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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.