Review Article The Mammary Gland Carcinogens: …downloads.hindawi.com/journals/ijbc/2013/640851.pdfReview Article The Mammary Gland Carcinogens: The Role of Metal Compounds and Organic

Hindawi Publishing CorporationInternational Journal of Breast CancerVolume 2013 Article ID 640851 10 pageshttpdxdoiorg1011552013640851

Review ArticleThe Mammary Gland Carcinogens The Role of MetalCompounds and Organic Solvents

Stephen Juma Mulware

Ion Beam Modification and Analysis Laboratory Physics Department University of North Texas1155 Union Circle 311427 Denton TX 76203 USA

Correspondence should be addressed to Stephen Juma Mulware stephenmulwaremyuntedu

Received 9 March 2013 Accepted 24 April 2013

Academic Editor Claudio Luparello

Copyright copy 2013 Stephen Juma Mulware This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The increased rate of breast cancer incidences especially among postmenopausal women has been reported in recent decadesDespite the fact that women who inherited mutations in the BRCA1 and BRCA2 genes have a high risk of developing breast cancerstudies have also shown that significant exposure to certain metal compounds and organic solvents also increases the risks ofmammary gland carcinogenesis While physiological properties govern the uptake intracellular distribution and binding of metalcompounds their interactionwith proteins seems to be themost relevant process formetal carcinogenicity than biding toDNAThefour most predominant mechanisms for metal carcinogenicity include (1) interference with cellular redox regulation and inductionof oxidative stress (2) inhibition of major DNA repair (3) deregulation of cell proliferation and (4) epigenetic inactivation ofgenes by DNA hypermethylation On the other hand most organic solvents are highly lipophilic and are biotransformed mainlyin the liver and the kidney through a series of oxidative and reductive reactions some of which result in bioactivation The breastphysiology notably the parenchyma is embedded in a fat depot capable of storing lipophilic xenobiotics This paper reviews therole of metal compounds and organic solvents in breast cancer development

1 Introduction

Breast cancer accounts for 16 of all cancer deaths amongwomen globally according to the report by theWorld HealthOrganization [1] It is the most common solid tumor diag-nosed in women [2] and there is also an increasing trend inmen Even though some women are genetically predisposedby inheriting the BRCA1 and BRCA2 genes studies showthat an elevated lifetime of estrogen exposure is also anotherrisk factor for breast cancer [3] The ability of estrogen andestrogen metabolites to generate oxygen reaction species(ROS) which can induce DNA synthesis increase phos-phorylation of protein kinases and activate transcriptionfactors like AP-1 NRF1 E2F and CREB which are foundto be responsive to oxidants (including solvent toxins andmetal compounds) embodies the basis of carcinogenesis byestrogen [4] Whereas the activation of transcription factorsplays a vital role in cell transformation cell cycle migrationand invasion and it increases the genetic instability [5]

Occupational and environmental exposure tometal com-pounds and organic solvents have contributed to increasingbreast cancer cases in the recent decades especially as manywomen have entered work places since 1960s [6] It has beenreported that metallic compounds could function as estrogendisruptors [7] as well as carcinogenic agents Generallymetal genotoxicity is caused by indirectmechanism includinginterference with cellular redox regulation and inductionof oxidative stress inhibition of DNA repair system andderegulation of cell proliferation by induction of signalingpathways or inactivation of tumor suppressor genes Inaddition the increased DNA methylation especially in aninvasive or tumor stage has been reported widely as a leadingfactor in breast carcinogenesis by various studies using RLGSFor instance studies of human breast tissues determinedthat NRG1 exon 1 (neuregulin 1) was partially methylatedin 14 out of 17 (824) of the invasive carcinomas samplestested while it was unmethylated in 8 out of 10 of the normalbreast tissues Partial methylation was also found in 9 out of

2 International Journal of Breast Cancer

14 (643) morphologically normal tissue samples adjacentto invasive carcinomas sites [8] Another study reportedthat DNA methylation exhibits various patterns in differentcancer types since methylation is most significantly linkedwith radical changes in conditional concordant relationships(CCRs) throughout the genome Hypermethylation of DNAthus enhances progression cell migration and oncogenicityin breast cancer [9] Some metals also undergo metabolictransformation such as reduction to lower oxidation state oralkylation [10] A unique feature of metal biology is the factthat even essential metals like iron and copper can becometoxic depending on the oxidation state complex form doseand mode of exposure

Organic solvents are widely and routinely used domes-tically as part of consumer products or in various indus-tries and they can get into the body through inhalationingestion or by dermal exposure While exposure is thehighest in some work places most of these solvents andother chemicals are commonly found in ambient air drinkingwater and consumer products [11 12] The detection ofsome solvents in the some human breast milk confirms thatafter exposure these compounds can find their way into thebreast tissues [13] Organic solvents and their metabolitesare believed to initiate or promote breast cancer throughgenotoxic or other related mechanisms including mutagenor tumorigen among others Generally the basis of organicsolvent carcinogenesis depends on the estrogenic propertiesof halogenated hydrocarbons which are implicated in theetiology of breast cancer Similarly another hypothesis isbased on the fact that the lipophilic substances and theirmetabolites can migrate to the adipose tissue in the breastswhere they can be biotransformed in situ and then excretedinto ductular systems where while in contact with breastparenchyma for long enough can initiate or promote carcino-genesis through genotoxic or relatedmechanism [14] Severalepidemiological studies in the recent past have establishedthat organic solvents play a role in breast carcinogenesisFor instance a well-designed epidemiological study amongyoung Danish women in occupations with greater exposureof solvents found elevated risks of breast cancer [15] Thisstudy established that the risk was doubled among womenwho had over 10 years of exposure Another case-registry-based study of Canadian women established elevated risksamong pre- and postmenopausal womenwhowere employedin two industries with high chemical exposureThose in a drycleaningwork place which used tetrachloroethylene recordedeven higher rates of breast cancer [16]This paper will discussbreast physiology as an enabling factor especially for organicsolvents absorption and distribution of carcinogens phys-iochemical properties and the general metal genotoxicitymechanisms It will then highlight specific metal compoundsand organic solvents that have been linked to breast cancer

2 Breast Parenchyma

In anatomical terms the parenchyma of a body part consti-tutes all the cells of that organ that have an essential functionBreast parenchyma is made of a series of apocrine glands

which includes the milk ducts and the glands that producethemilkThese epithelial cells which are arranged into lobulesconnected to ductular system of the breast end up at thenipple The breast parenchyma are embedded in fatty tissuethe amount of which varies from one woman to another andconnective tissues with rich supply of blood and lymphaticvessels The breast physiology comprises certain uniquefeatures that make it sensitive to various metal compoundsand organic solvents and their metabolites that may exposeit to cancer development First the apocrine glands thatmake up the breast parenchyma proliferate continuouslyfrom the menarche with increasing cell population duringevery ovulatory cycle of a female resulting in the developmentof the budding structure until approximately the age of 35[14] A mutation occurring during DNA transcription andother errors that may occur during such replication exposebreast tissues to high risk Furthermore the accumulation ofxenobiotics in the breast tissues is enhanced by physiologicalchanges that take place in the body during menstrual cycles

Due to reduction in the metabolic and clearance activityof the breast tissue the byproducts ofmetabolic oxidative andreductive processes (redox) remain in the breast parenchymafor too long to act as early stage initiators through changesin DNA bases and other hydroxyl radical-induced adversereactions [17] They can also act as promoters of alreadyinitiated cells with both theories consistent with the obser-vation of nearly 70 of breast tumors originating in theductular system [18] Exogenous carcinogens includingmetalcompounds and organic solvents are secreted into breastfluids as evidenced by a unique study among boat women ofAberdeen in Hong Kong The study found that these womenwho traditionally nursed their infants only from their rightbreast and not their left breast were as twice as likely todevelop breast cancer on the left breast due to stagnation ofthe milk there with the risk increasing more with age [19] Ina separate study breast secretions and colostrums especiallyamong farm women who were exposed to more carcinogenswere found to be mutagenic on an Ames test [20] Table 1shows organic solvents that have been detected in humanmilk

3 General Mechanism of MetalCarcinogenicity

Metals can be carcinogenic in various forms including freeions metal complexes or particles as well as soluble metalcompoundsThe physiochemical properties of variousmetalsgovern their respective toxicity Oxidation state charge andionic radii play significant role with regards to metal free ionswhile the coordination number the geometry and the typeof legand (ie their lipophilicity) determine their toxicityOn the other hand the soluble metal compoundsrsquo toxicitydepends in part on the particle size and crystal structures [10]If toxicmetal ions have similar physiochemical properties likecharge and size compared to essential metal ions they tendto compete for biological binding sites of the latter resultinginto structural perturbations leading to aberrant functionof biological macromolecules [21 22] In general metal

International Journal of Breast Cancer 3

Table 1 Organic solvents detected in human milk

Organic solvent ReferencesAcetaldehyde aBenzaldehyde aBenzene aCarbon disulfide andashcCarbon tetrachloride cChlorobenzene aChloroethane (ethyl chloride) aChloromethane aChloropentane aCrotonaldehyde aCyclohexane aCyclopentane aDichlorobenzene a1-2-Dichloroethane aDichloroethylene cEthyl alcohol aEthylbenzene bEthyl methyl ketone aΒ-Hexachlorocyclohexane aMethyl alcohol (methanol) aMethyl amyl ketone (2-heptanone) aMethyl ethyl ketone aMethyl isobutyl ketone aMethyl propyl ketone aMethylene chloride aStyrene a cTetrachloroethene a bToluene a111-Trichloroethene aTrichloroethyleneTrichloromethane (chloroform) aXylenes aa Pellizzari et al 1982 [23] b Wolff 1983 [24] c Jensen 1991 [25]

carcinogenicity and genotoxicity are based on three mainmechanisms namely oxidative stress DNA repair modula-tion and disturbances of signal transduction pathways

31 Induction of Oxidative Stress Ions of carcinogenic metalslike arsenic antimony chromium lead cobalt nickel andvanadium produce redox reactions in biological systemsThey induce the formation of reactive oxygen and nitrogenspecies in mammalian cells The oxidative concept in metalcarcinogenesis signifies that the complexes formed by thesemetals in vivo in the vicinity of the DNA catalyze redoxreactions oxidizing DNA in turn [26] The most significanteffect of reactive oxygen species (ROS) in the carcinogenicprogression is the DNA damage which in turn results intolesion-like strand breaks and the sister-chromatid exchange[27] Redox processes lead to the formation of hydroxylradicals by Fenton and Haber-Weiss reactions which inturn cause oxidative damage to lipids proteins and DNA

There is a fine balance between enzymatic (such as superoxide dismutase SOD glutathione peroxidase and catalase)and nonenzymatic (like ascorbic acid 120572-tocopherol and 120573-carotene and isoflavones) antioxidants and free radicals ineach cell A higher ROS generation can also lead to lipidperoxidation depletion of the sulfhydryl groups and changeof transduction pathways leading to cell apoptosis Althoughcadmium ions do not exert redox reactions in biologicalsystems they still generate oxidative stress by inhibitingantioxidative enzymes in vivo and in vitro

Iron and copper are also effective catalysts for fentonand fenton-type reactions The two metals are howeverheavily regulated with respect to uptake transport storagemobilization transfer to target molecules and excretionthus ensuring that the increased deliberation of free ions isrestricted to conditions of extreme overload genetic defectsin metal homeostasis andor metabolic stress [10] Copperplays a role in activation of more than 30 enzymes includingamong others ceruloplasmin cytochrome oxidase lysineoxidase dopamine hydroxylase and ascorbate oxidase someof which are involved in the synthesis of themain componentof connective tissues called collagen Iron also plays a vitalrole in oxygen transportation xenobiotic metabolism andoxidative phosphorylation and acts as prosthetic group inmany enzymes [28]

32 DNA Repair Inhibition The process of DNA repair inmammalian cells is a multipathway mechanism meant toprotect cells from the plethora of DNA damaging agentsknown to attack nuclear DNA Most of anticancer therapiesincluding ionizing radiation and chemotoxic therapies rely onthis capability to createDNA lesions leading to apoptosiscelldeath [29] Most carcinogenic metals usually are comu-tagenic which means that they enhance the mutagenicityof other genotoxic agents At low concentrations most ofthese metals inhibit repair of DNA damage caused by eitherxenobiotics or endogenous factors [30] Inhibition of DNArepairmechanisms including nucleotide excision repair baseexcision repair DNA-SSB rejoining and 1198746-methylguanine-DNA methyltransferase [31ndash33] is of high relevance forhuman carcinogenesis since DNA repair inhibition bycadmium for instance occurs at very low concentrationseven though most direct DNA damaging effects are usuallyobserved at higher concentrations Inhibition of DNA repairmay also explain the observation that cadmium despite beingnonmutagenic in bacteria enhances mutagenicity of methylnitrosourea and strongly enhancesUV-inducedmutagenicityin mammalian cells as well [34] DNA repair mechanismsare frequent targets for interference by carcinogenic metalcompounds Inhibition of repair and continuous DNA dam-age results in genomic instability which under conditionsof accelerated cell proliferation and impaired apoptosis maybecome deleterious

33 Deregulation of Cell Proliferation Deregulation of cellgrowth and differentiation are two main factors that char-acterize tumor development Carcinogenic metals can altermammalian cell growth by affecting the expression of growth


stimulating factors through activating mitogenic signalingpathways and inducing the expression of cellular protoonco-gens At the same time modified gene expression can resultfrom epigenetic mechanism like hypo- or hypermethylationof DNA andor disturbed histone acetylation The other waythe carcinogenic metals can alter mammalian cell growth isby inactivating growth control mechanism [10] In generalthe deregulation of cell proliferation that leads to tumorgrowth and invasive cancer stage is often imposed by viralagents heavy metals toxins and oxidants Some metal car-cinogens have been shown to inactivate the tumor suppressorproteins p53 Metal ions can also deregulate cell proliferationby inactivating apoptotic process resulting in adaptation tothe cytotoxicity of the metal

4 Specific Metal Mammary Gland Carcinogens

41 Arsenic Arsenic is commercially produced as a byprod-uct of nonferrous metal production precisely from coppersmelting Arsenic exposure constitutes one of the most widespread environmental carcinogens associated with numerouscancers Arsenites are found in drinking water some woodpreservatives insecticides and herbicides In the naturalwaters arsenic occurs in oxidation states III and V in theform of arsenous acid (H

3AsO3) and arsenic acid (H

3AsO5)

and their salts [35] at the same time smaller amounts ofmonomethylarsonic acid (MMA) and dimethylarsinic acid(DMA) can also be present The trivalent monomethylated(MMAIII) and dimethylated (DMAIII) arsenic species havebeen detected in lake water [36] The International Agencyof Research on Cancer (IARC) in its evaluations classifiedarsenic and its compounds as highly carcinogenic to humans[37] Among the cancers linked to arsenic compounds areskin bladder liver kidney lung and breast cancers [38]

Themain source of exposure to humans is through drink-ing ground water with high level of arsenic contaminationespecially in South Asia region This region witnessed widespread carcinogenic effects from the contaminated waterthat led USEPA to declare the maximum contaminant limitto 0010mgL in line with WHO guidelines [36] The riceplanted by irrigation in these regions has also throughuptake introduced arsenic into the human food Amongother major exposure mechanisms of arsenic to human foodis through consumption of contaminated fish and sea foodsThese exposure mechanisms can be easily reduced througheffective food evaluation by authorities and enhanced edu-cation to the populations in the regions affected alongsideminimizing industrial exposures

Various methods have been developed and improved forthe measurement of total arsenic exposure agents especiallyfoods and drinking water and have been widely used forthe evaluation of the quantitative or qualitative level ofcontamination and the resulting concentrations of arsenic inhumans Similarly analyticalmethods allowing arsenic speci-ation have attracted more research in light of its carcinogenicpotential The form of existence of the arsenic compoundsdictates its environmental fate and behavior bioavailability

and toxicity for instance the inorganic AsIII and AsV are farmore toxic than MMA and DMA [36]

Arsenic trioxide (As2O3) which has been used as a

component of Chinesemedicine for hematologicmalignancytreatment induces cell cycle arrest and apoptosis in solidtumors including breast cancer [39] It is hoped that newinsights into how the As

2O3binds to specific receptors

and how they trigger signaling pathways may help explainits anticancer strategies that may be helpful in the treat-ment of other solid tumors including breast cancer Highenvironmental concentration and thus exposure of arsenite(5 120583M065mgL) can induce both replications-dependentDNA double-strand breaks and homologous recombinationThe study found that the double-strand break was replicationdependent which might have resulted from conversion of aDNA single-strand break to double-strand break [40] Onthe other hand low arsenite concentration induces ROSproduction and ROS depolarization of the mitochondriamembrane When the ROS mediated DNA damage wasmeasured by the presence of 8-OHdG DNA adducts in thenuclei I120581B phosphorylation NF-120581B activation and increasein c-Myc and HO-1 protein levels were observed The roleof arsenic induced breast cancer cell MCF-7 recruitmentinto the S-phase of cell cycle and cell proliferation can beexplained by the above factorsThe study however concludedthat arsenates activates many pathways involved in MCF-7 cell proliferation leading to a suggestion that arseniteexposure may be a high risk cause to breast cancer [38]Accumulating evidence from cell culture studies and fromarsenic exposed humans suggests that arsenic changes theDNA methylation pattern hence affecting the expression ofoncogenes and tumor suppressor genes

42 Cadmium Cadmium is emitted to the air by minesmetal smelters and industries which use cadmium com-pounds for in the production of alloys batteries pigmentsand plastics [30] It is a widespread environmental pollutantthat has been declared carcinogenic to humans by theInternational Agency of Cancer Research [37] Both activeand passive smoking of all forms of tobacco is the singlemost means of exposure to humans since all forms oftobacco contain high levels of cadmium This is so sincethe absorption of cadmium in tobacco smoke from thelungs into the body cells is much greater than the gastroin-testinal tract absorption [41 42] It is important to notethat tobacco also contains other 16 carcinogenic compoundsapart from cadmium including benzo[a]pyrene (BaP) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) andN1015840-nitrosonornicotine (NNN) 2-naphthylamine 4-aminob-iphenyl formaldehyde 13-butadiene benzene vinyl chlo-ride ethylene oxide arsenic beryllium nickel compoundschromium VI and polonium-210 which have been classifiedby IARC as group 1 carcinogens [25] Since cadmium ions caneasily be absorbed and stored in plants roots stems leavesand fruits consumption of such affected parts of plants byanimals may lead to contamination of their milk and meatproducts which in effect can contaminate human food [42]


Sea foods such as mollusks and crustaceans have also been asource of contamination [43 44]

Cadmium is a ubiquitous carcinogenic pollutant asalready mentioned with multiple biological effects on livingcells and various case studies have correlated its exposure tobreast cancer [2 29 45 46] These studies observed a signif-icant increased risk of breast cancer in patients with higherurinary cadmium concentration Cadmium is believed tohave diverse effects in various cellular processes includingcell proliferation differentiation and apoptosis It is anendocrine disruptor that stimulates estrogen-receptor 120572 (ER-120572) activity promoting uterine and mammary gland growthwhile at the same time impairing the cancer protecting effectof selenium in female inbred C3H mice carrying murinemammary tumor virus [47] Cadmium changes intercellularsignals by modulating gene expression and affecting thepatterns of transcriptional activity It activates extracellularregulated kinases erk-1 and -2 in both ER-positive and ER-negative human breast cancer cells while high cadmiumconcentrations induce a proliferative response SKBR3 cellsand increase intracellular cAMP levels [48] Cadmium alsoincreases breast cancer proliferation in vitro by stimulatingAkt ERK12 and PDGFR120572 kinases activities most likely byactivating c-fos c-jun and PDGFA by an ER-120572-dependentmechanism [49] Another study also found that cadmiumdespite being able to promote carcinogenesis can also delaythe onset of tumors by inhibiting breast cancer cell-inducedangiogenesis [50]

43 Lead Lead exists both as free metal and also in variouscompounds It can also be found in plants animals air waterdust and soil Inorganic lead compounds like tetraethyl leadand tetramethyl lead are combined with carbon groups whilelead oxide and lead chloride are combinations of lead withother compounds The main exposure mode to human isthrough inhalation from dust or fumes and by swallowingMost observed mechanisms of lead carcinogenicity involvedirect DNA damage oxidative DNA damage through ROSgeneration clastogenicity or inhibition of DNA synthesis orrepair [51 52] Lead is also known to substitute for zinc inseveral proteins that function as transcriptional regulatorshence reducing the binding of these proteins to the recog-nition elements in the genomic DNA This process leads toa suggestion that lead is involved in epigenetic alteration ofgene expression [53]

In animal experiments of female C3H mice low con-centration of lead in drinking water was found to promotethe development and accelerate the growth of mammarymurine tumors [3] High levels of lead were found in bloodand hair of newly diagnosed patients of breast cancer bythe same study with the lead levels in the hair directlycorrelated to the volumes of the tumors present The samestudy also established that lead interacted with iodine anessential trace element that most likely protects againstbreast cancer by substituting it in the cell tissues Lead-zinc interactions in proteins can also cause posttranslationalchanges in the protein structure This occurs when leaddisplaces zinc in a tumor suppressor protein p53 resulting

in a structurally altered form with functional mutationconsequences involving deletion of p53 as observed withcadmium [54] As one molecular target with respect tobase excision repair lead inhibits the apurinicapyrimidinicendonuclease (APE1) in the low micromolar concentrationrange both in an isolate enzymic test system and in culturedAA8 cells This leads to an accumulation of apurinic sites inDNA and increase in MMS-induced mutagenicity [55] Leadalso interferes with the repair of DNA double strand breaksthrough interactionwith the stress response pathway inducedby ATM (a phosphoinositide-3-kinase) [56]

44 Nickel Most nickel on earth is mainly found in theiron-nickel molten ore which constitutes 10 of nickel Coaland oil contains considerable amounts of nickel since it isreadily absorbed in organic matter Human exposure occursthrough contaminated food and drinking water smokingcigarettes and contact with nickel contaminated soil or waterOccupational exposure is common in industries that handlenickel laced materials like high temperature oxidation ofnickel matte and nickel-copper matte electrolytic refinersand during nickel salt extraction in hydrometallurgical indus-try There has been reported experimental evidence thatnickel metal dust can become solubilized and bioavailableafter inhalation [57]

Nickel compounds are known carcinogens in both humanand animal models [58] The genotoxic effects of nickelcompounds may be indirect through the inhibition of DNArepair systems [59 60] while nickel carcinogenesis is believedto be mediated by oxidative stress DNA damage epigeneticeffects and the regulation of gene expression by activationof certain transcription factors [61] Nickel has been shownto stimulate cell growth in estrogen receptor (ER) positivebreast cancer cells MCF-7 [62] Another study by Ionescu etal [63] established highly significant nickel accumulation in20 breast cancer tissue biopsies compared to controls

45 Organic Solvents The toxicity of organic solvents inthe human body is governed by the extent of absorptiondistribution and metabolization Once they enter the bodythrough ingestion inhalation or cutaneous absorption theyenter the blood stream through which they are transportedto various organs [63] Most blood rich organs including thelungs kidney and liver take up much of the organic solventswhile the rest are distributed and absorbed by fatty tissues inother organs Once stored in the surrounding fatty tissues ofthe breast the organic solvents migrate into the lobules andthe ductular system as secretory products of the epithelialcells and by simple passive or active diffusion through cellmembranes by direct transport through water-filled pores inthe cell membranes [64]

5 Specific Organic Solvent MammaryGland Carcinogens

51 Benzene Benzene is a volatile organic compound widelyused in various chemical production including gasolineproduction storage transport vending and combustion It


is also a byproduct of processes like coke oven as well as beinga component of various consumer products like carpetspesticides and adhesive removers [65] Benzene is both airand water contaminant closely monitored by most states inthe USA Apart from air pollution resulting from industrialburning exhaust and gas fumes as well as cigarette smokecontamination also occurs through ingestion of contami-nated food and water

The International Agency for Research on Cancer andthe National Toxicology Program has labeled benzene asa definite human carcinogen Various studies point to acorrelation between benzene exposure and breast cancer riskLaboratory studies on mice have shown that a high levelof benzene exposure can lead to mammary cancer [66]Mice exposed to benzene displayed frequent mutations ofgenes that are responsible for suppressing the developmentof tumors [67] In one epidemiological study that lookedat relevant occupations among female Chinese workersthe occupations in which elevated risks for breast cancerwere found to include scientific research workers medicaland public health workers and electrical and electronicengineers as well as teachers librarians and accountantsBenzene exposure was associated with an elevated risk ofbreast cancer among exposed professionals [68] Results fromother recent studies support these conclusions includinga study examining occupational exposures among enlistedwomen in the US Army [69] and women in various profes-sions in Israel [70] Another study of a fairly small sampleof women for whom researchers had benzene exposure datafrom their work at a shoe factory in Florence Italy alsosupported a relationship between exposure to benzene andlater development of breast cancer [71]

52 Methylene Chloride This is a highly volatile compoundused in various consumer products like fabric cleaners paintstrippers wood sealant and stains spray paint adhesivesfurniture and shoe polish and art supplies among otherExposure occurs mainly during production and industrialuse of methylene chloride and dichloromethane alongsidethe environmental exposure resulting from the use of theconsumer products [72] High levels of exposure are associ-ated with benign mammary tumors in animal experimentsinvolving rats The study established increased incidences offibroadenomas of the mammary gland in female rats whoinhaled methylene chloride [65]

Once inhaled or absorbed into the body methylenechloride is converted to carbon monoxide which interfereswith oxygen delivery hence causing angina (chest pain)and making other heart symptoms worse in people withheart disease People with lung conditions smokers andoverweight or pregnant people may also be more sensitiveto methylene chloride When inhaled or absorbed throughthe skinmethylene chloride can reach the developing fetus inpregnant women through the placenta and also enter breastmilk Methylene chloride affects the nervous system (brain)and can cause headaches dizziness nausea clumsinessdrowsiness and other effects like those of being drunkWhenexposed to high levels of methylene chloride frequently over

months or years the nervous system effects can be long-lasting and possibly permanent Methylene chloride causescancer in laboratory animals and potentially can cause cancerin humans

53 Ethylene Oxide Ethylene oxide is used to sterilize med-ical equipment and other products like clothing cosmeticsand beekeeping equipment It is also found in tobacco smokeexhaust gases and some foods and spices Occupationalexposure is the greatest among people whowork directly withthe compound Ethylene oxide is a knownhuman carcinogenOne study found a twofold increased risk of breast cancer(standardizedmorbidity ratio) amongwomenwhoworked inan industrywith documented exposure [41] In a cohort studyof 7576 women employed for at least one year and exposedfor an average 107 years while working in commercialsterilization facilities breast cancer incidence (119899 = 319) wasascertained via interview death certificates cancer registriesand medical records [73] Despite contradictory data inthe recent literature other reports support the finding thatexposure to ethylene oxide is associated with increased riskfor breast cancer in women [74] Studies in which humanbreast cells grown in vitro were exposed to low doses ofethylene oxide demonstrated that the chemical exposureresulted in a significant increase in damage to the cellsrsquo DNA[74]

54 Styrene Styrene is used in manufacturing and is abyproduct of polystyrene (plastic) It is also used in thesynthetic rubber industry Many building materials homemaintenance products and several consumer products likecarpets paints adhesives hobby and craft supplies containstyrene [13 65] General exposure occurs by inhalation ofcontaminated air and tobacco smoke as well as ingestingcontaminated food and water

Styrene has been classified as a possible carcinogen bytheNational Toxicology Program [75] Several animal studieshave linked styrene with increased mammary tumors [65]Results from these studies may not be necessarily generalizedto humans because for a given mode of absorption majordifferences exist between species in uptake distribution andmetabolism [61] For example higher quantities of styreneoxide are produced by mice than rats or humans afterexposure to styrene Humans are also found to have thehighest capacity to metabolize styrene oxide than mice orrats [76] At the same time most animal studies are basedon exposure to a single organic solvent Human exposures onthe contrary are due to mixture exposures and other possiblecarcinogens and thus interactions between different solventsmay inhibit or potentiate known effects of individual solvents[11]

55 Tetrachloroethylene Tetrachloroethylene (PCE) alsoknown as perchloroethylene or perc is an important occu-pational chemical used in metal degreasing and dry clean-ing and a prevalent drinking water contaminant Humanexposure is mainly by inhalation of vapors by direct contactwith the skin or by ingesting contaminated water or food


The highest exposures trends to tetrachlorethylene occur inthe workplace especially among dry cleaning and degreasingworkers Workers in some other industries may also beexposed to tetrachlorethylene

Tetrachloroethylene has been categorized as carcinogenicby IARC There are hypothesized mode(s) of action onlyfor rat kidney tumors and mouse liver tumors For theformer the hypothesizedmodes of action includemutagenic-ity peroxisome proliferation 120572

2u-globulin nephropathy andcytotoxicity not associated with 120572

2u-globulin accumulationFor mouse liver tumors the hypothesized mode(s) of actioninclude mutagenicity epigenetic effects (especially DNAhypomethylation) oxidative stress and receptor activation(focusing on a hypothesized PPAR120572 activation mode ofaction) However the available evidence is insufficient tosupport the conclusion that either rat kidney or mouse livertumors are mediated solely by one of these hypothesizedmodes of action Epidemiological studies found elevatedlevels of breast cancer in working women in drycleaners[16] One population-based case control study of womenwhowere accidentally exposed to Perc leaching from improperlyprepared water pipes found an elevated risk of breast cancerassociated with exposure [77]

56 Other Organic Compounds There are several otherorganic solvents including industrial chemicals that werebelieved to be associated with breast cancer Some of theseinclude carbon tetrachloride urethane toluene diisocyanatemixtures isoprene nonylphenols and 1 3-butadiene amongothers Most of these chemicals enter the body by inhala-tion or ingestion in contaminated food and drinks TheOccupational Safety and Health Administration (OSHA)produces cancer risk estimates of various organic chemicalsto determine permissible exposure limits in workplacesWhereas these risk estimates are not specific to breast cancerthe overall risks are as high as one percent indicating thatworkers can face a substantial danger when exposed

6 Conclusion

Carcinogenic compounds including metals and organic sol-vents play a major role in the multistep processes that leadto breast cancer including initiation promotion progressionand metastasis A combination of biological processes andphysiochemical effects of each carcinogen in conjunctionwith other factors including genetics age and body sizecan contribute to development of the breast cancer Inspite of the wide range of physiochemical properties ofmetal compounds some common mechanism of metalcarcinogenesis emerges in general These include inductionof oxidative stress inhibition of DNA repair activation ofmitogenic signaling and epigenetic modification of geneexpression On the other hand organic solvents can causebreast cancer through various mechanism including intactsolvent molecules reaching the breast epithelium where theyare bioactivated into electrophilic metabolites that cannot bedetoxified due to reduced activity of the necessary enzymeswithin the breast cells some of electrophilic metabolites

produced in other organs like liver or kidney are transportedto the breast accumulating in the milk ducts and causingtoxic effects and finally estrogenic effects of endogenous andexogenous substances Even though little epidemiologicalevidence exists especially on the effects of organic solventsthe fact that these compounds have been categorized ascarcinogenic with some evidence in experimental animalsis enough to ensure appropriate regulation is in place toprotect environmental contamination of both carcinogenicmetal and organic solvents Occupational exposure must beminimized since this is the route through which the majorityare affected Human activity leading to environmental pol-lution must be monitored by authorized organs to ensurethat the populations are protected from the toxicity of thesepotentially dangerous compounds

References

[1] World Health Organization FS 2011 httpwwwwhointmediacentrefactsheetsfs297enindexhtml

[2] C M Gallagher J J Chen and J S Kovach ldquoEnvironmentalcadmium and breast cancer riskrdquo Aging vol 2 no 11 pp 804ndash814 2010

[3] O I Alatise and G N Schrauzer ldquoLead exposure a contribut-ing cause of the current breast cancer epidemic in NigerianWomenrdquo Biological Trace Element Research vol 136 no 2 pp127ndash139 2010

[4] A Florea and D Busselberg ldquoMetals and breast cancer riskfactors or healing agentsrdquo Journal of Toxicology vol 2011Article ID 159619 8 pages 2011

[5] V Okoh A Deoraj and D Roy ldquoEstrogen-induced reactiveoxygen species-mediated signalings contribute to breast can-cerrdquo Biochimica et Biophysica Acta vol 1815 no 1 pp 115ndash1332011

[6] Statistics Canada Women in Canada A statistical Report Cat-alogue no 89-503E Ministry of Supply and Services CanadaOttawa Canada 2nd edition 1990

[7] C L Siewit B Gengler E Vegas R Puckett and M CLouie ldquoCadmium promotes breast cancer cell proliferation bypotentiating the interaction between ER120572 and c-JunrdquoMolecularEndocrinology vol 24 no 5 pp 981ndash992 2010

[8] Z Fernandez C E Snider Y Z Wu I H Russo C Plass andJ Russo ldquoDNA methylation changes in a human cell model ofbreast cancer progressionrdquoMutation Research vol 688 no 1-2pp 28ndash35 2010

[9] P Qui and L Zhang ldquoIdentification of markers associated withglobal changes in DNA methylation regulation in cancersrdquoBMC Bioinformatics vol 13 supplement 13 article S7 2012

[10] D Beyersmann and A Hartwig ldquoCarcinogenic metal com-pounds recent insight into molecular and cellular mecha-nismsrdquo Archives of Toxicology vol 82 no 8 pp 493ndash512 2008

[11] L S Andrews and R Snyder ldquoToxic effects of solvents andvaporsrdquo inThe Basic Science of Poisons M O Amdur J Doulland C D Claassen Eds pp 681ndash722 McGraw-Hill TorontoCanada 1991

[12] J J Morris and E Seifter ldquoThe role of aromatic hydrocarbons inthe genesis of breast cancerrdquoMedical Hypotheses vol 38 no 3pp 177ndash184 1992

[13] J G Brody K B Moysich O Humblet K R Attfield G PBeehler and R A Rudel ldquoEnvironmental pollutants and breast


cancer epidemiologic studiesrdquo Cancer vol 109 supplement 12pp 2667ndash2711 2007

[14] F P Lambreche and M S Goldberg ldquoExposure to organicsolvents and breast cancer in women a hypothesisrdquo AmericanJournal of Industrial Medicine vol 32 pp 1ndash14 1997

[15] J Hansen ldquoBreast cancer risks among relatively young womenemployed in solvent-using industriesrdquo American Journal ofIndustrial Medicine vol 36 no 1 pp 43ndash47 1999

[16] P R Band N D Le R Fang M Deschamps R P Gallagherand P Yang ldquoIdentification of occupational cancer risks inBritish Columbia a population-based case-control study of 995incident breast cancer cases by menopausal status controllingfor confounding factorsrdquo Journal of Occupational and Environ-mental Medicine vol 42 no 3 pp 284ndash310 2000

[17] D C Malins E H Holmes N L Polissar and S J GunselmanldquoThe etiology of breast cancer characteristic alterations inhydroxyl radical-inducedDNAbase lesions during oncogenesiswith potential for evaluating incidence riskrdquo Cancer vol 71 no10 pp 3036ndash3043 1993

[18] J W Berg and R V P Hutter ldquoBreast cancerrdquo Cancer vol 75no 1 pp 257ndash269 1995

[19] N L Petrakis ldquoBreast secretory activity in nonlactatingwomenpostpartum breast involution and the epidemiology of breastcancerrdquo National Cancer Institute Monograph vol 47 pp 161ndash164 1977

[20] N L Petrakis M E Dupuy R E Lee et al ldquoMutagens in nippleaspirates of breast fluidrdquo in Banbury Report 13 Indicators ofGenotoxic Exposure pp 67ndash82 Cold Spring Harbor LaboratoryCold Spring Harbor NY USA 1982

[21] D Beyersmann ldquoPhysiochemical aspect of the interferenceof detrimental metal ions with normal metal metabolismrdquo inHandbook on Metal Ligand Interactions in Biological Fluids GMerthon Ed pp 813ndash826Marcel Dekker NewYork NY USA1995

[22] A Hartwig ldquoZinc finger proteins as potential targets for toxicmetal ions differential effects on structure and functionrdquoAntioxidants and Redox Signaling vol 3 no 4 pp 625ndash6342001

[23] E D Pellizzari T D Hartwell B S H Haris III R DWaddell D A Whitaker and M D Erickson ldquoPurgeableorganic compounds inmotherrsquosmilkrdquoBulletin of EnvironmentalContamination and Toxicology vol 28 no 3 pp 322ndash328 1982

[24] M SWolff ldquoOoccupationally derived chemicals in breastmilkrdquoAmerican Journal of Industrial Medicine vol 4 pp 259ndash2811983

[25] A A Jensen ldquoOccupational chemicals in human milkrdquo inChemical Contaminants in Human Milk A A Jensen and S ASlorach Eds pp 209ndash214 CRC Press Boca Raton Fla USA1991

[26] M Yaman ldquoComprehensive comparison of trace metal con-centrations in cancerous and non-cancerous human tissuesrdquoCurrent Medicinal Chemistry vol 13 no 21 pp 2513ndash25252006

[27] M Valko H Morris andM T D Cronin ldquoMetals toxicity andoxidative stressrdquoCurrentMedicinal Chemistry vol 12 no 10 pp1161ndash1208 2005

[28] A Anil K Puneet and K B Dalim ldquoTrace elements in criticalillnessrdquoThe Journal of Clinical EndocrinologyampMetabolism vol1 no 2 pp 57ndash63 2011

[29] M N Martin ldquoDNA repair inhibition and cancer therapyrdquoJournal of Photochemistry and Photobiology B vol 63 no 1ndash3pp 162ndash170 2001

[30] N Harrison ldquoInorganic contaminants in foodrdquo in Food Chem-ical Safety Contaminants D H Watson Ed pp 148ndash168Woodhead Publishing Ltd Cambridge Mass USA 1st edition2001

[31] P Calsou P Frit C Bozzato and B Salles ldquoNegative interfer-ence of metal (II) ions with nucleotide excision repair in humancell-free extractsrdquo Carcinogenesis vol 17 no 12 pp 2779ndash27821996

[32] T Hirano Y Yamaguchi and H Kasai ldquoInhibition of 8-hydroxyguanine repair in testes after administration of cad-mium chloride to GSH-depleted ratsrdquo Toxicology and AppliedPharmacology vol 147 no 1 pp 9ndash14 1997

[33] K Takahashi M Suzuki M Sekiguchi and Y KawazoeldquoEffect of metal ions on transcription of the ada genewhich encodes O6-methylguanine-DNA methyltransferase ofEscherichia colirdquoChemical and Pharmaceutical Bulletin vol 40no 9 pp 2483ndash2486 1992

[34] A Hartwig and D Beyersmann ldquoEnhancement of UV-inducedmutagenesis and sites-chromatid exchanges by nickel ions inV79 cells evidence for inhibition of DNA repairrdquo MutationResearch vol 217 no 1 pp 65ndash73 1989

[35] C N Sawyer P L McCarty and G F Parkin Chemistry forEnvironmental and Engineering Sciences Mc Graw Hill NewYork NY USA 5th edition 2003

[36] International Agency for Research on Cancer (IARC) IARCMonographs on the Evaluation of Carcinogenic Risks to HumansArsenic in Drinking Water vol 84-6A IARC Lyon France2004

[37] International Agency for Research on Cancer (IARC) IARCMonographs on the Evaluation of Carcinogenic Risks to Humansvol 1ndash58 IARC Lyon France 1993

[38] R Ruiz-Ramos L Lopez-Carrillo A D Rios-Perez A deVizcaya-Ruız and M E Cebrian ldquoSodium arsenite inducesROS generation DNA oxidative damage HO-1 and c-Mycproteins NF-120581B activation and cell proliferation in humanbreast cancer MCF-7 cellsrdquo Mutation Research vol 674 no 1-2 pp 109ndash115 2009

[39] X Wang P Gao M Long et al ldquoEssential role of cell cycleregulatory genes p21 and p27 expression in inhibition of breastcancer cells by arsenic trioxiderdquo Medical Oncology vol 28 no4 pp 1225ndash1254 2011

[40] S Ying K Myers S Bottomley T Helleday and H E BryantldquoBRCA2-dependent homologous recombination is required forrepair of Arsenite-induced replication lesions in mammaliancellsrdquoNucleic Acids Research vol 37 no 15 pp 5105ndash5113 2009

[41] Y Ming-Ho Environmental Toxicology Biological and HealthEffects of Pollutants chapter 12 CRC Press LLC Boca RatonFla USA 2nd edition 2005

[42] E Figueroa ldquoAre more restrictive food cadmium standardsjustifiable health safety measures or opportunistic barriers totrade An answer from economics and public healthrdquo Scienceof the Total Environment vol 389 no 1 pp 1ndash9 2008

[43] M I Castro-Gonzalez and M Mendez-Armenia ldquoHeavy met-als implications associated to fish consumptionrdquo Environmen-tal Toxicology and Pharmacology vol 26 pp 263ndash271 2008

[44] World Health Oorganization (WHO) Evaluation of CertainFood Contaminants Sixty-Fourth Report of the Joint FAOWHOExpert Committee on Food Additives Technical Report Seriesno 922 WHO 2006

[45] L Benbrahim-Tallaa E J Tokar B A Diwan A L Dill J FCoppin andM PWaalkes ldquoCadmiummalignantly transforms


normal human breast epithelial cells into a basal-like pheno-typerdquo Environmental Health Perspectives vol 117 no 12 pp1847ndash1852 2009

[46] C Martınez-Campa C Alonso-Gonzalez M D Mediavilla etal ldquoMelatonin inhibits both ER alpha activation and breast can-cer cell proliferation induced by a metalloestrogen cadmiumrdquoJournal of Pineal Research vol 40 no 4 pp 307ndash319 2006

[47] G N Schrauzer ldquoInteractive effects of selenium and cadmiumon mammary tumor development and growth in MMTV-Infected female mice A model study on the roles of cadmiumand selenium in human breast cancerrdquo Biological Trace ElementResearch vol 123 no 1ndash3 pp 27ndash34 2008

[48] X Yu E J Filardo and Z A Shaikh ldquoThe membrane estrogenreceptor GPR30 mediates cadmium-induced proliferation ofbreast cancer cellsrdquo Toxicology and Applied Pharmacology vol245 no 1 pp 83ndash90 2010

[49] M Brama L Gnessi S Basciani et al ldquoCadmium inducesmitogenic signaling in breast cancer cell by an ER120572-dependentmechanismrdquoMolecular andCellular Endocrinology vol 264 no1-2 pp 102ndash108 2007

[50] S Pacini T Punzi G Morucci M Gulisano and M RuggieroldquoAparadox of cadmium a carcinogen that impairs the capabilityof human breast cancer cells to induce angiogenesisrdquo Journal ofEnvironmental Pathology Toxicology and Oncology vol 28 no1 pp 85ndash88 2009

[51] A Hartwig R D Snyder R Schlepegrell and D BeyersmannldquoModulation by Co(II) of UV-induced DNA repair muta-genesis and sister-chromatid exchanges in mammalian cellsrdquoMutation Research vol 248 no 1 pp 177ndash185 1991

[52] J R Landolph ldquoMolecular mechanisms of transformation ofC3H10T12 C1 8 mouse embryo cells and diploid humanfibroblasts by carcinogenic metal compoundsrdquo EnvironmentalHealth Perspectives vol 102 no 3 pp 119ndash125 1994

[53] B Quintillina-Vega D J Hoover E K Silbergeld M Waalkesand L D Anderson ldquoInteraction between lead and protamine2 from human spermatozoardquo in Proceedings of the InternationalSymposium on Environment Lifestyle and Fertility AarhusDenmark 1997

[54] P Hainaut and J Milner ldquoA structural role for metal ions in thelsquowild-typersquo conformation of the tumor suppressor protein p53rdquoCancer Research vol 53 no 8 pp 1739ndash1742 1993

[55] D R McNeill H K Wong A Narayana and D M WilsonldquoLead promotes abasic site accumulation and co-mutagenesisinmammalian cells by inhibiting themajor abasic endonucleaseApe1rdquoMolecular Carcinogenesis vol 46 no 2 pp 91ndash99 2007

[56] J Gastaldo M Viau Z Bencokova et al ldquoLead contaminationresults in late and slowly repairable DNA double-strand breaksand impacts upon the ATM-dependent signaling pathwaysrdquoToxicology Letters vol 173 no 3 pp 201ndash214 2007

[57] International Agency for Research on Cancer (IARC) IARCMonographs on the Evaluation of Carcinogenic Risks to HumansNickel and Nickel Compounds vol 100C IARC Lyon France2012

[58] J N Feder A Gnirke W Thomas et al ldquoA novel MHC classI-like gene is mutated in patients with hereditary haemochro-matosisrdquo Nature Genetics vol 13 no 4 pp 399ndash408 1996

[59] Agency for Toxic Substances and Disease Registry (ATSDR)Toxicological Profile for Lead (Update) US Department ofHealth and Human Services Atlanta Ga USA 1996

[60] S J Rothenburg S Karchmer L Schnaas E Perroni F Zea andJ Fernandez Alba ldquoChanges in serial blood lead levels during

pregnancyrdquo Environmental Health Perspectives vol 102 no 10pp 876ndash880 1994

[61] C D Klaassen and K Rozman ldquoAbsorption distribution andexcreation of toxicantsrdquo in Casarett and Doullrsquos ToxicologyThe Basic Science of Poisons M O Amdur J Doull and CD Klaassen Eds pp 50ndash87 McGraw-Hill Torornto Canada1991

[62] M B Martin R Reiter T Pham et al ldquoEstrogen-like activityof metals in MCF-7 breast cancer cellsrdquo Endocrinology vol 144no 6 pp 2425ndash2436 2003

[63] J G Ionescu J Novotny V Stejskal A Latsch E Blaurock-Busch andM Eisenmann-Klein ldquoIncreased levels of transitionmetals in breast cancer tissuerdquo Neuroendocrinology Letters vol27 supplement 1 pp 36ndash39 2006

[64] M R Sim and J J McNeil ldquoMonitoring chemical exposureusing breast milk a methodological reviewrdquo American Journalof Epidemiology vol 136 no 1 pp 1ndash11 1992

[65] R A Rudel K R Attfield J N Schifano and J G BrodyldquoChemicals causing mammary gland tumors in animals signalnew directions for epidemiology chemicals testing and riskassessment for breast cancer preventionrdquo Cancer vol 109supplement 12 pp 2635ndash2666 2007

[66] J E Huff J K Haseman D M DeMarini et al ldquoMultiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1micerdquo Environmental Health Perspectives vol 82 pp 125ndash1631989

[67] C D Houle T V Ton N Clayton J Huff H H Hong andR C Sills ldquoFrequent p53 and H-ras mutations in benzene-and ethylene oxide-induced mammary gland carcinomas fromB6C3F1 micerdquo Toxicologic Pathology vol 34 no 6 pp 752ndash7622006

[68] S A Petralia W H Chow J McLaughlin F Jin Y T Gaoand M Dosemeci ldquoOccupational risk factors for breast canceramong women in Shanghairdquo American Journal of IndustrialMedicine vol 34 no 5 pp 477ndash483 1998

[69] C P Rennix M M Quinn P J Amoroso E A Eisen andD H Wegman ldquoRisk of breast cancer among enlisted Armywomen occupationally exposed to volatile organic compoundsrdquoAmerican Journal of Industrial Medicine vol 48 no 3 pp 157ndash167 2005

[70] J Shaham R Gurvich A Goral and A Czerniak ldquoThe riskof breast cancer in relation to health habits and occupationalexposuresrdquoAmerican Journal of Industrial Medicine vol 49 no12 pp 1021ndash1030 2006

[71] A S Costantini G Gorini D Consonni L Miligi L Giovan-netti and M Quinn ldquoExposure to benzene and risk of breastcancer among shoe factory workers in Italyrdquo Tumori vol 95no 1 pp 8ndash12 2009

[72] Institute for Research and Technical Assistance (IRTA)Methy-lene Chloride Consumer Product Paint Strippers Low-VOC LowToxicity Alternatives 2006

[73] K Steenland E Whelan J Deddens L Stayner and E WardldquoEthylene oxide and breast cancer incidence in a cohort studyof 7576women (United States)rdquoCancer Causes and Control vol14 no 6 pp 531ndash539 2003

[74] B Adam H Bardos and R Adany ldquoIncreased genotoxic sus-ceptibility of breast epithelial cells to ethylene oxiderdquoMutationResearch vol 585 no 1-2 pp 120ndash126 2005

[75] National Toxicology Program (NTP) Report on CarcinogensedUnited States Department of Health and Human Services(DHSS) National Toxicology Program Research Triangle ParkNC USA 11th edition 2005


[76] Agency for Toxic Substances and Disease Registry (ATSDR)ldquoToxicological profile for styrenerdquo Tech Rep TP-9125 USDepartment of Health and Human Services ATSDR AtlantaGa USA 1992

[77] A Aschengrau S Rogers and D Ozonoff ldquoPerchloroethylene-contaminated drinking water and the risk of breast canceradditional results from Cape Cod Massachusetts USArdquo Envi-ronmental Health Perspectives vol 111 no 2 pp 167ndash173 2003

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


14 (643) morphologically normal tissue samples adjacentto invasive carcinomas sites [8] Another study reportedthat DNA methylation exhibits various patterns in differentcancer types since methylation is most significantly linkedwith radical changes in conditional concordant relationships(CCRs) throughout the genome Hypermethylation of DNAthus enhances progression cell migration and oncogenicityin breast cancer [9] Some metals also undergo metabolictransformation such as reduction to lower oxidation state oralkylation [10] A unique feature of metal biology is the factthat even essential metals like iron and copper can becometoxic depending on the oxidation state complex form doseand mode of exposure

Organic solvents are widely and routinely used domes-tically as part of consumer products or in various indus-tries and they can get into the body through inhalationingestion or by dermal exposure While exposure is thehighest in some work places most of these solvents andother chemicals are commonly found in ambient air drinkingwater and consumer products [11 12] The detection ofsome solvents in the some human breast milk confirms thatafter exposure these compounds can find their way into thebreast tissues [13] Organic solvents and their metabolitesare believed to initiate or promote breast cancer throughgenotoxic or other related mechanisms including mutagenor tumorigen among others Generally the basis of organicsolvent carcinogenesis depends on the estrogenic propertiesof halogenated hydrocarbons which are implicated in theetiology of breast cancer Similarly another hypothesis isbased on the fact that the lipophilic substances and theirmetabolites can migrate to the adipose tissue in the breastswhere they can be biotransformed in situ and then excretedinto ductular systems where while in contact with breastparenchyma for long enough can initiate or promote carcino-genesis through genotoxic or relatedmechanism [14] Severalepidemiological studies in the recent past have establishedthat organic solvents play a role in breast carcinogenesisFor instance a well-designed epidemiological study amongyoung Danish women in occupations with greater exposureof solvents found elevated risks of breast cancer [15] Thisstudy established that the risk was doubled among womenwho had over 10 years of exposure Another case-registry-based study of Canadian women established elevated risksamong pre- and postmenopausal womenwhowere employedin two industries with high chemical exposureThose in a drycleaningwork place which used tetrachloroethylene recordedeven higher rates of breast cancer [16]This paper will discussbreast physiology as an enabling factor especially for organicsolvents absorption and distribution of carcinogens phys-iochemical properties and the general metal genotoxicitymechanisms It will then highlight specific metal compoundsand organic solvents that have been linked to breast cancer

2 Breast Parenchyma

In anatomical terms the parenchyma of a body part consti-tutes all the cells of that organ that have an essential functionBreast parenchyma is made of a series of apocrine glands

which includes the milk ducts and the glands that producethemilkThese epithelial cells which are arranged into lobulesconnected to ductular system of the breast end up at thenipple The breast parenchyma are embedded in fatty tissuethe amount of which varies from one woman to another andconnective tissues with rich supply of blood and lymphaticvessels The breast physiology comprises certain uniquefeatures that make it sensitive to various metal compoundsand organic solvents and their metabolites that may exposeit to cancer development First the apocrine glands thatmake up the breast parenchyma proliferate continuouslyfrom the menarche with increasing cell population duringevery ovulatory cycle of a female resulting in the developmentof the budding structure until approximately the age of 35[14] A mutation occurring during DNA transcription andother errors that may occur during such replication exposebreast tissues to high risk Furthermore the accumulation ofxenobiotics in the breast tissues is enhanced by physiologicalchanges that take place in the body during menstrual cycles

Due to reduction in the metabolic and clearance activityof the breast tissue the byproducts ofmetabolic oxidative andreductive processes (redox) remain in the breast parenchymafor too long to act as early stage initiators through changesin DNA bases and other hydroxyl radical-induced adversereactions [17] They can also act as promoters of alreadyinitiated cells with both theories consistent with the obser-vation of nearly 70 of breast tumors originating in theductular system [18] Exogenous carcinogens includingmetalcompounds and organic solvents are secreted into breastfluids as evidenced by a unique study among boat women ofAberdeen in Hong Kong The study found that these womenwho traditionally nursed their infants only from their rightbreast and not their left breast were as twice as likely todevelop breast cancer on the left breast due to stagnation ofthe milk there with the risk increasing more with age [19] Ina separate study breast secretions and colostrums especiallyamong farm women who were exposed to more carcinogenswere found to be mutagenic on an Ames test [20] Table 1shows organic solvents that have been detected in humanmilk

3 General Mechanism of MetalCarcinogenicity

Metals can be carcinogenic in various forms including freeions metal complexes or particles as well as soluble metalcompoundsThe physiochemical properties of variousmetalsgovern their respective toxicity Oxidation state charge andionic radii play significant role with regards to metal free ionswhile the coordination number the geometry and the typeof legand (ie their lipophilicity) determine their toxicityOn the other hand the soluble metal compoundsrsquo toxicitydepends in part on the particle size and crystal structures [10]If toxicmetal ions have similar physiochemical properties likecharge and size compared to essential metal ions they tendto compete for biological binding sites of the latter resultinginto structural perturbations leading to aberrant functionof biological macromolecules [21 22] In general metal















3AsO5)





































6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























3AsO5)





































6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















3AsO5)





































6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















6 Conclusion



References

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article The Mammary Gland Carcinogens: …downloads.hindawi.com/journals/ijbc/2013/640851.pdfReview Article The Mammary Gland Carcinogens: The Role of Metal Compounds and Organic