# Marine

# Algal 

# Toxins: Origins, Health Effects, 

# andTheir 

# IncreasedOccurrence

Frances M. 

### Van 

### Dolah

Marine Biotoxins Program, NOAANational Ocean Service, Center forCoastal Environmental Health and Biomolecular Research, Charleston, South Carolina USA

Certain marine algae produce potent toxins that impact human health through the consumption of contaminated shellfish and finfish and through water or aerosol exposure. Over the past three decades, the frequency and global distribution of toxic algal incidents appear to have increased, and human intoxications from novel algal sources have occurred. This increase is of particular

concern, since it parallels recent evidence of large-scale ecologic disturbances that coincide with trends in global warming. The extent to which human activities have contributed to their increase therefore comes into question. This review summarizes the origins and health effects of marine algal toxins, as well as changes in their current global distribution, and examines possible causes for the recent increase in their occurrence. Key words: amnesic shellfish poisoning, diarrhetic shellfish poisoning, dinoflagellates, domoic acid, global climate change, harmful algal blooms, marine toxins, neurotoxic shellfish poisoning, okadaic acid, paralytic shellfish poisoning.

- Environ Health Perspect 108(suppi 1):1 33-141 (2000). http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-1/133-141vandolah/abstract.html

Marine 

### algal toxins are 

### responsible for an 

### array 

### ofhuman 

### illnesses 

### associated with consumption 

### ofseafoodand, in some cases, respiratory 

### exposure to 

### aerosolized toxins. 

### Approximately 20% 

### ofall foodborne disease outbreaks in 

### the

### United States 

### result 

### from the consumption 

### of

### seafoods, with 

### halfof those 

### resulting from

### naturallyoccurring

### algal toxins 

### (1). On a

### worldwide

### basis, marine 

### algal toxins

are

### responsible formore 

### than 60,000 intoxication 

### incidents per

### year, 

### withan

### overallmortality rate 

### of 1.5%. In 

### addition to 

### their human 

### health 

### effects, algal toxins are 

### responsible for extensive

### die-offs offishand

### shellfishandhave been 

### implicated in 

### the 

### episodic mortalities of marine 

### mammals, 

### birds, and 

### other animals 

### dependent on 

### the marine 

### food web. The impacts 

### of

### algal toxins are 

### generally observed

as acute intoxications, 

### whereas the environ

### mental health effects 

### ofchronic exposure to 

### low 

### levels of

### algal toxins are 

### only poorly documentedandareanemerging issue 

### (2-5). The origins 

### ofmarine 

### algal toxins are 

### unicellular 

### algae that, in 

### response to 

### favorable conditions in

### theirenvironment, may

### proliferate 

### and/or aggregate to 

### formdense concentrations 

### ofcells or 

### "blooms." In

### manycases, toxic 

### species are

### normallypresent in 

### lowconcentra

### tions, 

### withno

### environmental or

### humanhealth impacts; toxicity in 

### general 

### depends on 

### their
presence in 

### high cell concentrations. 

### Phytoplankton species 

### that 

### produce toxins, 

### currently included under the 

### broad term 

### harmful 

### algal blooms 

### (HABs), 

### previouslywere 

### called red tides. 

### Only about 2% 

### (60-80 species) ofthe 

### estimated 

### 3,400-4,000 known 

### phytoplankton taxa are 

### harmful or toxic 

### (6). Of 

### these, members of two 

### algal groups, the 

### dinoflagellates and 

### diatoms, 

### produce toxins that impact 

### humans. 

### Filter-feeding 

### shellfish, zooplankton, and 

### herbivorous fishes 

### ingest these

### algaeand act asvectors tohumans 

### either 

### directly (e.g., 

### shellfish) or 

### through 

### further food web 

### transfer of 

### sequestered toxin to 

### higher 

### trophic levels. Consumption ofseafood 

### contaminated with 

### algal toxins 

### results in 

### five 

### seafoodpoisoning 

### syndromes (Table 

### 1): para

### lytic 

### shellfish poisoning, neurotoxic shellfish poisoning, amnesic 

### shellfish poisoning, 

### diarrhetic 

### shellfish poisoning, and ciguatera 

### fish poisoning. Most 

### ofthese toxins are neurotoxins 

### and all are 

### temperature stable, so 

### cooking 

### does not 

### ameliorate toxicity in 

### contaminated 

### seafoods. In 

### addition to 

### foodborne poisonings, toxins 

### from two 

### dinoflagellate sources
are 

### aerosolized 

### (brevetoxins) or 

### volatilized (a 

### putative Pfiesteria toxin) to 

### impact human health through

### therespiratoryroute. Over 

### the past 

### three 

### decades, the

occurrence 

### ofharmful or toxic 

### algal 

### incidents has 

### increased in many 

### parts 

### of the 

### world, both in 

### frequency and in 

### geographic distribution 

### (7-9). There are many 

### contributing 

### factors to 

### this expansion, not 

### the least of which is 

### increased awareness 

### of the issues 

### and consequent 

### establishment of research
programs 

### and surveillance systems, which in
turn 

### have 

### helped identifyproblems not 

### pre

### viouslyrecognized. In certain 

### instances, 

### however, 

### the expansion 

### of toxic 

### algal blooms to

new

### geographic areas, 

### resulting in 

### human illness or 

### environmental impacts, is 

### well docu

### mented. There has been much 

### speculation about the causes 

### and 

### significance of the observed 

### expansion; 

### however, few definitive studies have 

### been carried out to 

### date. 

### Ofpar

### ticular concern is 

### determining whether 

### the apparent increase in 

### harmful and toxic 

### algal blooms is a 

### consequence 

### of 

### anthropogenic activities, 

### which

### might therefore be modified
to reverse the current 

### trends. Human activities may contribute to 

### the 

### problem directly

or 

### indirectly through the introduction 

### of 

### nonindigenous species via 

### ballast water transport or 

### shellfish transplantation, local 

### and 

### regional environmental change caused 

### by 

### eutrophication or 

### contaminant 

### loading, large-scale climate 

### fluctuations (anomolous weather events; El Niflo), 

### and global climate 

### change mediated 

### by the 

### anthropogenic increase in 

### greenhouse gases. In 

### this review,

we 

### first summarize 

### the origins, 

### health 

### effects, and changes in 

### global distribution ofeach 

### of the toxin 

### classes 

### ofhuman health 

### significance, 

### and then 

### consider the current status 

### of

our 

### understanding ofthe causes 

### and 

### implications 

### of their 

### increased occurrences. The review 

### does not 

### attempt to address 

### nuisance 

### blooms or 

### freshwater algal toxins, 

### which can be 

### found in 

### previous reviews on 

### the 

### global increase in

### harmful algal 

### blooms (8-13). 

## Paralytic 

## Shellfish Poisoning Paralytic 

### shellfish poisoning (PSP) is 

### caused 

### by the consumption 

### ofmolluscan shellfish contaminated with a suite 

### ofheterocyclic 

### guanidines collectively called saxitoxins 

### (STXs) (Figure IA). On a

### global basis, 

### almost 2,000 

### cases 

### ofhumanpoisonings are 

### reported
per year, 

### with a 15% 

### mortality rate (8). In 

### addition to 

### human intoxications, PSP 

### has 

### been 

### implicated in 

### deaths 

### ofbirds (14) 

### and 

### humpback whales (15). An 

### ecologic role 

### for PSP toxins as a 

### chemical defense is 

### suggested 

### bythe sequestration 

### ofPSP 

### toxins in 

### the butter 

### clam, modulation 

### offeeding behavior in

sea otters 

### bytoxic 

### clams, 

### anda

### distribution of Alaskan sea otters 

### that coincides with nontoxic 

### clam

### populations 

### (16,17). STX 

### elicits its 

### effects 

### by binding with 

### high 

### affinity 

### (Kd

- 2 nM) to site 1 on 

### the 

### voltage-dependent sodium channel, inhibiting

### channel 

### conductance and therebycausing 

### blockade ofneuronal activity. 

### The primary site 

### of STX action in 

### humans is 

### the 

### peripheral nervous 

### system, where its 

### binding results in 

### rapid onset 

### of symptoms 

### (less than 1 

### hr) that are 

### classic for PSP: 

### tingling and numbness 

### ofthe 

### perioral area 

### and extremities, 

### loss of motor 

### control, drowsiness, 

### incoherence, and in 

### the case 

### of

### high doses, respiratory 

### paralysis. The lethal dose in humans is

Address correspondence to F.M. Van Dolah, Marine Biotoxins Program, NOAA National Ocean Service, Center for Coastal Environmental Health and Biomolecular Research, 219 Fort Johnson Rd., Charleston, SC 29412. Telephone: (843) 762-8529. Fax: (843) 762-8700. E-mail: 

### fran.vandolah@noaa.gov Received 6 October 1999; accepted 19 November 1999.

Environmental Health Perspectives * Vol 108, Supplement * March 2000 133F.M. VAN DOLAH

Table 1. Toxic syndromes associatedwithmarinealgal toxins.
Syndrome Causative organism Primaryvector Toxin Pharmacologic target

PSP Alexandriumspp. Shellfish Saxitoxins Voltage-dependent sodiumchannel

Gymnodiniumspp. Site 1 Pyrodiniumspp. NSP Gymnodiniumbreve Shellfish Brevetoxins Voltage-dependent sodiumchannel Site 5
CFP Gambierdiscus toxicus Reeffish Ciguatoxins Voltage-dependent sodiumchannel Site 5
ASP Pseudo-nitzschiaspp. Shellfish Domoicacid Glutamate receptors DSP Dinophysisspp. Shellfish Dinophysistoxins Ser/thrproteinphosphatases

Prorocentrumspp. Okadaic acid Estuary Pfiesteriapiscicida Water Unknown Unknown syndrome

A R4

XCH H

NH 1N NN

NH

H2N~~ N OH

..R3 B

Type 1

C

D

E c

- 

### /.. COOH

H , COOH COOH

H

Figure 1. Marine algal toxins that impacthuman health. (A) Saxitoxin, (B) brevetoxin, (C) ciguatoxin, (D) okadaicacid, (E) domoic acid. 1-4 mg 

### STX

### equivalents (18). Since 

### shellfish
may on rare occasions contain greater than 

### 10,000 

### pg/100 g STX

### equivalents, ingestion of

### only a few 

### shellfish meats may in 

### these instances 

### be 

### fatal. In a 

### study of a PSP out

### break in 

### Kodiak, Alaska, clearance of PSP toxins 

### from 

### the 

### blood was 

### complete in

< 24 

### hr, even in 

### patients who 

### experienced respiratory

### paralysis (19). The primary route of

### clearance was 

### the 

### kidney, as 

### has also 

### been 

### demonstrated in rats 

### (20) and cats 

### (21). There are

### currentlyover 21 

### known STX congeners 

### that are

### produced in

### varyingcombinations and 

### proportions 

### by several 

### gonyaulacoid and 

### gymnodinioid 

### dinoflagellate 

### species in 

### three genera: 

### Alexandrium, Gymnodinium, and

### Pyrodinium. PSP-producing dinoflagellates occur in 

### both temperate 

### and 

### tropical waters. In North 

### America, PSP occurs 

### seasonally both on the
east coast 

### (Newfoundland to 

### Massachusetts) and on 

### the west coast 

### (Alaska to 

### California). Anecdotal reports 

### identify PSP in 

### both regions 

### well before this century. Prior to 

### the 1970s PSP was 

### known to 

### be endemic 

### only to North

### America, 

### Europe, and

### Japan, 

### whereas, currently, PSP 

### outbreaks arealso

### documented in 

### SouthAmerica, 

### Australia, Southeast

### Asia, and India 

### (8). The reasons for 

### this 

### expansion into the 

### southern 

### hemisphere, or in some
cases 

### whether these in 

### fact represent 

### expansions of

### geographic ranges oftoxic 

### organisms,

are not

### entirelyclear. The 

### firstconfirmed out

### break of 

### PSP in South

### America occurred in 

### Chile in 1972 and was associated 

### with a 

### bloom of

### Alexandrium catenella. 

### Subsequent outbreaks occurred in 1981 and 1989 

### (22). Since 1991, 21 fatalities and several 

### hundred intoxications have occurred in 

### Chile 

### (23). A similarpattern of

### increased occurrence ofPSP is reported in

### Argentina, where the first PSP 

### outbreak, which occurred in 1980, was associated with a 

### bloom of 

### Alexandrium tamarense. 

### Following sporadic outbreaks 

### dur

### ing the 

### 1980s, shellfish toxicity associated with PSP has 

### been an annual occurrence 

### throughout the 1990s 

### along the 

### Argentine coast (24). As in North

### America, 

### however, anecdotal stories suggest 

### that PSP occurred in 

### both Chile 

### (22) and

### Argentina 

### (25) in the last 

### century, an 

### indication that the recent increase in 

### reported PSP events may be attributedat least inpart to the establishment 

### ofalgal andshellfish

### monitoringprograms. A similar scenario 

### occurred over the past two decades in the 

### Indo-Pacific. The causative organism for Indo-Pacific PSP intoxications is 

### Pyrodinium 

### bahamense var. compressum. The first reported outbreak of PSP in this region 

### occurred in 

### 1972 in Papua New Guinea and 

### subsequently spread to Brunei 

### beginning in 1976, central Philippines in 

### 1983, northern 

### Philippines in 1987, and 

### Malaysia in 

### 1988. In 

### the 

### Philippines alone,

Environmental Health Perspectives * Vol 108, Supplement l * March 2000

HO 

### Type 2 H. CHb CH3 CH3 H 0 R

H-, H _k

0

_ - 0

:H = 0 : f CP z H

0 0 0 0

H

HH

134MARINE ALGAL TOXINS



### approximately 2,000 cases 

### of PSP 

### occurred 

### between 1983 

### and 1998, 

### with a 

### mortality rate 

### of 5.8%; most cases 

### occurred among 

### the
young 

### (< 20 

### years 

### ofage) 

### (26). The expansion 

### of 

### Pyrodinium blooms in 

### this region appears to 

### be a 

### range extension in at 

### least

some 

### ofthese instances, as it is 

### absent 

### from phytoplankton 

### records in 

### the 

### Philippines prior to 

### the initial PSP 

### outbreak in 

### 1983 (27). 

### There is 

### compelling evidence to suggest 

### that the expansion 

### of toxic 

### blooms 

### of Pyrodinium in 

### the tropical 

### Pacific maycorre

### latewiththe occurrence 

### ofEl

### Niflo-Southern 

### Oscillation events 

### (28). Recurrent PSP events in 

### Tasmania 

### and 

### southern Australia 

### associated with the 

### dinoflagellate 

### Gymnodinium catenatum

### began in 

### late 1985 (8). 

### The 

### absence ofcysts 

### from sediments 

### before 1972 suggests 

### that this species was 

### introduced to 

### the region 

### around that time 

### (29). In 

### this case, 

### the route 

### of introduction has been 

### proposed to 

### be ballast water 

### transport 

### from

### Japan or 

### Europe, as 

### viable cysts

### havebeen isolated 

### fromvessel ballast water arriving in Tasmania (30). 

### However, 

### genetic 

### analysis 

### ofTasmanian 

### and Australian strains 

### has not 

### unequivocally identified theirgeographic origins 

### (31). 

## Neurotoxic 

## Shellfish 

## Poisoning

Neurotoxic

### shellfishpoisoning 

### (NSP) 

### generally results 

### from consumption 

### ofmolluscan shell

### fish contaminated

### withbrevetoxins (PbTx), a suite 

### of nine 

### structurally related ladderlike 

### polycyclic ether toxins 

### (Figure 1

### B). Brevetoxin congeners are 

### of two types 

### based

on 

### backbone structure: 

### brevetoxin B 

### backbone 

### (type 1; 

### PbTx-2,3,5,6,8,9) and brevetoxinA

### backbone (type 2; 

### PbTx-1,7,10). Brevetoxins 

### bind with 

### high 

### affinity 

### (Kd 1-50 

### nM) to site 5 on 

### the

### voltage-dependent sodium channel 

### (32). 

### Binding to 

### this site 

### both alters the

### voltage sensitivity 

### ofthe chan

### nel, resulting in 

### inappropriate opening 

### ofthe 

### channel under conditions in

### which it is nor

### mally 

### closed, and inhibits channel inactiva

### tion, 

### resulting in 

### persistent activation or 

### prolonged channel opening. 

### This 

### complex action is 

### believed to 

### result 

### from the inter

### calation 

### ofthe brevetoxin

### polyether backbone between transmembrane domains of the 

### sodium channel such that it interacts 

### with 

### boththe

### voltage sensor near 

### the

### outside ofthe channel andthe inactivationgate on

### the intracellular side 

### (33-37). Symptoms ofNSP 

### include nausea, 

### tingling and numbness ofthe 

### perioral area, 

### loss 

### ofmotor

### control, and severe 

### muscular ache. 

### Steidinger et 

### al. 

### (38) examine

an

### unusuallysevere intoxication 

### ofyoung

### children that occurred

### because of

### consumption of contaminated clams 

### (Chione 

### cancellata) and resulted in seizures 

### and unconsiousness. Unlike 

### PSP, NSP has not been 

### documented

as a

### fatal intoxication in

### humans. The occurrence 

### ofNSP 

### has 

### historically been limited to 

### the west coast 

### of Florida, 

### where blooms of the 

### dinoflagellate Gymnodinium breve initiate 

### offshore and are 

### subsequently carried inshore bywind and current 

### conditions (39). 

### Gulf of Mexico G. 

### breve 

### blooms are 

### occasionally 

### carried around the 

### Florida peninsula by the Loop Current 

### and 

### northward by 

### the GulfStream, 

### resulting in 

### red tides on 

### the east coast 

### of 

### Florida and, in a 

### single incident in 1987, as 

### far 

### north as 

### North Carolina (40). 

### The unprecedented 

### red tide in 

### North 

### Carolina, 

### which resulted in over 

### 48 cases 

### of

### shellfish poisoning, was 

### supported 

### by a 

### shoreward intrusion 

### ofwarm 

### Gulf Streamwater 

### onto 

### the narrow 

### continental 

### shelfwhich remained intact in 

### nearshore waters 

### for several 

### weeks (41). 

### Althoughthe 1987 

### outbreakofG. 

### breve is 

### often cited as a range 

### extension, low 

### but consistent 

### background concentrations 

### of G. 

### breve are 

### routinely 

### found in 

### the 

### Gulf Stream in 

### the South 

### Atlantic Bight (42). 

### Therefore, the 1987 

### bloom in 

### North Carolinamay

### be 

### theresult ofthe concurrence 

### ofa 

### large-scale sea

### surface temperature anom

### aly and local 

### conditions (43) rather 

### than 

### being a true 

### range extension 

### ofthe organism. In 

### 1993, an 

### unprecedented outbreak ofshell

### fish toxicity inNew

### Zealandwas 

### identifiedas NSP. 

### The source organisms 

### oftoxins in 

### this 

### outbreak were 

### novel 

### Gymnodinium species 

### (referred to as 

### Gymnodinium cf. breve) that 

### produceNSP-like toxins 

### (44). 

### Unlike most 

### other 

### dinoflagellates responsible for

### seafoodpoisonings, G. 

### breve is

an 

### unarmored 

### dinoflagellate that is 

### easily lysed in 

### turbulent water. G. 

### breve red 

### tides 

### therefore are 

### frequently associatedwith massive 

### fishkills. The extreme 

### sensivity

### of

### fish to 

### the Florida red tide may 

### result 

### from lysis of cells passing 

### through the 

### gills, with 

### direct 

### transferoftoxin across 

### the

### gill

### epithelium. An 

### additional route 

### of

### human exposure to 

### brevetoxins is 

### similarly through respiration, in 

### this

case 

### ofaerosolized toxin, 

### which is 

### the result ofcells 

### breaking due to wave action. A common symptom 

### associated with exposure to 

### aerosolized brevetoxin is irritation 

### and burning 

### ofthe throat 

### and upper 

### respiratory tract. In 1996 at 

### least 

### 149 manatees 

### diedduring an 

### unprecedented epizootic in 

### Florida concurrent 

### with a persistent 

### red tide. Immuno

### histochemical staining

### oftissues 

### fromaffected animals 

### revealedbrevetoxin immunoreactivity in 

### lymphocytes and 

### macrophages associated with 

### inflammatory lesions ofthe respiratory tract 

### and with 

### lymphoid tissues 

### (45). Molecular 

### modeling studies have 

### implicated brevetoxin as an 

### inhibitor ofa

### class of

### lysosomal 

### proteases, the 

### cysteine 

### cathepsins, which

are important in 

### antigen presentation 

### (46). The demonstration ofbrevetoxin immuno

### reactivity in 

### lymphoid tissue 

### ofthe manatees raises 

### thepossibilityofimmunosuppression as
a 

### secondmode 

### bywhich

### brevetoxin exposure may

### affecthumanhealth, particularlyin indi

### viduals with chronic exposure to 

### aerosolized toxin

### duringprolongedredtide incidents. 

## Ciguatera Fish 

## Poisoning Ciguatera 

### fish poisoning (CFP) is another seafood intoxication 

### caused 

### by ladderlike 

### polyether toxins, primarily attributed to the 

### dinoflagellate, Gambierdiscus toxicus 

### (47), which grows as an 

### epiphyte on 

### filamentous macroalgae associated with coral 

### reefs and 

### reef 

### lagoons. The 

### lipophilic precursors to ciguatoxin 

### produced by G. toxicus enter 

### the food web when these algae are 

### grazed upon 

### by

### herbivorous fishes and

### invertebrates. These precursors are 

### biotransformed to 

### ciguatoxins 

### (48) and 

### bioaccumulated in 

### the highest 

### trophic levels. 

### Large carnivorous fishes associ

### atedwith coral reefs are a 

### frequent source of ciguatera. 

### Baracuda, snapper, 

### grouper, and 

### jacks are 

### particularly notorious 

### for their 

### potential to carry

### high toxin 

### loads; however, smaller 

### herbivorous fishes may 

### also be ciguatoxic, 

### particularlywhenviscera

### are 

### consumed. CFP is 

### estimated to 

### affect over 

### 50,000 

### people 

### annuallyand is no 

### longer a

### disease limited to 

### the tropics

### becauseof

### travel to 

### the tropics 

### and shipping of tropical 

### fish species to 

### markets elsewhere in 

### theworld 

### (1). The symptoms 

### of ciguatera vary 

### somewhat 

### geographically as 

### well as 

### between 

### individuals and 

### incidents and may

### also vary 

### temporallywithin an area, 

### but 

### they

### generally include 

### early onset 

### (2-6 

### hr) 

### gastrointestinal 

### disturbance-nausea, vomiting, 

### and

### diarrhea-andmay

### be 

### followedbya 

### variety 

### of later onset 

### (18-hr) neurologic 

### sequelae such as 

### numbness of the 

### perioral

area 

### and extremities, 

### reversal 

### of temperature sensation, 

### muscle and joint 

### aches, headache, itching, tachycardia, 

### hypertension, blurred vision, 

### and

### paralysis. Ciguatera on rare occasions can

### be fatal. A

### chronic

### phasemay

### follow
acute intoxication 

### and can persist 

### for

### weeks, months, or evenyears 

### (49). Ciguatera symptoms in 

### the Caribbean 

### differ somewhat from those in 

### the 

### Pacific; 

### gastrointestinal symptoms 

### dominate in 

### the 

### former, whereas in 

### the 

### latter

### neurologic symptoms tend to

### dominate. This may

### reflect

### geographicdifferences in 

### the toxin

### congeners 

### involved 

### (50). The ciguatoxins 

### (CTXs) (Figure IC) are 

### structurally related to 

### the 

### brevetoxins and compete

### withbrevetoxin 

### for

### binding to site 

### 5

on 

### the 

### voltage-dependent sodium channel 

### with a

### high 

### affinity (Kd

- 0.04-4 

### nM) (51). The minimum 

### toxicity level to 

### humans is estimated at 0.5 

### ng/g 

### (52). Among the CTX 

### congeners, 

### binding 

### affinity correlates well 

### with toxic potency

### intraperitoneally in mice. 

### However, the toxic 

### potency 

### ofCTX in mice is several orders 

### of

### magnitude greater than that 

### of the brevetoxins 

### relative to their

Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000 135F.M. VAN DOLAH



### bindingaffinities at the 

### sodium channel (e.g., 

### for CTX1 

### and 

### PbTx3, LD50 = 

### 0.25 

### jig/kgvs

> 200 

### pg/kg, whereas Kd = 

### 0.04 nM vs 2 

### nM, 

### respectively). This may

### be 

### related to 

### dif

### ferences in 

### the 

### bioavailability ofthe toxins or to

### undefined toxic

### effects ofciguatoxin. 

### Although CFP 

### occurs 

### persistently at certain 

### locations, outbreaks are 

### sporadic and 

### unpredictable at 

### others. 

### Reefdisturbance due to storm 

### damage or 

### human activities 

### fre

### quently 

### precedes ciguateric 

### conditions 

### (53,54). The overgrowth ofcorals 

### bymacro

### algaebecause ofcoral

### bleaching, 

### overfishing, or 

### nutrient 

### enrichment (55,56) may 

### also promote ciguateric 

### conditions 

### by 

### providing increased

### substrate for

### the

### epiphytic G. toxicus. 

### Changes in sea 

### surface temperature 

### associated with 

### El Niflo events 

### also appear to 

### correlate 

### with 

### localized 

### changes in 

### the 

### frequency of ciguateracases in

### theAsian

### Pacific 

### (57). 

## Diarrhetic 

## Shellfish 

## Poisoning
Diarrhetic shellfish poisoning 

### (DSP) is a 

### comparativelymilderseafood intoxication 

### that consists 

### of

### rapid onset 

### (3 

### hr) gastrointestinal symptoms 

### such as 

### vomiting 

### and diarrhea that 

### generally 

### resolve within 2-3 

### days. The diar

### rhetic shellfish toxins 

### (DTX) are a 

### class of acidic 

### polyether toxins 

### consisting ofat 

### least 

### eight congeners 

### including the parent com

### pound, okadaic acid 

### (Figure 1D). The first 

### incidence 

### ofhuman 

### shellfish-related illness identified as DSP 

### occurred in

### Japan in

### thelate 1970s, where the

### dinoflagellate Dinophysisfortii was 

### identified as 

### the causative 

### organism; 

### the toxin 

### responsible was 

### termed

### dinophysistoxin 

### (DTX-1) (58,59). DSP is

### widespread in 

### its 

### distribution, with 

### essentially seasonal

occurrences in 

### Europe and

### Japan, but it 

### has also been 

### documented in 

### South America, South

### Africa, New

### Zealand and

### Australia, and 

### Thailand. The first 

### confirmed incidence of DSP in 

### North America 

### occurred in 

### 1990 in Nova 

### Scotia, Canada. 

### The causative 

### organism in

### this outbreakwas 

### the

### benthic

### dinoflagellate, Prorocentrum 

### lima (60,61), which was 

### found in association with 

### filamentous algae growing

on 

### raft cultures of

### mussels. Toxic P. 

### lima was 

### recently identified in Maine 

### coastal waters, 

### where thepresence

### ofDSP

### hasbeen

### suspected (62). P. 

### lima is a

### cosmopolitan

### dinoflagellate, with a 

### range 

### that extends from temperate waters to

### tropical reefs. Okadaic 

### acid, DTX-1, and DTX-2 are 

### the 

### primary congeners involved in 

### shellfish poisoning, with the 

### other congeners 

### believed to 

### be eitherprecursors or

### shellfishmetabolites ofthe active toxins. The DTXs are 

### inhibitors ofser/thr protein 

### phosphatases. Inhibitory 

### activity against protein 

### phosphatases is 

### selective for 

### classes PP2A 

### (okadaic acid 

### IC50

- 0.5 nM) and 

### PP1 (okadaic acid 

### IC50

- 50 

### nM), with PP2B 

### being inhibited 

### only at 

### high concentrations 

### (okadiac acid 

### IC50 > 10 

### pM) and PP2C 

### being insensitive. 

### The 

### binding site 

### for 

### okadaic acid resides on the 

### catalytic subunit of the 

### protein 

### phosphatase at 

### the active site 

### of the ezyme, as 

### determined 

### byX-ray 

### crystal structures 

### (63), molecular 

### modeling (64), and mutational 

### analyses (65). Ser/thr 

### protein 

### phosphatases

are critical 

### components of

### signaling cascades in

### eukaryotic cells 

### that

### regulatea

### diverse

### array of

### cellular 

### processes involved in 

### metabolism, ion

### balance, neurotransmission, andcell 

### cycle regulation (66). 

### Diarrhea associated with DSP is most 

### likelydue to the

### hyperphospho

### rylation of

### proteins, 

### including ion 

### channels, in the 

### intestinal 

### epithelia (67), resulting in 

### impairedwater

### balance and loss of

### fluids. The toxic 

### potency of

### okadaic acid is 

### much 

### lower than that of the 

### neurotoxin 

### polyethers, with

an 

### LD50 of 192 

### jg/kg (intraperitoneally) in mice 

### (68). However, okadaic acidlike 

### polyether toxins 

### have been identified as tumor 

### promotors (69,70), thus raising the question ofwhat 

### effect low levels ofchronic 

### exposure to DSP toxins 

### mayhave on

### humans as

### well as 

### wildlife suchasmarine

### turtles (3). 

## Amnesic Shellfish 

## Poisoning

Amnesic 

### shellfish poisoning (ASP) is the 

### only shellfish intoxication 

### caused

### bya

### diatom. The 

### first recorded occurrence 

### ofASPwas in 

### Prince Edward 

### Island, Canada in 

### 1987whenapproximately 100 

### people became ill andseveral died 

### after consuming contaminated mussels. None of

### theknownshellfish 

### toxinswere 

### foundtobe 

### involved in 

### the 

### outbreak; rather the toxic 

### agent was 

### identified as 

### domoic acid 

### (71,72). The source 

### ofdomoic acid was 

### the diatom 

### Pseudo-nitzschia 

### multiseries 

### (formerly known

as 

### Nitzschia

### pungensf multiseries) (73,74). Domoic 

### acid is a

### water-soluble tricarboxylic amino 

### acidthatacts as an

### analogoftheneurotransmitter 

### glutamate and is a 

### potent 

### glutamate 

### receptor agonist. Domoic 

### acid is 

### related 

### both 

### structurally and 

### functionally to 

### the exci

### tatoryneurotoxin

### kainic

### acidisolated

### fromthe 

### red 

### macroalga Digenea 

### simplex (75). Seven congeners to

### domoic acid

### havebeen identified 

### (Figure 1E). Of 

### these, three geometrical iso
### mers, 

### isodomoic acids D, E, 

### and F 

### and the 

### C5' diasteriomer are 

### found in 

### addition to 

### domoic acid in 

### small amounts in 

### both the diatomandin

### shellfish tissue 

### (76,77). The symptoms ofASP 

### include gastro

### intestinal 

### effects (e.g., nausea, vomiting, diar

### rhea) and

### neurologic effects suchas 

### dizziness, 

### disorientation, lethargy, seizures, and permanent 

### loss of 

### short-term memory. Domoic acid binds with 

### high affinity to both 

### kainate (Kd

- 5 

### nM) and 

### a-amino-3-hydroxy-5- 

### methyl-4-isoxazoleproprionic acid (Kd

- 9 

### nM) 

### subtypes of 

### glutamate receptor 

### (78,79). Persistent activation 

### of the 

### kainate 

### glutamate receptor results in 

### greatly elevated intracellular 

### Ca2+ through cooperative interactions 

### with 

### N-methyl-D-aspartate and 

### non-N-methyl-D-aspartate 

### glutamate receptor 

### subtypes followed

### by activation of

### volt

### age 

### dependent calcium channels 

### (80). Neurotoxicity due to 

### domoic acid results from toxic 

### levels of 

### intracellular 

### calcium, which leads to 

### neuronal cell 

### death and 

### lesions in areas 

### ofthe 

### brainwhere 

### glutaminergic

### pathways are

### heavilyconcentrated. The CA1 and 

### CA3 

### regions of 

### the

### hippocampus,

an area 

### responsible for 

### learning and 

### memory 

### processing, are 

### particularly susceptible 

### (81). However, memory 

### deficits occur at 

### doses below those 

### causing structural 

### damage 

### (82). In rats, 

### the 

### LD50 (intraperitoneally) for 

### domoic acid is 

### 4 

### mg/kg, whereas the oral 

### potency is 

### substantiallylower 

### (35-70 

### mg/kg) 

### (83). In 

### the 1987 

### outbreak, human 

### toxicity occurred at 

### 1-5 

### mg/kg, suggesting that sus

### ceptible individuals are more sensitive 

### than rodent 

### models to 

### the oral 

### toxicity of

### domoic acid. 

### Individuals found most 

### susceptible

were the 

### elderly and 

### those with 

### impared renal 

### function 

### resulting in 

### poor toxin 

### clearance. 

### A

### predisposing factor of

### impaired renal 

### clearance is consistent 

### with 

### results 

### observed in 

### studies on

### experimental animals 

### (84). No 

### human outbreaks of ASP 

### have occurred since the 

### original 1987 

### incident in 

### Canada. 

### However, since 

### the 1987 

### outbreak, domoic acid 

### has 

### been identified as 

### the causative 

### agent in 

### the mass 

### mortality of

### pelicans and cormorants in 

### Monterey 

### Bay, California, in 1991 

### (85,86) and in the extensive

### die-offof

### California sea 

### lions in 

### the same 

### region in 1998 

### (87,88). In

### both instances 

### the vector for toxin 

### transfer was 

### anchovy. The causative 

### organism in 

### both the 1991 and 1998 

### mortality events was 

### identified as 

### another member of the same 

### diatom 

### genus, 

### Pseudo-nitzschia australis. At 

### least seven 

### species of 

### Pseudo-nitzschia are now 

### recognized as 

### domoic acid

### producers. These toxin

### producing Pseudo-nitzschia species have since 

### been 

### identified in

### widelydiverse 

### geographic

areas 

### around the 

### world, including New 

### Zealand, Denmark, Spain, 

### Scotland, 

### Japan, and Korea 

### (89). The presence 

### of 

### Pseudo

### nitzschia in New 

### Zealand was 

### recorded as 

### earlyas 

### 1959. 

### However, domoic acidwas not 

### detected in New 

### Zealand until 

### after 

### implementation ofa 

### comprehensive marine toxin 

### monitoring program 

### following the 

### unprecedented NSP 

### shellfish 

### poisoning event in 1993. Domoic acid in New 

### Zealand mussels and 

### scallops occasionally reaches 

### levels that result in

### shellfishbed

### closures 

### (90).
Pfiesteriaand

### Estuary-Associated Syndrome 

### Pfiesteriapiscicida, a 

### fish-killing

### dinoflagellate first 

### identified in 

### aquaculture tanks in 

### North Carolina 

### (91,92), has been linked to 

### fishkills in the 

### mid-Atlantic region of the 

### United

Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000 136MARINE ALGAL TOXINS

States and is characterized by the presence of

open, ulcerative lesions (93). Pfiesteria has been termed an "ambush 

### predator" because it is

### believed to 

### release a toxin 

### that narcotizes or kills fish and then phagocytizes the sloughed tissue fromits prey 

### (94). Pflesteria has a complicated life cycle with numerous life cycle

stages 

### (94,95) including resting cysts, freeswimming flagellates (toxic and nontoxic), and amoeboid forms in which an amoeboid form is the dominant life-cycle stage. The cyst stage is viable under extreme conditions and is induced to excyst to form the toxic fla

### gellate stage in the presence of fish. Subsequent depletion of its food supply results in rapid encystment of the flagellate. The identity ofthe putative chemical stimulus for 

### Pfiesteria excystment has not yet been elucidated.
In addition to its effects on fish, Pfiesteria 

### has been linked to a 

### human intoxication syndrome, with symptoms that include fatigue, headache, respiratory irritation, skin lesions or burning sensations on contact, disorientation, and memory loss (96). An 

### epidemiologic study of

### people exposed to 

### Pfiesteria or 

### Pfiesteria-associated water

### demonstrated severe impairment in cognitive functions compared

to those of

### unexposed individuals from the

same occupational, educational, and geographic area (97). Because of the remaining uncertainty regarding the causal role of 

### Pfiesteria in 

### these impairments, 

### these symptoms have 

### conservativelybeen termed estuaryassociated 

### syndrome (98). Experimental injection of rats with Pfiesteria-containing aquarium water resulted in neurocognitive impairment in the rats when they were tested using a radial-arm maze 

### (99). The toxins 

### responsible for fish 

### lethality or 

### neurologic

symptoms have not yet been identified. There is currently no evidence that toxicity is transferredthrough food. 

### Pfiesteria differs from the 

### previously discussed 

### dinoflagellates in that it is a non

### photosynthetic, heterotrophic dinoflagellate. Nonetheless, there is compelling evidence that its occurrence at toxic levels coincides with the eutrophication of coastal waters through intensive swine and poultry agriculture in areas of North Carolina and 

### Maryland. Lagoon-stored and 

### land-applied

wastes from poultry and swine are a major

source ofnitrogen input from both runoff and atmospheric deposition and are suspected of supporting enhanced growth of 

### autotrophic algae that in turn support the proliferation of

### Pfiesteria (4,100). The study ofPfiesteriapiscida has led to recognition of the 

### widespread occurrence of

### heterotrophic dinoflagellates in estuarine waters, referred to

as the Pfiesteria-like complex. Pfiesteria-like dinoflagellates have been documented on the

east coast of the United States from Long Island to Florida. The historical distribution of these 

### dinoflagellates is not known nor is theirtoxicity ortheirrole(s) in fishkills firmly 

### established at this time. 

### Global 

## Increase in 

## the Occurrence of

## Algal Toxins Figure 2 

### illustrates the change in 

### global distribution of the occurrence ofalgal toxins ofhuman health concern over the past three decades. Of 

### particular significance is the

occurrence ofnovel toxic algal 

### syndromes not previously known as well as expansion of a number oftoxin classes from the northern to the southern hemisphere during this time frame. It is important to note that this distributional map is a composite picture that reflects both increases in reports due to increasedmonitoring for toxins aswell as true geographic expansions in the occurrence of toxic 

### outbreaks. Newly 

### established or expanded research and monitoring programs for algal toxins have been significant in identifying the presence of toxic or potentially toxic organisms in places never before docu

### mented. For 

### example, New 

### Zealand had no 

### reported algal toxins in 

### the 1970s but 

### following an 

### unprecidented toxic 

### outbreak in 1992 established a comprehensive monitoring program that has since 

### identified four or the five major toxin classes in shellfish at 

### levels sufficient to cause 

### occasional closures ofshellfish harvest. Improvement in toxin detection methods has further 

### contributed to expanded

ranges 

### reported in Figure 2. For 

### example, the

occurrence ofASP was unknown until the 1987 

### outbreak in 

### Canada. Ithas 

### subsequently been 

### implicated in 

### bird (1991) 

### and marine 

### mammal (1998) 

### mortalities on 

### the west coast ofNorth America. 

### Although these mortality

Figure 2. Global increase in reported incidence of algal toxins. Encircled areas indicate where outbreaks have occurred ortoxin has been detected at levels sufficient to impact human or environmental health.

Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000 

## QPSP ONSsP

ODSP OASP .:' 

### Ciguatera OpMies

137F.M. VAN DOLAH

events raise 

### significant alarm.in 

### light of the apparent increase in 

### the 

### global impacts 

### of 

### algal toxins, 

### unexplained 

### episodic marine 

### mammal 

### mortality events, some 

### ofwhich appear to have 

### similarities to the

### ASP-associ

### ated events, 

### have occurred every 

### fewyears on 

### the west 

### coast 

### ofNorthAmerica 

### for the past 

### several 

### decades (87). 

### Thus, retrospective 

### analysis of tissues 

### from earlier 

### mortality events, 

### where available, may

### provide insight into the 

### historical impacts oftoxic blooms of 

### Pseudonitzschia in 

### this region. In 

### other cases, the 

### distributions shown in 

### Figure 2 

### are 

### expansions in 

### the known geo

### graphic range 

### oftoxic 

### algal species at concen

### trations 

### sufficient to 

### impact 

### human or 

### environmental health. 

### The expansions 

### ofPSP in 

### southeast Asia 

### and SouthAmerica are 

### key 

### examples. The causes 

### ofthese expansions are 

### not 

### well 

### defined. 

### The lack of 

### long-term phytoplankton data 

### often hinders the 

### ability to

### determine if

### novel outbreaks are 

### the conse

### quence 

### of the 

### introduction oforganisms to

new regions, an increase in 

### the local abundance 

### ofa toxic organism 

### because ofchanges in 

### local or 

### regional nutrient 

### conditions, or 

### range extensions 

### due to 

### large-scale climatic 

### changes. The 

### key issue is to 

### what extent 

### human impacts on 

### the environment are 

### responsible for these increases. 

### The expansion 

### ofharmful and toxic 

### algal blooms is seen 

### by

some as a 

### bioindicator of

### large-scale marine 

### ecologic disturbances 

### (9,101,102). 

### The four primary means 

### bywhich 

### human activities 

### may

### contribute to 

### the expansion in 

### thedistribution of toxic 

### algae must 

### therefore be 

### viewed in 

### the 

### broader context 

### of

### human impacts on marine 

### ecosystem 

### health: transport 

### of exotic 

### species, 

### eutrophication of coastal waters, 

### anomolous weather events, 

### and

### global climate 

### change.


### Transport

A 

### principal mechanism for the 

### transfer of nonindigenous and invasive species among marine ecosystems is 

### through the movement 

### of

### ships' 

### ballast water 

### (103). Ballast water is 

### used to 

### stabilize 

### ships when they are not car

### rying cargo. Water is 

### pumped into a 

### ship's ballast tanks in 

### the port 

### of origin, 

### then released upon 

### arrival at its 

### destination port prior to 

### loading cargo. 

### If

### conditions are con

### ducive to 

### growth, organisms 

### carried in 

### the released ballast water 

### may 

### establish 

### populations in 

### the receivingport. It is 

### estimated that 10 billion tons 

### ofballastwaterare 

### transported each year, 

### making it a 

### major source 

### of inter

### national 

### pollution (104). Ballast water 

### has been 

### shown to 

### be 

### responsible for the transfer of

### pathogenic bacteria, protists, 

### algae, zoo

### plankton, benthic invertebrates, and 

### fish. A 

### number ofthese invasions 

### have 

### had 

### significant 

### ecologic and economic impacts 

### (105) or 

### human health 

### effects (106). Transport of toxic 

### algal cells 

### and cysts in 

### the ballast water of

### ships is a 

### documented mode oftransfer 

### of toxic 

### dinoflagellates and 

### diatoms to 

### previ

### ously 

### unaffected regions (30,107,108) and a likely source 

### ofPSP in

### Australian waters. To 

### address 

### this issue, open 

### ocean 

### exchange of ballast water 

### has been 

### recommended 

### by the International Maritime Organization (IMO), 

### under current 

### voluntary guidelines, as an 

### effective means to minimize 

### the introduction ofexotic 

### species 

### (104). 

### Further, a 

### joint 

### study group 

### on ballast 

### water and 

### sediments by the 

### International Council for Exploration of the 

### Seas, 

### the Intergovernmental Oceanographic Commission, 

### and the IMO 

### has since 

### been established to 

### develop mandatory 

### ballast water

### guidelines. Perhaps themost 

### directhuman impact on 

### the 

### distribution 

### of toxic 

### algal species is 

### through the transfer ofmolluscan shellfish 

### from growing waters in an 

### area 

### endemic to toxic 

### algal species to areas in 

### which toxic 

### blooms have not 

### previously occurred. When 

### shellfish are 

### transported from a toxic 

### area to 

### clean waters, 

### theymay 

### release cysts 

### and/or motile 

### algal cells 

### that may 

### seed a 

### bloom of the toxic 

### algae ifenvironmental conditions in 

### the receivingwaters are 

### conducive to 

### growth (109). 

### Thus, manycountries 

### have 

### established regulations to 

### prohibit 

### placing mussels from 

### potential PSP 

### risk areas to 

### other areas in an 

### effort to

### control 

### spreadingofblooms 

### (10). 

### Eutrophication Phytoplankton productivity in 

### oceanic, estuarine, 

### and coastal waters is 

### primarily lim

### ited by the 

### availability of nitrogen (12). Nitrogen 

### loading has been 

### implicated in 

### accelerated 

### phytoplankton production, or 

### eutrophication, which is most 

### notablymani

### fested as 

### algal blooms. A 

### major source 

### of 

### anthropogenically introduced nitrogen is 

### atmospheric deposition from 

### agricul

### tural, 

### urban, and industrial sources 

### (12). Atmospheric deposition by-passes estuarine processes 

### that filterterrestrial sources 

### ofnitrogen, 

### thereby 

### directly affecting both coastal and oceanic environments. 

### Coastal waters in 

### developed countries 

### have experienced a 

### longterm increase in 

### the 

### loading ofboth nitrogen 

### (N) and

### phosphorus (P), 

### bymore 

### than a 

### factor 

### of 

### four, compared with several decades
ago 

### (110). There is strong 

### evidence that coastal 

### eutrophication contributes to the 

### increased 

### incidence ofcertain 

### harmful 

### algal blooms 

### (4,8,9,12,111). An 

### often cited exam

### ple is 

### the correlation 

### between the 

### 8-fold increase in

### frequencyof

### algalblooms in

### Hong Kong 

### Harbor 

### from 1976 to 

### 1986 

### and a 

### 6-fold increase in 

### population 

### during that 

### period; the 

### latter was 

### accompanied by a 2.5 times increase in nutrient 

### loading (112). Although 

### long-term data sets on 

### phytoplankton 

### assemblages are not 

### available for many 

### areas, 

### changes in 

### dinoflagellate cyst 

### assemblages in surface sediments can be used to 

### document 

### eutrophication, as shown in 

### Tokyo Bay 

### (113). This 

### approachwas 

### critical in 

### identifying Gymnodinium catenatum as an introduced 

### organism inAustralianwaters 

### and is 

### currently

### being employed to 

### establish 

### the 

### historyof

### PSP-producing Pyrodinium blooms in

### SoutheastAsia. Not 

### only is 

### the total 

### concentration of enhanced nutrients 

### of

### significance, but the 

### altered ratios 

### of these nutrients relative to 

### those of

### other nutrients such as 

### silica are also 

### relevant. Long-term 

### data sets in 

### northern Europe 

### strongly support the 

### hypothesis that decreases in Si:N and Si:P ratios favor the 

### growth of 

### flagellates over 

### silica-dependent diatoms 

### (9.111,114). Similar 

### observations have 

### recentlybeen made in 

### conjunction with 

### Mississippi River 

### input to 

### the GulfofMexico (115). However, 

### the role ofcoastal eutrophication in the increased 

### incidence ofharmful 

### algal blooms may not 

### be generalized to all 

### HAB 

### species. For 

### example, there 

### currently is

no strong

### evidence to 

### suggest 

### that

### eutrophication 

### of coastal waters 

### contributes to 

### PSP (Alexandrium 

### tamarense) or NSP 

### (Gymno

### dinium breve) blooms that originate in 

### oligotrophic waters. 

### The 

### frequency and persistence 

### ofred tides on 

### the west coast 

### of 

### Florida, for 

### example, do not 

### appear to 

### have changed over the last 120 years 

### (Figure 

### 3). Each ofthe major range expansions 

### ofthese organisms in 

### North America 

### has coincided insteadwithunusual 

### climaticevents 

### (11,43).


### Anomolous

### WeatherEvents

It is

### well 

### established thatmany

### humandisease 

### outbreaks peak

### duringunusual climatic events 

### such as 

### drought, storm events 

### that produce 

### heavy 

### rainfall, and El Niiio 

### (57,106,116). 

### Similarly, El Niflo events are 

### linkedwith the

occurrence 

### ofdiseases in marine species, 

### including coral 

### bleaching and 

### shellfish diseases, 

### and

### possiblymarine 

### mammal 

### mortality events 

### (102). El Niflo occurs 

### when

### prevailing easterlywinds ofthe 

### tropical Pacific fail. This 

### ultimately suppresses 

### upwelling of cold nutrient-rich water in 

### the eastern 

### Pacific and creates a 

### pool ofwarm water in 

### the west. 

### Global precipitation 

### changes as a 

### consequence 

### ofEl Nifio are 

### generally increased 

### rainfall in 

### Southeast Asia 

### and 

### drought in

### Australia, Africa, and India. The occurrence 

### and/or expansion 

### ofhuman intoxication

### by PSP 

### and CFP in 

### the 

### Indo-Pacific have been com

### pellingly linked to 

### the occurrence 

### ofEl Nifio 

### conditions 

### (28,57). 

### Historically, El 

### Nifno events 

### have occurred at a 

### frequencyofone to two per 

### decade. However, since 

### the mid1970s 

### theyhaveoccurredmore

### frequentlyand 

### have 

### persisted 

### longer. The strongest 

### recorded El Nifno events 

### (1982-1983 and 

### 1997-1998) occurred

### duringthepast two

### decades, a

### period

Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000 138MARINE ALGAL TOXINS



### duringwhich the sea

### surface temperatures rose 

### and the incidence ofHABs 

### increased. The cooccurrence of these events late in this 

### century has led to 

### speculation that 

### global warming
maybe anunderlyingcause 

### (101,102).



### Global Climate 

### Change

An 

### observed increase in 

### the 

### global average 

### temperature during the past century 

### (0.80C between 1889 and 

### 1990) concurrent with 

### industrialization suggests that 

### the 

### world may be 

### entering a 

### period of 

### global warming 

### to 

### which 

### human activities have 

### contributed through production of 

### greenhouse gases 

### (117,118). The oceans, because of 

### their capacity as heat reservoirs, both 

### influence 

### and 

### respond to 

### global climate through 

### thermohaline 

### circulation, which 

### recirculates nutrients, oxygen, and CO2. 

### Long-term increases in sea 

### surface temperature are pre

### dicted to modify the behavior of 

### global oceanic 

### circulation, which 

### will further 

### alter marine 

### environmental regimes 

### (46). The 

### recent increases in 

### frequency and 

### emergence ofnovel 

### diseases affecting marine 

### organisms, from coral 

### bleaching to 

### shellfish 

### pathogens,

are 

### believed to 

### be linked to climate 

### change (101,102). The role 

### of

### global warming in 

### the 

### expansion oftoxic 

### algal blooms is difficult to 

### test, 

### however, because of the 

### complexity 

### of 

### overlying issues. First, the issue of 

### increased reporting oftoxic 

### algal incidents must be fac

### tored out. In addition, increased 

### utilization of coastal regions must be taken into
account. 

### Currently, 

### approximately 50% 

### of 

### the U.S. 

### population resideswithin the

### coastal

zone, 

### and this 

### figure is 

### predicted to increase. 

### Thus, in some instances, 

### the 

### increased human health 

### impacts of toxic algal 

### blooms

are a 

### result of increased 

### human exposure to 

### preexisting bloom activity rather than to 

### increasedbloomactivity, as is the case 

### for 

### the 

### rapidly developing west coast 

### of 

### Florida. Changes in 

### local environment due to 

### coastal development or 

### eutrophication also must be

14

-

12-

10

CD

4

137 113 16 1M 12 1954 15 1 19M 4 157 10 W02 1974 19 161 MI 193 193 1 13190 19 1

Figure 3. Occurrence of Gymnodiniumbrevered tides on the west coast of Florida (1878-1996), in months peryear.
Data from Steidinger (119). 

### factored out from 

### large-scale climatic 

### changes. Many 

### areas 

### of the world 

### where toxic 

### blooms have recently 

### expanded are



### areas 

### used heavily for 

### aquaculture. Aquaculture activitynot only

### results in 

### localized 

### nutrient 

### enrichment that may

### encourage growth of toxic 

### species but 

### places the 

### vector for 

### transmission of 

### toxin to 

### humans in 

### this 

### enriched environment. 

### Finally, manyareas 

### of the 

### world where toxic 

### blooms have 

### recently expanded lack long-term 

### historical phyto

### plankton records with 

### which to 

### determine the origins 

### of recent toxic 

### algal blooms. Many 

### of the time series 

### available that 

### might be 

### useful for 

### quantifying changes in 

### the 

### frequency of toxic 

### blooms are no 

### more 

### than a few

### decades in 

### length, not a 

### sufficiently long 

### period of time to 

### factor out 

### interannual to 

### decadal variability in 

### climate and 

### phytoplankton 

### abundance (13). 

### Therefore, until longer time 

### series are 

### available, itwill be 

### difficult to 

### demonstrate 

### definitively that the increases 

### observed are 

### true 

### long-term increases as 

### opposed to 

### recent 

### responses to 

### interannual or 

### decadal climate 

### variability. The

### distribution offossil cysts 

### ofcertain toxic 

### dinoflagellate species has 

### yielded 

### useful insight into 

### their

### distribution during

### previous

warmer 

### climate regimes and long-term vari

### ability in 

### abundance; thus, 

### paleoecology may 

### be a 

### useful tool 

### for developing potential dis

### tributional maps that 

### might be 

### encountered underwarmer

### global conditions 

### (8,46). 

## Conclusions

Marine 

### algal toxins 

### impact 

### human health 

### through 

### seafood consumption and respiratory
routes. 

### The 

### apparent increase in 

### their occurrence over 

### the past 

### three 

### decades has 

### raised alarm. A

### key issue is 

### whether the increase in 

### the occurrence 

### of toxic 

### algal blooms 

### reflects 

### large-scale marine 

### ecologic 

### disturbance due to 

### human activities 

### andwhether these 

### trends can 

### be 

### reversed. The 

### environmental conditions that 

### trigger toxic 

### algal blooms are not well 

### understood and differ 

### between different algal 

### species, making 

### generalizations inappropriate. Thus, 

### insight into 

### physiology and 

### bloom dymanics must be 

### addressed for 

### each 

### toxic species. It is 

### clear in 

### some cases that 

### human activities may

### directlycontribute to the 

### occurrence of 

### favorable growing 

### conditions for these 

### microalgae. In 

### other cases, the 

### potential indirect role 

### ofhuman 

### activities 

### through 

### large-scale changes in 

### our global 

### environment remains viable 

### but is 

### difficult to 

### establish. Insight into the 

### historical distributions of toxic 

### species through cyst analysis and 

### molecular 

### genetics may help 

### distinguish between changes in 

### geographic range oforganisms 

### and 

### proliferation due to 

### changes in 

### local 

### environmental 

### conditions 

### favoring bloom 

### formation. Establishment of

### algal and 

### toxin 

### monitoring
programs worldwide in the 

### past two 

### decades should assist in 

### providing time 

### series needed
to assess 

### interannual and 

### long-termvariability in

### algal andtoxin

### occurrence.

REFERENCES AND NOTES

1. Ahmed FE. Seafood Safety. Washington, DC:National Academy Press, 1991;432 pp. 2. Landsberg JH. Neoplasia and biotoxins in bivalves: Is there a connection? J Shellfish Res 15:203-230 (1996). 3. Landsberg JH, Balazs GH, Steidinger KA, Baden DG, Work TM, Russel DJ. The potential role of natural tumor promotors in marine turtle fibropapillomatosis. J Aquat Anim Health 11:199-210 (1999). 4. Burkholder JM. Implications of harmful microalgae and heterotrophic dinoflagellates in management of sutainable fisheries. EcolAppI 8:S37-S62 (1998).
5. Edmunds, JSG, McCarthy RA, Ramsdell JS. Ciguatoxin reduces larval survivability infinfish. Toxicon 37:1827-1832 (1999). 6. Smayda TJ. Harmful algal blooms: their ecophysiologyand general relevance to phytoplankton blooms in the sea. Limnol Oceanogr 42:1137-1153 (1997).
7. Anderson DM. Toxic algal blooms and red tides: a global perspective. In: Red Tides: Biology, Environmental Science and Toxicology (Okaichi T, Anderson DM, Nemoto T, eds). New York:Elsevier, 1989;11-16. 8. Hallegraeff GM. A review of harmful algal blooms and their apparent global increase. Phycologia 32:79-99 (1993). 9. Smayda TJ. Novel and nuisance phytoplankton blooms in the

sea: evidence for a global epidemic. In: Toxic Marine Phytoplankton (Graneli E, Sundstrom B, Edler L, Anderson DM, eds). NewYork:Elsevier, 1990;29-40 10. ShumwaySE. Areviewofthe effects ofalgal blooms on shellfish andaquaculture. JWorldAquaculture Soc 21:65-1104 (1990).
11. Anderson DM. Redtides. SciAm 271:52-58 (1994).
12. Pearl HW, Whitall DR. Anthropogenically-driven atmospheric nitrogen deposition, marine eutrophication and harmful algal bloomexpansion: isthere a link? Ambio 28:307-311 (1999).
13. Richardson K. Harmful or exceptional phytoplankton blooms in themarine ecosystem. AdvMarBiol 31:301-385 (1997).
14. Nisbet IC. Paralytic shellfish poisoning: effects on breeding

terns. Condor 85: 338-345 (1983). 15. Geraci JR, Anderson DM, Timperi RJ, St. Aubin DJ, Early GA,
Prescott JH, Mayo CA. Humpbackwhales fatallypoisoned by dinoflagellate toxin. Can J Fish Res Aquat Sci 46:1895-1898 (1989). 16. Kvitek RG, Beitler MK. A case for sequestering of paralytic shellfish toxins as a chemical defense. J Shellfish Res 7:629-636 (1988). 17. Kvitek RG, DeGange AR, Beitler MK. Paralytic shellfish poisoning toxins mediate feeding behavior in otters. Limnol Oceanogr 36:393-404 (1991). 18. Levin RE. Paralytic shellfish toxins: theirorigins, characteristics, and methods of detection: a review. J Food Biochem 15:405-417 (1992). 19. Gessnier BD, Bell P, Doucette GJ, Moczydlomski E, Poli MA, Van Dolah FM, Hall S. Hypertension and identification of toxin in

Environmental Health Perspectives * Vol 1 08, Supplement * March 2000 139F.M. VAN DOLAH

human urine and serum following a cluster of mussel-associated paralytic shellfish poisoning outbreaks. Toxicon 35:711-722(1997). 20. Hines HB, Naseem SM, Wannamacher RWJr. 3H-Saxitoxinol metabolism and elimination in the rat. Toxicon 31:905-908 (1993). 21. Andrinolo D, Michea LF, Lagos N. Toxic effects, pharmacokinetics and clearance of saxitoxin, a component of paralytic shellfishpoison (PSP), incats. Toxicon 37:447-464 (1999). 22. Benqvides H, Prado L, Diaz S, Carreto, JI. Anexceptional bloom ofAiexandriumcatenella in the Beagle Channel, Argentina. In: Harmful Algal Blooms (Lassus P, Arzul G, Erard E, Gentien P, Marcaillou C, eds). Paris:Lavoisier, 1995;113-119. 23. Suarez-lsla BA. Personal communication 24. Carreto JI, Montoya NG, Cucchi Colleoni AD, Akselman R. Alexandrium tamarense blooms and shellfish toxicity in the Argentine Sea: a retrospective view. In: Harmful Algae (Reguera B, BlancoJ, FernandezM, WyattT, eds). Santiago del Compostella, Spain:Xunta de Galacia and Intergovernmental Oceanographic Commission, 1998:131-134. 25. Carreto JI, Elbusto C, Sancho H, Carignan M, Cucci Colleoni D, de Marco S, Fernandez A. An exploratoryanalysis of the Mar del Plata shellfish toxicity area (1980-1990). Toxic Phytoplankton Blooms in the Sea (Smayda TJ, Shimizu Y, eds). NewYork:Elsevier, 1993;377-382. 26. Azanza R, CruzL. Personal communication. 27. FurioEF, FukuyoY, Matsuoka K, Gonzales CL. Thevertical distribution of resting cysts of PSP-producing dinoflagellate Pyrodinium bahamense var. compressum in Manila Bay, Philippines. In: Harmful and Toxic Algal Blooms (Yasumoto T, Oashima Y, Fukuyo Y, eds). Paris:lnternational Oceanographic Commission ofUNESCO, 1996:185-188. 28. Maclean JL. Indo-Pacific red tides, 1985-1988. Mar Pollut Bull 20:304-310 (1989). 29. McMinnA, Hallegraeff GM, Thomson P, Jenkinson AV, Heijnis H. Cystand radionucleotide evidence forthe recent introduction of the toxic dinoflagellate Gymnodinium catenatum into Tasmanianwaters. MarEcol ProgSer 161:165-172 (1997). 30. Hallegreaff GM. Transport of toxic dinoflagellates via ships' ballastwater: bioeconomic riskassessment and efficacyof possible ballast water management strategies. Mar Ecol Prog Ser 168:297-309 (1998). 31. BolchCJS, Blackburn S, Hallegraeff GM, Vaillancourt RE. Genetic variation among strains of the toxicdinofiagellate Gymnodinium catenatum(Dinophyceae). JPhycol 35:356-367 (1999). 32. Poli MA, Mende TJ, Baden DG. Brevetoxins, unique activators ofvoltage-sensitive sodium channels, bind to specific sites in
ratbrain synaptosomes. Mol Pharmacol 30:129-135 (1986). 33. Trainer VL, Baden DG, Caterall WA. Identification of peptide segments of the brevetoxin receptor sie of rat brain sodium channels. J Biol Chem 269:19904-19909 (1994). 34. Rein K, Baden DG., Gawley RE. Conformational analysis of the sodium channel modulator, brevetoxin A, comparison with brevetoxin B conformations, and a hypothesis about the common pharmacophore of the site 5 toxins. J Org Chem 59:2102-2106 (1994). 35. Rein K, Lynn B, GawleyR, Baden DG. Brevetoxin B: chemical modifications, synaptosome binding, toxicity, and anunexpected conformational effect. JOrgChem 59:2107-2113 (1994). 36. Gawley RE, Rein KS, Jeglitsch G, Adams DJ, Theodorakis EA, Tiebes J, Nicolau KC, Baden DG. The relationship of brevetoxin 'length' and a-ring functionality to binding and activity in neuronal sodiumchannels. ChemBiol Interact 2:533-541 (1995). 37. JeglitschG, ReinK, BadenDG, Adams DJ. Brevetoxin 3 (PbTx-3) and its derivatives modulate single tetrodotoxin sensitive sodium channels in rat sensory neurons. J Pharmacol Exp Therap284:516-525)1998). 38. Steidinger KA, Carlson P, Baden D, Rodriguez C, Seagle J. Neurotoxic shellfish poisoning due to toxin in the clam Chione canellata. In: Harmful Algae (Reguera B, Blanco J, Fernandez ML,Wyatt T, eds). Santiago del Compostella, Spain:Xunta de Galicia and Intergovernmental Oceanographic Commission, 1998;457-458. 39. Steidinger KA, Vargo GA, Tester PA, Tomas CR. Bloomdynamicsandphysiologyof Gymnodiniumbrevewith emphasis onthe Gulf of Mexico. In: Physiological Ecology of Harmful Algal Blooms (Anderson DM, Cembella AD, Hallegraeff GM, eds). Berlin:Springer-Verlag, 1998:133-154. 40. Tester PA, Steidinger KA. Gymnodiniumbreve red tide blooms: initiation, transport, and consequences of surface circulation. Limnol Oceanogr42:1039-1051 (1997). 41. Tester PA, Stumpf RP, Vukovich FM, Fowler PK, Turner JT. An expatriate red tide bloom: transport, distribution, and persistance. Limnol Oceanogr36:1053-1061)(1991). 42. Tester, PA, Geesey ME, Vukovich FM. Gymnodiniumbreve and global warming: what are the possibilities? In: Toxic Phytoplankton Blooms in the Sea (Smayda TJ, Shimizu Y, eds). 1993;67-72. 43. Tester PA. Climate change and marine phytoplankton. Ecosys Health 2:191-197 (1996). 44. Haywood A, MacKenzie L, Garthwaite I, Towers N. Gymnodiniumbreve 'look-alikes': three Gymnodinium isolates from New Zealand. In: Harmful and Toxic Algal Blooms (Yasumoto T, Oshima Y, Fukuyo Y, eds). Paris International Oceanographic Committee ofUNESCO, 1996;227-230. 45. Bossart GD, Baden DG, Ewing RY, Roberts B, Wright SD. Brevetoxicosis in manatees (Trichechus manatus latirostros) from the 1996 epizootic: gross, histologic, and immunochemical features. Toxicol Pathol 26:276-282 (1998). 46. Sudarsanam S, Virca DG, March CJ, Srinivasan S. An approach
to computer-based modeling: application to cathepsin.
J ComputAidMol Des 6:223-233 (1992). 47. Yasumoto T, Nakajima I, Bagnis R, Adachi R. Finding of a dinoflagellate as a likelyculprit of ciguatera. Bull Jpn Soc Sci Fish 43:1021-1026 (1977). 48. lewis RJ, Holmes MJ. Origin and transfer of toxins involved in ciguatera. Comp Biochem Physiol 106C:615-628 (1993). 49. Freudenthal AR. Public health aspects of ciguatera poisoning contracted on tropical vacations byNorthAmerican tourists. In: Toxic Marine Phytoplankton (Graneli E, Sundstron B, Edler L, Anderson DM, eds). NewYork:Elsevier, 1990;463-468. 50. Vernoux, J-P, Lewis RL. Isolation and characterization of Caribbean ciguatoxins from the horse-eye jack (Caranx latus). Toxicon 35:889-900 (1997). 51. Dechraoui M-Y, Naar J, Pauillac S, Legrand A-M. Ciguatoxins and brevetoxins, neurotoxic polyether compounds active on sodiumchannels. Toxicon 37:125-143 (1999). 52. Legrand AM. Ciguatera toxins: origin, transfer through food chain and toxicity to humans. In: Harmful Algae (Reguera B, Blanco J, Fernandez ML, Wyatt T, eds). Santiago del Compostella:Xunta de Galacia and llntergovernmental Oceanographic Commission, 1998;39-43. 53. Ruff TA. Ciguatera in the Pacific: a linkwith military activities. Lancet:201-205 (1989). 54. KalyUL, Jones GP. Test of the effect of disturbance on ciguatera inTuvalu. MemOdMus 34:523-532 (1994). 55. Kohler ST, Kohler CC. Dead bleached coral provides new surfaces fordinoflagellates implicated inciguatera fish poisonings. Environ Biol Fishes 35:413-416 (1992). 56. Bagnis RS. Ciguatera fish poisoning: an objective witness of coral reef stress. In: Human Impacts on Coral Reefs: Facts and Recommendations (Salvat B, ed). French Polynesia:Antenne Museum, 1987;241-253. 57. Hales S, Weinstein P, Woodward A. Ciguatera (fish poisoning), El Nifo, and Pacific sea surface temperatures. Ecosys Health 5:20-25 (1999). 58. Yasumoto T, Oshima Y, Yamaguchi M. Occurrence of a new type of shellfish poisoning inJapan and chemical properties of the toxin. In: Toxic Dinoflagellate Blooms (Taylor D, Seliger HH, eds). Amsterdam:Elsevier, 1979:495-502. 59. Yasumoto T, Oshima Y, Sugawara W, Fukuyo Y, Oguri H, Igarishi T, Fujita N. Identification of Dinophysis fortii as the causative organism of diarrhetic shellfish posioning. Bull Jpn Soc Sci Fish 46:1405-1411 (1980). 60. Quilliam MA, Gilgan M, Pleasance S, DeFrietas ASW, Douglas D, Fritz L, HuT, MarrJC, Smyth C, Wright JLC. Confirmation of

an incident of diarrhetic shellfish poisoning in eastern Canada. In: Toxic Phytoplankton Blooms in the Sea (Smayda TJ, Shimizu Y, eds). Amsterdam:Elsevier, 1993;547-552. 61. Lawrence JE, Bauder AG, Quilliam MA, Cembella AD. Prorocentrum lima: a putative link to diarrhetic shellfish poisoning in Nova Scotia, Canada. In: Harmful Algae (Reguera B, Blanc J, Fernandez ML, WyattT, eds). Santiago del Compostella:Xunta de Galacia and Intergovernmental Oceanographic Commission, 1998;78-79. 62. Morton SL, Leighfield TA, Haynes BL, Petipain DL, Busman MA, Moeller PD, Bean L, McGowan J, Hurst JL, Van Dolah FM. Evidence for diarrhetic shellfish poisoning along the coast of Maine. J Shellfish Res 18:679-684 (1999). 63. GaussC-M, SheppockJE, NairnAC, Chamberlin RA. Amolecular modeling analysis of the binding interactions between okadaic acid class of natural product inhibitors and the ser-thr phosphatases, PP1 and PP2A. Bioorg MedChem 5:1751-1773 (1997). 64. Bagu JR, Sykes BD, Craig MM, Holmes CFB. Amolecular basis for different interactions of marine toxins with protein phosphatase B1. Molecular models for bound moruporin, microcystins, okadaic acid and calyculin A. J Biol Chew 272:5078-5097 (1997). 65. Zhang Z, Zhao S, Long F, Zhang L, Bai G, Shima H, Nagao M, Lee EYC. A mutant of protein phosphatase-1 that exhibits altered toxin sensitivity. J Biol Chem 269:16997-17000 (1994). 66. Wera S, Hemmings B. Ser/thrproteinphosphatases. BiochemJ 311:17-29 (1995). 67. Cohen P, Holmes CFB Tsukitani Y. Okadaic acid: a newprobe for the study of cellular regulation. Trends Biochem Sci 15:98-102 (1990). 68. Yasumoto T, Murata M, Oshima Y, Matsumoto G, Clardy J. Diarrhetic shellfish poisoning. In: Seafood Toxins (Regalis EP, ed). Washington, DC:American Chemical Society, 1984;207-214. 69. Suganuma M, Fujiki H, Suguri H, Yoshizawa S, Hirota M, Nakayasu M, Ojika M, Wakamatsu K, Yamada K, Sugimura T. Okadaic acid

- an additional non-phorbol-12-tetradecanoate13-acetate-type tumor promoter. Proc NatI Acad Sci 85:1768-1771 (1988). 70. Fujiki H, Suganuma M, Suguri H, Yoshizawa S, Tagai K, Uda N, Wakamatsu K, Yamada K, Murata M, Yasumoto T, et al. Diarrhetic shellfish toxin, dinophysistoxin-1, is a potent tumor promotor onmouse skin. JpnJCancerRes 79:1089-1093 (1988). 71. Wright JLC, Boyd RK, Defrietas ASW, Falk M, Foxall RA, Jamieson WD, Laycock MV, McCulloch AW, Mcinnes AG, Odense P, et al. Identification ofdomoic acid, a neuroexcitatory amino acid, in toxic mussels from eastern P.E.I. Can J Chem 67:481-490 (1989). 72. Perl TM, Bedard L, Kosatsky T, Hockin JC, Todd ECD, Remic RS. An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N EngI J Med 322:775-1780 (1990). 73. Subba-Rao DV, Quilliam MA, Pocklington R. Domoic acid B a neurotoxic amino acid produced from the marine daitom Nitzschia pungens in culture. Can J Fish Aquat Sci 45:2076-2079 (1988). 74. Bates SS, Bird CJ, Defrietas ASW, Foxall R, Gilgan M, Hanic LA, Johnson GR, McCullochAW, Odense P, PocklingtonR, etal. Pennate diatom Nitzschia pungens as the primary source of domoic acid, a toxin in shellfish from eastern Prince Edward Island, Canada. J FishAquat Sci46(7):1203-1215 (1989). 75. Murakami S, Takemoto T, Shimizu Y. Studies on the effective principles of Diagenea simplexAq. I: Separation of the effective fraction by liquid chromatography. J Pharmacol Soc Jpn 73:1026-1028 (1953). 76. Wright JLC, FalkM, Mcinnes AG, Walter JA. Identification of isodomoic acid D and two new geometrical isomers of domoic acid in toxicmussels. CanJChem 68:22-25 (1990). 77. WalterJA, Falk M, Wright JLC. Chemistry of the shellfish toxin domoic acid: characterization of related compounds. Can J Chem 72:430-436 (1994). 78. Hampson DR, Huang X, Wells JW, Walter JA, Wright JLC. Interaction of domoic acid and serveral derivatives of kainic acid and AMPA binding sites in rat brain. Eur J Pharmacol 218:1-8 (1992). 79. Hampson DR, Manalo JL. The activation of glutamate receptors bykainic anddomoic acid. Natural Toxins 6:153-158 (1998). 80. Xi D, Ramsdell JS. Glutamate receptors and calcium entry mechanisms for domoic acid in hippocampal neurons. Neuroreport 7:1115-1120 (1996). 81. Peng YG, Taylor TB, Finch RE, Switzer RC, Ramsdell JS. Neuroexcitatory and neurotoxic actions of the amnesic shellfish poison, domoicacid. Neuroreport 5:981-985 (1994). 82. Clayton EC, Peng Y-G, Means LW, Ramsdell JS. Working memory deficits induced by single but not repeated exposures to domoic acid. Toxicon 37:1025-1039 (1999). 83. Iverson F, Truelove J, Nera E, Tryphonas L, Campbell J, Lok E. Domoic acid poisoning andmussel-associated intoxication: preliminary investigations into the response of mice and rats to toxic mussel extract. Food ChemToxicol 27:377-384 (1989). 84. Preston E, Haynie I. Transfer constants for blood-brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid. CanJNeurolog Sci 18:39-44 (1991). 85. Fritz L, Quilliam MA, Wright JLC, Beale AM, Work TM. An outbreak of domoic acid and poisoning attributed to the pennate diatom Pseudonitzschia australis. J Phycol 28:438-442 (1992). 86. WorkTM, Barr BB, BealeAM, Fritz L, Quilliam MA, Wright JLC. Epidemiology of domoic acid poisoning in brown pelicans (Pelicanus occidentalis) and Brandt's cormorants (Phalacrocorax pencillatus) inCalifornia. JZool Wildlife Med 24:54-62 (1993). 87. Guiland F. 1999. Unusual MortalityEvent

- DomoicAcidToxicity in California Sea Lions (Zalophuscalifomianus) Stranded along the Central California Coast, May-October 1998. NOAA Tachnical Memorandum NMFS-OPR-8. Wahington, DC:U.S. National Marine Fisheries Service, 1999;30 pp. 88. Scholin CA, Gulland F, Doucette GJ, Benson 5, Busman M, Chavez FP, Cordaro J, DeLong R, DeVogelaere A, Harvey J,

140 Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000MARINE ALGALTOXINS

etal. MortalityofsealionsalongtheCalifornia coast linkedtoa toxicdiatombloom. Nature 403:80-83 (2000). 89. Bates SS. Bloom dynamics and physiology of domoic acid producing Pseudo-nitzschia species. In: Physiological Ecology of Harmful Algal Blooms (Anderson DM, CembellaAD, Hallegraeff GM, eds). NewYork:Springer-Verlag, 1998;267-292. 90. Rhodes L, Scholin C, Garthwaite I. Pseudo-nitzschia in New Zealand andthe roleofDNAprobesand immunoassays inrefining marine biotoxin monitoring programmes. Natural Toxins 6:105-111 (1998). 91. Smith S, Noga E, Bullis RA. Mortality in Talapiadue to a toxic dinoflagellate bloom [Abstract]. Proceedings of the Third International Colloquium on Pathology in MarineAquaculture, GloucesterPoint, Virginia. 1998;167-168. 92. Noga EJ. Fungal diseases of marine and estuarine fishes. In: Pathobiology of Marine and Estuarine Organisms (Couch JA, FournieJW, eds). Boca,Raton, FL:CRCPress, 1993;85-100. 93. Burkholder JM, Noga EJ, Hobbs CW, Glasgow HB, Smith SA. New phantom dinoflagellate is the causative agent of major estuarine fishkills. Nature 358:407-410 (1992). 94. Burkholder JM, Glasgow HBJr. Pfiesteriapiscicida and other Pfiesteria-like dinoflagellates: behavior, impacts, and environmental controls. Limnol Oceanogr42:1052-1075 95. BurkholderJM, GlasgowHBJr. Trophic controls onstagetransformations of a toxic amnush-predator dinoflagellate. J Euk Microbiol 44:200-205. 96. GlasgowHB, Burkholder JM, Schmechel DE, Tester PA, Rublee PA. Insidious effects of a toxic dinoflagellate on fish survival andhumanhealth. JToxicol EnvironHealth46:101-122 (1995). 97. Grattan LM, Oldach D, PerI TM, Lowitt MH, Matuszak DL, Dickson C, Parrott C, Shoemaker RC, Kauffman CL, Wasserman MP, etal. Learning andmemorydifficulties afterenvironmental
exposure to waterways containing toxin-producing Pfiesteria andPfiesteria-likedinoflagellates. Lancet 352:532-539 (1998). 98. CentersforDiseaseControl. Results ofthepublichealthresponse to the Pfiesteriaworkshop-Atlanta, Georgia, September 29-30, 1997. MorbMortWeeklyRep46:951-952 (1997). 99. Levin ED, Schmechel DE, Burkholder JM, GlasgowHB, DeamerMelia NJ, MoserVC, HarryGJ. Persisting learning deficits in rate after exposure to Pfiesteria piscicida. Environ Health Perspect 1015:1320-1325(1997). 100. Pearl HW. Coastal eutrophication and harmful algal blooms: importance of atmospheric disposition and groundwater as "new' nitrogen and other nutrient sources. Limnol Oceanogr 42:1154-1165 (1997). 101. Epstein P, Sherman B, Spanger-Siegfried E, Langston A, Prasad S, Mckay B. Marine ecosystems: emerging diseases as indicatorsofchange. YearoftheOceans Special Report. Washington, DC:NOAAOfficeofGlobal Programs, 1998;85 pp. 102. Harvell CD, KimK, BurkholderJM, Colwell RR, Epstein PR, Grimes DJ, Hofmann EE, lipp EK, Osterhaus AD, Overstreet RM, et al. Marine ecology-emerging marine diseases-climate links and anthropogenic factors [Review]. Science285:1505-1510 (1999). 103. Cariton JT, Geller JB. Ecological roulette: the global transport ofnonindigenousmarine organisms. Science 261:78-82 (1993). 104. Rigby GR, Taylor AH, Hallegraeff GM, Mills P. Progress in research and management of ships' ballast water to minimise the transfer of toxic dinoflagellates. In: Harmful Marine Algal Blooms (Lassus P, Arzul G, Erard E, Gentien P, Marcaillou C, eds). Lavoisier:Paris, 1995;821-824 105. Ruiz GM, CarletonJT, HinesAH. Global invasions ofmarine and estuarine habitata by non-indiginous species: mechanisms, extent, andconsequences. AmZool 37:621-632 (1997). 106. Colwell R. Global climate and infectious disease: the cholera paradigm. Science 274:2025-2031 (1996). 107. Zhang FZ, Dickman M. Mid-ocean exchange ofcontainervessel ballast water. 1: Seasonal factors affecting the transport of harmful diatoms and dinoflagellates. Mar Ecol

- Prog Ser 176:243-251 (1999). 108. Dickman M, Zhang FZ. Mid-ocean exchange ofcontainervessel ballast water. 2. Effects of vessel type in the transport of diatoms and dinoflagellates from Manzanillo, Mexico, to Hong Kong, China. MarEcol

-ProgSer 176:253-262 (1999). 109. Scarratt AM, Scarratt DJ, Scarratt MG. Survival of live Alexandrium tamarense inmussel and scallop spat under simulatedconditions. J Shellfish Res 12:383-388(1993). 110. Nixon SW. Coastal marine eutrophication: a definition, social

causes andfuture concerns. Ophelia 41:199-220 (1995). 111. Reigman R. Species composition of harmful algal blooms in relation tomacronutrient dynamics. In: Physiological Ecologyof Harmful Algal Blooms (Anderson DM, Cembella AD, Hallegraeff GM, eds). NewYork:Springer-Verlag, 1998;475-488. 112. Lam CWY, Ho KC. Red tides in Tolo Harbor, Hong Kong. In: Red Tides: Biology, Environmental Science and Toxicology (Okaichi T, Anderson DM, Nemoto T, eds). NewYork:Elsevier, 1989;49-52. 113. Matsuoka K. Eutrophication process recorded in dinoflagellate cystassemblages

-acase ofYokohama Port, TokyoBay, Japan. SciTotal Environ 231:17-35 (1999). 114. Humbourg C, Tittekkot V, Cociasu A, Bodungen B. Effect of Danube River dam on Black Sea ecosystem structure. Nature 386:385-388 119971. 115. Turner RE, Rabelais NN. Coastal eutrophication near the Mississippi Delta. Nature 368:619-621 (1994). 116. Epstein PR. Perspectives: Medicine

- climate and health. Science 285:347-348 (1999). 117. National Research Council. Climate andweather, coastal hazards, and public health. In: From Monsoons to Microbes: Understanding the Ocean's Role in Human Health. Washington, DC:NationalAcademyPress,1999;17-42. 118. Mann ME, BradleyRS, Hughes MK. Global scale temperature patterns and climate forcing overthepast sixcenturies. Nature 392:779-787 (1998). 119. Steindinger KA. Unpublisheddata.

Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000 141