The Science Behind the Lawsuits

NDMA Is a Potent Genotoxic Carcinogen

N-nitrosodimethylamine, commonly called NDMA, belongs to a family of chemicals known as nitrosamines. Scientists and regulators have studied these compounds for decades because many nitrosamines can damage genetic material and cause cancer.

The International Agency for Research on Cancer classifies NDMA as probably carcinogenic to humans (Group 2A). IARC has reported that NDMA caused tumors in every animal species tested and through several routes of exposure, including ingestion and inhalation. Researchers observed tumors primarily in the liver, kidneys, and respiratory tract, although the organs affected varied by species and exposure conditions. Scientists have also demonstrated important similarities between the way human and animal tissues metabolize NDMA.

The FDA likewise classifies NDMA as a probable human carcinogen. This classification does not mean that every exposed person will develop cancer. Cancer risk depends on several factors, including the amount of NDMA, frequency and duration of exposure, the organs exposed to its reactive metabolites, individual susceptibility, and the time between exposure and diagnosis.

How NDMA Can Damage DNA

NDMA does not need to remain chemically unchanged to cause harm. After a person ingests it, enzymes, primarily the liver enzyme CYP2E1, metabolically activate the compound. This process produces unstable and highly reactive intermediates capable of transferring methyl groups to DNA.

These reactions can create DNA lesions known as methylated DNA adducts. One especially important lesion, O6-methylguanine, can cause a cell to misread its genetic instructions when it copies DNA. Instead of pairing normally, the damaged guanine may pair with the wrong DNA base. If the cell fails to repair that damage before dividing, the error can become a permanent mutation.

The body has DNA-repair systems that can remove some of this damage. However, those systems have limits. Repeated exposure can create new DNA damage faster than cells can repair it, allow mutations to accumulate, or affect genes that control cell growth, DNA repair, and programmed cell death. Over time, this process can contribute to the uncontrolled cellular growth that characterizes cancer.

NDMA acts as a genotoxic carcinogen. It can contribute to cancer by directly damaging genetic material. For genotoxic carcinogens, regulators generally do not treat one particular dose as a scientifically proven dividing line between “no risk” and “risk.” Instead, they establish very low intake limits to keep the estimated lifetime cancer risk within an acceptable regulatory range.

What the 96-Nanogram Limit Means

The FDA established an acceptable daily intake limit of 96 nanograms of NDMA. One nanogram equals one-billionth of a gram, so 96 nanograms represents an extremely small quantity.

The FDA derived this limit as a risk-management value based on a person consuming that amount every day for approximately 70 years. It does not operate like a poisoning threshold, and it does not prove that every exposure below 96 nanograms carries absolutely no risk. Rather, the FDA considers exposure at or below that level reasonably safe because it predicts a very small additional lifetime cancer risk.

For example, a product that exceeds 96 nanograms may not necessarily cause immediate illness, but repeated exposure above the limit may increase cumulative lifetime cancer risk. Likewise, the limit does not transform 96 nanograms into a scientifically guaranteed boundary between harmless and harmful exposure. With a DNA-damaging carcinogen, risk generally increases with cumulative exposure rather than suddenly beginning at one precise number.

A consumer’s cumulative exposure depends on more than the amount of NDMA in one tablet. It may also depend on:

• The NDMA concentration in each dose;
• Whether the consumer took 75-, 150-, or 300-milligram ranitidine products;
• How many doses the consumer took each day;
• How many months or years the consumer used ranitidine;
• The product’s age when the consumer took it;
• The temperatures and humidity the product encountered during shipping and storage; and
• Whether NDMA levels varied among manufacturers, lots, and formulations.

For a person who took ranitidine regularly for years, even modest amounts in individual doses could contribute to a much larger cumulative exposure.

Why Ranitidine Presented a Unique Problem

The NDMA problem in ranitidine did not involve only a contaminant accidentally introduced into an isolated manufacturing lot. Scientific testing identified a more troubling issue: the ranitidine molecule itself could degrade and generate NDMA.

Ranitidine’s chemical structure contains components capable of participating in reactions that produce NDMA. Researchers using isotopically labeled ranitidine confirmed that NDMA could form through reactions involving ranitidine molecules themselves. Research also identified heat, humidity, storage time, and aspects of the drug’s physical structure as factors that could influence the rate of degradation.

This instability distinguished ranitidine from a medication containing a fixed amount of contamination. The amount of NDMA in a ranitidine tablet did not necessarily remain the same from the day of manufacture until the day a patient consumed it. A tablet that initially tested below the FDA limit could develop higher NDMA levels as it aged or encountered heat.

What the FDA Found

During its investigation, the FDA detected NDMA in both ranitidine’s active pharmaceutical ingredient and finished drug products. The agency then found that NDMA levels in some ranitidine products increased over time under normal storage conditions. Higher temperatures produced still greater increases, and older samples generally contained more NDMA.

The FDA explained that ranitidine could encounter elevated temperatures during distribution, transportation, retail storage, or ordinary consumer use. A patient had no practical way to determine:

• How long a bottle had remained in storage;
• Whether it had spent time in a hot warehouse, delivery vehicle, mailbox, bathroom, or automobile;
• How much NDMA it contained when purchased;
• Whether its NDMA level continued increasing after purchase; or
• How much NDMA the patient consumed with each dose.

This uncertainty prevented the FDA from guaranteeing that ranitidine would remain within the acceptable NDMA limit throughout its shelf life. On April 1, 2020, the agency took the extraordinary step of requesting that manufacturers withdraw every prescription and over-the-counter ranitidine product from the U.S. market, not merely selected manufacturers or isolated lots.

Why Long-Term Use Matters

Cancer usually develops through a multistep process rather than immediately after a single exposure. A carcinogen may initiate DNA damage years before doctors diagnose a tumor. Additional genetic changes can accumulate as affected cells divide, evade repair mechanisms, and acquire the ability to grow uncontrollably.

This latency makes long-term medication use especially important. Many consumers took Zantac or generic ranitidine daily or almost daily for months or years. Some took multiple doses each day under a physician’s direction or relied on over-the-counter products without any warning that the medication could contain increasing levels of a probable human carcinogen.

Plaintiffs contend that each dose contributed to cumulative NDMA exposure and created additional opportunities for DNA damage. They also contend that ordinary pharmacy and medical records may understate total exposure because consumers could purchase ranitidine over the counter without a prescription and use it for years without every purchase appearing in a centralized record.

Laboratory, Toxicological, and Epidemiological Evidence

Plaintiffs’ experts evaluate several complementary forms of scientific evidence:

• Analytical chemistry: measures NDMA in ranitidine products and examines how storage time, temperature, humidity, and product composition affect its formation.
• Mechanistic evidence: explains how the body activates NDMA, how its metabolites bind to DNA, and how resulting mutations may contribute to cancer.
• Toxicology studies: examine whether NDMA causes tumors in living organisms, which organs it affects, and whether cancer rates rise as exposure increases.
• Animal studies: consistently demonstrate NDMA’s carcinogenic activity across numerous species and establish dose-response relationships.
• Epidemiological studies: compare cancer rates among groups of people with different exposure histories. These studies can provide important evidence, but short follow-up periods, incomplete prescription histories, unrecorded over-the-counter use, varying NDMA levels among products, and the long latency of cancer may obscure an association.
• Individual medical evidence: addresses each claimant’s ranitidine use, cancer diagnosis, exposure period, latency, treatment history, and other relevant risk factors.

No single study must answer every scientific question. Scientists commonly evaluate the totality of the evidence, considering whether findings from chemistry, toxicology, biological mechanisms, animal experiments, epidemiology, and individual exposure evidence support one another.

The Plaintiffs’ Scientific Position

Plaintiffs allege that ranitidine’s chemical instability created a continuing and foreseeable NDMA risk. They contend that manufacturers sold a medication capable of generating additional amounts of a powerful DNA-damaging carcinogen as the product aged and encountered ordinary storage conditions.

Plaintiffs further allege that regular and long-term users unknowingly consumed NDMA at levels exceeding what federal regulators considered acceptable. According to plaintiffs’ experts, the combination of ranitidine-specific testing, NDMA’s established carcinogenic properties, its known mechanism of DNA damage, animal evidence, epidemiological research, and individual exposure histories supports a causal connection between ranitidine use and certain cancers.

The lawsuits also allege that the manufacturers knew or should have known about ranitidine’s chemical instability and nitrosamine risk. Plaintiffs contend that the companies failed to conduct adequate stability testing, account for real-world storage conditions, warn patients and healthcare professionals, or act quickly enough to protect consumers.

The manufacturers deny that ranitidine causes cancer and continue to challenge plaintiffs’ scientific evidence. Courts have reached different conclusions about whether plaintiffs’ experts may present their opinions to juries. Those evidentiary rulings do not change the FDA’s findings that NDMA can increase in ranitidine over time and with heat or its decision to remove every ranitidine product from the U.S. market.