Keywords
cancer - gallbladder cancer - microplastics
India is among the leading countries for incidences of gallbladder cancer (GBC) globally,
with around 21,000 new cases diagnosed in 2022 accounting for >15% of the total cases
worldwide.[1] However, there is a wide geographic disparity in its distribution with the age-standardized
rates of the Northern and Eastern parts of the country being nearly 10 times that
of South India.[2] The incidence of GBC is especially high along the Gangetic belt.[2]
Residence along the Gangetic belt was found to be an important risk factor for the
development of GBC with an odds ratio ranging from 1.72 to 3.3 across studies.[3]
[4] The Ganga along with its tributaries originate in the Himalayas and flow through
major cities like Varanasi, Patna, Prayagraj, Kolkata, and Rishikesh before eventually
emptying into the Bay of Bengal. It is the longest river in the country and the river
basin with the highest population density in the world.[5] More than 400 million Indians depend on it for their daily activities.[5] As it flows through the Indian subcontinent, the river gets heavily contaminated
with untreated domestic sewage, industrial effluents, and agricultural runoff, making
it one of the most polluted rivers across the globe. It has been reported that the
Ganges is responsible for more than 70% of India's total gray water output.[6]
There are a few studies that have attempted to explain the increased prevalence of
GBC and its uneven distribution in India. Possible etiologies proposed for rising
GBC incidence along the Gangetic belt: infection with Helicobacter pylori and Salmonella typhi; contamination of Ganga with carcinogens like pesticides, nitrates, and heavy metals;
increased concentration of arsenic in groundwater; and use of adulterated mustard
oil for cooking (that is especially popular among the northern and northern-eastern
parts of the country) have been proposed as possible etiologies for rising GBC incidence
along the Gangetic belt.[7]
[8]
[9]
[10]
[11]
A case–control genome-wide association study to evaluate the genetic susceptibility
to GBC was performed and consisted primarily of patients from northern and northeastern
parts of India.[12] This study reported that the common variations in the ABCB1 and ABCB4 genes were
linked with the development of GBC.[12] ABCB1 gene codes for a glycoprotein linked with resistance to anticancer drugs,
while ABCB4 codes for a membrane protein responsible for transporting phospholipids
into the bile.[12] Phospholipids in bile protect against the emulsifying actions of bile salt and its
insufficient secretion due to mutations in the ABCB4 gene results in injury to the
biliary tract. Studies performed in mice reported that the absence of this gene was
associated with a higher risk of carcinogenesis on exposure to chemical carcinogens
in addition to the production of reactive oxygen species (ROS) and DNA damage.[12] In humans, mutations in the same gene were found to increase susceptibility to cholestasis,
cholelithiasis, liver cirrhosis, and hepatobiliary carcinoma.[12]
While a lot of these are explored as possible causative factors, pollution could be
the most pertinent one. But how does pollution cause GBC? And, why in regions in low-
and middle-income countries (LMICs) with heavily polluted water bodies? The answer
could lie in the famous statement from the movie, The Graduate–“I want to say one
word to you. Just one word: Plastics.”[13]
Microplastics are produced when plastic polymers are broken down into minute particles
of size less than or equal to 5 mm.[13] They are essentially nonbiodegradable, ubiquitous, and persistent in the environment.
They can enter the human body following ingestion after they accumulate in the food
chain, through inhalation from the atmosphere, or through direct skin contact.[13] Microplastics in the body are excreted primarily through the liver either by the
reticuloendothelial system through phagocytosis or by the biliary system as part of
fecal matter.[13] A small fraction is also removed by the kidney through the urine.
The exact effects of microplastics on the human body are not yet completely understood.
However, they are reported to bring about unwanted immune responses and inflammatory
reactions, increase oxidative stress, alter the gut microbiome, and interfere with
lipid metabolism.[14] There is a dearth of studies assessing the direct carcinogenic potential of microplastics;
however, multiple studies conducted in vitro and in vivo have shown their association
with genotoxicity, oxidative stress, and inflammatory reactions, suggesting a possible
association between the two.[15] Comprehensive studies are required before the role of microplastics in carcinogenesis
can be clearly understood.
Hepatotoxicity caused by a common microplastic polymethyl methacrylate (PMMA) was
studied in a highly sensitive liver injury model by Boran et al in 2023.[16] They reported that PMMA was associated with a notable release of ROS, increased
oxidative stress, the production of inflammatory cytokines such as tumor necrosis
factor-α and interleukin-6, and decreased antioxidant activity.[16] Oxidative stress can often lead to DNA damage and 8-OHdG is a biomarker used to
assess oxidative DNA damage.[16] The study also reported a concentration-dependent increase of 8-OHdG following PMMA
application, highlighting the potential of microplastics to produce DNA damage.[16]
Global plastic production as of 2019 was around 460 million tonnes.[17] The Ganga–Brahmaputra–Meghna River ranks 6th among the top 10 rivers dumping microplastics
into the sea.[18] It has been reported that 1 microplastic particle is present for every 20 L of water
in the Ganga. This river along with its tributaries dumps nearly 1 to 3 billion microplastics
into the Bay of Bengal every day.[19]
[20] Rayon (54%) was the predominant polymer detected with acrylic (23%) occupying the
second rank.[19] We propose that the increased incidence of GBC in the Gangetic belt could be attributed
to the high concentration of microplastics in the river.
Although there is no established association between the two, there exists strong
circumstantial evidence to support this claim. Continued ingestion or exposure to
water from Ganga could result in microplastic accumulation in the liver and biliary
tract over time. Accumulated microplastics may then produce oxidative stress, and
release ROS in the region, eventually resulting in the development of GBC. Given that
millions of Indians utilize water from the Ganga for their livelihood, this could
explain the high prevalence of GBC in the Gangetic belt.
Other regions with elevated GBC incidence also have rivers that are highly contaminated
with microplastics. Among the top 10 rivers responsible for dumping nearly 90% of
the total microplastics into the sea, around 5 of them flow through eastern Asia.[18] This region also has the highest incidence of GBC in the world with an estimated
46,000 cases recorded in 2022 compared with 5,000 in Northern America.[1]
The rising incidence of GBC in LMICs along with its low prevalence in developed nations
also points toward the possibility of an environmental factor like microplastics in
GBC. This potential association has not been given the due importance it deserves
and ours is one of the few papers on this topic. We believe the circumstantial evidence
presented in our perspective would encourage further research in this area. However,
currently, we do not have any direct concrete evidence linking GBC with microplastics,
which is the major limitation of our article. Correlation does not necessarily mean
causation and we feel extensive studies evaluating the role of microplastics in the
pathogenesis of GBC are essential before any conclusions can be reached on its carcinogenic
role.
