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Biomedical subjects

A J Ingram

Publications and source records attributed to A J Ingram.

At least 37 records · Page 2Linked to original sources
PubMed1991

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin.

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumour incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evidence for a non-genotoxic mechanism. Examples of such substances include croton oil, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.

Animals↗
PubMed1990

Carcinogenic oil fractionation and nuclear enlargement in mouse skin.

A non-solvent-refined oil, previously shown to produce tumours in a long-term skin painting assay and a positive result in the mouse skin nuclear enlargement test, was separated using silica gel elution techniques into eight fractions. Fraction 1, which contained saturated and 1-2 ring aromatic hydrocarbons, was used to dilute the other fractions to produce solutions equivalent to and twice their original concentration in the intact oil. Fraction 1, diluted fractions 2-8, the reconstituted oil, the original oil and a negative control oil were examined for their ability to produce nuclear enlargement. The degree of nuclear enlargement observed with fraction 1 was considered to indicate marginal or no carcinogenic activity. With the fraction that contained 2-3 ring aromatic compounds, weak carcinogenic activity could not be ruled out but it is unlikely that these components played a major role in the carcinogenicity of the oil. The greatest activity was identified in the fraction containing the total 3/4-6 ring polycyclic aromatic hydrocarbons (PAHs) and further fractionation of this suggested that the parent 4-6 ring PAHs were responsible for more than half the activity of the intact oil, despite being present at only 0.06%. The fraction that contained polar compounds showed no activity. The reconstituted oil showed slightly less activity than the original oil. Other fractions, which contained alkylated PAHs, did not seem to have much activity. These findings, which are in close agreement with published evidence on tumour induction by fractions of oils and coal liquids, suggest that the components responsible for inducing nuclear enlargement are the same as those responsible for skin tumour induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The chemical, physical and biological properties of a neat cutting oil during prolonged use in a large manufacturing facility.

A 5-year study was conducted to investigate changes in the chemical, physical and biological properties of a neat cutting oil during prolonged use in a large manufacturing facility. Samples of cutting oil and other materials as appropriate, were collected at regular intervals. They were analysed for individual and total 4-6 ring polycyclic aromatic hydrocarbons (PCAs), additive and wear elements, boiling range, viscosity and particulates and in addition they were tested biologically to determine irritancy, sensitization and carcinogenic potential. Records were kept of plant utilization data and all oil additions, including the headstock lubricant and hydraulic oil which entered the cutting oil as contaminants on a regular basis. The cutting oil was 'laundered' each year. This involved removal of water and particulates, the lowering of viscosity by addition of mineral seal oil and the adjustment of the additive balance. The total amount of new oil entering the system during the study period amounted to an oil renewal rate averaging 38% by volume per annum. The generation of individual PCAs during the use of the cutting oil was slow and the dilution effect of oil additions prevented their excessive build-up. An equilibrium was reached after 2-3 years. The low level of build-up of individual PCAs was sufficient to produce a measurable increase in total PCAs determined by a gravimetric method. Laundering had no effect on individual PCA content or on the presence of wear elements but was useful in maintaining the physical properties and additive content. No evidence of any increase in irritancy, sensitizing or carcinogenic potential was found in the course of the study. These findings may also be applicable to other cutting oil systems, if the manner of use, the solvent-refined quality of all oils used, rate of oil losses and additions and the volume of the systems, are comparable with those described in the study.

Animals↗
PubMed1987

Nuclear enlargement produced in mouse skin by carcinogenic mineral oils.

Ten oils of differing origin, degree of refinement and carcinogenicity, were examined for their ability to produce nuclear enlargement in mouse skin following repeated topical exposure over a 3 day period. Application of the oils was made in a vehicle of methyl ethyl ketone incorporating a promoter and assessment of epidermal nuclear size was made on tissue sections using a Quantimet 720 image analyser. One of the oils reported to be non-carcinogenic, was examined initially and its inability to induce enlargement of nuclei beyond the size seen in hyperplastic skin was confirmed. The same oil was then examined in combination with benzo(a)pyrene (BaP) and, from the dose-response obtained, it was clear that the oil did not prevent BaP induced nuclear enlargement. The other nine oils were examined by comparing them with the previously tested non-carcinogenic oil. Two oils gave rise to clear nuclear enlargement; these were non-solvent refined and gave rise to skin tumours in reported long-term studies. One solvent-refined oil, which gave a single papilloma in reported long-term studies, gave borderline (non-significant) nuclear enlargement; whereas the other solvent-refined oils, including five reported as non-carcinogenic and one reported as having weak (questionable) carcinogenic activity, gave no nuclear enlargement. Further examination of the data suggested that, within the limited series of oils examined, nuclear enlargement under these test conditions correlated well with carcinogenicity and might be used for predicting the skin carcinogenicity of an oil. Studies on a further 23 oils, on which long-term studies have been carried out but not published, support this conclusion.

Animals↗
PubMed1987

A three-generation reproduction study of Ponceau 4R in the rat.

Ponceau 4R was fed to three generations of rats, at dietary concentrations to provide 0, 50, 500 or 1250 mg/kg body weight/day. In each generation treated groups consisted of 36 rats of each sex while 60 females served as controls. Apart from the F0 generation, which started treatment as weanlings, treatment was continued throughout the study, providing in utero exposure of all offspring. The F0 generation was bred twice, on the first occasion to provide animals for the next generation and for a long-term study, and a second time to provide data on in utero and post-partum development. In each generation approximately one third of the females from each group were killed before parturition to provide data on in utero development. The foetuses from these animals were examined for skeletal abnormalities. Remaining animals were allowed to litter and the offspring were monitored for 21 days after birth for survival and development. All animals were killed and subjected to a post-mortem examination which, for a proportion of each group in each generation, included recording of organ weights. Although a few adult rats died during the study these deaths were not associated with treatment. Fur of the treated animals was coloured pink, and faeces and caecal contents of animals from the two highest dose groups were yellow, the faeces also being softer than those of the controls. Treatment had no observed effect on clinical observations, body weight or food and water intake at any stage of the study. Animals fed the two highest doses for prolonged periods had enlarged caeca, but this effect was not seen in weanling animals on the same treatment. Neither the caecal enlargement nor the liver weights seen in the F2 and F3 offspring were considered to be an adverse effect of treatment. No treatment-related effects were seen in the uterine contents of females at any generation, but the skeletons of treated foetuses showed a slightly more advanced development than those of the controls. Postnatal development of offspring was not affected by treatment at any stage of the study. Tissues from the F3 animals were examined by light microscopy and revealed no treatment-related effects. It is concluded that the no-adverse-effect level for Ponceau 4R is 1250 mg/kg body weight/day.

Abnormalities, Drug-Induced↗
PubMed1985

Nuclear enlargement--an early change produced in mouse epidermis by carcinogenic chemicals applied topically in the presence of a promoter.

A series of 27 compounds, including 11 polycyclic hydrocarbons, 8 proximate carcinogens and 8 other compounds, were tested for their ability to induce epidermal nuclear enlargement in mouse skin. The materials were applied topically in methyl ethyl ketone containing 0.1% croton oil, repetitively for 3 days. Nuclear enlargement present on the fourth day was determined with the aid of a Quantiment image-analysing computer. The results obtained indicated a close correlation between the topical carcinogenicity of the test compounds and their ability to induce epidermal nuclear enlargement in the presence of croton oil.

Administration, Topical↗
PubMed1982

Chondrolysis complicating slipped capital femoral epiphysis.

In a detailed study of 249 patients, 329 cases who had slipped capital femoral epiphysis treated at the Campbell Clinic during the period from 1935 to 1973, chondrolysis was found in 79 hips in 71 patients (28.9%). The incidence of chondrolysis is correlated with the number of factors, including sex, race, chronicity and severity of displacement, and method of treatment. On the basis of biopsy observations upon 23 patients who had chondrolysis, the natural history of the disease includes self-perpetuating synovitis, and progresses with abnormal mechanical stress on the articular cartilage and the development of osteoarthritis.

Cartilage Diseases↗
PubMed1982

Short-term toxicity study of metatartaric acid in rats.

Groups of rats were given metatartaric acid in the drinking-water in concentrations of 0 (control), 0.1, 0.5 or 3.0% for 18 wk. No effects associated with treatment were seen in the results of the haematological examinations and serum analyses. The treated animals consumed less water and food than the controls, probably because of the unpalatability of the test material. Administration of the 3% solution was associated in males with a reduced growth rate, some impairment of urine-concentrating ability during prolonged water deprivation (also seen in males on 0.5%) and histopathological changes in the stomach indicative of an inflammatory response in the submucosal layer. Both sexes of the 3% group showed an increase in relative kidney weight, without accompanying histopathological change. The no-untoward-effect level in this study was 0.1% metatartaric acid in the drinking-water, equivalent to a mean daily intake of 80 mg/kg body weight in the males and 130 mg/kg in the females.

Animals↗
PubMed1979

Interaction of benzo [A] pyrene and a hyperplastic agent in epidermal nuclear enlargement in the mouse. A dose response study.

Experiments were conducted on the effects of various dose levels of benzo [a]pyrene (BP) on nuclear size in mouse interfollicular epidermis over a 3-day period. Topical application of BP was made with or without croton oil (CO) (0.1 or 0.5%) in the vehicles acetone, toluene and methyl ethyl ketone (MEK). Nuclear size was measured on histological sections either manually or by Quantimet Image Analyser. Vehicle controls treated with 0.1 or 0.5% CO in acetone or MEK gave rise to epidermal hyperplasia with some nuclear enlargement and toluene without CO produced a similar response. It was found that when BP was applied in a vehicle capable of inducing hyperplasia, the nuclear enlargement produced was greater than that produced by either the vehicle control or BP in a non-irritant vehicle. The enhancement of response to BP when tested in the presence of a hyperplastic agent resulted in lower concentrations of BP being detectable. As the levels of BP detectable by nuclear enlargement under these conditions compared reasonably well with those detectable in long-term tests, this system might be usable as a basis for a short-term test for carcinogens.

Animals↗
PubMed1977

Nuclear enlargement and DNA synthesis in mouse epidermis treated with carcinogen and promotor.

An autoradiographic investigation was made into the causes of nuclear size increase observed in the mouse epidermis within a few days of topical benzpyrene treatment. The effects of croton oil pretreatment of posttreatment in combination with benzpyrene were examined to see what effect a growth stimulus had on this response. The degree of nuclear size increase induced in the epidermis suggested that some ploidy level increase resulted from combined croton oil and benzpyrene treatment and evidence was found of a G2 block occurring in association with this. Enhancement of nuclear size increase by croton oil highlighted the importance of a growth stimulus in carcinogen induced nuclear enlargement and the implications of this are discussed. Disappearance of enlarged nuclei was seen when mice were kept for 5 days after combined croton oil and benzpyrene treatment in spite of a reduced cell loss compared with croton oil treatment alone.

Animals↗
PubMed1975

Patch testing in the rabbit using a modified human patch test method. Application of histological and visual assessement.

A 5 h, semi-occlusive human patch test repeated daily for 5 days, was modified for use in the rabbit Using this method, the relative irritancy of three cosmetic samples of known human irritancy was determined in the rabbit. In addition, attention was paid to assessment methods and a detailed histological scoring system is described as well as two methods of visual assessment. In order to compare the effectiveness of these methods, the reaction to a series of concentrations of sodium lauryl sulphate was examined. All three assessment methods gave similar results and the merits of combining histological and visual assessment are discussed.

Acanthosis Nigricans↗
PubMed1972

The lethal and hepatocarcinogenic effects of dimethylnitrosamine injection in the newt Triturus helveticus.

Single intraperitoneal injections of dimethylnitrosamine (DMN) in concentrations of up to 16 mg/g body weight, failed to have any lethal effect in newts. This treatment also failed to induce tumours in newts maintained for one year after injection.Six or 7 injections of 16 mg/g body weight of DMN, administered over a period of 3-4 weeks, gave rise to a short-term lethal effect due to liver necrosis and in the long term to liver tumours. The tumours induced were of similar type to nitrosamineinduced tumours in rats, one being an anaplastic liver tumour and the other nodular hepatic cell tumours.Attempts to maintain the tumours by grafting failed, probably due to homograft rejection.

Animals↗