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animals, leading to spastic pareses and paralysis of

legs. Later on, the role of thiamin in the central ner-

vous system, especially in pyruvate metabolism of the

brain, could be demonstrated, too.

0030 Neurological signs are also characteristic of the

deficiency state in human beings. The classical mani-

festation of deficiency can be seen in beriberi. This

disease is endemic in several regions of East Asia.

Depending on how far the disease has progressed

and additional nutrients are involved (e.g., protein

deficiency), it is characterized by either polyneuro-

pathias and degenerative muscle wasting (dry or

atrophic form) or cardiac arrhythmias and edema

(wet or exudative form). The development of exuda-

tive beriberi predominates in cases of a high carbohy-

drate intake and increased physical activity. Protein

deficiency is probably involved, too. The Wernicke–

Korsakoff syndrome, the cerebral form of deficiency,

is characterized by mental confusion, memory dis-

turbances, ataxia, ophthalmoplegia, and nystagmus.

This syndrome can be interpreted as neuropathia of

the central nervous system and is most commonly

observed in malnourished alcoholics. The thiamin-

dependent PDH and KDH complexes are key

enzymes in the metabolic pathways of glucose and

other energy-delivery substrates. The activities of

both enzymes were found to play a rate-limiting

role in mammalian brain mitochondrial prepar-

ations. Thus, lactic acid accumulation, as a result

of the impaired glucose oxidation and disruption

of oxidative phosphorylation utilizing pyruvate, a-

ketoglutarate, and succinate as substrates has been

demonstrated in brain mitochondria from deficient

rats. There is some evidence that localized lactic

acid accumulation may contribute to the brain lesions

in the Wernicke–Korsakoff disease. Futhermore, it is

suggested that neurological symptoms may involve

an impairment of the cholinergic neurotransmitter

function. Acetylcholine and g-aminobutyrate are pri-

marily produced through the oxidative metabolism

of glucose or via the citric acid cycle with acetyl-

coenzyme A (acetyl-CoA) and a-ketoglutarate as

precursors. Although no change in regional brain

acetylcholine levels was found in thiamin-deficient

rats, acetylcholine utilization and turnover were re-

duced, and the central cholinergic mechanisms

appear to be depressed in a deficient state. These

alterations may be due to a decreased PDH and

thereby activity limited acetyl-CoA production.

0031Infantile beriberi occurring in breast-fed infants

between 2 and 6 months has particularly devastating

consequences. Symptoms include cyanosis, dyspnea,

tbl0004 Table 4 Symptoms of clinical thiamin deficiency

Deficiency form Neurological signs Cardiovascular signs Other signs Nutrient interactions

Atrophic beriberi (dry or

polyneuritic form)

Degenerative

polyneuropathia of

lower extremities,

paresthesia, reflex

disorders, dropfoot,

muscle waste,

convulsions

(Caloric restriction),

anorexia

Exudative beriberi (edematous

or cardiovascular form)

Sinus tachycardia,

cardiac arrhythmias,

heart dilatation

(beriberi heart),

pericardial effusion,

cardiac insufficiency

Lung and peripheral

edemas, ascites,

dyspnea, rarely lactic

acidosis without

edemas

(High carbohydrate

intake, protein

deficiency), intense

physical activity

Wernicke–Korsakoff

Syndrome (cerebral form)

Nystagmus,

ophthalmoplegia,

cerebellar ataxia,

paralysis of the sixth

brain nerve,

polyneuropathia

(burning feet

syndrome), reflex

disorders

Psychoses,

hallucinations,

memory loss,

irritability

Alcohol abuse

Infantile beriberi

(2–6 month)

Convulsions (increased

intracranial

pressure)

Tachycardia, cardiac

insufficiency

Vomiting, diarrhea,

abdominal

distension, anorexia,

cyanosis, dyspnea

Modified from Bitsch R (1997) Vitamin B

(thiamin). In: Biesalski HK, Schrezenmeier J, Weber P and Weiß H (eds) Vitamine, Physiologie, Pathophysiologie,

Therapie, pp. 67–74. Stuttgart: G. Thieme.

5778 THIAMIN/Physiology

tachycardia, abdominal distension, and convulsions.

Sudden death often occurs as a result of cardiac fail-

ure. Nursing mothers, however, often do not show

any signs of clinical deficiency. The thiamin defi-

ciency symptoms are summarized in Table 4.

Therapeutic Administration and Toxicity

0032 The importance of thiamin for the metabolism of the

central and peripheral nerve system, as is becoming

clear from the deficiency symptoms, implicates its

therapeutic application in all neurological system

disorders. The recommended doses are 100–300 mg

per day, often combined with pyridoxine and cobala-

min. Because of the limited gastrointestinal absorp-

tion, the dose should be split up over the day. In

progressive polyneuropathia and clinical beriberi,

the same dosage may be initially administered i.m.

or i.v., for a rapid tissue restoration, followed by oral

therapy.

0033 Lipid-soluble allithiamin derivatives can be given

in smaller doses, because of the improved absorption.

The passage of those derivatives across the blood–

brain barrier is alleviated, too, as has been shown in

animals. A significant improvement in the neuro-

pathia score by oral application of the lipophilic

benfotiamin has been observed in diabetic polyneur-

opathia patients as well.

0034 As with other water-soluble vitamins, thiamin tox-

icity is very small when given orally, because of the

limited absorption. In rare cases, with parenteral

dosages above 100 mg, impaired sensations or even

anaphylactic reactions have been observed, but it is

not clear as to what extent additional components of

the injection solution may interfere.

Thiamin-dependent Enzymopathies

0035 Thiamin-dependent enzymes are involved in four

rare hereditary enzymopathies: leucinosis, Leigh

syndrome, congenital lactacidosis, and thiamin-

dependent megaloblastic anemia.

0036In leucinosis or maple syrup disease, the degrad-

ation of branched chain amino acids is inhibited with

following accumulation of ketoanalogs. In the allevi-

ated or intermittent form, this disorder can be im-

proved by an intake of 10–150 mg of B

per day

under simultaneous protein restriction. If untreated,

severe neurological complications, physical, and

mental dysfunctions develop, followed by death.

0037Leigh syndrome is characterized by a necrotizing

encephalomyelopathia and is also observed in rumin-

ants. The exact biochemical defect is poorly under-

stood but is thought to be a hereditary malfunction of

thiamin triphosphate transferase, leading to impaired

TTP formation, occasionally combined with a de-

crease in the amount of ketoacid dehydrogenase.

Neurological symptoms develop, progressing from

nystagmus and paralysis of the external eye muscles

to convulsions, ataxias, and disorientation resem-

bling the Wernicke disease. Thiamin therapy may be

successful, particularly when lipophilic derivatives

(fursultiamin) are ingested up to gram dosages. Lact-

acidosis (which occurs at the same time) can be alle-

viated by oral intake of hydrogencarbonate combined

with a low-carbohydrate diet.

0038The clinical picture of congenital lactacidosis re-

sembles Leigh syndrome, and it is often impossible to

distinguish between the two. The primary cause is a

defect of the PDH or of partial enzymes of this com-

plex. Generally, the prognosis is deleterious. The

lactacidosis and the concomitant neurological symp-

toms could only in rare cases be affected by thera-

peutic thiamin doses.

0039Thiamin-responsive megaloblastic anemia has

until now been very rare. The characteristic symp-

toms are a very strange combination of anemia, laby-

rinthine deafness, and insulin-dependent diabetes.

The anemia can be improved only by oral doses of

tbl0005 Table 5 Congenital thiamin-responsive enzymopathies

Metabolic disorder Biochemicaldefect Clinicalsymptoms Therapy

Leucinosis (maple syrup disease) Ketoacid dehydrogenase for

metabolism of branched-

chain amino acids

Acidosis, ketosis, cerebral

degeneration

Leucin-, isoleucin-, and valin-

poor diet, thiamin (orally)

10–150 mg daily

Leigh syndrome (necrotizing

encephalomyelopathia)

TTP formation, keto acid

dehydrogenase

Lactacidosis, nystagmus,

ataxia, convulsions, mental

and psychic abnormal

development

Thiamin (orally) 2.0 g daily

(lipid-soluble derivatives)

Congenital lactacidoses PDH Lactacidosis, neurological

symptoms, mental

retardation

Thiamin lipid-soluble (?)

Thiamin-responsive

megaloblastic anemia

Thiamin transport in tissue

compartments

Megaloblastic anemia,

diabetes, labyrinthine

deafness

Thiamin (orally) 20–100 mg

daily (lipid-soluble

derivatives)

THIAMIN/Physiology 5779

20–100 mg of thiamin. Folate and vitamin B

admin-

istration is ineffective. In one case, the diabetes was

improved, and insulin therapy was no longer needed.

0040 The primary metabolic defect is unclear. Thiamin-

dependent enzymes remain unchanged, and there

may be an impairment in thiamin transport in certain

tissues. The enzymopathies are summarized in Table 5.

See also: Plant Antinutritional Factors: Characteristics;

Beriberi; Bioavailability of Nutrients; Nutritional

Assessment: Biochemical Tests for Vitamins and

Minerals; Functional Tests; Vitamins: Overview

Further Reading

Bitsch R (1997) Vitamin B

(Thiamin). In: Biesalski HK,

Schrezenmeier J, Weber P and Weiß H (eds) Vitamine,

Physiologie, Pathophysiologie, Therapie, pp. 67–74.

Stuttgart: G. Thieme.

Duran M and Wadman SK (1985) Thiamine-responsive

inborn errors of metabolism. Journal of Inherited Meta-

bolic Diseases 8(supplement 1): 70–75.

Finglas PM (1994) Thiamin. International Journal for Vita-

min and Nutrition Research 63: 270–274.

Food and Nutrition Board, Institute of Medicine (1998)

Dietary Reference Intakes for Thiamin, Riboflavin,

Niacin, Vitamin B

, Folate, Vitamin B

, Pantothenic

Acid, Biotin and Choline. Washington DC: National

Academy Press.

Frank T, Bitsch R, Maiwald J and Stein G (2000) High

thiamine diphosphate concentrations in erythrocytes

can be achieved in dialysis patients by oral administra-

tion of benfotiame. European Journal of Clinical

Pharmacology 56: 251–257.

Gregory JF (1997) Bioavailability of thiamin. European

Journal of Clinical Nutrition 51(supplement): 34–37.

Gubler CJ (1991) Thiamin. In: Machlin LJ (ed.) Handbook

of Vitamins, pp. 233–281. New York: Marcel Dekker.

Rindi G (1996) Thiamin. In: Ziegler EE and Filer Jr. LJ (eds)

Present Knowledge in Nutrition, pp. 160–166. Washing-

ton, DC: ILSI Press.

Rindi G, Patrini C, Laforenza U et al. (1994) Further studies

on erythrocyte thiamin transport and phosphorylation

in seven patients with thiamin responsive megaloblastic

anaemia. Journal of Inherited Metabolic Diseases 17:

667–677.

Souci SW, Fachmann W and Kraut H (2000) Food Compos-

ition and Nutrition Tables, 6th revised edn. Boca Raton,

FL: CRC Press/Medpharm Scientific.

Thin-layer Chromatography See Chromatography: Principles; Thin-layer Chromatography; High-

performance Liquid Chromatography; Gas Chromatography; Supercritical Fluid Chromatography; Combined

Chromatography and Mass Spectrometry

THIRST

D J Ramsay, University of Maryland at Baltimore,

Baltimore, MD, USA

This article is reproduced from Encyclopaedia of Food Science,

Introduction

0001 Thirst is a term which evokes many meanings. In most

nonhuman studies, it is equated with measurements of

water intake. In human studies, analog rating scales

are often used to evaluate answers to questions such

as: ’How thirsty are you?’’How dry is your mouth?’

or ’How unpleasant does your throat feel?’ Its use is

not restricted to an appetite for water. Depending on

culture, experience, and availability, a variety of fluids

such as soft drinks and nonalcoholic beverages, in

addition to water itself, may be consumed. It has

been suggested that the definition is best left in

general terms such as ’the disposition to drink’ or

’the tendency to drink,’ and those who wish to use

the word in a more specific sense should define it.

Role of Thirst

0002Water loss from terrestrial animals is continuous.

Ingestion of food results in the addition of osmotic-

ally active solutes to the body fluids either because

they are contained in the foods (e.g., sodium chloride)

or because the process of metabolism produces them

(e.g., oxidation of sulfur-containing amino acids to

sulfate). These solutes are usually excreted in the

5780 THIRST

urine accompanied by water in amounts determined

by the concentrating capacity of the kidney. Thus, if

the kidney can produce urine four times more concen-

trated than plasma – the situation in humans – 25%

of the volume of water will be lost compared to the

situation in which the kidneys could not concentrate

urine over plasma. Nevertheless, even kidneys produ-

cing low volumes of urine at maximal concentrations

result in loss of body fluid. Water is also lost from the

skin by insensible perspiration and sweating. These

amounts are highly variable, depending on the level of

activity, body temperature, and ambient temperature

and humidity. Breathing also results in fluid lost as

expired air is fully saturated with water at body tem-

perature, whereas inspired air is usually drier and at

a temperature lower than that of the body. Small

amounts of water are lost in the feces, although in

diseases accompanied by severe diarrhea, such as

cholera, large amounts of fluid can be lost by this

route. All these mechanisms cause a continuous inev-

itable loss of fluid. Thirst resulting in the ingestion of

an appropriate volume of an appropriate fluid is the

only way to repair the fluid deficit. Without thirst,

animals would die of dehydration. Human subjects

who lose the sensation of thirst as a result of disease

are very difficult to treat. Even the most stringently

prescribed timetable of water intake regime can fail.

Irreversible dehydration is the inevitable outcome of

the lack of thirst. (See Water: Physiology.)

Regulation of Thirst

0003 Water is the most abundant component of the body,

making up approximately 65% of body weight. The

transport of solutes throughout the body takes place

in physical solution, as do most of the physicochem-

ical processes which maintain life. The total osmotic

concentration of body fluids, or osmolality, is main-

tained within very narrow limits. In humans, as in

other animals, it rarely varies by more than 1% or

2%. This is important for two reasons. First, as water

can move freely through cell membranes, the osmol-

ality of intra- and extracellular compartments is

equalized by the movement of water down concen-

tration gradients or osmotic gradients. If plasma and

extracellular fluid osmolality increase, water will be

withdrawn from cells, resulting in cell shrinkage.

Thus, in situations of increased plasma osmolality,

extracellular fluid volume will expand and intracellu-

lar fluid volume will decrease. Acutely, cells behave as

perfect osmometers. It is therefore not surprising that

osmolality is maintained constant in order to main-

tain both blood volume and cell volume within

normal limits. Second, many bio-chemical reactions

and cell transport processes depend critically on the

concentrations of solutes. Thus accurate control of

water balance to insure constancy of the volume and

composition of body fluids is found in all mammals.

Cellular Dehydration Drinking

0004The correlation between total plasma solute concen-

tration or osmolality and drinking has been known

since the work of Mayer in 1900. More recently, the

relationship between plasma osmolality and drinking

has been described by a number of workers in a

number of species, including humans. The relation-

ship is generally investigated by determining the

effects of intravenous infusions of hypertonic sodium

chloride on water intake or, in the case of humans,

increased indications of thirst, as noted on analog

rating scales. In general, there is a linear increase in

thirst associated with increased plasma osmolality

similar to that seen in plasma vasopressin levels, the

major determinant of urinary concentration. Thus

increasing plasma osmolality leads to renal water

conservation and the stimulation of thirst, and

hence water-seeking behavior (Figure 1).

Extracellular Dehydration Drinking

0005Reduction of blood or extracellular fluid volume

without a change in its osmolality also stimulates

thirst. A number of maneuvres have been used to

investigate this phenomenon. Hemorrhage, restric-

tion of venous return by occluding the thoracic part

of the vena cava, or sequestration of fluid using sub-

cutaneous or intraperitoneal injections of colloid all

200

300

100

Water intake (ml)

Plasma vasopressin (pg ml

−1

)

Change in plasma osmolality

− 20

1.0

2.0

3.0

4.0

5.0

0+ 20

fig0001Figure 1 Increase in plasma osmolality stimulates vasopres-

sin secretion (——) and water intake (- - -) in dogs. Reproduced

from Thirst, Encyclopaedia of Food Science, Food Technology and

Nutrition, Macrae R, Robinson RK and Sadler MJ (eds), 1993,

Academic Press.

THIRST 5781

result in stimulation of drinking. In general, drinking

to extracellular fluid dehydration is less sensitive than

that to cellular dehydration. The reduction of ap-

proximately 10% in blood volume is usually required

to stimulate water intake, as is the case with stimula-

tion of vasopressin secretion. With larger reductions

in extracellular fluid volume, however, stimulation of

thirst and vasopressin secretion is marked. Presum-

ably, at the point where a reduction in extracellular

fluid volumes severely compromises circulatory

homeostasis, rapid restoration of blood volume be-

comes essential to insure survival.

Dehydration

0006 During periods of water deprivation, plasma osmol-

ality increases and extracellular fluid volume is re-

duced. It has already been emphasized that, under

normal circumstances, water is lost continually,

whereas drinking is a discontinuous process. Thus

animals are always in a situation of potentially having

to correct for dehydration by taking in fluids. In these

situations, raised plasma osmolality, or cellular dehy-

dration, is a more important input to the stimulation

of thirst than is extracellular fluid dehydration. In

primates, including humans, cellular dehydration

may make up 90% of the stimulus.

Satiety

0007 The stimuli responsible for the cessation of drinking

are different from those which cause it. For example,

dogs deprived of water for 24 h will make up fluid

deficits accurately within 5 min of being allowed

access to water. During this 5-min period, there is

no correction of the raised plasma osmolality or de-

creased extracellular fluid volume as water would not

have been absorbed from the gastrointestinal tract in

sufficient quantities. Indeed, dehydrated dogs with an

open gastric fistula will drink the same amount as

intact dogs. In studies on water-deprived humans,

subjects drank 65% of their total intake within

2.5 min. The remainder of the fluid deficit was con-

sumed over a longer period of time. This satiety effect

has been noted in a large variety of species; it is

associated with a rapid inhibition of vasopressin se-

cretion, and is based on oropharyngeal and gastric

factors. However, it is only a temporary phenomenon

and, unless drinking is followed by absorption of

fluid and correction of the cellular and extracellular

dehydration stimuli, drinking will be reinitiated. (See

Satiety and Appetite: Food, Nutrition, and Appetite.)

Normal Drinking

0008 Not all water intake depends on this simple deficit–

satiety model. The water content of food, and that

provided by its metabolism, can supply significant

amounts of intake. The amount of water consumed

on each occasion can depend heavily on learning and

may be greatly influenced by other behaviors and by

social factors. In humans the situation is even more

complex and fluid may be taken in in association with

caffeine or alcohol, and depend on specific tastes,

such as sweetness, and on flavor. In spite of these

factors, however, it should be noted than on average

the kidney produces urine more concentrated than

plasma. Thus renal-concentrating mechanisms are re-

sponding to a potentially dehydrating situation. In

light of this information it might be asked why

animals are not continually drinking. The answer is

that drinking is only one of a large number of specific

behaviors which may be expressed by an animal; if it

were continually engaged in a search for water, to the

exclusion of other behaviors such as feeding or repro-

duction, the animal would be incapacitated. Presum-

ably, the inputs to thirst become more severe as

dehydration proceeds, and water-seeking behavior

moves to the top of the behavioral hierarchy and is

expressed, resulting in water intake. In the long term,

physiological control mechanisms must underpin

drinking behavior. If inadequate quantities of fluid

are taken in, particularly when urinary concentration

becomes maximal, negative fluid balance and dehy-

dration are the inevitable outcome.

Mechanisms of Thirst

0009Since the pioneering work of Verney on the location

of osmoreceptors controlling vasopressin secretion, it

has been realized that these are located in the hypo-

thalamus. It now seems clear that receptors respond-

ing to physiological changes in extracellular fluid

osmolality are located in circumventricular organs

on the anterior wall of the third cerebral ventricle.

In dogs, lesions of the organum vasculosum laminae

terminalis result in the permanent loss of drinking

behavior to increases in plasma osmolality of up to

15 mosmol kg

1

. In other species, another forebrain

circumventricular organ, the subfornical organ may

be involved. Circumventricular organs lack the

normal blood–brain barrier, and thus can be more

easily influenced by the composition of the blood

that perfuses them. The connectivity between the cir-

cumventricular organs and other parts of the brain

concerned with drinking behavior and secretion of

vasopressin are shown in Figure 2. The nucleus med-

ianus plays a central role in the integration of inputs

which stimulate thirst. Lesions of this region result in

the permanent cessation of drinking to any stimulus.

0010When extracellular fluid volume is reduced,

information may reach the hypothalamus in two

5782 THIRST

main ways. Afferents from atrial and arterial baro-

receptors enter the hindbrain via the ninth and

tenth cranial nerves and synapse in the nucleus

tractus solitarius. From this region, there are a

number of inputs to the hypothalamus, including

the nucleus medianus. Reduction in extracellular

fluid volume also results in the stimulation of the

secretion of renin from the kidneys. Through the

renin–angiotensin cascade mechanism this results in

raised plasma angiotensin II levels. Angiotensin II

generated in the blood interacts with receptors in

forebrain circumventricular organs, particularly

the subfornical organ. Angiotensin II is a potent

dipsogen, particularly when injected directly into

the third cerebral ventricle. Thus extracellular fluid

volume reduction can stimulate thirst directly

through vagal afferents or more indirectly through

the renin–angiotensin system.

0011The physiological inputs to thirst and the connect-

ivity of the hypothalamic nuclei associated with these

inputs are beginning to be understood. However,

there is little information which links these with the

complex neuro-physiological mechanisms associated

with water-seeking and drinking behavior. The mech-

anisms which allow animals to choose drinking from

the vast repertoire of behaviors available to them are

also not clear. There is much to be learned of the

higher-nervous-system functions involved in the link

between a fluid deficit and the stimulation of thirst

and fluid intake.

Requirements for Fluid

0012It is obvious from the foregoing that the requir-

ement for fluid in humans must vary widely. In a

temperate environment, the average loss of water

Parvo

PVN

Magno

PVN

Arterial

baroreceptors

NTS

SFO

SON

PVPO

MPO

LPO

OVLT

Medial

septum

Atrial

baroreceptors

Parabrachial

nucleus

fig0002 Figure 2 Neuroanatomical interconnections between forebrain circumventricular organs and the nucleus medianus in the control of

water balance. SFO, subfornical organ; NM, nucleus medianus; OVLT, organum vasculosum laminae terminalis; MPO, medial preoptic

area; LPO, lateral preoptic area; PVPO, periventricular preoptic area; SON, supraoptic nucleus; PVN, paraventricular nucleus; NTS,

nucleus tractus solitarius. Reproduced from Thirst, Encyclopaedia of Food Science, Food Technology and Nutrition, Macrae R, Robinson

RK and Sadler MJ (eds), 1993, Academic Press.

THIRST 5783

from the skin by evaporation is 900 ml day

1

, in feces

100 ml day

1

and in urine 1500 ml day

1

. The aver-

age figure for the amount of water contained in foods

is 1000 ml day

1

; that produced by metabolism is

300 ml day

1

, leaving 1200 ml to be taken in in the

form of fluid. However, these amounts may vary

widely. For example, during moderate to severe

exercise, particularly in a warm environment, many

liters of fluid may be lost through sweating in order

to maintain normal body temperatures. Under such

circumstances, there is a marked stimulation of

thirst with the resulting intake of large amounts of

fluid. In the final analysis, in order to prevent

dehydration the amount of fluids taken in must

equal that which is lost.

0013 The nature of the fluid ingested depends largely on

cultural factors. For example, consumption of soft

drinks appears to be the most characteristic feature

of the USA. Beer, accompanied by milk (in the

UK) and coffee (in Germany) are typical of middle

Europe, and coffee and milk are the most popular

beverages in northern Europe. Thus, as with food,

culture is the major determinant of drink preference.

It is important also to note the link between food

intake and fluid intake. Under normal circumstances

much of the daily intake of fluid is associated with

eating.

0014 A number of other factors will also influence fluid

intake. During the luteal phase of the menstrual cycle,

there is downward resetting of osmotic thresholds for

both thirst and vasopressin secretion. These changes

may be even more marked during pregnancy, when

plasma osmolality may fall by about 10 mosmol kg

1

during the first few weeks of gestation. During this

period the osmotic thresholds of both thirst and vaso-

pressin are again reduced.

0015There is a reduction of thirst in the elderly. This is

evidenced by the tendency for spontaneous dehydra-

tion to occur in the elderly, and their reduced sensitiv-

ity to infusions of hypertonic saline and water

deprivation. The situation in the elderly is also com-

plicated by their diminished ability to excrete water

loads. For example, if an elderly individual with di-

minished thirst is encouraged to drink more fluid in

warm weather, overcorrection can result in overhy-

dration. Thus in the elderly, there may be problems of

over- or underhydration. (See Elderly: Nutritionally

Further Reading

Denton D (1982) The Hunger for Salt. Berlin: Springer-

Verlag.

Fitzsimons JT (1979) The physiology of thirst and sodium

appetite. Monographs of the Physiological Society 35.

Ramsay DJ and Booth DA (eds) (1991) Thirst: Physio-

logical and Psychological Aspects. Berlin: Springer-

Verlag.

Rolls BJ and Rolls ET (1982) Thirst. Cambridge:

Cambridge University Press.

Rundgren M and Hjelmqvist H (eds) (1989) Hypothalamus

and homeostasis Acta Physiologica Scandinavica

Supplementum 136 (583).

Thyroid Disease See Iodine: Properties and Determination; Physiology; Iodine-deficiency Disorders

Thyroid Hormones See Hormones: Adrenal Hormones; Thyroid Hormones; Gut Hormones; Pancreatic

Hormones; Pituitary Hormones; Steroid Hormones

5784 THIRST

TIN

T Y Toribara, University of Rochester, Rochester, NY,

USA

Background

0001 Tin does not occur freely in nature but occurs mostly

in the form of the dioxide and sometimes as the

sulfide. It is found combined in silicic rocks such as

granite and in small amounts in feldspar. The chemis-

try of tin has been examined in great detail, and much

of it has been published recently in a single book. It is

the intention to cover only those topics that have

some relevance to the occurrence and properties of

tin in food.

Occurrence in Food

0002 The presence of tin in food is primarily the result of

man’s use of the element. The greatest exposure is the

result of the use in cans in which food is preserved.

Rather strong acid solutions are necessary for dissol-

ution of the metal, so usually, very little of the element

found its way into food kept in metallic containers

which were either lined with tin or sealed with

solders, leaving tin as one of the ingredients. (See

Canning: Principles.)

0003 Its metallic form has been used from very early

times as a foil and in alloys such as Babbitt (Sn, Cu,

Sb), bronze (Sn, Cu), pewter (Sn, Pb), solder (Sn, Pb),

and type metal (Sn, Pb, Sb). Contact with these alloys

may allow tin to leach into foods.

0004 Although not in food, exposure to tin chemicals

may occur through their use in dentistry. Tin(ii) fluor-

ide is used as an aid in preventing tooth decay through

its presence in toothpastes, topical solutions, and

mouthwashes.

0005 More recently, a number of organotin compounds

have been used as a stabilizer for the plastic PVC, as a

fungicide in paints, and for wood treatment. In most

uses, there is no direct contact of the organotin com-

pounds with food products, and whatever appears in

the food chain is the result of extraction from the

material containing the organotin compound. These

compounds will be discussed in greater detail in

separate sections.

Properties of Tin Compounds

0006 The compounds of tin may be classified as inorganic

or organic. The properties of the various forms and

the reactions that would cause the element to appear

in the food chain are considered.

Inorganic

0007Tin usually occurs as the metallic element in pure or

alloyed state, or as compounds in the divalent stan-

nous form or the tetravalent stannic form. The use of

the metal to coat cans and other containers of food

has been common for many years. The occurrence of

compounds of inorganic tin most likely to be found in

food result from dissolution of the metal.

0008Initially, tin would be dissolved by an acid and

would be in the divalent form. To keep the metal in

this form, the solution must be quite acidic, and the

element forms complexes of the form [SnX

]



, where

X may be a halide or one of several other anions.

Also, to keep the tin in the divalent form, it must be

kept under an inert atmosphere such as carbon diox-

ide. In dilute solution, the Sn(ii) compounds undergo

hydrolysis, giving hydrated tin(ii) oxide, which is not

very soluble. The extent of hydrolysis depends upon

the pH of the solution. In the usual pH range natur-

ally encountered in foods, rather extensive hydrolysis

occurs. In concentrated solution in the presence of

oxygen (air), the divalent form is oxidized to the

tetravalent Sn(iv) state, the ease of oxidation increas-

ing with pH. In very strong alkaline solutions, spon-

taneous disproportionation to the metal Sn and Sn(iv)

can occur. The divalent stannous form is a strong

reducing agent, and it functions as such in many

reactions.

0009Most of the inorganic forms of tin found in solu-

tion or combined with some solid material are in the

tetravalent form. Tin(iv) oxide, the form most abun-

dant in nature, dissolves in aqueous solutions of both

acids and alkalis. The predominant species present in

acid solutions containing complexing anions is

[SnX

]

2

, where X may be a halide or one of several

other anions. In strongly alkaline solutions, the main

species is [Sn(OH)

]

2

. In dilute solution in the ab-

sence of complexing agents, all aqucous solutions of

Sn(iv) tend to hydrolyze to give a precipitate of

hydrated tin(iv) oxide. The halide SnCl

, is a liquid

with a boiling point of 114



Organic

0010Organic derivatives of both divalent and tetravalent

tin are produced by man in significant quantities for

various purposes. The preparations and structures

of many of these compounds have been studied

extensively. The divalent compounds are mostly of

TIN 5785

academic interest and would not be encountered eco-

logically. Tetra-, tri-, and disubstituted tin(iv) com-

pounds have been used extensively for a number of

purposes in recent years. Tetramethyltin is a very

good alkylating agent for the transfer of a single

methyl group. It has been used to convert inorganic

mercury to the monomethylmercury chloride for

measurement of small quantities by gas chromatog-

raphy. (See Mercury: Properties and Determination.)

0011 The property of most interest in the treatment of

samples for speciation is solubility. The dimethyltin

and trimethyltin chlorides and bromides are water-

soluble. Similar ethyl compounds are somewhat less

soluble in water. The tin compounds with larger alkyl

and phenyl groups are very slightly soluble or insol-

uble in water. The tetra-substituted compounds are

all insoluble in water.

0012 When the various compounds enter the environ-

ment, their fate is of importance. At near neutral pH

and normal environmental temperatures, alkyl and

aryl tin compounds are stable in the dark, but break-

down occurs in ultraviolet light. This has been ob-

served with compounds of trimethyltin, tributyltin,

and triphenyltin, in which sequential removal of the

alkyl groups occurs to yield finally inorganic Sn

4þ

Other mechanisms of breakdown by soil microorgan-

isms and fungi have been observed.

0013 The only significant formation of tin–carbon bonds

in the environment appears to be via methylation.

Monomethyltin was produced by an inoculum of

mixed microorganisms from Chesapeake Bay sedi-

ments with stannic chloride. An acrobic strain of

Pseudomonas (Ps 244) produced a variety of methyl-

tins from inorganic tin(iv) but very little from tin(ii).

Formation of methyltins by other organisms has also

been reported.

Analytical Methods

Sample Preparation

0014 In general, the analysis of the tin content of a sample

measures the total amount of the element. Most

methods used require a solution of the sample. To

extract the tin from an insoluble substance such as a

tin ore, an initial extraction with dilute nitric acid is

followed by a fusion of the insoluble residue with

sodium peroxide or an alkaline carbonate mixture.

Wet ashing procedures for samples such as tissues or

other biological material can be carried out using

concentrated nitric acid together with sulfuric acid.

Such a procedure will destroy the organic matter, so

that only the total tin content can be measured.

0015 For the successful analysis of an organotin

compound, some knowledge of the chemistry of the

compound is required. The solvent used for the first

extraction depends upon the compound of interest.

Aqueous combinations with tropolone with some or-

ganic solvent are the most common methods. The

method of analysis may be GC (gas–liquid chroma-

tography) or HPLC (high-performance liquid chro-

matography), again depending upon the compound

of interest. These methods will be discussed in a later

section. Sampling and the treatment of the sample are

of utmost importance. Tissue samples are usually

homogenized and then extracted. Complete extrac-

tion is difficult because of a relatively large emulsified

solids layer between the aqueous and organic layers.

One procedure to correct for this is to add a known

quantity of an organotin compound such as a tripro-

pyltin salt known not to be in the sample. The recov-

ery of this compound in the subsequent analysis will

give a correction factor for the compounds being

determined. For a number of compounds, the add-

ition of tropolone to the nonpolar solvent improves

the recovery in the extraction.

Instrumental Methods

0016In most laboratories, emission or absorption atomic

spectroscopy is usually used for measuring the tin

content of a sample. Tin can be analyzed with a

standard emission spectrometer. The newer high-

temperature DC (direct current) arc or ICP (induct-

ively coupled plasma) spectrometers are best.

0017Atomic absorption spectrometry is the most sensi-

tive method available. For the analysis of tin, a ni-

trous oxide–acetylene flame must be used. Modern

instruments with a graphite furnace are best. Here,

only a small sample (c.20ml) is required. Using the

programmed temperature facility, the sample is dried,

then volatilized and decomposed.

0018The detection limits for the atomic spectroscopic

methods are:

0019Emission spectroscopy 30 mgl

1

0020Flame atomic absorption (AA) 100 mgl

1

0021Hydride generation AA 4 mgl

1

0022Graphite furnace AA 0.2 mgl

1

Chemical Methods

0023The early methods for the analysis of tin were gravi-

metric and titrimetric, depending on the quantity to

be measured. These techniques required the separ-

ation of the element prior to the final measurement.

In the gravimetric method, tetravalent tin is precipi-

tated as metastannic acid, as the sulfide, or with a

reagent such as cupferron after first separating it from

interfering ions. The insoluble tin compound is

filtered off, ignited to SnO

, and weighed.

5786 TIN

0024 Titrimetric methods involve reducing the tin to

tin(ii) and then oxidizing it to tin(iv) with an iodine

or iodate solution. The stannous form is readily oxi-

dized in the presence of air, and for accurate work, the

reaction is carried out under an atmosphere of CO

A method using tin(iv) makes use of the oxalatostan-

nate complex, which will incorporate one molecule of

sulfide to form the oxalatothiometastannate com-

plex. The amount of sulfide may be measured by

titration with iodine.

Chromatographic Methods

0025 The early analyses of organotin compounds were by

GC, both conventional and, more recently, with ca-

pillary columns being used. The most common orga-

notin compounds are those that are used as fungicides

in paints or sprays. These include tetra-, tri-, and

dimethyltin compounds, and the homologous ethyl

compounds as well as some phenyl derivatives. GC,

which would seem to be an obvious choice to distin-

guish among the various substituted organotin com-

pounds, must be used with caution. The problem

arises from the fact that elevated temperatures must

be used to volatilize some of the compounds, and at

elevated temperatures, some of the compounds will

undergo transformation. There is a further compli-

cation if a mixture contains both tetramethyltin and a

dimethyltin compound. Tetramethyltin is a good

methylating agent, and the dimethyl compound will

be methylated to a trimethyltin compound. (See

Chromatography: Thin-layer Chromatography.)

0026 In order to be able to operate at lower tempera-

tures, some of the organotin compounds, such as

certain halides, are converted to more volatile species.

Among the more common methods used are the re-

placement of the halide by a methyl or ethyl group, or

the formation of the organotin hydride.

0027 HPLC has become the method of choice for many

analyses, as decomposition of the compounds being

analyzed does not occur in the liquid phase at the

lower temperatures used. For the separation of

methyltin compounds in HPLC, a mobile phase of

60 parts acetone and 40 parts n-pentane is used. For

ethyltin compounds, a mixture of 70 parts acetone

and 30 parts n-pentane is used. As elevated tempera-

tures are not used, the redistribution of species that

occurs during GC is not encountered. (See Chroma-

tography: High-performance Liquid Chromatog-

raphy.)

Effects of Dietary Tin

0028 Most of the tin ingested from canned food has been

inorganic and has been considered low because of

its poor absorption and retention in tissues. Many

studies have been conducted at cellular levels using

Escherichia coli and yeast cells to determine the effect

of tin. It is not certain whether these studies may be

applicable to humans.

0029By using controlled diets fed to weanling rats over

prolonged periods of time, Rader and coworkers have

made an extensive study of the effects of 100–1100 mg

per gram of dietary tin on tissue and bone minerals of

these weanling rats. The level of tin used in these

studies was within the range of values reported for

tin present in unlacquered cans. The total food con-

sumption was restricted to the amount consumed by

the rats fed 1100 mg of tin per gram. The amount of

tin in the food of any rat was constant for a period of

4 weeks Food consumption by rats fed diets contain-

ing 0, 100, and 330 mg of tin per gram was measured

weekly. After 4 weeks, the rats were sacrificed, and

serum was prepared from the blood. Soft tissues were

taken from liver, kidney, and duodenum. Femurs were

also taken for examination. Serum ceruplasmin and

cholesterol were then measured.

0030The results of these studies indicate that anemia

and growth depression are common effects of chronic

ingestion of inorganic tin. Low levels of dietary tin

primarily affect copper and zinc status. Pronounced

copper depletion in all tissues examined was observed

at tin levels as low as 30 mgg

1

. Growth depression

generally occurs when dietary tin levels exceed

500 mgg

1

. Diets high in copper and iron (50 and

250 mgg

1

) reduced the signs of anemia in rats fed

tin at levels up to 1500 mg of tin per gram.

0031In normal animals, about 90% of copper in plasma

is contained in ceruloplasmin. The finding of dietary

decreased ceruloplasmin in tin-treated rats is consist-

ent with the observation of decreased copper in

plasma of rats fed diets containing more than 200 mg

of tin per gram. Copper plays a major role in bone

metabolism through its involvement in collagen

cross-linking. The levels of copper and iron have

been shown to affect anemia in rats.

0032Reduced growth is a common symptom of zinc

deficiency. Low dietary tin adversely affects the

growth of rats fed zinc-adequate diets. These studies

on weanling rats indicate that many effects of inor-

ganic tin have effects that are not directly attributed

to tin, as in the case of reduced growth, even in zinc

adequate diets.

0033The effects of continuous ingestion of small

amounts of tin that reduce the quantity of essential

elements to the levels that slow down growth and

cause anemia have emphasized the importance of

reducing the possible intake of tin. Since the principal

source of tin is in containers used for food including

cans, and items such as cans, trays, and other items

TIN 5787