World Health Organization NDMA Investigation
The International Agency for Cancer Research (IARC), a unit of the World Health Organization, is the most recognized cancer research institution in the world. It brings together teams of scientists from multiple countries to investigate the cancer-causing potential of suspect chemicals and substances and publishes papers known as monographs to report the results.
After studying over 200 research papers on NDMA and the NDMA cancer risk, the IARC placed the chemical in the “Group 2A” category, meaning substances that are “probably carcinogenic to humans.” The agency found that NDMA is “carcinogenic in all animal species tested” and noted that the metabolism of NDMA by humans and animals is similar. NDMA was found to cause malignant tumor growth in multiple organs, in multiple species, by multiple routes of exposure (oral, inhalation, subcutaneous (under the skin), injections), with dose-response relationships appearing in several studies.
“N-nitrosodimethylamine should be regarded for practical purposes as if it were carcinogenic to humans.” – International Agency for Cancer Research, Monograph 17, available online here
International Agency Places NDMA in High Risk Group
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which establishes shared regulatory guidelines for nations worldwide, places NDMA among those chemicals with the highest potential for damaging DNA and causing cancer. The council refers to these chemicals as the “cohort of concern” because they could be associated with cancer risk even at very low exposure levels.
NDMA Cancer Mechanism
Cancer is known to be the result of chronic exposure to carcinogens, leading to repeated DNA damage, which the body is unable to fully repair, and finally, to genetic mutations. The NDMA cancer mechanism has been studied extensively. When NDMA enters the body, the body’s own defense system is activated. The “army” sent to destroy foreign invaders consists, in part, of a family of enzymes (proteins) known as cytochrome P450. These enzymes engage the foreign substances in complex chemical reactions.
One of the CYP450 “soldiers”—the one that is thought to target NDMA—is an enzyme known as CYP2E1. As a result of the NDMA-CYP2E1 interaction and subsequent chemical reactions, the organic compound methyldiazonium ion (MI) is formed. MI is referred to in scientific literature as an “ultimate carcinogen,” meaning that it interacts directly with cellular DNA to initiate carcinogenesis. MI does this through a process known as DNA methylation, the addition of a methyl group to the DNA molecule. DNA methylation is a normal process that affects the expression of genes—that is, the activation or suppression of the genetic instructions to make a particular product, generally a protein. Abnormal methylation caused by NDMA, however, can lead to cancer.
Scientists are also gaining detailed knowledge of the biochemical mechanisms used by the body to repair NDMA DNA damage and how those mechanisms play a role in the progression towards cancer.
How Zantac (Ranitidine) Makes NDMA
Recently, multiple generic forms of the blood pressure medication valsartan have been recalled due to contamination by NDMA and another carcinogen, N-Nitrosodiethylamine (NDEA). Investigators discovered that the NDMA in the generics was most likely produced by the actual chemical reactions that take place when valsartan is made. NDMA was introduced during the valsartan manufacturing process itself—not added later as a secondary contamination. This was a consequence of changes in the way valsartan was made.
With Zantac, the source of NDMA appears to be even more dangerous and problematic. In its initial batch testing of Zantac, which was performed according to FDA-recommended protocols, Valisure found levels of NDMA reaching as high as 3,267,968 ng (nanograms) per tablet. The FDA has set the acceptable daily intake of NDMA at 96 ng, or .096 mcg (micrograms). Valisure was looking at NDMA levels that were over 34,000 times higher than the FDA limit.
Wondering if the increased heat of the testing process may have contributed to these results, Valisure decided to test ranitidine in a different way, under conditions that simulated those found in the stomach (simulated gastric fluid with sodium nitrite). NDMA levels, while not as high, were still extraordinary, ranging from 23,600 ng to 304,500 ng, over 3,100 times the FDA’s “safe” limit.
The acidic conditions and nitrites found in the stomach appear to be the ideal environment to create NDMA from Zantac. As mentioned above, Zantac contains within its chemical structure the two ingredients necessary to make NDMA – the “N” (nitrite) and the “DMA” (dimethylamine). Valisure argues that once Zantac is ingested, the nitrite and DMA separate from the Zantac molecule. The remaining DMA may then attach to nitrites already in the stomach or the nitrite that came with the Zantac to form NDMA.
“Valisure’s testing reveals NDMA levels so high that the nitroso for NDMA likely comes from no other source than the ranitidine molecule itself.” [Nitroso refers to an atomic grouping of nitrogen and oxygen, such as found in the nitrite group of NDMA.] — Valisure Citizen Petition on Ranitidine, September 9, 2019. Available online here.
Valisure also points to a third mechanism that could lead to NDMA production after Zantac is ingested – an enzyme, dimethylarginine dimethylaminohydrolase (DDAH), that can react with ranitidine to “liberate” DMA from ranitidine, making it available to combine with nitrite from the ranitidine molecule, nitrite circulating in the body, or “other potential pathways particularly in weak acidic conditions such as that in the kidney or bladder.” This mechanism, according to Valisure, could generate millions of nanograms of NDMA throughout the body.
Stanford Study Supports Zantac Cancer Link
Additional evidence of a Zantac cancer link comes from research conducted by scientists at Stanford University. Their results were published in 2016 in the journal Carcinogenesis. The researchers tested urine samples from adult volunteers 24 hours before and after ingestion of a standard dose of 150 mg of ranitidine. They found that levels of NDMA in the urine increased 400-fold, from 110 ng to 47,600 ng. These levels, the authors wrote, severely underestimate the actual NDMA exposure in the body, since only a small fraction of the NDMA is actually excreted in the urine.
Epidemiological Studies of Zantac and Cancer
Very few epidemiological studies of patients taking Zantac have been conducted. In a study conducted by the National Cancer Institute, adult male health professionals with peptic ulcers were followed for 14 years (1986 – 2000). The subjects of the study were asked if they used either Tagamet or Zantac as a treatment. The authors of the study reported that use of either drug was associated with an increased risk of bladder cancer, though the increase fell short of statistical significance.
Zantac and Cancer
Since the formation of NDMA may occur throughout the body following Zantac ingestion, Zantac may be tied to many different cancers. Currently, the following cancers are being investigated:
- Bladder cancer
- Colon and rectal cancer
- Esophageal cancer
- Intestinal cancer
- Kidney cancer
- Liver cancer
- Lung cancer (non-smokers)
- Ovarian cancer
- Pancreatic cancer
- Prostate cancer
- Stomach cancer
- Testicular cancer
- Thyroid cancer
- Uterine cancer
The NDMA cancer connection is well established, and the biological mechanisms that underly the association are well understood. Recent research is now revealing a Zantac-NDMA-cancer connection, and the mechanisms underlying that relationship are being uncovered. It appears that daily exposure to NDMA at levels grossly in excess of FDA safety standards has been ongoing for years, and it is likely we have already seen the consequences. We just didn’t know the cause. Now we may finally have an answer.