Permitted daily exposure limits for noteworthy N‐nitrosamines
| Autor: | Sheroy Minocherhomji, George E. Johnson, Véronique Thybaud, B. Bhaskar Gollapudi, Krista L. Dobo, James Harvey, Julia Kenny, Andreas Zeller, Michelle O. Kenyon, Ryan P Wheeldon, John Nicolette, Anthony M. Lynch |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Nitrosamines Acceptable daily intake Epidemiology Guanine DNA repair Health Toxicology and Mutagenesis 010501 environmental sciences Pharmacology medicine.disease_cause 01 natural sciences DNA Adducts 03 medical and health sciences chemistry.chemical_compound medicine Animals Bioassay Genetics (clinical) Carcinogen 030304 developmental biology 0105 earth and related environmental sciences 0303 health sciences Mutation Environmental Exposure Rats chemistry Nitrosamine Carcinogens Female Carcinogenesis Water Pollutants Chemical |
| Zdroj: | Environmental and Molecular Mutagenesis. 62:293-305 |
| ISSN: | 1098-2280 0893-6692 |
| Popis: | A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N-nitrosamines, such as N-nitrosodiethylamine (NDEA), were later detected in other sartan products. N-nitrosamines are pro-mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6 -alkyl-guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA-methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error-free fashion and this can result in nonlinear dose responses and a point of departure or "practical threshold" for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench-mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans. |
| Databáze: | OpenAIRE |
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