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members of this group, more research will be needed before the magnitude of their potential to produce adverse human health effects is understood (Sato and Ueno, 1977).

Fumonisins Fumonisins are recently discovered mycotoxins produced by Fusarium moniliforme and several other Fusarium species. Corn products contaminated with Fusarium moniliforme are responsible for several agriculturally important diseases in horses and swine (Norred, 1993) and are being actively evaluated to determine how great a threat they pose to public health. Initial evidence of the involvement of F. moniliforme produced toxins in human disease was reported by Marasas et al. (1988). They found that an increased incidence of esophageal cancer was associated with the consumption of contaminated corn (maize) by humans in a region in South Africa. Corn borer insect pests cause damage to the developing grain, which enables spores of the toxin-producing Fusarium fungi to germinate. The fungus then proliferates, which leads to ear and kernel rot and the production of potentially hazardous levels of fumonisins. Corn varieties that express the Bt insecticidal protein have recently been shown to contain significantly reduced levels of fumonisin because the Bt protein significantly reduces corn borer–induced tissue damage in corn products (Munkvold et al., 1997; 1999; Masoero et al., 1999).

Zearalenone Another mycotoxin produced by Fusarium is zearalenone. It was first discovered during attempts to isolate an agent from feeds that produced a hyperestrogenic syndrome in swine, characterized by a swollen and edematous vulva and actual vaginal prolapse in severe cases (Stob et al., 1962). Zearalenone can occur in corn, barley, wheat, hay, and oats as well as other agricultural commodities (Mirocha et al., 1977). Zearalenone consumption can decrease the reproductive potential of farm animals, especially swine.

SUBSTANCES FOR WHICH

TOLERANCES MAY NOT BE SET

All of the contaminants of food described to this point are those associated with synthesis, growth, production, or storage and are regarded by the FDA as unavoidable. Because they are unavoidable, the FDA sets limits rather than banning them, as described earlier. The substances in this section are regarded as (1) avoidable or of such hazard that a safe level cannot be set, therefore the FDA has determined that food containing such substances is banned; or (2) beyond the control of the FDA and cannot be regulated (for example, substances produced in the home).

Toxins in Fish, Shellfish, and Turtles

There are a number of seafood toxins (to be distinguished from marine venoms), many of which are not confined to a single species (over 400 species have been incriminated in ciguatera toxicity) and are therefore most likely to be influenced by the environment. However, some seafood toxins are specific to a single species or genus. A complicating factor in the study of seafood toxins is the sporadic frequency and nonpredictability of the presence of the toxin.

Seafood toxins generally can be classified according to the location of the poison. For example: (1) ichthyosarcotoxin is concentrated in the muscles, skin, liver, or intestines or is otherwise not associated with the reproductive system or circulatory system,

(2) ichthyootoxin is associated with reproductive tissue, (3) ichthyohemotoxin is confined to the circulatory system, and (4) ichthy-

ohepatotoxin is confined to the liver. In general, seafood toxins under FDA policy have a zero tolerance, with any detectable level considered cause for regulatory action.

Dinoflagellate Poisoning (Paralytic Shellfish Poisoning or PSP; Saxitoxin) The etiologic agent in this type of poisoning is saxitoxin or related compounds and is found in mussels, cockles, clams, soft-shell clams, butter clams, scallops, and shellfish broth. Bivalve mussels are the most common vehicles. Saxitoxin, originally isolated from toxic Alaskan butter clams (Saxidomus giganticus) is actually a family of neurotoxins and includes neosaxitin and gonyautoxins 1 through 4. All block neural transmission at the neuromuscular junction by binding to the surface of the sodium channels and interrupting the flow of Na ions; atrioventricular nodal conduction may be suppressed, and there may be direct suppression of the respiratory center and progressive reduction of peripheral nerve excitability. The toxin produces paresthesias and neuromuscular weakness without hypotension and lacks the emetic and hypothermic action of tetrodotoxin. Moderate symptoms are produced by 120 to 180 g per person and are reversible within hours or days, while 80 g of purified toxin per 100 g of tissue (0.5 to 2 mg per person) may be lethal, due to asphyxiation, usually within 12 h of ingestion. The toxin is an alkaloid and relatively heat stable. The toxin is produced by several genera of plankton [Gonyaulax (now known as Alexandrium) catenella, Gonyaulax acatenella, Gonyaulax tamarensis, Pyrodinium spp., Ptychodiscus brevis, Gymnodinium catenaturm, and others]; and during red tides, blooms of these plankton may reach 20 to 40 million per milliliter. Toxic materials are stored in various parts of the body of shellfish. Digestive organs, liver, gills, and siphons contain the greatest concentrations of poison during the warmer months. Distribution is worldwide (Bryan, 1984; Clark et al., 1999; Liston, 2000).

Amnesic Shellfish Poisoning (Domoic Acid) Consumption of mussels harvested from the area off Prince Edward Island in 1987 resulted in gastroenteritis, and many of the older individuals affected or those with underlying chronic diseases experienced neurologic symptoms including memory loss. Despite treatment, three patients (71 to 84 years old) died within 11 to 24 days. The poisoning was attributed to domoic acid produced by the diatom

Nitzschia pungens f. multiseries, which had been ingested by the mussels during the normal course of feeding. Occurrence of domoic acid has also been reported in California shellfish, produced by Nitzschia pseudodelicatissima, and in anchovies (resulting in pelican deaths), produced by Nitzschia pseudoseriata (now called Pseudonitzchia australis). Domoic acid has been reported in shellfish in other provinces of Canada, Alaska, Washington, and Oregon; it may be as frequent as PSP toxins. Domoic acid has also been reported in seaweed. Domoic acid was reported in Japan in 1958 and was isolated from the red algae Chondria armata.

In the Canadian outbreak, mice injected with extracts (as in the PSP assay) died within 3.5 h. The mice exhibited a scratching syndrome uniquely characteristic of domoic acid, followed by increasingly uncoordinated movements and seizures until the mice fell on their sides, rolled over, and died. Levels of domoic acid40 g/g wet weight of mussel meat caused the mouse symptoms (Canadian authorities require cessation of harvesting when levels approach 20 g/g). Mice and rats can generally tolerate 30 to 50 mg/kg (mouse NOEL via intraperitoneal injection is 24 mg/kg). Domoic acid is dose-responsive in humans, with no effect at 0.2 to 0.3 mg/kg, mild (gastrointestinal) symptoms at 0.9 to 1.9 mg/kg,

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and the most serious symptoms at 1.9 to 4.2 mg/kg. Although rodents may appear to be more tolerant, the fatalities in humans were associated with underlying illness. Domoic acid is an analog of glutamine, a neurotransmitter, and of kainic acid; the toxicity of all three is similar as they are excitatory and act on three types of receptors in the central nervous system, with the hippocampus being the most sensitive. Domoic acid may be a more potent activator of kannic acid receptors than kannic acid itself. The stimulatory action may lead to extensive damage of the hippocampus but less severe injury to the thalamic and forebrain regions (Clark et al., 1999; Todd, 1993).

Ciguatera Poisoning The cigua in ciguatera is derived from the Spanish name for the sea snail Turbo pica, in which the symptoms were first reported. Ciguatera and related toxins (scaritoxin and maitotoxin) are ichthyosarcotoxic neurotoxins (anticholinesterase) and are found in 11 orders, 57 families, and over 400 species of fish as well as in oysters and clams. The penultimate toxin (gambiertoxin) is produced by the dinoflagellate Gambierdiscus toxicus, commonly isolated from microalgae growing on or near coral reefs that have ingested the dinoflagellate. The pretoxin appears to pass through the food chain and is biotransformed upon transfer to or by the ingesting fish to the active form, which is consumed by mammals. Other toxins, including palytoxin and okadaic acid, unrelated to gambiertoxin, may be present in ciguarteric fish and may not contribute to toxicity. The asymptomatic period is 3 to 5 h after consumption but may last up to 24 h. The onset of illness is sudden, and symptoms may include abdominal pain, nausea, vomiting, and watery diarrhea; muscular aches; tingling and numbness of the lips, tongue, and throat; a metallic taste; temporary blindness; and paralysis. Deaths have occurred. Recovery usually occurs within 24 h, but tingling may continue for a week or more. The intraperitoneal LD50 of maitotoxin in mice is 50 ng/kg (Bryan, 1984; Liston, 2000).

Puffer Fish Poisoning (Tetrodotoxin) Tetrodon or puffer fish poisoning may be caused by the improper preparation and consumption of any of about 90 species of puffer fish (fugu, blowfish, globefish, porcupine fish, molas, burrfish, balloonfish, toadfish, etc.) and has been found in newts, frogs, octopus, starfish, flatworms, various crabs, and gastropods. The toxin (tetrodotoxin) is located in nearly all the tissues, but the ovaries, roe, liver, intestines, and skin are the most toxic. Toxicity is highest during the spawning period, although a species may be toxic in one location but not another. Tetrodotoxin is associated with the presence of several bacteria on and in fish and shellfish and gives the fish an evolutionary advantage in providing protection against predators (i.e., they are endosymbiotic bacteria). A total of 21 species can produce tetrodotoxins including Vibrio, Pseudomonas, E. coli, and at least two strains of red algae.

Tetrodotoxin is a neurotoxin and causes paralysis of the central nervous system and peripheral nerves by blocking the movement of all monovalent cations. The toxin is water-soluble and is stable to boiling except in an alkaline solution. A fatal dose may be as little as 1 to 4 mg per person. The victim is asymptomatic for 10 to 45 min but may have a reprieve for as long as 3 h or more. Toxicity is manifest as a tingling or prickly sensation of the fingers and toes; malaise; dizziness; pallor; numbness of the lips, tongue, and extremities; ataxia; nausea, vomiting, and diarrhea; epigastric pain; dryness of the skin; subcutaneous hemorrhage and desquamation; respiratory distress; muscular twitching, tremor,

incoordination, and muscular paralysis; and intense cyanosis. Fatality rates are high (Bryan, 1984; Liston, 2000).

Moray Eel Poisoning Although the moray eel (Gymnothorax javanicus) and other carnivorous fish may accumulate ciguatoxin as the result of eating other contaminated fish, the Indo-Pacific moray eel (Lycodontis nudivomer) has been shown to posses a mucous skin secretion with hemolytic, toxic, and hemagglutinating properties. The hemolytic properties can be separated from the hemagglutinating properties. The hemolytic property is lost upon treatment with trypsin and is unstable in the presence of heat or acidic or alkaline media (Randall et al., 1981). The skin mucus of other species of eels, the common European eel (Anguilla anguilla) and pike eel (Muraenesox cinereus), was found to have proteinaceous toxins immunologically similar to that of the skin mucous toxin from the Japanese eel (Anguilla japonica) (Shiomi et al., 1994).

Fish Liver Poisoning This type of poisoning involves an ichthyohepatotoxin and may be related to or cause hypervitaminosis A. It occurs after the consumption of the liver of sawara (Japanese mackerel) and ishingai (sea bass, sandfish, and porgy). After an asymptomatic period of 30 min to 12 h, the victim experiences nausea, vomiting, fever, headache, mild diarrhea, rash, loss of hair, dermatitis, desquamation, bleeding from the lips, and joint pain (Bryan, 1984).

Fish Roe Poisoning This type of poisoning involves a group of ichthyootoxins found in the roe and ovaries of carp, barbel, pike, sturgeons, gar, catfish, tench, bream, minnows, salmon, whitefish, trout, blenny, cabezon, and other freshwater and saltwater fish. Poisonings have been reported in Europe, Asia, and North America. Within this group of ichthyootoxins are heat-stable toxins and lipoprotein toxins. The asymptomatic period is 1 to 6 h, followed by a bitter taste, dryness of the mouth, intense thirst, headache, fever, vertigo, nausea, vomiting, abdominal cramps, diarrhea, dizziness, cold sweats, chills, and cyanosis. Paralysis, convulsions, and death may occur in severe cases (Bryan, 1984; Furman, 1974).

Abalone Poisoning (Pyropheophorbide) Abalone poisoning is caused by abalone viscera poison (located in the liver and digestive gland) and is unusual in that it causes photosensitization. The toxin, pyropheophorbide a, is stable to boiling, freezing, and salting. It is found in Japanese abalone, Haliotis discus and Haliotis sieboldi. The development of symptoms is contingent on exposure to sunlight. The symptoms are of sudden onset and include a burning and stinging sensation over the entire body, a prickling sensation, itching, erythema, edema, and skin ulceration on parts of the body exposed to sunlight (Bryan, 1984; Shiomi, 1999). Paralytic shellfish toxin (PST) have been detected in abalone, probably through consumption of the mossworm, a plankton feeder that also clings to seaweed, and some shellfish (Takatani et al., 1997).

Sea Urchin Poisoning The etiologic agent forms during the reproductive season and is confined to the gonads. The sea urchins involved include Paracentrotus lividus, Tripneustes ventricosus, and Centrechinus antillarum. The symptoms include abdominal pain, nausea, vomiting, diarrhea, and migraine-like attacks (Bryan, 1984). The toxin has been shown to interfere with calcium uptake in nerve preparations (Zhang et al., 1998).

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Sea Turtle Poisoning (Chelonitoxin) The etiologic agent here is chelonitoxin, which is found in the liver (greatest concentration) but also in the flesh, fat, viscera, and blood. Toxicity is described as sporadic or even seasonal, indicating that the poison may be derived from toxic marine algae. Most outbreaks occur in the IndoPacific region. The turtles involved include the green sea turtle as well as the hawksbill and leatherback turtles. Local custom in Sri Lanka is to first offer the liver to crows, and if the birds eat it, the flesh is regarded as safe. However, because the symptoms appear over a few hours to several days, this bioassay requires patience. Symptoms of intoxication in humans include vomiting; diarrhea; sore lips, tongue, and throat; foul breath; difficulty in swallowing; a white coating on the tongue, which may become covered with pin-sized, pustular papules; tightness of the chest; coma; and death. The toxin has been reported transferred to nursing infants from intoxicated mothers. Postmortem examinations reveal congestion of internal organs, interstitial pulmonary edema, and necrosis of myocardial fibers. Fatality rates of 7 and 25 percent have been reported (Ariyananda and Fernando, 1987; Bryan, 1984; Champetier De Ribes et al., 1997; Chandrasiri et al., 1988).

Haff Disease Haff disease is a syndrome of unknown etiology that occurs following consumption of certain types of fish. The syndrome consists of rhabdomyolysis with a release of muscle cell contents into the blood. Patients are often rigid, sensitive to touch, and unable to move; their urine may have a dark brown color. Symptoms appear 18 h (with a range of 6 to 21 h) after consumption; they resolve within 2 to 3 days, and the fatality rate is approximately 1 percent. “Haff disease” was first reported in the 1920s along the Koenigsberg Haff, a brackish inlet on the Baltic Sea, although outbreaks have been reported in Sweden, the former Soviet Union, and in the United States beginning in 1984. U.S. poisonings have been associated with buffalo fish (Ictiobus cyprnellus) caught in California, Missouri (St. Louis), and Louisiana. No etiologic agent has been identified (Anonymous, 1998).

Microbiologic Agents—Preformed

Bacterial Toxins

Although the United States likely has the safest and cleanest food supply in the world, most U.S. food-related illness results from microbial contamination. If all the food-borne health concerns could be divided into two large categories—poisonings and infections— the former would include chemical poisonings (e.g., contaminants such as chlorinated hydrocarbons) and intoxications, which may have a plant, animal, or microbial origin. In the infections category, food acts as a vector for organisms that exhibit their pathogenicity once they have multiplied inside the body. Infections include the two subcategories enterotoxigenic infections (with the release of toxins following colonization of the GI tract) and invasive infections, in which the GI tract is penetrated and the body is invaded by organisms.

Food-borne disease outbreaks are tracked by the Centers for Disease Control and Prevention (CDC), which reports that there are approximately 400 outbreaks of food-borne disease per year, involving 10,000 to 20,000 people. However, the actual frequency may be as much as 10 to 200 times as high because (1) an outbreak is classified as such only when the source can be identified as affecting two or more people and (2) most home poisonings are mild or have a long incubation time; they are therefore not con-

nected to the ingested food and go unreported. Naturally, because of differences in virulence and opportunity, some species are more likely than others to cause outbreaks.

There are a number of food toxins of microbial origin; however, discussion in this chapter is limited to preformed bacterial toxins—that is, those toxins elaborated by bacteria concomitant to their residence and growth in or on the food prior to ingestion. There are a number of different types of toxins. An enterotoxin is a toxin having action on the enteric cells of the intestine and an endotoxin is generally a lipopolysaccharide membrane constituent released from a dead or dying gram-negative becteria. These toxins are nonspecific and stimulate inflammatory responses from macrophages, including but not limited to prostaglandins, thromboxans, interleukins, and other mediators of immunity. Exotoxins are synthesized and released (usually by gram-positive bacteria) and are not an integral part of the organism; however, they may enhance its virulence. Some bacteria, such as Shigella, Staphylococcus aureus, and E. coli (which releases the shiga-like Vero toxin), can elaborate both endotoxin and exotoxin.

Clostridium botulinum and Clostridium butyricum Food botulism, although now relatively rare, still occurs and is important because of its potency. All organisms of the Clostridium genus are gram-positive, spore-forming anaerobes. Botulism is due to the toxins A, B, E, and F, which may be produced by one or more strains of C. botulinum and C. butyricum (type E only); toxins C and D cause botulism in animals. Type G has not caused any human cases. C. botulinum organisms are categorized as group I to IV on the basis of toxin produced; additionally, group I is proteolytic in culture (liquefying egg white, gelatin, and other solid proteins). The toxin is elaborated in foods, wounds, and infant gut and is neurotoxic, interfering with acetylcholine at peripheral nerve endings. Although the spores are among the most heat-resistant, the toxins are heat-labile (the toxin may be rendered harmless at 80 to 100°C for 5 to 10 min). Botulinum toxins are large zinc-metalloproteins of ~150,000 Da, composed of two parts: a 50,000-Da piece, the catalytic subunit, and the 100,000-Da piece, containing an N-termi- nal translocation domain and a C-terminal binding domain. The structural features are similar to those of tetanus toxin. For types B, D, F, and G (and tetanus toxin), the target protein is VAMP/synaptobrevin, a protein associated with the synaptic vesicle. Types A and E cleave a protein associated with the presynaptic memberane, ANAP25. Botulinum toxin C cleaves SNAP25 and syntaxin, another protein involved in exocytosis. Although intracellular mechanisms of botulinum and tetanus toxins are similar, symptoms are different because different populations of neurons are targeted. The symptoms may include respiratory distress and respiratory paralysis that may persist for 6 to 8 months. The case fatality rate is 35 to 65 percent, and the poison is fatal in 3 to 10 days; a lethal dose is approximately 1 ng. Sources and reservoirs include soil, mud, water, and the intestinal tracts of animals. Foods associated with botulinum toxin include improperly canned lowacid foods (green beans, corn, beets, asparagus, chili peppers, mushrooms, spinach, figs, baked potato, cheese sauce, beef stew, olives, and tuna). The toxin also may occur in smoked fish, fermented food (seal flippers, salmon eggs) and improperly homecured hams. An increasing source of poisonings is from the use of flavored oils or oil infusion, most typically in garlic-in-oil preparations; in 1993, FDA required acidification of such preparations to prevent the growth of Clostridium. While a proteolytic strain of C. botulinum (group I) may cause the food to appear and smell

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“spoiled” (by-products include isobutyric acid, isovaleric acid, and phenylpropionic acid), this is not the case with nonproteolytic strains, many of which can flourish and elaborate toxin at temperatures as low as 3°C (Belitz and Grosch, 1999; Bryan, 1984; Crane, 1999; Hobbs, 1976; Loving, 1998; Lund and Peck, 2000).

The successful use of nitrates in meat to prevent spoilage by C. botulinum resulted in the petitioning of FDA by the USDA to have sodium and potassium nitrate approved for addition by “prior sanction” (21 CFR 181.33). The mechanism of nitrates is believed to be due to an inactivation by nitric oxide of iron-sulfur proteins such as ferrodoxin and pyruvate oxidoreductase within the germinated cells. The activity is dependent on the pH and is proportional to the level of free HNO2; 100 mg nitrate/kg of meat is necessary for the antimicrobial effect, although this effect can be enhanced with ascorbates and chelating agents. Other antibacterials that prevent C. botulinum include nisin (used in cheese spreads), parabens, phenolic antioxidants, polyphosphates and carbon dioxide (Belitz and Grosch, 1999; Lund and Peck, 2000).

Clostridium perfringens The primary reservoir for C. perfringens, unlike C. botulinum, is the intestinal tract of warm-blooded animals (including humans). Most incidences of C. perfringens food poisoning are associated with the consumption of roasted meat that has been contaminated with intestinal contents at slaughter, followed by roasting and inadequate storage, allowing C. perfringens growth and enterotoxin (CPE) to be elaborated (although some CPE may actually be released during a “second sporulation” process in the stomach of the victim). Virtually all food poisoning is produced by type A strain, although a particularly severe form (called “pig-bel”) is produced by type C strain and is only seen among natives of the New Guinea highlands. CPE is enterotoxic and follows an ordered series of events, first causing cellular ion permeability, followed by macromolecular (DNA, RNA) synthesis inhibition, morphologic alteration, cell lysis, villus tip desquamation, and severe fluid loss. This is manifest by abdominal cramping diarrhea occurring within 8 to 16 h, although symptoms are of short duration—1 day or less. Foods associated with C. perfringens poisoning include cooked meat or poultry, gravy, stew, and meat pies. The curious form called pig-bel follows feasting on pork by New Guinea highlanders, in whom low levels of proteases are inadequate to hydrolyze the toxins, which are subsequently absorbed. C. perfringens is also associated with the production of other 11 other toxins, including those associated with gas gangrene (Bryan, 1984; Crane, 1999; Duncan, 1976; Hauschild, 1971; Hobbs, 1979; Hobbs et al., 1953; Labbe, 2000; Walker, 1975).

Bacillus cereus B. cereus is also a gram-positive, spore-forming rod, but it is an aerobe. B. cereus is a causative agent of emetic or diarrheagenic exoand enterotoxins elaborated in food. The emetic thermostable toxin (surviving 259°F for 90 min) is called cerulide (a small cyclic peptide, of 1.2 kDa that acts on 5-HT3 receptors, stimulating the vagus afferent nerve) and is produced by serotypes 1, 3, and 8. The diarrheagenic thermolabile toxin (133°F for 20 min) is produced by serotypes 1, 2, 6, 8, 10, and 19 and may also be produced in situ in the lower intestine of the host. The diarrheal form may actually consist of three toxins, one of which is hemolytic. Reservoirs are soil and dust. Foods associated with this organism and its toxic properties include boiled and fried rice (principally the emetic form), while the diarrheal form has a wider occurrence and may be found in meats, stews, pudding, sauces, dairy products, vegetable dishes, soups, and meat loaf (Bryan, 1984;

Crane, 1999; Gilbert, 1979; Goepfert et al., 1972; Granum and Lund, 1997).

Evidence is accumulating that other species of Bacillus may elaborate food toxins, including Bacillus thuringiensis, Bacillus subtilis, Bacillus licheniformis, and Bacillus pumilis (Crane, 1999; Granum and Baird-Parker, 2000).

Staphylococcus aureus Staphylococcal intoxication includes staphlyloenterotoxicosis and staphylococcal food poisoning. S. aureus produces a wide variety of exoproteins, including toxic shock syndrome toxin-1 (TSST-1), the exfoliative toxins ETA and ETB, leukociden, and the staphylococcal enterotoxins (SEA, SEB, SECn, SED, SEE, SEG, SHE and SEI). TSST-1 and the staphylococcal enterotoxins (SE) are also known as pyrogenic toxin superantigens (PTSAgs) on the basis of their biological characteristics. Although enterotoxemia develops only from the ingestion of large amounts of SE, emesis is produced as the result of stimulation of the putative SE receptors in the abdominal viscera, following which there is a cascade of inflammatory mediator release. All the SE toxins share a number of properties: an ability to cause emesis and gastroenteritis in primates, superantigenicity, intermediate resistance to heat and pepsin digestion, and tertiary structural similarity, including an intramolecular disulfide bond. Sources of Staphylococcus include nose and throat discharges, hands and skin, infected cuts, wounds, burns, boils, pimples, acne, and feces. The anterior nares of humans are the primary reservoirs. Other reservoirs include mastitic udders of cows and ewes (responsible for contamination of unpasteurized milk) and arthritic and bruised tissues of poultry. Foods are usually contaminated after cooking by persons cutting, slicing, chopping, or otherwise handling them and then keeping the foods at room temperature for several hours or storing them in large containers. Foods associated with staphylococcal poisoning include cooked ham; meat products, including poultry and dressing; sauces and gravy; cream-filled pastry; potatoes; ham, poultry, and fish salads; milk; cheese; bread pudding; and generally high-protein leftover foods (Bryan, 1976, 1984; Bergdoll, 1979; Cohen, 1972; Crane, 1999; Dinges et al., 2000; Minor and Marth, 1976).

Escherichia coli Although E. coli does not produce a preformed toxin, it deserves mention because of the overwhelming publicity the emergent strain O157:H7 has received (H and O refer to flagellar antigens and virulence markers). There are four categories of E. coli associated with diarrheal disease: enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroinvasive (EIEC), and Vero cytotoxin–producing E. coli (VTEC). The classification VTEC also includes “shiga-like toxin”–producing E. coli (or SLTEC) and “shiga toxin”–producing E. coli (STEC). Enterohemorrhagic E. coli (EHEC) refers to those strains producing bloody diarrhea, which are a subset of VTEC. The reference to shiga toxin is the result of the clinical similarity of the bloody diarrhea caused by EHEC to that caused by Shigella. Each of the diseases presented by the four categories is also associated with one or more toxins (Willshaw et al., 2000).

Because cattle are a significant reservoir of E. coli, it is logical that most outbreaks in the United States have been associated with hamburgers and other beef products, although raw vegetables (often fertilized with manure) and unpasteurized apple cider and juice have been reported as souces of outbreaks. Outbreaks in Europe are more often associated with contamination of recreational waters (swimming pools, lakes, etc.). Other sources of con-

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tamination include person-to-person contact (especially among institutionalized persons and in families) and contact with farm animals, especially following educational farm visits (Karch et al., 1999).

The subject of organic food has increasingly captured the public interest. Within this issue is a debate concerning the use in organic and conventional farming of organic fertilizers (e.g., cow manure) that may contain E. coli O157:H7 (Stephenson, 1997). Data reported to the U.S. Centers for Disease Control and Prevention (CDC) in 1996 and tabulated in a CDC document entitled “Clusters/Outbreaks of E. coli O157:H7 reported to CDC in 1996” show that approximately 10 percent of all E. coli O157:H7 infections reported that year were from organically grown lettuce, although organic foods apparently account for less than 1 percent of the total food supply. This information, although much too preliminary for any meaningful conclusions, nonetheless suggests the need for careful evaluation of the use of manure in conventional and organic farming.

At the basis of the potential problem is the use of inadequately treated manure for fertilizer. Human cases of E. coli O157:H7 infection have been reported from consumption of contaminated lettuce, potatoes, radish sprouts, alfalfa sprouts, cantaloupe, and unpasteurized apple cider and juice (Karch et al., 1999). Adequate treating of manure requires composting the manure for a minimum of 3 months, during which the heap must reach a temperature of 60°C; although this may be adequate to kill vegetative pathogens, it will not destroy spore formers such as Clostridium perfringens or Clostridium botulinum. Survival of viruses and protozoa during composting is not known (Anonymous, 1999).

Bovine Spongiform Encephalopathy

Bovine spongiform encephalopathy (BSE) was first indentified in Great Britain in 1986. BSE is a neurologic disease classified as a transmissible spongiform encephalopathy (TSE) and is similar to TSEs in other species, including scrapie (sheep and goats), transmissible mink encephalopathy (ranch-bred mink), chronic wasting disease (mule deer and elk), exotic ungulate encephalopathy (captive exotic bovoids such as bison, orynx, and kudu), and feline spongiform encephalopathy (domestic cats, zoo Felidae). TSEs among humans include kuru, Creutzfeldt-Jakob disease (CJD) and “new variant” CJD (nvCJD).

Clinically, these diseases all present neurologic deterioration and wasting, with the incubation period and interval from clinical onset to inexorable death determined by the dose of infective agent, its virulence, and the genetic makeup of the victim. The incubation of BSE in cattle is generally 4 to 5 years (range of 20 months to 18 years) and an interval of 1 to 12 months from presentation of clinical signs to death. Characteristic histologic lesions in the brain and spinal cord are vacuolation and “spongiform” changes. BSE fibrils (long strands of host glycoprotein called prion protein or PrP) in spinal cord preparations may be seen with electron microscopy following detergent extraction and proteinase K digestion. Scrapie tissues with highest infectivity are brain and spinal cord, followed by spleen, tonsil lymph nodes, distal ileum, and proximal colon. The infective agent can be transferred using preparations of neural tissue from infected animals across species barriers. The most effective method of transfer is direct injection into the brain or spinal cord, but transfer has been reported with intraperitoneal injection and oral dosing. Vertical transfer (mother to offspring) has been reported among domestic cattle, and lateral

transfer through biting or injury (especially among mink) has also been reported. It is generally agreed that the infective agent is likely a variant of scrapie (endemic to sheep) and was transferred to cattle from rendered sheep via inadequately processed meat and bone meal protein supplement. Disputes have arisen about other details of BSE, its relationship to other TSEs, and its effects in humans because of an expectation of conformation by BSE to historical principles of disease.

There is mainstream agreement that the infective agents is a prion, a proteinaceous infective particle that does not possess nucleic acid. It is resistant to heat, animicrobials, ultraviolet rays, and ionizing radiation and is not consistently inactivated with alcohol, formaldehyde, glutaraldehyde, or sodium hydroxide. Phenol and sodium hypochlorite disinfection have had variable success.

PrP protein is not the infectious agent, but rather the product of a TSE infection which has switched on the PrP gene. While the infectious agent has not been elucidated, investigators have concluded that the agent in nvCJD and BSE is the same strain and that the same agent is also linked to feline spongiform encephalopathy and exotic ungulate encephalopathy. While this information might indicate a simple mode of transmission, workers with the highest potential incidence of exposure to BSE or TSE (sheep farmers, butchers, veterinarians, cooks, and abattoir workers) do not have an unusually high incidence of nvCJD (Collee, 2000; Prusiner, 1991). Likewise, hemophilic patients have not reflected an increased incidence of nvCJD, although CJD transmission has been documented as the result of injections of human growth hormone or gonadotrophin (derived from human pituitary gland), implantation of dura mater and corneas, and even infected EEG electrodes and neurosurgical instruments (Collee, 2000; Lee et al., 1998; Prusiner, 1994).

The final chapter on BSE and other TSEs will not be written for at least 15 to 20 years, the probable conclusion of the incubation period for those exposed to BSE in the late 1980s and early 1990s.

Substances Produced by Cooking

Tolerances cannot be set for contaminants produced as a result of an action taken by the consumer. An example of this type of contaminant is heterocyclic amines, which are generated during cooking. Heterocyclic amines (HCAs) were discovered serendipitously by Japanese investigators who, while examining the mutagenicity of smoke generated by charred foods, found that the extracts of the charred surfaces of the meat and fish were quantitatively more mutagenic than could be accounted for by the presence of polycyclic aromatic hydrocarbons (Sugimura et al., 1989). Collectively, there are more than 20 HCAs. They are formed as a result of hightemperature cooking of proteins (especially those containing high levels of creatinine) and carbohydrates. Normally, as a result of such heating, desirable flavor components are formed, for example, pyrazines, pyridines, and thiazoles. Intermediates in the formation of these substances are dihydropyrizines and dihydropyridines, which in the presence of oxygen form the flavor components; however, in the presence of creatinine, HCAs are formed (Table 30-28) (Chen and Chiu, 1998; Schut and Snyderwine, 1999).

These substances are rapidly absorbed by the GI tract, are distributed to all organs, and decline to undetectable levels within 72 h. HCAs behave as electrophilic carcinogens (Table 30-29). They are activated through N-hydroxylation by cytochrome P450 or

	CHAPTER 30		FOOD TOXICOLOGY			1083
Table 30-28
Amounts of Heterocyclic Amines in Cooked Foods
			Amount In Cooked Food, ng/g
SAMPLE		IQ	MeIQx	4,8-DIMeIQx	Trp-P-1	Trp-P-2
Broiled beef	0.19		2.11		0.21	0.25
Fried ground beef	0.70		0.64	0.12	0.19	0.21
Broiled chicken			2.33	0.81	0.12	0.18
Broiled mutton			1.01	0.67		0.15
Food-grade beef extract			3.10

SOURCE: Sugimura et al., 1989; Adamson, 1990, with permission.

P448, depending on the specific HCA. The N-hydroxy forms require further activation by O-acetylation or O-sulfonation to react with DNA. DNA adducts are formed with guanosine in various organs, including the liver, heart, kidney, colon, small intestine, forestomach, pancreas, and lung. Unreacted substances are subject to phase II detoxication reactions and are excreted via the urine and feces. In vitro, HCAs require metabolic activation, with some requiring O-acetyltransferase and others not requiring it. Although much of the mutagenicity testing has been carried out in TA98 and TA100, these substances are mutagenic in mammalian cells both in vitro and in vivo, Drosophila, and other strains of Salmonella (Skog et al., 1998; Sugimura and Wakahayashi, 1999)

Miscellaneous Contaminants in Food

Sometimes the items under the “miscellaneous” heading are the most interesting. For example, Rodricks and Pohland (1981)

Table 30-29

Mutagenicity and Carcinogenicity of Heterocyclic Amines

pointed out an interesting historical case of the possible transfer of a toxic botanic chemical from an animal to humans which was first identified by Hall (1979). It is found in the Bible, Book of Numbers, 11:31–33, which describes hungry Israelites inundated with quail blown in from the sea; those who ate the quail quickly died. Hall speculated that the quail had consumed various poisonous berries, including hemlock, while they overwintered in Africa. The hemlock berry contains coniine, a neurotoxic alkaloid to which quail are resistant and that can accumulate in their tissue. Humans are not resistant to coniine, and consumption of large quantities of quail tissue containing the neurotoxin could result in death as described in the biblical text.

Mountain laurel, rhododendron, and azaleas all possess andromedotoxin (now called acetylandromedol) and grayanotoxins (I, II, and II) in their shoots, leaves, twigs, and flowers. Honey made from flowers of these plants is toxic to humans, and after an asymptomatic period of 4 to 6 h, salivation, malaise, vomiting, di-

	NUMBER OF		Carcinogenicity
	REVERTANTS, u/g
HCA	(STRAIN TA98)	SPECIES	STATISTICALLY SIGNIFICANT TUMORS
MeIQ	47,000,000	Mouse	Liver, forestomach
		Rat	Zymbal gland, oral cavity, colon, skin, mammary gland
IQ	898,000	Mouse	Liver, forestomach, lung
		Rat	Liver, mammary gland, Zymbal gland
		Monkey	Liver, metastasis to lungs
MeIQx	417,000	Mouse	Liver, lung, lymphoma, leukemia
		Rat	Liver, Zymbal gland, clitoral gland, skin
Glu-P-1	183,000	Mouse	Liver, blood vessels
		Rat	Liver, small and large intestine, brain, clitoral gland, Zymbal gland
DiMeIQx	126,000	No data
Trp-P-2	92,700	Mouse	Liver, lung
		Rat	Liver, clitoral gland
Trp-P-1	8,990	Mouse	Liver
		Rat	Liver, metastasis to lungs
PhIP	1,800	Mouse	Liver, lung, lymphoma
		Rat	Colon, mammary gland
Glu-P-2	930	Mouse	Liver, blood vessels
		Rat	Liver, small and large intestine, Zymbal gland, brain, clitoral gland

SOURCE: Adapted from Sugimura et al., 1989, with permission.

1084	UNIT 7 APPLICATIONS OF TOXICOLOGY

arrhea, tingling of the skin, muscular weakness, headache, visual difficulties, coma, and convulsions occur. Life-threatening bradycardia and arterial hypotension may ensue. Needless to say, beekeepers maintain apiaries well away from these species of plants. A similar poisoning occurs with oleander (Nerium oleander and Nerium indicum), where honey made from the flowers, meat roasted on oleander sticks, or milk from a cow that eats the foliage can produce prostrating symptoms. The oleander toxin consists of a series of cardiac glycosides: thevetin, convallarin, steroidal, helleborein, ouabain, and digitoxin. Sympathetic nerves are paralyzed; the cardiotoxin stimulates the heart muscles much as digitalis does, and gastric distress ensues (Anderson and Sogn, 1984; VonMalottki and Weichmann, 1996).

Other contaminations include contamination of milk with pyrrolizidine and other alkaloids after a cow has fed on tansy ragwort (Senecio jacobaea) and tremetol contamination of milk from white snakeroot (Eupatorium rugusum).

CONCLUSIONS

Food toxicology differs in many respects from other subspecialties of toxicology largely because of the nature and chemical complexity of food. Food consists of hundreds of thousands of chemical substances in addition to the macroand micronutrients that are essential to life. The federal law defining food safety in the United States, the FD&C Act, provides a workable scheme for establishing the safety of foods, food ingredients, and contaminants. While the act does not specify how the safety of food and its com-

ponents and ingredients is to be demonstrated, it emphasizes the need for reasonable approaches in both the application of tests and their interpretation. The specific examples of reasonable approaches and interpretations of safety data discussed in this chapter illustrate both the means and the necessity for reasonableness. New policies, consistent with the safety provisions of the act, are being developed to provide guidance for determination of the safety-in-use of novel foods and those foods derived from new plant varieties.

Contaminants found in food may be divided into two large classes: those that are unavoidable by current good manufacturing practice and those that are not. The former class is represented by substances such as certain chlorinated organic compounds, heavy metals, and mycotoxins that have been determined to be unavoidable by current food manufacturing practice and for which tolerances or action levels may be established. Additionally, pesticide residues and residues of drugs used in food-producing animals may have tolerances established when necessary to protect public health. For an avoidable class of contaminants, tolerances are not set either because public health concerns dictates that the mere presence of the substance or agent demands immediate regulatory action or because contamination results from food preparation in the home, which is beyond FDA control.

It is important to emphasize that the vast majority of foodborne illnesses in developed countries are attributable to microbiologic contamination of food arising from the pathogenicity and/or toxigenicity of the contaminating organism. Thus, the overwhelming concern for food safety in the United States remains directed toward preserving the microbiologic integrity of food.

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