Thomas H. Connor

Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers

Objective: This study evaluated health care worker exposure to antineoplastic drugs. Methods: A cross-sectional study examined environmental samples from pharmacy and nursing areas. A 6-week diary documented tasks involving those drugs. Urine was analyzed for two specific drugs, and blood samples were analyzed by the comet assay. Results: Sixty-eight exposed and 53 nonexposed workers were studied. Exposed workers recorded 10,000 drug-handling events during the 6-week period. Sixty percent of wipe samples were positive for at least one of the five drugs measured. Cyclophosphamide was most commonly detected, followed by 5-fluorouracil. Three of the 68 urine samples were positive for one drug. No genetic damage was detected in exposed workers using the comet assay. Conclusions: Despite following recommended safe-handling practices, workplace contamination with antineoplastic drugs in pharmacy and nursing areas continues at these locations.

Preventing Occupational Exposures to Antineoplastic Drugs in Health Care Settings

The toxicity of antineoplastic drugs has been well known since they were introduced in the 1940s. Because most antineoplastic drugs are nonselective in their mechanism of action, they affect noncancerous as well as cancerous cells, resulting in well‐documented side effects. During the 1970s, evidence came to light indicating health care workers may be at risk of harmful effects from antineoplastic drugs as a result of occupational exposure. Since that time, reports from several countries have documented drug contamination of the workplace, identified drugs in the urine of health care workers, and measured genotoxic responses in workers. Evidence also exists of teratogenic and adverse reproductive outcomes and increased cancers in health care workers. During the past 30 years, professional organizations and government agencies have developed guidelines to protect health care workers from adverse effects from occupational exposure to antineoplastic drugs. Although many safety provisions were advanced to reduce worker exposure in the 1980s, recent studies have shown that workers continue to be exposed to these drugs despite safety policy improvements. In 2004, the National Institute for Occupational Safety and Health (NIOSH) published an alert reviewing the most recent information available and promoting a program of safe handling during their use.

Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device

Purpose. Surface contamination with the antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil was compared in 22 US hospital pharmacies following preparation with standard drug preparation techniques or the PhaSeal® closed-system drug transfer device (CSTD). Methods. Wipe samples were taken from biological safety cabinet (BSC) surfaces, BSC airfoils, floors in front of BSCs, and counters and analyzed for contamination with cyclophosphamide, ifosfamide, and 5-fluorouracil. Contamination was reassessed several months after the implementation of the CSTD. Surface contamination (ng/cm2) was compared between the two techniques and evaluated with the Signed Rank Test. Results. Using the CSTD compared to the standard preparation techniques, a significant reduction in levels of contamination was observed for all drugs (cyclophosphamide: p < 0.0001; ifosfamide: p < 0.001; 5-fluorouracil: p < 0.01). Median values for surface contamination with cyclophosphamide, ifosfamide, and 5-fluorouracil were reduced by 95%, 90%, and 65%, respectively. Conclusions. Use of the CSTD significantly reduces surface contamination when preparing cyclophosphamide, ifosfamide, and 5-fluorouracil as compared to standard drug preparation techniques.

Hazardous anticancer drugs in health care: environmental exposure assessment.

Abstract:  Exposure of healthcare workers to anticancer drugs became problematic in the 1970s. Shortly thereafter, studies began documenting exposure of healthcare workers to these drugs. Investigations employing biological markers, such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, and micronuclei, demonstrated associations between occupational exposures and elevated marker levels. Other analytical methods emerged to monitor workplaces where drugs were handled. These contemporary studies uncovered widespread contamination of drugs on work surfaces, trace amounts in air samples, and their presence in the urine of workers. Vials containing these drugs are often contaminated with the drug when they are shipped. Most workplace surfaces are contaminated with the drugs being prepared and used in that area. Other anticancer/hazardous drugs would most likely be used in these areas. The interior surfaces of biological safety cabinets and isolators, floors, countertops, carts, storage bins, waste containers, treatment areas, tabletops, chairs, linen, and other items are all potential sources of exposure to anticancer drugs. Patient body fluids contain the drugs and/or metabolites, often more biologically active than the parent compounds. An exposure assessment of areas where anticancer/hazardous drugs are handled must consider every potential source and route of exposure. Data from surface contamination and inhalation studies suggest that dermal exposure is the primary route of exposure. Assessment of exposure is the first step in providing a safe work environment for these workers. However, because of the many drugs to which they are exposed, any assessment can only be an estimation of the overall exposure.

Reproductive health risks associated with occupational exposures to antineoplastic drugs in health care settings: a review of the evidence.

Objectives:Antineoplastic drugs are known reproductive and developmental toxicants. Our objective was to review the existing literature of reproductive health risks to workers who handle antineoplastic drugs. Methods:A structured literature review of 18 peer-reviewed, English language publications of occupational exposure and reproductive outcomes was performed. Results:Although effect sizes varied with study size and population, occupational exposure to antineoplastic drugs seems to raise the risk of both congenital malformations and miscarriage. Studies of infertility and time to pregnancy also suggested an increased risk for subfertility. Conclusions:Antineoplastic drugs are highly toxic in patients receiving treatment, and adverse reproductive effects have been well documented in these patients. Health care workers with long-term, low-level occupational exposure to these drugs also seem to have an increased risk of adverse reproductive outcomes. Additional precautions to prevent exposure should be considered.

Sampling and mass spectrometric analytical methods for five antineoplastic drugs in the healthcare environment

Context. Healthcare worker exposure to antineoplastic drugs continues to be reported despite safe handling guidelines published by several groups. Sensitive sampling and analytical methods are needed so that occupational safety and health professionals may accurately assess environmental and biological exposure to these drugs in the workplace. Objective. To develop liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analytical methods for measuring five antineoplastic drugs in samples from the work environment, and to apply these methods in validating sampling methodology. A single method for quantifying several widely used agents would decrease the number of samples required for method development, lower cost, and time of analysis. Methods for measuring these drugs in workers’ urine would also be useful in monitoring personal exposure levels. Results. LC-MS/MS methods were developed for individual analysis of five antineoplastic drugs in wipe and air sample media projected for use in field sampling: cyclophosphamide, ifosfamide, paclitaxel, doxorubicin, and 5-fluorouracil. Cyclophosphamide, ifosfamide, and paclitaxel were also measured simultaneously in some stages of the work. Extraction methods for air and wipe samples were developed and tested using the aforementioned analytical methods. Good recoveries from the candidate air and wipe sample media for most of the compounds, and variable recoveries for test wipe samples depending on the surface under study, were observed. Alternate LC-MS/MS methods were also developed to detect cyclophosphamide and paclitaxel in urine samples. Conclusions. The sampling and analytical methods were suitable for determining worker exposure to antineoplastics via surface and breathing zone contamination in projected surveys of healthcare settings.

Exposure to hazardous drugs in Healthcare: An issue that will not go away

The Journal of Oncology Pharmacy Practice (JOPP) was first published in June 1995 as the official journal of the International Society of Oncology Pharmacy Practitioners (ISOPP). In a supplement to that issue, as part of a review of the ISOPP IV symposium presentations, an article by Professor Graham Sewell was included titled ‘Pharmaceutical issues: preparation and handling’. This article raised concerns about various aspects of quality and safety associated with cytotoxic drug reconstitution. It discussed the use of cytotoxic safety cabinets versus isolators, the use of early ‘closed systems’ and even the possible future use of robotics. In the 15 years since that first publication, interest in the handling of hazardous drugs used to treat cancer patients has not waned. At the recent ISOPP XII symposium held in Prague in May 2010, ten presentations and seven submitted abstracts on the topic of safe handling were included. From the highly technical use of robotics and the use of specialized closed systems to the basic use of personal protective equipment (PPE) in under-resourced countries, this subject remains highly topical. One reason for the interest in this topic is the inability to quantify the occupational risk of handling anticancer drugs. It is well recognized that patients treated with therapeutic doses of these drugs may develop second cancers years later. However, the risk associated with long-term very low level exposure to these agents is not currently measurable. A basic tenet of employment is the provision of a safe workplace. It may be impossible to remove all risk but it is imperative that risk is minimized. Large pharmaceutical companies manufacturing anti-cancer drugs do so in totally enclosed environments with workers wearing full respirator suits reminiscent of movies of outbreaks of a deadly virus. But it is financially completely beyond individual hospitals, institutions and clinics to supply such protective equipment. The smaller the preparation facility, the less viable it is to introduce expensive protective measures. Many pharmaceutical companies have improved the presentation of their anti-cancer drug products in several ways. The drugs are generally presented, when stability allows, in liquid form – this means less manipulation is required to prepare a dose. The drugs are generally packaged in plastic containers – this means less chance of vial breakage. When compatibility problems arise and do not permit plastic packaging, and glass containers are required, these are generally protected in some way to avoid breakage and leakage e.g., an ‘overcoat’ of plastic is placed over the vial. These improvements in packaging are applauded. However, it is known that external chemical contamination of drug vials arriving from the manufacturer is a problem. Manufacturers must accept responsibility for ensuring that only clean product leaves their facilities. It is discouraging when every safeguard is taken to protect staff preparing anti-cancer drugs, to find that a major source of contamination is the outside of the drug vials themselves. Before we place all the responsibility onto the manufacturers, we must first ensure that we are doing everything possible ourselves to reduce the contamination of the environment and ourselves and we still have quite a long way to go. The paper by Shin-ichi Sugiura et al. ‘Risks to health professionals from hazardous drugs in Japan: a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide’ in this issue of The Journal describes a pilot study performed in 2006 looking at cytotoxic drug environmental contamination in two similar hospital departments.

Surface wipe sampling for antineoplastic (chemotherapy) and other hazardous drug residue in healthcare settings: Methodology and recommendations.

ABSTRACT Surface wipe sampling for various hazardous agents has been employed in many occupational settings over the years for various reasons such as evaluation of potential dermal exposure and health risk, source determination, quality or cleanliness, compliance, and others. Wipe sampling for surface residue of antineoplastic and other hazardous drugs in healthcare settings is currently the method of choice to determine surface contamination of the workplace with these drugs. The purpose of this article is to review published studies of wipe sampling for antineoplastic and other hazardous drugs, to summarize the methods in use by various organizations and researchers, and to provide some basic guidance for conducting surface wipe sampling for these drugs in healthcare settings.  Recommendations on wipe sampling methodology from several government agencies and organizations were reviewed. Published reports on wipe sampling for hazardous drugs in numerous studies were also examined. The critical elements of a wipe sampling program and related limitations were reviewed and summarized.  Recommendations and guidance are presented concerning the purposes of wipe sampling for antineoplastic and other hazardous drugs in the healthcare setting, technical factors and variables, sampling strategy, materials required, and limitations. The reporting and interpretation of wipe sample results is also discussed.  It is recommended that all healthcare settings where antineoplastic and other hazardous drugs are handled consider wipe sampling as part of a comprehensive hazardous drug “safe handling” program. Although no standards exist for acceptable or allowable surface concentrations for these drugs in the healthcare setting, wipe sampling may be used as a method to characterize potential occupational dermal exposure risk and to evaluate the effectiveness of implemented controls and the overall safety program. A comprehensive safe-handling program for antineoplastic drugs may utilize wipe sampling as a screening tool to evaluate environmental contamination and strive to reduce contamination levels as much as possible, using the industrial hygiene hierarchy of controls.

Safe handling of oral antineoplastic medications: Focus on targeted therapeutics in the home setting

Introduction With the growing number of oral targeted therapies being approved for use in cancer therapy, the potential for long-term administration of these drugs to cancer patients is expanding. The use of these drugs in the home setting has the potential to expose family members and caregivers to them either through direct contact with the drugs or indirectly by exposure to the parent compounds and/or their active metabolites in contaminated patients’ waste. Methods A systematic literature review was performed and the known adverse health effect of 32 oral targeted therapeutics is summarized. In particular, the carcinogenicity, genotoxicity, and embryo-fetal toxicity, along with the route of excretion were evaluated. Results Carcinogenicity testing has not been performed on most of the oral targeted therapeutics and the genotoxicity data are mixed. However, the majority of these drugs exhibit adverse reproductive effects, some of which are severe. Currently, available data does not permit the possibility of a health hazard from inappropriate handling of drugs and contaminated patients waste to be ignored, especially in a long-term home setting. Further research is needed to understand these issues. Conclusions With the expanding use of targeted therapies in the home setting, family members and caregivers, especially those of reproductive risk age, are, potentially at risk. Overall basic education and related precautions should be taken to protect family members and caregivers from indirect or direct exposure from these drugs. Further investigations and discussion on this subject are warranted.

Detection and measurement of surface contamination by multiple antineoplastic drugs using multiplex bead assay

Objectives Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) are sensitive and accurate but expensive. Since immunochemical methods may be cheaper and faster than instrumental methods, we wanted to explore their use for routine drug residue detection for preventing worker exposure. Methods In this study we examined the feasibility of using fluorescence covalent microbead immunosorbent assay (FCMIA) for simultaneous detection and semi-quantitative measurement of three antineoplastic drugs (5-fluorouracil, paclitaxel, and doxorubicin). The concentration ranges for the assay were 0–1000 ng/ml for 5-fluorouracil, 0–100 ng/ml for paclitaxel, and 0–2 ng/ml for doxorubicin. The surface sampling technique involved wiping a loaded surface with a swab wetted with wash buffer, extracting the swab in storage/blocking buffer, and measuring drugs in the extract using FCMIA. Results There was no significant cross-reactivity between these drugs at the ranges studied indicated by a lack of response in the assay to cross analytes. The limit of detection (LOD) for 5-fluorouracil on the surface studied was 0.93 ng/cm2 with a limit of quantitation (LOQ) of 2.8 ng/cm2, the LOD for paclitaxel was 0.57 ng/cm2 with an LOQ of 2.06 ng/cm2, and the LOD for doxorubicin was 0.0036 ng/cm2 with an LOQ of 0.013 ng/cm2. Conclusion The use of FCMIA with a simple sampling technique has potential for low cost simultaneous detection and semi-quantitative measurement of surface contamination from multiple antineoplastic drugs.