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Ciguatera Toxins: Where
Do
We
Go
from
Here?
NORMAN J. DOORENBOS Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 24, 2018 | https://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch007
University of Wisconsin-Eau Claire, Eau Claire, WI 54701
Although much useful information on ciguetera toxins has been generated, the presence of these toxins in some seafood remains a serious international health problem. Future research goals should include the development of practical tests for product safety, the development of specific antidotes for the toxins, the introduction of methods to minimize the accidental consumption of toxic seafood, the discovery of the genesis of the toxins and methods to control the problem, and the development and dissemination of an information base on all aspects of this and other seafood toxin problems for the seafood industry, health personnel, researchers, and the public. It i s almost presumptuous for me to present a paper at the quarter point of t h i s Symposium on Seafood Toxins on the subject "Where Do We Go From Here?" This morning, we heard a number of fine presentations on the need for and the results of research on seafood toxins. We w i l l learn even more i n the three remaining half-day sessions. Please l e t me share with you the observations and r e f l e c t i o n s of a chemist with a long time interest i n toxicology, who has also experienced the d i f f i c u l t i e s and frustrations of investigating seafood toxins. The points which I would l i k e to make can be i l l u s t r a t e d i n large measure by an examination of the ciguatera problem. Ciguatera i s an international problem as made clear i n H a l s t e a d ^ Poisonous and Venomous Marine Animals of the World 01). It i s a threat to public health and has c u r t a i l e d f i s h e r i e s development. L e t s look at some recent reports. Dr. Nabil A. Mansour C2), University of Alexandria, noted that ciguatera i s a Red Sea problem and may prevent the planned development of an Egyptian Red Sea f i s h e r i e s . Hundreds of ciguatera cases are recorded annually i n S r i Lanka (3) and A u s t r a l i a (4). The annual totals are thought to be i n the thousands. New Guinea f i s h e r i e s researchers (5) believe that thousands are poisoned each year but most incidents go unreported because they are attributed to a sorcerer*s claims over the victims. Recently, an I t a l i a n outbreak (6), traced to f i s h caught i n f
0097-6156/ 84/ 0262-0069S06.00/ 0 © 1984 American Chemical Society
Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.
Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 24, 2018 | https://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch007
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the western P a c i f i c , led to one death and over f i f t y h o s p i t a l i z a t i o n s . Some islands i n the western P a c i f i c have been abandoned because of l o c a l ciguatera problems. Ciguatera has been a major obstacle i n the development of lagoon resources and aquaculture i n the southern P a c i f i c . A bottom fishery i n Samoa i s required to discard a l l red snappers, as much as 50% of the catch, because of p o t e n t i a l t o x i c i t y (7). Ciguatera has prevented the development of commercial f i s h e r i e s i n many parts of the Caribbean (8). Some outbreaks affect many i n d i v i d u a l s . For example, the president of a well known company i n Venezuela recently wrote that he and several associates speared 30 snappers i n the waters of I s l a Los Roques (9). The f i s h were shared with friends, poisoning over 200 and causing several deaths. Ciguatera i s also an American problem and i s grossly underreported. My f i l e s contain numerous reports of poisonings which occurred while on vacation or from f i s h obtained i n a hot area. The Center for Disease Control publishes an Annual Survey of Foodborne Disease for the f i f t y states, Guam, Puerto Rico and the U. S. V i r g i n Islands. The number of confirmed outbreaks l i s t e d for 1976 through 1980 ranged from three to 19 per year. The number of outbreaks l i s t e d for 1980 (10), the l a t e s t available survey, was at the high end, namely 15 and involved 52 i n d i v i d u a l s . Please note: f i f t e e n outbreaks and 52 i n d i v i d u a l s . My records for 1980 include such reports as nine persons suffered ciguatera poisoning i n October from eating a grouper i n a Montgomery County, Maryland, restaurant (11), the CDC received numerous i n q u i r i e s from physicians about ciguatera symptoms on behalf of physicians returning from Puerto Rico and the U. S. V i r g i n Islands (12), the Washington Post on July 21 described a F l o r i d a study (probably Don DeSylva's study) reporting that 1,500 south F l o r i d a residents contract ciguatera each year, and Dr. Joe Mac M i l l a n of the College of the V i r g i n Islands established that during one period 30-40 persons per week were receiving emergency room treatment for ciguatera poisoning at just one of the hospitals on St. Thomas (13). The CDC survey for 1980 includes no reports for Maryland, F l o r i d a , Puerto Rico, or the U. S. V i r g i n Islands. The f i f t e e n outbreaks l i s t e d each occurred i n Hawaii. Similar underreporting has been noted annually. It has been our observation that most people i n high r i s k areas do not seek help for ciguatera poisoning. Hence, they are not included i n any compiled s t a t i s t i c s . They know that the g a s t r o i n t e s t i n a l symptoms and headaches may be treated with overthe-counter medications and that l i t t l e can be done for the neurol o g i c a l and cardiovascular symptoms. The incidence i n these areas can be high. Over 80% of the resident adults we surveyed i n the U.S. and B r i t i s h V i r g i n Islands had been poisoned at least once. Victims are not only made i l l but often cannot work during the early stages of the recovery period. Ciguatera continues to be a serious health and economic problem. Physicians outside the "hot areas" seldom recognize the symptoms of ciguatera poisoning. As a consequence inappropriate time, resources, diagnostic tests, and treatments are used often leaving a frustrated, seriously-depressed, sometimes emotionallydisturbed sick patient whose f i n a n c i a l resources have been
Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.
Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 24, 2018 | https://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch007
7.
DOORENBOS
Ciguatera Toxins: Where Do We Go from Here?
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compromised. An a r t i c l e "Physicians: Know Thy Ciguatera Symptoms" published i n the November 1982 issue of the American Journal of Public Health (14) i s an attempt to educate physicians. C l i n i c a l data, now supported by research data generated by several research groups represented i n t h i s Symposium, suggest that ciguatera i s caused by several d i f f e r e n t toxins. We have sometimes noted s i g n i f i c a n t differences between the l i s t of symptoms reported by victims of d i f f e r e n t outbreaks i n the Caribbean, suggesting a d i f f e r e n t set of toxins. We have also recorded symptoms of victims i n the Cayman and V i r g i n Islands which, to the best of our knowledge, have not been noted i n victims elsewhere i n the world. For example, many of these victims have reported blood in the urine, d i f f i c u l t y i n urinating, and pain on urination along with other symptoms commonly associated with ciguatera. Dr. van der Sar of the Netherlands A n t i l l e s , who has treated many ciguatera victims, disclosed that cardiovascular i r r e g u l a r i t i e s are additional symptoms often observed i n St. Martin but never i n Aruba, Bonaire or Caracao (15). The i s o l a t i o n and characterization of more than one ciguatera toxin, coupled with the progress being made i n understanding the physiologic properties of the toxin i n such laboratories as those at Southern I l l i n o i s University at Carbondale, makes me optimistic about the future. The chemical studies of ciguatera have been p a r t i c u l a r l y f r u s t r a t i n g — s h o r t a g e s of research materials, p u r i f i c a t i o n d i f f i c u l t i e s , i n s t a b i l i t y of some i s o l a t e d toxin f r a c t i o n s , extremely small quantities present i n ciguatoxic f i s h , lack of a r e l i a b l e highly-sensitive assay to follow the i s o l a t i o n and p u r i f i c a t i o n of toxins, the complex mixtures present i n toxic fractions and the complex structures of the toxins. I admire the accomplishments Professor Scheuer and others have made i n spite of these obstacles. The discoveries that p o l y c y c l i c ethers may be responsible f o r ciguatera as well as some of the other known seafood toxins i s an exciting development. P o l y c y c l i c ethers, both natural and synt h e t i c , have become "cutting edge" tools i n the investigation of certain l i v i n g membrane phenomena. The fascinating physiologic effects of p o l y c l y i c ethers selected for study has been attributed in part to their a b i l i t y to complex one or more of the physiol o g i c a l l y important cations and to a f f e c t cation transport through membrances. On the side, this causes me to wonder i f the diterpenoid toxins of Rhododendrons, known as grayanotoxins, which mimic the physiologic e f f e c t s of ciguatoxins, also chelate metal cations. These diterpenoids, although not c y c l i c polyethers, do contain several oxygen functional groups and may assume conformations which could favor the formation of such complexes. P o l y c y c l i c ethers are biosynthesized by a v a r i e t y of microorganisms. Several were c l i n i c a l a n t i b i o t i c candidates i n the 1960*8 and 1970*s. The discovery that such substances may have a wide d i s t r i t u t i o n i n the marine environment raises i n t r i g u i n g questions. Is the genetic c a p a b i l i t y of d i r e c t i n g the biosynthesis of p o l y c y c l i c ethers widely distributed? What are the functions of these substances? In the mid-1970 s we i s o l a t e d cultures of Gram negative marine b a c i l l i from four ciguatoxic surgeon f i s h speared i n the 1
Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.
Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 24, 2018 | https://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch007
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waters of Salt Island i n the B.V.I. The cultures appeared i d e n t i c a l and elaborated, i n submerged laboratory culture, a toxin resembling ciguatoxin. These observations caused our speculation that t h i s b a c i l l u s might be the source of ciguatoxin and l a t e r to speculate that i t may be the source of toxin observed i n Gambriadiscus toxicus when attempts to produce the toxin i n cultures of t h i s dinoflagellate failed. F a i l u r e to produce ciguatoxins i n culture has been attributed to a missing factor. The missing factor may be an appropriate stress or a chemical substance produced by another microorganism. There are numerous examples i n both the plant and animal kingdoms of the biosynthesis of substances stimulated by environmental stresses or the presence of another l i v i n g organism. Continued research i s needed to characterize and understand these toxins, their d i s t r i b u t i o n i n the marine environment, their biosynthesis and their function, how to detect them and to minimize their impact on the seafood industry. Ciguatoxins appear to be stored for long periods i n f i s h and humans. This i s a most unusual phenomenon. Animal species and e s p e c i a l l y man have well developed mechanisms for reducing the t o x i c i t y of foreign chemicals and rapidly eliminating them from the body. Thus, i t i s surprising that f i s h appear to store ciguatoxins for a l i f e t i m e and that humans may also store these toxins for a long time. The slow recovery of victims, which often takes months to years, i s evidence of long term storage. Of course, t h i s could be due to other factors such as the slow repair or replacement of b i o l o g i c a l structures damaged by the t o x i n ( s ) . Other evidence for long term storage i n humans includes the numerous observations of increased s e n s i t i v i t y to ciguatera, l a s t i n g several months or longer, among ciguatera victims. Specific antidotes to ciguatera poisoning might be discovered among chemical derivatives of the toxins or simpler synthetic p o l y c y l i c ethers. I am suggesting that some of these substances might function as competitive antagonists displacing toxins from c r i t i c a l binding s i t e s and allowing the body to dispose of them. Where do we go from here? Increased support needs to be provided for seafood toxin research. The progress thus f a r made i n this most challenging research f i e l d has been nothing short of phenomenal. This has been accomplished with a very modest investment of research d o l l a r s . I compliment the leadership F.D.A. i s providing i n funding and coordinating research i n seafood toxins. This l e v e l of support needs to be greatly expanded and j o i n t l y funded by F.D.A., National Marine Fisheries, and the N.I.H. Every opportunity to collaborate and communicate with researchers i n other countries should continue to be encouraged. Among the important challenges hanging out there are: 1) To develop highly s e n s i t i v e , rapid, inexpensive tests to support research a c t i v i t i e s and researchers for the Seafood industry, 2) To characterize the various seafood toxins, i d e n t i f y factors contributing to their entry into food products, and to develop procedures for minimizing the consumption of toxic seafood, 3) To discover mechanisms of t o x i c i t y and to develop e f f e c t i v e safe antidotes for the treatment of victims of seafood poisoning, and
Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.
7.
DOORENBOS
Ciguatera Toxins: Where Do We Go from Here?
4) To develop and u t i l i z e an improved information base on a l l aspects of seafood toxin problems f o r the seafood industry, health personnel, the public and researchers. It may not be possible to eliminate ciguatera, PCP and other seafood toxin problems but the kind of research i n progress should make i t possible to manage these problems, to e f f e c t i v e l y treat victims, and to minimize economic and health impacts.
Literature Cited Downloaded by UNIV OF MASSACHUSETTS AMHERST on May 24, 2018 | https://pubs.acs.org Publication Date: September 19, 1984 | doi: 10.1021/bk-1984-0262.ch007
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Halstead, B. "Poisonous and Venomous Marine Animals of the World"; U.S. Government Printing Office: Washington, D.C., 1967, Vol. II, pp. 63-604. Mansour, N.A., personal communication. St. Louis Post Dispatch, January 22, 1978. Sutherland, S., personal communication. Lili, P., personal communication to Christopher Kohler, Southern Illinois University-Carbondale. Teoboli, A . , personal communication. Fields, R., personal communication. Brady, R. W. Proc. 24th Ann. Gulf and Caribbean Fisheries Institute, 1972, p. 100. Comenges, F . , personal communication to J . Randall, Bishop Museum. "Foodborne Disease Annual Summary 1980," Center for Disease Control, 1983. Ragelis, E., personal communication. Glaso, R., personal communication. McMillan, J., personal communication. Dembert, M. L.; Pearn, J . H . , Am. J. Pub. Health 1982, 72, 1298. van der Sar, A . , personal communication.
RECEIVED March 2, 1984
Ragelis; Seafood Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1984.
