[CANCER RESEARCH 42, 4792-4796,
0008-5472/82/0042-OOOOS02.00
November 1982]
Exposure of Pharmacy Personnel to Mutagenic Antineoplastic
Drugs1
Tot V. Nguyen, Jeffrey C. Theiss,2 and Thomas S. Matney
School of Public Health [T. V. N.. J. C. T.] and Graduate School of Biomédical Sciences [T. S. M.], University
Houston, Texas 77025
ABSTRACT
The Salmonella reversion test was used to measure the
mutagenic activities of urine concentrates from individuals pre
paring cancer chemotherapy agents for i.v. administration.
Longitudinal studies were performed in which the total urine
produced in 24-hr periods was collected, starting on a Sunday
at 7 p.m. after a duty-free weekend and extending over an 8day period. There was no detectable increase in mutagenic
activity in the urine concentrates of three pharmacy administra
tors who had no contact with these drugs. All six individuals
admixing drugs in open-faced, horizontal laminar flow hoods
displayed a 2-fold increase in mutagenesis by the fourth day
with peak values of 2.7- to 24-fold occurring on Days 5 and 6,
reduced values by Day 7, and a return to the spontaneous level
by Day 8. When four of the six positive individuals in the
preceding experiment admixed comparable amounts of chemotherapeutic drugs in a closed-face, vertical laminar flow hood,
no increase in mutagenic activity was detected in their urine
concentrates over the 8-day period.
INTRODUCTION
Many widely used cancer chemotherapeutic agents are car
cinogenic in animals, such as doxorubicin (3, 14), dacarbazine
(9), cyclophosphamide (9, 24), c/s-platinum (9, 12), and isophosphamide (9). Of these, cyclophosphamide
has been
judged to be a human carcinogen (9). All of the above named
drugs are strongly mutagenic in the Salmonella reversion-microsome activation test (2, 5, 15, 19, 22).
Several studies have provided evidence that professional
groups involved with the administration of these drugs to can
cer patients may be exposing themselves in the process. Falck
ef al. (6) examined the mutagenic activity in the Monday and
Thursday urine concentrates of a group of 7 nurses handling
cancer chemotherapeutic
agents. Most of the urine concen
trates exhibited mutagenicity, and the activity was higher in the
urine samples collected on Thursday afternoon. Norppa ef al.
(17) concluded from a study of oncology nurses that the
exposure to cancer chemotherapeutic agents was probably the
cause of the observed increase in frequencies of sister chromatid exchange in a group having daily contact with such
agents. Waksvik ef al. (23) also found increased frequencies
of chromosome gaps and a slight increase in sister chromatid
exchange frequencies in 10 nurses handling cancer chemo
therapeutic agents for prolonged periods of time.
The results of these studies increased our concern for a
group of professionals who are potentially exposed to these
cancer chemotherapeutic
agents, namely, hospital pharma' This research was supported
by NIH Biomedicai
Research Support Grant
S07RR05828 and by Department of Energy Contract DE-AS05-76EV04024.
2 To whom requests for reprints should be addressed.
Received April 26, 1982; accepted August 17, 1982.
4792
of Texas Health Science
Center at Houston,
cists and pharmacy technicians. The possibility of exposure in
this group is heightened by the fact that virtually all drugs,
including the genetically
toxic cancer chemotherapeutic
agents, are prepared for i.v. administration in open-faced hor
izontal laminar flow hoods in most hospital pharmacies (8).
While these hoods are designed to minimize bacterial contam
ination of i.v. admixture fluids, they do not protect the operator.
The air is filter sterilized and passed through ports in the rear
of the hood directly forward into the face of the technician, thus
exposing them to any aerosol which may have been generated
during the admixing process. The exposure level would vary
from one individual to another and depend upon the individual
work habits and manipulative techniques. Indeed, a wide range
of airborne fluorouracil and cefazolin sodium levels were found
after these substances had been prepared by several individ
uals in a horizontal laminar flow hood (10). Several papers
have appeared discussing the possible risk in preparing cancer
chemotherapeutic agents (4, 8,13,16) and proposing precau
tionary measures to be taken when preparing them (7,11, 26).
These reports indicated the need to determine by ascertain
ing the presence of mutagens in their urine if pharmacy per
sonnel admixing genotoxic chemotherapeutic drugs in openfaced horizontal laminar flow hoods were being subjected to
an occupational exposure. A longitudinal approach was taken
in this human-monitoring study for 2 reasons. First, with the
relatively small number of pharmacy personnel available at the
University of Texas M. D. Anderson Hospital for examination,
the most convincing demonstration of exposure would be to
find a temporal variation in mutagenicity of the urine samples
which concided with the time of potential exposure to these
mutagenic drugs. Each individual would be his/her own con
trol. The second reason is that only the longitudinal approach
assures the detection of excretory forms of such a diverse
group of drugs (Table 1). The pharmacology and pharmacokinetics of each of these drugs are unique, predicting different
rates of absorption and excretion. The collection of total urine
for 8 consecutive days in a longitudinal study optimizes the
detection of mutagenic activity under these diverse conditions.
MATERIALS
AND METHODS
Bacteria. Salmonella typhimurium strains TA 1538, TA 98, TA 1535,
TA 100, and TA 1975 were kindly provided by Dr. Bruce N. Ames,
University of California, Berkeley, CA. Strain UTH 8414 was con
structed in this laboratory by infecting TA 1975, an excision repairpositive equivalent of the uvrB containing TA 1535, with the pKM101
plasmid. UTH 8414 was included in the screening procedure so that
more of the known genotoxic drugs admixed in this study (Table 1)
would give a positive mutagenic response. Strains TA 1538 and TA 98
contain the -1 frame-shift mutation hisD3052 while the remaining
strains contain the base-pair substitution mutation hisG46.
Chemicals. The cancer chemotherapy drugs listed in Table 1 were
supplied by the Pharmacy Department of the University of Texas M. D.
Anderson Hospital. All drugs were dissolved and/or diluted in sterile
CANCER
RESEARCH
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VOL. 42
Exposure of Personnel to Mutagenic Antineoplastic
Drugs
Table 1
Genotoxicity
DoseDoxorubicin
of cancer chemotherapeutic agents prepared by pharmacy personnel
Mutagenicity8prepared(g)
Dose pre153833 UTH 84 14
TA 100
(mg)14050040002502500200020040Total
(Adriamycin)DacarbazineCyclophosphamide
MAc/s-PlatinumIsophosphamide
(cytoxan)
MA6-MercaptopurineDaunorubicin
(ifosfamide)
(daunomycin)Mitomycin
(mutamycin)pared23316811042371359range
-, <2x background: +. 2x background; ++, <5x
1 Suspected carcinogen.
: Insufficient data to establish as animal carcinogen.
+84
+440
+1
-93
1
+26
T1
+0.4
++
+++
++
+
background;
+ + + , >5x
Labora
columns,
Bio-Rad
sulfatase
was purchased from Sigma Chemical Co., St. Louis, Mo.; it was used
to deconjugate glucuronides and sulfates in the urine. The S9 liver
microsome fraction was purchased from Litton Bionetics, Kensington,
Md. Microsomal activation was necessary to demonstrate the mutagenie activity of bleomycin, Cyclophosphamide, and isophosphamide.
Urine concentrates were not treated with S9 fraction.
Urine Collection and Treatment. The total urine produced during a
24-hr period was voided into a polyethylene container. These sample
volumes varied from 300 to 2400 ml. Urine collection began at 7 p.m.
on a Sunday following a duty-free weekend and continued for 8
consecutive days. Urine samples were taken from 3 male pharmacy
administrators who had no direct contact with cancer chemotherapeutic
agents and from 8 individuals (6 males and 2 females) preparing cancer
chemotherapeutic
agents in the open-faced horizontal laminar flow
hoods. Among these 8 subjects, 6 were evening-shift technicians of
the central pharmacy. Every 6 weeks, they were assigned to prepare
chemotherapy agents for 5 to 6 days. The remaining 2 subjects worked
in an outpatient clinic pharmacy where one technician (Table 2, Subject
6) prepared these agents 8 hr a day, 5 days per week on a continuous
basis. The other subject (Table 2, Subject 5) prepared these drugs
only when the primary technician was on vacation or absent.
The 4 technicians from the central pharmacy who had nontoxic urine
concentrates participated in a second 8-day longitudinal study in which
they prepared comparable numbers of genotoxic agents in a closedface, vertical laminar flow hood.
All subjects recorded their food and drug intake. Subject 6, the only
smoker, recorded from 8 to 10 cigarettes smoked per day throughout
the course of study.
Urine samples were placed in a -20° freezer within 2 hr after
collection. They were thawed at room temperature on the day of
analysis and transferred to sterile flasks. Five thousand units of ßglucuronidase were added to each flask, and they were placed on a
rotary shaker and incubated at 37° for 16 hr. After filtering through
Whatman No. 1 filter paper, the treated urine was extracted and
concentrated according to a modification of the procedure described
by Yamasaki et al. (25). All operations were carried out at room
temperature. Urine samples were loaded onto columns containing
freshly washed XAD-2 resin. The washing process consisted of swirling
the resin with 30 volumes
same volumes of absolute
flow rate varied from 1 to 3
20 hr to complete. Larger
of acetone and decanting followed by the
methanol and distilled water. The effluent
ml/min with some samples requiring almost
columns will be used with total 24-hr urine
samples in the future. After loading, nitrogen was introduced into the
top of the column for a few sec to remove the residual aqueous phase
but not to dry the resin. Then, 1.5 ml of distilled water were added to
the column to remove residual histidine, and the column was again
1982
TA 1535
+
TA
++
animals+
98
hu
mans99
In
14+
+ +
99,
++ +
++
+++
T
+
+ +
—¿
++
++ +
—¿
24+
9,12918e+
+
+ +
+ +
1421In
+ + +Carcinogen
water. XAD-2 resins were purchased from Applied Sciences
tories, State College, Pa. The resins were used in glass Econo
0.7 cm (inside diameter) x 10 cm (height), obtained from
Laboratories, Richmond, Calif. /3-Glucuronidase with traces of
NOVEMBER
¡cityTA
background;
MA, metabolic activation required; T, toxic.
freed of the aqueous phase with nitrogen. The adsorbed components
were eluted into glass test tubes in 10 ml of acetone. The eluted
fractions were then evaporated to dryness in a constant-temperature
heating block at 65° under a flow of nitrogen, a process usually
requiring about 30 min. The residue was taken up in 1.0 ml of DMSO.3
However, the first longitudinal study was performed with Subject 6,
and the acetone residues were taken up in 1.5 ml DMSO before it was
realized that the smaller volume was sufficient.
Mutation Test. A 2-step scheme was utilized in testing the urine
concentrates for mutagenic activity. First, 100 /il of each urine concen
trate were used in a standard plate incorporation assay (1) with each
of the 4 test strains TA98, TA1535, TA100, and UTH8414. Then, for
each individual, the strain giving the greatest mutagenic response in
the first step was used alone in a dose-response study in which the
urine concentrates were diluted 1:2 and 1:4 in DMSO; each concen
tration was plated in duplicate. The S9 liver fraction was not used in
this study since the drugs would have been metabolized before being
excreted.
RESULTS
Table 1 lists the cancer chemotherapeutic drugs that were
prepared during the course of this study which were also
known to be positive in the Salmonella mutagenicity test (2,
19). The results of the tests performed in this study are shown.
Not only did dacarbazine prove mutagenic, but with the inclu
sion of UTH8414 in the test set dacarbazine permitted us to
detect mitomycin C. In addition, 59 doses of 4 experimental
drugs were noted which also proved to be mutagenic (anthracenedione,
etoposide,
tenoposide,
and aziridinylbenzoquinone). The details of the mutagenicity tests of all experi
mental drugs currently admixed at the University of Texas M.
D. Anderson Hospital will be presented in a separate study."
These 588 doses of mutagenic drugs constituted less than
one-half of the 1474 antineoplastic admixtures prepared by
the 6 subjects during this brief investigation. Besides the doses
of each mutagenic drug, Table 1 also records the average
amount per dose and the total amounts prepared.
The urine concentrates from 2 central pharmacy technicians
working at open-faced horizontal laminar flow hoods were toxic
to all tester strains including UTH 8414 and were discarded.
The urine concentrates from another central pharmacy tech
nician, Subject 4, were toxic to the uvrB strains but were not
toxic to UTH 8414. The toxicity was reduced by diluting to onehalf in DMSO. The number of net revendants induced by 10C
3 The abbreviation used is: DMSO. dimethyl sulfoxide.
* Manuscript in preparation.
4793
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f. V. Nguyen et al.
fi\ of these urine concentrates was normalized by multiplying
by a factor of 2. Since 1.5 ml of DMSO were utilized to obtain
the urine concentrates from Subject 6, the numbers of net
revenants induced by 100 ftl of these urine concentrates were
multiplied by 1.5.
A comparison of potential exposure with observed mutagenicity in urine concentrates of 6 subjects preparing cancer
chemotherapeutic agents in open-faced horizontal laminar flow
hoods is presented in Table 2. Each of the 6 subjects exhibited
elevated mutagenic activity in his/her 24-hr urine samples
during the exposure period. The data shown in Table 2 indicate
that for all 3 strains of uvrB bacteria the mean number of net
revertants induced in the group of 6 subjects was zero on Day
1, increased on Days 2 and 3 exceeded 2 times background
on Day 4, peaked on Day 5 decreased on Days 6 and 7, and
returned to zero on Day 8. The pharmacy administrators
showed no mutagenicity with any strain on any of the 8 con
secutive days. As shown in Table 2, each outpatient pharmacy
subject prepared about 3 times more cancer chemotherapeutic
agents than did each central pharmacy technician.
Each individual exhibited a unique pattern of mutagenic
activity in his/her urine concentrates, with a peak occurring on
Days 5, 6, and 7. The time when 2-fold mutagenic activity was
first detected also varied among individuals. Subjects 4 and 6
exhibited 2-fold mutagenic activity on Day 2 while Subject 2
did not exhibit this level of mutagenicity until Day 6 and the
remaining 3 subjects on Day 4.
No elevation in mutagenic activity toward UTH 8414 was
found in any urine concentrate.
The mutagenic activity in the urine concentrates of the same
4 central pharmacy subjects working in vertical flow hoods is
given in Table 3. No detectable elevation of mutagenic activity
in the urine concentrates of these subjects was seen when
they prepared a comparable amount of cancer chemothera
peutic agents in vertical flow hoods.
DISCUSSION
It is clear from this study that all 6 individuals preparing
cancer chemotherapeutic
agents in horizontal laminar flow
hoods were exposed to these drugs as indicated by the ele
vation of mutagenic activity in their urine (Table 2). It is inter
esting to note that, when the data from these individuals are
grouped, as indicated by the mean of the total number of net
revertants, there was a 3-day delay from the start of exposure
until the mutagenicity in the urine concentrates exceeded 2
times background. This 3-day delay coincides with the work of
Falck ef al. (6) who also found elevation of mutagenicity in the
urine of the nurses 3 days after exposure to cancer chemo
therapeutic agents.
Recently, Staiano et al. (20) conducted a study of pharma
cists preparing cancer chemotherapeutic
agents at NIH in
which urine samples were collected 2 days before exposure,
at the time of exposure, and 48 hr after exposure. The subjects
were exposed to only 3 drugs that are positive with the usually
used S. typhimurium uvrB test strains (cyclophosphamide,
daunorubicin, and doxorubicin) for only a single exposure of 4
to 6 hr. These investigators detected no mutagenic activity in
the urine of the pharmacists participating in the study. This
negative result may very well be explained by the skillful
4794
manipulative technique of these pharmacists as the authors
suggested. However, had our study been limited to one urine
sample taken 48 hr after a single exposure, it would certainly
have yielded negative results.
There is no direct correlation between the number of doses
of i.v. solutions prepared and the mutagenic activity in the urine
concentrates. For instance, within the group of central phar
macy technicians, Subject 2 had the greatest potential expo
sure but the least mutagenic activity in the urine while Subject
4 had less potential exposure but the greatest mutagenic
response. Also, among the 2 outpatient pharmacy subjects,
Subject 6, who prepared a total of 239 genotoxic cancer
chemotherapeutic i.v. solutions during the sampling week, had
far less mutagenic activity in his urine compared to the other
outpatient pharmacy subject as well as to any of the central
pharmacy technicians.
The variation of mutagenic activity in the urine concentrates
of the participants in this study may be due to individual
differences in metabolism, storage, and excretion of drugs. It
may also be due to induced metabolism following prolonged
exposure to these agents, as would be in the case of Subject
6, who was the only individual who prepared these drugs on a
continuous basis. Most likely, however, this variation depends
more on the work habits and the manipulative skills of each
individual. Subject 6, who prepared the largest number of
drugs and developed the least mutagenicity, was also the most
experienced in working with these drugs. Kleinberg and Quinn
(10) also concluded that manipulative technique was the major
factor in air contamination when they found a wide range in the
levels of fluorouracil and cefazolin sodium generated in a
horizontal laminar-flow hood following preparation by several
individuals.
When an occupational exposure to a toxic substance has
been detected, the most reliable intervention is to institute
engineering controls to prevent further exposure. The advan
tage of this approach is that it is not necessary to depend on
the manipulative skills of individuals to minimize or prevent
exposure. The engineering control utilized in this particular
case was the use of closed-face, vertical laminar flow hoods.
This type of hood protects the sterility of the solutions during
drug preparations while at the same time minimizing the contact
of the worker with these solutions. The fact that no elevation of
mutagenic activity was seen in the urine samples of the same
subjects preparing cancer chemotherapeutic agents in vertical
laminar-flow hoods (Table 3) indicates that their use is an
effective intervention for preventing exposure of pharmacy
personnel to these drugs.
As a result of this study, a closed-face, vertical laminar-flow
hood was purchased and instaüedin the outpatient pharmacy
where the heaviest load of cancer chemotherapeutic agents
are prepared. Additional vertical laminar-flow hoods have been
ordered so that all cancer chemotherapeutic agents will be
prepared for i.v. administration in an environment which mini
mizes the chance of occupational exposure to the pharmacy
personnel of the University of Texas M. D. Anderson Hospital
and Tumor Institute in Houston.
ACKNOWLEDGMENTS
The authors wish to thank Roger Anderson, Director of the Department of
Pharmacy, University of Texas M. D. Anderson Hospital and Tumor Institute, and
his associates for their participation in the planning and conduct of this study.
CANCER
RESEARCH
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VOL. 42
Exposure of Personnel to Mutagenic Antineoplastic
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This study was approved by the Committees for the Protection of Human
Subjects of both the University of Texas System Cancer Center M. D. Anderson
Hospital and Tumor Institute and the University of Texas Health Science Center
at hHouston. All subjects participating in the study were informed of the results as
soon as they became available.
sooRE1.2.3.4.5.6.7.8.9.10.11.12.13.14.15.16.17.18.19.20.21.22.23.24.25.26.
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4796
CANCER
RESEARCH
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1982 American Association for Cancer Research.
VOL. 42
Exposure of Pharmacy Personnel to Mutagenic Antineoplastic
Drugs
Tot V. Nguyen, Jeffrey C. Theiss and Thomas S. Matney
Cancer Res 1982;42:4792-4796.
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