Gfflotox1city describes a dclctenous action on a cell's ecnctic IJllllrriAJ alTectina
iu lntqrity (I lu, 20()..&) It 11 • propcrt> possnscd by s,omo substances chat mal.cs them
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A substance that has the property of gcnotoxicity is known as a genotoxin.
There Bte three primary effects that genotoxins can have on organisms b y affecting their genetic information. Genotoxins can be carcinogens, or cancer-causing agents, mutagens, or mutation<ausing agents, or teratogens, birth defect-causing agents (Phillips and Arlt, 2009). Synthetic chemicals, pcsticides,herbicidcs, insecticides, rodenticidcs, food preservatives, and fertilizers Bte poUuting soil, water, and air, bllrming both the environment and human health . Since decades, in various counoies, people hnvc been and still ore exposed to inorganic arscnite (As) through gCQgenieally c-0ntamin11ted drinking ,vntcr, with pentavalent arsenate being the predominant chemical species of As in aerobic ,vater sources.
Free radicals and oxidatjve stress (other reactive oxygen species (ROS) are produced os II normol consequence or biochemical processes in the body and as a rcsuJt or increased exposure 10 environmental and or dietary pollutants. Free-radical mechanisms have been implicated in the pathology or several human diseases.
including cancer, mnlnria. rbcumntoid orthritis and neurodegenerativc di.sea.9':S (Bates.
1992). The generation of n:activc oxygen spc<:ies beyond the antioxidant capacity of a
biological system gives rise to oxidative stress (Bates. 1992; Beclccrman et al; 1977).
Genotoxicity induces cancer and some degenerative diseases in moo Md animnls.
Some gmotoxiru, such os those thtlt affect cancer-suppressing genes, are considered carcinogenic, as they can le.id to cancer. Cancer is the uncontrolled GJ'O"ih of cells v.ithin the body, and onm h.a.s genetic causes Substance, thtlt are �cnoto:-oc can cause:
muw.sons in cells thtlt cause them to divide and grov. uncontrollably 'They am
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also have damaging effects on various proteins and other substances that normally prevent such uncontrolled cell growth. When these substances do not act as they
should, some cells are much more likely to mutate and djvide uncontroUably. In most cases, genotoxicity leads to mutations in various cells and other bodily systems Mutations can lead to a host of other problems, from cancer 10 a wide variety of different diseases. Sometimes, mutations caused by genetics llTC completely harmless and can go completely uMoriccd ln many other cases, the effects of genot.o:<ins can be deadly. Mutations can come in many different forms; genetic information can be
dupli ca ted. deleted. or inserted (W\V\V ,visegeck.com/what is genotoxic:ity htm septe.mber -2010) There are substances that can reduce the activity of ge_notoxins.
These comJ><>uods arc knoown as ant.igcnotoxins Vitamins. mineral ions. (Sylianco �, al, 1991), amino acids (Syliaoco and Guevera, 1991) nnd plant foods ( Syltanco, 1991 ) have been sho,vn to exhibit antigcootoxic activities.
2.2.J CENOTOXJCITY TESTING -General Principles
Gcnotcrcicny lCSU CU1 be dcfUICd o.s In vfrro ;md In \lt\o tQts dcs,gn,cd to dc:tcct compounds llu1 tnducc gcncllc ci.uragc by v:i.nous rncxb-VJimu (Jc:sn �, al. 2002). lbc:sc U:stS co.able lrn:nrd uknttficanoa w1lh respect to d:ilJqgc to DNA and tts fiunoo. F°L'Cllloo of d.unsgc to DNA lll the fOffll of gene mut:wons, � ICllc chromo&oaul cbm"BC or ru:.omb111a1aon lS g.mcni.lly considacd tot>-- C'RC'llAI fOI' bucblo cffccu and ui lhc mutlHtcp procns of �hpncy, a co,npla procc11 m v.luch g,mctic clrn.gca imy pb� ooJ) o po.rt.
Nwnmcal duomolOmc c.h.anp bs,-c: a1so bem tnl!Xtllol Yol\b hl""""'lc.'DCSis cd cm LDdtCalc
• JIOCOMYI Cf.V ano,ploidy 10 sum .:ells Campounda th&l an pc.ib,"C in ICltS lh:ll detect JUCb
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�irh ol dw.p bl,c the polCffti&J to be h1111w, "'M'C�fm' ..s.lcr � - 8 crne dw
n-ld,on .... jp bd,t.ece UJ)ULWl'C ID �-l&b, dlcmia.b aad CMC .... IV!U II a&eblc:bzd !ar
hl:l:�s. •Wsl • mrubr rcbtlffls!11p bu t:>«11 d.if1"icull ro PfO" b llcri&able dill=--:s.
•�kit) 1e..ts i.,._ bea IDCd awnJy (o, the pndic!JOD of� s. n.rdll;iaa.
t,«,,.11191r p:.a * GIIITJ!IOM lff clear!) llJC"'taled • th t,..,_a tlOllllal. Ille lp;:k:itt J o:x:�a:DII af&!tl ladl,c,,t llcriD.ble cfTtc&I ill couidcnd to be j as tcnOUS • lbc '1<t:SJ'<10ft
Um • compound mighl induce canc .. t. lo edJiuoo. the Oll'a>me or p:a� lal)' CCSLJ cm be ,..iusblc: for the i.nccrprcUltioo of can:1.ooptc:uy mxhcs
Se\'.:nl In ritro mammalim cell systcmS arc -.idcJ, .:a:d lod ea be cazm:ac:d
mffic:icnlly \-.,lid�tcd, lbc In ,,,tro mc:bpl\ue chromMcl«l!IC M>UIIIZk)D MIii)' .• lbc bJ �'O
mk:a wu <kus assay and the mou,c lymphoma U 178'1' cell d p:rv:
(Shelby, 19U� Aodmon ,, al, 19CM). � ttuoc us;avs
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ciqaalJy a;,proprias.c and thcfffore !�him� bc:n mcd rc_c'l.ber ,10 ea
armro:Jdry acm in a mnd.vd bencry far lntlnl of pbllffll.1CC1mc:ah.
bt mo 11:'Sl(t) fo, Cffld&e wma lhouJd "5'mll)' l'C! • pm,
po.� ld;:l:;tica! tell=\ Ckto,1 (�"'lllfflln.
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/11 1•ilro and In vl,•o tests thnt measure chromosomal aberrations in melaphase cells can detect o \vide spectrum of changes in chromosomal integrity. Brcalcage of chromatids or chromosomes can result in mjcronucleus fonnation if on acentric fragment is produced; therefore 11SS11ys thnt detect either chromosomal abcoations or mjcronuclei arc nppropriote for detecting clostogens. Micronuclei can also result from logging of one or more whole chromosome(s) at anaphase ond thus micronuclcus tcst.S have the potential to detect some aneuploidy inducers (Schmid., 1976). The mouse lymphoma cell mutotion o.ssny detects mutotions in the tk gene that result from both gene mullltions and changes in chromosome integrity. There is some evidence that the mouse lymphoma BSSll)' con olso detect chromosome (Morita �, of; 1997).
There ore severnl additional In vivo assays that can be used in the bancry or a.s follo,v-up tests to develop ,\-eight of evidence in assessing results of In virro or In vil'o nssays. Negative results in appropriate in ,,l\·o ossays (usually t\\-o). ,vith ndequ:ue justification for the endpoints measured, ond demons1.ration of expo� is sufficient to
demonstrate absence of gcnotox.ic activity.
2.2.2 Description o(the Two Options for the St.&odard Battery
The follo,ving , .. ,-o options for the st.ondlll'd bllnery arc considocd cqu:ill) suhoblc:
Option I
i. A test for gene mutotlnn In b:lctcrio;
II. A cytogcnctlc test for chromosomal dllmAgc (the In 1·11TO mel3ph:1$e
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chromosome aberration test or In vitro micronucleus test), or an In ,,frro mouse lymphoma tk gene mutation assny;
iii. An In vi\'O test for gcnotoxiciry, generally a test for chromosomal damage using rodent hcm4topoietic cells. either for micronucle1 or for chromosomal nberrnllons in metapbase ccLIJ.
Option 2
i. A test for gene mutation in bacteria;
ii. An in vl\'O a.sscssment of genotoxicity with two tissues, usually an nmy for rnicronuclei using rodent bemntopoietic cells and 11 second in """' nss:\}'
Under both stnndiud battery options, the In vl,'O genotoxicity 8SS.1l)'$ can oflen be integrated into repcot-<losc toxicity studies "'hen the doses arc suffieicnL Under Option 2, if dosciexposurc is not nppropriote, an ocute In ,•/1'0 study (incorporating t\\'O gcnotoxicity assays in one srudy "'here possible) should be performed to optimize dose sel ec tion based on c:,,cposurc/toxicity or Option I, including on in ,iitro m:,mm:iliao <":CU IISSlly, should be follo\\'Cd.
For compounds thnt give ncgotlve results, the completion of either tc:sl b.i.ttc:r).
performed and evnluotcd in occordrulcc ,vith cum:nt rccommcndlltions. \\ill USU3ll) provide sufficient o.ssuronec of the obscncc of genotoxic acti,1ty ond no odditioMl tests will be needed. Compound, thot gh-c positive results in the sl!lnd:ud test batter) �.
depending on their thempcutlc use. need 10 be 1cs1cd more cx1cnsiv1:ly. The sund:ud
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battery does not include a required independent lest designed spccificalJy to test for aneuploidy. However, information on numerical changes can be derived from the mammalian cell assays in vitro and from the mjcronucleus assays . .Elements of the sLandard protocols that provide such inforrna1ioo are elevations in the mitotic index, polyploidy induction and micronucla.is evaluation. There is also experimental evidence
that spindle poisons can be detected in the mouse lympbolD4 tk assay The preferred in vn-o eytogcnctic test under Option 2 in v,�.,, genoto:<iciry assays may be integrated into existing (repeat dose) toxicity studies when the dose levels nre justifiable and the protocols are compatible.
2.3 APOPTOSIS AND CANCER.
The development or cancer results when I.here is a failure in the control of the fundamental mccharusms I.hat govern ccll growth and cell death (Ash.kenlZl and Doot
1998) The processes that regulate both cell proli.faatioo and the destruction of po1en1ially harmful cells arc so clolCly linked thAI the inappropriate activation of growth-promoting oncogenes onen ,nillntes cell death In a healthy org;uns:m. ccll.s typically die via 11poptosis (Kuroda. 1990, \Vall et al 1990, �letcr et al, 2000).
however, the uninhibited cell prohfcnit,on chM'actcnst,c of most cancer cells rcqwres
tJw apopcosu be supprc5scd. A!1 solid lumors continue to grow. the resuitlJlg
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