Dinitrogen oxide

Endpoint summary

Additional information

Currently, very limited information is available in the literature concerning the N₂O concentration – dose response relationships in humans. The concentration of N₂O in the blood at any one time will depend on several factors. The blood/gas solubility coefficient of N₂O is ~30x that of nitrogen, therefore the number of N₂O molecules given up by the blood to air will exceed the number of nitrogen and oxygen molecules absorbed by the blood. As a result the pressure in confined spaces will increases, typically N₂O anaesthesia will increase intracranial pressure after air is introduced into brain ventricles for pneumoencephalography (removal of CSF from brain / spinal cord and replaced with oxygen to allow the brain to be imaged more clearly). A review and discussion of these health effects have been summarised below from existing literature (Eger 1985; EIGA 2008; EHC 1997).

Central nervous system effects

Several studies have examined the effects of trace concentrations of N₂O on perceptual, cognitive and motor skills. The conclusions drawn from these studies are that impairment of mental function is unlikely to result from inhalation of trace levels of N₂O encountered in operating rooms. When this work was carried out the trace level of N₂O in un-scavenged operating rooms was estimated to be 130 ppm N₂O and with waste anaesthetic gases scavenged concentrations of N₂O were 50 ppm.

Reaction times on a choice-decision test do not increase significantly until 10 to 20% (100000 to 200000 ppm) N₂O is breathed. Short term memory performances decrease with 30% (300000 ppm) N₂O. Tinnitus, nausea, paresthesias and disorientation also occur at 20 and 30% (200000 to 300000 ppm) N₂O. These levels are 200 – 400x greater than the average levels reported in non-scavenged operating rooms.

N₂O induced neuropathy is characterised by numbness of the distal extremities, hypoactive reflexes and an “electric shock” sensation travelling upward from the feet after flexion of the neck, psychomotor symptoms, including impaired memory function, difficulties in thinking clearly and depression. Most of these symptoms disappear slowly when N₂O inhalation is stopped, but in some cases debilitating neurological symptoms remain.

Cardiovascular and respiratory effects

In normal patients, N₂O slightly increases pulmonary vascular resistance. In patients with increased pulmonary vascular resistance, especially very young patients, N₂O may increase resistance further and thus increases shunting and impair oxygenation. N₂O has little effect on hypoxia-induced pulmonary vasoconstriction.

When inhaling N₂O tidal volume decreases with respiratory rate and minute ventilation increasing whilst PaCO₂remains normal. The ventilatory response is depressed by N₂O, resulting in increased PaCO₂. Like other inhaled agents, N₂O depresses the ventilatory response to hypoxia profoundly. The greater density of N₂O produces slightly more airway resistance than oxygen or air. Alveolar collapse by absorption of gases in an obstructed lung segment may be greater with N₂O than with nitrogen. N₂O directly depresses human neutrophil chemotaxis and through this or other actions may increase the incidence of postoperative respiratory complications.

Fertility and developmental effects

Regular exposure to N₂O during pregnancy in the normal course of occupations such as anaesthetist, dental staff and midwife has been of concern since the first studies of N₂O in pregnant animals demonstrated the capacity to cause teratogenic effects. In these animal studies the teratogenic effects are only caused by the most extreme conditions of exposure, such continuous exposure during critical stages of foetal development. Alternatively, when the exposure is to a lower concentration or the duration is shorter then such severe effects are not observed. Two studies have shown higher levels of congenital abnormalities in the offspring of women exposed to anaesthetics, these studies however have serious flaws which would tend to lead to an overestimate of such risks. Review of all other available human data has not identified any excess of congenital abnormalities in the offspring of mothers exposed to N₂O under various circumstances.

While exposures in excess of 10% N₂O for various durations have shown some evidence of effects on fertility this seems to be associated with methionine synthase inactivation in that longer daily durations of exposure seem to have the greatest effect. No study has shown any effect on fertility in animals at daily exposures of 1000 ppm or below. This would indicate that occupational exposure is unlikely to have any effect on fertility and the limited clinical data available indicate no male fertility effects. The clinical data which claim to show an effect on female fertility are based on very small numbers of participants and a questionnaire design which almost certainly attracted participation by women who believed that occupational exposure may have been the reason for their infertility. In the context of the available data on animal effects and mechanism there is little likelihood that any effects seen in those studies are resultant from occupational exposure to N₂O.

Much of the uncertainty regarding the reproductive risks of N₂O has come from poorly constructed retrospective clinical studies plus animal studies that were not designed to provide answers to the current questions. The evidence from mechanistic studies and some clinical studies provides reassurance that the risks are negligible.