© 2005 American Thoracic Society
"Low-Level" Carbon Monoxide Administration May Carry RiskTo the Editor:We were concerned by the article of Dr. Mayr and colleagues, which describes exposures of healthy subjects to inhaled carbon monoxide (CO) (1). In this study, conducted in Austria, 13 volunteers were injected with intravenous LPS and asked to breathe 500 ppm CO for 1 hour. The authors sought to determine whether CO has antiinflammatory effects in human endotoxemia as previously claimed in mice (2). The authors acknowledged CO's known toxicity, but claimed the exposures were safe because blood carboxyhemoglobin (HbCO) levels were at 10% or less. They reasoned that since smokers experience similar blood concentrations, such levels are "innocuous." In 2000, Emanuel and coworkers published seven requirements for clinical research to be ethical (3). This study appears to violate at least one of them, that of a favorable risk–benefit ratio. This requirement necessitates that risk be minimized and be proportionate to the benefits to the subject and society. We believe that the CO exposures used by Mayr and coworkers should not have been assumed to be low risk. A simple comparison of blood levels to those of a different but potentially toxic exposure does not prove safety. Chronic CO exposure may have different effects in smokers than acute exposures in nonsmokers, and endotoxemia is not present in apparently healthy smokers. Finally, such "low-level" CO exposures in normal volunteers have demonstrated toxicity: neuropsychologic impairment in subjects breathing up to 100 ppm CO for 1.5 to 2.5 hours (4). In the United States, the National Institute for Occupational Safety and Health has set a ceiling limit for maximum CO exposure at 200 ppm, an 8-hour workday limit of 50 ppm, and a maximum HbCO level of 5% (5, 6). The authors noted that the antiinflammatory effect they sought was seen in prior murine studies both in vitro and in vivo. Thus, at a minimum, it would seem appropriate to demonstrate the effect at a reasonable CO concentration in vitro before exposing human volunteers to a recognized toxin. If it could not be demonstrated in human cells in vitro, there would have been little or no reason to proceed to human studies. Despite the fact that the authors' local ethics committee approved the study, it appears not to meet accepted standards for ethical research. If questionable studies such as this are published, other investigators may be encouraged to pursue similar work and cause needless harm to research participants.
a Virginia Mason Medical Center, Seattle, Washington FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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