Aluminium is an element of increasing clinical importance. It not only has uses as a medicinal substance but also in recent years it has been shown to be the cause of considerable toxicity, particularly in the setting of chronic renal failure. Diseases that have been shown to be associated with aluminium, or in which it has been implicated, include dialysis dementia, renal osteodystrophy and Alzheimer's disease. This thesis has studied aspects of the interaction between aluminium and the kidney. The work has addressed two major issues. Firstly, a study is described where Malvin's stop-flow technique was used to determine any excretory/absorptive tubular site for Al in the pig kidney. Al was found to be excreted in the distal nephron of the pig kidney. Secondly, the toxic effects of Al in vitro on the DNA of pig kidney cell line LLC-PKl were investigated, in an attempt to elucidate some of the mechanisms of toxic action. DNA synthesis was measured using ³H-TdR incorporation. Over increases of both time (9-72 h) and Al concentration (0.01-8.0 mM), ³H-TdR incorporation was diminished. Effects were evident at concentrations as low as 0.05 mM Al. The production of DNA strand breaks was assessed by the increase in size of cell nucleoids (ie DNA in supercoiled form). Nucleoid size was analyzed in a Epics 753 Fluorescence Activated Cell Sorter interfaced with an MDADSII data acquisition and analysis system. After 90 min incubation with Al (over the concentration range 0.001-32 mM), an increase in nucleoid size was noted at concentrations above 0.05 mM. The data demonstrate that Al exerts an effect on kidney cells in vitro which is expressed as diminished DNA synthesis and production of DNA strand breaks. These effects on DNA may have important long-term implications on various disease states associated with Al toxicity.

Recent evidence strongly suggests that aluminum toxicity is important in determining the structural and functional characteristics of freshwater communities affected by acid precipitation. To determine the effect dissolved aluminum has on lotic invertebrates previously unexposed to anthropogenic acidification, experiments were carried out in a second-order headwater stream 50 km east of Vancouver, British Columbia during August 1982. In three separate experiments, HC1 and/or A1C1₃ were added to Mayfly Creek during daylight hours, increasing acidity from pH 6.9 - 7.0 to pH 5.8 - 6.0 and total aluminum from < 0.1 mg/L to > 1.0 mg/L. Biological response was monitored by sampling invertebrate drift with 86 Mm nets. Relative to an unmanipulated, upstream control site, drift density doubled in response to added H⁺ alone (pH 5.9). When Al₃⁺ was added (pH 5.9) drift density increased fourfold. Following 48 h continuous dosing with HC1 (pH 5.9) there was an even greater response to added Al₃⁺. Ephemeroptera were able to detect dissolved aluminum and responded almost immediately (within 45 min). Similarly, Trichoptera and Chironomidae detected increased H⁺ concentrations and responded immediately. Response to augmented Al₃⁺ by Trichoptera, Hydracarina, and Chironomidae was delayed 6 h. However, pre-exposing animals to 48 h HC1 resulted in enhanced aluminum sensitivity for Chironomidae and for Simulium and Plecoptera, which had not responded within 10 h to H⁺ or Al₃⁺ alone. It is proposed that rapid increases in drift density are due to behavioral escape responses, while delayed responses are probably associated with physiological impairment. Evidence was also obtained suggesting that during early stages of morphological development Ephemeroptera and Chironomidae are more sensitive to increased Al₃⁺ and H⁺ concentrations than during later developmental stages. In laboratory experiments using artificial stream channels, Chironomidae larvae and Ephemeroptera nymphs were exposed to CI⁻ and H⁺ concentrations, equal to those during field experiments. Results showed that drift behavior in these animals is not stimulated by mildly elevated chloride concentrations. These studies demonstrate that increased dissolved aluminum concentrations intensify biological response to acidification, and confirm acid sensitivity patterns for Ephemeroptera and Chironomidae reported by others. The observed acid insensitivity of Plecoptera, simuliids, and Trichoptera also conforms to previously described patterns. Experimentally manipulating this community produced results closely resembling those obtained in similar studies for areas currently affected by acid precipitation. The major difference in results between studies is that invertebrate communities previously unexposed to acidification contain more species sensitive to mild acidification. These latter animals are particularly sensitive to the presence of elevated dissolved aluminum concentrations. / Science, Faculty of / Zoology, Department of / Graduate