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G J Oliver

Publications and source records attributed to G J Oliver.

12 recordsLinked to original sources
PubMed1990

The international validation of a fixed-dose procedure as an alternative to the classical LD50 test.

In an international study involving 33 laboratories in 11 countries, the acute oral toxicity to the rat of 20 substances and preparations was evaluated using a fixed-dose procedure and the results compared with those obtained for the test materials using the classical LD50 test. The study has shown that the fixed-dose approach to acute oral toxicity testing: (1) produces consistent results that are not substantially affected by inter-laboratory variations; (2) provides adequate information for risk assessment purposes on signs of toxicity, including their nature, time to onset, duration and outcome; (3) uses fewer animals than the current internationally agreed OECD procedure (Guideline 401-revised); (4) subjects animals to less pain and distress than the classical LD50 test and causes less compound-related mortality; and (5) enables substances and preparations to be ranked according to the EEC classification system on the basis of their acute oral toxicity, such ranking being compatible with that allocated by the results of classical LD50 studies.

Administration, Oral↗
PubMed1987

Urinary enzymes and protein patterns as indicators of injury to different regions of the kidney.

Acute experimental models of renal damage to the proximal tubular, glomerular, and papillary regions of the rat were produced by administration of hexachloro-1:3-butadiene (HCBD), puromycin aminonucleoside (PAN), and 2-bromoethylamine (BEA), respectively. Several routine indicators of nephrotoxicity, the enzymes alkaline phosphatase and N-acetyl-beta-glucosaminidase, and the molecular weight of protein excretion were determined on urine samples. Tubular damage produced by HCBD or BEA was discriminated both quantitatively and qualitatively from glomerular damage produced by PAN. The latter was characterized by a pronounced increase in protein excretion, especially proteins with molecular weight greater than 40,000 Da. In contrast, protein excretion in tubular damage was raised only slightly and characterized by excretion of proteins of a wide range of molecular weights. Proximal tubular damage caused by HCBD and papillary damage caused by BEA were distinguished both by conventional urinalysis (volume and specific gravity) and by measurement of the two urinary enzymes. Alkaline phosphatase and glucose were markedly and transiently elevated in proximal tubular damage and N-acetyl-beta-glucosaminidase showed a sustained elevation in papillary damage. It is concluded that both selective urinary enzymes and the molecular weight pattern of urinary proteins can be used to provide diagnostic information about the possible site of renal damage.

Animals↗
PubMed1987

A quantitative assessment of pyrethroid-induced paraesthesia in the guinea-pig flank model.

Pyrethroids are known to induce cutaneous effects in man which are distinct from the classical irritation and vascular responses. These effects are characterised by transient facial burning and tingling sensations. The aetiology of this cutaneous effect is related to the ability of pyrethroids to produce trains of nerve impulses in afferent nerves by prolonging the opening of the neuronal sodium channel. The veratrum alkaloids which are structurally dissimilar to the pyrethroids are known to affect the sodium channel in a similar manner. Using the guinea-pig flank model which has been developed to study this cutaneous phenomenon we have constructed dose-response curves to three structurally related pyrethroids (permethrin, cypermethrin and deltamethrin) and to a mixture of veratrum alkaloids (veratrine). In addition we have examined the time course over which these chemicals elicit a response.

Animals↗
PubMed1987

A balanced approach to the detection, characterisation and mechanism of the toxicity of industrial chemicals.

Several thousands of new chemical entities are synthesised each year in the laboratories of the world. Currently there are estimated to be some 100,000 substances used commercially of the 7 million chemicals recorded by chemical abstracts (Ca 1.5%). Public attention is mainly attracted to the potential life threatening and ill health effects of chemicals such as systemic poisoning, carcinogenicity, teratogenicity and mutagenicity, although there are relatively few proven human chemical carcinogens, teratogens or mutagens. Many substances have been examined in animal toxicity studies for their acute toxic effects, far fewer for chronic toxic effects. The public's perception is that chemicals are toxic. In our laboratory, minimal to no lethal toxic effects were recorded for more than 60% of substances examined at doses below 2000 mg/kg/bwt by either oral or dermal routes. A similar spectrum of chemicals did not elicit skin or ocular irritant or skin sensitisation response in 70-80% of studies. Perversely although toxicity studies reasonably predict the probable human response following exposure, they are a focus of a strong public lobby supported by many scientists to curtail studies in experimental animals. Consequently, much effort is devoted towards the development of "alternative" in vitro and ex-vivo procedures. Often these are empirically based without consideration of the underlying fundamental physiology, biochemistry or toxic mechanism of action. Consequently there can be an over-estimation or expectation of their ability to predict potential toxicity. Attention is seldom directed towards the design requirements of the validation studies needed to test, performance and reproducibility and the evaluation of the parameters of sensitivity and specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

An in vitro epidermal slice technique for identifying chemicals with potential for severe cutaneous effects.

We have developed an in vitro model, using epidermal slices, to identify skin-corrosive potential. Such potential has been correlated with the ability to lyse stratum corneum, indicated by a lowered electrical resistance of the skin slice. Using 41 corrosive and 22 irritant chemicals, a comparison of in vitro and in vivo classifications has shown that this in vitro technique identifies corrosive agents with high precision. Therefore the model has considerable potential as a prescreen to conventional animal tests and, unlike in vivo screening tests, can provide both objective and quantifiable data.

Animals↗
PubMed1982

A comparison of techniques for the measurement of transepidermal water loss.

An Evaporimeter and a ventilated chamber technique have been compared in their ability to measure transepidermal water loss (TEWL) through rat skin. These techniques measure TEWL under very different conditions; the Evaporimeter measures the net TEWL under ambient relative humidity (RH) whereas the ventilated chamber employs a constant atmosphere, usually of low RH and thus measured the uni-directional diffusion of water. Paired Evaporimeter and ventilated chamber measurements were made of TEWL through normal skin and through skin whose barrier properties had been altered by tape-stripping (15 applications) or single applications of n-hexadecane (28.4 mumol cm-2). Both measuring techniques indicated the same level of TEWL through normal skin (mean 0.3 mg cm-2 h-1) and during increases in TEWL induced by n-hexadecane (max TEWL c 3.5 mg cm-2 h-1). However, the Evaporimeter was found to underestimate the higher rates of TEWL induced by tape-stripping, ie above TEWL raters of 7.5 mg cm-2 h-1. The Evaporimeter is portable, easy to use and suitable for measurements of net water loss up to 7.5 mg cm-2 h-1; it can only be used for comparative assessment of epidermal barrier function if used at a particular ambient RH. The more cumbersome ventilated chamber is to be preferred for accurate assessments of barrier function where high rates of TEWL occur.

Adhesives↗
PubMed1975

The mannosylation of dolichol-diphosphate oligosaccharides in relation to the formation of oligosaccharides and glycoproteins in pig-liver endoplasmic reticulum.

In the chain-lengthening of the oligosaccharide chains of endogenous dolichol-diphosphate oligosaccharides (DOL-P-P-oligosaccharides) by a pig liver microsomal preparation dolichol-monophosphate mannose (Dol-P-Man) was a more efficient donor of mammose (a maximum of 35% transferred by 5 min) than was GDP-Man (reaching 16% by 45 min). The effects of an excess of GDP, an excess of GDP-Man, a lack of Mn2+ and an excess of EDTA showed that the transfer from GDP-Man was via Dol-P-Man. The evidence also indicated the presence of two pools of Dol-P-Man one of which was difficult to extract and which was possibly closely associated with the Dol-P-P-oligosaccharides and the appropriate transferase. After 1 h of incubation transfer of 14C to 'insoluble polymer' from GDP-[14C]Man, Dol-P-[14C]Man and Dol-P-P-[14C]oligosaccharides reached approximately 3%, 3% and 13% respectively, of that available. The result of adding excess unlabelled GDP-Man to an incubation with GDP-[14C]Man in progressconfirmed the sequence GDP-Man leads to Dol-P-Man leads to Dol-P-P-oligosaccharide leads to insoluble polymer. Solubilisation with sodium dodecyl sulphate of the radioactive 'insoluble polymer' followed by gel chromatography showed the presence of radioactive glycoprotein and oligosaccharide when either GDP-[14C]Man or Dol-P-P-[14C]oligosaccharide was used as donor. The proportion of oligosaccharide formed rose sharply when excess EDTA was present and GDP-[14C]Man was the donor. Under these conditions the oligosaccharide contained 5--6 units and all of the radioactivity could be released by alpha-mannosidase. The glycoprotein was susceptible to proteolysis.

Animals↗
PubMed1975

The transfer of mannose to dolichol diphosphate oligosaccharides in pig liver endoplasmic reticulum.

The transfer, catalysed by pig liver microsomal preparations, of mannose, from GDP-mannose, to lipid-linked oligosaccharides and the properties of the products are described. Solubility, hydrolytic and chromatographic data suggest that they are dolichol diphosphate derivatives. The presence of two N-acetyl groups in at least part of the heterogenous oligosaccharide portion was tentatively deduced. Reduction with borohydride of the oligosaccharide showed that the newly added mannose residues were not at its reducing end. Periodate oxidation suggested that 60% of these were at the non-reducing terminus and that 40% were positioned internally. T.l.c. showed the presence of seven oligosaccharide fractions with chromatographic mobilities corresponding to glucose oligomers with 7-13 residues. The molar proportions of the oligosaccharide fractions in the mixture were determined by borotritiide reduction and the number of mannose residues added to each oligosaccharide fraction during the incubation was calculated. Two of the oligosaccharide fractions had received on average one, or slightly more than one, mannose residue per chain during the incubation; four of the other fractions were each shown to be a mixture, 20-25% of which had received one mannose residue during the incubation and 75-80% of which had not been mannosylated during the incubation. This supported other evidence for the presence of endogenous lipid-linked oligosaccharides in the microsomal preparation which had been formed before the incubation in vitro. Evidence for the possibility of two pools of dolichol monophosphate mannose, one being more closely associated with mannosyl transfer to dolichol diphosphate oligosaccharides than the other, is also discussed.

Animals↗
PubMedDate not supplied

An in vitro skin corrosivity test--modifications and validation.

An in vitro rat epidermal slice technique has been developed for identifying chemicals with potential to cause a corrosive lesion in animal skin in vivo. This potential has been correlated with the ability to lyse stratum corneum and has been measured as a lowering of the electrical resistance of the skin slice. Initial validation of the technique with 63 chemicals resulted in a high sensitivity for corrosive chemicals but a lower specificity for irritant chemicals. Subsequent modification relating to chemical contact resulted in an improved specificity (i.e. fewer false positives) at the expense of a small loss in sensitivity (i.e. an increase in the number of false negatives). An intralaboratory double blind trial with 34 corrosive chemicals and 36 irritants showed the technique to have total sensitivity (i.e. no false negatives) and a specificity of 88%. The results of the initial validation and the double blind trial illustrate the robust nature and high reproducibility of this in vitro technique for identifying skin-corrosive chemicals. Overall the model has considerable potential as a pre-screen for conventional animal tests with the additional advantage of providing objective and quantifiable information.

Animals↗