Tumorigenesis by Oxygenated Nitrosopiperidines in Rats2

Lijinsky, William; Hw, Taylor

doi:10.1093/jnci/55.3.705

Cited by 19 publications

(12 citation statements)

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“…The carcinogenicity of 3-hydroxy- N -nitrosopiperidine was evaluated in rats (15 males, 14 females) after administration via drinking water for 36 weeks (total study duration 50 weeks) resulting in adjusted daily doses of 2.38 (males) and 3.40 mg/kg/day (females). 35 A TD 50 of 0.819 mg/kg/day (CI 0.44–1.6) was calculated for the predominant tumor site (nasal cavity [12/15 males and 10/14 females]) using the more sensitive sex. An untreated control group was not included in the study; therefore, taking a conservative approach, a background tumor incidence of 0 in 15 was assumed for purposes of supporting the calculation.…”

Section: Resultsmentioning

confidence: 99%

“…There was one carcinogenicity study reported in the literature for 1-nitrosopiperidine-4-one, where the N -nitrosamine was administered daily (5 days/week) in drinking water to Sprague–Dawley rats for 36 weeks with a total study duration of 60 weeks. 35 The total cumulative administered dose of 1-nitrosopiperidin-4-one was 3.2 mmol, with corresponding adjusted daily doses in male and female rats of 1.95 and 2.80 mg/kg/day, respectively ( Table S5 ). Both male (14/15) and female (14/15) rats developed adenocarcinomas of the nasal cavity, which was the most sensitive tumor site.…”

Section: Resultsmentioning

confidence: 99%

“…Direct comparison of NPIP carcinogenic potency to that of NPIPs with various substitutions was investigated by administering equal molar doses of NPIP and substituted NPIPs to small groups of rats. 35 , 41 From these studies, it was concluded that methyl substitution at the 3- and 4-positions of the piperidine ring has little to no impact on the carcinogenic potency relative to NPIP; 41 also, there was little difference in the carcinogenic potency of NPIP when compared to 1-nitrosopiperidine-4-one, 1-nitrosopiperidine-4-ol, and 1-nitrosopiperidin-3-ol. 35 The similarity in carcinogenic potencies is reflected by overlapping CIs in Figure 3 .…”

Section: Discussionmentioning

confidence: 99%

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Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

Dobo

Kenyon

Dirat

et al. 2022

Chem. Res. Toxicol.

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The potential for N -nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N -Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N , N -dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N -nitrosamine impurities, and in cases where a significant risk of N -nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N -nitrosamine impurity. A significant proportion of N -nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N -nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N -nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N -nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N -nitrosamine impurities. The AIs of several N -nitrosamine groups were found to be considerably higher than those for the simple N , N -dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

Dobo

Kenyon

Dirat

et al. 2022

Chem. Res. Toxicol.

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“…Nitroso-3-hydroxypiperidine (56u) and nitroso-4-hydroxypiperidine (56t) are carcinogens of potency approximately equal to 56 in rats. Like 56t, 56u induces tumors of the esophagus and nasal mucosa, 333 but 56t also induces many liver tumors, especially in fcmale rats [139]. Thc ketone, nitroso-4-piperidone (56s), like the alcohol 56t gives rise only to tumors of the nasal cavity and liver in SpragueDawley rats [139], but in Fischer 344 rats 56s induces tumors of the liver and esophagus, and is somewhat less potent than 56 [140].…”

Section: Effects Of Substituenl~ In Cyclic Nitrosarninesmentioning

confidence: 99%

“…Like 56t, 56u induces tumors of the esophagus and nasal mucosa, 333 but 56t also induces many liver tumors, especially in fcmale rats [139]. Thc ketone, nitroso-4-piperidone (56s), like the alcohol 56t gives rise only to tumors of the nasal cavity and liver in SpragueDawley rats [139], but in Fischer 344 rats 56s induces tumors of the liver and esophagus, and is somewhat less potent than 56 [140]. Nitroso-3-methyl-4-piperidone (56v) is considerably more potent than 56s, but not more potent than 56, and induces only tumors of the esophagus and tongue, but no liver tumors [140].…”

Section: Effects Of Substituenl~ In Cyclic Nitrosarninesmentioning

confidence: 99%

Structure-activity relations in carcinogenesis by N-nitroso compounds

Lijinsky

1987

Cancer Metast Rev

Self Cite

111

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For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made. Nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses. There are also large differences in the types of tumor induced in rats and in hamsters. In all the studies doses of the various compounds, equimolar to the extent that was possible, are administered orally. Continuous doses (in drinking water or food) often produce a response different from that after administration of the same compound in pulsed doses (by gavage), even though the same total dose is delivered. Continuous doses of nitrosamines are usually more effective than pulsed doses, but with the nitrosoalkylureas, the reverse is more generally the case. Rat and hamster liver is a common target of many nitrosamines, but rarely of nitrosamides. The most common site of tumor induction in rats by N-nitroso compounds is the esophagus, but the hamster esophagus never responds. The pancreas duct of the hamster is a common target of nitrosamines containing a beta-oxygenated propyl group, but pancreas duct tumors are never seen in rats. Nitrosomethyl-n-alkylamines (with an even numbered carbon chain) induce bladder tumors in rats and hamsters. Many nitrosoalkylureas induce tumors of the nervous system in rats, as well as a great variety of other tumors. In hamsters, nitrosoalkylureas give rise only to tumors of the forestomach and spleen, but no tumors of the nervous system. The similar carcinogenic actions of certain groups of N-nitroso compounds can be related to their generation, directly or by metabolism, of similar simple moieties having certain organs as their target.

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The short‐term effects of carcinogens and sulphur dioxide on the nuclear size of rat nasal epithelial cells

Fowlie

Grasso

Benford

1990

J of Applied Toxicology

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Enlarged nuclei have been observed frequently as an early carcinogen-induced change in both cultured cells and in target tissues in vivo. The purpose of this work was to examine the occurrence of nuclear enlargement in the upper respiratory tract of rats to provide further evidence of whether nuclear enlargement is a reliable marker of carcinogenesis, and if it could be used as a short-term test for respiratory carcinogens. Carcinogen-induced nuclear enlargement is best demonstrated in vivo when the tissue involved has been undergoing rapid replication. Male Wistar albino rats were simultaneously exposed to an atmosphere containing sulphur dioxide (which caused a hyperplastic response in the nasal cavity) and received an i.p. injection of a nitrosamine. Sections were prepared from the nasal cavity, and the nuclear areas of respiratory epithelial cells were measured. There were some increases in nuclear size 24 and 72 h after the start of treatment. The reversal of this effect 120 h after the start of treatment may have been due to the loss of the normal ciliated mucosal epithelium, and subsequent loss of metabolic capability.

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Tumorigenesis by Oxygenated Nitrosopiperidines in Rats2

Cited by 19 publications

References 0 publications

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

Structure-activity relations in carcinogenesis by N-nitroso compounds

The short‐term effects of carcinogens and sulphur dioxide on the nuclear size of rat nasal epithelial cells

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