|
Hazards summary :
The major hazards encountered in the use and handling of cyclophosphamide
stem from its toxicologic properties. Exposure to this odorless, white,
crystalline powder may occur from its manufacture, formulation, or
distribution for use as an antineoplastic drug. Effects from exposure may
include fever, chills, shortness of breath, dizziness, fatigue, headache,
nausea, hemorrhagic colitis, hepatitis, leukopenia, and pneumonitis or
interstitial pulmonary fibrosis. Cyclophosphamide has been indicated as a
human carcinogen (Group 1) by the International Agency for Research on
Cancer (IARC). Exposure should be controlled by mechanical ventilation
with high-efficiency particulate arrestors (HEPA) or charcoal filters to
minimize the amount of the substance in exhausted air. In activities or
situations where over-exposure may occur, wear protective clothing and a
carefully fitted respirator. Potentially exposed skin should be thoroughly
washed with soap and water. Contaminated clothing should be removed and
discarded or left at the work site for cleaning before reuse. Smoking,
eating, and drinking should be prohibited in cyclophosphamide work areas.
Cyclophosphamide should be stored and transported in securely sealed glass
bottles or ampoules, which are in turn placed inside strong screw-cap or
snap-top containers. Also, the material should be stored cool (below 30
deg C), dry, and shielded from light. This substance is a good candidate
for disposal by rotary kiln, or fluidized bed forms of incineration.
**PEER REVIEWED**
Protective Equipment and Clothing :
PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be
available./ ... Safety pipettes should be used for all pipetting. ... In
animal laboratory, personnel should ... wear protective suits (preferably
disposable, one piece & close fitting at ankles & wrists), gloves, hair
covering & overshoes. ... In chemical laboratory, gloves & gowns should
always be worn ... however, gloves should not be assumed to provide full
protection. Carefully fitted masks or respirators may be necessary when
working with particulates or gases, & disposable plastic aprons might
provide addnl protection. ... gowns ... /should be/ of distinctive color,
this is a reminder that they are not to be worn outside the laboratory. /
Chemical Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch,
E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L.
Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory:Problems of Safety. IARC Scientific Publications No. 33. Lyon,
France: International Agency for Research on Cancer, 1979. 8]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable
closed-front gown or coveralls, disposable utility gloves over disposable
latex gloves, NIOSH-approved air-purifying half-mask respirator equipped
with a high efficiency filter, and eye protection should be worn. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations,
both horizontal and vertical airflow (with no containment
characteristics), are inappropriate engineering controls for handling
hazardous drugs because they provide no personnel protection and permit
environmental contamination. Although there are no engineering controls
designed specifically for the safe handling of hazardous chemicals as
sterile products, Class II contained vertical-flow biological safety
cabinets (biohazard cabinets) have been adopted for this use. Biohazard
cabinetry is, however, designed for the handling of infectious agents, not
hazardous chemicals. ... Based on design, ease of use, and cost
considerations, Class II contained-vertical-flow biohazard cabinetry is
currently recommended for use in preparing sterile doses of hazardous
drugs. Class II cabinetry design and performance specifications are
defined in NSF Standard 49. Biological safety cabinets selected for use
with hazardous drugs should meet NSF Standard 49 specifications to ensure
the maximum protection from these engineering controls. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free,
disposable surgical latex gloves of good quality when preparing hazardous
drugs. Selection criteria for gloves should include thickness (especially
at the fingertips where stress is the greatest), fit, length, and tactile
sensation. ... The practice of double gloving is supported by research
that indicates that many glove materials vary in drug permeability even
within lots; therefore, double gloving is recommended. ... In general,
surgical latex gloves fit better, have appropriate elasticity for double
gloving and maintaining the integrity of the glove-gown interface, and
have sufficient tactile sensation (even during double gloving) for
stringent aseptic procedures. ... Powdered gloves should be avoided. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by
the containment environment of a biohazard cabinet should use respiratory
protection when handling hazardous drugs. Respiratory protection should be
an adjunct to and not a substitute for engineering controls. Surgical
masks of all types provide no respiratory protection against powdered or
liquid aerosols of hazardous drugs. In situations where workers may be
exposed to potential eye contact with hazardous drugs, an appropriate
plastic face shield or splash goggles should be worn. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous
drugs (eg, crushing, dissolving, and preparing an ointment), workers
should wear low permeability gowns and double gloves. Compounding should
take place in a protective area such as a disposable glove box. If
compounding must be done in the open, an area away from drafts and traffic
must be selected, and the worker should use appropriate respiratory
protection. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 95. Bethesda, MD:
American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements
1995). 757]
Other Preventative Measures :
PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food
or of food & beverage containers or utensils, & the application of
cosmetics should be prohibited in any laboratory. All personnel should
remove gloves, if worn, after completion of procedures in which
carcinogens have been used. They should ... wash ... hands, preferably
using dispensers of liq detergent, & rinse ... thoroughly. Consideration
should be given to appropriate methods for cleaning the skin, depending on
nature of the contaminant. No standard procedure can be recommended, but
the use of organic solvents should be avoided. Safety pipettes should be
used for all pipetting. /Chemical Carcinogens/ **PEER REVIEWED**
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A.
Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical
Carcinogens in the Laboratory:Problems of Safety. IARC Scientific
Publications No. 33. Lyon, France: International Agency for Research on
Cancer, 1979. 8]
PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should
remove their outdoor clothes & wear protective suits (preferably
disposable, one piece & close fitting at ankles & wrists), gloves, hair
covering & overshoes. ... clothing should be changed daily but ...
discarded immediately if obvious contamination occurs ... /also,/ workers
should shower immediately. In chemical laboratory, gloves & gowns should
always be worn ... however, gloves should not be assumed to provide full
protection. Carefully fitted masks or respirators may be necessary when
working with particulates or gases, & disposable plastic aprons might
provide addnl protection. If gowns are of distinctive color, this is a
reminder that they should not be worn outside of lab. /Chemical
Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G.
Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W.
Davis (eds.). Handling Chemical Carcinogens in the Laboratory:Problems of
Safety. IARC Scientific Publications No. 33. Lyon, France: International
Agency for Research on Cancer, 1979. 8]
PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth &
purification ... should be carried out under well ventilated hood.
Analytical procedures ... should be carried out with care & vapors evolved
during ... procedures should be removed. ... Expert advice should be
obtained before existing fume cupboards are used ... & when new fume
cupboards are installed. It is desirable that there be means for
decreasing the rate of air extraction, so that carcinogenic powders can be
handled without ... powder being blown around the hood. Glove boxes should
be kept under negative air pressure. Air changes should be adequate, so
that concn of vapors of volatile carcinogens will not occur. /Chemical
Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G.
Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W.
Davis (eds.). Handling Chemical Carcinogens in the Laboratory:Problems of
Safety. IARC Scientific Publications No. 33. Lyon, France: International
Agency for Research on Cancer, 1979. 8]
PRECAUTIONS FOR "CARCINOGENS": Vertical laminar flow biological safety
cabinets may be used for containment of in vitro procedures ... provided
that the exhaust air flow is sufficient to provide an inward air flow at
the face opening of the cabinet, & contaminated air plenums that are under
positive pressure are leak tight. Horizontal laminar flow hoods or safety
cabinets, where filtered air is blown across the working area towards the
operator, should never be used ... Each cabinet or fume cupboard to be
used ... should be tested before work is begun (eg, with fume bomb) &
label fixed to it, giving date of test & avg air flow measured. This test
should be repeated periodically & after any structural changes. /Chemical
Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G.
Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W.
Davis (eds.). Handling Chemical Carcinogens in the Laboratory:Problems of
Safety. IARC Scientific Publications No. 33. Lyon, France: International
Agency for Research on Cancer, 1979. 9]
PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem
lab also apply to microbiological & cell culture labs ... Special
consideration should be given to route of admin. ... Safest method of
administering volatile carcinogen is by injection of a soln. Admin by
topical application, gavage, or intratracheal instillation should be
performed under hood. If chem will be exhaled, animals should be kept
under hood during this period. Inhalation exposure requires special
equipment. ... unless specifically required, routes of admin other than in
the diet should be used. Mixing of carcinogen in diet should be carried
out in sealed mixers under fume hood, from which the exhaust is fitted
with an efficient particulate filter. Techniques for cleaning mixer & hood
should be devised before expt begun. When mixing diets, special protective
clothing &, possibly, respirators may be required. /Chemical Carcinogens/
**PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G. Della Porta,
L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.).
Handling Chemical Carcinogens in the Laboratory:Problems of Safety. IARC
Scientific Publications No. 33. Lyon, France: International Agency for
Research on Cancer, 1979. 9]
PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin,
animals should be kept in cages with solid bottoms & sides & fitted with a
filter top. When volatile carcinogens are given, filter tops should not be
used. Cages which have been used to house animals that received
carcinogens should be decontaminated. Cage cleaning facilities should be
installed in area in which carcinogens are being used, to avoid moving of
... contaminated /cages/. It is difficult to ensure that cages are
decontaminated, & monitoring methods are necessary. Situations may exist
in which the use of disposable cages should be recommended, depending on
type & amt of carcinogen & efficiency with which it can be removed. /
Chemical Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch,
E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L.
Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the
Laboratory:Problems of Safety. IARC Scientific Publications No. 33. Lyon,
France: International Agency for Research on Cancer, 1979. 10]
PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in
lab could build up during conduct of expt, periodic checks should be
carried out on lab atmospheres, surfaces, such as walls, floors & benches,
& ... interior of fume hoods & airducts. As well as regular monitoring,
check must be carried out after cleaning up of spillage. Sensitive methods
are required when testing lab atmospheres. ... Methods ... should ...
where possible, be simple & sensitive. ... /Chemical Carcinogens/ **PEER
REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L.
Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.).
Handling Chemical Carcinogens in the Laboratory:Problems of Safety. IARC
Scientific Publications No. 33. Lyon, France: International Agency for
Research on Cancer, 1979. 10]
PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has
occurred, such as spillage, should be decontaminated by lab personnel
engaged in expt. Design of expt should ... avoid contamination of
permanent equipment. ... Procedures should ensure that maintenance workers
are not exposed to carcinogens. ... Particular care should be taken to
avoid contamination of drains or ventilation ducts. In cleaning labs,
procedures should be used which do not produce aerosols or dispersal of
dust, ie, wet mop or vacuum cleaner equipped with high efficiency
particulate filter on exhaust, which are avail commercially, should be
used. Sweeping, brushing & use of dry dusters or mops should be
prohibited. Grossly contaminated cleaning materials should not be reused
... If gowns or towels are contaminated, they should not be sent to
laundry, but ... decontaminated or burnt, to avoid any hazard to laundry
personnel. /Chemical Carcinogens/ **PEER REVIEWED** [Montesano, R., H.
Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B.
Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in
the Laboratory:Problems of Safety. IARC Scientific Publications No. 33.
Lyon, France: International Agency for Research on Cancer, 1979. 10]
PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens
are used ... should be marked distinctively with appropriate labels.
Access ... limited to persons involved in expt. ... A prominently
displayed notice should give the name of the Scientific Investigator or
other person who can advise in an emergency & who can inform others (such
as firemen) on the handling of carcinogenic substances. /Chemical
Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G.
Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W.
Davis (eds.). Handling Chemical Carcinogens in the Laboratory:Problems of
Safety. IARC Scientific Publications No. 33. Lyon, France: International
Agency for Research on Cancer, 1979. 11]
SRP: Contaminated protective clothing should be segregated in such a
manner so that there is no direct personal contact by personnel who handle,
dispose, or clean the clothing. Quality assurance to ascertain the
completeness of the cleaning procedures should be implemented before the
decontaminated protective clothing is returned for reuse by the workers.
Contaminated clothing should not be taken home at end of shift, but should
remain at employee's place of work for cleaning. **PEER REVIEWED**
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the
health-care environment, resulting in exposure of personnel, patients,
visitors, and family members to hazardous substances, is prevented by
maintaining the physical integrity and security of packages of hazardous
drugs. 1. Access to all areas where hazardous drugs are stored is limited
to specified authorized staff. 2. A method should be present for
identifying to personnel those drugs that require special precautions (eg,
cytotoxics). One way to accomplish this is to apply appropriate warning
labels to all hazardous drug containers, shelves, and bins where the drug
products are stored. ... 3. A method of identifying, for patients and
family members, those drugs that require special precautions in the home
should be in place. This may be accomplished in the health-care setting,
by providing specific labeling for discharge medications, along with
written instructions. 4. Methods for identifying shipping cartons of
hazardous drugs should be required from manufacturers and distributors of
these drugs. 5. Written procedures for handling damaged packages of
hazardous drugs should be maintained. Personnel involved in shipping and
receiving hazardous drugs should be trained in these procedures, including
the proper use of protective garments and equipment. Damaged shipping
cartons of hazardous drugs should be received and opened in an isolated
area (eg, in a laboratory fume hood, if available, not in a vertical
laminar airflow biological safety cabinet used for preparing sterile
products). /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 95. Bethesda, MD:
American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements
1995). 753]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts,
counters, and trays) for storing hazardous drugs are designed to prevent
breakage and to limit contamination in the event of leakage. Bins, shelves
with barriers at the front, or other design features that reduce the
chance of drug containers falling to the floor should be used. Hazardous
drugs requiring refrigeration should be stored separately from
nonhazardous drugs in individual bins designed to prevent breakage and to
contain leakage. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 95. Bethesda,
MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or
lack thereof) associated with handling hazardous drugs within a safety
program have been substantiated, staff who are pregnant or breast-feeding
should be allowed to avoid contact with these drugs. Policies should be in
effect that provide these individuals with alternative tasks or
responsibilities if they so desire. /Antineoplastic agents/ **PEER
REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide
access to information on toxicity, treatment of acute exposure (if
available), chemical inactivators, solubility and stability of hazardous
drugs (including investigational agents) used in the workplace. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Appropriate engineering controls
should be in place to protect the drug product from microbial
contamination and to protect personnel and the environment from the
potential hazards of the product. These engineering controls should be
maintained according to applicable regulations and standards. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Biological safety cabinets should
be cleaned and disinfected regularly to ensure a proper environment for
preparation of sterile products. For routine cleanups of surfaces between
decontaminations, water should be used (for injection or irrigation) with
or without a small amount of cleaner. If the contamination is soluble only
in alcohol, then 70% isopropyl or ethyl alcohol may be used in addition to
the cleaner. In general, alcohol is not a good cleaner, only a
disinfectant, and its use in a biohazard cabinet should be limited. The
biohazard cabinet should be disinfected with 70% alcohol before any
aseptic manipulation is begun. The excessive use of alcohol should be
avoided in biohazard cabinets where air is recirculated ... because
alcohol vapors may build up in the cabinet. A lint-free, plastic-backed
disposable liner may be used in the biological safety cabinet to
facilitate spill cleanup. ... If used, the liner should be changed
frequently ... /or/ whenever it is overtly contaminated. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 755]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The biological safety cabinets
should be decontaminated on a regular basis (ideally at least weekly) and
whenever there is a spill or the biological safety cabinet is moved or
serviced, including for certification. ... Currently, no single reagent
will deactivate all known hazardous drugs; therefore, decontamination of a
biological safety cabinet used for such drugs is limited to removal of
contamination from a nondisposable surface (the cabinet) to a disposable
surface (eg, gauze or towels) by use of a good cleaning agent that removes
chemicals from stainless steel. The cleaning agent selected should have a
pH approximating that of soap and be appropriate for stainless steel.
Cleaners containing chemicals such as quaternary ammonium compounds should
be used with caution, because they may be hazardous to humans and their
vapors may build up in any biological safety cabinet where air is
recirculated. Similar caution should be used with any pressurized aerosol
cleaner; spraying a pressurized aerosol into a biological safety cabinet
may disrupt the protective containment airflow, damage the high efficiency
particulate air filter, and cause an accumulation of the propellant within
a biological safety cabinet where air is recirculated, resulting in a fire
and explosion hazard. During decontamination, the operator should wear a
disposable closed front gown, disposable latex gloves covered by
disposable utility gloves, safety glasses or goggles, a hair covering, and
a disposable respirator, because the glass shield of the biological safety
cabinet occasionally must be lifted. The blower must be left on, and only
heavy toweling or gauze should be used in the biological safety cabinet to
prevent it from being "sucked" up the plenum and into the high efficiency
particulate air filter. Decontamination should be done from top to bottom
(areas of lesser contamination to greater) by applying the cleaner,
scrubbing, and rinsing thoroughly with distilled or deionized water. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 755]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The high efficiency particulate
air filters /or other exhaust scrubbing system/ of the biohazard cabinet
must be replaced whenever they restrict required airflow velocity or if
they are overtly contaminated (eg, by a breach in technique that causes
hazardous drug to be introduced onto the clean side of the supply high
efficiency particulate air filter). Personnel and environmental protection
must be maintained during replacement of a contaminated high efficiency
particulate air filter. Because replacement of a high efficiency
particulate air filter generally requires breaking the integrity of the
containment aspect of the cabinet, this procedure may release
contamination from the filter into the pharmacy or intravenous preparation
area if carried out in an inappropriate manner. Before replacement of a
high efficiency particulate air filter contaminated with hazardous drugs,
the biological safety cabinet service agent should be consulted for a
mutually acceptable procedure for replacing and subsequently disposing of
a contaminated high efficiency particulate air filter. One procedure would
include moving the biological safety cabinet to a secluded area or using
plastic barriers to segregate the contaminated area. Protective clothing
and equipment must be used by the servicer. The biological safety cabinet
should be decontaminated before filter replacement. /Antineoplastic agents/
**PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During removal of gloves, ...
avoid touching the inside of the glove or the skin with the contaminated
glove fingers. ... The worker should wear a protective disposable gown
made of lint free, low-permeability fabric with a solid front, long
sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous
drugs. Washable garments are immediately penetrated by liquids and
therefore provide little, if any protection. /Antineoplastic agents/
**PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary Service
- Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When double gloving, one glove
should be placed under the gown cuff and one over. The glove-gown
interface should be such that no skin on the arm or wrist is exposed.
Gloves and gowns should not be worn outside the immediate preparation
area. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 95. Bethesda, MD:
American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements
1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Eyewash fountains should be
available in areas where hazardous drugs are routinely handled. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Although noninjectable dosage
forms of hazardous drugs contain varying proportions of drug to nondrug
(nonhazardous) components, there is potential for personnel exposure and
environmental contamination with the hazardous components. Procedures
should be developed to avoid the release of aerosolized powder or liquid
into the environment during manipulation of these drugs. Drugs designated
as hazardous should be labeled or otherwise identified as such to prevent
their improper handling. Tablet and capsule forms of these drugs should
not be placed in automated counting machines, which subject them to stress
and may introduce powdered contaminants into the work area. During routine
handling of hazardous drugs and contaminated equipment, workers should
wear one pair of gloves of good quality and thickness. The counting and
pouring of hazardous drugs should be done carefully, and clean equipment
dedicated for use with these drugs should be used. ... When hazardous drug
tablets in unit-of-use packaging are being crushed, the package should be
placed in a small sealable plastic bag and crushed with a spoon or pestle;
caution should be used not to break the plastic bag. Disposal of unused or
unusable oral or topical dosage forms of hazardous drugs should be
performed in the same manner as for hazardous injectable dosage forms and
waste. ... Hazardous drug work areas should have a sink (preferably with
an eyewash fountain) and appropriate first aid equipment to treat
accidental skin or eye contact according to the protocol. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 757]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A distinctive warning label with
an appropriate CAUTION statement should be attached to all hazardous drug
materials, consistent with state laws and regulations. This would include,
for example, syringes, IV containers, containers of unit-dose tablets and
liquids, prescription vials and bottles, waste containers, and patient
specimens that contain hazardous drugs. /Antineoplastic agents/ **PEER
REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 757]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Supplies of disposable gloves and
gowns, safety glasses, disposable plastic-backed absorbent liners, gauze
pads, hazardous waste disposal bags, hazardous drug warning labels, and
puncture-resistant containers for disposal of needles and ampuls should be
conveniently located for all areas where hazardous drugs are handled.
Assembling a "hazardous drug preparation and administration kit" is one
way to furnish nursing and medical personnel with the materials needed to
reduce the risk of preparing and administering a hazardous drug. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 758]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Prospective temporary and
permanent employees who may be required to work with hazardous drugs
should be so notified and should receive adequate information about the
policies and procedures pertaining to their use. This notification should
be documented during the interview process and retained as part of the
employment record for all employees. /Antineoplastic agents/ **PEER
REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All personnel involved with the
transportation, preparation, administration, and disposal of cytotoxic and
hazardous substances should continually be updated on new or revised
information on safe handling of cytotoxic and hazardous substances.
Policies and procedures should be updated accordingly. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 754]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The work area should be designed
to provide easy access to those items necessary to prepare, label, and
transport final products; contain all related waste; and avoid inadvertent
contamination of the work area. /Antineoplastic agents/ **PEER REVIEWED**
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each health-care setting should
have an established first aid protocol for treating cases of direct
contact with hazardous drugs, many of which are irritating or caustic and
can cause tissue destruction. Medical care providers in each setting
should be contacted for input into this protocol. The protocol should
include immediate treatment measures and should specify the type and
location of medical follow-up and work-injury reporting. Copies of the
protocol, highlighting emergency measures, should be posted wherever
hazardous drugs are routinely handled. /Antineoplastic agents/ **PEER
REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 757]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only individuals trained to
administer hazardous drugs should be allowed to perform this function.
Training programs should contain information on the therapeutic and
adverse effects of these drugs and the potential, long term health risk to
personnel handling these drugs. Each individual's knowledge and technique
should be evaluated before administration of these drugs. This should be
done by written examination and direct observation of the individual's
performance. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 95. Bethesda,
MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 757]
Stability/Shelf Life :
AQ SOLN KEEPS FOR A FEW HR @ ROOM TEMP, BUT HYDROLYSIS OCCURS ABOVE 30 DEG
C, REMOVES CHLORINE ATOMS; DARKENS ON EXPOSURE TO LIGHT /MONOHYDRATE/
**PEER REVIEWED** [IARC. Monographs on the Evaluation of the Carcinogenic
Risk of Chemicals to Man. Geneva: World Health Organization, International
Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V9 136
(1975)]
SENSITIVE TO OXIDATION, MOISTURE ... /MONOHYDRATE/ **PEER REVIEWED**
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals
to Man. Geneva: World Health Organization, International Agency for
Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 166 (1981)]
Shipment Methods and Regulations :
PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ...
should be avoided. To avoid spilling, carcinogens should be transported in
securely sealed glass bottles or ampoules, which should themselves be
placed inside strong screw-cap or snap-top container that will not open
when dropped & will resist attack from the carcinogen. Both bottle & the
outside container should be appropriately labelled. ... National post
offices, railway companies, road haulage companies & airlines have
regulations governing transport of hazardous materials. These authorities
should be consulted before ... material is shipped. /Chemical Carcinogens/
**QC REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L.
Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.).
Handling Chemical Carcinogens in the Laboratory:Problems of Safety. IARC
Scientific Publications No. 33. Lyon, France: International Agency for
Research on Cancer, 1979. 13]
PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following
procedure must be adopted. The carcinogen should be enclosed in a securely
sealed, watertight container (primary container), which should be enclosed
in a second, unbreakable, leakproof container that will withstand chem
attack from the carcinogen (secondary container). The space between
primary & secondary container should be filled with absorbent material,
which would withstand chem attack from the carcinogen & is sufficient to
absorb the entire contents of the primary container in the event of
breakage or leakage. Each secondary container should then be enclosed in a
strong outer box. The space between the secondary container & the outer
box should be filled with an appropriate quantity of shock-absorbent
material. Sender should use fastest & most secure form of transport &
notify recipient of its departure. If parcel is not received when expected,
carrier should be informed so that immediate effort can be made to find
it. Traffic schedules should be consulted to avoid ... arrival on weekend
or holiday ... /Chemical Carcinogens/ **QC REVIEWED** [Montesano, R., H.
Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B.
Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in
the Laboratory:Problems of Safety. IARC Scientific Publications No. 33.
Lyon, France: International Agency for Research on Cancer, 1979. 13]
Storage Conditions :
Cyclophosphamide should be preserved in tight containers, at a temperature
between 2 and 32 deg C. **PEER REVIEWED** [American Medical Association,
Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American
Medical Association, 1986. 263]
Protect from light. **PEER REVIEWED** [Reynolds, J.E.F., Prasad, A.B.
(eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The
Pharmaceutical Press, 1982. 199]
PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as
practicable to lab in which carcinogens are to be used, so that only small
quantities required for ... expt need to be carried. Carcinogens should be
kept in only one section of cupboard, an explosion proof refrigerator or
freezer (depending on chemicophysical properties ...) that bears
appropriate label. An inventory ... should be kept, showing quantity of
carcinogen & date it was acquired ... Facilities for dispensing ... should
be contiguous to storage area. /Chemical Carcinogens/ **PEER REVIEWED**
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A.
Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical
Carcinogens in the Laboratory:Problems of Safety. IARC Scientific
Publications No. 33. Lyon, France: International Agency for Research on
Cancer, 1979. 13]
Cleanup Methods :
PRECAUTIONS FOR "CARCINOGENS": A high efficiency particulate arrestor
(HEPA) or charcoal filters can be used to minimize amt of carcinogen in
exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal
rooms ... Filter housing that is designed so that used filters can be
transferred into plastic bag without contaminating maintenance staff is
available commercially. Filters should be placed in plastic bags
immediately after removal ... The plastic bag should be sealed immediately
... The sealed bag should be labelled properly ... Waste liquids ...
should be placed or collected in proper containers for disposal. The lid
should be secured & the bottles properly labelled. Once filled, bottles
should be placed in plastic bag, so that outer surface ... is not
contaminated ... The plastic bag should also be sealed & labelled. ...
Broken glassware ... should be decontaminated by solvent extraction, by
chemical destruction, or in specially designed incinerators. /Chemical
Carcinogens/ **PEER REVIEWED** [Montesano, R., H. Bartsch, E.Boyland, G.
Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W.
Davis (eds.). Handling Chemical Carcinogens in the Laboratory:Problems of
Safety. IARC Scientific Publications No. 33. Lyon, France: International
Agency for Research on Cancer, 1979. 15]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all
materials needed to clean up spills of hazardous drugs should be assembled
or purchased. These kits should be readily available in all areas where
hazardous drugs are routinely handled. If hazardous drugs are being
prepared or administered in a nonroutine area (home setting or unusual
patient-care area), a spill kit should be obtained by the drug handler.
The kit should include two pairs of disposable gloves (one outer pair of
utility gloves and one inner latex pair); low-permeability, disposable
protective garments (coveralls or gown and shoe covers); safety glasses or
splash goggles; respirator; absorbent, plastic-backed sheets or spill
pads; disposable toweling; at least 2 sealable thick plastic hazardous
waste disposal bags (prelabeled with an appropriate warning label); a
disposable scoop for collecting glass fragments; and a puncture-resistant
container for glass fragments. All individuals who routinely handle
hazardous drugs must be trained in proper spill management and cleanup
procedures. Spills and breakages must be cleaned up immediately according
to the following procedures. If the spill is not located in a confined
space, the spill area should be identified and other people should be
prevented from approaching and spreading the contamination. Wearing
protective apparel from the spill kit, workers should remove any broken
glass fragments and place them in the puncture-resistant container.
Liquids should be absorbed with a spill pad; powder should be removed with
damp disposable gauze pads or soft toweling. The hazardous material should
be completely removed and the area rinsed with water and then cleaned with
detergent. The spill cleanup should proceed progressively from areas of
lesser to greater contamination. The detergent should be thoroughly rinsed
and removed. All contaminated materials should be placed in the disposal
bags provided and sealed and transported to a designated containment
receptacle. Spills occurring in the biohazard cabinet should be cleaned up
immediately; a spill kit should be used if the volume exceeds 150 ml or
the contents of one drug vial or ampule. If there is broken glass, utility
gloves should be worn to remove it and place it in the puncture-resistant
container located in the biohazard cabinet. The biological safety cabinet,
including the drain spillage trough, should be thoroughly cleaned. If the
spill is not easily and thoroughly contained, the biological safety
cabinet should be decontaminated after cleanup. If the spill contaminates
the high efficiency particulate air filter, use of the biological safety
cabinet should be suspended until the cabinet has been decontaminated and
the high efficiency particulate air filter replaced. /Antineoplastic
agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 95. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1995 (Plus Supplements 1995). 758]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely
prepared or administered in carpeted areas, special equipment is necessary
to remove the spill. Absorbent powder should be substituted for pads or
sheets and left in place on the spill for the time recommended by the
manufacturer. The powder should then be picked up with a small vacuum unit
reserved for hazardous drug cleanup. The carpet should then be cleaned
according to usual procedures. The vacuum bag should be removed and
discarded or cleaned, and the exterior of the vacuum cleaner should be
washed with detergent and rinsed before being covered and stored. The
contaminated powder should be discarded into a sealable plastic bag and
segregated with other contaminated waste materials. Alternatively,
inexpensive wet or dry vacuum units may be purchased for this express use
and used with appropriate cleaners. All such units are contaminated, once
used, and must be cleaned, stored, and ultimately discarded /properly/ ...
The circumstances and handling of spills should be documented. Health-care
personnel exposed during spill management should also complete an incident
report or exposure form. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 95.
Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 759]
Disposal Methods :
Generators of waste (equal to or greater than 100 kg/mo) containing this
contaminant, EPA hazardous waste number U058, must conform with USEPA
regulations in storage, transportation, treatment and disposal of waste.
**PEER REVIEWED** [40 CFR 240-280, 300-306, 702-799 (7/1/92)]
A potential candidate for rotary kiln incineration at a temperature range
of 820 to 1,600 deg C and residence times of seconds for liquids and gases,
and hours for solids. A potential candidate for fluidized bed
incineration at a temperature range of 450 to 980 deg C and residence
times of seconds for liquids and gases, and longer for solids. **PEER
REVIEWED** [USEPA; Engineering Handbook for Hazardous Waste Incineration
p.3-12 (1981) EPA 68-03-3025]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables
should be contained in sealable bags for transfer to larger waste
containers. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 95. Bethesda, MD:
American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements
1995). 755]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as
contaminated waste after decontamination of the biohazard cabinet. All
protective apparel (gown, gloves, goggles, and respirator) should be
discarded as contaminated waste. /Antineoplastic agents/ **PEER REVIEWED**
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 95. Bethesda, MD: American Society of Hospital Pharmacists,
Inc., 1995 (Plus Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be
removed, bagged in thick plastic and prepared for disposal in a hazardous
waste dump site or incinerator licensed by the Environmental Protection
Agency (EPA). /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 95. Bethesda,
MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The gown should be removed and
placed in a sealable container before removal of the inner gloves. The
inner gloves should be removed last and placed in the container with the
gown. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 95. Bethesda, MD:
American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements
1995). 756]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Hazardous drug waste should be
placed in specially marked (specifically labeled CAUTION: HAZARDOUS
CHEMICAL WASTE) thick plastic bags or leakproof containers. These
receptacles should be kept in all areas where the drugs are commonly used.
All and only hazardous drug waste should be placed in them. Receptacles
used for glass fragments, needles, and syringes should be puncture
resistant. Hazardous drug waste should not be mixed with any other waste.
Waste containers should be handled with uncontaminated gloves. ... Gloves,
gowns, drug vials, etc, should be sealed in specially labeled (CAUTION:
HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. ...
All hazardous waste collected from drug preparation and patient-care areas
should be held in a secure place in labeled, leakproof drums or cartons
(as required by state or local regulation or disposal contractor) until
disposal. This waste should be disposed of as hazardous or toxic waste in
an EPA-permitted state-licensed hazardous waste incinerator. Transport to
an offsite incinerator should be done by a contractor licensed to handle
and transport hazardous waste. ... If access to an appropriately licensed
incinerator is not available, transport to and burial in an EPA-licensed
hazardous waste dump site is an acceptable alternative. While there are
concerns that destruction of carcinogens by incineration may be incomplete,
newer technologies and stringent licensing criteria have improved this
disposal method. ... Chemical deactivation of hazardous drugs should be
undertaken only by individuals who are thoroughly familiar with the
chemicals and the procedures required to complete such a task. The IARC
recently published a monograph describing methods for chemical destruction
of some cytotoxic (antineoplastic) drugs in the laboratory setting. The
chemicals and equipment described, however, are not generally found in the
clinical setting, and many of the deactivating chemicals are toxic and
hazardous. Most procedures require the use of a chemical fume hood. The
procedures are generally difficult, and the deactivation is not always
complete. Serious consideration should be given to the negative aspects of
chemical deactivation before one commits to such a course of action. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 758]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Regulatory agencies such as the
EPA and state solid and hazardous waste agencies and local air and water
quality control boards must be consulted regarding the classification and
appropriate disposal of drugs that are defined as hazardous or toxic
chemicals. EPA categorizes several of the antineoplastic agents as toxic
wastes, while many states are more stringent and include as carcinogens
certain cytotoxic drugs and hormonal preparations. EPA also allows
exemptions from toxic waste regulations for small quantity generators,
whereas certain states do not. It is critical to research these
regulations when disposal procedures are being established. /
Antineoplastic agents/ **PEER REVIEWED** [McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 95. Bethesda, MD: American
Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). 759]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If the biological safety cabinets
is equipped with a drainpipe and valve, it may be used to collect rinse
water. The collection vessel used must fit well around the drain valve and
not allow splashing. Gauze may be used around the connection to prevent
aerosol from escaping. The collection vessel must have a tight fitting
cover, and all rinse water (gauze, if used) must be disposed of as
contaminated waste. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 95.
Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 755]
|
|
Evidence For Carcinogenicity :
Classification of carcinogenicity: 1) evidence in humans: sufficient; 2)
evidence in animals: sufficient. Overall summary evaluation of
carcinogenic risk to humans is Group 1: The agent is carcinogenic to
humans. /From table/ **PEER REVIEWED** [IARC. Monographs on the Evaluation
of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health
Organization, International Agency for Research on Cancer,1972-PRESENT.
(Multivolume work).,p. S7 61 (1987)]
The Carcinogen Assessment Group in EPA's Research and Development Office
has evaluated cyclophosphamide for carcinogenicity. According to their
analysis, the weight of evidence for cyclophosphamide is group C, which is
based on inadequate evidence in humans and limited evidence in animals. As
a group C chemical, cyclophosphamide is considered a possible human
carcinogen. **PEER REVIEWED** [USEPA; Methodology for Evaluating Potential
Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to
Cercla Section 102 (1986) OHEA-C-073]
Medical Surveillance :
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated,
in particular when exposure to a carcinogen has occurred, ad hoc decisions
should be taken concerning ... /cytogenetic and/or other/ tests that might
become useful or mandatory. /Chemical Carcinogens/ **PEER REVIEWED**
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A.
Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical
Carcinogens in the Laboratory:Problems of Safety. IARC Scientific
Publications No. 33. Lyon, France: International Agency for Research on
Cancer, 1979. 23]
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for
routine monitoring of personnel for evidence of hazardous drug exposure.
Tests for the presence of mutagens or chromosomal damage are not drug
specific and are of value only in controlled studies. Chemical analysis of
urine for the presence of hazardous drugs at the sensitivity level needed
to detect occupational exposure is limited to a few drugs and is not yet
commercially available. /Antineoplastic agents/ **PEER REVIEWED** [McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 95.
Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus
Supplements 1995). 759]
Human Toxicity Excerpts :
LEUKOPENIA IS INEVITABLE SIDE EFFECT & IS USED AS INDEX OF DOSAGE ...
HYPOPROTHROMBINEMIA ... . **PEER REVIEWED** [Osol, A. (ed.). Remington's
Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing
Co., 1980. 1088]
THE CLINICAL TOXICITY OF CYCLOPHOSPHAMIDE DIFFERS FROM THAT OF OTHER
NITROGEN MUSTARDS IN THAT SIGNIFICANT DEGREES OF THROMBOCYTOPENIA ARE MUCH
LESS COMMON, BUT THERE IS FREQUENT OCCURRENCE OF ALOPECIA. PATIENTS SHOULD
BE FOREWARNED OF THIS POSSIBLE EVENT, WHICH IS USUALLY REVERSIBLE EVEN
WITHOUT INTERRUPTION OF THERAPY. NAUSEA & VOMITING ARE COMMON AND OCCUR
WITH EQUAL FREQUENCY WHETHER THE DRUG IS GIVEN BY THE ORAL OR IV ROUTE.
MUCOSAL ULCERATIONS, DIZZINESS OF SHORT DURATION, TRANSVERSE RIDGING OF
NAILS, INCR SKIN PIGMENTATION, INTERSTITIAL PULMONARY FIBROSIS, & HEPATIC
TOXICITY HAVE BEEN REPORTED. EXTRAVASATION OF THE DRUG INTO SUBCUTANEOUS
TISSUES DOES NOT PRODUCE LOCAL REACTIONS AND THROMBOPHLEBITIS DOES NOT
COMPLICATE INTRAVENOUS ADMINISTRATION. THE OCCURRENCE OF STERILE,
HEMORRHAGIC CYSTITIS HAS BEEN REPORTED IN 5 TO 10% OF PATIENTS. THIS HAS
BEEN ATTRIBUTED TO CHEM IRRITATION PRODUCED BY REACTIVE METABOLITES OF
CYCLOPHOSPHAMIDE ... . **PEER REVIEWED** [Gilman, A.G., T.W. Rall, A.S.
Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis
of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1218]
THERE WAS INCR IN NUMBER OF CHROMOSOMAL ABERRATIONS IN THE PERIPHERAL
BLOOD LYMPHOCYTES OF CHILDREN TREATED WITH CYCLOPHOSPHAMIDE (3-5 MG DAILY
FOR 6-8 MONTHS) FOR NONMALIGNANT CONDITIONS AND OF PATIENTS WITH
RHEUMATOID ARTHRITIS FOLLOWING CYCLOPHOSPHAMIDE TREATMENT. SIMILAR INCR
WERE OBSERVED IN LYMPHOCYTES OF WOMEN WITH RECURRENT OVARIAN OR UTERAL
CARCINOMA 3 OR 24 HR AFTER AN IV ADMIN OF 2.0 G AND IN THE BONE MARROW AND
LYMPH NODE CELLS OF PATIENTS WITH LYMPHOGRANULOMATOSIS 24-72 HR AFTER
SINGLE DOSE OF 400 MG CYCLOPHOSPHAMIDE. INCR LEVELS OF SISTER CHROMATID
EXCHANGE IN PERIPHERAL BLOOD LYMPHOCYTES HAVE BEEN OBSERVED IN PATIENTS
TREATED WITH CYCLOPHOSPHAMIDE. THESE HAVE INCLUDED PATIENTS WITH MALIGNANT
LYMPHOMA AND NEPHROTIC SYNDROME, A PATIENT WITH RETICULOSARCOMA, 3
PATIENTS WITH UNSPECIFIED MALIGNANT TUMORS AND 1 PATIENT WITH ACUTE
GLOMERULONEPHRITIS. /MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World
Health Organization, International Agency for Research on Cancer,1972-
PRESENT. (Multivolume work).,p. V26 181 (1981)]
LIMB REDUCTION DEFECTS HAVE BEEN OBSERVED IN TWO CASES OF INFANTS EXPOSED
TO CYCLOPHOSPHAMIDE IN UTERO. ONE MOTHER RECEIVED 100 MG/DAY DURING HER
ENTIRE PREGNANCY: HER INFANT HAD NO BIG TOES OR THEIR RESPECTIVE
METATARSALS AND PHALANGES; THE LEFT FIFTH FINGER HAD A HYPOPLASTIC
MIDPHALANGE; THE INFANT ALSO HAD A PROMINENT PALATAL GROOVE. /MONOHYDRATE/
**PEER REVIEWED** [IARC. Monographs on the Evaluation of the Carcinogenic
Risk of Chemicals to Man. Geneva: World Health Organization, International
Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 180
(1981)]
THERE HAVE BEEN AT LEAST 30 CASE REPORTS OF MALIGNANCY IN PATIENTS TREATED
WITH CYCLOPHOSPHAMIDE FOR NONMALIGNANT DISORDERS, MAINLY RHEUMATOID
ARTHRITIS AND CHRONIC GLOMERULONEPHRITIS. THESE INCLUDED 17 ACUTE
NONLYMPHOCYTIC LEUKEMIAS, ONE CHRONIC NONLYMPHOCYTIC LEUKEMIA, ONE ACUTE
LYMPHOCYTIC LEUKEMIA, ONE CHRONIC LYMPHOCYTIC LEUKEMIA, TWO BLADDER
CANCERS, ONE SQUAMOUS CELL CANCER OF THE SKIN, THREE RETICULUM CELL
SARCOMAS, ONE HODGKIN'S DISEASE, ONE MELANOMA, TWO CEREBRAL GLIOMAS, ONE
CERVICAL CANCER AND ONE PLEURAL SARCOMA. /MONOHYDRATE/ **PEER REVIEWED**
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals
to Man. Geneva: World Health Organization, International Agency for
Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 182 (1981)]
In children treated with cyclophosphamide a transient blurring of vision
has been reported in 5 out of 59, coming on in minutes after intravenous
injection in two and within 24 hours in the other three. The duration of
blurring ranged from one hour to two weeks, but vision returned to normal
in all. **PEER REVIEWED** [Grant, W.M. Toxicology of the Eye. 3rd ed.
Springfield, IL: Charles C. Thomas Publisher, 1986. 299]
Cyclophosphamide can cause sterility in people of either sex. It can
damage the germinal cells in prepubertal, pubertal and adult males, and
causes premature ovarian failure in females. **PEER REVIEWED** [IARC.
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on
Cancer,1972-PRESENT. (Multivolume work).,p. V26 180 (1981)]
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in
patients taking antineoplastic therapy, especially with the alkylating
agents. In general, these effects appear to be related to dose and length
of therapy and may be irreversible. Prediction of the degree of testicular
or ovarian function impairment is complicated by the common use of
combinations of several antineoplastics, which makes it difficult to
assess the effects of individual agents. However, there have been numerous
reports of gonadal suppression with use of cyclophosphamide, which seems
to depend on dose, duration, and state of gonadal function at the time of
therapy, sterility may be irreversible in some patients. **PEER REVIEWED**
[USP Convention. USPDI - Drug Information for the Health Care
Professional. 16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical
Convention, Inc. 1996 (Plus updates). 1125]
Paternal use of cyclophosphamide prior to conception has been associated
with cardiac and limb abnormalities in an infant. **PEER REVIEWED** [USP
Convention. USPDI - Drug Information for the Health Care Professional.
16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical Convention, Inc.
1996 (Plus updates). 1125]
Cyclophosphamide crosses the placenta. Use in humans has resulted in both
normal and malformed (missing fingers and/or toes, cardiac anomalies,
hernias) newborns; risk seems to be less in the second and third
trimesters. Low birth weight is also a risk with exposure of the fetus to
antineoplastics. First trimester: It is usually recommended that use of
antineoplastics, especially combination chemotherapy, be avoided whenever
possible, especially during the first trimester. Although information is
limited because of the relatively few instances of antineoplastic
administration during pregnancy, the mutagenic, teratogenic, and
carcinogenic potential of these medications must be considered. Other
hazards to the fetus include adverse reactions seen in adults. **PEER
REVIEWED** [USP Convention. USPDI - Drug Information for the Health Care
Professional. 16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical
Convention, Inc. 1996 (Plus updates). 1125]
... A treated mother gave birth to a 1900 gm infant with multiple
anomalies including 4 toes on each foot, flattening of the nasal bridge
and a hypoplastic 5th finger. The clinical picture was compatible with
fetal injury occurring during an intensive course of intravenous therapy
(1,800 mg) given at about the 77th to 82nd day of gestation. **PEER
REVIEWED** [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore,
MD: The Johns Hopkins University Press, 1986. 159]
One of the major and dose limiting adverse effects of cyclophosphamide is
hematologic toxicity, which is usually reversible after discontinuance of
the drug. Hematopoietic adverse effects include leukopenia,
thrombocytopenia, hypothrombinemia, and anemia. Leukopenia is considered
to be an expected effect of cyclophosphamide therapy and may be severe.
Leukopenia nadirs generally occur at 8-15 days following a single dose of
cyclophosphamide and recovery usually occurs within 17-28 days.
Thrombocytopenia is reportedly less common, with nadirs occurring 10-15
days after administration of the drug. Anemia, particularly after large
doses or prolonged therapy, and rarely hypoprothrombinemia have been
reported. Rarely, cyclophosphamide has been reported to produce positive
direct antiglobulin (Coombs') test results and hemolytic anemia. **PEER
REVIEWED** [McEvoy G.K. (ed.). American Hospital Formulary Service-Drug
Information 96. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 1996 (Plus Supplements). 658]
Sterile hemorrhagic cystitis has been reported to occur in up to 20% of
patients (especially children) on long-term cyclophosphamide therapy. The
effect, which rarely can be severe and even fatal, is attributed to
chemical irritation by active metabolites of cyclophosphamide that
accumulate in concentrated urine. Hematuria usually resolves spontaneously
within a few days after discontinuance of cyclophosphamide therapy but may
persist for several months. Fibrosis of the bladder (sometimes extensive),
with or without cystitis, also has occurred, but less frequently. Atypical
epithelial cells may be found in the urinary sediment. These adverse
effects appear to be related to the dosage and duration of
cyclophosphamide therapy. Nephrotoxicity, including hemorrhagic ureteritis
and renal tubular necrosis, has been reported; such lesions reportedly
resolve in most instances following discontinuance of cyclophosphamide
therapy. **PEER REVIEWED** [McEvoy G.K. (ed.). American Hospital Formulary
Service-Drug Information 96. Bethesda, MD: American Society of Health-
System Pharmacists, Inc. 1996 (Plus Supplements). 658]
Patients who receive high dose of cyclophosphamide over prolonged periods
may develop interstitial pulmonary fibrosis, which can be fatal. In some
cases, discontinuance of the drug and administration of corticosteriods
has failed to reverse this syndrome. **PEER REVIEWED** [McEvoyG.K. (ed.).
American Hospital Formulary Service-Drug Information 96. Bethesda, MD:
American Society of Health-System Pharmacists, Inc. 1996 (Plus
Supplements). 659]
Cardiotoxicity, which is uncommon at usual dosages, has been reported in
patients receiving high doses of cyclophosphamide (120 (i.e., 60 mg/kg
daily) to 270 mg/kg over a period of a few days), generally as part of an
intensive, multiple-drug antineoplastic regimen or in conjunction with
transplantation procedures. Potentially fatal cardiotoxicity also has
occurred when cyclophosphamide (given concomitantly with mesna /2-
mercaptoethane sulfonic acid sodium salt/ and followed with autologous
bone marrow transplant) was administered inadvertently in a dosage of 4 g/
sq m daily for 4 doses rather than in a total dose of 4 g/sq m
administered over 4 days in equally divided doses of 1 g/sq m daily as
part of a phase I protocol. Deaths have occurred from diffuse hemorrhagic
myocardial necrosis and from a syndrome of acute myopericarditis when
cyclophosphamide was used in high doses alone or in combination regimens;
severe, sometimes fatal congestive heart failure has occurred rarely
within a few days after the first dose of cyclophosphamide in such cases.
Hemopericardium secondary to hemorrhagic myocarditis and myocardial
necrosis, and pericarditis without evidence of hemopericardium, also has
been reported. **PEER REVIEWED** [McEvoy G.K. (ed.). American Hospital
Formulary Service-Drug Information 96. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 1996 (Plus Supplements). 659]
Specimens of whole bronchial tissue from the main or lobar bronchi and
peripheral parenchyma were removed at surgery of 21 male patients
undergoing lung resection for lung cancer (n= 18) or other, non-neoplastic,
lung diseases (n= 3). Post-mitochondrial S-12 fractions were obtained. In
parallel, the same preparations were used to assess the activation of a
promutagen, cyclophosphamide (CPA, 4000 ug/plate), to metabolites
reverting his(-) Salmonella typhymurium strain TA1535. Parenchyma compared
favorably to bronchus preparations in activating CPA to mutagenic
metabolites (n= 6 paired observations). **PEER REVIEWED** [Petruzzelli S
et al; Am Rev Respir Dis 140 (2,1): 417-22 (1989)]
Sister chromatid exchanges (SCE) and lymphocyte subsets of children with
acute lymphoblastic leukemia (ALL) were investigated during chemotherapy.
The treatment followed protocol ALL-BFM-90. Children with ALL at the time
of diagnosis showed statistically significant higher SCE frequencies (4.9
+ or - 0.77) than healthy controls (3.6 + or - 0.93; P = 0.002). The in
vivo effects of cyclophosphamide (CP) resulted in a dramatic increase of
the SCE frequency (20.5 + or - 3.76). This increased SCE level of
lymphocytes might reflect an instability of DNA or a deficiency of DNA
repair. One could suggest that lymphocytes of children with ALL might have
a higher susceptibility to harmful influences; and this could be a co-
factor towards the development of the malignant disease. However,
immediately 1 wk after the admin of CP, the SCE rate decreased. This
decline of SCE frequency correlated with a severe reduction of the
absolute number of T lymphocytes. The observed reduction of SCE frequency
may be due to a loss of T lymphocytes, or SCE became repaired during 1
week. **PEER REVIEWED** [Mertens R et al; Leukemia 9 (3): 501-5 (1995)]
... We now described five patients receiving monthly cycles of iv CP /
cyclophosphamide/ whose allergic reactions included clinical features of
type I hypersensitivity but were atypical in their markedly delayed onset
(i.e., 8 to 16 hr in patients 1 to 4 and 10 days in patient 5) ... The
objective was to investigate these late-developing clinical reactions by
skin testing with CP and two of its major metabolites ... The five
patients and a control group receiving iv CP uneventfully were studied by
the same skin test protocol ... The four individual in the control group
were unreactive to CP or its metabolites. All five patients with late-
onset allergic reactions had positive immediate skin test results to CP
metabolites but not to CP itself. We propose that the allergic reactions
in patients 1 to 4 were mediated, wholly or in major part, by IgE
antibodies reactive with allergens derived from time-dependent drug
metabolites. **PEER REVIEWED** [Popescu NA et al; J Allergy Clin Immunol
97 (1 Pt 1): 26-33 (1996)]
In the present study a cancer risk assessment of occupational exposure to
cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was
carried out following two approaches based on (1) data from an animal
study and (2) data on primary and secondary tumors in CP-treated patients.
Data on the urinary excretion of CP in health care workers were used to
estimate the uptake of CP, which ranged from 3.6 to 18 ug/day. Based on
data from an animal study, cancer risks were calculated for a health care
worker with a body weight of 70 kg and a working period of 40 yr, 200 days/
yr (linear extrapolation). The life-time risks (70 yr) of urinary bladder
cancer in men and leukemias in men and women were found to be nearly the
same and ranged from 95 to 600 per million. Based on the patient studies,
cancer risks were calculated by multiplication of the 10-yr cumulative
incidence per gram of CP in patients by the estimated mean total uptake in
health care workers over 10 yr, 200 days/yr. The risk of leukemias in
women over 10 yr ranged from 17 to 100 per million using the secondary
tumor data (linear extrapolation). Comparable results were obtained for
the risk of urinary bladder tumors and leukemias in men and women when
primary tumor data were used. Thus, on an annual basis, cancer risks
obtained from both the animal and the patient study were nearly the same
and ranged from about 1.4 to 10 per million. In The Netherlands it is
proposed that, for workers, a cancer risk per cmpd of one extra cancer
case/million/year should be striven for ("target risk") and that no risk
higher than 100/million/year ("prohibitory risk") should be tolerated.
**PEER REVIEWED** [Sessink PH et al; Int Arch Occup Environ Health 67 (5):
317-23 (1995)]
Non-Human Toxicity Excerpts :
TWO GROUPS OF 10 MALE AND 10 FEMALE, 4 TO 24 WEEK OLD NZB/NZW HYBRID MICE /
WHICH DEVELOPED AUTOIMMUNE COMPLEX NEPHRITIS/ WERE GIVEN DAILY SC
INJECTIONS OF 1 MG/KG BODY WT OR 8 MG/KG BODY WT CYCLOPHOSPHAMIDE IN 0.1
ML SALINE FOR UP TO 93 WK; 20 MALES AND 20 FEMALES WERE INJECTED WITH
SALINE ALONE AND SERVED AS CONTROLS. FIFTY PERCENT OF MALE CONTROLS HAD
DIED BY THE 31ST WK OF THE STUDY, COMPARED WITH 41 AND 60 WK FOR THOSE
GIVEN THE LOW AND HIGH DOSE LEVELS. FIFTY PERCENT OF MALE CONTROLS HAD
DIED BY 57 WK, COMPARED WITH 71 AND 80 WK FOR THE TREATED ANIMALS. TUMORS
WERE OBSERVED IN TREATED MALES AFTER 60 WK OF TREATMENT AND IN FEMALES
AFTER 40 WEEKS. EIGHT MALES & 9 FEMALES GIVEN THE HIGHEST DOSE LEVEL
DEVELOPED NEOPLASMS, INCL 3 GENERALIZED LYMPHORETICULAR NEOPLASMS IN MALES
AND 3 IN FEMALES AS WELL AS A POORLY DIFFERENTIATED SARCOMA. 3 SQUAMOUS
CELL CARCINOMAS OCCURRED AT THE SITE OF INJECTION IN FEMALES. PULMONARY
ADENOMAS WERE ALSO OBSERVED IN 3 MALE AND 1 FEMALE MICE. OF ANIMALS GIVEN
THE LOW DOSE LEVEL, 3 MALES AND 1 FEMALE DEVELOPED NEOPLASMS. AMONG
CONTROLS 2 MALE AND 1 FEMALE MICE HAD RETICULUM CELL SARCOMAS. /
MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization,
International Agency for Research on Cancer,1972-PRESENT. (Multivolume
work).,p. V26 170 (1981)]
A GROUP OF 50 FEMALE NMRI MICE, 65 DAYS OLD, RECEIVED 52 WEEKLY SC
INJECTIONS OF 26 MG/KG BODY WT (7% OF LD50) CYCLOPHOSPHAMIDE (TOTAL DOSE,
1352 MG/KG BODY WT); ANOTHER GROUP OF 50 FEMALES SERVED AS CONTROLS. THE
AVERAGE LIFESPAN OF TREATED AND CONTROL ANIMALS WAS 630 + OR - 130 DAYS.
IN THE CONTROL GROUP, 3/46 (6%) MICE DEVELOPED STEM CELL LEUKEMIA AND NO
OTHER MALIGNANT TUMOR WAS OBSERVED. OF THE TREATED MICE, 28/46 (61%)
DEVELOPED MALIGNANT TUMORS: 3 LEUKEMIAS, 12 MAMMARY CARCINOMAS & 1 OTHER
MAMMARY TUMOR, 4 OVARIAN CARCINOMAS, 1 FIBROSARCOMA OF THE THORAX, 1 SKIN
CARCINOMA, 2 SARCOMAS @ INJECTION SITE & 4 LUNG TUMORS. /MONOHYDRATE/
**PEER REVIEWED** [IARC. Monographs on the Evaluation of the Carcinogenic
Risk of Chemicals to Man. Geneva: World Health Organization, International
Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 171
(1981)]
FOUR GROUPS OF 15 MALE AND 15 FEMALE A/J MICE, 4-6 WK OLD, WERE GIVEN IP
INJECTIONS OF CYCLOPHOSPHAMIDE IN WATER 3 TIMES A WK FOR 4 WK (TOTAL DOSES,
420, 135, 34 AND 8 MG/KG BODY WT). OF 165 MALE AND 195 FEMALE CONTROLS
INJECTED WITH WATER ONLY, 37% OF MALE AND 27% OF FEMALE SURVIVORS
DEVELOPED LUNG TUMORS WITHIN 39 WK, WITH 0.48 AND 0.29 TUMORS/MOUSE. AFTER
39 WK, 4/30, 27/30, 26/30 AND 30/30 ANIMALS WERE STILL ALIVE IN THE
RESPECTIVE DOSE GROUPS. AMONG SURVIVING ANIMALS, THE NUMBERS WITH LUNG
NEOPLASMS WERE 2/4 (2.5 TUMORS/MOUSE), 20/27 (74%; 1.3 TUMORS/MOUSE), 11/
26 (42%; 0.6 TUMORS/MOUSE) AND 12/30 (40%; 0.4 TUMOR/MOUSE, RESPECTIVELY.
THE INCIDENCE OF LUNG TUMORS IN TREATED MICE WAS SIGNIFICANTLY GREATER
THAN THAT IN CONTROLS ONLY FOR THOSE GIVEN THE SECOND HIGHEST DOSE LEVEL. /
MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization,
International Agency for Research on Cancer,1972-PRESENT. (Multivolume
work).,p. V26 171 (1981)]
A GROUP OF 29 DD MICE AND A GROUP OF 25 A MICE OF BOTH SEXES, 4-5 WK OLD,
RECEIVED IP INJECTIONS OF 5 MG/KG BODY WT CYCLOPHOSPHAMIDE IN SALINE TWICE
WEEKLY FOR 15 SUCCESSIVE WK; 20 AND 16 CONTROL MICE OF EACH STRAIN WERE
INJECTED WITH ISOTONIC SALINE ONLY. NEOPLASMS DEVELOPED IN VARIOUS ORGANS
IN 12/22 DD MICE THAT SURVIVED MORE THAN 48 WK AFTER THE BEGINNING OF THE
TREATMENT; THESE OCCURRED PREDOMINANTLY IN LUNG, LIVER, TESTIS & MAMMARY
GLAND. 3 OF 10 CONTROL DD MICE THAT LIVED BEYOND THE SAME PERIOD ALSO HAD
NEOPLASMS. NEOPLASMS DEVELOPED IN 6/16 STRAIN A MICE THAT SURVIVED MORE
THAN 42 WK AND INCLUDED 6 IN THE LUNG AND 1 IN THE ORBIT. TWO OF 11
CONTROL A MICE HAD NEOPLASMS, BOTH IN THE LUNG. /MONOHYDRATE/ **PEER
REVIEWED** [IARC. Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Man. Geneva: World Health Organization, International Agency
for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 171 (1981)]
TWO GROUPS, EACH OF 25 MALE AND 25 FEMALE OUTBRED SWISS-WEBSTER-DERIVED
MICE, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 12 OR 25 MG/KG BODY WT
CYCLOPHOSPHAMIDE 3 TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED OVER 100
DAYS WERE OBSERVED FOR UP TO 12 FURTHER MO, AT WHICH TIME THEY WERE
KILLED. LUNG NEOPLASMS OCCURRED IN 7/30 MALES COMBINED FROM BOTH TREATMENT
GROUPS AND IN 10/35 FEMALES; BLADDER PAPILLOMAS WERE FOUND IN 4/30 MALES.
THE INCIDENCES OF THE TWO TUMOR TYPES WERE REPORTED TO BE STATISTICALLY
GREATER THAN THOSE IN POOLED CONTROLS. THE WORKING GROUP CONSIDERED THAT
THE INADEQUATE REPORTING OF CERTAIN ITEMS, SUCH AS SURVIVAL TIMES, THE
AMALGAMATION OF VARIOUS EXPERIMENTAL GROUPS AND TUMOR TYPES, AS WELL AS
THE LACK OF ADE-ADJUSTMENT IN THE ANALYSES PRECLUDED A COMPLETE EVALUATION
OF THIS STUDY. /MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World
Health Organization, International Agency for Research on Cancer,1972-
PRESENT. (Multivolume work).,p. V26 171 (1981)]
TWO GROUPS, EACH OF 25 MALE AND 25-28 FEMALE CHARLES RIVER CD RATS, 6 WK
OLD, WERE GIVEN IP INJECTIONS OF 5 OR 10 MG/KG BODY WT CYCLOPHOSPHAMIDE 3
TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED OVER 100 DAYS WERE OBSERVED FOR
12 FURTHER MO, AT WHICH TIME THEY WERE KILLED. MAMMARY CARCINOMAS OCCURRED
IN 9/53 FEMALES COMBINED FROM BOTH TREATMENT GROUPS AND IN 1/50 MALES, &
MAMMARY ADENOMAS OCCURRED IN 24/53 FEMALES. THE INCIDENCE OF
ADENOCARCINOMAS IN CONTROL FEMALES WAS 13/181; THE INCIDENCES OF THE TWO
MAMMARY TUMOR TYPES WERE REPORTED TO BE INCR TO A STATISTICALLY
SIGNIFICANT EXTENT OVER THOSE IN POOLED FEMALE CONTROLS. THE WORKING GROUP
CONSIDERED THAT THE INADEQUATE REPORTING OF CERTAIN ITEMS, SUCH AS
SURVIVAL TIMES, THE AMALGAMATION OF VARIOUS EXPERIMENTAL GROUPS AND TUMOR
TYPES, AS WELL AS THE LACK OF AGE ADJUSTMENT IN THE ANALYSES PRECLUDED A
COMPLETE EVALUATION OF THIS STUDY. /MONOHYDRATE/ **PEER REVIEWED** [IARC.
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on
Cancer,1972-PRESENT. (Multivolume work).,p. V26 172 (1981)]
A GROUP OF 32 MALE SPRAGUE DAWLEY RATS, 3 MO OLD RECEIVED WEEKLY IV
INJECTIONS OF 13 MG/KG BODY WT CYCLOPHOSPHAMIDE (TOTAL DOSE, 670 MG/KG
BODY WT). A GROUP OF 52 UNTREATED RATS SERVED AS CONTROLS. MALIGNANT
TUMORS DEVELOPED IN 14/32 TREATED RATS WITHIN 510 + OR - 90 DAYS: THERE
WERE 3 RETICULUM CELL SARCOMAS, 6 HEMANGIOENDOTHELIOMAS IN VARIOUS ORGANS,
1 NEUROGENIC SARCOMA OF MEDIASTINUM, 1 SARCOMA OF THE HEART & 1 LEUKEMIA;
TWO RATS HAD 2 MALIGNANT TUMORS. EACH: ONE HAD OSTEOSARCOMA OF PARANASAL
SINUS & A PHEOCHROMOCYTOMA, AND THE OTHER HAD AN ANGIOSARCOMA OF THE
ABDOMEN AND A PHEOCHROMOCYTOMA. OF THE CONTROLS, 6/52 DEVELOPED MALIGNANT
TUMORS WITHIN 670 + OR - 150 DAYS: 3 RETICULUM CELL SARCOMAS, 1
PHEOCHROMOCYTOMA, 1 HEMANGIOSARCOMA OF THE LUNG AND 1 SARCOMA OF THE
KIDNEY. /MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World
Health Organization, International Agency for Research on Cancer,1972-
PRESENT. (Multivolume work).,p. 26 173 (1981)]
A SINGLE IP DOSE OF CYCLOPHOSPHAMIDE CAUSES MARKED NECROSIS OF THE BLADDER
AND OF THE TUBULAR AND PELVIC EPITHELIUM IN MICE, RATS, & DOGS; RELATIVELY
LITTLE DAMAGE WAS OBSERVED IN LIVER, EVEN AFTER PROLONGED ADMINISTRATION.
NECROSIS OF BLADDER TISSUE IS FOLLOWED BY RAPID EPITHELIAL REGENERATION OF
DIPLOID CELLS & LATER PRODUCTION OF TETRAPLOID, OCTOPLOID & OCCASIONAL
HYPERPLOID CELLS. /MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World
Health Organization, International Agency for Research on Cancer,1972-
PRESENT. (Multivolume work).,p. V9 143 (1975)]
CYCLOPHOSPHAMIDE IS TERATOGENIC IN SEVERAL SPECIES, INCL MICE, RATS,
RABBITS, & CHICKENS. IT PRODUCES A VARIETY OF SKELETAL, SOFT TISSUE &
OTHER MALFORMATIONS & INCR NUMBER OF RESORPTIONS; THE TYPE AND FREQUENCY
OF MALFORMATIONS ARE STRICTLY DOSE & TIME DEPENDENT. /MONOHYDRATE/ **PEER
REVIEWED** [IARC.Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Man. Geneva: World Health Organization, International Agency
for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 176 (1981)]
CYCLOPHOSPHAMIDE IS ALSO TERATOGENIC IN THE RHESUS MONKEY WHEN GIVEN
INTRAMUSCULARLY FOR VARIOUS PERIODS BETWEEN DAYS 25 AND 43 OF PREGNANCY AT
DOSES RANGING BETWEEN 2.5 AND 20 MG/KG BODY WT. THE INDUCED ABNORMALITIES
INCLUDED CLEFT LIP WITH CLEFT PALATE, EXOPHTHALMUS, A MARKED
UNDERDEVELOPMENT OF THE MIDFACIAL BONES AND MENINGOENCEPHALOCELE. /
MONOHYDRATE/ **PEER REVIEWED** [IARC. Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization,
International Agency for Research on Cancer,1972-PRESENT. (Multivolume
work).,p. V26 176 (1975)]
TERATOGENIC EFFECTS WERE INDUCED IN OUTBRED MICE BY TREATMENT OF 8 WK OLD
PREGNANT FEMALES WITH 1 OF 5 DIFFERENT DOSES (5, 10, 20, 30, & 40 MG/KG,
IP) OF CYCLOPHOSPHAMIDE. MOST MALFORMATIONS WERE INDUCED WITH 20, 30 OR 40
MG/KG, WHEREAS 5 AND 10 MG OF CYCLOPHOSPHAMIDE/KG CAUSED NO ALTERATIONS OF
THE FETUSES. **PEER REVIEWED** [REZNIKG, HECHT J; ARZNEIM-FORSCH 29 (3):
479 (1979)]
TEN PREGNANT FEMALE RABBITS WERE TREATED WITH A DAILY INJECTION OF 50 MG
CYCLOPHOSPHAMIDE (DNA SYNTHESIS INHIBITOR), FROM DAY 11 TO DAY 14, WHICH
IS A PERIOD THAT PRECEDES FORMATION OF THE FACE. THE CONTROL SAMPLE
COMPRISED FIVE FEMALE RABBITS. THE FETUSES WERE OBTAINED BY CESAREAN
SECTION ON DAY 28 & STAINED WITH ALIZARIN. SIX OF THE TEN TREATED ANIMALS
PRODUCED OFFSPRING THAT HAD TEMPOROMANDIBULAR JOINT SYNOTOSIS (TMJ).
**PEER REVIEWED** [BACON W; AM J ORTHOD 83 (6): 507-12 (1983)]
Pregnant CBA/CA mice were injected subcutaneously with 0, 4, 20, or 40 mg/
kg of cyclophosphamide 60 hr after copulation. At each of the doses tested,
cyclophosphamide significantly reduced the number of blastocyst cells and
caused dose related increase in chromosome aberrations in the blastocysts.
Cyclophoshamide increased the number of cells with chromosome breaks at
all three doses and also increased chromosome rearrangements in the 20 and
40 mg/kg treated groups. The number of cells with ring chromosomes in the
40 mg/kg group was significantly increased. Cyclophosphamide inhibited the
synthesis of DNA and of histones in the 20 and 40 mg/kg groups. On a
subsequent culture study, it was observed that treatment of the mothers
with 20 or 40 mg/kg, significantly inhibited the in vitro hatching of
blastocysts from the zona pellucida. Trophoblast expansion and the
attachment of embryos to the glass coverslip were also inhibited. **PEER
REVIEWED** [Kola I et al; Teratog Carcinog Mutagen 6: 115-27 (1986)]
Five groups of C57BL/6J pregnant mice were treated as follows: 1) 1 ug/g
daily iv of saline or cyclophosphamide on day 9-12 or 14-17 of gestation
(vehicle and drug were given by injection into the tail vein); 2) 5 ug/g
iv vehicle or cyclophosphamide on day 12 of gestation; 3) 1, 2.5, or 5 ug/
g ip vehicle or cyclophosphamide on day 12 of gestation; 4) 5, 10, or 20
ug/g ip vehicle or cyclophosphamide on day 17 of gestation; and 5) 10 or
20 ug/g ip vehicle or cyclophosphamide on day 17 of gestation. Number of
offspring per female at weaning was similar in controls and all groups
except for group 2 in which no offspring of treated dams survived. No
gross terata were present. No effect on cell mediated or immune function
was observed in offsprings of treated dams. The 5 and 9 week old progeny
exposed to 20 ug/g on gestational day 17 had reduced body weight.
Decreased numbers of antibody forming cells per spleen were found in 8
week old offspring in group 3. **PEER REVIEWED** [Luebke RW et al; J
Toxicol Environ Health 18: 25-39 (1986)]
CYCLOPHOSPHAMIDE ... HAS BEEN TESTED BY INJECTION INTO THE ANTERIOR
CHAMBER OF RABBIT EYES, BUT PROVED EXCESSIVELY DAMAGING TO THE CORNEA TO
ALLOW ITS USE IN TREATMENT OF EPITHELIAL INVASION OF THE ANTERIOR CHAMBER.
HOWEVER, INJECTIONS INTO THE VITREOUS BODY IN RABBITS IN CONCENTRATIONS UP
TO 10 MG/ML HAVE BEEN TOLERATED WITHOUT EXCESSIVE INFLAMMATION ... .
**PEER REVIEWED** [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield,
IL: Charles C. Thomas Publisher, 1986. 299]
Cyclophosphamide and two of its metabolites, 4-hydroxycyclophosphamide and
phosphoramide mustard were analyzed for their ability to induce sister
chromatid exchanges in mouse peripheral blood lymphocytes in vitro and in
vivo. In the in vivo experiments each animal received a single ip
injection of the compound in question at varying doses. In the first
experiment on phosphoramide mustard effects, the SCEs/metaphase was 16.04
at a dose of 19.0 uM/kg, the only result significantly different from the
control (13.24). In a second experiment, exposure to 50 uM/kg of either
cyclophosphamide or phosphoramide mustard induced sister chromatid
exchange frequencies of 28.06 and 21.81, compared with the control, 12.02.
In the third experiment, both phosphoramide mustard and 4-
hydroxycyclophosphamide induced dose dependent increases in sister
chromatid exchange frequency (maximum, about 30 at 150 uM/kg for each
compound compared with the control of about 10). At equimolar
concentrations of 1 uM, the mean sister chromatid exchange frequency was
about 10 for the control and cyclophosphamide, about 21 for phosphoramide
mustard, and about 26 for 4-hydroxycyclophosphamide. The in vitro
exposures used mononuclear lymphocytes isolated from whole blood pooled
from 18 male mice. Lymphocytes were then inoculated into 1 ml of culture
media containing 1 uM of either cyclophosphamide phosphoramide mustard, or
4-hydroxycyclophosphamide. and incubated for 21 hr. The cells were then
washed and the medium replenished, this time without mitogen but
containing 5 uM 5-bromo-2'-deoxyuridine. **PEER REVIEWED** [Bryant MF et
al; Mutat Res 222 (3): 271-7 (1989)]
The carcinogenic agent cyclophosphamide was sc admin at 0 (controls), 13,
and 26 mg/kg for life to groups of 30 female AKR mice, and to groups of 30
NMRI mice. No symptoms of acute or subacute toxicity were observed. CPA
dose-dependently incr the median life span in AKR mice by 27% at 13 mg/kg
(from 188 to 238 days) and 76% at mg/kg (to 330 days), and decr the
incidence in leukemias by 17% and 37%. In NMRI mice, cyclophosphamide
significantly increased the incidence of leukemias by 46% at the low dose
and 26% at the high dose, respectively. The number of benign and malignant
tumors for the high, low, and control groups were 16, 19, and 4 an 3 for
NMRI mice. For AKR mice, the tumor numbers were 22, 27, and 30,
respectively. Histologically, malignant tumors of the lymphoproliferative
system were found to be lyphocytic leukemias (98%) and the malignant
thymomas (2%). **PEER REVIEWED** [Petru E et al; Cancer Lett 44 (3): 221-6
(1989)]
Virtually all nonobese diabetic/WEHI mice spontaneously develop a
lymphocytic infiltration of pancreatic islets (insulitis), but very few
progress to diabetes ( < 10% in females and < 1% in males at 220 days of
age). Cyclophosphamide was admin to non-obese diabetic/WEHI mice at 0, 50,
100, 150, 200, or 300 mg/kg ip in 200 ul phosphate-buffered saline.
Diabetes was produced in both sexes 10 to 16 days after admin. There were
no significant changes in body wt, and the mortality was < 5% within 28
days. Diabetes incidence decr with decr doses of cyclophosphamide and with
< 100 mg/kg, there is no incr in incidence over controls. Cells in the
insulitis lesion were mainly T-lymphocytes with an initial preponderance
of L3T4 cells. Cyclophosphamide dramatically depleted splenic cell numbers
from a baseline of (1.2 + or - 0.4) x 10+8 to (1.4 + or - 0.5) x 10+7 by
day 4. In expt 2, 3 mice of each sex from the strains Biozzi, BALB/c, BALB/
c nude, C3H/He, C3H/HeJ, C57BL/6, C57/Bg, C57 nude, DBA/2, CBA/Ca and CBA
nude were injected twice at a 14 day interval with 300 mg/kg ip
cyclophosphamide. Non-obese diabetic/WEHI mice (19 female and 15 male)
received the same treatment and served as controls. No mice were
hyperglycemic 14 days after the second dose, except for the non-obese
diabetic mice (13 females and 8 males. Normal islets were found in all non-
obese diabetic mice. In exp 3, male non-obese diabetic/WEHI mice were
given either an organcultured fetal pancreas isograft, or cyclophosphamide
followed 3 days later with a pancreas isograft. Beta cell damage and
insulitis in the host pancreas were paralleled in the fetal pancreas
isograft. Admin of cyclophosphamide to mice 3 days before grafting caused
greater graft infiltration and beta cell loss, and in some cases, no beta-
cells were present in the graft. In exp 4, 20 normoglycemic female non-
obese diabetic/WEHI mice received a 300 mg/kg ip dose of cyclophosphamide
and then either given: (1) (n= 12) iv injections at 8, 24, 48, 96, and 168
hr, with 300 uL of mononuclear cell suspension from female non-obese
diabetic/WEHI mice; (2) (n= 12) also injected with phosphate-buffered
saline/FCS at the same time; (3) (n= 4) injections with cells obtained
from acutely diabetic non-obese diabetic mice. The transfer of lymph node
and spleen mononuclear cells to non-obese diabetic mice given
cyclophosphamide prevented diabetes. The transfer of sufficient lymphoid
cells from young (nondiabetic) mice prevented the **PEER REVIEWED**
[Charlton B et al; Diabetes 38 (4): 441-7 (1989)]
The Drosophila wing somatic mutation and recombination test was applied to
a series of chemicals to determine its suitability in genotoxicity
screening. The 48 hour feeding proved most suitable for testing
cyclophosphamide, an indirect acting mutagen. Concentrations used were 0.1,
0.5, 1.0, and 5.0 mM, feeding periods were 48, 72 and 96 hours. **PEER
REVIEWED** [Graf U et al; Mutat Res 222 (4): 359-73 (1989)]
To investigate the early ovarian changes after cyclophosphamide treatment,
immature rats primed for 48 hr with pregnant mare serum gonadotropin were
given injections ip of cyclophosphamide (100 mg/kg) at 1, 2, 4, 16, and 24
hr before decapitation. Serum estradiol dropped significantly after 24 hr
of exposure to cyclophosphamide (p< 0.001). Following 16 and 24 hr of
cyclophosphamide exposure, the number of granulosa cells expressed from
each ovary decr (p< 0.05 and p< 0.01, respectively); the number of
nucleated bone marrow cells decr (p< 0.01 and p< 0.01), and their median
nuclear size was significantly reduced (p< 0.05 and p< 0.05) as measured
by Coulter Counter and C-256 channelyzer; and the mean follicular diameter
and the number of follicles with diameters > 300 uM were significantly
lower than in control. After 4, 16, and 24 hr of exposure, median
granulosa cell nuclear size significantly incr (p < 0.05, p < 0.01, and p
< 0.01, respectively), DNA cross-link in granulosa cells, measured by
alkaline elution, reached a max at 2 hr of exposure and decr thereafter.
**PEER REVIEWED** [AtayaKM et al; Cancer Res 49 (7): 1660-4 (1989)]
Swiss Webster mice treated orally with cyclophosphamide (1, 2.5 or 5 mg/
kg) once daily on gestational days 6 through 18 gave birth to pups which
appeared to be normal and the majority of which survived to adulthood.
There were no overt signs of maternal toxicity or any changes in maternal
body wt gains. Treatment caused a reduction of mean pup weight at birth
(1.5 at 5 mg/kg cyclophosphamide vs 1.8 for controls, and an incr in
cumulative pup mortality (32/151 at 5 mg/kg cyclophosphamide vs 5/76 for
controls). However, pregnancy outcome and mean pup body, spleen, and
thymus weights, when measured at 4 weeks of age, were within the control
ranges. Hematological profiles, serum immunoglobulin (IgG, IgM) levels and
histology of lymphoid tissue (spleen and thymus), assessed at 4 weeks of
age, were not affected by the maternal treatment. Treatment with 7.5 mg/kg
Cyclophosphamide not only resulted in reduced litter size (5.6 + or - 1.0
vs 12.6 + or - 0.3, but also increased the cumulative pup mortality (71/68
vs 5/76 for controls). With 7.5 mg/kg cyclophosphamide, histopathological
changes were observed in the thymus in 2 and 3 week old pups. The
morphology of the thymus in 4 week old pups was unremarkable. At the dose
of 10 mg/kg, no live births were recorded. Treatment with 7.5 or 10 mg/kg
cyclophosphamide resulted in significant reduction in the maternal wt gain,
compared with controls. **PEER REVIEWED** [Liakopoulou A et al; Res Comm
Chem Pathol Pharmacol 64 (2): 241-54 (1989)]
The cytostatic agent cyclophosphamide (1X10-5, 10-7 and 10-9 mg/ml) was
tested in the initiator tRNA acceptance assay for carcinogens in the
presence of 2 concn of microsomal enzymes and NADPH. Treatment of tRNA
resulted in a 75% inhibition of its acceptance of L-methionine.
Cyclophosphamide also inhibited the charging of unfractionated tRNA from
rat liver with L-alanine, L-lysine, L-phenylalanine and L-valine. **PEER
REVIEWED** [Hradec J et al; Carcinogenesis 10 (8): 1413-7 (1989)]
Studies in animals have shown that cyclophosphamide is teratogenic in mice,
rats, rabbits, and monkeys given 0.02, 0.08, 0.5, and 0.07 times the
human dose, respectively. **PEER REVIEWED** [USP Convention. USPDI - Drug
Information for the Health Care Professional. 16th ed. Volume I. Rockville,
MD: U.S. Pharmaceutical Convention, Inc. 1996 (Plus updates). 1125]
7 to 10 mg/kg were administered to rats and with treatment on the 11th or
12th day the fetuses developed skeletal defects, cleft palates and
exencephaly or encephalocele. This compound was shown to be relatively
more embryolethal than chloroambucil when the fetal-maternal toxicity
ratios of the two were compared. The compound was found to be teratogenic
in mice. In the rabbit, a high incidence of cleft lip and-or palate and
reduction defects of the extremities using intravenously 30 mg/kg on
single days 11, 12 or 13 was found. In the rhesus monkey, 10 mg/kg on days
27 through 29 produced facial clefts and when given on days 32 through 40,
meningoencephalocele was observed. **PEER REVIEWED** [Shepard, T.H.
Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins
University Press, 1986. 159]
A number of studies of the metabolism of cyclophosphamide and its products
in in vitro cultures with rat embryos have shown that the compound must be
bioactivated by a liver monofunctional oxygenase system in order to be
teratogenic. The morphologic changes found in vitro were very similar to
those seen in vivo. Phosphoramide mustard in equimolar doses caused
effects similar to those of bioactivated cyclophosphamide in vitro and
when given intraamnioticaly. Acrolein was toxic but its effect was
difficult to assess because of protein binding. The other stable
metabolite, 4-ketocyclophosphoramide, was only weakly teratogenic in
vitro. /It was/ concluded that phosphoramide mustard was the active
teratogenic metabolite in a mouse blastocyst system. The monofunctional
form of phosphoramide mustard (with only one chloroethyl side chain) has
been shown to have the same embryotoxicity as cyclophosphamide. **PEER
REVIEWED** [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore,
MD: The Johns Hopkins University Press, 1986. 159]
1.4, 3.4 or 5.1 mg/kg were administered daily before mating to male rats.
On the day of mating the males were not treated. Minimal changes in the
male reproductive tract were found but malformations and retardation of
growth were found in the offspring of the untreated females they bred
with. There was a dose-dependent increase in resorptions and fetal deaths.
In the offspring of males treated at 7-9 weeks there were 4 defects in 57
compared to one in 254 of the controls. The defects were hydrocephalus,
micrognathia and edema. Growth retardation occurred in 7% of the fetuses
in this group. **PEER REVIEWED** [Shepard, T.H. Catalog of Teratogenic
Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986.
159]
When used clinically, the important side effects of cyclophosphamide are
bone marrow suppression, with both leukopenia and thrombocytopenia. Nausea
and vomiting are rare. Sterile necrotizing hemorrhagic cystitis has been
associated with chronic administration and is a cause for stopping
therapy. To decrease the incidence of this cystitis, which is manifested
by bloody urine, the drug should be administered in the morning and
animals should be encouraged to urinate frequently. Alopecia occurs
occasionally in dogs with continuous hair growth (eg, Poodles, Old English
Sheepdogs). **PEER REVIEWED** [Booth, N.H., L.E. McDonald (eds.).
Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State
University Press, 1982. 789]
The mouse micronucleus assay has long been used as an indicator of in vivo
genotoxicity. Recently, it was shown that no single protocol is adequate
to detect all clastogens. As a first step in developing a potentially more
sensitive assay, micronucleus induction by cyclophosphamide (CP) was
assessed in an in vivo/in vitro system using rat bone marrow and spleen
cells. In each of two independent experiments, two rats/dose were treated
ip with 0, 20, or 40 mg CP/kg and killed 6 hr later. Cultures were then
established in the presence of growth stimulants (interleukin-3 and
granulocyte-macrophage colony stimulating factor for bone marrow;
lipopolysaccharide and concanavalin A for spleen) and cytochalasin B, a
cytokinesis inhibitor. Bone marrow cells were harvested and slides
prepared 24 hr after initiation, while spleen cells were harvested at 48
hr ... A dose-related cell cycle delay was observed in both tissues in
both experiments. Bone marrow showed a 6% average background frequency of
micronucleated BN cells, while the low dose induced an average of 20%, and
the high dose 31%. For spleen, the average control frequency of
micronucleated BN cells was 3%, the low dose induced a 40% average
frequency, and the high dose 65%. Also in splenocytes, a dose-dependent
increase in the chromosome aberrations was observed, with an almost 40-
fold increase observed over the control value at the high dose. **PEER
REVIEWED** [Moore FR et al; Mutat Res 335 (2): 191-9 (1995)]
Treatment of male rats with low dosages of cyclophosphamide causes a
dramatic increase in early embryo death among their progeny without
significantly affecting the general health of the male. It is hypothesized
that cyclophosphamide exerts its effects by targeting specific components
of spermatozoal nuclei. The purpose of the present studies was to
investigate the effects of chronic cyclophosphamide treatment on
spermatozoal DNA. Two approaches were pursued. The first was to determine
total DNA damage by using the alkaline elution method. The second was to
study spermatozoal DNA template function by using an in vitro DNA
synthesis system. Adult male rats were treated with saline or
cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6 wk. Cauda epididymal
spermatozoa were collected and subjected to alkaline elution using DNA-DNA
dot hybridization to quantify the fractionated DNA. One week of treatment
with cyclophosphamide caused DNA single strand breaks that could be
detected only in the presence of proteinase K in the lysis solution; no
DNA cross-links were observed in the animals that received l-wk drug
treatment. In contrast, 6 wk of treatment with cyclophosphamide induced a
significant increase in both DNA single strand breaks and cross-links in
spermatozoal nuclei; the cross-links were attributable primarily to DNA-
DNA linkages. The availability of spermatozoal DNA for template function
was not affected by 1 wk of treatment with cyclophosphamide but was
markedly affected after 6 wk of treatment with this drug. It is proposed
that during chromatin transition processes the male genome may be in an
open dynamic state with many exposed sites that are vulnerable to
alkylating agents. Since there is no DNA repair during spermiogenesis,
damage to the genome by alkylation at this stage may be cumulative,
resulting in the production of dysfunctional germ cells. **PEER REVIEWED**
[Qiu J et al; Biol Reprod 53 (6): 1465-73 (1995)]
Exposure of the male germ cell to cyclophosphamide during spermatogenesis
and sperm maturation can interfere with development of the embryo. When
male rats were treated with a chronic low dose of cyclophosphamide for 4
wk there was a dramatic increase in early postimplantation loss in their
progeny, characterized by implantation sites selectively lacking in
embryonic tissues. The present study was designed t determine the earliest
appearance of a paternal effect of cyclophosphamide treatment and to
examine whether the embryonic lineage was selectively affected. Male
Sprague-Dawley rats were orally dosed for 4-5 wk with saline or 6 mg/kg
per day of cyclophosphamide; their progeny were obtained on Days 2, 2.5, 3,
4, and 4.5 of gestation. Paternal cyclophosphamide treatment had no
effect on the mean number of embryos per pregnant female. However, as
early as Day 3 of gestation, there was a significant decrease in cell
number among the embryos sired by cyclophosphamide-treated males,
increasing to a greater than 50% decrease in cell number by Day 4. The
cell doubling time in embryos sired by treated males (16 hr) was longer
than that of controls (12 hr). This decreased proliferation rate was
confirmed by a dramatic decrease in the capacity of both Day 3 and Day 4
embryos sired by cyclophosphamide-treated males to incorporate (3)H-
thymidine over a 26-hr culture period. Cytogenetic analysis in a limited
number of blastomeres entering metaphase revealed no evidence of
chromosomal abnormalities. Both the trophectoderm and the inner cell mass
cells were proportionally decreased in Day 4.5 embryos sired by
cyclophosphamide-treated males. Thus, paternal cyclophosphamide exposure
affected both cell lineages in the conceptus as early as Day 3 of
gestation. **PEER REVIEWED** [Austin SM et al; Biol Reprod 50 (1): 55-64
(1994)]
A study of cyclophosphamide (CP)-induced DNA damage and repair occurring
in vivo was conducted in the brown Norway rat myelocytic leukemia (BNML)
model. DNA single-strand breaks (SSB), DNA-DNA interstrand cross-links
(DIC), DNA-protein cross-links (DPC), and DNA double-strand breaks (DSB)
were measured by alkaline and neutral elution. After ip injection of 50 ng/
kg CP, DIC were detectable at 1 hr and peaked at 8 hr. DPC were detectable
at 2 hr and peaked at 6 hr. Both DIC and DPC persisted at a relatively
high level until 28 hr. Dose-response curves for both DIC and DPC were
determined at 4 hr after CP injection over the dose range of 25-150 mg/kg.
These doses ranged from the minimally effective dose to doses curative for
rats bearing this leukemia (1- to 9-log kill of leukemia cells). No SSB or
DSB was observed at 4 hr after CP injection over the dose range of 15-250
mg/kg, but a low level of SSB was observed at 18-28 hr after CP treatment.
These data suggest that the cytotoxic effect of CP in vivo is mediated
mostly by DIC and DPC. SSB appearing late after CP injection in vivo may
be a reflection of repair of DIC and DPC and an indication of the optimal
timing for administration of DNA-repair inhibitors. This observation is of
interest since our earlier work demonstrated that hydroxyurea can
potentiate the therapeutic benefit of CP in this model when it is given
over the 4-day period immediately after CP treatment. **PEER REVIEWED**
[Wang JY et al; Cancer Chemother Pharmacol 31 (5): 381-6 (1993)]
Strain differences in cytochrome P450 (P450) expression were investigated
in Sprague-Dawley (SDs) compared with Fischer 344s (F344s) rats after
admin of cyclophosphamide (CPA). Animals received a single dose of CPA
with sacrifice occurring 6 days post-treatment. At 130 mg/kg, male F344s
displayed a greater sensitivity to CPA, as evidenced by a 68% loss of
total hepatic microsomal P450 compared with only 35% in SDs. The most
dramatic change in P450 was the loss of 2C11 (84% in F344s, 52% in SDs).
In the SD, individual rat 2C11 activity was correlated (r sq = 0.76), with
the level of plasma thyroxine in that animal. In male F344s admin CPA at
50 mg/kg, 43 and 44% losses in 2C11 activity (P < 0.05) and thyroxine (P <
0.01), respectively, were observed, whereas activities characteristic of
P450s 2C11, 3A2, 2A2, 2C6 and 2E1/1A2 were unaffected in SDs at this dose.
CPA also produced suppression of P450 in female SDs, including female-
specific 2C12. Correlation was observed between the loss of P450
expression and change in body weight after treatment in both male and
female animals, suggesting that CPA downregulated P450 expression
secondary to decr caloric intake. The anorectic effect of CPA is believed
to result from potent central nervous system stimulation, accompanied by a
state of adaptive hypothyroidism. **PEER REVIEWED** [KranerJC et al; J
Pharmacol Exp Ther (276) 1: 258-64 (1996)]
CP /cyclophosphamide/ decreased the activity of the female rat hepatic
enzymes 2A1, 2C6 and/or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17
beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its admin.
The decr in the activity of the enzymes 2E1 and NADPH-P450 oxidoreductase
were accompanied by a corresponding change in the amt of enzyme protein
indicating that the alteration in expression of these enzymes occurred via
changes in transcription and/or translation or protein degradation ... CP
also impaired its own activation 7 days after its admin to the female rat
... The change in female enzyme profile was accompanied by a reduction in
the hormones oestradiol, T4 and T3 7 days after CP admin ... Despite an
apparent trend for an incr in activity on day 5, a decr on day 8 and a
subsequent incr on day 11, repeat doses of CP to the male rat generally
did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-
oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase
... Chronic admin of CP to the male rat significantly reduced erythromycin
demethylase and NADPh-P450 oxidoreductase 8 days following commencement of
dosing and significantly incr statistically significant incr in pulmonary
2B 5 days following commencement of dosing ... Plasma testosterone and TSH
were unchanged following repeated dosing with CP while T3 was
significantly decr on days 5, 8 and 11 and T4 was significantly decr on
day 8. **PEER REVIEWED** [Angley MT et al; Xenobiotica 25 (10): 1051-62
(1995)]
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