Moses and Aaron did as the Lord commanded; in the sight of Pharaoh and in the sight of his servants, he lifted up the rod and struck the water that was in the Nile, and all of the water that was in the Nile turned to blood. And the fish in the Nile died; and the Nile became foul, so that the Egyptians could not drink water from the Nile; and there was blood throughout all of the land of Egypt (1).

INTRODUCTION

The consequences of toxic microalgal blooms (2, 3, 3A, 4, 5) have been recognized (and feared) by humans for millennia. Blooms that manifest themselves as “red tides” can foul rivers, estuaries, and coastlines with blood-red water and substantive mortality among exposed fish and other animals; such tides may have contributed to the description, cited above, of the first plague visited on Pharaoh before the exodus of the Israelites from Egypt (ca. 1290 BC). Chinese literature contains reports of red tides dating back to the T'ang dynasty, and American Indian lore describes deaths among persons consuming shellfish after red tides in Alaska and the Pacific Northwest. Reports of illness that may represent ciguatera (associated not with red tides, but proliferation of other toxic dinoflagellates on tropical coral reefs) date to the 1500s in the Caribbean (6); in the South Pacific, symptoms of ciguatera were reported as early as 1606 among sailors accompanying the Spanish explorer de Quiros (7).

Only a small fraction of the thousands of species of microalgae that form the base of the marine food chain are potentially toxic or harmful (2, 3, 3A). When these latter microorganisms proliferate (“bloom”), they can cause mortality in fish and other marine life through a variety of mechanisms. Species that cause visible blooms (“red tides”) affect ecosystems by shading, oxygen depletion, or even mechanical irritation (for example, damage to gills of fish). Some species also produce toxins. Human illness results when people are exposed to certain of these toxins, by either eating shellfish or fish that have accumulated the toxin or by direct (e.g. respiratory or skin) contact with affected waters. If toxins are potent enough or are accumulated over time in fish or shellfish, smaller numbers of organisms (less than the number required to produce visible discoloration of water) may be sufficient to cause ecosystem damage and/or human illness. Most microalgal species that produce toxins associated with human disease are dinoflagellates, an ancient lineage of unicellular eukaryotic organisms. Dinoflagellates are mobile, with two dimorphic flagella; they meet their food needs by photosynthesis (autotrophy), phagocytosis of food sources (heterotrophy), or combinations of these strategies (mixotrophy).

There is a perception by marine scientists that the number of harmful algal blooms and the geographic range of toxic species are increasing (2, 3, 8, 9, 9A, 9B). In the United States, harmful algal blooms have, in the past, occurred in geographically limited areas, such as the west coast of Florida and the coastlines of Alaska and Maine; blooms now threaten virtually every coastal state, with involvement of increasing numbers of toxic species (Figure 1). More quantitative data (albeit still limited in time and space) are available from Pacific regions of Asia and areas of Northern Europe. For example, Figure 2 shows data from Hong Kong Harbor, where there was an eightfold increase in the number of red tides between 1976 and 1986 (9A). Data in this figure are overlaid on population data, highlighting the hypothesized link between the occurrence of algal blooms and human impact on the environment. Unfortunately, data of this type are available from only a few geographic areas. Global reports of increases in harmful algal blooms may reflect “real” increases in incidence or simply better recognition and reporting. It has been postulated that increases in incidence are caused by human-related phenomena such as nutrient enrichment of waterways (for which the best supportive data are available), disruption of ecosystems, and/or climatic change (2, 3, 8, 9, 9A, 10, 11, 12). Again, however, data are seldom quantitative, and causal links are poorly documented (12A).

When considering the public health outcomes of “environmental protection,” attention has traditionally focused on the direct human health consequences of pollution; for example, there is now widespread recognition of the health effects of lead and the corresponding need to limit release of lead into the environment (13). As outlined above, harmful algal blooms fit more closely with an alternative and more complex paradigm, in which human-induced stress on ecologic systems leads to the emergence of new, potentially harmful microorganisms or the reemergence of “old” pathogens from previously restricted environmental niches. Other examples of this process are also gaining recognition, from the possible effects of global warming on the spread of cholera and malaria (14, 15) to the impact of widespread use of antimicrobial agents (in medicine and agriculture) on the emergence of highly resistant, virtually untreatable human bacterial pathogens (16, 17).

Development and substantiation of these conceptual models is not easy; these are extremely complex systems (12A), crossing multiple scientific disciplines, with major “data gaps.” However, from a public health and regulatory standpoint, such models are essential if we are to develop appropriate control strategies for the associated diseases. This review summarizes clinical, pathophysiologic, epidemiologic, ecologic, and economic data for the six human clinical syndromes currently associated with harmful algal blooms (Table 1); material is organized by disease, with a public health focus, reflecting the author's background as a physician. In not all instances is it possible to show a direct link between human activity and increased occurrence of illness, nor is it completely clear that the incidence of illness is increasing for all clinical entities. Nonetheless, by examining what is known about harmful algal blooms, their causes, and their impact on humans, it is hoped that strengths and weaknesses of the proposed model can be highlighted, and data needs assessed and prioritized.

TABLE 1

Human illness associated with harmful algal blooms

CIGUATERA FISH POISONING

Ciguatera fish poisoning is a clinical syndrome with characteristic gastrointestinal and neurologic symptoms, which occurs after eating tropical reef fish (Table 1) (18, 19, 20, 21, 22, 23). The toxin or toxins that cause the syndrome originate in the dinoflagellate Gambierdiscus toxicus and other benthic algae that grow on reefs (24, 25, 26, 27, 28). Fish that eat the algae become toxic, and the effect is amplified through the food chain so that large predatory fish become the most toxic.

Clinical Characteristics and Diagnosis

The diagnosis of ciguatera fish poisoning is based on a distinctive clinical sequence of gastrointestinal and neurologic symptoms (4, 18, 19, 20, 21, 22, 23). Gastrointestinal symptoms (e.g. diarrhea, vomiting, and abdominal pain) occur first, usually within 24 h of eating a toxic fish. In severe cases, patients may be hypotensive, with, paradoxically, a slow pulse bradycardia (20, 22). These acute symptoms are accompanied or followed by neurologic manifestations, which may persist for weeks or months. Neurologic symptoms include pain and weakness in the lower extremities [a very characteristic symptom in the Caribbean (20, 22)] and numbness and tingling around the mouth (circumoral paresthesias) and in the hands and feet. More bizarre symptoms such as temperature reversal (e.g. ice cream tastes hot, or hot coffee seems cold) and “aching teeth” are frequently reported (18, 21, 22, 29) and may prompt psychiatric referrals among physicians unacquainted with the disease. In very severe cases (particularly in the South Pacific), neurologic symptoms may progress to coma and respiratory arrest within the first 24 h of illness (30).

Although most patients recover completely within a few weeks, intermittent recrudescence of symptoms can occur over a period of months to years. These recrudescences can be triggered by a number of factors, including consuming fish and drinking alcohol (32). Immunity does not occur after an initial intoxication; if anything, intoxication may increase sensitivity to subsequent episodes of illness. There is a subset of patients who have long-term, chronic symptoms of fatigue and paresthesias that last for months or years (23). These symptoms can be quite severe, resulting in almost total disability.

There is no confirmatory test [such as a serologic assay (33)] that will establish that an individual patient has the disease. Ciguatoxic fish have traditionally been identified by one of a number of bioassays, including, in endemic areas, feeding of suspect fish to the family cat (32). Hokama and colleagues in Hawaii have worked for a number of years on development of a rapid “stick” immunoassay (34) and a solid-phase immunobead assay for toxic fish (35). The immunobead assay has excellent sensitivity (of 1037 fish tested, all illnesses occurred among persons eating fish identified as “positive” or “borderline”). However, specificity (as measured by occurrence of disease) is not as good; illness was reported in association with only 4 of 232 “borderline” fish and 5 of 17 “positive” fish.

Toxicology/Pathophysiology

There appear to be multiple toxins responsible (either alone or in combination) for the clinical manifestations of ciguatera (25, 26, 27, 28, 36, 37, 38, 39). These vary among geographic areas, among fish species, and across time. Vernoux & Lewis (28) have recently suggested adoption of a standard nomenclature: CTX is used to indicate toxins that accumulate in fish to levels likely to cause ciguatera symptoms in humans; a letter code is used to indicate source (Pacific Ocean, Indian Ocean, Atlantic Ocean, or Caribbean Sea); and a numbering system is used to indicate the chronologic order of identification of the compound.

Pacific ciguatoxins have been best characterized to date. P-CTX-1 (36) is a small, lipid-soluble polyether with a molecular weight of 1112 and a molecular formula of C₆₀H₈₈O₁₉. Two other distinct but closely related toxins, P-CTX-2 and P-CTX-3 (37, 38), have also been identified in ciguatoxic fish, together with at least 11 minor P-CTX congeners (36). In recent work, Lewis and colleagues (28, 36) have identified toxic compounds present in Caribbean Caranx latus [one of the leading causes of ciguatera in the Caribbean (32)]; these toxins, which differ from the Pacific family of ciguatoxins, were designated C-CTX-1 and C-CTX-2.

Scaritoxin, a lipid-soluble neurotoxin, has also been associated with ciguatera by some investigators. This toxin depresses oxidative metabolic processes in rat brain and has a depolarizing action on excitable membranes. Maitotoxin is a water-soluble toxin that appears to interfere with or modify calcium movement or calcium conductance in tissues (40). Palytoxin, which can cause respiratory distress and severe muscle spasms, has also been isolated from some fish implicated as a cause of ciguatera (41).

While recognizing the diversity of toxins that may be present in ciguatoxic fish, there are certain general pathophysiologic responses that have been associated with ciguatera toxins and toxic fish extracts. The gastrointestinal symptoms (diarrhea) seen in patients with ciguatera appear to result from direct stimulation of mucosal ion transport, without accompanying damage to the intestinal mucosa. Extracts from toxic fish cause a striking increase in transepithelial electrical potential difference and short-circuit current in Ussing chambers, with secretion apparently mediated by calcium (42). Neurologic symptoms appear to be related to the direct effect of toxin on mammalian nerves, associated with prolongation of sodium channel activation (36, 43, 44, 45). Patients may have characteristic electrophysiologic findings, including slowing of sensory conduction velocity and prolongation of the absolute refractory, relative refractory, and supernormal periods (46). Toxins and toxic extracts can also affect the cardiovascular system. In animal models, low doses of ciguatoxin cause mild hypotension and bradycardia. Higher doses give a biphasic response with an initial hypotension/bradycardia followed by hypertension/tachycardia; very high doses produce a phrenic nerve block with respiratory arrest (19).

Epidemiology

Ciguatera is a significant cause of morbidity in areas in which consumption of reef fish is common, including the Caribbean, southern Florida, Hawaii, the South Pacific, and Australia. More than 400 fish species are said to have the potential for becoming toxic (6). However, the risk of toxicity is greatest for carnivorous, predatory fish, such as barracuda (>70% of which may be toxic). Toxicity is also associated with fish size, with large fish within a species having a greater risk of toxicity. Viscera tend to have higher concentrations of toxin than fish flesh.

The reported incidence of ciguatera in the South Pacific from 1973 to 1983 was 97 cases/100,000 population/year (47); 219 cases/100,000 population were reported in 1987 (48). It has been estimated that the actual incidence in these areas is fivefold higher (47), with substantive variation in case numbers from island to island; for example, between 1960 and 1984, each of the 500–600 inhabitants of the Gambier Archipelago was reported to have had an average of 5.7 attacks of ciguatera (10). In a randomized, stratified community survey conducted in the U.S. Virgin Islands, the calculated incidence rate was 730 cases/100,000 population/year (32). In Puerto Rico, 45 cases were reported to the Puerto Rico Poison Control Center in 1992. In an associated telephone survey, 7% of persons contacted reported that at least one family member had at one time had ciguatera (49). In Miami, on the edge of an endemic area, 129 cases of ciguatera were reported to the Dade County Health Department between 1972 and 1976, for an annual incidence of 5 cases/100,000 population; the actual incidence was estimated to be 10–100 times this figure (i.e. 50–500 cases/100,000 population/year) (21). In Reunion Island in the Indian Ocean, reported incidence between 1986 and 1994 was 7.8 cases/100,000 population/year (50).

The problem in all such epidemiologic studies is the dependence on clinical criteria for diagnosis. For physicians practicing in endemic areas, the local clinical presentation is distinctive enough so that there is seldom any hesitation in making the diagnosis. However, as noted above, “ciguatera” may be caused by one or more of a variety of toxins, with data suggesting that clinical presentation can vary among (and within) geographic areas (18, 22, 50A). Until we have better diagnostic tools and can clearly link specific disease manifestations with specific toxins (and, in turn, with specific harmful algal species), it is difficult to make comparisons from region to region. Epidemiologic assessments are also complicated by the poor public health infrastructure and reporting systems in many of the affected areas (48). In light of these difficulties, it is difficult to assess global increases (or decreases) in the incidence of ciguatera.

Ecology

G. toxicus, an epibenthic dinoflagellate, has been implicated as the primary source of ciguatera-associated toxin(s) (24, 25). Although other toxic algal species share the same habitat and entry route into the food chain (2, 26), their role as a cause of human illness remains to be determined. G. toxicus is most prolific in shallow waters, associated with coral reefs and protected embayments (2). Distribution of G. toxicus within a reef area tends to be patchy, and there may be rapid, localized changes in the concentration of the species. Correspondingly, the occurrence of toxic fish tends to be localized (local lore on an island often identifies certain areas as toxic), but localization is not consistent, and toxic fish may occur sporadically anywhere in a reef or island location (5, 20, 51).

Long-time island residents report that fish are more likely to be toxic after major storms or other activities (such as airport construction), which disrupt the reef ecosystem (10, 47, 52). There is some substantiation for these anecdotal reports, including data suggesting that there were increases in the incidence of ciguatera in areas of the South Pacific after military activities (10). Studies in the Mayotte Island reef complex in the Indian Ocean have shown some linkage between increases in G. toxicus densities and anthropogenic disturbances (11). Rougerie & Bagnis, working in Tahiti, have proposed a model in which reef disruptions result in seepages of nutrient-rich endo-upwelling interstitial waters (53); because these nutrients cannot be used by the stressed algal-coral ecosystem, they are taken up by epibenthic organisms such as G. toxicus, with a corresponding sharp increase in population density (and subsequent fish toxicity).

Economic Impact

Although difficult to directly quantitate, the economic impact of ciguatera appears to be substantial, particularly in light of its widespread distribution and high incidence in areas dependent on reef fish for food. Costs fall into two general categories: (a) cost of illness, including direct medical costs and lost wages and productivity and (b) costs associated with loss of income from fish sales, as well as costs of finding alternative food sources.

There are no good data on direct medical costs in endemic areas, and as demonstrated in one outbreak investigation (20), local populations familiar with the syndrome frequently do not seek medical attention. The costs associated with lost productivity may be more substantial. With projected incidence rates in the range of 500 cases/100,000 population/year in parts of the Caribbean and South Pacific, a high proportion of the population may be expected to have at least one episode of illness during their lifetime. In studies in the Virgin Islands (22), it was found that ill persons spent a median of three days in bed before returning to work and other normal activities.

Costs of lost fisheries are also difficult to estimate. Although island populations may have no choice but to accept the risk of eating fish caught off of the local reef, this same risk makes it extremely difficult to commercialize fisheries. In some parts of the South Pacific, ciguatera is an important contributor to out-migration from more isolated outer islands, owing both to a lack of markets for fish (often the only exportable commodity) and to the difficulties in obtaining alternative foods for island residents (47). In the Caribbean, risks associated with toxic fish (and the tendency of tourists to be litigious) lead to a situation in which restaurants serving tourists (who think they are eating “fresh” island seafood) serve only fish imported from “safe” mainland sources.

PARALYTIC SHELLFISH POISONING

Paralytic shellfish poisoning (PSP) is a syndrome characterized by acute onset of paresthesias and (in severe cases) respiratory paralysis, occurring after eating shellfish that carry saxitoxins produced by Alexandrium spp. and other dinoflagellates (2, 5).

Clinical Characteristics and Diagnosis

Symptoms of PSP are primarily neurological (circumoral paresthesias and paresthesias of the hands and feet) and usually appear within an hour of eating toxic shellfish (4, 5, 54, 55, 56). In more severe cases, there may be unsteady gait, difficulty swallowing, and changes in mental status. Hypertension may be seen, with blood pressure measurements corresponding with the toxin dose ingested (57). In the most severe cases, respiratory paralysis occurs (generally within the first 24 h of illness), leading to death if respiratory support is not available. In a retrospective review of PSP outbreaks occurring in Alaska between 1973 and 1992, 29 (25%) of 117 ill persons required an emergency flight to a hospital, four (3%) required intubation, and 1 died (56). Recovery is complete, with symptoms usually resolving within hours to days after shellfish ingestion.

The diagnosis of PCP is based on clinical presentation and a history of having eaten potentially toxic shellfish immediately before onset of symptoms. Limited neurophysiologic data suggest that patients have prolonged distal motor and sensory latencies, slowed conduction velocities, and moderately diminished amplitudes, compatible with incomplete sodium channel blockade (58). On an experimental basis, it has been possible to demonstrate saxitoxins in serum during acute illness and in urine after acute symptoms are resolved (57). Measurement of toxicity in shellfish is based on a standard mouse bioassay. Alternative assays, such as a recently described receptor binding assay (59), are under active development. Surveillance of “high-risk” harvest areas in the United States is routinely conducted by state health departments, and areas are closed to harvesting when toxin levels in shellfish exceed 80 g/100 g.

Toxicology/Pathophysiology

Saxitoxins (≥12 of which have been identified) are responsible for the symptoms seen in persons with PSP (60, 61). These compounds block the propagation of nerve and muscle action potentials by acting at the metal cation-binding site in the sodium channels of the nerve membrane and interfering with changes in sodium permeability (62). Strains of toxic dinoflagellates develop characteristic toxin profiles that usually contain six to eight saxitoxins. Shellfish feeding on dinoflagellate blooms ingest all toxins, but may selectively retain or biologically modify some derivatives, resulting in toxin profiles in the shellfish that differ from those of the dinoflagellate (63, 64, 65).

Epidemiology

PSP has been reported from both hemispheres, with cases concentrated in temperate coastal regions. In the United States, PSP is primarily a problem in the New England states and Alaska, California, and Washington (2, 3, 5, 55). Blooms of the causative Alexandrium spp. occur several times each year, primarily from April through October. Shellfish become toxic and remain toxic for several weeks after the bloom subsides; there are also some shellfish species that remain constantly toxic (i.e. butter clams in parts of Washington state and Alaska). Between 1976 and 1986, the Centers for Disease Control and Prevention received reports of 12 PSP outbreaks in the United States, involving 134 people, with 1 death (5). This relatively small number of cases is owing in large part to the aggressive surveillance of shellfish by health departments in high-risk states and closure of areas with toxic shellfish. Cases that do occur are often associated with noncommercial harvesting of shellfish in closed areas.

Cases of PSP are also being recognized with increasing frequency in coastal regions of China and in the Philippines (12A). As in North America, filter-feeding bivalve shellfish (which feed on toxic dinoflagellates) are the primary vehicles for illness; however, illness has also been reported after consumption of carnivorous or scavenging gastropods, which appear to acquire toxicity by feeding on bivalves (66, 67). A total of 40 PSP outbreaks (resulting in 23 fatalities and 423 nonfatal cases) were reported in Zhejiang Province in southeastern China between 1967 and 1979 (66). There have been subsequent reports of PSP in Fujian and Guandong Provinces, as well as continuing case reports from Zhejiang. China is known to have an increasing problem with red tides, with 40–50 now reported each year (66). Only a few of these are likely to be toxic; however, because shellfish monitoring is minimal and strong public health surveillance and reporting infrastructure are absent, PSP is probably under-recognized and under-reported.

Ecology

The dinoflagellates Alexandrium catenella (West Coast) and A. tamarenses (East Coast) are responsible for most illness seen in the United States. Large blooms of A. catenella were observed in southern Chile and southern Argentina in 1991 and 1992, with very high toxin levels in shellfish. Anderson and colleagues have isolated A. tamarenses from the coast of Guandong Province (66); a toxic strain of A. tamarenses from Taiwan was subsequently reclassified by this group as A. minutum Halim (67). A. minutum was detected in Brittany in 1988, and it has now spread along the French coast. A. excavatum was observed in the Argentinean Sea in 1980, with subsequent increases in frequency and range of blooms. Pyrodinium bahamense var. compressa has been linked with PSP in some tropical countries (8).

A complex interplay of factors contributes to Alexandrium bloom formation and dissolution, including sunlight, wind velocities and tidal fronts, temperature, local hydrography, preceding blooms of other plankton, and populations of other marine organisms (8). Alexandrium species can grow in relatively pristine waters, and, at least for the United States, there is no body of data to support the hypothesis that human-associated nutrient inputs are a key element in the occurrence of blooms (3). Blooms in the Far East have been linked with pollution (66), and pollution may be a factor in the occurrence of increasing algal blooms (including Alexandrium spp.) in the Northern Adriatic (8). Outbreaks of PSP have also been reported in association with aquaculture in the Philippines and Morocco (8); although the factors operational in these outbreaks are not well defined, these would clearly be nutrient-rich environments.

In considering possible human effects other than nutrient loading, it has been suggested that the large blooms that occurred at the tip of the South American continent in 1991 and 1992 were related in part to increased radiation from the Antarctic ozone hole [Alexandrium apparently can withstand an increase in UV radiation much better than zooplankton (8)]. Humans may also be involved in distribution of toxic species. For example, Alexandrium and Gymnodinium species may have been introduced into Australian harbors in ballast water released by visiting cargo ships (8).

Economic Impact

As with ciguatera, there are inadequate data to accurately estimate the economic impact of PSP. Costs would include (a) costs of medical care and lost productivity, (b) cost of monitoring of potentially toxic areas, and (c) loss of product sales. Todd, from Health Canada, estimated medical and lost productivity costs for a projected 150 PSP cases/year in Canada at $225,000 in the late 1980s/early 1990s. In 1988, the cost of the Canadian PSP control program was $3,300,000; costs of the U.S. control program during the same time period were ∼$1,000,000/year. The cost of a single PSP outbreak in Maine was estimated to be $6 million (68). The value of sustainable Alaskan shellfish resources that can not be exploited because of PSP was estimated (in 1984) to be $50 million/year (69).

NEUROTOXIC SHELLFISH POISONING

Neurotoxic shellfish poisoning is associated with blooms of G. breve, which produce brevetoxin (5, 54). Symptoms after eating toxic shellfish include circumoral paresthesias and paresthesias of the extremities, dizziness and ataxia, muscle aches, and gastrointestinal symptoms. Symptoms tend to be mild and resolve quickly and completely. In contrast to PSP, respiratory paralysis and mortality do not occur. In outbreaks that occurred in 1987 in North Carolina (70), median duration of illness was 17 h (range, 1–72 h). Of 48 affected persons in these outbreaks, 12 (25%) required 1 day of bed rest; one person was hospitalized briefly. Respiratory and eye irritation have also been reported in association with G. breve blooms. This appears to be caused by aerosolization of the toxin by wind and wave action during red tides; symptoms are most commonly reported from along the Atlantic coast of Florida (71).

Red tides caused by G. breve have occurred along the Florida coast for centuries, with associated fish kills and mortality in seabirds and marine mammals [in 1996, >150 manatees died during a prolonged red tide along the southwest Florida coast (3)]. Blooms are most common on the west coast of Florida, between Clearwater and Sanibel Island; red tides have been reported in this area in 21 of the last 22 years. However, blooms have also been reported as far south as the Yucatan and as far north as the coast of North Carolina (3, 72). In New Zealand, for the first time, >180 shellfish-related illnesses attributed to neurotoxic shellfish poisoning were reported in January 1993, and G. breve was identified in coastal waters (8).

In the Gulf of Mexico, G. breve blooms are initiated at the continental shelf rather than in near-shore waters. Currents and winds generally determine whether a bloom moves onshore. However, once near the shore, G. breve can use land-based nutrients and grow rapidly, provided that salinity does not fall below 24‰. Dense blooms inshore generally cannot be sustained without inputs of new nutrients from human sources (3).

Costs of red tides are related to losses associated with shellfish and fish and, for resort areas, to loss of tourist income. In the early 1970s, costs of red tides in Florida were estimated at $15–20 million. The 4- to 6-month red tide in North Carolina in 1987–1988 was estimated to have cost the coastal community approximately $25 million (72).

DIARRHETIC SHELLFISH POISONING

Diarrhetic illness from shellfish poisoning results from eating mussels, scallops, or clams that have been feeding on Dinophysis fortii or D. acuminata. In addition to diarrhea, symptoms of diarrhetic shellfish poisoning include nausea, vomiting, and abdominal pain (5). Although okadaic acid appears to be the primary toxin responsible for the observed clinical syndrome, other toxic compounds also have been isolated from these species (73, 74). Case reports came initially from Japan; however, diarrhetic shellfish poisoning has occurred in France and other parts of Europe, and Dinophysis spp. are spreading along the French and Spanish coasts. Episodes of diarrhetic shellfish poisoning have been reported in Canada (8), and a Dinophysis bloom resulted in temporary closure of the mussel industry in southern Chile; the organism has also been identified in New Zealand waters, and it may have contributed to the 1993 neurotoxic shellfish-associated poisoning outbreaks in New Zealand (8). There have been no confirmed U.S. cases, although the causative organisms have been identified in U.S. coastal waters (2, 3).

AMNESIC SHELLFISH POISONING

Amnesic shellfish poisoning results from ingestion of shellfish containing domoic acid, produced by the diatom Pseudo-nitzschia pungens (3). A series of cases caused by this toxin were reported in the Atlantic provinces of Canada in 1987 (3, 8, 75). Symptoms included vomiting, abdominal cramps, diarrhea, headache, and loss of short-term memory. On neuropsychological testing several months after the acute intoxication, patients were found to have severe antegrade memory deficits with relative preservation of other cognitive functions; patients also had clinical and electromyographic evidence of pure motor or sensorimotor neuropathy or axonopathy. Neuropathological studies in four patients who died demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala (76). Canadian authorities now analyze mussels and clams for domoic acid, and they close shellfish beds to harvesting when levels exceed 20 μg/g.

Domoic acid has also been shown to be produced by Pseudo-nitzschia spp. on the West Coast of the United States, including P. australis, P. multiseries, and P. pungens (3). In September 1991, >100 brown pelicans and cormorants were found dead or suffering from unusual neurological symptoms in Monterey Bay, CA. An investigation implicated P. australis species present in the Bay (ingested by anchovies, which, in turn, were consumed by the seabirds) as the cause of the outbreak. Subsequent studies have demonstrated the persistence of Pseudo-nitzschia spp. in this area, with low levels of domoic acid detectable in the marine food web (3). In 1991, domoic acid was also identified in razor clams and Dungeness crabs on the Oregon and Washington coasts (3). No human illnesses were confirmed, although there are anecdotal reports of ≤24 associated illnesses (8). Toxin-producing blooms have been documented from the Maine and Texas coasts, and low levels of domoic acid produced by P. pseudodelicatissima have been reported from the Bay of Fundy and Danish and Norwegian waters (8). Although no clear-cut human cases of amnesic shellfish poisoning have been identified outside of the original Canadian outbreaks, the clinical significance of ingestion of low levels of domoic acid (as may be occurring in persons eating shellfish and anchovies from Monterey Bay and other areas where Pseudo-nitzschia are present) is unknown.

Canadian studies suggest that Pseudo-nitzschia blooms are dependent on available nitrates, which increase in the fall after rain and strong winds. Local conditions in the inner estuaries are felt to be important, and agricultural run-off, rather than upwelling of nutrients, is thought to be the most likely source of nitrates (8). In Monterey Bay, blooms of P. australis are most common during the summer to autumn months, when sea surface temperatures are warmer and (in contrast to observations in Canada) there are lower concentrations of organic nutrients (2).

Illness-related costs and lost business associated with the 1987 Canadian outbreak have been estimated at $8,400,000. In 1988, the cost for implementing a domoic acid monitoring program in Canada was $1,390,000 (8).

PFIESTERIA-ASSOCIATED SYNDROME

Pfiesteria piscicida was identified in the early 1990s as a cause of massive fish kills in the Neuse River and Albemarle-Pamlico estuarine system of North Carolina (77, 78). In 1997, Pfiesteria spp. were found in the Pocomoke River and other estuaries in Tangier Sound in the Chesapeake Bay, again associated with fish kills. A range of symptoms, including difficulties with learning and memory, have been reported among laboratory investigators working with the organism (79) and persons with high levels of environmental contact with Pfiesteria-affected waterways (80).

Clinical Characteristics and Diagnosis

Shortly after the initial identification of the organism, laboratory investigators working with toxic Pfiesteria cultures began to note problems with respiratory and eye irritation, skin rashes, gastrointestinal symptoms (stomach cramps, nausea, and vomiting) and, most disturbingly, cognition and personality changes (79). There were also anecdotal reports of a comparable symptom complex among commercial fishermen (watermen) exposed to North Carolina waterways where Pfiesteria spp. were known to be present (79).

In subsequent studies in the Chesapeake Bay region (80), a significant association was found between the degree of exposure to Pfiesteria-affected waterways and objective deficiencies in learning, memory, and higher-order cognitive function (as reflected by deficiencies in divided attention). Results were most striking on the Rey Auditory Verbal Learning and Memory test (Rey AVLT), on which 75% of persons with high levels of exposure to affected waterways (daily exposure, 6–8 h/day, over a period of months) scored below the second percentile, as compared with national age- and educationally matched norms. There was a significant dose-response effect, with persons with less exposure being less likely to be symptomatic. When affected persons were tested 3 and 6 months later, all had scores that were within normal ranges. In these studies, exposed persons also complained of headaches, skin lesions (81), and, at times, a burning sensation in skin directly exposed to water where P. piscicida Pfiesteria or Pfiesteria-like species appeared to be active.

Persons with exposure to Maryland waterways where there were findings suggestive of very high levels of Pfiesteria activity (as seen during active fish kills) reported acute respiratory and eye irritation, similar to that described by exposed laboratory workers. There were also reports of an acute, transient confusion syndrome in this setting. In a case control study in North Carolina, persons with exposures to affected waterways were found to have significant deficiencies in visual contrast sensitivity, an indicator of impairment in human visual-system function; findings are similar to those seen in organic-solvent–exposed workers, although cases (exposed persons) and controls (persons working offshore, with no Pfiesteria exposure) did not differ in their history of exposure to such compounds (82).

Diagnosis of Pfiesteria-associated syndrome is currently based on clinical presentation and results of formal neurocognitive testing. As noted above, the most sensitive measure of cognitive deficiencies identified in initial neurocognitive screening batteries appears to be the Rey AVLT. A panel of neurocognitive specialists is currently working with the Centers for Disease Control and Prevention to identify optimal testing batteries for persons with suspected environmental exposure to the organism. Methodology for detection of the organism in the environment is under rapid development, with a multiplex polymerase chain reaction technique showing great promise for rapid, sensitive, and specific identification of Pfiesteria strains.

Toxicology/Pathophysiology

Toxin production by P. piscicida is triggered by the presence of fish (or fish feces); toxins appear to kill fish, may cause sloughing of fish skin, and may affect fish behavior. Fish in affected areas (particularly Atlantic menhaden) frequently have a characteristic “punched-out” skin lesion, occurring most often in the anal region (Figure 3). Pathologic examination of lesions indicates that they are caused by fungal infection; it has been hypothesized that this reflects secondary infection at sites of toxin-mediated skin damage (83, 84). In one laboratory animal study, injection into rats of water from aquaria containing toxic P. piscicida resulted in a persistent learning deficit, compatible with the hypothesis that toxin(s) cause deficits in higher-order cognitive function in mammals (85)

Toxins responsible for the observed effects in fish, animals, and humans have not yet been purified. There are suggestions that the organism produces multiple toxins, including water- and lipid-soluble compounds.

Epidemiology

Because of the associated diagnostic uncertainties, it is not possible to estimate the extent of Pfiesteria-related illness in areas where the organism is known to be present. The route of acquisition of the toxin is not known, although it is likely to be via aerosols (analogous to what is seen at times with G. breve toxins) or, possibly, through prolonged skin contact 86). In contrast to syndromes associated with other marine biotoxins, Pfiesteria-associated illness is not associated with eating fish or shellfish.

Maryland and other mid-Atlantic states have developed policies for closure of waterways when the organism appears to be present and active, as manifested by signs of toxicity in fish (87). Until there is a better understanding of Pfiesteria toxins and their mode of action, it has been recommended that persons who must come in contact with such waterways, particularly in the midst of an active Pfiesteria-related fish kill, wear protective clothing and respiratory protective gear.

Ecology

P. piscicida has a complex life cycle that may include up to 24 life stages. In North Carolina, Burkholder has estimated that 75% of toxic Pfiesteria outbreaks occur in nutrient-enriched waters (88). In studies in her laboratory, phosphate enrichment at levels ≥100 μg PO₄⁻³P liter (reported to be typical of conditions in the Pamlico and Neuse estuaries) resulted in a >30-fold increase in zoospore counts (79). Excessive nutrient loading creates an environment rich in microbial prey and organic matter, which Pfiesteria spp. use as a food supply; by increasing the concentration of Pfiesteria spp., nutrient loads may increase the likelihood of a toxic outbreak. However, high nutrient concentrations are not essential for P. piscicida and Pfiesteria-like dinoflagellates to turn toxic. As noted above, the key factor in toxicity appears to be the presence of chemical cues that are secreted or excreted by fish (88).

In Maryland, particular attention has been focused on the possible role of phosphorus in stimulating proliferation of P. piscicida and Pfiesteria-like species. In the Pocomoke River watershed, ∼82% of the phosphorus load (and 74% of the nitrogen load) is from agricultural sources. Much of this loading can be attributed to use of chicken manure on fields; manure, in turn, is a by-product of the large-scale commercial chicken production that occurs on the Maryland eastern shore of the Chesapeake Bay. These concerns resulted in new state regulations requiring farmers to consider/develop plans for phosphorus use on their fields. However, it was recognized that there was a high level of uncertainty in this approach, as reflected in the deliberations of a governor's commission appointed in 1997 in Maryland to assess the available scientific data on P. piscicida and propose a state action plan (88). Although the commission ultimately recommended regulatory efforts to reduce nutrient loading, it acknowledged the lack of definitive data linking the 1997 Pfiesteria bloom with agricultural run-off and admitted relying in part on the feeling that “reducing the nutrient levels in the Bay is generally good for aquatic live, human health, and water quality, and should be a focus of our pollution control efforts.”

Economic Impact

As with other toxic dinoflagellates, costs associated with P. piscicida include both direct medical and productivity losses and the resultant impact on fisheries and tourism. Fishery losses are the most striking and best quantified, with an estimated loss of $43 million resulting from decreased fish and shellfish sales during the 1997 Maryland Pfiesteria outbreak.

SUMMARY

As outlined in the preceding pages, we have an increasing appreciation of the clinical syndromes caused by toxic algal species. These syndromes represent a substantive global public health problem, as well as an important economic issue related to loss of fisheries and (for poorer nations) the associated loss of protein food sources. However, it is also clear that we have a great deal yet to learn.

There is an expanding general body of ecologic/environmental data relating to eutrophication and other factors contributing to the occurrence of algal blooms (89). Basic mathematical models for algal blooms have been proposed (12A, 89), and there is an increasing appreciation of the potential strengths and utility of such models. However, each toxic species has its own complex ecology. Without a full understanding of this ecology, it is difficult to predict (or model) the impact of nutrient loading and other human activities on occurrence of blooms. Development of models is further complicated by the fact that the diagnosis of each of the associated clinical syndromes is based almost entirely on clinical presentation: a single clinical syndrome, related to a specific toxin or toxin complex, may be caused by several different microalgal species, each with slightly different ecologic characteristics.

In the absence of objective diagnostic tests (and in light of the lack of public health infrastructure in many areas where toxic algal blooms occur), it is also difficult to get a true picture of the extent of these toxin-related illnesses. The impression is that incidence is increasing. However, we lack the systematic surveillance data necessary to document this impression, and to correlate disease occurrence with blooms of specific harmful algal species. The hypothesized linkages among human stress on the environment, harmful algal blooms, and human disease are plausible, but data are needed to substantiate these relationships (12A).

While difficult to obtain, such data are essential if we are to identify appropriate public health strategies for preventing the diseases caused by harmful algal blooms. As noted above, the ideal approach would involve development of models that incorporate both human and environmental data. These are extremely complex models, requiring ongoing data input and analysis, and currently we are far from being able to use such models for development of even limited interventions. However, as human populations expand (with associated pressure on the environment), there will be a clear public health and regulatory need for models, and for associated control measures (90). This is a field in urgent need of further research, and one which will, hopefully, attract the multidisciplinary attention that it deserves.