INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 24
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World Health Orgnization
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ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM
1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES
1.1.1. Properties and analytical methods
1.1.2. Sources and uses
1.1.3. Environmental levels and exposures
1.1.4. Chemobiokinetics and metabolism
1.1.5. Effects on experimental animals and man
1.1.6. Evaluation of health risks
1.2. Recommendations for further studies
2. PROPERTIES AND ANALYTICAL METHODS
2.1. Chemical and physical properties
2.2. Analytical methods
2.2.1. Air analysis
2.2.2. Water analysis
2.2.3. Food analysis
2.2.4. Analysis of biological materials
3. SOURCES OF ENVIRONMENTAL POLLUTION
3.1. Natural occurrence
3.2. Industrial production
3.3. Uses of titanium
3.4. Disposal of wastes
4. ENVIRONMENTAL LEVELS AND EXPOSURES
4.1. Levels in air, soil, water, and other media
4.1.2. Soils and sediments
4.2. Occupational exposure
4.3. Cosmetic and medical uses
4.4. Estimate of exposure of man through environmental media
5. CHEMOBIOKINETICS AND METABOLISM
5.1. Absorption, distribution, and excretion
5.1.1. Animal studies
5.1.2. Human studies
5.1.3. Biological half-life
6. EFFECTS ON ANIMALS
6.1. Acute toxicity
6.2. Subacute toxicity
6.3. Long-term toxicity
6.6. Teratogenicity and effects on reproduction
7. EFFECTS ON MAN - CLINICAL AND EPIDEMIOLOGICAL STUDIES
7.1. Clinical studies
7.2. Epidemiological studies
8. EVALUATION OF HEALTH RISKS TO MAN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM
Professor M. Berlin, Institute of Environmental Health,
University of Lund, Lund, Sweden
Dr R. Dolgner, Medical Institute for Environmental Hygiene,
Düsseldorf, Federal Republic of Germany
Dr G.J. Van Esch, State Institute of Public Health, Bilthoven,
Professor A. Furst, Institute of Chemical Biology, Harney
Science Center, University San Francisco, California, USA
Dr J.K. Piotrowski, Department of Chemical Toxicology,
Institute of Environmental Research & Bioanalysis, Medical
Academy of Lodz, Poland
Representatives of Other Agencies
Dr W. Hunter, Health and Safety Directorate, Commission of the
European Communities, Luxembourg
Dr E. Loeser, Institute for Toxicology, Wuppertal, Federal
Republic of Germany
Dr Y. Hasegawa, Medical Officer, Control of Environmental
Pollution and other Hazards, Division of Environmental
Dr R. Horton, WHO Collaborating Center for Air Pollution
Control, National Environmental Research Center, Research
Triangle Park, NC, USA (Temporary Adviser)
Health Organization, Geneva, Switzerland
Dr V.B. Vouk, Chief, Control of Environmental Pollution and
other Hazards, Division of Environmental Health, World Health
Organization, Geneva, Switzerland (Secretary)a
a Present address: National Institute for Environmental
Health Sciences, Department of Health and Human Services,
Research Triangle Park, North Carolina, USA.
NOTE TO READERS OF THE CRITERIA DOCUMENTS
While every effort has been made to present information in the
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delaying their publication, mistakes might have occurred and are
likely to occur in the future. In the interest of all users of the
environmental health criteria documents, readers are kindly
requested to communicate any errors found to the Division of
Environmental Health, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda which
will appear in subsequent volumes.
In addition, experts in any particular field dealt with in the
criteria documents are kindly requested to make available to the
WHO Secretariat any important published information that may have
inadvertently been omitted and which may change the evaluation of
health risks from exposure to the environmental agent under
examination, so that the information may be considered in the event
of updating and re-evaluation of the conclusions contained in the
* * *
A detailed data profile and a legal file can be obtained from
the International Register of Potentially Toxic Chemicals, Palais
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM
Further to the recommendations of the Stockholm United Nations
Conference on the Human Environment in 1972, and in response to a
number of World Health Assembly resolutions (WHA23.60, WHA24.47,
WHA25.58, WHA26.68) and the recommendation of the Governing
Council of the United Nations Environment Programme, (UNEP/GC/10, 3
July 1973), a programme on the integrated assessment of the health
effects of environmental pollution was initiated in 1973. The
programme, known as the WHO Environmental Health Criteria
Programme, has been implemented with the support of the Environment
Fund of the United Nations Environment Programme. In 1980, the
Environmental Health Criteria Programme was incorporated into the
International Programme on Chemical Safety (IPCS). The result of
the Environmental Health Criteria Programme is a series of criteria
The first draft of the present document was prepared by
Dr L. Fishbein, National Center for Toxicological Research, US Food
and Drug Administration, Jefferson, AZ, USA. The draft was
reviewed by the Task Group on Environmental Health Criteria for
Titanium and then revised and updated by Dr H. Nordman, Institute
of Occupational Health, Helsinki, Finland. Finally, the revised
document was circulated to the members of the Task Group for their
comments, in March 1982.
The Secretariat wishes to thank Dr H. Nordman for his help in
the preparation and scientific editing of the final draft.
The document is based primarily on original publications listed
in the reference section. However, several publications reviewing
the health effects of titanium have also been used. These include
reviews by Berlin & Nordman (1979), Browning (1969), CEC (1974),
Katari et al. (1977), Lynd & Hough (1980), Schroeder et al. (1963),
Stamper (1970), Stokinger (1963), US EPA (1973), Valentin &
Schaller (1980), and Vinogradov (1959).
Details of the WHO Environmental Health Criteria Programme,
including definitions of some of the terms used in the documents,
may be found in the general introduction to the Environmental
Health Criteria Programme, published together with the
environmental health criteria document on mercury ( Environmental
Health Criteria I - Mercury, Geneva, World Health Organization,
1976) and now available as a reprint.
* * *
Partial financial support for the development of this criteria
document was kindly provided by the Department of Health and Human
Services through a contract from the National Institute of
Environmental Health Sciences, Research Triangle Park, North
Carolina, USA - an IPCS Lead Institution.
1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES
1.1.1. Properties and analytical methods
Titanium is a grey metal with an atomic number of 22 and a
relative atomic mass of 47.9. It is extremely resistant to
corrosion and, in the form of a powder or dust, is highly flammable
and explosive. The most common oxidation state of titanium is +4,
but +3 and +2 states also exist. Titanium occurs in both a cationic
state (e.g., titanium chlorides, phosphates, and sulfates) and an
anionic state (e.g., calcium, iron, and sodium titanates). Metallic
titanium, titanium dioxide, and titanium tetrachloride are the
compounds most widely used in industry.
A wide variety of analytical methods has been used for the
determination of titanium in various media. Spectrographic and
photometric methods have been employed for the determination of
titanium in food and water. X-ray fluorescence and neutron
activation analysis have been widely used for the measurement of
titanium in air. Spark-source mass spectrography has been used to
determine titanium in biological samples, food, and water. Titanium
does not easily atomize and has a tendency to form refractory
oxides, which may influence the use of atomic absorption assays.
The detection limit for titanium in air using atomic absorption
spectrophotometry (AAS) is about 0.07 µg/m3. Using X-ray
fluorescence for the determination of titanium in air, a detection
limit of 0.011 µg/m3 can be achieved; for human tissues, a
detection limit of 0.3 mg/kg has been reported. Proton-induced
X-ray emission spectrometry can be used for the determination of
titanium in air and water.
1.1.2. Sources and uses
Titanium, the ninth most abundant element in the earth's crust,
is widely distributed. Metallic titanium is mainly used in the
aircraft industry and in the production of high-strength,
corrosion-resistant alloys. It is also used in the chemical
industry as a lining material, because of its corrosion-resistant
properties. Titanium dioxide is extensively used as a white
pigment in paints, enamels, plastics, and cosmetics as well as a
colouring agent in food. Titanium carbide is important in the
production of cutting tools. Titanium tetrachloride is the common
intermediate in the production of titanium catalysts and is also
used for the synthesis of organic titanium compounds. Smaller
amounts of titanium compounds are used in the electrical and dyeing
The main sources of contamination of the general environment
with titanium are the combustion of fossil fuels and the
incineration of titanium-containing wastes. In occupational
settings, exposure mainly occurs during the processing of titanium-
containing minerals, metallic titanium, and titanium dioxide.
1.1.3. Environmental levels and exposures
Owing to its great affinity for oxygen and other elements,
titanium does not exist in the metallic state in nature. The
average concentration in the earth's crust is 4400 mg/kg. Titanium
concentrations in the urban air are mostly below 0.1 µg/m3, though
levels exceeding 1.0 µg/m3 have been reported, especially in
industrialized areas. In rural air, concentrations are still
lower. In working environments, the air concentration may reach
several mg/m3. The titanium concentration in drinking-water
supplies is generally low, having an approximate range of 0.5-15
µg/litre. Large variations in the concentrations of titanium in
different types of foods have been reported. A typical diet may
contribute some 300-400 µg/day, but higher intakes ranging up to 2
mg per day have been reported.
1.1.4. Chemobiokinetics and metabolism
Quantitative information on absorption through inhalation is
lacking. Absorption of titanium from the gastrointestinal tract
takes place, but the extent of this absorption is not known. Based
on average titanium concentrations found in human urine of about 10
µg/litre, it can be calculated that the absorption is about 3%,
assuming a daily intake of at least 500 µg.
The highest concentrations of titanium have usually been found
in the lungs, followed by the kidney and liver. In most studies on
concentrations of titanium in blood, levels reported have been
about 0.02-0.07 mg/litre. Titanium crosses the blood-brain barrier
and is also transported through the placenta into the fetus. It
seems to accumulate with age in the lungs, but not in other organs.
In the two reports available, the biological half-life for titanium
in man has been calculated to be about 320 days and 640 days,
Most ingested titanium is eliminated unabsorbed. In man,
titanium is probably excreted with urine at an approximate average
rate of 10 µg/litre. Excretion by other routes is unknown.
1.1.5. Effects on experimental animals and man
There is no evidence of titanium being an essential element for
man or animals.
Studies on experimental animals as well as human clinical
studies have shown that titanium in implants and prostheses is
extremely well tolerated by osseous and soft tissues. This is
shown by lack of irritation, normal wound-healing, and
encapsulation of the metal by fibrous tissues. Titanium dioxide,
salicylate, oxide, and tannate have been used in various
dermatological and cosmetic formulations, without any known adverse
effects. However, exposure to different titanium compounds appears
to induce various levels of slight pulmonary fibrosis.
Titanium dioxide is a frequently used compound in lung
clearance studies, where a biologically inert substance is
required. Acute and subacute toxicity studies have not shown any
detrimental effects of titanium dioxide in the lungs. In some
experimental studies in which rats and guinea-pigs were exposed to
titanium dioxide dusts, slight fibrosis was occasionally found in
the lung tissue. However, the exposure in these studies was not to
pure titanium dioxide and a possible explanation for the fibrogenic
activity may be concomitant exposure to other elements, such as
silica (SiO2). Autopsy studies on workers exposed to titanium
dioxide for long periods have not shown any evidence of fibrogenic
activity. This is consistent with the few epidemiological surveys
made on working populations exposed to titanium dioxide dusts. In
one report, slight fibrosis was observed, but this may have been
due to the coating material containing aluminium silicate rather
than the titanium dioxide.
In studies on rats, intratracheal administration of 50 mg of
titanium nitride induced a weak fibrogenic effect after 6 months.
Slight fibrosis was detected in similar studies in which rats were
exposed to titanium hydride, boride, or carbide. Data on the
exposure of man to such titanium compounds are lacking.
Results of long-term toxicity studies showed that titanium, in
the form of a soluble salt, administered to mice in the drinking-
water at a concentration of 5 mg Ti/litre from weaning to natural
death, did not significantly affect life span. Feeding technical
grade titanium dioxide to guinea-pigs (0.6 g/day), rabbits (3
g/day), cats (3 g/day), and one dog (9 g/day) for 390 days did not
cause any adverse effects in the animals. Few data exist on the
systemic effects of titanium and its compounds. Intratracheal
administration of 50 mg of titanium hydride to rats induced
dystrophic changes in the myocardium, liver, and kidneys. Similar
effects were seen after administration of titanium boride or
carbide to rats.
A dose-related mortality rate was found in mice exposed to
hydrolytic products of titanium tetrachloride through inhalation
for 2 h (titanium compounds plus hydrochloric acid).
Accidental splashing of workers with titanium tetrachloride and
exposure to aerosols of titanic acid and titanic oxychloride led to
skin burns with scarring, and congestion of the mucosa in the upper
respiratory tract, followed later by cicatrization and laryngeal
stenosis. Accidental exposure to liquid titanium tetrachloride,
which was then washed off, resulted in severe burning of the skin,
due to an exothermic reaction between the titanium tetrachloride
The only carcinogenic effect of titanium, so far reported,
consisted of the development of fibrosarcomas at the site of
injection in rats injected with either titanium metal or titanocene
suspended in trioctanoin.
In a 3-generation study on rats, titanium potassium oxalate (5
mg/litre) in the drinking-water caused a marked reduction in the
numbers of animals surviving to the third generation.
1.1.6. Evaluation of health risks
Titanium compounds are poorly absorbed from the gastro-
intestinal tract, which is the main route of exposure for the
general population. Available data on the occurrence of titanium
and titanium compounds in the environment, as well as data on
toxicity, indicate that the current level of exposure of the
general population does not present a health risk. In the
occupational environment, exposure occurs through inhalation and
titanium is retained in the lungs. Dose-effect and dose-response
relationships have not yet been established for any of the effects
of various titanium compounds.
Titanium metal in surgical implants is well tolerated by
tissues and titanium compounds, such as titanium dioxide,
salicylate, and tannate, have been used in cosmetics and in
pharmaceutical and food products, without any reported adverse
A variety of animal and human studies have shown that inhaled
titanium dioxide is biologically inert. Weak fibrosis, found in
association with exposure to various titanium dusts, is likely to
be due to concomitant exposure to other components rather than to
the titanium dioxide.
According to animal studies, titanium nitride, hydride,
carbide, and boride may have fibrogenic effects. These compounds
have also been observed to cause liver and kidney dystrophy.
Titanium tetrachloride causes skin burns and is strongly irritant
to mucous membranes and the eyes. Powdered titanium metal may
induce fibrosarcomas and lymphosarcomas in rats, when injected
intramuscularly, but there is no evidence of titanium being
carcinogenic in man.
Administration of a soluble titanate disturbed reproduction in
a 3-generation study on rats. Teratogenic effects of titanium have
not been reported.
1.2. Recommendations for Further Studies
There is not sufficient information available on titanium, to
estimate the actual exposure of the general population from all
environmental media. Dose-effect and dose-response relationships
have not been established and it is therefore proposed that more
information be generated to cover the following aspects:
(a) environmental aspects; size distribution of particles in
ambient and occupational environments;
(b) metabolic aspects; balance studies including metabolic
(c) toxicological aspects; effects of various types of
titanium dust, taking into account differences in crystal
lattices; effects of titanium compounds such as the
nitride, hydride, boride, and carbide in short- and
(d) occupational aspects; effects of exposure to titanium
tetrachloride and organotitanium compounds.
2. PROPERTIES AND ANALYTICAL METHODS
2.1. Chemical and Physical Properties
Titanium (atomic number 22; relative atomic mass 47.90; density
4.507 g/cm3 at 20°C) is a silvery grey metal in group IV of the
periodic table and is a member of the first transition series of
elements. Titanium has both metallic and non-metallic
characteristics. Its most common oxidation state is +4 (titanic
compounds), but +3 (titanous compounds) and +2 forms are also
known, in addition to oxy forms such as titanyl chloride (TiOCl2).
The metallic characteristics of titanium are shown in compounds
such as titanium chloride, phosphate, sulfate, and nitrate, whereas
the non-metallic characteristics are exhibited in a series of
titanates, e.g., calcium, iron, and sodium titanates. Titanium(IV)
compounds are easily hydrolysed into titanium dioxide (Stamper,
1970; ACGIH, 1973; Weast, 1980).
Table 1. Some physical and chemical data on titanium and selected titanium
Compound Melting Boiling Solubility
point point Soluble Insoluble
Titanium (Ti) 1660±10 3297 dilute acids cold & hot water
- dioxide (TiO2) 1830-1850 2500-3000 alkalies, cold & hot water
- tetrachloride -25 136.4 cold water, decomposes in hot
(TiCl4) alcohol, water
- sulfate diluted acids cold & hot water,
(Ti[SO4]3) alcohol, ether
- carbide (TiC) 3140±90 4820 aqua regia, cold & hot water
a Adapted from: Weast (1980).
The metal is highly resistant to corrosion by many agents
including concentrated nitric acid, 5% sulfuric acid, and sea
water. Titanium powders are highly pyrophoric and molten titanium
burns in air. Thus, an explosion hazard is associated with the
production of the metal. Titanium and its alloys may react
strongly with oxidizing agents, especially when in the form of
powdered metal (Mogilevskaja, 1972; ACGIH, 1973). Titanium dioxide
(TiO2) is a white, tasteless powder. It exists in three crystalline
forms; anatase, brookite, and rutile.
Titanium tetrachloride is a liquid, which is stable in dry air,
but decomposes in cold water to form titanium oxide and hydrochloric
acid. The physical and chemical properties of titanium and some of
its compounds are listed in Table 1 (Stamper, 1970; Weast, 1980).
A large number of organotitanium compounds are known. The most
common types are the alkyl and aryl titanates of the general
formula Ti(OR)4. In addition, there are complex organic compounds
of titanium such as titanocene. Titanium has an atomic radius
similar to, and thus is capable of substitution for, other
transitional metals, e.g., vanadium, iron, cobalt, nickel, and zinc
(Barksdale, 1966; Stamper, 1970; Katari et al., 1977).
2.2. Analytical Methods
A wide variety of analytical procedures has been used for
the determination of titanium in various media. Spectrographic
and photometric methods have been employed for the determination
of titanium in food and water. X-ray fluorescence has been
widely used for the determination of titanium in air. Neutron
activation analysis has been employed to estimate titanium levels
in air and spark-source mass spectrography to determine titanium
concentrations in biological samples, food, and water.
Atomic absorption spectroscopy (AAS) is the generally preferred
method for the determination of trace elements. However, titanium
is not easily atomized in flame media and has a tendency to form
refractory oxides, which detracts from the usefulness of atomic
absorption assays. Nevertheless, a variety of atomic absorption
techniques has been reported using high-temperature reducing flames
such as the nitrous oxide-acetylene flame (Kirkbright et al.,
1969). Slavin & Manning (1963) achieved a sensitivity of 12
mg/litre (1% absorption) when determining titanium in an alcohol
solution. In order to obtain a higher sensitivity, indirect atomic
absorption techniques have been developed. The sensitivity
obtainable in the AAS determination of molybdenum being higher
than that of titanium, Kirkbright et al. (1969) used the
molybdenumtitanium ratio (11:2) in molybdotitanophosphoric acid.
The sensitivity obtained at 1% absorption was 0.0013 mg/litre. An
indirect method reported by Ottaway et al. (1970) is based on the
enhancement of the atomic absorption signal of iron by titanium.
This method is suitable for the determination of titanium in
concentrations of 0.01-10 mg/litre. Suppression of the absorbance
of strontium by titanium was used by Chakrabarti & Katyal (1971) in
an assay with which it was possible to determine titanium in
concentrations of 0.2-10 mg/litre. Atomic absorption spectrometry
for the determination of titanium in pharmaceutical products has
been reported by Mason (1980).
Potentiometric and photometric methods of titration have been
reported for the determination of titanium but most of these
methods are not very sensitive (Skaravskij, 1965; Ozawa, 1971).
2.2.1. Air analysis
The determination of trace metal particulates, including
titanium, in atmospheric samples by X-ray fluorescence (XRF)
techniques has been widely reported (National Air Pollution
Control Administration, 1969; Shono & Shinra, 1969; Dittrich &
Cothern, 1971; Frigieri et al., 1972; Rhodes et al., 1972). For
example, trace metals collected on filter paper by a high volume
air sampler for 25 h were analysed by Dittrich & Cothern (1971)
using the XRF technique. Elements in the periodic table between
titanium and caesium were found to have a sensitivity limit of
0.5 µg/m3 of air. The XRF technique has the advantage of being
non-destructive, and a single analysis provides simultaneous
estimates of several metals. The method can be easily automated.
Rhodes et al. (1972) measured titanium among other elements in
samples of suspended particulate matter, collected in 38 air
quality control network stations in Texas. The X-ray fluorescence
method proved useful for air particulate survey measurements and
for pollution source location. No sample preparation was necessary.
Once loaded with samples, the apparatus could operate unattended.
The detection limit of XRF for titanium was 0.011 µg/m3. In an
analytical study described by Giauque et al. (1974), sensitivities
routinely established within a 20-min counting interval corresponded
to less than 0.01 µg/m3 of air.
Non-destructive neutron activation analysis has also been used
for the determination of trace elements in aerosols (Dams et al.,
1970, 1972; Zoller & Gordon, 1970; Harrison et al., 1971). The
multi-elemental specificity of activation analysis aids in the
determination of the chemically complex and highly variable
composition of an aerosol. A useful irradiation-counting scheme
and simplified flow diagram of automated spectrum analysis has been
developed by Dams et al. (1970) with detection limits for titanium
of the order of 0.2 µg.
Most techniques in which neutron activation analysis is used
require a large nuclear reactor, with the minimum flux for best
overall performance acknowledged to be around 1012 neutrons/second
per cm2. However, it was suggested by Dittrich & Cothern (1971)
that the future availability of californium (252Cf5) should provide
adequate portable activation sources for atmospheric trace metal
The determination of a variety of metals in atmospheric
particulate matter by atomic absorption spectroscopic (AAS)
procedures has also been widely reported (Beyer, 1969; Burnham et
al., 1970; Ranweiler & Moyers, 1974). Ranweiler & Moyers (1974)
described an AAS procedure for the determination of 22 metals
including titanium in 24-h, high-volume samples of atmospheric
particulate matter collected on a polystyrene filter. The
practical detection limit for titanium was 0.07 µg/m3.
Johansson et al. (1975) used proton X-ray emission spectroscopy
for the determination of titanium and 13 other elements in airborne
particles. In this method, particles were collected and segregated
according to size, using cascade impactors.
2.2.2. Water analysis
The determination of trace metals, including titanium, in water
has been accomplished principally by X-ray fluorescence (Blasius et
al., 1972), spectrography (Durum & Haffty, 1961), spark-source mass
spectrophotometric (Crocker & Merritt, 1972; Hamilton & Minski,
1972), and photometric techniques (Nikitina & Basargin, 1970).
Elements in the periodic table between titanium and caesium were
detectable by X-ray fluorescence with sensitivities of the order of
30 µg/kg for metals in the particulate form and 0.4 µg/kg for
metals in the ionic form (Blasius et al., 1972).
Problems with the XRF technique are primarily concerned with
sample preparation and matrix effects. However, the most important
need defined by Blasius et al. (1972) was the determination of the
chemical and/or the physical form in which the metal occurred. It
appeared that some of the metals were in the suspended state, while
the rest were either ionized or attached to colloidal particles.
Proton-induced X-ray emission spectrometry has been used for
the determination of titanium in water (Johansson, 1974; Johansson
et al., 1975).
Crocker & Merrit (1972) and Hamilton & Minski (1972) used
spark-source mass spectroscopy for the determination of trace
elements, including titanium, in water. A selective and sensitive
photometric method employing tichromin was developed by Nikitina &
Basargin (1970) for the determination of 0.1 mg titanium/litre in
highly mineralized thermal waters of volcanic origin.
2.2.3. Food analysis
Titanium levels in various food sources have mainly been
determined by spectrographic and colorimetric techniques. Emission
spectrum analysis has been used for the determination of titanium
in canned fruit and vegetable juices (Klyacko et al., 1971, 1972).
The determination of titanium dioxide in cheese was accomplished by
Leone (1973) using the procedure of Kolthoff & Sandell (1952) in
which titanium solutions are treated with hydrogen peroxide and the
resulting yellow-orange colour due to (TiO2(SO4)2) is measured
The occurrence of titanium together with a large number of
other chemical elements in samples of prepared diets from the
United Kingdom and the possible relationship with environmental
factors has been determined by Hamilton & Minski (1972/1973) using
spark-source mass spectrometry (Hamilton et al. 1972/1973; Hamilton
& Minski, 1972/1973) and X-ray fluorescence (Hamilton et al.,
2.2.4. Analysis of biological materials
Titanium in biological samples has mainly been determined by
photometric (Lojko, 1967; Urusova, 1969; Mal'ceva, 1973a,b) and
spectroscopic (Timakin & Bagdasarova, 1969; Cekotilo & Torohtin,
1970) techniques. Mal'ceva (1973a,b) determined titanium in ashed
bone samples with a detection limit of 0.16 mg/kg of bone tissue,
or 350 µg/kg of biological material or litre of urine.
Titanium in tissues was measured by Schroeder et al. (1963)
using chromotropic acid in a colorimetric microanalytical
technique of Sandell (1959). The method was sensitive to about
0.025 mg/kg. A colorimetric method using the sodium salt of
chromotropic acid was used for the determination of titanium in
biological samples by Urusova (1969).
The determination of titanium in excreta and human diets using
arc-emission spectroscopy has been reported by Tipton & Stewart
(1969) and Tipton et al. (1969). The limits of detection expressed
as mg/kg ash were: food sample, 2; faeces, 9; and urine, 0.03.
Carroll et al. (1971) described the use of electron probe
microanalysis for the determination of localized concentrations of
titanium in various human tissues, both normal and pathological, as
well as in human blood, bone marrow, leukocytes, and lymph nodes.
The estimated detection limit was about 10-8 µg of metallic atoms
per cell (Carroll & Tullis, 1968).
The concentration and distribution, in healthy human tissues,
of a large number of stable elements including titanium was studied
by Hamilton et al. (1972, 1973). The methods of analysis were
spark-source mass spectroscopy and X-ray fluorescence. The
detection limits for titanium in human tissues were 0.007 mg/kg for
spark-source mass spectroscopy and 0.3 mg/kg wet weight for the XRF
Alternating current polarographic determination of titanium in
tissues has also been reported (Hoff & Jacobsen, 1971; Petit,
A histochemical method for the identification of titanium and
iron oxides in pulmonary dust deposits was described by DeVries &
Meijer (1968). The technique was especially developed for the
study of pneumoconiosis in workers employed in industries
processing these minerals. In this procedure, the oxides are
converted, under heating, into water-soluble sulfates by fumes of
sulfuric acid, after which the corresponding sulfates are
identified by staining reactions.
3. SOURCES OF ENVIRONMENTAL POLLUTION
3.1. Natural Occurrence
Titanium is the ninth most abundant element in the earth's
crust. It is widely distributed and occurs at an average
concentration of 4400 mg/kg (Mason, 1966). It is usually found
in the form of stable minerals, e.g., the end products of the
weathering of basic rocks, principally ilmenite and rutile, and
in the form of impurities or dispersions in many aluminosilicates
(Vinogradov, 1959). Owing to its great affinity for oxygen and
other elements, titanium does not exist in the metallic state in
nature. A variable amount of titanium occurs in unweathered
particles of clay, in amphibole, laepidomelane, and micas (Joffe &
Pugh, 1934). The most common titanium minerals are ilmenite
(TiFeO3), which can contain a maximum concentration of titanium
dioxide (TiO2) of 530 g/kg, and rutile, which is 100% titanium
dioxide. Titanium-bearing minerals such as anatase and brookite
are associated with ilmenite and rutile. Other titanium minerals
are known which are locally abundant in some deposits, but have not
been used commercially. These include sphene (CaTiSiO5),
pyrophanite (MnTiO3), and perovskite (CaTiSiO5) (Stamper, 1970).
Both rock and sand deposits contain titanium minerals of
economic importance. Some sand deposits containing less than 1%
of titanium dioxide are commercially workable, if the principal
titanium mineral is rutile. Titanium also occurs to a lesser
degree in rocks such as brookite, anatase, and in feldspars, micas,
biotites, and others in the form of isomorphic impurities. Rutile,
ilmenite, brookite, and other common titanium minerals accumulate
in sedimentary rocks and sometimes in certain soils as the end
products of metamorphism of titanium-containing minerals and rocks.
It is present in the form of titanium(IV) compounds; the rarer
oxidation form of titanium(III) is also known in certain iron
minerals as are complex titanium(IV) compounds (Vinogradov 1959;
Stamper, 1970). Titanium levels in coal and oil have been reported
to average 500 and 0.1 mg/kg, respectively (Bertine & Goldberg,
3.2. Industrial Production
Titanium is mined commercially from rock and sand deposits by
open-pit and dredging operations. Mechanical beneficiation methods
are used for concentrating the major minerals, ilmenite and rutile.
The production of elemental titanium is a comparatively difficult
process since titanium in the molten state has a great affinity for
oxygen, nitrogen, and moisture in the air, as well as for carbon
and most refractory materials. The principal method for the
commercial production of titanium sponge metal is the Kroll
process, which involves the reduction of titanium tetrachloride
with magnesium metal in an inert atmosphere. Present commercial
production by this method yields a titanium alloy of 99.5% purity
that differs in hardness and strength from the pure titanium metal
prepared from the thermal decomposition of titanium iodide (TiI4).
Titanium metal powder is usually produced by reaction of the metal
with hydrogen; the resulting brittle titanium hydride is then
crushed before heating in a vacuum to remove the hydrogen (Stamper,
Titanium dioxide of pigment quality is made by two distinct
processes. In the sulfate process (Stamper, 1970; Katari et al.,
1977), ground ilmenite or titanium slag is dissolved in sulfuric
acid, reducing the iron present to the ferrous state. The
titanium dioxide is then precipitated by hydrolysis together with
part of the iron in the form of hydrated iron sulfates (copperas).
The precipitated titanium dioxide is calcined at 900-1000°C,
treated by proprietary finishing processes, and ground to pigment
size. In the chloride process (Katari et al., 1977), titanium
tetrachloride is oxidized with air or oxygen and the resulting
titanium dioxide calcined at approximately 500-600°C to remove
residual chlorine and any hydrogen chloride that may have formed in
the reaction. Aluminium chloride is added to the titanium
tetrachloride to assure that virtually all of the titanium is
oxidized in the rutile crystalline form. After calcination, the
titanium dioxide is treated by proprietary finishing processes as
in the sulfate process.
There are about 30 commercially available grades of pure
titanium and alloys. Elements in titanium alloys fall into two
categories, i.e., those that strengthen and stabilize the alpha or
room temperature modification, and those that strengthen the beta
or high temperature modification. An alloy containing 6% aluminium
and 4% vanadium comprises almost 50% of the total mill products
used. Other alloys used widely include those containing either, 8%
aluminium, 1% each of molybdenum, and vanadium, or 5% aluminium and
2.5% tin. Further aspects of the procedures dealing with the
preparation and refining of titanium dioxide, titanium metal
powder, and alloys have been dealt with in various monographs
(Stamper, 1970; CEC, 1974; Katari et al., 1977).
The total world production of titanium concentrates in 1979 was
3.49 million tonnes of ilmenite (including leucoxene), 0.36 million
tonnes of rutile, and 0.77 million tonnes of titaniferrous slag
(Lynd & Hough, 1980). The approximate amount of titanium produced
can be estimated knowing that rutile is 100% titanium dioxide and
ilmenite has a theoretical maximum content of titanium dioxide of
53% (Stamper, 1970). Four countries together produced over 85% of
the global production of ilmenite, i.e., Australia (33%), Norway
(24%), USA (17%), and USSR (12%). Australia produced 77% of the
total known world production (359 000 tonnes) of rutile.
Practically all of the titaniferrous slag is produced by Canada
(61.4%) and South Africa (38.5%) (Lynd & Hough, 1980). The world
production figures for titanium concentrates are given in Table 2.
Table 2. World production of titanium concentrates in 1979
(Values expressed in short tonnes = 907 kg)a
Country Ilmenite Rutile Titaniferrous
and leucoxene slag
Australia 1 280 646 305 773
Brazil 20 000 400
Canada 525 840
Finland 145 000
India 165 000 10 000
Malaysia 206 000
Norway 903 576
Sierra Leoneb 11 000
South Africab 46 000 330 000
Sri Lanka 39 000 15 000
USA 639 292 Wc
USSRb 450 000 10 000
World total 3 848 714 398 173 856 040
a From: Lynd & Hough (1980).
c W = witheld company proprietary data.
The recovery of titanium from secondary sources has so far been
very modest, probably not exceeding 1% of the total production.
However, it is likely to increase in the future. It has been
calculated that the world demand for titanium in the year 2000 will
range between 2.1 and 4.5 million tonnes. An estimate of ilmenite
and rutile reserves is given in Table 3.
Table 3. Estimated world reserves of ilmenite and rutilea
Country Million short tonnesb
Ilmenite Titanium Rutile Titanium
Australia 20 5 4.0 2.0
Canada 100 25 0.5 0.250
India 60 15 0.1 0.050
Norway 120 30 - -
Sierra Leone - - 3.0 1.50
Sri Lanka 5 1 0.3 0.150
United Arab 40 10 - -
USA 100 25 0.5 0.250
USSR 100 25 0.3 0.150
Otherc 25 6 - -
a From: Stamper (1970).
b US short tonne = 907 kg.
c Includes Brazil, China, Finland, Japan, Malaysia, Spain.
3.3. Uses of Titanium
Titanium, used as a construction material, is usually in the
form of alloys, most of which have higher strength than pure
titanium and enhanced corrosion resistance. About 95% of the
titanium metal consumed in the USA is for aerospace applications,
including aircraft and space craft. The remainder is used in the
chemical and electrochemical processing industries, for handling
some of the most corrosive processes, and in marine and ordnance
Titanium is used in the paper pulp industry, because of its
excellent resistance to organic acids, sulfides, and strong
bleaches. It is also used in tubing, and in liners for vessels etc.
in the production of nitric acid and acetaldehyde. The first
large-scale industrial application of titanium was in the aluminium
anodizing industry, where the metal supporting racks were made
almost exclusively of titanium. Platinized titanium anodes are
used in electroplating with gold, platinum, copper, silver, and
other metals of high purity. Similar anodes are used in cathodic
protection systems of ships, harbour installations, water heaters,
and cleaning lines in the production of stainless steel strip.
Another still expanding use of titanium metal is in surgical
implant materials and prostheses.
Titanium dioxide (TiO2) is by far the most important titanium
compound. Because of its extreme whiteness and brightness, as well
as its high index of refraction, titanium dioxide is extensively
used as a white pigment primarily in surface coatings such as
paints, lacquers, and enamels. It is estimated that over half of
all non-permanent white or light-coloured surface coatings include
a titanium dioxide level of 0.1-0.3 kg/litre. Over 17% of titanium
dioxide is used in paper coatings or as paper fillers to improve
opacity, brightness, and printability. The third largest and
apparently fastest growing application of titanium dioxide is in
the plastics industry, because of its resistance to degradation by
ultraviolet light, high refractive index, whiteness, and chemical
inertness (Stamper, 1970).
In addition, titanium dioxide is used in ceramic capacitors and
electromechanical transducers, welding-rod coatings, and in the
production of glass fibres. Miscellaneous applications of titanium
dioxide pigment and other titanium compounds include the production
of floor coverings, mainly of the synthetic resin types, rubber
tyres, porcelain enamels, inks, wall coverings, artificial leather,
oilcloth, upholstery materials, and other coated fabrics. Titanium
dioxide is also used in the production of titanium carbides.
To a much lesser extent, titanium dioxide is used as a colour
additive in the confectionery (Lorenz & Maga, 1973), food (Bone,
1967), and dairy industries (Kosikowski & Brown, 1969), as a
potential additive for bread flours, replacing the normally used
flour-bleaching agents (Lorenz & Maga, 1973), as a clouding agent
for incorporation in dry beverage mixes (Carlson et al., 1972), and
in tobacco wrapping (Detert & Buchholz, 1971).
Another commercially important compound is titanium
tetrachloride (TiCl4). It is primarily an intermediate in the
production of titanium metal and pigments. It is also a component
of Ziegler catalysts used for the low pressure polymerization of
ethylene, propylene, and other hydrocarbons. Titanium tetrachloride
is also widely employed as the intermediate raw material for the
production of most organic titanium compounds, such as alkyl esters
of titanium, alkyl titanates, other titanium esters, and butyl
titanate (Feld & Cowe, 1965), which are used as cross-linking
agents and catalysts.
Titanium trichloride (TiCl3) is used for polymerization
catalysts and as a colouring agent in molasses. It is prepared by
reducing titanium tetrachloride. Some of the most common
applications of titanium and its compounds are listed in Table 4.
Table 4. Some main applications of titanium and its compounds
titanium (Ti) in alloys, aerospace, chemical processing
titanium dioxide pigments, paints, lacquers, printing,
(TiO2) ceramics, as food additive, drug and
titanium tetrachloride polymerization (Ziegler type) catalyst,
(TiCl4) starting material for most organic
titanium trichloride polymerization catalyst
titanium carbide (TiC) structural metals, alloys
organic titanium cross-linking agents, catalysts
3.4. Disposal of Wastes
The mining and concentration of titanium and the production of
titanium dioxide generate large quantities of wastes. Disposal of
these wastes and especially those generated by titanium pigment
production is an important environmental problem for the industry.
The waste also contains weak sulfuric acid. Large amounts of such
processing wastes are dumped into the sea or river water (Peschiera
& Freiherr, 1968; Elik, 1969; Fader, 1972; Weber, 1972; Häfele,
1974; Walsh, 1974; Katari et al., 1977). In the mining and
beneficiation processes of ilmenite and in the production of
titanium dioxide pigment, air pollutants are generated and sulfur
dioxide and particulate matter containing titanium are emitted
(Katari et al., 1977). Incineration of titanium-containing
products such as paper, plastics, inks, and painted wood may
contribute to the pollution of the air by titanium, which may
subsequently enter the soil.
4. ENVIRONMENTAL LEVELS AND EXPOSURES
4.1. Levels in Air, Soil, Water, and Other Media
Titanium concentrations in urban air are mainly below 0.1 µg/m3
and are still lower in rural air (Tabor & Warren, 1958; McMullen et
al., 1970; US Environmental Protection Agency, 1973; Giauque et al.,
1974). Concentrations exceeding 1.0 µg/m3 have occasionally been
reported in urban air and especially in industrialized areas (Japan
Environmental Sanitation Centre, 1967; National Air Pollution
Control Administration, 1969; Dams et al., 1970; US Environmental
Protection Agency, 1973).
Tabor & Warren (1958), employing a semi-quantitative
spectrographic method, studied the distribution of a number of
metals including titanium in the atmosphere of several American
cities. In 754 samples examined, detectable amounts of titanium
(0.01 µg/m3) were not found in 23.3% of the samples, medium
concentrations (0.01-0.1 µg/m3) were found in 71.4%, and high
concentrations (0.1-0.3 µg/m3) in 5.3% of the samples. The
combustion of coal and oil results in a discharge of trace amounts
of several elements, including titanium, into the atmosphere. The
principal sites of fossil fuel consumption are in the mid-latitudes
of the Northern Hemisphere. Consequently, as was pointed out by
Bertine & Goldberg (1971), the contribution to the titanium
concentrations in air and natural waters will be most evident at
these latitudes. Average concentrations of titanium of 500 mg/kg
in coal and 0.1 mg/m3 in oil, have been reported.
Johansson (1974) determined the variation of titanium abundance
with particle size in aerosols from North Florida, sampled near to
the ground by a 5-stage cascade impactor in mainly unpolluted
inland and coastal locations. The 32 separate size distributions
were determined by proton-induced X-ray emission spectroscopy.
Since titanium coheres with iron in most samples, and the ratios
found were constant and close to the geochemical average of the
ratios of these elements in soils, it was suggested that titanium
had originated mainly from a soil source (yielding particles of 1
µm). For the smallest particles (0.25 µm), there was an indication
of elevated titanium/iron ratios that might arise from an
additional source of small particle titanium.
4.1.2. Soils and sediments
Though titanium is ubiquitous in its geographical distribution,
regional levels vary considerably according to conditions such as
weathering, fallout from consumption of fossil fuels, and
incineration of refuse. Sandy soils, e.g., sand, bog, loess, and
calcareous soils contain less titanium than heavy clay soils.
According to an extensive review by Vinogradov (1959) of titanium
values in soils from various parts of the world (e.g., Robinson,
1914; Tamm, 1925, 1930/1931); Agatomoff, 1928; Askew, 1930; Malac,
1931; Hirai & Buichiro, 1937; Ivanova & Koposov, 1937; Salminen,
1938; Lee, 1941; Monier-Williams, 1950), the average concentration
in soil appears to be below 5 g/kg. However, some soils contain
titanium dioxide at a concentration of about 10-100 g/kg.
Grabarov (1970) found that the titanium content of soils in
Kazakhstan, USSR, ranged from 2 to 7 g/kg but that only 10-50 mg/kg
was in a readily soluble form. Hussain & Islam (1971) measured
titanium in soil, silt, and clay fractions of a number of soils
from the Barind tract in Bangladesh. The mean titanium dioxide
content in the soils ranged from 6 to 12 g/kg with an average
value of 8 g/kg. The content in the clay fraction was higher than
that in the silt fraction, with these soils showing signs of the
development of argillic horizons.
Soils in the vicinity of power and incineration plants and
industrial discharges may be enriched in heavy metals and trace
elements. Klein & Russel (1973) reported that soils around a coal-
burning power plant contained higher levels of trace metals than
surrounding areas. The average level of titanium in soils in the
vicinity of this power plant was 92 mg/kg compared with a back-
ground level of 56 mg/kg. The enriched area covered 300 km2 with
the enrichment confined to the upper 2 cm of soil.
The concentration of titanium in water depends on both the
amount of titanium dissolved in the water and on the quantity of
titanium particles dispersed in the water. Titanium has been
reported in all samples from 15 rivers in the USA and Canada in
concentrations ranging from 2 to 107 µg/litre (Durum & Haffty,
1961). Durfor & Becker (1964) found titanium in 81% of 42
municipal water supplies in the USA at a mean concentration of
2.1 µg/litre with a range of 0.5-15 µg/litre.
Titanium levels in sea water have been reported to range from
1 to 9 µg/litre (Bowen, 1966; Mason, 1966). Titanium was found in
21% of the 24 samples collected along the entire coast of
California, USA, the two highest concentrations being 0.7 µg/litre
and 0.9 µg/litre (Silvey 1967). Ishibashi (1966) reported the
distribution of 50 elements in sea water with levels of titanium
averaging 0.65 µg/litre.
In studies by Hallsworth & Adams (1973), the heavy metal
content of rainfall ash was compared with that of the fly ash from
several power stations in the East Midlands of the United Kingdom.
Levels of titanium in rainfall, which ranged from 6 to 7.8 g/kg of
residues were roughly comparable with levels of titanium in the fly
ash, which ranged from 3.6 to 7.5 g/kg.
Titanium, like aluminium, is found in relatively abundant
quantities in the lithosphere and in soils, but is poorly absorbed
and retained by plants (Underwood, 1977). Average titanium levels
of approximately 1 mg/kg have been reported for a wide variety of
plants (Bertrand & Voronca-Spirt, 1929a, 1929b). It has been
suggested that levels in herbage samples are indicators of soil
contamination (Barlow et al., 1960). Mitchell (1957) reported mean
levels of titanium of 1.8 mg/kg (dry weight) in red clover (range
0.7-3.8 mg/kg) and 2.0 mg/kg in ryegrass (range 0.9-4.6 mg/kg)
grown on different soils. In Kazakhstan, grain crops absorbed
titanium levels of 50-100 g/ha and legumes 123-398 g/ha from soil
containing levels of titanium of 1.2-7 mg/kg (Grabarov, 1970).
More titanium was found in maple and elm leaves than in the leaves
of other plants while the content of titanium in brush was 50-820
Large variations in the concentrations of titanium in different
types of foods have been demonstrated. Schroeder et al. (1963)
found whole grains, some vegetables and fruits, and common fish
meat contained little or no detectable titanium (level of
sensitivity = 0.025 mg/kg for tissues and 0.01 mg/kg for other
materials) while higher levels ranging from 1.76 to 2.42 mg/kg wet
weight were found in milled grains, butter, corn oil, corn-oil
margarine, and lettuce. Wheat flour from the USA and Japan was
found to contain 0.41 and 0.99 mg/kg (wet weight), respectively;
corn oil and corn-oil margarine levels were 0.83 and 1.80 mg/kg
(wet weight), respectively. In a study by Asmaeva & Il'vickij
(1969), levels of titanium in grains were related to the region of
growth and climatic conditions.
Though titanium is poorly absorbed and retained by both animals
and plants (Monier-Williams, 1950; Underwood, 1977), higher
concentrations of titanium can potentially occur in food crops in
localized areas as a result of soil contamination by: fly ash
fallout (Hallsworth & Adams, 1973; Klein & Russel, 1973; Capes et
al., 1974); industrial contamination (Tarabrin, 1970); and use of
industrial, household, and sewage residues for the fertilization of
vegetable plots (Lescenko et al., 1972). Some algae are able to
accumulate titanium up to 10 000 times and possess the potential to
introduce large quantities into the food chain (Schroeder et al.,
High concentrations of titanium in food, especially cheese, can
arise from the use of titanium dioxide as a whitener in the
manufacture of mozzarella cheese (Kosikowski & Brown, 1969; Leone,
1973). Titanium is also used in the production of niva and Edam
cheese to accelerate aging and improve quality (Palo, 1966, 1967).
4.2. Occupational Exposure
Nearly all exposures to titanium are to dusts, though
some exposure to fume and vapour occurs in handling titanium
tetrachloride. Occupational exposure to titanium mainly occurs in
the mining and production of the metal, and in the production and
processing of titanium dioxide and carbide. During the extraction
and recovery of titanium from its major ores such as ilmenite and
rutile, the atmospheric concentrations of the ores may reach
levels commonly regarded as the maximum permissible for inert or
nuisance dusts. In the preparation of raw materials, i.e.,
crushing, grinding, mixing, and sieving of rutile concentrates and
technical grade titanium dioxide - the concentration of dust
depends on the humidity of the air and on the materials treated.
According to Kokorev et al. (1960), the dust concentration in the
air of crushing rooms, containers, and transporters, amounted to 4-
6 mg/m3. Considerable concentrations of titanium tetrachloride
vapour were found in the chlorine department. In some other
departments, such as the crushing and classification departments,
the concentration of titanium dust (titanium-rich slag containing
about 70% titanium dioxide) may reach 30-50 mg/m3.
Exposure to titanium and its compounds occurs not only in the
production of metallic titanium, but also in processes in which it
is used. According to Mezenceva et al. (1963), in the production of
hard alloys, the dust concentration in the air during the sieving
of titanium carbide ranged from 20.3 to 40.2 mg/m3, while in the
process of carbonization, it amounted to 22 mg/m3.
Skurko & Brahnova (1973) reported high concentrations of
titanium dust in the breathing zone of workers employed in the
manufacture of titanium hydride. High mean concentrations up to
500 mg/m3 were found in the hydrogenation shop, manual handling,
screening, and packaging of the powder. Cleaning of the retort
resulted in a mean concentration of 210 mg/m3.
4.3. Cosmetic and Medical Uses
A variety of drug and cosmetic applications for titanium
dioxide exist based primarily on its effectiveness: as a short-wave
ultraviolet sunscreen (Vickers, 1967; MacLeod & Frain-Bell, 1971);
in the treatment of herpes simplex (Scott, 1969; Shuster 1971) and
photosensitive cheilitis (Rich et al., 1971); in dermatological and
cosmetic formulations (Rudowska, 1967; Miller & Gilmore, 1971); as
an anti-acne ointment (Fuga, 1967) and an anti-inflammatory
ointment for gums and oral mucosas (Lakovska et al., 1971); in
removal, by tattooing, of facial haemangiomas (Hage, 1967); and in
a variety of tablet-coating formulations (Lindberg & Jonsson, 1972;
Mention should be made of the increasing use of titanium in
metal plates, pins, nuts, and bolts in contact with various tissues
(Beder & Eade, 1956; Beder et al., 1957).
4.4. Estimate of Exposure of Man through Environmental Media
Food is the principal source of exposure to titanium for man.
This is obvious from the concentrations of titanium in food, water,
and air (sections 4.1.1-4.1.5). As titanium has not been proved to
be an essential element for man and is not very noxious, only a few
dietary intake and balance studies have been undertaken. Recent
studies are not available and the results from earlier studies are
not always very representative.
Because of the variations in diet, as well as the variations
in total food consumption in different parts of the world (Hamilton
& Minski, 1972/1973), it is very difficult to estimate the daily
intake of titanium. Typical American diets were estimated by
Schroeder et al. (1963) to provide approximately 300 µg of titanium
daily. Tipton et al. (1966) reported the 30-day mean total American
dietary titanium intakes of two individuals to be 370 and 410
µg/day. The daily titanium intake for two men (23 and 25 years
old), over a period of 50 weeks, was reported by Tipton et al.
(1969) to be 750 ± 80 µg and 2000 ± 400 µg, respectively. The
dietary content of titanium was measured from estimated (i.e., not
weighed) duplicates of every ingested item. Hamilton & Minski
(1972/1973) reported a daily intake of about 800 µg from the United
Kingdom and ICRP (1959) arrived at an estimate of 540 µg. The
daily intake of titanium from drinking-water is usually very low,
probably below 5 µg/day.
Outside occupational settings, the amount of titanium absorbed
via the lungs is of little significance in relation to the intake
from food, and the intake by inhalation is less than 1% of the
total intake. Assuming a respiratory volume of 15 m3/day, the
intake would vary from almost none to 4.5 µg with an average of
about 0.75 µg, but it can be expected that only one-third or less
of the inspired titanium is retained in the lungs (Schroeder et
al., 1963). Woolrich (1973), basing his estimates on surveys in
four American cities, calculated the daily intake from air to be
approximately 3.8 µg of titanium assuming that 20 m3 air per day
is respired, with a maximum concentration of 0.19 µg/m3.
In the working environment, where the air concentration may
reach several mg/m3, exposure through inhalation is of greater
importance. Data on pulmonary retention as well as absorption of
swallowed particles are insufficient to make any estimate of the
exposure in various occupational environments. However, several
autopsy studies on workers occupationally exposed to titanium
dioxide dust have shown the presence of titanium in the lungs in
concentrations clearly exceeding those found in the lungs of
unexposed subjects (Schmitz-Moorman et al., 1964; Elo et al., 1972;
Ophus et al., 1979).
5. CHEMOBIOKINETICS AND METABOLISM
5.1. Absorption, Distribution, and Excretion
5.1.1. Animal studies
Data on the absorption of titanium compounds are very limited
and very little quantitative information is available with regard
to absorption by inhalation. Ingested titanium is apparently
absorbed from the gastrointestinal tract (Schroeder et al., 1964)
but there is little information regarding the extent of absorption,
and comparative studies using different titanium compounds have not
been made. Lloyd et al. (1955) tested the suitability of titanium
dioxide as a marker for digestibility. The recovery of only 92% of
the titanium dioxide fed to rats at a dietary level of 2.5 g/kg
remained largely unexplained. The minute absorption of titanium
from the gastrointestinal tract was demonstrated in a study in
which mice were given 44Ti intragastrically (without marker). The
whole body count after 24 h did not exceed the background level
(Thomas & Archuleta, 1980). A comparison of organ contents of 44Ti
after oral and intravenous administration of the isotope (3 µCi),
indicated a gastrointestinal absorption of less than 5% in lambs
(Miller et al., 1976). When male and female rats were fed a diet
containing titanium dioxide (100 g/kg) for a period of about 32
days, a significant retention of titanium of 0.06 and 0.11 mg/kg
wet weight was found only in the muscles; no retention was observed
in the liver, spleen, kidney, bone, plasma, or erythrocytes (West &
Wyzan, 1963). The same authors administered 5 g of titanium dioxide
to 5 male adult volunteers on 3 consecutive days. This did not
cause any significant increase in the urinary content of titanium.
The clearance of titanium dioxide from the lungs was studied in
rats after inhalation of 15 or 100 mg/m3. The average median
aerodynamic diameter of the titanium dioxide particles was 1.48 µm.
After a single exposure, about 40-45% of the deposited particles
were cleared from the lung in 25 days. At 15 mg/m3, 0.7% was found
in the hilar lymph nodes indicating penetration of titanium dioxide
particles from alveoli into the lymphatic system and partial
clearance by the lymphatic route. The clearance rate was similar
after intra-tracheal administration of titanium dioxide. At an
exposure of 100 mg/m3, the clearance rate decreased drastically
(Ferin & Feldstein, 1978). Elo et al. (1972) demonstrated the
presence of titanium dioxide in the lymphatic systems of 3 workers
employed in processing titanium dioxide pigments.
The distribution of titanium in the organs of mice following
the administration of a tetravalent, soluble titanium salt
(titanium potassium oxalate) in drinking-water at a concentration
of 5 mg/litre was reported from a life span study by Schroeder et
al. (1964). The results were compared with organ concentrations in
control mice fed drinking-water without the addition of titanium,
and in wild field mice (Table 5). Organs of treated and wild
animals displayed concentrations of roughly the same order of
magnitude, whereas untreated mice showed lower levels, the
differences being more pronounced in males.
Table 5. Titanium concentrations in the organs of mice given
titanium in the drinking-water at 5 mg/litre throughout the life
span (values in mg/kg wet weight)a
No. Heart Lung Spleen Liver Kidney
Male 41 8.80 4.81 6.83 1.81 2.86
Female 37 4.10 1.66 3.70 2.05 2.89
Male 31 0.34 0.13 0.94 0.38 0.33
Female 51 1.08 0.66 1.10 0.67 0.55
Wild field mice 9 6.93 3.03 - 4.10 1.03
a From: Schroeder et al. (1964).
Following intravenous injection of rats with 50 mg of titanium
dioxide (250 mg/kg body weight), there was an exponential
disappearance rate with only about 30% remaining after 10 min.
After intravenous injection of 250 mg/kg body weight of titanium
dioxide in rats, about 70% of the injected dose was detected in the
liver, 5 min after administration, and almost 80%, 15 min after
injection. The highest concentration was found in the liver
followed by the spleen after 6 h, whereas, after 24 h, the highest
concentration was found in the celiac lymph nodes, which filter the
lymph from the liver. One year after the injection, the highest
concentrations were still found in these lymph nodes (Huggins &
5.1.2. Human studies
Little information is available on the absorption of titanium
compounds by man. With respect to absorption by inhalation, there
is evidence showing that titanium containing particles in the air
are in the upper respirable size range (Johansson, 1974). The
titanium retained in the peripheral part of the lungs does not seem
to account for the observed titanium levels in lung tissue
(Schroeder et al., 1963). Experiments on rats suggest that
titanium may be taken up by the lungs from the blood. On the basis
of rather rough calculations, Schroeder et al. (1963) concluded
that a third or less of the inspired titanium may be retained in
Few studies have been reported on the absorption of titanium
from the gastrointestinal tract in man. Perry & Perry (1959)
reported a mean concentration of 10 µg/litre in pooled urine
indicating absorption; however, the extent of the absorption is not
known. Accepting this amount in the urine, and assuming a daily
intake of 300 µg of titanium, Schroeder et al. (1963) calculated
that about 3% of the dietary dose would be absorbed.
Wide variations in titanium levels in different organs in man
have been found, the lungs frequently containing the highest
amount. Hamilton et al. (1972/1973) using X-ray fluorescence found
concentrations of 3.7 mg/kg wet weight in the lung and 0.8 mg/kg in
the brain, demonstrating that titanium passes the blood-brain
barrier. Earlier, Tipton & Cook (1963) and Schroeder et al. (1963)
had also found that concentrations in lung tissue were higher than
in other human tissues. In a male worker not occupationally exposed
to metals, the highest concentration was found in the hilar lymph
nodes (150 mg/kg dry weight) followed by the lung (33 mg/kg dry
weight) (Teraoka, 1980). Comparison of tissue levels of titanium
between American subjects and people from other geographical areas
showed similar high concentrations in pulmonary tissues (Perry et
In the study by Schroeder et al. (1963), accumulation of
titanium started in the lung after the third decade and did not
occur in the kidney, skin, or aorta. Infant kidneys contained
several times the adult concentration of titanium (Tipton & Cook,
Metal and mineral concentrations in the lungs of West Virginian
bituminous coal miners were studied by Crable et al. (1967, 1968).
The mean concentration of titanium, among other metallic
constituents, in the lungs of 26 miners (with 23-50 years service)
was 119 mg/kg dry weight compared with a normal level of 19 mg/kg.
Röthig & Wehran (1972) found concentrations of titanium in the
lungs of patients with silicosis ranging from 4 to 24.3 mg/kg.
Levels in the lymph nodes ranged from 12.2 to 120 mg/kg. The
average titanium concentration rose with increasing severity of
silicosis, the concentration of titanium in the hilar lymph nodes
being much higher than that found in the lungs.
A mean titanium concentration in blood of 0.07 mg/litre was
reported by Hamilton et al. (1972/1973), not much different from
the 0.02-0.03 mg/litre previously reported by Maillard & Ettori
(1936a; 1936b). A somewhat higher mean level of 0.123±0.005
mg/litre was found in 20 healthy subjects, 20-43 years of age, by
Mozajceva (1970). Timakin et al. (1967) reported a mean level of
0.054±0.002 mg/litre in the serum of 200 healthy persons from the
USSR. Smysljaeva et al. (1971) determined the distribution of
titanium in the blood of children in the age range of 1-14 years.
They found a ratio of 2:3 between erythrocytes and plasma; this
ratio decreased slightly with age. The range of the ratios was
Titanium was qualitatively detected in leukocytes, using
electron probe microanalysis (Carroll & Tullis, 1968). There are
some indications that titanium levels in the blood may change in a
variety of diseased states (Bredihin & Soroka, 1969; Kas'janenko &
Kul'skaja, 1969; Mozajceva, 1970; Alhimov et al., 1971).
Schroeder et al. (1963) demonstrated the presence of titanium
in the tissues of newborn infants, indicating that titanium passes
the placenta. The fact that titanium was not detectable in all
fetuses may reflect the sensitivity of the analytical methods used;
however, Scanlon (1975) interpreted this finding as evidence of
titanium not being an essential element for man.
Most of ingested titanium is eliminated unabsorbed with the
faeces. Under normal circumstances, titanium is excreted with the
urine probably at a rate of about 10 µg/litre (Perry & Perry, 1959;
Schroeder et al., 1963). Higher urinary excretion levels of 0.41
and 0.46 mg/litre have been reported in two adults (Tipton et al.,
1966). Other routes of excretion are not known.
5.1.3. Biological half-life
Few attempts have been made to calculate the biological half-
life of titanium in man or experimental animals. The lung is
considered to be the primary target organ in man and the residence
time of titanium dioxide in the lung has been regarded as long
(ICRP, 1959). In one report, the biological half-life of titanium
in man was calculated to be 320 days (ICRP, 1959). Following the
intraperitoneal and intravenous administration of 44Ti in mice, a
mean biological half-life of 640 days was calculated. On the basis
of experience with the biological half-life of uranium dioxide in
rats, monkeys, and dogs, the authors speculated that the whole-body
retention of titanium in man may be even longer than the reported
640 days in mice (Thomas & Archuleta, 1980).
6. EFFECTS ON ANIMALS
6.1. Acute Toxicity
When administered to rats as a single intraperitoneal injection
of 25 mg (139-156 mg/kg body weight) (Sethi et al., 1973) or an
intravenous injection of 250 mg/kg body weight (Huggins &
Froehlich, 1966), titanium dioxide behaved as an inert substance.
Studies on titanates suspended in corn oil revealed that the
intraperitoneal LD50 for rats was 3.0 g/kg body weight for barium
titanate, 2.2 g/kg body weight for bismuth titanate, 5.3 g/kg for
calcium titanate, and 2.0 g/kg for lead titanate. The corresponding
oral LD50 was more than 12 g/kg body weight (Brown & Mastromatteo,
Titanium dioxide (TiO2) has been used as inert dust particles
in lung clearance studies on animals (Ferin 1971a, 1971b, 1972;
Ferin & Leach, 1973). Observations made 2 months after
intratracheal injection of titanium dioxide (20 mg/animal) in rats
did not reveal any reactions other than non-specific responses to
dust particles (Göthe & Swensson, 1970).
Short-term exposure of guinea-pigs to titanium dioxide aerosol
did not induce any inflammatory response; the number of leukocytes
and macrophages remained normal, whereas dusts with a toxic
potential, such as the dioxides of silicon (SiO2) and manganese
(MnO2) caused an increase in the number of leukocytes (Rylander et
al., 1979). The biological inertness of titanium dioxide was
further demonstrated in that it did not exert any demonstrable
effect on the viability of alveolar macrophages (Määttä & Arstila,
1975); moreover, titanium dioxide did not cause fibroblasts to
produce hydroxyproline indicating a lack of fibrogenicity
(Heppleston, 1971). When the synthesis of collagen increases, the
level of proline hydroxylase (EC 126.96.36.199) in lung tissue
increases. This was shown to occur in rats a few weeks after
exposure to silica (Halme et al., 1970). In a study by Zitting &
Skyttä (1979), a suspension containing 50 mg of titanium dioxide
dust in 0.5 ml saline was administered to rats by pipetting into
the pharynx. This did not result in increased levels of proline
hydroxylase. In vitro haemolysis of erythrocytes has been
suggested as a model for the biological activity of dusts (Macnab &
Harrington, 1967). It was, however, noted that while rutile
pigments did not have any haemolytic effect in vitro, the anatase
pigments as well as a mixture of anatase and rutile did exhibit
such an effect (Zitting & Skyttä, 1979). The reasons for
differences in the effects of rutile and anatase dusts could not be
explained, but the report points to the importance of studying
titanium dioxide pigments in relation to their type of crystal
Inhalation of titanium tetrachloride (aerosols of its
hydrolitic products, i.e., titanium compounds and hydrogen
chloride) caused a higher death rate and more rapid development of
lung oedema in mice than inhalation of an equivalent concentration
of hydrogen chloride (Mel'nikova, 1958; Mezenceva et al., 1963;
Mogilevskaja, 1973). This higher toxicity appears to be associated
with the adsorption of hydrogen chloride on particles of hydrated
titanium oxide which penetrate to the deeper parts of the lung not
usually reached by the highly soluble hydrogen chloride. Particles
containing intermediate products of titanium tetrachloride
hydrolysis are deposited in the alveoli, where hydrolysis continues
causing additional damage to the lung tissue.
Similar effects were observed in mice and rats by Sanockij
(1961). Titanium tetrachloride also caused purulent conjunctivitis
and corneal opacity in rabbit eyes.
6.2. Subacute Toxicity
The general inertness of titanium metal has been demonstrated
in various implantation studies. Beder & Eade (1956) studied the
effects of discs of titanium metal implanted in the muscle tissue
of dogs and left in situ for 7 months. The tolerance of soft
tissue and bone to contact with titanium was illustrated by lack of
irritation, normality of wound-healing and the encapsulation of the
metal by fibrous tissue. Similar inertness and lack of response in
the bone tissue of dogs was reported by Beder et al. (1957), 120-
180 days after the plating and fixation of fractures using titanium
Studies on the intratracheal injection of 400 mg of titanium
dioxide in rabbits and observation after 3 months did not reveal
any reactions other than non-specific responses to dust particles,
such as an increase in numbers of phagocytes (Dale, 1973).
Intratracheal instillation of a total dose of 75 mg of barium
tetratitanate suspended in saline (50 g/litre), given in 3 weekly
doses to guinea-pigs did not induce any signs of fibrotic reaction,
up to 12 months after administration (Pratt et al., 1953). Similar
results were achieved by Wozniak et al. (1976), who gave rats 50 mg
of titanium dioxide intratracheally. No fibrosis was found in the
lungs after 3 months.
A fibrotic effect on eosinophilic infiltration was noted in
guinea-pigs (Lenzi, 1936) following repeated titanium dioxide
inhalation over various time intervals ranging from 5 days to 4
months. The dose administered was not reported but the compound
used was characterized as "pure".
A single intratracheal injection of a suspension of 50 mg of
metallic titanium dust or titanium dioxide dust was administered to
5-7 rats. Sacrifice of some animals after 6 months and sacrifice
of the remaining animals, which had been injected a second time,
after 11 months did not reveal any nodular processes or
interstitial sclerosis. Minor effects on the lungs after the
second injection were limited to some lympho-histiocytic reaction
around the particles (Mogilevskaja, 1956). In another study
Mogilevskaja, (1961) administered 50 mg of a titanium concentrate
(ilmenite) intratracheally to 8 rats and sacrificed the animals
after 5 and 7 months. She found slight fibrogenic activity in the
lungs. The ilmenite contained silica (SiO2) at 15-20 g/kg,
aluminium(III)oxide (Al2O3) at 5-35 g/kg, iron(II)oxide (FeO) at
270-320 g/kg, and iron(III)oxide (Fe2O3) at 170-230 g/kg.
Schlipköter et al. (1971) administered 48 mg of titanium
dioxide and 2 mg of quartz (particle size, 5 µm) intratracheally
to 60 rats. Thirty of the rats were injected subcutaneously every
8 weeks with 2 ml of a solution of poly-vinylpyridine-N-oxide
(PVNO) (20 g/litre). When sacrificed after 12 months, the animals
treated with only the titanium-silica dust showed advanced
fibrosis, whereas the PVNO-treated rats were found to have an inert
deposition of dust in the lungs and lymph nodes without any sign of
fibrosis. The hydroxyproline content of the lungs in PVNO-treated
animals did not differ significantly from that in rats treated with
only titanium dioxide but was lower than that in rats given
titanium-silica dust. As PVNO inhibits silica (SiO2) specifically,
the fibrogenic activity was likely to be due to the quartz added to
the titanium dioxide.
Inhalation studies using needle-like potassium octatitanate
fibres (average length 6.7 µm, diameter 0.2 µm) in doses ranging
from 2.9 to 41.8 x 106 fibres (5 µm in length) per litre for 3
months (6 h daily) induced a dose-related fibrosis in rats,
hamsters, and guinea-pigs, 15-24 months later (Lee et al., 1981).
A dose-related fibrosis was also noted in rats receiving titanium
phosphate fibres (length 10-20 µm, diameter 0.2-0.3 µm)
intratracheally. The titanium phosphate fibre is a man-made fibre
that has a potential use for replacing asbestos in various
applications (Gross et al., 1977).
Intratracheal administration of 50 mg of titanium nitride (TiN)
to rats was reported to induce a weak fibrogenic effect after 6
months (Brahnova & Samsonov, 1970). The oxyproline content of the
lungs of rats exposed to titanium hydride (TiH2) dust was
increased, but the increase was only about 16-20% of that induced
by silica. These effects were accompanied by dystrophic changes in
the myocardium, liver, and kidneys (Skurko & Brahnova, 1973) as
well as biochemical changes that, according to the authors,
indicated abnormalities in protein metabolism (Brahnova & Skurko,
1973). Brahnova (1969) compared the effects on animals of different
dusts containing transition metal borides or carbides, including
those of titanium, over a 1-12 month period with respect to their
electron structure. An elevated fibrogenic action and pronounced
dystrophy of the liver, kidneys, and sometimes of the myocardium
were found to occur to a greater extent with the borides than with
A group of 10 male and 10 female rats was given N.F. grade
titanium dioxide in the diet at 100 g/kg, for 30-34 days. A second
group did not receive the titanium dioxide. All animals remained
healthy and behaved normally. Weight gain and food intake were
comparable for the 2 groups. No relevant gross pathology was
observed at autopsy (West & Wyzan, 1963).
Three groups of 2 dogs each, were respectively given 0.05, 0.1,
and 0.15 g of titanium dioxide, orally. Every 5 days, the dose was
increased by the original amount. One dog out of each group was
kept for 1 month, the other, for 2 months. No toxic effects were
seen with regard to haematology, gross pathology, and histopathology.
Three dogs received weekly subcutaneous injections of a suspension
of titanium dioxide in oil; the initial dose of 500 mg was raised
progressively to 3 g over 7 weeks. The 3 dogs survived without
adverse effects. A fourth dog, which initially received 250 mg/kg
rising to 2 g/kg body weight, died, but death, according to the
author, was not causally connected with the administration of
titanium dioxide (Vernetti-Blina, 1928).
6.3. Long-term Toxicity
Schroeder et al. (1964) administered titanium potassium
oxalate, at a concentration of 5 mg/litre, in the drinking-water of
Swiss Charles River mice, from weaning to natural death. The
control group consisted of 88 female and 61 male mice compared with
53 female and 54 male mice in the treated group. The survival rate
after 18 months was 75% females and 50% males for the control
animals, and 70% females and 40% males for the treated group. The
body weights of the animals in the titanium-fed group were higher
than those in the control group.
Two guinea-pigs, 2 rabbits, 2 cats, and 1 dog were fed
technical grade titanium dioxide for 390 days. The dog received 9
g/day, the rabbits and cats, 3 g/day, and the guinea-pigs, 0.6
g/day. Two additional cats received 3 g titanium dioxide daily for
175 and 300 days, respectively. Adverse effects were not seen in
any of the animals and histopathological examination did not reveal
any abnormalities (Lehman & Herget, 1927).
Christie et al. (1963) did not find any evidence of pathological
response in the lungs of rats that had inhaled titanium dioxide
dust (air concentrations in the range of 10-328 million particles
per cubic foot) 4 times daily, 5 days per week for periods up to 13
months, followed by a 7-month period of fresh air. The inhalation
of titanium dioxide did not affect the weight of the rats.
Evidence of mutagenic activity of titanium or its compounds
is scant. Levan (1945) described cytological reactions induced in
the stems of Allium cepa by a large variety of inorganic salt
solutions. Titanium salts induced sticky chromosomes manifested by
the formation of anaphase bridges. Titanium tetrachloride has been
claimed to be non-mutagenic (Hsie et al., 1979). Some titanium
compounds have been tested using the "rec-assay" with Bacillus
subtilis. The following compounds were found to be negative in the
"rec-assay": titanium tetrachloride (TiCl4), titanium trichloride
(TiCl3), titanium boride (TiB2), titanium carbide (TiC), titanium
fluoride (TiF4), and titanium dioxide (TiO2) (Kada et al., 1980).
Few studies have been carried out on the carcinogenicity of
titanium and its compounds.
Furst (1971) reported that titanium metal (pure powder of at
least 200 mesh) injected intramuscularly in 6 monthly doses, each
of 6 mg in 0.2 ml trioctanoin, induced 2 fibrosarcomas in 25 male
and 25 female Fisher-344 inbred rats and lymphosarcomas in 3 out of
25 males. Fibrosarcomas or lymphomas were not seen in the controls
given trioctanoin alone. Treated rats survived up to 820 days and
controls up to 935 days.
When a suspension of lead titanate in saline (10 g/litre) was
administered intratracheally to 6 guinea-pigs (0.3 ml, once every 3
months) for a total of 6 injections, it did not give rise to
tumours (Steffee & Baetjer, 1965).
In the longevity study by Schroeder et al. (1964), described in
section 6.3, the mice receiving titanium throughout their life-time
did not show any increase in the tumour incidence compared with the
Titanocene, a laboratory experimental compound, was shown
to be carcinogenic, when suspended in trioctanoin and injected
intramuscularly into Fischer-344 rats, once a month, to give a
total administered dose of 200 mg. Fibrosarcomas developed in the
thigh muscle at the site of injection. In addition, some of the
treated animals developed hepatomas and malignant lymphomas of the
spleen. The control compound, titanium dioxide was reported to
have induced only 3 fibrosarcomas in 3 out of 50 rats. Details of
the study were not reported (Furst & Haro, 1969).
It has recently been shown that metallocene dichlorides,
(C5H5)2MCl2, where M = titanium, vanadium, molybdenum, or nobium,
exhibit cancerostatic activity against the Ehrlich ascites tumour
system in mice, and that treatment with such metals has lead to
total cures. According to Köpf-Maier & Köpf (1980), the mechanism
behind the cancerostatic effect of titanocene dichloride is not
known. The antitumor activity has been investigated in mice, using
single intraperitoneal injections of titanocene dihalides at doses
ranging from 10 to 240 mg/kg body weight. Survival times without
manifestations of tumours, were significantly longer in treated,
than in control animals (Köpf-Maier et al., 1980a, 1980b; Köpf-
Maier & Krahl, 1981).
On the basis of available data, titanium has generally been
considered to belong to the group of metals of low carcinogenicity
(Sunderman, 1978; Radding & Furst, 1980; Valentin & Schaller,
6.6. Teratogenicity and Effects on Reproduction
Schroeder & Mitchener (1971) studied the toxic effects of
titanium on the reproduction of mice and rats. Breeding mice of the
Charles Rivers CD strain and rats of the Long-Evans BLUE: (LE)
strain were exposed in separate studies to titanium in the form of
a soluble salt in the drinking-water (concentration 5 mg Ti/litre).
Each group was carried through 3 generations. The data on rats are
summarized in Table 6.
Table 6. Results of a 3-generation study on rats receiving titanium
in the drinking-watera
Number Average M/F Maternal Dead Young Runts No.
litters litters ratio deaths litters deaths rats
control 10 11.4 1.14 0 0 0 0 114
titanium 11 9.4 1.43 0 0 1 23 103
control 10 11.3 1.10 0 0 0 1 113
titanium 16 10.9 0.99 1 0 24 14 174
control 11 11.0 1.06 0 0 1 0 121
titanium 2 8.0 0.60 0 0 0 6 16
a From: Schroeder & Mitchener (1971).
In rats, the titanium was toxic with a marked reduction in the
numbers of animals surviving to the third generation, only 2
litters appearing in this generation. The male/female ratio was
progressively reduced. The controls continued to breed for 4
generations with few deaths and runts occurring.
7. EFFECTS ON MAN - CLINICAL AND EPIDEMIOLOGICAL STUDIES
7.1. Clinical Studies
Elo et al. (1972) examined lung specimens from 3 factory
workers employed for 9 years in processing titanium dioxide
pigments. Significantly higher titanium levels were found in the
lungs of these patients compared with lung specimens from a general
autopsy population. Deposits in pulmonary interstitium were
associated with cell destruction and slight fibrosis. Titanium
dioxide was found in the lymphatic system, suggesting that it was
cleared via this route. Electron-microscopic studies revealed
titanium dioxide particles within lysosomes of the alveolar
macrophages. It was suggested that industrially processed titanium
dioxide, either alone or in conjunction with other compounds such
as silica, may behave as a mild pulmonary irritant. Using X-ray
microanalytical light and electron-microscopic methods, open lung
biopsy samples and sputum specimens from 3 former workers exposed
to titanium dioxide were studied by the same investigators. These
studies revealed that, in addition to titanium, the alveolar
macrophages contained small amounts of silicon, aluminium, iron,
and potassium. As industrial titanium dioxide is mostly coated with
various other elements such as aluminum and silicon, and because
these substances were localized in different structures of the
lung, it was postulated that the weak fibrogenic effect was exerted
by silica or silicon compounds rather than by the titanium dioxide
(Määttä & Arstila, 1975).
Autopsy studies on workers exposed to titanium dust have
generally corroborated experimental animal studies showing that
titanium dioxide dust does not exert any fibrogenic effect on lung
tissues. Extensive titanium dioxide deposits were found in the
lungs of a worker who had been exposed to titanium dioxide dust for
15 years. However, no inflammatory or fibrotic changes could be seen
(Schmitz-Moorman et al., 1964). In a more recent autopsy study on
a 55-year old man who had been exposed to titanium dioxide, the
crystal modification was taken into consideration. The methods
used included scanning and transmission electron microscopy,
electron X-ray diffractometry, and atomic absorption spectroscopy.
Considerable deposits of rutile were found, but there were not any
signs of fibrotic changes (Ophus et al., 1979). Husten (1959)
reported fibrosis in a worker who had been exposed in the hard
metal industry. The study is quoted as an indication of a possible
fibrogenic effect of titanium (American Conference of Governmental
Industrial Hygienists, 1973). However, this worker had been exposed
to other elements more likely to be responsible for the fibrosis, a
feature occasionally seen in workers in the hard metal industry
(Parkes, 1974; Konietzko et al., 1980).
Accidental exposure to titanium tetrachloride (TiCl4) fumes
was described by Heimendinger & Klotz (1956). Splashing with
titanium tetrachloride at 100 °C and inhalation of fumes of titanic
acid and titanic oxychloride led to surface skin burns with
scarring. The mucosa of the pharynx, vocal cords, and trachea was
markedly congested with cicatrization and laryngeal stenosis as
late sequelae. Histology showed titanium dioxide phagocytosed in the
lungs. Larger dust deposits were associated with small areas of
focal emphysema, but no specific lesion was seen. Lawson (1961)
reported 3 cases of accidental exposure to titanium tetrachloride
liquid, which was then washed off. Contact with water resulted in
severe burns due to the exothermic reaction between titanium
tetra chloride and water. Later sequelae were pigmentation and
scarring. Nine other mild cases showed less severe burns, without
subsequent permanent skin changes. However, contact with a 10%
solution of titanium tetrachloride can cause second and third
degree burns in man (Mogilevskaja, 1973), and precautions have to
be taken in handling titanium tetrachloride to protect occupationally-
exposed workers (Kokorev et al., 1960; American Conference of
Governmental Industrial Hygienists, 1973).
The lack of toxicity of titanium and its compounds in contact
with the skin has been demonstrated by its use in the therapy of
skin disorders. Titanium compounds (salicylate, peroxide, oxides,
tannate) have been used for many skin disorders (Ereaux, 1955).
During the Second World War, a protective film of cream containing
titanium dioxide was used on exposed parts of the body to prevent
flash burns (Fairhall, 1969). Déribéré (1941) has described its
innocuous use as a constituent of cosmetic preparations.
Titanium is accepted as a biocompatible implant material in
orthopaedics, oral surgery, and neurosurgery. It has extremely
high corrosion resistance and does not cause adverse tissue
reaction (Williams & Adams, 1976; Palmer et al., 1979; Solar et
al., 1979; Schroeder et al., 1981). Small amounts of titanium may
occasionally be found in tissues adjacent to the implant (Laing et
al., 1967; Meachim & Williams, 1973). The mechanism of the release
of titanium is not well understood as it seems to be unrelated to
wear processes (Williams & Adams, 1976; Solar et al., 1979). No
harmful effects have been reported to follow such a release of
titanium from implants. Harmful immunological reactions to
titanium have not been demonstrated (Lyell, 1979; Brun & Hunziker,
7.2. Epidemiological Studies
Epidemiological surveys have focused, almost exclusively, on
the possible fibrogenicity of titanium dioxide dusts. An early
study conducted by Vernetti-Blina (1928) on men exposed to titanium
dust for prolonged periods did not reveal any sign of abnormality
in the clinical, radiological, or blood picture. Uragoda & Pinto
(1972) investigated the health of 136 workers in an ilmenite
extracting plant, in Sri Lanka. The workers were exposed to a
number of minerals, the principal ores of which were ilmenite,
rutile, and zircon. The prevalence of changes in the chest radio-
graphs did not differ between the workers and a reference group
drawn from the general population. Furthermore, Moschinski et al.
(1959) did not detect any fibrosis in titanium dioxide-exposed
Daum et al. (1977) studied 207 workers exposed to titanium
dioxide in a plant producing the dioxide from ilmenite ore using
the sulfate process. Ninety per cent of the workers had been
exposed for 20 years or more. Spirometry revealed obstruction of
the airways in 47%, but pneumoconiotic changes in the chest
radiographs were "relatively few and unrelated to the respiratory
abnormalities observed". It was pointed out by the authors, and by
Parkes (1977), that the sulfate process may cause irritation of the
upper respiratory tract, and that this probably caused the
abnormalities found in the study, rather than the titanium dioxide
In a survey of workers in factories manufacturing titanium
tetrachloride, Kokorev et al. (1960) found a significant number of
damaged respiratory pathways (hyperaemia, thinning of mucosa, toxic
bronchitis). The author considered these effects were caused by
titanium tetrachloride and the products of its hydrolysis.
8. EVALUATION OF HEALTH RISKS TO MAN
There is no evidence indicating that titanium is an essential
element for man or animals. According to available data on the
toxicity of titanium and titanium compounds and their presence in
various environmental media, there is no reason to believe that
exposure to titanium would constitute any health risks for the
general population. Studies on titanium alloys, used in implants,
do not indicate any adverse local effects on tissues, suggesting
that titanium is a biologically compatible element.
Accidental exposure to titanium tetrachloride constitutes a
hazard in industrial settings, as contact with either the substance
or the fumes emitted will cause burns.
Occupational exposure to titanium dioxide occurs frequently
and the level of exposure may be high. Studies on experimental
animals, clinical studies including autopsies, as well as some
epidemiological surveys on exposed working populations have shown
convincingly that titanium dioxide is biologically inert and does
not possess fibrogenic characteristics. This has been corroborated
by in vitro investigations, where, however, different titanium
dioxide dusts were shown to have various degrees of haemolytic
activity, rutile being practically inert and anatase having a
measurable haemolytic activity. This emphasizes the importance of
considering titanium dioxide dusts of different composition and
mineralogical structure separately, always stating clearly the
characteristics of a tested compound.
In studies where fibrosis has been reported in association with
exposure to titanium dioxide dusts, the etiological relationship
has not been convincingly proved. Moreover, in these studies
concomitant exposure to other elements such as silica seems to
offer a more likely explanation of the fibrosis than the titanium
Other titanium compounds, such as the hydride, carbide, and
boride, may have fibrogenic properties according to experimental
animal studies. Man-made fibres such as potassium octatitanate or
titanium phosphate fibres are also fibrogenic in laboratory
Available data do not suggest that titanium or titanium
compounds induce any mutagenic or teratogenic effects. However,
few studies on these aspects have been made. Intramuscular
injection of powdered titanium metal has induced fibrosarcomas and
lymphosarcomas in rats. Titanocene, an organotitanium compound,
has induced fibrosarcomas in rats. Available data on the
carcinogenicity of titanium in man do not indicate any such effect,
and adverse immunological reactions to titanium have not been
It is not possible from the available data to establish dose-
effect or dose-response relationships for any effect associated
with exposure to titanium or its compounds. Thus no quantitative
assessment of the human health risk from exposure to titanium or
titanium compounds in occupational or non-occupational
environmental situations can be made.
AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS
(1973) Hygienic Guide Series. Titanium. Am. Ind. Hyg. Assoc.
J., 34(6): 275-277.
AGATOMOFF, U. (1928) Soil types of France. Soil Res.
(Berlin), 1: 67.
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