French drugmaker Sanofi recently announced a recall of over-the-counter Zantac, the widely used acid reflux medication, in the U.S. and Canada over concerns of possible contamination from a probable carcinogen. This action followed recalls by manufacturers and retailers of generic versions of the drug, called ranitidine. The recalls have prompted questions about whether the drugs’ levels of a chemical called N-nitrosodimethylamine (NDMA)—which has been linked to cancer in animals—pose a more serious health risk than initially reported.

Several blood pressure medications, including the angiotensin receptor II blockers valsartan, losartan and irbesartan, were recalled last year over NDMA contamination. The U.S. Food and Drug Administration first flagged the possible contamination of ranitidine products this September. At that time, the FDA said the NDMA levels found in preliminary tests “barely exceed amounts you might expect to find in common foods.” But the agency released a statement on Oct. 2 calling the levels “unacceptable.” Asked to elaborate, FDA spokesperson Jeremy Kahn says, “Although the FDA has detected NDMA in limited ranitidine samples at low levels, these levels still exceed what [the] FDA considers acceptable for these products.”

The online pharmacy company Valisure first alerted the agency in June, after it said it detected concerning levels of NDMA in ranitidine medications during some routine testing. The company filed a detailed citizen petition to the FDA in September, alleging it had found “extremely high levels of [NDMA] ... in every lot tested, across multiple manufacturers and dosage forms of the drug ranitidine.” The petition states that Valisure detected levels greater than three million nanograms per tablet—far exceeding the FDA’s permissible daily intake of 96 nanograms.

But these high levels may have been a result of the testing method Valisure used, which involves heating the sample. “That method is not suitable for testing ranitidine because heating the sample generates NDMA,” the FDA said in its Oct. 2 statement. Instead the agency recommends using one of two techniques: liquid chromatography–high-resolution mass spectrometry (LC-HRMS) or liquid chromatography–tandem mass spectrometry (LC-MS). Employing LC-HRMS, the FDAfound much-lower NDMA levels than Valisure had reported. “Valisure only showed detectable NDMA after exposing ranitidine to extreme artificial conditions—when they heated ranitidine to 266 degrees Fahrenheit [130 degrees Celsius]…or when they added artificial nitrite far beyond what is ordinarily seen in humans,” says Sanofi spokesperson Nicolas Kressmann in an email. But Valisure says it developed a version of its testing technique that could detect NDMA even when samples were only heated to 37 degrees Celsius at conditions that more closely approximate those of the human body—in simulated gastric fluid with varying amounts of nitrites, which are found in foods such as processed meats. Neither Sanofi nor the FDA would comment on the specific NDMA levels they found using the latter’s approved methods.

Sanofi has stated that it issued the voluntary recall as a precautionary measure. “Sanofi takes this issue very seriously, and we are currently conducting our own robust evaluations to ensure the safety of Zantac OTC, which has been used by consumers for over two decades,” Kressmann says. The company is testing both the active ingredient ranitidine by itself and the finished product. “We have announced inconsistent preliminary test results of the active ingredient sourced in the U.S. and Canada products,” says Sanofi spokesperson Ashleigh Koss in an email. “At this time, we don’t have any additional information to share about the specific test results.”

Tracing the Risks

In its petition, Valisure also claimed that the NDMA is likely formed as the result of an inherent instability of the ranitidine molecule. “We think the problem is much worse than contamination,” says Valisure CEO David Light. He alleges that the drug itself may break down to form NDMA.

Some research indirectly supports this idea. A 2016 study at Stanford University gave 10 healthy volunteers 150 milligrams of Zantac and found that subsequent NDMA levels in their urine exceeded 47,000 nanograms. Because most of the NDMA would have been metabolized before reaching the urine, the actual amount in the body could have been much higher, the researchers wrote. And a 2004 study of people with peptic ulcers found that those who were taking either Zantac or another antacid, Tagamet (cimetidine), had a heightened risk of bladder cancer—but it did not distinguish between which of the two medications each subject was taking. (Scientific American sought comment from Tagamet’s manufacturer, Prestige Brands, but did not receive a response by the time of publication.)

Sanofi notes that the 2016 study also used a method that involved exposing the samples to high temperatures and adding reference chemicals—both of which, the company says, could create NDMA. Sanofi also says that Zantac was not approved for sale in the U.S. until the 1980s and that nearly all of the ulcers reported in the 2004 study were formed before then. “Numerous studies since the 2004 study have shown the safety of ranitidine,” Sanofi’s Kressmann says. He cites a 2013 meta-analysis examining the link between acid-suppressing drugs—including H2 blockers such as ranitidine—and gastric cancer, which did not find a statistically significant association for the long-term use of H2 blockers. But the same analysis did find a statistically significant cancer risk within five years of use, and the authors concluded that “acid suppressive drugs are associated with an increased risk of gastric cancer.” (They noted some limitations, however, including the fact that this conclusion was based on observational studies.)

Another potential concern is that if ranitidine breaks down into NDMA, it could enter the sewage-treatment system and contaminate drinking water. NDMA from rocket fuel is a known water contaminant, and Valisure’s Light thinks the concentrations of this chemical in ranitidine medications could be large enough to pose a problem. “If you throw away these pills, [NDMA] can now enter the water supply,” Light says. He encourages people to take their medicines back to their doctor or pharmacy to dispose of them safely.

A Complex Chemistry

Ranitidine has been widely used for decades. If it poses a risk to human health, how could that have gone unnoticed for so long? Light alleges that there were some limitations in early safety studies involving Zantac in the 1980s. Glaxo—a company that eventually merged into GlaxoSmithKline (GSK)—Zantac’s original manufacturer, published a study of ranitidine’s metabolites in urine in 1981, but Light says that study appears not to have looked for NDMA. Glaxo published another study in 1987 that tested the stomach contents of people taking ranitidine, concluding that there was “no significant increase” in the concentration of nitrosamines, a group of chemicals—many of them carcinogenic—that includes NDMA. But Light says the detection method used in that paper was designed for food products and does not directly measure nitrosamines. In addition, the study discarded all stomach samples that contained ranitidine because they could have “falsely high” concentrations of nitrosamines, so any NDMA produced by the breakdown of ranitidine would not have been detected.

In a statement to Scientific American, GSK says it had considered the potential formation of nitrosamines in the body—during ranitidine’s development, during its regulatory review and in subsequent studies. Scientists had hypothesized that any drugs that raised the stomach’s pH could increase the growth of bacteria that produce nitrites, which could interact with chemicals called amines to produce nitrosamines. Although several studies did find that taking ranitidine could increase the concentration of nitrites in the stomach—and at least one found a statistically significant increase in nitrosamines—that does not mean they cause cancer, GSK says. The company adds that ranitidine was not carcinogenic in studies of rodents whose diet and bacterial metabolism were similar to those of humans and claims that “extensive pharmacovigilance monitoring, regular safety reviews and substantive epidemiological studies have not linked ranitidine to raised cancer risks.”

Further, the issue of nitrosamine formation in the body “is fundamentally different to the current regulatory interest in the presence of NDMA in drug substance and drug product,” says GSK, which has issued a recall of its generic version of Zantac. “The reason for the current precautionary recall of ranitidineis due to an emerging finding that some sources of drug substance and therefore drug product may contain very small amounts of nitrosamine. While the manufacturers, suppliers and regulatory authorities clarify the root cause of this issue, we have stopped supply and recalled product from the market as a precautionary measure.”

Nevertheless, the recalls suggest a level of caution may be justified. The FDA says that consumers taking over-the-counter medications containing ranitidine could consider using other approved drugs and that patients who are taking prescription ranitidine and want to stop should consult their doctors about alternative options. The agency has asked ranitidine manufacturers to test their own products for NDMA and to send it samples of them. Kahn says the agency “continues to test ranitidine samples and will provide information as it becomes available.”