Is nitrous oxide a genotoxic carcinogen?

Nitrous oxide (N2O) has been widely used as a dental and surgical anaesthetic for over 150 years. However, results from a recent study suggested that increased DNA damage was seen in lymphocytes from surgical patients and this led to its continued clinical use to be questioned. The data can be challenged on technical grounds and must be considered with other studies in order to assess any possible risk. There are other studies indicating that N2O has weak genotoxicity in man, but these are confused by exposure of the populations to other anaesthetic gases including isoflurane and sevoflurane, both of which have also been reported to increase DNA damage. It should be noted that the suggested genotoxic mechanisms are all indirect, including folate deficiency, oxidative stress and homocysteine toxicity. Further, results from in vitro studies indicate that N2O has no direct DNA reactivity as negative results were obtained in a bacterial mutation (Ames) test and an assay for mutation at the hprt locus in Chinese hamster lung cells. Although not performed to definitive study designs, no evidence of carcinogenicity was seen in two long-term tests in mice and another in rats. Although there is some evidence that N2O is weakly genotoxic in humans, this appears to be similar to that reported for isoflurane and sevoflurane and all the postulated mechanisms have clear thresholds with no evidence of direct DNA reactivity. Because any potential genotoxic mechanism would have a threshold, it seems reasonable to conclude that neither occasional high exposure to patients as an anaesthetic nor low-level exposure to staff within published recommended exposure limits presents any significant carcinogenic risk.