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Paracetamol is the most common drug taken in overdose in the UK. Although it has been used in overdose for about 50 years, there are many aspects of its toxicity and treatment that are not fully understood. In this thesis a series of related studies on paracetamol overdose are reported. The nephrotoxic effects of paracetamol in overdose have long been recognised. To better understand the mechanisms of this effect the effect of acute paracetamol overdose on plasma electrolytes were investigated, both retrospectively and, more intensively, prospectively. The results of these studies showed paracetamol overdose is associated with dose-related hypokalemia, and kaliuresis of short duration (<24h), suggesting a specific renal effect of paracetamol in overdose, perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol. In the third study the possible impact of features at admission, including renal impairment, on outcomes in a large cohort of patients who developed severe liver injury following paracetamol overdose was evaluated retrospectively. The key finding was that plasma creatinine, and gamma glutamyl transpeptidase, at first admission appeared to be useful predictors of poor outcome. The last three studies focus on antidote treatment of paracetamol overdose. Intravenous acetylcysteine (NAC) has been used as treatment of choice for over 30 years in patients who are at risk of hepatotoxicity. There are reports of liver failure and death in patients who have “non-toxic” plasma paracetamol concentrations on the UKL nomogram, and who are therefore not treated. To better understand this, the frequency of liver failure in patients who had low paracetamol was assessed by examining retrospective data from the Scottish Liver Unit over a 12-year period. Similar data was collected in the University of Newcastle upon Tyne by colleagues there. Only a small percentage of patients developed hepatotoxicity when initial paracetamol was low. It was concluded that on a cost-benefit basis the current thresholds for antidote treatment should not be lowered. The final 2 studies examine adverse reactions (ADRs) to NAC, a common clinical problem. The pattern and mechanisms of ADRs in man are not well described or understood. Factors influencing the frequency of adverse effects were studied in a prospective manner. Paracetamol concentration and male gender were protective and family history of allergy was a risk factor for adverse effects in this cohort. In a smaller focussed study the roles of histamine and other biomarkers as underlying pathophysiological mechanisms in ADR occurrence were studied. The severity of ADRs correlated with the extent of histamine release, which was independent of tryptase increase, suggesting a non-mast cell source. The mechanisms by which paracetamol might lessen histamine release require further investigation.

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The primary aim of this thesis was to establish the mode of action of the heavy metal, copper, on the cardiac physiology of the blue mussel, Mytilus edulis. Exposure of specimens of M.edulis to dissolved copper led to a decrease in heart rate and an increase in heart rate variability (HRV). The concentration of copper causing a 50% reduction in heart rate was found to be 0.8µM, while the concentration causing a 50% increase in HRV was 0.06µM (48 h EC50s). Simultaneous measurements of valve activity indicated that the observed bradycardia was not caused by valve closure. Subsequently, it was considered that copper might directly affect cardiac physiology by disrupting important cellular functions of the heart. Four different ionic currents were identified and characterised in M.edulis ventricular myocytes: two outward potassium currents, a sodium current and a calcium conductance. Copper ions had no effect on the ionic currents of M.edulis heart cells at concentrations shown to inhibit the cardiac activity of whole animals. Clearly, the bradycardia measured in whole animals was not due to a change in the configuration of the ventricular action potential. It was recognised that copper could still directly affect cardiac physiology in mussels by altering excitation-contraction coupling, contractile protein function or myocardial energy production. To determine whether this was the case, recordings of heart contractions from isolated ventricular strips were made using an isometric force transducer. Using isolated strips, inhibition of cardiac activity was only induced by exposure to copper concentrations ≥1 mM. Thus, the fall in heart rate measured in the whole animals dosed with copper could not be attributed to direct cardiomyopathy. Control of the. beating of M. edulis heart is known to be exercised by nerves from the visceral ganglion (VG) that contains both excitatory and inhibitory fibres. Following the removal of the VG (in vivo), exposure to copper had no effect on the heart rate of whole animals as occurred in the initial experiments. This suggests that copper affects the heart rate in M.edulis via a neuronal pathway. The principal cardioexcitatory and cardioinhibitory transmitters in molluscs are thought to be serotonin and acetylcholine, respectively, The effect of copper on the heart rate of M.edulis could not be abolished by depletion of the monoamine content of the animal using reserpine. However, pre-treatment of mussels with α-bungarotoxin considerably reduced the sensitivity of the heart to copper. These results indicated that the influence of copper on the heart of M.edulis might be mediated by a change in the activity of cholinergic nerves to the heart. Acetylcholine is known to have a biphasic action on the heart of M.edulis, low doses depress and high doses excite (the endpoint of both responses resulting in a cessation of the heart beat). In the final experiments of this series, mussels were injected with either benzoquinonium or D-tubocurarine, prior to copper exposure, in an attempt to selectively block the inhibitory or excitatory cholinoreceptors of the heart. Only benzoquinoniuin decreased the susceptibility of the heart to copper, suggesting that copper affects the cardiac activity of blue mussels by stimulating inhibitory cholinergic nerves to the heart. It is suggested that there may be a chemosensory mechanism present in mussels which responds to increased levels of metals in seawater leading to changes in a number of physiological functions. The last result chapter of this thesis examined the effects of the organophosphorous pesticide, dimethoate, on cardiac and acetylcholinesterase (AChE) activity in the common shore crab Carcinus maenas. Cardiac activity was measured non-invasively before and during dimethoate exposure. Heart rates decreased in a concentration-dependent manner. Serial measurements of AChE activity in haemolymph samples taken from crabs before and after exposure indicated that 2 mg 1ˉ¹ dimethoate also significantly reduced AChE activity. The percentage inhibition in AChE activity was correlated with the percentage reduction in heart rate following dimethoate exposure. This suggests that organophosphates may directly affect neuronal control of the heart. These experiments indicate that non-destructive, serial measurements of cardiac activity and AChE activity are valuable biomarkers of organophosphate exposure and adverse effects.

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To ensure oil sands process water (OSPW) is suitable for discharge into the environment, advanced water treatment technologies are required. In this study, integrated ozonation-biodegradation was investigated as a potential treatment option for OSPW. The treatment efficiency was evaluated in terms of naphthenic acid (NA) degradation, chemical oxygen demand (COD), carbonaceous Biological oxygen demand (CBOD), and acute toxicity reduction. Degradation of NAs of more than 99% was achieved using a semi-batch ozonation system at a utilized ozone dose of 80 mg/L combined with subsequent biodegradation. The results also show that ozone decreased the amount of COD while increasing the biodegradability of COD. It was noted that the carbon number and number of NA rings influenced the level of NA oxidation. With a utilized ozone dose of approximately 100 mg/L, the ozonated and biodegraded treated OSPW showed no toxic effect towards bacterium Vibrio fischeri. The results of this study indicate that integrated ozonation-biodegradation is a promising treatment technology for OSPW. / Environmental Engineering

Thesis (Ph. D.)--University of Adelaide, 1989. / Includes bibliographical references (leaves 116-138).

Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1999. / Erratum tipped in before chapter 1. Bibliography: leaves 226-248.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references (leaves 63-77). Also available via the Internet.

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