Philippe Shubik

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

The formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and (in some experiments) dimethylamine was blocked by ascorbic acid. The extent of blocking depended on the compound nitrosated and on the experimental conditions. Urea and ammonium sulfamate were less effective as blocking agents. The possibility of in vivo formation of carcinogenic N-nitroso compounds from drugs could be lessened by the combination of such drugs with the ascorbic acid.

Skin tumorigenesis in mice by petroleum asphalts and coal-tar pitches of known polynuclear aromatic hydrocarbon content

Abstract Benzene solutions of eight petroleum asphalts and two coal-tar pitches of known polynuclear aromatic hydrocarbon content were applied topically to Swiss mice. Epidermal carcinomas and papillomas were observed in over 90% of coal-tar pitch treated animals. Only one carcinoma and 5 papillomatous growths were observed in 218 mice treated with asphalts. The relatively low tumor incidence resulting from the asphalt treatments precluded an evaluation of a possible relationship between polynuclear aromatic hydrocarbon content and tumorigenicity. An analytical method for determining the polynuclear aromatic hydrocarbon content of asphalt and coal-tar pitch is presented, and values are given for 17 such compounds in each of the test materials.

Transplacental effects of diethylstilbestrol on the genital tract of hamster offspring

Summary The effect of diethylstilbestrol (DES) was investigated in Syrian golden hamster progeny exposed during the terminal stages of gestation. Eleven pregnant hamsters were treated with 40 or 20 mg/kg body weight (b.w.) of DES. This treatment led to hyperplastic and neoplastic lesions in the reproductive system of most female progeny and was associated with continuous estrogenic stimulation. Seventy per cent of the male progeny developed spermatic granulomas of the epididymis and testis. The incidence and severity of these lesions were proportional to the dose of DES.

Carcinogenic effects of niridazole

Swiss mice received chronic treatment with the schistosomacide, niridazole, at 3 dose levels. Tumors were found in several organs, including stomach, lung, manary gland, ovary and bladder. Niridazole is, without doubt, carcinogenic to mice.

Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine

Groups of male MRC Wistar rats were treated for 2 years either with morpholine (10 g/kg food) together with sodium nitrite (3 g/l drinking water) or with N-nitrosomorpholine (NM, 0.15g/l drinking water). In both cases, a group of rats was given sodium ascorbate (22.7 g/kg food) in addition to these treatments. When ascorbate was present, the liver tumors induced by morpholine and nitrite showed a 1.7-fold longer induction period, a slightly lower incidence, and an absence of metastases in the lungs, indicating that ascorbate had inhibited the in vivo formation of NM. Ascorbate did not affect liver tumor induction by the performed NM. The group treated with morpholine, nitrite, and ascorbate had a 54% incidence of forestomach tumors, including an 18% incidence of squamous cell carcinomas, possibly because ascorbate promoted NM action in this organ.

Lack of toxicity and carcinogenicity of some commonly used cutaneous agents

The potential carcinogenicity and toxicity of several commonly used cutaneous agents (benzophenone, propylene glycol, isopropyl myristate, resorcinol, 2-ethyl-1,3-hexanediol, p-aminobenzoic acid and pyrogallol) were studied in female Swiss mice by administering repeated applications of the chemicals on the skin for the life-span of the animals. Tumors seen in both control and treated animals were mainly lymphomas, hemangiomas of the liver and lung adenomas, as well as tumors of other organs. A statistically significant increase in tumor incidence caused by the chemical treatment was not seen. Skin lesions, slight inflammation and ulceration were seen, but no persistent cutaneous abnormalities occurred. A few skin tumors were seen in treated areas as well as in untreated areas and in control animals. Thus a carcinogenic or toxic potential which would affect the use of these agents in man was not detected.

Inhibitory Effect of Ascorbic Acid on the Acute Toxicity of Dimethylamine Plus Nitrite in the Rat

Summary Gastric intubation of 1500 mg dimethylamine·HCl (DMA·HCl) plus 125 mg NaNO2/kg produced severe liver necrosis and an elevation of serum glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase levels. These effects, which are attributed to in vivo formation of dimethylnitrosamine (DMN), were completely prevented by simultaneous intubation of sodium ascorbate at doses of 90-720 mg/kg. A dose–response study on DMN indicated that apparent DMN yield in the DMA plus nitrite experiment was at least 40 mg/kg, and that the ascorbate reduced this yield to at most 10 mg/kg. Ascorbate (360 mg/kg) had no effect on the action of DMN itself and did not react in vitro with DMA, so that its effect was probably due to reaction with the nitrite. The results support our suggestion that ascorbate might be administered together with readily nitrosatable drugs, to inhibit possible in vivo formation of N-nitroso compounds. We thank Drs. P. Issenberg and L. Wallcave for useful discussions and Miss Kay Devish for technical assistance. The study was supported by Contract PH 43-68-959 with the National Cancer Institute and Grant BC-39 from the American Cancer Society.

Lifespan carcinogenicity tests with native carrageenan in rats and hamsters

Native carrageenan (Gelcarin), a widely used food additive, was tested for carcinogenicity in MRC rats and Syrian golden hamsters through lifespan studies. Three groups of 30 males and 30 females from these species received carrageenan at dose levels of either 5%, 2.5% or 0.5% in the diet daily for the animals lifespan. A trend toward an increased incidence of benign mammary tumors in females and testicular neoplasms in males occurred at the median dose level (2.5%); however, the incidence of these tumors was not statistically significant. Hamsters did not develop neoplasms in response to treatment at any dose levels. From the results of this experiment, carrageenan demonstrated no carcinogenic effects in either species.

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.

Tumur induction by 7H‐dibenzo[c,g] carbazole in the respiratory tract of Syrian hamsters

The respiratory tract of male and female Syrian golden hamsters was treated intratracheally with 7H-dibenzo[c,g]carbazole (DBC), a tobacco smoke component. The carcinogen was given by multiple instillations at two dose levels. At the lower dose (9 mg), 35 of 46 hamsters (72%) developed respiratory tract tumors. The group receiving treatment at the higher dose level (30 mg) died earlier because of the toxicity of the compound. In this group, 15 of 45 animals (33%) had respiratory tract tumors. These occurred in the larynx, trachea, bronchi, and lungs, but predominated in the trachea and bronchi. Morphologically, most tumors were papillomas and squamous cell carcinomas. This study indicates the highly potent carcinogenic effect of DBC and that respiratory tumors can be induced in this model system without any carrier dust.