1212569_21823227.jpg logo_mu_cerne.gif 1212570_28446780.jpg logo_mu_cerne.gif Cytotoxic drugs adverse effects, risks, monitoring Luděk Bláha, Lenka Doležalová, Pavel Odráška RECETOX, Masaryk University, Brno, Czech Republic Masaryk Memorial Cancer Institute, Brno, Czech Republic www.mou.cz 1212569_21823227.jpg logo_mu_cerne.gif CYTO project - Czech Republic http://www.cytostatika.cz n2006-2010, specific research grant 2B06171 ØHospital pharmacy ØPharma company Ø~ 3 full time persons n Objectives üstudy / evaluate occupational risks of cytostatics in the Czech Republic (pharmacies) üto evaluate existing measures & suggest possible improvements üsuggest (reasonable) monitoring procedures New Image 1212569_21823227.jpg logo_mu_cerne.gif n„Hazards“ (will be discussed in detail) n nGenotoxicity (urine mutagenicity, micronuclei) n nReproduction toxicity nTeratogenicity / developmental toxicity n nOrgan toxicity at low doses (hepatotoxicity, immunotoxicity) n nCarcinogens (13 therapies - IARC class 1) • CYTOTOXIC DRUGS - „hazardous drugs“ 1212569_21823227.jpg logo_mu_cerne.gif n„Hazards“ cytotoxic drugs may cause adverse effects nPresent situation – increased occupational risks nMore patients with malignant tumors nMore treatments and their combinations, higher doses nDrugs with higher efficiency, new procedures n nSource of the occupational „hazard“ problem nPrimary focus – safety of the patient nQA/QC in preparation, microbiological safety … nSecondary … workers safety (pharmacists etc.) CYTOTOXIC DRUGS - „hazardous drugs“ 1212569_21823227.jpg logo_mu_cerne.gif •Hazard: inherent capacity of a chemical to cause effects •Risk: probability of the effect occurrence • Risk Assessment - definitions 1212569_21823227.jpg logo_mu_cerne.gif risk 1 Exposure to HAZARD RISK Examples – HAZARD vs. RISK 1212569_21823227.jpg logo_mu_cerne.gif •Goal: identification of the adverse effects which a substance has the inherent capacity to cause •Method: gathering and evaluating data on the types of health effects or disease that may be produced by a chemical and exposure conditions under which damage, injury or disease will be produced • •Hazard of cytotoxic drugs – 2 scenarios –Therapeutic doses (patients) –Occupational exposures (workers) Risk Assessment step 1: Hazard identification 1212569_21823227.jpg logo_mu_cerne.gif Hazard - carcinogenicity Group 1 (Carcinogenic to humans) Group 2A (Probably carcinogenic) IARC - INTERNATIONAL AGENCY FOR RESEARCH ON CANCER www.iarc.fr 1212569_21823227.jpg logo_mu_cerne.gif Hazards – effects observed at THERAPEUTIC doses US Food & Drug Administration (FDA) – Drug hazard during pregnancy REPRODUCTION RELATED EFFECTS - Reproduction toxicity - Developmental toxicity (embryotoxicity, teratogenicity) Other organs-specific toxicity - Hepatotoxicity, Renal toxicity, Cardiotoxicity … - Growing tissues (cell replication) – Dermal, Hair, GIT, Haemopoesis (Immunotox.) 1212569_21823227.jpg logo_mu_cerne.gif US FDA 45 drugs – „D“ 5 drugs „X“ 1212569_21823227.jpg logo_mu_cerne.gif •Some studies indicate „risks“ •K. Falck et al.: Mutagenicity in urine of nurses handling cytostatic drugs. Lancet, 1979;1:1250-1251 •R.W. Anderson et al. Risk of handling injectable antineoplastic agents. Am J Hosp Pharm 1982;39:1881-1887 (mutagens in urine) •Barbara G. Valanis et al.: Association of antineoplastic drug handling with acute adverse effects in pharmacy personnel. Am J Hosp Pharm 1993;50:455-462 (hair loss, headache, irritations, miscarriage) •Saurel-Cubizolles et al. Ectopic Pregnancy and Occupational Exposure to Antineoplasic Drugs. The Lancet, Vol.341:May 8, 1993. 11691171. … (cytostatics - 10% increased risk of 95% CI = (1.02 – 56.2), P=0.02) •Skov et al.: Risk for physicians handling antineoplastic drugs. Lancet 1990;336: 1446 (leukemia risk – 2.85, 95% CI = (0,51– 16,02)) • •Some studies don’t… •Valanis et al. Occupational Exposure to Antineoplastic Agents: Self-Reported Miscarriages and Stillbirth Among Nurses and Pharmacists. J of Occup & Environ Med 41(8):638,1999 (no significant effect of cytostatics) • Effects at lower doses ? (occupational exposure) 1212569_21823227.jpg logo_mu_cerne.gif ‘Hazard’ identification Exposure assessment (DI) Effect assessment (PNEL) Risk characterisation DI / PNEL Quality criteria (safe levels) Risk assessment – principal steps Yes, hazard of cytotoxic drugs identified 1212569_21823227.jpg logo_mu_cerne.gif •Purpose: assessment or prediction of the exposure dose (concentration) of a chemical • •Methods –monitoring and/or prediction (models) –accounting for release, pathways and rates of movement of the substance, its transformation and degradation • •Result: –Predicted Exposure Concentration - PEC –Human: Daily Intake - DI (dose …) EXPOSURE assessment 1212569_21823227.jpg logo_mu_cerne.gif •Purpose: assessment of concentrations (doses) that may cause toxic effects • •Method: –Toxicological studies –Epidemiological studies • •Result: –Humans: Tolerable Daily Intake – TDI Predicted No Effect Level - PNEL –Predicted No Effect Concentration - PNEC – EFFECT assessment 1212569_21823227.jpg logo_mu_cerne.gif 1 Effect assessment Toxicological studies Dose-Response relationship Assessment of LD50 & „safe“ values (LOEC, NOEC) 1212569_21823227.jpg logo_mu_cerne.gif •No threshold for carcinogens exists (no safe value can be established) • –Each dose (single molecule) is considered effective / genotoxic • –Doses only increase probability of the cancer development EFFECT assessment – carcinogens … a special case 1212569_21823227.jpg logo_mu_cerne.gif 1 Mutagens Carcinogens Other (general) toxicants 1212569_21823227.jpg logo_mu_cerne.gif Effect characterization for carcinogens •Derivation of the slope factor (SF) –SF [mg . kg b.w. -1 . day-1] –Higher SF -> more effective carcinogen • • SF1 SF2 1212569_21823227.jpg logo_mu_cerne.gif •Purpose: integration of the three previous steps –Hazard ID –PNEC and PNEL –PEC and TDI • •Method – calculation for traditional chemicals: –Human: DI (Intake) / PNEL (Safe level) = Margin of Safety= MOS •(or Hazard Index …) –Environment: PEC/PNEC ratio = risk quotients = RCR • Risk CHARACTERIZATION 1212569_21823227.jpg logo_mu_cerne.gif Hazard identification Base set of data Exposure assessment Effects assessment DI PNEL Risk characterisation DI / PNEL > 1 < 1 Risk CHARACTERIZATION 1212569_21823227.jpg logo_mu_cerne.gif RISK CALCULATION for carcinogens •Slope factor (SF) –SF - mg . kg b.w. -1 . day-1 –Higher SF -> more effective carcinogen • • •RISK = SF x CDI = probability (e.g. 2x10-5) –CDI - chronic daily intake (averaged 70years) •Result = „extra cancer incidences“ • •Question: what risk of cancer is „acceptable“ ? 1212569_21823227.jpg logo_mu_cerne.gif Risk MANAGEMENT 1212569_21823227.jpg logo_mu_cerne.gif CYTOTOXIC DRUGS ASSESSMENT and MANAGEMENT of RISKS 1212569_21823227.jpg logo_mu_cerne.gif nOccupational / work safety (current laws no. 309/2006 coll., 361/2007 coll.) n General work with any type of carcinogen (cystostatics are considered carcinogens) Employer duties - manipulation in controlled & protected areas - to adapt measures that minimize exposures - e.g. break after 2h of work, minimum 15min … - analytical procedures to detect contamination - monitoring of workers’ health status ! No details on analytics, monitoring … Safety of cytotoxic drugs – example EU (Czech Rep.) 1212569_21823227.jpg logo_mu_cerne.gif •Drug preparation • •Storage •Transport • •Administration • •Waste management •Sanitation • Hazardous activities à EXPOSURE 1212569_21823227.jpg logo_mu_cerne.gif •Major routes of exposure to cytotoxic drugs • •AIR –Aspiration of drugs (gaseous phase, bound to particules, aerosols) – •Surfaces - hand contamination –Direct permeation of skin –Hands -> mouth : food - accidental ingestion • EXPOSURE PATHWAYS 1212569_21823227.jpg logo_mu_cerne.gif •What to monitor ? • •Drug levels –In the air –On the surfaces –In workers (blood, urine) – •Effects (? of the drugs or other factors ?) –Health status –Biomonitoring (e.g. lymphocyte cytogenetics) • Assessment of the exposure - MONITORING 1212569_21823227.jpg logo_mu_cerne.gif n„Genotoxic“ changes in exposed persons nChromosomal aberations in blood leukocytes nMicronuclei formation nDNA damage (comet assay) n… and many others n nRather non-specific nCannot be directly linked to occupational exposures nOther variables more significant (e.g. smoking, lifestyle) n nRelationships to health consequences (?) nDNA damage does not mean cancer Notes on biomonitoring 1212569_21823227.jpg logo_mu_cerne.gif Biomonitoring DNA damage (comet assay) Int Arch Occup Environ Health (2006) 80:134-140 DNA damage in lymphocytes 1212569_21823227.jpg logo_mu_cerne.gif •- Physico-chemical properties of the compound determine evaporation, aerosol formation etc. • - limited data available • •- Stability in the air ? (? Oxidation, photodegradation ?) •- Air circulation & distribution, air-conditioning ? • - site specific, usually no information • •Protection (partial) - Safety cabinets, isolators AIR CONTAMINATION (?) 1212569_21823227.jpg logo_mu_cerne.gif Vapour pressure [Pa] Paclitaxel 0.024 Doxorubicin 0.002 Dacarbazin 0.004 Ethanol 5 851 •Generally low numbers … BUT ! IN EQUILIBRIA (closed system) values correspond to milligrams / m3 Studies of the AIR CONTAMINATION New Image 1212569_21823227.jpg logo_mu_cerne.gif DOXORUBICIN (VP=0.002) Start 12 hours PACLITAXEL (VP=0.024) Start 12 hours 40% „disappeared“ Studies of the EVAPORATION (steel) New Image 1212569_21823227.jpg logo_mu_cerne.gif AIR contamination - results New Image 1212569_21823227.jpg logo_mu_cerne.gif •Levels in the air ? • AIR SAMPLING - complicated • LEVELS usually low - sensitive analytical methods needed • • - often: negative results • - maximum observed levels 200 ng / m3 (8h continuous exposure, 100% intake ~ 672 ng/person) • • CONCLUSION - AIR CONTAMINATION: air contamination by cytotoxic drugs should be considered but further research is needed to develop reasonable methods AIR contamination - conclusion 1212569_21823227.jpg logo_mu_cerne.gif •More data available than for air • •Several studies • - Preparatory rooms • - Vials (external surfaces) • •Other areas - less information • - Storage rooms • - Manipulation and transport • - Drug administration • - Toilets, sanitary areas … Exposure: SURFACES 1212569_21823227.jpg logo_mu_cerne.gif •1) SAMPLING • •- Standardized procedures are being adopted e.g. MEWIP project - Germany http://www.pharma-monitor.de/ • • • Exposure assessment - SURFACES New Image 1212569_21823227.jpg logo_mu_cerne.gif •2) ANALYSES • •- each drug needs specific methods • - GC, HPLC, AAS, voltametry … •- recent developments • - Mass Spectrometry (GC-MS/MS…) - more affordable (lower prices), low detection limits • •(use of bioassays - e.g. genotoxicity of wipe samples) • • Exposure assessment - SURFACES New Image 1212569_21823227.jpg logo_mu_cerne.gif Brno 2008 - clean preparatory room (3 sampling periods) Examples - contamination New Image 1212569_21823227.jpg logo_mu_cerne.gif Examples - contamination Brno 2008 – daily outpatient clinic administration room (3 sampling periods) New Image 1212569_21823227.jpg logo_mu_cerne.gif Examples - contamination Brno 2008 - hospital room (patient bedroom) (3 sampling periods) New Image 1212569_21823227.jpg logo_mu_cerne.gif RESULTS – surfaces contamination New Image 1212569_21823227.jpg logo_mu_cerne.gif •Dr. Rudolf Schierl (Munich, Germany) Exposure levels - SURFACES 1212569_21823227.jpg logo_mu_cerne.gif Cyclophosphamide – two sampling campaigns 15 pharmacies (Czech Rep.) [pg/cm2] Table Floor Fridge Table Floor Storage Preparation RESULTS – surfaces contamination New Image 1212569_21823227.jpg logo_mu_cerne.gif •numbers of drug preparations per day Cyclophosphamide Platinum Surface contamination vs. Work-load New Image „contamination“ „contamination“ 1212569_21823227.jpg logo_mu_cerne.gif •Dr. Rudolf Schierl (Munich, Germany) Contamination example – an accident 1212569_21823227.jpg logo_mu_cerne.gif Exposure pathway: Surfaces à Hands à Body exposure SKIN GIT 1212569_21823227.jpg logo_mu_cerne.gif •Dr. Paul Sessink (Exposure Control B.V., NL) www.exposurecontrol.nl 1212569_21823227.jpg logo_mu_cerne.gif Breakthrough time [min] [mm] CP PX DX FU Vinyl 0.12 60 240 n.d. n.d. Latex 0.16-0.3 60-360 n.d. n.d. n.d. Nitrile 0.14 n.d. n.d. n.d. n.d. Max. permeability [ng/cm2.min] [mm] CP PX DX FU Vinyl 0.12 160 3 n.d. n.d. Latex 0.16-0.3 5-72 n.d. n.d. n.d. Nitrile 0.14 n.d. n.d. n.d. n.d. Cheaper gloves permeated – rather by small molecules CP, PX: vinyl, latex / 160 ng/cm2.min Nitrile gloves (seems) to provide sufficient protection GLOVES PERMEATION New Image 1212569_21823227.jpg logo_mu_cerne.gif Contamination of HANDS New Image Median & Maximum values for cyclophosphamide (CP) and platinum (Pt) Pd – frequency of the positive samples 1212569_21823227.jpg logo_mu_cerne.gif Hirst et al. 1984. The Lancet 323(8370), 186-188 x 100 Cyclophosphamide in the URINE New Image 1212569_21823227.jpg logo_mu_cerne.gif •Dr. Paul Sessink (Exposure Control B.V., NL) www.exposurecontrol.nl 1212569_21823227.jpg logo_mu_cerne.gif •ADDITIONAL CANCER RISK - cyclophosphamide • •„Extra cancer cases“ in exposed workers • •34 – 986 cases / million workers / year •Vandenbroucke,J; Robays, H. 2001: How to protect environment and employees against cytotoxic agents, the UZ Ghent experience Journal of Oncology Pharmacy Practice 6: 4,146-152 • •17 – 100 cases / million workers / year •Sessink, P. J. M., Kroese, E. D., Vankranen, H. J., & Bos, R. P. 1995a. Cancer Risk Assessment for Health-Care Workers Occupationally Exposed to Cyclophasphamide. International Archives of Occupational and Environmental Health, 67(5), 317-323 • • „Acceptable“ risk Strive risk ……….. 1 extra case „Not acceptable“ Prohibitory risk …. > 100 extra cases RISK CHARACTERIZATION - cyclophosphamide 1212569_21823227.jpg logo_mu_cerne.gif •ADDITIONAL CANCER RISK - cyclophosphamide • • •MEASURED VALUES •Czech Republic (CYTO project) ~ 0.14 ug CP in urine / day • • •MEASURED VALUES •(Dr. Paul Sessink (Exposure Control B.V., NL) , www.exposurecontrol.nl) • •Technicians - 0.18 ug CP in urine/day • (~ 1.4 - 10 extra cancer cases/million workers a year) • •Nurses - 0.8 ug CP in urine/day • (~ 10 - 50 extra cancer cases/million workers a year) • RISK CHARACTERIZATION - cyclophosphamide New Image ? Acceptable risk ? 1212569_21823227.jpg logo_mu_cerne.gif •Dr. Paul Sessink (Exposure Control B.V., NL) www.exposurecontrol.nl 1212569_21823227.jpg logo_mu_cerne.gif •G. Dranitsaris et al. Are health care providers who work with cancer drugs at an increased risk for toxic events? Systematic review and metaanalysis of the literature. J Oncol Pharm Practice 2005; 11: 69-78 – –14 studies found (1966-2004); 7 valid and further analyzed – –Some results (statistically non-significant) •Developmental malformations RR = 1,64, 95% CI = (0,91 - 2,94) •Dead newborns RR = 1,16, 95% CI = (0,73 – 1,82) •Acute effects •Carcinogenicity – RISKS TO WORKERS – metaanalysis study 1212569_21823227.jpg logo_mu_cerne.gif •G. Dranitsaris et al. 2005 – –Spontaneous miscarriage RR = 1,46 95% CI = (1,11 – 1,92) Conclusion: Sufficient plausibility of health effects related to cytostatics RISKS TO WORKERS – metaanalysis study 1212569_21823227.jpg logo_mu_cerne.gif •Why to monitor ? • •What to monitor ? • •How to monitor ? • •How to use monitoring data ? Final notes on MONITORING 1212569_21823227.jpg logo_mu_cerne.gif •Why to monitor ? • • - check yourself (QA/QC in drug safety as well as in drug preparation) • • - results of the monitoring minimize contamination • - MEWIP study (Germany) • - CYTO project (Czech Republic) Final notes on MONITORING 1212569_21823227.jpg logo_mu_cerne.gif MONITORING - rising awarness – improving situation Cyclophosphamide – two sampling campaigns 15 pharmacies (Czech Rep.) [pg/cm2] Table Floor Fridge Table Floor Storage Preparation 1212569_21823227.jpg logo_mu_cerne.gif •What to monitor ? • • - dozens of drugs administered • - „representative“ drug should be selected • • - selection criteria: • - used often • - in high amounts • - analytical methods available • - should be hazardous • - literature data available à CYCLOPHOSPHAMIDE Final notes on MONITORING 1212569_21823227.jpg logo_mu_cerne.gif Dr. Thekla Kieffmeyer (IUTA, Germany) 1212569_21823227.jpg logo_mu_cerne.gif Models: Fluorouracil, Cisplatin, Cyclophosphamide, Paclitaxel, Doxorubicin CYTO project model compounds New Image 1212569_21823227.jpg logo_mu_cerne.gif •How to monitor ? (recommendations) • • - surfaces • - easy and standardized sampling • - correlate with exposures/doses • - periodically - 1-2times/year - standardized and sensitive methods available • - biomonitoring (complementary) - cyclophosphamide in urine • - passive sampler „dosimeters“ • - health status & cytogenetics Final notes on MONITORING 1212569_21823227.jpg logo_mu_cerne.gif •How to use monitoring results ? • • - manage risks: adapt procedures and protective measures to improve yourself (periodic samplings) • -> example • • - compare your situation with others (anonymously) -> example Final notes on MONITORING 1212569_21823227.jpg logo_mu_cerne.gif Managing exposure & risks – Czech examples CYTO projekt 119 IMG_4937 Wall-mounted holders multi-channel administration sets toilets with self cleaning seats www.mou.cz 1212569_21823227.jpg logo_mu_cerne.gif Surface contamination by cyclophosphamide (before / after of safety measure application) 1212569_21823227.jpg logo_mu_cerne.gif Dr. Thekla Kieffmeyer (IUTA, Germany) - MEWIP project Compare yourself with the others 1212569_21823227.jpg logo_mu_cerne.gif nCytotoxic drugs represent hazard to workers nRisks can be managed n nRisk assessment and management tools nEducation and training (all personel) nProtective measures nControl mechanisms nMonitoring and biomonitoring n nFurther development nStandardized procedures to be adopted GENERAL SUMMARY