Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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shortening the computational run, and gives insight

into the ‘worst-case scenario’: when there is little

convective heating, then the temperature differences

between different regions of a food mixture will

be more pronounced. A number of computational

models for the heating of two-phase mixtures have

been developed and validated; if the physical proper-

ties of the materials are known, it is possible to

predict the heating rates and patterns that will result.

0029 The aim of simulations is to demonstrate the nature

and extent to which effects might arise in real situ-

ations. The finite element method is expensive in

computer time, although advances in hardware have

made it possible to use high-end personal computers

rather than workstations. It is best as a design and

research tool rather than as the basis for a control

system.

Design of Formulations and Processes

0030 Using electrical heating it is possible to heat a solid–

liquid mixture very rapidly. The key physical param-

eter is electrical conductivity, both of the mixture and

of the individual phases. The overall electrical con-

ductivity governs the power that can be supplied to

the system. In any given system there will be limits on

the voltage and current density that can be sustained.

Voltage limits arise through the cost of transformers.

Current is limited by the acceptable current densities

on the electrode, recommended as < 4000 A m

2

for

the APV system. Locally, however, the electrical con-

ductivity of individual regions of the system controls

the heating rate.

0031 Once it has reached the required state, it is vital to

cool the food as rapidly as possible to avoid loss of

product quality. From the heater, material will pass to

the holding section and then to cooling. In a con-

ventional process the holding section allows thermal

equilibration between particle and liquid and holds

the material at temperature long enough for the re-

quired level of sterility. In electrical heating equilibra-

tion may not be needed because particle and liquid

temperatures are closely matched. For process con-

trol, it is useful if the particle temperature at the end

of the heating section exceeds the liquid, as the liquid

temperature is simplest to measure. However, any

overheating of particles may impair quality, because

it is necessary to remove heat by conduction during

cooling. Any design should thus consider the effect of

the whole process on the product.

0032 Care must be taken in the design of formulations

to eliminate temperature variations, and quality

assurance protocols developed to insure that the elec-

trical conductivity of the ingredients lies between

acceptable limits. All the physical properties of the

system must be known over the whole range of pro-

cess temperatures, and the heating rates checked

under batch conditions. The successful application

of electrical heating produces a product of very high

quality: developments in electrical equipment design

and in process understanding will enhance the ability

of food processors to use the technique.

See also: Canning: Cans and their Manufacture; Food

Handling; Quality Changes During Canning;

Convenience Foods; Cooking: Domestic Use of

Microwave Ovens; Heat Transfer Methods; Heat

Treatment: Ultra-high Temperature (UHT) Treatments;

Chemical and Microbiological Changes; Quality

Assurance and Quality Control

Further Reading

Davies LJ, Kemp MR and Fryer PJ (1999) The geometry of

shadows: effects of inhomogeneities in electrical field

processing. Journal of Food Engineering 40: 245–258.

de Alwis AAP, Halden K and Fryer PJ (1989) Shape and

conductivity effects in the ohmic heating of foods.

Chemical Engineering Research and Design 67: 159–

168.

Halden K, de Alwis AAP and Fryer PJ (1990) Changes in

electrical conductivity of foods during ohmic heating.

International Journal of Food Science and Technology

25: 9–25.

Kim HJ, Choi YM, Yang TCS et al. (1996) Validation

of ohmic heating for quality enhancement of food

products. Food Technology 50: 253–261.

Kim HJ, Choi YM, Yang A et al. (1996) Microbiological

and chemical investigation of ohmic heating of particu-

late foods using a 5 kW ohmic system. Journal of Food

Processing and Preservation 20: 41–58.

Parrott DL (1992) Use of ohmic heating for aseptic process-

ing of particles. Food Technology 46: 68–72.

Sastry SK and Palaniappan S (1992) Influence of particle

orientation on the effective electrical resistance and

ohmic heating rate of a liquid–particle mixture. Journal

of Food Processing and Engineering 15: 213–227.

Stirling R (1987) Ohmic heating – a new process for the

food industry. Power Engineering Journal 1(6): 365–

371.

Yongsawatdigul J, Park JW, Kolbe E, Dagga YA and Mor-

issey MT (1984) Ohmic heating maximises gel function-

ality of pacific whiting surimi. Journal of Food Science

60: 10–14.

Zhang L and Fryer PJ (1994) Food sterilization by electrical

heating: sensitivity to process parameters. American In-

stitute of Chemical Engineering Journal 40: 888–898.

HEAT TREATMENT/Electrical Process Heating 3049

HEAVY METAL TOXICOLOGY

G L Klein and W R Snodgrass, University of Texas

Medical Branch, Galveston, TX, USA

Introduction

0001 This article deals in brief with the toxic effects of the

heavy metals, including Cadmium: Properties and

Determination; Lead: Properties and Determination;

and Mercury: Properties and Determination – each

covered in depth in other articles – as well as nickel

and bismuth. The latter two, although not obviously

dietary toxicants, are nevertheless considered to be

heavy metals; they do enter the body and can cause

toxicity.

Lead

Toxic Effects

0002 Children appear to be more susceptible to the effects

of lead than adults. Manifestations of lead poisoning

are neurological, hepatic, hematological, renal and

endocrine, and genetic and reproductive.

0003 Neurological Overt lead encephalopathy, consisting

of delirium, truncal ataxia, irritability, lethargy,

visual disturbances, vomiting, and coma, is less fre-

quently seen than in the past. Peripheral neuropathy

and paralysis are still reported in adults as a late sign

of lead intoxication. Most striking, however, are the

reports of learning difficulties and a small but widely

confirmed and apparently irreversible reduction in

intelligence quotient in children, leading to poor

school performance. Contributing to the learning dis-

ability is a lead-associated hearing loss, especially of

the high frequencies. These learning disabilities occur

with blood lead concentrations previously thought to

be safe. Adults also manifest behavioral changes at

low blood lead levels. These include fatigue and

impaired concentration.

0004 Animal data, primarily but not exclusively from

studies using rats, show that exposure to lead from

birth can lead to hemorrhages, neuronal edema and

necrosis, and mitochondrial dysfunction in both cere-

brum and cerebellum. Rats exposed to lead beginning

on day 10 of life had these changes only in the

cerebellum. Rats exposed to lead beginning on days

20–24 of life had none of these alterations in

histology. Other documented effects of lead on

the nervous system include inhibition of calcium-

stimulated neurotransmitter release at presynaptic

terminals while stimulating spontaneous release of

neurotransmitters, resulting in mini end-plate poten-

tials. When combined with manganese, lead has

produced increased peroxidation in rat brains. Lead

has also recently been shown to inhibit nitric oxide

synthase activity in mouse brain. In addition, lead

has produced necrosis of photoreceptor cells in

the rat retina and swelling of endothelial cells lining

the retinal vessels, with consequent luminal

narrowing. Lead can also cause hearing reduction

and possible auditory nerve damage in rats. More-

over, there is a report describing disruption of brain

microtubular assembly by organic but not inorganic

lead.

0005Hepatic Animal studies have shown that when lead

acetate is added to rat hepatocytes, there is decreased

binding of l-tryptophan to hepatocellular nuclei,

suggesting that lead may alter certain aspects of

hepatocyte function as well.

0006Hematological Lead produces a microcytic anemia,

primarily by interference with two enzymes neces-

sary for heme biosynthesis, d-aminolevulinic acid

dehydratase (ALAD) and ferrochelatase. The latter

enzyme catalyzes the incorporation of iron into pro-

toporphyrin. Increased erythrocyte protoporphyrin

results from this inhibiting effect of lead. With

prolonged elevation of blood lead levels, erythrocyte

survival time decreases.

0007The hematological effects of lead are similar in

animals and humans, with the exception that in

animals lead has been reported to inhibit the pentose

phosphate shunt and glucose-6-phosphate dehydro-

genase, thus providing a possible explanation for

decreased erythrocyte survival seen with chronic

lead poisoning. Also of interest is a lead-binding

protein in kidney, which limits lead inhibition of

ALA activity in kidney but not in liver.

0008Renal and endocrine At low blood lead levels, lead

may contribute to hypertension. It may also produce

proximal tubular dysfunction, leading to glycosuria,

aminoaciduria, and hyperphosphaturia. Recent

studies by the US National Institute of Occupational

Health and Safety (NIOSH) suggest that lead expos-

ure altered glutathione S-transferase expression in

rabbit kidney, suggesting that the kidney may be

more susceptible to peroxidative damage. Gout may

develop as a result of hyperuricemia. Furthermore,

3050 HEAVY METAL TOXICOLOGY

lead impairs the function of the renal enzyme 25-

hydroxyvitamin D-1a hydroxylase, which converts

25-hydroxyvitamin D to the biologically active com-

pound 1,25-dihydroxyvitamin D.

0009 Renal and endocrine effects in animals include

not only the enhancement of lead absorption in

calcium deficiency but also the involvement of 1,25-

dihydroxyvitamin D

in the increased absorption of

lead as well as calcium. Furthermore, osteoclasts

develop pyknotic nuclei and nuclear and cytoplasmic

inclusion bodies that may lead to reduced bone re-

sorption. Lead accumulated in bone can be released

by resorption, increasing the local tissue lead concen-

tration. This may be a mechanism by which calcium

influx into osteoblasts is blocked by lead. Also, lead

appears to reduce the natriuretic response to extra-

cellular volume expansion and reduces binding of

follicle-stimulating hormone to receptors in the Ser-

toli cells of the testes. Lead crossing the placenta in

hamsters, chicks, and rats has produced urogenital,

rectal, and vertebral malformations in the fetus.

0010 Genetic and reproductive Lead has recently been

shown to affect chromatin in cells by inhibiting

DNA binding to zinc finger proteins, thus altering

transcription. It is also possible that transplacental

lead gives rise to congenital anomalies in humans as

well as in animals, although the data are inconsistent.

There is no convincing documentation of male repro-

ductive organ toxicity of lead in humans, although

this has been reported in animals. Similarly, there is

no convincing evidence that lead is a carcinogen in

humans.

Dietary and Environmental Sources of Lead

0011 Although there is no known biological requirement

for lead in humans, it is ubiquitous in an industrial

environment. Ingestion or inhalation by children or

adults occurs as a result of environmental contamin-

ation, including food and water. Children, especially

underprivileged inner-city children, may ingest chips

from lead-based paint surfaces and can mouth items

containing lead from paint, dust, or soil. High levels

of lead in soil and house dust have been associated

with elevated blood lead levels in children. Lead is

still present in unleaded gasoline; thus lead continues

to be released into the atmosphere by all gasoline-

burning vehicles. Lead from vehicle exhausts may be

retained by crops, especially leafy vegetables. Acidic

foods may leach lead from lead solder in cans; lead

from soldered water pipes can contaminate tap water.

The US Environmental Protection Agency (EPA)

estimates that 20% of the American population

consumes drinking water containing > 20 mg of lead

per liter (0.1 mmol l

1

); this includes more than 3.8

million children.

Significance of Levels in the Diet

0012Individuals who are also subject to dietary iron defi-

ciency, calcium and/or zinc deficiency risk increased

lead absorption. Adults may absorb approximately

15% of ingested lead, while pregnant women and

children may absorb up to 50%. Once in the blood,

99% of lead associates with erythrocytes, while 1%

remains in plasma and is not available for tissue entry.

Blood lead not retained is excreted in urine or bile. In

single-exposure studies, lead has a biological half-life

in blood of 25 days, in soft tissue of 40 days, and in

bone up to 25 years. The latter pool can be mobilized

without further intake under conditions of stress,

such as pregnancy, lactation, and chronic disease.

The significance of dietary and experimental expos-

ure to lead is the impact these exposures have

on blood lead concentrations and their effect on

enzymes. Thus inhibition of ALAD occurs at a

blood lead concentration of 5–10 mgdl

1

(0.25–

0.5 mmol l

1

); decreased erythrocyte ferrochelatase

occurs at blood lead concentration of 15 mgdl

1

(0.70 mmol l

1

). Inhibition of the renal enzyme

25-hydroxyvitamin D-1a hydroxylase occurs at

25 mgdl

1

(1.2 mmol l

1

) of blood lead, and subtle

neurobehavioral changes will occur with blood lead

concentrations of 10–15 mgdl

1

(0.5–0.7 mmol l

1

Intake Limits

0013Because of the neuropsychological changes that can

occur with blood lead concentrations between 10 and

15 mgdl

1

(0.5–0.7 mmol l

1

), several states in the

USA require physicians to report blood lead concen-

trations greater than 25 mgdl

1

(1.2 mmol l

1

). The

US Occupational Safety and Health Administration

has made mandatory the periodic blood lead deter-

minations of workers exposed to ambient air lead

concentration of 50 mgm

3

for over 30 days per

year. If workers have blood lead levels exceeding

40 mgdl

1

(1.9 mmol l

1

), the employer is obliged to

remove the employees from excessive exposure until

blood lead concentrations fall below 40 mgdl

1

(1.9 mmol l

1

). The US EPA requires that the

lead content of air be less than 1.5 mgm

3

, of un-

leaded petrol 0.01 g l

1

(0.05 g per US gal), and

of leaded petrol 0.03 g l

1

(0.10 g per US gal). In the

USA the maximum amount of lead permitted in water

is 50 mgl

1

, but this may be reduced to 5 mgl

1

. The

US Food and Drug Administration Advisory Panel

suggests that no more than 100 mg of lead per day be

consumed from food, and the Consumer Product

Safety Commission suggests that the lead content

HEAVY METAL TOXICOLOGY 3051

of paint be no more than 0.06% (600 p.p.m.) dry

weight.

Management of Lead Poisoning

0014 Management of lead poisoning involves separation of

the patient from the lead source, identification and

treatment of anyone exposed to the source, and iden-

tification and correction of other nutrient deficiencies

such as those of iron, zinc, and calcium. Aggressive

screening of the population is also required. A recent

survey of blood lead levels in Galveston, Texas in

1570 children 6 months to 8 years of age revealed

that 19% of them had blood lead concentrations

10 mgdl

1

(0.5 mmol l

1

). Chelation therapy with

oral dimercaptosuccinic acid should be started in

anyone with a blood lead concentration of 25–55 mg

1

(1.2–2.65 mmol l

1

). Two more recent oral

chelating agents are dimercaptosuccinic acid and

2,3-dimercaptopropane-1-sulfonate; the latter is not

commercially available in the USA. Both are water-

soluble derivatives of dimercaprol, a chelating agent.

A mobilization test using a chelator and noninvasive

measurement of bone lead content by K-type X-ray

fluorescence may be performed in selected patients

above 18 years of age due to reproducibility of

measurements based on bone calcium. (See Lead:

Properties and Determination; Toxicology.)

Cadmium

Toxicity in Humans and Animals

0015 Humans can be exposed to cadmium through either

diet or industrial contact. The placenta is generally

an efficient barrier against transmission of cadmium

from an occupationally exposed mother to fetus.

However, exposed mothers may exhibit hypertension

during pregnancy and give birth to small-for-gesta-

tional-age infants with high blood cadmium concen-

tration. Placental function may also be adversely

affected as the presence of cadmium in human pla-

cental cultures decreases microvillous vesicle uptake

of a-aminoisobutyric acid, a neutral amino acid. In

addition, there is increased placental cadmium in

women smokers. Thus cadmium may be one of the

factors involved in the relationship between low-

birth-weight babies and maternal smoking.

0016 In the Jinzu river basin in Toyama Prefecture in

Japan, primarily premenopausal women consuming

a low-calcium diet were exposed to excessive cad-

mium as a contaminant of water and rice. These

women developed itai-itai disease, manifested by

bone pain, osteoporosis, pseudofractures, and a

higher incidence of renal disease, including protein-

uria (a- and b-microglobulin) and glycosuria. Other

nonindustrial exposures have occurred in the past

from leaching of cadmium from cadmium-plated con-

tainers by acidic drinks such as fruit juices. Cadmium-

plated containers are now banned by public health

laws in many American states.

0017Among the symptoms of chronic cadmium food

poisoning are increased salivation, persistent

vomiting, abdominal pain, and diarrhea. Also of con-

cern is renal tubular damage. Since cadmium absorp-

tion is only 2–8% of dietary intake, and acute

cadmium ingestion is almost always followed by

vomiting, most clinically significant cadmium expos-

ure occurs by inhalation of fumes or dust. Respiratory

absorption of cadmium has been reported as any-

where from 12 to 30%. However, it is the total

inhaled cadmium that is most likely to result in toxi-

city. Symptoms of acute toxicity include dyspnea,

uncontrollable cough, cyanosis, followed by fever,

gastrointestinal symptoms including abdominal

pain, diarrhea, and vomiting, emphysema, and heart

failure. In nonfatal cases the first symptoms are often

throat irritation and chest soreness. Also experienced

are headaches, nausea, vomiting, diarrhea, chills

and weakness. In chronic respiratory exposure, fa-

tigue, anosmia, dyspnea, weight loss, anemia, renal

tubular dysfunction, hepatic dysfunction, and bone

marrow involvement have been reported. The most

prominent features are emphysema and proteinuria.

Urinary cadmium excretion of approximately 200 mg

(1.78 mmol) per day and a concentration of 200 mgof

cadmium per gram of renal cortical tissue is associ-

ated with tubular proteinuria. Chronic rhinitis, osteo-

porosis, and pseudofractures may also be seen. A

recent study in rats suggests that cadmium-associated

nephrotoxicity may be mediated by oxidative stress-

induced proteolysis of sodium–potassium adenosine

triphosphatase. Mouse studies have shown that cad-

mium administration reduces the erythrocyte count

and interleukin-1b and tumor necrosis factor, both of

which would play a role in producing osteoporosis.

0018There is epidemiological evidence that cadmium

exposure may be carcinogenic. A study of a cohort

of 600 workers exposed to cadmium in a smelting

plant for at least 6 months between 1940 and 1978

revealed a higher mortality rate from respiratory tract

cancers than the rate in the general US population.

Workers exposed for more than 2 years had an even

greater mortality rate.

0019In animals, the range of toxic effects is greater.

They include the following: testicular necrosis;

placental destruction; abortion; fetal resorption or tera-

togenic malformation, including exencephaly, renal

tubulopathy and glycosuria; liver damage; dental

changes; deficiencies of calcium iron, copper, and

zinc; skeletal decalcification; anemia; haemorrhagic

3052 HEAVY METAL TOXICOLOGY

lesions of sensory ganglia; hypertension; pulmonary

edema; and emphysema. In animals, cadmium is

transiently bound to an unidentified plasma compon-

ent and then appears in erythrocytes as whole blood

concentration rises.

0020 After ingestion or injection, cadmium is taken up

by most tissues, but liver and kidney contain 50–75%

of total body burden. Among the chief histopatho-

logical changes are peribronchial and perivascular

fibrosis and emphysema in the lungs, and fatty

infiltration of kidney and liver. Chronic exposure in

rats is manifested by weight loss, anemia, leukocyto-

sis, and infertility. Sarcomas have been observed at

the site of subcutaneous injection of cadmium

powder to rats.

0021 Cadmium also produces neurological toxicity in

some species. Cadmium crosses the blood–brain

barrier more readily in neonatal rats than in adult

rats. In vitro cadmium serves as a blocking agent at

both adrenergic and cholinergic synapses. Adult rats

given an intraperitoneal injection of cadmium show

decreased exploration responses up to 9 days after

cessation of cadmium dosing. A single intraventricu-

lar injection of cadmium to rats causes alterations in

neurotransmitter levels throughout the brain. In add-

ition, some fish show abnormal behavior after cad-

mium exposure via water contamination. In kidney

and liver, cadmium binds to metallothionein. When

intracellular accumulation exceeds metallothionein-

binding capacity, toxicity is thought to occur. There

is also a recent report suggesting that metallothionein

may be protective against various toxic effects of

cadmium.

Place in the Food Chain

0022 Cadmium is found primarily as cadmium sulfide in

ores containing zinc, lead, and copper. Cadmium

volatilizes more rapidly than other metals when the

ore is being smelted, and it condenses to form fine

airborne particles that react immediately with oxygen

to form cadmium oxide fumes. Cadmium is used

industrially to plate other metals, in pigments, batter-

ies, stabilizers for plastics, metallurgy, nuclear reactor

rods, and semiconductors. Cadmium is deposited in

soil and water near the industrial source. It is taken up

by various marine organisms, especially plankton,

molluscs, and shellfish. Brown meat of edible crabs

may contain as much as 5–15 mg of cadmium per kg.

Certain sea birds, both plankton-eating and fish-

eating, have high liver cadmium levels – 20–50 mg

per kg wet weight. Otherwise, there is no significant

cadmium concentration in marine food chains since

cadmium is toxic to fish and fish embryos.

0023 Cadmium is a normal plant constituent and can be

absorbed through both leaves and roots. Plants have

no excretory mechanism for cadmium. Cadmium

from soil is freely exchangeable, especially from acid

soils, but its concentration there is normally low –

0.02–0.5 mgkg

1

. However, cadmium may be high in

plants grown near the contaminating industrial site.

Accumulation is greater at the roots than at the top

of the plant, restricting the movement of cadmium

through food chains. In domestic animals reared for

human consumption the cadmium burdens are low.

In cattle and other mammals the mammary gland is

an efficient barrier to cadmium since only small

amounts (1 mgdl

1

) are excreted in milk.

Significance of Levels in the Diet

0024In foodstuffs of animal origin, cadmium is present

bound to metallothionein. Its bioavailability after

exposure to gastric acid is unknown. Plankton and

shellfish have the highest levels of cadmium. After

absorption, cadmium is transported to tissue, where

it binds to metallothionein, leaving the blood concen-

tration less than 1 mgdl

1

(0.1 mmol l

1

). Estimates of

biological half-life are 17–33 years in human kidney

and approximately 7 years in liver. The absorption of

cadmium antagonizes, and is antagonized by, zinc,

copper, ferrous and ferric ions, and calcium. Zinc

and selenium protect against many acute effects of

cadmium in animals, including testicular necrosis,

placental damage, and teratogenicity. Copper pre-

vents cadmium-induced anemia. Conversely, with

marginal copper intake (3 mg kg

1

diet), low cad-

mium levels (1.5 mgkg

1

diet) interfere with copper

metabolism in rats and reduce plasma ceruloplasmin

activity. Higher intakes of cadmium (6–18 mgkg

1

diet) exacerbate those effects and reduce bone density.

The presence of cadmium at a concentration of

12 mgkg

1

in the maternal diet reduces copper stor-

age in newborn lambs. The mechanism of cadmium

antagonism to zinc and copper is unknown but may

involve competition for transport sites on metallo-

thionein. Iron transport in chicken duodenum is

significantly reduced by dietary cadmium. In

addition, calcium deficiency may increase dietary

cadmium uptake. Furthermore, cadmium may in-

hibit conversion of 25-hydroxyvitamin D to 1,25-

dihydroxyvitamin D, the biologically active form

which acts as a steroid hormone.

Intake Limits

0025A lethal dose of cadmium following dust or fume

exposure is 0.1 mg m

3

of air for 1 h. The US

NIOSH occupational exposure limit is 5 mgm

3

air

level per 40-h week. The amount of atmospheric

cadmium inhaled by chronically exposed workers

varies widely and cannot be correlated at any one

HEAVY METAL TOXICOLOGY 3053

time with atmospheric cadmium. A study of 53 jig

solderers in the UK showed that 32 workers

employed (exposed) for more than 5 years and 11 of

21 exposed for less than 5 years had elevated blood

and urine cadmium levels. Thirty of the 43 workers

with elevated cadmium levels had urine cadmium

concentrations exceeding 10 nmol mmol

1

creati-

nine. Normal daily urinary cadmium excretion is

2–5 mg (0.02–0.045 mmol), while in unexposed indi-

viduals normal blood cadmium is less than 1 mgdl

1

(0.1 mmol l

1

0026 Kidney cadmium, as measured in vivo by neutron

activation, increased linearly to 15 years of exposure

and then reached a plateau. Liver cadmium content

increased linearly up to 20 years of exposure. Urinary

-microglobulin and retinol-binding protein were

greater than the 95th percentile in 20 of 51 subjects.

In 9 of the 20, urine protein values were less than

twice the upper normal limit, suggesting tubular dys-

function. Both proteins remained within the normal

range for up to 15 years of exposure and then in-

creased dramatically. Urinary albumin concentration,

a marker of glomerular function, was normal in 48 of

51 subjects. Blood and urinary cadmium concentra-

tions by themselves are only indications of recent

exposure, not of cadmium toxicity. Thus in vivo

neutron activation measurements of tissue cadmium

may be a better indicator of toxicity.

Management

0027 The dithiocarbamates appear to be more effective

than either dimercaprol or calcium disodium ethy-

lenediaminetetraacetic acid (EDTA) in chelating

cadmium in animals. In humans, calcium disodium

EDTA has been used, as have dimercaprol, d-

penicillamine, and diethyldithiocarbamate (a metab-

olite of disulfiram). Diethylenetriaminepentaacetic

acid also increases renal cadmium excretion. (See

Cadmium:PropertiesandDetermination;Toxicology.)

Mercury

Toxic Effects in Humans and Animals

0028 Mercury may enter the body in two forms:

inorganic mercury, absorbed through skin, or from

vapor escaping from mercury-containing ‘silver’

dental amalgam, or through the gastrointestinal

tract as an organic salt, primarily of methyl mercury.

In children, a symptom complex called acrodynia

develops, consisting of redness of lips, throat, and

tongue, loss of teeth, swelling, and redness of the

skin with pink-red fingertips, palms, and soles.

Redness of the conjunctival membranes of the eye

and photophobia, enlarged cervical lymph nodes,

joint pain, anorexia, and vascular thrombosis are

also described. Effects on the nervous system include

irritability, withdrawn behavior, proximal muscle

weakness, loss of muscle tone, and reduced tendon

reflexes.

0029Occupational exposure to mercury vapor in adults

can give rise to acute respiratory distress and renal

failure, as well as flu-like symptoms. With more pro-

longed exposure the chief manifestation is proteinuria

resulting from renal tubular damage. This is thought

to be caused by a mercury-induced autoimmune

response. With long-term mercury vapour exposure

in some workers, neurological symptoms develop,

including reduced muscle strength and coordination,

decreased sensation, and an increase in abnormal

reflexes. In individuals who consumed fish contamin-

ated by mercury from an industrial plant near Mina-

mata Bay in Japan and those in Iraq who consumed

bread made from wheat contaminated by a mercury-

containing fungicide, symptoms of methyl mercury

poisoning were primarily neurological, severe, and

irreversible.

0030Exposed infants developed cerebral palsy-like

symptoms, including psychomotor retardation,

microcephaly, flaccid or spastic paralysis, unsteady

gait, abnormal hand motions, visual field narrowing,

and tonic convulsions. Exposure of pregnant women

led to fetal toxicity, including low birth weight, cere-

bral and cerebellar histopathology, and severe mental

retardation. Mercuric chloride can produce DNA

damage in a human fetal hepatic cell line, as can

lipid peroxidation.

0031In animals, mercury toxicity is much the same as in

humans. Additional insights into the pathophysiology

of mercury have been obtained. Thus mercuric chlor-

ide injection into rats can produce renal proximal

tubular necrosis. However, in the brown Norway rat,

mercuric chloride produces antiglomerular basement

membrane antibodies, antiproximal tubular base-

ment membrane antibodies, alterations in helper

and suppressor T lymphocytes, and appearance of

autoantibodies in peritubular capillaries. With regard

to neurotoxicity, injection of pregnant rats with

methyl mercuric chloride resulted in appearance of

methyl mercury in the fetal nervous system within 2 h.

Early changes included mitochondrial degeneration

of the endothelium of cerebral capillaries, leading to

hemorrhaging, which distorts the pattern of neuron

development and migration. Methyl mercury is also

believed to disrupt neuronal microtubular assemblage

and to interact with sulfhydryl groups of tubular

and membrane proteins, causing peroxidative injury.

Inhaled mercury can cause respiratory distress and

death in mice who lack metallothionein; the latter

may be protective, as it is with lead.

3054 HEAVY METAL TOXICOLOGY

Sources of Mercury

0032 Inorganic mercury is primarily inhaled as dust or

vapor from dental amalgams or industrial processing.

When inorganic mercury is released into either fresh

or salt water, it is converted to methyl mercury by

methanogenic bacteria and enters the aquatic food

chain. Two major epidemics of methyl mercury

poisoning in Japan occurred as a result of consump-

tion of contaminated fish from Minamata Bay in

Japan following release into the bay of mercury-

contaminated waste from an acetaldehyde plant.

Agricultural contamination may occur as a result of

the use of mercury-contaminated pesticides, such as

occurred in Iraq. Finally, poultry products and eggs

from hens raised on mercury-contaminated fish meal

have varying quantities of mercury. Most of the

poultry products fall within the Food and Agriculture

Organization/World Health Organization (FAO/

WHO) limits for acceptable mercury contents of

foods other than fish.

0033 Recently, the adjuvant of the hepatitis B vaccine as

well as hepatitis B immune globulin were identified

as being contaminated with mercury. Corrective

measures are now being taken.

Significance of Levels in the Diet

0034 Dietary intake of mercury is generally not well

documented outside of major epidemics. FAO/WHO

limits for dietary mercury intake are 0.3 mg mercury

per person per week, of which no more than 0.2 mg

mercury should be present as the methyl mercury ion.

Seafood is probably the primary source of dietary

contamination with mercury. Acid rain has increased

mercury concentration in the edible tissues of fish,

resulting in the closure of many American lakes and

rivers to sport fishing. Furthermore, shark and

swordfish sales have been restricted because of the

high mercury content of these fish. Most poultry

products fall below FAO/WHO acceptable limits of

mercury of 50 p.p.b. In addition, children, especially

toddlers, mouth objects contaminated with soil or

household dust, either of which might be mercury-

contaminated.

Intake Limits

0035 Whole-blood mercury levels greater than 50 nmol l

1

(1 mgdl

1

) or urinary mercury concentration of

greater than 100 nmol l

1

(20 mgl

1

) indicate recent

mercury ingestion or inhalation. Symptoms of acro-

dynia have been reported in toddlers with urinary

mercury concentration of 249 nmol l

1

(50 mgl

1

Whole-blood mercury levels in cases of acute occupa-

tional exposure, with nephrotoxicity and neurotoxi-

city, have been reported to be 24 and 27 mmol l

1

(48

and 54 mgdl

1

). Hair mercury content is reported to

be a reliable indicator of methyl mercury load. Distri-

bution of hair and whole-blood mercury concentra-

tions are in equilibrium, with hair mercury being

about 250 times greater than whole-blood mercury.

Treatment of choice at present is chelation with

dimercaptosuccinic acid to reduce the body burden

of mercury. (See Mercury: Properties and Determin-

ation; Toxicology.)

Other Heavy Metals

Nickel

0036Toxicity Nickel is a heavy transition metal, atomic

weight 58.69, to which the general population is

exposed primarily as an industrial emission rather

than as a dietary component or contaminant. Its con-

centration in the ambient air in the vicinity of indus-

trial plants is generally less than 1 mgm

3

, and this is

not considered dangerous to the general public. How-

ever, workers exposed to nickel dust in industries such

as stainless-steel and nickel alloy production, electro-

plating, and battery and coinage manufacture are at

risk of developing respiratory or nasal neoplasms.

Extensive epidemiological studies of cohorts of nickel

workers suggest that prolonged exposure to oxides

and sulfides of nickel in ambient concentrations

exceeding 1 mg m

3

is associated with increased risk

of lung and nasal tumors. Pulmonary tissue nickel

concentration in one study in Germany showed that

in high nickel-emission areas in the Ruhr valley

pulmonary nickel was threefold greater than in a

low-exposure population. Pulmonary nickel concen-

tration in 6 patients who developed bronchial carcin-

oma ranged from 0.6 to 20.6 mgg

1

dry weight,

compared to concentrations in low-exposure control

lungs of 0.04–0.36 mgg

1

dry weight of lung tissue.

Half-life studies performed in rats exposed to

nickel monosulfide by aerosol inhalation revealed a

20-h half-life in the rat lung. This contrasted with

a 221-month half-life for green nickel oxide. No ma-

lignancies were seen with the shorter half-life. The

mechanism for the causation of respiratory malignan-

cies is uncertain, but may involve nickel induction of

chromosome abnormalities and oncogene amplifica-

tion, as occurs in the production of experimental

renal tumors in rats given nickel subsulfide. It has

also been shown in rats that nickel administration

results in a decreased number of antibody-forming

cells in lung-associated lymph nodes, suggesting that

alteration of the immune response may play a role in

tumorigenesis. In another study, administration of

nickel to women showed an increase in serum levels

of interleukin-5 4 h after ingestion and a decrease in

HEAVY METAL TOXICOLOGY 3055

CD4 and increase in CD8 lymphocytes 24 h after

nickel inhalation. Antioxidants may have a protective

effect.

Bismuth

0037 Bismuth is primarily ingested as an antiulcer medica-

tion in the form of colloidal bismuth subcitrate or

colloidal bismuth subsalicylate.

0038 Toxicity in humans There have been many reports

of neurotoxicity in Europe and Australia in individ-

uals ingesting large quantities of bismuth subcitrate

or subgallate. There have been isolated cases of pa-

tients taking large doses of bismuth subsalicylate and

subcitrate, both without impaired renal function. Al-

though bismuth is reported to be poorly soluble in

biological fluids, solubility in digestive secretions is

increased by the presence of urine or ascorbic acid.

Neurotoxic manifestations include numbness and

tingling of the extremities, irritability, insomnia,

poor concentration, impaired short-term memory,

tremors, ataxia, and abnormal electroencephalo-

graphic tracings. These symptoms are reversible

with discontinuation of the bismuth compounds

and with the use of a chelating agent, such as 2,3-

dimercapto-1-propane sulfonic acid. Nephropathy

following bismuth overdose has also been reported,

as has osteoarthropathy. One case of acute reduction

in blood platelets has also been reported with bismuth

subcitrate. This effect may have been the result of an

idiosyncratic drug reaction.

0039 Distribution and toxicity in animals Animal studies

indicate that most absorbed bismuth accumulates in

the kidneys and only trace amounts in the brain.

Tissue distribution of bismuth in humans is unknown.

Experimental bismuth neurotoxicity has been

produced in mice. Reproduction of tremors, ataxia,

myoclonus, and convulsions was associated with

hydrocephalus and an average of 8 mg bismuth per

gram of brain tissue. Animals with brain bismuth

concentration of 4 mgg

1

did not show evidence of

neurotoxicity but did manifest hydrocephalus with

no other histopathology. When brain bismuth

concentration was 1 mgg

1

there was no evidence of

hydrocephalus, neurotoxicity, or histopathology.

0040 Sources of bismuth Average dietary intake in

humans is not well quantified, but is probably < 5 mg

day

1

. It is poorly absorbed from the gastrointestinal

tract, but with chronic medication small amounts can

accumulate in blood, although generally this amount

does not exceed 50 mgl

1

. The rate of urinary clear-

ance of bismuth when ingested in the subcitrate form

decreases by approximately 2.6% per day and

reaches a steady state by 2 weeks after discontinu-

ation of the compound. However, persistence of urin-

ary bismuth concentration of as much as 250 mgl

1

(1.2 mmol l

1

) suggests that there is tissue accumula-

tion of bismuth, and slow mobilization.

0041Intake limits Data from over 1000 cases of bismuth

neurotoxicity in France suggest that a whole-blood

bismuth level greater than 180 mgl

1

(0.86 mmol l

1

)

is associated with neurotoxicity; if whole-blood

bismuth concentration is greater than 100 mgl

1

(0.48 mmol l

1

), bismuth compounds should be dis-

continued. With whole-blood levels between 50 and

100 mgl

1

(0.25–0.48 mmol l

1

), individuals should

be monitored for signs of neurotoxicity, and if less

than 50 mgl

1

, no monitoring is needed.

See also: Cadmium: Properties and Determination;

Toxicology; Lead: Properties and Determination;

Toxicology; Mercury: Properties and Determination;

Toxicology

Further Reading

Agency for Toxic Substances and Disease Registry (1988)

The Nature and Extent of Lead Poisoning in Children in

the United States; A Report to Congress.

Bierer DW (1990) Bismuth subsalicylate: history, chemistry

and safety. Reviews of Infectious Diseases 12 (suppl. 1):

S3–S8.

Browning E (1969) Toxicity of Industrial Metals, pp.

98–103. Oxford: Butterworth Heinemann.

Cooper GP and Manalis RS (1983) Influence of heavy

metals on synaptic transmission: a review. Neurotoxi-

cology 4: 69–83.

Froomes PR, Wan AT, Keech AC et al. (1989) Absorption

and elimination of bismuth from oral doses of tripotas-

sium dicitrate bismuthate. European Journal of Clinical

Pharmacology 37: 533–536.

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.

Mertz W (ed.) (1987) Trace Elements in Human and

Animal Nutrition, 5th edn, vols I and II. London:

Academic Press.

National Institute for Occupational Safety and Health

(1978) Occupational Health Guidelines for Chemical

Hazards, pp. 1–5. Cincinnati: US Department of Health

and Human Services.

National Institute for Occupational Safety and Health

(1984) Cadmium (Cd). Current Intelligence Bulletin

42, pp. 1–9. Cincinnati: US Department of Health and

Human Services.

Needleman HL, Schell A, Bellinger D et al. (1990) The

long-term effects of exposure to low doses of lead in

3056 HEAVY METAL TOXICOLOGY

childhood. An 11-year follow-up report. New England

Journal of Medicine 322: 83–88.

Report of the International Committee on Nickel Carcino-

genesis 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 Envir-

onmental Medicine, pp. 1–20. Atlanta: US Department

of Health and Human Services, Public Health Service.

Shukla G and Singhal R (1983) The present status of bio-

logical effects of toxic metals in the environment: lead,

cadmium, manganese. Canadian Journal of Physiology

and Pharmacology 62: 1015–1031.

Smith NJ, Topping MD, Stewart JD and Fletcher JI (1986)

Occupational cadmium exposure in jig solderers. British

Journal of Industrial Medicine 43: 663–666.

Wagstaff AJ, Benfield P and Monk JP (1988) Colloidal

bismuth subcitrate. A review of its pharmacodynamic

and pharmacokinetic properties and its therapeutic use

in peptic ulcer disease. Drugs 36: 132–157.

Webb M (1975) Cadmium. British Medical Bulletin 31:

246–250.

HEMAGGLUTININS (HAEMAGGLUTININS)

G P Savage, Lincoln University, Canterbury,

New Zealand

This article is reproduced from Encyclopaedia of Food Science,

Background

0001 The presence of heat-labile toxic factors in plant

products, mainly in leguminous seeds, makes them

unsuitable as food for humans unless they are

properly cooked. There is evidence, however, that

leguminous seeds were an important part of the

diet of prehistoric man, and the use of fire for

cooking must have had an important bearing on the

safe use of leguminous seeds in the diet. In the late

eighteenth century, it was noticed that plant lectins,

or phytohemagglutinins (hemagglutinins) occurred in

castor bean seeds and that these compounds could

agglutinate red blood cells. (See Legumes: Dietary

Importance.)

0002 The ingestion of raw or incompletely cooked beans

regularly leads to incidents that at first appear to be

cases of food poisoning. When no causative organism

appears to be involved, high concentrations of hemag-

glutinins are usually implicated. Vomiting and diar-

rhea usually occur within 2–3 h after consumption.

As few as four or five beans are often the cause. In

many instances, the beans have been soaked for a few

hours and then eaten without further cooking.

General Properties

0003 Hemagglutinins are proteins that possess a specific

affinity for certain sugar molecules. Since carbohy-

drate units exist in most animal cell membranes, the

hemagglutinins may attach to these receptor groups.

This attachment will occur only if the lectin molecule

has at least two active groups. Hemagglutinins are

characterized and detected by their action on red

blood cell membranes, causing the blood cells to

clump together. Other cells can also be affected. The

receptor site on the cell surface must be exposed in

order to react with a specific lectin. Pretreatment of

red blood cells with a protein-digesting enzyme, such

as papain, trypsin, or pronase, activates the cells and

presumably exposes the receptor sites.

Structure

0004All plant lectins are proteins. Some contain a range of

covalently bound sugars and can therefore be called

glycoproteins. Lectins from different legumes show

a remarkable range of specificity towards various

animal red blood cells, which suggests that there is a

considerable range of structures in this group. (See

Protein: Food Sources.)

Location

0005Most hemagglutinins of higher plants are found in

seeds, but tubers and plant sap are also sources of

lectins. Lectins are most commonly found in legum-

inous seeds. They have been observed in potatoes and

cereals, but the amounts in these foods do not appear

to have any adverse effects.

Lectin Content of Edible Leguminous

Seeds (see Table 1)

0006The seeds of a wide range of edible legumes are

known to contain proteins that agglutinate red

blood cells. Some of these hemagglutinins have been

suggested to contribute to the poor nutritive value of

raw beans. The level of toxicity of kidney beans has

HEMAGGLUTININS (HAEMAGGLUTININS) 3057

been shown to be directly related to the lectin content

and hence hemagglutinating activity. Using rat

growth experiments and hemagglutinin tests on a

range of leguminous seed lines available in the UK,

leguminous seeds have been classified into four broad

groups. In this study, group A seeds from most var-

ieties of kidney (Phaseolus vulgaris), runner (P. cocci-

neus) and tepary (P. acutifolius) beans showed high

reactivity with red blood cells from a range of differ-

ent species and were also highly toxic (none of the

rats survived the feeding experiment). Group B con-

tained seeds from lima or butter beans (Phaseolus

lunatas) and winged bean (Phosphocarpus tetagono-

lobus), and they agglutinated only human and prona-

setreated rat erythrocytes. The seeds did not support

proper growth, but the animals did survive the feed-

ing experiment. Seeds included in group C were

lentils (Lens culinaris), peas (Pisum sativum), chick-

peas (Cicer arietinum), black-eye peas (Vigna

sinensis), pigeon peas (Cajanus cajan), mung beans

(Phaseolus aureus), field or broad beans (Vicia faba),

and adzuki beans (Phaseolus angularis). These

generally had a low reactivity with all cells and were

nontoxic. Group D contained soya (Glycine max)

and pinto (Phaseolus vulgaris) beans, which generally

had a low reactivity with all cells but caused

growth depression at certain levels of inclusion in

the diet. It was thought that the growth depression

in this group was due to antinutritive factors

other than lectins. The experiment showed that no

single erythrocyte type could be used as a sole indica-

tor of toxicity. The potential toxicity could, however,

be predicted from the response to various erythro-

cytes. The usefulness of animal feeding trials was

clearly shown by these experiments. (See Beans;

Peas and Lentils.)

Assay Methods

0007The detection of lectins in plant extracts is generally

performed by a serial dilution technique followed by

visual estimation of the end point. Washed red blood

cells are activated by pretreatment with a suitable

proteinase (pronase, trypsin, papain), and the test is

always carried out in saline solution (0.9%). A more

quantitative method is based on the photometric meas-

urement of the density of red blood cells that have not

been agglutinated by the extracted lectin. Hemaggluti-

nin activity is usually expressed as hemagglutinin units

per milligram of sample. One unit is usually defined as

the lowest amount of sample required for agglutin-

ation under the test conditions, but has also been

defined as the amount of material per milliliter in the

last dilution giving 50% agglutination.

0008The rather subjective nature of this test makes it

quite difficult to compare results between different

research centers, but it gives good results in the

hands of experienced workers. Many workers use a

standard reference material to calibrate their own

experiments. Wide use of a reference sample between

research centers would make comparison of pub-

lished data more feasible.

Biological Effects of Hemagglutinins

0009The in vitro precipitation of red blood cells does not

explain the in vivo effects of lectins. Lectins cause

agglutination or ‘clumping together’ of cells by bind-

ing to the saccharides branching from lipid and pro-

tein molecules of the cells’ outer surface. A definite

relationship between the lectin content of legume-

containing diets and the nutritive value has been

made. The feeding of lectin preparations from some

legumes has been shown to cause definite growth

retardation and, in extreme cases, death. In contrast,

it has been shown that white pea hemagglutinin has

no growth-depressing or toxic effects on rats when

fed at a level of 1% in the diet.

0010Many ingested lectins cause toxicity by binding to

the surface of intestinal epithelial cells, which results

in the reduced absorption of nutrients across the in-

testinal wall. Suppression of intestinal disaccharidase

activity and proteolytic activity has also been ob-

served. Since the disaccharidases are involved in the

breakdown of carbohydrates to monosaccharides

prior to absorption in the small intestine, their re-

duced activity would be expected to lead to reduced

digestibility of dietary carbohydrates. The decreased

proteolytic activity would also lead to reduced avail-

ability of amino acids and peptides for absorption.

The growth inhibition caused by lectins can therefore

be attributed to the reduction in absorption of

tbl0001 Table 1 Hemagglutinin content of a number of legumes

Legume Hemagglutinin

(units per gram

dry wt)

Hemagglutinin removed

(%) on soakinginwater

for18 h

Phaseolus vulgaris

Red kidney beans 37 000–53 000 22–66

White kidney beans 17 000–43 000 18–36

Rose coco beans 39 000 18

Lens culinaris

Red lentils 77 000 22

Green lentils 18 000 19

Split peas 1 000–16 000 11

Pisum sativum

Garden peas 5 100 65

Vigna sinensis

Black-eye beans 1 000 100

From Bender AE (1983) Haemagglutinins (lectins) in beans. Food

Chemistry 11: 309–320.

3058 HEMAGGLUTININS (HAEMAGGLUTININS)