G. Eisenbrand

Nitrate and Nitrite in Saliva

A survey is given on the occurrence of nitrate and nitrite in human saliva and the influence of the dietary nitrate intake. Nitrate, after its absorption in the upper gastrointestinal tract, reaches the salivary glands via the blood circulation where it is secreted into the oral cavity and partially reduced to nitrite by the oral microflora. There is a linear relationship between the amounts of nitrate ingested and amounts of nitrate and nitrite found in saliva. The ability of the oral microflora to reduce nitrate to nitrite depends on he individual ages. Mean salivary nitrite was found to increase from well below 1 ppm in infants of up to 6 months to about 7 ppm in adults. a remarkably different situation has been found in areas of high esophageal cancer incidence in Iran: although dietary intake of nitrate and nitrite is very low, nitrite levels in saliva, especially in children of this area tend to be much higher than those in children of western European countries.

Volatile nitrosamines in food.

The results of the systematic survey of food from the German market in regard to the occurrence of volatile nitrosamines are presented. The average daily intake for male persons amount to 1.1 microgram for N-nitrosodimethylamine (NDMA) and 0.1-0.15 microgram for N-nitroso-pyrrolidine (NPYR). About 64% of this total daily intake for NDMA is found in beer, 10% result from cured meat products. The surprising contamination of beer is formed during the drying (kilning) of malt and can be eliminated.

Carcinogenicity of methapyrilene hydrochloride, mepyramine hydrochloride, thenyldiamine hydrochloride, and pyribenzamine hydrochloride in Sprague-Dawley rats.

SummaryFour 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.

Urinary excretion of N-nitrosodiethanolamine in rats following its epicutaneous and intratracheal administration and its formation in vivo following skin application of diethanolamine

Urinary excretion of unchanged N-nitrosodiethanolamine (NDElA) following its epicutaneous and intratracheal administration was determined. Excretion rate was between 73–89% of the given dose, which was between 24 and 184 mg/animal. Formation in vivo of NDElA was demonstrated by NDElA exretion in urine in nitrite-fed rats after skin treatment with the parent amine diethanolamine (DElA). The data suggest the possibility of biological monitoring of human NDElA exposure by analysing its urinary excretion.

Carcinogenicity in rats of high oral doses of N-nitrosocarbaryl, a nitrosated pesticide

N-Nitrosocarbaryl was administered orally to 31 male Sprague-Dawley rats at doses of 130 mg/kg body weight (b.w.) twice weekly. Of the treated animals 29% died with squamous cell carcinomas of the forestomach after an average inductiom time of 167 days. The first carcinoma was observed as early as 63 days after the beginning of the experiment. In addition, 19% of the treated animals died with hyperkeratoses and 6% with papillomas in the forestomach. In contrast to the untreated controls, which had a normal life expectancy, treated animals had a very short life span due to high cumulative toxicity and the early appearance of tumors.

Urinary excretion of N-nitrosodiethanolamine administered orally to rats

N-Nitrosodiethanolamine (NDE1A) was administered by gavage to male rats in single doses of 1000, 500 and 100 mg/kg body wt. More than 70% of a given dose was excreted unchanged in the urine, essentially within the first 24 h after exposure. This high excretion rate might explain the relatively low carcinogenic potential of NDE1A, and also offers a possible method of monitoring exposure to this compound under occupational and/or environmental conditions.

Carcinogenicity of N-nitrosopyrrolidine: Dose-response study in rats

Results from a dose-response study in rats are reported, in which daily oral doses of 10, 3, 1, and 0.3 mg/kg bodyweight/day respectively were administered. The three highest dose levels resulted in incidences of liver cancer of 46, 84, and 32% respectively. In the lowest dose group (0.3 mg/kg/ day) no statistically significant increase in tumor rate compared to untreated controls was found. Ergebnisse einer Dosis-Wirkungs-Untersuchung an Ratten werden berichtet, bei welcher tägliche orale Dosen von 10, 3, 1 bzw. 0,3 mg/kg/Tag gegeben wurden. Bei den drei höchsten Dosis-Gruppen ergaben sich Leber-Krebs-Raten von 46, 84 bzw. 32%. In der Dosis-Gruppe mit 0,3 mg/kg/Tag konnte keine statistisch signifikante Erhöhung der Tumorrate im Vergleich zu unbehandelten Kontrollen beobachtet werden.

Carcinogenicity of N-nitrosoephedrine in rats.

N-nitrosoephedrine was administered orally to 32 male Srague--Dawley rats at doses of 120 mg/kg body wt. twice weekly. Of the treated animals, 50% died with preneoplastic and malignant lesions mainly in the liver, lung and forestomach. The median time of death of tumor bearing animals was 522 days after the beginning of the experiment. The observation of hyperkeratosis, papillomas, and 1 squamous cell carcinoma of the forestomach suggests that the compound not only exhibits systemic effects but is probably also a weak local carcinogen.

Occurrence of volatile N-nitrosamines in animal diets

46 samples of commercially available diets for experimental animals have been analysed for their content of volatile N-nitrosamines by use of a nitrosamine-specific detection method (TEA-detector). 80% of all analysed samples were positive for N-nitrosodimethylamine with a maximum content of 79 ppb (μg/kg) found in one sample. 59% of the samples were positive for N-nitrosopyrrolidine with 26 ppb as highest content. In 3 samples trace quantities (<1 ppb) of N-nitrosodiethylamine were found, one sample contained N-nitrosopiperidine (4 ppb). 46 Proben kommerziell erhältlicher Futtermittel für Versuchstiere wurden mittels eines Nitrosamin-spezifischen (TEA) Detektors auf den Gehalt an flüchtigen Nitrosaminen untersucht. 80% aller untersuchten Proben enthielten N-Nitrosodimethylamin, der höchste gefundene Wert lag bei 79 ppb (μg/kg). 59% der Proben enthielten N-Nitrosopyrrolidin mit einem Maximalwert von 26 ppb in einer Probe. Drei Proben enthielten Spuren (<1 ppb) von N-Nitrosodiäthylamin, eine N-Nitrosopiperidin (4 ppb).

Anticancer Activity of New Nitrosoureas against Walker Carcinosarcoma 256 and DMBA-Induced Mammary Cancer of the Rat

Three new nitrosoureas and chlorozotocin were screened for anticancer activity against Walker carcinoma 256 and DMBA-induced mammary cancer of the rat. High single doses (80% of LD50) of water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylencarboxamido)urea and 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethansulfonate effected a similar tumor weight inhibition than BCNU in treatment of subcutaneously implanted Walker 256. In dose-response studies low doses of the new analogs effected a higher tumor weight inhibition than BCNU in the treatment of subcutaneously implanted Walker 256. The therapeutic index calculated as LD50/ED50, was 2.7 and 2.4 for the new compounds in comparison to BCNU with 2.1. Chlorozotocin and 1-(methylenecarboxyethyl)-1-nitroso-3-phenylurea were not active. Against DMBA-induced mammary cancer the new BCNU analogs yielded a greater tumor weight inhibition than adriamycin and BCNU. At a dose-level of approximately LD10, the remission rates of individual tumors, which were at least 0.6 g at the beginning of treatment were 46% (13/28) for therapy with 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethanesulfonate, 32% (9/28) for 1-(2-chloroethyl)-1-nitro-3-(methylenecarboxamido)urea, 26% (6/23) for chlorozotocin, 21% (7/33) for adriamycin and 17% for BCNU, respectively. As single agents the 2 new analogs 2[3-(1-chloroethyl)-3-nitrossureido[ethylmethanesulfonate, the water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)urea and chlorozotocin were the most effective compounds against DMBA-induced mammary cancer of the rat.