The MFBSC Center Closed in 2006.
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  Background
Clinical Presentation
Diagnosis
Management and Treatment
Chemical Structure
Molecular Mechanism of Action
References and Sites

 
 

 

Background

In humans, two distinct clinical entities, depending on the route of exposure, are associated with exposure to the Florida Red Tide toxins. With the ingestion of contaminated shellfish, Neurotoxic Shellfish Poisoning (NSP) presents as a milder gastroenteritis with neurologic symptoms compared with Paralytic Shellfish Poisoning (PSP). With the inhalation of the aerosolized Red Tide toxins, especially the brevetoxins, from the sea spray exposure associated with Florida Red Tide with and without accompanying fish kills, respiratory irritation and possibly other health effects in humans and other mammals occur (Baden 1995, Fleming 1998a&b, Fleming 1999, Bossart 1998).

Walker was the first to record NSP in 1880 on the West Coast of Florida. The associated red tides are often characterized by patches of discolored water, dead or dying fish and respiratory irritants in the air. Since then, NSP has been reported from the Gulf of Mexico, the East Coast of Florida, and the North Carolina coast. Recent prolonged red tides in the Gulf of Mexico have been associated with significant environmental, human health and economic impacts. Beaches in the Texas were closed, as well as shellfish beds from Florida to Texas. Significant die-offs of endangered manatees and double-rested cormorants, as well as reported human health effects, resulted secondary to the inhalation of the Red Tide toxins (Bossart 1998, Hopkins 1997, Kreuder 1998).

Organisms and Toxins

The classic causative organism, Gymnodinium breve, is a dinoflagellate restricted to the Gulf of Mexico and the Caribbean, although similar species occur throughout the world. It is found especially during red tides in the late summer and autumn months almost every year off the West Coast of Florida with massive fish and bird kills. Fish kills associated with these red tides have been estimated up to 100 tons of fishes per day. Recently, these red tides are increasing in incidence, time length and geographic spread. Although the possibility of anthropogenic influences such as nutrient run-off is being investigated, it should be noted that these red tides in Florida occurred even prior to significant pollution from human population (Tester 1997, Tester 1991).

G. breve produces 2 types of lipid soluble toxins: hemolytic and neurotoxic. The neurotoxic toxins are known as brevetoxins. The major brevetoxin produced is PbTx-2; lesser amounts of PbTx--1, PbTx-3, and hemolytic components are produced. The massive fish kills are due to the neurotoxin exposure, with possible contribution of the hemolytic fraction. As with all the marine toxins, the brevetoxins are tasteless, odorless, and heat and acid stable. These toxins cannot be easily detected nor removed by food preparation procedures (Baden 1993).

The G. breve organism is relatively fragile. Therefore, particularly in wave action along beaches, the organism is easily broken open, releasing the toxins. During an active in-shore red tide, the aerosol of contaminated salt spray will contain the toxins and organism fragments both in the droplets and attached to salt particles; this can be carried in land depending on wind and other environmental conditions (Pierce 1990, Pierce 1989).

Exposure

Traditionally, aerosolized Red Tide toxins respiratory irritation is associated with significant Florida Red Tide blooms (including significant fish kills with dead fish on the beaches). Nevertheless, exposure to aerosolized Red Tide toxins can cause respiratory irritation in even non-asthmatics even without obvious fish kills or high dinoflagellate cell counts in the seawater within a few feet of the seashore (K Steidinger, Florida Dept of Environmental Protection, verbal communication). The symptoms in non-asthmatic persons usually end rapidly within a few hundred feet of the seashore or upon entering significantly air-conditioned cars or homes. Also of interest, reportedly research has shown that the bevetoxins can be highly concentrated in the aerosol of sea spray generated by waves hitting the shore during a Red Tide (Pierce 1990, Pierce 1989). It is not known how far inshore this Red Tide toxins aerosol will travel, especially given strong off-shore winds during a Red Tide bloom. Although water sampling for both the dinoflagellates and the toxins has been performed for many years, Red Tide toxins air monitoring is presently experimental. Air monitoring could provide qualitative and quantitative time- and geographic-based data.

There is very little published literature or formal epidemiologic studies on the human health effects of the diseases, either ingestion NSP or inhalation aerosolized Red Tide toxins respiratory irritation. As a non-reportable disease, NSP is highly under--reported and under-diagnosed; for example, there are no existing statistics for the incidence of NSP or aerosolized Red Tide toxins respiratory irritation, even in endemic areas, nor on possible chronic health effects in humans. There are no established biomarkers for either of the Florida Red Tide toxins-associated conditions in humans, nor have there been any formal published studies of aerosolized Red Tide toxins respiratory irritation surveillance monitoring. There is very little information on appropriate treatment and prevention methodologies (Fleming 1995, Fleming 1998, Fleming 1999).

Clinical Presentation

The two forms of Red Tide toxins-associated clinical entities first characterized in Florida are an acute gastroenteritis with neurologic symptoms following ingestion of contaminated shellfish (i.e. NSP), and an apparently reversible upper respiratory syndrome following inhalation of aerosols of the dinoflagellate toxins (i.e. aerosolized red tide toxins respiratory irritation) as well as possibly other human health effects (Baden 1995, Fleming 1999, Fleming 1998a, Fleming 1998b, Morris 1991).

Aerosolized red tide toxins respiratory irritation consists of conjunctival irritation, copious catarrhal exudates, rhinorrhea, nonproductive cough, and bronchoconstriction with the inhalation of the aerosol of Florida Red Tides, the toxins of G. breve. Some people also report other symptoms such as dizziness, tunnel vision and skin rashes. In the normal population, the irritation and bronchoconstriction are usually rapidly reversible by leaving the beach area or entering an air conditioned area (Steidinger 1984, Baden 1983). However, asthmatics are apparently particularly susceptible, a finding confirmed in recent investigations with an asthmatic sheep aerosolized Red Tide toxins respiratory irritation model (W Abraham, verbal communication). Furthermore, there are anecdotal reports of prolonged lung disease, especially in susceptible populations such as the elderly or those with chronic lung disease. Of note, the Red Tide toxins inhalation manatee die-off investigation in 1996 revealed severe catarrhal rhinitis, pulmonary hemorrhage and edema, and non-suppurative leptomeningitis, as well as possible chronic hemolytic anemia with multi-organ hemosiderosis and evidence of neurotoxicity in the dead manatees (Bossart 1998).

Diagnosis

The diagnosis of Florida Red Tide toxins-associated clinical entities has been based on the clinical scenario of persons becoming ill with gastrointestinal and neurologic symptoms after eating shellfish or with acute respiratory symptoms similar to asthma after inhaling aerosols associated with exposure to Florida Red Tide toxins. There is a mouse bioassay with crude toxic residue extracted with ethyl ether and a mosquito fish bioassay. Recent promising research includes: an FPLC methodology for the identification of the G. breve toxins, as well as antibodies to brevetoxin and a possible cell based assay (Templeton 1988, Melinek 1994, Fairey 1997, Ishida 1996, Whitney 1997, Poli 1995).

Work with Florida manatees (apparently killed due the inhalation of the Red Tide toxins) has lead to the development of a qualitative immunocytochemical stain for the Florida Red Tide toxins found within the macrophages and lymphocytes in nasal mucosa, lung and other tissues (Bossart 1998). This technique has also been used in marine birds exposed to red tide toxins (Jessup 1998, Kreuder 1998). This biomarker can be used as both an indicator of exposure and effect. Based on recent research in a sheep animal model using a modified immunocytochemical technique on the bronchial lavage specimens of animals exposed to aerosolized red tide toxins, this biomarker holds promise as a diagnostic and prognostic tool. Initial work shows that the immunocytochemical staining of throat and nasal swab specimens reflect the bronchial lavage results, thus allowing for a more human-applicable biomarker.

Management and Treatment

In the case of aerosolized Red Tide toxins respiratory irritation, the use of particle filter masks or retreat to air conditioned environment will anecdotally provide relief from the airborne irritation. In sheep exposed to aerosolized red tide toxinss, the use of cromolyn or chlorpheniramine may treat, and if used prophylactically, even prevent the bronchoconstrictive response; this may have implications for asthmatics and other susceptible persons exposed to aerosolized Red Tide toxins (W Abraham, verbal communication).

The Florida Department of Environmental Protection (DEP) since the mid 1970s has conducted a control program with the closure of shellfish beds when G. breve concentrations are greater than 5000 cells/liter, until 2 weeks by testing for toxin with mouse bioassay testing. This should prevent cases of ingestion NSP related to contaminated shellfish consumption in most of the Florida human population, but not the respiratory irritation associated with exposure to aerosolized Red Tide toxins. There is monitoring of these red tides with their characteristic discoloration and massive fish kills by the Florida DEP, as well as unsolicited reports of respiratory irritation to the Florida Dept of Health. Although other states such as Texas have done otherwise, in Florida where the Red Tides are almost a yearly occurrence, beaches are not closed to recreational or occupational activities, even during very active near-shore blooms.

In 1999, the Florida Dept of Health added NSP to their list of reportable diseases; however, aerosolized Red Tide toxins respiratory irritation is not a reportable illness. The Florida Poison Information Center at the University of Miami initiated a toll free 24 hour/day Marine Hotline (1-888-232-8635) in 1997 to increase the reporting of marine related illness, including the marine toxin associated diseases; any cases of reportable illnesses are passed on by the Poison Information Center to the Florida Dept of Health for official reporting purposes. The Poison Control Center specialists have received specialized training in the recognition and triage of the marine toxin related illnesses through CDC funding for Estuarine Associated Syndrome. Efforts are on-going to increase knowledge and reporting of these illnesses by healthcare providers and public health officials, including a Video Conference on the Human Health Effects of Marine Toxins in Florida in June 1999 with a video and educational materials by the NIEHS Center through funding from CDC, the Florida Dept of Health and AHEC

Chemical Structure

Molecular Mechanism of Action

Fish, birds and mammals are all susceptible to the brevetoxins. The mouse LD50 is 0.20 mg/kg body weight (0.15-0.27) intraperitoneally. In human cases of NSP, the brevetoxin concentrations present in contaminated clams have been reported to be 30-18 ug (78-120 ug/mg).

The brevetoxins are lipid soluble polyethers with molecular weights around 900. These toxins are depolarizing substances that open voltage gated sodium (Na+) ion channels in cell walls, leading to uncontrolled Na+ influx into the cell (Baden 1983). This alters the membrane properties of excitable cell types in ways that enhance the inward flow of Na+ ions into the cell; this current can be blocked by external application of tetrodotoxin (Gallagher 1980, Baden 1983, Halstead 1988, Poli 1986, Viviani 1992, Trainer 1991).

It is believed that the respiratory problems associated with the inhalation of aerosolized Florida Red Tide toxins are due in part to the opening of sodium channels by the brevetoxin (Baden 1993, Asai 1982, Borison 1980, Franz 1989). In sheep, Abraham found that the bronchospasm can be blocked by atropine (verbal communication). In addition, there appears to be a role for mast cells; in sheep, the bronchospasm can be effectively blocked by cromolyn and chlorpheniramine (W Abraham PhD, verbal communcation). Watanabe et al (1988) noted that brevetoxin can combine with a separate site on the h gates of the sodium channel, causing the release of neurotransmitters from autonomic nerve endings. In particular, this can release acetylcholine, leading to smooth tracheal muscle contraction, as well as massive mast cell degranulation.

Since brevetoxins are also enzymatic inhibitors of the lysosomal proteinases known as cathepsins found in phagocytic cells such as the macrophages and lymphocytes, it is also possible that acute and chronic immunologic effects (including the release of inflammatory mediators that culminate in fatal toxic shock) may be associated with exposure to aerosolized Red Tide toxins, especially with chronic exposure and/or susceptible populations (Bossart 1998), although recent work by Baden et al cast doubt on the cathepsin mechanism (D Baden, verbal communication).

References and Sites

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Baden DG. Analyses of biotoxins (red tide) in manatee tissues. Miami: Report #MR148, Marine and Freshwater Biomedical Sciences Cener, National Institute of Environmental Health Sciences, Rosenstiel School of Marine and Atmospheric Sciences, 1996.

Baden, DG, Reins KS, Gawley RE, Jeglitsch G, Adams DJ. The a-ring lactone of brevetoxin PbTx-3 is required for sodium channel orphan receptor binding and activity. Natural Toxins 1993.

Baden DG, Mende TJ. Toxicity of tow toxins from the Florida red tide marine dinoflagellate, Gymnodinium breve. Toxicon 1982,20:457-461

Baden DG. Marine food-borne dinoflagellate toxins. Intemational Review of Cytology 1983;82: 99-150.

Baden D, Fleming LE, Bean JA. Chapter: Marine Toxins. in: Handbook of Clinical Neurology: Intoxications of the Nervous System Part H. Natural Toxins and Drugs. FA deWolf (Ed). Amsterdam: Elsevier Press, 1995. pgs. 141-175.

Borison HL, Ellis S, McCarthy LE. Central respiratory and circulatory effect of Gymnodinium breve toxin in anaesthetized cats. British Journal of Pharmacology 1980;70: 249-256.

Bossart GD, Baden DG, Ewing R, Roberts B, Wright S. Brevetoxicosis in Manatees (Tnchechus manatus latirostris) from the 1996 epizootic: gross, histopthologic and immunocytochemical features. Tox Path 1998;26(2):276-282.

Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: Lawrence Frlbaum Associates, 1988.

Fairey ER, Edmunds JS, Ramsdell JS. A cell based assay for brevetoxins, saxitoxins and ciguatox ins using a stably expressed c-fos-luciferase reporter gene. Anal Biochem 1997;251-129-32.

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Hopkins RS, Heber S, Hammond R. Water related disease in Florida: continuing threats require vigilance. J Florida Med Ass 1997;84:441-445.

Ishida H, Muramatsu N, Nukay H, Kosuge T, Tzuji K. Study on neurotoxic shellfish poisoning involving the oyster, Crassostrea gigas, in New Zealand. Toxicon 1996;34:1050-3.

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Kreuder C, Bossart GD, Elle M. Clinicopathologic features of an epizootic in the double-crested cormorant (Phalacrocorax auritus) along the Florida Gulf coast. Proc Wildlife Dis Assoc. Madison, WI: 1998.

Melinek R, Rein KS, Schultz DR, Baden DG. Brevetoxin PbTx-2 immunology: differential epitope recognition by antibodies from two goats. Toxicon 1994;32:883-90.

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Pierce, R., M. Henry, S. Boggess and A. Rule. Marine toxins in bubble-generated aerosol. In: The Climate and Health Implications of Bubble-Mediated Sea-Air Exchange (E. Monahan and P. van Patton, eds.), Connecticut Sea Grant Publications, 1989: 27-42.

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Poli M, Mende TJ, Baden DG. Brevetoxins, unique activators of voltage-sensitve sodium channels bind to specific sites in rat brain synaptosomes. Molecular Pharmacology 1986;30: 129-135.

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Trainer VL, Thomsen WJ, Catterall WA, Baden DG Photoaffinity labeling of the brevetoxin receptor on sodium channels in rat brain synaptosomes. Molecular Pharmacology 1991:40:988-994.

Viviani, R. Eutrophication, marine biotoxins, human health. Science for the Total Environment -Supplement 1992:631-62.

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