{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:22:03Z","timestamp":1790760123152,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:00:00Z","timestamp":1688342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New Zealand Ministry of Business, Innovation and Employment\u2014Seafood Safety research programme","award":["CAWX1801"],"award-info":[{"award-number":["CAWX1801"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Paralytic shellfish poisoning is a worldwide problem induced by shellfish contaminated with paralytic shellfish toxins. To protect human health, a regulatory limit for these toxins in shellfish flesh has been adopted by many countries. In a recent study, mice were dosed with saxitoxin and tetrodotoxin mixtures daily for 28 days showing toxicity at low concentrations, which appeared to be at odds with other work. To further investigate this reported toxicity, we dosed groups of mice with saxitoxin and tetrodotoxin mixtures daily for 21 days. In contrast to the previous study, no effects on mouse bodyweight, food consumption, heart rate, blood pressure, grip strength, blood chemistry or hematology were observed. Furthermore, no histological findings were associated with dosing in this trial. The dose rates in this study were 2.6, 3.8 and 4.9 times greater, respectively, than the highest dose of the previous study. As rapid mortality in three out of five mice was observed in the previous study, the deaths are likely to be due to the methodology used rather than the shellfish toxins. To convert animal data to that used in a human risk assessment, a 100-fold safety factor is required. After applying this safety factor, the dose rates used in the current study were 3.5, 5.0 and 6.5 times greater, respectively, than the acute reference dose for each toxin type set by the European Union. Furthermore, it has previously been proposed that tetrodotoxin be included in the paralytic shellfish poisoning suite of toxins. If this were done, the highest dose rate used in this study would be 13 times the acute reference dose. This study suggests that the previous 28-day trial was flawed and that the current paralytic shellfish toxin regulatory limit is fit for purpose. An additional study, feeding mice a diet laced with the test compounds at higher concentrations than those of the current experiment, would be required to comment on whether the current paralytic shellfish toxin regulatory limit should be modified.<\/jats:p>","DOI":"10.3390\/toxins15070437","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T01:42:47Z","timestamp":1688434967000},"page":"437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Sub-Acute Dosing Study of Saxitoxin and Tetrodotoxin Mixtures in Mice Suggests That the Current Paralytic Shellfish Toxin Regulatory Limit Is Fit for Purpose"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-5843","authenticated-orcid":false,"given":"Sarah C.","family":"Finch","sequence":"first","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Private Bag 3123, Hamilton 3240, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0967-6395","authenticated-orcid":false,"given":"Nicola G.","family":"Webb","sequence":"additional","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Private Bag 3123, Hamilton 3240, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Boundy","sequence":"additional","affiliation":[{"name":"Cawthron Institute, Private Bag 2, Nelson 7042, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7222-5979","authenticated-orcid":false,"given":"D. Tim","family":"Harwood","sequence":"additional","affiliation":[{"name":"Cawthron Institute, Private Bag 2, Nelson 7042, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-5247","authenticated-orcid":false,"given":"John S.","family":"Munday","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Science, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M.","family":"Sprosen","sequence":"additional","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Private Bag 3123, Hamilton 3240, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanatda","family":"Somchit","sequence":"additional","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Private Bag 3123, Hamilton 3240, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ric B.","family":"Broadhurst","sequence":"additional","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Private Bag 3123, Hamilton 3240, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.hal.2011.10.012","article-title":"The globally distributed genus Alexandrium: Multifaceted roles in marine ecosystems and impacts on human health","volume":"14","author":"Anderson","year":"2012","journal-title":"Harmful Algae"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/BF00350064","article-title":"Comparative study on paralytic shellfish toxin profiles of the dinoflagellate Gymnodinium catenatum from three different countries","volume":"116","author":"Oshima","year":"1993","journal-title":"Mar. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/nt.2620020503","article-title":"Growth and toxin production of the toxic dinoflagellate Pyrodinium bahamense var","volume":"2","author":"Usup","year":"1994","journal-title":"compressum in laboratory cultures. Nat. Toxins"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.3390\/md8072185","article-title":"Neurotoxic alkaloids: Saxitoxin and its analogs","volume":"8","author":"Wiese","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_5","first-page":"197","article-title":"Human intoxication with paralytic shellfish toxins: Clinical parameters and toxin analysis in plasma and urine","volume":"38","author":"Lagos","year":"2005","journal-title":"Biol. Res."},{"key":"ref_6","unstructured":"EFSA (2009). Scientific opinion of the panel on contaminants in the food chain on a request from the european commission on marine biotoxins in shellfish\u2014Saxitoxin group. EFSA J., 1019, 1\u201376."},{"key":"ref_7","unstructured":"Mons, M.N., Van Egmond, H.P., and Speijers, G.J.A. (1988). Paralytic Shellfish Poisoning: A Review, Rijksinstituut voor Volksgezondheid en Milieu RIVM. RIVM Report 388802005."},{"key":"ref_8","unstructured":"FAO, IOC, and WHO (2023, March 01). Available online: https:\/\/www.fao.org\/3\/au629e\/au629e.pdf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1093\/oxfordjournals.aje.a117499","article-title":"Paralytic Shellfish Poisoning in Alaska: A 20-Year Retrospective Analysis","volume":"141","author":"Gessner","year":"1995","journal-title":"Am. J. Epidemiol."},{"key":"ref_10","unstructured":"Horwitz, W., and Latimer, G.W. (2005). Official Methods of Analysis of AOAC International, AOAC International. [18th ed.]."},{"key":"ref_11","unstructured":"(2011). Commission Regulation (EU) No 15\/2011 amending Regulation (EC) No 2074\/2005 as regards recognised testing methods for detecting marine biotoxins in live bivalve molluscs. Off. J. Eur. Union, Available online: https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2011:006:0003:0006:EN:PDF."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.tifs.2016.09.015","article-title":"Derivation of toxicity equivalency factors for marine biotoxins associated with Bivalve Molluscs","volume":"59","author":"Botana","year":"2017","journal-title":"Trends Food Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"EFSA CONTAM Panel (EFSA Panel on Contaminants in the Food Chain), Knutsen, H.K., Alexander, J., Barreg\u00e5rd, L., Bignami, M., Br\u00fcschweiler, B., Ceccatelli, S., Cottrill, B., Dinovi, M., and Edler, L. (2017). Scientific opinion on the risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods. EFSA J., 15, 4752.","DOI":"10.2903\/j.efsa.2017.4752"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S1043-4526(06)52004-2","article-title":"Tetrodotoxin Poisoning","volume":"Volume 52","author":"Hwang","year":"2007","journal-title":"Advances in Food and Nutrition Research"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"325","DOI":"10.5740\/jaoacint.SGEMcNabb","article-title":"First Detection of Tetrodotoxin in the Bivalve Paphies australis by Liquid Chromatography Coupled to Triple Quadrupole Mass Spectrometry With and Without Precolumn Reaction","volume":"97","author":"McNabb","year":"2014","journal-title":"J. AOAC Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21009","DOI":"10.2807\/1560-7917.ES2015.20.2.21009","article-title":"Detection of the pufferfish toxin tetrodotoxin in European bivalves, England, 2013 to 2014","volume":"20","author":"Turner","year":"2015","journal-title":"Eurosurveillance"},{"key":"ref_17","unstructured":"Regulation (EC) No 853\/2004 of the European Parliament and of the Council of 29 April 2004; Laying down specific hygiene rules for food of animal origin. Off. J. Eur. Union, L226. Available online: https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2004:139:0055:0205:en:PDF."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Finch, S.C., Boundy, M.J., and Harwood, D.T. (2018). The acute toxicity of tetrodotoxin and tetrodotoxin\u2013saxitoxin mixtures to mice by various routes of administration. Toxins, 10.","DOI":"10.3390\/toxins10110423"},{"key":"ref_19","unstructured":"Commission, C.A. (2006, January 18\u201322). Joint FAO\/WHO food standards programme, Codex Committee on Fish and Fishery Products. Proceedings of the Twenty-Eigth Session, Beijing, China."},{"key":"ref_20","unstructured":"Standard for Live and Raw Bivalve Molluscs. Codex Alimentarius International Food Standards: 2008. Standard No. CODEX STAN 292-2008. Available online: https:\/\/www.fao.org\/fao-who-codexalimentarius\/sh-proxy\/en\/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B292-2008%252FCXS_292e_2015.pdf."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.toxicon.2020.02.018","article-title":"Paralytic shellfish toxins\u2014Call for uniform reporting units","volume":"178","author":"Turnbull","year":"2020","journal-title":"Toxicon"},{"key":"ref_22","first-page":"436","article-title":"An outbreak of paralytic shellfish poisoning","volume":"72","author":"Tennant","year":"1955","journal-title":"Can. Med. Assoc. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.foodchem.2008.09.018","article-title":"Effect of steam cooking on distribution of paralytic shellfish toxins in different tissue compartments of scallops Patinopecten yessoensis","volume":"114","author":"Wong","year":"2009","journal-title":"Food Chem."},{"key":"ref_24","first-page":"1","article-title":"Paralytic shellfish poisoning on the Canadian Atlantic coast","volume":"75","author":"Medcof","year":"1947","journal-title":"Fish. Res. Board Can."},{"key":"ref_25","unstructured":"EFSA (2009). Scientific Opinion of the Panel on Contaminants in the Food Chain on a request from the European Commission on Marine Biotoxins in Shellfish\u2014Summary on regulated marine biotoxins. EFSA J., 1306, 1\u201323."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"EFSA Scientific Committee (2012). Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data. EFSA J., 10, 2579.","DOI":"10.2903\/j.efsa.2012.2579"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Finch, S.C., Webb, N.G., Boundy, M.J., Harwood, D.T., Munday, J.S., Sprosen, J.M., Cave, V.M., Broadhurst, R.B., and Nicolas, J. (2021). Sub-acute feeding study of saxitoxin to mice confirms the effectiveness of current regulatory limits for paralytic shellfish toxins. Toxins, 13.","DOI":"10.3390\/toxins13090627"},{"key":"ref_28","unstructured":"Interdepartmental Group on Health Risks from Chemicals (2003). Uncertainty Factors: Their Use in Human Health Risk Assessment by UK Government, MRC Institute for Environment and Health."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Boente-Juncal, A., Otero, P., Rodr\u00edguez, I., Cami\u00f1a, M., Rodriguez-Vieytes, M., Vale, C., and Botana, L.M. (2020). Oral chronic toxicity of the safe tetrodotoxin dose proposed by the European Food Safety Authority and its additive effect with saxitoxin. Toxins, 12.","DOI":"10.3390\/toxins12050312"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1177\/0192623310388431","article-title":"Gavage-related reflux in rats: Identification, pathogenesis, and toxicological implications (review)","volume":"39","author":"Damsch","year":"2011","journal-title":"Toxicol. Pathol."},{"key":"ref_31","first-page":"18","article-title":"Mice fed radiolabeled protein by gavage show sporadic passage of large quantities of intact material into the blood, an artifact not associated with voluntary feeding","volume":"38","author":"Craig","year":"1999","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127937","DOI":"10.1016\/j.chemosphere.2020.127937","article-title":"Acute toxicity of dihydroanatoxin-a from Microcoleus autumnalis in comparison to anatoxin-a","volume":"263","author":"Puddick","year":"2021","journal-title":"Chemosphere"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Botana, L.M. (2014). Seafood and Freshwater Toxins: Pharmacology, Physiology, and Detection, CRC Press. [3rd ed.].","DOI":"10.1201\/b16662"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.toxicon.2021.11.001","article-title":"Acute toxicity of decarbamoyl gonyautoxin 1&4 to mice by various routes of administration","volume":"204","author":"Boundy","year":"2021","journal-title":"Toxicon"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Finch, S.C., Boundy, M.J., Webb, N.G., and Harwood, D.T. (2023). The Effect of Experimental Protocol on the Toxicity of Saxitoxin in Mice. Toxins, 15.","DOI":"10.3390\/toxins15040290"},{"key":"ref_36","unstructured":"Falconer, I.R. (1993). Algal Toxins in Seafood and Drinking Water, Academic Press."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.chroma.2015.01.086","article-title":"Development of a sensitive and selective liquid chromatography\u2013mass spectrometry method for high throughput analysis of paralytic shellfish toxins using graphitised carbon solid phase extraction","volume":"1387","author":"Boundy","year":"2015","journal-title":"J. Chromatogr. A"},{"key":"ref_38","unstructured":"OECD (2008). Test No. 407: Repeated Dose 28-Day Oral Toxicity Study in Rodents, OECD Publishing."},{"key":"ref_39","unstructured":"Hartig, F. (2020). DHARMa: Residual diagnostics for hierarchical (multi-level\/mixed) regression models. R Package Version 0.3, 3, Available online: https:\/\/cran.r-project.org\/web\/packages\/DHARMa\/vignettes\/DHARMa.html."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fox, J., and Weisberg, S. (2018). An R Companion to Applied Regression, Sage Publications.","DOI":"10.32614\/CRAN.package.carData"},{"key":"ref_41","unstructured":"R Core Team (2022). R: A Language and Environmental for Statistical Computing, R Foundation for Statistical Computing."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/7\/437\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:05:04Z","timestamp":1760126704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/7\/437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,3]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["toxins15070437"],"URL":"https:\/\/doi.org\/10.3390\/toxins15070437","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,3]]}}}