Report of the Expert Meeting on Ciguatera Poisoning. Rome, 19–23 November 2018

Type Book / Conference proceedings
Date 2020
Language English
Author(s) FAO
Contributor(s) Hess PhilippORCID
DOI 10.4060/ca8817en
Publisher Food and Agriculture Organization of the United Nations (FAO)
Note 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)

Ciguatera poisoning (CP) is reported in historical documents of the sixteenth century.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 dinoflagellates of the genera Gambierdiscus and Fukuyoa. Ciguatera is a worldwide problem that is expanding due, among other reasons, to climate change. In general, CP can be regarded as the most significant non‑bacterial poisoning associated with fish consumption worldwide. A typical sign of the poisoning is cold allodynia, and there are more than 175 gastrointestinal, cardiovascular and neurological symptoms. It is unclear whether the toxins cause harm to those herbivorous or carnivorous fish that take them through the food chain. In 2016, at the Thirty‑Second Session of the Codex Committee on Fisheries and Fishery Products, the Pacific Nations raised CP as an issue that is increasingly affecting the tropical and subtropical regions of the Pacific Ocean, Indian Ocean and Caribbean Sea between the latitudes of 35°N and 35°S. Indeed, it was noted that, due to climate change, the frequency of storms and hurricanes is increasing, as is the sea surface temperature, which affects the distribution and proliferation of CTXs and makes the occurrence of CP less predictable. The issue of CP was raised at the Eleventh Session of the Codex Committee on Contaminants in Food. The Committee agreed to request scientific advice from FAO/WHO to enable the development of appropriate risk management options, in particular: full evaluation of known CTXs (toxicological assessment and exposure assessment), including geographic distribution and rate of illness, congeners, and methods of detection; and guidance for the development of risk management options. There are now 16 described Gambierdiscus species: G. australes, G. balechii, G. belizeanus, G. caribaeus, G. cheloniae, G. carpenteri, G. carolinianus, G. excentricus, G. pacificus, G. polynesiensis, G. scabrosus, G. toxicus, G. silvae, G. lapillus, G. honu and G. jejuensis. Recently, two globular species Gambierdiscus have been reclassified as Fukuyoa (F. yasumotoi and F. ruetzleri), and a new species described (F. paulensis). Both F. ruetzleri and F. paulensis produce toxins. Optimum growth takes place between 26.5 °C and 31.1 °C, with thermal limits from 15–21 °C to 31–34 °C, and salinities from 24.7 g/litre to 35 g/litre with light irradiances below 231 μmol photons per square metre per second. A variety of techniques can be considered for the identification of species at any given site, including optical microscopy as a screening tool, and scanning electronic microscopy (SEM) and/or molecular techniques (sequencing, PCR, RFLP, FISH probes, etc.) as confirmation tools. Gambierdiscus cells are distributed in a very patchy manner; coefficients of variation among adjacent samples range from 50 percent to > 150 percent. The frequency distributions of average cell densities are similar in both the Atlantic and Pacific. Ten percent of the abundance estimates are between 1 000 cells/g wet weight algae and 10 000 cells/g wet weight algae, with 5 percent exceeding 100 000 cells/g wet weight algae. More than 425 species of fish have been linked to ciguatera events. Coral reef fishes contribute to the expansion of CP intoxications. Reef fish known to potentially accumulate these toxins are: barracuda (Sphyraenidae), amberjack (Seriola), grouper (Serranidae), snapper (Lutjanidae), po’ou (Labridae spp.), jack (Carangidae spp.), trevally (Caranx spp.), wrasse (Labridae spp.), surgeon fish (Acanthuridae spp.), moray eel (Muraenidae spp.), roi (Cephalopholis spp.), and parrotfish (Scaridae spp.). A large variety of marine invertebrates including urchins, gastropods, bivalves and echinoderms have also been reported to contain CTXs, but their implication in CP is far less important than fish. Due to world trade, and consumption of imported fish there are poisoning reports in many geographic areas, such as Canada, Germany (e.g. Hamburg), the Paris area (France) and California, New York, Rhode Island and Vermont (the United States of America), and also CP has been reported after returning to their countries by patients having consumed ciguateric fish in endemic areas. Global warming is facilitating the expansion of Gambierdiscus, but there are bodies of water that are warm enough to depress their growth. Several reports indicate the presence of Gambierdiscus in new areas (Brazil, Morocco or Thailand), but there is no solid link yet to this being caused by climate change. Another subject not yet clarified is how the change in pH and carbon dioxide (CO2) levels and in sea surface temperatures may affect toxin production, as the growth of microalgae is influenced by these parameters. The approach followed by many countries is to impose fish size restrictions as a ciguatera risk management action, but the toxicity of some species is associated to seasonal variations and for most species, there is no proven correlation between the toxicity of fish and their size/weight. Ciguatoxins (CTXs) are a class of large polyether ladder‑like lipid‑soluble compounds that are thermostable and resistant to mild pH changes; they contain 13–14 fused rings. Representative backbone structures of CTXs identified to date are represented by CTX4A, CTX3C and C‑CTX1. The diastereoisomers 52‑epi‑54‑deoxyCTX1B and 54‑deoxyCTX1B (also known as CTX2 and CTX3, respectively) represent less oxidized forms of CTX1B. The only difference between CTX1B, 52‑epi‑54‑deoxyCTX1B and 54‑deoxyCTX1B involves modification at one end of the CTX. The backbone structure of CTX3C toxins differs from CTX4A group on the E‑ring (i.e. an eight‑membered ring in CTX3C and a seven‑membered ring in CTX4A) and by the absence of an aliphatic side chain on the A‑ring. Several toxic Caribbean CTX analogues have been identified and isolated from fish. The major Caribbean toxin is C‑CTX1 and its 56‑epimer C‑CTX2. C‑CTX2 was found as a minor analogue in fish. The C‑CTX backbone shares characteristics with CTX4A and CTX3C but does not possess the aliphatic side chain on the A‑ring and it contains an additional ring on the right wing of the molecule. Additional Caribbean CTXs have been reported in several studies but have yet to be structurally elucidated. An Indian Ocean group has also been described, and although masses have been reported in the literature, no molecular structures have been determined to date. The most toxic analogue described to date is CTX1B, which is stable at 100 °C, 1 N NaOH, and in sunlight for 1 h, but loses toxicity in 1 N HCl after 10 min. Ciguatoxins are odourless, tasteless, heat stable and present at very low (typically < ppb) levels in contaminated seafood, making them difficult to detect without advanced detection methods. The toxic potency of CTXs has been shown to increase as they become more oxidized. Analogues isolated from the Pacific are currently thought to be the most potent and have been well characterized. Some CTXs are metabolites generated through the process of enzyme‑mediated biotransformation in invertebrates and fish. Experimental CTX1B oral and intraperitoneal dosing studies in mice have confirmed the rapid absorption capacity of CTXs, and their ability to cross the blood–brain barrier. There is a similar compartmentalization of toxins across tissues into liver, spleen, brain, muscle, gonads, fat and bone. A remarkable feature of Gambierdiscus is its unique biochemical machinery, responsible for the production of multiple structurally complex polyether toxins, including CTXs, gambierol, gambierone, gambieroxide, gambieric acids and maitotoxins. Three families of CTXs have commonly been classified according to their geographical location, i.e. Pacific CTXs, Caribbean CTXs (C‑CTXs) and Indian Ocean CTXs (I‑CTXs). However, it is now possible and appropriate to classify CTXs based on the known chemical structures. The structural characteristics of CTXs actually allow further classification into two separate groups based on their chemical structure, i.e. CTX3C vs CTX4A backbones and their derivatives. The Caribbean CTXs represent a third group. To date, only two Caribbean CTXs have been structurally elucidated (C‑CTX1 and C‑CTX2). A classification into five groups has been suggested, and this report uses this classification: CTX3C, CTX4A, C‑CTX, I‑CTX (the existence of this group is still speculative as the structure elucidation is pending), and other Gambierdiscus metabolites. None of the methods described has been reported to have undergone single‑ or multi‑laboratory validation. While some laboratories have produced reference materials and quantified standards on a small scale, recent data have most consistently reported CTX3C equivalents, owing to commercial availability. Several assays for the screening of fish samples for CTXs have been described, based on in vitro assays (N2A‑MTT assay, immunoassays, receptor binding assay [RBA]) and in vivo (mouse) bioassays. These in vitro assays all have high throughput capacity due to the 96‑well plate formats used, which allow parallel measurements at the respective endpoints of each assay. However, reliable quantification of the bioactivities and/or toxicity of CTXs in seafood extracts requires a certified reference and, where possible, a matrix‑matched reference. Liquid chromatography coupled with mass spectrometry (LC‑MS) is a suitable approach for the identification and confirmation of CTXs and related compounds in a range of matrices. Information on fish consumption, particularly in countries with high rates of CP, is fragmentary. The estimated doses eliciting CP are in the range 48.4–429 pg/kg bw CTX1B equivalents. The minimum eliciting dose of 48.4 pg/kg bw CTX1B equivalents provides an estimate of a lowest observed adverse effect level (LOAEL) for CP in humans. Both the United States Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA) have proposed a fish CTX concentration of 0.01 μg CTX1B/kg fish flesh as being unlikely to elicit symptoms of CP. This concentration is just below the lowest concentrations seen in fish samples associated with CP cases (0.02 μg CTX1B equivalents/kg fish flesh). As documented by mouse ip LD50, variability in the potencies exists between some different analogues of CTXs. On the basis of LD50 estimates in mice, oral CTX1B (also known as CTX1) (0.22 μg/kg bw) was similar in potency to ip CTX1B (0.25 μg/kg bw). CTX1B and CTX4C have a cumulative effect on the cardiac tissue at a dose of 0.1 μg/kg bw for 15 days. A medium term low dose CTX1B exposure impairs spatial learning and reference memory in rats. Repeated exposures of rats (every 3 days for 8 weeks) to a low dose of CTX1B (0.065 μg/kg bw) after an initial high dose (0.26 μg/kg bw) leads to the development of anxiety‑like behaviour learning and memory deficits, and decision‑making impairment. Neurotoxic effects in rats are similar to symptoms reported in humans. After about 18 weeks, mice treated with 0.1 μg/kg bw show hypertrophy and histological changes in the heart. No effects are observed in mice treated with 0.05 μg/kg bw. A non‑observable adverse effect level (NOAEL) for heart toxicity is 0.05 μg/kg bw (after 40 weeks, once a week). None of these studies were considered suitable to establish a health‑based guidance value (acute or chronic). Human data allowed identification of a LOAEL of 50 pg CTX1B/kg bw after actute exposure. The main target of CTXs is the voltage‑gated sodium channel (VGSC, Nav), causing hyperexcitability of the nerve membrane, eliciting spontaneous and repetitive action potentials by interacting with receptor‑site 5 of the alpha subunit pore of the VGSC. Ciguatoxins show affinity for all the VGSC isoforms (Nav 1.1–1.9), with differences in potency between the different toxin types. CTX binding to the VGSC causes a shift in voltage dependence of Na+ conductance to more negative membrane potentials, allowing an increase in Na+ influx and spontaneous action potential firing. The overall effect is an increase in excitability. This action, especially in peripheral nerves where binding of CTXs to Nav is long‑lasting, explains most of the effects of the group. Data on CTX toxicokinetics in humans are very limited. Many ciguatera cases express central nervous system symptoms, suggesting that CTXs can enter the brain. Ciguatoxins have been measured in blood several hours after ingestion. However, toxins may not persist long in blood as they are undetectable in serum, plasma or urine 90 hours after poisoning. Ciguatoxins have been detected in human liver in an autopsy of a lethal case six days after fish consumption. Case reports describing symptoms among infants of ciguatera‑affected mothers suggest that women may eliminate toxins via breast milk, and that toxins may be resorbed through breast milk. Transplacental toxin transfer is possible. The consumption of ciguatoxic fish is followed by the onset within 48 hours of specific, incident neurological symptoms: cold allodynia (which may be considered as nearly pathognomonic), paraesthesia, dysaesthesia, pruritus, myalgia, arthralgia and/or dizziness. Unspecific symptoms such as severe fatigue and any kind of pain (e.g. myalgia, arthralgia and dentalgia) are very common. More than 175 different symptoms have been reported to date. Chronic ciguatera symptoms are those that persist beyond three months after the initial poisoning, and concern at least 20 percent of ciguatera‑affected persons. Ciguatera poisoning may have neurological, psychiatric and/or general symptoms that can persist for months or years after the initial poisoning. There is no specific treatment. The fatality rate has been estimated as < 0.5 percent, but in some contexts may exceed 10 percent. Death due to CTX exposure often follows cardiovascular and/or complications of the central nervous system. It might be preventable by avoiding consumption of fish heads, liver and viscera, or possibly through better clinical management practices. If, as suspected, only 10–20 percent of actual intoxications are formally reported to the authorities, the problem of CP poisoning is much larger than official figures show. Although there are many gaps in the available information about CP, there are some needs that require urgent attention regarding both risk management and research. The main needs for risk management are for the definition of clear protocols to avoid the risk of consuming toxic fish, mainly by local people and tourists, but also consumers purchasing imported fish from certain areas. This includes a well‑defined information and outreach programme, and a clear identification of the geographic distribution of fish and causative organisms. The main research needs refer to detection methods, both screening and analytical, and the need to have a stable supply programme of analytical standards.

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FAO, WHO (2020). Report of the Expert Meeting on Ciguatera Poisoning. Rome, 19–23 November 2018. Food and Agriculture Organization of the United Nations (FAO).