In 2020 and 2021, trace amounts of N-nitrosodimethylamine (NDMA) were found in several lots of metformin extended release (ER), a drug used to treat type II diabetes (or prevent the development of type II diabetes in individuals with prediabetes), at levels above or approaching the FDA’s acceptable intake limit (96 ng/day). NDMA is classified as “probably carcinogenic to humans” by the International Agency for Research on Cancer (IARC) (IARC, 2021). In addition, NDMA is classified by the EPA as a “probable human carcinogen” (EPA IRIS, 2002), based on sufficient evidence of carcinogenicity in animals. The FDA stated that it does “not anticipate that shorter-term exposure [to NDMA] at levels above the acceptable intake limit would lead to an increased risk of cancer” (FDA, 2020). 

Animal studies performed in the mid- to late-20^th century found that mice and rats developed cancer when exposed to extremely high doses of NDMA and other nitrosamines (as much as 1,000-fold greater doses than are eaten via food or drugs) (Takayama and Oota, 1965; Terracini et al., 1967; Peto et al., 1984, 1991). As is their common practice, regulatory agencies in the U.S., Canada, and Europe used a model with low dose linearity, which has tenuous biological validity, in an effort to estimate the cancer risk for humans. Based on the data from a study by Peto et al. (1984) in rats, they derived an acceptable daily intake of 96 ng/day for NDMA, which approximates a theoretical cancer risk of 1:100,000 assuming 70 years of exposure. This level of risk is one that has been deemed “acceptable” by the FDA and other regulatory agencies. To put this in perspective, approximately 4 in 10 Americans (e.g., 40,000 in 100,000) will develop cancer at some point during their lifetimes (National Cancer Institute, 2020).

The FDA stated that “NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of NDMA” (FDA, 2020). For example, it is estimated that a typical nonsmoking adult is exposed to between 350 and 1,120 ng of NDMA per day from food, beer, drinking water, and ambient air (WHO, 2008), which is between 3.6 and 11.6 times higher than the FDA acceptable daily intake of 96 ng/day. In addition, NDMA is produced in the human stomach endogenously in quantities ranging from approximately 22,900 ng/day (Fristachi and Rice, 2007), to up to 1.26 million ng/day (Gough et al., 1983; Hrudey et al., 2013), which is between 238 and 13,125 times the FDA acceptable daily intake of 96 ng/day.

No studies in human populations have established a causative link between NDMA ingestion, or even endogenous NDMA production, and any type of cancer. A small number of studies have reported associations between dietary NDMA intake or endogenous NDMA production and certain types of cancer, but these studies were unable to accurately measure intake of nitrosamines due to foods or account for lifestyle factors such as obesity, alcohol intake, and consumption of other ingredients that are known to increase the risk of cancer.

Manufacturers of metformin ER have voluntarily recalled several lots of metformin as the investigation continues. The FDA has stated the following in their May 2020 press release:

“Patients should continue taking metformin tablets even after recalls occur, until they consult with their health care professional who can prescribe a replacement. Patients with type 2 diabetes could face dangerous health risks if they stop taking their prescribed metformin. The FDA recommends that health care professionals continue to prescribe metformin when clinically appropriate; FDA testing has not shown NDMA in immediate release (IR) metformin products (the most commonly prescribed type of metformin)” (FDA, 2020).

How Can Paustenbach and Associates Help?

Our firm understands that personal injury litigation surrounding nitrosamine impurities in pharmaceuticals has been increasing in the past few years. We recommend that those who have detected nitrosamine impurities in their products conduct a thorough health risk assessment so they can fully characterize the possible health risks to users, as well as the strength of their defense if they are drawn into the courtroom. As we have shown in the past, when agencies identify acceptable daily intakes or tolerance levels, they often imbed many conservative assumptions that can produce risk estimates that are not representative of the risks potentially posed to the vast majority of users. In addition, the FDA has stated that “[i]mproved technology enables the detection of even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA” (FDA, 2020).

Paustenbach and Associates scientists have over 40 years of experience in conducting pharmaceutical safety assessments and in evaluating the potential health risks of impurities in consumer products. We have conducted hundreds of risk assessments over the years.  We have assisted several firms who have faced challenges involving nitrosamines in their product(s) as they deal with the press, regulatory agencies, and litigation. Please contact us for more information regarding our capabilities.

References

EPA IRIS (2002). N-Nitrosodimethylamine; CASRN 62-75-9. U. S. E. P. Agency.

FDA (2020). FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products, U.S. Food & Drug Administration,.

Fristachi, A. and G. Rice (2007). “Estimation of the total daily oral intake of NDMA attributable to drinking water.” Journal of Water and Health. 5(3): 341-355.

Gough, T. A., K. S. Webb and P. F. Swann (1983). “An examination of human blood for the presence of volatile nitrosamines.” Food and Chemical Toxicology. 21(2): 151-156.

Hrudey, S. E., R. J. Bull, J. A. Cotruvo, G. Paoli and M. Wilson (2013). “Drinking water as a proportion of total human exposure to volatile N-nitrosamines.” Risk Analysis. 33(12): 2179-2208.

IARC (2021), December 10, 2021. “IARC Monographs on the Identification of Carcinogenic Hazards to Humans.” Retrieved December 30, 2021, from https://monographs.iarc.who.int/list-of-classifications.

National Cancer Institute (2020), September 25, 2020. “Cancer Statistics.” Retrieved December 21, 2021, from https://www.cancer.gov/about-cancer/understanding/statistics.

Peto, R., R. Gray, P. Brantom and P. Grasso (1984). “Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters).” IARC scientific publications.(57): 627-665.

Peto, R., R. Gray, P. Brantom and P. Grasso (1991). “Effects on 4080 rats of chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine: a detailed dose-response study.” Cancer Research. 51(23 Pt 2): 6415-6451.

Takayama, S. and K. Oota (1965). “Induction of Malignant Tumors in Various Strains of Mice by Oral Administration of N-Nitrosodimethylamine and N-Nitrosodiethylamine.” Japanese Journal of Cancer Research. 56: 189-199.

Terracini, B., P. N. Magee and J. M. Barnes (1967). “Hepatic pathology in rats on low dietary levels of dimethylnitrosamine.” British Journal of Cancer. 21(3): 559-565.

WHO (2008). N-Nitrosodimethylamine in Drinking Water. W. H. Organization. Geneva, Switzerland.