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SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION PAGE 3
Definition of Hazardous Drugs
HDs require careful handling by healthcare personnel and others who come in
contact with them to minimize the adverse health effects of exposure and reduce
contamination of the workplace. A definition of HDs is essential so that clinicians
recognize the drugs for which the safe handling recommendations apply. Drugs
are classified as hazardous when they possess any one of the following six charac-
teristics (ASHP, 1990, 2006; National Institute for Occupational Safety and Health
[NIOSH], 2004).
- Genotoxicity , or the ability to cause a change or mutation in genetic material; a
mutagen.
- Carcinogenicity , or the ability to cause cancer in humans, animal models, or
both; a carcinogen. The International Agency for Research on Cancer (IARC)
classifies agents as carcinogens if they are capable of increasing the incidence
of cancers, reducing the latency period before cancer development, or increas-
ing the severity of growth of a malignancy. In some cases, an agent’s ability to
induce benign tumors was also evidence used to classify an agent as a carcino-
gen (IARC, 2006).
- Teratogenicity , or the ability to cause defects in fetal development or fetal mal-
formation; a teratogen.
**- Fertility impairment or reproductive toxicity.
- Serious organ toxicity at low doses** in humans or animal models. - Chemical structure and toxicity profile that mimic existing drugs determined to
be hazardous by the five previous criteria. This additional criterion to the def-
inition of HDs was first published by NIOSH in 2004 and serves as a reminder
that new drugs should be critically evaluated using existing information and ex-
trapolating data from similar agents. ASHP (2006) recommends that organiza-
tions evaluate the hazardous potential for all drugs, approved and investigation-
al, when they are first introduced into the facility.
HDs may include antineoplastic or cytotoxic agents, biologic agents, antiviral
agents, immunosuppressive agents, and drugs from other classes. OSHA (1995) rec-
ommends that all investigational agents be regarded as potentially hazardous until
information establishing their safety becomes available. In the event that data pro-
vided to the principal investigator about an investigational agent are insufficient to
make a decision, it is prudent to handle the agent as though it is hazardous (ASHP,
2006; NIOSH, 2004). ASHP (2006) specifies that all drugs should be considered
hazardous if the information obtained about the drug is insufficient to make an in-
formed decision as to whether it is hazardous. Certainly, healthcare providers must
recognize that erring on the side of caution is essential to protecting workers’ health
and safety and the safety of the work environment.
The first step for organizations in creating an environment that is safe from HD
exposure is to determine what HDs are used in the setting. Organizations should
develop a list of all HDs used and ensure that a method is in place to regularly re-
view and update the list. A comprehensive list of all drugs currently considered
hazardous does not exist in the literature. Given the large number of new drug
approvals each year, organizations must have a process for evaluating the medica-
tions they use to determine whether they are hazardous. Table 1 provides resourc-
es that will aid clinicians in evaluating whether a pharmaceutical agent should be
handled as hazardous.
Clinicians should be aware that many drug classifications include medications
that are hazardous. Examples of HDs in addition to traditional chemotherapy in-
clude thalidomide, interferon alpha, conjugated estrogens, and ganciclovir (NIOSH,
PAGE 4 SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION
Table 1. Resources for Developing a List of Hazardous Drugs
Resource Description American Hospital Formulary Ser- vice (AHFS) Pharmacologic-Thera- peutic Classification System The AHFS Pharmacologic-Therapeutic Classification System is a widely accepted system for classification of drugs into categories based on mechanism of action. The system designates all antineoplastic agents as category 10; all category 10 drugs are hazardous. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Monographs categorize the drugs, viruses, and other substances as
- Group 1: The agent is carcinogenic to humans.
- Group 2A: The agent is probably carcinogenic to humans.
- Group 2B: The agent is possibly carcinogenic to humans.
- Group 3: The agent is not classifiable as to its carcinogenicity to humans.
- Group 4: The agent is probably not carcinogenic to humans. Material safety data sheets (MSDS) MSDS are developed by manufacturers to describe the chemical properties of a product, includ- ing
- Health effects and first aid for exposure
- Storage, handling, and disposal information
- Personal protection
- Procedures for cleaning in the event of a spill. Manufacturers are required to provide MSDS for all drugs that are deemed hazardous or contain hazardous components. National Toxicology Program’s Report on Carcinogens Carcinogens listed in this report are classified either as known human carcinogens or reason- ably anticipated to be human carcinogens. The report can be obtained at http://ntp.niehs.nih.gov/ go/roc. NIOSH Appendix A of Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings contains a table with a sample list of drugs that should be handled as hazardous. The hazardous drug list was updated in 2010 and can be found at www.cdc.gov/ niosh/docs/2010-167/pdfs/2010-167.pdf. Package inserts for specific pharma- ceutical agents Package inserts for all U.S. Food and Drug Administration–approved medications contain infor- mation to assist clinicians in determining whether a drug should be classified as hazardous, in- cluding
- Drug classification
- Pregnancy category and reproductive toxicity
- Organ toxicities
- Secondary cancers that may develop with exposure
- Drug warnings. Note. Based on information from American Society of Health-System Pharmacists, 2010; International Agency for Research on Cancer, 2006; National Insti- tute for Occupational Safety and Health, 2004; U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, 2010.
2004). Because HDs are administered in multiple clinical areas, it is imperative that
safe handling training extend beyond the oncology unit. HD safe handling is an or-
ganizational issue.
Adverse Effects of Hazardous Drug Exposure
The adverse effects of HDs in treated patients are well known and generally seen
as outweighed by the benefits of treatment, and measures are implemented to pre-
vent or minimize these hazardous effects. The adverse effects of occupational expo-
sure to HDs in HCWs, on the other hand, have no associated benefit. Precautions
that will prevent or minimize occupational exposure to HDs are recommended in
the literature. However, despite the existence of published research studies, guide-
lines, and recommendations, HCWs do not always follow measures to reduce HD
exposure. This lack of action places HCWs at risk for myriad adverse effects. Adverse
effects of occupational HD exposure are listed by system in Table 2.
PAGE 6 SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION
Table 3. Hazardous Drug Exposure: Biologic and Health Effects
Study Purpose Design Sample Measurement Results Krepinsky et al., 1990 Evaluate possi- ble genetic dam- age caused by HD exposure and to compare the ef- fectiveness of three methods of detection Matched case- controlled 10 exposed and 10 unexposed nurs- es and 10 patients with cancer receiv- ing chemotherapy in Canada CAs and SCEs in PBLs. Ames test for mu- tagenicity in urine. Samples collected before and after expo- sure. PPE use was not moni- tored. SCE assay detected treated patients and 2 nurses who smoked. Ames test detected treated patients but not smok- ers. CAs detected in 4 out of 9 patients (data missing for 1 patient) and in exposed nurs- es after several days, which was not likely due to exposure. Oestreicher et al., 1990 Evaluate possible genetic damage caused by HD ex- posure Matched case- controlled 8 nurses handling HDs without pro- tection for years, 8 exposed pharma- cy personnel using precautions, 8 unex- posed nurses CAs and SCEs in PBLs CAs significantly increased in exposed nurses when com- pared to unexposed nurses and pharmacists using pre- cautions (p < 0.01). SCEs not significantly different between groups. Stücker et al., 1990 Analyze relation- ship between SAs and occupational exposure to HDs among nurses Matched case- controlled 4 French hospitals 466 women, 534 pregnancies Questionnaire 26% SA in 139 pregnancies in exposed women 15% SA in 357 pregnancies in unexposed women OR = 1.7 (95% CI 1.2–2.8) Cooke et al., 1991 Determine the oc- currence of CAs in nurses and phar- macists exposed to HDs in United Kingdom Case- controlled 50 pharmacists, 11 nurses, 12 controls, and 6 patients Analysis of blood for CAs in PBLs No significant differences be- tween exposed pharmacists or nurses compared to controls No correlation between amount of drugs handled and CAs Thiringer et al., 1991 Determine the rela- tionship between urine mutagenicity, urinary thioethers, SCEs, and micro- nuclei and occu- pational exposure to HDs Matched case- controlled 60 Swedish nurses exposed to HDs and 60 unexposed con- trols Analysis of urine for mutagenicity and thioethers and blood for SCEs and mi- cronuclei in PBLs For urine mutagenicity, there was a significant difference between exposed and unex- posed workers (p < 0.01). For SCEs, there was a signifi- cant difference between ex- posed and unexposed work- ers (p < 0.05). No significant difference for thio- ethers and micronuclei Goloni- Bertollo et al., 1992 Determine the rela- tionship between CAs and SCEs and occupational exposure to HDs Matched case- controlled 15 nurses and nurse aides in Brazil pre- paring and adminis- tering HDs Controls: 15 nurs- es on nononcology wards and 15 office workers Analysis of blood for SCEs and micronuclei in PBLs Significantly more frequent CAs and SCEs in exposed nurses compared to controls Harris et al., 1992 Determine the rela- tionship between CAs and micro- nuclei and occu- pational exposure to HDs Matched case- controlled 64 nurses in United States (24 low ex- posure, 21 medium exposure, 19 high exposure) and 15 patients with cancer Analysis of blood for CAs and mi- cronuclei in PBLs No association between expo- sure classification and CAs or micronuclei CAs and micronuclei significant- ly associated with glove use of less than 100% of time com- pared to 100% use (Continued on next page)
SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION PAGE 7
Table 3. Hazardous Drug Exposure: Biologic and Health Effects (Continued)
Study Purpose Design Sample Measurement Results Skov et al., 1992 Describe the risk for cancer and ad- verse reproductive outcomes among Danish nurses handling HDs Descriptive, retrospec- tive record review 1,282 female nurses from Danish hospi- tals preparing or ad- ministering HDs and 2,572 unexposed nurses working in the same hospitals Danish health re- cords (1973–
Hospital employ- ment records Significantly increased relative risk for leukemia. Overall risk estimates were not increased for adverse reproductive out- comes. The study included the time be- fore as well as the time after implementation of safe han- dling measures. Stücker et al., 1993 Determine the rela- tionship between birth weight and exposure to HDs during and before pregnancy Matched case- controlled 4 French hospitals 466 women; 420 live births, 298 births to unexposed women, 107 births to nurses exposed during and before pregnancy Questionnaire Birth weight of infants of ex- posed mothers was 85 g less than that of infants of unex- posed mothers but was not statistically significant. Expo- sure data missing for 15. Valanis et al., 1993a Determine the rela- tionship between occupational ex- posure to HDs and acute symp- toms among nurs- ing personnel Descriptive, cross- sectional 1,932 nurses and 152 nurse aides from more than 200 healthcare facilities currently handling HDs Questionnaire (handling ac- tivities, use of PPE, and symptoms ex- perienced in the previous three months) Handling HDs increased the number of symptoms. Use of protection decreased the number of reported symptoms. Skin contact while cleaning up spills or handling patient ex- creta was a predictor of symp- toms. Valanis et al., 1993b Determine the rela- tionship between occupational ex- posure to HDs and acute symptoms among pharmacy personnel Descriptive, cross- sectional 533 pharmacists and technicians current- ly handling HDs and 205 pharmacists and technicians who never mixed HDs Questionnaire (handling ac- tivities, use of PPE, and symptoms in the previous three months) Diarrhea and chronic cough were increased in exposed study subjects over controls. Self-reported skin contact was a predictor of symptoms. Hansen & Olsen, 1994 Determine cancer incidence among HD handlers Archived data analysis Female Danish phar- macy technicians identified in cancer registry Comparison of Danish cancer registry data to expected can- cer incidence rates 1.5-fold elevated risk of nonmel- anoma skin cancer; 3.7-fold increased risk for non-Hodg- kin lymphoma Sessink et al., 1994 Compare urinary CP excretion and CAs in four groups of hospital work- ers with various levels of HD ex- posure Descriptive 17 Dutch and 11 Czech hospital workers handling HDs, and 35 Dutch and 23 Czech work- ers not handling HDs Analysis of urine for CP and blood for CAs in PBLs The percentage of aberrant cells was increased in ex- posed Dutch and Czech work- ers. Results suggest additive effect of exposure and smok- ing. CP was detected in urine samples of 3 out of 11 Dutch workers and 8 out of 11 Czech workers handling HDs. Fuchs et al., 1995 Determine the oc- currence of DNA damage in nurses handling antineo- plastic agents Descriptive 91 nurses from four hospitals in Ger- many who handled chemotherapy and 54 unexposed con- trols Blood samples for DNA single- strand breaks and alkali labile sites in PBLs Questionnaire and demo- graphic data A 50% higher level of DNA strand breaks and alkali labile sites were detected in nurses not using precautions as com- pared to controls. After imple- menting recommended safe- ty precautions, strand breaks decreased to the level of con- trols. (Continued on next page)
SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION PAGE 9
Table 3. Hazardous Drug Exposure: Biologic and Health Effects (Continued)
Study Purpose Design Sample Measurement Results Maluf & Erdtmann, 2000 Part 1: Analyze the relationship be- tween micronuclei and occupational exposure to HDs among nurses and pharmacists Matched case-con- trolled 10 Brazilian pharma- cists and nurses ex- posed to HDs and 10 unexposed work- ers Analysis of blood for micronuclei in PBLs Significant difference between exposed workers and controls (p = 0.038) Part 2: Analyze the relationship be- tween micronuclei and comet assay and modifications to work schedules among nurses and pharmacists Matched case-con- trolled fol- lowing re- duction in work hours 12 Brazilian pharma- cists and nurses ex- posed to HDs and 12 controls Analysis of blood for micronuclei and comet as- say in PBLs No difference between exposed workers and controls for mi- cronuclei Significant difference between exposed workers and controls for comet assay (p = 0.0006) Burgaz et al., 2002 Determine frequen- cy of CAs in PBLs of nurses exposed to HDs Matched case-con- trolled 20 nurses handling HDs and 18 controls CAs in PBL; CP excreted in urine 2.5-fold increase in CAs, includ- ing chromatid breaks, gaps, and acentric fragments for nurses handling HDs as com- pared to controls (p < 0.05) CP excretion rate for 12 nurses was 1.63 mcg/24 hours, indi- cating exposure. Cavallo et al., 2005 Evaluate genotoxic effects of antineo- plastic exposure Laboratory analysis 25 exposed nurses, 5 pharmacy techni- cians, and 30 unex- posed controls from administrative offic- es in a large Italian hospital Micronuclei test and analysis of CAs with lym- phocytes and exfoliated buc- cal cells No difference between exposed study subjects and controls for micronuclei in lymphocytes Higher values for micronuclei in exfoliated buccal cells of ex- posed workers CAs were 2.5–5-fold higher in exposed groups. Martin, 2005b Determine the ef- fects of chemo- therapy handling among nurses and their offspring Descriptive, correla- tional 2,427 nurses who re- ported handling 3 or more doses of HDs per day for at least one year and re- ported giving birth within 10 years of exposure Total of 3,399 off- spring Questionnaire HD handling before age 25 in- creased odds of infertility. More years of HD handling re- sulted in higher rate of mis- carriage. Handling 9 or more doses per day increased preterm labor and preterm birth. Learning disabilities increased in offspring of nurses who rarely wore gloves during HD handling. Increased cancer occurrence existed among exposed nurs- es. Yoshida et al., 2006 Analyze the rela- tionship between DNA damage and occupational HD exposure in nurs- es and pharma- cists Case-con- trolled 37 nurses in a hospi- tal in Japan: 18 un- exposed and 19 ex- posed nurses Analysis of blood for comet as- say, tail length Tail length, 5.1 mcm in unex- posed and 8.5 mcm in ex- posed study subjects Significant difference, p = 0. (Continued on next page)
PAGE 10 SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION
Several studies have documented the adverse reproductive outcomes of oc-
cupational exposure. Fransman, Roeleveld, et al. (2007) compared outcomes in
4,393 exposed and unexposed (control) nurses in the Netherlands. Exposure to
antineoplastic drugs was estimated using dermal measurements based on han-
dling tasks. Nurses who were highly exposed, defined as 0.74 mcg/week expo-
sure, took longer to conceive, had infants with lower birth weight, and had a high-
er incidence of preterm labor. Similarly, Martin (2005b) reported an inverse re-
lationship between compliance with HD handling guidelines and adverse repro-
ductive outcomes among nurses surveyed. Significant findings in exposed versus
unexposed nurses included infertility in those who handled chemotherapy be-
fore age 25; miscarriages, preterm birth, and preterm labor in nurses who admin-
istered more than nine doses per day; and an increase in learning disabilities in
offspring, which correlated to glove use. When a Danish study of exposed versus
unexposed nurses found a similar risk of fetal malformations, miscarriages, low
birth weight, or preterm delivery, the researchers concluded that a well-protect-
ed setting (e.g., one with proper safe handling precautions) reduces occupation-
al HD exposure (Skov et al., 1992).
Valanis, Vollmer, Labuhn, and Glass (1993a) reported the occurrence of acute
symptoms of HD exposure in 2,084 nurses and nurse aides. These included cardi-
ac, gastrointestinal, neurologic, allergic, infectious, and systemic symptoms. The re-
searchers found that skin contact with HDs, especially during spill cleanup, was asso-
ciated with less use of personal protective equipment (PPE) and more acute symp-
toms, leading the authors to conclude that skin contact is a major source of exposure.
Table 3. Hazardous Drug Exposure: Biologic and Health Effects (Continued)
Study Purpose Design Sample Measurement Results Fransman, Roeleveld, et al., 2007 Determine repro- ductive effects of HD exposure Survey 4,393 exposed and unexposed nurses Estimated HD ex- posure based on self-reported tasks Reproductive out- comes Nurses highly exposed to HDs took longer to conceive than unexposed nurses. Expo- sure was associated with pre- mature delivery and low birth weight. Ikeda et al., 2007 Analyze the rela- tionship between SCEs and occu- pational exposure to HDs among mixed population Determine epirubi- cin in urine and plasma of mixed population Case- controlled; laboratory analysis Pharmacists, nurs- es, and physicians in Japan with rotat- ing duties SCE: 11 exposed workers and 2 con- trols Urine and plasma analysis: 13 ex- posed workers and 3 controls SCEs in periph- eral blood Epirubicin in urine and plas- ma No correlation was found be- tween hours worked per week and SCEs. No epirubicin was detected in urine or plasma. Testa et al., 2007 Determine the inci- dence of CAs in PBLs of nurses occupationally ex- posed to HDs Case- controlled 76 oncology nurses occupationally ex- posed to HDs and 72 controls from two hospitals in Italy CAs in PBLs Mean total number of CAs for exposed nurses was 3.7 times (11.2 versus 3.04) that of con- trols (p < 0.0001). Chromatid- and chromosome-type aberra- tions were 3.4 and 4.16 times that of controls. ANA—American Nurses Association; CA—chromosomal aberration; CI—confidence interval; CP—cyclophosphamide; DNA—deoxyribonucleic acid; HD— hazardous drug; ONS—Oncology Nursing Society; OR—odds ratio; PBLs—peripheral blood lymphocytes; PPE—personal protective equipment; SA—spon- taneous abortion; SCE—sister chromatid exchanges
PAGE 12 SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION
tant route for uptake of these drugs. This is supported by an earlier report that
detected cyclophosphamide both in the urine of volunteers who had the drug
applied to their skin and in two nurses who prepared and administered cyclo-
phosphamide without respiratory protection or PPE (Hirst, Tse, Mills, Levin,
& White, 1984).
Additional studies using assays indicated exposure, uptake, and metabolism
of HDs during routine work activities even when no obvious source of exposure
was identified. Nygren and Lundgren (1997) detected increased platinum (from
platinum-containing HDs such as cisplatin) in the blood of staff nurses (those
involved in patient care) but not in graduate nurses (those involved in HD han-
dling) or pharmacists. They concluded that exposure most likely occurred dur-
ing routine care of treated patients rather than during HD preparation or ad-
ministration, where PPE use was more likely. Pethran et al. (2003) found HDs
in the urine of 40% of study participants despite the use of biologic safety cab-
inets (BSCs).
Environmental Monitoring for Hazardous Drug Exposure
Early support for precautions while handling HDs focused on the biologic ef-
fects in exposed individuals. Following the implementation of HD safe handling
guidelines in most settings, pharmacists and nurses continued to demonstrate
evidence of exposure despite the use of precautions such as BSCs, gloves, and
gowns. The most plausible source of exposure is an environment that is contam-
inated with HDs.
Exposure From Contaminated Surfaces
One method of measuring environmental contamination with HDs is surface
wipe sampling. Surfaces in work areas where HDs are handled are evaluated for the
presence of HD residue. The sample areas are measured, moistened with 0.03 M
sodium hydroxide, and wiped with paper towels until dry. The towels are placed in
plastic containers and sent for analysis for the presence of several drugs (Connor,
Anderson, Sessink, & Spivey, 2002).
Minoia et al. (1998) analyzed surface wipe samples, pads placed on gowns, air
samples, and gloves of 24 workers involved in HD preparation and administra-
tion for the presence of cyclophosphamide and ifosfamide. In addition to posi-
tive air and urine samples, many of the wipe samples taken from inside and out-
side of the BSC, including the floor and door handles, were contaminated with
the two drugs. Many of the pads and gloves were also contaminated. The authors
concluded that inadequate performance of the BSC may result in worker con-
tamination. They suggested that using a plastic-backed paper liner inside the BSC
may interfere with airflow and affect BSC performance. No subsequent studies
have evaluated the effect of BSC liners on airflow. The study further demonstrat-
ed that gloves are routinely contaminated during HD handling and should be
changed periodically. Guidelines recommend that gloves be discarded after no
more than 30 minutes of use.
In a multisite study in the United States and Canada, surface contamination with
three cytotoxic agents was measured by more than 200 wipe samples (Connor, An-
derson, Sessink, Broadfield, & Power, 1999). The results revealed that 75% of wipe
samples from drug preparation areas and 65% of samples from drug administra-
tion areas had measurable levels of one or more of the drugs. The investigators
concluded that surface contamination with HDs is common and that workers who
are not directly involved in HD handling may be exposed to drug residue on these
SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION PAGE 13
surfaces. Other investigators have reported similar findings with cyclophosphamide
(Kiffmeyer et al., 2002) and platinum (from cisplatin and/or carboplatin) in ad-
dition to ifosfamide (Mason et al., 2005; Nygren & Aspman, 2004; Schmaus, Schi-
erl, & Funck, 2002).
Fransman, Vermeulen, and Kromhout (2004, 2005) evaluated workers’ poten-
tial and actual dermal exposure to cyclophosphamide during the performance
of common hospital tasks in two studies. The investigators placed pads on sev-
eral body locations of nurses, pharmacy technicians, and cleaning personnel.
They also analyzed gloves worn during handling activities, hand-wash water used
after handling activities, patient body fluids, and linens from patients who had
received cyclophosphamide. The gloves were commonly contaminated. Nurses
were found to have skin contamination under gloves, especially following han-
dling of patients’ urine. These findings confirmed dermal exposure during nor-
mal patient care activities and led the authors to conclude that hands are a com-
mon site of HD exposure for HCWs.
Several studies have detected drug contamination on the outside of drug vials
when delivered by the manufacturers (Connor et al., 2005; Nygren, Gustavsson,
Strom, & Friberg, 2002; Sessink et al., 1992). Cyclophosphamide, fluorouracil, ifos-
famide, and platinum have all been detected on vial exteriors using various wipe
sampling and washing techniques. These findings indicate that nurses and phar-
macists are at risk for skin exposure if they do not wear PPE while handling un-
opened drug vials.
Results from the many environmental monitoring studies demonstrate that
the work areas where HDs are prepared and administered are commonly con-
taminated with the drugs. Workers who normally wear PPE for direct drug-han-
dling activities can be exposed when touching unknowingly contaminated sur-
faces with unprotected hands. Every study measuring environmental contami-
nation using surface wipe sampling found evidence of surface contamination
(see Table 4).
Inhalation Exposure
Several investigators have identified low levels of HDs in air samples collect-
ed in areas where the drugs are handled (Kiffmeyer et al., 2002; Kromhout et al.,
2000; Mason et al., 2005). Although this exposure route is less likely for workers
who use a BSC, the risk is high for drug preparation outside of a primary engi-
neering control (PEC), including inhalation of aerosols during the crushing of
tablets (Dorr & Alberts, 1992). In addition, some authors have reported vapor-
ization of several antineoplastic drugs (Connor, Shults, & Fraser, 2000; Kiffmeyer
et al., 2002). A few authors have proposed that inhalation exposure may be high-
er than previously thought because earlier methods used to measure air samples
were not sufficiently sensitive (Hedmer, Jonsson, & Nygren, 2004; Larson, Khaza-
eli, & Dillon, 2003b). Therefore, workers should consider inhalation as a pos-
sible route of HD exposure and avoid performing any drug preparation activi-
ties outside of a BSC.
To summarize, ongoing evidence shows that occupational HD exposure can and
does occur. Few laboratories in the United States perform the assays described in
this section, which makes routine monitoring impractical. In the absence of mea-
sured contamination in the workplace, nurses should consider the possibility of
environmental contamination. Because a safe level of HD exposure does not ex-
ist, HCWs must take steps to minimize their exposure. Additional studies are need-
ed that evaluate the magnitude of HD exposure of HCWs who consistently use safe
handling precautions.
SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION PAGE 15
Table 4. Hazardous Drug Exposure: Environmental Monitoring
(Continued)
Study Purpose Design Sample Measurement Results Favier et al., 2001 Measure environmen
tal contamination with HDs in BSCs and iso
lators Laboratory analysis 6 French pharmacies, 3 with BSCs and 3 with isolators Measurement of 5-FU on work sur
faces in BSCs and isolators and several other locations Comparable samples from the 3 BSCs, 1 of 6 > LOD Samples from isolators, 5 of 6 > LOD Values post-cleaning were lower. 25 of 30 preps in isolator > LOD 1 of 30 preps in BSCs > LOD Some other glove and environmental con
tamination was reported. Kiffmeyer et al., 2002 Measure environmen
tal contamination with HDs Laboratory analysis HD preparation areas Measurement of carmustine, cispl
atin, CP, etoposide, and 5-FU in air samples Measurement of CP in wipe sam
ples and urine of workers who prepared CP. Particulate CP was found in the air of 6 of 20 preparation sites. Gaseous CP was found in 7 of 15 sites. CP was present on 17 of 26 surfaces. No CP was found in the urine of 3 tested workers. Nygren et al., 2002 Measure external vial contamination with HDs Laboratory analysis 6 vials of platinum-con
taining drugs from 3 different manufactur
ers in Sweden Wipe sample analysis using adsorp
tive voltammetry Drug vials were contaminated on the out
side when delivered by the manufacturer. Schmaus et al., 2002 Measure environmen
tal contamination with HDs Laboratory analysis 7 standard locations in each of 14 hospital pharmacies in Germany Wipe sample analysis using gas chromatography-mass spectrom
etry and voltammetry for CP, IF, 5-FU, and platinum 100% of samples tested positive for plati
num, which has a low limit of detection. 0%–25% tested positive for CP and IF; 40%–80% tested positive for 5-FU. Volume of drugs prepared did not predict the amount of contamination. Work practices in some settings reduced contamination. Favier et al., 2003 Measure external vial contamination Laboratory analysis 739 vials tested for 6 drugs from several manufacturers Drug packaging tested for 5-FU and etoposide Vials immersed in solvent with rota
tion for 30 seconds in water HPLC used for 5-FU, etoposide, doxorubicin, and docetaxel Gas chromatography used for CP and IF 100% of vials were contaminated 0.5– 2,447 ng/vial. 5-FU drug packaging was contaminated. No contamination was seen on etoposide packaging. Larson et al., 2003a Method development Laboratory analysis Development of a meth
od for detecting 5-FU, IF, CP, doxorubicin, and paclitaxel in air samples Air samples collected and filtered with Anasorb ®^ 708 (SKC, Inc.) solid sorbent tube Greater than 90% recovery for both CP and ifosfamide; 5-FU, doxorubicin, and paclitaxel were detected and measured. All 5 agents of interest were detected at minimal LOD of 0.5 mcg/ml. (Continued on next page)
PAGE 16 SAFE HANDLING OF HAZARDOUS DRUGS, SECOND EDITION
Table 4. Hazardous Drug Exposure: Environmental Monitoring
(Continued)
Study Purpose Design Sample Measurement Results Larson et al., 2003b Validate a new monitor
ing method for evalua
tion of airborne HDs Laboratory analysis Filters and sorbent tubes used for recovering CP, IF, and 5-FU from air samples Air monitoring for HDs using reverse- phase HPLC/mass spectrometry CP was recovered from filters and then evaporated, becoming gaseous. HEPA filters trap particles but not vapors. Recirculating BSCs may result in worker exposure. Fransman et al., 2004 Evaluate dermal expo
sure to CP Laboratory analysis Pharmacy technicians, oncology nurses, and cleaning personnel in 3 Dutch hospitals dur
ing the performance of 5 tasks Analysis of cotton pads attached to body surfaces Analysis of wipe samples of fore
heads Assays of used gloves, wash water, wash cloths, towels, and bed
sheets for CP CP was detected on pads, gloves, wipe samples, wash cloths, and bed linens. CP was found on foreheads of technicians and nurses. Cleaning personnel had CP on their gloves. Contamination of hand-wash samples was highest during handling of urine. Hedmer et al., 2004 Validation of methods for detecting CP on sur
faces and in the air Laboratory analysis Air and surface samples Wipes made of different materials to clean up CP Several filter types for recovering CP from air LOD for CP was 0.02 ng per sample for wipes and 0.03 ng for air samples. Nygren & Aspman, 2004 Validation of x-ray fluo
rescence as a meth
od for assessment of aerosol distribution Laboratory analysis Surfaces in a drug prep
aration room of an on
cology clinic Wipe samples analyzed for platinum Platinum was recovered from every wipe sample except from a corridor outside the preparation room. The level of plat
inum was highest in the BSC and de
creased with increasing distance from the BSC. Connor et al., 2005 3 studies evaluating ex
ternal vial contamina
tion with HDs Laboratory analysis Unopened vials of HDs Study 1: wipe sampling for CP and
IF
Study 2: wipe sampling for CP and
5-FU
Study 3: analysis for cisplatin using two vial washing techniques and polymer sleeves Surface contamination was detected on most commercially available drug vials tested. Improved decontamination in combina
tion with sleeves reduced contamination by 90%. Fransman et al., 2005 Measure dermal expo
sure to CP during var
ious handling activ
ities Laboratory analysis Personnel handling HDs or caring for people who receive HDs Analysis of cotton pads attached to body surfaces Analysis of wipe samples of fore
heads Assays of used gloves, wash water, wash cloths, towels, and bed
sheets for CP CP was detected on pads, gloves, wipe samples, wash cloths, and bed linens. Most CP was found on hands. Nurses who wore gloves had skin contamination of their hands, most often after handling urine. (Continued on next page)
