Studies

Healthcare workers may be exposed to HDs at many points during manufacture, distribution, receipt, storage, transport, compounding, and administration, as well as during waste handling and care of treated patients. All workers involved in these activities, as well as in equipment maintenance and repair, have the potential for contact with uncontained drug. One study of worker contact with surfaces contaminated with HDs identified a number of job categories not traditionally expected to be exposed. Unit clerks, transport workers, ward aides, dietitians, and oncologists were observed touching contaminated surfaces. A follow-up study documented cyclophosphamide in the urine of these workers, concluding that workers in the drug administration setting, even those who were not responsible for administering the drugs to patients (i.e., volunteers, oncologists, ward aides, and dietitians), had the largest proportion of samples exceeding the limit of detection (LOD) for cyclophosphamide. These results suggest that it is reasonable to expand the list of potentially exposed workers. Recent studies have also begun to examine the impact on families and caregivers of home treatments with HDs; however, the scope of these guidelines is limited to workers in healthcare settings. Significant advances in the awareness of safe handling of HDs have been made since the previous version of these guidelines was published in 2006. NIOSH has created a topics page to maintain a bibliography of NIOSH HD documents, publications on occupational exposure to antineoplastic and other HDs, and research on safe handling drawn from the published literature. After more than 30 years of published guidance, international research indicates that occupational exposure to HDs continues, negative reproductive outcomes continue, and barriers to adherence to safe handling guidance remain. Because newer studies have shown that contamination is widespread in healthcare settings and that more workers than previously thought are exposed, these guidelines should be implemented wherever HDs are received, stored, prepared, transported, administered, or disposed. Comprehensive reviews of the literature covering anecdotal and case reports of surface contamination, worker exposure, and risk assessment are available from NIOSH, the Occupational Safety and Health Administration (OSHA), and individual authors. Reproductive studies on healthcare workers have shown an increase in fetal abnormalities, fetal loss, and fertility impairment resulting from occupational exposure to these potent drugs. An extensive study published in 2012 documented increased spontaneous abortions in nurses exposed to HDs in the workplace. An increase in learning disabilities among offspring as a result of occupational exposure to these potent drugs has also been reported. Antineoplastic drugs and immunosuppressants are some of the types of drugs included on lists of known or suspected human carcinogens by the National Toxicology Program and the International Agency for Research on Cancer. Although the increased incidence of cancers for occupationally exposed groups has been investigated, with varying results, related studies described evidence of drug uptake (drug being incorporated into workers’ bodies) and chromosomal changes in oncology workers exposed to workplaces contaminated with HD residue. The DNA of exposed workers showed a statistically significant increase in the frequency of damage to chromosome 5 or 7 and an increase in frequency of damage to chromosome 5 alone. As signature lesions in chromosomes 5, 7, and 11 have been shown to be associated with chemotherapy treatment-related myelodysplastic syndrome and acute myeloid leukemia, these results provide additional evidence of harmful effects from occupational exposure to HDs. These conclusions are bolstered by recent meta-analyses of comet assay, micronuclei and chromosomal aberration data in healthcare workers that have shown increases in chromosomal damage in workers exposed to antineoplastic drugs. Continuing exposure Before the publication of the 2004 NIOSH Alert, a 1999 study done in 3 cancer treatment centers in the United States and 3 in Canada provided strong evidence of surface contamination with antineoplastic HDs in compounding and infusion areas. Measurable amounts of cyclophosphamide, ifosfamide, and fluorouracil were detected in 75% of the pharmacy wipe samples and 65% of the infusion area wipe samples. The number of positive wipe sampling results was related to the amount of drug prepared and administered. A NIOSH-sponsored study of 3 university-based U.S. cancer centers published in 2010 re-examined HD contamination and other risk points from the 1999 study. The 2010 study measured surface contamination of at least 1 of the 5 drugs (cyclophosphamide, ifosfamide, fluorouracil, paclitaxel, and cytarabine) in 75% of the pharmacy wipe samples and 43% of the infusion wipe samples. The study confirmed that HD contamination is generally widespread, even with engineering controls such as class II biological-safety cabinets (BSCs). Most importantly, this study confirmed that there had been little progress in reducing HD contamination in similar healthcare settings in the United States in the 10 years between the studies. A series of multisite studies on HD contamination was published by a research team in British Columbia. Through interviews and observations, job categories with the potential for HD exposure by dermal contact with potentially contaminated surfaces were identified within 6 medical sites. In addition to those workers traditionally thought to be exposed, workers who had possible dermal contact with HDs included receiving staff, unit clerks, ward aides, and even volunteers. In investigating contaminated surfaces, the researchers noted that although the BSC had the highest frequency of contact in the compounding area, the pen inside the BSC and the isopropyl alcohol spray bottle were frequently touched. I.V. pumps, countertops, and waste containers were the most contacted surfaces in the infusion areas. The team collected surface wipe samples at the participating sites, using cyclophosphamide as the marker drug. Of the 275 surface samples collected, 35% were above the LOD. As in the 2010 U.S. study, the pharmacy compounding areas had the majority of contaminated wipes (47 of 85) and the highest concentration of drug. Additional surface wipe sampling done at the same 6 medical sites produced a total of 438 samples from 55 categories of surfaces in 5 drug handling stages (delivery, preparation, transport, administration, and waste), with 159 (36%) having concentrations above the LOD. The most-contaminated surfaces by stage were the drug delivery elevator button, drug preparation pen (possibly from the BSC), transport bin for drug pickup, drug administration i.v. pump, and waste elevator button. Measurable HD contamination on elevator buttons is concerning for workers, and visitors may also be exposed to this risk. In addition, this research team sought to determine whether healthcare workers from the earlier studies were at risk of cyclophosphamide uptake through dermal contact with contaminated surfaces or by other means. Participants identified from the prior studies as potentially exposed agreed to provide urine samples to quantify the urine concentration of nonmetabolized cyclophosphamide. Cyclophosphamide levels greater than the LOD were found in 55% of urine samples. Participants from departments where drug preparation and drug administration do not occur (i.e., shipping/receiving, transport, nutrition, and materials management) had the highest average urinary concentration levels of cyclophosphamide. When the results were stratified by job title, unit clerks had the highest average urinary cyclophosphamide concentration. The authors identified 2 factors associated with cyclophosphamide uptake: (1) whether a worker had a duty to handle antineoplastic HDs and (2) whether a worker received training on safe drug handling and concluded that interventions to minimize this risk should be more broadly applied. A review of studies of healthcare worker exposure to antineoplastic HDs published in the United States, Canada, and Europe after publication of the 2004 NIOSH HD Alert revealed no decrease in contamination. Numerous studies have shown the presence of HDs in the urine of healthcare workers. In a review of 20 studies from 1992 to 2011 examining biomarkers of exposure in healthcare workers handling antineoplastic HDs, 17 studies found drug in workers’ urine. One of the studies in that review described no response in 50 subjects, but the study did note that all subjects demonstrated post shift exposure to platinum. A study by Wick et al., which was not included in the review, demonstrated that 6 of 8 participants’ 24-hour urine samples had cyclophosphamide and ifosfamide levels above the LOD. Hon et al. collected 201 urine samples from 103 subjects, including those in job categories with low expectation of exposure; 55% had levels exceeding the LOD for cyclophosphamide, with unit clerks having the highest average level. HDs may enter the body through inhalation, dermal absorption, accidental injection, ingestion of contaminated foodstuffs, or mouth contact with contaminated hands. More recent studies, especially those looking at healthcare workers not directly involved with HD compounding and administration, support the theory that dermal contact with contaminated surfaces is the primary route of exposure. An alternative to dermal absorption, where HDs penetrate unprotected skin after contact with contaminated surfaces, is that surface contamination transferred to hands may be ingested via the hand-to mouth route. Researchers have examined hand sampling as a measure of exposure. Using a technique of wipe sampling, similar to that done for work surfaces, healthcare workers’ hands may be swabbed to check for HD contamination. One study of workers at 6 sites analyzed a total of 225 wipe samples, 20% of which were above the LOD for cyclophosphamide. Contaminated hands may transfer HD residue to other surfaces and other workers as well as contribute to hand-to-mouth transfer. Hand sampling may offer an alternative to surface sampling in monitoring. Environment It has long been shown that HD contamination is widespread in healthcare settings, even when primary compounding controls are in place. Hazardous waste containment and disposal EPA hazardous waste regulations have not kept up with drug development, with over 100 chemotherapy drugs not listed by EPA. The recommendation, therefore, is to manage all antineoplastic drugs as hazardous waste through a permitted hazardous waste treatment, storage, and disposal facility. Many drugs described in this document as hazardous are acutely toxic or are known or suspected human carcinogens; many more cause adverse reproductive outcomes. Decades of literature show that HD contamination in the healthcare work environment is absorbed into healthcare workers. Marker HDs have been measured in the urine of workers who routinely handle HDs during the course of patient care. HD levels have also been found in the urine of workers not directly responsible for HD compounding or administration. This continued worker exposure has prompted many groups to advocate that healthcare workers tasked with handling HDs be identified and enrolled in medical screening programs before job placement and periodically during employment and that they be maintained in a systematic medical surveillance program.