In the spring of 2020, the FDA found certain batches of ranitidine (Zantac), an over-the-counter and prescription drug used to prevent and treat heartburn, to contain elevated concentrations of nitrosamines, including N-nitrosodimethylamine (NDMA). The investigation determined that the impurity was found in higher concentrations in batches stored at room temperature or higher. The FDA reported that the NDMA content in some batches of ranitidine rose to levels above the acceptable daily intake level (96 ng/day) when stored for unspecified lengths of time or at higher temperatures (FDA, 2020b). 

Animal studies carried out in past decades indicate that NDMA is carcinogenic to animals at relatively high doses  (Takayama and Oota 1965; Terracini, Magee, and Barnes 1967; Peto et al. 1984; Peto et al. 1991; ATSDR 1989). However, the effects of long-term exposure to low concentrations of NDMA in humans are not known. Regulatory agencies in the U.S., Canada, and Europe used a low-dose linearity model (which has limited biological validity) to extrapolate the risks to humans at low doses. Using results from a rat study by Peto et al. (1984), they derived an “acceptable” intake of 96 ng/day for NDMA, which approximates an excess cancer risk of 1 per 100,000 people assuming 70 years of exposure. 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).

All individuals are exposed to NDMA, which is commonly found in food and beverages, including beer, dairy products, and smoked or grilled meats  (FDA 2020a). It is estimated that a typical nonsmoking adult will ingest between 350 and 1,120 ng of NDMA per day from outside sources (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, Webb, and Swann 1983; Hrudey et al. 2013), which is between 238 and 13,125 times the FDA acceptable daily intake of 96 ng/day.

By and large, studies in human populations have established that there is no causative link between nitrosamine exposure, whether from food, pharmaceuticals, or endogenous formation, and any type of cancer (Risch et al. 1985; Rogers et al. 1995; Jakszyn et al. 2006a; Zeilmaker et al. 2010; Loh et al. 2011). A small number of studies have reported associations between nitrosamine intake or endogenous nitrosamine production and certain types of cancer (Knekt et al. 1999; Zhu et al. 2014), but these studies were unable to accurately measure nitrosamine exposure or account for factors such as obesity, alcohol intake, smoking and consumption of other chemicals that are known to increase the risk of cancer.

How Can Paustenbach and Associates Help?

Thousands of patients who took Zantac and were subsequently diagnosed with cancer at least one year later have initiated personal injury litigation against drug companies (Drugwatch 2022). From this emerged a class-action lawsuit in federal court dedicated to bladder, liver, pancreatic, stomach, and esophageal cancers; the first trials are expected to begin in late 2022 (Lawsuit Information Center Blog 2022). Cancer lawsuits in state courts are also underway. In the meantime, ultra-sensitive testing methods will continue to reveal the presence of NDMA and other nitrosamines in food, pharmaceuticals, and consumer products, with lawsuits almost certain to follow—despite the levels of these compounds being insignificant when compared to the quantities formed in the stomach.

Paustenbach and Associates scientists have considerable experience in studying the nitrosamines going back to the temporary ban of the sale of Treflan which was one of the most important herbicides in history (1977). We also have ample experience in  ligitation efforts for firms who have inconsequential concentrations of the nitrosamines in their products (including all 9 of the most common nitrosamines).  We have conducted numerous consumer product safety assessments to evaluate the potential health risks of certain impurities. Please contact us for more information regarding our capabilities.

References

ATSDR. Toxicological Profile for N-Nitrosodimethylamine. In: Service USPH, editor.: Agency for Toxic Substances and Disease Registry; 1989. p. 132.

Drugwatch. Zantac Lawsuit 2022. Available from: https://www.drugwatch.com/zantac/lawsuits/.

FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products [Internet]. U.S. Food & Drug Administration; 2020a; May 28, 2020 [cited December 21, 2021]. Available from: https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin

FDA. FDA Requests Removal of All Ranitidine Products (Zantac) from the Market. 2020b.

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National Cancer Institute. Cancer Statistics 2020 [updated September 25]. Available from: https://www.cancer.gov/about-cancer/understanding/statistics.

Peto R, Gray R, Brantom P, Grasso P. 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. 1984(57):627-65. Epub 1984/01/01. PubMed PMID: 6533057.

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