A study of tobacco carcinogenesis, LIII: carcinogenicity of N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustela vison).

In an earlier study, young male and female mink (Mustela vison) were found to be highly susceptible to the carcinogenic effect of N'-nitrosonornicotine (NNN). In this follow-up study we tested (i) the importance of the age of the animals with regard to the carcinogenic effect of NNN, (ii) the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and (iii) the combined carcinogenic effect of NNN plus NNK. (I) In the previous study, the latency of nasal tumor induction by NNN (11.9 mM) averaged 84 +/- 40 weeks upon twice weekly applications, starting at the age of 3 weeks and continuing for 38 weeks. In this bioassay, giving NNN in 28 weeks but starting at the age of 3 months, it took, on the average, 97 +/- 29 weeks to induce malignant nasal tumors, primarily esthesioneuroepithelioma with invasion of the brain. (ii) NNK (6.3 mM), given by s.c. injection, induced nasal carcinoma with invasion of the forebrain after 77 +/- 39 weeks. (iii) NNN (11.9 mM) plus NNK (6.3 mM) led to the same type of carcinoma but at an accelerated pace, namely after 71 +/- 57 weeks. This study supports the earlier observation that tobacco-specific N-nitrosamines induce malignant tumors of the nasal cavity with invasion of the brain, dependent to some degree on the age of the mink at first application. NNK appears to be a stronger carcinogen than NNN in mink which follows the observations made with mice, rats and hamsters. It is suggested that combined administration of NNN with NNK induces a stronger carcinogenic effect than NNN or NNK given alone.

A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

Plasma glucose, ketone bodies, insulin, glucagon and enteroglucagon in cows: diurnal variations related to ketone levels before feeding and to the ketogenic effects of feeds.

Ingestions of a moderately ketogenic silage twice daily were followed by transient increments in plasma insulin and ketone bodies and decreases in plasma glucose. Ketone bodies and glucose were negatively correlated throughout the day, but the insulin elevations culminated before the maximal effects on ketone bodies and glucose were established. Cows with varying glucose levels before morning feeding reacted to a highly ketogenic silage by decreasing their glucose level uniformly to about 3 mmol/l, in spite of a widely varying feeding-induced insulin increment. Hay-feeding caused insulin increments of the same magnitude as silage-feeding, but the glucose decrease and the ketone increment was much smaller. The results indicate some direct action of ketone bodies on blood sugar regulation, in addition to effects mediated by insulin. The role of ketone bodies as the insulinotropic factor was not confirmed. The insulin level after feeding seems to be determined by the carbohydrate status of the animal before feeding. No significant changes in plasma glucagon were observed after feeding, and no consistent differences in plasma levels of this hormone were found when non-ketonemic, ketonemic, and clinically ketotic cows were compared. The plasma level of enteroglucagon (GLI) was positively correlated to the relative amount of concentrates consumed, but no relation to plasma glucose was found.

[Changing food habits]. / Kostvaner i endring.

The main goal of the Norwegian policy on food and nutrition for the period 1975-1990 is to reduce the proportion of fat in the diet to 35 per cent of the energy supply. This should be achieved through a gradual change in diet. Figures on food supply and consumption show that this target has been reached. The dietary changes have probably contributed considerably to the decrease in cardiovascular disease since the early 1970s. It is most likely that public health can still gain much from further changes in the Norwegian diet.

Nitrite as a food additive.

Nitrite is used for its colouring, antimicrobial and flavouring effects as a food additive for several meat, fish and cheese products. Nitrite combines readily with secondary amines to form carcinogenic nitrosamines. Nitrosamines are found in many food products after nitrite addition and sometimes even without addition. Nitrite is regarded as an effective growth inhibitor for Clostridium botulinum and thereby its production of the lethal toxin. Today this is considered to be the main reason for addition of nitrite to food products. It should be possible to limit the addition of nitrite to a few special food products where Cl botulinum really represents a hazard to human health, i e to canned meat that is not sterilized by heat and some cured and fermented products. In Norway the use of nitrite is limited to products where growth of clostridia is possible, but in a few products nitrite is also allowed as a colour stabilizer. It is reasonable to expect that other countries will decide upon similar regulations. The naturally occurring nitrates in vegetables have to be included in the discussion due to the possibility of microbial reduction to nitrites.

Mutagenicity of nitrovin--a nitrofuran feed additive.

Nitrovin, a nitrofuran feed additive, is shown to be directly mutagenic in Salmonella typhimurium TA 98 and TA 100 between 0.1 and 2.5 microgram per plate (0.09--2.3 micrometer). Addition of a rat-liver homogenate reduces the mutation rates. Nitrovin inhibits growth of the same bacteria in suspension cultures at concentrations above 0.09 micrometer.