title: Risk assessment of N-nitrosodimethylamine formed endogenously after fish-with-vegetable meals.
abstract: The consumption of fish and nitrate-rich vegetables may lead to the formation of the genotoxic carcinogen N-nitrosodimethylamine (NDMA) in the stomach. To assess human cancer risk associated with this formation, a dynamic in vitro gastrointestinal model was used to simulate NDMA formation in the stomach after a fish + vegetable meal. The experimental results were combined with statistical modeling of Dutch food consumption data resulting in predicted exposures to endogenously formed NDMA in the population. The 95th percentile of the long-term exposure distribution was around 4 ng/kg-bw in young children and 0.4 ng/kg-bw in adults. By comparing this exposure with the Benchmark Dose Lower bound (BMDL) 10 for liver cancer in a chronic carcinogenicity study, a chronic margin of exposure (MOE) was calculated of 7000 and 73,000 for young children and adults. Furthermore, the long-term exposure distribution was combined with a dose-response analysis of the liver cancer incidence data to obtain a cancer risk distribution for the human population. The 95th percentile of that distribution was 6 x 10(-6) extra risk for 5-year-old children and 8 x 10(-7) for adults. The liver cancer data allowed for the analysis of the relationship between tumor incidence and time to tumor. For an extra risk of 10(-6), the decrease in time to tumor was conservatively estimated at 3.8 min in the rat, equivalent to 0.1 days in humans. We also combined acute exposure estimates with the BMDL10 from an acute carcinogenicity study for NDMA, resulting in an acute MOE of 110,000. We conclude that the combined consumption of fish and nitrate-rich vegetables appears to lead to marginal increases of additional cancer risk.
authors.affiliation: Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. marco.zeilmaker@rivm.nl
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Zeilmaker
authors.forename: Martine I
authors.initials: MI
authors.lastname: Bakker
authors.forename: Ronald
authors.initials: R
authors.lastname: Schothorst
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
mesh_terms: D015197:Carcinogenicity Tests; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005502:Food; D006801:Humans; D018570:Risk Assessment; D017747:Seafood; D014675:Vegetables
chemical_list: D004128:Dimethylnitrosamine