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PHN A: C CHT HC I CNG CHNG I MT S VN C BN V C CHT HCNi dung chng 1 nhm gii thiu mt s khi nim c bn trong c cht hc nh: c cht hc, cht c, c tnh, c lc, ng c, cc ngun gy c, cch phn loi cht c, phn loi ng c... Cc kin thc v cc qu trnh ng hc, c ch gy ng c v cc yu t nh hng n tc dng ca cht c cng c cp n trong chng ny. 1. Mt s khI nim 1.1. c cht hc a. nh ngha v i tng ca c cht hc c cht hc l mt ngnh khoa hc chuyn nghin cu v cc cht c, bao gm vic pht hin ra cc cht c, c tnh l ho hc ca chng v nhng nh hng sinh hc cng nh bin php x l nhng hu qu do chng gy ra. c cht hc - toxicology c ngun gc t ting Hy Lp: toxikon - cht c, logos - khoa hc. T xa xa, i tng ca c cht hc ch l mt s t cht c c s dng u c ngi v sc vt. Ngy nay, c cht hc hin i nghin cu tnh cht l ha ca cc cht c c ngun gc thc vt, khong v tng hp, c ch gy c, mi tng tc gia cht c v c th. c cht hc Th y l mn khoa hc nghin cu v cc cht c v tc ng ca chng i vi c th ng vt. c cht hc th y l mt phn c bit ca c cht hc, l mn hc thc nghim lm sng. i tng ca mn hc l nghin cu v tnh cht, tc dng, ngha ca cht c, nguyn nhn gy ng c, sinh bnh hc, triu chng, chn on v iu tr ng c. b. S lin quan ca c cht hc th y vi cc mn hc khc L mn hc thc nghim lm sng, c cht hc th y c lin quan n hng lot cc mn hc: - Mn ha hc v dc l hc cung cp nhng hiu bit c bn v tnh cht ha hc, ng hc, c ch tc dng ca cc cht c c ngun gc v c v hu c. - Mn thc vt, vi sinh vt v ng vt gip nghin cu cc c t thc vt, ng vt, nm v cn trng. c cht hc c bit c quan h gn gi vi cc mn hc: - Sinh l bnh: nghin cu v sinh bnh hc, v tin trin ca bnh do ng c. - Ho sinh: c th b ng c gy ra nhiu bin i cc ch tiu ha hc, hm lng v cht lng men, hm lng cc hormon gi vai tr quan trng trong trao i cht. Xc nh nhng bin i ny bng cc phng php nghin cu ho sinh l rt cn thit phn tch tin trin ca qu trnh ng c.

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2- Bnh l hc: cung cp phng php m khm v phn tch cc bnh tch i th, vi th gip chn on ng c. - Dch t hc: gip phn bit bnh do ng c vi cc bnh truyn nhim, k sinh trng. - V sinh th y v thc n gia sc lin quan n phng php phng ng c. c. Cc lnh vc nghin cu ca c cht hc Cc lnh vc nghin cu ca c cht hc lin quan n nhn y v th y gm: - c cht hc m t: nh gi nguy c do phi nhim vi cht c hoc mi trng thng qua cc kt qu thu c t cc xt nghim c tnh. - c cht hc c ch: Gii thch c ch gy c, t c th d on nguy c v c s khoa hc iu tr ng c. - c cht hc lm sng: Nghin cu cc bnh do ng c, nhim c, cch chn on v iu tr ng c, nhim c. - c cht hc phn tch: Nghin cu cc phng php pht hin v th nghim cht c v cc cht chuyn ho ca chng trong vt phm sinh hc v mi trng. y l mt ngnh ca ho phn tch. - c cht hc mi trng: Nghin cu s chuyn vn ca cht c v cc cht chuyn ho ca chng trong mi trng, trong chui thc phm v tc dng c ca cc cht ny trn c th v trn qun th. - c cht hc cng nghip: Nghin cu v nh hng c hi ca mi trng lao ng cng nghip i vi ngi v sc vt. - c cht hc php y: Cc xt nghim c cht v khm lm sng cc trng hp ng c, nhim c mang tnh php l. 1.2. Cht c a. Khi nim cht c Cht c (poison) l nhng cht v c hay hu c c ngun gc thin nhin hay do tng hp, khi nhim vo c th v t n nng nht nh c th gy hiu qu dc hi cho c th sng. Gary D. Osweiler li a ra nh ngha v cht c nh sau: cht c l nhng cht rn, lng hoc kh, khi nhim vo c th theo ng ung hoc cc ng khc s gy nh hng n cc qu trnh sng ca cc t bo ca cc c quan, t chc. Cc tc ng ny ph thuc vo bn cht v c lc ca cc cht c. Khi nim khc ca cht c l c t (toxin) c dng ch cc cht c c sn sinh (c ngun gc) t cc qu trnh sinh hc ca c th v c gi l c t sinh hc (biotoxin). Trong qu trnh nghin cu v cht c cn lu mt s im sau: - Cht c l mt khi nim mang tnh nh lng. Mi cht u c mt liu no v cng v hi vi liu rt thp. Gii hn gia 2 liu l phm vi cc tc dng sinh hc. Theo Paracelsus (1493 - 1541): tt c mi cht u l cht c, khng c cht no khng phi l cht c. Liu lng thch hp s phn bit c mt cht c v mt thuc. Aspinrin (acid acetyl salicylic) l thuc h st chng vim c dng trong iu tr t nhiu

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3nm nay, nhng c th gy cht ngi vi liu 0,2 - 0,5 g/Kg. St, ng, magne, km l nhng nguyn t vi lng cn thit trong thnh phn thc n chn nui, nhng nu qu liu th c th gy ng c. - V mt sinh hc, mt cht c th c vi loi ny nhng li khng c vi loi khc. Carbon tetraclorid gy c mnh cho gan trn nhiu loi, nhng t hi hn i vi g. Mt s loi th c th n l c c dc c cha belladon. - Mt cht c th khng c khi dng mt mnh, nhng li rt c khi dng phi hp vi cht khc. Piperonyl butoxid rt t c vi loi c v v cn trng khi dng mt mnh, nhng c th lm tng c tnh rt mnh ca cc cht dng cng do n c tc dng c ch cc enzym chuyn ho cht l (xenobiotic - metabolizing enzymes) ca c th. - c tnh ca mt cht c c th thay i khi xm nhp vo c th qua cc ng khc nhau nh: qua ng ung, ng h hp, qua da, qua ng tim... b. Khi nim c tnh v c lc - Khi nim c tnh: c dng miu t tnh cht gy c ca cht c i vi c th sng. - Khi nim c lc: l lng cht c trong nhng iu kin nht nh gy nh hng c hi hoc nhng bin i sinh hc c hi cho c th. Khi nghin cu v c lc, cn quan tm n mi quan h gia liu lng cht gy c v p ng ca c th b ng c. Theo quy nh quc t, liu lng ca cht c c tnh bng milligram (mg) cht c/1kg khi lng c th gy nh hng sinh hc nht nh. mt s loi ng vt hoang d hoc loi c, c lc c th hin bng nng cc cht c trong thc n ng vt hoc nc. Nng gy t vong (LC - Lethal Concentration) l nng cht c thp nht trong 1 kg thc n chn nui hoc trong 1 lt nc (i vi c) gy cht ng vt. c lc trong ng c cp tnh c tnh theo LC50 nng gy cht 50% ng vt. * Mt s khi nim v liu lng c s dng xc nh c lc ca cht c: - ED50 (Effective Dose): liu c tc dng vi 50% ng vt th nghim. - Liu ti a khng gy c (HNTP - Highest Nontoxic Dose): l liu lng ln nht ca thuc hoc cht c khng gy nhng bin i bnh l cho c th. - Liu thp nht c th gy c (TDL - Toxic Dose Low): Khi cho gp i liu ny s khng gy cht ng vt. - Liu gy c (TDH - Toxic Dose High): l liu lng s to ra nhng bin i bnh l. Khi cho gp i liu ny s gy cht ng vt. - Liu cht (LD - Lethal Dose): l liu lng thp nht gy cht ng vt. LD c cc t l khc nhau nh: LD1- liu gy cht 1% ng vt; LD50: liu gy cht 50% ng vt; LD100: liu gy cht 100% ng vt. * an ton ca thuc: c xc nh da trn cc ch s: - Ch s iu tr (TI - Therapeutic Index): l t s gia LD50 v ED50. LD50 TI = ED50

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4- Tiu chun an ton (SSM- Standart Safety Margin) l t s gia LD1 v ED99: LD1 SSM = ED99 c. Phn loi cht c Cht c c th c phn loi theo nhiu cch: theo ngun gc, bn cht l ho ca cht c, phng php phn tch cht c, c lc, tc ng ca cht c trn cc h c quan ca c th v ngun ly nhim cht c. * Phn loi theo ngun gc cht c: - Cht c c ngun gc thin nhin: ng vt, thc vt, vi sinh vt. - Cht c c ngun gc tng hp, bn tng hp. * Phn loi theo bn cht l ho ca cht c: - Cc cht c dng kh, lng, cht rn. - Cc cht c v c: kim loi, kim, axit, baz. - Cc hp cht hu c: cc hp cht cha carbon, cc loi thuc tr su, aldehyd, cc axit hu c, cc ester, cc hp cht cha nit, cc hp cht cha lu hunh, cc alcaloid, glycosid. * Phn loi theo phng php phn tch cht c: theo Stas-Otto - Cht c ho tan trong nc hay cc dung dch axit, kim. - Cht c ho tan trong ether. - Cht c c th chit tch c trong cc dung mi hu c. * Phn loi cht c theo c lc Bng 1.1. Phn loi cht c theo c lc Phn loi Rt c (extremely toxic) c lc cao (highly toxic) c lc trung bnh (moderately toxic) c lc thp (slightly toxic) Khng gy c (practically nontoxic ) Khng c hi (relatively harmless) c lc (LD50) < 1mg/kg 1 - 50 mg/kg 50-500 mg/kg 0,5 - 5 g/kg 5 - 15g/kg >15g/kg

* Phn loi theo tc ng ca cht c trn cc h c quan ca c th: - Cc cht c tc ng trn h thn kinh: cafein, strychnin, cyanid, ch, hexachlorophen, thuc tr su clo hu c... - Cc cht c tc ng trn h tiu ho: asen, selen, canxi clorua, sulfat ng, mui thy ngn v c...

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5- Cc cht c tc ng trn gan, mt: tetraclorua carbon, phenol, aflatoxin, fumonisin, acetaminophen, toluen, ng... - Cc cht c tc ng trn thn: thuc khng sinh nhm aminoglycosid, oxytetracyclin, sulfonamid, kim loi nng, ochratoxin... - Cc cht c tc ng trn h h hp: carbon monoxid, kim loi nng, carbon dioxid, formaldehyd, thuc tr su phospho hu c, fumonisin... - Cc cht c tc ng trn h tim, mch: digitalis, digitoxin, cafein, cocain, monesin, amphetamin... - Cc cht c tc ng trn h mu: aspirin, benzen, chloramphenicol, chlorpromazin, estrogen, phenylbutazol, T2 mycotoxin (y l cc cht gy thiu mu). - Cc cht c tc ng trn h sinh sn: testosteron, zearalenon, dicoumarol, corticosteroid, fumonisin, ch, cadmi, selen... - Cc cht c tc ng trn da: acid, base, formaldehyd, iodin, mui thy ngn, phenol, cc cht nhy cm quang hc... * Phn loi theo tc dng c bit ca cht c: - Cht c gy ung th: + Cc cht c c ngun gc thin nhin: aflatoxin B1, alcaloid pyrolizidin, aquilid A trong cy dng x, alcanylbenzen trong cy de vng. + Hp cht ung th hnh thnh khi ch bin thc phm: nitrosamin, cc cht hydratcarbon a vng thm, cc amin d vng. + Mt s thuc th y: diethylstibestrol (DES). - Cht c gy t bin: Hu ht cc cht gy ung th u c tc dng gy t bin. - Cht c gy qui thai: cc hp cht este phospho hu c, thuc tr su loi carbamat, thuc dit nm cha thy ngn, cloramphenicol. * Phn loi theo ngun gy c: - Cc cht gy nhim khng kh, nc v thc phm - Cc cht ph gia trong thc phm - Cc ho cht trong cng nghip v cc dung mi. - Thuc bo v thc vt, thuc th y. - Cc ngun khc. d. Cc ngun cht c Con ngi v ng vt c th b ng c bi rt nhiu cht c n t nhiu ngun trong cuc sng. * Cc cht gy nhim khng kh, nc v thc phm - Bn cht cc cht gy nhim khng kh, nc, thc phm v ngun gy nhim thng lin quan n vng a d. - Ngun chnh gy nhim khng kh l do cc phng tin giao thng, cc qu trnh cng nghip, cc loi nh my in. Cc cht gy nhim khng kh thng gp l: CO, cc oxit nit, cc oxit lu hunh, cc hydro carbon.

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6- Nc thng b nhim bi cc ho cht, cc cht hu c t cng rnh, t nc thi ca cc nh my, t rung ng c dng ho cht bo v thc vt... - Cc cht gy nhim lng thc thc phm, thc n chn nui c th tn ti trong thc phm dng th, dng nu chn hoc qua ch bin. C nhiu loi c: c t ca vi khun (nh ngoi c t ca Clostridium botulinum), c t ca nm (aflatoxin ca aspergilus), c t ca ng vt, alcaloid ca cy, cc tn d ca thuc tr su... * Cc cht ph gia trong thc phm, thc n chn nui Cc cht ph gia c cho vo thc phm, thc n chn nui vi nhiu l do khc nhau: bo qun (khng khun, khng nm hoc chng oxy ho); thay i tnh cht vt l, nht l trong qu trnh ch bin; thay i hng v, thay i mu hoc mi. Ni chung, cc cht ny u an ton v khng c c tnh trng din. Tuy nhin, hin nay c ti hng trm, thm tr hng nghn cht ph gia c s dng trn ton th gii, v rt nhiu cht trong s cn cha c cc bin php thch hp pht hin v nh gi. Ngoi ra cn cha bit c cc tc dng tng h (tng tc) gia nhng cht ny hoc gia chng vi thc phm, thc n chn nui. * Cc ho cht trong cng nghip v cc dung mi Trong cng nghip, rt nhiu ho cht c s dng v chng tn ti mi trng lm vic vi nng cao, c th gy c. Bao gm: - Cc cht v c: cc kim loi ch, ng, thu ngn, km, cadmi, kh carbon monoxyd, fluoride. - Cc cht hu c: Hydrocarbon mch thng (hexan) hydrocarbon mch vng (benzen, toluen, xylen), hydro carbon gn halogen (dicloromethan, tricloroethylen), cn (methanol, ethylenglycol), cc dn xut nitro (nitrobenzen). Cc dung mi thng gp mi trng cng nghip, trong nghin cu v trong cuc sng hng ngy. Ngoi tc dng ti ch trn da (ty m, kch ng), nhiu cht gy dc ton thn (h thn kinh trung ng, to mu). Cc dung mi thng gp l: - Hydrocarbon mch thng: hexan... -Hydrocarbon mch thng c halogen: methylen diclorid, cloroform, carbon tetraclorid... - Ru mch thng: methanol, ethanol... - Hydrocarbon mch vng thm: benzen, toluen... * Ha cht bo v thc vt Ha cht bo v thc vt bao gm thuc tr su, thuc dit c, thuc tr bnh...Cc cht ny tuy c c tnh chn lc trn c hoc cn trng nhng khi s dng vn gy nhim khng kh, t, nc...v t c th gy c cho ngi v sc vt. * Thuc th y dng iu tr gia sc gia cm Thuc th y, nht l cc thuc c c tnh cao nu dng khng ng, qu liu, khng ng ch nh, s tng tc gia cc thuc khi dng phi hp c th gy ng c thuc th y vt nui. e. S vn chuyn ca cht c trong mi trng Cc cht ho hc nh ho cht bo v thc vt, cc kh thi cng nghip c gii phng ra mi trng him khi c lu li ti ch hoc gi nguyn dng. Nhiu ho cht sau

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7 b phn gii bi vi khun v nm ri nhanh chng b kh c, thng b ct vn thnh hp cht c th nhp vo chu trnh carbon, nit v oxy. Cc cht khc c bit l hu c cha halogen, l nhng cht t nhiu khng b chuyn ho bi vi khun v tn ti trong t nh cht nhim, li nhp vo cc cy lng thc - thc phm... v d DDT v cht chuyn ho chnh ca n DDE c th tn ti nhiu nm sau khi ngng phun DDT. - Cc cht c d tan trong m s d b c th hp thu khi phi nhim trong khng kh, t, nc v dn dn c tch lu cho n khi t nng gy c. S tch ly ha cht bo v thc vt trong chui sinh hc thc phm c th hin nh sau: * Ha cht bo v thc vt tch ly trong t: ng vt khng xng sng t ng vt c xng sng t D phm trong t Cy mc t t ng vt n c ngi c * Ha cht bo v thc vt tch ly trong nc: D phm trong nc sinh vt ni chim n c, ngi v ng vt. 1.3. Ng c a. Khi nim ng c Ng c l trng thi ri lon nhng hot ng sinh l bnh thng ca c th do cht c gy ra. Cht c c ch mt s phn ng sinh ho hc, c ch chc nng ca enzym. T cht c c th c ch hoc kch thch qu lng cc hormon, h thn kinh hoc cc chc phn khc ca t bo lm cho c th c nhng triu chng, phn ng khc thng. b. Phn loi ng c C nhiu cch phn loi ng c. Trong th y ch yu phn loi theo thi gian xy ra ng c. Tu thuc vo tng cht v phn ng ca c th, tc dng gy c thng xut hin rt sm. Tuy nhin, c cht gy tc dng chm (chloaramphenicol gy thiu mu suy tu sau khi ngng dng thuc hng tun), hoc rt chm, 20 - 30 nm sau khi tip xc vi ho cht c mi thy xut hin ung th. * Ng c cp tnh: Ng c tnh cp tnh l nhng biu hin ng c xy ra rt sm sau mt hoc vi ln c th tip xc vi cht c. Ty thuc vo cht gy c, ng xm nhim cht c, biu hin ng c c th xy ra 1- 2 pht hoc 30 pht n 60 pht sau khi c th hp thu cht c v thng l di 24 gi. a s trng hp ng c cp tnh chuyn sang dng cp tnh hoc mn tnh. * Ng c bn cp ( cp tnh) Xy ra sau nhiu ngy, c khi sau 1- 2 tun. Sau khi iu tr, khi nhanh nhng thng li nhng di chng th cp vi nhng biu hin nng n hn. V d ng c oxit carbon. Ng c cp tnh c khi chuyn sang thnh dng mn tnh. * Ng c mn tnh Ng c mn tnh ch xut hin sau nhiu ln phi nhim vi c cht, c khi l hng thng, hng nm. V vy, nhng biu hin ca nhim c thng l nhng thay i rn nc v lp gip xc khng xng sng n mi chim/loi c v n mi

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8rt su sc v cu trc v chc phn ca t bo, kh iu tr. V d: tc dng gy ung th, gy t bin gen, gy qui thai, gy c cho gan, thn, h thn kinh dn n suy gim chc nng khng hi phc. Ng c mn tnh cng c th tr thnh cp tnh trong nhng iu kin nht nh (ng c ch). Cng mt cht li c th biu hin tc dng c khc nhau tu theo nhim c cp hoc mn: nhiu hydrocarbon gn clor khi nhim c cp (liu cao) th gy c trn thn kinh trung ng, nhng khi nhim c mn (liu thp trong thi gian di) th li c biu hin gy ung th (gan), rt t tc dng c trn thn kinh. * Tc dng tim n: l loi phn ng khng c th hin trong nhiu ngy, thng hay thm ch hng nm (v d nh tc dng gy ung th v gy c thn kinh ca mt s cht hu c). Tc dng tim n thng xy ra sau khi ngng phi nhim vi cht c mt thi gian di. 2. ng hc ca cht c ng hc ca cht c (toxicokinetics) chuyn nghin cu cc qu trnh chuyn vn ca cht c (ni chung l cc cht l-xenobiotics) t lc c hp thu vo c th cho n khi b thi tr hon ton. Cc qu trnh l: S hp thu (Absorption); S phn b (Distribution); S chuyn ha (Metabolism); S thi tr (Excretion, Elimination). 2.1. S xm nhp ca cht c Cc cht c trc khi nhp vo c th, phi vt qua nhiu hng ro bo v ca c th (da, nim mc, cc m,...), v vy s xm nhp ca cht c ph thuc mt phn vo bn cht cc hng ro v mt phn vo chnh cc c im phn t ca cht c ( ln phn t, tnh ho tan trong m/nc, pH, mc ion ho,...). a. Cht c xm nhp qua mng sinh hc * Cu to mng sinh hc Cc mng sinh hc c vai tr lm hng ro, ngn cn s hp thu cc cht c. Da, nim mc ng tiu ho, nim mc ng h hp u l nhng hng ro, khc nhau v dy mng, nhng u c tnh cht chung c bn sau: - L nhng l mng, bn cht l lipoprotein c to bi 2 hng phn t ch yu l phospholipid v cholesterol m nhng cc k nc quay ra 2 pha v c to bi protein. Cc cc k nc gi cho cu trc liporotein ca mng c ton vn. - T l lipid: protein thay i t 5:1 cho mng myelin n 1:5 cho cu trc bn trong ca ty th. T l ny rt nh hng n s xm nhp ca cht c. Gia cc mng ny c cc ng dn, ng knh thay i t 40 (mng t bo mao mch no) n 450 (mng cu thn), c th cho qua cc phn t nh khng tan trong lipid, trng lng phn t t 100 - 200 dalton. Cc cht c khng ion ho d khuch tn qua mng sinh hc hn cc cht ion ho. Cc acaloid nh strychnin b ion ho mnh mi trng acid ca d dy (sc vt n tht, n tp) nn khng biu hin tc dng c, nhng khi vo n mi trng kim ca rut, strychnin khng b ion ho, c hp thu v gy c. S lng dng ion ho v khng ion ho ph thuc vo pKa ca cht c v pH ca mi trng. pKa l logarit m ca hng s phn ly acid. Theo phng trnh Henderson - Hasselbach: i vi 1 acid yu: Dng khng ion ho Log Dng ion ho = pKa - pH

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9i vi 1 base yu: Dng ion ho Log Dng khng ion ho Tuy nhin, cn c nhng ngoi l nh pralidoxim (2 - PAM), paraquat, diquat li vn c hp thu nhiu di dng ion. Thng s th 2 c nh hng n s xm nhp ca cht c vo c th l h s phn tn (partition coeffcient) c o bng nng cht c trong pha lipid/nng cht c trong pha nc. Nh vy, cht c c h s phn tn cao d tan trong lipid, c tnh a m (lipophilcity) cao v d xm nhp vo c th hn. * Cht c xm nhp qua mng sinh hc Cht c c th xm nhp qua mng sinh hc bng cc phng thc sau: - Phng thc lc: Nhng cht c trng lng phn t thp (100 200 dalton) tan c trong nc nhng khng tan c trong m s qua c cc l lc trn mng t bo (d = 4 - 45A0) do s chnh lch p lc thu tnh. a s cc cht c c trng lng phn t cao nn vn chuyn theo ng ny khng nhiu. - Phng thc khuch tn th ng: Cch vn chuyn ny chim u th i vi phn ln cc cht c. Cc cht t b ion ho v c nng cao b mt mng d khuch tn qua mng. S khuch tn ca cht c l acid v base yu ph thuc vo hng s phn ly pKa ca cht c v pH ca mi trng. V d phenobarbital l mt acid yu c pKa = 7,2; nc tiu bnh thng c pH cng bng 7,2 nn phenobarbital b ion ho 50%. Khi nng pH ca nc tiu ln 8, ion ho ca thuc s l 86%, do thuc khng thm c vo t bo. V vy, trong iu tr nhim c phenobarbital: truyn dung dch NaHCO3 1,4% kim ho nc tiu, tng thi tr thuc i vi cht c dng kh, hi (v d thuc m bay hi), s khuch tn t khng kh ph nang vo mu ph thuc vo p lc ring phn ca cht kh gy m c trong khng kh th vo v ho tan ca kh m trong mu. - Vn chuyn tch cc: Cht c c chuyn t bn ny sang bn kia mng sinh hc nh cht vn chuyn (carrier) c hiu c sn trong mng sinh hc. Nu cht c c cu trc ho hc tng t cht ni sinh th n s s dng chung carrier. V d: 5 - fluorouracil c vn chuyn bi h vn chuyn pyrimidin, ch c vn chuyn bi h vn chuyn calci. C ch ny cn cho php vn chuyn c nhng cht t tan trong lipid. b. Cch cht c xm nhp vo c th Cch cht c xm nhp vo c th gi l ng phi nhim hay ng hp thu cht c Cht c c th xm nhp vo c th qua 3 ng c bn: qua da, qua ng tiu ho v qua ng h hp. y l nhng ng hp thu t nhin khi c th tip xc vi mi trng. Sc vt c th b ng c thuc th y theo cc ng khc nh tim, tht trc trng. * Cht c xm nhp qua da Da l mt m phc tp, nhiu lp, chim khong 10% trng lng c th. Da hu nh khng thm vi phn ln cc ion v dung dch nc, tuy nhin li thm vi nhiu cht c pha rn, lng hoc kh. Tu theo tng vng, lp biu b c dy khc nhau. Ch dy th nhiu keratin hn, lp ny to nn hng ro ca biu b, nhng ng thi cng l ni d tr cht c. Mt s dung mi hu c gy tn hi lp lipid (aceton, methanol, ether) s lm tng tnh thm ca da. = pKa - pH

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10Cc cht khng gy tn hi lp lipid (ether c chui di, du olive) lm gim tnh thm. Da cng cha cc enzym chuyn ho thuc, cht c. Hot tnh chuyn ho ca ton b da bng khong 2 - 6% ca gan. * Cht c xm nhp qua ng tiu ho L ng ch yu hp thu cc cht c vi mt s c im sau: - C th hp thu mt lng ln cht c - B chuyn ho mt phn khi qua gan ln th nht. - C pH thay i t acid (1 - 3 d dy ), tng dn ti kim (6 - 8 rut) nn hp thu cc cht c c pKa khc nhau. - C qu trnh vn chuyn tch cc d hp thu, nht l khi cht c c cu trc ging vi cht dinh dng ca c th. * Cht c xm nhp qua ng h hp S hp thu qua ng h hp c 2 c im quan trng: (1) Nim mc hp thu c din tch rt rng ( ngi l 80 - 100 m2) bng khong 50 ln din tch da. (2) Khong cch gia din hp thu vi tun hon ch dy 1 - 2 mm, v vy kh c c th vo tun hon sau vi giy. V s xm nhp cc cht c qua ng h hp, cn lu mt s c im sau: - Trong chu k h hp, lun c mt th tch kh tn lu li trong phi, v vy cc kh c chm thi tr v s d b hp thu tr li. - Cc cht c hp thu qua ng h hp c phn lm 2 loi: (1) Cc cht tun theo cc nh lut v cht kh, bao gm: dung mi, hi v kh. (2) Cc cht khng tun theo nh lut trn, bao gm cc dng ht, kh dung, my m, khi... Rt nhiu y t c th lm d dng hoc ngn cn s xm nhp ny. Cc ht c ng knh > 5 mm thng lng ng trong vng mi hng. Cc ht < 2 mm lng ng trong cc nhnh kh ph qun, , cc nim mao nim dch s y chng ra vi tc 1 mm/pht v thi gian bn thi < 5 gi. Khong 80% thanh thi ca phi l qua ng ny. Khi ti thanh mn cc bi thi s c nut vo ng tiu ho hoc ho, khc y ra ngoi. Ngoi ra, hin tng thc bo trn ng h hp cng ng vai tr rt tch cc trong vic thanh thi cc cht c. Cc thc bo s a cht c vo bch mch v c th s tch lu trong mt thi gian di. Cc ht 1 mm c th vo n tn ph nang, hnh thnh cc nt cng vi s pht trin mt mng li si reticulin. Cc cht kh s qua ph nang vo mu, cht no c ho tan cao s c hp thu nhiu thi gian t c thng bng kh: mu ph nang thng > 10 pht i vi cc kh t tan. Cc kh c cng d tan th thi gian t c cn bng cng di, c khi ti 1 gi. Cha thy c s vn chuyn tch cc ng h hp, tuy nhin, thm bo (pinocytosis) c th c vai tr quan trng. 2. 2. S phn b cht c Cc dch trong c th c phn vo 3 gian c bn: nc trong huyt tng, nc trong khe gian bo v nc trong t bo. Huyt tng ng vai tr quan trng trong vic phn phi cc cht c c hp thu. Cht c sau khi c hp thu vo mu, mt phn s gn vo protein huyt tng, phn t do s qua c thnh mch chuyn vo cc m, vo ni tc dng, vo m

10

11d tr, hoc b chuyn ho ri thi tr. Nhiu khi cc sn phm chuyn ho li c hn cht m, tr li vng tun hon li c phn phi li vo c quan v gy c (S 1.1). S khc bit ln gia thuc v cht c l thuc c t l tan trong nc cao hn v d b ion ho hn, v vy d b thi tr. Cn cht c hi d tan trong lipid khng b ion ho nn thng gn mnh vo m, gy c hoc tch lu lu trong c th. Trong mu, thuc gn ch yu vo phn albumin ca protein huyt tng. V cc cht c thng rt a m nn li hay gn mnh vo lipoprotein. S gn ny cng xy ra cc ni d tr (gan, thn, m m,...), hoc v tr tc dng (hemoglobin, m thn kinh,...). Dng cht c t do huyt tng, dch khe lun c gi trng thi cn bng, v vy khi nng dng t do gim th cht c li c gii phng t kho d tr ra. y l c ch ca nhim c mn tnh. Do c tnh ho hc khc nhau nn mi loi cht c c i lc c bit vi cc m. V d: flo thng ng li xng v rng do to cc hp cht florophosphat calci: cc kim loi nng, tc dng vi gc thio (-SH) c nhiu trong t bo sng (lng, tc, mng); ch c gi li trong huyt cu; cc cht tr su c halogen (DDT, lindan) gn nhiu t bo m. S phn b ca cng mt loi cht c trong ng c cp tnh v mn tnh nhiu khi cng khc nhau: trong ng c cp tnh ch, thng thy n c nhiu gan v thn; nhng trong ng c mn tnh li thng thy ch tu xng, tc, huyt cu.

Phi nhim vi cht c Cht c xm nhp vo c th

S phn phi

Thi tr

Chuyn ho thnh cht c

Chuyn ho thnh sn phm lin hp Phn phi li

Chuyn ho thnh cht t c

Tng tc vi cc phn t ln (Protein, DNA, RNA, receptor,...)

Lun chuyn v sa cha

Cc tc dng c (Di truyn, ung th, qui thai, min dch,...)

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12S 1.1: S phn b cht c trong c th * Cht c tch ly - Khi nhim c lin tc trong nhiu ngy d gy tch ly cht c. S tn lu cht c trong c th lu ngy khi gy ng c v gy cht c gi l tch ly cht c. - Tch ly ha hc: l loi tch ly trc khi bin thnh cht khng c hi v o thi ra ngoi mt liu th li nhim thm mt liu khc mi. iu ny gii thch hin tng tch ly ca strychnin v asen. 1.3. S chuyn ho cht c a. Vai tr ca s chuyn ho cht c Cht c c coi l nhng cht l (xenobitics), khng th dung np c, phi b thi tr. Cht c thng l nhng phn t tan c trong m, khng b ion ho v vy d thm qua mng sinh hc, thm nhp vo trong t bo v gi li trong c th. Mun thi tr, nhng cht ny phi c chuyn ho thnh cc phn t c cc, d b ion ho, do s t tan trong m, kh gn vo protein, kh thm vo t bo, v v th, tan trong nc, d b thi tr (qua thn, phn,...). * Cc enzym chnh xc tc qu trnh chuyn ho cht l Qu trnh chuyn ha c th xy ra mt s ni trong c th vi s xc tc ca mt s enzym nh sau: - Cc cht l (xenobiotic) thng c chuyn ha thnh cc dng khc nhau nh h cc men oxy ha c chc nng hn hp (MFOs - micrsomal mixed function oxidase). Li ni m trn l ni MFOs khu tr v hot ng, c bit l gan, hot ng ca enzym tng ln ng k trong vng mt vi ngy c th phi nhim vi cht c. Cytocrom P450 gi vai tr quan trng trong chuyn ha nhiu xenobiotics. H MFO hot ng trrc ht trn cc hp cht thn m khng phn cc. MFOs thm vo cc nhm chc nng c cc v t thn m hn. - Men protease, lipase, decarboxylase xc tc chuyn ha cht c ti nim mc rut. - Huyt thanh: esterase - Vi khun rut: reductase, decarboxylase - H thn kinh trung ng: mono amin oxydase, decarboxylase. b. Cc phn ng chuyn ho chnh Cc phn ng chuyn ha cht c dc chia lm 2 giai on (2 pha): * Chuyn ha giai on 1 y l cc phn ng chuyn ha giai on 1, chun b xenobiotic cho chuyn ha giai on 2. - Cc phn ng giai on 1 c th c kch hot nh phn ng enzym. H MFOs c kch hot tng hot tnh bng s gii phng trc 1 hp cht ngoi lai y ht hay tng t, thng ln lt tng quy trnh chuyn ha sinh hc ca nhng hp cht ny. Barbiturat, hydro carbon, halogen v steroid ni sinh ln tc nhn gy cm ng enzym MFOs. - Chuyn ha giai on 1 c th b c ch (v d bng pyperonyl, butoxide, c s dng tng tnh c trong cn trng).

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13Qua phn ng pha ny, cht c dng tan c trong m s tr nn c cc, d tan trong nc. Nhng v mt tc dng sinh hc, cht c c th mt hot tnh, hoc ch gim hot tnh, hoc i khi l tng hot tnh, tr nn c hot tnh. - Cc phn ng chnh pha ny gm: + Phn ng oxy ho: l phn ng rt thng gp, c xc tc bi cc enzym ca microsom gan, c bit l hemoprotein, cytocrom P450. + Phn ng thu phn do cc enzym esterase, amidase, protease,... Ngoi gan, huyt thanh v cc m khc (phi, thn,...) cng c cc enzym ny. + Phn ng kh carboxyl (kh COO): decarboxylase. * Chuyn ha giai on 2 L mt chui cc phn ng lin hp c lin quan n nhng xenobiotic c chuyn ha giai on 1 thnh nhng phn t c cc, mang nhm chc hydroxyd, amino, carboxyl hoc halogen c th tham gia d dng cc phn ng lin hp vi cc cht chuyn ho ni sinh nh ng, acid amin, glutathion, sulfat,... - Qu trnh lin hp to ra mt hp cht t thn m hn v tan nhiu trong nc hn cht ban u. - Cc sn phm ca qu trnh lin hp d o thi hn trong nc tiu v thng t c hn hp cht m hoc cc cht chuyn ha ca giai on 1. - Cc sn phm lin hp thng l acid glucuronic, acid amin, cc acetat, sulfat v glutathione. Cc phn ng lin hp chnh: cc phn ng lin hp vi axit glycuronic, axit sulfuric, axit amin (ch yu l glycin), phn ng acetyl ho, methyl ho. Cc phn ng ny i hi nng lng v c cht ni sinh. Mt s cht hon ton khng b chuyn ho, l nhng hp cht c cc cao (nh axit, base mnh), khng thm qua c lp m ca microsom. Phn ln c thi tr nhanh nh hexamethonium, methotrexat. Mt s hot cht khng c cc cng c th khng b chuyn ho; barbital, ether, halothan, dieldrin. * Cc yu t nh hng n qu trnh chuyn ho cht c - Bnh gan: gan l c quan chuyn ha quan trng nht ca c th. Cc bnh lm gim qu trnh chuyn ha sinh hc gan l x gan, nhim c gan, caxinom v mt (sp xp theo mc nh hng) do lm gim hot ng ca MFOs. - S ti sinh cc m gan b tn thng lm tng qu trnh chuyn ha sinh hc. - S nh v cht c trong cc m cng vi hot ng MFOs c th nh hng n qu trnh chuyn ha sinh hc. Cc tc nhn b phn chia mnh trong m m, xng hay no s khng tham gia cc qu trnh chuyn ha sinh hc. - Tui sc vt: sc vt s sinh v sc vt gi c th thiu enzym cn thit cho qu trnh chuyn ha sinh hc. - Thiu cht dinh dng dn n thiu cc cht ha hc cn thit cho qu trnh tng hp cc enzym hay cc cht lin hp. v d: thiu cht khong nh canxi, ng, st, magie, km, cc vitamin E, C, B v cc protein.

13

14Loi, ging gia sc khc nhau, hot ng ca enzym giai on 1 v 2 khc nhau (v d, hot ng ca enzym N - dimethylation chut lang yu hn so vi cc ng vt khc). - Tnh bit c th nh hng n qu trnh chuyn ha sinh hc. con c, hot lc ca MFO thng cao hn, lin quan n steroid ni sinh nh testosterol. - ng phi nhim vi cht c c th c nh hng n tc dng gy c. Cht c nhim qua ng ming s qua gan trc khi vo h c quan khc lm tng kh nng chuyn ha sinh hc. - Nhit c th gim lm gim hot tnh ca cc enzym microsom. - S bin i ca cc cytocrom P450 v glutathione kh (GSH) theo ngy v m lin quan n qu trnh bin i sinh hc. - Cht gy cm ng enzym chuyn ho: c tc dng lm tng sinh cc enzym microsom gan, lm tng hot tnh cc enzym ny. 1.4. S o thi cht c Cht c thng c thi tr khi qua chuyn ho. a. o thi cht c qua thn y l ng thi tr quan trng nht ca cc cht tan trong nc, c trng lng phn t nh hn 300. * Qu trnh thi tr Lc th ng qua cu thn: hot cht dng t do, khng gn vo protein huyt tng c lc y. Bi tit tch cc qua ng thn: qu trnh ny xy ra ch yu ng ln gn, do phi c cht vn chuyn nn ti y c s canh tranh thi tr. Ti hp thu ng thn: l qu trinh khuch tn th ng qua ng thn, qu trnh ny xy ra ng ln gn v ng ln xa. Cc cht tan trong lipid, khng b ion ha pH nc tiu tuy thi tr trong nc tiu ban u li c ti hp thu vo mu. * ngha lm sng Lm tng thi tr iu tr nhim c: kim ho nc tiu, lm tng ion ho ca phenobarbital, tng thi tr khi b nhim c phenobarbital. b. o thi cht c qua mt Sau khi chuyn ho gan, cc cht chuyn ho c trng lng phn t ln hn 300 s thi tr qua mt theo phn ra ngoi. Phn ln sau khi b chuyn ho thm rut s c ti hp thu vo mu thi tr qua thn. Mt s cht sau khi thi tr qua mt xung rut li c ti hp thu v gan theo ng tnh mch gnh li vo vng tun hon, c gi l cht c chu k rut - gan. Nhng cht ny tch lu trong c th, lm ko di tc dng (morphin, tetracylin, digitalis tr tim...). c. o thi cht c qua phi Cc cht c th hi, c tnh cht bay hi thi tr qua phi, bao gm: (1) Cc cht bay hi nh ru, tinh du (eucalyptol, menthol). (2)Cc cht kh: halothan. Ether etylic.

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15d. o thi cht c qua sa Cc cht tan mnh trong lipid (cc alcaloid, barbiturat, cc cht chng vim phi steroid, tetracycilin..), c trng lng phn t di 200 thng d dng thi tr qua sa. V sa c pH hi acid hn huyt tng nn cc cht l acid yu c nng thp hn v cc cht l base yu c th nng trong sa hi cao hn huyt tng. 3. C ch tc dng ca cht c Ni dung phn 3 bao gm: (1) C s phn t ca tn thng t bo do ng c, nhim c: Cc cht c (xenobiotics) khi qua chuyn ha to thnh cc cht a in t (Electrophile), gc t do (Free radical), cht i nhn (Nucleophile), cht phn ng oxy ha kh (Redox). C ch tc dng ca cht c c gii thch da trn tc hi ca cc cht chuyn ho ny. (2) C ch gy c c trng trn c quan, t chc c gii thch i vi tng c quan, h c quan ca c th. 3.1. C s phn t ca tn thng t bo do ng c, nhim c Tn thng t bo l c s ca hu ht cc tc dng c hi. Tc dng gy c ca cht c l kt qu ca s ri lon chc nng mt s qu trnh sinh hc trong c th. S phc tp ca p ng c hi in vivo c th c gii thch do tng tc ca cc t bo trong cc m, nh hng ln nhau gia cc c quan v i vi ton b c th. Khi c th b ng c, cc qu trnh sinh hc trong c th c th b ngng tr hoc vt qu gii hn sinh l bnh thng v nh hng n cc h c quan chu s iu khin ca chng. p ng t bo i vi cc ho cht c xy ra thng qua 2 c ch: nh hng n cu trc v nh hng n chuyn ho trong t bo. - nh hng n cu trc: Tnh ton vn ca mng t bo b thay i s nh hng n s vn chuyn cc th dch v cht in phn, n s iu chnh th tch t bo. - nh hng n chuyn ho: (1) Lm gim nng lng sn c cho qu trnh vn chuyn tch cc, tng hp cc cao phn t v duy tr cn bng thm thu (bm kali natri) (2) Lm xo trn iu khin axit nucleic, gy bin tnh protein cu trc dn n ngng tr tng hp protein. Qu trnh tng trng b nh hng (hin tng tng sinh hay ung th) do DNA b ph hu, khng c sao chp ng hoc vt qu kh nng iu khin s n nh ni mi (3) Gy tch ly cc cht bo v cc sc t bt thng. Mt s xenobiotics (acid mnh, base mnh, nicotine, aminoglycoside, ethylene oxide, methyliscyanate, kim loi nng, HCN, CO) l cht c trc tip, trong khi c tnh ca cc cht khc li ph thuc phn ln vo cc cht chuyn ha ca chng. Qu trnh chuyn ha sinh hc cc xenobiotics thnh nhng sn phm c hi c gi l s hot ha. i vi mt s xenobiotics, sau chuyn ha sinh hc, tnh cht l, ha hc b thay i dn n tc dng c hi lm thay i cu trc hoc vi mi trng ca qu trnh sinh hc. V d : acid oxalic c hnh thnh t ethylen glycol c th gy nhim acid v gim canxi huyt cng nh tc ng thn do kt ta canxi oxalat. Mt s cht c phn ng vi enzym hoc th th. V d: hp cht phospho hu c parathion c chuyn ha thnh cht c ch men cholinesterase. Tuy nhin, hay gp nht l cc cc trng hp xenobiotics khi qua chuyn ha to thnh cc phn t khc nhau trong c th, l: - Electrophile: cht i in t (a in t)

15

16- Free radical: gc t do - Nucleophile: cht i nhn (a nhn) - Redox active reactant: cht phn ng oxy ha kh. a. S hnh thnh cht a in t Cc hp cht l (xenobiotics) qua chuyn ho sinh hc, di tc ng ca cc men micrsom oxyha c chc nng hn hp (MFOs - micrsomal mixed function oxidase) s chuyn thnh dng trung gian a in t (electrophyle). Electrophile l cc phn t cha mt nguyn t thiu electron c th phn ng bng cch dng chung in t vi nguyn t giu in t. MFOs l mt h enzyme khng c hiu, c vai tr ch yu trong chuyn ho giai on 1 (oxy ho cc cht c a m) chun b cho qu trnh lin kt v bi tit cc xenobiotic trong li ni tng. Cc cht trung gian a in t mi c to thnh qua chuyn ha s lin kt ng ho tr vi cc cao phn t quan trng trong t bo (lipid, protein, DNA) v lm chng b bin tnh. Lin kt ng ho tr ca cht c vi cc cao phn t lin quan n tn thng t bo v qu trnh gy ung th (carcinogenesis), mc d vai tr ca lin kt ng ho tr trong nhng trng hp ny cn cha c chng minh bng thc nghim. Cc electrophiles ng thi cng lin kt vi glutathione kh (GSH). S lin kt ny c coi l c ch phng v trong t bo. b. S hnh thnh cc gc t do * Gc t do v s hnh thnh gc t do Trong cu trc nguyn t v phn t, cc in t lun dng cp i v cc cp i ny lun vn chuyn ti mt vng qu o xc nh, xung quanh ht nhn gi l qu o phn t. Mt in t trong mi cp in t c s nng lng quay (spin quantum number) + 1/2 v in t cn li c s nng lng quay l - 1/2. Gc t do l dng xut hin khng ph thuc, c lp theo ng ngha t do, l mt nguyn t hoc mt mnh phn t cha mt hoc nhiu hn in t khng cp i ch c mt mnh quay trn qu o Bng 1.2. Mt s v d v gc t doTn gc t do Nguyn t hydro Trichloromethyl Cng thc gc H*

ngha Gc t do n gin nht - Gc c carbon trung tm (in t khng cp i kt hp vi carbon), CCl3* c hnh thnh trong qu trnh chuyn ha ca dung mi carbon tetraclorid trong gan v gy tc ng c hi cho dung mi - Gc c carbon trung tm thng c s dng phn ng nhanh vi O2 to gc peroxyl theo phn ng sau: CCl3* + O2 CCl3O2 Gc c oxy trung tm, phn ng rt hn ch Gc c oxy trung tm, phn ng mnh, c hot tnh rt mnh, tn cng mi phn t trong c th ngi. Gc c oxy trung tm, c hnh thnh trong qu trnh ph v peroxyd hu c, k c cc con ng khc. Oxyd nitric (NO*) c hnh thnh trong c th t amin L-arginin

CCl3*

Superoxyd Hydroxyl Peroxyl Alkoxyl Oxyd ca nit

O2

*

OH* RO2* RO* NO*

16

17NO2* Nit dioxyd (NO2*) c hnh thnh khi cho NO* phn ng vi O2 v xut hin trong khng kh b nhim hoc khi ca cc cht hu c b t chy (khi thuc l).

(du hnh * ch loi gc t do) Gc t do n gin nht l nguyn t ca nguyn t hydro vi 1 proton v 1 in t n. V d: paraquat, doxorubincin v nitrofurantoin c th nhn mt in t t men kh to thnh gc t do (free radical). Nhng gc ny c th chuyn mt in t cho oxy phn t to thnh ion gc t do O2- (superoxide anion radical) v phc hi xenobiotic m tip tc to thnh cc gc t do mi. * Hot ng ca gc t do v tnh c hi ca n Mt s ha cht c (v d paraquat herbicides) khi b oxy ho bi MFOs thnh cc gc t do cng vi s chuyn electron cho oxy, to thnh gc superoxid-02-. Gc superoxid (gc a oxy) phn ng vi lipid cha no (polyunstatared), quy np 1 chui phn ng t xc tc, to thnh cc gc lipid t do v sau peroxid ho lipid. GSH (glutation kh) c th b gim hot tnh, t thc y qu trnh ph hu oxy v dn n kt qu l t bo b cht. Cc tc nhn lm gim hot tnh GSH li lm tng nhy cm ca t bo i vi qu trnh peroxid ho lipid. Sau khi hnh thnh cc gc t do, xut hin mt s tc dng c hi nh ph hy t chc, hoc l mt trong nhng nguyn nhn gy ung th. Gc lipid phn ng vi oxy to thnh gc peroxid. Cc phn t lipid t phn ng vi cc gc t do tr thnh cc gc lipid t do v to ra chui phn ng ph hu (cn gi l chui peroxid ha mng t bo). Qu trnh peroxid ha lipid ph hu cc mng t bo v ni bo quan, lm gim s ton vn cu trc v gim kh nng kim sot s hp th chn lc v vn chuyn ch ng qua mng t bo. S 1.2. S hnh thnh cc gc t do do ho cht c v tc hi ca chng Ho cht c hoc sn phm chuyn ho c hi

c ch chuyn ho nng lng lm yu ATP

Tch lu natri v canxi trong dch bo tng

Na+/K+ ATPase gim

Mg+/Ca+ ATPase gim

Nc trn vo

phospholipase hot ha canxi

17

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Ho cht v cc sn phm chuyn ho c hi lm trit tiu gradien H+ trong ty th dn n c ch qu trnh phosphoryl oxy ho lm hn ch s dng oxy v lm gim qu trnh to ATP, t l ADP/ATP tng, ng thi to ra nhiu gc phospho v c, gy bin dng, t nt mng ty th. Do mng ty th b tn thng nn vo bn trong t bo nhiu, K+ thot ra ngoi v Ca++ i vo th Mg++ cng thot ra ngoi, do nh hng n s hot ho ATP ase. Nhng bin i ca ty th (trung tm cung cp nng lng cho mi hot ng sng ca t bo) lm cho nng lng d tr trong t bo gim i r rt, qu trnh ng phn ym kh tng ln, tch t nhiu axit lactic gy gim pH ca bo tng lm nh hng ti nhn, mng t bo v cc bo quan khc. Mng t bo l mng khng thm do c tnh duy tr s cn bng bn trong ca cc ion v H2O thng qua bm Natri trn mng t bo. Bm ny vn chuyn ion Na+ v ion K+ vo t bo, hot ng ny tiu tn ATP. ATP gim lm hot ng ca bm Natri suy yu. Kt qu l cc ion Na+ vo t bo nhiu v K+ thot ra ngoi, mi ln di chuyn theo mt gradient H+ . Trong t bo, t l Na+/K+ tng, t bo cng mt ion v tch t Ca++, t l Ca++/ Mg++ tng. Sc khng mng t bo yu, bm Natri mt tc dng, nc thm vo t bo, t bo trng phng ln. Lysosome cng b trng ln, tnh thm mng tng, cc enzym thot ra vo dch t bo tham gia qu trnh hu t bo. S mt cn bng canxi gy hot ho phospholipase, mng t bo t tiu hu, mt chc nng lm hng ro, t bo sng v b tn thng khng phc hi dn n hoi t t bo (S 1.3.). - Cc nhm thiol protein (v d, glutathionic) trong t bo cng c th b cc gc t do lm gim hot tnh v cc t bo cao phn t b tn thng nng n hn. c/ S bo v chng li cc gc t do nh cc tc nhn chng oxyho - antioxidant (1) Men SOD - Superoxid dismutase: xc tc qu trnh kh anion superoxid O2- thnh hydrogen peroxid H2O2 . Men MnSOD c tm hot ng l mangan c th loi tr c anion superoxid O2- sinh ra ngay ty th. Men SOD lin kt vi ng v km (CuZnSOD) c tm hot ng l Cu, c hot tnh cao v c nhiu trong bo tng (cystosol), loi b gc anion superoxid O2- thot ra ngoi bo tng. Nh hai enzym ny nn gc anion superoxid O2khng n c mng t bo.

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19(2) Men catalase c tp trung nhiu trong peroxisome ca t bo v xc tc phn ng bin hydro peroxid thnh nc v oxy. Hydroperoxyd H2O2cng l mt cht c hot tnh cao nn c hi. H enzym catalase v glutathion peroxydase (GSHPX) c th loi tr n: H2O2 catalase 2H2O + 3O2 Catalase vn chuyn H2O2 thnh 2 cht hon ton v hi l nc v oxy tam bi. Nhng catalase ch th hin tc dng xc tc khi nng H2O2 ln hn 10-8 mol/l. Di nng , catalase khng c tc dng. (3) Men glutathion peroxidase GSHPX, 1 enzym cha selen xc tc phn ng bin hydroperoxid thnh nc v ru. Hot GSHPX ph thuc nng Se trong huyt thanh. Khi H2O2 c nng ln hn 10-8 mol/l, enzym catalase b bt hot do mt c ch cha r. Khi nng H2O2 gim xung di tr s ni trn, GSHPX c hot ha, v xc tc cho phn ng kh H2O2 bng glutathion: H2O2 + 2GSH GSHPX GSSG + 2 H2O Glutathion dng oxy ha GSSG li chuyn v dng kh nh enzym glutathion reductase. Ging nh cc enzym SOD, catalase v GSHP X c ni bo, ty th v H2O2 cng l mt sn phm ca h hp t bo nh O2 -. Hai men ny hu nh khng c mt dch ngoi bo. Cn lu l superoxyd. H2O2 thng xuyn sinh ra do s phn hy peroxyd, ng thi thng xuyn mt i do tc dng ca catalase v GSHP X , nn tn ti mt nng cn bng no . Nng cn bng ny lun nh hn 10-8 mol/l. Superoxyd O2- v peroxyd hydro H2O2 cng tn ti trong t bo nng cn bng ca chng, tuy l rt nh, nhng s phn ng vi nhau. y l mt phn ng rt quan trng, v sn sinh ra 2 sn phm: 1O2 (oxy n bi) rt nguy hi v - OH (gc hydroxyl) li cn nguy hi hn nhiu. Chnh gc - OH l sn phm nguy hi nht do h hp t bo sinh ra: O2- + H2O2 = -OH + OH- + 1O2 Phn ng ny c gi l phn ng Haber Weiss, c th tin hnh khng cn xc tc. Cc ion st, ng lm xc tc phn ng ny, lm tc ca n tng ln rt nhiu. Phn ng trn nu c xc tc c gi l phn ng Fenton. (4) Vitamin E ng vai tr l mt cht chng oxy ho sinh hc, trong alpha tocopherol l quan trng hn c, c nhm hydroxyl trn vng benzen c vai tr lm gim gc t do, ngn cn cc phn ng oxy ha cht bo, ngn cn s hy hoi mng t bo v s cht ca t bo. c. S hnh thnh nucleophile S hnh thnh nucleophile l mt c ch khng ph bin (t gp, v d: s to thnh cyanid t amygdalin di tc dng ca men bacterial b - glucosidase trong bnh gut ngi). Carbon monoxide l cht chuyn ha c hi ca dihalomethane do kh halogen oxy ha. Mt s cht trung gian chuyn ha nuleophile c to thnh trong gan nh qu trnh hydroxylation nh hydroxylamin c th to methaemoglobin.

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20d. S hnh thnh cht phn ng oxy ha kh Trong qu trnh kh nitrat thnh nitrit v d: methaemoglobin to thnh khi nitrat chuyn thnh nitrit v gy c Mt s xenobiotics khng tng tc hoc khng ch tng tc vi cc t bo ch ni sinh gy c, chng lm thay i vi mi trng sinh hc. Gm c: (1) Cc tc nhn lm thay i nng ion trong pha nc (aqueos biophase), nh acid v cc cht chuyn ha thnh acid, nh methanol v ethylene glycol, nh 1,4-dinitrophenol v pentachlorophenol phn ly cc proton phenolic trong khu vc khun (matrix) ca ty lp th lm trit tiu proton gradient, do tr hon tng hp ATP; (2) Cc dung mi v cht ty lm thay i pha lipid trong mng t bo v ph hy chc nng mng; (3) Cc xenobiotics khc gy c bng cch chim ch: v d mt s ha cht nh ethylene glycol hnh thnh cht kt ta trong ng thn. Bng cch chim v tr lin kt bilirubin vi albumin, hp cht nh sulfonamid gy bnh vng nhn no (kernicterus) tr s sinh. Carbon dioxid chim ch oxygen trong ph nang gy ngt th. 3.2. C ch gy c c trng trn c quan, t chc a. C ch gy tn thng ha hc C ch gy tn thng ho hc trc tip trn cc m lm thay i cc chc nng iu khin s n nh ni mi ph thuc mng ca t bo. S ph hy ny thng xy ra khi mng t bo tip xc vi nhng cht n mn mnh nh axit, baz, cc hp cht gy ng vn protein hoc c tc dng ph hu lipid mng t bo. S tn ph do ha cht thng xy ra tc th (c ngha l khng c giai on tim n), ti ch v khng c hiu. Nhng vng nhy cm nht vi tn thng ho hc l da, mt, ng h hp trn v xoang ming. Cc cht hay gy tn thng ho hc trc tip l axit, baz, phenol, aldehid, cn, sn phm ct ca du v mt s mui kim loi nng. b. C ch gy hoi t t bo biu m c t sinh hc c th gy hoi t biu m trn khp c th. Hoi t biu m thng xy ra cc t bo c hot tnh chuyn ho v kh nng sao chp mnh, l t bo ca ng thn, ti mt, tu xng v biu m rut. Cht c thng nh hng n cc enzyme ch cht hoc cc qu trnh chuyn ho trung gian trong cc t bo ni trn. C ch gy thiu ht nng lng (gim hoc ngng qu trnh sn sinh adnosin triphosphate (ATP)) lm gim kh nng vn chuyn ch ng v iu chnh cc cht in phn v nc ca t bo. Gim tng hp cc enzyme hoc cc protein cu trc. Cc cht c gy thiu mu cc b (gim dng chy ca mu) s gy ra thiu oxy m bo, dn n tnh trng thiu ht nng lng v s ph hu cc t bo. c. C ch tc ng thng qua c ch hoc cnh tranh enzyme Thng thng, cc enzyme xc tc cc phn ng ca t bo trong iu kin nhit v nng nht nh. Do tng tc ho hc trc tip vi cht c, cc enzyme c th b c ch hoc thay i hot tnh. Qu trnh c ch hay cnh tranh enzyme bao gm c s thay i cu trc khng gian bc 3, 4 ca cc enzyme. S tng tc enzyme - cht c mnh hay yu nh hng n mc v thi gian ng c. c ch cnh tranh l khi nim ni v nh hng ca cht c n hot tnh ca enzyme. c ch t ti a khi cht cnh tranh c cu trc tng t enzyme. Phc hp enzyme - cht c ch c tnh thun nghch v phn t cht c ch khng b thay i trong phn ng.

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21V d nh axid oxalic (c t thc vt) v fluorcacetate (rodenticid - cht dit loi gm nhm) c ch ln lt succinic dehydrogenase v aconitase trong chu trnh axid tricarboxylic. Thuc dit cn trng organophosphate v carbamate c ch cholinesterase. d. C ch gy c do nh hng n cc qu trnh chuyn ho hoc tng hp ca c th Cc cht c tc ng theo c ch ny thng nh hng n cc sn phm cn cho nng lng, cho cu trc hoc qu trnh tng trng. Phosphoryl - oxy ho l qu trnh gii phng nng lng trong chui vn chuyn electron, phosphoryl ho adenosine diphosphate (ADP) thnh adenosine triphosphate (ATP). Cc cht ph ghp, in hnh l cc cht dit nm 2,4 dinitrophenol (DNP), chlorophenol v arsenate lm tng s dng oxy. Nng lng b tiu hao di dng nhit ch khng lu tr trong lin kt phosphate giu nng lng, do nhit c th tng. Cc cht dit nm cha thic c 3 nhm th c ch phosphoryl oxy ho lm hn ch s dng oxy v gim qu trnh to ATP. Kt qu l c th cng mt mi v yu dn tng t nh tc dng ca cc cht ph ghp (oxidative uncouple) nhng khng b st. Cht c gy tn thng DNA hoc gn vi ribosome trong qu trnh vn chuyn hoc phin m dn dn c ch tng hp acid nucleic v c ch tng hp protein. Nhiu cht c ch kt hp vi tiu phn ribosome ln hoc nh. Mt s cht c alki ho DNA, c ch s sao chp hoc phin m. C ch ny thng gp giai on tr hon hoc tim n ca cht c trc khi xut hin cc triu chng lm sng. V d nh nhim c aflatoxin, cc hp cht thy ngn hu c v amantine (c t nm Amanita phalloides). Cht c tc ng n h li ni m th cn tr qu trnh chuyn ho m. Kt qu ca c ch ny l: (1) Gim tng hp protein nhn (lipid acceptor protein). (2) Gim kt hp phospholipide v triglyceride trong qu trnh vn chuyn lipoprotein dn n tch lu m trong t bo. e. C ch tc dng trn h thn kinh Cc phn x bnh thng c th c tng cng thng qua phong to s dn truyn thn kinh c ch ca cung phn x. Kt qu l c th khng iu khin c cc phn x v kt thc bng cc cn co git nh bnh un vn. C ch tc dng ny thng gp trong ng c strichnin, do phong to glycin (cht trung gian ha hc ca qu trnh c ch) trong h thng phn x tu sng. Cht c c th lm thay i tnh thm ca mng t bo thn kinh i vi cc ion. Cc dng natri v kali b cht c nh DDT v pyrethrin lm thay i, dn n thay i ngng tc ng trn mng t bo. Cht c c ch cc enzym thit yu cho chc nng cn bng, lm thay i c tnh dn truyn qua xinap thn kinh (V d: thuc tr su loi phospho hu c c ch men cholinesterase). C ch gy tn thng h thn kinh trung ng (CNS) hoc h thn kinh ngoi vi nh hng n chc nng nron v dn truyn trc thn kinh. Nhng tn thng thn kinh ny thng l mn tnh v c th l vnh vin. Hoi t nron l do tc ng trc tip hoc gin tip ca cht c n cc nron. (1) Tc ng trc tip: cc hp cht thy ngn hu c lm suy yu s tng hp protein thn kinh thit yu. (2) Tc ng gin tip: thiu oxy m do cacbon monooxide hay cyanide gy tn thng thn kinh th pht.

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22Cht c hy myelin (demyelination) nh hng n dn truyn thn kinh do thay i s lan truyn ca hiu th vn ng dc trc thn kinh. f. C ch gy tn thng h mch (mao qun) v mu Cht c tc ng trc tip ca n cc t bo tu xng lm gim hoc ngng sn sinh t bo mu. Qu trnh tng hp huyt sc t c th chu tc ng ca cht c theo mt s c ch sau: (1) Gim tng hp huyt sc t hoc tng lng tin thn huyt sc t dn n tnh trng thiu mu, t dn n ri lon chuyn ho porphyrin. (2) St trong hemoglobin c th b oxy ho t st ho tr II thnh st ho tr III, to thnh methemoglobin khng c kh nng vn chuyn oxy (methemoglobin c to ra trong ng c nitrit). (3) Qu trnh oxy ho lm bin cht hemoglobin, to ra cc th Heinz lm tng c 2 qu trnh thc bo hng cu v tan mu t nhin. Hemoglobin mo rt mn cm vi qu trnh to cc th Heinz. Cacbon monoxide rt ging hemoglobin, c th gn vi hemoglobin to thnh carbonxyhemoglobin khng vn chuyn c oxy. Bnh ng mu do c tnh ca vitamin K dn n xut huyt th pht. Cc cht dit loi gm nhm nh narfarin v brodifacoum ngn s ti hot ho ca vitamin cn thit cho qu trnh tng hp prothrombin v cc yu t VII, IX v X. g. Cc cht c tc dng tng t nhng sn phm chuyn ho v cht dinh dng thng thng Tc dng ca cc hormon estrogen ngoi sinh c th ging tc ng ca cc hormon ni sinh bnh thng. c t nm estrogen, c t thc vt v cht b sung thc n c th lm thay i chu k sinh sn. Cc thnh phn dinh dng nh vitamin D, selen v iod nu vt qu ngng cn thit c th gy nhim c cc c quan b nh hng khi thiu cc cht ny. h. C ch lm suy gim p ng min dch (immunosuppression) y l phn ng ca c th i vi cc cht c cng nghip v c t t nhin. Cc cht c ny nh hng n c min dch dch th v min dch t bo gin tip, gim tng hp khng th, ngn cn b th v mt s qu trnh khc. Chc nng trung tnh ca t bo lympho thay i v gim s hnh thnh t bo lympho (lymphoblastogenesis). Cc cht c nh hng n min dch gm: kim loi nng, dioxin v c t nm (mycotoxins). i. C ch tc dng gy qui thai, cht thai Mt trong cc nguyn nhn gy qui thai, cht thai l do c t nh hng n cc t bo mn cm trong qu trnh hnh thnh cc c quan (organogenesis). Cht c tc ng trong ba thng u tin mang thai thng dn n nhng hu qu nghim trng e do s sng ca bo thai. Hu ht cc tc dng lm thay i hnh thi ca bo thai, gy qui thai xy ra trong ba thng u tin mang thai. Cht c tc ng trong trimester th ba lm gim s tng trng, pht trin hnh thi ca bo thai. k. C ch tc dng gy ung th Giai on u ca ung th do tc ng ca cht c thng kt hp vi s ph hu DNA vt tri hoc qu trnh khi phc khng hon thin DNA b ph hu.

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23Cc cht ho hc gy kch thch m hoc gy tn thng cc cao phn t thc y qu trnh ung th. Du hiu ca ung th do cht c thng khi u bng s ph hu DNA. 3.3. nh hng c hi ca cht c nh hng c hi ca cht c bao gm: (1) nh hng mang tnh dc l, nh c ch qu mc h thng thn kinh trung ng ca barbiturat (chnh l tc dng dc l c dng trong iu tr, nhng qu mc); (2) nh hng c hi bnh l, v d acetaminophen gy tn thng gan; tc dng c hi v gen, nh m tc nit (nitrogen mustard) gy ung th. Khi nng ho cht trong m cha t ngng gii hn th tc dng thng s hi phc. Khi m b tn thng, n vn c kh nng ti to li. Tuy nhin, cc tn thng trn h thn kinh trung ng gn nh khng hi phc c v cc nron khng c kh nng phn chia v ti to. Trong cc nh hng c hi ca cht c c th ni n: - nh hng ti ch v nh hng ton thn: Tc dng ti ch l c tnh xy ra ngay ti ni tip xc vi cht c: cc cht n mn gy tn thng ng tiu ho khi ung. Tc dng ton thn xy ra sau khi cht c c hp thu vo tun hon s gy tn thng cho h thn kinh trung ng. Phn ln cc cht c h thng s ch gy c cho mt vi c quan ch v c quan ch cha hn l ni tch lu nhiu cht c nht: DDT tch lu rt nhiu m m, nhng khng gy mt tc dng c no c. Theo th t, tc dng c thng xy ra h thng thn kinh trung ng, mu, h to mu, gan, thn, phi. - nh hng hip ng xy ra khi hiu qu kt hp 2 hoc nhiu cht c ln hn nhiu so vi tng hiu qu ring l. Tc dng ny xy ra nu mt cht ha hc nh hng n ha tan, kh nng lin kt, chuyn ha hay qu trnh thi tr ca mt cht khc. - nh hng tng tim lc xy ra khi mt cht lm tng c tnh ca mt cht khc, thm ch cht tng c lc ch c c lc rt thp hoc khng c. - nh hng i khng xy ra khi 2 cht kt hp lm nh hng n tc dng ca nhau. nh hng i khng c th: (1) L mt phn ng sinh l, nh tc dng ca epinephrin i khng vi tc dng lm gim huyt p ca phenobarbital. (2) L mt qu trnh chuyn ha, v d cn ethyl cnh tranh vi ethylene glycol trong cht chng ng, cn tr qu trnh hot ha cc sn phm chuyn ha c. (3) Mang tnh cht ha hc, nh cht cng cua (EDTA) to chelat bn vi ch, lm gim c tnh ca ch. Cht c xm nhp vo c th qua cc ng nhau, sau mt thi gian ngn u c phn b vo ton c th. Ty theo tnh cht l ha v iu kin xm nhp vo c th, cht c c th tn lu mt s b phn. Cht c tc dng ngay vo cc t bo sng v lm ri lon hot ng ca chng. a. nh hng n h thn kinh Phn ln cc cht c u t nhiu tc dng ln h thn kinh gy ri lon chc nng vn ng, cm gic. Cc loi thuc m nh cloroform tc dng ln no v ty sng lm mt phn x, cui cng tc dng ln hnh ty gy ngng th. Nhiu trng hp gy hn m nh thuc ng, thuc phin, ru etynic. Cc cht thuc nhm amphetamin, long no, atropin v th phm, clo hu c gy kch thch, vt v. Strychnin v m tin gy co cng (kch thch ty sng qu mc).

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24Cc cht gy ri lon cm gic nh Streptomycin, quinin, salicylat gy chng mt, Santonin, quinacrin lm hoa mt, Streptomycin, kanamycin, neomycin gy ic. Mt s cht tc dng ln h giao cm, gy gin ng t mt nh adrenalin, ephedrin, atropin, nicotin. Ngc li mt s cht nh eserin, acetylcolin, prostigmin lm co ng t mt. b. nh hng n b my tiu ha Cc cht c khi xm nhp vo c th qua ng tiu ha thng gy nn ma, l phn ng u tin ca c th (ng c thy ngn, thuc phin, photpho hu c); nhng cng do tc dng ca cht c trn h thn kinh lm co bp mnh c honh. Cc cht c nh photpho hu c, nm v mt s kim loi nh ch, thy ngn, bitmut c th gy tit nc bt nhiu; ngc li atropin lm kh ming; axit, kim kch thch ng tiu ha nh; thuc chng ng mu, dn xut salicylat gy chy mu ng tiu ha. c. nh hng n gan Gan l mt c quan nm ng t ng tiu ha. T tnh mch ca, gan nhn tt c cc cht do chuyn ha thc n cung cp v cc cht c. Mt khc, cc cht cha trong mu qua h thng i tun hon u cc tc dng n gan. Hu nh trng hp ng c no cng c tn thng gan. Ru lm x ha gan, thoi ha m trong ng c photpho, asen; vng da trong ng c AsH3 . d. nh hng n tim mch Cc cht tr tim dng qu liu u gy c. Cafein, adrenalin, amphetamin... lm tng nhp tim. Digitalin, eserin, photpho hu c lm gim nhp tim. c bit trong ng c gan cc v nha da cc mch khng u; trong ng c quinidin, imipramin c th gy ngng tim. Mt s cht nh hng n s co gin mch. Acetylcolin lm gin mch, ca la mch lm co mch mu. e. nh hng n mu Cc thnh phn huyt tng, hng cu, bch cu v tiu cu trong mu u c th b thay i di tc dng ca cht c: (1) Huyt tng: Cc thuc m (cloroform, ete) l gim pH, h thp d tr kim v tng kali ca huyt tng. Nc rn Viperide lm tng kh nng ng mu, ngc li loi Colubride lm mt kh nng . (2) Hng cu: S lng hng cu trong mt cm3 tng ln trong trng hp ng c gy ph phi (clo, photgen, cloropicrin) do huyt tng thot ra nhiu nn mu b c li. Hng cu b ph hy khi b ng c ch, nhim tia X, benzen hoc cc dn xut ca amin thm. Khi oxit cc bon lin kt vi hemoglobin to ra cacboxyhemoglobin lm mt kh nng vn chuyn oxy nn c th b ngt. Cc dn xut nitro thm, anilin, nitrit oxy ha st II, chuyn hemoglobin thnh methemoglobin lm ngng kh nng vn chuyn oxy. (3) Bch cu: S lng bch cu gim trong ng c benzen, gy thiu mu. Ngc li trong ng c kim loi nng bch cu tng. (4) Tiu cu: S lng tiu cu c th h xung cn vi chc nghn trong ng c benzen. Mt khc di tc dng ca cht c mt s thnh phn mi xut hin: V d trong ng c ch xut hin cht copropocphirin; trong ng c axit mnh xut hin hematopocphirin. C th da vo nhng cht ny chn on ng c.

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25f. nh hng n b my h hp Cc cht c xm nhp vo c th qua ng h hp c th gy: (1) Ti ch nh ho, km theo chy nc mi, nc bt. V d: cc hi c, hi ngt. (2) Tc dng ton thn nh kh CO gy tm ti. Cht c c ch h hp gy ngt th tin ti ngng th nh thuc phin, cyanic, thuc ng. Mt s cht c th gy ph phi nh: hydrosulphit, photpho hu c. g. nh hng n thn Cht c c th tc ng ln cc chc phn ca thn. Thy ngn, ch, cadimi lm tng ure v albumin trong nc tiu. Axit oxalic, thuc chng ng mu, cantharit gy i ra mu. Cc dung mi hu c c clo gy vim thn. Nhiu cht gy v niu nh thy ngn, sulphamid, mt c trm. Nc tiu l mt loi mu th quan trng trong kim nghim c cht. 4. cc yu t nh hng n tc dng ca cht c c tc dng gy c, cc cht c hoc cc sn phm chuyn ha ca chng phi t c nng cao trong khong thi gian nht nh trong c th (ty loi cht c). Cc yu t khi tng tc vi nhau c th lm thay i p ng ca c th i vi cht c, nh hng n p ng liu lng v chn on ng c. Mc d tng yu t khng gy nh hng ln, nhng nu nhiu yu t cng tc ng th nh hng ca chng s tr nn c ngha. Cc yu t nh hng n tc dng ca cht c bao gm: - Cc yu t thuc v cht c: thng c nh hng n qu trnh tng tc ca cht c vi th th hoc mng t bo. - Cc yu t trong ng vt ch: thng lm thay i mc gy c, gii c hoc s thch ng ca c th vi cht c. - Cc yu t trong mi trng c nh hng n cht c hoc ng vt ch. 4.1. Cc yu t thuc v cht c a. Bn cht vt l v ho hc ca cht c Bn cht vt l v cu to ho hc ca cht c c nh hng n tc dng gy c ca cht . V d: hp cht trioxit arsenic As2O3 dng kt tinh th tc dng chm v t c, dng mnh ca As2O3 l loi cht c nguy him. Nhiu cht c tan trong du c hn l tan trong nc (cc cht ho hc c phosphor v thuc tr su). Phospho vng l rt c cn phospho li c t l nht nh no trong c th. Phospho ho tr 3 c hn phospho ho tr 5. Bari cacbonat rt c song bari sunfat li khng c. c tnh ca cc hp cht hu c l do cc cu trc c hiu. Thay i cc nhm chc lm thay i tnh c. V d: thay nhm metyl C9 ca dimidium bromid bng 1 nhm ethyl thnh ethyldium bromid s gy c gan. * tinh khit ca mt cht c th lm thay i c tnh ca cht . V d: ch phm thng mi dioxin (2, 3, 7, 8 Detra clorodibenzon p. dioxin) - TCDD, do hnh thnh cc phn chnh 2, 4, 5 - T to ra cht c mu da cam rt nguy him cho ngi v gia sc. * S bin i cc phn t hot ng c bn lm thay i cc tnh cht ha hc v p ng ca th th. V d nh s trao i cc anion to thnh cc mui khc nhau (sulfat ng thnh oxt ng) v to chelat vi cc kim loi nhm tng cng hp ph cc cht c kim loi nng.

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26* S khng n nh ca cht c do iu kin s dng c th nh hng n c tnh. Thuc tr su phospho hu c coumaphos c th phn hy trong thng ng c su thnh protosan, c c tnh cao hn i vi loi nhai li. * ha tan, tnh phn cc v s ion ha Cht c l cht lng hoc ha tan trong dung mi tc dng nhanh v mnh hn nhng cht th rn. Nhng cht khng ha tan trong nc, cn, du, m th khng hp thu vo c th. V d: Sullimat (HgCl2) ha tan nn gy c. Calomen (HgCl) khng ha tan trong nc nn tc dng km hoc khng c tc dng. - Cc cht c tan mnh trong lipid d hp thu qua lp lipoprotein mng t bo hn l cc cht khng c c tnh ny. - Cc cht khng phn cc c trng lng phn t thp d hp thu qua mng t bo hn cc phn t phc hp c trng lng phn t cao. - Cc cht cha cc nhm ion ha iu kin pH sinh l tan nhiu trong nc hn v kh hp thu qua mng t bo. Gm cc amin, carboxyl, phosphat v sulfat. - S lin kt ca cht c vi protein (v d albumin) lm gim c tnh ca cht c thng qua vic hn ch s hp thu qua mng t bo. Lin kt cht c- protein cn lm chm qu trnh o thi do kh nng lc qua tiu cu thn ca cht c b gim. b. nh hng ca t dc Dung mi ha tan cht c l mi trng pha long v vn chuyn mt cht ha hc hay thuc, gm nc, propylene glycol, dung mi hu c, cc loi gm hoc keo tng hp hoc t nhin. Cht c ha tan trong nc tc dng mnh hn trong du m, trong cn mnh hn c trong cc loi dung mi ni trn. - T dc lng khng phn cc v tan trong m c th vn chuyn cc cht c ha hc qua hu ht cc mng t bo sinh hc. - Cc thnh phn hot cht trong dng huyn ph (th vn) hoc nh tng c c tnh hn l nu chng ha tan trong t dc lng. - T dc (i khi l cc thnh phn kh tr) c th gy c, v d sc vt b ng c bi cht vn ti hydrocarbon trong thuc tr su. Vic s dng nhng cht vn ti cha c kim nghim (chng hn nh kerosence) s gy ng c. - S hnh thnh cc bt ht m, huyn ph v nh tng nh hng n tc ng (duy tr) cc cht c trn lng v da sc vt v tc hp thu cc cht ny qua ng tiu ha. V d: thuc bo v thc vt gy ng c do c th ng li trn lng v da ng vt gy tch ly mt lng thuc vt qu gii hn cho php. - Thuc bt hay nh tng khng c trn u trong qu trnh bo ch lm thay i nng hot cht trong hn hp thuc. Mt phn trong hn hp thuc c nng hot cht cao, phn cn li nng hot cht li thp. c. Tng tc ha hc trc tip Cc ha cht khi dng phi hp trc tip c th to dng kt ta khng tan, lm gim hoc c tnh hoc tc dng. Nhng tng tc lm thay i thnh phn ha hc c th lm thay i c tnh sn c ca cht c , v d: - S thay i cc anion trong mui ng (v d nh sulfat ng thnh oxyd ng) c th thay i c tnh ca ng

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27- S thy phn cc nhm este ca cc hp cht hu c, v d nh thuc tr su organophosphat c th lm gim c tnh. d. Liu lng cht c Tc dng ca cht c ln c th ph thuc vo liu lng ca chng. Liu lng ny c th l: (1) Liu iu tr: lng cht c dng iu tr bnh; (2) Liu gy c: gy nhng trng thi bnh l; (3) Liu cht: gy cht ng vt. c tnh ca cht c xc nh bi LD50 - liu gy cht 50% ng vt th nghim. LC50 (Lethal Concentration 50): Liu gy cht ngt (tnh cho cc loi kh c- mg/m3) 50% ng vt trong vng 4 gi. ALD (Apperoximathy Lethal Doses): Liu gy c - th hin cc du hiu nhim c (nhng ng vt khng cht). TED (Toletance Effectiviv Dose): Liu tc ng ti a c th c th chu ng c. * S nhc li liu c: S nhc li liu c dn ti gy c r hn l s dng liu c ch mt ln. Khi nhim c li lm cho chc nng c th kh c th hi phc do t chc b tn hi. Tuy nhin cng c trng hp khi lp liu gy c nhiu ln dn n s iu chnh chng li cht c (liu cp tnh) v min dch thc s. Vi cc loi c cht bi tit nhanh, th 1 liu c mnh c tc dng gy c mnh hn s lp li liu cp tnh. V d th vi mt liu gy c cp tnh ko di ca cyanid c th khng gy c v c bin i thnh thiocyanat. 4.2. Cc yu t thuc v c th a. Loi ng vt Cht c c th c vi ny m khng c vi loi vt khc. iu ny rt c ngha trong vic sn xut thuc tr su, dit cn trng v cc cht iu tr ho hc. V d morphin t c i vi gia sc hn vi con ngi. Gia cm khng vi nhiu cht c hn l gia sc. V d thuc tr su DDT c th gy c qua tip xc vi da, c bit lp kitin ca cn trng. i vi gia sc t c hn v t hp thu qua da. Hp thu cht c qua ng nim mc tiu ho ch rt nhanh, ch cn 1 lng nh gy triu chng ng c. Trong gan th cha 1 ester c th ph hu rt nhanh atropin nn th khng b ng c c c dc. Mt loi hnh ty bin mu c tc dng dit cn trng, su b nhng li khng c vi chut ng. S mn cm vi mt s cht c cc loi gia sc cn cha c gii thch r. V d: Morphin gy yn tnh thn kinh ngi v ch nhng li gy kch thch i vi mo v cc loi gia sc khc. B ging Priesishen Kall c n 23 - 42 mg Gossypol/kg trng lng (cht c chit t ht bng) b cht. Ging b Jersey Kalle n ti 82 mg/kg P li khng b ng c. Sc vt nhai li mn cm vi cc hp cht kim loi nng hn cc loi vt khc (nga, ch, mo, ln). Liu cht ca carbonat ch nga l 500-700gam nhng tru, b ch 50gam. i vi sc vt nhai li: c t thc vt li t gy c hn so vi cc loi khc. V d: tru, b cho n l ngn phi kh t 25 - 30 gam trong 4 ngy lin tc cng khng b ng c. Trong khi nga ch n 30 gam trong 1 ln l b cht ngay. C th gii thch l hot cht gy c v cc glucozid khc trong l ngn v mt s cht c c ngun gc thc vt khc b phn hy do qu trnh ln men ca vi sinh vt trong d c. Cht c b pha long d c ca ng vt c sng. Sc vt c h thn kinh cng pht trin th cng mn cm hn vi mt s cht c.

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28V d: Liu cht ca morphin th l 300 - 400mg, nhng ngi l 6 mg. Nh vy, th c th chu ng c liu c cao hn gp xp x 70 ln so vi ngi. 5mg atropin gy c nng ngi nhng ch v th n vi lng ln hn 100 ln (500 mg) vn khng cht. - Gia sc c sng rt mn cm vi tetracyclin, chloroform v kim loi nng c bit l thy ngn. - Nga mn cm vi c t nm c bit l stachybotrys alternans v dendrodochium toxicum v stibium kalium tartaricum. - Gia cm mn cm hn vi mui n, cyanhydric. - Mo mn cm vi a. carbonic. Korneven (1912) sp xp th t mn cm ca gia sc i vi a s cht c nh sau: 1: La; 6: Ln; 2: La; 7: Gia cm; 3: Nga; 8: Tru, b; 4: Mo; 9: D, cu; 5: Ch; 10: Th. - Gia cm thng t mn cm hn vi c t nm; ch vi du crotono; mo vi apomorphin; d vi thuc l, ht thu du; g vi strychnin; th vi atropin (Radkevich, 1952). * c im gii phu cc loi ng vt khc nhau nh hng n tc dng ca cht c - ng vt nhai li lu gi mt lng ln thc n trong d c, lm ko di thi gian hp thu cht c. c tnh ca cht c gim do cht c qua chuyn ha bi hot ng ca vi sinh vt trong d c. Tuy nhin, qu trnh chuyn ha sinh hc trong d c cng c th hot ha dn n lm tng c tnh ca mt s tc nhn gy c (v d, nitrat chuyn ha thnh nitrit). - Nga, chut, th khng c kh nng nn sinh l do cu to gii phu, v vy cht c lu gi trong ng tiu ha, gy c mnh hn so vi nhng ng vt c th nn c. - Nhng con vt thiu sc t da s d b tc ng ca cc cht c gy nhim c quang hc (phototoxicosis). - Hng ro mu - no ngn cn cht c xm nhp vo trong no. mt s ng vt, hng ro mu - no km pht trin, to iu kin cho cht xm nhp vo no, dn n ng c (v d, ng c ivermertin ch Colli). * c im chuyn ha lin quan n loi v gen nh hng n tc dng ca cht c - nh hng ca chuyn ha giai on 1: S chuyn ha cc cht c thnh cht c c tnh cao hn gia cc loi l rt khc nhau. ch, qu trnh chuyn ha cht dit loi gm nhm fluoroacetate thnh fluorocitrate xy ra nhanh hn v c tnh ca n ln hn gp 6- 8 ln i vi chut. chut v cu ch hnh thnh mt lng rt nh c t aflatoxin c hot tnh sinh hc, v vy chng c sc khng vi c t ny tt hn so vi cc loi khc. - nh hng ca chuyn ha giai on 2: gia cc loi c s khc nhau ca cc qu trnh chuyn ha giai on 2, dn n chm chuyn ha v chm thi tr cht c. - mo v chut Gunn s hnh thnh glucuronic gim v do vy nhiu kh nng b nhim c cc cht nh phenol nhiu ng vt ny l cao.

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29- Qu trnh lin hp vi acid sulfuric ca cc cht c ln xy ra yu hn so vi cc loi vt khc. - Acid mercapturic t c hnh thnh chut lang. - Khng thy c qu trnh acetyl ha cc hp cht amin thm ch. b. C th C th trong cng loi c th phn ng khc nhau vi cht c. Tc dng gy c c xc nh theo p ng ca c th i vi cht c. - D ng: l kt qu ca min dch trung gian v qu trnh cm ng trc i vi mt cht ha hc. Nhng phn ng ny c coi l phn ng qu mn. Nhiu cht ha hc c th gy d ng. Phn ng d ng thng c trng cho loi v khng lin quan n liu lng. nhng ng vt nhy cm, liu lng thp c th gy d ng nghim trng vi mt cht c. Thng quan st thy phn ng d ng cc c quan h tiu ha , h tim mch, phi, mt, v da. - Phn ng c ng: nguyn nhn c th do mt qu trnh chuyn ha hoc gii c bt thng trong c th v thng c tnh di truyn. Phn ng xy ra tng t nh c th bnh thng nhng vi liu lng rt thp. Trng hp t gp hn l p ng ca nhng ng vt c nhng phn ng bt thng i vi mt ha cht c nht nh. c. Tnh bit Phn ng vi cc cht c cng khc nhau theo gii tnh (ci v c) v d nh thuc tr su Parathion hay Potasan c vi chut ci hn l c. C th chng c mi lin quan vi hoocmon sinh dc c. sc vt non cha trng thnh, rt t c s khc bit trong phn ng i vi xenobiotics gia con c v con ci. Gia sc ci thng c sc khng vi cht c km hn con c, c bit l con c cha, liu rt nh ca cu la mch (Clavicep purpurea) gy sy thai. S mn cm khc nhau vi cht c con c, con ci c lin quan n trng thi ca c quan sinh sn. Tuy nhin, cc con ci b ct bung trng v con c b thin khng quan st thy s khc nhau ny. * S khc nhau v hormon. Hm lng testosteron cao v khng thay i con c gip qu trnh chuyn ha cht c mnh hn so vi con ci. Cc c t c tc dng ging hormon (v d, mycotoxin zearalenone) c nh hng ln n tnh bit ca sc vt. Thi k con vt c cha v cho con b to ra s thay i r rt v hormon v chuyn ha: kch thc cc c quan nh gan, tuyn thng thn, bung trng, t cung v hm lng protein tng r rt. Mt s trong lng protein tng cng (protein microsomal) thc y qu trnh chuyn ha ca cht c. S pht trin ca nhau thai lm tng chuyn ha mt s xenobiotics. B ang cho sa nu nhim c mt s c t thn m (DDT, polychlorirelted biphenyls (PCBs) thng b nh hn sc vt khc v mt phn cht c c thi qua sa. Qu trnh tit sa cn lm tng kch thc v trng lng ca rut non, cho php pha long cc c t c hp ph qua ng ming.

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d. Tui Cng tc ng ca cht c ph thuc nhiu vo la tui. Sc vt non, sc vt gi u mn cm vi cht c hn l sc vt trng thnh do c th sc vt non cha hon thin, chc nng gii c km, cn sc vt gi th cc c quan gii c li b suy yu, sc khng gim. Ch cn b m mn cm vi santonin gp 100 ln so vi ch trng thnh. Tuy nhin ch con lai chu c liu atropin cao hn ch ln. S a dng trong phn ng c th ca sc vt non i vi cc cht c c gii thch bng s pht trin cha y (cha hon thin) ca cc c quan, t chc v hnh thi cng nh v chc nng (ch yu l h thn kinh) v s thay i nhanh chng v trng lng c th. Theo Radkevich, liu cht ca cht c nu nga 4-15 tui l 1 th nga 1tui l 1/2, 6 thng tui l 1/4, 3 thng tui l 1/8 v 1 thng tui l 1/16 - 1/24. Sc vt s sinh mn cm c bit vi chloroform, morphin nht l b, ngh, nga con. * Tui sc vt nh hng n kh nng hp ph cht c qua mng t bo: Nim mc ng tiu ha v hng ro mu - no con vt non km pht trin hn, vn chuyn ch ng hiu qu km hn con trng thnh. sc vt non, lng enzym chuyn ha cht c t hn v cht lng km hn sc vt trng thnh. Nhng thay i trong cu to c th nh hng n s phn b v tng tr cht c. C th sc vt s sinh cha nhiu nc hn v t m hn, trong khi nhng ng vt gi mt i cc protein cu trc nhng li tng tch ly m v collagen. e. Khi lng c th i gia sc c th chu c c cao hn so vi tiu gia sc v i gia sc cht c c pha long hn trong mu dn n tc dng ca cht c yu i. Nu liu gy c hoc liu cht ca nga v tru, b l 1 th ln s l 1/5 - 1/20, ch, d, cu l 1/10 - 1/20, mo v chim l 1/20 - 1/50 (Frohner - Volker). Gia sc bo b ng c cc cht c tch ly trong m liu cao hn gia sc gy. f. nh hng ca qu trnh phn b v o thi n tc dng ca cht c. * S phn b v tng tr cht c lm tng hoc gim nng ca chng cc th th Cc cht tan nhiu trong m c th tch ly trong mt s c quan nht nh (v d thuc tr su DDT tch ly trong m thn kinh). S lin kt xenobiotics vi cc cht ni sinh, nh protein huyt tng lm tng tch ly xenobiotics trong c th nhng c th hn ch bt c tnh. Bnh gan vi triu chng mt ngn cn qu trnh bi tit, dn n tch ly mt s cht c trong mu. Khi cc sc t thc vt bi tit trong mt c lu gi la trong mu v vn chuyn ln da s xut hin s cm quang do nh sng mt tri lm cho cc sc t ny bin thnh photodinamic. * Cc cht l c th cnh tranh nhau v tr lin kt vi protein huyt tng S lin kt vi protein huyt tng hn ch hp thu cht c qua mng t bo, ngn cn gn chng vi th th. Cht t c hoc khng c c th chim ch cht c trong lin kt vi protein huyt tng, kt qu l: (1) Cht c b chim ch chuyn thnh dng t do v c tnh ca n tng

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31thm. V d phenylbutazole chim ch warfarin trong lin kt vi protein huyt tng, do tng c tnh ca warfarin; (2) Cht c thay th trong lin kt vi protein huyt tng c th c bi tit nhiu hn, dn n gim c tnh. * S khc nhau trong vn chuyn ch ng cc acid hay cc base qua thn S vn chuyn ny c th nh hng n s o thi cht c (v d s bi tit cht dit c 2, 4 - dichlorophenoxyacetic ch km do h vn chuyn cht hu c km pht trin). g. Yu t bnh l Bnh gan c th l nguyn nhn lm gim cc qu trnh tng hp cc cao phn t lin kt c chc nng bo v, dn n tng tc dng ca cht c. Glutathione, ligandin v metallothionein l nhng v d v cao phn t lin kt do gan tng hp. Kh nng b ng c cao khi c bnh gan, thn ni m cht c b tiu c v o thi. Bnh thn lm thay i qu trnh ti hp thu ca thn, nh hng n o thi cht c. Kch thch nhu ng rut non s lm gim thi gian vn chuyn v hp thu cht c theo ng ung. Trong trng hp vim hoc lot d dy lm tng hp thu cht c. - Sc vt sau khi lm vic nng nhc, mt mi d b ng c hn. Theo Ivanov Cmoleski khi b cng thng thn kinh hoc thn kinh trung ng b c ch hoc kch thch u d b nhim c hn trng thi bnh thng. h. Hin tng c th nhn vi cht c L hin tng mt s c th dn dn t thch nghi v c sc chng chu vi liu lng c th gy c hoc gy cht cc c th khc. Sc vt hay nhn vi cc cht c nh: asen, atropin, morphin, ricin. V d: Ch b quen vi morphin ch sau 3 ln s dng. Hin tng quen, nhn c th gp hu ht cc cht c. Sc khng ca c th vi mt cht c b suy gim khi mc bnh truyn nhim, k sinh trng, ng c cc cht khc... Trong cng mt c th quen vi cht c nh morphin hoc cocain nhiu trng hp h thn kinh c th chu c vi liu gy c cao hn nhng cc c quan khc nh rut, gan, thn... li mn cm hn vi nhng cht ny. 4.3. Cc yu t mi trng a. ng xm nhim cht c Cht c c th xm nhim vo c th qua ming, da v ng h hp. Trong iu tr c th qua ng tim (bp, di da, tnh mch). ng xm nhim nh hng n qu trnh chuyn ha cht c. Cht c qua ming v xoang bng trc tin l n gan, trong khi cht c xm nhp qua ng h hp li tip cn trc tin vi phi. - Cht c xm nhim qua ng tiu ha: Ph thuc vo cc yu t nh rng ca d dy, kh nng nn sinh l. Nhng sc vt nh ln, ch, mo.. khi n phi cht c c tnh cht kch thch nim mc ng tiu ha (sulphat ng) th cht c d b loi thi do nn. V vy t thy nhng sc vt ny b ng c nhng cht . - Cht c nhim qua da: sc vt thng b trng c c t nc rn, cn trng t, cc thuc tr ngoi k sinh trng khi bi, phun ln da... - Cht c bay hi nhim qua ng h hp. * V tr, loi m hp thu cht c c th nh hng n c tnh ca cht c

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32- Kh nng hp thu qua cc vng da khc nhau ca c th l khc nhau. V d, vng da mng nhiu mch mu nh vng bn d hp thu cht c hn nhng vng da dy hoc vng da b sng ha. - Tim vo vng c nhiu mo mch s thc y qu trnh hp thu cht c. - S tch ly trong m lin kt v kho d tr m lm chm qu trnh hp thu cht c. * S Phn nh liu lng hng ngy lm gim c tnh i vi cc cht gy ng c cp tnh, c chuyn ha v bi tit nhanh. Nu tc nhn gy c l mt cht c tch ly, c tc dng mn tnh, c tnh t b nh hng bi s phn nh liu lng hn. b. Khi lng v nng ca cht c * Khi lng v nng ca cht c nh hng n mc v t l phi nhim cht c. Mt cht c th gy c vi liu lng thp nu c pha long trong thc n cho sc vt n c ngy theo ch t do. * Quy tc v khi lng v nng cho php nh gi c lc ca cht c qua phi nhim t nhin. V d, liu lng nitrat gy c a qua ng thng vo ng tiu ha l 200 mg/kg th trng i vi tru b, nhng li l 1000- 2000 mg/kg th trng nu c phn b t nhin trong c. c. Nhit mi trng - Nhit mi trng thp s y nhanh qu trnh chuyn ha cht c trong c th. Trong trng hp ny c th do hot ng chuyn ha ca c th tng gi m cho c th ng vt. - Nhit c th nh hng n lng v kiu tiu th thc n ca sc vt, do s phi nhim vi c t trong thc n cng thay i. - Nhit mi trng cao lm tng lng nc tiu th, tng phi nhim cht c qua nc. Sc vt kht nc c th ung nhanh v hp thu mt lng cht c qua nc. - Nhit mi trng cao lm tng s mn cm ca c th i vi cht c, thay i qu trnh chuyn ha hoc iu tit nhit. Cc cht oxy ha lm tng nhit c th v tc dng gy c ca chng tng khi tri nng. Nhim c thuc tr su qua da c th nng hn khi thi tit nng. Lc ny, mu chuyn nhiu n da lm mt da, nhng mu tp trung nhiu li to iu kin hp thu nhanh thuc tr su. d. p sut khng kh Nhng thay i p ng ca c th vi cc cht c thng lin quan n nhng thay i v p sut oxy trong mi trng. Kh oxy cao p c s dng x l nhim c carbon monoxide, barbiturat, cyanide. e. Ch n ung v dinh dng - Cc cht c c th b kh c tnh bi thnh phn thc n t nhin hoc cc tc nhn tr liu c a vo c th. V d: Acid phytic (inositol hexaphosphate) thc vt c th to chelat vi cc kim loi v khong cht, t lm gim s hp thu ca chng. - Canxi v km trong thc n thc t nh hng n qu trnh hp thu ch, cnh tranh ln nhau h vn chuyn cation ha tr 2. - Tanin v protein to phc vi cc cht c v gim s hp thu ca chng.

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33* S ngon ming c th lm tng lng cht c c a vo c th. V d, cht dit loi gm nhm c v thm bao parafin c dng lm tng s ngon ming, v vy tng lng tiu th vi loi gm nhm. * Thiu hoc qu tha dinh dng nh hng n tc dng ca cht c. - Sc vt b n s b thiu nng lng, glucose trong mu gim dn n gim hot tnh cc enzym chuyn ha cht c. - Thc n thiu protein lm suy yu tng hp enzym, hot tnh ca men MFO, nng glutathione trong gan gim. - Thiu vitamin, c bit l vitamin E v C chng oxy ha dn n lm tng qu trnh tn thng t bo do hnh thnh gc t do. f. Nguyn nhn gy ng c Nguyn nhn gia sc b ng c thng l do n phi hoc ung, th hoc qua da nhng cht c c trong t nhin hay do con ngi gy ra. + Ngun khong cht gy c: Ch yu l nc c cha flor, nitrat c th gy cht ngi v gia sc. Molypden, selen c ngun gc t t c th gy c cho b. + c t thc vt: C nhiu loi cht c t thc vt + Cht c cng nghip: Ch (Pb) v arsen (As) l sn phm nhim ca cng nghip. Kh flor, bi, khi c cha flor cng l sn phm ca cc nh my cng nghip - Nhim c ng, molypden, nh hng tia phng x qua cc nh my in nguyn t, nc thi t cc nh my c cha phenol. + Ha cht bo v thc vt: gy nn ng c cho nhiu loi gia sc. c bit ng c thuc tr su vi gia cm trong quan trng nht l phospho v phospho km. + Thuc th y: Dng qu liu. + Thc n v nc ung: C (c 3 l) c cha dicumarol, solanin mm khoai ty, sn phm ln men t thc n thiu, i, cc loi c, ht, nm c, v.v... nitrat, petrol, ether, kim loi nng trong nc l nguyn nhn gy ng c cho gia sc, gia cm.

Cu hi n tp 1. Khi nim c cht hc v cc lnh vc nghin cu ca c cht hc? 2. i tng, nhim v ca c cht hc th y? 3. Khi nim cht c v phn loi cht c? 4. Khi nim ng c v phn loi ng c? 5. Trnh by s xm nhp ca cht c qua mng t bo?

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346. Nu cc cch xm nhp ca cht c vo c th? 7. Gii thch s phn b v chuyn ho cht c trong c th? 8. Nu cc ng thi tr cht c? 9. Nu khi nim cht a in t (Electrophile) v tc hi ca n? 10. Nu khi nim gc t do (Free radical) v tc hi ca n? 11. Nu khi nim cht i nhn (Nucleophile) v tc hi ca n? 12. Nu khi nim cht phn ng oxy ha kh (Redox) v tc hi ca n? 13. Trnh by c ch gy c c trng trn c quan, t chc ca cht c? 14. Gii thch nh hng ca cht c n cc c quan, t chc? 15. Trnh by cc yu t c th nh hng n tc dng ca cht c? 16. Trnh by cc yu t thuc v cht c nh hng n tc dng ca cht c? 17. Trnh by cc yu t mi trng nh hng n tc dng ca cht c?

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35 Chng II Chn on v iu tr ng cNi dung chng 2 bao gm cc kin thc v cc bc chn on ng c. Cc bin php phng v iu tr ng c cng c gii thch c th trong chng ny. 1. Chn on ng c 1.1. Khi nim Chn on ng c l vic nh gi, pht hin cc du hiu, triu chng ca s ri lon chc nng ca cc c quan, t chc ca c th tm ra nguyn nhn gy ng c, nhm iu chnh nhng tc dng ca cht c, x l v iu tr ng c, nhim c. Chn on ng c bao gm cc loi sau: a. Chn on lm sng (clinical diagnosis): c thc hin trc tin xc nh cc h c quan no b nh hng bi cht c (v d: sc, ng kinh nghim trng, ngng h hp), theo di v khng ch cc triu chng cu sng bnh sc. b. Chn on tn thng bnh l (lesion diagnosis) c thc hin m t nhng bin i bnh l m, t chc (v d: hoi t trung tm tiu thy gan). c. Chn on bnh cn (etiologic diagnosis): y l chn on quan trng nht, nhm xc nh nguyn nhn gy c hoc ngun gy c, l c s tin hnh cc bin php tr liu v phng chng c th. Trong qu trnh chn on nguyn nhn gy ng c cho sc vt cn lu : - Khi cha chn on c nguyn nhn gy c khng nn s dng cc loi thuc i khng gii c. - Bo v sc kho cng ng, trnh nhng cht c tn ng trong chui thc n thng qua vic khng nh c cht c th gy c. - Xc nh trch nhim v trnh c thit hi do ng c, nhim c gy ra. 1.2. Chn on ng c Ng c l loi bnh xy ra hng lot vi mt lng ln sc vt. V vy vic chn on sm v chnh xc l bc rt quan trng phng v iu tr ng c c hiu qu. Chn on ng c bao gm cc bc sau: a. Thu thp thng tin v nguyn nhn v iu kin gy ng c. Vai tr ca cn b th y l tm c nhiu thng tin c th s dng trong thc t chn on. Qua hi trc tip nhng ngi chn nui, ch gia sc. Thu cc thng tin v loi, s lng sc vt b ng c, loi thc n cho gia sc n trc vi tun v thi im xy ra ng c. Ng c thng xy ra do khu cho n, chm sc v s dng sc vt. Mt trong nhng nguyn nhn gy ng c thng xuyn nht i vi gia sc chn th l cy c c. i vi sc vt nui nht, ngoi cc thc vt c ra, sc vt cn b ng c bi thc n b hng, i thiu, thc n nhim nm mc, vi khun v c t ca chng. Gia sc, gia cm cn b ng c bi cc ha cht BVTV, nh cc hp cht clor hu c, phosphor hu c, mt s hp cht v c nh carbamid, mui n, sulfat ng, calci v natri asenat, natri fluorid, phosphot km... cc cht ha hc l phn hu c cng c th gy ng c. Ngoi ra sc vt cn b ng c bi nc c khi b ng vt c cn (rn, nhn, ong...).

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36Cn xc nh xem c xy ra s phi nhim vi loi cht c (c t) c bit n hoc b nghi ng khng? Hi ch gia sc nhng thay i v a im, ngun thc n, vic s dng cht ho hc (v d: phun thuc dit cn trng, bn phn cho ng c, s dng thuc th y iu tr cho sc vt) v nhng ng dng khc c th gy ng c, nhim c (bng 2.1). Nu cn thit phi kim tra ni nui nht sc vt. S c mt ca mt loi cht c trong mi trng hay thm ch sc vt n phi cht c cha khng nh c nguyn nhn gy ng c. y mi ch l nhng gi cho phng hng iu tra tip theo, l: - Khng nh c s phi nhim vi cht c l gy ng c. - Ghi li cc triu chng lm sng, nhng bin i v trao i cht, bin i cc m in hnh trong qu trnh sc vt phi nhim vi vi cht c b nghi ng. - Xc nh mc gy c ca cht c i vi c quan hay m ch. Bng 2.1. Nhng thng tin cn thu thp chn on ng c, nhim c vt nui 1. D liu v ch gia sc Ngy: Tn ch gia sc: a ch: S in thoi: 2. D liu v bnh sc Loi: Ging: Tnh bit: Trng lng: Tui:

* Tiu s tnh trng sc kho ca bnh sc Tnh hnh bnh tt trong 6 thng trc khi sc vt b ng c. Tnh hnh phi nhim vi cht c ca cc sc vt khc trong vng 30 ngy trc khi xy ra ng c. Lch tim phng Cc bin php tr liu, phun, ty thuc... trong 6 thng v trc Ln khm bnh cui cng ca bc s th y. Quy m n (i vi sc vt nui theo n). Sc vt mua v hay c nui ti gia nh. Tnh trng m, cht ca n (i vi sc vt nui theo n). C th u tin b ng c (b m) c pht hin: cn tm hiu con vt ny sng kho mnh trong thi gian bao lu? Hin tng ng c xut hin trong n khi no? * D liu v mi trng Thu thp cc d liu v: - Ni ca sc vt (v d: ng c, rng, l t, feedlot, gn sng hoc ao; Chung nui, Khu nh kn c h thng thng gi; trn sn g git trn h phn, gn ng tu ho, gn khu cng nghip, gn bi rc).

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37- Nhng thay i gn nht v s phi nhim vi mi trng (v d: s di chuyn, phun cht dit cn trng, cht dit loi gm nhm, xy dng mi, ci to cc khu nh c, di chuyn phn). * D liu v khu phn n, nc ung ca sc vt - Ch n: Nhng thay i v khu phn n gn y (s ln c th c lin quan n cc triu chng quan st c). S thay i phng thc cho n (v d: t phng thc cho n hn ch sang phng thc cho n t do). S c mt ca cc thc n i tha v b hng. - Ngun nc ung, thay i trong vic cung cp nc ung. b. Kim tra cc triu chng lm sng. Bnh do ng c thng c phn bit vi cc bnh khc do s a dng v cc triu chng lm sng. Nguyn nhn y l do ngun gc, tnh cht l ha, ng hc ca cht c, s mn cm ca sc vt. chn on ng c cn quan st cc triu chng lm sng sau: Bng 2.2: Triu chng lm sng thng gp gia sc b ng c Mt iu ho Tit nc bt M/th gic Trm cm Vui v ng kinh Khn ting Cc loi khc (m t r) Nn ma a chy Phn c mu en n nhiu Kht nhiu a niu Kh th Vng da Chy mu Hemoglobin-niu Huyt niu Kit sc St Yu

Ng c cp thng xy ra vi cc triu chng lin quan n cc h c quan: tiu ha, thn kinh, h hp, tun hon, tit niu... Nhng du hiu thng xuyn nht ca ng c ng tiu ha l: Tit nc bt, nn, chng hi, a chy, c th to bn vi s bin i ca phn (cha cht nhy, mu...), au bng v i khi ni m ay. Cc du hiu ca ng c thn kinh thng l: tng qu trnh hng phn thn kinh biu hin: bn chn khng yn, trng thi thao cung (c xu hng di chuyn v pha trc, chn trc co v p mnh), co git, th mnh, co git kiu ng kinh v kiu git rung thng quan st thy ng c ch, atropin, veratrin, anconitin v picrotoxin. Sau trng thi co git (hoc ngay lp tc) c biu hin c ch, th hin t lit v lit. Cc du hiu v h hp thng l th gp, th kh, ngt th, ho, chy nc mi, tm ti, bn chn... Cc triu chng v tim mch: mch nhanh, yu. Cc triu chng v tit niu: c hin tng i nhiu, i dt, xut hin albumin niu, huyt niu, t bo biu m thn trong nc tiu hoc b i trong mt s trng hp.

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38Khi b ri lon trao i kh, sc vt rt kh th, mch nhanh, kt mc mt , co git, thn nnhit h, hn m, cht (ng c cc sn phm thc vt cha cyano, ng c nitrat, nitrat...). Ri lon ng mu khi b rn c cn (do c t cardiotoxin trong nc rn). Vim dp da do cht nhy cm quang hc cha trong mt s loi c lm thc n chn nui (Fagopyrum vulgare, Fagopyrum esculentum). Nhng triu chng lm sng thng l nhng thng tin c gi tr c s dng chn on ng c. Tuy nhin, nu ch da vo cc triu chng lm sng cng cha kt lun v cht gy ng c v hng ngn cc cht ho hc khc nhau c th gy ra nhng triu chng tng t mt s c quan nht nh ca c th (ni cch khc l c quan v m c th c phn ng tng t vi nhiu cht ho hc khc nhau). Nhiu bnh do nhim khun, ri lon ni tit, ri lon trao i cht gy ra cc triu chng ging ng c (v d nh nn, ng kinh). S tin trin ca cc triu chng lm sng cng c gi tr chn on trong ng c. Bc s th y khi khm bnh c th ch thy c mt trong cc giai on tin trin ca cn bnh. V vy cn hi ch gia sc v nhng triu chng khc nu c. Thi gian xut hin v thi gian duy tr cc triu chng lm sng c th gip nhn dng mt vi cht c v loi b nhng cht c khc. T l sc vt b ng c v t l cht cng c th gip xc nh loi cht c, s tn ti v hm lng ca cht c. Ngoi ra cn c cc yu t khc c th nh hng n kh nng mn cm ca sc vt vi cht b nghi l gy c, l: (1) Loi gia sc; (2) Tnh bit; (3) S tng tc gia cht c vi cc cht dinh dng, cc loi thuc iu tr hay cht ho hc khc; (4) Stress hay tn thng bnh l c quan, t chc trc khi b ng c. * Tin trin bnh Ph thuc vo: - Ng c ti cp: t xy ra. Xy ra trong vng 1 - 2 gi hoc thi gian ngn hn (acid silinic, kali cyanit, nitrit) - Ng c cp: xy ra t ngt, tin trin nhanh sau khi n thc n c c hoc nhim c. Gia sc thng b cht. - Ng c bn cp: tin trin trong vi ngy, sau khi iu tr c th khi, c trng hp cht. - Ng c mn: tin trin chm, triu chng lm sng khng r, thng xy ra khi sc vt b nhim cht c thng xuyn, ko di. Triu chng thng l ng tiu ha hn l thn kinh. * Tin lng (prognose) Tin lng ca bnh do ng c c xc nh da trn mc nng nh ca bnh, bn cht v liu lng cht c cng nh kh nng trung ha, o thi cht c khi c th. - Trong cc triu chng v thn kinh, triu chng kch thch thn kinh c coi l c tin lng tt hn l trng thi trm ut. Xu nht l triu chng bi lit, thng dn n cht. Co git khng phi lc no cng c tin lng xu.

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39- Bn cht ca cht c c ngha trong vic nh gi tin lng. Loi vt n c khi b ng c c t thc vt thng c tin lng tt hn ng c cc cht c c ngun gc khong hoc tng hp, do kh xc nh c lng cc cht ny hp thu vo mu v chng thng c chm thi tr ra khi c th (v d, asen, ch, thy ngn...) - Cc triu chng nim mc d dy, rut xut huyt nht l sc vt non, suy gim hot ng tim mch, try tim mch. - Sc vt b ng c nhng nn c c tin lng tt hn l khng nn. c. Kim tra cc tn thng bnh l Vic xc nh chnh xc cc c quan, m v cc qa trnh trao i cht chu nh hng nhiu nht bi cht c l mt yu t quan trng trong chn on ng c. c tnh ca cc h c quan c th s dng a ra nhng chn on phn bit ph hp vi nhng du hiu lm sng. Cc cht c khc nhau c th gy nhng bin i c trng cc c quan, t chc. Nu bnh sc b cht, cn m khm k v thu thp cc mu thch hp. Vic m khm tng th xc bnh sc cn c thc hin bi chuyn gia c cht hc v chuyn gia bnh l. Nhng tn thng bnh l do ng c thng l: vim d dy rut, gan nhim m, hoi t gia tiu thy gan, sng v thn, hemoglobin niu, tim ph i, tch nc xoang ngc, ph k phi, mt sng ty. Nhiu cht c gy cc tn thng bnh l i th v vi th c trng. Cht cha d dy, rut cn c kim tra v mu sc, s c mt ca cy c, cc vt l, vin thuc, nang thuc... Cc mu t chc cn c bo qun trong dung dch m formalin 10% kim tra bnh tch vi th. Ribac v Gorii da vo tc ng ca cht c n cc c quan ca c th v nhng bin i bnh l cc c quan ny, chia cht c thnh 6 nhm: - Cht c ng rut: gm: hp cht phosphor, asen, thy ngn, bari, bismus... v mt s saponin, alcaloid (morphin, protoveratrin...) glycoalcaloid (solanin...). Cc cht c ny bin i ch yu rut gi, gan v cc c quan tiu ha khc. - Cht c thn: tn thng ch yu nhu m thn. Gm phosphor, asen, st, ng, ch, thy ngn v mt s thc vt gy c. - Cht c mu: Mu mu socola: methemoglobin- nitrat, nitrit. Gy hy huyt (hemolyse): saponin. Tng nht ca mu: toxanbumin. - Cht c gy dn mch, h huyt p: lm tn thng thnh mch: cc mui bari, asen... - Cht c xng: gy osteonopoza (thy ngn), tng pht trin m xng (ng c cp cc hp cht phosphor, fluor). - Cht c da: gy tn thng da nh phosphor, clor, iod, cc cht photosensibiliti. Cn lu l s phn chia trn y ch mang tnh cht tng i. Cht c trong cc nhm trn khng phi lc no cng gy ra nhng bin i nh miu t. i khi cc cht c gy ra nhng bin i bnh l rt a dng v vi mc khc nhau cc sc vt b ng c. Bin i bnh l thng r nt trong cc trng hp ng c mn tnh. - Ng c alcaloid thng i lin vi cc bin i bnh l nh: kh th, cc c quan mu, xut huyt. Khi m khm xc nh ng vt b ng c, c th thy mi c trng.

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40d. Cc xt nghim c bn cn thit Cc xt nghim c bn gip pht hin mc hu hoi c trng i vi cc c quan, t chc, gp phn xc nh cht gy c v nh hng trong iu tr. Cc xt nghim ny bao gm: * Cc xt nghim mu: (1) Cc ch tiu sinh l mu: S lng hng cu, bch cu, cng thc bch cu. Tc mu ng (prothrombin time- PT, thrombopastin time - PTT); (2) Cc ch tiu sinh ha mu: hot mt s enzym nh SGOT, SGPT, choliesterase... in gii mu (canxi, magi, kali, natri). pH mu, kim d tr trong mu, thm thu huyt tng (osmolality)... * Cc xt nghim nc tiu: huyt niu, bilirubin, hemoglobin, tr niu v oxalat. Ngoi ra trong nhng iu kin cho php cn trin khai: * in tm : trong ng c nhng cht gy ri lon nhp tim nh digitalis, quinidin, ng c c u Tu, trng cc, l ngn... * Chp X quang phi: ng c cc cht gy ph phi, xp phi. * Cc xt nghim c cht Phn tch cht c bao gm cc xt nghim v: - Thc vt: xc nh loi thc vt gy c. - Nm: Xc nh s c mt ca nm mc gy c v c t ca chng. - Vi khun: Xc nh s c mt ca vi khun gy c v c t ca chng. - Phn tch ha nghim: Xc nh cht c trong thc n, nc ung, trong cht cha d dy, d c, diu (gia cm), dch rut, mt s c quan ni tng nh gan, thn... - Sinh hc: cho sc vt n nhng thc n nghi c nhim cht c, xc nh gy c ca thc n bng mt s phng php trong c cht hc. S c mt, hm lng ca cht c, c t hay dng chuyn ho ca n trong cc t chc thng l du hiu quan trng nht xc nh ng c. chn on ng c, cc phn tch ho nghim khng nn s dng c lp v mt s l do sau: - Hm lng ho cht c pht hin thy trong m thng tng thch vi tnh trng ng c; tuy nhin, mt s ho cht gy ng c nhng li c mt trong t chc hm lng rt thp (di gii hn kim tra). - Mt s cht ho hc (v d nh cc hp cht phospho hu c) c th gy ng c m khng pht hin thy trong m bng cc phng php phn tch thng thng. - Mt s ho cht c c th tch lu vi hm lng cao mt s m nht nh m khng gy ng c (v d: hp cht clo hu c tch ly trong m m...). - S kt hp ca cht c vi cc tc nhn hoc cht dinh dng khc c th lm gim hot tnh cht c lu gi trong m (v d nh thu ngn c th kt hp vi selen v protein to thnh mt phc hp lu tr trong m m khng gy c). * Cc phng php xt nghim c cht hin nay bao gm:

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41- Sc k lp mng: ch yu nh tnh cht c. c th pht hin hu ht cc cht gy c thng thng nh thuc tr su (PPHC, clo hu c), thuc dit chut, thuc ng, cc cht c trong cy (alcaloid, glycosid) - Cc my quang ph khi, sc k kh, sc k lng hiu nng cao c th nh lng nng cht c, tuy nhin ch mt s phng th nghim hin i mi c trang b nhng my ny. 1.3. Ly mu cho cc xt nghim chn on ng c a. Cc nguyn tc ly mu kim tra ng c * Cc mu bnh phm: Khi ly mu bnh phm xt nghim, cn lu : - Mu l mi trng chnh vn chuyn cht c trong c th. - Ly mu cht nn hoc phn khi sc vt b ng c qua ng tiu ha. Mt s cht c c o thi qua phn. - Nc tiu l ng chnh bi tit nhiu cht c, c t. - Da v tc rt quan trng i vi cc trng hp phi nhim vi cht c qua da. Trong tc tch lu kim loi v mt s hp cht hu c gy c mn tnh. * Cc c quan quan trng cn phi ly mu xt nghim cht c: - Gan l c quan chnh tham gia chuyn ho v bi tit cht c. - Thn l ng bi tit quan trng i vi nhiu cht c. - D dy v rut non phn nh ng c do mi phi nhim vi cht c qua ng ming nhng khng quan trng i vi nhng cht tch ly hoc gy ng c mn tnh. * Cc mu t mi trng: Kt qu xt nghim cc mu mi trng gp phn tm ra ngun cht c hoc l nhng gi v ngun phi nhim. Cc mu s bao gm: - Nhng mu thc n, nc mi c s dng. - Cy c b nghi l gy ng c. - Mi, b c cha cht c. - Cc cht ho hc, thuc dit cn trng, dung mi v cc vt dng m sc vt c th tip xc. - Cc loi thuc c th gy ng c cho sc vt hoc gn y c s dng trong tr liu. - Thc n, nc, cy c m ng vt n rt cn thit cho vic pht hin cc ngun gy c. Mt iu quan trng phi lu l nhng loi thc n gy ng c c th khng cn tn ti n thi im kim tra. b. Cc mu bnh phm v mu t mi trng cn thit cho chn on ng c Bng 2.3: Cc mu bnh phm v mu t mi trng cn thit cho chn on ng c Mu bnh phm Lng mu ngha chn on 1. Trc khi bnh sc b cht

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42

pht hin s phi nhim vi hu ht kim loi, cc nguyn t vi lng, chotinesterase, thuc tr su v glycol ethylene, gip nh gi hnh thi hng cu v bch cu, Huyt 5 - 10 ml Xc nh cht in gii, nit ur, nit ammoniac v chc nng cc thanh c quan ca c th; cc kim loi, thuc th y v vitamin. Nc tiu 50 ml Pht hin ancaloit, kim loi, cht in phn, khng sinh, thuc, sulfonamides v oxalates. Phn 250 g Pht hin cc cht c qua ng ming, cc loi thuc, cht c c bi tit trc tin qua mt. Cht nn 250 g Pht hin tt c cc loi cht c hp th, c bit l nhng cht c khng th tm thy trong m (phospho hu c, ionophores). Tc 5 - 10 g Pht hin s phi nhim vi cc cht dit cn trng, s tch lu mn tnh mt s kim loi (v d asen, selen) 2. Sau khi bnh sc b cht Gan 100 g L ni xy ra cc phn ng chuyn ho chnh ca c th, ni tch lu cc kim loi, cc cht dit cn trng c hi, alkaloit, phenol v mt s mycotoxin: Ti mt c dng pht hin ra cc c t tp trung trong mt (v d nh ch). Mu cn c bo qun lnh. Thn 100 g C quan bi tit chnh i vi cc cht khng sinh v cc loi thuc khc, cc cht c qua chuyn ho, alkaloit, cht dit c, mt s kim loi, hp cht phenol, oxalate. Cht cha 500 g Xcnh cc cht c phi nhim qua ng ming trong thi gian d dy gn nht. Cht cha 500 g Xc nh cc cht c phi nhim qua ng ming. d c Mt s cht c c th b thoi bin d c (v d nh nitrate, c t nm). nh lng cht c kh do c s khc nhau v nng v thiu s tng quan gia hm lng cht c trong d c vi hm lng cht c trong m. Mu ly t vi v tr trong d c v c bo qun lnh. M 250 g Pht hin cc cht c tch lu trong m (v d cht dit c clo hu c, dioxin) Dch mt Ton b Pht hin cht in phn (v d natri, canxi, kali, magi) nit mt amoniac, nitrat, nit ur, hm lng kali v ur, s dng d on thi im con vt b cht. Tch ring thu dch v thu tinh dch. No Ton b Pht hin mt s c t thn kinh (v d thuc tr su clo hu c, no pyrethrin, natri, thu ngn). Tch ring no theo mt ct dc v tch nhn ui pht hin cholinesterase. Na bn cu no c bo qun lnh, 1/2 c nh trong dung dch m fomalin 10%. Mi 2 Kg Nn ly cc mu i din v sau trn ln thnh mt mu trng hn hp composite hoc gi li cc mu ring l (nhm pht hin thc n nguy c khc nhau trong thcn). C xanh, 5 kg Mu c t nhiu v tr trn ng c hay trong nh kho. thc n Silage nn c x l lnh trnh b mc v hng. chua Mu 5 - 10 ml

42

43Mi, b Nc Tt c 0,5 - 1lt Ton b s mi, b v nhn mc b nghi gy c cn gi li xt nghim. Pht hin nitrat, sulphat, kim loi, to v thuc bo v thc vt. Trc khi ly mu t ging hay b cha cn nc chy lm sch ng. Mu nc c ly t khu vc nghi phi nhim vi cht c v c gi sch n khi phn tch. Mu t c ly t su ca r nu thy c hin tng ng c do cy ci. Mu t ly t nhiu v tr v c s c vn ca cc nh khoa hc v nng hc v t.

t

1kg

c. Bo qun mu gi xt nghim Vic bo qun mu, gi xt nghim l rt cn thit c th tin hnh phn tch mt cch y . Cc mu bnh phm c gi xt nghim km theo danh sch mu, cc pht hin trong qu trnh chn on, kt qu m khm (bng 2.3). Mu bnh phm phi c gi sch, khng b h hng. Mi mu c ng trong ti nha hoc bnh thy tinh trong ring bit, v trng. Cc mu cn xt nghim thuc tr su, cc hp cht hu c hm lng thp c ng trong l thy tinh tt hn l ti nha. Vic bo qun cc mu bnh phm l rt quan trng. Hu ht cc mu cn c lm lnh tr khi nhng phn tch c th i hi cch x l khc. Lm lnh mu nhm trnh cho cc cht c khi b phn hy, trnh c s pht trin ca vi khun v nm mc, ngn khng cho cho cc tc nhn d bay hi bin mt (v d nh amoni hay cyanide). Tuy nhin nhit lnh c th c ch hot tnh mt s men trong cc test nhy cm, lm kt qu khng chnh xc. V vy, nu c nghi ng v bin php bo qun cn s t vn t phng th nghim c cht hc. Huyt thanh cn c tch khi phn mu ng