Journal of Surgical Oncology 2006;93:640–643

Environmental Pollutants in Gallbladder Carcinogenesis

MANOJ PANDEY, MS*Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Gallbladder cancer is a common malignancy of the gastrointestinal tract that showswide geographical variation in its distribution. Cause of gallbladder cancer is stillobscure; however, various etiological factors have been proposed. Of these gallstonesand inflammation of the gallbladder is commonest. Despite three decades of activeresearch no conclusive evidence is available as to what causes gallbladder cancer? Inthis article we reviewed the evidence on the role of environmental pollutants ongallbladder carcinogenesis. A detailed search of Medline was carried out whichrevealed only 12 articles. A number of heavy metals like nickel, cadmium, etc. havebeen implicated; however, the evidence is not robust enough to conclude itsassociation. Role of radiation and pesticides in river water have also been evaluatedwithout any conclusive evidence of its association with gallbladder cancer. Betterdesigned case-control studies or cohort studies looking at exposure are required beforeit could be accepted as one of the causes of GBC.J. Surg. Oncol. 2006;93:640–643. � 2006 Wiley-Liss, Inc.

KEY WORDS: gallbladder; carcinogenesis; heavy metals; cadmium; nickel;radiation; radon; water; pesticides

INTRODUCTION

Primary carcinoma of the gallbladder (GBC) is themost common malignant lesion of the biliary tract andfifth commonest lesion of the digestive tract [1,2].Published reports have developed a characteristic patternof late diagnosis and ineffectual treatment. With therecent development in imaging modalities the detectionrate of the GBC has increased; however, the overalloutcome still remains bleak.The figures from Indian cancer registry (2002) [3]

showed the highest incidence from New Delhi 8.9of 100,000 followed by Bhopal and Bombay (2.5 of100,000); however, the incidence in South India isbelow 1 of 100,000 [3]. At Varanasi, the gallbladdercancer represented 17.6% of all malignancies and 3.14%of total admissions in a single surgical unit [4,5] an almostfourfold rise over the 1985 figures. This apparent increaseprobably reflects increased use of newer imagingmodalities leading to increased detection or specialinterest of this unit in GBC rather than true rise inincidence and hence a selection bias. Absence of ahospital or population-based registry in this areamake these figures unrealistic. Unpublished reports claima higher incidence in other parts of Northern India,namely Chandigarh and Kashmir; however, in absence of

population-based registries these figures too cannot berelied upon.Although GBC was described over two centuries ago

[6] its etiology is still obscure. Several causative factorshave been proposed. The commonest factor implicatedin gallbladder carcinogenesis is gallstones [7]. Otherproposed factors are cholecystitis [7,8], xanthogranulo-matous cholecystitis [9,10], inflammatory bowel diseases[11], blood group [12], anomalous pancreatic-biliaryunion [13,14], chemical carcinogens [15], occupationalexposure [16], free radicals and lipid peroxidationproducts [17–21], secondary bile acids [22], bacterialinfection [23] and degradation of bile acids [24], typhoidcarrier state [25,26], diet, and life style factors [27,28].Beside these a number of authors have proposed a role ofenvironmental carcinogens and water and air pollution ingallbladder carcinogensis. These include heavy metalslike nickel, cadmium, and cobalt among others. Thepresent article is aimed at reviewing the evidence on role

*Correspondence to: Manoj Pandey, MS, Department of SurgicalOncology, Institute of Medical Sciences, Banaras Hindu University,Varanasi 221 005, India. Fax: 91-542-2368856.E-mail: manojpandey@vsnl.com

DOI 10.1002/jso.20531

Published online in Wiley InterScience (www.interscience.wiley.com).

� 2006 Wiley-Liss, Inc.

of these environmental pollutants on gallbladder carci-nogenesis.

MATERIALS AND METHODS

A detailed search of the Pubmed was carried out usingthe strategy detailed below:

#1Search gallbladder or gall bladder.#2Search cancer or carcinoma.#3Search #1 and #2.#4Search heavy metal.#5Search nicotine.#6Search pollution.#7Search #6 and water.#8Search polluted water.#9Search #4 or #5 or #7 or #8.#10Search #3 and #9.

RESULTS

This search revealed 88 articles. The abstracts of these88 articles were screened to exclude those who werefound irrelevant to present review and those not onhumans. This led to rejection of 76 articles, a total of 12articles were thus retained and reviewed [16,23,29–38].Only a few of these were case-control studies andmajority of the studies suffered deficiency in design.

DISCUSSION

Wide geographical distribution of gallbladder cancerhas always fascinated the scientist. The first cause thathad been thought is the environmental factors that couldlead to gallbladder carcinogenesis. Pollution of riverwater is first to be investigated. Varanasi, an area of highincidence lie downstream on Ganges which is the mainsource of drinking, irrigation, and bathing water in theseparts and also receives treated and untreated domesticsewage and industrial and agricultural waste [39]. Themain source of pollution appears to be the leathertanneries upstream in Kanpur, which uses heavy metal-based compounds for leather tanning [39]. High con-centration of cadmium has been reported in sewage,irrigation water, and vegetables grown in this area. Theheavy metal concentrations recorded are much higherthan WHO recommendations. Metals especially cad-mium, are excreted by liver and concentrate in gall-bladder, and are known carcinogens [29].

To investigate the association of toxic heavy metalswith GBC Shukla et al. [33] carried out a case-controlstudy. The results showed significantly higher biliaryconcentrations of cadmium, chromium, and lead inthe bile of cancer patients when compared to biliaryconcentrations among patients with gallstones [30].

However, the authors failed to make an associationwith the heavy metal levels in the drinking water andfood. This observation can also be attributed to reducegallbladder contractility and increased emptying timethus having a concentrating effect on biliary metalconcentrations limiting the scope of the study.

Metallothionein (MT) are sulfur rich, low molecularweight intracellular metal binding proteins with apossible role in human carcinogenesis. These proteinsare typically found in liver and kidney and also in heart,testes, and brain. They bind to heavy metals throughclusters of thiolate bonds. Their primary function is inregulation of trace metal metabolism, storage of theseions in the liver, and as a protective mechanism againstheavy metal toxicity [40]. Other functions include controlof intracellular redox potential, a role as a free radicalscavenger, and protection against ionizing radiation. MTover expression has been found to be associated withresistance to anticancer drugs and thus it serves as amarker for prognosis in cancer. Experimental studies inanimals reveal that normal tissue deficient in MT is moreprone to cadmium-induced carcinogenesis. Shukla et al.[34] studied the immunohistochemical expression of MTin a case-control study. MT expression was significantlyhigher in cases with GBC (70.4% vs. 25%) and it wasabsent in normal gallbladder. They concluded thatincrease MT expression in GBC may represent anincreased exposure to heavy metals, and may play animportant role in carcinogenesis as heavy metal exposureis known to cause cancer. It may also be relevant to poorprognosis and chemotherapy resistance seen in thesecases [34].

Environmental water pollution by agricultural chemi-cals in Niigata plain is proposed to be associated with theoccurrence of GBC. To investigate whether or not therewas a difference in concentrations of diphenyletherherbicide, chlornitrofen (CNP) and its reduction product(CNP-amino) in river and faucet water between Niigataand Joetsu Cities, a study was undertaken by Adachi [31].The results showed significant difference in concentrationof two between two cities with Niigata having higherconcentration [31]. This suggested a possible role forCNP in gallbladder carcinogenesis. Moran reported anassociation with asbestos pollution exposure and increasein gallbladder cancer from California [41].

Ecological correlation analysis was made between thesource of drinking water and standardized incidenceratios (SIRs) of malignant neoplasms registered inNiigata, Japan [38]. To study this and to generate someclues for a working hypothesis that the contamination ofdrinking water with environmental chemicals especiallyof endocrine disrupting chemicals in big rivers may berelated to the occurrence of cancers sources of drinkingwater in the year 1974 were classified into two categories:

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one from the Shinano and Agano and their downstreamrivers, and the other from small rivers flowing into thesebig rivers, rivers originating from the mountain areas,underground, and reservoirs. After excluding registeredcases under 20 years of age, the registry data (1992–1994) were sub-divided into two categories according tothe source of drinking water. The SIRs were calculated byusing two different standard populations: Niigata totaland ‘‘The other group.’’ Positive associations wereobserved in the following: esophagus, colon, rectum,liver, gallbladder, etc., bronchus and lung, prostate,bladder in males, and colon, rectum, gallbladder, etc.,bronchus and lung, breast in females. The authorconcluded that a trend can be seen from these results;however, one should be cautious till the consistency ofassociation can be confirmed by using more reliableincidence data, as the difference in the death certificatesonly (DCO) rate between the two groups might haveplayed as a bias [38]. The use of mortality data may be analternative way to evaluate the present findings in termsof the consistency of association [38].Role of natural, occupational, or therapeutic radiation in

gallbladder carcinogenesis too has been studied. Inskip et al.evaluated the women who had undergone uterine radiationand found that these women had higher mortality; however,the mortality from gallbladder cancer showed a decline[42]. Their results suggested that gallbladder does not getenough radiation during intracavitatory radiation so as tocause carcinogenesis. Similar results were shown amongplutonium worker in British Nuclear fuels who too showeda decline in incidence of gallbladder cancer [32]. On thecontrary Tomasek et al. found higher incidence among thoseexposed to radon [36].Nutrient deficiency in developing countries can be

considered a significant contributory factor modifying themultistage process of carcinogenesis. Shukla et al. eval-uated the micronutrient deficiency in carcinoma of thegallbladder [35]. Selenium (Se), zinc (Zn), copper (Cu),manganese (Mn), ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E) were estimated in the serum, bile,and gallbladder tissue of patients with GBC, cholelithiasis,and only in the serum of age- and sex-matched healthycontrols. Lower mean serum levels of Se, Zn, Mn, vitaminE, and vitamin C were found in GBC (P< 0.001) whencompared with cholilithiasis and healthy controls. How-ever, no significant difference was observed in tissueconcentration of Mn, vitamin C, and vitamin E. Cu levelsand Cu/Zn ratio showed a highly significant (P< 0.001)increase in serum, bile, and gallbladder tissue in GBCcompared to the others. Their results support an associa-tion between lower levels of Se, Zn, vitamin E, and risk ofcarcinoma of the gallbladder and suggest that Cu/Zn ratiocould be a useful parameter in evaluating the patients ofcarcinoma of the gallbladder [35].

Serum molybdenum concentrations were determinedby neutron activation analysis in apparently healthysubjects and in patients with diseases of the liver andbiliary system [37]. The serum molybdenum level(mean� SD) was observed to be definitely increased inpatients with gallstones (1.28� 0.38), tumors of thegallbladder or extrahepatic bile ducts (1.64� 0.44), andcarcinoma of the head of the pancreas (1.61� 0.91). Theetiologic mechanism and the clinical importance of theobserved abnormality remains to be established [37].

CONCLUSIONS

Carcinoma of the gallbladder is common in certainparts of the world. The disease is usually diagnosed lateand hence the prognosis is poor. The etiology of GBC ispoorly understood. Several attempts have been made tostudy the effects of environmental pollutants on gall-bladder cancer; however, there is no robust data tosupport this hypothesis. Better designed case-controlstudies or cohort studies looking at exposure are requiredbefore it could be accepted as one of the causes of GBC.

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