EXPOSURE TO ANTINEOPLASTIC AGENTS IN THE PHARMACY LABORATORY SETTING AND ONGOING NIOSH STUDIES THOMAS H. CONNOR, Ph.D. Senior Service Fellow National Institute for Occupational Safety and Health Cincinnati, OH

EXAMPLES OF HAZARDOUS DRUGS l Antineoplastic agents l Antiviral agents l Hormonal agents l Immunosuppressant agents l Some antibiotics

DEFINITION OF HAZARDOUS DRUGS l Carcinogenicity l Teratogenicity/developmental toxicity l Reproductive toxicity l Organ toxicity at low doses l Genotoxicity l Structure/activity similar to known hazardous drug

ANTINEOPLASTIC AGENTS RECENT CONCERNS l More cancer patients l More combinations of drugs l Higher doses of drugs l More potent drugs l New procedures/settings

ANTINEOPLASTIC AGENTS l Agents l Alkylating agents l Antibiotics l Antimetabolites l Biologicals l Hormonal agents l Monoclonal antibodies l Nitrogen mustard derivatives l Plant alkaloids l Others

CARCINOGENICITY OF ANTINEOPLASTIC AGENTS IARC Classification l Class 1 (human carcinogen) 9 plus 2 combinational therapies l Class 2A (probable human carcinogen) 9 l Class 2B (possible human carcinogen) 10 l Combinational therapies currently being evaluated by IARC

POTENTIALLY EXPOSED GROUPS l Workers in manufacturing l Pharmacists and technicians l Nursing personnel l Physicians l Operating room personnel l Housekeeping and laundry personnel l Veterinarians l Retail pharmacists

NATURE OF THE PROBLEM l Primary concern is for the safety of the patient n Drugs must be prepared aseptically n Contamination can be fatal to the patient l Secondary concern is the safety of the healthcare worker n Exposure to hazardous drugs must be kept as low as possible n Many opportunities for exposure

WORKER PROTECTION l Horizontal cabinets should not be used for hazardous drug preparation l Class II or Class III BSCs (+/-) must be used l Vented BSCs recommended l Leur-lock, needle-less and closed systems should be used for preparation and administration

ROUTES OF EXPOSURE l INHALATION n Droplets/particulates n Vapors l DERMAL l ORAL

COMMON SOURCES OF EXPOSURE l DRUG PREPARATION n Drug dilution and transfer l DRUG ADMINISTRATION n Priming tubing n Disconnecting lines n Instillation procedures l DISPOSAL OF DRUGS AND WASTE n Emptying waste containers and cleaning contaminated areas

SURFACE CONTAMINATION STUDY l SIX CANCER CENTERS IN U.S. AND CANADA l PHARMACIES AND TREATMENT AREAS l THREE DRUGS-CP, FU, IF l BSCs, COUNTERS, CARTS, FLOORS, CHAIRS, TABLES l 75 % PHARMACY AND 65 % TREATMENT AREA SAMPLES POSITIVE FOR AT LEAST ONE DRUG l ADJACENT AREAS CONTAMINATED Connor et al, AJHP (1999)

DRUG RECONSTITUTION WITH NEEDLE AND SYRINGE

DRUG TRANSFER WITH NEEDLE AND SYRINGE

OTHER SOURCES OF EXPOSURE l CONTACT WITH CONTAMINATED SURFACES n Drug vials, counter tops, keyboards, IV bags, tables, chairs, waste containers l CONTAMINATION IN AREAS THOUGHT TO BE DRUG-FREE n Locations adjacent to work areas l POSSIBLE PASSAGE THROUGH HEPA FILTERS n Vapors

FLOOR CONTAMINATION FROM CYCLOPHOSPHAMIDE SPILL DAYS NG/CM 2

OCCUPATIONAL MONITORING l WIPE SAMPLES n Since 1992, 13 studies reported in literature l AIR SAMPLES n Since 1983, 12 studies reported in literature

OCCUPATIONAL MONITORING l WIPE SAMPLES n All studies that have used wipe samples to monitor environmental contamination have demonstrated measurable levels of the drugs. n 1-5 Drugs sampled

OCCUPATIONAL MONITORING l WIPE SAMPLES n Drugs that are commonly used for wipe sample studies – Cyclophosphamide – Ifosfamide – Fluorouracil – Methotrexate

OCCUPATIONAL MONITORING l WIPE SAMPLES n Locations that have been sampled – Pharmacy and Preparation areas – Treatment Areas – Adjacent Areas

OCCUPATIONAL MONITORING l AIR SAMPLING n Drugs that are commonly used for air sampling – Cyclophosphamide – Ifosfamide – Fluorouracil

OCCUPATIONAL MONITORING l AIR SAMPLING n Air sampling often does not detect drugs or detects low levels of drugs n May be due to technical problems – Glass fiber or paper filter materials – Drugs in vapor phase

OCCUPATIONAL MONITORING l URINE ANALYSIS FOR SELECTED DRUGS n Most studies have been performed in Europe n In 18 studies, all but two studies detected drugs in the urine n In four studies, drugs were found in the urine of workers who were not handling them

OCCUPATIONAL MONITORING l URINE ANALYSIS FOR SELECTED DRUGS n Approximately 100 individuals/3years n 14 German hospitals n Cyclophosphamide 40% n Ifosfamide 14% n Anthracyclines 4.5% Pethran et al, Int Arch Occup Environ Health (2003)

DERMAL EXPOSURE PATHWAY l THREE WORKPLACE SURVEYS n Contamination from IV systems n Contamination from patient urine n Analysis of air particulates Kromhout et al, Ann Occup Health (2000)

SOURCES OF EXPOSURE l CONTAMINATION FROM PATIENT URINE n Added a fluorescent material to bedpans and urinals to track possible drug contamination n Frequent and widespread contamination was seen… n Soles of shoes n Skin of patients and nurses

CURRENT NIOSH ACTIVITIES l PERSONAL PROTECTIVE EQUIPMENT STUDY n ASTM Standard for Chemotherapy Gloves n Four drugs n Several types of glove/gown materials

CURRENT NIOSH ACTIVITIES l NIOSH ALERT ON HAZARDOUS DRUGS n All hazardous drugs n Focus on antineoplastic drugs n Release expected summer, 2003

CURRENT NIOSH ACTIVITIES l NIOSH WORKING GROUP ON HAZARDOUS DRUGS n NIOSH, OSHA, FDA, VA n ONS, ASHP, ASTM, ANA, JCAHO n PHARMACISTS, NURSES, HOME HEALTH CARE n DRUG, BSC MANUFACTURERS n RESEARCHERS

CURRENT NIOSH ACTIVITIES l OCCUPATIONAL EXPOSURE STUDY OF HEALTHCARE WORKERS n 3-4 Institutions n Pharmacy and nursing personnel n Minimum 50 exposed/50 non-exposed n Several environmental and biological endpoints

CURRENT NIOSH ACTIVITIES l VIAL CONTAMINATION STUDY n 4-6 Drugs n Wipe outside of vials n Determine extent of contamination of vials

Thomas H. Connor, Ph.D. OCCUPATIONAL EXPOSURE RELATED TO ANTINEOPLASTIC AGENTS