should be tapped to remove air bubbles. Any bubbles should be expelled into a closed container.
Nonliquid HD's. The handling of nonliquid forms of HD's requires special precautions as well. Tablets which may produce dust or potential exposure to the handler should be counted in a BSC. Capsules, i.e., gel-caps or coated tablets, are unlikely to produce dust unless broken in handling. These are counted in a BSC on equipment designated for HD's only, because even manual counting devices may be covered with dust from the drugs handled. Automated counting machines should not be used unless an enclosed process isolates the hazard from the employee(s).
Compounding should also occur in a BSC. A gown and gloves should be worn. (If a BSC is unavailable, an appropriate NIOSH-approved respirator must be worn.)
Work Practices. Safe work practices when handling HD's should include the following:
A large number of investigational HD's are under clinical study in health care facilities. Personnel not directly involved in the investigation should not administer these drugs unless they have received adequate instructions regarding safe handling procedures. Literature regarding potential toxic effects of investigational drugs should be evaluated prior to the drug's introduction into the workplace.65
The increased use of HD's in the home environment necessitates special precautions. Employees involved in home care delivery should follow the above work practices and employers should make administration and spill kits available. Home health care workers should have emergency protocols with them as well as phone numbers and addresses in the event emergency care becomes necessary.3 Waste disposal for drugs delivered for home use and other home contaminated material should also be considered by the employer and should follow applicable regulations.
Equipment. Thick, leak-proof plastic bags, colored differently from other hospital trash bags, should be used for routine accumulation and collection of used containers, discarded gloves, gowns, and any other disposable material. Bags containing hazardous chemicals (as defined by Section C of HCS), shall be labeled in accordance with Section F of the Hazard Communication Standard where appropriate. Where the Hazard Communication Standard does not apply, labels should indicate that bags contain HD-related wastes.
Needles, syringes, and breakable items not contaminated with blood or other potentially infectious materials should be placed in a "sharps" container before they are stored in the waste bag. Such items that are contaminated with blood or other potentially infectious material must be placed in a "sharps" container. Similarly, needles should not be clipped or capped nor syringes crushed if contaminated by blood or other potentially infectious material, except for a rare instance where a medical procedure requires recapping. The waste bag should be kept inside a covered waste container clearly labeled "HD WASTE ONLY." At least one such receptacle should be located in every area where the drugs are prepared or administered. Waste should not be moved from one area to another. The bag should be sealed when filled and the covered waste container taped.
Disposal. Hazardous drug-related wastes should be handled separately from other hospital trash and disposed of in accordance with applicable EPA, state, and local regulations for hazardous waste.24,110 This disposal can occur at either an incinerator or a licensed sanitary landfill for toxic wastes, as appropriate. Commercial waste disposal is performed by a licensed company. While awaiting removal, the waste should be held in a secure area in covered, labeled drums with plastic liners.
Chemical inactivation traditionally has been a complicated process that requires specialized knowledge and training. The MSDS should be consulted regarding specific advice on cleanup. IARC13 and Lunn et al.58 have validated inactivation procedures for specific agents that are effective. However, these procedures vary from drug to drug and may be impractical for small amounts. Care must be taken because of unique problems presented by the cleanup of some agents, such as by-product formation.57 Serious consideration should be given to alternative disposal methods.
Clean-up of Large Spills. When a large spill occurs, the area should be isolated and aerosol generation avoided. For spills larger than 5 ml, liquid spread is limited by gently covering with absorbent sheets or spill-control pads or pillows. If a powder is involved, damp cloths or towels should be used. Specific individuals should be trained to clean up large spills.
Protective apparel, including respirators, should be used as with small spills when there is any suspicion of airborne powder or that an aerosol has been or will be generated. Most CD's are not volatile; however, this may not be true for all HD's. The volatility of the drug should be assessed in selecting the type of respiratory protection.
As discussed under waste disposal, chemical inactivation should be avoided in this setting. All contaminated surfaces should be thoroughly cleaned three times with detergent and water. All contaminated absorbent sheets and other materials should be placed in the HD disposal bag.
Spill Kits. Spill kits, clearly labeled, should be kept in or near preparation and administrative areas. The MSDS'S include sections on emergency procedures, including appropriate personal protective equipment. The ASHP recommends that kits include: chemical splash goggles, two pairs of gloves, utility gloves, a low-permeability gown, 2 sheets (12" x 12") of absorbent material, 250-ml and 1-liter spill control pillows, a "sharps" container, a small scoop to collect glass fragments, and two large HD waste-disposal bags.3
Prior to cleanup, appropriate protective equipment should be donned. Absorbent sheets should be incinerable. Protective goggles and respirators should be cleaned with mild detergent and water after use.
Receiving Damaged HD Packages. Damaged shipping cartons should be opened in an isolated area or a BSC by a designated employee wearing double gloves, a gown, goggles, and appropriate respiratory protection. Individuals must be trained to process damaged packages as well.
The ASHP recommends that broken containers and contaminated packaging mats be placed in a "sharps" container and then into HD disposal bags.3 The bags should then be closed and placed in receptacles, as described in the section on Waste Disposal. The appropriate protective equipment and waste disposal materials should be kept in the area where shipments are received, and employees should be trained in their use and the risks of exposure to HD's.
Transport. HD's should be securely capped or sealed, placed in sealed clear plastic bags, and transported in containers designed to avoid breakage. Personnel involved in transporting HD's should be trained in spill procedures, including sealing off the contaminated area and calling for appropriate assistance.
All HD containers should be labeled as noted in Drug Preparation Work Practices. If transport methods that produce stress on contents (such as pneumatic tubes) are used, guidance from the OSHA clarification of 29 CFR 1910.1030 with respect to transport (M.4.b.(8)(c)) should be followed. This clarification provides for use of packaging material inside the tube to prevent breakage. These recommendations that pertain to the Bloodborne Pathogens Standard are prudent practice for HD's, e.g. padded inserts for carriers.
Workers who are potentially exposed to chemical hazards should be monitored in a systematic program of medical surveillance intended to prevent occupational injury and disease.3,71,72 The purpose of surveillance is to identify the earliest reversible biologic effects so that exposure can be reduced or eliminated before the employee sustains irreversible damage. The occurrence of exposure-related disease or other adverse health effects should prompt immediate re-evaluation of primary preventive measures (e.g., engineering controls, personal protective equipment). In this manner, medical surveillance acts as a check on the appropriateness of controls already in use.62
For detection and control of work-related health effects, job-specific medical evaluations should be performed, as follows:
This information should be collected and analyzed in a systematic fashion to allow early detection of disease patterns in individual workers and groups of workers.
Recognized occupational medicine experts in the HD area recommend these exams to update the employee's medical, reproductive, and exposure histories. They are recommended on a yearly basis or every two to three years. The interval between exams is a function of the opportunity for exposure, duration of exposure, and possibly the age of the worker at the discretion of the occupational medicine physician, guided by the worker's history. Careful documentation of an individual's routine exposure and any acute accidental exposures are made. The physical examination and laboratory studies follow the format outlined in the preplacement examination.64
Postexposure evaluation is tailored to the type of exposure (e.g., spills or needle sticks from syringes containing HD's). An assessment of the extent of exposure is made and included in the confidential database (discussed below) and in an incident report. The physical examination focuses on the involved area as well as other organ systems commonly affected (i.e. for CD's the skin and mucous membranes; for aerosolized HD's the pulmonary system). Treatment and laboratory studies follow as indicated and should be guided by emergency protocols.
The exit examination completes the information on the employee's medical, reproductive and exposure histories. Examination and laboratory evaluation should be guided by the individual's history of exposures and follow the outline of the periodic evaluation.
Exposure assessment of all employees who have worked with HD's is important, and the maintenance of records is required by 29 CFR 1910.1020. The use of previously outlined exposure surrogates is acceptable, although actual environmental or employee monitoring data is preferable. An MSDS can serve as an exposure record. Details of the use of personal protective equipment and engineering controls present should be included. A confidential database should be maintained with information regarding the individual's medical and reproductive history, with linkage to exposure information to facilitate epidemiologic review.
The examining physician should consider the reproductive status of employees and inform them regarding relevant reproductive issues. The reproductive toxicity of hazardous drugs should be carefully explained to all workers who will be exposed to these chemicals, and is required for those chemicals covered by the HCS. Unfortunately, no information is available regarding the reproductive risks of HD handling with the current use of BSC's and PPE. However, as discussed earlier, both spontaneous abortion and congenital malformation excesses have been documented among workers handling some of these drugs without currently recommended engineering controls and precautions. The facility should have a policy regarding reproductive toxicity of HD's and worker exposure in male and female employees and should follow that policy.
This paragraph is for informational purposes only and is not a substitute for the requirements of the Hazard Communication Standard.
According to HCS Appendix A, agents with any of the following characteristics are considered hazardous:
Both human and animal data are to be used in this determination. HCS Appendix C lists sources of toxicity information.
In accordance with requirements in the Hazard Communication Standard, the employer must maintain MSDS's accessible to employees for all covered HD's used in the hospital. Specifics regarding MSDS content are contained in the Standard. Essential information includes: health hazards, primary exposure routes, carcinogenic evaluations, acute exposure treatment, chemical inactivators, solubility, stability, volatility, PPE required, and spill procedures for each covered HD. MSDS's shall also be made readily available upon request to employees, their designated representatives, or the Assistant Secretary of OSHA.
Employees must be informed of the requirements of the Hazard Communication Standard, 29 CFR 1910.1200, as follows:
Any workplace exposure record created in connection with HD handling shall be kept, transferred, and made available for at least 30 years and medical records shall be kept for the duration of employment plus 30 years in accordance with the Access to Employee Exposure and Medical Records Standard (29 CFR 1910.1020).108 In addition, sound practice dictates that training records should include the following information:
Training records should be maintained for three years from the date on which the training occurred.
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50. Kleinberg, M.L. and Quinn, M.J. 1981. "Airborne drug levels in a laminar-flow hood." Am. J. Hosp. Pharm. 38:1301-3.
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53. Laidlaw, J.L., Connor, T.H., Theiss, J.C., et al. 1984. "Permeability of latex and polyvinyl chloride gloves to 20 antineoplastic drugs." Am. J. Hosp. Pharm. 41:2618-23.
54. Laidlaw, J.L., Connor, T.H., Theiss, J.C., et al. 1985. "Permeability of four disposable protective-clothing materials to seven antineoplastic drugs." Am. J. Hosp. Pharm. 42:2449-54.
55. Lee, S.B. 1988. "Ribavirin - Exposure to health care workers." Am. Ind. Hyg. Assoc. 49:A13-A14.
56. LeRoy, M.L., Roberts, M.J., and Theisen, J.A. 1983. "Procedures for handling antineoplastic injections in comprehensive cancer centers." Am. Hosp Pharm. 40:601-3.
57. Lunn, G. and Sansone, E.B. 1989. "Validated methods for handling spilled antineoplastic agents." Am. J. Hosp. Pharm. 46:1131.
58. Lunn, G., Sansone, E.B., Andrews, A.W., and Hellwig, L.C. 1989. "Degradation and disposal of some antineoplastic drugs." J. Pharm. Sciences 78:652-9.
59. Matthews, T. and Boehme, R. 1988. "Antiviral activity and mechanism of action of ganciclovir." Rev. Infect. Diseases 10(suppl 3):s490-94.
60. McDevitt, J.J., Lees, P.S.J., and McDiarmid, M.A. 1993. "Exposure of Hospital Pharmacists and Nurses to Antineoplastic Agents." J. Occup. Med. 35:57-60.
61. McDiarmid, M.A., Egan, T., Furio, M., et al. 1988. "Sampling for airborne fluorouracil in a hospital drug preparation area." Am. J. Hosp. Pharm. 43:1942-5.
62. McDiarmid, M.A. and Emmett, E.A. 1987. "Biological monitoring and medical surveillance of workers exposed to antineoplastic agents." Seminars in Occup. Med. 2:109-17.
63. McDiarmid, M.A., and Jacobson-Kram, D. 1989. "Aerosolized pentamidine and public health." Lancet ii:863-864.
64. McDiarmid, M.A. 1990. "Medical surveillance for antineoplastic drug handlers." Am. J. Hosp. Pharm. 47:1061-6.
65. McDiarmid, M.A., Gurley, H. T., and Arrington, D. 1991. "Pharmaceuticals as hospital hazards: Managing the risks." J. Occup. Med. 33:155-8.
66. McDiarmid, M.A., Kolodner, K., Humphrey, F., et al. 1992. "Baseline and phosphoramide mustard-induced sister-chromatid exchanges in pharmacists handling anticancer drugs." Mutation Research 279:199-204.
67. McDiarmid, M.A., Schaefer, J., Richard, C.L., Chaisson, R.E., and Tepper, B.S. 1992. "Efficacy of engineering controls in reducing occupational exposure to aerosolized pentamidine." Chest 102:1764-6.
68. McEvoy, G. K., ed. 1993. American Hospital Formulary Service Drug Information. Bethesda: American Society of Hospital Pharmacists.
69. McLendon, B.F. and Bron, A.F. 1978. "Corneal toxicity from vinblastine solution." Br. J. Ophthalmol. 62;97-9.
70. National Sanitation Foundation. 1990. Standard No. 49 for Class II (Laminar Flow) Biohazard Cabinetry. Ann Arbor: National Sanitation Foundation.
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73. Neal, A.D., Wadden, R.A., and Chiou, W. L. 1983. "Exposure of hospital workers to airborne antineoplastic agents." Am. J. Hosp. Pharm. 40:597-601.
74. Nikula E., Kiviniitty K., Leisti J., and Taskinen, P. "Chromosome aberrations in lymphocytes of nurses handling cytostatic agents." Scand. J. Work Environ. Health. 1984;10:71-4.
75. Norppa, H., Sorsa, M., Vainio, H., et al. 1980. "Increased sister chromatid exchange frequencies in lymphocytes of nurses handling cytostatic drugs." Scand. J. Work Envir. Health 6:299-301.
76. Nguyen, T.V., Theiss, J.C., and Matney, T.S. "Exposure of pharmacy personnel to mutagenic antineoplastic drugs." Cancer Research 42:4792-6.
77. Palmer, R.G., Dore, C.J., and Denman, A.M. 1984. "Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative." Lancet i:246-9.
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81. Pyy, L., Sorsa, M., and Hakala, E. 1988. "Ambient monitoring of cyclophosphamide in manufacture and hospitals." Am. Ind. Hyg. Assoc. J. 49:314-7.
82. Reich, S.D. and Bachur, N.R. 1975. "Contact dermatitis associated with adriamycin (NSC-123127) and daunorubicin (NSC-82151)." Cancer Chemotherap. Reports 59:677-8.
83. Reynolds, R.D., Ignoffo, R., Lawrence, J., et al. 1982. "Adverse reactions to AMSA in medical personnel." Cancer Treat. Rep. 66:1885.
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85. Rogers, B. and Emmett, E.A. 1987. "Handling antineoplastic agents: Urine mutagenicity in nurses." IMAGE Journal of Nursing Scholarship. 19:108-113
86. Rosner, F. 1976. "Acute leukemia as a delayed consequence of cancer chemotherapy." Cancer 37:1033-6.
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Appendix VI:2-1 is not all-inclusive, should not be construed as complete, and represents an assessment of some, but not all, marketed drugs at a fixed point in time. Appendix VI:2-1 was developed through consultation with institutions that have assembled teams of pharmacists and other health care personnel to determine which drugs should be handled with caution. These teams reviewed product literature and drug information when considering each product.
Sources for this appendix are the "Physicians Desk Reference," Section 10:00 in the American Hospital Formulary Service Drug Information,68 IARC publications (particularly Volume 50),43 the Johns Hopkins Hospital, and the National Institutes of Health, Clinical Center Nursing Department. No attempt to include investigational drugs was made, but they should be prudently handled as hazardous drugs until adequate information becomes available to exclude them.
Any determination of the hazard status of a drug should be periodically reviewed and updated as new information becomes available. Importantly, new drugs should routinely undergo a hazard assessment.
Ribavirin is a synthetic nucleoside with antiviral activity against respiratory syncytial virus (RSV). It appears to restrict synthesis of viral proteins by interfering with mRNA production, but the exact mechanism of action remains unknown.34 It is reconstituted from a lyophilized powder for aerosol administration.
Ribavirin is usually administered in the aerosolized form via mask or oxygen tent for 12-18 hours per day for 3 to 7 days. A small particle aerosol generator (SPAG) creates respirable particles of 1.3 micrometer median diameter. Under current practice, excess drug is exhausted into the patient's room, causing additional exposures.
Studies have shown Ribavirin to be teratogenic in rodents and embryolethal in rabbits. Ribavirin induces cell transformation in an in-vitro mammalian system (Balb/C 3T3 cell line). In vivo carcinogenicity studies are incomplete.
Human studies on nurses who administer the drug by oxygen tent calculate that the absorbed dose of ribavirin per workshift is 13.5 mg/kg.31 This estimated dose exceeded 1/100 (the safety factor) of the short term daily dose levels toxic in animal models described above. No symptoms were reported by any health care worker in this study. However, minor pulmonary function abnormalities have been seen among healthy adult volunteers in clinical studies.12,18
Aerosolized pentamidine isethionate (4,4'-diami-dinophenoxypentane) is FDA-approved for the treatment and prophylaxis of pneumonia caused by the protozoan Pneumocystis carinii. The exact mode of action is not fully understood; some studies indicate that pentamidine interferes with nuclear metabolism, inhibiting the synthesis of DNA, RNA, phospholipids, and proteins. It possesses two amidine groups and resembles other compounds called electrophiles which form DNA adducts. Pentamidine is administered as an aerosol after being reconstituted from a lyophilized powder.
No studies have been performed to evaluate the potential carcinogenic, mutagenic, or reproductive effects of pentamidine in animals or humans.63
Studies among health care workers have demonstrated pentamidine uptake by those personnel who administer the drug. Side effects include coughing, sneezing, mucous membrane irritation, headache, and bronchospasm. Pulmonary function tests have demonstrated transitory decreases in carbon monoxide diffusing capacity (DLCO). However, one respiratory therapist followed for 14 months has not returned to baseline after exposure.29Back to Top
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