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

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These seeds contain several lathyrogens, which cause

both neurological and skeletal abnormalities when

they are eaten in large amounts for an extended

period.

0033 Fungi Many species of poisonous mushrooms are

known. Harvesting mushrooms in the wild can

be a hazardous practice, even for those skilled in

mushroom identification. Several different types of

naturally occurring toxicants exist in poisonous

mushrooms.

0034 The most hazardous of the mushroom toxins are

the Group I toxins. Amatoxin is the best example and

is produced by Amanita phalloides, the so-called

death cap mushroom. The symptoms of amatoxin

poisoning begin 6–24 h after ingestion of the mush-

rooms. The first stage of the intoxication involves the

gastrointestinal tract with abdominal pain, nausea,

vomiting, diarrhea, and hyperglycemia. A short

period of remission follows. The third and often

fatal stage of the illness involves severe liver and

kidney dysfunction with symptoms including abdom-

inal pain, jaundice, renal failure, hypoglycemia, con-

vulsions, coma, and death. Death from hypoglycemic

shock occurs 4–7 days after the onset of symptoms.

Recovery is possible but requires at least 2 weeks of

intensive therapy.

0035 The Group II toxins are hydrazines, with gyromi-

trin being the premier example, which is produced by

Gyromitra esculenta mushrooms. Usually, the symp-

toms include a bloated feeling, nausea, vomiting,

watery or bloody diarrhea, abdominal pain, muscle

cramps, faintness, and a loss of motor coordination

occurring 6–12 h after consumption.

0037 The classic example of a Group III toxin is coprine,

which causes symptoms only when ingested with al-

coholic beverages. Symptoms begin about 30 min

after consumption of alcohol along with mushrooms

containing Group III toxins such as Corpinus atra-

mentarius. Symptoms include flushing of the face and

neck, distension of the veins in the neck, swelling and

tingling of the hands, metallic taste, tachycardia, and

hypotension, progressing to nausea and vomiting.

Symptoms can last for up to 5 days.

0036 The Group IV toxins, characterized by muscarine,

affect the autonomic nervous system. Symptoms in-

clude perspiration, salivation, and lacrimation with

blurred vision, abdominal cramps, watery diarrhea,

constriction of the pupils, hypotension, and a slowed

pulse. Death does not usually occur unless the Group

III toxins are present in a mushroom such as fly agaric

(Amanita muscarina), which also contains Group I

toxins. With fly agaric, a fatal combination of symp-

toms can occur.

0038The Group V and VI toxins act primarily on the

central nervous system to cause hallucinations. The

Group V toxins include ibotenic acid and muscimol,

which cause dizziness, incoordination, staggering,

muscular jerking and spasms, hyperkinetic activity, a

coma-like sleep, and hallucinations beginning 30 min

to 2 h after ingestion. Fly agaric, in addition to its

content of Group I and Group IV toxins, is also a

good source of Group V toxins. The Group VI toxins

include psilocybin and psilocin, whose symptoms

include pleasant or aggressive mood, unmotivated

laughter and hilarity, compulsive movements, muscle

weakness, drowsiness, hallucinations, and sleep.

Symptoms usually begin 30–60 min after ingestion

of the mushrooms, and recovery is often spontaneous.

Psilocybe mexicana, the so-called Mexican mush-

room, is a well-known source of the Group VI toxins.

Although Mexican mushrooms (also known as magic

mushrooms or simply ’shrooms’) have been used as

recreational drugs for their hallucinogenic effects, it

must be recognized that the dose of the Group VI

toxins in these mushrooms varies widely (more than

100-fold). Exposure to high amounts of the Group VI

toxins has led to prolonged and severe side-effects,

even death. Often, patients experience persistent

sequelae and are admitted to mental institutions.

(See Mushrooms and Truffles: Classification and

Morphology.)

Naturally Occurring Constituents Eaten in

Abnormally Large Amounts

0039The dose of a toxic chemical is the major determinant

of the degree of hazard that it poses in the diet. Many

naturally occurring foodborne toxicants are present

at levels that do not constitute a hazard to normal

consumers eating a normal diet. However, if un-

usually large amounts of foods containing these toxi-

cants are consumed, intoxication may occur. One

classic example is the presence of cyanogenic glyco-

sides in lima beans and cassava.

0040Many plants contain cyanogenic glycosides, which

are sugars that can release cyanide on exposure to

certain enzymes present in the plant tissues or by

acid in the stomach of the consumer. Linamarin in

lima beans is one example of a cyanogenic glycoside.

Commercial varieties of lima beans contain very little

linamarin, but wild lima bean varieties can have sub-

stantial amounts. Cyanide is a classic toxicant that

binds to heme proteins in the mitochondria and

hemoglobin in the blood. Cyanide prevents oxygen

binding to hemoglobin, thus causing cyanosis, notice-

able as a bluish discoloration of the skin and mucous

membranes. It also inhibits cellular respiration by

binding to the mitochondrial heme proteins. The

5818 TOXINS IN FOODS – NATURALLY OCCURRING

symptoms of cyanide poisoning include the rapid

onset of peripheral numbness and dizziness, mental

confusion, stupor, cyanosis, twitching, convulsions,

coma, and death. Cyanide is rapidly absorbed, and

the lethal dose is 0.5–3.5 mg of cyanide per kilogram

of body weight. Commercial lima bean varieties re-

lease about 10 mg of cyanide per 100 g of beans.

Assuming that the lethal dose is 0.5 mg kg

1

, a 70-

kg adult would need to ingest 35 mg of cyanide or

350 g of lima beans. Though this is not impossible, it

is certainly very unlikely.

0041 Cassava can release as much as 50 mg of cyanide

per 100 g of food. Cassava intake is substantial in

Africa and South America in certain locales when

other foods are scarce. The major source of cyanide

intoxication remains the intentional ingestion of fruit

pits that contain amygdalin, also known as laetrile,

under the mistaken belief that laetrile counteracts

cancer. The level of cyanogenic glycosides in fruit

pits is considerable, and several deaths have occurred

from their ingestion. (See Cassava: The Nature of the

Tuber.)

0042 In addition to the cyanogenic glycosides, plants

contain an enormous variety of other potentially haz-

ardous chemicals that are not typically evident unless

large quantities of these foods are eaten. Examples

include glycoalkaloids in potatoes and tomatoes, goi-

trogens in cruiciferous vegetables, nitrate in spinach,

celery, and lettuce, oxalates in rhubarb and spinach,

estrogens and saponins in soybeans, and tannins and

phytoalexins in many plant foods. Symptoms do

not occur after ingestion of these foods in typical

amounts.

Naturally Occurring Constituents Eaten by

Consumers with Genetic Abnormalities

0043 Some naturally occurring constituents of foods are

hazardous only for consumers with allergies or in-

tolerance to that food. Food allergies and intolerances

are the subject of a separate review in this volume.

(See Food Intolerance: Food Allergies; Milk Allergy.)

Naturally Occurring Constituents from Foods

Processed or Prepared in an Unusual Manner

0044 Many naturally occurring foodborne toxicants are

removed or inactivated during processing or prepar-

ation. For example, raw soybeans contain trypsin

inhibitors, lectins, allergens, amylase inhibitors, sap-

onins, and antivitamins along with other potentially

hazardous factors. However, humans never ingest

raw soybeans. The trypsin inhibitors and lectins are

inactivated by heating the soybeans. Fermentation in

the preparation of tofu destroys certain toxic factors

in soybeans. (See Trypsin Inhibitors.)

0045Intoxications have occurred from the ingestion of

undercooked or raw kidney beans. Kidney beans, like

soybeans, are legumes. They contain lectins, which

can bind to sugar residues on the surfaces of cell

membranes, causing hemolysis of red blood cells

and intestinal damage. The lectins from kidney

beans can be inactivated by thorough cooking. If

not inactivated, the lectins will cause nausea, abdom-

inal pain, vomiting, and bloody diarrhea. In England,

intoxications have occurred among immigrants un-

familiar with proper cooking practices for this

common item in the British diet. These consumers

simply soaked the raw beans and ate them with little

or no cooking, resulting in the prompt onset of gas-

trointestinal symptoms. (See Hemagglutinins (Hae-

magglutinins).)

See also: Aflatoxins; Alkaloids: Toxicology; Cassava:

The Nature of the Tuber; Clostridium: Botulism; Food

Additives: Safety; Food Intolerance: Food Allergies;

Milk Allergy; Hemagglutinins (Haemagglutinins);

Mushrooms and Truffles: Classification and

Morphology; Mycotoxins: Toxicology; Trypsin

Inhibitors; Staphylococcus: Food Poisoning

Further Reading

Beier RC and Nigg HN (1994) Toxicology of naturally

occurring chemicals in foods. In: Hui YH, Jr., Gorham

R, Murrell KD and Cliver DO (eds) Foodborne Disease

Handbook, Volume 3: Diseases Caused by Hazardous

Substances. New York: Marcel Dekker.

D’Mello JPF (1997) Handbook of Plant and Fungal Toxi-

cants. Boca Raton, FL: CRC Press.

National Research Council (1996) Carcinogens and Anti-

carcinogens in the Human Diet. Washington, DC:

National Academy Press.

Shibamoto T and Bjeldanes LF (1993) Introduction to Food

Toxicology. San Diego, CA: Academic Press.

Spoerke DG, Jr. (1994) Mushrooms: Epidemiology and

medical management. In: Hui YH, Jr., Gorham R, Mur-

rell KD and Cliver DO (eds) Foodborne Disease Hand-

book, Volume 3: Diseases Caused by Hazardous

Substances. New York: Marcel Dekker.

Taylor SL and Schantz EJ (1990) Naturally occurring toxi-

cants in foods. In: Cliver DO (ed.) Foodborne Diseases.

San Diego, CA: Academic Press.

Whittle K and Gallacher S (2000) Marine toxins. British

Medical Journal 56: 236–253.

TOXINS IN FOODS – NATURALLY OCCURRING 5819

TRACE ELEMENTS

F H Nielsen, USDA, ARS, Grand Forks Human Nutrition

Research Center, Grand Forks, ND, USA

Introduction

0001 In the earlier part of the 20th century, scientists could

qualitatively detect small amounts of several mineral

elements in living organisms. In reports, these elem-

ents were described as being present in ’traces’ or

’trace amounts.’ Not surprisingly, these elements

became known as trace elements. The trace elements

found in living organisms may be essential, i.e., indis-

pensable for performing functions necessary for life,

or they may be nonessential, fortuitous reminders of

our geochemical origins or indicators of environmen-

tal exposure. Some of the nonessential trace elements

can be beneficial to health through pharmacological

action. All the trace elements are toxic when intake is

excessive.

Definition of Trace Elements

0002 Presently, mineral elements considered to be trace

elements are those that occur in the body in mg kg

1

of body weight or less amounts. Essential trace

elements are generally required by humans in mg

day

1

amounts. Since 1980, the term ’ultratrace

element’ has appeared in the nutritional literature.

Ultratrace elements have been defined as those elem-

ents with estimated dietary requirements usually less

than 1 mg kg

1

, and often less than 50 mgkg

1

of diet

for laboratory animals. For humans, the term is often

used to indicate an element with an established,

estimated, or suspected requirement of less than

1 mg day

1

, or generally indicated by mg day

1

Essential and Possibly Essential Trace

and Ultratrace Elements

0003 In the 1960s and 1970s, the standard to establish

a nutrient as essential was liberalized for mineral

elements that could not be fed in amounts low enough

to cause death or interrupt the life cycle (interfere

with growth, development, or maturation such that

procreation is prevented). Thus, an essential element

during this time period was defined as one whose

dietary deficiency consistently and adversely changed

a biological function from optimal, and this change

was preventable or reversible by physiological

amounts of the element. This definition of essentiality

became less acceptable when a large number of elem-

ents was suggested to be essential based on small

changes in physiological or biochemical variables.

Many of these changes were questioned as to whether

they were necessarily the result of a suboptimal func-

tion, and sometimes were suggested to be the conse-

quence of a pharmacological or toxic action in the

body, including an effect on intestinal microorgan-

isms. As a result, if the lack of an element cannot be

shown to cause death or to interrupt the life cycle,

many scientists, perhaps a majority, now do not con-

sider an element essential unless it has a defined bio-

chemical function. However, there are still scientists

who base essentiality on the older definition. Thus,

there is no universally accepted list of essential trace

and ultratrace elements.

0004Copper, iron, manganese, zinc, cobalt, iodine,

molybdenum, and selenium are elements with

evidence for essentiality that is substantial and non-

controversial. Specific biochemical functions have

been defined for all of them. Boron and chromium

also belong in the list of trace elements accepted as

essential. Boron has recently been found to be

required to complete the life cycle of fish and frogs.

A defined biochemical function for chromium has

recently been identified.

0005Circumstantial evidence is often used to contend

that an element is essential. This evidence generally

fits into four categories. These are:

0006A dietary deprivation in some animal model con-

sistently results in changed biological function,

body structure, or tissue composition that is pre-

ventable or reversible by an intake of an apparent

physiological amount of the element in question.

0007The element fills the need at physiological concen-

trations for a known in vivo biochemical action to

proceed in vitro.

0008The element is a component of known biologically

important molecules in some life forms.

0009The element has an essential function in lower

forms of life.

0010An element is considered to have strong circum-

stantial support for essentiality if all four types of

evidence exist for it. There is strong circumstantial

evidence for the essentiality of arsenic, nickel, silicon,

and vanadium; thus, they are considered possibly

essential elements.

0011If an element has only one or two types of circum-

stantial evidence to support essentiality, it generally

does not receive widespread support for being a

5820 TRACE ELEMENTS

possibly essential element. However, some of these

elements have beneficial pharmacological actions

(fluoride prevents caries; lithium is an antimanic

agent), and some may eventually be found to be

of some nutritional importance. Elements that fit

in this category include aluminum, bromine, cad-

mium, fluorine, germanium, lead, lithium, rubidium,

and tin.

Importance in the Diet

0012 Trace and ultratrace elements have five known roles

in living organisms:

0013 In close association with enzymes, some elements

are integral parts of catalytic centers at which the

biochemical reactions necessary for life occur.

Working in concert with a protein, and frequently

with another organic coenzyme, an element

attracts a substrate molecule and facilitates its

conversion into a specific end product.

0014 Some elements donate or accept electrons in reac-

tions of reduction or oxidation. In addition to the

generation and utilization of metabolic energy,

redox reactions frequently involve the chemical

transformation of molecules.

0015 Some elements, particularly iron, bind, transport

and release oxygen within living organisms.

0016 Some elements have structural roles, imparting

stability and three-dimensional structure to im-

portant biological molecules.

0017 Some elements have regulatory roles. They control

important biological processes through such

actions as inhibiting enzymatic reactions, facilitat-

ing the binding of molecules to receptor sites on

cell membranes, altering the structure or ionic

nature of membranes to prevent or allow specific

molecules or ions to enter a cell, and inducing

genes to express themselves, resulting in the

formation of proteins involved in life processes.

0018 Although trace and ultratrace elements play key

roles in a variety of processes necessary for life, except

for iodine and iron, the occurrence of overt, simple,

or uncomplicated deficiency of any trace element in

humans is not common. The reasons for this are the

powerful homeostatic mechanisms involved in ab-

sorption, storage, and excretion that work to

maintain a rather constant amount of trace elements

in the body despite varying intakes; and the consump-

tion of diets with different types of foods from differ-

ent sources which increases the opportunity to

achieve adequate intakes. Nonetheless, reductions in

health and well-being because of suboptimal status in

some trace elements are probably not uncommon

because of other factors. That is, most important

in making trace and ultratrace elements of nutritional

concern is that their metabolism or utilization can be

impaired or their need can be increased by nutri-

tional, metabolic, hormonal, or physiological stres-

sors. This is exemplified by selenium, for which it is

difficult to produce signs of pathology caused by a

simple dietary deficiency in animals and humans.

A stressor such as vitamin E deficiency or a viral

infection is needed with selenium deficiency to obtain

marked pathology such as that seen with Keshan

disease, a cardiomyopathy that primarily affects

children and women of child-bearing age in some

areas of China.

Nutritional and Physiological Aspects of

Specific Elements

0019Nutritional and physiological aspects of the essential

elements copper, iron, zinc, iodine, selenium, and

chromium are described in separate sections in

this encyclopedia, and thus will not be described

further here. For the other elements mentioned

above, Table 1 and the following give a brief sum-

mary of findings that support their essentiality, pos-

sible physiological and biochemical functions, and

conditions that might enhance susceptibility to patho-

logical consequence because of low dietary intake.

Aluminum

0020The suggestion that aluminum might be essential is

relatively new. It was recently reported that depriving

goats of aluminum results in increased abortions,

depressed growth, incoordination and weakness in

hind legs and decreased life expectancy. Aluminum

deficiency has also been reported to depress growth in

chicks. In vitro biochemical actions which add cir-

cumstantial support to aluminum essentiality include

the activation of the enzyme adenylate cyclase,

enhancement of calmodulin activity, stimulation of

DNA synthesis in cell cultures, and stimulation of

osteoblasts to form bone. A concern about the evi-

dence for essentiality is that the only deficiency sign

found in more than one species is depressed growth.

More of the other reported signs need to be confirmed

by additional research groups or in other species.

Moreover, in the deficiency studies to date, rather

high amounts of aluminum were fed to supplemented

controls; this gives the possibility that aluminum may

have acted pharmacologically rather than nutrition-

ally in these studies. The reported signs of deficiency

do not give much insight into a possible biological

function for aluminum. However, the in vitro findings

suggest that it could possibly function as an enzyme

activator.

TRACE ELEMENTS 5821

Arsenic

0021 Signs of arsenic deprivation have been described for

several animal species, including the chicken, goat,

hamster, rat, and pig. In the goat, rat, and miniature

pig, the most consistent signs of arsenic deficiency

have been depressed growth and abnormal reproduc-

tion characterized by impaired fertility and elevated

perinatal mortality. Other notable signs of depriv-

ation described for goats include myocardial damage

and death during lactation. Some biochemical changes

that have been found in arsenic-deficient animals in-

clude depressed serum triglycerides in goats, depressed

plasma taurine concentrations in hamsters, depressed

hepatic S-adenosylmethionine and elevated hepatic

S-adenosylhomocystine in hamsters and rats, and

depressed hepatic putrescine, spermidine, and sper-

mine concentrations and S-adenosylmethionine

decarboxylase activity in rats. Factors enhancing the

response to low dietary arsenic are stressors that

affect sulfur amino acid or labile methyl group me-

tabolism, including high dietary arginine and selen-

ium, low dietary methionine, zinc, selenium and

choline, and taurine and guanidoacetic acid supple-

mentation.

0022 In vitro findings that support arsenic essentiality

include its ability to activate some enzymes, enhance

DNA synthesis in unsensitized and stimulated human

lymphocytes, and induce the isolated production of

certain proteins known as heat shock or stress pro-

teins. The control of production of stress proteins

is apparently at the transcriptional level, and may

involve changes in methylation of core histones.

Arsenic can increase the methylation of the p53 pro-

moter in human lung cells. Interestingly, although

arsenic is thought to be carcinogenic by many, it has

recently been found to be effective in the treatment of

some forms of leukemia. Moreover, it has been sug-

gested that arsenic can play an important role in

human health because it was found that injuries of

the central nervous system, vascular diseases, and

cancer were correlated to markedly decreased serum

arsenic concentrations.

0023A biochemical function for arsenic has not been

identified in lower forms of life, although a bacter-

ium, Chrysiogenes arsenatis, reduces As

5þ

to As

3þ

to gain energy for growth. However, there are

enzymes in higher animals and humans that methyl-

ate arsenic with S-adenosylmethionine as the methyl

donor. Arsenite methyltransferase methylates arsenite

to monomethylarsenic acid, which is methylated by

monomethylarsenic acid methyltransferase to yield

dimethylarsinic acid, the major form of arsenic in

urine. Findings to date indicate that arsenic might

tbl0001 Table 1 Human adult body content, adequate or typical daily dietary intake, and dietary sources of some trace and ultratrace

elements

Element

(symbol)

To t a l a d u l t

body content

Adequate dailyintake (ADI)

or typical dailyintake (TDI)

Dietarysources

Aluminum (Al) 30–50 mg 2–10 mg (TDI) Baked goods containing baking powder, grains, vegetables, tea

Arsenic (As) 1–2 mg 12–15 mg

(ADI) Fish, shellfish, grains, cereal products

Boron (B) 10–20 mg 0.5–1.0 mg

(ADI) Noncitrus fruits, nuts, leafy vegetables, pulses, legumes

Bromine (Br) 100–350 mg 2–8 mg (TDI) Nuts, grains, fish

Cadmium (Cd) 5–20 mg 10–20 mg (TDI) Shellfish, grains, leafy vegetables, organ meats

Cobalt (Co) 1.5 mg 2.4 mg as vitamin B

(ADI) Green leafy vegetables, organ meats

Fluorine (F) 3 g

3.0–4.0 mg

(ADI) Seafood, fluoridated water, tea

Germanium (Ge) 3 mg 0.4–3.4 mg (TDI) Wheat bran, vegetables, leguminous seeds

Lead (Pb) 120 mg 15–100 mg (TDI) Shellfish, plant foodstuffs from high-lead soils

Lithium (Li) 350 mg 200–600 mg (TDI) Eggs, meat, fish, milk products, potatoes, leafy vegetables

Manganese (Mn) 10–20 mg 1.8–2.3 mg

(ADI) Whole grains, nuts, legumes

Molybdenum (Mo) 10 mg 45 mg

(ADI) Milk products, vegetables, organ meats, pulses, grains, legumes

Nickel (Ni) 1–2 mg 100 mg

(ADI) Nuts, chocolate, pulses, grains, legumes

Rubidium (Rb) 360 mg 1–5 mg (TDI) Fruits, vegetables (especially asparagus), poultry, fish

Silicon (Si) 2–3 g 5–20 mg

(ADI) Whole grains, cereal products, root vegetables

Tin (Sn) 7–14 mg 1–40 mg (TDI) Nuts, canned foods

Vanadium (V) 100 mg 6–10 mg

(ADI) Shellfish, mushrooms, condiments, prepared foods

Estimated by author through extrapolation of data from animals.

Estimated by author using data from both animals and humans.

Recommended dietary intake (Co, Mo) and adequate intake (F, Mn) for adults 19 and older established by The Food and Nutrition Board, Institute of

Medicine, National Academy of Sciences in Dietary Reference Intakes for Calcium, Phosphorus, Magnesium,Vitamin D and Fluoride (1997); Dietary Reference

Intakes for Thiamin, Riboflavin, Niacin, Vitamin B

,Folate,VitaminB

, Pantothenic acid, Biotin and Choline (1998);andDietary Reference Intakes for Vitamin A,

Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc (2001). Washington, DC: National

Academy Press. For Flourine and Manganese, the first value is for women, the second value for men.

Mostly in bone; about 30 mg in soft tissue.

5822 TRACE ELEMENTS

have a function that affects the formation and utiliza-

tion of labile methyl groups arising from methionine.

Through this effect on methyl group metabolism,

arsenic probably affects the methylation of important

molecules such as DNA, which can affect the suscep-

tibility to certain types of cancer.

Boron

0024 Knowledge about the role and clinical aspects of

boron in nutrition is just emerging. The biological

function of boron has not been identified, but boron

apparently has a role that influences the metabolism

and utilization of several other nutrients. Thus, de-

scribed deficiency signs and the pathological conse-

quences of inadequate boron intake, because they can

be affected by the intake of several other dietary

substances, are numerous and variable. In humans,

boron apparently affects calcium metabolism and

hormone action. Among the various responses to

low dietary boron are decreased serum 25-hydroxy-

cholecalciferol, triglycerides, and ceruloplasmin; de-

creased erythrocyte superoxide dismutase; increased

serum calcitonin, glucose, and creatinine; increased

blood urea concentration; and decreased urinary

hydroxyproline excretion. Boron deprivation also

depresses the elevation in serum 17b-estradiol and

plasma copper caused by estrogen ingestion; alters

electroencephalograms such that they suggest

impaired behavioral activation (e.g., more drowsi-

ness) and mental alertness; and impairs psychomotor

skills and the cognitive processes of attention and

memory. A number of signs of deficiency have been

found in animals that may eventually have some

counterparts in humans. Signs of deficiency in the

frog include increased necrotic eggs; high frequency

of abnormal gastrulation in embryos; abnormal

development of the gut, craniofacial region, and eye;

visceral edema and kinking of the tail during organo-

genesis; and delayed tail absorption during meta-

morphosis. Signs of boron deficiency in the

zebrafish include embryo death during the zygote

and cleavage periods before the formation of a blas-

tula during embryo development, and photophobia

characterized by photoreceptor dystrophy in adults.

Signs of boron deficiency in rats include the exacerba-

tion of distortion of marrow sprouts and delay in the

initiation of cartilage calcification in bones during

marginal vitamin D deficiency, and decreased circu-

lating concentrations of natural killer cells and

CD8a

/CD4



cells during antigen-induced arthritis.

Factors enhancing the response to low dietary boron

are stressors that affect calcium metabolism and util-

ization, especially low dietary intakes of vitamin D or

calcium, and stressors that affect cell membrane

function or signal transduction, including low dietary

intakes of magnesium, potassium, or copper.

0025Over 70 years after being found essential for plants

to complete their life cycle, a biochemical function

apparently has been identified for boron in plants.

Boron has a structural role in the cell wall, and also

apparently a functional role in the cell membrane.

These roles support the hypothesis that in humans

and higher animals boron has a role in cell membrane

function that influences the response to hormone

action, transmembrane signaling, or transmembrane

movement of regulatory cations or anions. It has also

been hypothesized that boron is a metabolic regulator

through its ability to complex with a variety of sub-

strate or reactant compounds in which there are hy-

droxyl groups in favorable positions; the regulation is

mainly negative.

Bromine

0026Evidence supporting bromine essentiality includes

findings showing that bromide can substitute for

part of the chloride requirement for chicks; bromide

can alleviate growth retardation induced in chicks

and mice fed iodinated casein; and insomnia ex-

hibited by some hemodialysis patients has been asso-

ciated with bromide deficit. The insomnia finding is

tempered by the knowledge that, before barbiturates

were used, doctors prescribed bromide for sleep. Re-

cently it was reported that, when compared to goats

fed 20 mg bromide kg

1

diet, goats fed 0.8 mg brom-

ide kg

1

diet exhibited depressed growth, fertility,

hemoglobin, hematocrit, and life expectancy, and in-

creased spontaneous abortions. Although these latest

findings give more credibility to the concept of brom-

ine essentiality, the findings are still too limited. In

other words, the deficiency signs of bromine need to

be confirmed in additional species, preferably in an-

other research setting. The evidence presented to sup-

port essentiality does not provide much insight into a

possible biochemical role for bromine. Because it can

partially substitute for chloride, bromide could

possibly have a function similar to chloride.

Cadmium

0027Cadmium is best known for its intoxicating proper-

ties. However, in a study of goats, it was found that 9

kids from goats fed 15 mg cadmium kg

1

diet, when

compared to kids from goats fed 300 mg cadmium

1

diet, exhibited muscular weakness; they were

stiff and clumsy when they moved. Six of the 9 kids

finally could not raise their heads and died; the other

3 were fed the 300 mg cadmium kg

1

diet which re-

stored their mobility, feed intake, and growth. Muscle

weakness that led to death also occurred in some

TRACE ELEMENTS 5823

lactating goats fed the low-cadmium diet. It should be

emphasized that the amounts of dietary cadmium in

this study were much lower than those used in toxi-

cological studies; these usually involve quantities

measured in mg kg

1

diet and larger. Thus, the possi-

bility that cadmium is an essential element in ultra-

trace quantities cannot be dismissed. Other findings

supporting cadmium essentiality are that cadmium

slightly stimulated the growth of suboptimally grow-

ing rats, and cadmium showed transforming growth

factor activity or stimulated the growth of cells in soft

agar. Because it is consistently associated with metal-

lothionein, cadmium may have some biochemical

effects via this biosubstance. Further study is needed

before any substantial hypothesis about a biochem-

ical function or physiological role, and conditions

that might enhance the need for cadmium, can be

presented.

Cobalt

0028 Among the elements required for human health,

cobalt is unique because its need cannot be satisfied

by the mineral form. The only known function

for cobalt is as the essential component at the center

of the corrin ring of cyanocobalamin. Cyanocobal-

amin, also known as vitamin B

, is a cofactor

for three mammalian enzymes: methylmalonyl-

coenzyme A mutase, methionine synthase and leucine

2,3-aminomutase. Biochemical signs of vitamin B

deficiency include increased plasma homocysteine

and urinary formiminoglutamate and methylmalo-

nate; physiological signs include megaloblastic

anemia, spinal cord demyelination, and peripheral

neuropathy. Pathological consequences of vitamin

deficiency include pernicious anemia, memory

loss, dementia, irreversible neurological disease,

called subacute combined degeneration of the spinal

cord, and death. It has been suggested that cardiovas-

cular disease associated with elevated plasma homo-

cysteine is another consequence of inadequate

vitamin B

intake. Factors enhancing the suscepti-

bility to vitamin B

deficiency include atrophic gas-

tritis, Helicobacter pylori infection, gastrointestinal

bacteria overgrowth caused by achlorhydria, celiac

disease, drugs such as proton pump inhibitors and

oral biguanides (used in the treatment of type II dia-

betes), vegetarian diets, and nitrous oxide anesthesia.

0029 Cyanocobalamin is made in nature only by micro-

organisms; some of these are found in the rumen of

ruminants. Thus, ruminants are the only animals that

can have their vitamin B

requirement fulfilled by

the dietary intake of cobalt. Like other nonruminant

animals, humans must get their requirement for

cobalt by consuming foods rich in vitamin B

Fluorine

0030It has been reported that goats fed less than 0.3 mg

fluoride kg

1

diet, when compared to goats fed 1.5–

2.5 mg fluoridekg

1

diet, exhibited decreased feed

efficiency, depressed growth, histological changes in

kidney and endocrine organs, and reduced life expect-

ancy. These rather general effects have not been well

accepted as evidence that fluorine is essential, because

it is known that high or pharmacologic doses of fluor-

ide have apparently beneficial effects such as the pre-

vention of tooth caries; improvement of back pain

and bone density in patients suffering from osteopor-

osis; improvement in iron absorption or utilization in

mice and rats fed a diet marginally sufficient in iron;

and slight improvement in the growth of subopti-

mally growing rats and chicks. High or pharmaco-

logic amounts of fluoride also have been found to

depress lipid absorption, alleviate nephrocalcinosis

induced by high dietary phosphorus, and alter soft-

tissue calcification caused by magnesium deprivation.

0031Although fluoride is not generally considered an

essential in the classical sense for humans, it is still

considered a beneficial element because of its ability

to protect against pathological demineralization of

calcified tissues (especially teeth). However, the pos-

sibility that fluoride is an essential nutrient should not

be dismissed. It seems possible that fluoride could

have a role in biological mineralization.

Germanium

0032Of all the elements discussed here, the evidence for

essentiality is probably the weakest for germanium.

Nonetheless, it is included here because of the atten-

tion germanium is receiving as an over-the-counter

supplement. Germanium is touted as having anti-

cancer properties because some organic complexes

of this element have been found to inhibit tumor

formation in animal models. It has been suggested

that these compounds have such an effect because

they influence immune function. A low germanium

intake has also been found to alter bone and liver

mineral composition and decrease tibial DNA in the

rat. Additionally, germanium has been found to re-

verse changes in rats caused by silicon deficiency.

However, more extensive and specific deprivation

signs by at least one more research group are required

before germanium can be considered a serious candi-

date for essentiality.

Lead

0033Lead is best known for its intoxicating properties.

Nonetheless, some scientists strongly contend that

lead is an essential element. One research group has

reported that rats and/or pigs fed about 30 mg lead

5824 TRACE ELEMENTS

1

diet, when compared to those fed about 0.8 mg

lead kg

1

diet, exhibited depressed growth; anemia;

elevated serum cholesterol, phospholipids, and bile

acids; disturbed iron metabolism; decreased liver

glucose, triglycerides, low-density-lipoprotein choles-

terol and phospholipids; increased liver cholesterol;

and altered blood and liver enzymes. Another

research group reported findings that indicated lead

enhanced growth and improved hematocrits and

hemoglobin concentrations of iron-deficient rat pups

through a pharmacological action. Confirmation of

the substantial animal deprivation findings by add-

itional research groups is not likely to produce any

widespread acceptance of lead having properties

other than toxic. A defined biochemical function for

lead will probably be required before this element is

accepted as essential. Many of the reported apparent

signs of lead deficiency are associated with iron

metabolism; thus, lead possibly has a function that

affects the absorption or utilization of iron. Further-

more, if lead is required, its need most likely would be

enhanced by the stressor of suboptimal iron status.

Lithium

0034 Like fluoride, lithium is another element with bene-

ficial pharmacological properties; it has been used

effectively in the treatment of manic-depressive

psychosis. Lithium deficiency (<1.5 mg kg

1

diet)

reportedly results in depressed fertility, birth weight,

and life span, and altered activity in several liver and

blood enzymes in goats. In rats, lithium deprivation

(5–15 mgkg

1

diet) results in depressed fertility, birth

weight, litter size, and weaning weight. Additionally,

these lithium-deficient rats had a decreased lithium

content in testes, seminal vesicles, and epididymis,

and relatively high concentrations of lithium in the

pituitary and adrenal glands even after two gener-

ations on a low-lithium diet. These findings suggest

that lithium may have a role in the regulation of some

endocrine function. Other in vitro biochemical

actions providing circumstantial support for lithium

essentially include the stimulation of growth of some

cultured cells and insulinomimetic action. Its ability

to affect mental function perhaps explains the report

that the incidence of violent crimes is less in areas

with drinking water containing relatively high

amounts of lithium.

0035 Although two research groups using two animal

species have reported similar signs of lithium

deficiency (depressed growth and fertility), the signs

were not very marked or specific; this has inhibited

the widespread recognition that lithium is possibly

essential. Additionally, the wide difference between

apparent deficient intakes (based on rat experiments)

and typical daily intakes inhibits the suggestion that

lithium could be of practical nutritional importance.

Thus, although more credence should probably be

given to lithium essentiality, this most likely will not

occur until a specific biochemical function is identi-

fied for this element.

Manganese

0036The essentiality of manganese for animals has been

known for over 50 years. Deficiency causes testicular

degeneration (rats), slipped tendons (chicks), osteo-

dystrophy, severe glucose intolerance (guinea-pigs),

ataxia (mice, mink), depigmentation of hair, and

seizures. Manganese is a cofactor for enzymes in-

volved in protein and energy metabolism, antioxidant

action, and mucopolysaccharide synthesis. These

enzymes include the metalloenzymes manganese-

dependent superoxide dismutase, pyruvate carboxy-

lase and arginase, and the manganese-activated

enzymes phosphoenolpyruvate carboxykinase, glyco-

syl transferases, glutamine synthetase, and farnesyl

pyrophosphate synthetase.

0037With such extensive knowledge about the essential

nature of manganese, it is surprising that only a few

descriptions of possible human manganese deficiency

have come forth. The only description of an un-

equivocal case of human manganese deficiency was

of a child with postoperative short bowel receiving

over 90% of her nutrition parenterally, which was

low in manganese; she developed short stature and

brittle bones. In one attempt to induce manganese

deficiency, men were fed a purified diet providing

only 0.11 mg of manganese per day. They exhibited

decreased serum cholesterol and a fleeting dermatitis.

Calcium, phosphorus, and alkaline phosphatase

activity increased in blood. However, short-term

manganese supplementation (10 days) did not reverse

these changes; perhaps a longer period of supplemen-

tation would have. Regardless of the lack of descrip-

tions of human manganese deficiency, manganese is

thought to be of nutritional importance by some sci-

entists because low dietary manganese or low blood

and tissue manganese has been associated with osteo-

porosis, epilepsy, atherosclerosis, impaired wound

healing, and increased susceptibility to cancer. Thus

conditions under which a low manganese status

results in pathological consequences for humans

needs to be determined. Perhaps exposure to a stres-

sor that enhances the need for one of the manganese

metalloenzymes, or high intakes of inhibitors of man-

ganese absorption such as calcium, phosphorus, iron,

fiber, phytate and polyphenolic compounds, will

result in changes that demonstrate the nutritional

importance of manganese for humans.

TRACE ELEMENTS 5825

Molybdenum

0038 Descriptions of human molybdenum deficiency are

few. A patient receiving prolonged parenteral nutri-

tion acquired a syndrome described as ’acquired

molybdenum deficiency.’ This syndrome, exacer-

bated by methionine administration, was character-

ized by high blood methionine, low blood uric acid,

and low urinary uric acid and sulfate concentrations.

The patient suffered mental disturbances that pro-

gressed to a coma. Pathological changes occurring in

individuals with a genetic disease that results in a

sulfite oxidase (a molybdoenzyme) deficiency include

increased plasma and urine sulfite, sulfate, thiosul-

fate, S-sulfocysteine and taurine; seizures, brain

atrophy/lesions, and mental retardation; dislocated

lenses; and death at an early age.

0039 Molybdenum functions as an enzyme cofactor. In

humans, three molybdoenzymes have been identified;

these are aldehyde oxidase, xanthine oxidase/dehy-

drogenase, and sulfite oxidase in which molybdenum

exists as a small nonprotein factor containing a pterin

nucleus. Molybdoenzymes oxidize and detoxify vari-

ous pyrimidines, purines, and pteridines; catalyze the

transformation of hypoxanthine to xanthine and

xanthine to uric acid; and catalyze the conversion of

sulfite to sulfate. A high sulfur amino acid intake

could possibly be a stressor that would help induce

signs of molybdenum deficiency in humans. In

addition, because all of the molybdoenzymes can be

involved in the detoxification of xenobiotic com-

pounds, perhaps humans stressed by an exposure

to certain xenobiotics have an enhanced need for

molybdenum.

Nickel

0040 The reported signs of nickel deprivation are extensive

and are from several animal species. However, many

of the described signs, especially those from early

studies of nickel essentiality, may be of questionable

validity because of the possibility that they were

manifestations of pharmacological actions of nickel.

More nutritionally designed subsequent studies indi-

cate that signs of nickel deprivation include increased

blood pressure, kidney damage, decreased sperm

number and motility, and altered cyanocobalamin

(vitamin B

), glucose, triglyceride and sulfur amino

acid metabolism. As with other ultratrace elements,

the nature and severity of nickel deprivation signs are

affected by diet composition or nutritional stressors;

these include low dietary protein, inadequate dietary

iron, high dietary simple sugars, and stressors that

alter sulfur amino acid or labile methyl metabolism

such as cyanocobalamin, folic acid or pyridoxine de-

ficiency, or homocysteine supplementation.

0041Nickel has an essential function as an enzyme

cofactor in lower forms of life. Nickel is a component

of urease from bacteria, mycoplasma, fungi, yeast,

algae, higher plants, and invertebrates. Nickel is pre-

sent in hydrogenases from over 35 species of bacteria;

it may be a common constituent of hydrogenases

that function physiologically to oxidize rather than

evolve H

. Nickel is a component of carbon monox-

ide:(acceptor) oxidoreductase found in acetogenic,

methanogenic, phototrophic, and sulfate-reducing

anaerobic bacteria, and of a tetrapyrrole known as

factor F

430

found in methyl-S-coenzyme-M reductase

that converts CO

to methane in methanogenic bac-

teria. Nickel is required for the hydrogenase gene to

be expressed in Bradyrhizobium japonicum. These

essential functions suggest that nickel may have a

role in higher animals, including humans as a cofactor

or structural component in an enzyme. It is also pos-

sible that nickel has a very basic function at the mo-

lecular level because in vitro studies show that nickel

is a calcium channel blocker and can activate the

2þ

’receptor’ on the osteoclast to elicit cytosolic

2þ

signals.

0042The findings showing that nickel is so dynamic

in lower forms of life, and that experimental

animals are affected by nickel deprivation, provide

almost overwhelming circumstantial evidence that

nickel is essential for humans. Only the lack of a

defined biochemical function in some higher form

of life inhibits the general acceptance of nickel

essentiality.

Rubidium

0043Rubidium is another recent addition to the list of

possibly essential elements. Compared to goats fed

1 or 10 mg rubidium kg

1

diet, goats fed less than

0.28 mg rubidium kg

1

diet exhibited decreased

food intake, growth, and life expectancy, and in-

creased spontaneous abortions. These rather general

deprivation signs need to be confirmed in additional

species, preferably in another research setting,

before strong consideration can be given to the possi-

bility of rubidium essentiality. The reported signs of

deficiency do not give insight into a possible bio-

chemical function for rubidium. Because rubidium

resembles potassium, it may have a role similar to

potassium. Also, some findings have been obtained

suggesting that rubidium possibly has a neuro-

physiological function. The rubidium content of

brain differs significantly between defined functional

regions, and rubidium can apparently enhance the

turnover of brain norepinephrine (noradrenaline)

and cause electroencephalogram activation in

monkeys and rats.

5826 TRACE ELEMENTS

Silicon

0044 Most of the signs of silicon deficiency indicate an

aberrant metabolism of connective tissue and bone.

Silicon-deprived chicks exhibit structural abnormal-

ities of the skull, depressed collagen content in bone,

and decreased tibial articular cartilage, water, hexo-

samine, and collagen. Silicon-deprived rats exhibit

skull structural changes, increased humerus hexose,

decreased humerus hydroxyproline and alkaline and

acid phosphatase activity, and decreased plasma

ornithine aminotransferase activity (a key enzyme in

collagen synthesis). The response to silicon depriv-

ation can be modified by low dietary calcium and

high dietary aluminum. For example, rats fed a diet

low in silicon and calcium and high in aluminum

accumulated high amounts of aluminum in the brain;

silicon supplements prevented the accumulation.

0045 Silicon essentiality in higher animals is supported

by its essentiality for lower forms of life; it has a

structural role in diatoms, radiolarians, and some

sponges and affects gene expression in diatoms. It is

required by some higher plants, including rice. Other

findings supporting essentiality include findings that

silicon is localized in the active growth area, or osteoid

layer, and within the osteoblasts in young bone of mice

and rats; silicon is chemically combined with the

glycosaminoglycan fraction in several types of con-

nective tissue; and silicon is required for maximal

bone prolylhydroxylase activity in bone tissue culture.

0046 The distribution of silicon in the body and the

biochemical changes in bone caused by silicon depriv-

ation indicate that silicon has an essential function

that influences bone formation by affecting cartilage

composition, and ultimately cartilage calcification. It

is also likely that silicon has a function important for

collagen formation; thus, it may be needed for proper

wound healing.

Tin

0047 The evidence for tin essentiality is quite weak.

One research group has reported that tin deficiency

results in impaired growth, decreased feed efficiency,

alopecia, depressed response to sound, and changes in

mineral concentrations in various organs. Other find-

ings supporting tin essentiality include findings that it

influences heme oxygenase activity, and has been

associated with thymus immune and homeostatic

functions. The oxidation reduction potential for

2þ

,Sn

4þ

is 0.13 V, which is near the potential of

flavin enzymes. Thus, tin possibly has a role in some

redox reaction.

Vanadium

0048 The most substantive evidence for vanadium essenti-

ality has come from deficiency studies with goats and

rats. Compared to goats fed 500 mg vanadium kg

1

diet, goats fed 1–9 mg vanadium kg

1

diet exhibited

an elevated abortion rate and depressed milk produc-

tion. About 40% of kids from deficient goats died

between days 7 and 91 of life, with some deaths

preceded by convulsions; only 8% of kids from

vanadium-supplemented goats died during the same

time. Also, skeletal deformations were seen in the fore

legs, and fore foot tarsal joints were thickened. Van-

adium deprivation in the rat reportedly increases

thyroid weight and decreases growth. The rat studies

also showed that stressors that change thyroid status

or iodine metabolism enhanced the response to

vanadium deprivation. Factors that reduce vanadium

absorption, including high dietary iron, aluminum

hydroxide and chromium, may also enhance the

response to a low dietary vanadium intake.

0049Vanadium has an essential function as an enzyme

cofactor in lower forms of life. Vanadium is a com-

ponent of some nitrogenases that reduce nitrogen gas

to ammonia in bacteria, and for bromoperoxidase,

iodoperoxidase, and chloroperoxidase in algae,

lichens, and fungi, respectively. The haloperoxidases

catalyze the oxidation of halide ions by hydrogen

peroxide, thus facilitating the formation of a

carbon–halogen bond. Other findings supporting

vanadium essentiality have come from in vitro studies

with cells and pharmacologic studies with animals.

These studies show that vanadium has insulin-

mimetic properties, stimulates cell proliferation

and differentiation, affects cell phosphorylation–

dephosphorylation, and affects oxidation reduction

processes.

0050Because vanadium is so pharmacologically active,

identification of a specific biochemical function for

vanadium in higher animals and humans will be

necessary to define the nutritional importance of

this element. Based on the circumstantial evidence

for essentiality, vanadium possibly has an essential

function in some enzyme reaction, perhaps one that

is involved in thyroid metabolism.

See also: Arsenic: Properties and Determination;

Requirements and Toxicology; Boron; Cadmium:

Properties and Determination; Toxicology; Cobalamins:

Physiology; Copper: Properties and Determination;

Physiology; Fluoride; Lead: Properties and

Determination; Toxicology; Lithium; Manganese; Tin