Permitted daily exposure limits for noteworthy N‐nitrosamines

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 0.6 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.

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

“…The gene mutation assay can prove useful in establishing in vitro / in vivo correlations for mutagenicity of novel N -nitrosamines. Additionally, data from the transgenic mutation assay can be used to support a conclusion whether an N -nitrosamine lacks mutagenic and carcinogenic risk (when results are clearly negative) or to support a quantitative assessment of a compound’s mutagenic potency (in the case of positive results), , which may be useful for setting a control limit. Efforts toward developing a framework for deriving AIs based on data from a transgenic mutation assay are ongoing; however, potency comparisons with known animal carcinogenic N -nitrosamines should be helpful in differentiating highly potent CoC N -nitrosamines from those which are less potent.…”

Exploring the molecular and functional cellular response to hydrazine via transcriptomics and DNA repair mutant cell lines

“…Likewise, the genotoxic carcinogen, N ‐nitrosodimethylamine (NDMA), may be metabolized to induce DNA adducts, like O 6 ‐alkyl‐guanine (Encell et al, 1996 ), potentially giving rise to DNA replication errors and genomic instability. However, in response to the formation of these DNA adducts, the DNA repair enzyme, methylguanine DNA‐methyltransferase, can restore DNA integrity in an error‐free manner, which can result in nonlinear dose response or “practical threshold,” as has recently been described (Johnson et al, 2021 ). These two examples highlight the need to incorporate additional mechanistic experimental studies (including those conducted in this manuscript) for an enhanced and more quantitative risk assessment (MacGregor et al, 2015a , 2015b ).…”

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

“…MoA: Formation of alkylated DNA adducts and consequent mutagenesis and genomic instability are likely the most prevalent cancer-related mechanism of nitrosamines [ 529 , 533 , 536 , 543 ]…”

“…The lack of identification of nitrosamines as “known human carcinogens” is largely a consequence of the low levels of human exposure to these compounds. Using the benchmark approach, permissible daily exposures (PDE) for cancer and mutagenicity were calculated to be 6.2 and 0.6 μg/person/day for N -nitrosodimethylamine and 2.2 and 0.04 μg/person/day for NDEA, respectively [ 543 ].…”