Valsartan is angiotensin receptor blocker used by millions of Americans to treat high blood pressure. In July of 2018, the FDA had announced a voluntary recall of several drugs containing valsartan. This recall was because of contamination with an impurity, the possible carcinogen and hepatotoxic chemical N-nitrosodimethylamine, or NDMA. NDMA consumption has been associated with either liver or lung cancer. NDMA previously was used to make rocket fuel, however this stopped after dangerously high levels of this chemical compound were found in air, water, and soil samples collected near a rocket fuel manufacturing plant. NDMA can be unintentionally formed during various manufacturing processes at many industrial sites. It can also found in the air, water and soil from reactions involving other chemicals called alkylamines. The FDA had traced the recalled drugs to Chinese manufacturers Zhejiang Huahais and Zhejiang Tianyu as well as Hetero Labs Limited in India. In September of 2018, the FDA had found another toxic chemical in valsartan batches called N-nitrosodiethylamine (NDEA). Combinations drugs such as (amlodipine and valsartan) (amlodipine, valsartan and hydrochlorothiazide), and (valsartan and hydrochlorothiazide) were also effected. Other medications in the ARB class, such as losartan and irbesartan were also found to have these contaminants.
The term carcinogen refers to any substance, organism, agent, or environmental factor that has the ability to cause cancer. Natural environmental factors like ultraviolet rays from sunlight and certain viruses, as well as human activities such as automobile exhaust emissions and cigarette smoke, can contribute to the presence of carcinogens. Most carcinogens work by producing mutations in the cell through interacting with the cell’s DNA. The US Department of Health and Human Services National Toxicology Program, and the World Health Organization's International Agency for Research on Cancer both document substances that are known or reasonably anticipated to be human carcinogens using evidence based approaches. Being exposed to a carcinogen doesn't guarantee the development of cancer. Several factors come into play, such as the quantity and duration of exposure, other environmental influences, and the individual's genetic makeup, determining whether a person exposed to a carcinogen will eventually develop cancer.
Some examples of carcinogens include N-nitrosodimethylamine (NMDA), formaldehyde, asbestos, tobacco, radon, or processed meat. NMDA is a known environmental contaminant found in water, foods (such as dairy products, vegetables, grilled meats), and multiple industrial processes. It is classified as a probable human carcinogen according to the International Agency for Research on Cancer, due to animal studies in which the animals ate NMDA and developed liver, lung, kidney, and testicular cancers. Additionally, NMDA has been found in Zantac, or ranitidine, in 2019. Ranitidine is a H2-receptor antagonist (H2RA) to reduce the production of gastric acid in patients with gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). According to the National Library of Medicine, the FDA had set the acceptable daily intake limit for NDMA at 0.096 micrograms or 0.32 parts per million for ranitidine. However, testing of ranitidine products showed that NDMA levels were as much as nine times greater than the FDA’s recommended limit. Therefore, many manufacturers and retailers have voluntarily recalled ranitidine worldwide. Not long after, NDMA was detected in another antihistamine, nizatidine.
Formaldehyde, a strong smelling and colorless chemical which is a gas at room temperature, naturally occurs in the environment. This includes some foods and in our own bodies as well. However, while it is natural, it is also used widely in some industries as well, especially as food preservatives, building materials and household products. Some examples are pressed-wood products, such as particleboard, plywood, and fiberboard, glues and adhesives, permanent-press fabrics, paper product coatings, and some insulation materials. Therefore, people can be exposed to formaldehyde by inhaling it, which is the main way people are exposed, absorbing it through the skin, or eating foods or drinking liquids containing formaldehyde. According to the American Cancer Society, studies in rats found that inhaled formaldehyde is linked to cancers inside the nose and to leukemia and formaldehyde found in drinking water has been linked with an increase in tumors in the stomach and intestines.
Overall, while the public is exposed to carcinogens from the environment on a daily basis, the FDA is still responsible for regulating the amount going into medications and other products. However, it is still important to make a conscious effort to avoid carcinogens as much as possible. Some initiatives include quitting smoking, consuming a healthy diet, limiting alcohol consumption, and screening for early detection. The pharmacist's role is to counsel patients on these healthy habits and emphasize its positive effects.
References:
https://www.genome.gov/genetics-glossary/Carcinogen#:~:text=Definition,exhaust%20fumes%20and%20cigarette%20smoke).
https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsDetails.aspx?faqid=883&toxid=173#:~:text=Animals%20that%20ate%20NDMA%20developed,human%20carcinogen%20(Group%202B).
https://www.cancer.org/cancer/risk-prevention/chemicals/formaldehyde.html#:~:text=The%20International%20Agency%20for%20Research,cause%20nasopharyngeal%20cancer%20and%20leukemia.