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Abstract
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 0.6μg/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 26.5ng 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.
Highlights
N-Alkyl-nitrosamines, such as N-nitrosodimethylamine (NDMA) and Nnitrosodiethylamine (NDEA), are well-studied environmental mutagens
The analysis provides an opportunity to compare permissible daily exposures (PDE) exposure limits derived from in vivo mutagenicity data with those from cancer-studies for both compounds and thereby build on the experience with the use of mutagenicity data for benchmark dose (BMD) based risk assessments
Since the NDMA contamination issue in 2018, NDMA, NDEA, and the whole class of nitrosamines have received extensive regulatory values calculated using TD50 values, are 65-fold and 83-fold lower than the cancer PDEs calculated in the present report for NDMA and NDEA, respectively
Summary
N-Alkyl-nitrosamines, such as N-nitrosodimethylamine (NDMA) and Nnitrosodiethylamine (NDEA), are well-studied environmental mutagens. In the absence of carcinogenicity data, detailed analyses of transgenic rodent (TGR) mutagenicity dose–response data (using MutaMouse) were used to determine NOEL and Td values and modeof-action mechanisms to support a threshold-based risk assessment Their studies were used to define (a) safety factors differentiating the NOEL and the maximum human exposure level in patients who had received EMS-contaminated nelfinavir (Viracept; later shown to be a 454-fold safety margin) (Muller et al, 2009) and (b) a regulatory exposure limit below which the likelihood of a mutagenic effect was considered negligible (i.e., the PDE) (Gocke et al, 2009a; Gocke & Wall, 2009; Muller & Gocke, 2009). The values are subsequently evaluated via comparisons with the default TTC for non-nitrosamines as well as for known or estimated human exposures to nitrosamines via foods or therapeutic products (e.g., valsartan)
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