Assessing Exposures of Health-Care Personnel to Aerosols of Ribavirin -- California

In April 1986, a hospital in the San Francisco Bay area asked the Occupational Health Surveillance and Evaluation Program (OHSEP) of the California Department of Health Services to evaluate occupational risks to health-care workers of exposure to aerosols of ribavirin, an antiviral agent effective against many RNA and DNA viruses. OHSEP subsequently asked the National Institute for Occupational Safety and Health (NIOSH) for technical assistance in assessing environmental exposures.

From December 1986 through March 1987, OHSEP investigators performed surveys in the pediatric intensive-care units (ICUs) of four San Francisco Bay area hospitals to evaluate exposure levels associated with the various methods of administering ribavirin aerosol. Twelve personal-breathing-zone air samples from 10 nurses and two respiratory therapists and 14 air samples from the bedside area were collected during the administration of ribavirin aerosols through oxygen tents, mist masks, or ventilators. The health-care workers studied spent an average of 50% of their workshifts (range: 20%-80%) at the bedsides of patients who received such therapy. Shifts lasted 7-12 hours, and several health-care workers wore surgical masks while delivering direct patient care.

Personal-breathing-zone air samples were collected on 37-mm glass fiber filters using personal sampling pumps held in open-faced cassettes attached to the lapels of the exposed health-care workers . Samples were collected over full shifts during which workers provided care for patients receiving aerosolized ribavirin, including periods when the workers were away from ribavirin-delivery areas. Air samples were collected in the bedside area with similar pumps and cassettes placed at the heads of the beds of treated patients. NIOSH analyzed environmental samples for aerosolized ribavirin using high-performance liquid chromatography (detection limit: 1.0-1.4 ug per sample). Four of the general bedside-air samples were collected in duplicate for independent confirmatory analysis by a radioimmunoassay technique.

Of the 12 workers evaluated, the six nurses and two respiratory therapists providing direct care to patients who received ribavirin through an oxygen tent were exposed to the highest air levels over the workshift (mean ribavirin concentration in personal air samples: 161 ug/m3, range: 69-316 ug/m3). The three nurses attending patients who received ribavirin through a ventilator were exposed to the lowest air concentrations (range: less than 1 to 6 ug/m3), and one nurse providing care for a patient who received ribavirin through a mist mask was exposed to a mean concentration of 62 ug/m3. Bedside area samples, collected continuously in the ribavirin-delivery areas, showed generally higher ribavirin concentrations than the corresponding personal samples, averaging 317 ug/m3 during administration through an oxygen tent. Samples analyzed by radioimmunoassay confirmed the results obtained by high- performance liquid chromatography. In four of the six measurements performed, ventilation in the ICUs exceeded the minimum room-air exchange rate recommended by the U.S. Department of Health and Human Services for hospital ICUs (6 air changes per hour) (1). No correlation between unit ventilation and the results of personal or area sampling was noted.

To evaluate the absorption of ribavirin by exposed hospital personnel, samples of serum, red blood cells (RBCs), and urine were collected from each participant at each of three sampling times: before, immediately after, and 3-7 days after the first workshift with ribavirin exposure. Biological samples were analyzed for ribavirin by a radioimmunoassay technique with a detection limit of 0.002 ug/mL (2).

Eight nurses and two respiratory therapists submitted a total of 30 serum samples, 30 RBC samples, and 30 urine samples. Ribavirin was not detected in any urine or serum samples but was detected at a concentration of 0.44 ug/mL in one RBC sample collected from a nurse 5 days after the first shift in which she gave direct care to a patient receiving ribavirin through an oxygen tent. Environmental samples collected during the work shift of this nurse showed the highest concentrations of ribavirin in air (personal: 316 ug/m3, bedside area: 1048 ug/m3) observed in the study. This nurse did not report any unusual or increased activity related to patient care that might have resulted in increased exposure.

No symptoms were reported by any health-care workers in this study. Reported by: R Harrison, MD, J Bellows, MPH, D Rempel, MD, L Rudolph, MD, Occupational Health Surveillance and Evaluation Program; KW Kizer, MD, California Dept of Health Svcs; A Jin, MS, J Guglielmo, Pharm D, Univ of California, San Francisco; BB Bernard, MD, Northern California Occupational Health Center. Hazard Evaluations and Technical Assistance Br, Div of Surveillance, Hazard Evaluations, and Field Studies, and Measurements Research Support Br, Div of Physical Sciences and Engineering, National Institute for Occupational Safety and Health, CDC.

Editorial Note

Editorial Note: Ribavirin (1-B-5-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole*))is a synthetic nucleoside analog that appears to restrict the synthesis of viral proteins and interferes with formation of the cap on viral-messenger RNA (3). In 1986, the Food and Drug Administration approved it for aerosol treatment of infants and young children with severe respiratory syncytial virus infection (4-6). Ribavirin is usually administered through a specific aerosol generator, which produces respirable particles (mass median diameter approximately 1.3 um) at a rate of 12.5 L of ribavirin/ air mixture per minute. The aerosol/air mixture is delivered through a mist mask or oxygen tent to the patient; the excess is exhausted directly into the room. Ribavirin may also be used as an investigational drug administered through a ventilator, with the excess aerosol in expired air being filtered to limit release into patient-care areas (7). The administration route is usually determined by clinical considerations. Duration of treatment is generally 3-5 days for 12-20 hours each day, although longer periods may also be employed.

Ribavirin causes reabsorption of the fetus in pregnant rabbits and malformations in the offspring of all rodent species tested (8,9). It also causes tubular atrophy in the testes of adult rats (8). Based on data from studies in animals, ribavirin is contraindicated for use in pregnant women (10,11).

Pharmacokinetic studies indicate that absorbed ribavirin is concentrated in the RBCs of humans (12). In the only previous study of occupational exposure, ribavirin was not detected in the RBCs, plasma, or urine of nurses administering ribavirin aerosol; air samples were not collected in that study (13). A simple mathematical model, incorporating breathing-zone air level, respiratory minute volume, and a factor of 70% (14) for the fraction of the inhaled dose absorbed, estimates an average absorbed dose per workshift (8-12 hours) of 13.5 ug/kg body weight for nurses in the present study who attended patients receiving ribavirin through oxygen tents (15). This estimated absorbed dose exceeds 1/100 of the short-term, daily-dose levels that were teratogenic in hamsters and embryolethal in rabbits (8).

Until a specifically designed control system is developed to reduce aerosol emissions, health-care workers who are pregnant or may become pregnant should be advised of the potential risks of exposure during direct patient care when patients are receiving ribavirin through oxygen tent or mist mask and should be counseled about risk-reduction strategies, including alternative job responsibilities. Also, because visitors may spend considerable time in close proximity to a patient's bedside, female visitors who are pregnant or may become pregnant should be informed of the potential risks of exposure to aerosolized ribavirin. Because all area samples were obtained only in direct proximity to the bedside, these data cannot be extrapolated reliably to assess possible risks to persons working elsewhere in a room or ward where ribavirin is being administered through oxygen tent or mask.

Ribavirin exposure levels that do not cause adverse health effects cannot be specified because of the lack of dose-response data in humans. Nevertheless, because of the potential for exposure to a potent animal teratogen, employers should develop procedures designed to reduce employee exposure. Use of surgical masks to reduce inhaled ribavirin dose is unlikely to be effective (16) and therefore does not warrant recommendation as a protective measure. Although patient-care considerations typically determine the route of ribavirin administration, hospital staff should be aware that in this study, exposures to personnel were greatest when ribavirin was administered by oxygen tent, less by mist mask, and least by ventilator. Worker exposures in this and other health-care settings deserve increased attention as the extent and complexity of occupational hazards in this environment become apparent.

References

1. Health Resources and Services Administration. Minimum requirements for construction and equipment of hospital and medical facilities. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, 1982.

2. Austin RK, Trefts PE, Hintz M, Connor JD, Kagnoff MF. Sensitive radioimmunoassay for the broad-spectrum antiviral agent ribavirin. Antimicrob Agents Chemother 1983;24:696-701.

3. Smith RA. Background and mechanisms of action of ribavirin. In: Smith RA, Knight V, Smith JAD, eds. Clinical applications of ribavirin. Orlando, Florida: Academic Press, 1984.

4. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double blind study. N Engl J Med 1983;308:1443-7.

5. Hall CB, McBride JT, Gala CL, Hildreth SW, Schnabel KC. Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease. JAMA 1985; 254:3047-51.

6. Taber LH, Knight V, Gilbert BE, et al. Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics 1983;72:613-8.

7. Demers RR, Parker J, Frankel LR, Smith DW. Administration of ribavirin to neonatal and pediatric patients during mechanical ventilation. Respiratory Care 1986;31:1188-95.

8. Hillyard IW. The preclinical toxicology and safety of ribavirin. In: Smith RA, Kirkpatrick W, eds. Ribavirin: a broad spectrum antiviral agent. New York: Academic Press, 1980.

9. Kilham L, Ferm VH. Congenital anomalies induced in hamster embryos with ribavirin. Science 1977;195:413-4.

10. Food and Drug Administration. Ribavirin aerosol approved for severe cases of RSV in infants and young children. FDA Drug Bull 1986;16:7.

11. ICN Pharmaceuticals, Inc. VirazoleTM (ribavirin): prescribing information. Costa Mesa, California: ICN Pharmaceuticals, Inc., 1987.

12. Catlin DH, Smith RA, Samuels AI. 14C-ribavirin: distribution and pharmacokinetic studies in rats, baboons and man. In: Smith RA, Kirkpatrick W, eds. Ribavirin: a broad spectrum antiviral agent. New York: Academic Press, 1980.

13. Rodriguez WJ, Dang Bui RH, Connor JD, et al. Environmental exposure of primary care personnel to ribavirin aerosol when supervising treatment of infants with respiratory syncytial virus infections. Antimicrob Agents Chemother 1987;31:1143-6.

14. Connor JD, Hintz M, Van Dyke R. Ribavirin pharmacokinetics in children and adults during therapeutic trials. In: Smith RA, Knight V, Smith JAD, eds. Clinical applications of ribavirin. Orlando, Florida: Academic Press, 1984.

15. California Department of Health Services. Health care worker exposure to ribavirin aerosol: field investigation FI-86-009. Berkeley, California: California Department of Health Services, Occupational Health Surveillance and Evaluation Program, 1986.

16. Tuomi T. Face seal leakage of half masks and surgical masks. Am Ind Hyg Assoc J 1985;46:308-12. *Use of trade names is for identification only and does not imply endorsement by the US Department of Health and Human Services or the Public Health Service.

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