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

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performed by adding acid or an acid mixture to the

test portion and boiling until digestion is complete.

0028Numerous wet oxidation procedures have been

proposed but they all fit basically into three categories

of digestion mixtures: (1) HNO

and H

, (2)

HCl, H

,andH

and (3) mixtures containing

HClO

. Wet digestion is frequently criticized because

elemental loss by volatilization can occur if the tem-

perature of the digestion vessel is greater than 250



A variety of procedures have been developed using

different types of digestion apparatus to retain vola-

tile elements. ‘Hot-block’ digesters have been used for

improved temperature control and their reflux cap-

abilities and ‘PTFE (polytetrafluoroethylene) bomb’

digesters have been used because digestion can take

place in a sealed vessel, thereby retaining volatile

elements.

0029The latest papers tend to suggest that the method of

wet digestion in a microwave oven is perhaps the

most interesting development in sample preparation

tbl0001 Table 1 Cadmium levels (ng g

1

) in individual food categories

Food category Cdlevel Foodcategory Cd level

Milk and dairy products

Butter 0.26–1.33

Dairy products 1–3

Cheese 0.42–0.84

Icecream, mixed 1.85–5.55

0.18–0.55

3–40

3.15–5.63

Cheese, processed 0.35–57.8

Pasteurized milk 0.69–0.89

Milk, whole 0.13–0.80

Yogurt, mixed 0.38–1.60

0.044

0.56

1–2

Meat and poultry

Meat 2–36

Luncheon meat,

canned

1.13–5.09

Beef steak, raw 0.56–4.73

Pork sausage 20–36

i, j

Beef meat 1–40

Meat products 3–75

Pork, raw 0.46–15.8

Veal, raw 0.64–9.09

Pork, cured 2.90–14.7

Lamb, raw 0.53–1.73

Ham, boiled and

cold

37–51

i, j

Poultry, raw 0.76–3.14

Meat organs 85.1–167

Eggs 0.42–5.02

1–2

Fish

Fresh-water fish,

raw

0.54–7.72

Fish canned 8.36–13.8

Marine fish, raw 1.21–1.87

Fish and shellfish 20.4–300

Fish 7–97

Shellfish 8.10–38.6

Crayfish 0.032

Soups

Soups, meat,

canned

1.71–5.13

Tomato soups,

canned

7.64–15.1

Bakery goods and cereals

Apple pie 5.21–10.2

Oatmeal cereal 1.68–15.5

Bread 3–27

Pasta, plain,

cooked

15.6–39.3

Cake, chocolate 8.10–15.8

Pizza 13.6–27.5

Cake, white and

yellow

2.97–8.45

Rice cereal,

cooked

5.23–12.7

Cereal 3–15

Waffles and

pancakes

6.25–14.7

Cookies, all 13.3–20

White bread, all 17.2–35.9

Corn cereal 1.64–5.18

Wheat and bran

cereals

45.3–70.7

Crackers 17.5–26.8

Wheat flour 23.6–33.4

Danish and donuts 9.88–15.5

Vegetables

Beans, raw 1.38–3.76

Onions, raw 7.07–44.2

Broccoli, raw and

cooked

6.08–22.3

Peas, raw 1.92–4.04

Carrots, raw 17.8–38.9

Peppers, green

and red

11.5–22.8

Cauliflower, raw 4.59–28.2

Potatoes, raw 14.0–61.1

5–61

Celery 3.74–46.2

Potato chips 63.6–129.5

Corn, raw 1.86–23.6

Tomatoes, raw 5.51–13.4

Cucumber, raw 0.77–3.10

Tomatoes,

canned, ketchup,

sauce

25.8–42.2

Lettuce 5.63–71.1

Vegetables 4–17

Mushrooms, raw 5.05–18.2

Fruits and fruits juices

Apples 0.17–0.46

Fruits 1–2

Bananas 0.16–0.66

Melons 2.69–8.41

Citrus fruit, raw 0.14–1.91

Peaches, raw 1.38–4.88

Citrus juice 0.02–0.33

Pears, raw 1.57–6.05

Cherries, raw and

canned

0.70–27.4

Plums, raw 0.11–10.9

Grapes 0.22–1.05

Strawberries 11.0–22.7

Fats and oils

Fats and oils 0.3–1

Peanut butter

and peanuts

31.1–62.2

Margarine 0.35–2.38

Sugar and candies

Sugar 0.20–0.48

Honey 0.12–2.61

2–20

Syrup 0.13–0.25

Candy,

chocolate

8.60–19.5

Jams 1.70–9.78

Candy, other 0.18–3.38

Beverages

Alcoholic

beverages

Soft drinks 0.07–0.32

Coffee 0.08–1.73

Wines 0.20–0.88

Tea 0.03–0.80

Beer, cans 0.08–1.61

Dabeka RW and MacKenzie AD (1995) J. Assoc. Off. Anal. Chem.78:

897–909.

Larsern EH and Rasmussen L (1991) Lebensm. Unters. Forsch. 192:

136–141.

Gabrielli Favretto L (1990) Food Add. Cont. 7: 425–432.

Zurera G, Sa

nchez PJ, Amaro MA and Moreno R (1997) Food Add. Cont.

14: 475–481.

Jeng SL, Lee SJ and Lin SY (1994) J. Dairy S ci., 77: 945–949.

Urieta I, Jalo

n M and Eguileor I (1996) Food Add. Cont. 13: 29–52.

Moreno R, Sa

nchez PJ and Amaro MA. y Zurera (1999) Milchwissenschaft

54: 210–212.

Kramer HL, Steiner JW and Valley PJ (1983) Environ. Cont. Toxicol.30:

595–599.

Yban

ez N, Montoro R, Catala R and Flores J (1982) Rev. Agroqui. Tecno.

Alimentos 22: 419–425.

Yban

ez N, Montoro R and Bueso A (1983) Rev. Agroqui. Tecno. Alimentos 23:

510–520.

Rinco

n F, Zurera G and Pozo R (1988) Archv. Environ. Cont. Toxicol.17:

251–256.

Harrison N (1993) In: Watson DH (ed.) Safety of Chemicals in Food. Chemical

Contaminants. England: Ellis Horwood.

736 CADMIUM/Properties and Determination

techniques. Current systems incorporate many fea-

tures to improve digestion time, element recoveries,

contamination, and safety. Improved recoveries can

be achieved with systems operating under power-

regulated control of pressure because these systems

allow digestion to be completed without venting vola-

tile elements. Sealed digestion vessels also reduce acid

consumption and, in combination with Teflon con-

struction, reduce contamination problems.

0030 The advantages of microwave digestion with re-

spect to the dry-ashing sample preparation method

(at 550



C) are rapid dissolution, complete digestion,

sample integrity, minimal reagent use, lower reagent

blank, simultaneous multiple sample digestion, pos-

sible automation, and contamination-free digested

samples.

0031 For the determination of cadmium in brine shrimp,

four different digestion procedures were compared

(dry ashing, wet ashing on a hot-block, high-pressure

bomb digestion and microwave-oven digestion) and

the conclusion was that microwave digestion (in

polyethylene autosampler cups) was an excellent

technique for the rapid digestion of submiligram

amounts of biological materials.

0032 Dry ash digestions use a long, slow ashing step,

usually performed overnight in a muffle furnace,

accomplished by high-temperature oxidation. The

critical requirements are: (1) the nature of the ashing

vessel; (2) position in the muffle furnace; (3) ashing

temperature; and (4) time. Silica is probably one of

the best materials for the ashing vessel, although glass

beakers and well-glazed porcelain crucibles are also

suitable. A critical initial requirement is to keep the

temperature sufficiently low to prevent flaming or

burning.

0033 The ashing process is completed by the addition of

a small quantity of inorganic acid to the residue and

evaporation on a hot plate. The residue is redissolved

in acid and the solution is brought to volume with

distilled or deionized water. Element loss during the

ashing process is greater for dry ash procedures than

for wet ash procedures and ‘ashing aids’ are often

employed to prevent loss of the more volatile elem-

ents. The addition of 1:1 dilute sulfuric acid to food

materials prior to dry ashing eliminates losses of cad-

mium, although losses due to volatilization are pos-

sible as well as lack of recovery due to the formation

of insoluble silicates.

0034 Both techniques, wet oxidation and dry ashing,

give reasonably comparable results and, in may in-

stances, it is the analyst who makes the difference

whichever technique is employed. However, wet

digestion is recommended, using sulfuric acid and

hydrogen peroxide: dry ashing can result in low

recoveries since cadmium is volatile at temperatures

over 500



C, temperatures of below 450



C being

more appropriate. Furthermore, the digestion proced-

ure selected needs to be tested for appropriate quality

assurance and quality control guidelines that include

the use of contamination control, digestion blanks,

spiked test portions, replicate analyses, an appropri-

ate reference material, and recovery calculations.

Analytical Techniques

0035Analysts nowadays have a number of techniques to

choose from when making an elementary assay. The

choice to be made depends on a number of factors, such

as accuracy, precision, detection limit, sensitivity, the

user’s experience, performance with standard samples,

and safety considerations. However, it may be the more

practical considerations of instrument availability,

cost, and sample form and quantity that become the

governing factors rather than the choice being based on

the above criteria. The analyst’s skill, past experience,

or lack of experience may dictate the selection of the

analytical technique chosen. Personal preference may

equally be a significant factor in this decision. (See

Analysis of Food; Heavy Metal Toxicology.)

0036Spectrometric techniques are most commonly used

and include flame atomic absorption spectrometry

(FAAS), graphite furnace, or electrothermal atomiza-

tion atomic absorption spectrometry (ETAAS) and

inductively coupled plasma-atomic emission spec-

trometry (ICP-AES). (See Spectroscopy: Atomic

Emission and Absorption.)

0037The general trend for solid sample introduction is

slurry atomization. The slurries are prepared by grind-

ing the sample with 3-mm diameter ZrO

beads in a

laboratory shaker or mixing by ultrasonic agitation

with dilute HNO

. For determination of cadmium in

protein foodstuffs and vegetables by ETAAS, the

samples were stabilized with a thixotropic agent (Vis-

calex HV-30); to aid ashing O

was added during the

ashing phase of the furnace program and matrix

modifiers (NH

and Pt) were included. The

size of the food sample particles determined the sta-

bility of the slurry and also influenced the extent of

matrix and chemical interferences. With respect to

the direct insertion of solid samples into a graphite

furnace, the use of a novel graphite tube described as

a ‘ring chamber tube’ is reported; this obtains good

accuracy for National Bureau Standards (NBS) and

Standards Reference Materials (SRMs).

0038The main area of research in liquid sample intro-

duction is based on flow injection systems to improve

the analytical sensitivity. Preconcentration proced-

ures are described, such as the use of microcolumn

packed with a chelating resin. The compounds used

most commonly as ligands are dithiocarbamates such

as ammonium pyrrolidine dithiocarbamate (APDC),

CADMIUM/Properties and Determination 737

diphenyl thiocarbazone (dithiozone), and others.

They vary in their selectivity and are usually very

dependent on the pH at which extraction is carried

out. The organic solvent used most is methyl isobutyl

ketone (MIBK).

0039 The gaseous sample introduction is of a particular

interest in the food industry, for technological and

toxicological reasons, to determinate Sn, Se, As, and

Hg in food samples by hydride generation AAS. For

analysis of cadmium in food, the hydride generation

is not used extensively.

0040 Developments in methodology for atomic absorption

spectrometry Atomic absorption spectrometry has

been the most popular method for metal determin-

ation in general and the most widely used technique

for analyses of trace elements in foods. The popular-

ity of this method arises from its analytical specificity,

good detection limits, excellent precision, and rela-

tively low cost. The atomic absorption spectropho-

tometer consists of a light source (wavelength for

Cd ¼ 228.8 nm), an atomization source, and a disper-

sion/detection device. Three types of atomizers are

commonly used: flame, graphite-furnace and chem-

ical vaporization.

0041 With regard to FAAS, the air–acetylene gas mixture

is the most commonly used, producing a flame of

about 2400



C, but it is not totally interference-free.

There are various ways to improve FAAS sensitivity

for determination of cadmium in foods, such as the

use of slotted quartz tubes, atom-trapping techniques

(water-cooled and slotted-tube atom traps), where

atoms are trapped (condensed) on to a cool silica

tube which is situated in an air-C

flame and flow

injection systems with incorporation of miniprecon-

centration columns.

0042 Graphite furnace or ETAAS has been used for

the measurement of selected elements, including

cadmium, when FAAS detection limits were insuffi-

cient. Perhaps the main development has been the

introduction of graphite probe atomization to

ETAAS.

0043 The main problems with FAAS and ETAAS analy-

sis are matrix and spectral interferences. Deuterium

arc and Zeeman-effect background corrections have

been applied to reduce spectral interference in cad-

mium analysis. While deuterium arc background

corrections are generally inadequate, Zeeman-effect

background correction appears to be satisfactory for

routine analysis. Various ‘matrix modifiers’ (organic

and inorganic reagents) have been used to reduce

matrix effects, such as molybdenum, lanthanum,

and ammonium dihydrogen phosphate. Solvent ex-

traction of cadmium complexes is another approach

taken to minimize matrix effects.

Developments in Multielement Analysis

0044Inductively coupled plasma (ICP) excitation has

revolutionized the field of emission spectroscopy,

providing the analyst with a powerful multielement

technique with good sensitivity for cadmium at

214.440 or 226.502 nm. Food and food products

can be prepared for ICP analysis by either wet oxida-

tion or dry ashing and samples with a wide range of

elemental concentrations can usually be handled

without the need to dilute or concentrate, since the

ICP has a fairly large dynamic range. The current

qualities of ICP – high speed, low detection limits

(less than 0.01 mg kg

1

for cadmium), and excellent

instrument stability – make this technology attractive

for a wide range of analytical applications.

0045ICP-AES is used preferentially due to the possibility

of handling a wide range of samples with minimum

interference and of quantifying many of the metals,

reducing analysis time, and providing a more sensi-

tive determination of refractory elements. The poten-

tial of inductively coupled plasma mass spectrometry

(ICP-MS) is affected by polyatomic interferences

for some mineral elements that can be overcome by

different sample introduction methods (hydride gen-

eration, flow injection, slurry nebulization) or separ-

ating procedures with chelating resins.

X-Ray Fluorescence (XRF) and Neutron Activation

Analysis (NAA)

0046X-ray fluorescence (XRF) and neutron activation

analysis (NAA) are the two main methods for non-

invasive in vivo determination of heavy-metal con-

centrations in humans. Various XRF techniques

have been developed for the measurement of cad-

mium, mercury, and lead, primarily in occupationally

exposed persons to evaluate whether these cadmium

concentrations could reveal previous occupational

cadmium exposure in humans. Today, the technique

can also be used for measuring kidney cadmium levels

in the general population.

0047Both techniques are being used in foods for the

analysis of trace elements. In XRF, a powdered

sample is bombarded with X-rays and the Ka line of

the element is measured using one of several different

detectors depending on the wavelength of the emitted

radiation. This technique is somewhat limited in

scope as to detected elements and their concentration

range. By XRF spectrometry is able to determine Cd

in food with a detection limit of 2.5 mgg

1

0048In NAA, the sample is bombarded with elementary

particles to light atomic nuclei to generate radioactive

nuclides. The properties and intensity of the resulting

radioactivity permit the identification and quantita-

tive determination of the elements present in the

738 CADMIUM/Properties and Determination

bombarded sample. The main advantages of neutron

activation are the excellent accuracy at microgram

and picogram ranges, matrix effects are minimal,

and the sample can be either liquid or solid in form.

For determination of Cd, the characteristics pertain-

ing to neutron activation are nuclear reaction with

114

Cd (n, g)

Cd, the half-life of the product is 54 h,

and sensitivity (g) 10

8

Electrochemical Methods

0049 The electrochemical methods are polarographic, both

direct and alternating current, and anodic or cathodic

stripping voltametry and polarography. Both tech-

niques rely on the fact that different metals require

the application of different electrical potentials before

they are deposited from solution on to the cathode.

The polarographic methods are suitable for dilute

solutions with sensitivities of 10

6

to 10

9

mol l

1

0050 Anodic or cathodic stripping voltametry is even

more sensitive than usual polarography. After the

cadmium ions have been preconcentrated from the

solution and amalgamated into a stationary hanging

mercury drop electrode, the process is reversed by

using a more negative potential than the reduction

potential of cadmium. Cadmium is oxidized and

stripped anodically, using a slowly increasing positive

potential. The measured current recorded during the

stripping step is a direct linear function of the bulk

concentration of cadmium. The detection limit for

cadmium determined by anodic stripping voltam-

metry was 1  10

9

mol l

1

0051 AOAC International indicates a multielementary

method including the determination of cadmium in

foods (AOAC Official Method 986, 15, 1996)

adopted as a Codex Alternative Approved Method

(type III) for anodic stripping voltammetry of cad-

mium, lead, and zinc in all foods, and another anodic

stripping voltammetry method for the determination

of Cd and Pb in foods (AOAC Official Method 982,

23, 1996), which is not applicable to fats and oils.

Speciation Studies

0052 The role of atomic spectrometric techniques in chem-

ical speciation is well documented using separation

techniques prior to cadmium detection. The type of

fractionation technique and its coupling to atomic

spectrometers can only produce meaningful results

when particular attention is paid to the methods

used for sample collection, pretreatment, and storage

to avoid the changes that can occur. The principal

applications in this field have been the use of ICP-

MS or ICP-AES as a multielement detector for high-

performance liquid chromatography (HPLC) for the

analysis of cadmium bound to metallothionein. Other

applications are ETAAS coupled with HPLC for the

determination of inorganic species. (See Chromatog-

raphy: High-performance Liquid Chromatography.)

0053All methods must be validated by the laboratory

prior to routine sample analysis by quality assurance/

quality recommended procedures to avoid variability

in reporting elemental contents in foods and improve

the quality and reliability of published analytical

results and data quality indicators. (See Quality As-

surance and Quality Control.)

See also: Heavy Metal Toxicology; Quality Assurance

and Quality Control

Further Reading

Benton Jones J Jr (1984) Developments in the measurement

of trace metal constituents in foods. In: Gilbert J (ed.)

Analysis of Food Contaminants, pp. 157–202. Barking:

Elsevier.

Codex Committee of Food Additives and Contaminants

(1999) Discussion Paper on Cadmium. CX/FAC 99/21.

Food Research Institute (1993) Food Safety, pp. 319–322.

New York: Marcel Dekker.

Harrinson N (1993) Metals. In: Watson DH (ed.) Safety of

Chemicals in Food. Chemical Contaminants, pp. 113–

115. London: Ellis Horwood.

Reilly C (ed.) (1991) Metal Contamination of Food, 2nd

edn. London: Elsevier.

Shibamoto T and Bjeldanes LF (1993) Introduction to Food

Toxicology, pp. 136–139. London: Academic Press.

Toxicology

M Nordberg, Karolinska Institutet, Stockholm, Sweden

Introduction

0001Cadmium toxicology has been extensively reviewed

during the last decades. Focus on food sciences and

nutrition has been directed to dietary food intakes

of cadmium in the population. Toxicity of metals

depends on the bioavailability, species, source, and

route of exposure. Nutritional factors such as protein,

calcium, zinc intake and iron status have an impact

on the toxicity of cadmium. Acidification of lakes

and soils influences the mobility of cadmium. In the

population, different groups and subjects, e.g. with a

low iron status (mainly women) have been identified

as being more susceptible to cadmium exposure. It

is thus important to identify vulnerable groups

when setting recommendations for daily intake of

cadmium.

CADMIUM/Toxicology 739

Importance

0002 Cadmium is considered an important world-wide

pollutant. In the environment, humans are exposed

to cadmium via food and drinking water. Cadmium

bromide and iodide is used in photography and

photoengraving, and cadmium sulfide (cadmium

yellow) is used in high-quality paints, glazes, inks,

and artists’ pigments. Cadmium is present in the air

as a result of incineration of household wastes and

emission from industry, and mining. Cadmium par-

ticles can be transported in the air over long distances,

and thus the ground and water can be contaminated

far away from the emission source. Cadmium

remains at levels depending on pH, bound to other

compounds, in the soil and water. The body burden of

cadmium is higher in smokers than in nonsmokers,

because tobacco often contains cadmium. The mech-

anism for toxicity of cadmium involves metallothio-

nein (MT), which also can be used as a biomarker in

environmental exposure to cadmium and in bio-

logical monitoring.

0003 Excessive exposure to cadmium gives rise to several

human diseases, with itai-itai disease being the most

severe. Cadmium has been shown to cause damage to

the reproductive organs and to induce carcinogenesis

in laboratory animals in organs such as the prostate

and testes. Long-term human exposures have given

rise to lung cancer in industrial workers. Cadmium

was classified in 1993 as a human carcinogen (Group

1) by the International Agency for Research on

Cancer (IARC), based on experience in experimental

animals and in welding environments, where inhaled

cadmium could cause lung cancer. Some uncertainty

exists in this assessment, based on recent data.

Because of the toxicological properties of cadmium,

legislation implying considerable restrictions in its use

has been passed in some countries. Industrial expos-

ures as well as exposures in the general environment

have to be kept below recommended exposure limits

in order to avoid adverse health effects.

0004 Discovered in 1917, cadmium is a soft, silver–white,

tasteless, and odorless metal. It is a group IIB element in

the periodic table with an atomic number of 48 and an

atomic mass of 112.411. It appears together with zinc,

but is softer, and is used, to some extent, in a similar

way to zinc. Cadmium is found as an impurity of

zinc carbonate, which, upon heating, changes color

due to cadmium impurities. Several natural isotopes

of cadmium exist. The melting and boiling tempera-

tures are 320.9 and 765



C, respectively.

0005 Cadmium occurs in the earth’s crust with an aver-

age distribution of 0.1 mg kg

1

and occurs naturally,

associated with zinc, in the geosystem. It is found in

sulfide ores, and many of the inorganic compounds,

e.g., chloride and sulfate, are soluble in water. Cad-

mium oxides and sulfides are regarded as almost

insoluble species of cadmium. Knowledge of cad-

mium’s solubility in biological media is limited.

Occurrence

0006The frequent use of fertilizer explains the increased

cadmium concentrations in the most heavily polluted

areas. Cadmium occurs naturally, is widely dispersed

in the environment, and is produced as a byproduct in

the production of other metals. Human exposure

occurs as a result of inhalation of cadmium-contain-

ing dust in industry and consumption of cadmium-

containing food in the general population. Owing to

its natural occurrence in the geo-environment, some

farming products, including tobacco, may be high in

cadmium. The concentration of cadmium can be 1–

2 mg per cigarette.

0007Cadmium is present in food as a natural component.

Foodstuff contains cadmium, with the highest con-

centrations being found in liver, kidney, cadmium-

contaminated rice, and shellfish.

0008The Swedish National Board of Food Safety has

calculated the contribution of cadmium from food-

stuff to give a daily intake of 12 mg per day. This

assumption is based on the concentrations of cad-

mium in foodstuff: meat, fish, and fruit 1–5; cereals,

potatoes, root fruits 10–50; bran 150 and kidney and

liver 100–400 mgkg

1

Metabolism and Kinetics

Absorption

0009Uptake of cadmium via inhalation is 5–35%,

depending on the aerodynamic properties, solubility,

and particle size. Higher uptake values are related to

aerosols with a small particle size, e.g., cadmium in

tobacco smoke. Uptake via the gastrointestinal tract

in humans is estimated to be 4.6–7%. For humans

with low iron stores, absorption values of up to 20%

can be seen. Nutritional factors and dose influence

the proportion that is absorbed. Conditions increas-

ing the uptake of cadmium via the gastrointestinal

tract include low intake of calcium, iron, zinc, and

copper. A high intake of fiber can result in a lower

level of intestinal absorption of cadmium.

Excretion/elimination

0010Excretion of cadmium via urine or feces largely

depends on the route of exposure. Urinary excretion

of cadmium has been demonstrated in a number of

experimental studies in laboratory animals to repre-

sent about 0.01–0.02% of the total body burden

740 CADMIUM/Toxicology

upon long-term exposure. In many mammalian

species, urinary excretion increases slowly upon

exposure to cadmium, and after renal damage has

occurred, excretion of cadmium increases. For

humans, it has been estimated that approximately

0.01% of the body burden is excreted in urine. Urin-

ary excretion, like the body burden of cadmium, is

age-dependent. If tubular proteinuria occurs, cad-

mium excretion increases. A high level of cadmium

excretion without proteinuria may occur in short-

term, high-level exposure. Cadmium is excreted in

urine bound to MT.

0011 Since it is not possible to distinguish net gastro-

intestinal excretion from unabsorbed cadmium in

feces, it is very difficult to study net fecal excretion

of cadmium. In oral cadmium exposure, approxi-

mately 95% of fecal cadmium represents unabsorbed

cadmium. Fecal cadmium can be used as an indicator

of oral intake. Studies of injected cadmium in experi-

mental animals show that, initially, fecal excretion is

greater than urinary excretion, calculated on a per-

centage basis. This is probably due to contribution

from the bile. Data on fecal excretion of cadmium in

humans are almost nonexistent.

Biological Half-life

0012 The biological half-life of cadmium in the kidneys is

estimated to be around 20 years in humans. Such a

long biological half-life explains why cadmium accu-

mulates constantly up to approximately 50 years

of age in humans. Cadmium accumulating in the

kidneys is probably largely bound to MT that is syn-

thesized de novo. This process may be responsible for

the long biological half-life of cadmium in the kidneys

and its accumulation in long-term exposure.

Toxicokinetics

0013 Cadmium accumulates in the body with age and has

an extremely long biological half-life. Because of its

long biological half-life of around 20 years, long-term

toxicity is of particular interest. Also, short-term

toxicity can be of interest. The kinetics of cadmium

is related to chemical species of cadmium. Cadmium

in the form of inorganic cadmium ions has a different

metabolic pathway in the body compared with cad-

mium as metallothionein. For all types of damage

caused upon cadmium exposure, MT is involved.

0014 Toxicokinetic aspects including the mechanism for

transport of cadmium to the kidneys by MT have

been extensively studied in mammals and have pro-

vided evidence indicating that MT is important for

transport of cadmium to the kidneys and that intra-

cellular MT protects renal tubule cells from toxic

insult by cadmium. The ratio of MT bound cadmium

and nonMT bound cadmium is highly important.

0015After a single exposure, cadmium in blood plasma

is mainly bound to albumin and other larger proteins

immediately after uptake from the gastrointestinal

tract or the lungs. There is time dependence, with a

larger proportion of plasma cadmium being bound to

low-molecular-weight plasma proteins (probably

MT) at longer time intervals after a single adminis-

tration. Cadmium bound to albumin is taken up in

liver. In liver cells, cadmium–MT complex is dissoci-

ated, cadmium not bound to MT induces de novo

synthesis of MT in liver cells, and the proportion of

liver-cadmium bound to MT increases. In long-term

exposure, there is a slow release of cadmium-MT

from the liver to the blood. As mentioned before,

after a single administration of cadmium, plasma-

cadmium is mainly bound to albumin, and this form

of cadmium is not taken up by the kidneys to any

great extent. However, for cadmium injected into

plasma as MT, the opposite is found, which means

that a major part is taken up in the kidneys. In

the tubular cells of the kidneys, the cadmium–MT

complex is transported into the lysosomes, where

MT is catabolized. The rate of influx of cadmium–

MT into the renal tubular cell and the rate of de novo

synthesis of MT in these cells regulates the pool of

intracellular ‘free’ cadmium ions that can interact

with cellular membrane targets in the tubules. When

cadmium–MT influx into the lysosomes is limited,

MT synthesis may be sufficient to produce enough

MT to bind the limited amounts of cadmium. The

‘free’ cadmium pool is small, and no membrane

damage occurs. Calcium transport in the cell is

normal. When cadmium–MT influx into the lysoso-

mal compartment is high, and de novo synthesis of

MT is deficient, the ‘free’ cadmium pool is sufficiently

large to interact with membrane targets to block cal-

cium transport routes. This results in impaired uptake

and transport of calcium through the cell with subse-

quent cell damage and increased excretion of calcium

and proteins in urine. Cadmium–MT injection has

frequently been used as a model to study several

features of nephrotoxicity seen in long-term exposure

to cadmium.

0016There has been some controversy over the role of

cadmium–MT as a sequestering agent in the course

of cadmium-induced renal tubular toxicity, and also

the sensitive site in the cell has not been identified.

0017A role of metallothionein in transport of cadmium

and nephrotoxicity, in modulating cadmium hepato-

toxicity was advanced in the 1970s and has gained

further support over the years. Cadmium bound to

albumin is taken up in the liver. By transplanting

cadmium-containing livers to noncadmium-exposed

animals, i.e., animals with almost no tissue concen-

tration of cadmium, a gradual uptake of cadmium in

CADMIUM/Toxicology 741

the kidneys was demonstrated. These results support

the transport model of cadmium in the body.

0018 Iron deficiency increased levels of MT-1 in bone

marrow of rats with hemolytic anemia, whereas the

unchanged concentrations in liver and with a reduced

renal concentration of MT indicate that MT-1 in

blood reflects erythropoietic activity. This might ex-

plain how iron deficiency increases the absorption of

cadmium. Cadmium is also recognized as a potent

inducer of MT synthesis. Heavy exposure to cadmium

gives rise to hemolytic anemia with increased urinary

excretion, supporting the involvement of MT.

Health Problems Upon Cadmium

Exposure

0019 Cadmium has health effects upon both acute and

long-term exposure.

Acute Toxicity

0020 Cases of acute toxicity have been described in the past

from ingestion of cadmium-contaminated food or

drink. The symptoms of acute toxicity are nausea,

vomiting, and abdominal pain. Acute toxicity after

ingestion of drinks with more than 15 mg per liter of

cadmium occurred in children after exposure to

cadmium via a soft-drink machine. High cadmium

concentrations can occur if acid food comes into

contact with cadmium-plated utensils. A fatal case

has been described after oral intake of a high dose

of cadmium–iodine.

Chronic Toxicity

0021 Human disease has occurred in some special situ-

ations, such as itai-itai disease in Japan, and renal

dysfunction and increased occurrence of bone effects

in Belgium and in China as a result of long-term

effects related to cadmium pollution of the general

environment.

0022 Long-term exposure to cadmium via air, food, or

water increases the cadmium concentration in the

kidneys and gives rise to kidney disease. Other

adverse effects that may be caused by cadmium

exposure are lung damage, bone effects, liver dys-

function, and reproductive toxicity.

0023 Chronic cadmium poisoning occurs as a result of

long-term intake of food with increased cadmium

concentrations or long-term inhalation of airborne

cadmium in industry. Inhalation of cadmium affects

the lungs. The most prominent adverse health effects

upon long-term exposure to cadmium, regardless of

exposure route, are renal tubular dysfunction and

glomerular disturbance.

0024 One of the most extreme forms of disease related

to cadmium exposure by the oral route is itai-itai

disease, described in Japan in the 1960s. Itai-itai

disease is characterized by osteomalacia, osteo-

porosis, renal tubular dysfunction, malabsorption,

and anemia. The bone effects are prominent features

in humans suffering from itai-itai disease. The char-

acteristics are multiple fractures and deformities of

the spine and the long bones, and so far, these have

been described only in Japan. Patients would suffer

a considerable reduction in body height due to

deformities of the spine, resulting from multiple

compression fractures. In the long bones, characteris-

tic pathologic fractures with osteoid formation (Milk-

mans pseudofractures) occurred, which is a typical

finding in osteomalacia. Other characteristics in-

cluded increased excretion of cadmium in urine and

kidney damage with proteinuria. Itai-itai disease was

a form of renal osteomalacia. The cadmium contam-

ination of rice was due to cadmium contamination

from a smelter that discharged material into the Jinzu

River, which was used for irrigation of rice fields.

Postmenopausal women were affected almost exclu-

sively. The low calcium content of Japanese food may

have been a contributing factor, like the tradition of

dress to screen away from the sunshine, which gave

the women only a low contribution of vitamin D,

synthesized by the action of UV-light on the skin.

0025Epidemiological studies starting in the 1980s from

Belgium, e.g., Cadmibel and PheeCad, concerning

adverse health effects in humans in Belgium in the

general environment reported an increased incidence

of health effects occurring at much lower tissue con-

centrations of cadmium than were previously con-

sidered to be related to adverse effects by cadmium.

It is interesting to investigate whether bone mineral

disorders due to oral intake of cadmium can be re-

lated to the estrogen receptor, since it is known that

itai-itai disease occurred almost exclusively in post-

menopausal women. It has been reported that poly-

morphism for the estrogen receptor alpha is related to

a reduction of bone mineral density in postmenopau-

sal women in Japan. The genetic distribution of the

receptor was, however, the same in itai-itai disease

subjects. Nothing has been reported for the estrogen

beta-receptor.

0026Epidemiological evidence indicates that diabetics

might have an increased susceptibility to develop

renal dysfunction upon cadmium exposure.

Kidney

0027Cadmium is a toxic metal with an extremely long

biological half time, 15–20 years in humans. Upon

exposure, adverse health effects may occur primarily

as renal tubular dysfunction. Thus, the kidney is

regarded as a critical organ independent of the

exposure route. Cadmium is classified as a human

742 CADMIUM/Toxicology

carcinogen based on the occurrence of lung cancer

after inhalation.

0028 After uptake cadmium in the blood is initially

taken up by the liver and subsequently slowly redis-

tributed to the kidneys because of its binding to

the low-molecular-weight protein, MT. Cadmium

bound to this protein in blood accumulates selectively

in the kidneys. In long-time exposures, cadmium

gradually accumulates, particularly in the kidneys

but also in other tissues. When the concentration in

the kidney cortex reaches 50 mg kg

1

or higher,

damage to renal tubular cells may occur in the most

sensitive persons, and the kidneys have a decreased

ability to reabsorb proteins with increased concen-

trations of low-molecular-weight proteins and cal-

cium in urine. As a result of long-term calcium

losses and other metabolic changes related to the

renal damage, osteoporosis, and, in severe cases,

osteomalacia, occur (itai-itai disease; see Chronic

Toxicity).

0029 Cadmium-induced renal dysfunction influences

cellular calcium metabolism. Cadmium accumulates

in the kidneys, probably largely bound to MT that is

synthesized de novo. This process may be responsible

for the long biological half-life of cadmium in the

kidneys and its accumulation after long-term expos-

ure. The biological half-life of cadmium in the kidney

is estimated to be around 20 years in humans. This

explains why cadmium accumulates constantly up to

approximately 50 years of age in humans. Renal tox-

icity develops when the total tissue concentration of

cadmium in the renal cortex reaches levels between

50 and 300 mgg

1

. Renal tubular dysfunction occurs

in various individuals at different total concentrations

of cadmium in the kidney, depending on the variation

among individuals in the ability to synthesize MT and

other protective components.

Liver

0030 Liver toxicity caused by cadmium can be modified by

MT. Cadmium bound to albumin is taken up in the

liver. Upon catabolism of MT, unbound cadmium is

free to cause toxicity to liver cells. This happens after

high cadmium exposure when MT levels are not high

enough to handle all nonbound cadmium ions, e.g.,

the ‘free’ cadmium ions, Genetic polymorphism can

influence the toxicity of cadmium, which is supported

by studies in laboratory knock-out animals. The

role of MT in cadmium-induced hepatotoxicity and

nephrotoxicity, as well as in zinc-induced protection

showed that MT-null mice were more sensitive to i.p.

CdCl

hepatotoxicity. Zinc pretreatment by subcuta-

neous injection increased hepatic MT 80-fold in con-

trol mice, but not in MT-null mice, and prevented

CdCl

hepatotoxicity in control mice only.

Endocrine Effects

0031Cadmium does not pass the blood–brain barrier,

except when exposure is via nasal mucosa. Low-

level cadmium exposure of lactating rats caused alter-

ations in brain serotonin levels in the offspring.

0032Epidemiological evidence indicates an increased

susceptibility in diabetics to developing cadmium-

induced renal dysfunction, which might be related

to changes in MT expression in diabetics.

0033Experimental studies on cadmium–MT nephro-

toxicity show an increase in genetically diabetic as

compared with normal Chinese hamsters. The Chi-

nese hamster develops a subnormal pancreatic insulin

release, insulin resistance in the liver, and sometimes

hyperinsulinemia. These animals develop diabetic

nephropathy with glomerular and increased effects

of the glomerulus. The exact mechanisms behind

cadmium-induced renal damage in diabetics need to

be elucidated by further studies.

Physiological Conditions and Pregnancy

0034Pregnant rats have a faster decrease in hepatic cad-

mium levels and a faster increase in kidney cadmium

levels compared with nonpregnant rats. Pregnant rats

also have higher plasma cadmium levels and MT levels

compared with nonpregnant rats. It is known from that

that placental necrosis, fetal death and a condition in

the dam similar to ‘toxemia of pregnancy’ develops

after injection of cadmium in the late stages of preg-

nancy, including congenital malformations. Changes in

brain development and related changes in brain

enzymes have been reported in pups from rats treated

orally with cadmium during pregnancy and lactation.

Cadmium does not pass the placental barrier. This may

have several explanations, including a sequestering role

of MT. MT increases in the placenta of smoking preg-

nant women. The fetus is likely to be protected from

cadmium exposure because the MT concentration in-

creases in placental tissue. Human fetal liver contains

MT rich in copper. There is a tendency in non-/ex-

smokers towards increasing cadmium-blood levels

during pregnancy, reaching a maximum at delivery,

whereas an opposite tendency has been shown for

smokers. The increase in nonsmokers may be related

to the mobilization of cadmium from the liver to the

blood during pregnancy.

Biological Monitoring

0035Biological monitoring of cadmium can be performed

by measurements of cadmium in blood and urine.

Cadmium in blood indicates ongoing or recent expos-

ure to cadmium, and cadmium in urine reflects body

burden. However, after external exposure to cadmium

CADMIUM/Toxicology 743

has stopped, blood cadmium also reflects the body

burden as the cadmium stored in the liver is released

into the bloodstream. A metabolic model for cadmium

can be used to estimate closeness to renal failure. Con-

centrations in urine and blood related to the risk of

adverse effects are presented in the section on Risk

Assessment below. Placental samples, if taken correctly,

constitute a useful material for monitoring cadmium

exposure in the human population. However, it is im-

portant to be aware that differences in cadmium within

parts of the human placenta exist. Placental cadmium

concentrations were four and six times higher than

maternal and umbilical cord blood cadmium, respect-

ively, Calcium, protein, and magnesia are excreted in

urine after exposure to cadmium.

0036 Cadmium analyses in biological samples should be

handled carefully. The risk of contamination during

sampling is largely due to contamination from

smokers and if the persons handling the samples are

smokers. Lack of knowledge of the smoking habits of

the subject such as whether they are a present smoker,

a previous smoker, or a person who has never

smoked, is an another pitfall in interpreting concen-

tration results in the sample. The long biological half-

life of cadmium can influence the results up to 10

years after cessation of smoking. It is important to

take into account smoking habits when drawing con-

clusions about the status of cadmium exposure and

risk of development of adverse health effects due to

cadmium exposure present or past. MT can be used

as a bioindicator in monitoring both exposure and

effects related to metal exposure. Humans with a low

iron status and diabetics have been found to be more

sensitive to cadmium exposure.

Risk Assessment

0037 Risk assessment serves as a basis of preventive action

for avoidance of adverse health effects in populations

exposed to chemicals. Whether an agent causes

reversible or irreversible effects is of importance in

determining whether an effect is to be classified as a

critical effect. It is important to define which charac-

teristics and which cut-off level are chosen. The crit-

ical effect of cadmium exposure both in the general

and work environment is renal tubular dysfunction.

Renal damage occurs at a much lower cadmium con-

centration than previously estimated. Evaluations of

recent studies in the general population concluded

that an average level of cadmium in urine of 2.5 mg

per gram of creatinine is related to a few percent

excess prevalence of renal tubular dysfunction. A

kidney cadmium concentration of 50 mg per gram of

cortex wet weight, is reached after decades of a daily

cadmium intake of 50 mg and results in excretion of

cadmium in urine of 2.5 mg per gram of creatinine.

This constitutes a higher risk of tubular damage than

indicated by earlier estimates. These risk estimates are

made for a population group in total. Estimates of

risks for the development of renal tubular dysfunction

have to be made for certain identified groups with

increased risk, such as subjects with low iron stores

and smokers. It has been suggested that a small per-

centage (1–5%) of such groups may develop renal

tubular dysfunction with a lifelong daily intake of as

little as 15 mg.

0038Oral intake of cadmium in high single dose via

food or drink gives rise to vomiting, abdominal

pain, and diarrhea in humans. Drinks of 16 mg of

cadmium per liter and higher, corresponding to a

dose of 3 mg and higher can result in the aforemen-

tioned symptoms. Long-term exposure via food in the

form of rice with concentrations of around 1 mg kg

1

which corresponds to an intake of 600 mg of cadmium

per day, causes signs of malabsorption and some less

pronounced symptoms. A weekly intake of 7 mg per

kilogram of body weight corresponds to a daily

intake of 70 mgor1mg per kilogram of body weight,

which is equal to the provisional tolerable weekly

intake (PTWI) for cadmium set at 500 mg. Lower

lifelong exposures via food or drinks cause renal

dysfunction in humans. This will likely reduce the

present PTWI considerably.

0039After intake of 43 mg per kilogram of body weight

as a single oral dose, early symptoms from the gastro-

intestinal tract in humans can be seen. This dose is set

as an estimated lowest-observed-adverse-effect level

(LOAEL) for a single dose of cadmium. Calculations

based on LOAEL and a safety factor of 3–10 give a

tolerable single dose between 0.3 and 1 mg (4–14 mg

per kilogram of body weight). Long-term exposure,

e.g. from months to a few years of daily intakes of

200 mg of cadmium (3 mg per kilogram of body

weight), might be tolerated with the lack of symp-

toms from the gastrointestinal tract.

0040These doses for humans have not, at present, been

connected with convincing evidence to cause repro-

ductive or developmental effects. Because of this, a

daily intake above 1 mg per kilogram of body weight

should not be acceptable because of sensitive subpo-

pulations such as children and pregnant or lactating

women and humans low in iron status.

0041The PTWI is set to allow a certain variation of intake

during a week provided that the weekly intake is not

exceeded. Exposures above PTWI have to be compen-

sated for by intakes below the PTWI for some time in

order to avoid effects of the cumulative dose by long-

term effects, e.g., renal dysfunction. Dietary intake of

cadmium has been estimated to be 12–50 mgperdayon

average in various countries. The FAO/WHO has set a

744 CADMIUM/Toxicology

PTWI of cadmium to 400–500 mg for adult persons,

which corresponds to approximately 1 mg per kilogram

of body weight for each day of the week.

0042 A drinking-water guideline value of 5 mgl

1

has

been set by the WHO, which the US Environmental

Protection Agency allows in drinking water. The

Environmental Protection Agency regulates the

cadmium concentration in lakes, rivers, waste sites,

and cropland. The US Food and Drug Administration

has a cadmium limit in food colors of 15 mg kg

1

Sweden lacks threshold limit values for cadmium in

food and is actively encouraging international organ-

izations to set recommendations for the concentra-

tion of cadmium in food. A national recommendation

restricts the intake of mammalian liver and kidney

to one to two per week, or no consumption at all,

depending on the age of the animal.

See also: Copper: Properties and Determination;

Physiology; Zinc: Properties and Determination;

Physiology; Risk Assessment