Occupational Exposure Risks

L. Bressler

November, 1997

  1. Occupational Exposure Risks
  2. Effects on Pregnancy Outcomes
  3. Selected Recommendations



1. Describe the risks, potential or actual, related to occupational exposure to cytotoxic drugs.

2. Discuss the outcomes that have been reported in the literature and know the difference between potential and actual risks.

3. Develop a written plan for minimizing occupational exposure to cytotoxic drugs. Explain the rationale for each step included in such a plan.



1. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs; Am J Hosp Pharm 47:1033-1049, 1990




Three "negative outcomes" or risks of occupational exposure to cytotoxic drugs might be: MUTAGENICITY, CARCINOGENICITY and ADVERSE OUTCOMES OF PREGNANCY.

MUTAGENICITY - causing an alteration in one or more genes (ie. a change in DNA)

DNA repair is an ongoing process. For our purposes, the importance of mutagenic properties of cytotoxic drugs lies in the fact that many carcinogens are mutagens. Mutagenicity is easier to study than carcinogenicity.

CARCINOGENICITY - causing cancer

In ANIMALS, some cytotoxic drugs are carcinogenic. Clinically, cytotoxic drugs have been implicated as carcinogens in PATIENTS RECEIVING THERAPEUTIC DOSES OF THESE DRUGS. Most commonly, ALKYLATING AGENTS (eg. chlorambucil, nitrogen mustard, melphalan) have been reported to cause SECONDARY LEUKEMIAS. More equivocal is a relationship between antibiotics and carcinogenicity, and the antimetabolites are thought to be the "safest" with regard to carcinogenicity.

There are no conclusive reports of cancers developing in health personnel as a result of occupational exposure to cytotoxic drugs.

Obviously, occupational exposure is much, much less than therapeutic exposure.

ROUTES of occupational exposure are via INHALATION of aerosolized particles and TRANSCUTANEOUS absorption. Various manipulations in the preparation and administration of cytotoxic drugs could lead to exposure by these routes. Aerosolization might occur when one breaks open an ampul, withdraws solution form a vial, or injects liquid into a powder. Transcutaneous absorption could occur following spills on the skin.

Drug "contamination" in the environment around areas of preparation has been documented (ie. aerosolization has been measured).

Anecdotal reports of adverse effects (eg. dizziness) in health professionals working with cytotoxic drugs prompted much attention to this issue in recent years. More controlled studies (albeit with limitations related to urine mutagenicity studies) demonstrated exposure to drugs in health professionals, and demonstrated the protective effect of vertical-flow biological-safety cabinets.

What is not known is the "safe level" of occupational exposure. Is exposure cumulative??? Is there a level of exposure above which irreversible damage might occur??? Several methods have been used for detecting low levels of exposure to potentially carcinogenic substances:


1. AMES TEST FOR MUTAGENICITY: Utilizes a strain of Salmonella bacteria sensitive to mutagenic changes. The bacteria require histidine to grow. In the test system, urine from the subject "exposed" is incubated with the bacteria. Bacterial growth in a histidine-free medium indicates that the Salmonella has mutated, thus there are "mutagenic substances" in the urine.

Both positive and negative results have been reported using urinary mutagenicity tests. Some of the discrepancy may be that, in fact, negative results represent prevention/minimizing exposure. Timing might also be a factor. The mutagenic substance must be excreted into the urine and this might occur at various times following exposure, depending on the particular drug. Cigarette smoke, other non-cytotoxic drugs, or some dietary factors may also be responsible for mutagenic activity in the urine, resulting in false positive urine mutagenicity tests.

2. Analytical methods (eg. HPLC) for determination of CYTOTOXIC DRUG (or metabolite) CONCENTRATION in BLOOD or URINE.

These methods have been developed primarily for use in patients receiving therapeutic doses of cytotoxic drugs. They may lack the sensitivity to detect the low levels assumed to be associated with occupational exposure.

3. CYTOGENETIC EFFECTS - analysis of CHROMOSOMAL DAMAGE (eg. structural chromosome aberrations [CA], sister chromatid exchanges [SCE]) in peripheral blood lymphocytes.

Both positive and negative results have been reported. The persistence of the cytogenetic effect also depends on the type of damage (ie. SCE are short-lived while CA persist for years). In addition, there may be a wide distribution of SCE in normal individuals (ie. SCE without exposure to cytotoxic drugs).

4. Measurement of NUCLEIC ACID ADDUCTS - ie. determination of drug/DNA complex in the urine, has been suggested as a means of monitoring occupational exposure. At present this technique is not perfected to the point of being useful in the workplace.

None of these methods for detecting low levels of exposure are routinely utilized in the workplace. There is no standard "test" for detecting exposure or monitoring for potential adverse consequences that can be recommended at the present time.



Several papers have addressed the incidence of SPONTANEOUS ABORTIONS and MALFORMATIONS in the offspring of health professionals with occupational exposure to cytotoxic drugs. The conclusions have met with some questions and concerns.

A study in Finland examined outcomes in nurses exposed to anesthetic gases, sterilizing gases and soaps, x-rays and cytotoxic drugs. Data on exposure were obtained retrospectively by means of questionnaires sent to head nurses. Cytotoxic exposure in the first trimester was reported to be associated with malformations in offspring.

The same investigators, in a subsequent study, reported an increased risk of spontaneous abortions (not malformations) in nurses exposed to cytotoxic drugs. Again, data were obtained retrospectively by questionnaire. One wonders about the ability to recall how many does per week were prepared several years prior. Spontaneous abortions occurred in women who also had (other) risk factors for spontaneous abortion.

In both studies, nurses were responsible for preparing, as well as administering, cytotoxic drugs. Both studies covered a period in time before attempts at minimizing exposure were recommended in the literature.

QUANTITATIVE ASSESSMENT OF RISK - We cannot quantitate the risk of exposure at this time. Much of the risk appears to be POTENTIAL (based on known effects of therapeutic doses in patients, or animal data), NOT ACTUAL. However, because of the seriousness of the potential risk, it makes sense to minimize occupational exposure to cytotoxic drugs as much as possible.


A VERTICAL FLOW BIOLOGICAL SAFETY CABINET (as opposed to horizontal laminar flow) should be used for preparation of cytotoxic drugs. This offers protection of the product AND the operator. Most commonly used is a Class II biological safety cabinet, in which 30% of the air is filtered and recirculated (or alternatively, vented to the outside).

When no vertical flow hood is available, it has been recommended that a quiet work space, away from heating and cooling vents and other personnel be used. (ie. not a horizontal flow hood)

GLOVES - SURGICAL LATEX GLOVES appear to offer the best protection. In general, the shorter the contact time (with drug) and the thicker the glove, the less penetration through the glove. Gloves should be changed after 30 minutes of continuous wearing (or sooner if a spill occurs).

GOWNS - closed front and cuffs



NEGATIVE PRESSURE to withdraw solutions from vials (ie. inject less air than the volume to remove.) This will minimize aerosolization. Alternatively, several devices that absorb or prevent aerosolization have been marketed for use in the preparation of cytotoxic drugs.

For related issues (eg. pregnancy), the policies and procedures at specific institutions, as well as current laws, should be reviewed.

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