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Risk of human exposure to paralytic toxins of algal origin
M.C.C. Bator´ ua,∗ , E. Diasb , P. Pereirab , S. Francab e
b a Faculty of Pharmacy, Laboratory of Toxicology, Av. Prof. Gama Pinto, 1649-043 Lisbon, Portugal Laboratory of Microbiology and Ecotoxicology, National Health Institute, Dr. Ricardo Jorge, Lisbon, Portugal
Abstract The most signiﬁcant neurotoxins produced by harmful algal blooms (HABs) are paralytic shellﬁsh toxins (PSTs) found in shellﬁsh and freshwater. Human exposure to neurotoxins through the food consumption represents a severe hazard to human health and the exposure through contaminated water represents an added risk often difﬁcult to recognize. Furthermore, there is an insufﬁcient knowledge of toxicokinetics of these complex toxins produced by HABs. If human acute exposure occurs, the diagnosis of intoxication is typically based upon symptomatology and analysis of shellﬁsh tissue by mouse bioassay, HPLC-FLD analysis and mouse neuroblastoma assay. However, the health risks due to chronic exposure should also be considered and its prevention could be reached with a better understanding of sub-lethal doses of these toxins. In this context, information required for development of a diagnostic protocol should include knowledge about toxicokinetics and toxicodynamics of these neurotoxins. We emphasise the importance of research on biomarkers to prevent, predict and diagnose acute and chronic human exposure to PST. © 2005 Elsevier B.V. All rights reserved.
Keywords: Paralytic shellﬁsh toxins; Neurotoxicity; Human exposure; Toxicokinetics; Biomarkers; PST monitoring
1. Introduction Phytoplanktonic organisms are natural components of water environments that, under favourable environmental conditions (such as light, temperature, oxygen and nutrients) or due to anthropogenic action (fertilizers input) may proliferate at a high rate (Hallegraeff, 1993). When particular species dominate the phytoplanktonic community, they accumulate and may form a visible and dense biomass ﬁlm in water surface commonly known as algal blooms. This phenomenon is called harmful algal bloom (HAB), namely when the proliferating species produce toxins (phycotoxins) that may be a threat to human health. In the sea HABs are mainly caused by dinoﬂagellates (Anderson, 1994) while in freshwater toxic blooms are due to cyanobacteria (Carmichael, 1994). Some of these phycotoxins are neurotoxins (Table 1), and are usually denominated by the effects that they cause or by the name of producer specie. In marine environments,
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dinoﬂagellates are responsible for the occurrence of paralytic shellﬁsh toxins (PSTs), produced by several species, and brevetoxins, produced only by Karenia brevis. Also some species of the bacillariophycea pseudo-nitzschia, are capable of producing the neurotoxin, domoic acid, responsible for amnesic shellﬁsh poisoning (ASP). Crustaceous, mollusc and ﬁsh that feed from phytoplankton accumulate those toxins, transmitting them to humans through food chain (Hallegraeff, 1993). In freshwater, several cyanobacterial species may also produce PST and anatoxins (ﬁrstly attributed to Anabaena sp.) that can also accumulate in the food chain or be transmitted to humans through the ingestion of contaminated water (Negri and Jones, 1995; Chorus et al., 2000). Paralytic shellﬁsh poisoning (PSP) is a very well known human syndrome caused by an acute intoxication after the ingestion of shellﬁsh contaminated with paralytic toxins. PSP symptoms in mammal’s ranges from nausea, vomiting, numbness of the lips and tongue and muscle paralysis to death by cardio-respiratory arrest (Price et al., 1991). The most current diagnostic methodologies are the clinical history and the toxin analysis in seafood. Nevertheless, no stud-
1382-6689/$ – see front matter. © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2004.12.002
. The ﬁrst description of paralytic shellﬁsh poisoning dates from 1793 and in 1927 a serious epidemic intoxication in San Francisco was ascribed with certainty as paralytic shellﬁsh poisoning. Also.v. Karenia brevis Diatoms Pseudo-nitzschia spp. 1993). PST PST PST Water Molluscs Crustaceans Fish ies on biomarkers to control and/or identify intoxications due to acute or chronic human exposure to these natural contaminants have been reported. similar programs are mandatory since the 1990s (Van Egmond et al. 2).. three occurrences of cyanobacterial blooms associated with PST were detected between 1995 and 1999 (Fig.. In Portugal. PST production by cyanobacteria was also found in freshwater supplies worldwide (Sivonen and Jones. In vitro assays with rat and human cell lines pointed out to the role of an active transport system involved in PST intestinal absorption (Andrinolo et al. there is not much research about their toxicokinetics in mammals and the few available data are still inconclusive. administration in cats) distribution through liver. 1999). spleen and central nervous system. After the implementation of monitoring program in 1986 the few reported cases were asTable 2 Reported human paralytic shellﬁsh poisoning Country/region North America UK Guatemala Morocco Norway Portugal Chile East Timor Year 1900–1989 1968 1987 1994 1901–1992 1946/1994 1972/98 2002 No. death by PSP episodes occurred mainly in those countries where prevention programs were not still adopted. for example. Dinoﬂagellates were associated with that intoxication and the Californian’s PSP prevention program was implemented (Price et al. Neurotoxins PST PST Brevetoxins ASP Intoxication vehicle Molluscs Crustaceans Fish Anatoxins. Nowadays. Despite the mechanism of toxicity of saxitoxin and its derivatives is known at molecular and cellular level. in turn. The singly sulphated gonyautoxins present a moderate to high toxicity and the double sulphated C-toxins are the less toxic class.402 M. More recently (in the past decade). In Europe. 1). 3. There are many reports of PSP worldwide associated with human severe intoxication and death (Table 2). and an oral LD50 of 263 g/kg bw (WHO. of intoxications 1399 78 187 77 32 132 329 1 No. In 1993. are related with their speciﬁc toxicities (Table 3). 1989). 1998).. 2000. Bator´ u et al. like saxitoxin that presents an LD50 after an i. 1980) (Fig. these authors reported saxitoxin (i. 2002a) suggest that PST absorption occurs exclusively via intestinal epithelium and the excretion mainly involves glomerular ﬁltration. blocking neuronal transmission and causing a generalised nerve dysfunction (Easthaugh and Shepherd. Studies with cats administrated orally with gonyautoxins 2–3 (Andrinolo et al. In Portugal.C. they also con- .. In a previous study.. PST occurrences in marine and freshwater PSP has been considered a serious risk for shellﬁsh consumers for many centuries ago. PST toxicity PST are a group of carbamate alkaloid compounds that can be divided in three classes according to their degree of sulphatation (Oshima. 1984). 2002b). 1999). of deaths 90 – 26 4 2 7 23 1 sociated with the disrespect of shellﬁsh consumption prohibition (Carvalho et al. The class of non-sulphated compounds includes the most potent toxins. the estimated incidence was 2000 cases per year with 15% of mortality (Hallegraeff. 1993). indicating that toxin is capable of crossing the blood–brain barrier (Andrinolo et al. 1995) that. injection in mice of only 10 g/kg bw. PST Anatoxins.C.. (Pereira et al. Those were attributed to different species of Aphanizomenon spp. 2001). the most important episode of PSP occurred in 1946 when 100 people was intoxicated and 6 patients died after the consumption of PST contaminated shellﬁsh from Obidos Lagoon (Franca. 2. globally many programs have been established in several susceptible regions (Hallegraeff. Freshwater Cyanobacteria Anabaena spp. In this study. Cylindrospermopsis sp. PST act by reversible binding to the sodium ion channels of nerve membranes (Catterall. 1991). 1991). Lyngbya sp. Aphanizomenon spp.p. / Environmental Toxicology and Pharmacology 19 (2005) 401–406 e Table 1 Neurotoxins produced by phytoplanktonic species Environment Sea water Producer organism Dinoﬂagellates Gymnodinium catenatum Alexandrium spp. 1993).
(2002) reported a case study where he compares the PST contents in the gut and urine of an intoxicated victim. cluded that STX was only eliminated by urine and that mammals cannot metabolise this toxin. 2. Table 3 Structure and speciﬁc toxicity of paralytic shellﬁsh toxins (adapted from Oshima. there are . Bator´ u et al. However. 1995) Toxin STX neoSTX dcSTX GTX1 GTX2 GTX3 GTX4 GTX5 GTX6 C1 C2 C3 C4 R1 H OH H OH H H OH H OH H H OH OH R2 H H H H H OSO3 − OSO3 − H H H OSO3 − H OSO3 − R3 H H H OSO3 − OSO3 − H H H H H H OSO3 − H R4 CONH2 CONH2 H CONH2 CONH2 CONH2 CONH2 CONHSO3 − CONHSO3 − CONHSO3 − CONHSO3 − CONHSO3 − CONHSO3 − Speciﬁc toxicity (MU /mol) 2483 2295 1220 2468 892 1584 1803 160 180 15 239 33 143 Fig. which reveal a decrease in toxicity of urine saxitoxin derivatives. Occurrence of cyanobacterial blooms associated with paralytic shellﬁsh toxins in Portuguese freshwater reservoirs. detecting an alteration in PST proﬁle. Thus. PST plugs and blocks the voltage-dependent Na+ channel in neurons (adapted from Boelsterli. 1995) and in intoxicated humans (Gessner et al. 1. Llewellyn et al. Other assays performed in rats (Stafford and Hines. / Environmental Toxicology and Pharmacology 19 (2005) 401–406 e 403 Fig.M.. conﬁrmed that the main route of excretion of saxitoxin derivatives is the urine.C. 1997). 2003). being 50% excreted as unchanged saxitoxin compounds.C.
Studies on imunoenzymatic methods to detect PST (Metcalf and Codd.. This is particularly important in small water reservoirs.. However. 2002). 2001). 4. accumulate PSTs without signiﬁcant biochemical changes. 1995. in part.. chlorination) (Duy et al. Besides. This is due. such as copper sulphate. which may lead to changes in net toxicity and in toxin accumulation. have presented some difﬁculties and optimisation processes are still required to its implementation. like ELISA. There are several analytical and biological methods to detect the toxins in shellﬁsh. Restriction in saxitoxin and derivatives manufacture and use are due to the fact that those compounds are listed by the Organization for the Prohibition of Chemical Weapons (OPCW) as a Schedule 1 (Andrinolo et al. the massive destruction of cyanobacterial biomass by cell lyses causes the release of toxins from intracellular medium to water (Hrudey et al. 4. if the risk of PSP can be controlled in shellﬁsh. 2003). Current technology and the timely sampling of outbreakrelated specimens offer the opportunity for a rapid increase in the control and prevention of human exposure to these toxins.. Mouse bioassay is the ofﬁcial method for PST monitoring in shellﬁsh (AOAC. Effect of repeated exposure to low PST doses It should be emphasised that populations served by water resources with a high frequency of neurotoxic blooms may be continuous exposure to low doses of PST. There is also scarce knowledge regarding the accumulation/transformation of toxins through the several trophic levels. some of those organisms are reported as PSP toxin vectors and considered as good indicators to be used in monitorization programs whereas others undergo extensive toxin biotransformation and can be useful to predict the timing and duration of blooms (Bricelj and Shumway. Efﬁciency of water treatment systems in removing toxins from water supplies Algaecides. according to the safety value of 80 g STX eqv/100 g of shellﬁsh tissue. if cell numbers are high. 2003) have been developed in order to avoid animal use and to improve the detection limit. only few studies have been conducted in order to develop alternative methodologies for removal of cyanotoxins. toxin biotransformation may vary greatly among species. There is no antidote for paralytic shellﬁsh poisoning and the only therapeutic actions are to carry out supportive therapy to the patients and adopt rigorous preventing measures. where high toxin levels may accumulate and persist for long periods (Dias. Biological methods quantify toxicity as saxitoxin (STX) equivalents but they do not distinguish between different PST components. that can present a serious health hazard to higher predators such as ﬁsh. Monitoring and prevention of human exposure to PST In aquatic environments. Mass spectrometry (MS) and LC–MS have also been used (Harada et al. 4. it is limited by the low availability of analytical standards for all PST variants. PST enter in the food web via ﬁlter feeding molluscs and crustaceans. are commonly used to control cyanobacterial growth in freshwater reservoirs. However. no mandatory limit or even a guideline value for PST in drinking water was adopted (Chorus et al.. the prohibition of bathing in recreational areas and change the drinking water source. No studies at the moment have been conducted in order to evaluate the health . such as the monitoring of toxins in water. the available data still not enables the complete clariﬁcation of differences in toxin production ability by cyanobacterial species and to distinguish between toxic and non toxic strains. Bator´ u et al. to the following gap knowledge’s.3. Besides. may present marked interspeciﬁc differences in PST sensitivity. the dissolved toxins are not effectively removed from water by the conventional water treatment systems (coagulation. and some species of crustaceans such as crabs. according to their trophic level. / Environmental Toxicology and Pharmacology 19 (2005) 401–406 e still many opened questions related with PST toxicokinetics that should be investigated in order to contribute to a better diagnosis and treatment of human poisoning. Similar preventive measures should be applied to freshwater systems. consequently. 1999). In fact. to estimate the human exposure doses to cyanobacterial neurotoxins in water and.. Therefore. 1984). 2000).C. 4. marine mammals and humans (Bretz et al.. several HPLC methods with ﬂuorescent detection have been developed (Oshima. 2002a). to identify individual PST and to quantify each PST components. Although HPLC has been found very satisfactory. Knowing that the majority are sedentary species. Thus. Duy et al. Monitoring programs to assess toxin levels in shellﬁsh and banning the shellﬁsh harvesting in suspected areas.1.404 M. However. 1998). Lawrence and Niedzwiadek. 2000. Some studies demonstrated that biota. it has also been reported that some ﬁlter-feeding shellﬁsh as the bivalve molluscs. 1999). to identify and prevent the risk at the origin. it is still not possible to predict HAB occurrences. 2000).C. sedimentation. birds. ﬁltration. Despite its relative high speciﬁcity. the same is not applied to bathing and drinking water..2. Dynamics of PST production by cyanobacteria and toxin transmission to humans through the food chain Regardless the numerous reports on the occurrence of neurotoxic blooms worldwide. In this case. of environmental factors that inﬂuence toxin production. had proved to be of a great value. 2001). of mechanisms of toxin release into extracellular medium and the toxin stability in water. which are necessary for peak conﬁrmation. Despite the severe acute effects and the serious threat to public health. other biological systems such as mammalian neuroblastoma cell lines (Louzao et al. there are some difﬁculties in assessing the risk of human exposure to PSTs through freshwater.
A. Anderson. 1389–1397. Toxic effects. • investigate the toxicokinetic and toxicodynamic of saxitoxin and derivatives. Conclusions PSP caused by the ingestion of shellﬁsh that feed from toxic dinoﬂagellates and accumulate their toxins is considered a serious threat to human health. Lagos. Preventive measures include the monitoring of toxic cyanobacteria and PST in freshwater. in cats. 2002a. S. • conﬁrm an acute PSP for immediate curative action. a real risk of human exposure to PST through freshwater must be considered. Toxicon 40. Toxins responsible for this poisoning also occur in freshwater environments but. Bator´ u et al. through the human and rat intestinal epitheliums. Iglesias. Ofﬁcial Methods of Analysis of the Association of Ofﬁcial Analytical Chemists. an accidental ingestion of 100 mL of PST contaminated water may be sufﬁcient to cause mild PSP symptoms. high proportions of PST may also be found in water for human consumption given the ineffectiveness of water treatment plants in removing cyanotoxins. Interactions of xenobiotics with ion transporters. but as the cells become senescent.F. Garcia. (Ed. particularly after a toxic bloom collapse. Furthermore. Duy et al. • re-evaluate the mandatory limit in shellﬁsh and establish a guideline value for PST in freshwater. At the moment. Contrarily. During cell growth. In: Williams. 2002b. Lagos. only few preventive measures may be adopted. despite they may be exposed even to high PST concentrations. Thus. Assuming that in natural environment the same concentrations may be expected.). pp.C. Therefore. there is not any sign of cyanobacterial contamination and if no warning of health risk is signalled. in many cases the occurrence of neurotoxic species is very frequent. Sci. D. 276–281.. toxins are massively released to water (Negri et al. the development of speciﬁc and sensitive biomarkers of PST in biological samples would contribute to: • alert to the risk of human exposure to repeated PST low doses. Thus.C. the potential health risk associated with cyanobacterial neurotoxic blooms.. 52–58. V. bathers do not avoid water contact. 1997. L. NY. 2001). (1991). Andrinolo. N. 4.. D.. Boelsterli. Fraga. there was recently a proposal for an alert level of 3 g STX eqv/L for drinking water (Llewellyn et al. 2000). There are also reports of animal poisoning with PST due to the ingestion of water from reservoirs after a neurotoxic bloom occurrence (Negri et al. Andrinolo. N.. even if the cell densities may not reach the concentrations that can trigger an acute symptomatology. 447–464... the changing of raw water source for production of drinking water and the prohibition of bathing in contaminated recreational water. Gomes. ing of PST in shellﬁsh by mouse bioassay (and toxin identiﬁcation by HPLC-FLD) and the shellﬁsh harvesting prohibition if toxin levels exceed 80 g STX eqv/100 g edible tissue. D. preventive and regulatory measures have been adopted in many countries since some decades ago. 2003. VA. / Environmental Toxicology and Pharmacology 19 (2005) 401–406 e 405 impact of this situation.. Red Tides. Michea. 5. Despite all of these gaps. An in vitro study with toxic Aphanizomenon strain cultures revealed that extracellular PST levels might reach 2700 g STX eqv/L (Dias et al. 2002). References AOAC. Toxicon 40. 1995). • correlate the biomarker levels and the probable development of delayed neurotoxic effects. According to Price et al. some ﬁeld and laboratory studies have revealed that high proportions of toxins may be found in freshwater.4.. 1999. unless signiﬁcant dilution occurs and/or effective operating techniques are used to remove dissolved toxins from contaminated water. Finally.. Paralytic shellﬁsh poison. which emphasise. N. effects of animal and human repeated exposure to PST doses are still not identiﬁed. Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats. U. pp. epidemiological and toxicological data still not enable the establishment of a PST guideline for freshwater. 699–709. P...). a paralytic shellﬁsh poison toxin. the search for biomarkers of exposure and effect may be useful to predict and prevent human exposure to PST and contribute to the diagnosis and the recovery follow-up of human acute or chronic PSP.. pharmacokinetics and clearence of saxitoxin.M. where they may persist for 1–2 months (Dias. Mechanistic Toxicology. Toxicon 37. In this situation. a component of paralytic shellﬁsh poison (PSP). However. • follow-up the patient’s recovery through the analysis of toxin levels. Taylor & Francis. 1984.M.. in this case. 2002). S. P. Lagos. Am. 271.A. D. (Ed.. Soares. Andrinolo.. there is some information regarding the effects of other cyanobacterial toxins (hepatotoxins) on humans after the ingestion of raw water (Chorus et al. 2001). Besides raw water. Although ecological. In: Boelsterli. Biological methods. Dias et al. The goal of all these measures is the prevention of acute human intoxication with PST. proﬁle and detoxiﬁcation compounds. 344–345.. U. Arlington. there are insufﬁcient scientiﬁc data that enables the implementation of regulatory policy. 1994. 2000.. AOAC Inc. Epidemiological data on human PSP in freshwater sources Absence of any report on human acute intoxication by PST through freshwater environments also restrict risk assessment of PSP caused by toxic cyanobacteria. 500–2000 g STX eqv cause moderate PSP symptoms and doses above 2000 g STX eqv are lethal.. since not all symptoms and signs are highly speciﬁc to this intoxication. 200–500 g STX eqv cause mild PSP symptoms. These include the monitor- ... C. Transport of the organic cations gonyautoxin 2/3 epimers.. toxins are mainly restricted to intracellular compartment. once more.
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