A Model for Estimation of Human Exposure to Endogenous N-Nitrosodimethylamine

Tannenbaum, Steven R.

doi:10.1159/000225442

Cited by 17 publications

(4 citation statements)

References 17 publications

(18 reference statements)

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“…Significant human exposure is also derived from endogenous formation of NDMA in the stomach and possibly in other body compart-ments (5)(6)(7)(8). Accurate, direct estimation of endogenous exposure to NDMA is not possible, but, based on indirect evidence, it has been suggested that this mode of exposure may greatly exceed that arising from exogenous sources and may constitute a significant cancer risk factor for man (9,10). Although epidemiological studies have provided evidence compatible with a carcinogenic role of NDMA in man, such evidence is far from conclusive, possibly because the effectiveness of these studies was compromised by the difficulty of estimating the true extent of total NDMA exposure (11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Souliotis¹

1998

Carcinogenesis

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Groups of lambda lacZ transgenic mice were treated i.p. with N-nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed for up to 14 days in various tissues. Adduct induction in the liver exceeded by at least one order of magnitude than observed in the next nearest target tissue (lung), and was approximately linearly related to dose, except for O6-methylguanine after the first dose of 1 mg/kg which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days. Small but marginally significant increases in mutant frequency were consistently observed in the spleen after all three modes of treatment. A lack of proportionality between mutation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-related cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant frequency), NDMA was found to increase the frequency of GC-->AT mutations (with a concomitant shift of their preferential location from CpG sites to GpG sites), which made up approximately 60% of the induced mutations. Surprisingly, NDMA also caused a significant increase in deletions of a few (up to 11) base-pairs (22%).

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Section: Introductionmentioning

confidence: 99%

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Souliotis¹

1998

Carcinogenesis

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“…Despite the multiple possible sources of error in the estimates of endogenous formation of NDMA we have derived, it seems clear that formation rates approaching 1 mg/day are usual and in some individuals such formation can be significantly greater. Notably, Tannenbaum estimated that up to 670 μg/day of NDMA was formed endogenously using similar methodology.…”

Section: Discussionmentioning

confidence: 88%

Drinking Water as a Proportion of Total Human Exposure to Volatile N‐Nitrosamines

Hrudey

Bull²,

Cotruvo³

et al. 2013

Risk Analysis

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Some volatile N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), are recognized as products of drinking water treatment at ng/L levels and as known carcinogens. The U.S. EPA has identified the N-nitrosamines as contaminants being considered for regulation as a group under the Safe Drinking Water Act. Nitrosamines are common dietary components, and a major database (over 18,000 drinking water samples) has recently been created under the Unregulated Contaminant Monitoring Rule. A Monte Carlo modeling analysis in 2007 found that drinking water contributed less than 2.8% of ingested NDMA and less than 0.02% of total NDMA exposure when estimated endogenous formation was considered. Our analysis, based upon human blood concentrations, indicates that endogenous NDMA production is larger than expected. The blood-based estimates are within the range that would be calculated from estimates based on daily urinary NDMA excretion and an estimate based on methylated guanine in DNA of lymphocytes from human volunteers. Our analysis of ingested NDMA from food and water based on Monte Carlo modeling with more complete data input shows that drinking water contributes a mean proportion of the lifetime average daily NDMA dose ranging from between 0.0002% and 0.001% for surface water systems using free chlorine or between 0.001% and 0.01% for surface water systems using chloramines. The proportions of average daily dose are higher for infants (zero to six months) than other age cohorts, with the highest mean up to 0.09% (upper 95th percentile of 0.3%).

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“…Nevertheless, these data suggest that a large part of human exposure to NDMA (and presumably to NOC in general) may arise from endogenous formation. Moreover, by applying a similar methodology and formulating a simple mathematical model to estimate the order of magnitude of the NDMA flux, based on blood concentrations and assuming a quasi-steady state between formation and metabolism, Tannenbaum estimated that up to 670 µg/day of NDMA can be formed endogenously (Tannenbaum 1980 ).…”

Section: Exposure To N -Nitrosating Agents: the Co...mentioning

confidence: 99%

Commentary of the SKLM to the EFSA opinion on risk assessment of N-nitrosamines in food

Eisenbrand,

Buettner,

Diel

et al. 2024

Arch Toxicol

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Dietary exposure to N-nitrosamines has recently been assessed by the European Food Safety Authority (EFSA) to result in margins of exposure that are conceived to indicate concern with respect to human health risk. However, evidence from more than half a century of international research shows that N-nitroso compounds (NOC) can also be formed endogenously. In this commentary of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG), the complex metabolic and physiological biokinetics network of nitrate, nitrite and reactive nitrogen species is discussed with emphasis on its influence on endogenous NOC formation. Pioneering approaches to monitor endogenous NOC have been based on steady-state levels of N-nitrosodimethylamine (NDMA) in human blood and on DNA adduct levels in blood cells. Further NOC have not been considered yet to a comparable extent, although their generation from endogenous or exogenous precursors is to be expected. The evidence available to date indicates that endogenous NDMA exposure could exceed dietary exposure by about 2–3 orders of magnitude. These findings require consolidation by refined toxicokinetics and DNA adduct monitoring data to achieve a credible and comprehensive human health risk assessment.

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A Model for Estimation of Human Exposure to Endogenous N-Nitrosodimethylamine

Cited by 17 publications

References 17 publications

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Drinking Water as a Proportion of Total Human Exposure to Volatile N‐Nitrosamines

Commentary of the SKLM to the EFSA opinion on risk assessment of N-nitrosamines in food

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