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The enzymes prostaglandin synthetase (PGS) and lipoxygenase can cooxidise a variety of xenobiotics to reactive intermediates during the metabolism of arachidonic acid (AA). PGS exhibited a gradient of activity within the kidney which was greatest in the papilla and least in the cortex. Rabbit and rat renal microsomes metabolised the model compound, tetramethylphenylenediamine (TMPD), in the presence of AA by pathways which were predominantly PGS and lipoxygenase-dependent, respectively. Therefore, both enxymes may play a role in the development of site-specific nephrotoxicity within the kidney. The model papillotoxin 2-bromoethanamine (2-BEA) which exhibits target selective toxicity for the renal papilla, was found to be significantly more toxic to medullary interstitial cells than to proximal tubule cells in culture. Toxicity was enhanced significantly by AA whereas inhibitors of cyclooxygenase (indomethacin, aspirin), prostaglandin hydroperoxidase (propylthiouracyl) and lipoxygenase (nordihydrogauaretic acid) all significantly decreased 2-BEA toxicity. This suggests that toxicity is mediated either by the hydroperoxidase component of PGS or by lipoxygenase. Thromboxane A₂ (TxA₂) is thought to play a pivotal role in cyclosporin A (CsA) induced nephrotoxicity. Administration of a thromboxane synthetase inhibitor (TSI) normalised TxB₂ excretion but only partially protected against other factors involved. However, treatment with angiotensin converting enzyme inhibitor either alone or in combination with TSI did not affect CsA nephrotoxicity. Tubular toxicity, manifest as N-acetyl-β-D-glucosaminidase (NAG) enzymuria, glycosuria, vacuolation, calcification and chronic tubule damage, may contribute to the CsA-induced reduction in renal function. In addition to protecting against CsA-induced nephrotoxicity, the administration of TSI to CsA-treated rats also partially reversed pre-existing renal damage.

The effects of ultrasound on the cell membrane of HeLa cells have been investigated using 750 KHz and 1.5 MHz transducers. The insonation chamber was designed to present minimum perturbance to ultrasound, while a castor-oil filled cylinder was used to reduce unwanted reflections and subsequent interference. Cells were insonated in monolayers and cell suspensions using continuous wave ultrasound with peak intensities up to 7 W/cm² for both transducers and temperatures up to 45^oC. The insonations were carried out in progressive wave and standing wave fields. Scanning Electron Microscopy revealed damage to cell membrane of cells insonated in suspension in the standing wave fields. No damage was inflicted on HeLa cells in the monolayers which were insonated under otherwise identical conditions. Furthermore, the damage was absent in both the cell suspensions and monolayers when insonated in the progressive wave fields. The observed damage progressed through distinct stages and it was temperature and intensity dependent. Cavitation monitoring indicated the presence of oscillating gas bubbles rather than collapse cavitation. In general, all these findings have given support to shearing stresses as the likely mechanism responsible for the damage. The severity of damage produced in the HeLa cell membrane strengthens the view held by other workers that the cell membrane is a major target for ultrasound damage. Coulter Counter study has also demonstrated the dependence of cell damage on the geometry of the container and highlights the importance of specifying the precise insonation conditions. ESR spin labelling technique has been employed in this study to probe the ultrasound effect on the fluidity of cell membrane. This preliminary investigation indicated that ultrasound increases the fluidity of the cell membrane. The implication of this increase in fluidity has been discussed.

North Sea oil drilling operations employ oil-based muds which contain aromatic compounds likely to be genotoxins. Recent legislation has controlled use and discharge of the muds to try to minimise their effects. In an attempt to include a procedure in the ongoing monitoring programme in the North Sea, which could detect genotoxic effects, the sister chromatid exchange (SCE) technique has been developed in the plaice, <i>Pleuronectes platessa</i>. Preliminary work on the plaice involved developing the techniques for cytological examination and for obtaining sister chromatid differentiation. A standard technique using kidney tissue was adopted and is described and compared with that of other studies. SCE levels were measured after intra peritoneal (ip) injections of various substances in order to test the technique. Mitomycin C (MMC) commonly used as a positive control in genotoxicity studies, elicited a significant increase in SCEs when administered at 10^-4mg/g fish and resulted in mitotic inhibition at a dosage of 10^-3mg/g fish. Diesel oil and low toxicity base oil (used in drilling muds) were injected at 1.0ml/100g fish and the fish killed after periods of time. Diesel produced a peak in SCE level, almost significantly higher than control levels 7 days after injection. The low tox oil produced a significantly increased level of SCEs at 5 days after injection. Results are discussed in context of other similar studies. Environmental conditions were simulated in an experiment by exposing fish to sediments mixed with diesel and low tox oil based drilling cuttings to give sediments with theoretical oil concentrations of 5 and 50 ppm. Results show a slight but insignificant increase in SCE levels in fish exposed to sediments containing 50 ppm diesel. In a subsequent experiment fish were exposed to diesel based and different low tox oil based drilling muds in sediments, at theoretical oil concentrations of 30 ppm. No difference in SCE levels was found between any of the groups. Suggestions are put forward to explain these inconclusive results and problems encountered with the technique are discussed. A field sampling programme was carried out where plaice were collected from areas close to drilling installations in the North Sea and from control areas. SCE levels in both groups of fish were low and not significantly different. Sediment sample analysis showed that the control area was contaminated with oil, thus fish were probably exposed to higher levels of oil than in experiments. Results are discussed and an assessment of the use of the technique at sea was made. Results were analysed using analysis of variance (AOV) on transformed data, and by high SCE frequency analysis (HFC) (Carrano & Moore, 1982) in order to compare the sensitivity of the two methods. There was little difference in the sensitivity of the methods, and HFC analysis appears to have no advantage over the more established AOV. It was concluded that although the SCE technique was successfully developed in the plaice, several limitations were recognised and further studies are required before the assay could be used routinely in monitoring studies.

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