Food Reviews International
For Peer Review Only
A global retrospective study on human cases of tetrodotoxin (TTX) poisoning after seafood consumption
Journal: Food Reviews International
Manuscript ID LFRI-2019-0012.R1
Manuscript Type: Review
Date Submitted by the n/a Author:
Complete List of Authors: Guardone, Lisa; Universita degli Studi di Pisa, Veterinary Sciences, FishLab Maneschi, Andrea; Universita degli Studi di Pisa, Veterinary Sciences Meucci, Valentina; Universita degli Studi di Pisa, Veterinary Sceinces Gasperetti, Laura; Istituto Zooprofilattico Sperimentale Lazio e Toscana Nucera, Daniele; Universita degli Studi di Torino, Department of Agriculture, Forest and Food Science Armani, Andrea; Universita degli Studi di Pisa, Veterinary Sceinces
Keywords: Pufferfish, marine toxins, human poisoning, toxic fish species, risk
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1 2 3 1 Title: 4 5 6 2 A global retrospective study on Hhuman cases of tetrodotoxin (TTX) 7 8 9 3 poisoning intoxication due to the ingestion ofafter seafood products 10 11 4 containing tetrodotoxin: a global retrospective study consumption 12 13 14 5 15 16 17 6 Running head: 18 For Peer Review Only 19 7 Human cases of TTX poisoning worldwide 20 21 22 8 Lisa Guardonea, Andrea Maneschia, Valentina Meuccia, Laura Gasperettib, 23 24 c a* 25 9 Daniele Nucera , Andrea Armani 26 27 10 28 29 a 30 11 FishLab, Department of Veterinary Sciences, University of Pisa, Viale delle Piagge 2, 31 32 12 56124, Pisa, Italy; 33 34 13 bIstituto Zooprofilattico Sperimentale Lazio e Toscana, S.S. dell’Abetone e del Brennero 35 36 37 14 4, 56123 Pisa, Italy; 38 39 15 cDepartment of Agriculture, Forest and Food Science, University of Turin, Largo 40 41 16 Braccini 2, 10095, Grugliasco – Turin, Italy. 42 43 17 44 45 46 18 47 48 19 *corresponding author: 49 50 20 Postal address: FishLab, Department of Veterinary Sciences, University of Pisa, Viale 51 52 53 21 delle Piagge 2, 56124, Pisa (Italy) 54 55 22 Tel: +390502210207; Fax: +390502210213 56 57 23 Email: [email protected] 58 59 60
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1 2 3 25 Abstract 4 5 6 26 The presentA global retrospective study on human cases of tetrodotoxin (TTX) 7 8 27 intoxication caused by seafood consumption was conductedaimed at updating the 9 10 28 relative risk according to seafood product categories and geographical areas. Overall, 11 12 29 3032 cases from five continents were collected, mainly from Asia. OverMore than half 13 14 15 30 of them cases were attributed to fish, followed by gastropods, arthropods and 16 17 31 cephalopods. The intoxication source and its origin varied between geographical 18 For Peer Review Only 19 32 regions: iIn South East and East Asia intoxications derived from all the aforesaid 20 21 22 33 seafood product categories, locally sourced; in Oceania, Sub-Saharan Africa and 23 24 34 Centre-South America from local pufferfish. In Europe dated cases were caused by 25 26 35 imported Asian products, as in North America. However, recent intoxications in Spain 27 28 29 36 and in Middle East and North Africa, caused by locally caught products, confirm the 30 31 37 occurrence of TTX even in areas previously marginally not affected by this public 32 33 38 health issue. 34 35 39 36 37 38 40 Keywords: 39 40 41 Pufferfish, marine toxins, human poisoning, toxic fish species, public health, 41 42 42 tetrodotoxin, risk 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 44 1. Introduction 4 5 6 45 Tetrodotoxin (TTX) is one of the most potent neurotoxins known [1] and the 7 8 46 most commonly involved in lethal marine poisoning [2]. In fact, TTX intoxication can 9 10 47 be defined as a paralytic syndrome and it is part, together with ciguatera poisoning and 11 12 48 Paralytic Shellfish Poisoning (PSP), of a group of major marine intoxications with 13 14 15 49 neurological involvement [2]. TTX is a water-soluble heterocyclic guanidine that blocks 16 17 50 Na+ conductance (Isbister and Kiernan 2005), inhibiting theits passage of this ion into 18 For Peer Review Only 19 51 the membranes of excitable cells, such as muscle and nerve tissue, leading to 20 21 22 52 immobilization [3]. Clinical signs develop rapidly, usually between 10 minutes and 15 23 24 53 hours after ingestion of contaminated seafood products [4-6]. Early neurological 25 26 54 symptoms include perioral and distal limb numbness and may be associated to nausea 27 28
29 55 and vomiting. Severe poisoning causes generalized flaccid paralysis and cardiovascular 30 31 56 effects. The severity of symptoms is dose-dependent, and death mainly occurs due to 32 33 57 respiratory failure [1-2]. Since no specific antidote is available, therapy is mainly 34 35 58 represented by aggressive supportive and symptomatic treatment [7]. 36 37 38 59 Tetrodotoxin (TTX) is one of the most potent neurotoxins known (Hwang and Noguchi 39 40 60 2007) and the most commonly involved in lethal marine poisoning (Isbister and Kiernan 41 42 61 2005). The name TTX derives in fact from the Teleost fish order Tetrodontiformes 43 44 45 62 (Nagashima & Arakawa 2016Hanifin 2010), as the toxin has been isolated from 46 47 63 members of this taxa, in particular from Tetraodontidae (pufferfish) [8-9]. In Japan 48 49 64 pufferfish are considered a delicacy and TTX intoxication is an historically known issue 50 51 52 65 [10]. In the past TTX was believed to be exclusively present in this taxonomic group 53 54 66 (Noguchi and Arakawa 2008). However, TTX has been subsequently isolated also 55 56 67 fromin other marine organisms such as tropical fish of the of the Gobiidae family in 57 58 68 Asian [11], marine gastropods [12-15], bivalves [16-19], cephalopods (only 59 60
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1 2 3 69 Hapalochlaena spp., family: Octopodidae) [20], arthropods (only Carcinoscorpius 4 5 6 70 rotundicauda and crabs of the Xanthidae family) [1, 21], as well as Echinodermata 7 8 71 (starfish, Astropectinidae), several taxa of worms (Turbellaria, Nemertinea, Anellida 9 10 72 Polychaeta, Chaetognata) and algae [9]. Besides this wide range of marine species, TTX 11 12 73 has also been isolated from a single class of terrestrial vertebrates (Amphibia: frogs and 13 14 15 74 newts) [22]. Subsequently, an exogenous origin of TTX [9, 23] with marine bacteria as 16 17 75 a primary source [17] has been hypothesized. Further discovers, such as TTX 18 For Peer Review Only 19 76 production by marine bacteria and the absence of TTX toxicity in farmed pufferfish fed 20 21 22 77 with non-toxic diets, together with the widespread occurrence of TTX in numerous 23 24 78 phylogenetically unrelated taxa, allowed hypothesizing an exogenous origin 25 26 79 (Magarlamov, Melnikova, and Chernyshev 2017; Noguchi and Arakawa 2008) with 27 28 29 80 marine bacteria as a primary source (EFSA CONTAM Panel 2017). According to a 30 31 81 recent literature review, 31 different bacteria genera able to produce TTX have been 32 33 82 isolated until 2017, among which the most common is Vibrio spp. [23]. However, the 34 35 83 pathway of TTX bioaccumulation in marine ecosystems is still subject to debate [23- 36 37 38 84 24]. 39 40 85 TTX intoxication can be defined as a paralytic syndrome and it is part, together 41 42 86 with ciguatera poisoning and Paralytic Shellfish Poisoning (PSP), of a group of major 43 44 45 87 marine intoxications with neurological involvement (Isbister and Kiernan 2005). TTX is 46 47 88 a water-soluble heterocyclic guanidine that blocks Na+ conductance (Isbister and 48 49 89 Kiernan 2005), inhibiting the passage of this ion into the membranes of excitable cells, 50 51 52 90 such as muscle and nerve tissue, leading to immobilization (Denac, Mevissen, and 53 54 91 Scholtysik 2000). Clinical signs develop rapidly, usually between 10 minutes and 15 55 56 92 hours after ingestion (Arakawa et al. 2010; Chew et al. 1983; Chowdhury et al. 2007). 57 58 93 Early neurological symptoms include perioral and distal limb numbness and may be 59 60
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1 2 3 94 associated to nausea and vomiting. Severe poisoning causes generalized flaccid 4 5
6 95 paralysis and cardiovascular effects. The severity of symptoms is dose-dependent, and 7 8 96 death mainly occurs due to respiratory failure (Hwang and Noguchi 2007; Isbister & 9 10 97 Kiernan 2005). Since no specific antidote is available, therapy is mainly represented by 11 12 98 aggressive supportive and symptomatic treatment (Salzman, Madsen and Greenberg 13 14 15 99 2006). 16 17 100 Considering the high severity of TTX poisoning and since intoxication following 18 For Peer Review Only 19 101 consumption of pufferfish is well known worldwide, many governments have banned or 20 21 22 102 restricted their consumption and trade. In Asia, where the problem is historically known 23 24 103 and TTX intoxication is one of the most frequent fish poisonings [25], many countries 25 26 104 developed specific legislation. Japan is the country in which legislation is more 27 28 29 105 articulate and establishes, since 1958, that the chefs must have a license to cook dishes 30 31 106 based on puffer fish. Moreover, an official list concerning edibility of various species of 32 33 107 pufferfish and their tissues exists since 1983 [9] and is regularly updated [26]. Beside 34 35 108 this country, restrictions are in place in China [27], Thailand [28], Taiwan [29], 36 37 38 109 Vietnam [30], in the USA [31] and in Europe [32]. 2011), Taiwan (Huang et al. 2014) 39 40 110 and Vietnam (Cong and Tuan have banned or restricted the use of pufferfish. Limitation 41 42 111 are in place also in the USA, where a single company is allowed to import Takifugu 43 44 45 112 rubripes for restaurants. Moreover, consumption of local pufferfishes caught in coastal 46 47 113 waters of the mid-Atlantic (between New York and Virginia state) is admitted since 48 49 114 these are considered free from the toxin, while the State of Florida currently has a ban 50 51 52 115 on both commercial and recreational harvesting of pufferfish 53 54 116 (https://www.fda.gov/food/recallsoutbreaksemergencies/safetyalertsadvisories/ucm0854 55 56 117 58.htm; 57 58 118 https://www.fda.gov/InternationalPrograms/Agreements/MemorandaofUnderstanding/u 59 60
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1 2 3 119 cm107601.htm). Europe has a very stringent legislation as regards poisonous fish and 4 5 6 120 marine biotoxins. In fact, according to the Reg. (CE) n. 853/2004 "Fishery products 7 8 121 obtained from poisonous fish of the following families must not be placed on the 9 10 122 market: Tetraodontidae, Molidae, Diodontidae and Canthigasteridae". 11 12 123 TtThe very wide range of organisms that can host TTX, the complexity of the 13 14 15 124 global seafood market, together with human intervention on the environment and 16 17 125 climate change, has enhanced the risk of consumption of TTX-contaminated food also 18 For Peer Review Only 19 126 in countries not historically affected by this issue. Increasing worldwide trade of 20 21 22 127 seafood products favors TTX intoxication due to fraudulent episodes [28, 33] or to 23 24 128 illegal importation [34-35]. The arrival in 2003 of the toxic pufferfish Lagocephalus 25 26 129 sceleratus from the Red sea (Akyol et al. 2005), favored by 27 28 29 130 AAanthropogenic environmental modification and climate change have 30 31 131 introduced TTX as an emerging public health problem in the Mediterranean area [36- 32 33 132 37] due to the arrival in 2003 of the toxic pufferfish Lagocephalus sceleratus from the 34 35 133 Red sea (Akyol et al. 2005). At least eleven species of the family Tetraodontidae have 36 37 38 134 been reported in the Mediterranean Sea [38]. The arrival in 2003 of the toxic Lessepsian 39 40 135 species L. sceleratus from the Red Sea aroused strong interest as it represents a potential 41 42 136 public health hazard. In fact, several studies have confirmed the presence of TTX in this 43 44 45 137 species [36, 39-42]. In addition, the toxin was also found in Lagocephalus. 46 47 138 lagocephalus [43] and recently in Torquigener flavimaculosus [44] and L. suezensis 48 49 139 [42]. Similar factors are believed to be responsible of the spreading of TTX along the 50 51 52 140 North East Atlantic Ocean coasts [45M. J. Silva et al. 2012]. 53 54 141 The aim of the present work was to conduct a global retrospective study on human cases 55 56 142 of intoxication due to the ingestion of seafood products containing TTX, considering 57 58 143 that a single outbreaks are often described in case reports and a similar comprehensive 59 60
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1 2 3 144 review on this topic is lacking. Therefore, . In fact,Although other available reviews on 4 5 6 145 TTX intoxication exist (EFSA CONTAM Panel 2017; Hwang and Noguchi 2007; Lago 7 8 146 et al. 2015; Noguchi and Arakawa 2008; Panao et al. 2016) , they deal with general 9 10 147 characteristics of the toxin and only report some intoxications cases from different 11 12 148 geographical area. Besides, many single outbreaks are described in case reports and. 13 14 15 149 Since all these fragmentary data are fragmentary and had not been systematically 16 17 150 reviewed altogether. , the aim of the present work was to conduct a global retrospective 18 For Peer Review Only 19 151 study on human cases of intoxication due to the ingestion of seafood products 20 21 22 152 containing TTX. Specific attention was paid to the geographical area of the intoxication, 23 24 153 the source and its origin (local or imported). in order to better characterize the risk 25 26 154 factors mainly involved in human intoxication. from by gathering fragmentary data on 27 28 29 155 TTX intoxication, outcomes from the present study could be useful to fulfil the actual 30 31 156 knowledge gap on the relative risk related to different food products and geographical 32 33 157 areas associated to this hazard, in order. This is particularly relevant in the light of 34 35 158 complex anthropogenic and environmental factors, including climate change, that could 36 37 38 159 modify the patterns of human intoxication. In fact, the complex anthropogenic and 39 40 160 environmental scenario influences possible patterns of intoxication. 41 42 161 2. Materials and methods 43 44 45 162 2.1. Literature search and selection of cases 46 47 163 To review global cases of TTX intoxication in humans, literature data was searched on 48 49 164 PubMed and Google Scholar databases using the following keywords: (Tetrodotoxin 50 51 52 165 OR TTX) AND (Poisoning) AND (Human OR Human case) AND (Europe OR 53 54 166 America OR United States OR USA OR Africa OR Oceania OR Australia OR Asia). 55 56 167 The search was conducted using the terms altogether or differently combined in order to 57 58 168 retrieve the maximum number of records. Cases described in Japan were excluded from 59 60
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1 2 3 169 the analysis, since the traditional consumption of pufferfish in this country makes the 4 5 6 170 cases of intoxication very common and consequently not always reported in scientific 7 8 171 articles in English. Thus, a literature search could be biased and give incomplete 9 10 172 information on the real incidence of cases in this country. Furthermore, data on the 11 12 173 incidence and prevalence of TTX intoxications in Japan are already available [1, 4, 9, 13 14 15 174 46]. An updated list of cases occurred between 2003 and 2017 is also reported , on the 16 17 175 website of the Ministry of Health, Labour and Welfare of Japan [47]. The reference list 18 For Peer Review Only 19 176 of the screened articles was also checked for eligible new records and Google Scholar 20 21 22 177 search option “cited by” was also used. Papers published in English, French, Italian, 23 24 178 Spanish and Portuguese were included. Articles in other languages were also used if 25 26 179 they presented an English abstract with sufficient details (see below). The search was 27 28 29 180 concluded in April 2018. After deduplication, cases were considered eligible and 30 31 181 included in the study when the following information was provided: i) number of 32 33 182 intoxicated people; ii) geographical location/place of intoxication (at least at country 34 35 183 level); iii) source of intoxication (at least the category of seafood responsible of 36 37 38 184 intoxication). Cases included in the study were supported by clinical (including 39 40 185 anamnesis and typical symptoms) and/or laboratory diagnosis. 41 42 186 2.2. Data Extraction 43 44 45 187 For each study, besides the minimal information (number of intoxicated people; 46 47 188 geographical location/place of intoxication; source of intoxication) the following 48 49 189 additional data were extracted, when available: date of intoxication, number of fatalities, 50 51 52 190 age, sex, geographical origin of the source of intoxication and the part of the food 53 54 191 source consumed (available only for fish products). All data were extracted using 55 56 192 predefined fields in an Excel file. In order to process data from countries with similar 57 58 193 geographical characteristics and bordering the same sea/ocean, the cases relating to 59 60
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1 2 3 194 America were subdivided into North America and Centre/South America, while data 4 5 6 195 from Asia and Africa were further subdivided and regrouped in the following sub-areas: 7 8 196 South-east and East Asia, Middle East and North Africa and Sub-Saharan Africa. This 9 10 197 division will be maintained in the subsequent analysis and discussion of the data. For 11 12 198 the purposes of this work, products originating from the same geographical sub-area 13 14 15 199 where the case of intoxication was reported from were considered locally sourced, as 16 17 200 opposite, the others were defined imported. 18 For Peer Review Only 19 201 2.3. Statistical analysis 20 21 22 202 Associations among variables were investigated using chi-square test for finding 23 24 203 significant differences. Results were considered significant when p<0.05 and highly 25 26 204 significant when p<0.001. Investigated couples of associated variables were: i) 27 28 29 205 geographical location of the intoxication and total number of cases; ii) geographical 30 31 206 location and number of fatal cases; iii) intoxication source and total number of cases; iv) 32 33 207 intoxication source and number of fatal cases; v) geographical location of the 34 35 208 intoxication and origin of the intoxication source. All statistical analyses were 36 37 38 209 performed using the software SPSS ® vs 15 for windows. 39 40 210 3. Results 41 42 211 3.1. Literature search, cases of intoxication, fatality rate, age and sex distribution 43 44 45 212 Totally, 142 scientific articles were selected and analyzed. The articles included in the 46 47 213 study mainly described single outbreaks occurred in different areas of the world. 48 49 214 Besides, data were collected also from 7 reports or newspaper articles cited in the 50 51 52 215 reference list of some articles. Out of all these records, 3032 cases matched the 53 54 216 inclusion criteria. In the large majority of the cases, no laboratory analysis was carried 55 56 217 out to confirm the toxin involved and the TTX intoxication was clinically diagnosed on 57 58 218 the basis of the anamnesis and of the symptoms (n=2641, 87.1%). Only 375 cases were 59 60
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1 2 3 219 supported by a wide range of toxicological tests, often combined (detailed in Table 4 5 6 220 1SM). In addition, in 16 cases it was reported that the presence of TTX in the source 7 8 221 was confirmed, but the test used was not specified. 9 10 222 Out of the 3032 cases, at least 341 were fatalities (11.2%). Overall, precise age 11 12 223 was available only for 304 cases of intoxications (10.0%). In these cases, the 13 14 15 224 intoxication showed the highest frequency in children under 10 (23.3%), followed by 16 17 225 thirties (20.3%), forties (18.0%), fifties (11.5%), under 20 (11-20 years of age) (10.5%), 18 For Peer Review Only 19 226 twenties (9.5%), over sixty (6.5%). In addition, in 169 cases the mean age was reported 20 21 22 227 and in 517 cases an age range was indicated. The overall range was 4-74. As regards the 23 24 228 sex ratio, gender was available for 1335 cases (44.0%): 898 were males (67.3%) and 25 26 229 437 were females (32.7%). 27 28 29 230 3.2. Geographical location 30 31 231 Cases were reported from five continents (Fig. 1). The vast majority of the cases were 32 33 232 described in Asia (Japan excluded, see section 2.1) (n=2686, 88.6%), followed by 34 35 233 Africa (n= 203, 6.7%), America (n=90, 3.0%), Oceania (n=39, 1.3%) and Europe 36 37 38 234 (n=14, 0.5%). As mentioned, data from America were subdivided into North America 39 40 235 (n=23, 0.8%), Centre/South America (n=67, 2.2%), while data from Asia and Africa 41 42 236 were further subdivided and regrouped as follows: South-East and East Asia (n=2668, 43 44 45 237 87.9%), Middle East and North Africa (n=168, 5.5%) and Sub-Saharan Africa (n=53, 46 47 238 1.7%). Complete details are given in Table 1. A significant difference in the fatality rate 48 49 239 was observed in relation to the geographical area, both in terms of continents and in 50 51 52 240 terms of sub-regions. As regards continents, Asia showed the lowest fatality rate 53 54 241 (10.4%), while the other 4 continents were comparable (15.4-21.4%). As regards the 55 56 242 sub-areas, Sub-Saharan Africa, Europe and North America showed statistically higher 57 58 243 fatality rates (20.8-30.4%) (Table 2). 59 60
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1 2 3 244 3.3. Source of intoxication 4 5 6 245 The source of intoxication was represented by fish in 1817 cases (59.9%), gastropods in 7 8 246 634 cases (20.9%), arthropods in 492 (16.2%) and cephalopods in 89 (2.9%) (Fig. 2). 9 10 247 Data on the source of intoxication are detailed in Table 3 and briefly presented below. 11 12 248 Among the fish category, most of the cases (n=1703, 93.7%) were due to the ingestion 13 14 15 249 of fishes of the order Tetraodontiformes. Of these, 123940 were generically indicated as 16 17 250 pufferfish. The remaining cases were due to the ingestion of species of different 18 For Peer Review Only 19 251 Tetraodontidae genera such as Takifugu, Lagocephalus, Arothron, Tetrodon, 20 21 22 252 Sphoeroides, or to the ingestion of Diodon spp. (n=10) (Diodontidae - Porcupinefish) or 23 24 253 of species of the Ostraciidae family (n=4) (Boxfish). The other fish species belonged to 25 26 254 the family Gobiidae (Perciformes) (n=33, 1.8%) or were not identified (n=82, 4.5%) 27 28 29 255 (Table 3). As regards gastropods, the large majority of intoxications (n=618, 97.5%) 30 31 256 were attributed to the consumption of members of the order Neogastropoda, family 32 33 257 Nassaridae and especially to species of the genus Nassarius spp. (n=468). A small 34 35 258 number of cases was attributed to Natica fasciata, Charonia lampas, Oliva spp., 36 37 38 259 Neverita didyma and to not identified gastropod species. Interestingly, intoxications due 39 40 260 to the consumption of arthropods were exclusively due to Carcinoscorpius 41 42 261 rotundicauda (horseshoe crab). Similarly, only one species, Hapalochlaena fasciata 43 44 45 262 (blue-lined octopus), was involved in the cases related to the consumption of 46 47 263 cephalopods (n=89) (Table 3). 48 49 264 A significant difference in the fatality rate was observed in relation to categories 50 51 52 265 of the sources involved. In fact, the fatality rate was significantly higher following the 53 54 266 consumption of fish products (16.3%) rather than other products categories (gastropods 55 56 267 4.9%, arthropods 2.4% and cephalopods 2.2%). 57 58 268 3.3.1 Source of the intoxication in relation to the geographical sub-area 59 60
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1 2 3 269 The distribution of the different categories of product implicated in cases of 4 5 6 270 intoxications in relation to the sub-areas are summarized in Fig. 3 and described in 7 8 271 detail in Table 1 and Table 2SM. Only in South East and East Asia all the categories 9 10 272 were implicated: fish was responsible for around half of the intoxications (n=1454, 11 12 273 54.5%), followed by gastropods (n=633), arthropods (n=492) and cephalopods (n=89). 13 14 15 274 The only other sub-area where two categories were implicated was Europe (Table 1). 16 17 275 As regards South East and East Asia more in details, most intoxications caused by fish 18 For Peer Review Only 19 276 were attributed to species belonging to the order Tetraodontiformes (n=1354, 93.1%). 20 21 22 277 Other fish species responsible for intoxications were gobiids, which do not belong to 23 24 278 this order and were reported as intoxication source exclusively from Asia, mainly from 25 26 279 China (n=22) and to a lesser extent from Taiwan (n=11). Of the 633 cases attributed to 27 28 29 280 gastropod consumption in Asia, the vast majority of them (n=547, 86.4%) occurred in 30 31 281 China, followed by Taiwan (n=74, 86.4%) and Vietnam (n=547, 86.4%). 32 33 282 C. rotundicauda intoxications (n=492) mostly occurred in Thailand (n=457), followed 34 35 283 by Malaysia (n=30) and China (n=5). Intoxication cases caused by the consumption of a 36 37 38 284 cephalopod retrieved in this study were found in Taiwan and Vietnam (n=2 and n=87 39 40 285 respectively). 41 42 286 In Middle-East and North Africa, except for 12 cases for which the fish species was not 43 44 45 287 identified, the remaining 156 cases were generically attributed to pufferfish (n=62) or 46 47 288 specifically to Lagocephalus sceleratus (n=94). This species was the only responsible 48 49 289 for intoxication in Israel (n=16) and Lebanon (n=2) and the responsible for most of the 50 51 52 290 cases occurred in Egypt (n=76/147). Similarly, the limited number of TTX poisonings 53 54 291 in Centre and South America (n=67) were generically attributed to pufferfish (n=47) or 55 56 292 to a single pufferfish species, which in this subarea was Sphoeroides spp. (n=18). Also, 57 58 293 the 53 cases reported in Sub-Saharan Africa, were exclusively caused by the 59 60
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1 2 3 294 consumption of pufferfish. They mainly occurred in the islands of the Western Indian 4 5 6 295 Ocean, in particular on the Island of Reunion (n=33), Madagascar (n=17) and Zanzibar 7 8 296 (n=1). As regards Oceania, TTX intoxications were mainly described in Australia 9 10 297 (n=31, 79.5%) and exclusively caused by several species of fish belonging to the order 11 12 298 Tetraodontiformes. In North America 23 TTX intoxications were reported, only from 13 14 15 299 the United States and exclusively caused by pufferfish. The most implicated genera 16 17 300 were Lagocephalus, in particular L. lunaris (n=4) and Arothron (n=4). Other identified 18 For Peer Review Only 19 301 species were Diodon hystrix (n=1) and Sphoeroides testudineus (n=1). 20 21 22 302 Finally, as regards Europe, the numerically scarce intoxications (n=14) are for 23 24 303 the most part fairly dated and caused by pufferfish (n=13). The only remaining case 25 26 304 occurred in October 2007 in Malaga, Spain, following the consumption of marine 27 28 29 305 gastropods (Charonia lampas lampas) caught in the Southern coast of Portugal. 30 31 306 3.3.2. Anatomical part of the seafood consumed 32 33 307 The anatomical part consumed was indicated only for fish and in 287 cases of 34 35 308 intoxication (16.8%). Flesh was consumed in 121 cases (42.2%), gonads in 73 cases 36 37 38 309 (25.4%) and liver in 33 cases (11.5%) (Fig. 4). Different combinations of these body 39 40 310 parts were ingested in the remaining 60 cases. 41 42 311 3.3.3. Geographical origin of the source of intoxication 43 44 45 312 Overall, data on the geographical origin of the food source was available for 1114 cases 46 47 313 (36.7%). The large majority were locally sourced (n=1090, 97.8%), while the remaining 48 49 314 cases were imported (n=24, 2.2%). Differences related to the geographical areas were 50 51 52 315 observed: in South East and East Asia, all the cases with known origin derived from 53 54 316 locally sourced seafood products. Similarly, in Middle East and North Africa, the 27 55 56 317 cases with known origin were all due to local specimens, originating from the 57 58 318 Mediterranean or the Red Sea. Also, in Centre-South America, Sub-Saharan Africa and 59 60
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1 2 3 319 Oceania all the cases with known origin were due to locally fished species. On the 4 5 6 320 contrary, in North America all the cases with known origin were related to fish imported 7 8 321 from Asia (China, South Korea, Japan). Finally, as regards Europe, 13 of the 14 9 10 322 reported cases were due to imported fish (92.9%) while one case was due to the 11 12 323 consumption of local gastropod (Table 2SM). 13 14 15 324 4. Discussion 16 17 325 4.1. Cases of intoxications and diagnosis, fatality rate and toxicity of the seafood 18 For Peer Review Only 19 326 category 20 21 22 327 4.1.1. Cases of intoxications and diagnosis 23 24 328 The diagnosis of TTX intoxication is generally clinical [2], often supported by a 25 26 329 medical history that indicates the previous consumption of seafood products. Also, the 27 28 29 330 identification of the species responsible for the intoxication, for example by the 30 31 331 alimentary remains, can decisively direct the diagnosis [48-51]. The present results 32 33 332 confirmed this trend, as in 87.1% of the cases, no laboratory analysis was performed (or 34 35 333 not reported), neither to evaluate the toxicity of the products, nor to identify the toxin. 36 37 38 334 Although the lack of a supporting laboratory analysis represents a limit of the present 39 40 335 study, the exclusion of cases relying only on clinical diagnosis would strongly 41 42 336 underestimate the global occurrence of cases. However, toxin identification might be 43 44 45 337 important to differentiate TTX intoxication compared to saxitoxin (STX) intoxication, 46 47 338 both inducing similar symptoms. Moreover, both toxins can be isolated from the same 48 49 339 species, including pufferfish [13, 50]. To this end, the use of the mouse bioassay 50 51 52 340 (MBA), important to quantify toxicity, if used alone as it results in 102 cases (3.4%) 53 54 341 included in the present work (Table 1SM), is not useful to discriminate the two toxins 55 56 342 [17]. For the identification of the specific toxin it is therefore important to apply 57 58 343 chemical-analytical or serological methods for analysing the fishery product, the food 59 60
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1 2 3 344 residue or the patient's blood or urine should be applied [2], as occurred in 273 cases 4 5 6 345 (9%)(Table 1SM)., for analysing the fishery product, the food residue or the patient's 7 8 346 blood or urineThe research ofor TTX by HPLC allows its simple quantification of TTX 9 10 347 in urine and serum. However, while TTX ins serum TTX maybe is undetectable after 11 12 348 12-24h, TTXit can last up to 5 days in urine up to 5 days (Isbister and Kiernan 2005; 13 14 15 349 Oda et al. 1989; O'Leary, Schneider, and Isbister 2004). 16 17 350 4.1.2. Fatality rate and toxicity of the seafood category 18 For Peer Review Only 19 351 Although the number of TTX intoxication cases in Asia is the highest, it is interesting to 20 21 22 352 note that the fatality rate (10.4%) is statistically significantly lower than the other 23 24 353 continents (Table 2). Beside the consumption of categories of products (arthropods and 25 26 354 gastropods) associated with a low fatality rate (see section 3.3), maybe this can also be 27 28 29 355 explained in terms of a quicker recognition of symptoms by clinicians and of a better 30 31 356 clinical management of intoxications, acquired over time in this region, as already 32 33 357 hypothesized by Yin et al. [51] (Yin et al. 2005). A similar low fatality rate (8.3%) was 34 35 358 in fact reported for Japan [1]. 36 37 38 359 The reason behind the higher fatality rate associate to fish products was 39 40 360 investigated collecting the results of the MBA for the cases related to fish ingestion 41 42 361 (available in 137 cases out of 1817, 7.5%) (Table 3SM). Fish eggs, and more rarely 43 44 45 362 liver and skin, may overcome the toxic threshold of 1000 MU/g. Values between 100- 46 47 363 1000 MU/g were frequently observed for the same tissues. MBA data from gastropods 48 49 364 involved in intoxications (available in 109 cases out of 634, 17.2%) showed more 50 51 52 365 frequently moderate toxicity (100-1000 MU/g). These concentrations, together with the 53 54 366 utilization of different part of the fish as traditional food in some countries [52], might 55 56 367 be the explanation of the statistically significant differences observed for higher fatality 57 58 368 rate. 59 60
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1 2 3 369 Data on MBA results were not available for C. rotundicauda (horseshoe crab) 4 5 6 370 and Hapalochlaena spp. in the studies included in the analysis. However, the a low 7 8 371 toxicity of the horseshoe crab was evaluated in several works showning low toxicity 9 10 372 level in Thailand [53], Bangladesh and Cambodia [54-55]. Toxicological Ddata on the 11 12 373 toxicological profile of species of Hapalochlaena are described in scarce. In a few 13 14 15 374 studies showingy the presence of the toxin in different organs was shown [56-58]. 16 17 375 Recently, the evolution and origin of TTX acquisition in the blue-ringed octopus has 18 For Peer Review Only 19 376 been reviewed [59]. 20 21 22 377 4.2. Geographical location, source of intoxication and its origin 23 24 378 4.2.1. South East and East Asia 25 26 379 4.2.1.1. Source of intoxication. The fact that Mmost cases of TTX intoxications (88.6%) 27 28 29 380 occurred in Asia is not surprising and is in agreement with the literature data [1-2, 60- 30 31 381 61]. In fact, until 2005, TTX was mainly present in the warm waters of East and 32 33 382 Southeast Asia [10], and in particular Japan [34], Korea [62], China [63-64], Taiwan 34 35 383 [65-66], Thailand [67] and Bangladesh [21, 68]. 36 37 38 384 Fish products. The present study supports the fact that TTX intoxications caused 39 40 385 by pufferfish are still widespread in all Asia coastal countries (M. S. Islam et al. 2011). 41 42 386 In Thailand, which was found as the country with the highest number of intoxications 43 44 45 387 (29.5% of the total intoxications in South-East and East Asia), pufferfish is in great 46 47 388 demand for its cheapness and its neutral taste (Chulanetra et al. 2011). Pufferfish are 48 49 389 caught and is frequently sold illegally, whole, in pieces and in the form of fish-balls, 50 51 52 390 mixed with meat of other species, and they are available in specific restaurants called 53 54 391 "Moo-Kata", which have become popular for this product. Their fraudulent sale of 55 56 392 fishballs sold as salmon but containing toxic pufferfish resulted in about 115 57 58 393 poisonings and 15 deaths in the country in 2007 [28]. In Taiwan and China, although 59 60
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1 2 3 394 people do not consume pufferfish as frequently as in Japan and there are large 4 5 6 395 restrictions in place, poisoning for consumption of wild specimens occurs fairly 7 8 396 frequently (Arakawa et al. 2010). Also iIn Taiwan, poisoning cases are often due to 9 10 397 substitution of edible species with puffer roe or muscle [1]. In Bangladesh, while the 11 12 398 coastal communities seem to be aware regarding the potential toxicity of pufferfish, 13 14 15 399 the3 main outbreaks, involving 141 people in 2008, occurred in inland areas where the 16 17 400 inhabitants, differently from coastal communities, ignored the potential toxicity of these 18 For Peer Review Only 19 401 species [69]. Poverty and food shortages affecting a large part of the population of the 20 21 22 402 country, together with a lack of control measures by the food safety authorities, increase 23 24 403 the risk of poisoning, as pufferfish or their wastes not properly disposed of, are easily 25 26 404 available in local markets at low cost [60, 69]. The socio-economic context of Ppoverty 27 28 29 405 and malnutrition may also partly explain the high mortality rate in this country, around 30 31 406 20.2%, almost twice the Asian average (11.3%). In Vietnam, especially in rural areas, 32 33 407 pufferfish are believed to be frequent responsible for intoxication since they are readily 34 35 408 available and considered a delicacy, although their commercialization is actually banned 36 37 38 409 [30]. 39 40 410 The intoxications due to Gobiidae were observed only in China and Taiwan, 41 42 411 likely due to the fact this seafood is usually consumed in Chinese coastal regions [70]. 43 44 45 412 To date only 4 species of the Gobiidae family are known to be toxic due to the presence 46 47 413 of TTX and currently the sale or consumption of gobiids in China is not restricted. 48 49 414 Interestingly, several intoxicated patients declared that they were not aware of the 50 51 52 415 toxicity of these fish and that they had consumed them previously, without any 53 54 416 consequence [71]. 55 56 417 Gastropod products. Most cases occurred in Taiwan and China, countries with a 57 58 418 long tradition of consumption of small detritivorous gastropods, considered a delicacy 59 60
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1 2 3 419 in fishing villages and an economic nutritive food [72]. Marine gastropods are 4 5 6 420 historically involved in intoxications (Arakawa et al. 2010; Noguchi and Arakawa 7 8 421 2007)since they can effectively concentrate TTX if present in the marine environment 9 10 422 [10], even by the consumption of dead puffers [73]. Therefore, prevention must include 11 12 423 the prohibition of consumption of gastropods in Asian areas affected, unless coming 13 14 15 424 from certified marine areas (Shui et al. 2003). 16 17 425 18 For Peer Review Only 19 426 Arthropod products. Cases of intoxications due to its consumption were only 20 21 22 427 reported from Thailand, Malaysia and China. In fact, eggs of the horseshoe crab C. 23 24 428 rotundicauda are frequently used to prepare traditional Thai dishes [74]. In Malaysia, 25 26 429 horseshoe crabs’ eggs or flesh are consumed mainly in coastal regions, where the 27 28 29 430 inhabitants claim to know which parts of the animal need to be discarded to avoid 30 31 431 adverse effects [75]. In addition, the misidentification of C. rotundicauda with a similar 32 33 432 morphologically similar edible species, Tachypleyus gigas, enhances the intoxication 34 35 433 risk [1]. The incorrect local beliefs that the toxin is inactivated by cooking, or that it is 36 37 38 434 possible to distinguish between toxic and non-toxic C. rotundicauda specimens, are 39 40 435 additional causes. C. rotundicauda is also consumed in Bangladesh, but studies on 41 42 436 specimens caught in the local Bay of Bengal have shown a very low TTX content [55] 43 44 45 437 and. In fact, no intoxications from this product were reported in this country. 46 47 438 Cephalopod products. Octopus of the genus Hapalochlaena spp. inhabit the 48 49 439 shallow waters of Australia and Southeast Asia [20]. Hapalochlaena spp. octopus were 50 51 52 440 found to be frequently responsible for TTX poisoning following inoculation through the 53 54 441 bite, for example in Australia and Singapore [56, 76], while the intoxication as a result 55 56 442 of food consumption is believed to be rare, as confirmed by the present study. 57 58 59 60
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1 2 3 443 4.2.1.2. Origin of the source of intoxication. All the South East and East Asian cases 4 5 6 444 with known origin derived from locally sourced seafood products. Even for cases not 7 8 445 reporting this information the origin could be considered as local based on the 9 10 446 distribution area of the species responsible for intoxication. This is not surprising 11 12 447 considering that in Asia the presence of TTX is an endemic problem [10]. In addition, 13 14 15 448 factors such as culinary traditions, poverty and weak control by the competent 16 17 449 authorities in some countries, as well as legislative deficiencies, favour the intoxication 18 For Peer Review Only 19 450 occurrence (How et al. 2003; M. S. Islam et al. 2011; Q. T. Islam et al 2011; Lewis 20 21 22 451 2017). 23 24 452 For this reasonreason,, Consequently, several Asian countries issued a specific 25 26 453 legislation. In China a ban on trading and consuming products derived from pufferfish 27 28 29 454 remained in force from 1990 to 2016, although breeding for export was allowed. At the 30 31 455 end of 2016, this ban was removed and two farmed species (Takifugu rubripes and 32 33 456 Takifugu obscurus) were reintroduced on the internal market 34 35 457 [27http://www.newschinamag.com/newschina/articleDetail.do?article_id=910§ion_ 36 37 38 458 id=26&magazine_id=]. Among the other Asian countries also Thailand [28], Taiwan 39 40 459 [29] and Vietnam [30] have banned or restricted the use of pufferfish. 41 42 460 4.2.2. Middle East and North Africa 43 44 45 461 Intoxication in this region were frequently attributed to L. sceleratus. Interestingly, the 46 47 462 intoxication cases caused by this species are quite recent (91 after 2005 and 3 in which 48 49 463 the date is not specified but reported by recent works). These data are related to the 50 51 52 464 recent invasion of the Mediterranean Sea by this species that reached the Eastern 53 54 465 Mediterranean in 2003 [77], following a Lessepsian migration through the Suez Canal 55 56 466 (Guardone et al. 2018). In addition to these cases, a serious case of intoxication by L. 57 58 467 sceleratus was registered in August 2013 in Tunisia, in the inland town of Gafsa [78]. 59 60
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1 2 3 468 Since no sufficient details were available for the intoxication (number of patients 4 5 6 469 involved), it was not included in the analysis. This incident occurred despite a national 7 8 470 awareness campaign following the commercialization of L. sceleratus in the internal 9 10 471 areas of the country, where people, as in Bangladesh (Islam et al. 2011b), were not 11 12 472 aware of the risks posed by this species (Ben Souissi et al. 2014). Considering the high 13 14 15 473 toxicity and the widespread diffusion of L. sceleratus in the Mediterranean Sea [38], it 16 17 474 is reasonable to assume that this speciesit may also be involved in part of the remaining 18 For Peer Review Only 19 475 74 intoxications in this geographical area (of which at least 60 occurred after 2003), 20 21 22 476 although the source was identified only as "generic pufferfish", "unidentified fish" and 23 24 477 "Tetraodontidae". 25 26 478 Data arising from the analysis of the origin of the intoxication source which, when 27 28 29 479 available, was always local, support the role of L. sceleratus as an emerging problem of 30 31 480 food safety and public health in the Mediterranean [36-38]. This issue lead in fact to 32 33 481 various informative interventions and initiatives to prevent its consumption in the 34 35 482 countries bordering the Mediterranean basin (Andaloro et al. 2016; Ben Souissi et al. 36 37 38 483 2014; Kalogirou 2013). 39 40 484 4.2.3. Central-South America 41 42 485 Although pufferfish is not a typical dish of Brazilian cuisine, and intoxications are rare 43 44 45 486 [50], in some regions of the north-east of the country it is consumed routinely [79]. The 46 47 487 involvement of the genus Sphoeroides is in agreement with its geographical distribution 48 49 488 and toxicity. In fact, it is one of the most common pufferfish genus in the waters facing 50 51 52 489 Brazil [80]. This widespread occurrence favours the local origin of the source of 53 54 490 intoxication. In Brazil, in fact, the intoxication by pufferfish mainly occurred as a family 55 56 491 event, often involving at the same time people from the same family or groups of 57 58 492 fishermen who consumed the fish they caught [50, 80]. 59 60
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1 2 3 493 As for Mexico, the second country in the area by number of intoxication cases, 4 5 6 494 tThe pufferfish species found along the Mexican coast have long been considered non- 7 8 495 toxic and edible and consequently no legislative measures have been adopted. 9 10 496 Interestingly, at the beginning of 2000s, Mexico was one of the largest exporters of 11 12 497 pufferfish in the world, with almost 200 tons caught near Baja California [81]. 13 14 15 498 However, TTX was found in at least one organ, in 4 of the 5 species fished near the 16 17 499 Mexican Peninsula of Baja California (Sphoeroides annulatus, Sphoeroides lobatus, 18 For Peer Review Only 19 500 Arothron meleagris and Canthigaster punctatissima) [82] where poisonings were 20 21 22 501 reported between 1970 and 1995 [83]. 23 24 502 4.2.4. Sub-Saharan Africa 25 26 503 Cases of poisoning by pufferfish in the south-west Indian Ocean do not occur 27 28 29 504 frequently, therefore people are often unaware of the potential toxicity of these fish. The 30 31 505 most recent case involved an entire family in Reunion in 2013, following the 32 33 506 consumption of L. sceleratus, fished by the father and cooked as a local dish called 34 35 507 carri which involves the use of different parts mixed together, in such a way that might 36 37 38 508 have favoured the general contamination with TTX. Since the island is a French 39 40 509 department, the European legislation that prohibits the commercialization of specimens 41 42 510 of the family Tetraodontidae and its derivatives is in force, but the inhabitants of the 43 44 45 511 place do not seem to be aware of this , so it would be useful to implement information 46 47 512 campaigns to raise awareness the population at risk [52]. 48 49 513 4.2.5. Oceania 50 51 52 514 In this region a presumed TTX poisoning was first documented when Captain James 53 54 515 Cook and his crew, in 1774, stopped off the New Caledonia and decided to consume a 55 56 516 soup made with liver and gonads of a locally purchased fish . The subsequent detailed 57 58 517 description of the symptomatology allows hypothesizing that the food consumed was a 59 60
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1 2 3 518 pufferfish [84]. Although pufferfish intoxications in this area are described as rare, the 4 5 6 519 risk of TTX poisoning exists given the presence of several species of pufferfish in many 7 8 520 Australian coastal regions [2]. In fact, an interesting biodiversity was observed in the 9 10 521 source of intoxication in Oceania:. In particular, other than Tetraodontidae also 11 12 522 Ostraciidae and Diodontidae (among which Diodon hystrix) were reported as 13 14 15 523 responsible for human cases. Even though boxfish (family Ostraciidae) and 16 17 524 porcupinefish (family Diodontidae) are considered as “non-toxic species” [85] in a 18 For Peer Review Only 19 525 study by Elshaer [86] TTX has beenwas extracted from ovary and muscle of D. hystrix. 20 21 22 526 Therefore, the toxicity of these species of Tetraodontiformes needs to be further 23 24 527 clarified. 25 26 528 Similarly, to Central-South America, the origin of the source of intoxication was 27 28 29 529 always local and in most of the cases it involved products caught during recreational 30 31 530 fishing sessions and consumed together with the family (Table 2SM) (Maillaud et al. 32 33 531 2016; Tibbals 1988; Torda, Sinclair, and Ulyatt 1973; Trevett, Mavo, and Warrell 34 35 532 1997). 36 37 38 533 4.2.6. North America 39 40 534 In North America TTX intoxications were exclusively caused by pufferfish. The most 41 42 535 implicated genera were Lagocephalus, in particular L. lunaris, involved in cases after 43 44 45 536 1996, and Arothron, responsible for very dated cases occurred in Hawaii between 1903 46 47 537 and 1925 [1]. In addition, for 3 out of 13 cases generically attributed to pufferfish it is 48 49 538 possible to hypothesize that the species involved was L. lunaris [33]. As in Oceania, a 50 51 52 539 case of intoxication was related to the consumption of D. hystrix [87]. 53 54 540 The 12 oldest intoxication occurred between 1903 and 1986 in Hawaii and in Florida, 55 56 541 which caused at least 7 deaths, are unfortunately poorly detailed. More details are 57 58 542 available for the 11 more recent poisonings, between (1996- and 2014). All were 59 60
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1 2 3 543 caused by products imported from Asia. In 1996 in California 3 cooks were intoxicated 4 5 6 544 by a ready-to-eat product made of fugu bought in Japan and illegally brought to the 7 8 545 USA ([34]. 9 10 546 Subsequently, 7 cases occurred between 2006 and 2007 were traced back to a 11 12 547 Californian wholesaler who supplied local vendors and restaurants in different countries 13 14 15 548 with products labelled as gutted and beheaded monkfish of Chinese origin. In 4 of these, 16 17 549 substitution with L. lunaris (whose muscle contains TTX) was confirmed by molecular 18 For Peer Review Only 19 550 identification and, probably, this species was involved in all 7 cases [33]. Finally, in 20 21 22 551 2014 a pufferfish intoxication occurred in Virginia, in a person who had received a 23 24 552 parcel from relatives in South Korea, [35https://www.foodsafetynews.com/2014/01/fda- 25 26 553 investigating-puffer-fish-poisoning-in-virginia/#.W1WZ5NIzbIX]. This framework 27 28 29 554 shows that the risk of TTX intoxication in the USA comes mainly from imported 30 31 555 products, despite the stringent legislation in force. In fact, a single company is allowed 32 33 556 to import Takifugu rubripes for restaurants. Moreover, as regards consumption of local 34 35 557 pufferfishes, consumption of those caught in coastal waters of the mid-Atlantic 36 37 38 558 (between New York and Virginia state) is admitted since these are considered free from 39 40 559 the toxin, while the State of Florida currently has a ban on both commercial and 41 42 560 recreational harvesting of pufferfish [31]. The ban was established after the largest 43 44 45 561 outbreak due to pufferfish intoxication in the US history [88], which however was 46 47 562 caused by saxitoxinSTX and not by TTX (these cases were not included in our 48 49 563 analysis). 50 51 52 564 On the contrary, endemic pufferfish represented an important source of protein 53 54 565 and income for the East Coast populations of the USA during the Second World War 55 56 566 and in the following decades (Sibunka and Pacheco 1981). Despite the TTX poisonings 57 58 567 recorded in Florida (Benson 1956; Black, Cox, and Horwitz 1978) the East Coast 59 60
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1 2 3 568 pufferfish of the United States were considered as safe for a long time (Quilliam et al. 4 5 6 569 2002). However, between 2002 and 2004, 28 pufferfish poisonings occurred and were 7 8 570 attributed to specimens caught in Florida (Bodager 2002; Landsberg et al. 2006), 9 10 571 representing the largest outbreak due to pufferfish intoxication in the US history (Deeds 11 12 572 et al. 2008). The responsible toxin was identified as saxitoxin and not TTX, therefore 13 14 15 573 these cases were not included in our analysis. Prior to 2002, no toxicity from pufferfish 16 17 574 originating from the region had ever been reported and the same 7 cases reported above 18 For Peer Review Only 19 575 in Florida had been caused by specimens caught outside this specific area (Deeds et al. 20 21 22 576 2008). Following this event, the FDA imposed a ban on the capture and consumption of 23 24 577 local pufferfish in force only for certain counties on the east coast of the State of 25 26 578 Florida, while the specimens fished in the Middle Atlantic remain fishable and tradable 27 28 29 579 as non-toxic between the states of Virginia and New York (FDA, 30 31 580 2014https://www.fda.gov/food/recallsoutbreaksemergencies/safetyalertsadvisories/ucm 32 33 581 085458.htm). However, a risk of TTX intoxication due to the presence of highly toxic 34 35 582 Sphoeroides species is potentially present in the area Deeds et al. (2008).4.2.7. Europe 36 37 38 583 All the 13 dated cases occurred in Europe were always due to the ingestion of imported 39 40 584 mislabelled pufferfish. In addition, intoxications occurred in France due to mislabelling 41 42 585 of fillets of pufferfish sold as burbot (Lota lota) (de Haro et al. 2008) and a mass 43 44 45 586 hospitalization of the crewmembers of a tanker off Crete Island was reported, following 46 47 587 the consumption of L. sceleratus. However, since it was not possible to obtain sufficient 48 49 588 data (number of patients involved) on these cases, they were not included in the 50 51 52 589 analysis. 53 54 590 As mentioned, tThe 13 dated poisonings caused by pufferfish, are all related to the 55 56 591 consumption of Asian Taiwan imported frozen pufferfish, fraudulently labelled as 57 58 592 anglerfish, food and all occurred Italy (Table 2SM): 7 in Iesolo and 3 in Rome in 1977 59 60
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1 2 3 593 (Pocchiari 1977) and 3 in Pavia in the following year (Viviani et al. 1978). The 4 5 6 594 responsible product was frozen pufferfish, imported from Taiwan and fraudulently 7 8 595 labelled as anglerfish (Pocchiari 1978), similarly to the intoxication occurred in France 9 10 596 (de Haro et al. 2008). In addition, a similar intoxication occurred in France due to 11 12 597 mislabelling of fillets of pufferfish sold as burbot (Lota lota) [89] and a mass 13 14 15 598 hospitalization of the crewmembers of a tanker off Crete Island was reported, following 16 17 599 the consumption of L. sceleratus. However, since it was not possible to obtain sufficient 18 For Peer Review Only 19 600 data (number of patients involved) on these cases, they were not included in the 20 21 22 601 analysis. 23 24 602 Interestingly, Tthe remaining recent European case of European intoxication due 25 26 603 the consumption of a marine gastropod caught in Portugal [13, 90] is, on the contrary, 27 28 29 604 due to a locally sourced product. This poisoning from C. lampas lampas is a very 30 31 605 important event from an epidemiological point of view as it is the first confirmed case 32 33 606 of TTX intoxication caused by a fishery product from the European coasts, and as it 34 35 607 testifyiesing the presence of TTX also in the Atlantic Ocean [90], which was further 36 37 38 608 confirmed by the study of M. J. Silva et al. [15] on gastropods from North Portugal. 39 40 609 Subsequently, TTX was found in bivalves (Mytilus edulis and Crassostrea gigas) 41 42 610 collected in the English Channel between February 2013 and October 2014 [18, 91] and 43 44 45 611 in oysters and mussels collected from different Dutch production areas in 2015 and 46 47 612 2016 [17]. Recently, Leão et al. [92], reported the occurrence of TTX associated to 48 49 613 marine Vibrio spp. in bivalves from the Galician Rias, while Turner et al. [45] found 50 51 52 614 high levels of TTX in a new invasive nemertean species in England. In the 53 54 615 Mediterranean Sea, the toxin has been reported in specimens of L. sceleratus caught in 55 56 616 the Aegean Sea in 2007 [39] and along the Spanish coast in 2014 [37], as well as in 57 58 617 specimens of Mytilus galloprovincialis and Venus verrucosa caught in the seas of 59 60
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1 2 3 618 Greece in different periods (2006-2012, 2012 and 2014) [19] and, more recently, in 4 5 6 619 shellfish from Northern and Southern Italy [93-94]. These findings highlight the need of 7 8 620 a new risks based approach to control this food safety issues, also considering that until 9 10 621 now a maximum TTX level in seafood has not been established by the current European 11 12 622 legislation [17]. Currently, EU regulation only manages the risk by prohibiting the 13 14 15 623 marketing of fishery products obtained from fish of the Tetraodontidae families, 16 17 624 Molidae, Diodontidae and Canthigasteridae [32], thus not yet considering the other 18 For Peer Review Only 19 625 product categories that could potentially carry the TTX. 20 21 22 626 It is likely that the presence of TTX was favoured by different factors such as 23 24 627 global warming (Danovaro, Umani, and Pusceddu 2009) and the "Lessepsian" migration 25 26 628 of tropical species, including pufferfish species, which transported TTX and TTX 27 28 29 629 producing bacteria to new areas (Akyol et al. 2005; Bentur et al. 2008; Corsini et al. 30 31 630 2006; Katikou et al. 2009; Por 2012; Rambla-Alegre et al. 2017; M. J. Silva et al. 2012). 32 33 631 In fact, until 2005 TTX distribution mainly affected the warm waters of Southeast Asia 34 35 632 (Bane et al. 2016). 36 37 38 633 Such discovery inevitably has an impact on food safety, as it has determined the 39 40 634 need to manage a risk linked to a new toxin previously not subject to adequate 41 42 635 regulation (Rodriguez et al. 2008). In fact, there are no Health Based Guideline Values 43 44 45 636 (HBGVs) for TTX worldwide and noa maximum TTX levels in seafood in the EU has 46 47 637 nit been established by the current European legislation (EFSA CONTAM Panel 2017). 48 49 638 which EU regulation manages the risk only by prohibiting the marketing of fishery 50 51 52 639 products obtained from fish of the Tetraodontidae families, Molidae, Diodontidae and 53 54 640 Canthigasteridae (Reg. (CE) No. 853/2004), not considering the other product 55 56 641 categories that could potentially carry the TTX. 57 58 642 5. Conclusions 59 60
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1 2 3 643 The present study shows that different food products and geographical context 4 5 6 644 influence the risk of TTX intoxication. 7 8 645 TTX poisoning is confirmed to be a main issue in South East and East Asia. In 9 10 646 this geographical area most of the cases where described following the ingestion of all 11 12 647 the seafood product categories (fish, gastropods, arthropods, cephalopods). 13 14 15 648 Interestingly, it was the only geographical sub-area where intoxications from C. 16 17 649 rotundicauda (arthropod) and Hapalochlaena spp. (cephalopod) were reported. In 18 For Peer Review Only 19 650 Oceania, Sub-Saharan Africa and Central-South America the poisoning cases were 20 21 22 651 caused exclusively by pufferfish, with sporadic frequency and mainly during family 23 24 652 consumption of locally caught specimens. In North America, where cases were 25 26 653 described exclusively in the United States, the consumption of illegally imported or 27 28 29 654 mislabeled Asian products was generally implicated. The same occurred for the few 30 31 655 dated intoxications reported historically in Europe. However, the recent spread of TTX 32 33 656 towards new marine environments, such as the Mediterranean Sea and the Atlantic 34 35 657 Ocean, represent an emerging risk in Europe, in Middle East countries and North 36 37 38 658 Africa, as confirmed by the recent cases of intoxication in these regions. 39 40 659 Even though, in view of the large geographical area and period of time analyzed, 41 42 660 it is possible that a few cases reported in grey literature might have escaped the analysis, 43 44 45 661 outcomes from this comprehensive global survey furnish an update scenario on TTX 46 47 662 intoxication according to geographical area and the implicated seafood. It therefore 48 49 663 represents a useful source of data to feed risk assessment by taking into account the 50 51 52 664 changing environmental and anthropogenic factors. Consequently, risk management 53 54 665 should be updated, also considering that there are no Health Based Guideline Values for 55 56 666 TTX worldwide. Beside issuing updated regulation, increasing awareness of all the 57 58 59 60
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1 2 3 667 stakeholders, such as policy makers, food business operators and consumers is strongly 4 5 6 668 needed. 7 8 669 9 10 670 Even though, in view of the large geographical area and period of time analysed, 11 12 671 it is possible that a few cases reported in grey literature might have escaped the analysis, 13 14 15 672 this work represents the first comprehensive global survey, providing epidemiological 16 17 673 data useful for risk assessment. 18 For Peer Review Only 19 674 TTX intoxication is confirmed to be a main issue in South East and East Asia, 20 21 22 675 where most of the intoxications where described. Intoxications occurred in this sub-area 23 24 676 derived from the widest variety of product categories: beside fish, which was common 25 26 677 to all geographic areas investigated, most of the intoxications caused by marine 27 28 29 678 gastropods occurred in South East and East Asia, which was also the only geographical 30 31 679 sub-area where intoxications from C. rotundicauda (arthropod) and Hapalochlaena spp. 32 33 680 (cephalopod) were reported. 34 35 681 In North America cases were described exclusively in the United States, mainly 36 37 38 682 due to the consumption of illegally imported or mislabelled Asian products. Similarly, 39 40 683 the few dated intoxications reported historically in Europe were all referable to 41 42 684 mislabelled products imported from Asia. However, the present study highlights the 43 44 45 685 spread of TTX towards new marine environments, as confirmed by the recent cases of 46 47 686 intoxication, occurred in Europe (Spain), in Middle East countries (Israel and Lebanon) 48 49 687 and North Africa (Egypt, Morocco and Tunisia). Therefore, there is a strong need to 50 51 52 688 reassess the risk related to TTX intoxication, taking into account the changed 53 54 689 environmental and anthropogenic factors. 55 56 690 Word count: 57 58 691 6942 59 60
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1 2 3 692 Funding 4 5 6 693 This study was supported by the Italian Ministry of Health (Current Research Grant IZS 7 8 694 LT 08/14 RC). 9 10 695 Contribution of authors 11 12 696 LG: study selection and data extraction and writing review; AM: bibliographic search, 13 14 15 697 study selection and data extraction; DN: statistical analysis; VM: revision of the 16 17 698 manuscript; LG: bibliographic search; AA: experimental design, supervising of all 18 For Peer Review Only 19 699 phases and writing review. 20 21 22 700 Declaration of interest statement 23 24 701 No conflict of interest to declare 25 26 702 Acknowledgments 27 28 29 703 The authors wish to thank Dr. Lara Tinacci for drawing the image representing 30 31 704 pufferfish anatomy in Figure 4. 32 33 705 34 35 706 36 37 707 38 39 708 40 41 709 42 43 44 710 45 46 711 47 48 712 49 50 713 51 52 714 53 54 715 55 56 716 57 58 717 59 60
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1 2 3 937 71. You, J.; Yue, Y.; Xing, F.; Xia, W.; Lai, S.; Zhang, F. Tetrodotoxin poisoning caused by 4 5 938 Goby fish consumption in southeast China: a retrospective case series analysis. Clinics 6 939 2015, 70(1), 24-29. 7 8 940 72. Lin, C. L.; Hsieh, C. H.; Hsieh, Y. L.; Tai, Y. C.; Hwang, D. F. Application of LC- 9 941 MS/MS in identification of toxin in the causative gastropod and victim samples. Journal 10 11 942 of Marine Science and Technology 2013, 21: 52-57. 12 13 943 73. Noguchi, T.; Onuki, K.; Arakawa, O. Tetrodotoxin poisoning due to pufferfish and 14 944 gastropods, and their intoxication mechanism. ISRN toxicology 2011. 15 16 945 doi:10.5402/2011/276939 17 946 74. Kanchanapongkul, J. Tetrodotoxin poisoning following ingestion of the toxic eggs of the 18 For Peer Review Only 19 947 horseshoe crab Carcinoscorpius rotundicauda, a case series from 1994 through 2006. 20 21 948 Southeast Asian Journal of Tropical Medicine and Public Health 2008, 39(2): 303. 22 949 75. Robert, R.; Muhammad Ali, S. H.; Amelia-Ng, P. F.Demographics of horseshoe crab 23 24 950 populations in Kota Kinabalu, Sabah, Malaysia with emphasis on Carcinoscorpius 25 951 rotundicauda and some aspects of its mating behaviour. Pertanika Journal of Tropical 26 27 952 Agricultural Science 2014, 37(3), 375-388. 28 953 76. Cavazzoni, E.; Lister, B.; Sargent, P.; Schibler, A. Blue-ringed octopus (Hapalochlaena 29 30 954 sp.) envenomation of a 4-year-old boy: a case report. Clinical Toxicology 2008, 46(8), 31 32 955 760-761. 33 956 77. Akyol, O.; Ünal, V.; Ceyhan, T.; Bilecenoglu, M. First confirmed record of 34 35 957 Lagocephalus sceleratus (Gmelin, 1789) in the Mediterranean Sea. Journal of Fish 36 958 Biology 2005, 66(4), 1183-1186. 37 38 959 78. Ben Souissi, J.; Rifi, M.; Ghanem, R.; Ghozzi, L.; Boughedir, W.; Azzurro, E. 39 Lagocephalus sceleratus (Gmelin, 1789) expands through the African coasts towards the 40 960 41 961 Western Mediterranean Sea: a call for awareness. Management 2014, 5(4), 357-362. 42 43 962 79. Neto, S.; de Lima, P.; Aquino, E. C. M. D.; Silva, J. A. D.; Amorim, M. L. P.; Oliveira 44 963 Júnior, A. E. D.; Júnior H. Envenenamento fatal por baiacu (Tetrodontidae): relato de 45 46 964 um caso em criança [Fatal poisoning by puffer fish (Tetrodontidae): report of a case in 47 965 child]. Revista da Sociedade Brasileira de Medicina Tropical 2010, 92-94. 48 49 966 80. de Souza Simões, E. M.; Mendes, T. M. A.; Adão, A.; Junior V. H. Poisoning after 50 51 967 ingestion of pufferfish in Brazil: report of 11 cases. Journal of venomous animals and 52 968 toxins including tropical diseases 2014, 20(1), 54. 53 54 969 81. Núñez-Vázquez, E. J.; Yotsu-Yamashita, M.; Sierra-Beltrán, A. P.; Yasumoto, T.; 55 970 Ochoa, J. L. Toxicities and distribution of tetrodotoxin in the tissues of puffer fish found 56 57 971 in the coast of the Baja California Peninsula, Mexico. Toxicon 2000, 38(5), 729-734. 58 972 82. Ochoa, J. L.; Sánchez-Paz, A.; Cruz-Villacorta, A.; Nunez-Vázquez, E.; Sierra-Beltrán, 59 60 973 A. Toxic events in the northwest Pacific coastline of Mexico during 1992–1995: origin
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1 2 3 974 and impact. In Asia-Pacific Conference on Science and Management of Coastal 4 5 975 Environment (pp. 195-200). Dordrecht: Springer, 1997. 6 976 83. Sierra-Beltran, A. P.; Cruz, A.; Nunez, E.; Del Villar, L. M.; Cerecero, J.; Ochoa, J. L. 7 8 977 An overview of the marine food poisoning in Mexico. Toxicon 1998, 36(11), 1493-1502. 9 978 84. Fuhrman, F. A. Tetrodotoxin, tarichatoxin, and chiriquitoxin: historical perspectives. 10 11 979 Annals of the New York Academy of Sciences 1986, 479(1), 1-14. 12 13 980 85. Nagashima Y.; Ohta, A.; Yin, X.; Ishizaki, S.; Matsumoto, T.; Doi, H.; Ishibashi, T. 14 981 Difference in uptake of Tetrodotoxin and Saxitoxins into liver tissue slices among 15 16 982 Pufferfish, Boxfish and Porcupinefish. Marine drugs 2018, 16(1), 17. 17 983 86. Elshaer, F. M. Comparative histopathological studies on kidney and liver of rat treated 18 For Peer Review Only 19 984 by tetrodotoxin (TTX) extracted from gonads and muscles of porcupine fish 20 21 985 species. International Journal of Fisheries and Aquatic Studies 2016, 4, 355-360. 22 986 87. Sims, J. K.; Ostman, D. C. Pufferfish poisoning: emergency diagnosis and management 23 24 987 of mild human tetrodotoxication. Annals of emergency medicine 1986, 15(9), 1094-1098. 25 988 88. Deeds, J. R.; White, K. D.; Etheridge, S. M.; Landsberg, J. H. Concentrations of 26 27 989 saxitoxin and tetrodotoxin in three species of puffers from the Indian River Lagoon, 28 990 Florida, the location for multiple cases of saxitoxin puffer poisoning from 2002 to 2004. 29 30 991 Transactions of the American Fisheries Society 2008, 137(5), 1317-1326. 31 32 992 89. de Haro, L. Intoxications par organismes aquatiques [Intoxications by aquatic 33 993 organisms]. Médicine Tropicale 2008, 68, 367-374. 34 35 994 90. Fernández-Ortega, J. F.; Morales-de los Santos, J. M.; Herrera-Gutiérrez, M. E.; 36 995 Fernández-Sánchez, V.; Loureo, P. R.; Rancaño, A. A.; Téllez-Andrade, A. Seafood 37 38 996 intoxication by tetrodotoxin: first case in Europe. The Journal of emergency medicine 39 2010, 39(5), 612-617. 40 997 41 998 91. Turner, A.; Dhanji-Rapkova, M.; Coates, L.; Bickerstaff, L.; Milligan, S.; O’Neill, A.; 42 43 999 Faulkner, D.; McEneny, H.; Baker-Austin, C.; Lees, D. N.; Algoet, M. Detection of 44 1000 tetrodotoxin shellfish poisoning (TSP) toxins and causative factors in bivalve molluscs 45 46 1001 from the UK. Marine drugs 2017, 15(9), 277. 47 1002 92. Leão, J.; Lozano-Leon, A.; Giráldez, J.; Vilariño, Ó.; Gago-Martínez, A. Preliminary 48 49 1003 results on the evaluation of the occurrence of tetrodotoxin associated to marine Vibrio 50 51 1004 spp. in bivalves from the Galician Rias (Northwest of Spain). Marine drugs 2018, 16(3), 52 1005 81. 53 54 1006 93. Pigozzi, S.; Ceredi, A.; Pompei, M.; Bordin, P.; Bille, L.; Dell’Aversano, C.; 55 1007 Tartaglione, L.; Sidari, L.; Zanolin, B.; Cacitti, A. et al. First detection of tetrodotoxin in 56 57 1008 shellfish from Northern Italy. In Proceedings of the Book of abstracts of 6th 58 1009 International Symposium Marine and Freshwater Toxins Analysis, Baiona, Spain, 22–25 59 60 1010 October 2017; Abstract no. P8. pp. 60–1.
37 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] Food Reviews International Page 38 of 65
1 2 3 1011 94. Dell’Aversano, C.; Tartaglione, L.; Polito, G.; Dean, K.; Giacobbe, M.; Casabianca, S.; 4 5 1012 Capellacci, S.; Penna, A.; Turner, A. D. First detection of tetrodotoxin and high levels of 6 1013 paralytic shellfish poisoning toxins in shellfish from Sicily (Italy) by three different 7 8 1014 analytical methods. Chemosphere 2019, 215, 881–892. 9 1015 10 11 12 1016 13 14 1017 Figure captions 15 16 1018 Fig. 1 Global map reporting the distribution per country of the cases included in 17 For Peer Review Only 18 1019 the present study. 19 20 21 1020 Fig. 2 Graphic representation of the seafood categories responsible for the case of 22 23 1021 intoxications collected in the present study. 24 25 1022 Fig. 3 Distribution of the seafood categories responsible for the case of 26 27 28 1023 intoxications per sub area. SE-E Asia: South East and East Asia; ME-N Africa: 29 30 1024 Middle East and North Africa; C-S America: Central and South America; SS 31 32 1025 Africa: Sub-Saharan Africa; OC: Oceania; NAmerica: North America; EU: 33 34 1026 Europe. 35 36 37 1027 Fig. 4 Most relevant fish anatomical part responsible for intoxications 38 39 1028 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 5 6 7 8 9 10 11 For Peer Review Only 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 40 of 65
1 2 3 2.9% 4 5 6 16.2% 7 8 9 10 11 For Peer Review Only 12 13 14 15 16 17 18 19 20 20.9% 59.9% 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Fish URL:Gastropods http:/mc.manuscriptcentral.com/lfriArthropods Email: [email protected] 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 41 of 65 Food Reviews International
1 2 3 4 5 6 7 8 9 SE-E Asia 10 11 12 13 14 ME15 N Africa 16 17 18 For Peer Review Only 19 C-S20 America 21 22 23 24 25 SS Africa 26 27 28 29 30 31 Oc 32 33 34 35 36N America 37 38 39 40 41 42 EU 43 44 45 46 0 500 1000 1500 2000 2500 3000 47 48 fish gastropods arthropods cephalopods 49 50 51 52 53 54 55 56 57 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 58 59 60 Food Reviews International Page 42 of 65
1 2 3 4 Flesh: 121 cases (42.2%) 5 6 7 8 9 10 11 For Peer Review Only 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Gonads: 73 cases (25.4%) 35 36 37 38 39 Liver: 33 cases (11.5%)URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 43 of 65 Food Reviews International
1 2 Table 1. Details of the total number of cases of human intoxication by TTX worldwide, divided in non-fatal and fatal cases, according to the different 3 geographical regions and to the different sources of intoxications. ain the case of USA (sub-area North America); *minimum number 4 5 Sub-area N of fatal N of non-fatal Source of intoxication (total n of cases/n of fatalities) 6 (n cases (% of Total n of Country/Statea cases (% of the 7 countries/ the total cases total number) Fish Gastropods Arthropods Cephalopods 8 states) number) 9 generic pufferfish (9/2) 10 India 10 (50%) 10 (50%) 20 Chelonodon patoca (3/2) 11 Tetrodon spp. (8/6) 12 For Peer Reviewgeneric pufferfish (106/25) Only 13 Arothron stellatus (48/7) 14 Bangladesh 268 (79.8%) 68 (20.2%) 336 15 Takifugu oblongus (127/19) 16 Tetrodon spp. (55/17) 17 Carcinoscorpius rotundicauda (457/8) 18 Thailand 765 (97.1%) 23 (2.9%)* 788 19 generic pufferfish (325/15) 20 Tetrodon spp. (6/0) 21 Carcinoscorpius 22 Malaysia 74 (85.1%) 13 (14.9%)* 87 rotundicauda (30/3) 23 generic pufferfish (57/10) 24 generic pufferfish (34/0)
25 (11) Singapore 215 (100%) 0 215 Sphoeroides maculatus (17/0) 26 Arothron reticularis (1/0) 27 Indonesia 0 6 (100%) 6 generic pufferfish (6/6) 28 Cambodia 48 (84.2%) 9 (15.8%) 57 generic pufferfish (57/9) South-East and East Asia 29 Nassarius spp. (7/3) 30 Natica fasciata 31 (5/0) Vietnam 96 (91.4%) 9 (8.6%) 105 32 Hapalochlaena fasciata 33 (87/2) 34 generic pufferfish (6/4) 35 unidentified fish (64/8) 36 Chelonodon patoca (1/1) 37 Nassarius spp. Taiwan 222 (89.5%) 26 (10.5%)* 248 38 (64/5) 39 Lagocephalus lunaris (19/3) 40 Oliva spp. (1/0) 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 44 of 65
1 2 Hapalochlaena fasciata 3 (2/0) 4 Takifugu niphobles (6/0) 5 Gobiidae (11/0) 6 generic pufferfish (71/9) 7 unknown gastropod 8 (8/0) 9 Neverita didyma 10 (1/0) 11 Sphoeroides maculatus (16/0) 12 For Peer ReviewGobiidae (22/0) Only Nassaridae (547/23) 13 China 65571 (95.23%) 33 (4.78%) 704688 14 generic pufferfish (114/9) 15 Carcinoscorpius 16 rotundicauda (5/1) 17 Lagocephalus lunaris (2/0) 18 South Korea 230 (73.7%) 82 (26.3%) 312 generic pufferfish (307/81) 19 unidentified fish (3/1) 20 Subtotal South- 21 East and East 2389 (89.5%) 279 (10.5%) 2668 1454/234 633/31 492/12 89/2 22 Asia Lagocephalus sceleratus 23 Israel 16 (100%) 0 16 24 (16/0) 25 Lebanon 2 (100%) 0 2 Lagocephalus sceleratus (2/0) 26 generic pufferfish (59/14)
(4) Lagocephalus sceleratus 27 Egypt 120 (81.6%) 27 (18.4%) 147 28 Africa (76/12) 29 unidentified fish (12/1) Tetraodontidae (gen.
30 Middle East and North Morocco 2 (66.7%) 1 (33.3%) 3 31 pufferfish) (3/1) Subtotal Middle 32 East and North 140 (83.3%) 28 (16.7%) 168 168/28 33 Africa 34 generic pufferfish (28/3) Brazil 37 (90.2%) 4 (9.8%) 41 35 Sphoeroides spp. (13/1) 36 unidentified fish (3/1) 37 French Guyana 4 (80%) 1 (20%) 5 38 Sphoeroides testudineus (2/0)
America (4) generic pufferfish (18/NR) 39 Centre-South Mexico 18 (90%) 2 (10%)* 20 40 Sphoeroides spp. (2/2) 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 45 of 65 Food Reviews International
1 2 Puerto Rico 1 (100%) 0 1 generic pufferfish (1/0) 3 Subtotal Centre- 60 (89.6%) 7 (10.4%) 67 67/7 4 South America Arothron spp. (A. hispidus 4) 5 Madagascar 12 (70.6%) 5 (29.4%) 17 6 (17/5) Tanzania 7 0 1 (100%) 1 generic pufferfish (1/1) (Zanzibar) 8 (4) Lagocephalus sceleratus 9 La Reunion Island 30 (90.9%) 3 (9.1%) 33 (10/0) 10 generic pufferfish (23/3)
11 Sub-Saharan Africa South Africa 0 2 (100%) 2 generic pufferfish (2/2) 12 Subtotal Sub- For Peer Review Only 42 (79.2%) 11 (20.8%) 53 53/11 13 Saharan Africa 14 generic pufferfish (17/1) 15 Lagocephalus sceleratus (3/0) 16 Ostraciidae (4/0) 17 Diodontidae (1/0) 18 Australia 28 (90.3%) 3 (9.7%) 31 19 Arothron spp. (Arothron
(3) nigropunctatus) (4/1) 20
Oceania Sphoeroides spp. (S. 21 liosomus) (1/1) 22 Tetroctenas glaber (1/0) 23 New Guinea 1 (33.3%) 2 (66.7%) 3 Diodon hystrix (3/2) 24 Fiji 4 (80%) 1 (20%) 5 Diodon hystrix (5/1) 25 26 Subtotal Oceania 33 (84.6%) 6 (15.4%) 39 39/6 27 California 5 (100%) 0* 5 generic pufferfish (5/0) 28 Illinois (Chicago) 2 (100%) 0 2 Lagocephalus lunaris (2/0) Minnesota 29 2 (100%) 0 2 Lagocephalus lunaris (2/0) 30 (Minneapolis) 31 New Jersey 1 (100%) 0* 1 generic pufferfish (1/0)
32 (7) Virginia 1 (100%) 0 1 generic pufferfish (1/0) 33 Diodon hystrix (1/0)
North America Hawaii 1 (20%) 4 (80%) 5 34 Arothron spp. (4/4) 35 Sphoeroides testudineus (1/1) Florida 4 (57.1%) 3 (42.9%)* 7 36 generic pufferfish (6/2) 37 Subtotal North 16 (69.6%) 7 (30.4%) 23 23/7 38 America 39 40 Italy 10 (76.9%) 3 (23.1%) 13 generic pufferfish (13/3) ope Eur 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 46 of 65
1
(2) Charonia lampas 2 Spain 1 (100%) 0 1 3 (1/0) 4 Subtotal Europe 11 (78.6%) 3 (21.4%) 14 13/3 1/0 5 Total 2691 (88.7%) 341 (11.3%) 3032 1817 634 492 89 6 7 8 9 10 11 12 For Peer Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 47 of 65 Food Reviews International
1 2 3 Table 2 Fatality rates across continents and geographical sub-regions. Significant differences are 4 evidenced in the column Difference: same letters indicate non statistically different proportions. 5 6 7 Continent Fatality rate (%) Difference Statistics 8 Asia 10.5 A 9 Africa 19.2 B 10 X2=18,4 15.6 B 11 America p=0,01 12 Oceania 15.4 B 13 Europe 21.4 B 14 Overall mean 16.4 15 Sub-areas Fatality rate (%) Difference Statistics 16 17 South-East and East Asia 10.5 A 18 Middle East and NorthFor Africa Peer Review16.7 Only A 19 Sub-Saharan Africa 20.8 B X2=21,8 20 North America 30.4 B 21 p=0,001 Centre and South America 10.4 A 22 23 Europe 21.4 B 24 Oceania 15.4 A 25 Overall mean 17.9 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Table 3. Details of the source of intoxication subdivided by taxonomic groups 4 5 Total n of Taxonomic group and species % Fatalities % 6 cases 7 Fish 1817 59.9 296 86.8 8 Generic "pufferfish" 123940 68.3 200 67.6 9 10 Takifugu spp. (Tetraodontidae, Tetraodontiformes) 133 7.3 19 6.4 11 Lagocephalus sceleratus (Tetraodontidae, Tetraodontiformes) 107 5.9 12 4.1 12 Lagocephalus lunaris (Tetraodontidae, Tetraodontiformes) 25 1.4 3 1.0 13 Tetrodon spp. (Tetraodontidae, Tetraodontiformes) 69 3.8 23 7.8 14 15 Arothron spp. (Tetraodontidae, Tetraodontiformes) 74 4.1 17 5.7 16 Sphoeroides spp. (Tetraodontidae, Tetraodontiformes) 365 1.9 5 1.7 17 Chelonodon patoca (Tetraodontidae, Tetraodontiformes) 4 0.2 3 1.0 18 For Peer Review Only Tetroctenas glaber (Tetraodontidae, Tetraodontiformes) 1 0.1 0 0.0 19 20 Diodon spp. (Diodontidae, Tetraodontiformes) 10 0.6 3 1.0 21 Ostraciidae (Tetraodontiformes) 4 0.2 0 0.0 22 Total Tetraodontiformes 1703 93.7 285 96.3 23 Gobiidae (Perciformes) 33 1.8 0 0.0 24 25 Unidentified fish 82 4.5 11 3.7 26 Gastropod 634 20.9 31 9.1 27 Nassaridae, Neogastropoda 618 97.5 31 100 28 Natica fasciata (Naticidae, Littorinimorpha) 5 0.8 0 0.0 29 Charonia lampas (syn. Lampas lampas) (Ranellidae, 30 1 0.2 0 0.0 31 Littorinimorpha) 32 Oliva spp. (Olividae, Neogastropoda) 1 0.2 0 0.0 33 Neverita didyma (Naticidae, Littorinimorpha) 1 0.2 0 0.0 34 Unknown species 8 1.3 0 0.0 35 492 16.2 12 3.5 36 Arthropod 37 Carcinoscorpius rotundicauda (Limulidae, Xiphosuridae) 492 100 12 100 38 Cephalopod 89 2.9 2 0.6 39 Hapalochlaena fasciata (Octopodidae, Octopoda) 89 100 2 100 40 Total 3032 341 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Table 1SM. Toxicological tests used in the studies included in the analysis 4 5 6 7 Toxicological analysis N 8 No analysis 2641 9 10 Mouse Bioassay (MBA) 102* 11 MBA and High-Performance Liquid Chromatography (HPLC) 67* 12 13 MBA and Liquid Chromatography-Mass Spectrometry (LC-MS) 12 14 15 MBA, HPLC and Thin-layer chromatography (TLC) 43 16 MBA, HPLC and LC-MS 8 17 18 MBA, HPLC and GC-MSFor Peer Review Only 12 19 MBA, HPLC, LC-MS and GC-MS 1 20 21 HPLC 38 22 LC-MS 34 23 24 GC-MS 7 25 26 LC-MS and GC-MS 6 27 TLC, electrophoresis and HPLC 7 28 29 Enzyme-linked immunosorbent assays (ELISA) 38 30 TTX confirmed but test not specified 16 31 32 33 *test on samples collected from the same seashore area of the poisoning (n=8 in MBA and HPLC and n=42 34 in MBA) 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 Table 2SM. Data on the number of cases and fatalities in relation to the geographical region, the source of intoxication, the origin of the source, the year and 3 information on the identification of TTX. 4 TTX Number 5 Geographical region Number Source of intoxication Local Imported n.a. Years identifie of References 6 and country/state of cases 7 d fatalities 8 Europe 1977- Viviani et al., 1978; Pocchiari 9 Italy generic pufferfish (F) 0 13 0 Yes 13 3 10 1978 1977 Fernandez-Ortega et al., 2010; 11 Spain Charonia lampas (G) 1 0 0 2007 Yes 1 0 12 For Peer Review Only Rodriguez et al., 2008 13 North America 14 1996, California generic pufferfish (F)*** 0 5 0 No 5 0a CDC, 1996; Cohen et al., 2009 15 2006 16 Illinois (Chicago) Lagocephalus lunaris (F) 0 2 0 2007 Yes 2 0 Cohen et al., 2009 17 Minnesota Lagocephalus lunaris (F) 0 2 0 2014 Yes 2 0 Cole et al., 2014 18 (Minneapolis) 19 New Jersey generic pufferfish (F)*** 0 1 0 2007 No 1 0a Cohen et al., 2009 20 Virginia generic pufferfish (F) 0 1 0 2014 No 1 0 Report FDA, 2014 21 Diodon hystrix (F) 0 0 1 1986 No 1 0 Sisms and Ostman, 1986 22 Hawaii 1903- Arothron spp. (F) 0 0 4 No 4 4 Helfrich, 1963 23 1925 24 1954- Sphoeroides testudineus (F) 0 0 1 No 1 1 Benson, 1956 25 1955 Florida 26 1951- Benson, 1956; Philips and generic pufferfish (F) 0 0 6 No 6 2a 27 1974 Brady, 1953 28 Centre-South 29 America 30 1984- Silva et al., 2010; Haddad et generic pufferfish (F) 0 0 28 No 28 3 31 2009 al., 2004 Brasil 32 Neto et al., 2010; de Souza et Sphoeroides spp. (F) 12 0 1 n.a., 2008 No 13 1 33 al., 2014 ; Ferreira et al., 2010. 34 unidentified fish (F) 0 0 3 n.a. Yes 3 1 Villa et al., 2010 French Guyana 35 Sphoeroides testudineus (F) 2 0 0 1990 No 2 0 Hommel et al., 1992 36 1970- generic pufferfish (F) 0 0 18 No 18 2a Sierra-Beltran et al., 1998 37 Mexico 1996 38 Sphoeroides spp. (F) 0 0 2 1995 No 2 2 Ochoa et al., 1997 39 Puerto Rico generic pufferfish (F) 0 0 1 n.a. No 1 0 Joy-Sobrino et al., 1985 40 Oceania 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 51 of 65 Food Reviews International
1 2 Yes (7, 2001- Field et al., 1998; Isbister et Isbiter et 3 generic pufferfish (F) 5 0 12 2006, n.a. 17 1 al., 2002 ; Maillaud et al., al., 4 (5) 2016 ; Torda et al., 1973 5 2002) 6 Lagocephalus sceleratus (F) 3 0 0 1996 No 3 0 Ellis and Jelinek, 1997 7 Ostraciidae (F) 0 0 4 1996 No 4 0 Maillaud et al., 2016 Australia 8 Diodontidae (F) 0 0 1 2007 No 1 0 Maillaud et al., 2016 9 Arothron spp. (Arothron 4 0 0 2014 No 4 1 Maillaud et al., 2016 10 nigropunctatus) (F) 11 Sphoeroides spp. (S. 1 0 0 1950 No 1 1 Sutherland, 1985 12 liosomus) (F)For Peer Review Only 13 Tetroctenas glaber (F) 1 0 0 n.a. No 1 0 Tibbalds, 1988 14 New Guinea Diodon hystrix (F) 3 0 0 n.a. No 3 2 Trevett et al., 1997 15 Fiji Diodon hystrix (F) 0 0 5 1967 No 5 1 Sorokin, 1973 16 Middle East and 17 North Africa 18 2005- Bentur et al., 2008; Eisenmann 19 Israel Lagocephalus sceleratus (F) 15 0 1 2008 (13), No 16 0 et al., 2008 ; Kheifets et al., 20 n.a.(3) 2012 21 Awada et al., 2010; Chamandi Lebanon Lagocephalus sceleratus (F) 0 0 2 2008 No 2 0 22 et al., 2009 23 2008- Zaki, 2004; El Masry and 24 generic pufferfish (F) 11 0 48 2010 (48); No 59 14 Fawzi, 2011 25 n.a. (11) 26 Egypt 2006, Lagocephalus sceleratus (F) 1 0 75 No 76 12 El Masry and Fawzi, 2011 27 2010 28 2008, unidentified fish (F) 0 0 12 No 12 1 El Masry and Fawzi, 2011 29 2010 30 Morocco Tetraodontidae (F) 0 0 3 n.a. No 3 1 Ababou et al., 2000 31 Sub-Saharan Africa 32 Ravaonindrina et al., 2001; Arothron spp. (A. hispidus 4) 1993- 33 Madagascar 0 0 17 No 17 5 Champetier de Ribes et al., (F) 1998 34 19998 35 Tanzania (Zanzibar) generic pufferfish (F) 0 0 1 1967 No 1 1 Chopra, 1967 36 Lagocephalus sceleratus (F) 10 0 0 2013 Yes 10 0 Puech et al., 2014 37 La Reunion Island 1950- 38 generic pufferfish (F) 0 0 23 No 23 3 Quod et al., 1990 1985 39 Mills and Passmore, 1988; South Africa generic pufferfish (F) 0 0 2 1845 No 2 2 40 Hwang and Noguchi, 2007 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 52 of 65
1 2 Asia 3 2007- Behera et al., 2008; Chandra generic pufferfish (F) 0 0 9 No 9 2 4 2008; n.a. Sekaran et al., 2010 5 India Chelonodon patoca (F) 3 0 0 1954 No 3 2 Jones, 1956 6 1942- Tetrodon spp. (F) 6 0 2 No 8 6 Jones, 1956 7 1950 8 Yes (10, Islam QT et al., 2011; Islam 9 Islam 2001- MS et al., 2011 ; Chowdury et 10 generic pufferfish (F) 43 0 63 QT et 106 25 2014 al., 2007 ; Chowdury, Hasan et 11 al., al., 2007 12 For Peer Review 2011)Only 13 Arothron stellatus (F) 48 0 0 2008 No 48 7 Islam QT et al., 2011 14 Yes (38, 15 Bangladesh Islam 16 QT et 1998- al., Islam QT et al., 2011; Ahmed, 17 Takifugu oblongus (F) 127 0 0 127 19 18 2008 2011, 8 2006 ; Mahmud et al., 1999 19 Mahmu 20 d et al., 21 1999) 1988- 22 Tetrodon spp. (F) 29 0 26 No 55 17 Mahmud et al., 2000 23 1996 Carcinoscorpius 1994- Kanchanapongkul, 2008; Joob 24 0 0 457* No 457 8 25 rotundicauda (A) 2014 et al., 2015 26 Chulanetra et al., 2011; Samitsuwan et al., 2005; 27 1989- Thailand Kanchanapongkul, 2001 ; 28 generic pufferfish (F) at least 140 0 185 2008, n.a. No 325a 15a Kanchanapongkul, 2009; 29 (30) Kanchanapongkul and 30 Tatraphon, 1993 31 Tetrodon spp. (F) 6 0 0 1988 No 6 0 Laobripathr et al., 1990 32 Carcinoscorpius 33 30 0 0 2011 Yes (7) 30 3 Suleiman et al., 2017 rotundicauda (A) 34 Malaysia 1987- Chua and Chew, 2009; Loke 35 generic pufferfish (F) 26 0 31 2008; No 57 10a and Tan, 1997; Chan and 36 n.a.(5) David, 1987, Lyn 1985 37 1982 (1); Phua, 2013; Yong et al., 2013; 38 generic pufferfish (F) 0 0 34 No 34 0 n.a. (3) Tan, 1980 ; Chew et al., 1983 39 Singapore Sphoeroides maculatus (F) 0 0 1 1982 No 1 0 Chew et al., 1983 40 41 Sphoeroides maculatus (F) 0 0 16 n.a. No 16 0 Chew et al., 1984 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 53 of 65 Food Reviews International
1 2 Arothron reticularis (F) 0 0 1 n.a. No 1 0 Tambyah et al., 1994 3 Indonesia generic pufferfish (F) 6 0 0 2001 No 6 6 Kungsuwan et al., 2001 4 2003- Cambodia generic pufferfish (F) 0 0 57 No 57 9 Ngy et al., 2008 5 2007 6 2006- Yes (12, Nassarius spp. (G) 7 0 0 7 3 Ha and Sato, 2010 7 2007 Ha & 8 Sato, Natica fasciata (G) 5 0 0 2007 5 0 Ha and Sato, 2010 9 Vietnam 2010) 10 Hapalochlaena fasciata (C) 87 0 0 2004 No 87 2 Williams, 2008 11 generic pufferfish (F) 0 0 6 n.a. No 6 4 Cong and Tuan, 2006 12 For Peer Review YesOnly (23, Hwang and Noguchi, 2007; 13 n.a. (30), Hwang, Hwang and Lin, 2012; Hwang, 14 unidentified fish (F) 30 0 34 1988- Cheng et 64 8 Cheng et al., 1995; Chi and 15 2000 al., Wu, 2001; Deng et al., 1991 16 1995) 17 Chelonodon patoca (F) 1 0 0 2009 Yes 1 1 Wu et al., 2011 18 Yes (3, 19 Jen et 20 al., 21 2008 ; 1, 22 Lin et 23 al., 24 2013 ; 2 25 Liu et 26 Taiwan al., 27 2004 ; 5 Lin et al., 2013; Yang et al., 28 Hwang 1995; Hwang et al., 1995; 1994- Shiu et Hwang et al., 2005; Yin et al., 29 Nassarius spp. (G) 24 0 40** 64 5a 30 2012 al., 2005 ; Hwang Shiu et al., 31 2002 ; 2002; Liu et al., 2004; Jen et 32 26 al., 2008 Hwang 33 et al., 34 1995; 17 35 Yang et 36 al., 37 1995 ; 6 38 Hwang 39 et al., 40 2005 e 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 54 of 65
1 2 Yin et 3 al., 4 2005) 5 Yes (6, 6 How et 7 al., 8 2003; 1 Hsieh et 9 Wu et al., 2008; Yang, Liao al., 10 1988- and Deng 1996; Hwang et al., Lagocephalus lunaris (F) 6 0 13* 2003 ; 5 19 3a 11 2008 2002; Hsieh et al., 2003; How Hwang 12 For Peer Review Only et al., 2003; Tsai et al., 2006 et al., 13 2002; 3 14 Wu et 15 al., 16 2008) 17 Oliva spp. (G) 0 0 1 2002 Yes 1 0 Hwang et al., 2003 18 Hapalochlaena fasciata (C) 0 0 2* 2010 Yes 2 0 Wu et al., 2014 19 20 Yes (5, n.a.; 2000 Hsieh et Hsieh et al., 2002; Chen et al., 21 Takifugu niphobles (F) 5 0 1 6 0 (5) al., 2010 22 2002) 23 Yes (1 Lan et al., 1999; Lin et al., 24 1994- Lan et 1999 ; Yang, Liao and Deng, Gobidae (F) 2 0 8 11 0 25 1998 al., 1996 ; Hwang and Noguchi, 26 1999) 2007 ; Lin and Hwang, 2012 27 Yang, Liao and Deng, 1996; 1988- 28 generic pufferfish (F) 0 0 71 No 71 9 Hwang & Noguchi, 2007; Lin 2003 29 and Hwang, 2012 30 unknown gastropod (G) 0 0 8 2009 No 8 0 Lin et al., 2013 31 Neverita didyma (G) 0 0 1 2000 Yes 1 0 Shiu et al., 2003 32 Sphoeroides maculatus (F) 0 0 16 n.a. No 16 0 Chew et al., 1984 33 34 Gobidae (F) 22 0 0 2012 Yes 22 0 You et al., 2015 35 Yes (31, Shui et al., 2003; Sui et al., 36 1977- Sui et 2002; Takatani et al., 2005; China Nassaridae (G) 340** 0 207..0.0 547 23 37 2005 al., Zhang et al., 2007 ; Wang et 38 2002) al., 2008 1992- Yes (2, 39 Liu et al., 2005; Sun et al., generic pufferfish (F) 14 0 100 2007; Chen & 114 9 40 1994 ; Lau et al., 1995 ; Chen n.a.(10) Huang, 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 55 of 65 Food Reviews International
1 2 2013; 4 & Huang, 2013 ; Wan et al., 3 Wan et 2007 ; Liu et al., 2011 4 al., 5 2007) Carcinoscorpius 6 5 0 0 2014 Yes 5 1 Huang et al., 2016 7 rotundicauda (A) 8 Lagocephalus lunaris (F) 0 0 2* n.a. No 2 0 Wi, 2013 9 1971- Hyun et al., 2011; Kim et al., 10 South Korea generic pufferfish (F) 0 0 307 2011; n.a. No 307 81 2003; Lee & Kim, 1987 ; Mun 11 (1) et al., 1998 ; Wi, 2012 12 unidentified fishFor (F) Peer3 0 Review0 2010 OnlyYes 3 1 Cho et al., 2012 13 14 a 15 minimum number; *considering its geographical distribution, the origin may be considered local; **considering the local tradition of eating fresh nassariids, the origin may be 16 considered local; ***two cases in California in 2006 and one in New Jersey in 2007 probably due to Lagocephalus lunaris. 17 18 19 References 20 21 Ababou, A., Mosadik, A., Squali, J., Fikri, K. O., Lazreq, C., & Sbihi, A. (2000). Intoxication par le poisson coffre. In Annales francaises d'anesthesie et de reanimation (Vol. 19, 22 No. 3, pp. 188-190). Elsevier Masson. 23 Ahmed, S. (2006). Puffer fish tragedy in Bangladesh: an incident of Takifugu oblongus poisoning in Degholia, Khulna. African Journal of Marine Science, 28(2), 457-458. 24 Awada, A., Chalhoub, V., Awada, L., & Yazbeck, P. (2010). Coma profond aréactif réversible après intoxication par des abats d’un poisson méditerranéen. Revue 25 neurologique, 166(3), 337-340. 26 Behera, A., Dash, B. K., & Barik, B. K. (2008). Rare puffer fish poisoning–A case report. Medico-Legal Update, 8(2), 5-6. 27 Benson, J., (1956). Tetradon (blowfish) poisoning. A report of two fatalities. J Forensic Sci, 1, 119-126. 28 Bentur, Y., Ashkar, J., Lurie, Y., Levy, Y., Azzam, Z. S., Litmanovich, M., ... & Eisenman, A. (2008). Lessepsian migration and tetrodotoxin poisoning due to Lagocephalus 29 sceleratus in the eastern Mediterranean. Toxicon, 52(8), 964-968. 30 Centers for Disease Control and Prevention (CDC) (1996). Tetrodotoxin poisoning associated with eating puffer fish transported from Japan--California, 1996. MMWR. Morbidity and mortality weekly report, 45(19), 389. 31 Chamandi, S. C., Kallab, K., Mattar, H., & Nader, E. (2009). Human poisoning after ingestion of puffer fish caught from Mediterranean Sea. Middle East journal of 32 anesthesiology, 20(2), 285-288. 33 Chan, M. K., & David, P. (1987). Nine fatal cases of puffer fish poisoning in Sabah, Malaysia. Med. J. Malaysia 42(3) 199-200 34 Champetier de Ribes, G., Ranaivoson, G., Ravaonindrina, N., Rakotonjanabelo, A. L., Rasolofonirina, N., Roux, J., & Yasumoto, T. (1998). Un problème de santé réémergent à 35 Madagascar: les intoxications collectives par consommation d’animaux marins (1993-1998). Archives de l'Institut Pasteur de Madagascar, 64(1). 36 Chandrasekaran, V., Pothapregada, S., & Subramanian, M. (2010). Fish egg poisoning: An unusual cause of respiratory paralysis. Indian journal of pediatrics, 77(4), 462-462. 37 Chen HYH, Juan CHW, Kao TL, Liu CHY. (2010) Central nervous system effects of puffer fish (Tetrodotoxin) poisoning. J Emerg Crit Care Med; 21: 162 – 166. 38 Chen, L., & Huang, G. Z. (2013). Poisoning by toxic animals in China—18 autopsy case studies and a comprehensive literature review. Forensic science international, 232(1), 39 e12-e23. 40 Chew, S. K., Chew, L. S., Wang, K. W., Mah, P. K., & Tan, B. Y. (1984). Anticholinesterase drugs in the treatment of tetrodotoxin poisoning. The Lancet, 324(8394), 108. 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 56 of 65
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1 2 Yang, C. C., Han, K. C., Lin, T. J., Tsai, W. J., & Deng, J. F. (1995). An outbreak of tetrodotoxin poisoning following gastropod mollusc consumption. Human & experimental 3 toxicology, 14(5), 446-450. 4 Yang, C. C., Liao, S. C., & Deng, J. F. (1996). Tetrodotoxin poisoning in Taiwan: an analysis of poison center data. Veterinary and human toxicology, 38(4), 282-286. 5 Yin, H. L., Lin, H. S., Huang, C. C., Hwang, D. F., Liu, J. S., & Chen, W. H. (2005). Tetrodotoxication with Nassauris glans: a possibility of tetrodotoxin spreading in marine 6 products near Pratas Island. The American journal of tropical medicine and hygiene, 73(5), 985-990. 7 Yong, Y. S., Quek, L. S., Lim, E. K., & Ngo, A. (2013). A case report of puffer fish poisoning in Singapore. Case reports in medicine, 2013. 8 You, J., Yue, Y., Xing, F., Xia, W., Lai, S., & Zhang, F. (2015). Tetrodotoxin poisoning caused by Goby fish consumption in southeast China: a retrospective case series 9 analysis. Clinics, 70(1), 24-29. Zaki; A.M.: 2004, Tetrodoxin poisoning associated with eating puffer fish in Suez City (Egypt). In:1st International Conference on Natural Toxins October 6 University – Egypt 10 18-19 December 2004. 11 Zhang, N., Liu, H. X., Su, J., Li, L. F., Ruan, X. Y., & Wang, X. P. (2007). Nassariids and their toxicity. Chin Fish, 376(3), 72-73. 12 For Peer Review Only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 61 of 65 Food Reviews International
1 2 3 Table 3SM: Toxicity resulting from mouse bioassay (MBA) in fish and gastropods reported in literature. 4 5 6 Reference Fish Location Number of Number of Toxicity resulting from mouse bioassay 7 intoxicated fatalities (MBA) 8 9 Puech et al., 2014 Lagocephalus sceleratus La Reunion 10 0 Liver: 95 MU/g; Flesh: 5 MU/g 10 Ahmed et al., 2006 Takifugu oblongus Bangladesh 36 7 Skin: 13.2–18.9 MU/g; 11 Flesh: 2.7–4.4 MU/g 12 For Peer Review OnlyLiver: <2.0–4.9 MU/g Gonads: <2.0–132.0 13 MU/g 14 Viscera: 14.8–37.0MU/g 15 Mahmud et al., 1999 Takifugu oblongus Bangladesh 8 5 Eggs: 24.5-323.8 MU/g 16 Other tissues: <2-21.3 MU/g 17 18 Laobhripatr et al., 1990 Tetraodon fangi Thailand 6 0 Skin: 209-2268 MU/g 19 Gonads: 0-712 MU/g 20 Flesh: 5-457 MU/g 21 Liver: 19-225 MU/g 22 Intestine: 21-224 MU/g 23 Total specimen toxicity: 562-3070 MU 24 Deng et al., 1991 Pesce non identificato Taiwan 30 1 Two food remains: 54 MU/g e 287 MU/g 25 Hsieh et al., 2003 Lagocephalus lunaris Taiwan 1 0 Dried eggs: 3450 MU/g 26 Hwang et al., 2002° Lagocephalus lunaris Taiwan 5 0 Dried fillet: 253 MU/g 27 Hsieh et al., 2002 Takifugu niphobles Taiwan 5 0 Coocked liver: 280±20 MU/g; 28 Liver (fished specimens): 29 Range 840±30-1810±30 MU/g 30 Eggs: 31 Range 870±10-1400±110 MU/g 32 Flesh: 33 34 Range 27±4-54±6 MU/g 35 Lan et al., 1999; Hwang Yongehichtys nebulosus Taiwan 1 0 Flesh: 25 MU/g 36 e Noguchi, 2007 37 Lin et al., 1999 Yongehichtys nebulosus Taiwan 2 0 Mean Value (Maximum value) 38 Flesh: 117±142 MU/g (394); 39 Skin: 124±69 (282) MU/g; 40 Pinne: 360±162 MU/g (654); 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 62 of 65
1 2 Testa: 368±237 MU/g (662); 3 Viscera: 285±170 MU/g (624); 4 Eggs 311±169 (510) MU/g. 5 Total toxicity range of specimens: 5150±1510 6 MU 7 Yang et al., 1996 Lagocephalus lunaris Taiwan 2 1 Flesh: 120 MU/g; 8 “ Lagocephalus lunaris Taiwan 2 1 Eggs: 1200 MU/g; 9 Flesh: 45 MU/g 10 11 “ Generically puffer fish Taiwan 2 0 Eggs: 1100 MU/g 12 “ Generically pufferFor fish PeerTaiwan Review3 1 OnlyFlesh: 150 MU/g 13 “ Generically puffer fish Taiwan 4 0 Eggs: 150 MU/g 14 Chen et al., 2010 Takifugu niphobles Taiwan 1 0 Eggs: 300 MU/g 15 Wu et al., 2008 Lagocephalus lunaris Taiwan 3 NR Eggs: 425±80 MU/g 16 Hwang et al., 1995° Unidentified fish Taiwan 2 1 Flesh 45 MU/; 17 Skin 150 MU/g; 18 Eggs 1,200 MU/g 19 “ Unidentified fish Taiwan 5 1 Flesh 120 MU/g 20 “ Unidentified fish Taiwan 2 1 Eggs: 1100 MU/g 21 “ Unidentified fish Taiwan 3 1 Flesh: 150 MU/g 22 “ Unidentified fish Taiwan 4 0 Eggs: 150 MU/g 23 24 Reference Gastropod Location Number of Number of Toxicity resulting from mouse bioassay 25 intoxicated fatalities (MBA) 26 Fernandez-Ortega et al., Charonia lampas Spain 1 0 Digestive gland: 1432* MU/g; 27 2010; Rodriguez et al., lampas Flesh: 8.48* MU/g. 28 2008 29 Ha e Sato, 2012 Nassarius spp. Vietnam 3 2 Soft tissues: 70 MU/g 30 “ Nassarius spp. Vietnam 5 0 <10 MU/g TTX and STX 31 “ Nassarius spp. Vietnam 4 1 <10 MU/g TTX and STX 32 Jen et al., 2007 Nassarius spp. Taiwan 1 0 Flesh: 645 MU/g; 33 Digestive gland: 540 MU/g 34 TTX and PSP 35 Jen et al., 2008 Niotha clathrata Taiwan 3 0 Digestive gland mean value (maximum 36 value): 353.93±135 (618*) MU/g; 37 38 Flesh: 179.77±89.9 (393*) MU/g; 39 Mean total toxicity of specimens: 40 202.24±135* MU. 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 63 of 65 Food Reviews International
1 2 Liu et al., 2004 Nassarius papillosus e Taiwan 2 1 Two specimens: 320 and 386 MU/g 3 Nassarius gruneri 4 Hwang et al., 2002b Zeuxis sufflatus e Niotha Taiwan 5 0 Digestive gland mean value (maximum 5 clathrata value): 1117±477 (2310) MU/g and 683±113 6 (804) MU/g respectively in two species; 7 Other tissues: 8 497±258 (1020) MU/g and 289±169 (525) 9 MU/g respectively in two species; 10 Hwang et al., 2003 Olividae Taiwan 1 0 O. miniacea: 18 MU/g; 11 O. mustelina: 10 MU/g; 12 For Peer Review Only 13 O. hirasei: 27 MU/g 14 Hwang et al., 1995b Niotha clathrata e Taiwan 26 NR Mean total toxicity of specimens of Niotha 15 Zeuxis scalaris spp.: 150±126 MU e 345±192 MU; 16 Mean total toxicity of specimens of Z. 17 scalaris: 13±9 MU e 98±46 MU 18 Yang et al., 1995 Nassarius conoidalis e Taiwan 17 1 Mean total toxicity of specimens: 150±126 19 Nassarius castus MU in Nassarius conoidalis; 20 13±9 MU in Nassarius castus 21 Lin et al., 2013 Nassarius papillosus Taiwan 3 1 Mean total toxicity of specimens: 1044±706 22 MU 23 “ Niotha clathrata e Taiwan 1 0 Mean value (maximum value) Digestive 24 Zeuxis scalaris gland: 245±98 (330) MU/g in N. clathrata; 25 203±110 (320) MU/g in Z. scalaris 26 27 Yin et al., 2005; Hwang Nassarius glans Taiwan 6 2 Mean value (maximum value) Digestive 28 et al., 2005 gland: 538±608 (2048) MU/g; Flesh 29 1167±557 (2992) MU/g. Mean total toxicity 30 of specimens: 5188±1959 MU. 31 Sui et al., 2001 Zeuxis samiplicutus China 31 0 Digestive gland: 370±118 (532) MU/g; Edible 32 parts: 307±192 (688) MU/g. Mean total 33 toxicity of specimens: 111±45 MU. 34 35 36 37 38 39 40 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Food Reviews International Page 64 of 65
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1 2 Mahmud, Y., Tanu, M. B., & Noguch, T. (1999). First occurrence of a food poisoning incident due to ingestion of Takifugu oblongus, along with a toxicological report on 3 three marine puffer species in Bangladesh. Food Hygiene and Safety Science (Shokuhin Eiseigaku Zasshi), 40(6), 473-480. 4 Puech, B., Batsalle, B., Roget, P., Turquet, J., Quod, J. P., Allyn, J., ... & Vandroux, D. (2014). Family tetrodotoxin poisoning in Reunion Island (Southwest Indian Ocean) 5 following the consumption of Lagocephalus sceleratus (Pufferfish). Bull. Soc. Pathol. Exot, 107, 79-84. 6 Rodriguez, P., Alfonso, A., Vale, C., Alfonso, C., Vale, P., Tellez, A., & Botana, L. M. (2008). First toxicity report of tetrodotoxin and 5, 6, 11-trideoxyTTX in the trumpet 7 shell Charonia lampas lampas in Europe. Analytical chemistry, 80(14), 5622-5629. 8 Sui, L. M., Chen, K., Hwang, P. A., & Hwang, D. F. (2002). Identification of tetrodotoxin in marine gastropods implicated in food poisoning. Journal of natural toxins, 9 11(3), 213-220. 10 Wu, Y. J., Jen, H. C., Deng, J. F., & Hwang, D. F. (2008). Identification of toxin and species of causative fish roe implicated into a food poisoning incident. 臺灣水產學 11 會刊, 35(4), 359-367. 12 For Peer Review Only Yang, C. C., Han, K. C., Lin, T. J., Tsai, W. J., & Deng, J. F. (1995). An outbreak of tetrodotoxin poisoning following gastropod mollusc consumption. Human & 13 experimental toxicology, 14(5), 446-450. 14 Yang, C. C., Liao, S. C., & Deng, J. F. (1996). Tetrodotoxin poisoning in Taiwan: an analysis of poison center data. Veterinary and human toxicology, 38(4), 282-286. 15 Yin, H. L., Lin, H. S., Huang, C. C., Hwang, D. F., Liu, J. S., & Chen, W. H. (2005). Tetrodotoxication with Nassauris glans: a possibility of tetrodotoxin spreading in 16 marine products near Pratas Island. The American journal of tropical medicine and hygiene, 73(5), 985-990. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 URL: http:/mc.manuscriptcentral.com/lfri Email: [email protected] 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60