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Chromosome Effects in Oncology Workers Handling Chemotherapy Agents and Implications for Safe Handling REGIONAL OCCUPATIONAL HEALTH CONFERENCE Saturday, October 18, 2014 Laurel, MD Melissa A. McDiarmid, MD, MPH, DABT University of Maryland School of Medicine Division of Occupational and Environmental Health Historical Background Mustard gas development WWI Alkylating agents used clinically 1940’s Regular part of cancer treatment 1960’s Second malignancies reported 1970’s Falck report – mutagenicity 1979 ASHP Safe Handling Guidelines 1985 Mechanism of Action of Selected Classes of Antineoplastic Agents Topoisomerase II Inhibitors •Damage DNA •Prevent repair (Adapted) From: McDiarmid, MA. Antineoplastics, Anesthetic Agents, Sex Steroid Hormones in Paul, M Occupational and Environmental Reproductive Hazards, 1993. Anticancer drug Chemical Oncogene Electrophilic Reactant (R) +Cellular Macromolecules (M) R-M Fate of Cell Normal Harris: Cancer 1976 Death Mutant Transformed (potential cancer) Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents Drug Class Alkylating Agents Developmental Toxicity Animal T E Human + + + Genotoxicity PM + CE + Antibiotics + + + + + Antimetabolites + + + + + Mitotic Function + + + - + Topoisomerase II Function + + + + + (+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects The Antineoplastic Drug Hazard These Drugs are: • 18 (16+2) of 107 IARC Group I (Human Carcinogens) • 11 of 58 Group 2As (Probable Carcinogens) • 13 of 249 Group 2Bs (Possible Carcinogens) • Well documented reproductive and developmental toxicants in animals and humans (Alkylating Agents, Antimetabolites); some male-mediated • Associated with biologically plausible health effects in studies of exposed populations (myelodysplastic syndrome, ‘secondary malignancies’) http://content.nejm.org/cgi/content/full/352/15/1591/T1 ROUTES OF EXPOSURE • INHALATION – Droplets/particulates – Vapors • DERMAL • ORAL Incidence of Cancer among Nurses Handling Antineoplastic Drugs in Oncology Departments SITE OBS EXP RR (95% CI) 14 11.69 1.20 (0.65-2.01) 3 0.56 5.37 (1.11-15.7) NHL (ICD-7 200, 202) 0 0.20 - - Hodgkin's disease (ICD-7 201) 1 0.12 8.35 (0.21-46.5) Multiple myeloma (ICD-7 203) 0 0.05 - - Leukemia (ICD-7 204) 2 0.19 10.65 Mycosis fungoides (ICD-7 205) 0 0.01 - All malignant neoplasms (ICD-7 140-205) Lymphatic and heamatopoietic Issues (ICD-7 200-205) From Skov, et al: Br.J.Int.Med. 1992,49:860 (1.29-38.5) - Relative Risk for Leukaemia and NonHodgkin Lymphoma among Danish Physicians Handling Antineoplastic Drugs CASES Site REFERENTS Exposed NonExposed Nonexposed exposed RR* (95%CI) Leukaemia 3 17 6 74 2.85(0.51-16.02) Non-Hodgkin lymphoma 2 23 10 90 0.74(0.13-4.26) Both sites combined 5 40 16 164 1.39(0.41-4.75) *Adjusted for sex and age by conditional logistic regression analysis of matched pairs. from Skov, et al; The Lancet Dec. 8, 1990. Receiving and Storage Waste Disposal Drug Compounding Waste Collection Patient Treatment Area Laundry NIOSH estimates > 8 million workers are exposed to Hazardous Drugs. Rationale for Study • Many positive biomonitoring studies of exposed oncology workers revealed uptake of anticancer drugs measured in urine, including some in non-drug handlers. • Previous studies have shown excesses in non-specific measures of genotoxic outcomes (SCE, MN, total CAs). • No previous study has looked for the ‘signature’ chromosomal lesions associated with tMDS/t-AML on Chromosomes 5,7, and 11 in workers. NIOSH Health Care Worker Study • Multicenter study • Three health care facilities – University of Maryland, Baltimore – University of North Carolina, Chapel Hill – University of Texas MD Anderson Cancer Center, Houston • Collaborator – John Hopkins University, Baltimore Genetic Pathways in t-MDS and t-AML Figure 1. Pedersen-Bjergaard, J. et al. Blood 2002;99:1909-1912 FISH Detection of Deletion Health Care Worker Study Inclusion/Exclusion Criteria • Inclusion: – Age 18-50 – > 6 month history of handling drugs – 24hrs. working in week prior to sampling – Non-exposed employed in same job title w/o drug handling • Exclusion: – Current smokers – Current/previous treatment with chemotherapeutics or XRT – Current treatment with other genotoxic meds. (e.g., accutane, hormones) Exposure Frequency from Diary of Drug Handling Events • • • • • • • • Compounding/Preparing Checking (Dose/calculations) Infusion IV Push Prime Tubing Spill Splash Urine/vomit exposure From McDiarmid, et al. (2010) JOEM 52:(10)1028-1034 From McDiarmid, et al. (2010) JOEM 52:(10)1028-1034 Results-Wipe Samples • Total Number – Pharmacy-80 – Nursing-65 • >LOD for at least 1 Drug – Pharmacy-75% – Nursing-43% Surface Wipe Samples • Pharmacy Surface Wipe Samples • Pharmacy – Work surface of BSCs Surface Wipe Samples • Pharmacy – Airfoil of BSCs Surface Wipe Samples • Pharmacy – Counter tops Surface Wipe Samples • Pharmacy – Waste containers Surface Wipe Samples • Pharmacy – Drug trays Surface Wipe Samples • Pharmacy – Pass-through windows Surface Wipe Samples • Pharmacy – Floors Surface Wipe Samples • Nursing – – – – – – Nursing Station IV Bag Storage Floors Patient Rooms Waste Containers Results-Wipe Samples • Total Number – Pharmacy-80 – Nursing-65 • >LOD for at least 1 Drug – Pharmacy-75% – Nursing-43% Biologic Monitoring Results for Drug in Urine • 2/63 samples positive for cyclophosphamide • 1/63 samples positive for paclitaxel Statistical Analyses CA frequency examined as a function of frequency of drug handling: 1. Categorical variable (no, lo, hi) exposure 2. Continuous variable (# drug handling events) Categorical Analysis Results No differences in CA frequency when comparing the exposed to the non-exposed. From McDiarmid, et al. (2010) JOEM 52:(10)1028-1034 Continuous Variable Results • Used Poisson regression to model association between drug handing events and CAs. • Used Incidence Rate Ratio (IRR) statistic • Compared CAs at specific handling event frequencies to the non-exposed. From McDiarmid, et al. (2010) JOEM 52:(10)1028-1034 From McDiarmid, et al. (2010) JOEM 52:(10)1028-1034 From McDiarmid, et al. Environmental and Molecular Mutagenesis 55:369374374 (2014) Elements of Existing Guidelines Include a Combination of Controls: • Engineering Controls/Closed System • Work Practices/Administrative Controls • PPE • Training • Medical Surveillance http://www.cdc.gov/niosh/docs/2004-165/ NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 DHHS (NIOSH) Publication No. 2010-167 (September 2010) NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2014 DHHS (NIOSH) Publication No. 2014-138 (September 2014) NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2014 DHHS (NIOSH) Publication No. 2014-138 (September 2014) Medical Surveillance for Healthcare Workers Exposed to Hazardous Drugs DHHS (NIOSH) Publication No. 2013-103 (2013) - supersedes 2007-117 November 2012 (http://www.cdc.gov/niosh/docs/wp-solutions/2013-103/) Summary • Biologically important exposure to genotoxic drugs is occurring in oncology work settings • Resulting in a dose dependent increase in chromosomal aberrations in exposed healthcare workers • Despite hospital “endorsement” of ‘Safe Handling Practices’ THANKS Questions?
