Abstract
Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.
Highlights
In July 2018, the US Food and Drug Administration (US FDA) announced the recall of several drug products containing valsartan, a widely used angiotensin II receptor blocker (ARB), after the detection of the nitrosamine N-nitrosodimethylamine (NDMA) [1]
NDMA and other nitrosamines were detected in additional ARBs, certain histamine-2 blockers used to treat heartburn and gastroesophageal reflux disease (GERD), and in an antihyperglycemic medication used to treat type 2 diabetes
NDMA has two methyl groups and is the simplest member of the NMAs, while the structurally similar nitrosamine NDEA has two ethyl groups attached to the second nitrogen
Summary
In July 2018, the US Food and Drug Administration (US FDA) announced the recall of several drug products containing valsartan, a widely used angiotensin II receptor blocker (ARB), after the detection of the nitrosamine N-nitrosodimethylamine (NDMA) [1]. US FDA issued the first voluntary recall alert for the antismoking drug varenicline following detection of another nitrosamine, N-nitrosovarenicline [3]. The nitrosamine contaminants that prompted the US FDA recall announcements are NDMA, N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA; N-nitrosomethyl-3-carboxypropylamine), and N-nitroso-varenicline. NMBA, induces bladder and kidneyProtection tumors in Agency rats [11,12]. In internationally harmonized third contaminant, NMBA, induces and tumors in rats. The third guidance on impurities in pharmaceuticals, based on their mutagenic properties and no data are available for as no carcinogenicity carcinogenicity data are available for as no contaminant, NMBA, induces bladder and kidney tumors in rats [11,12].
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