Tổng quan độc tố sinh học biển

590 Tuyen tap Hpi nghj KHOA HQC TOAN QUQc V^ SINH HQC BI^N VA PHAT TRI^N B £ N V O N G<br /> <br /> <br /> <br /> <br /> TONG QUAN DOC TO SINH HOC BIEN<br /> <br /> Pham Quoc Long', Nguyen Van Son' va Pham Minh Quan^<br /> 7- Viin Hod hpc cdc Hap chdt thien nhien, Viin Khoa hpc vd Cong ngh? Viit Nam<br /> 2- Truang Dai hpc Bach khoa Hd Npi, Bp Giao due vd Ddo tao<br /> <br /> I. Md DAU<br /> LTnh vyc dgc tl, dac bift la dgc td bien da thu hiit dugc sy quan tam dac bift cua cac nha<br /> khoa hgc biln fren khip thi gidi. Dgc to bien mgt mat la hiem hoa nguy hiem den sure khoe cua<br /> con ngudi va dgng thyc vat, mat khac cac chat dgc sinh hgc nay lai cd the dugc sir dung de giai<br /> ma cac ca chi sinh hgc, tin cong cac te bao ung thu hay dimg lam thudc giam dau. Nghien ciru<br /> dgc to hgc co the giai quyet cac van de cd lien quan den cau tnic, tinh chat boa hgc, boat tinh<br /> sinh hgc, nguon san xuat ciing nhu cac anh hudng kinh te cua chiing. Phan Idn nhirng vy ngp<br /> dgc sinh vat bien la do an ca hoac cac dgng vat bien khac bj nhiem dgc, mac dii vay cung co<br /> trudng hgp bj ngo dgc thong qua tiep xuc da va ngay ca thdng qua hd hap.<br /> Phin Idn cac chat dgc bien la san pham dugc tao ra tir vi tao (microalgae), dugc bift la<br /> tao giap (dinoflagellates). Co mgt sd it dugc tao ra tir khuan bien (marine bacteria), va rat it<br /> dugc tao ra tir tao Idn (macroalgae). Ngoai ra, mgt sd dgng vat bien cd the sinh tdng hgp ra<br /> cac dgc to peptit va protein va su dung nhu nhirng vu khi sinh hgc de ty ve cung nhu tan<br /> cong con mdi. Cac dgc td cd mat khap nai trong he sinh thai bif n, phan Idn chiing la nhirng<br /> hgp chat phan tir nho va khong chua lien ket peptit, ben vdi nhift va axit. Do dd, no gan nhu<br /> khong bj phan buy bdi qua trinh che bien thong thudng nhu xao nau hay ngay ca trong cac<br /> thyc pham dong lanh [1,2]. Mgt lugng rat nho dgc to bien cd the gay ngg dgc, vi du lieu<br /> lugng gay ngg dgc ciia Ciguatoxin ddi vdi ngudi la 70ng/kg [3]. Maitotoxin con dugc cho la<br /> CO dgc tinh manh ban Ciguatoxin vdi gia tri LD50 fren chugt thi nghifm la 50ng/kg. Nguon<br /> goc sinh ra dgc td la vo ciing da dang va no cd the tac dung len hang loat cac chirc nang sinh<br /> bgc khac nhau [4]. Cac dgc to nay chu yeu tan cdng vao cac kenh van chuyen ion hoac uc<br /> che cac thu the nhan biefnicotin, tuy nhien ciing co mgt vai trudng hgp la cac chat dgc tac<br /> dgng den qua trinh frao ddi oxy hay pha buy hong cau...<br /> Cho den nay da co nhieu dgc to bien dugc sir dung de nghien ciru cac ca che gay dgc<br /> doi vdi dgng vat, dat bift la nghien ciru sy boat dgng cua cac kenh van chuyen ion. Vi dy<br /> dien hinh la Tefrodotoxin dugc su dung rgng rai frong vifc nghien cuu kenh van chuyen<br /> Natri [9], hay vifc su dung axit okadaic trong viec nghien cuu cac enzym protein<br /> phosphatase [10]. Ngoai ra, cung da co vai chuc hgp chat dang dugc thu nghifm trong cac<br /> giai doan lam sang va tien lam sang phat frien thuoc, trong do da cd mgt vai chat dang luu<br /> hanh fren thj trudng nhu Trabectedin^"^ (Ecteinascidin 743) [II], Aplidine [12] va<br /> Ziconotide , conotoxin dau tien dugc luu hanh tren thj trudng lam thudc giam dau [14].<br /> Mgt nhom dgc to dugc nghien ciru dac bift trong suot 20 nam qua do la cac dgc to<br /> peptit (conotoxin) dugc tao ra bdi loai dc coi Conus sp. [13]. Co khoang tren 500 loai 6c coi<br /> khac nhau co kha nang tong hgp conopeptit, trong ngc dgc ciia mdi loai lai phat hifn tren<br /> dudi 100 conopeptit rieng bift, do dd co it nhit khoang 50,000 conopeptit dgc dugc sinh<br /> tong hgp bdi cac loai 6c cdi nay. Cac conotoxin khong nhirng da dang ve cau true hoa hgc<br /> va chiing con co pho tac dgng rgng len cac kenh van chuyen ion khac. Do kich thudc phan<br /> tir tuang doi nhd (^0 ^A, O H 0. ,>' ..<br /> O O ; OH I HO •('' "•••• Y OH<br /> ,OH<br /> k^OH<br /> " K " K I " X " H° A r OH<br /> " " ^^X.. HC^--<br /> OH<br /> \-<<br /> 6H<br /> '•.'' -^ --' X.<br /> ^-' OH<br /> HO»..^.^.I^„<br /> - -^ ,- -w ,0. : -—^ ,-*^ -,->-, ,--^ .^<br /> <br /> "H«-^.-''OH°" ""<br /> AH<br /> <br /> <br /> <br /> <br /> Palytoxin dugc cho la nguyen nhan gay nen cac vy ngg dgc ca Trich [85], ngg dgc cua<br /> xanthid [65] va ngg dgc ca filefish [33]. Cac dan xuat ciia Palytoxin da dugc phan lap tir rong<br /> Do Chondria armata [86], tir tao giap Osteropsis sp. [87], va tir rat nhieu dgng vat song trong<br /> ran san ho tii' cac cum xanthid.<br /> <br /> 7. Doc to tir Giun bien<br /> Cac dgc to trong cac nganh giun bien chu yeu dugc phan lap trong djch dgc ciia cac loai<br /> giun san mdi. Phan Idn cac chat dgc td bien nay co cau triic giong vdi nicotin va co ca che gay<br /> dgc giong vdi nicotin, tuy nhien nhieu chat con dgc hon nicotin rat nhieu lan va tan cong len tat<br /> ca cac thu the nhan biet nicotin dugc biet cho den nay.<br /> <br /> 7.7. Alkaloit tir Giun dot bien<br /> Loai giun nhieu ta Lumhriconereis brevicirra tiet ra mgt chat nhay cd chira dgc to khi<br /> chiing bj quay ray. thanh phan hoa hgc mang dgc to trong djch nhay nay dugc xac dinh la<br /> .Nereistoxin (48). mgt dimet\lamin co chira \6ng 1,2-dithioIan. Day la mgt chat dgc dii vdi<br />  602 Tuyen tjp HOi nghi KHOA HQC T O A N Q U 6 C V £ SINH HOC Bl^N vA P H A T T R I ^ N B £ N VLTNG<br /> <br /> <br /> <br /> dgng vat co vu, LD50 fren chugt la 30mg/kg, chat nay dong thdi dgc doi vdi ca va cd boat tinh<br /> dift con trimg. Nereistoxin iirc chi thy the nhan biet nicotin axetylcholin va tryc tiep khoa kenh<br /> van chuyen nay.<br /> <br /> <br /> <br /> <br /> 48<br /> <br /> 7.2. Alkaloit tir Giun voi bien<br /> Gan day cac nha khoa hgc phat hien ra rang trong ngc dgc ciia loai giun voi san moi co<br /> chira cac pyridine alkaloit co chiire nang la nhiing chat dgc te lift khi chiing san moi. Cac dgc to<br /> alkaloit nay tan cong vao thu the nhan biet nicotin axetylcholin gay te lift va mit chuc nang van<br /> dgng cua con moi.<br /> Anabaseine, 2-(3-pyridyl)-3,4,5,6-tetrahydropyridin (49) la alkaloit diu tien frong nhom<br /> nay dugc phan lap va nhan dang tir cac loai giun vdi san moi, trong do nong do ciia dgc to nay<br /> kha cao frong loai Paranemertes peregrina [89]. Mgt anabaseine khac (50) co ciu friic giong<br /> nicotin co kha nang kich thich tat ca cac thu the nhan bilt nicotin axetylcholin dugc bilt cho tdi<br /> nay, trong khi do nicotin mdi chi kich thich cac thu thi nhan bilt nicotin thugc nao bg [89]. Din<br /> xuat 3-benzylliden anabaseine, GTS-21 (51), da dugc chi ra la cd kha nang tang cudng kha nang<br /> tri nhd va hgc t|p cua dgng vat thi nghifm trong cac thir nghifm lam sang va tien lam sang [91].<br /> Day la hgp chat dau tien dugc phat hifn co kha nang kich thich chgn lgc thu the nhan biet<br /> nicotin axetylcholin dang a7.<br /> <br /> <br /> <br /> <br /> O ^ 0-^= ^y^^. CH,<br /> <br /> 50<br /> <br /> <br /> <br /> <br /> Mgt loai giun voi san moi khac dugc tim thiy d biln Tay bic Atlantic va Thai Binh Duang,<br /> loai Amphiporus angulatus, chira it nhit 15 pyridin alkaloit khac nhau [92]. 2,3'-Bipyridyl (52)<br /> CO the lam te lift con moi chi vdi lugng vlt trong ngc dgc ciia giun voi. NemerteUin (53) la mgt<br /> pyridin alkaloit co ham lugng Idn nhit trong giun voi la mgt tefrapyridyl cd nhilu diem tuong<br /> dong vdi fripyridyl nicotin (Nicotellin) co trong thuoc la, frong dd Nicotellin co ciu triic 3 vong<br /> B,C,D ciia nemertellin [91]. Hoat tinh sinh hgc ciia NemerteUin vin con chua dugc hieu ro rang,<br /> tuy nhien no da dugc chung minh co kha nang iirc chi qua trinh bam gia cua iu trimg dgng vat<br /> chan to [93].<br /> <br /> <br /> <br /> <br /> II<br /> <br /> <br /> Co 6 loai frong nganh giun Ham Ta co thi tao ra Tetrodotoxin [94]. Co gia thilt cho ring<br /> vdTn6 "" " '"^ ^^'^ ^° tetrodotoxin tir loai khuin Phiy Vibrio alginolyticus sing cgng smh<br /> Tieu ban: HOAT C H A T SINH HOC BI^N 603<br /> <br /> <br /> <br /> 8. Doc to tir Nhuyen thi<br /> Cac loai hai manh vo va cac loai 6c la cac dgng vat an lgc (filter-feeding) do d6 chiing co<br /> the an toan bg cac loai vi sinh vat bao gom cac loai tao giap, tao lam hay tao cat ma chiing lgc<br /> dugc, trong dd co ca cac loai co mang dgc td. Cac dgc to nay sau do dugc tich luy trong cac ca<br /> quan tieu hoa ciia nhuyen the va da gay nen hang loat cac vu ngg dgc doi vdi con ngudi va dgng<br /> vat [22,33,95]. Cac dgc to vi sinh vat da dugc trinh bay chi tift frong cac phan trudc do do chiing<br /> toi chi diem qua nhirng dgc to quan frgng trong nganh nhuyen thi.<br /> <br /> 8.1. PSP (Paralytic shellfish poisoning, su ngp dpc gay te Hit)<br /> Saxitoxin, Neosaxitoxin va hon hai muai dan xuat cua chiing dugc tao ra tir tao giap va tich<br /> luy trong tuyen tieu hoa cua nhuyen the dugc cho la nguyen nhan chinh gay nen cac vy ngg dgc<br /> te lift fren the gidi do tieu thy cac loai dgng vat co vo vj nhiem dgc. Cac vu ngg dgc cd lien quan<br /> den dgng vat bj nhiem dgc Saxitoxin fren nen kha pho bien va co xu hudng ra tang trong thdi<br /> gian gan day. Sy ngg dgc te lift cd the dan tdi tir vong trong mgt sd trudng hgp va hifn tai van<br /> chua CO mgt phuang phap thich hgp trong viec phan buy dgc to va dieu frj bfnh nhan.<br /> <br /> 8.2. DSP (Diarrhetic shellfish poisoning, su ngp dpc gdy tieu chay)<br /> Ke tir lan dau tien dugc cong bd vao nam 1976 d Nhat Ban, rat nhifu trudng hgp ngg dgc<br /> tieu chay cd lien quan den qua trinh tieu thy dgng vat bien co vo bj nhiem dgc da dugc thdng<br /> bao fren pham vi toan the gidi. Axit Okadaic va cac dan xuat ciia no chinh la cac dgc to chinh<br /> gay nen cac vy ngd dgc tren. Ngoai ra, Yessotoxin cung bj cho la nguyen nhan ciia cac vu ngg<br /> dgc nay, tuy nhien dgc td nay sau dd dugc loai ra khdi danh sach cac boat chat gay ngg dgc<br /> chinh do dgc tinh cua chiing qua dudng udng thap va khong co boat tinh gay tieu chay doi vdi<br /> chugt nghien curu.<br /> <br /> 8.3. AZP (Azaspiracid shellfish poisoning, sur ngp dpc Azaspiracid)<br /> Sy ngg dgc Azaspiracid co cac bieu hien giong vdi sy ngg dgc gay tieu chay (DSP) sau khi<br /> an nhuyen the nhiem dgc to Azaspiracid. Sy ngg dgc Azaspiracid lan dau tien dugc cong bo nam<br /> 1995 tai Chau Au. Sd dT ggi la sy ngg dgc Azaspiracid do dgc to chinh gay ra cac vu ngg dgc<br /> fren la cac azaspiracid. Cho tdi nay da co fren 30 dan xuat cua azaspiracid dugc cdng bo [96].<br /> Azaspiracid mdi chi dugc phan lap tir cac loai than mem, tuy nhien frong cac vu ngg dgc<br /> azaspiracid deu thay c6 lien quan tdi loai tao giap Protoperidinium crassipes.<br /> Azaspiracid-l (54), la mgt polyete co chira Nita, chat nay la mgt chat dgc vdi dgng vat cd<br /> vu, gia fri LD50 fren chugt la 110-200pg/kg, ngoai ra no con la mgt chat dgc to te bao, ICso<br /> khoang 10''-10"* M, va gay quai thai [97]. Ca che boat dgng ciia azaspiracid tucmg doi giong vdi<br /> Yessotoxin, tac dgng len kenh van chuyen Canxi.<br />  604 Tuyen tgp Hpi nghi KHOA HQC T O A N Q U O C V ^ SINH HOC B | £ N V A P H A T T R I ^ N B £ N VLTNG<br /> <br /> <br /> <br /> 8.4. NSP (Neurotoxic shellfish poisoning, su ngp dpc than kinh)<br /> Sy ngg dgc thin kinh do an phai cac loai nhuyen the hai manh vo co cac bieu hien giong<br /> vdi sy ngg dgc Ciguatera. Hoat chat chinh gay ra cac vu ngg dgc than kinh dugc chimg minh la<br /> do la Brevetoxin va cac dan xuit ciia no, dugc tich luy trong ca the dgng vat nhuyen the hai<br /> manh vo loai Karenia brevis.<br /> <br /> 8.5. ASP (Amnesic shellfish poisoning, su ngp dpc gdy mat tn)<br /> Cac vu ngg dgc dac bift mit tri nhd trong mgt thdi gian ngan do tieu thu cac loai nhuyen<br /> the lin diu tien dugc ghi nhan d Canada nam 1987 [98,99]. Dgc chat chinh gay nen cac vu ngg<br /> dgc nay la axit Domoic va cac dan xuat ciia no dugc san sinh ra tir loai tao cat Pseudonitzschia<br /> multiseries va mgt so loai tao cat cimg chi khac [41]. Tren the gidi cung cd ghi nhan mgt so<br /> trudng hgp dgng vat bj chet hang loat do an phai cac con moi bi nhiem dgc axit domoic [98].<br /> <br /> 8.6. Dpc to peptit tir Oc coi "<br /> Dgc to conopeptit tir loai 6c coi la dgc to peptit duy nhat dugc de cap trong bai t6ng quan<br /> nay do nhirng tinh chat ly thii ciia no. Conotoxin (Hinh 01) dugc nghien ciru dac biet trong suot<br /> 20 nam qua, chat nay dugc tao ra bdi loai 6c coi Conus sp. [13]. Hien nay da phat hifn co<br /> khoang tren 500 loai 6c coi khac nhau co kha nang sinh t6ng hgp Conopeptit, trong ngc dgc ciia<br /> m6i loai lai phat hifn tren dudi 100 Conopeptit rieng biet, do do co it nhit khoang 50,000<br /> Conopeptit dgc dugc sinh t6ng hgp bdi cac loai 6c c6i nay. Cac Conotoxin khong nhirng da dang<br /> ve cau triic hoa hgc va chung con co pho tac dung rgng len cac kenh van chuyen ion khac. Them<br /> vao do do co kich thudc phan tir tuong doi nho, (10-30 don vj amino'axit) lai df ting hgp, cac<br /> conopeptit dugc nghien ciru rgng rai frong vifc phat triln thuoc. Nam 2007, qua nhilu nam<br /> nghien ciiu lam sang va tien lam sang, conotoxin dau tien da dugc luu hanh tren thj trudng lam<br /> thuoc giam dau, ten thuang mai ciia no la Ziconotide™ [14].<br /> <br /> <br /> <br /> <br /> Hinh 1. c i u triic khong gian cua to-conotoxin<br /> <br /> Cac Conotoxin dugc phan chia thanh a-conotoxin, ire chi thu thi nhan bilt nicotin<br /> axenlcl<br /> ylcholin [108]; 6-conotoxin ire chi sy phan hoat hoa kenh van chuyin natri [109]; K-<br /> conotoxm uc che kenh van chuyen kali [110]; p-conotoxm ire chi kenh van chuyin natri trong<br /> ca [111] va (o-conotoxm tic che kenh van chuyen canxi dang N [112]. Doc tinh cung nhu tac<br /> dyng cua cac conotoxin ciing rat khac nhau. co-conotoxin co tac dung Idn gip khoang 100-1000<br /> lan so vdi morphin [113].<br /> Tieu ban: HOAT C H A T SINH HOC B I ^ N 605<br /> <br /> <br /> 9. Doc to tir dong vat Chan dot, Reu bien va dong vat Da gai<br /> Trong khi cua Xanthid chira Palvtoxin. Saxitoxin va/hoac Tetrodotoxin [35,100] thi cua<br /> mong ngya lai chira Sa.xitoxin hoac Tetrodotoxin [101], cac dgc t6 tren deu co ngu6n gdc tir vi<br /> sinh vat. Loai sao bien Asteropecten polyacanthus cung duac thong bao la co chira Tefrotoxin<br /> [102].<br /> Tir loai Reu bien Alcyonidium gelatinosum phan lap dugc mgt chat dgc to co chira luu<br /> huynh (2-hydroxietyl)dimetylsulfoxonium (55), day la mgt boat chat gay dj ting kha ph6 bien<br /> tai khu vyc bien Bac [103]. Ngoai ra hgp chat tren cung dugc phan lap tir hai mien [90].<br /> <br /> HO CH-<br /> <br /> <br /> <br /> <br /> Hgp chat saponin (dgc to glycosit) dau tien ten Holothurin dugc phan lap tir loai dua chugt<br /> bifn Holothuria vagabunda nam 1955 [104], cau true cua Holothurin A (56) dugc lam sang to<br /> vao nam 1978 [33]. Holothurin la cac triterpenoit tao bdi mgt aglycon lien ket vdi mgt vai phan tir<br /> dudng [105] va the hifn nhieu boat tinh sinh hgc rgng bao g6m boat tinh gay phan buy h6ng cau,<br /> dgc d6i vdi ca va khang vi sinh vat [33]. Asterosaponin A (57) la mgt steroidal saponin dugc phan<br /> lap tir sao bien va the hifn nhieu boat tinh tucmg ty cac Holothurin [105] . Trong vai thap nien frd<br /> lai day mgt so lugng Idn cac saponin da dugc phan lap tir hai mien, rugt khoang va da gai.<br /> <br /> <br /> <br /> <br /> HO XXX^<br /> HO<br /> <br /> <br /> <br /> <br /> 10. Doc to tir nganh Co ao va Ca "<br /> Ldp hai tieu co chira rit nhieu hgp chat chuyen hoa thir cap, mgt vai frong so chiing the<br /> hifn dgc tinh dii vdi dgng vat co vu [66], Pictamin (58), mgt quinolizidin alkaloit phan lap tir<br /> loai hai tieu Clavelina picta va Lepadin B (59), mgt Decahdroquinolin alkaloit tir loai C,<br /> lepadiformis khoa thu thi nhan bilt nicotin a.xetylcholin than kinh tai nong di) pM [106], trong<br /> khi do Lepadiformin (60) phan lap tir loai Clavelina sp. lai ire che kenh van chuyen kali [107].<br />  606 Tuyen t$p HOi nghj KHOA HQC T O A N Q U 6 C Vfe SINH HQC BI^N vA P H A T TRifeN BfeN VLTNG<br /> <br /> <br /> <br /> Cung phai noi lai ring Tefrodotoxin dugc phat hifn frong ca noc va nhieu loai dgng v^it<br /> khac. Dgc ti'nh ciia chit nay da kha r5 rang, tuy nhien hang nam fren the gidi van xay ra nhieu vy<br /> ngg dgc do an ca noc, chii yeu la do sy chu quan cua ngudi dan cung nhu sy quan ly kem ciia<br /> cac nha quan ly. Chi rieng tai Nhat Ban con s6 thong ke frong 10 nam (1954-1963) cho thiy<br /> nude Nhat co tdi 1.962 ngudi bj ngg dgc do an ca ndc, trong dd 1153 ngudi bj tir vong (87,76%<br /> so ngudi mac) [60].<br /> <br /> III. KET LUAN<br /> Sy ngd dgc thyc pham bien va sy chet hang loat dgng vat bien dang la moi quan tam ciia<br /> toan the gidi. Day la nhirng hifm boa thyc sy d6i vdi sire khoe cgng ddng va gay thift hai n$ng<br /> ne cho cac ngu trudng. Nhiing phat frien gan day ciia c6ng nghf sinh hgc va hoa hgc da gop<br /> phan nhan dang ra ngu6n g6c gay dgc trong cac vu ngg dgc thyc pham bien. Tinh cho den nay<br /> thi cac nha khoa hgc da nhan ra tam quan frgng ciia vi sinh vat bien frong hf sinh thai bien. Sy<br /> da dang ve boa hgc cua cac hgp chat thien nhien la vugt froi so vdi cac hgp chat thien nhien fren<br /> can, tuy nhien van con mgt so vin de con bo ngd.<br /> - Thiir nhat, do sy kho khan trong vifc lay mau cgng vdi ndng dg rat nhd cua cac hgp chat<br /> chuyen hoa thir cap tir bien da lam cho so lugng cac hgp chat thien nhien bien dugc phan lap con<br /> qua nho so vdi tiem nang (khoang 20.000 hgp chat so vdi ban 200.000 tong s6 cac hgp chat<br /> thien nhien dugc phan lap).<br /> - Thir hai, nghien ciru nguon goc thyc sy cua cac hgp chit chuyin boa nay, cac nghien cuu<br /> gan day deu chi ra rang cac dgc td phan tir lugng nho phan Idn cd ngudn goc tir vi sinh vat va<br /> dugc di chuyen dgc theo chuoi thirc an ciia sinh vat.<br /> Tiem nang cua tai nguyen sinh v^t biln vo ciing da dang phong phu va giau cd. Cac sinh v$t<br /> bien sinh ra toxin la mgt frong nhirng tilm nang ay. Cac toxin, cd y nghTa dac bift trong y dugc,<br /> coi nhu la mgt dugc lifu quy va la nhiing boat chit khu6n miu din dudng ly tudng cho cong<br /> nghf tong hgp bift dugc. Tuy ring, cho tdi nay, vifc sir dyng toxin chua dugc rgng rai, nhung<br /> nhimg boat chat sinh hgc nay co mgt triln vgng frong tuong lai diy hua hen. Do dd, chiing ta<br /> can phai quan tam dung miirc, dl cd chiln luge khai thac, sir dung mgt each cd hifu qua nhihig<br /> ngudn gen quy hilm iy, dua nhimg gia frj dd vao thyc tl ddi song kinh t l quoc dan.<br /> <br /> IV. TAI LIEU THAM KHAO<br /> 1. Teitelbaum JS, ZatoiTe RJ, Carpenter S, Gendron D, Evans AC, Gjedde A, Cashman NR<br /> (1990) Neurologic sequelae of domoic acid intoxication due to the ingestion of<br /> contaminated mussels. N Engl J Med 322:1781 -1787.<br /> 2. Perl TM, Bedard L, Kosatsky T, Hockin JC, Todd EC. 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