HEALTH CARE WORKERS across multiple settings are at risk for adverse health consequences from hazardous drug exposure1-5 because of their involvement in the transport, handling, preparation, administration, or disposal of such medications used to treat patients. More than 8 million health care workers are employed in settings where they are potentially exposed to the dangers of hazardous drugs.6 Certain medications are considered hazardous drugs when they have the potential to cause negative health effects. Characteristics of hazardous drugs include genotoxicity, carcinogenicity, teratogenicity, reproductive toxicity, serious organ toxicity at low doses, or if their chemical structure mimics existing hazardous drugs.7

Some of these drugs and/or metabolites may be potentially more biologically active (toxic/hazardous) in body fluids than the parent drug.1,8 Health care workers who dispose of body fluids of individuals taking particular medications are at risk for adverse health consequences. However, because they are not considered part of the chain of custody of medication administration, this group of health care workers is often overlooked as a population at risk. This systematic review was conducted to identify evidence-based strategies for protecting all health care workers, from those involved in handling packaged hazardous drugs to those who dispose of body fluids of individuals taking these medications.

SEARCH STRATEGY

Databases used for the purpose of this review included PubMed, CINAHL (Cumulative Index to Nursing and Allied Health), the Cochrane Library, and EMBASE. All searches were limited to the English language. Boolean phrases, truncation, and Medical Subject Headings9 were used as follows: hazardous drug* AND exposure, environmental contamination AND hazardous drug*, safe handling AND precautions NOT infection, medical surveillance AND hazardous drug*, occupational exposure AND hazardous drug*, MH "occupational safety" AND hazardous drug,* and (MH "Environmental Monitoring+") AND hazardous drug.* Additional search terms used were as follows: hazardous substance,* pharmaceutical preparations [MH] OR occupational exposure. A hand search of reference lists was also conducted to identify source documents.

The review included years from 1979 to 2014. The starting year for the search was when a sentinel publication by Falck et al10 in 1979 first documented mutagenic changes in nurses handling hazardous drugs. Included were publications focusing on hospital personnel (eg, nurse, physician, pharmacist, technician, and/or therapist). Excluded were publications that focused on anesthetic gases, radiation, phthalates, other chemicals or disinfectants (eg, formaldehyde, mercury), occupations outside health care, and workplace violence. A second level of review was used to exclude publications that focused on the problems associated with hazardous drugs but that did not address control measures or strategies for risk prevention. Supplemental Digital Content Figure 1 (available at: http://links.lww.com/JNCQ/A228) provides the flow of information through the systematic review article process.

RESULTS

Description of publications in review

The search strategy yielded 29 publications that met final review criteria. These 29 publications were evaluated according to specific guidelines to rate the quality and strength of evidence.11 Supplemental Digital Content Table 1 (available at: http://links.lww.com/JNCQ/A221) provides the database publications included in the review, beginning with the highest level (2A) to the lowest (3B). There were no publications with level 1 evidence. Supplemental Digital Content Table 2 (available at: http://links.lww.com/JNCQ/A222) provides publications that are guidelines, expert opinions, and case reports (levels 4A-5B). There were 14 "high-quality" (level A) and 15 "good-quality" publications (level B). Publications rated as "low quality" (level C) were not included in the summary of evidence.

Across the set of publications, 5 major strategies were identified: engineering controls,1,7,12-32 personal protective equipment (PPE),* medical and environmental monitoring,+ hazard identification,1,7,12,15,20-32,36,37 and the need for a comprehensive hazardous drug control program that includes education and training for health care workers.26,27,31,32,36

Engineering controls

On the basis of an association between an elevated frequency of chromosomal aberrations and an increased incidence of cancer,2 McDiarmid et al20 conducted a study across 3 university hospital-based cancer centers in the United States. They identified a 20% increase in chromosomal abnormalities of health care workers who had a "moderate" level of hazardous drug handling (>=100 handling events of chemotherapy within a 6-week period). Of particular concern was the fact that each cancer center involved endorsed safe-handling practices for both preparation and administration of chemotherapy. Only 1 hospital-based cancer center in the study, however, used a closed-system transfer device (CSTD) in pharmacy. None of the institutions used a CSTD for both preparation and administration, or achieved full compliance with PPE for hazardous drug handling as recommended by the Oncology Nursing Society in 2009.39

The effectiveness of reducing surface (environmental) contamination with CSTDs is well established.13,17-19 In 2010, Sessink et al13 collected 114 wipe samples across 22 pharmacies in the United States. Chemotherapy agents tested were cyclophosphamide, ifosfamide, and fluorouracil (5-FU). Multiple sites were tested pre- and postimplementation of a CSTD. A significant difference in contamination for all drugs was observed (cyclophosphamide: P < .01; ifosfamide: P < .05; 5-FU: P < .0001). Similarly, Clark and Sessink17 analyzed the effectiveness of a CSTD within an ambulatory chemotherapy infusion center. Both pharmacy and nursing sites were tested, showing no evidence of contamination with the third and final wipe test after implementation of a CSTD.

Various guidelines from NIOSH (National Institute for Occupational Safety and Health), ASHP (American Society of Health-System Pharmacists), and the USP Chapter <797> provide recommendations for the type of biological safety cabinets (BSCs) required for hazardous drug preparation. According to NIOSH,40 a CSTD mechanically prohibits the transfer of environmental contaminants into the system and prevents hazardous drug or vapor outside the system. Both NIOSH and ASHP recommend a class 2 type B2, class 3, or a compounding aseptic containment isolator. The classes of BSCs are distinguished by the amount of air (if any) that is recirculated in the hood (70% recirculated with class 2 type A2, 30% recirculated with class 2 type B1, and no recirculation with class 2 type B2). In addition to 100% exhaustion through a HEPA (high efficiency particulate air) filter, class 3 BSCs have a complete physical barrier between the hazardous drug and the worker.

Personal protective equipment

Multiple factors affect the extent of hazardous drug exposure experienced by health care workers, including the inherent toxicity of a drug and the range of cytotoxic risks, the frequency and duration of handling, the route of administration, and the availability of proper PPE. The recommendations for proper PPE for handling hazardous drugs established by the Oncology Nursing Society, ASHP, and NIOSH are consistent. All 3 guidelines recommend chemotherapy-resistant gowns made from low-permeability fabric (eg, vinyl or polyethylene) with a solid front, back-closure, knit or elastic cuffs, and lint-free. Gloves should be chemotherapy resistant and should be used by any personnel involved with preparation, handling, administration, or handling excreta. Both NIOSH and ONS endorse double gloving with all handling activities, ideally with one pair of gloves under the gown cuff and the second pair over the cuff. Double gloving, however, is controversial and not universally practiced.12 Face shields and eye protection are also recommended whenever the risk of splashing may occur. NIOSH-approved respirators are recommended in the event of a spill.

The availability of appropriate PPE does not imply that it will be used.37 Both the work environment and personal factors can impact compliance with recommendations. In a descriptive, cross-sectional survey by Polovich and Clark,38 barriers to compliance with PPE included discomfort with attire and coworkers not using PPE. Significant predictors of hazardous drug precautions included fewer numbers of patients per day, fewer barriers to PPE use, and better workplace safety climate (R² = 0.29; P < .001).38

Medical and environmental monitoring

Methods for monitoring occupational exposure to hazardous drugs are challenging to implement and may be difficult to interpret. In general, medical surveillance can focus on the worker or environment. Biological monitoring of employees usually involves methods such as urine mutagenicity assays, urine tandem mass spectrometry, or analysis of chromosomal aberrations and sister chromatid exchanges in peripheral blood lymphocytes.2,41,42 Biomarkers of exposure, for example, detectable levels of chemotherapy agents in urine, blood, or tissues, can demonstrate uptake or absorption of hazardous drugs in health care workers.

Chromosomal aberrations were analyzed in a descriptive cohort study of oncology personnel handling chemotherapy drugs.20 Sixty-three "exposed" workers were matched with 46 "nonexposed" workers across 3 university hospital-based cancer centers. Data for both drug-handling frequency and use of PPE were collected via 6-week diary. Abnormalities in chromosomes 5, 7, and 11 were analyzed with FISH (fluorescent in situ hybridization) analysis. The highly exposed group had significantly higher structural abnormalities in chromosome 5 (P = .04) and total changes in chromosome 5 (P = .01); a 20% increase in abnormality frequency in chromosome 5 or 7 was observed in the exposed group (P = .01). Of particular concern is that all centers involved endorsed safe handling practices, including drug preparation in a BSC, work practices to prevent aerosolization, and glove use for handling events. Ideally, a CSTD would be used in both pharmacy and nursing departments. However, a CSTD was only used in 1 center in the pharmacy. Other measures to reduce exposure were not fully assessed, including other types of PPE (gown, mask, eye shield), or cleaning/disinfection practices.

Environmental sampling via surface or air testing can be a proxy measure to assess exposure potential in the health care worker. In a study by Fransman et al,22 3 cross-sectional surveys were examined to analyze trends in occupational exposure across hospital workers in the Netherlands, using a combination of wipe tests, glove tests, and urine sampling. After regulations and updated guidelines were implemented, the percentage of nurses' urine samples with detectable cyclophosphamide levels decreased 4-fold from 1997 to 2000. During that same time period, a 1.7-fold reduction in overall surface contamination and a 20-fold reduction in glove contamination were identified.22

Hazard identification

Hazard identification is an essential requirement in any hazardous drug control program. Disseminating this information to health care workers is also critical. Kaestli et al27 extended that strategy by creating and sharing a methodology for evaluating hazardous drugs. This methodology was based on intrinsic toxicity, risk of exposure (ie, drug formulation, administration route, and nature of employee's reproductive status), assessment of protective measures (matching precautions with risk), and comparison with published hazardous drug lists (eg, NIOSH and the University Health System Consortium Consensus). An algorithm was developed and implemented in multiple departments, consistent with NIOSH guidelines and the University Health System Consortium Consensus statement.

Similarly, Massoomi et al31 conducted a formulary assessment at their community-based hospital in Nebraska. Each hazardous drug was electronically tagged in the hospital computer system. Preparation and storage areas were marked with a caution sign indicating the presence of hazardous drugs, important since there is currently no universal symbol for hazardous drugs.

Comprehensive hazardous drug control program

Across publications describing a comprehensive hazardous drug control program, education and training were critical for success.26,27,31,32,36 The prospective intervention study by Keat et al15 demonstrated the importance of combining strategies to improve health care provider safety. They evaluated a series of interventions and assessed compliance with safety measures among 96 nurses across 15 hospital wards in Malaysia. Interventions included a CSTD, as well as educational courses, workshops, and policy updates.

DISCUSSION

A comprehensive hazardous drug control program should include engineering controls, PPE, medical and environmental monitoring, and hazard identification. Despite consensus among safe handling guidelines, no evidence was found to demonstrate the difference in environmental or worker contamination with one type of BSC compared with another, specifically for class 2 type A2 versus class 2 type B2. This differentiation is important, as primary engineering controls such as BSCs are expensive to obtain and upgrade. There is no controversy, however, that class 1 BSCs are inappropriate for hazardous drug preparation because they do not protect drug products from microbial contamination. Similarly, class 3 BSCs are not required for hazardous drugs, and these are typically reserved for high-risk infectious or biological agents.

Respiratory protection is an area in which additional research is needed. N-95 or N-100 masks are typically recommended for spill cleanups, but these masks by design protect against particles and not vapors. It is currently unknown if cartridge respirators protect against hazardous chemotherapy drug vapors. Furthermore, all hazardous drug PPE recommendations endorsed in the guidelines are for nonsterile environments. No clear guidelines exist for hazardous drug PPE for sterile environments, such as intravesical administration or heated intraperitoneal chemotherapy administration in the operating room.

Despite the evidence of harms associated with hazardous drug exposure, it is unclear if the precautions for chemotherapy are needed for noncytotoxic hazardous drugs. It is not known how noncytotoxic hazardous drugs are excreted from the body (biologically active or not), how they should be measured, and the potential impact of this to health care workers. While there is an association between hazardous drug exposure and negative health outcomes, prospective studies are needed to assess causality. Research is also needed to assess the risks for male health care workers exposed to hazardous drugs with respect to reproductive risks. In addition, best methods are needed for cleaning and decontamination after hazardous drug preparation, administration, spill, or exposure.

One challenge with both wipe testing and air sampling is that no minimum acceptable exposure levels exist for chemotherapy or other hazardous drugs. Employers can use results, however, to evaluate effectiveness of hazardous control measures and highlight areas for improvement. Testing workers urine and/or blood samples may be difficult to operationalize across large health care systems. Financial and ethical implications must be considered, specifically with how to counsel staff members with positive results of urine samples and/or blood tests.

With 184 drugs on the 2014 NIOSH hazardous drug list,43 safe handling of hazardous drugs requires a comprehensive hazardous drug control program. Given the body of evidence associated with hazardous drug exposure, the need to advance the knowledge and competency of the health care workforce is paramount.

RECOMMENDATIONS FOR PRACTICE

Based on OSHA's (Occupational Safety and Health Administration's) hierarchy of controls,44 the most effective measure for reducing risk is through elimination or substitution. As patients require treatments with hazardous drugs, elimination is not feasible. Thus, engineering controls provide the next best level of protection. Strong support for BSCs and CTSDs was identified in this systematic review. Staff nurses and nursing leaders must implement measures to ensure that all chemotherapy drugs be prepared in pharmacy under a BSC. Similarly, CTSDs should be used for both preparation and administration of all chemotherapy drugs.

To address the needs of frontline staff, hospitals must have appropriate PPE available for nurses and other health care workers to don when potential exposure is expected. Placing PPE at the point of use is important to promote compliance. However, since PPE alone does not mitigate risk, it is essential to educate nurses and other health care workers about the risks and ensure adherence to PPE via monitoring. Barriers such as understaffing, the physical layout of a unit, and time constraints can negatively impact adherence.38 Monitoring compliance with PPE can help nurse leaders identify barriers, provide opportunities for coaching and feedback, and make quality improvement recommendations.

In addition to medical surveillance of employees, a practical approach to measuring effectiveness of control measures is to monitor the environment for common chemotherapy agents. Wipe tests can be conducted in multiple areas where hazardous chemotherapy drugs are handled, prepared, or administered. Repeated wipe tests of such sites can identify whether contamination exists or if levels increase or decrease. Increasing levels of contamination should prompt changes in safe handling practices and/or cleaning and decontamination methods. Collaboration across multiple departments (pharmacy, nursing, environmental services, occupational and environmental health) is warranted to address the implications of such findings.

Nurses and other health care workers must know when they are working with hazardous drugs to minimize their risks. Transparency at every step in the chain of custody is needed. In addition to electronic identifiers and physical signs or labels, clear instructions that prompt the worker what to do are needed. Hazardous drug identification should include easily visible and accessible resources to make the environment safe for staff, patients, and families.

SUMMARY

Absent data on causality of health risks and hazardous drug exposure, multiple strategies are needed to minimize those risks. The cost of providing education to health care workers and ensuring proper PPE and compliance with those protections undoubtedly outweighs the cost to those individuals in terms of the immediate and future health risks. Given the increasing use of chemotherapy and hazardous drugs beyond the setting of oncology,2,45 as well as the known dangers associated with hazardous drug exposure, evidence-based recommendations are needed to protect health care workers.

This systematic review identified the need to address 5 key areas in the mitigation of hazardous drug exposure for health care workers: (1) engineering controls (BSCs, CSTDs), (2) PPE, (3) medical and environmental monitoring, (4) hazard identification, and (5) a comprehensive hazardous drug control program. Easily accessible education is needed for health care workers to increase their awareness of hazardous drugs and how to manage risks of exposures with safety practices including proper PPE. Monitoring of health care workers' use of proper PPE will be important to access compliance and for understanding barriers and facilitators of use. Finally, obtaining data from environmental testing for the presence of common chemotherapeutic drugs will be useful to inform and improve controls measures to protect the nation's health care workers involved in the chain of custody of hazardous drugs.

REFERENCES