Localization of the nephron site of gentamicin-induced hypercalciuria in the rat: a micropuncture study.

In vivo renal micropuncture techniques were used to locate the nephron site of hypercalciuria induced by acute gentamicin infusion in anaesthetized Sprague Dawley rats. Three series of experiments were conducted. The effect of gentamicin on calcium reabsorption in the proximal tubule (Series I) and loop of Henle (Series II) was investigated using in vivo microperfusion whereas the effect on distal calcium handling (Series III) was studied using in vivo microinfusion. In all three experimental series, acute systemic gentamicin infusion at 0.28 mg kg(-1) min(-1) caused significant hypercalciuria within 30 min of commencing drug infusion. Gentamicin had no effect on the rates of urine flow or sodium excretion. Acute gentamicin infusion had no effect on unidirectional calcium reabsorption in the proximal tubule or loop of Henle despite a simultaneous and highly significant hypercalciuria at the whole kidney level. Net fluid reabsorption was also unaffected by the drug in these nephron segments. Acute gentamicin infusion significantly increased the urinary recovery of calcium following microinfusion into early distal tubules, whereas urinary calcium recovery was decreased after microinfusion into late distal tubules. We conclude that acute gentamicin-induced hypercalciuria is mediated by a decrease in calcium reabsorption in the early distal tubule. Thus, the acute hypercalciuric effect of gentamicin occurs at a different nephron site to the nephrotoxic effects associated with longer-term administration of the drug. It is, therefore, unlikely that gentamicin-induced hypercalciuria is involved in the pathogenesis of subsequent proximal tubular cell injury.

Acute gentamicin-induced hypercalciuria and hypermagnesiuria in the rat: dose-response relationship and role of renal tubular injury.

1. Standard renal clearance techniques were used to assess the dose-response relationship between acute gentamicin infusion and the magnitude of hypercalciuria and hypermagnesiuria in the anaesthetized Sprague-Dawley rat. Also investigated were whether these effects occurred independently of renal tubular cell injury. 2. Acute gentamicin infusion was associated with a significant hypercalciuria and hypermagnesiuria evident within 30 min of drug infusion. The magnitude of these responses was related to the dose of drug infused (0.14-1.12 mg kg(-1) min[-1]). Increased urinary electrolyte losses resulted from a decreased tubular reabsorption of calcium and magnesium. 3. A rapid dose-related increase in urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion was also observed in response to gentamicin infusion. However, there was no evidence of renal tubular cell injury and no myeloid bodies were observed within the lysosomes of the proximal tubular cells. Gentamicin may thus interfere with the mechanisms for cellular uptake and intracellular processing of NAG causing increased NAG release into the tubular lumen. 4. The absence of changes in renal cellular morphology indicates that the excessive renal losses of calcium and magnesium were an effect of gentamicin per se and not the result of underlying renal tubular injury. The renal effects described in this paper were apparent after administration of relatively low total drug doses, and with plasma concentrations calculated to be within the clinical range. These findings suggest that disturbances of plasma electrolyte homeostasis could occur in the absence of overt renal injury in patients receiving aminoglycoside antibiotics.

Hepatotoxicity of N-methylformamide in mice--I. Relationship to glutathione status.

In order to investigate the link between hepatotoxicity caused by N-methylformamide (NMF) and its ability to deplete hepatic glutathione experiments were conducted in three strains of mouse which differ in their susceptibility towards NMF-induced liver damage. NMF toxicity was measured by changes in plasma levels of sorbitol dehydrogenase and alanine and aspartate transaminases. In BALB/c mice, the most susceptible strain, a hepatotoxic dose of NMF (200 mg/kg) caused a depletion of hepatic glutathione to 21% of control levels 2 hr after drug administration. In CBA/CA and BDF1 mice the same dose of NMF depleted glutathione to 53% of control levels and did not cause hepatotoxicity. In BALB/c mice depletion of hepatic glutathione by pretreatment with buthionine sulfoximine decreased the hepatotoxic dose threshold of NMF from 150 mg/kg to 100 mg/kg. Conversely, pretreatment of mice with cysteine or N-acetylcysteine protected against both glutathione depletion and NMF-induced hepatotoxicity. The results are in accordance with the suggestion that the hepatotoxicity of NMF is associated with its metabolism to an intermediate which reacts with glutathione.

Glutathione depletion in the guinea pig and its effect on the acute cochlear toxicity of ethacrynic acid.

There is controversy as to whether or not the acute cochlear toxicity of ethacrynic acid (EA) is dependent upon its metabolic conversion to EA-cysteine via conjugation with glutathione. In order to investigate this we examined the acute effects of EA on cochlear potentials in guinea pigs in which glutathione levels were decreased by prior administration of (+/-)-buthionine sulphoximine (BSO), an inhibitor of glutamylcysteine synthetase. First, we determined the effects of BSO on hepatic and renal glutathione levels in the guinea pig. Guinea pigs (pigmented animals of both sexes or male albino animals) were killed at intervals up to 72 hr after i.p. administration of 1.6 g kg-1 BSO. Livers, and also kidneys in the case of pigmented guinea pigs, were removed and total glutathione (GSH + GSSG) measured. Glutathione levels reached a nadir in the liver at 24-48 hr (11% of control) and in the kidneys at 24 hr (14% of control) after administration of BSO. Hepatic but not renal levels approached control values by 72 hr. There were no sex or strain differences. Pigmented guinea pigs were anaesthetised and their endocochlear potential and a.c. cochlear potential in response to a 4 kHz tone were measured using an intracochlear microelectrode. The depression of these potentials by i.v. administration of 60 mg kg-1 EA was not affected by administration of 1.6 g kg-1 BSO 24 hr earlier, despite profound depletion of glutathione. Also prior p.o. administration of N-acetyl-L-cysteine did not affect hepatic glutathione levels nor modify the toxicity of EA. These results suggest that the acute cochlear toxicity of EA is not altered by glutathione depletion, a finding which argues against a role for the metabolic activation of EA in its ototoxicity.

Hepatotoxicity of N-methylformamide in mice--II. Covalent binding of metabolites of [14C]-labelled N-methylformamide to hepatic proteins.

Incubation of the hepatotoxin N-methylformamide (NMF) labelled either in the methyl group (OHCNH14CH3) or the formyl group (OH14CNHCH3) with mouse hepatic microsomes in the presence of NADPH, but not in its absence, led to covalent binding of metabolites to microsomal proteins. When [14C]NMF was injected into BALB/c mice radioactivity was found to be associated with liver and, to a much lesser extent, with kidney proteins. Association of radioactivity derived from OHCNH14CH3 with hepatic proteins was higher in BALB/c mice than in CBA/CA mice and in these it was higher than in BDF1 mice. Association of label derived from either isotopomer was significantly reduced but not abolished by pretreatment of mice with cycloheximide suggesting both covalent binding and metabolic incorporation of NMF metabolites. Depletion of hepatic glutathione by pretreatment of mice with buthionine sulfoximine or diethyl maleate prior to administration of OH14CNHCH3 enhanced the association of label with hepatic proteins measured 1 hr after drug injection. Covalent binding of [14C]NMF to hepatic microsomes in vitro was abolished in the presence of glutathione. It is argued that the generation of the toxic lesion and the association of NMF metabolites with hepatic proteins may be causally related even though certain mechanistic and enzymatic details of this link remain obscure.

The relative hypolipidaemic activity and hepatic effects of ciprofibrate enantiomers in the rat.

The aim of this study was to establish whether the individual enantiomers of racemic ciprofibrate, a potent hypolipidaemic agent and peroxisome proliferator, differ significantly in either pharmacological potency or toxic potential. After a single oral dose to male Fischer F344 rats at dosages below 10 mg/kg, S(-) ciprofibrate produced slightly, but statistically significantly, greater reductions in plasma concentrations of cholesterol than R(+) ciprofibrate. Similarly, at low concentrations in F344 rat hepatocyte cultures, S(-) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal beta-oxidation activity than R(+) ciprofibrate. However, after seven daily doses, the differences in pharmacological effects of the two enantiomers were no longer apparent. Furthermore, in contrast to its effects in vitro, R(+) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal beta-oxidation activity in vivo than S(-) ciprofibrate. These observations may be possibly explained on the basis that following multiple dosing, plasma concentrations of R(+) ciprofibrate 24 hr post-dose were greater than those of its optical antipode. Thus the slightly greater potency of the S(-) enantiomer after a single dose may have been overcome by the greater plasma concentrations of the less potent enantiomer. Both enantiomers produced similar reductions in plasma concentrations of thyroxine. The data indicate that at low dosages S(-) ciprofibrate is a slightly more potent hypolipidaemic agent after a single dose in rats and a slightly more potent peroxisome proliferator at low concentrations in vitro. However, following multiple dosing, both enantiomers produced changes in plasma concentrations of lipids, hepatic enzyme activities and plasma concentrations of thyroxine which were of comparable magnitude to those produced by the racemate. Since these early changes have been linked mechanistically to the chronic toxicity of the racemate in the rat, it could be predicted that the individual enantiomers of ciprofibrate under conditions employed in chronic safety studies, would produce the same spectrum of rodent toxicity as the racemate.

Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent.

In a wide range of preclinical studies of gadodiamide injection (Omniscan, Sanofi Winthrop, New York, NY, and Nycomed AS, Oslo, Norway), the pharmacokinetics of the compound have been delineated and its safety demonstrated. The pharmacokinetic behavior of gadodiamide was consistent with its extracellular distribution. Its half-life in rats, rabbits, and monkeys was short, 18, 38, and 75 minutes, respectively. Gadodiamide was shown to be excreted rapidly, primarily through the kidneys. In rats, 94% of the administered dose was excreted in the urine within the first 24 hours after administration. Approximately 1% to 4% appeared in the feces during the same period. Gadodiamide injection has been shown to have a remarkably low acute lethal toxicity, superior to that of gadopentetate dimeglumine injection (Magnevist, Berlex Laboratories, Wayne, NJ, and Schering AG, Berlin, Germany) or gadoterate meglumine (Dotarem, Laboratoire Guerbet, Aulnay-Sous-Bois, France). In comparison with gadopentetate dimeglumine injection, gadodiamide injection had fewer effects on cardiovascular and hemodynamic function after rapid intravenous injection in anesthetized dogs and, in vitro at high concentrations, on erythrocyte fragility and arterial wall tension. The lesser effects might be attributable, at least in part, to the lower osmolality of gadodiamide injection, although it remains to be seen whether this will translate into any advantage for gadodiamide injection at the lower doses used for imaging procedures in patients. Similar to all known intravenously administered diagnostic imaging agents, gadodiamide injection produces vacuolization of the proximal tubular cells in the kidney, without any change in renal function. However, the single-dose threshold for this effect is greater than 0.5 mmol/kg in the rat; even after a dose of 10 mmol/kg, the vacuolization was only "moderate" in degree and was shown to have regressed partially during the 7 days after administration. In monkeys, administration of 0.25 mmol/kg daily for 28 days had no effect on the kidney, thus providing reassurance of the wide margin of safety for any effect of this compound on the kidney. Although intended for single administration in patients, gadodiamide injection has been studied extensively in a range of subchronic studies in rats and monkeys. The compound was well tolerated in monkeys even when administered at doses up to 1.25 mmol/kg daily for 28 consecutive days. In rats, significant toxicity occurred only at high doses, particularly in male animals, and the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism. Gadodiamide injection produced no significant irritation when administered by a variety of intravascular and extravascular routes.

The antitumour effect and toxicity of cis-platinum and N-methylformamide in combination.

N-Methylformamide (NMF), currently undergoing phase II clinical evaluation for the treatment of cancer, and the established antitumour agent cis-platinum (CDDP) have nonoverlapping toxicities, with the exception of gastrointestinal side effects. The major target organs for the toxicities of the compounds are the liver (NMF) and the kidney (CDDP). Furthermore, NMF is nonleukopenic. In view of this, and of recent evidence that NMF enhances the cytotoxic effect of CDDP in vitro the activity of NMF and CDDP against the M5076 sarcoma implanted in mice was investigated, together with the various toxicities in mice and rats. The antitumour effect of NMF in combination with CDDP was additive, but NMF did not alter the leukopenia produced by CDDP in the tumour-bearing mice. CDDP produced only a minimal increase in the hepatotoxicity of NMF in mice, and NMF did not augment the nephrotoxicity of CDDP in rats (except for a small effect on calcium excretion). The results support suggestions that clinical evaluation of combination chemotherapy with NMF and CDDP is warranted.

Assessment of renal function during high-dose cis-platinum therapy in patients with ovarian carcinoma.

Five courses of cis-dichlorodiammine platinum (II) (100 mg/m2) were given to 22 patients with advanced stage III and IV ovarian cancer. Renal function was assessed by measurement of creatinine clearance, urinary osmolality and urinary B2-microglobulin (B2MG) in all patients, and by urinary alanine aminopeptidase (AAP) and N-acetyl-B-glucosaminidase (NAG) excretion in seven patients. Serum creatinine, creatinine clearance, urinary osmolality, and urinary B2-microglobulin were within the reference ranges and did not change significantly after five courses of cis-platinum in any patient. There was a significant increase in the urinary excretion of both enzymes (AAP and NAG) within 2 days of cis-platinum administration (NAG P less than 0.05 and AAP P less than 0.07). There was evidence of a cumulative effect during treatment for AAP (P less than 0.025).

Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats.

PURPOSE: Results of a previous report showed that, if administered by intraventricular injection to access tissue normally protected by the blood-brain barrier, gadopentetate dimeglumine produced acute excitation, persistent ataxia, and widespread brain lesions in rats at 5-micromol/g brain but not at 3.8-micromol/g brain. The present study using gadodiamide was undertaken to see whether the effects were agent-specific. METHODS: Rats, surgically prepared with a lateral ventricular cannula, were administered a slow injection at 2 microL/min of gadodiamide into the lateral ventricle, and behavioral and neuropathologic changes were noted. RESULTS: Both gadodiamide and gadopentetate dimeglumine produced focal and generalized myoclonus over several hours. Gadodiamide did not produce the medium-term tremor or persistent ataxia seen after treatment with gadopentetate dimeglumine. Neuropathologic changes developed over 1 to 3 days and took three distinct forms: vacuolated thalamic lesions closely resembling those produced by gadopentetate dimeglumine; small but similar vacuolated symmetrical caudate lesions not produced by gadopentetate dimeglumine; and severe swelling and astrocytic hypertrophy and hyperplasia in the cerebellar vermis, again not produced by gadopentetate dimeglumine. Unlike gadopentetate dimeglumine, gadodiamide produced no spinal cord lesions. The cerebellar changes were seen at 1.25-micromol/g brain and above, behavioral changes at 2.5-micromol/g brain and above, and thalamic and caudate lesions at 10-micromol/g brain, the maximal dose used. Markedly reducing the rate of injecting the same volume over 28 hours prevented the acute excitation but did not reduce the severity of the morphologic effects. CONCLUSION: The acute excitatory effects of high intraventricular doses of gadopentetate dimeglumine and gadodiamide are similar and appear to be attributable to local action at the infusion site, but differences exist between the two agents in the character and topography of the distant morphologic changes. The cerebellum was the brain area most sensitive to gadodiamide in this experimental model. It is unlikely that gadodiamide would gain access to the brain at these tissue doses when used intravenously for conventional clinical imaging, but our experimental model suggested that it had some unexpectedly specific neuropathologic potential.

A study of the nephrotoxicity of three cephalosporins in rabbits using 1H NMR spectroscopy.

Male New Zealand White rabbits received a single intravenous injection of 125 mg/kg cephaloridine, 500 mg/kg cefoperazone or 1000 mg/kg cephalothin. Histological examination of kidneys at 48 h post-dose confirmed the presence of bilateral necrosis of the proximal convoluted tubules in the cephaloridine-treated animals. 1H-NMR urinalysis of cephaloridine-treated rabbits detected drug-related resonances, decreased hippurate and increased glucose at 0-24 h post-dose accompanied by elevated levels of lactate, glycine, citrate, glutamine/glutamate and alanine at 24-48 h post-dose. No histopathological changes were observed following administration of cefoperazone or cephalothin. 1H-NMR spectra of urine collected from these animals showed drug-related resonances and decreased hippurate levels at 0-24 h post-dose, and increased glucose levels at 24-48 h post-dose. Analysis of urine by conventional clinical-chemistry failed to reveal any statistically significant differences between the treatment groups. Under the conditions of this study, the nephrotoxic effects of cephaloridine and the minimal effects of cefoperazone and cephalothin could be clearly distinguished by 1H-NMR urinalysis but not by conventional urinalysis.

Abolition of the negative endocochlear potential as a consequence of the gentamicin-furosemide interaction.

The DC endocochlear potential and the AC cochlear potential in response to a 4 kHz tone were recorded in pigmented guinea pigs before and during ototoxic damage induced by sequential administration of the aminoglycoside antibiotic, gentamicin, and the loop diuretic, furosemide. Within 4 h significant diminution of the amplitude of the AC cochlear potential was accompanied by an almost complete abolition of the negative diffusion potential revealed by either furosemide administration or terminal anoxia. Thus, one of the effects of this interaction appears to involve a reduction in the potassium permeability of the cochlear partitions.

Toxic effects of non-steroidal anti-inflammatory drugs in a human intestinal epithelial cell line (HCT-8), as assessed by the MTT and neutral red assays.

The human ileocaecal adenocarcinoma cell line HCT-8 was characterized for its potential as an in vitro organ-specific model for gastro-intestinal toxicity. HCT-8 cells showed typical epithelial cell morphology, with microvilli and intercellular junctional complexes, and formed domes, consistent with transepithelial fluid secretion. The cells express three intestinal brush-border enzyme activities (alkaline phosphatase, leucine aminopeptidase and alpha-glucosidase), and adenylate cyclase can be stimulated with vasoactive intestinal peptide. The toxicity of eight non-steroidal anti-inflammatory drugs (NSAID; indomethacin, mefenamic acid, ketoprofen, ibuprofen, sulindac, aspirin, phenylbutazone and naproxen) were assessed using the MTT and neutral red uptake assays. The MTT assay was consistently a more sensitive measure of NSAID-induced toxicity, which suggests that perturbation of mitochondrial function may be an early event in NSAID-induced cellular damage. Comparing the rankings observed in acute studies in the rat in vivo with those observed with HCT-8 cells, there are some general agreements. Indomethacin, a potent ulcerogen in vivo, was consistently among the most toxic in vitro, while aspirin and phenylbutazone have comparatively low rankings in vitro and in vivo. In man, with chronic administration, indomethacin is again ranked as a potent ulcerogen, as is aspirin, in contrast to the in vitro data with HCT-8. Therefore, NSAID-induced toxicity in HCT-8 cells assessed by the MTT or neutral red assays, can only partially predict toxicity in vivo, which suggests that local gastro-intestinal environmental factors, such as luminal acidity, may play a role in vivo. The ability of HCT-8 cells to reconstitute intact epithelial layers, thereby allowing such environmental factors to be mimicked, allows further development of these cells as a model for the in vitro prediction of in vivo gastro-intestinal toxicity.

In vitro toxicity of cephalosporin and aminoglycoside antibiotics to LLC-PK(1) cells assessed by changes in glucose uptake.

Nephrotoxin-induced damage to cultured kidney cells (LLC-PK(1)) was investigated using assays of general cytotoxicity (neutral red uptake) and of functional impairment (glucose accumulation). The latter correctly ranked both the cephalosporin and aminoglycoside antibiotics (acute and chronic proximal tubule toxicants respectively) in terms of their relative in vivo toxicities. Functional impairment after low-dose long-term exposure to the aminoglycosides occurred at sublethal drug concentrations. Assessment of general cytotoxicity correctly ranked only the aminoglycoside antibiotics.

Comparison of LDH, (51)Cr, and BCECF efflux as indices of non-steroidal anti-inflammatory drug-induced toxicity in human gastro-intestinal (HGT-1, HCT-8 and T84) cell lines: BCECF efflux is not an index of plasma membrane integrity.

Toxicity induced by non-steroidal anti-inflammatory drugs (NSAIDs) was assessed in vitro in three human gastro-intestinal epithelial cell lines (gastric HGT-1, ileo-caecal HCT-8 and colonic T84) using three proposed indices of cell plasma membrane integrity. Lactate dehydrogenase (LDH) and (51)CR efflux from cells over 5 hr under control conditions was small (about 3 and 9%, respectively). In contrast, the efflux of 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) was much greater, ranging from 45% in HGT-1 cells to 76% in HCT-8 and T84 cells over 5 hr. Indomethacin increased LDH and (51)Cr efflux at concentrations >/= 5 mm. The rank order for the toxicity of four NSAIDs, assessed by (51)Cr efflux in HCT-8 cells, was indomethacin > sulindac > ketoprofen = aspirin. In contrast, the effects of indomethacin on BCECF efflux were bimodal. At concentrations ranging from 10 mum to 5 mm, depending on the cell line, indomethacin reduced BCECF efflux to a minimum of approximately 20% of the control efflux rate. With higher concentrations of indomethacin, BCECF efflux increased to levels similar to, but not exceeding, control rates. Sulindac (0.01-10 mm) and ketoprofen (1-10 mm), but not aspirin (0.01-10 mm) also reduced BCECF efflux. The reduction in BCECF efflux observed with low concentrations of NSAIDs, and the very high rate of BCECF efflux under control conditions, negates the use of this tracer as an index of plasma membrane integrity. However, this inhibition could itself be a sensitive index of toxicity. The mechanism of inhibition of BCECF efflux is suggested to be due to inhibition of transport-mediated flux, and this is a possible site for NSAID action.

Studies of a potential in vitro test for estimation of toxicity of aminoglycoside antibiotics and polyamines.

The electrophoretic mobility of phosphatidyl inositol liposomes at pH 7.4, 25 degrees C, was reduced by aminoglycoside antibiotics, neamine and several polyamines in general accordance with the number of amino-groups on each molecule. There was good agreement between the relative position of the tested compounds on the mobility-concentration graph and available information about their relative mammalian toxicities in vivo. The slope of the graph for netilmicin was distinctively flat; a comparatively flat dose-response curve for netilmicin has been reported also from in vivo studies of nephrotoxicity. Investigation of a homologous series of alpha,omega straight chain diaminoalkanes revealed that hydrophobicity did not contribute significantly to the observed interaction in this system. L-Lysine showed the weakest effect amongst all compounds tested, supporting the view that the overall positive charge on the molecule was the major determinant of the observed effect. Further structure-activity work is required to confirm whether this 'in vitro' test is predictive of the toxicity of aminoglycoside antibiotics in man.

Interaction of aminoglycoside antibiotics with phospholipid liposomes studies by microelectrophoresis.

Microelectrophoresis was found to be a rapid method for studying the interaction between aminoglycoside antibiotics and liposomes prepared from acid phospholipids. The ability to cause charge reversal of liposomes prepared from phosphatidyl inositol was ranked in the order neomycin greater than gentamicin greater than tobramycin greater than amikacin greater than kanamycin greater than ribostamycin greater than streptomycin greater than dihydrostreptomycin greater than Ca2+. Similar results were obtained with liposomes prepared from a mixture (8: 2) of phosphatidyl choline and phosphatidic acid, but no effect was detectable with neutral liposomes made from phosphatidyl choline only. The results support the view that the attraction between positively charged nitrogen groups on the antibiotics and the negatively charged groups of acidic phospholipids are predominantly responsible for the interaction. Extension of the studies to ionic strengths and calcium concentrations similar to those found in vivo showed a reduction, but not elimination, of the observed effects.

The quantification of kanamycin ototoxicity in the rat using conditioned tone discrimination.

Twelve male Lister hooded rats were conditioned to discriminate an 8 kHz tone (56.5 +/- 0.5 dB re 0.0002 dyne cm-2) and were subsequently injected subcutaneously with kanamycin (400 mg kg-1 day-1) for 28 days; during this time and for five weeks after dosage was stopped, the nature and extent of the resultant hearing deficits were studied. The animals' Preyer reflex thresholds were determined at intervals during the study. Only one rat was unaffected by the kanamycin dosage. The onset of hearing impairment (reduced discrimination performance), which was gradual in some rats and sudden in others, generally occurred during the fourth week of kanamycin dosage although the earliest onset was towards the end of the second week. In most animals the hearing impairment progressed after kanamycin was stopped and in one rat there was a latency between the end of drug dosage and onset of hearing impairment. Hearing impairment was irreversible in five rats. One rat, whose impairment was slight, recovered normal hearing. Some rats showed a reduced discrimination performance at a time when their Preyer reflex threshold showed no elevation suggesting that kanamycin, at least initially, caused a threshold elevation rather than reduced sensitivity to intense sounds.

Toxicology of sensory systems: a perspective.

This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings.

An evaluation of the use of scanning and transmission electronmicroscopy in a study of the gentamicin-damaged guinea-pig organ of Corti.

Scanning electronmicroscopy and transmission electronmicroscopy were used to study the normal and gentamicin-damaged guinea-pig organ of Corti. Scanning electronmicroscopy was principally used to locate the lesion and quantify the cell loss but also permitted and detailed study to be made of the degenerative surface changes. However, since consistent surface changes are not seen until intracellular degeneration has progressed to a great extent, scanning electronmicroscopy is not a suitable technique for identifying early degenerative changes in the sensory cells of the organ of Corti. Consequently, before conclusions may be drawn about the absence of pathological changes in the neuro-epithelium it also should be examined using transmission electron-miscroscopy.