Report of the Expert Meeting on Ciguatera Poisoning: Rome, 19-23 November 2018
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Phytoplankton blooms, micro-algal blooms, toxic algae, red tides, or harmful algae, are all terms for naturally occurring phenomena that have occurred throughout recorded history. About 300 hundred species of micro algae are reported at times to form mass occurrence, so called blooms. Nearly one fourth of these species are known to produce toxins. Even non-toxic algal blooms can have devastating impacts when they lead to kills of fish and invertebrates by generating anoxic conditions. Some algal species, although non-toxic to humans, can produce exudates that can cause damage to the delicate gill tissues of fish (raphidophytes Chattonella, Heterosigma, and dinoflagellates Karenia, Karlodinium) . Aquatic animals can suffer devastating mortalities, which could lead economical and food losses, and eventually became a food security problem.
Of greatest concern to humans are algal species that produce potent neurotoxins that can find their way through shellfish and fish to human consumers where they evoke a variety of gastrointestinal and neurological illnesses (paralytic shellfish poisoning (PSP), amnesic shellfish poisoning (ASP), diarrhoeic shellfish poisoning (DSP), neurotoxic shellfish poisoning (NSP), azaspiracid shellfish poisoning (AZP) and ciguatera fish poisoning (CFP)). Worldwide, ciguatoxins are estimated to cause around 50 000 cases of ciguatera fish poisoning annually; neurological effects may last for weeks or even years and one percent of these cases are fatal .
Climate change and costal water over enrichment create an enabling environment for harmful algal blooms, which seem to have become more frequent, more intense and more widespread in the past decades.
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Report of the Expert Meeting on Ciguatera Poisoning - Food and Agriculture Organization of the United Nations
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FAO and WHO. 2020. Report of the Expert Meeting on Ciguatera Poisoning. Rome, 19–23 November 2018. Food Safety and Quality No. 9. Rome. https://doi.org/10.4060/ca8817en.
The designations employed and the presentation of material in this information product do not imply the expression of any opinion whatsoever on the part of the Food and Agriculture Organization of the United Nations (FAO) or World Health Organization (WHO) concerning the legal or development status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or products of manufacturers, whether or not these have been patented, does not imply that these have been endorsed or recommended by FAO or WHO in preference to others of a similar nature that are not mentioned.
The views expressed in this information product are those of the author(s) and do not necessarily reflect the views or policies of FAO or WHO.
ISSN 2415-1173 [Print]
ISSN 2664-5246 [Online]
ISBN 978-92-5-132518-6 (FAO)
ISBN 978-92-4-000629-4 [electronic version] (WHO)
ISBN 978-92-4-000630-0 [print version] (WHO)
E-ISBN 978-92-5-133091-3 (EPUB)
© FAO and WHO, 2020
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Cover photographs [from left to right]:
© Institut Louis Malardé, © Marie-Yasmine Dechraoui Bottein
CONTENTS
Tables and figures
Contributors
Abbreviations and acronyms
Declarations of interest
Executive summary
CHAPTER 1
INTRODUCTION
1.1 Background
1.2 Objectives
1.3 Meeting approach
CHAPTER 2
OCCURRENCE OF CAUSATIVE ORGANISMS AND CTXs
2.1 Occurrence of Gambierdiscus species
2.2 Distribution of CP causative organisms
2.3 Methods for species identification
2.3.1 Polymerase chain reaction (PCR)
2.3.2 Fluorescence in situ hybridization (FISH) probes
2.3.3 Restriction fragment length polymorphism (RFLP) typing
2.3.4 High-throughput sequencing (HTS) metabarcoding
2.4 Sampling strategies
2.5 Gambierdiscus abundance
2.6 Toxicity of CP causative organisms
2.6.1 Detection of CTXs in Gambierdiscus and Fukuyoa and in the environment
2.7 Occurrence of CTXs in seafood
CHAPTER 3
CHEMISTRY AND BIOSYNTHETIC PATHWAYS
3.1 Chemistry
3.1.1 Structures
3.1.2 Chemical characteristics
3.1.3 Biosynthetic pathways
3.2 Ciguatoxin classification
CHAPTER 4
DETECTION METHODOLOGIES FOR CTXs
4.1 Screening assays for ciguatoxins
4.1.1 In vitro assays
4.1.1.1 N2A-MTT assay for ciguatoxins
4.1.1.2 Receptor binding assay (RBA) for ciguatoxins
4.1.1.3 Immunological assays
4.1.2 In vivo assays
4.2 Structure-based confirmatory methods
4.3 Concluding remarks
CHAPTER 5
HAZARD IDENTIFICATION
5.1 Absorption, distribution, metabolism and excretion (ADME)
5.1.1 Animal data
5.2 Toxicological studies
5.2.1 Acute toxicity
5.2.2 Short-term studies
5.2.3 Medium-term studies
5.2.4 Long-term studies
5.2.5 Repeated versus acute toxicity
5.2.6 Conclusion from toxicological studies in rodents
5.3 Mode of action
CHAPTER 6
HUMAN DATA
6.1 ADME
6.2 Clinical features and toxicity
6.2.1 Acute symptoms
6.2.2 Chronic symptoms
6.2.3 Acute recurrence/exacerbation of ciguatera symptoms
6.2.4 Lethality
6.3 Epidemiology
6.4 Treatments
CHAPTER 7
EXPOSURE ASSESSMENT
7.1 Introduction
7.2 Detection frequency of CTXs and levels of contamination
7.3 Consumption
7.3.1 Mean estimates of fish consumption
7.3.2 High percentile estimates of fish consumption
7.4 Ciguatoxin doses causing Ciguatera poisoning
7.5 Dietary exposure to ciguatoxins
CHAPTER 8
CONCLUSIONS
8.1 Risk management considerations
REFERENCES
ANNEX
CP FLOW DIAGRAM, AND RESEARCH PROJECTS
Research projects
Ciguatools
Eurocigua
AlertoxNet
TABLES
1. Biological activity reported in Gambierdiscus and Fukuyoa species
2. Relative ciguatoxin-like toxicities of Gambierdiscus and Fukuyoa species reported to date
3. Minimum fish weight to require CTX analysis in the Canary Islands, Spain
4. Fish and marine invertebrates reported to bioaccumulate CTXs and their locations
5. Classification of CTXs and abbreviation synonyms
6. Gambierdiscus metabolites other than CTXs
7. Available screening assays and confirmation methods
8. Acute toxicity and relative potency of CTXs
9. Common chronic symptoms of ciguatera poisoning.
10. Factors contributing to the recurrence or exacerbation of symptoms
11. Ciguatera as a global health problem
12. Highest incidence rates per 10 000 population in selected locations
13. Poisoning cases with causative fish and toxins
14. Summary of studies on the ciguatoxin content of marine fish
15. Scenario-based estimation of acute dietary CTX exposure
16. Marine species in specific regions that are known to exhibit high site fidelity
FIGURES
1. Gambierdiscus: G. belizeanus (A), G. australes (B), G. caribaeus (C)
2. Gambierdiscus and Fukuyoa occurrence in the Caribbean and adjacent seas
3. Gambierdiscus and Fukuyoa occurrence in Macaronesia, Europe and the Near East
4. Gambierdiscus and Fukuyoa occurrence in the Pacific Ocean, N=162
5. Global Gambierdiscus and Fukuyoa occurrence from published records, 2009-2018
6. Mean Gambierdiscus abundances from 46 studies
7. Ciguatoxin toxin profiles found in the microalga Gambierdiscus polynesiensis, in the herbivorous fish Chlorurus microrhinos (ex. Scarus gibbus) and in the carnivorous fish Gymnothorax javanicus
8. Ciguatoxin classification
9. Gambierdiscus metabolites other than CTXs
10. Example of reported acute symptoms of ciguatera poisoning
11. Distribution of doses of CTX1B equivalents associated with CP cases in Guadeloupe
A1. Flow of CP responses and needs
CONTRIBUTORS
EXPERTS
Ann Abraham, Division of Seafood Science and Technology, United States Food and Drug Administration
Nathalie Arnich, Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), France
Mireille Chinain, Institut Louis Malardé, Laboratoire de Recherche sur les Biotoxines Marines, French Polynesia
Peter Cressey, Institute of Environmental Science and Research Limited, New Zealand
Marie-Yasmine Dechraoui Bottein, Radioecology Laboratory of the IAEA Environment Laboratories, Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Monaco
Jorge Diogène Fadini, IRTA, Marine and Continental Waters Program, Spain
Miriam Friedemann, German Federal Institute for Risk Assessment, Department Exposure, Centre for Documentation and Assessment of Poisonings, Germany
Ana Gago-Martínez, Universidad de Vigo, Department of Analytical and Food Chemistry, Spain
Clémence Gatti, Institut Louis Malardé, Laboratoire de Recherche sur les Biotoxines Marines, French Polynesia
Arjen Gerssen, RIKILT Wageningen University and Research, Netherlands
Matthew O. Gribble, Department of Environmental Health, Department of Epidemiology, Emory University Rollins School of Public Health, United States of America
Tim Harwood, Cawthron Institute, New Zealand
Philipp Hess, Ifremer, Atlantic Center, Laboratoire Phycotoxines, France
James M Hungerford, Applied Technology Center, Pacific Northwest Laboratory, Office of Regulatory Affairs, United States Food and Drug Administration, USA
Iddya Karunasagar, Department of International Relations, NITTE University, India
Raphaёle Le Garrec, Univ Brest, LIEN, F-29200 Brest, France
Naomasa Oshiro, Marine Biotoxin Laboratory, Division of Biomedical Food Research, National Institute of Health Sciences, Japan
Alison Robertson, Marine Ecotoxicology Laboratory, Department of Marine Sciences, University of South Alabama and Dauphin Island Sea Laboratory, United States of America
Patricia Tester, Ocean Tester, United States of America
Martin van den Berg, Institute for Risk Assessment Sciences, Utrecht University, Netherlands
Jean-Paul Vernoux, Normandy University, UNICAEN, ABTE Research Team, France
OBSERVERS
Henrik Enevoldsen, Intergovernmental Oceanographic Commission of UNESCO, IOC Science and Communication Centre on Harmful Algae, Marine Biological Section, University of Copenhagen
SECRETARIAT
Verna Carolissen, Codex Secretariat, Joint FAO/WHO Food Standards Programme, Food and Agriculture Organization of the United Nations
Gracia Brisco, Codex Secretariat, Joint FAO/WHO Food Standards Programme, Food and Agriculture Organization of the United Nations
Vittorio Fattori, FAO Secretariat, Food Safety and Quality Unit, Agriculture and Consumer Protection Department, Food and Agriculture Organization of the United Nations
Markus Lipp, FAO Secretariat, Food Safety and Quality Unit, Agriculture and Consumer Protection Department, Food and Agriculture Organization of the United Nations
Esther Garrido Gamarro, FAO Secretariat, Fisheries and Aquaculture Department, Food and Agriculture Organization of the United Nations
Angelika Tritscher, WHO Joint Secretary, Department of Food Safety and Zoonoses, World Health Organization
Lisa Scheuermann, WHO Joint Secretary, Department of Food Safety and Zoonoses, World Health Organization
Luis M. Botana, Department Pharmacology, Faculty of Veterinary Medicine, Campus Lugo, University of Santiago de Compostela, Spain
ABBREVIATIONS AND ACRONYMS
ADME absorption, distribution, metabolism and excretion
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
C-CTX Caribbean ciguatoxin
CBA cell bioassay
CDC Centers for Disease Control and Prevention
CP ciguatera poisoning
CIFOCOss FAO/WHO Chronic Individual Food Consumption database
CTX ciguatoxin
EFSA European Food Safety Authority
ELISA enzyme-linked immunosorbent assay
FAO Food and Agricultural Organization of the United Nations
FDA Food and Drug Administration (the United States of America)
FISH fluorescence in situ hybridization
GABA gamma amino butyric acid
GEADE Global Estimate of Acute Dietary Exposure
HRMS high-resolution mass spectrometry
HTS high-throughput sequencing
I-CTX Indian Ocean ciguatoxin
IAEA International Atomic Energy Agency
ICR Institute of Cancer Research
IESTI, International Estimate of Short-term Intake
InsP3 inositol triphosphate
ip intraperitoneal
iv intravenous
JECFA Joint FAO/WHO Expert Committee on Food Additives
LC-MS liquid chromatography coupled with mass spectrometry
LD lethal dose
LOAEL lowest observed adverse effect level
LOD limit of detection
LOQ limit of quantitation
MBA mouse bioassay
MTT 3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyltetrazolium bromide
MTX maitotoxin
MU mouse unit
N2A (N2a) mouse neuroblastoma assay
NMDA N-methyl-D-aspartic acid
NOAA National Oceanic and Atmospheric Administration
NOAEL non-observable adverse effect level
P-CTX Ciguatoxins (CTX) initially isolated from biota from the pacific region
PbTx brevetoxin
PCR polymerase chain reaction
PICTs Pacific island countries and territories
PKS polyketide synthase
PSS Poison Severity Score
qPCR quantitative polymerase chain reaction
RASFF Rapid Alert System for Food and Feed
RBA receptor binding assay
RFLP restriction fragment length polymorphism
SEM scanning electronic microscopy
SP substance P
SPATT solid phase adsorption toxin tracking
STX saxitoxin
TEF toxicity equivalency factor
TRPA1 transient receptor potential ankyrin 1
TTX tetrodotoxin
UHPLC ultra-high-pressure liquid chromatography
Vd volume of distribution
VGSC voltage-gated sodium channel
VGPC Voltage-gated potassium channel
WHO World Health Organization
DECLARATIONS OF INTEREST
All participants in the Joint FAO/WHO Expert Meeting on Ciguatera Poisoning completed a declaration of interest form in advance of the meeting. In relation to the subject of this Expert Meeting, the following declarations were made: (i) Ann Abraham, James M. Hungerford and Clémence Mahana declared having paid employment; (ii) Mireille Chinain, Ana Gago-Martínez, David Timothy Harwood, Philipp Hess, Iddya Karunasagar and Clémence Mahana declared having received or anticipating research support; (iii) Marie-Yasmine Dechraoui Bottein, Jorge Diogene, Ana Gago-Martinez, David Timothy Harwood and Clémence Mahana reported participating in an expert committee or scientific advisory group; (iv) Peter Cressey and Jorge Diogene have provided expert opinion or testimony as part of a regulatory, legislative, judicial, or other governmental process; and (v) David Timothy Harwood indicated knowledge of a technology that could be impacted by the outcome of the meeting.
Following the FAO Guidance Document for Declaration of Interests, the declarations noted above were assessed as to the extent to which each interest could be reasonably expected to affect and exercise influence on the experts’ judgement. The declared interests of Ann Abraham, Mireille Chinain, Peter Cressey, Marie-Yasmine Dechraoui Bottein, Jorge Diogene, Ana Gago, David Timothy Harwood, Philipp Hess, James M. Hungerford, Iddya Karunasagar and Clémence Mahana were considered unlikely to impair their objectivity or have a significant influence on the impartiality, neutrality and integrity of the work. Meeting participation by these individuals was neither reasonably expected to create unfair competitive advantages, nor were the meeting outcomes reasonably foreseen to affect the individuals’ declared interests. Neither FAO nor WHO received any public comments in response to the online posting of the names and brief biographies of the individuals considered for participation in the Expert Meeting. The interests of all participants were disclosed to all attendees at the beginning of the Expert Meeting.
EXECUTIVE SUMMARY
Ciguatera poisoning (CP) is reported in historical documents of the sixteenth century. The first report of the organism Gambierdiscus (originally referred to as Goniodoma sp.) dates from October 1948, in Cabo Verde. Today, the term ciguatera identifies poisoning caused by the ingestion of certain reef fish and shellfish from tropical and subtropical regions, especially the South Pacific Ocean, Indian Ocean and the Caribbean Sea. Through the food chain, these fish and shellfish have accumulated certain lipid-soluble toxins (ciguatoxins [CTXs]) that are produced by