1. Update on Safe Handling of Hazardous Drugs: Stakeholder Activities
Melissa A. McDiarmid, MD, MPH
August 1, 2002

2. ASHP Hazardous Drug Criteria
1. Genotoxicity (i.e., mutagenicity and clasto-
genicity in short-term test systems)
2. Carcinogenicity in animal models, in the patient
population, or both as reported by IARC
3. Teratogenicity or fertility impairment in animal
studies or in treated patients
4. Evidence of serious organ or other toxicity at low
doses in animal models or treated patients.

3. Historical Background

4. Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents
Developmental Toxicity Genotoxicity
Animal
Drug Class T E Human PM CE
Alkylating Agents
BCNU
Busulfan
Chlorambucil
Cyclophosphamide
Ifosfamide
Nitrogen Mustard
Thiotepa
Cis-diaminedichloroplatinum
Antibiotics
Actinomycin
Adriamycin
Bleomycin
Daunomycin
(+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects

5. Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents
Developmental Toxicity Genotoxicity
Animal
Drug Class T E Human PM CE
Antimetabolites
Cytosine arabinoside
5-Fluorouracil
6-Mercaptopurine
Methotrexate
Mitotic Function
Vincristine
Vinblastine
Taxol
Miscellaneous
DTIC (Dacarbazine)
Procarbazine ± +
Topoisomerase II Function
Etoposide*
(+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects
*Data summarized from Sorsa M, Hemminki K, Vainio H. Occupational exposure to anticancer drugs: potential and real hazards. Mutat Res 1985;154: Updated by McDiarmid, MA. Antineoplastics, Anesthetic Agents, Sex Steroid Hormones in Paul, M Occupational and Environmental Reproductive Hazards, 1993.

6. Severity of the Hazard Hazardous Drugs are:
11 of 70-odd IARC Group I Carcinogens
8 of Group 2A; and 7 of Group 2B
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

7. SUMMARY OF STUDIES OF ADVERSE REPRODUCTIVE OUTCOMES IN WORKERS EXPOSED TO ANTINEOPLASTIC DRUGS
Key: (+) = effect seen, (-) = no effect seen, (*) = statistically significant effect seen
(F) = female; (M) = male; (LBW) = low birth wt; (SGA) = small for gestational age.

8. SUMMARY OF STUDIES OF ADVERSE REPRODUCTIVE OUTCOMES IN WORKERS EXPOSED TO ANTINEOPLASTIC DRUGS
Key: (+) = effect seen, (-) = no effect seen, (*) = statistically significant effect seen, (F) = female; (M) = male; (LBW) = low birth wt; (SGA) = small for gestational age.

9. Exposure Opportunity
1,250,000 new cancer patients in US (ACS) in 2000; 500,000 will die
Use of drugs for non-malignant disease (RA, SLE)
Anti-viral agents for HIV treatment and other viral illnesses
Investigational (IND) Drug Development/Clinical Trials

10. Exposure Opportunities in “Life Cycle” of Hazardous Drugs

11. SOURCES OF CONTAMINATION
Contaminated vials
Drug preparation and administration
Leaks
Spills
Drug relocation
Spread of spills
BSC/HVAC

12. ROUTES OF EXPOSURE Dermal Oral Inhalation
Particulates (droplets, dusts)
Vapors

13. SURFACE CONTAMINATION
SESSINK ET AL, 1992a CP, 5-FU, METH
SESSINK ET AL, 1992b CP, 5-FU, METH
McDEVITT ET AL, CP
PETHRAN ET AL, CP, IF
MINOIA ET AL, CP, IF
CONNOR ET AL, CP, 5-FU, IF
RUBINO ET AL, FU, METH,CY, GC
SESSINK, ET AL, CP, 5-FUFU

14. AIR SAMPLING (PARTICULATES)
SESSINK ET AL, 1992a METH/CP/IF
SESSINK ET AL, 1992b METH/CP/
5-FU
McDEVITT ET AL, CP
PETHRAN ET AL, CP
MINOIA ET AL, CP/IF

15. VIAL CONTAMINATION SESSINK ET AL, 1992b CP, METH
HEPP & GENTSCHEW, SEVERAL
AGENTS
PETHRAN ET AL, CP,IF
DELPORTE ET AL, FU

16. URINE ANALYSIS HIRST ET AL, 1984 CP + VENITT ET AL, 1984 PT -
EVELO ET AL CP +
SESSINK ET AL, 1992a CP -
1992b CP, IF +
ENSSLIN ET AL a PT +
1994b CP, IF +
SESSINK ET AL, 1994a FU +
1994b MTX +
1994c CP
1994d CP
PETHRAN ET AL, DOX

17. CONNOR ET AL, 1999 SIX CANCER CENTERS IN U.S. AND CANADA
PHARMACIES AND TREATMENT AREAS
CP, 5-FU, IF
BSCs, COUNTERS, CARTS, FLOORS, CHAIRS, TABLES
75 % PHARMACY AND 65 % TREATMENT AREA SAMPLES POSITIVE FOR AT LEAST ONE DRUG
ADJACENT AREAS CONTAMINATED

18. VAPORIZATION OF ANTINEOPLASTIC AGENTS
VAPOR PRESSURE*
DRUG 20ºC 25ºC 40ºC
5-FU CP IF
CIS
ETOP
BCNU
SCHMIDT ET AL, *mPa

19. CONNOR ET AL, 2000 VAPORIZATION OF AGENTS
DRUG 23ºC 37ºC
BCNU CP IF
THIO +
MUST

20. Existing Handling Guidelines for Hazardous Drugs
Source Year
OSHA , 1995
American Society of Health
System Pharmacists , 1990
AMA Council on Scientific
Affairs
Oncology Nursing Society 1988

21. Elements of Existing Guidelines Include a Combination of Controls:
Substitution
Engineering
Work Practices/Administrative Controls
PPE
Training
Medical Surveillance

22. OSHA Hazardous Drug Document - 1995
Enlarges domain of drugs considered
ASHP definition of a hazardous drug
Includes agents in tablet form
Aerosolized agents
Hazard Communication Standard
Updated Appendix with source listed
Reproductive Hazards Policy

23. Evidence of Adherence to Guidelines
Not systematically studied
Poor adherence is frequently cited in individual studies in the literature
Uncommonly cited by OSHA general duty clause
Not consistently surveyed by JCAHO

24. Safe Handling of Hazardous Drugs
New Initiative
NIOSH Working Group on
Safe Handling of Hazardous Drugs
Federal Agencies (NIOSH, OSHA, NIH, FDA)
Stakeholders
Drug Manufactures
Professional Organizations (ASHP, ONS)
Home Care Providers
Accreditation Bodies (JCAHO, ACHC, CHAP)
Academia

25. Pharm Participants Carmel Pharma Abbott Laboratories
Bristol Myers Squibb
Amgen Inc.
Glaxo Smith Klein
Super Gen
Eli Lilly
Bochringer Ingilbeim
Merck & co.
Johnson & Johnson

26. Purpose:
Gather Public Health Agencies having jurisdiction and affected stakeholders to
review current handling practices of hazardous drugs in healthcare in light of new evidence suggesting current practices are not adequately proactive;
recommend work practice changes and training needs required to more adequately protect HCWs;
identify research needs;
and commit to work group.

27. Personal Protective Equipment
Three Sub-groups
Engineering Controls
Work-Practices
Personal Protective Equipment

28. “Universal Precautions”
Consider a new type of
“Universal Precautions”
for handling these agents
Performance-based
Includes aspects of existing guidelines and
those to be added by working group

29. FUTURE NIOSH ALERT HARMONIZATION OF GUIDELINES
ADDITIONAL RECOMMENDATIONS

30. www.OSHA.gov/outreach/technical links/
controlling occupational exposure to
hazardous drugs