Biomedical subjects
P Shubik
Publications and source records attributed to P Shubik.
Toxicology, disappointments and promise.
The development of toxicology during the past 50 years is traced, with particular reference to chronic testing and carcinogenesis. The increasing dichotomy between the study of human disease and the accumulation of routine experimental data is examined. It is suggested that a drastic change is needed in toxicological approaches that replaces rote testing with more thoughtful scientific research. The relationship between toxicology and human disease needs to be re-emphasized and the medical profession encouraged to take a more active role in this field.
Carcinogenicity of methapyrilene hydrochloride, mepyramine hydrochloride, thenyldiamine hydrochloride, and pyribenzamine hydrochloride in Sprague-Dawley rats.
Four histamine antagonists, methapyrilene, thenyldiamine, mepyramine and pyribenzamine were tested for carcinogenicity in rats by continuous application in drinking water. Only methapyrilene displayed significant carcinogenic effects, inducing liver tumors in a dose-related pattern. Analogues not containing a thiophene ring (mepyramine, pyribenzamine) did not exhibit neoplastic effects under the experimental conditions.
Carcinogenic activity of hexachlorobenzene in mice and hamsters.
Hexachlorobenzene (HCB) has been used as a fungicide, is a contaminant of various pesticides and is a by-product in the manufacture of many other chlorinated hydrocarbons. In Turkey, HCB caused an epidemic of toxic porphyria involving several thousand people between 1955 and 1959. The aim of the present studies was to determine the chronic toxicity of HCB after prolonged oral administration and we report here that HCB is carcinogenic in mice and hamsters. Mice and hamsters were given dietary HCB at doses of 50, 100 and 200 ppm for life, with deaths due to toxic manifestations of HCB occurring in group HCB 200. All survivors were killed after 120 weeks. In both mice and hamsters, exposure to HCB increased the incidence of liver-cell tumours but no such tumours were observed in the controls. A significant increase in the incidence of thyroid tumours and liver haemangioendotheliomas was observed in hamsters treated with HCB. Our findings that HCB is carcinogenic in mice and hamsters, together with other results showing the same effect in rats, provide sufficient experimental evidence to recommend great caution in the use of this material.
Zeranol and 17 beta-estradiol: a critical review of the toxicological properties when used as anabolic agents.
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Saccharin/cyclamates; laboratory evidence.
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Oral contraceptives and breast cancer: laboratory evidence.
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Isoniazid: laboratory evidence.
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Carcinogenicity evaluation and regulatory decisions.
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Evaluation of the toxicity and carcinogenicity of hair dyes in Swiss mice.
The chronic toxicologic and carcinogenic potential of two oxidative and twelve non-oxidative hair dyes has been evaluated. The dyes were skin painted up to 3 times weekly on groups of 60 male and 60 female Eppley Swiss mice. Treatments were carried out for 20 months followed by terminal sacrifice. Nine months after treatments were initiated an intermediate sacrifice of ten mice per sex per group was carried out. Body weights and survival differed little between appropriate male and female treatment and control groups. Differences between treated and control groups in absolute and relative liver and kidney weights and in hematological and urinary values were not considered to be indicative of toxicologic effects. Microscopic examinations of the skin revealed occasional hyperplasia, necrosis, ulceration and other lesions not significantly increased by dye treatment. Chronic inflammation of the skin was observed in the control and treated mice and was significantly increased by one non-oxidative dye. The predominant tumors diagnosed were liver hemangioma, lung adenoma and malignant lymphoma. There was a statistically significant increase in the incidence of malignant lymphoma in female mice in 3 treated groups when compared to control group 2, but the differences were not significant when these groups were compared to control group 1. In addition the values in these 3 groups were within the range of control values for this tumor in female mice in the Eppley colony. No other tumors occurred at significantly increased frequencies in treated mice. We conclude that toxicological and carcinogenic effects were not clearly induced by the hair dye formulations.
Progression and promotion.
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Chemical and viral oncogenesis.
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Lack of carcinogenicity of DDT in hamsters.
Syrian golden hamsters were fed for their lifespan a diet containing 0, 125, 250 and 500 parts per million (ppm) of ddt. The incidence of tumour bearing animals was 13% among control females and ranged between 11-20% in treated females. In control males 8% had tumours. The incidence of tumour bearing animals among treated males ranged between 17-28%. The incidence of adrenal cortex tumours showed a dose-related increase among the DDT-treated males. A liver-cell tumour and 2 liver hemangioendotheliomas were observed in 3 males treated with 250 ppm DDT. No liver-cell tumours were observed in the controls. No significant difference in tumour incidence was observed in treated versus control Syrian golden hamsters.
Effects of long-term intake of DDT on rats.
DDT is a pesticide used in malaria-control programmes throughout the world. Its potential carcinogenicity was studied in MRC Porton rats (Wistar-derived) which received dietary concentrations of 0, 125, 250 and 500 parts per million DDT (technical-grade) for life. The treatment had no adverse effects on body growth or survival rate. Various types of tumours were observed in animals in all groups: exposure to DDT resulted in statistically significant increased incidence of liver-cell tumours only in female treated rats; one such tumour was observed in control rats. No metastases of these tumours were found.
Vascularization of tumors: a review.
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Initiation and promotion at different ages and doses in 2200 mice. I. Methods, and the apparent persistence of initiated cells.
Delay between initiation and promotion on mouse skin was in 1949 reported by Berenblum and Shubik not to affect tumour yields, and this led to the important concept of the irreversibility of initiation and stimulated the development of multistage models. Subsequent reports have, however, suggested that delay does decrease tumour yields, and this is confirmed by the present study of 2200 mice initiated at 8, 48, or 68 weeks with 10, 30, 100, or 300 microgram of DMBA and promoted by a standard dose of TPA for 15 weeks, after various delays. However, our data suggest that the decrease in tumour yields is chiefly or wholly due to a reduction, among ageing mice, of the ability to respond to promoters, and not to any substantial loss of initiated cells, for late initiation with immediate promotion also yielded a less rapid response than early initiation with immediate promotion. Interpretation of all such studies is complicated by the few weeks that the skin needs to repair ulceration and other damage induced by the higher doses of DMBA, for if promotion with TPA begins before such repair is complete the tumour yield may be misleadingly increased.
Initiation and promotion at different ages and doses in 2200 mice. II. Decrease in promotion by TPA with ageing.
Using the data described in Paper I, we compare the effects of the same treatment timings and doses given at different ages. Initiation with DMBA at 68 weeks of age, followed 3 weeks later by TPA, has a significantly (P less than 0.0001) less rapid effect on subsequent tumour incidence than does initiation at 8 or at 48 weeks of age, followed 3 weeks later by TPA. We suggested that this is chiefly due not to changes in the numbers of cells initiated by DMBA, but rather to a decrease in the promotional efficacy of TPA in ageing mice.