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.
Natalie Eshaghian & Donna Salib
Cancer Causing Ingredients
Have you ever stopped to look at the back of a product label and wonder what that endless ingredient list really consists of? Many of the daily use products we use contain chemicals/ingredients that can cause harm to our bodies and can even be carcinogenic. Some products that are found to be carcinogenic are phthalates, parabens, formaldehyde, fragrances, synthetic colors, PEGs, triclosan, along with many others. It is important to understand what these products are and why we should or should not have them in our products.
Formaldehyde is one of those ingredients listed in products used as a preservative but is seen to be a human carcinogen. In 1981, The National Toxicology Program (NTP) first listed formaldehyde in the 2nd Report on Carcinogens as reasonably anticipated to be a human carcinogen. You can find formaldehyde in many of our adhesive products, such as eyelash glue, hair gel, shampoos, and soaps, as well as binders for wood and plastic.(1) Formaldehyde is able to create cross-links between DNA-DNA and DNA-protein due to its ability to bind to DNA. This is seen to be the relation of formaldehyde’s cytotoxic ability.(2) Formaldehyde releasers are also found which are chemicals that slowly release formaldehyde into a product in order to preserve it. A few of these formaldehyde-releasing agents include imidazolidinyl urea, DMDM hydantoin, and Diazolidinyl urea. What makes it so hard to find these names on the label is that there can be variations of the names of these formaldehyde-carrying agents. In Europe, a concentration of 0.02% for formaldehyde-releasing agents is allowed while in the U.S., a concentration of up to 0.1 ppm is allowed due to Americans having more ventilation for these products than Europe. When formaldehyde is present in the air at levels higher than 0.1 parts per million (ppm), some people may experience watery eyes, burning sensations of the eyes, nose, and throat, coughing, wheezing, nausea, and skin irritation. According to the European Cosmetic Directive, all products containing formaldehyde or its releasers must be labeled “contains formaldehyde” when the concentration of formaldehyde in the finished product exceeds 0.05% (500 ppm). Since formaldehyde is common in many household products, it is difficult to completely remove it from the air but you can try to reduce how much of its levels are in your home by increasing ventilation.
Triclosan is another example of an ingredient to look out for, which is an antimicrobial compound that has been used in consumer products for about 40 years, found in 75% of liquid hand soap and 30% of bar soap. Triclosan is what makes many of our soaps antibacterial and works by denaturing proteins and disrupting membranes. Per various studies, triclosan seems to harm immune function, endocrine function, and reproductive health. In studies conducted on rats, triclosan affects the levels of estrogen, testosterone, and thyroid seen in their bodies. Triclosan in antimicrobial soap has not been found to be superior to washing hands with regular soap therefore in September 2016, TCS was banned from soap products following the risk assessment by the U.S.A. Food and Drug Administration (FDA) However, TCS still remains allowed in toothpaste, hand sanitizer, and mouthwash as it is widely utilized to help fight gingivitis.(3)
The European Union (EU) also banned TCS from all human hygiene biocidal products in January 2017(4). Some researchers were also concerned that using triclosan for long periods of time would create more antibacterial-resistant bacteria. The issue of triclosan-resistant organisms arises due to its use, an example being salmonella enterica. Ultimately, washing your hands with good old-fashioned hand soap is the way to go!
Every day we are exposed to many different chemicals in our environment, including those in personal care products. “Less is more” is certainly the lesson to be taken away from these examples. Although it can be difficult, less chemical exposure means less risk of cancer. It’s become increasingly clear that most mainstream cosmetic and personal care products contain at least one hazardous chemical compound, some of which have been deemed toxic by the National Institute of Occupational safety. Cosmeticsdatabase.com is a great resource to find what chemicals are in your personal care products and what risks are associated with these chemicals. This database is provided by EWG, The Environmental Working Group, a non profit organization that specializes in research of toxic chemicals. Since we know that the FDA does not assess the safety of personal care products or their ingredients, it is up to consumers to protect themselves by educating themselves and identifying the best possible choices when shopping.
References:
(1) Bosetti C, McLaughlin JK, Tarone RE, Pira E, La Vecchia C. Formaldehyde and cancer risk: a quantitative review of cohort studies through 2006. Ann Oncol. 2008;19(1):29-43. doi:10.1093/annonc/mdm202
(2) Allegra A, Spatari G, Mattioli S, et al. Formaldehyde Exposure and Acute Myeloid Leukemia: A Review of the Literature. Medicina (Kaunas). 2019;55(10):638. Published 2019 Sep 25. doi:10.3390/medicina55100638
(3) Weatherly LM, Gosse JA. Triclosan exposure, transformation, and human health effects. J Toxicol Environ Health B Crit Rev. 2017;20(8):447-469. doi:10.1080/10937404.2017.1399306
(4)Juncker J-C. Commission impementing decision not approving triclosan as an existing active substance for use in biocidal products for product-type 1. 2016.
CANCER CAUSING INGREDIENTS - Dr. Michelle Lam
(1) Cancer Causing Ingredients - Power Point
(2) Outline
(3) Script for Power Point
n-Nitrosodimethylamine also known as NDMA is a yellow odorless liquid that is a known carcinogen that is produced in the US only as a research chemical. It can also form naturally in the environment as a result of chemical reactions involving alkylamines. Recently, the FDA recalled all ranitidine products because it found that NDMA levels increased over time creating a patient safety risk. In 2019 the FDA found NDMA in ranitidine from an independent lab. When they conducted their own testing, they found NDMA in low levels which were not considered a risk for cancer. The FDA continued their investigations and later found that at normal temperatures the amounts of NDMA increased over time. Because there was no way of ensuring stability, storage, and quality the FDA ordered that all products be removed from shelves. NDMA is known to be harmful to the liver of animals and humans. In trials conducted, animals that came into contact with NDMA (through food, drinks or breathing) for several weeks eventually developed lung cancer, and either liver damage or liver cancer.
https://www.ajmc.com/newsroom/fda-recalls-all-ranitidine-products-zantac-citing-increased-risk-of-cancer
https://www.atsdr.cdc.gov/phs/phs.asp?id=882&tid=173
There are alot of cancer causing agents that surround us everyday. Not many people realize it but viruses can also cause cancer. Cervical cancer affects the cervix, a small donut-shaped structure located at the top of the vagina. It occurs when the cells of the cervix grow abnormally and spread to neighboring tissues. Almost all cases of cervical cancer are caused by specific strains of human papillomavirus (HPV), a double-stranded DNA virus. HPV is the most common sexually transmitted infection in the United States. There have been more than 170 HPV types identified, and over 40 of these subtypes can infect human epithelial cells in areas such as the genital tract and the oral mucosa. In most cases, HPV resolves on its own without causing any signs or symptoms. However, there are cases in which HPV remains active and can lead to warts, precancerous or dysplastic lesions and several types of cancers. Luckily, scientists have been able to isolate specific HPV proteins known to be cancerous. Gardasil 9 contains inactive HPV proteins, specifically types 6 L1,11 L1, 16 L1, 18 L1, 31 L1, 33 L1, 45 L1, 52 L1, and 58 L1. These proteins create neutralizing antibodies that work to prevent cancers of the cervix, vulva, vagina, and anus.
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually transmitted infections among US women and men: Prevalence and incidence estimates, 2008. Sex Transm Dis 40(3):187–93. 2013.
de Villiers EM, Cross-roads in the classification of papillomaviruses. Virology. 2013;445:2-10.
https://www.cdc.gov/nchs/products/databriefs/db280.htm#ref1
Another class of medication that has a risk of causing cancer is androgenic steroid hormones. These agents have been associated with prostate cancer because this type of cancer is androgen-sensitive and responds to androgen-deprivation therapy. Such a correlation between androgens and prostate carcinoma occurrence is biologically very likely, and prostate cancer could be regarded as a disturbance of the mechanisms that regulate the normal balance between "androgen effects on cellular differentiation and androgen effects on cell proliferation and cell death rates in the prostate".
Another article mentioned the risk of Leydig cell tumor. The negative impact of androgenic steroid hormones damage the expression of enzymes involved in testosterone biosynthesis and is again suspected to be at the basis of certain carcinogenic mechanisms. Additionally, easily accessible drugs like nandrolone and stanozolol are affecting a young group of population.
Both articles mention the need for further investigations for the potential link between androgenic steroid hormones abuse and cancer.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922407/
https://link.springer.com/chapter/10.1007/978-1-4613-9208-8_29
Another category of medication that is known to increase the chance of cancer, specifically breast cancer are hormonal contraceptives. About 2 out of 3 breast cancers are hormone receptor-positive. Their cells have receptors (proteins) that attach to the hormones estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers). For these cancers, researchers are not entirely definitive if the correlation is due to estrogen or progesterone but they did propose it could be the high estrogen levels that are helping the cancer cells grow and spread. In some studies, patients who had progesterone-only shot Depo-Provera have also been found to have higher rates of breast cancer. Hence, hormonal contraceptives have a slight increase in breast cervical cancer in current and recent users. However, birth control pills containing both estrogen and progesterone can lower the risk of endometrial and ovarian cancer. The longer duration of use, the lower the risk. The benefit seems to last for at least a decade after discontinuation.
A nationwide prospective cohort study was done in Denmark assessed the associations between the use of hormonal contraception and the risk of invasive breast cancer in an involving all women in 15 and 49 years of age found a
that among "1.8 million women who were followed on average for 10.9 years, 11,517 cases of breast cancer occurred. The relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26) as compared with women who had never used hormonal contraception".
https://www.nejm.org/doi/full/10.1056/NEJMoa1700732
https://www.cancer.org/latest-news/birth-control-cancer-which-methods-raise-lower-risk.html
On March 1st, 2019 the FDA announced that the company Torrent Pharmaceuticals Limited would be recalling their losartan products because of the chemical N-Nitroso N-Methyl 4-Amino Butyric Acid (NMBA) being detected in their product. Torrent voluntarily recalled their products with an NMBA level above the acceptable daily intake level released by the FDA because of trace amounts of an unexpected impurity found in an active ingredient manufactured by Hetero Labs Limited. The acceptable intake is a daily exposure to these compounds NDMA, NDEA, or NMBA that has an estimated 1:100,000, cancer risk after 70 years exposure. FDA is not recalling losartan with NMBA below 9.82 ppm at the consumer level. Losartan is indicated to treat hypertension, hypertensive patients with Left Ventricular Hypertrophy and nephropathy in Type 2 diabetic patients. Losartan potassium and hydrochlorothiazide products were also recalled due to contamination. NMBA belongs to the same class of compounds such as N-nitrosodimethylamine or NDMA, and N-nitrosodiethylamine (NDEA), which contains a -NH2 and a -NO radical. These radicals found in this chemical group have carcinogenic and mutagenic properties especially in the liver and lungs. On April 18th, 2019 the losartan recall from Torrent was expanded to include even more products.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/updated-torrent-pharmaceuticals-limited-issues-voluntary-nationwide-recall-losartan-potassium-0
https://www.ncbi.nlm.nih.gov/mesh/68009602
Another medication that has been found to have a cancer causing agent, NMDA, (N-nitrosodimethylamine) is Metformin. Metformin is a standard medication and first line therapy for patients with Type 2 Diabetes. It helps to control high blood sugar and is well known to all patients and healthcare providers. The FDA’s investigation has found low levels of NDMA in metformin drugs. An online pharmacy, Valisure, announced that there are high levels of NDMA that was found. About 22 companies selling metformin and a total of 38 batches revealed 11 of the companies and 16 batches where the levels were high and above the daily intake limit of 96 nanogram. This showed that it was not a specific company, but spread across different pharmaceutical companies.
https://www.reuters.com/article/us-health-diabetes-fda/fda-probes-diabetes-drug-metformin-for-carcinogen-ndma-idUSKBN1Y92UN
https://www.europeanpharmaceuticalreview.com/news/114709/online-pharmacy-finds-high-levels-of-ndma-in-metformin/
https://www.pharmacytimes.com/news/updates-on-nmda-contaminations-in-medications