Manifestations of Lead Toxicity Perhaps due to their increased absorption of lead from the diet, children appear to be more susceptible to the toxic effects of lead.. Although peripheral
Trang 1significance of such findings has not been
estab-lished, but the studies clearly indicate that
perchlo-rate can enter lettuce, presumably from growing
conditions in which perchlorate has contaminated
water or soil
Milk has also been shown to be subject to
per-chlorate contamination A small survey of seven
milk samples purchased in Lubbock, Texas,
indi-cated that perchlorate was present in all of the
sam-ples 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 4 mg/l for perchlorate
in drinking water, whereas the EPA has yet to
estab-lish 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
per-chlorate may lead to serious effects, such as
carci-nogenicity, neurodevelopmental and developmental
changes, reproductive toxicity, and
immunotoxi-city 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
metabo-lism disorders
Ammonium perchlorate was found to be
nonge-notoxic in a number of tests, which is consistent
with the fact that perchlorate is relatively inert
under physiological conditions and is not
metabo-lized 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
perchlo-rate/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 expo-sure 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 Acry-lamide in Foods Washington, DC: US Food and Drug Admin-istration, Center for Food Safety and Applied Nutrition Friedman M (2003) Chemistry, biochemistry, and safety of acry-lamide 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 Tech-nology 37: 4979–4981.
Sharp R and Walker B (2003) Rocket Science: Perchlorate and the Toxic Legacy of the Cold War Washington, DC: Environmen-tal 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 ani-mals 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, cad-mium, nickel, and bismuth
Trang 2How Does Lead Contaminate Food?
Although lead is primarily known as an
environmen-tal contaminant that is ingested in paint chips by
young children in urban slums or from
contami-nated 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,
espe-cially 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
Environ-mental Protection Agency is 15 mg (0.07 mmol l1)
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
micronutri-ent deficiencies are prone to experience increased
absorption of lead in the diet Thus, depletion of
iron, calcium, and zinc may promote lead
absorp-tion 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
expla-nation 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 dl1(0.25–0.5 mmol l1)
Another enzyme active in heme biosynthesis,
erythrocyte ferrochelatase, is inhibited at a blood
lead level of 15 mg dl1 (0.75 mmol l1) Reduction
of the renal enzyme 25-hydroxyvitamin D-1-
hydroxylase, which converts circulating
25-hydroxy-vitamin D to its biologically active steroid hormone,
1,25-dihydroxyvitamin D (1,25(OH)2D) or
calci-triol, is observed at a blood lead concentration of
25 mg dl1 (1.25 mmol l1) Behavioral changes and
learning problems may begin to occur at blood
levels previously thought to be normal, 10–15 mg dl1
(0.5–0.75 mmol l1)
Manifestations of Lead Toxicity 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 ner-vous 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
Neurologic Full-blown lead encephalopathy, includ-ing delirium, truncal ataxia, hyperirritability, altered vision, lethargy, vomiting, and coma, is not com-mon Although peripheral nerve damage and paraly-sis may still be reported in adults, the most common toxicity observed is learning disability and an asso-ciated high-frequency hearing loss occurring in chil-dren with blood lead levels previously assumed to be safe At low blood levels of lead (less than
10 mg dl1), 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, neu-ronal 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
31
2weeks 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 photo-receptor 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
Trang 3rats 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
ferro-chelatase, which are critical to heme biosynthesis
Although the pathogenesis of the decreased red blood
cell survival is not clear in humans, animal data
indi-cate that the pentose phosphate shunt and
glucose-6-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
expansion This latter effect of lead exposure may possibly offer an explanation of how lead accumula-tion may contribute to hypertension
Vitamin D endocrine system and bone As previously mentioned, lead can contribute to the reduced con-version 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 accumu-lating in bone has been reported to cause osteo-clasts 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 func-tion 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
Table 1 Heavy metal toxicities by tissues
Tissue Heavy metal Dietary source(s) Toxicity
Neurologic Lead Green, leafy vegetables,
canned food with lead solder, water
Learning disability, ataxia, encephalopathy, irritability
Mercury Seafood, agricultural crop
contamination
Psychomotor retardation, paralysis, microcephaly, convulsions, choreoathetotic movements Bismuth Medications Paraesthesias, tremors, ataxia, reduced short-term memory Bone Lead See above Reduced conversion of vitamin D to active form,
?reduced osteoclast function Mercury See above ?Reduced bone formation and bone density Cadmium Seafood, plant roots in
contaminated soil
?High bone turnover, secondary hyperparathyroidism Bone marrow Lead See above Decreased hemoglobin synthesis, decreased erythrocyte
survival Mercury See above Increased hemolysis, alteration of T helper and
T suppressor lymphocytes Cadmium See above ?Reduced erythrocyte count Nickel Vegetables, especially
legumes, spinach and nuts
Decreased helper T cells and increased suppressor
T cells Gastrointestinal Lead See above Decreased binding of L -tryptophan to hepatocellular nuclei
Mercury See above Anorexia, fetal hepatic cell damage Cadmium See above Abdominal pain, vomiting, diarrhea Renal Lead See above Proximal tubular dysfunction: glycosuria, aminoaciduria,
hyperphosphaturia, decreased renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the biologically active form
Mercury See above Renal tubular dysfunction, proteinuria, autoimmune
damage Cadmium See above Proteinuria, glycosuria
Trang 4binding 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
pro-duced urogenital, vertebral, and rectal
malforma-tions 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 l1 (1.2 mmol l1), as shown in
Table 2
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
follow-ing the release of inorganic mercury from an
acet-aldehyde 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
unfortu-nate consequence of seafood contamination with
methyl mercury is the contamination of fish meal
used to feed poultry, resulting in mercury
accumu-lation in the poultry as well as in the eggs
Addi-tionally, 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
con-tained mercury
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 l1) Hair mercury content is used as a marker of methyl mercury burden
Dietary Mercury: Absorption and Consequences Although the precise mechanism of mercury absorp-tion and transport has not been clarified, one possi-bility is its use of molecular mimicry Studies of methyl mercury show that it binds to reduced sulf-hydryl groups, including those in the amino acid cysteine and glutathione Methyl mercury-1-cysteine
is similar in conformation to the amino acid methio-nine and may be taken up by the methiomethio-nine trans-port 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 preg-nant mothers and the concentration of methyl mer-cury 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 2 Recommended management of toxic symptoms caused by heavy metal contaminants in food
Lead Dimercaptosuccinic acid Blood lead levels greater than 25 mg (1.2 mmol) l1; treatment of children with
blood levels exceeding 10 mg (0.5 mmol) l1advocated due to learning problems Mercury Dimercaptosuccinic acid Dimercaprol and D -penicillamine have also been used, but dimercaprol
complicated by increased amount of mercury in brain Cadmium Diethyldithiocarbamate Also used: dimercaprol, D -penicillamine, and dicalcium disodium EDTA
Nickel Insufficient studies for
recommended agent
Parenteral administration of diethyldithiocarbamide for acute toxicity may
be helpful but unproven Bismuth Insufficient studies for
recommended agent
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
Trang 5consequent effects on the blood cells, immune
sys-tem, 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
photopho-bia 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
stimu-late T lymphocytes to produce a glomerular
anti-basement membrane antibody, which produces
suf-ficient 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
necro-sis However, it is not clear that this theory is
cor-rect 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
retarda-tion, flaccid paralysis, microcephaly, ataxia,
chor-eoathetotic motions of the hands, tonic seizures,
and narrowing of the visual fields (Table 1) Studies
of neonatal rats injected with methyl mercuric
chlor-ide reported postural and movement changes during
the fourth week of life These were associated with
degeneration of cortical interneurons, which
pro-duce -aminobutyric acid (GABA) as a
neurotrans-mitter In the caudate nucleus and putamen, these
GABAergic and somatostatin immunoreactive
inter-neurons manifested the abnormalities Pregnant rats
given methyl mercury by intraperitoneal injection
demonstrated rapid (within 2 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 peroxida-tive injury to the neurons Following intracerebral injection in the rat, methyl mercuric chloride distri-butes in the Purkinje and Golgi cells of the cerebel-lum 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 mer-cury caused an increased, although delayed, phos-phorylation of certain proteins The 12- to 24-h time course from mercury exposure to phosphor-ylation 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 mar-row would explain the abnormalities in red cell production, immune cell production, and bone for-mation (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 lympho-cytes and in B lympholympho-cytes 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 mer-cury exposure may be at least in part due to perox-idative damage inasmuch as studies on workers chronically exposed to mercury vapors demonstrate
a reduction in erythrocyte enzyme activity of glu-tathione peroxidase and superoxide dismutase, as well as in G6PD
Finally, although the effects of mercury exposure
on bone have not been studied in humans, experi-ments in mice indicate that the administration of an anti-metallothionein antibody and mercury results in
Trang 6decreased 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
redis-tribution of mercury by fetal hepatic tissue have
been previously discussed Abnormalities described
with in utero exposure to mercury during the
epi-demics 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
recom-mended (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
indus-trial 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
cad-mium then condenses to form cadcad-mium 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
con-sumed However, contamination of the human food
supply is limited by this route since cadmium is
toxic to fish and fish embryos In contrast to
sea-food, vegetables are affected differently because
cad-mium 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
contami-nated 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.
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 3 or 4 mg per day The
Provisional Tolerable Weekly Intake (PTWI)
estab-lished by FAO/WHO is 7 mg kg1 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 gastroin-testinal 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 cad-mium’s effects on the gastrointestinal tract are not certain Whether these toxicities stem from an irri-tative effect of the metal or whether there is cel-lular 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 There-fore, it is possible that cadmium interferes with autonomic nervous system influence on gastroin-testinal motility
Renal toxicity Renal tubular dysfunction is mani-fest 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) g1 of renal cortical tissue has been associated with tubular dysfunction In the kidney, cadmium is bound to metallothionein When the amount of intracellular cadmium accumu-lation exceeds metallothionein binding capacity, this
is the point at which renal toxicity is hypothesized
to occur
Bone marrow and bone In short-term accumula-tion of cadmium in the marrow, there is a prolifera-tion of cells in the myeloid/monocyte category However, with longer term burden, marrow hypo-plasia is reported, including decreased production of
Trang 7erythropoietin 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
forma-tion (osteocalcin) and resorpforma-tion
(deoxypyridino-line) 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
cad-mium 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,
dimerca-prol, D-penicillamine, or diethyldithiocarbamate
(Table 2)
Nickel and Bismuth
Dietary Contamination
Nickel and bismuth are not considered to be
com-mon 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
man-ufacturing process Soft drinking water and
acid-containing beverages can dissolve nickel from pipes
and containers Daily nickel ingestion can be as high
as 1 mg (0.017 mmol) but averages between 200 and
300 mg (3.4 and 5.1 mmol).
Permissible Intakes
The maximum permissible intake of nickel is not
known Bismuth intake is related to whole blood
bismuth levels If these levels exceed 100 mg l1,
bismuth-containing medication should be discontinued
Toxicity
Nickel ingestion by women resulted in an increase in
interleukin-5 levels 4 h after ingestion and a decrease
in CD4þand an increase in CD8þlymphocytes 24 h
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 oxi-dative For bismuth, neurotoxicity, including irrit-ability, numbness and tingling of the extremities, insomnia, poor concentration, impairment of short-term memory, tremors, dementia masquerading as Alzheimer’s disease, and abnormal electroencepha-lograms, has been reported Discontinuation of the bismuth may result in restoration of normal neuro-logical function Production of these symptoms in animals was associated with a brain bismuth
con-centration of 8 mg g1brain tissue; a brain bismuth
concentration of 4 mg g1 brain tissue was not associated with these neurotoxic manifestations
However, hydrocephalus was reported At 1 mg
bismuth g1 brain tissue, no neurotoxic features were observed in animals Nephropathy, osteoar-thropathy, and thrombocytopenia have also been reported with bismuth toxicity
Management Insufficient controlled clinical trials have been per-formed 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 encephalo-pathy 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
Further Reading 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 Environ-mental 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.
Trang 8Burger 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
anti-metallothionein antibody and mercury treatment decreases
bone mineral density in mice Toxicology and Applied
Phar-macology 115: 98–110.
Knowles S, Donaldson WE, and Andrews JK (1998) Changes in
fatty acid composition of lipids in birds, rodents, and
pre-school 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 D 3 (calcitriol) pulse therapy for bone
lesions in a murine model of chronic cadmium toxicosis
Inter-national 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.
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 Environ-mental Health 49: 1–648.
Royce SC and Needleman HL (1990) Agency for Toxic Sub-stances 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 Associa-tion 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
fruc-tose in the food supply, the estimated intake of frucfruc-tose
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, preser-vation, 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 com-posed 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 pre-ferred sweetener used by the soft drink industry, although HFCS-42 is also commonly used as a sweet-ener in many processed food products Concentrated