What is NDMA?
N-Nitrosodimethylamine (NDMA), also known as dimethyl
nitrosamine (DMN) with the formula (CH3)2NNO. It is one
of the simplest members of a large class of N-nitrosamines. The formation of
nitrosamines is generally only possible when secondary or tertiary amines react
with nitrous acid. Nitrous acid itself is unstable but can be formed in situ
from nitrites (NO2) under acid conditions.
NDMA is highly soluble in
water and other solvents. NDMA is a known environmental contaminant and found
in water and foods, including meats, dairy products, and vegetables.
What is the effect of NDMA on human body?
Various studies conclude
that NDMA may be carcinogenic to human body.
Exposure to high levels
of NDMA may cause liver damage in humans (jaundice
and swelling) and low platelet counts and internal bleeding.
NDMA
is also mutagenic and clastogenic (giving
rise to or inducing disruption or breakages, as of chromosomes.)
International Agency for
Research on Cancer (IARC) which is a part of World Health Organization (WHO),
classifies NDMA as Group 2A.
What are the other sources through which NDMA enters human body?
The
primary sources of human exposure to NDMA are tobacco smoke, chewing tobacco,
diet [cured meats (particularly bacon), beer, fish, cheese, and other food
items], etc.
In
addition, NDMA can form in the stomach during digestion of
alkylamine-containing foods.
Infants
may be exposed to NDMA from the use of rubber
baby bottle nipples and pacifiers which may contain very small amounts of NDMA.
Occupational
exposure may happen in a large number of places including industries such as
tanneries, pesticide manufacturing plants, rubber and tire manufacturing
plants, alkylamine manufacture/use industries, fish processing industries,
foundries, and dye manufacturing plants. Researchers making or handling NDMA
may also be exposed to this compound if It passes through the rubber gloves
they wear during laboratory work.
How was NDMA’s presence in medicines identified?
In July 2018, the European Medicines Agency (EMA)
recalled certain batches of valsartan and valsartan/hydrochlorothiazide
film-coated tablets distributed in some countries of Europe and Canada. Active
pharmaceutical ingredient (API) used in valsartan and
valsartan/hydrochlorothiazide film-coated tablets was manufactured by a
pharmaceutical company based in China. It is claimed that API manufactured by
China based pharmaceutical company was contaminated by N-nitrosodimethylamine
(NDMA).
Further, in June 2019, an online pharmacy firm during
its routine testing discovered that a famous brand for heartburn having
Ranitidine content had low levels of NDMA. This further resulted in recalling
of batches from the market and even the molecule being banned in about 12
countries worldwide
Role of health authorities across the world in controlling presence of NDMA in pharmaceutical products.
EMA (European Medicines Agency) has asked its
marketing authorization holders to conduct a risk evaluation to identify
products at risk of N-nitrosamine formation or (cross-) contamination and
report the outcome by 26 March 2020 at the latest. Templates for “No risk
identified response”, “Risk identified response”, “No Nitrosamine detected
response” and “Nitrosamine detected response” are provided on its website.
USFDA has advised companies to recall their ranitidine if
testing shows levels of NDMA above the acceptable daily intake (96 µg or 0.32
parts per million for ranitidine). Also on its website, USFDA has published test
methods that may be considered when determining nitrosamine content in the API
or FPP.
Singapore health regulatory agency, Health Science Authority (HSA)
has issued recall for 3 batches of metformin products which have been detected
to contain trace amounts of N-nitrosodimethylamine (NDMA) beyond the
internationally acceptable level.
Brazil agency (ANVISA), in its resolution 283/2019 mentioned
that if Nitrosamine impurities above the established provisional limits are
identified, companies must immediately suspend the manufacture, distribution,
marketing, use and handling of the drugs with the API involved, and must segregate
the stock in the company, collect the batches of medicines and the API and notify
ANVISA within 48 (forty-eight) hours.
Confusing conclusion:
As per studies and reports, NDMA is not good for human
consumption. However, the kind of panic it has created worldwide and the studies
which are available on NDMA are quite confusing and contradictory. Below are
such points observed during course of data search for writing this article:
- There is no confirmed evidence that NDMA causes cancer in human body.
- There are no observed reports or cases of cancer caused due to NDMA in human body.
- Available reports and studies are based on tests and trials conducted on laboratory animals
- Based only on animal studies, nitrosamine impurities have been classified as a probable or possible human carcinogen.
- Furthermore, even International Agency for Research on Cancer (IARC) which is a part of World Health Organization (WHO), classifies NDMA as Group 2A meaning that it is a probable cancer agent.
- Health Canada, on its official website, under “Recalls and Safety alerts” states below sentence:
Nitrosamines are
not expected to cause harm when ingested at low levels. For example, a person
taking a drug that contains NDMA at or below the acceptable level every day for
70 years is not expected to have an increased risk of cancer.
With so many established studies which state that NDMA
causes cancer in animals and not even single study or evidence confirming NDMA
being carcinogen in humans, still there is state of panic in some health
agencies. Owing to this, some health agencies have issued deadline to check the
availability in all the products marketed in their country. Some agencies have
banned the drugs suspicious to have NDMA content while some agencies have
issued notice to even suspend the manufacture, distribution, marketing, use and
handling of the drugs with the APIs found to have NDMA content in them.
There are only few health agencies who are going by
available study reports and are taking actions accordingly.
It has to be noted that medicines are NOT THE ONLY
SOURCES through which chemicals like NDMA enters human body. As mentioned
above, the
primary sources of human exposure to NDMA are tobacco smoke, chewing tobacco,
diet [cured meats (particularly bacon), beer, fish, cheese, and other food
items], etc.
Based on above fact by
which NDMA enters human body, by now more than half of the world should have
been suffering carcinogenicity due to NDMA.
Worldwide companies and health agencies are already doing
their best to safeguard its citizens by ensuring supply of safest health products
in market. Doubting a specific sector, company or a country seems ethically
incorrect when there is no evidence of cause of cancer in humans.
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