Marine Algal Toxins: Origins, Health Effects, and Their Increased Occurrence

Frances M. Van Dolah

Marine Biotoxins Program, NOAA National Ocean Service, Center for Coastal 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 1 08(suppi 1):1 33-141 (2000).

http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-1/133-14 1 vandolah/abstract.html

Marine algal toxins are responsible for an

array of human illnesses associated with consumption of seafood and, in some cases, respiratory exposure to aerosolized toxins.

Approximately 20% of all foodborne disease

outbreaks in the United States result from the

consumption of seafoods, with half of those

resulting from naturally occurring algal toxins

(1). On a worldwide basis, marine algal toxins

are responsible for more than 60,000 intoxication incidents per year, with an overall mortality rate of 1.5%. In addition to their human

health effects, algal toxins are responsible for

extensive die-offs of fish and shellfish and have

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 environmental health effects of chronic exposure to

low levels of algal toxins are only poorly

documented and are an emerging issue (2-5).

The origins of marine algal toxins are

unicellular algae that, in response to favorable

conditions in their environment, may proliferate and/or aggregate to form dense concentrations of cells or "blooms." In many cases, toxic

species are normally present in low concentrations, with no environmental or human health

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), previously were

called red tides. Only about 2% (60-80

species) of the 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 algae and act as vectors to humans either

directly (e.g., shellfish) or through further

food web transfer of sequestered toxin to

higher trophic levels. Consumption of seafood

contaminated with algal toxins results in five

seafood poisoning syndromes (Table 1): paralytic shellfish poisoning, neurotoxic shellfish

poisoning, amnesic shellfish poisoning, diarrhetic shellfish poisoning, and ciguatera fish

poisoning. Most of these 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 the respiratory route.

Over the past three decades, the

occurrence of harmful 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 identify problems not previously recognized. In certain instances, however, the expansion of toxic algal blooms to

new geographic areas, resulting in human illness or environmental impacts, is well documented. There has been much speculation

about the causes and significance of the

observed expansion; however, few definitive

studies have been carried out to date. Of particular 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 of each of

the toxin classes of human health significance, and then consider the current status of

our understanding of the 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 of molluscan shellfish

contaminated with a suite of heterocyclic

guanidines collectively called saxitoxins

(STXs) (Figure IA). On a global basis, almost

2,000 cases of human poisonings are reported

per year, with a 15% mortality rate (8). In

addition to human intoxications, PSP has

been implicated in deaths of birds (14) and

humpback whales (15). An ecologic role for

PSP toxins as a chemical defense is suggested

by the sequestration of PSP toxins in the butter clam, modulation of feeding behavior in

sea otters by toxic clams, and a 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 thereby causing

blockade of neuronal 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 of the 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 133
F.M. VAN DOLAH

Table 1. Toxic syndromes associated with marine algal toxins.

Syndrome Causative organism Primary vector Toxin Pharmacologic target

PSP Alexandrium spp. Shellfish Saxitoxins Voltage-dependent sodium channel

Gymnodinium spp. Site 1

Pyrodinium spp.

NSP Gymnodinium breve Shellfish Brevetoxins Voltage-dependent sodium channel

Site 5

CFP Gambierdiscus toxicus Reef fish Ciguatoxins Voltage-dependent sodium channel

Site 5

ASP Pseudo-nitzschia spp. Shellfish Domoic acid Glutamate receptors

DSP Dinophysis spp. Shellfish Dinophysistoxins Ser/thr protein phosphatases

Prorocentrum spp. Okadaic acid

Estuary Pfiesteria piscicida Water Unknown Unknown

syndrome

A R4

XCH

H

NH

1N NNNH

H2N~~ N OH

.. R3

B

Type 1

C

D

E c

- /.. COOH

H

,

COOH COOH

H

Figure 1. Marine algal toxins that impact human health. (A) Saxitoxin, (B) brevetoxin, (C) ciguatoxin, (D) okadaic acid,

(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 outbreak 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 currently over 21 known STX congeners that are produced in varying combinations 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 are also documented

in South America, 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 of toxic organisms,

are not entirely clear. The first confirmed outbreak 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

similar pattern of increased occurrence of PSP

is reported in Argentina, where the first PSP

outbreak, which occurred in 1980, was associated with a bloom of Alexandrium

tamarense. Following sporadic outbreaks during 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

attributed at least in part to the establishment

of algal and shellfish monitoring programs.

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

H H

134
MARINE 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 of age) (26). The expansion of Pyrodinium blooms in this region

appears to be a range extension in at least

some of these 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 may correlate with the occurrence of El 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 of cysts 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 have been isolated from vessel ballast water arriving in Tasmania (30).

However, genetic analysis of Tasmanian and

Australian strains has not unequivocally

identified their geographic origins (31).

Neurotoxic Shellfish Poisoning

Neurotoxic shellfish poisoning (NSP) generally

results from consumption of molluscan shellfish contaminated with brevetoxins (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 brevetoxin A 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 of the channel, resulting in inappropriate opening of the

channel under conditions in which it is normally closed, and inhibits channel inactivation, resulting in persistent activation or

prolonged channel opening. This complex

action is believed to result from the intercalation of the brevetoxin polyether backbone

between transmembrane domains of the

sodium channel such that it interacts with

both the voltage sensor near the outside of the

channel and the inactivation gate on the intracellular side (33-37). Symptoms of NSP

include nausea, tingling and numbness of the

perioral area, loss of motor control, and severe

muscular ache. Steidinger et al. (38) examine

an unusually severe intoxication of young 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 of NSP has historically

been limited to the west coast of Florida,

where blooms of the dinoflagellate

Gymnodinium breve initiate offshore and are

subsequently carried inshore by wind 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 Gulf Stream,

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 of warm Gulf Stream water onto

the narrow continental shelf which remained

intact in nearshore waters for several weeks

(41). Although the 1987 outbreak of G. 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

Carolina may be the result of the concurrence

of a large-scale sea surface temperature anomaly and local conditions (43) rather than

being a true range extension of the organism.

In 1993, an unprecedented outbreak of shellfish toxicity in New Zealand was identified as

NSP. The source organisms of toxins in this

outbreak were novel Gymnodinium species

(referred to as Gymnodinium cf. breve) that

produce NSP-like toxins (44).

Unlike most other dinoflagellates

responsible for seafood poisonings, G. breve is

an unarmored dinoflagellate that is easily

lysed in turbulent water. G. breve red tides

therefore are frequently associated with massive fish kills. The extreme sensivity of fish to

the Florida red tide may result from lysis of

cells passing through the gills, with direct

transfer of toxin across the gill epithelium. An

additional route of human exposure to brevetoxins is similarly through respiration, in this

case of aerosolized toxin, which is the result

of cells breaking due to wave action. A common symptom associated with exposure to

aerosolized brevetoxin is irritation and burning of the throat and upper respiratory tract.

In 1996 at least 149 manatees died during an

unprecedented epizootic in Florida concurrent with a persistent red tide. Immunohistochemical staining of tissues from affected

animals revealed brevetoxin immunoreactivity

in lymphocytes and macrophages associated

with inflammatory lesions of the respiratory

tract and with lymphoid tissues (45).

Molecular modeling studies have implicated

brevetoxin as an inhibitor of a class of lysosomal proteases, the cysteine cathepsins, which

are important in antigen presentation (46).

The demonstration of brevetoxin immunoreactivity in lymphoid tissue of the manatees

raises the possibility of immunosuppression as

a second mode by which brevetoxin exposure

may affect human health, particularly in individuals with chronic exposure to aerosolized

toxin during prolonged red tide 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 associated with 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, particularly when viscera are consumed.

CFP is estimated to affect over 50,000 people

annually and is no longer a disease limited to

the tropics because of travel to the tropics and

shipping of tropical fish species to markets

elsewhere in the world (1). The symptoms of

ciguatera vary somewhat geographically as

well as between individuals and incidents and

may also vary temporally within an area, but

they generally include early onset (2-6 hr)

gastrointestinal disturbance-nausea, vomiting, and diarrhea-and may be followed by a

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 phase may follow

acute intoxication and can persist for weeks,

months, or even years (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 geographic differences in the

toxin congeners involved (50).

The ciguatoxins (CTXs) (Figure IC) are

structurally related to the brevetoxins and

compete with brevetoxin 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 of CTX 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 135
F.M. VAN DOLAH

binding affinities at the sodium channel (e.g.,

for CTX1 and PbTx3, LD50 = 0.25 jig/kg vs

> 200 pg/kg, whereas Kd = 0.04 nM vs 2

nM, respectively). This may be related to differences in the bioavailability of the toxins or

to undefined toxic effects of ciguatoxin.

Although CFP occurs persistently at

certain locations, outbreaks are sporadic and

unpredictable at others. Reef disturbance due

to storm damage or human activities frequently precedes ciguateric conditions

(53,54). The overgrowth of corals by macroalgae because of coral 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

ciguatera cases in the Asian Pacific (57).

Diarrhetic Shellfish Poisoning

Diarrhetic shellfish poisoning (DSP) is a

comparatively milder seafood intoxication that

consists of rapid onset (3 hr) gastrointestinal

symptoms such as vomiting and diarrhea that

generally resolve within 2-3 days. The diarrhetic shellfish toxins (DTX) are a class of

acidic polyether toxins consisting of at least

eight congeners including the parent compound, okadaic acid (Figure 1D). The first

incidence of human shellfish-related illness

identified as DSP occurred in Japan in the late

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 outbreak was 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 the presence of DSP has been 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 either precursors or shellfish metabolites

of the active toxins. The DTXs are inhibitors

of ser/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 by X-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 regulate a diverse array

of cellular processes involved in metabolism,

ion balance, neurotransmission, and cell cycle

regulation (66). Diarrhea associated with

DSP is most likely due to the hyperphosphorylation of proteins, including ion channels,

in the intestinal epithelia (67), resulting in

impaired water 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

of what effect low levels of chronic exposure

to DSP toxins may have on humans as well as

wildlife such as marine turtles (3).

Amnesic Shellfish Poisoning

Amnesic shellfish poisoning (ASP) is the only

shellfish intoxication caused by a diatom. The

first recorded occurrence of ASP was in Prince

Edward Island, Canada in 1987 when approximately 100 people became ill and several died

after consuming contaminated mussels. None

of the known shellfish toxins were found to be

involved in the outbreak; rather the toxic

agent was identified as domoic acid (71,72).

The source of domoic acid was the diatom

Pseudo-nitzschia multiseries (formerly known

as Nitzschia pungensf multiseries) (73,74).

Domoic acid is a water-soluble tricarboxylic

amino acid that acts as an analog of the neurotransmitter glutamate and is a potent glutamate receptor agonist. Domoic acid is related

both structurally and functionally to the excitatory neurotoxin kainic acid isolated from the

red macroalga Digenea simplex (75). Seven

congeners to domoic acid have been identified

(Figure 1E). Of these, three geometrical isomers, isodomoic acids D, E, and F and the

C5' diasteriomer are found in addition to

domoic acid in small amounts in both the

diatom and in shellfish tissue (76,77).

The symptoms of ASP include gastrointestinal effects (e.g., nausea, vomiting, diarrhea) and neurologic effects such as 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 voltage 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 of the brain where glutaminergic pathways are heavily concentrated. 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 substantially lower (35-70 mg/kg)

(83). In the 1987 outbreak, human toxicity

occurred at 1-5 mg/kg, suggesting that susceptible 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-off of 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 toxinproducing Pseudo-nitzschia species have since

been identified in widely diverse geographic

areas around the world, including New

Zealand, Denmark, Spain, Scotland, Japan,

and Korea (89). The presence of Pseudonitzschia in New Zealand was recorded as

early as 1959. However, domoic acid was not

detected in New Zealand until after implementation of a 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 shellfish bed closures (90).

Pfiesteria and Estuary-Associated

Syndrome

Pfiesteria piscicida, a fish-killing dinoflagellate

first identified in aquaculture tanks in North

Carolina (91,92), has been linked to fish kills

in the mid-Atlantic region of the United

136 Environmental Health Perspectives * Vol 108, Supplement 1 * March 2000
MARINE 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 from its 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 flagellate stage in the presence of fish.

Subsequent depletion of its food supply

results in rapid encystment of the flagellate.

The identity of the 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 conservatively been 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

transferred through food.

Pfiesteria differs from the previously

discussed dinoflagellates in that it is a nonphotosynthetic, 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 of nitrogen 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

of Pfiesteria piscida 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

their toxicity or their role(s) in fish kills firmly

established at this time.

Global Increase in the

Occurrence of Algal Toxins

Figure 2 illustrates the change in global

distribution of the occurrence of algal toxins

of human health concern over the past three

decades. Of particular significance is the

occurrence of novel toxic algal syndromes not

previously known as well as expansion of a

number of toxin 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

increased monitoring for toxins as well 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 documented. 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 of shellfish

harvest. Improvement in toxin detection

methods has further contributed to expanded

ranges reported in Figure 2. For example, the

occurrence of ASP was unknown until the

1987 outbreak in Canada. It has subsequently

been implicated in bird (1991) and marine

mammal (1998) mortalities on the west coast

of North America. Although these mortality

Figure 2. Global increase in reported incidence of algal toxins. Encircled areas indicate where outbreaks have

occurred or toxin has been detected at levels sufficient to impact human or environmental health.

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

QPSP ONSsPODSP OASP .:' Ciguatera OpMies

137
F.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 of which

appear to have similarities to the ASP-associated events, have occurred every few years on

the west coast of North America for the past

several decades (87). Thus, retrospective

analysis of tissues from earlier mortality

events, where available, may provide insight

into the historical impacts of toxic blooms of

Pseudonitzschia in this region.

In other cases, the distributions shown in

Figure 2 are expansions in the known geographic range of toxic algal species at concentrations sufficient to impact human or

environmental health. The expansions of PSP

in southeast Asia and South America are key

examples. The causes of these expansions are

not well defined. The lack of long-term

phytoplankton data often hinders the ability

to determine if novel outbreaks are the consequence of the introduction of organisms to

new regions, an increase in the local abundance of a toxic organism because of changes

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

of harmful and toxic algal blooms is seen by

some as a bioindicator of large-scale marine

ecologic disturbances (9,101,102). The four

primary means by which human activities

may contribute to the expansion in the distribution 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 carrying 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 conducive to growth, organisms carried in the

released ballast water may establish populations in the receiving port. It is estimated that

10 billion tons of ballast water are transported

each year, making it a major source of international pollution (104). Ballast water has

been shown to be responsible for the transfer

of pathogenic bacteria, protists, algae, zooplankton, benthic invertebrates, and fish. A

number of these 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 of transfer of

toxic dinoflagellates and diatoms to previously unaffected regions (30,107,108) and a

likely source of PSP 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

of exotic 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 the most direct human impact on

the distribution of toxic algal species is

through the transfer of molluscan 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, they may release cysts and/or

motile algal cells that may seed a bloom of

the toxic algae if environmental conditions in

the receiving waters are conducive to growth

(109). Thus, many countries have established

regulations to prohibit placing mussels from

potential PSP risk areas to other areas in an

effort to control spreading of blooms (10).

Eutrophication

Phytoplankton productivity in oceanic,

estuarine, and coastal waters is primarily limited by the availability of nitrogen (12).

Nitrogen loading has been implicated in

accelerated phytoplankton production, or

eutrophication, which is most notably manifested as algal blooms. A major source of

anthropogenically introduced nitrogen

is atmospheric deposition from agricultural, urban, and industrial sources (12).

Atmospheric deposition by-passes estuarine

processes that filter terrestrial sources of nitrogen, thereby directly affecting both coastal

and oceanic environments. Coastal waters in

developed countries have experienced a longterm increase in the loading of both nitrogen

(N) and phosphorus (P), by more than a factor of four, compared with several decades

ago (110). There is strong evidence that

coastal eutrophication contributes to the

increased incidence of certain harmful algal

blooms (4,8,9,12,111). An often cited example is the correlation between the 8-fold

increase in frequency of algal blooms 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 approach was critical

in identifying Gymnodinium catenatum as an

introduced organism in Australian waters and

is currently being employed to establish the

history of PSP-producing Pyrodinium blooms

in Southeast Asia.

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 recently been made in conjunction with

Mississippi River input to the Gulf of Mexico

(115). However, the role of coastal eutrophication in the increased incidence of harmful

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 (Gymnodinium breve) blooms that originate in oligotrophic waters. The frequency and

persistence of red tides on the west coast of

Florida, for example, do not appear to have

changed over the last 120 years (Figure 3).

Each of the major range expansions of these

organisms in North America has coincided

instead with unusual climatic events (11,43).

Anomolous Weather Events

It is well established that many human disease

outbreaks peak during unusual climatic events

such as drought, storm events that produce

heavy rainfall, and El Niiio (57,106,116).

Similarly, El Niflo events are linked with the

occurrence of diseases in marine species,

including coral bleaching and shellfish diseases, and possibly marine mammal mortality

events (102). El Niflo occurs when prevailing

easterly winds of the tropical Pacific fail. This

ultimately suppresses upwelling of cold

nutrient-rich water in the eastern Pacific and

creates a pool of warm water in the west.

Global precipitation changes as a consequence

of El Nifio are generally increased rainfall in

Southeast Asia and drought in Australia,

Africa, and India. The occurrence and/or

expansion of human intoxication by PSP and

CFP in the Indo-Pacific have been compellingly linked to the occurrence of El Nifio

conditions (28,57). Historically, El Nifno

events have occurred at a frequency of one to

two per decade. However, since the mid1970s they have occurred more frequently and

have persisted longer. The strongest recorded

El Nifno events (1982-1983 and 1997-1998)

occurred during the past two decades, a period

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

during which the sea surface temperatures rose

and the incidence of HABs increased. The cooccurrence of these events late in this century

has led to speculation that global warming

may be an underlying cause (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 predicted to modify the behavior of global

oceanic circulation, which will further alter

marine environmental regimes (46). The

recent increases in frequency and emergence

of novel 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 of toxic algal blooms is difficult to

test, however, because of the complexity of

overlying issues. First, the issue of increased

reporting of toxic algal incidents must be factored out. In addition, increased utilization

of coastal regions must be taken into

account. Currently, approximately 50% of

the U.S. population resides within 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

increased bloom activity, 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 Gymnodinium breve red tides on the west coast of Florida (1878-1996), in months per year.

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 activity not 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, many areas of

the world where toxic blooms have recently

expanded lack long-term historical phytoplankton 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, it will 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 of fossil cysts of certain toxic

dinoflagellate species has yielded useful

insight into their distribution during previous

warmer climate regimes and long-term variability in abundance; thus, paleoecology may

be a useful tool for developing potential distributional maps that might be encountered

under warmer 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 and whether 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 directly contribute to the occurrence of favorable growing conditions for

these microalgae. In other cases, the potential

indirect role of human 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 of organisms 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-term variability

in algal and toxin occurrence.

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