Methoxyflurane is a fluorinated hydrocarbon which readily produces vapour at room temperature. It was originally developed as an anaesthetic agent, wherein the patient was administered a flow of methoxyflurane vapour along with gasses including oxygen. Methoxyflurane is no longer used as an anaesthetic, but for decades has instead been in limited use as an inhaled analgesic. Recently, awareness and availability of methoxyflurane as an analgesic option has increased, and thus more patients and healthcare providers are exposed to methoxyflurane vapour.

Despite increasing use, questions persist about the safety associated with inhalation of vapour both for patients and those occupationally exposed. Historical research demonstrated toxic effects in anaesthetic doses, and much of the contemporary research has been associated with the medication manufacturer. Therefore, this thesis undertakes an independent consideration of a number of aspects relevant to the safety profile of this agent.

Previously utilised methods of investigation of methoxyflurane occupational safety have included extrapolation over several orders of magnitude, and single-field modelling of local environmental contamination. Extrapolation introduced a wide range of uncertainty, particularly because an appropriate model for fitting methoxyflurane data is not known. The single-field model ignored potential for treating clinicians proximal to the inhaler to be exposed to higher concentrations than found in the remainder of the clinical environment.

The frequency and duration of ambulance officer exposure to methoxyflurane was determined from analysis of patient report forms. Methoxyflurane was more likely to be utilised by all Ambulance Officers (AOs) at all practice levels. Serum fluoride of Emergency Medical Technicians (EMTs) in the same ambulance service was analysed over a two-year period. No evidence of serum fluoride accumulation was identified from that analysis, suggesting occupational safety from acute renal toxicity for those EMTs, although the study could not exclude the possibility of some risk of increased bone density due to fluoride deposition. AOs in that ambulance service had median ~3 to 4 exposures per month, for median 32 minutes per exposure. Therefore, it is possible relative occupational safety was due to infrequent AO exposures to methoxyflurane.

Two models were presented for prediction of ambulance local environmental contamination with methoxyflurane vapour: a two-field model which simulates treating officer proximity to the patient

and the methoxyflurane inhaler; and a Computational Fluid Dynamics model which simulated airflow through the treatment compartment. Exposure predicted by the two-field model was consistent with AO exposure reported in multiple studies in the literature. If in-ambulance methoxyflurane administration was repeated hourly for eight hours, the predicted Time Weighted Average (TWA) exposure would be 2 to 3 times that predicted elsewhere, but nonetheless below a previously suggested (TWA) Maximum Exposure Limit (MEL) safety threshold of 15 ppm. However, short-term exposure may exceed international limits, suggesting a need for adequate ventilation and exposure monitoring to ensure safety.

A pharmacokinetic model of human methoxyflurane absorption from the lungs, equilibration, metabolism, and excretion was developed. Parameters for this model were identified, and the model was able to simulate serum fluoride concentration following a variety of exposure scenarios. Such prediction suggests safety from renal toxicity for patients receiving a single dose of methoxyflurane up to 6mL, ambulance workers exposed to local environmental contamination for a single case, and healthcare workers in a clinic exposed to local environmental contamination for a single day.

This thesis contributes a thorough analysis of several aspects of the safety of modern exposure to methoxyflurane which were previously underdeveloped in the literature. Two particularly novel contributions are presented: First, the comparison of serum fluoride levels of occupationally exposed workers against identified health thresholds. Second, the development of a model for prediction of serum fluoride concentration following methoxyflurane inhalation.