Permitted daily exposure limits for noteworthy <i>N?nitrosamines</i>

A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs 2018, and other N-nitrosamines, such N-nitrosodiethylamine (NDEA), were later sartan products. N-nitrosamines are pro-mutagens that can react with DNA following metabolism to produce adducts, O6-alkyl-guanine. The adducts result replication miscoding errors leading GC>AT mutations increased risk of genomic instability carcinogenesis. Both NDMA NDEA known rodent carcinogens male female rats. repair enzyme, methylguanine DNA-methyltransferase restore integrity via the removal alkyl groups from guanine an error-free fashion this nonlinear dose responses point departure or “practical threshold” for mutation at low doses exposure. Following International recommendations (ICHM7; ICHQ3C ICHQ3D), we calculated permissible daily exposures (PDE) using published cancer bioassay vivo mutagenicity data determine benchmark values define points adjusted appropriate uncertainty factors (UFs). PDEs 6.2 0.6 ?g/person/day mutation, respectively, NDEA, 2.2 0.04 ?g/person/day. higher than acceptable intake (96 ng 26.5 NDEA) by regulatory authorities simple linear extrapolation carcinogenicity data. These PDE calculations bench-mark approach provide more robust assessment exposure limits compared extrapolations better inform patients exposed contaminated sartans.