344 FOOD SAFETY/Heavy Metals significance of such findings has not been established, but the studies clearly indicate that perchlorate can enter lettuce, presumably from growing conditions in which perchlorate has contaminated water or soil Milk has also been shown to be subject to perchlorate contamination A small survey of seven milk samples purchased in Lubbock, Texas, indicated that perchlorate was present in all of the samples at levels ranging from 1.12 to 6.30 mg/l To put such findings in perspective, the State of California has adopted an action level of mg/l for perchlorate in drinking water, whereas the EPA has yet to establish a specific drinking water limit Toxicological Considerations Perchlorate is thought to exert its toxic effects at high doses by interfering with iodide uptake into the thyroid gland This inhibition of iodide uptake can lead to reductions in the secretion of thyroid hormones that are responsible for the control of growth, development, and metabolism Disruption of the pituitary–hypothalamic–thyroid axis by perchlorate may lead to serious effects, such as carcinogenicity, neurodevelopmental and developmental changes, reproductive toxicity, and immunotoxicity Specific concerns relate to the exposures of infants, children, and pregnant women because the thyroid plays a major role in fetal and child development The ability of perchlorate to interfere with iodide uptake is due to its structural similarity with iodide In recognition of this property, perchlorate has been used as a drug in the treatment of hyperthyroidism and for the diagnosis of thyroid or iodine metabolism disorders Ammonium perchlorate was found to be nongenotoxic in a number of tests, which is consistent with the fact that perchlorate is relatively inert under physiological conditions and is not metabolized to active metabolites in humans or in test animals Workers exposed to airborne levels of perchlorate absorbed between 0.004 and 167 mg perchlorate per day These workers showed no evidence of thyroid abnormality, and a No Observed Adverse Effect Level was established at 34 mg absorbed perchlorate/day Perchlorate does not accumulate in the human body, and 85–90% of perchlorate given to humans is excreted in the urine within 24 h See also: Cancer: Epidemiology and Associations Between Diet and Cancer Fish Food Intolerance Food Safety: Mycotoxins; Pesticides; Bacterial Contamination; Heavy Metals Further Reading Becher G (1998) Dietary exposure and human body burden of dioxins and dioxin-like PCBs in Norway Organohalogen Compounds 38: 79–82 Buckland SJ (1998) Concentrations of PCDDs, PCDFs and PCBs in New Zealand retain foods and assessment of dietary exposure Organohalogen Compounds 38: 71–74 Environmental Protection Agency (2001) Dioxin: Scientific Highlights from Draft Reassessment Washington, DC: US Environmental Protection Agency, Office of Research and Development Food and Drug Administration (2002) Exploratory Data on Acrylamide in Foods Washington, DC: US Food and Drug Administration, Center for Food Safety and Applied Nutrition Friedman M (2003) Chemistry, biochemistry, and safety of acrylamide A review Journal of Agricultural and Food Chemistry 51: 4504–4526 Jimenez B (1996) Estimated intake of PCDDs, PCDFs and co-planar PCBs in individuals from Madrid (Spain) eating an average diet Chemosphere 33: 1465–1474 Kirk AB, Smith EE, Tian K, Anderson TA, and Dasgupta PK (2003) Perchlorate in milk Environmental Science and Technology 37: 4979–4981 Sharp R and Walker B (2003) Rocket Science: Perchlorate and the Toxic Legacy of the Cold War Washington, DC: Environmental Working Group Tareke E, Rydberg P, Karlsson P, Eriksson S, and Tornqvist M (2002) Analysis of acrylamide, a carcinogen formed in heated foodstuffs Journal of Agricultural and Food Chemistry 50: 4998–5006 Urbansky ET (2002) Perchlorate as an environmental contaminant Environmental Science and Pollution Research 9: 187–192 Zanotto E (1999) PCDD/Fs in Venetian foods and a quantitative assessment of dietary intake Organohalogen Compounds 44: 13–17 Heavy Metals G L Klein, University of Texas Medical Branch at Galveston, Galveston TX, USA ª 2005 Elsevier Ltd All rights reserved Food that we are culturally habituated to consume is usually thought to be safe However, some foods are naturally contaminated with substances, the effects of which are unknown Crops are sprayed with pesticides while they are being cultivated; some animals are injected with hormones while being raised Meanwhile, other foods are mechanically processed in ways that could risk contamination This article discusses food contamination with heavy metals, the heavy metals involved, their toxicities, and their sources in the environment A brief consideration of medical management is also included Five metals are considered in this category: lead, mercury, cadmium, nickel, and bismuth FOOD SAFETY/Heavy Metals 345 Lead Manifestations of Lead Toxicity How Does Lead Contaminate Food? Perhaps due to their increased absorption of lead from the diet, children appear to be more susceptible to the toxic effects of lead These involve the nervous system, including cognitive dysfunction; the liver; the composition of circulating blood; kidney function; the vitamin D endocrine system and bone (Table 1); and gene function, possibly with resultant teratogenic effects Chronic exposure results in high blood pressure, stroke, and end-stage kidney disease in adults Although lead is primarily known as an environmental contaminant that is ingested in paint chips by young children in urban slums or from contaminated soil or inhaled in the form of house dust or automobile exhaust, it may also enter the food and water supply Ways in which this can occur include fuel exhaust emissions from automobiles that may contaminate crops and be retained by them, especially green leafy vegetables Animals used for food may graze on contaminated crops and thus may also be a potential source of lead Moreover, lead from soldered water pipes may contaminate tap water used for drink or for food production Permissible Intakes In the United States, the maximum quantity of lead in the water supply that is permitted by the Environmental Protection Agency is 15 mg (0.07 mmol lÀ1) The Food and Drug Administration (FDA) Advisory Panel recommends that no more than 100 mg (50 mmol) of lead per day should be ingested from food products Dietary Lead: Absorption and Consequences People with certain macronutrient and micronutrient deficiencies are prone to experience increased absorption of lead in the diet Thus, depletion of iron, calcium, and zinc may promote lead absorption through the gastrointestinal tract Whereas adults may normally absorb approximately 15% of their lead intake, pregnant women and children may absorb up to 3.5 times that amount, and the explanation for this difference is not clear The effects of the entry of lead into the circulation depend on its concentration Thus, the inhibition of an enzyme active in hemoglobin synthesis, -amino levulinic acid dehydratase (ALAD), occurs at blood lead concentrations of 5–10 mg dlÀ1 (0.25–0.5 mmol lÀ1) Another enzyme active in heme biosynthesis, erythrocyte ferrochelatase, is inhibited at a blood lead level of 15 mg dlÀ1 (0.75 mmol lÀ1) Reduction of the renal enzyme 25-hydroxyvitamin D-1- hydroxylase, which converts circulating 25-hydroxyvitamin D to its biologically active steroid hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) or calcitriol, is observed at a blood lead concentration of 25 mg dlÀ1 (1.25 mmol lÀ1) Behavioral changes and learning problems may begin to occur at blood levels previously thought to be normal, 10–15 mg dlÀ1 (0.5–0.75 mmol lÀ1) Neurologic Full-blown lead encephalopathy, including delirium, truncal ataxia, hyperirritability, altered vision, lethargy, vomiting, and coma, is not common Although peripheral nerve damage and paralysis may still be reported in adults, the most common toxicity observed is learning disability and an associated high-frequency hearing loss occurring in children with blood lead levels previously assumed to be safe At low blood levels of lead (less than 10 mg dlÀ1), children may lose IQ points, possibly due to the interference of lead in normal calcium signaling in neurons and possibly by blocking the recently reported learning-induced activation of calcium/phospholipid-dependent protein kinase C in the hippocampus The physicochemical basis of these changes derives largely from small animal data Rats exposed to lead from birth develop mitochondrial dysfunction, neuronal swelling, and necrosis in both the cerebrum and the cerebellum Exposure on day 10 of life elicited only the cerebellar pathology, and lead exposure after 312 weeks of life failed to produce any of these changes In combination with manganese, lead has also produced peroxidative damage to rat brains and has been shown to inhibit nitric oxide synthase in the brains of mice Additionally, an increase in blood arachidonic acid and in the ratio of arachidonic to linoleic acid following lead exposure in several species, including humans, may provide evidence in support of a peroxidative mechanism of damage to neural tissue following lead exposure Lead has also produced necrosis of retinal photoreceptor cells and swelling of the endothelial lining of retinal blood vessels in rats Lead may also damage the auditory nerves in rats, and it may be partially responsible for the high-frequency hearing loss observed in humans Finally, organic lead compounds may also disturb brain microtubular assembly Liver Although there are no outwardly recognizable manifestations of lead toxicity to the liver, studies in 346 FOOD SAFETY/Heavy Metals Table Heavy metal toxicities by tissues Tissue Heavy metal Dietary source(s) Toxicity Neurologic Lead Green, leafy vegetables, canned food with lead solder, water Seafood, agricultural crop contamination Medications See above Learning disability, ataxia, encephalopathy, irritability Mercury Bone Bismuth Lead Mercury Cadmium Bone marrow Gastrointestinal Renal Lead See above Seafood, plant roots in contaminated soil See above Mercury See above Cadmium Nickel Lead Mercury Cadmium Lead See above Vegetables, especially legumes, spinach and nuts See above See above See above See above Mercury See above Cadmium See above rats indicate that amino acid binding to hepatocyte nuclei may be altered by lead Thus, liver function may be subtly or subclinically affected and further studies are needed to elucidate this possibility Blood composition The major consequences of lead toxicity to the blood are microcytic anemia and decreased erythrocyte survival The anemia is largely due to the inhibition of ALAD and erythrocyte ferrochelatase, which are critical to heme biosynthesis Although the pathogenesis of the decreased red blood cell survival is not clear in humans, animal data indicate that the pentose phosphate shunt and glucose6-phosphate dehydrogenase (G6PD) are inhibited by lead, suggesting that increased hemolysis may also contribute to the reduction in erythrocyte survival Kidney function Studies from the US National Institute of Occupational Safety and Health have reported that lead exposure reduced glutathione S-transferase expression in the kidneys of rabbits, indicating increased susceptibility to peroxidative damage Renal proximal tubular dysfunction is described with lead intoxication and can result in glycosuria, aminoaciduria, and hyperphosphaturia as well as a reduced natriuretic response to volume Psychomotor retardation, paralysis, microcephaly, convulsions, choreoathetotic movements Paraesthesias, tremors, ataxia, reduced short-term memory Reduced conversion of vitamin D to active form, ?reduced osteoclast function ?Reduced bone formation and bone density ?High bone turnover, secondary hyperparathyroidism Decreased hemoglobin synthesis, decreased erythrocyte survival Increased hemolysis, alteration of T helper and T suppressor lymphocytes ?Reduced erythrocyte count Decreased helper T cells and increased suppressor T cells Decreased binding of L-tryptophan to hepatocellular nuclei Anorexia, fetal hepatic cell damage Abdominal pain, vomiting, diarrhea Proximal tubular dysfunction: glycosuria, aminoaciduria, hyperphosphaturia, decreased renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the biologically active form Renal tubular dysfunction, proteinuria, autoimmune damage Proteinuria, glycosuria expansion This latter effect of lead exposure may possibly offer an explanation of how lead accumulation may contribute to hypertension Vitamin D endocrine system and bone As previously mentioned, lead can contribute to the reduced conversion of 25-hydroxyvitamin D to 1,25(OH)2D The extent to which this action may contribute to vitamin D deficiency is not known, but there is at least the potential for lower circulating levels of 1,25(OH)2D to play a role in reduced intestinal calcium absorption This in turn may result in further lead absorption Additionally, lead accumulating in bone has been reported to cause osteoclasts to develop pyknotic nuclei and manifest inclusion bodies, possibly lead, in the nucleus and cytoplasm Although it has yet to be proven, these findings suggest a reduction in the resorptive function of osteoclasts This may be a protective mechanism by the body to prevent the liberation of lead stored in bone, but at the same time lead may prevent the uptake by bone of additional calcium Genetic/teratogenic effects Lead has been reported to alter gene transcription by the reduction of DNA FOOD SAFETY/Heavy Metals binding to zinc finger proteins This interruption of transcription has the potential to produce congenital anomalies in animals or humans Studies have reported that lead crossing the placenta has produced urogenital, vertebral, and rectal malformations in the fetuses of rats, hamsters, and chick Management Chelation therapy with dimercaprol succinic acid is recommended for anyone with a blood lead level higher than 25 mg lÀ1 (1.2 mmol lÀ1), as shown in Table Mercury How Does Mercury Contaminate Food? The primary portal of mercury contamination of food is via its industrial release into water, either fresh or salt water, and its conversion to methyl mercury by methanogenic bacteria As the marine life takes up the methyl mercury, it works its way into the food chain and is ultimately consumed by humans This is the scenario that occurred following the release of inorganic mercury from an acetaldehyde plant into Minimata Bay in Japan in 1956 and 1965 and is responsible for the so-called ‘Minimata disease.’ Furthermore, acid rain has increased the amount of mercury available to be taken up by the tissues of edible sea life and can enhance the toxicity of certain fish An unfortunate consequence of seafood contamination with methyl mercury is the contamination of fish meal used to feed poultry, resulting in mercury accumulation in the poultry as well as in the eggs Additionally, mercury-containing pesticides can contaminate agricultural products In Iraq in 1971 and 1972, wheat used in the baking of bread was contaminated with a fungicide that contained mercury 347 Permissible Intakes Limits of mercury intake set by the UN Food and Agriculture Organization (FAO) and the World Health Organization (WHO) are 0.3 mg per person per week, of which no more than 0.2 mg should be methyl mercury Furthermore, FAO and WHO have set limits of mercury contamination of foods as not to exceed 50 parts per billion wet weight (50 mg lÀ1) Hair mercury content is used as a marker of methyl mercury burden Dietary Mercury: Absorption and Consequences Although the precise mechanism of mercury absorption and transport has not been clarified, one possibility is its use of molecular mimicry Studies of methyl mercury show that it binds to reduced sulfhydryl groups, including those in the amino acid cysteine and glutathione Methyl mercury-1-cysteine is similar in conformation to the amino acid methionine and may be taken up by the methionine transport system in the intestine Also, inasmuch as it has been shown that deep-frying of fish, with or without breading, will increase the mercury content, it has been postulated that mercury may be absorbed with the oil from the frying process A Swedish study reported a direct correlation between the amount of seafood consumed by pregnant mothers and the concentration of methyl mercury in their umbilical cord blood Although fetal tissue mercury concentration is generally lower than the maternal concentration, the exception to this is liver According to a Japanese study, mercury is stored in the fetal liver, bound to metallothionein With development, the amount of metallothionein decreases and the mercury in liver is redistributed primarily to brain and kidney In studies of offspring of animals exposed to mercury vapors, behavioral changes have been detected With regard to toxicity, mercury affects the skin, kidneys, nervous system, and marrow, with Table Recommended management of toxic symptoms caused by heavy metal contaminants in food Element Agent Comments Lead Dimercaptosuccinic acid Mercury Dimercaptosuccinic acid Cadmium Nickel Diethyldithiocarbamate Insufficient studies for recommended agent Insufficient studies for recommended agent Blood lead levels greater than 25 mg (1.2 mmol) lÀ1; treatment of children with blood levels exceeding 10 mg (0.5 mmol) lÀ1 advocated due to learning problems Dimercaprol and D-penicillamine have also been used, but dimercaprol complicated by increased amount of mercury in brain Also used: dimercaprol, D-penicillamine, and dicalcium disodium EDTA Parenteral administration of diethyldithiocarbamide for acute toxicity may be helpful but unproven Dimercaprol has been used anecdotally and reversed the symptoms of myoclonic encephalopathy; many choose to stop bismuth-containing drugs with a gradual resolution of symptoms Bismuth 348 FOOD SAFETY/Heavy Metals consequent effects on the blood cells, immune system, and bone formation Manifestations of Mercury Toxicity Skin Mercury produces a symptom complex called acrodynia Its main features are redness of the lips and pharynx, a strawberry tongue, tooth loss, skin desquamation, and pink or red fingertips, palms, and soles The eyes are also affected, and photophobia and conjunctivitis are seen In addition, there is enlargement of the cervical lymph nodes, loss of appetite, joint pain, and, occasionally, vascular thromboses, possibly by the induction of platelet aggregation, which has been shown in in vitro experiments There is also a neurological component to this symptom complex: irritability, weakness of the proximal muscles, hypotonia, depressed reflexes, apathy, and withdrawal Kidneys Mercury has been hypothesized to stimulate T lymphocytes to produce a glomerular antibasement membrane antibody, which produces sufficient damage to lead to the proteinuria observed with mercury toxicity (Table 1) The basis for this theory derives from studies in rats in which mercuric chloride injection produced these antibodies, both as IgG and IgM There was also an observed increase in CD8þ (suppressor) T cells in the glomeruli In addition, the rats developed proximal tubular necrosis However, it is not clear that this theory is correct because methyl mercury can induce apoptosis, or programmed cell death, of the T lymphocytes, possibly by damaging mitochondria and inducing oxidative stress Nervous system In the large epidemics of methyl mercury ingestion reported in both Japan and Iraq, infants were reported to have psychomotor retardation, flaccid paralysis, microcephaly, ataxia, choreoathetotic motions of the hands, tonic seizures, and narrowing of the visual fields (Table 1) Studies of neonatal rats injected with methyl mercuric chloride reported postural and movement changes during the fourth week of life These were associated with degeneration of cortical interneurons, which produce -aminobutyric acid (GABA) as a neurotransmitter In the caudate nucleus and putamen, these GABAergic and somatostatin immunoreactive interneurons manifested the abnormalities Pregnant rats given methyl mercury by intraperitoneal injection demonstrated rapid (within h) effects on their fetuses, including mitochondrial degeneration of cerebral capillary endothelial cells, which led to hemorrhage In turn, the bleeding disrupted normal neuronal migration In addition, methyl mercury may disrupt neuronal microtubular assembly and, perhaps by molecular mimicry (as described previously), may bind to the sulfhydryl groups of glutathione, causing peroxidative injury to the neurons Following intracerebral injection in the rat, methyl mercuric chloride distributes in the Purkinje and Golgi cells of the cerebellum as well as in three different layers of cerebral cortical cells—III, IV, and VI Mercury exposure in humans can result in deficits in attention and concentration, especially under pressure of time deadlines One report suggests that this may be due to mercury damage to the posterior cingulate cortex, where these functions are regulated Finally, in vitro studies of rat cerebellar granular cells suggested that incubation with methyl mercury caused an increased, although delayed, phosphorylation of certain proteins The 12- to 24-h time course from mercury exposure to phosphorylation was believed to be consistent with the alteration of gene expression by mercury Thus, the effects of mercury on the nervous system are multiple Bone marrow: Immune cells, blood cells, and bone formation A toxic effect of mercury on bone marrow would explain the abnormalities in red cell production, immune cell production, and bone formation (Table 1); all of the cells involved arise from stem cells found in the marrow and are presumably affected by mercury With regard to the immune cells, mercury induces an autoimmune response manifested by an increase in CD4þ (helper) and CD8þ (suppressor) T lymphocytes and in B lymphocytes in peripheral lymphoid tissue This may explain in part the autoimmune nephropathy as well as the enlarged lymph nodes of acrodynia, previously described Additionally, mercury may impair integrin signaling pathways in neutrophils, which may give rise to neutrophil dysfunction Hemolysis of red blood cells resulting from mercury exposure may be at least in part due to peroxidative damage inasmuch as studies on workers chronically exposed to mercury vapors demonstrate a reduction in erythrocyte enzyme activity of glutathione peroxidase and superoxide dismutase, as well as in G6PD Finally, although the effects of mercury exposure on bone have not been studied in humans, experiments in mice indicate that the administration of an anti-metallothionein antibody and mercury results in FOOD SAFETY/Heavy Metals decreased biochemical markers of bone formation and decreased bone mineral density The mechanism for this is unknown, but mercury interference with differentiation of osteogenic precursor cells is postulated Genetic/teratogenic effects The uptake and redistribution of mercury by fetal hepatic tissue have been previously discussed Abnormalities described with in utero exposure to mercury during the epidemics in Japan and Iraq have included low birth weight, malformation of the brain (both cerebrum and cerebellum), an abnormal migratory pattern of neurons, mental retardation, and failure to achieve developmental milestones This remains a problem today for pregnant women who consume seafood The FDA recommends that intake of large predator fish, such as swordfish and shark, be limited since they contain large amounts of mercury Even tuna is considered to contain more mercury than most other seafood Management Chelation with dimercaptosuccinic acid is recommended (Table 2) Cadmium How Does Cadmium Contaminate Food? Cadmium enters the food chain in much the same way that lead and mercury do—by means of industrial contamination Cadmium is often used as a covering of other metals or in the manufacture of batteries and semiconductors; it readily transforms into a gas as the metal ores are smelted The cadmium then condenses to form cadmium oxide, which deposits in soil and water near the source Cadmium accumulates in lower marine life, such as plankton, mollusks, and shellfish, and continues through the food chain as these organisms are consumed However, contamination of the human food supply is limited by this route since cadmium is toxic to fish and fish embryos In contrast to seafood, vegetables are affected differently because cadmium is taken up by the leaves and roots of plants, so those near industrial sources may be very high in cadmium Permissible Intakes A 1991 study of adults consuming rice contaminated with cadmium in the Kakehashi River Basin of Ishikara, Japan, correlated cadmium intake with renal tubular dysfunction and established a maximum allowable intake of 110 mg per day 349 Canadian studies have estimated daily intake in study populations to be approximately half that, and the French have estimated cadmium exposure in the diet as being only or mg per day The Provisional Tolerable Weekly Intake (PTWI) established by FAO/WHO is mg kgÀ1 body weight per week, a slightly more conservative estimate than the Japanese study but still in general agreement with it Dietary Cadmium: Absorption and Consequences Fortunately, only 2–8% of dietary cadmium is absorbed and significant cadmium ingestion is accompanied by vomiting Therefore, the gastrointestinal route is not as significant as inhalation of dust particles as a source of significant exposure Manifestations of Toxicity Toxic manifestations of cadmium ingestion include renal dysfunction, osteoporosis and bone pain, abdominal pain, vomiting and diarrhea, anemia, and bone marrow involvement (Table 1) Gastrointestinal toxicity The mechanisms for cadmium’s effects on the gastrointestinal tract are not certain Whether these toxicities stem from an irritative effect of the metal or whether there is cellular damage has not been resolved in animal or in vitro studies One possibility is that in vitro studies of neural tissue suggest that cadmium blocks adrenergic and cholinergic synapses Therefore, it is possible that cadmium interferes with autonomic nervous system influence on gastrointestinal motility Renal toxicity Renal tubular dysfunction is manifest in patients with itai itai disease as glycosuria and proteinuria, including excessive excretion of - and -microglobulin Approximately 50–75% of cadmium accumulation in the body occurs in the liver and kidneys Urinary cadmium excretion of 200 mg (1.78 mmol) gÀ1 of renal cortical tissue has been associated with tubular dysfunction In the kidney, cadmium is bound to metallothionein When the amount of intracellular cadmium accumulation exceeds metallothionein binding capacity, this is the point at which renal toxicity is hypothesized to occur Bone marrow and bone In short-term accumulation of cadmium in the marrow, there is a proliferation of cells in the myeloid/monocyte category However, with longer term burden, marrow hypoplasia is reported, including decreased production of 350 FOOD SAFETY/Heavy Metals erythropoietin Although a reduction in marrow cells may indicate that the osteogenic precursors in the marrow may also be reduced (Table 1), this is not borne out by studies both in humans and in rats In these cases, biochemical markers of bone formation (osteocalcin) and resorption (deoxypyridinoline) are both increased, indicating a high turnover state In rats, circulating parathyroid hormone levels are also elevated, suggesting that the high turnover is due to secondary hyperparathyroidism and subsequent inability of the bone matrix to mature and bind calcium and phosphate Parenteral administration of 1,25-dihydroxyvitamin D has been reported to decrease circulating parathyroid hormone in the rat and to reduce bone turnover Moreover, other animal studies report that cadmium interferes with hydroxyapatite nucleation and growth, thus making it difficult for bone matrix to bind to calcium Management Chelation therapy is recommended using calcium, disodium ethylene diaminetetraacetic acid, dimercaprol, D-penicillamine, or diethyldithiocarbamate (Table 2) Nickel and Bismuth Dietary Contamination Nickel and bismuth are not considered to be common dietary contaminants Nickel is mainly inhaled as a dust by workers, whereas bismuth is mainly ingested in bismuth-containing medications such as Pepto-Bismol Vegetables contain more nickel than other foods, and high levels of nickel can be found in legumes, spinach, lettuce, and nuts Baking powder and cocoa powder may also contain excess nickel, possibly by leaching during the manufacturing process Soft drinking water and acidcontaining beverages can dissolve nickel from pipes and containers Daily nickel ingestion can be as high as mg (0.017 mmol) but averages between 200 and 300 mg (3.4 and 5.1 mmol) following the nickel intake Thus, alterations in the immune response may be associated with excessive nickel ingestion, consistent with reports of tumor production in animals and humans by inhalation of nickel-containing dust or powders The mechanism for nickel-associated toxicity is purported to be oxidative For bismuth, neurotoxicity, including irritability, numbness and tingling of the extremities, insomnia, poor concentration, impairment of shortterm memory, tremors, dementia masquerading as Alzheimer’s disease, and abnormal electroencephalograms, has been reported Discontinuation of the bismuth may result in restoration of normal neurological function Production of these symptoms in animals was associated with a brain bismuth concentration of mg gÀ1 brain tissue; a brain bismuth concentration of mg gÀ1 brain tissue was not associated with these neurotoxic manifestations However, hydrocephalus was reported At mg bismuth gÀ1 brain tissue, no neurotoxic features were observed in animals Nephropathy, osteoarthropathy, and thrombocytopenia have also been reported with bismuth toxicity Management Insufficient controlled clinical trials have been performed to make clear-cut recommendations for pharmacotherapy for toxicity from either nickel or bismuth Diethyl dithiocarbamide chelation therapy when promptly administered intravenously has been reported to be effective in acute nickel carbonyl poisoning In addition, there have been anecdotal case reports of the reversal of myoclonic encephalopathy caused by bismuth with use of dimercaprol However, no recommendations can be given at the present time See also: Ascorbic Acid: Physiology, Dietary Sources and Requirements; Deficiency States Food Safety: Other Contaminants Vitamin D: Physiology, Dietary Sources and Requirements Permissible Intakes Further Reading The maximum permissible intake of nickel is not known Bismuth intake is related to whole blood bismuth levels If these levels exceed 100 mg lÀ1, bismuth-containing medication should be discontinued Bierer DW (1990) Bismuth subsalicylate: History, chemistry and safety Reviews of Infectious Disease 12(supplement 1): S3–S8 Bjomberg KA, Vahter M, Peterson-Grawe K et al (2003) Methyl mercury and inorganic mercury in Swedish pregnant women and in cord blood: Influence of fish consumption Environmental Health Perspectives 111: 637–641 Blumenthal NC, Cosma V, Skyler D et al (1995) The effect of cadmium on the formation and properties of hydroxyapatite in vitro and its relation to cadmium toxicity in the skeletal system Calcified Tissue International 56: 316–322 Toxicity Nickel ingestion by women resulted in an increase in interleukin-5 levels h after ingestion and a decrease in CD4þ and an increase in CD8þ lymphocytes 24 h FRUCTOSE Burger J, Dixon C, Boring CS et al (2003) Effect of deep frying fish on risk from mercury Journal of Toxicology and Environmental Health 66: 817–828 Jin GB, Inoue S, Urano T et al (2002) Induction of antimetallothionein antibody and mercury treatment decreases bone mineral density in mice Toxicology and Applied Pharmacology 115: 98–110 Knowles S, Donaldson WE, and Andrews JK (1998) Changes in fatty acid composition of lipids in birds, rodents, and preschool children exposed to lead Biological Trace Element Research 61: 113–125 Kollmeier H, Seeman JW, Rothe G et al (1990) Age, sex and region adjusted concentrations of chromium and nickel in lung tissue British Journal of Industrial Medicine 47: 682–687 Kurata Y, Katsuta O, Hiratsuka H et al (2001) Intravenous 1-,25 (OH)2 vitamin D3 (calcitriol) pulse therapy for bone lesions in a murine model of chronic cadmium toxicosis International Journal of Experimental Pathology 82: 43–53 Murata K, Weche P, Renzoni A et al (1999) Delayed evoked potential in children exposed to methylmercury from seafood Neurotoxicology and Teratology 21: 343–348 351 Needleman HL, Schell A, Bellinger D et al (1990) The long-term effects of exposure to low doses of lead in childhood An 11-year follow-up report New England Journal of Medicine 322: 83–88 Report of the International Committee on Nickel Carcinogenesis in Man (1990) Scandinavian Journal of Work and Environmental Health 49: 1–648 Royce SC and Needleman HL (1990) Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine, pp 1–20 Atlanta: US Department of Health and Human Services, Public Health Service Simon JA and Hudes ES (1999) Relationship of ascorbic acid to blood lead levels Journal of the American Medical Association 281: 2289–2293 Watanabe C, Yoshida K, Kasanume Y et al (1999) In utero methylmercury exposure differentially affects the activities of selenoenzymes in the fetal mouse brain Environmental Research 80: 208–214 Worth RG, Esper RM, Warra NS et al (2001) Mercury inhibition of neutrophil activity: Evidence of aberrant cell signaling and incoherent cellular metabolism Scandinavian Journal of Immunology 53: 49–55 Fortification see Food Fortification: Developed Countries; Developing Countries FRUCTOSE N L Keim, US Department of Agriculture, Davis, CA, USA P J Havel, University of California at Davis, Davis, CA, USA Published by Elsevier Ltd Fructose, a monosaccharide, is naturally present in fruits and is used in many food products as a sweetener This article reviews the properties and sources of fructose in the food supply, the estimated intake of fructose in Western diets, the intestinal absorption of fructose, and the metabolism of fructose and its effect on lipid and glucose metabolism The health implications of increased consumption of fructose are discussed, and inborn errors of fructose metabolism are described Properties and Sources of Fructose Fructose has a fruity taste that is rated sweeter than sucrose Sweetness ratings of fructose are between 130% and 180% (in part dependent on the serving temperature) compared to the standard, sucrose, rated at 100% Both sucrose and fructose are used extensively in foods to provide sweetness, texture, and palatability These sugars also contribute to the appearance, preservation, and energy content of the food product Natural sources of dietary fructose are fruits, fruit juices, and some vegetables In these foods, fructose is found as the monosaccharide and also as a component of the disaccharide, sucrose (Table 1) However, the primary source of fructose in Western diets is in sugars added to baked goods, candies, soft drinks, and other beverages sweetened with sucrose and high-fructose corn syrup (HFCS) HFCS is produced by hydrolyzing the starch in corn to glucose using -amylase and glucoamylase This is followed by treatment with glucose isomerase to yield a mixture of glucose and fructose The process typically produces a HFCS composed of 42% fructose, 50% glucose, and 8% other sugars (HFCS-42) By fractionation, a concentrated fructose syrup containing 90% fructose can be isolated (HFCS-90) HFCS-42 and HFCS-90 are blended to produce HFCS-55, which is 55% fructose, 41% glucose, and 4% other sugars HFCS-55 is the preferred sweetener used by the soft drink industry, although HFCS-42 is also commonly used as a sweetener in many processed food products Concentrated ... learning problems may begin to occur at blood levels previously thought to be normal, 10–15 mg dlÀ1 (0.5–0.75 mmol l 1) Neurologic Full-blown lead encephalopathy, including delirium, truncal ataxia,... Blood lead levels greater than 25 mg (1.2 mmol) l 1; treatment of children with blood levels exceeding 10 mg (0.5 mmol) l 1 advocated due to learning problems Dimercaprol and D-penicillamine... disability and an associated high-frequency hearing loss occurring in children with blood lead levels previously assumed to be safe At low blood levels of lead (less than 10 mg dlÀ1), children