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) R - M Fate of Cell +Cellular Macromolecules (M) Normal Death Mutant Transformed (potential cancer) Harris: Cancer 1976
Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents Developmental Toxicity Genotoxicity Animal Drug Class T E Human PM CE Alkylating Agents + + + + + Antibiotics + + + + + Antimetabolites + + + + + Mitotic Function + + + - + Topoisomerase II Function + + + + + (+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects
These Drugs are: The Antineoplastic Drug Hazard 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 All malignant neoplasms (ICD-7 140-205) SITE OBS EXP RR (95% CI) Lymphatic and heamatopoietic Issues (ICD-7 200-205) 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 (1.29-38.5) Mycosis fungoides (ICD-7 205) 0 0.01 - - From Skov, et al: Br.J.Int.Med. 1992,49:860
Relative Risk for Leukaemia and Non- Hodgkin Lymphoma among Danish Physicians Handling Antineoplastic Drugs Site CASES Exposed Nonexposed REFERENTS Exposed Nonexposed 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 Drug Compounding Patient Treatment Area Waste Disposal Waste Collection 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 t- MDS/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%
Pharmacy Surface Wipe Samples
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?