SECTION
VI: CHAPTER 2
CONTROLLING OCCUPATIONAL EXPOSURE TO HAZARDOUS DRUGS
Contents:
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
|
Introduction
Categorization of Drugs as Hazardous
Background: Hazardous Drugs as Occupational Risks
Work Areas
Prevention of Employee Exposure
Medical Surveillance
Hazard Communication
Training and Information Dissemination
Record keeping
References
|
Appendix VI:2-1. Some
Common Drugs Considered Hazardous
Appendix VI:2-2. Some Aerosolized Drugs
I.
INTRODUCTION.
A.
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
B.
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.
C.
This review will:
§
Provide criteria for
classifying drugs as hazardous.
§
Summarize the evidence
supporting the management of HD's as an occupational hazard.
§
Discuss the equipment and
worker education recommended as well as the legal requirements of standards
for the protection of workers exposed and potentially exposed to HD's.
§
Update the important aspects
of medical surveillance.
§
List some common HD's
currently in use.
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.
II.
III.
CATEGORIZATION
OF DRUGS AS HAZARDOUS.
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.
A.
CHARACTERISTICS. The ASHP Technical Assistance Bulletin (TAB)
described four drug characteristics, each of which could be considered
hazardous:
§
genotoxicity;
§
carcinogenicity;
§
teratogenicity or fertility
impairment; and
§
serious organ or other toxic
manifestation at low doses in experimental animals or treated patients.
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.
B.
HAZARD
DEFINITION BASED ON PHARMACOLOGY/TOXICOLOGY.
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:
§
Is the drug designated as
Therapeutic Category 10:00 (Antineoplastic Agent) in the American Hospital
Formulary Service Drug Information?68
§
Does the manufacturer
suggest the use of special isolation techniques in its handling,
administration, or disposal?
§
Is the drug known to be a
human mutagen, carcinogen, teratogen or reproductive toxicant?
§
Is the drug known to be
carcinogenic or teratogenic in animals (drugs known to be mutagenic in multiple
bacterial systems or animals should also be considered hazardous)?
§
Is the drug known to be
acutely toxic to an organ system?
Some of
the abbreviations used in this review are listed in Table VI:2-1 below.
TABLE VI:2-1. LIST OF ABBREVIATIONS
|
ANSI
|
|
American National Standards Institute
|
ASHP
|
American Society of Hospital Pharmacists
|
BSC
|
Biological Safety Cabinet
|
CD
|
Cytotoxic Drug
|
EPA
|
Environmental Protection Agency
|
HD
|
Hazardous Drug
|
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
|
|
IV.
BACKGROUND:
HAZARDOUS DRUGS AS OCCUPATIONAL RISKS.
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
A.
MECHANISM OF
ACTION. 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.
B.
ANIMAL DATA. 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.
C.
HUMAN DATA AT
THERAPEUTIC LEVELS.
1.
Many HD's are known human
carcinogens, for which there is no safe level of exposure. The development
of secondary malignancies is a well-documented side effect of chemotherapy
treatment.52,86,90,115 Leukemia has been most frequently observed.
However, other secondary malignancies, such as bladder cancer and lymphoma,
have been documented in patients treated for other, usually solid, primary
malignancies.52,114
2.
Chromosomal aberrations can
result from chemotherapy treatment as well. One study, on chlorambucil,
reveals chromosomal damage in recipients to be cumulative and related to
both dose and duration of therapy.77 Numerous case reports have linked
chemotherapeutic treatment to adverse reproductive outcomes.7,88,91,98 Testicular and ovarian dysfunction, including permanent
sterility, have occurred in male and female patients who have received CD's
either singly or in combination.14 In addition, some antineoplastic agents are known
or suspected to be transmitted to infants through breast milk.79
3.
The literature also
documents the effects of these drugs on other organ systems. Extravasation
of some agents can cause severe soft-tissue injury, consisting of necrosis
and sloughing of exposed areas.23,78,87 Other HD's, such as pentamidine and zidovudine
(formerly AZT), are known to have significant side effects (i.e.,
hematologic abnormalities), in treated patients.4,33 Serum transaminase elevation has also been
reported in treated patients.4,33
A.
OCCUPATIONAL
EXPOSURE: AIRBORNE LEVELS.
1.
Monitoring efforts for cytotoxic
drugs have detected measurable air levels when exhaust biological safety
cabinets (BSC) were not used for preparation or when monitoring was
performed inside the BSC.50,73 Concentrations of fluorouracil ranging from 0.12
to 82.26 ng/m3 have been found during monitoring of drug
preparation without a BSC, implying an opportunity for respiratory
exposure.73 Elevated concentrations of cyclophosphamide were
found by these authors as well. Cyclophosphamide has also been detected on
the HEPA filters of flow hoods used in HD preparation, demonstrating
aerosolization of the drug and an exposure opportunity mitigated by
effective engineering controls.81
2.
A recent study has reported
wipe samples of cyclophosphamide, one of the class I IARC carcinogens, on
surfaces of work stations in an oncology pharmacy and outpatient treatment
areas (sinks and countertops). Concentrations ranged from 0.005 to 0.035
mcg/cm2, documenting opportunity for dermal exposure.60
3.
Administration of drugs via
aerosolization can lead to measurable air concentrations in the breathing
zone of workers providing treatment. Concentrations of up to 18 mcg/m3
have been found by personal air sampling of workers administering
pentamidine.67 Similar monitoring for ribavirin has found
concentrations as high as 316 mcg/m3.31
B.
OCCUPATIONAL
EXPOSURE: BIOLOGICAL EVIDENCE OF ABSORPTION.
1.
Urinary
Mutagenicity.
a. Falck et al. were the first to note evidence of mutagenicity in the
urine of nurses who handled cytotoxic drugs.26 The extent of this effect increased over the
course of the work week. With improved handling practices, a decrease in
mutagenic activity was seen.27 Researchers have also studied pharmacy personnel
who reconstitute antineoplastic drugs. These employees showed increasingly
mutagenic urine over the period of exposure; when they stopped handling the
drugs, activity fell within 2 days to the level of unexposed controls.5,76 They also found mutagenicity in workers using
horizontal laminar flow BSC's that decreased to control levels with the use
of vertical flow containment BSC's.76
b. Other studies have failed to find a relationship between exposure
and urine mutagenicity.25 Sorsa99 summarizes this information and discusses the
factors, such as differences in urine collection timing and variations in
the use of PPE, which could lead to disparate results. Differences may also
be related to smoking status; smokers exposed to CD's exhibit greater urine
mutagenicity than exposed nonsmokers or control smokers -- suggesting
contamination of the work area by CD's and some contribution of smoking to
their mutagenic profile.9
2.
Urinary
Thioethers are glutathione conjugated
metabolites of alkylating agents, which have been evaluated as an indirect
means of measuring exposure. Workers who handle cytotoxic drugs have been
reported to have increased levels compared to controls and also have
increasing thioether levels over a 5-day work week.44,48 Other studies of nurses who handle CD's and of
treated patients have yielded variable results, which could be due to
confounding by smoking, PPE, and glutathione-S-transferase activity.11
3.
Urinary
Metabolites. Venitt assayed the urine
of pharmacy and nursing personnel handling cisplatin and found platinum
concentrations at or below the limit of detection for both workers and
controls.112 Hirst found cyclophosphamide in the urine of two
nurses who handled the drug, documenting worker absorption.35 (Hirst also documented skin absorption in human
volunteers by using gas chromatography after topical application of the
drug.) Urinary pentamidine recovery has also been reported in exposed
health care workers.94
C.
OCCUPATIONAL
EXPOSURE: HUMAN EFFECTS.
1.
Cytogenetic
Effects.
a. A number of studies have examined the relationship of exposure to CD's
in the workplace to chromosomal aberrations. These studies have looked at a
variety of markers for damage, including sister chromatid exchanges (SCE),
structural aberrations (e.g., gaps, breaks, translocations), and
micronuclei in peripheral blood lymphocytes. The results have been somewhat
conflicting. Several authors found increases in one or more markers.74,75,80,113 Increased mutation frequency has been reported as
well.17
b. Other studies have failed to find a significant difference between
workers and controls.99,101 Some researchers have found higher individual
elevations28 or a relationship between the number of drugs
handled and SCE's.8 These disparate results are not unexpected. The
difficulties in quantitating exposure have resulted in different exposure
magnitudes between studies; workers in several negative studies appear to
have a lower overall exposure.101 In addition, differences in the use of PPE and
work technique will alter absorption of CD's and resultant biologic
effects.
c. Finally, techniques for SCE measurement may not be optimal. A
recent study that looked at correlation of phosphoramide-induced SCE levels
with duration of anticancer drug handling found a statistically significant
correlation coefficient of zero.63,66 Taken together, the evidence indicates an excess
of markers of mutagenic exposure in unprotected workers.
2.
Reproductive
Effects.
a. Reproductive effects associated with occupational exposure to CD's
have been well documented. Hemminki et al.32 found no difference in exposure between nurses
who had spontaneous abortions and those who had normal pregnancies.
However, the study group consisted of nurses who were employed in surgical
or medical floors of a general hospital. When the relationship between CD
exposure and congenital malformations was explored, the study group was
expanded to include oncology nurses, among others, and an odds ratio of 4.7
was found for exposures of more than once per week. This observed odds
ratio is statistically significant.
b. Selevan et al.89 found a relationship between CD exposure and
spontaneous abortion in a case-control study of Finnish nurses. This
well-designed study reviewed the reproductive histories of 568 women (167
cases) and found a statistically significant odds ratio of 2.3. Similar
results were obtained in another large case-control study of French nurses,102 and a study of Baltimore-area nurses found a
significantly higher proportion of adverse pregnancy outcomes when exposure
to antineoplastic agents occurred during the pregnancy.85 The nurses involved in these studies usually
prepared and administered the drugs. Therefore, workplace exposure of these
groups of professionals to such products has been associated with adverse
reproductive outcomes in several investigations.
3.
Other Effects.
a. Hepatocellular damage has been reported in nurses working in an
oncology ward; the injury appeared to be related to intensity and duration
of work exposure to CD's.96 Symptoms such as lightheadedness, dizziness,
nausea, headache, and allergic reactions have also been described in
employees after the preparation and administration of antineoplastic drugs
in unventilated areas.22,86 In occupational settings, these agents are known
to be toxic to the skin and mucous membranes, including the cornea.69,82
b. Pentamidine has been associated with respiratory damage in one
worker who administered the aerosol. The injury consisted of a decrease in
diffusing capacity that improved after exposure ceased.29 The onset of bronchospasm in a
pentamidine-exposed worker has also been reported.22 Employees involved in the aerosol administration
of ribavirin have noted symptoms of respiratory tract irritation.55 A number of medications including psyllium and
various antibiotics are known respiratory and dermal sensitizers. Exposure
in susceptible individuals can lead to asthma or allergic contact
dermatitis.
V.
WORK AREAS.
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.
A.
PHARMACY OR
OTHER PREPARATION AREAS.
1.
In large oncology centers,
HD's are usually prepared in the pharmacy. However, in small hospitals,
outpatient treatment areas, and physicians' offices they have been prepared
by physicians or nurses without appropriate engineering controls and
protective apparel.16,20 Many HD's must be reconstituted, transferred from
one container to another, or manipulated before administration to patients.
Even if care is taken, opportunity for absorption through inhalation or
direct skin contact can occur.35,36,73,116
2.
Examples of manipulations
that can cause splattering, spraying, and aerosolization include:
§
withdrawal of needles from
drug vials;
§
drug transfer using syringes
and needles or filter straws;
§
breaking open of ampules;
and
§
expulsion of air from a
drug-filled syringe.
Evaluation
of these preparation techniques, using fluorescent dye solutions, has shown
contamination of gloves and the sleeves and chest of gowns.97
3.
Horizontal airflow work
benches provide an aseptic environment for the preparation of injectable
drugs. However, these units provide a flow of filtered air originating at
the back of the work space and exiting toward the employee using the unit.
Thus, they increase the likelihood of drug exposure to both the preparer
and other personnel in the room. As a result, the use of horizontal BSC's
is contra-indicated in the preparation of HD's. Smoking, drinking, applying
cosmetics, and eating where these drugs are prepared, stored, or used also
increase the chance of exposure.
B.
ADMINISTRATION
OF DRUGS TO PATIENTS.
1.
Administration of drugs to
patients is generally performed by nurses or physicians. Drug injection
into the IV line, clearing of air from the syringe or infusion line, and
leakage at the tubing, syringe, or stopcock connection present
opportunities for skin contact and aerosol generation. Clipping used
needles and crushing used syringes can produce considerable aerosolization
as well.
2.
Such techniques where
needles and syringes are contaminated with blood or other potentially
infectious material are prohibited by the Bloodborne Pathogens Standard.109 Prohibition of clipping or crushing of any needle
or syringe is sound practice.
3.
Excreta from patients who
have received certain antineoplastic drugs may contain high concentrations
of the drug or its hazardous metabolites. For example, patients receiving
cyclophosphamide excrete large amounts of the drug and its mutagenic
metabolites.46,92 Patients treated with cisplatin have been shown
to excrete potentially hazardous amounts of the drug.112 Unprotected handling of urine or urine-soaked
sheets by nursing or housekeeping personnel poses a source of exposure.
C.
DISPOSAL OF DRUGS
AND CONTAMINATED MATERIALS.
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.
D.
SURVEY OF
CURRENT WORK PRACTICES.
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.
VI.
PREVENTION OF
EMPLOYEE EXPOSURE.
A.
HAZARDOUS DRUG
SAFETY AND HEALTH PLAN.
1.
Where hazardous drugs, as
defined in this review, are used in the workplace, sound practice dictates
that a written Hazardous Drug Safety and Health Plan be developed.
Such a plan assists in:
§
Protecting employees from
health hazards associated with HD's.
§
Keeping exposures as low as
reasonably achievable.
2.
When a Hazardous Drug
Safety and Health Plan is developed, it should be readily available and
accessible to all employees, including temporary employees, contractors,
and trainees. The ASHP recommends that the Plan include each of the
following elements and indicate specific measures that the employer is
taking to ensure employee protection:3
§
Standard operating
procedures relevant to safety and health considerations to be followed when
health care workers are exposed to hazardous drugs.
§
Criteria that the employer
uses to determine and implement control measures to reduce employee
exposure to hazardous drugs, including engineering controls, the use of
personal protective equipment, and hygiene practices.
§
A requirement that
ventilation systems and other protective equipment function properly, and
specific measures to ensure proper and adequate performance of such
equipment.
§
Provision for information
and training.
§
The circumstances under
which the use of specific HD's (that is, FDA investigational drugs) require
prior approval from the employer before implementation.
§
Provision for medical
examinations of potentially exposed personnel.
§
Designation of personnel
responsible for implementation of the Hazardous Drug Safety and Health
Plan including the assignment of a Hazardous Drug Officer (who is an
industrial hygienist, nurse, or pharmacist health and safety
representative) and, if appropriate, establishment of a Hazardous Drug
Committee or a joint Hazardous Drug Committee/Chemical Committee.
3.
The ASHP further recommends
that specific consideration of the following provisions be included where
appropriate:
§
Establishment of a
designated HD handling area.
§
Use of containment devices
such as biological safety cabinets.
§
Procedures for safe removal
of contaminated waste.
§
Decontamination procedures.
The ASHP
recommends that the Hazardous Drug Safety and Health Plan be
reviewed and its effectiveness reevaluated at least annually and updated as
necessary.
4.
A comparison of OSHA 200 log
entries to employee medical clinic appointment or visit rosters can be made3 to establish if there is evidence of disorders
that could be related to hazardous drugs. Previous health and safety
inspections by local health departments, fire departments, regulatory, or
accrediting agencies may be helpful for the facility's planning purposes as
well as any OSHA review of hazards and programs in the facility. Joint
Commission on Accreditation of Healthcare Organizations (JCAHO), or College
of American Pathologists (CAP) review of facilities may contain information
on hazardous drugs used in the facility.
B.
DRUG PREPARATION
PRECAUTIONS.
1.
Work Area. The ASHP recommends that HD preparation be
performed in a restricted, preferably, centralized area. Signs restricting
the access of unauthorized personnel are to be prominently displayed.
Eating, drinking, smoking, chewing gum, applying cosmetics, and storing
food in the preparation area should be prohibited.71 The ASHP recommends that procedures for spills
and emergencies, such as skin or eye contact, be available to workers,
preferably posted in the area.3
2.
Biological
Safety Cabinets. Class II or
III Biological Safety Cabinets (BSC) that meet the current National
Sanitation Foundation Standard49,70,72 should minimize exposure to HD's during
preparation. Although these cabinets are designed for biohazards, several
studies have documented reduced urine mutagenicity in CD-exposed workers or
reduced environmental levels after the institution of BSC's.5,51,61 If a BSC is unavailable, for example in private
practice office, accepted practice is the sharing of a cabinet (e.g.,
several medical offices share a cabinet) or sending the patient to a center
where HD's can be prepared in a BSC. Alternatively, preparation can be
performed in a facility with a BSC and the drugs transported to the area of
administration. Use of a dedicated BSC, where only HD's are prepared, is
prudent practice.
3.
Types Of BSC's.
a. Four main types of Class II BSC's are available. They all have
downward airflow and HEPA filters. They are differentiated by the amount of
air recirculated within the cabinet, whether this air is vented to the room
or the outside, and whether contaminated ducts are under positive or
negative pressure. These four types are described below:
§
Type A cabinets recirculate
approximately 70% of cabinet air through HEPA filters back into the
cabinet; the rest is discharged through a HEPA filter into the preparation
room. Contaminated ducts are under positive pressure.
§
Type B1 cabinets have higher
velocity air inflow, recirculate 30% of the cabinet air, and exhaust the
rest to the outside through HEPA filters. They have negative-pressure
contaminated ducts and plenums.
§
Type B2 systems are similar
to Type B1 except that no air is recirculated.
§
Type B3 cabinets are similar
to Type A in that they recirculate approximately 70% of cabinet air.
However, the other 30% is vented to the outside and the ducts are under
negative pressure.
b.
Class III cabinets are
totally enclosed with gas tight construction. The entire cabinet is under
negative pressure, and operations are performed through attached gloves.
All air is HEPA filtered.
c. Class II, type B, or Class III BSC's are recommended since they
vent to the outside.3 Those without air recirculation are the most
protective. If the BSC has an outside exhaust, it should be vented away
from air intake units.
d. The exhaust fan or blower on the vertical airflow hood should be
on at all times, except when the hood is being mechanically repaired or
moved. If the blower is turned off, the hood should be decontaminated
before reuse.3,72 Each BSC should be equipped with a continuous
monitoring device to allow confirmation of adequate air flow and cabinet
performance. The cabinet should be in an area with minimal air turbulence;
this will reduce leakage to the environment.6,70 Additional information on design and performance
testing of BSC's can be found in papers by Avis and Levchuck,6 Bryan and Marback,10 and the National Sanitation Foundation.70 Practical information regarding space needs and
use of BSC's is contained in the ASHP's 1990 technical assistance bulletin.3
e. Ventilation and biosafety cabinets installed should be maintained
and evaluated for proper performance in accordance with the manufacturer's
instructions.
4.
Decontamination.
a. The cabinet should be cleaned according to the manufacturer's
instructions. Some manufacturers have recommended weekly decontamination,
as well as whenever spills occur, or when the cabinet requires moving,
service or certification.
b. Decontamination should consist of surface cleaning with water and
detergent followed by thorough rinsing. The use of detergent is recommended
because there is no single accepted method of chemical deactivation for all
agents involved.13,45 Quaternary ammonium cleaners should be avoided
due to the possibility of vapor build-up in recirculated air.3 Ethyl alcohol or 70% isopropyl alcohol may be
used with the cleaner if the contamination is soluble only in alcohol.3 Alcohol vapor build-up has also been a concern,
so the use of alcohol should be avoided in BSC's where air is recirculated.3 Spray cleaners should also be avoided due to the
risk of spraying the HEPA filter. Ordinary decontamination procedures,
which include fumigation with a germicidal agent, are inappropriate in a
BSC used for HD's because such procedures do not remove or deactivate the
drugs.
c. Removable work trays, if present, should be lifted in the BSC so
the back and any sump below can be cleaned. During cleaning, the worker
should wear PPE similar to that used for spills. Ideally, the sash
should remain down during cleaning, however, a NIOSH-approved respirator appropriate
for the hazard must be worn by the worker if the sash will be lifted during
the process. The exhaust fan/blower should be left on. Cleaning should
proceed from least to most contaminated areas. The drain spillage trough
area should be cleaned at least twice since it can be heavily contaminated.
All materials from the decontamination process should be handled as HD's
and disposed of in accordance with federal, state, and local laws.
5.
Service and
Certification.
a. The ASHP recommends that BSC's be serviced and certified by a
qualified technician every six months or any time the cabinet is moved or
repaired.3,71 Technicians servicing these cabinets or changing
the HEPA filters should be aware of HD risks through hazard communication
training from their employers and should use the same personal protective
equipment as recommended for large spills.
b. Certification of the BSC includes performance testing as outlined
in the procedures of the National Sanitation Foundation's Standard Number
49.70 Helpful information on such testing can be found
in the ASHP 1990 technical assistance bulletins,3 the BSC manufacturer's equipment manuals, and
Bryan and Marback's paper.10 HEPA filters should be changed when they restrict
airflow or if they are contaminated by an accidental spill. They should be
bagged in plastic and disposed of as HD's. Any time the cabinet is turned
off or transported it should be sealed with plastic.
6.
Personal
Protective Equipment.
a. 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.
b. 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.
c. Respiratory Protection. A BSC is essential for the
preparation of HD's. Where a BSC is not currently available, a
NIOSH-approved respirator appropriate for the hazard must be worn to afford
protection until the BSC is installed. [NIOSH recommendation at the time
of this publication is for a respirator with a high-efficiency filter,
preferably a powered, air-purifying respirator.] The use of respirators
must comply with OSHA's Respiratory Protection Standard,105 which outlines the aspects of a respirator
program, including selection, fit testing, and worker training. Surgical
masks are not appropriate since they do not prevent aerosol inhalation.
Permanent respirator use, in lieu of BSC's, is imprudent practice and
should not be a substitute for engineering controls.
d. 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:
§
a respirator with a full
face piece; or
§
a plastic face shield or
splash goggles complying with ANSI standards2 when using a respirator of less than full-face
piece design.
Eyewash facilities should also be made available.
e. PPE Disposal and Decontamination. All gowns, gloves,
and disposable materials used in preparation should be disposed of
according to the hospital's hazardous drug waste procedures and as
described under this review's section on Waste Disposal. Goggles, face
shields and respirators may be cleaned with mild detergent and water for
reuse.
C.
D.
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.
E.
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
1.
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.
a. Labeling. In addition to standard pharmacy labeling
practices, all syringes and IV bags containing HD's should be labeled with
a distinctive warning label, such as:
SPECIAL HANDLING/DISPOSAL PRECAUTIONS
|
2.
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.
b. Needles. The ASHP recommends that all syringes and needles
used in the course of preparation be placed in "sharps"
containers for disposal without being crushed, clipped or capped.3,103
c. Priming. Prudent practice dictates that drug administration
sets be attached and primed within the BSC, prior to addition of the drug.
This eliminates the need to prime the set in a less well-controlled
environment and ensures that any fluid that escapes during priming contains
no drug. If priming must occur at the site of administration, the
intravenous line should be primed with non-drug containing fluid or a back-flow
closed system should be used.3
d. 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.
e. 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.
f. Packaging HD's for Transport. The outside of bags or
bottles containing the prepared drug should be wiped with moist gauze.
Entry ports should be wiped with moist alcohol pads and capped. Transport
should occur in sealed plastic bags and in containers designed to avoid
breakage. Shipped HD's that are subject to EPA regulation as hazardous
waste are also subject to Department of Transportation (DOT) regulations as
specified in 49 CFR part 172.101.
g. 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 worm)
3.
Drug
Administration.
a. Personal Protective Equipment. The National Study
Commission on Cytotoxic Exposure has recommended that personnel
administering HD's wear gowns, latex gloves, and chemical splash goggles or
equivalent safety glasses as described under the PPE section, preparation.71 NIOSH-approved respirators should be worn when
administering aerosolized drugs.
b. Administration Kit. Protective and administration equipment
may be packaged together and labeled as a HD administration kit. Such a kit
could include:
§
personal protective
equipment;
§
gauze (4" × 4")
for cleanup;
§
alcohol wipes;
§
disposable plastic-backed
absorbent liner;
§
puncture-resistant container
for needles and syringes;
§
a thick sealable plastic bag
(with warning label); and
§
accessory warning labels.
c. Work
Practices. Safe work practices when handling HD's should include the
following:
§
Hands should be washed
before donning and after removing gloves. Gowns or gloves that become
contaminated should be changed immediately. Employees should be trained in
proper methods to remove contaminated gloves and gowns. After use, gloves
and gowns should be disposed of in accordance with ASHP recommendations.
§
Infusion sets and pumps,
which should have Luer-lock fittings, should be observed for leakage during
use. A plastic-backed absorbent pad should be placed under the tubing
during administration to catch any leakage. Sterile gauze should be placed
around any push sites; IV tubing connection sites should be taped.
§
Priming IV sets or expelling
air from syringes should be carried out in a BSC. If done at the
administration site, ASHP recommends that the line be primed with non-drug
containing solution or that a back-flow closed system be used. IV
containers with venting tubes should not be used.3
§
Syringes, IV bottles and
bags, and pumps should be wiped clean of any drug contamination with
sterile gauze. Needles and syringes should not be crushed or clipped. They
should be placed in a puncture-resistant container, then into the HD
disposal bag with all other HD-contaminated materials.
§
Administration sets should
be disposed of intact. Disposal of the waste bag should follow HD disposal
requirements. Unused drugs should be returned to the pharmacy.
§
Protective goggles should be
cleaned with detergent and properly rinsed. All protective equipment should
be disposed of upon leaving the patient care area.
§
Nursing stations where these
drugs will be administered should have spill and emergency skin and eye
decontamination kits available and relevant MSDS's for guidance. The HCS
requires MSDS'S to be readily available in the workplace to all employees
working with hazardous chemicals.
§
PPE should be used during
the administration of oral HD's if splashing is possible.
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.
d. Aerosolized Drugs. The administration of aerosolized HD's
requires special engineering controls to prevent exposure to health care
workers and others in the vicinity. In the case of pentamidine, these
controls include treatment booths with local exhaust ventilation designed
specifically for its administration. A variety of ventilation methods have
also been used for the administration of ribavirin. These include isolation
rooms with separate HEPA filtered ventilation systems and administration
via endotracheal tube.30,47 Engineering controls used to manage employee
exposure to anesthetic gases is a traditional example of occupational
chemical management. Both isolation and ventilation are used for these
volatile HD's.
4.
Caring for
Patients Receiving HD's. In accordance
with the Bloodborne Pathogens Standard, universal precautions must be
observed to prevent contact with blood or other potentially infectious
materials. Under circumstances in which differentiation between body fluid
types is difficult or impossible, all body fluids should be considered
potentially infectious materials and must be managed as dictated in the
Bloodborne Pathogens Standard.109
a. Personal Protective Equipment. Personnel dealing with
excreta, primarily urine, from patients who have received HD's in the last
48 hours should be provided with and wear latex or other appropriate gloves
and disposable gowns, to be discarded after each use or whenever
contaminated, as detailed under Waste Disposal. Eye protection should be
worn if splashing is possible. Such excreta contaminated with blood, or
other potentially infectious materials as well, should be managed according
to the Bloodborne Pathogen Standard. Hands should be washed after removal
of gloves or after contact with the above substances.
b. Linen contaminated with HD's or excreta from patients who
have received HD's in the past 48 hours is a potential source of exposure
to employees. Linen soiled with blood or other potentially infectious
materials as well as contaminated with excreta must also be managed
according to the Bloodborne Pathogens Standard.109 Linen contaminated with HD's should be placed in
specially marked laundry bags and then placed in a labeled impervious bag.
The laundry bag and its contents should be prewashed, and then the linens
added to other laundry for a second wash. Laundry personnel should wear
latex gloves and gowns while handling prewashed material.
5.
c. Reusable Items. Glassware or other contaminated reusable
items should be washed twice with detergent by a trained employee wearing
double latex gloves and a gown.
6.
Waste Disposal.
a. 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.
b. Handling. Prudent practice dictates that every precaution
be taken to prevent contamination of the exterior of the container.
Personnel disposing of HD waste should wear gowns and protective gloves
when handling waste containers with contaminated exteriors. Prudent
practice further dictates that such a container with a contaminated
exterior be placed in a second container in a manner that eliminates
contamination of the second container. HD waste handlers should also
receive hazard communication training as discussed below under Paragraph
VIII: D of this chapter.
c. 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.
7.
Spills. Emergency procedures to cover spills or
inadvertent release of hazardous drugs should be included in the facility's
overall health and safety program. Incidental spills and breakages should
be cleaned up immediately by a properly protected person trained in the
appropriate procedures. The area should be identified with a warning sign
to limit access to the area. Incident reports should be filed to document
the spill and persons exposed.
a. Personnel Contamination. Contamination of protective
equipment or clothing, or direct skin or eye contact should be treated by:
§
Immediately removing the
gloves or gown.
§
Immediate cleansing of the
affected skin with soap and water.
§
Flooding an affected eye at
an eyewash fountain or with water or isotonic eyewash designated for that
purpose for at least 15 minutes, for eye exposure.
§
Obtaining medical attention.
(Protocols for emergency procedures should be maintained at the designated
sites for such medical care. Medical attention should also be sought for
inhalation of HD's in powder form.)
§
Documenting the exposure in
the employee's medical record.
b. Clean-up
of Small Spills. The ASHP considers small spills to be those less than
5 ml. The 5-ml volume of material should be used to categorize spills as
large or small. Spills of less than 5 ml or 5 gm outside a BSC should be
cleaned up immediately by personnel wearing gowns, double latex gloves, and
splash goggles. An appropriate NIOSH-approved respirator should be used
for either powder or liquid spills where airborne powder or aerosol is or
has been generated.
§
Liquids should be wiped with
absorbent gauze pads; solids should be wiped with wet absorbent gauze. The
spill areas should then be cleaned three times using a detergent solution
followed by clean water.
§
Any broken glass fragments
should be picked up using a small scoop (never the hands) and placed in a
"sharps" container. The container should then go into a HD
disposal bag, along with used absorbent pads and any other contaminated
waste.
§
Contaminated reusable items,
for example glassware and scoops, should be treated as outlined above under
Reusable Items.
c.
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.
d. Spills in BSC's. Extensive spills within a BSC necessitate
decontamination of all interior BSC surfaces after completion of the spill
cleanup. The ASHP3 recommends this action for spills larger than 150
ml or the contents of one vial. If the HEPA filter of a BSC is
contaminated, the unit should be labeled and sealed in plastic until the
filter can be changed and disposed of properly by trained personnel wearing
appropriate protective equipment.
d.
e. 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" × 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
e.
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.
8.
Storage and
Transport.
a. Storage Areas. Access to areas where HD's are stored should
be limited to authorized personnel with signs restricting entry.72 A list of drugs covered by HD policies and
information on spill and emergency contact procedures should be posted or
easily available to employees. Optimally, facilities used for storing HD's
should not be used for other drugs, and such facilities should be designed
to prevent containers from falling to the floor, e.g. bins with barrier
fronts. Warning labels should be applied to all HD containers, as well as
the shelves and bins where these containers are permanently stored.
b. 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.
c. 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 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.
VII.
MEDICAL
SURVEILLANCE.
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:
§
before job placement;
§
periodically during
employment;
§
following acute exposures;
and
§
at the time of job
termination or transfer (exit examination).
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.
§
PRE-PLACEMENT
MEDICAL EXAMINATIONS.
1.
Sound medical practice
dictates that employees who will be working with HD's in the workplace have
an initial evaluation consisting of a history, physical exam, and
laboratory studies. Information made available, by the employer, to the examining
physician should be:
§
A description of the
employee's duties as they relate to the employee's exposure.
§
The employee's exposure
levels or anticipated exposure levels.
§
A description of any
personal protective equipment used or to be used.
§
Information from previous
medical examinations of the employee, which is not readily available to the
examining physician.
2.
The history details the
individual's medical and reproductive experience with emphasis on potential
risk factors, such as past hematopoietic, malignant, or hepatic disorders.
It also includes a complete occupational history with information on extent
of past exposures (including environmental sampling data, if possible) and
use of protective equipment. Surrogates for worker exposure, in the absence
of environmental sampling data, include:
§
records of drugs and
quantities handled;
§
hours spent handling these
drugs per week; and
§
number of
preparations/administrations per week.
3.
The physical examination
should be complete, but the skin, mucous membranes, cardiopulmonary and
lymphatic systems, and liver should be emphasized. An evaluation for
respirator use must be performed in accordance with 29 CFR 1910.134, if the
employee will wear a respirator. The laboratory assessment may include a
complete blood count with differential, liver function tests, blood urea
nitrogen, creatinine, and a urine dipstick. Other aspects of the physical
and laboratory evaluation should be guided by known toxicities of the HD of
exposure. Due to poor reproducibility, interindividual variability, and
lack of prognostic value regarding disease development, no biological
monitoring tests (e.g., genotoxic markers) are currently recommended for
routine use in employee surveillance. Biological marker testing should be
performed only within the context of a research protocol.
§
PERIODIC MEDICAL
EXAMINATIONS.
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
EXAMINATIONS. 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.
§
EXIT
EXAMINATIONS. 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-HEALTH
OUTCOME LINKAGE. 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.
§
REPRODUCTIVE
ISSUES. 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.
I.
HAZARD
COMMUNICATION.
This paragraph is for informational purposes only and is not a
substitute for the requirements of the Hazard Communication Standard.
§
DISCUSSION.
1.
The Hazard Communication
Standard (HCS)107 is applicable to some drugs. It defines a
hazardous chemical as any chemical that is a physical hazard or a health
hazard. Physical hazard refers to characteristics such as combustibility or
reactivity. A health hazard is defined as a chemical for which there is
statistically significant evidence based on at least one study conducted in
accordance with established scientific principles that acute or chronic
health effects may occur in exposed employees. Appendixes A and B of the
HCS outline the criteria used to determine whether an agent is hazardous.
2.
According to HCS Appendix A,
agents with any of the following characteristics are considered hazardous:
§
Carcinogens;
§
Corrosives;
§
Toxic or highly toxic
(defined on the basis of median lethal doses);
§
Irritants;
§
Sensitizers; and
§
Target organ effectors,
including reproductive toxins, hepatotoxins, nephrotoxins, neurotoxins,
agents that act on the hematopoietic system, and agents that damage the
lungs, skin, eyes, or mucous membranes
Both human
and animal data are to be used in this determination. HCS Appendix C lists
sources of toxicity information.
3.
As a result of the February
21, 1990, Supreme Court decision,21 all provisions of the HCS [29 CFR 1910. 1200]107 are now in effect for all industrial segments.
This includes the coverage of drugs and pharmaceuticals in the non-manufacturing
sector. On February 9, 1994, OSHA issued a revised Hazard Communication
Final Rule with technical clarification regarding drugs and pharmaceutical
agents.
4.
The HCS requires that drugs
posing a health hazard (with the exception of those in solid, final form
for direct administration to the patient, i.e., tablets or pills) be
included on lists of hazardous chemicals to which employees are exposed.107 Their storage and use locations can be confirmed
by reviewing purchasing office records of currently used and past used
agents such as those in Appendix VI:2-1. Employee exposure records, including workplace
monitoring, biological monitoring, and MSDS's as well as employee medical
records related to drugs posing a health hazard must be maintained and
access to them provided to employees in accordance with 29 CFR 1910.1020.
Training required under the HCS should include all employees potentially
exposed to these agents, not only health care professional staff, but also
physical plant, maintenance, or support staff.
5.
MSDS's are required to be
prepared and transmitted with the initial shipment of all hazardous
chemicals including covered drugs and pharmaceutical products. This
excludes drugs defined by the Federal Food, Drug, and Cosmetic Act that are
in solid, final form for direct administration to the patient (e.g.
tablets, pills, or capsules) or that are packaged for sale to consumers in
a retail establishment. Package inserts and the Physician's Desk Reference
are not acceptable in lieu of requirements of MSDS's under the Standard.
Items mandated by the Standard will use the term shall instead of should.
§
WRITTEN HAZARD
COMMUNICATION PROGRAM.
1.
Employers shall develop, implement,
and maintain at the workplace a written hazard communication program for
employees handling or otherwise exposed to chemicals, including drugs that
represent a health hazard to employees. The written program will describe
how the criteria specified in the Standard concerning labels and other
forms of warning, MSDS's, and employee information and training will be
met. This also includes the following:
§
A list of the covered
hazardous drugs known to be present using an identity that is referenced on
the appropriate MSDS.
§
The methods the employer
will use to inform employees of the hazards of nonroutine tasks in their
work areas.
§
The methods the employer
will use to inform employees of other employers of hazards at the work
site.
2.
The employer shall make the
written hazard communication program available, upon request, to employees,
their designated representatives, and the Assistant Secretary of OSHA in
accordance with requirements of the HCS.
§
MSDS's. 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.
I.
TRAINING AND
INFORMATION DISSEMINATION.
§
DISCUSSION.
1.
In compliance with the
Hazard Communication Standard, all personnel involved in any aspect of the handling
of covered HD's (physicians, nurses, pharmacists, housekeepers, employees
involved in receiving, transport or storage) must receive information and
training to appraise them of the hazards of HD's present in the work area.71
Such information should be provided at the time of an employee's initial
assignment to a work area where HD's are present and prior to assignments
involving new hazards. The employer should provide annual refresher
information and training.
2.
The National Study
Commission on Cytotoxic Exposure has recommended that knowledge and
competence of personnel be evaluated after the first orientation or
training session, and then yearly, or more often if a need is perceived.71 Evaluation may involve direct observation of an
individual's performance on the job. In addition, non-HD solutions should
be used for evaluation of preparation technique; quinine, which will
fluoresce under ultraviolet light, provides an easy mechanism for
evaluation of technique.
§
EMPLOYEE
INFORMATION. Employees must be informed
of the requirements of the Hazard Communication Standard, 29 CFR 1910.1200,
as follows:
1.
Any operation/procedure in
their work area where drugs that present a hazard are present.
2.
The location and
availability of the written hazard communication program.
3.
Any operations or procedure
in their work area where other HD's are present.
4.
The location and
availability of any other plan regarding HD's.
§
EMPLOYEE
TRAINING.
1.
Employee training must
include at least the following elements:
§
Methods and observations
that may be used to detect the presence or release of an HCS-covered
hazardous drug in the work area (such as monitoring conducted by the
employer, continuous monitoring devices, visual appearance or odor of
covered HD's being released, etc.).
§
The physical and health
hazards of the covered HD's in the work area.
§
The measures employees can
take to protect themselves from these hazards. This includes specific
procedures that the employer has implemented to protect the employees from
exposure to such drugs, such as identification of covered drugs and those
to be handled as hazardous, appropriate work practices, emergency
procedures (for spills or employee exposure).
§
Personal protective
equipment, and the details of the hazard communication program developed by
the employer, including an explanation of the labeling system and the MSDS,
and how employees can obtain and use the appropriate hazard information.
2.
It is essential that workers
understand the carcinogenic potential and reproductive hazards of these
drugs. Both females and males should understand the importance of avoiding
exposure, especially early in pregnancy, to the drugs, so that they can
make informed decisions about the hazards involved. In addition, the
facility's policy regarding reproductive toxicity of HD's should be
explained to workers. Updated information should be provided to employees
on a regular basis and whenever their jobs involve new hazards. Medical
staff and other personnel who are not hospital employees should be informed
of hospital policies and of the expectation that they will comply with
these policies.
I.
RECORDKEEPING.
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:
§
Dates of the training
sessions;
§
Contents or a summary of the
training sessions;
§
Names and qualifications of
the persons conducting the training; and
§
Names and job titles of all
persons attending the training sessions.
Training
records should be maintained for three years from the date on which the
training occurred.
II.
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worksite." J. Occup. Med. 34:149-55.
112. Venitt, S., Crofton-Sleigh, C., Hunt, J., et al.
1984. "Monitoring exposure of nursing and pharmacy personnel to
cytotoxic drugs: Urinary mutation assays and urinary platinum as markers of
absorption." Lancet i:74-6.
113. Waksvik, H., Klepp, O., and Brogger, A. 1981.
"Chromosome analyses of nurses handling cytostatic agents." Cancer
Treat. Reports 65:607-10.
114. Wall, R.L. and Clausen, K.P. 1975.
"Carcinoma of the urinary bladder in patients receiving
cyclophosphamide." New England J. Med. 293:271-3.
115. Weisburger, J.H., Griswold, D.P., Prejean J.D.,
et al. 1975. "Tumor induction by cytostatics. The carcinogenic
properties of some of the principal drugs used in clinical cancer
chemotherapy." Recent Results Cancer Res. 52:1-17.
116. Zimmerman, P.F., Larsen, R.K., Barkley, E.W., and
Gallelli, J.F. 1981. "Recommendations for the safe handling of
injectable antineoplastic drug products." Am. J. Hosp. Pharm.
38:1693-5.
APPENDIX VI: 2-1. SOME COMMON DRUGS THAT ARE
CONSIDERED HAZARDOUS.
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.
CHEMICAL/GENERIC NAME
|
SOURCE*
|
ALTRETAMINE
|
C
|
AMINOGLUTETHIMIDE
|
A
|
AZATHIOPRINE
|
ACE
|
L-ASPARAGINASE
|
ABC
|
BLEOMYCIN
|
ABC
|
BUSULFAN
|
ABC
|
CARBOPLATIN
|
ABC
|
CARMUSTINE
|
ABC
|
CHLORAMBUCIL
|
ABCE
|
CHLORAMPHENICOL
|
E
|
CHLOROTIANISENE
|
B
|
CHLOROZOTOCIN
|
E
|
CYCLOSPORIN
|
E
|
CISPLATIN
|
ABCE
|
CYCLOPHOSPHAMIDE
|
ABCE
|
CYTARRABINE
|
ABC
|
DACARBAZINE
|
ABC
|
DACTINOMYCIN
|
ABC
|
DAUNORUBICIN
|
ABC
|
DIETHYLSTILBESTROL
|
BE
|
DOXORUBICIN
|
ABCE
|
ESTRADIOL
|
B
|
ESTRAMUSTINE
|
AB
|
ETHINYL ESTRADIOL
|
B
|
ETOPOSIDE
|
ABC
|
FLOXURIDINE
|
AC
|
FLUOROURACIL
|
ABC
|
FLUTAMIDE
|
BC
|
GANCICLOVIR
|
AD
|
HYDROXYUREA
|
ABC
|
IDARUBICIN
|
AC
|
IFOSFAMIDE
|
ABC
|
INTERFERON-A
|
BC
|
ISOTRETINOIN
|
D
|
LEUPROLIDE
|
BC
|
LEVAMISOLE
|
C
|
LOMUSTINE
|
ABCD
|
MECHLORETHAMINE
|
BC
|
MEDROXYPROGESTERONE
|
B
|
MEGESTROL
|
BC
|
MELPHALAN
|
ABCE
|
MERCAPTOPURINE
|
ABC
|
METHOTREXATE
|
ABC
|
MITOMYCIN
|
ABC
|
MITOTANE
|
ABC
|
MITOXANTRONE
|
ABC
|
NAFARELIN
|
C
|
PIPOBROMAN
|
C
|
PLICAMYCIN
|
BC
|
PROCARBAZINE
|
ABCE
|
RIBAVIRIN
|
D
|
STREPTOZOCIN
|
AC
|
TAMOXIFEN
|
BC
|
TESTOLACTONE
|
BC
|
THIOGUANINE
|
ABC
|
THIOTEPA
|
ABC
|
URACIL MUSTARD
|
ACE
|
VIDARABINE
|
D
|
VINBLASTINE
|
ABC
|
VINCRISTINE
|
ABC
|
ZIDOVUDINE
|
D
|
* Sources
A The National Institutes of Health,
Clinical Center Nursing Department
B Antineoplastic drugs in the
Physicians' Desk Reference
C American Hospital Formulary,
Antineoplastics
D Johns Hopkins Hospital
E International Agency for Research on
Cancer
APPENDIX VI:2-2. SOME
AEROSOLIZED DRUGS.
RIBAVIRIN
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
PENTAMIDINE
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.29
|