C H A P T E R
57
Titanium
TAIYI JIN AND MATHS BERLIN
ABSTRACT
There is no evidence that titanium is an essential ele-
ment for humans or other animals. Titanium belongs
to the first transition group of the periodic table of the
elements; its chemical behavior is similar to that of
silicon and zirconium. Although titanium compounds
are, in general, absorbed poorly by ingestion and inha-
lation, titanium still can be detected in the blood, brain,
and parenchymatous organs of individuals in the
general population, with the highest concentrations
being found in the hilar lymph nodes and the lungs.
Titanium is excreted in the urine; information on other
routes of excretion is lacking.
Studies on titanium alloys used in implants and
titanium compounds—such as its salicylate, oxide,
and tannate derivatives-—used in cosmetics and phar-
maceuticals have not indicated any significant local
effects on tissues, although under certain circum-
stances inflammatory reactions and systemic effects
have been observed. Thus, titanium cannot always
be considered as inert and biocompatible, as was
once believed. Titanium tetrachloride, a strong irri-
tant to mucous membranes and the eyes, can cause
skin burns through accidental exposure. Experimental
animal studies, clinical studies, and some epidemio-
logical surveys have indicated that titanium dioxide is
generally biologically inert, but cases of adverse reac-
tions have been reported. In experimental studies on
animals, titanium carbide, hydride, nitride, and boride
have exhibited slight fibrogenic activity. Artificial
fibers—such as potassium octatitanate and titanium
phosphate fibers—possess fibrogenic properties.
Bronchoalveolar lavage cells from rats instilled
endotracheally with TiO2 particles induce Hrpt gene
mutations in rat alveolar cells in vitro. Intramuscular
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00057-3
injections of powdered titanium metal have induced
fibrosarcomas and lymphosarcomas in rats; similarly,
the organotitanium compound titanocene has induced
fibrosarcomas in rats. Several epidemiological stud-
ies have suggested that TiO2 dust has no carcinogenic
effect on human lungs. The International Agency for
Research on Cancer has listed titanium dioxide in
Group 2B. There is sufficient evidence from experi-
mental animal studies to suggest the carcinogenicity
of TiO2, but no adequate evidence exists for the carci-
nogenicity of titanium oxide in humans. A soluble tita-
nate given to rats in their drinking water was found to
disturb their reproduction in a three-generation study.
Environmental pollution caused by the use of
titanium nanoparticles (TNPs) has recently become
important, and is increasing. Although a few epidemi-
ological studies have shown no increased risk of respi-
ratory cancer, further evaluation on toxicity of TNPs
needs to be performed.
1  PHYSICAL AND CHEMICAL PROPERTIES
Titanium (Ti): Chemical Abstracts Service (CAS)
No. 7440-32-6; atomic weight, 47.9; atomic number, 22;
density, 4.5 g/cm3 at 20°C; melting point, 1660 ± 10°C;
boiling point, 3287°C; silver-gray; water insoluble. Tita-
nium is one of the most common components of the
Earth’s crust (ninth in abundance). It occurs naturally
as ilmenite (iron titanate) and rutile (titanium diox-
ide). Titanium exhibits both metallic and nonmetallic
characteristics: metallic compounds include titanium
chloride, phosphate, sulfate, and nitrate; nonmetallic
properties are exemplified by the calcium, iron, and
sodium titanates. Titanium forms four distinct oxides:
titanium monoxide (TiO), dititanium trioxide (Ti2O3),
1287 Copyright © 2015 Elsevier B.V. All rights reserved.
1288 Taiyi Jin and Maths Berlin
titanium dioxide (TiO2), and titanium trioxide (TiO3).
The most common oxidation states are +4 (TiO2) and
+3 (titanous, Ti2O3); compounds with oxidation state
+2 (TiO) are less stable, as are oxycompounds such as
titanyl chloride (TiOCl2).) A number of organometallic
compounds of titanium, such as titanocene, are known;
the most common are the alkyl- and aryltitanates, with
the general formula Ti(OR)4. Complex titanium com-
pounds possessing organic ligands are also known.
Titanium metal displays excellent corrosion resis-
tance: it is as resistant as platinum against many agents,
including concentrated nitric acid, moist chlorine gas,
and common salt solution. An important property of
titanium is that, on exposure to air or various liquids,
it rapidly develops a layer of oxide, which reduces its
reactivity (Kasemo, 1983). No metal or alloy is, how-
ever, completely inert in vivo. Elevated titanium con-
centrations have been reported in the blood, urine, and
nails of humans with titanium-containing implants
(Bianco et al., 1996; Berglund and Carlmark, 2011).
Titanium dioxide (CAS No. 13463-67-7) exists in three
crystalline forms: anatase, brookite, and rutile (WHO,
1982). Titanium tetrachloride (CAS No. 7550-45-0)
occurs as a colorless to light-yellow liquid that is solu-
ble in water, but decomposes in hot water (HHS, 1993).
2  METHODS AND PROBLEMS
OF ANALYSIS
Methods applied to the detection of titanium in
water and food include spectrography and photom-
etry. Although various atomic absorption techniques
have also been reported, the use of a high-temperature
reducing flame is desirable, because of the poor atomi-
zation of Ti and its tendency to form refractory oxides.
Inductively coupled plasma optical emission spec-
trometry (ICP-OES) techniques have been developed
for the rapid determination of titanium in foods after
acid digestion (Lomer et al., 2000). TiO2 is usually mea-
sured as the metal. Inductively coupled argon plasma
atomic emission spectroscopy (ICP-AES) is an alterna-
tive method for determining titanium dioxide in air,
with detection limits in the parts-per-billion range and
excellent recovery (96%) (NIOSH, 1994d). This method
can also be used to assay titanium in urine and tissues,
with a detection level of 20 ppb and a good level of
recovery (86%) (NIOSH, 1994a).
Proton-induced X-ray emission spectroscopy
has also been used with practical detection limits of
c. 0.001 μg for titanium in air and below 0.001 μg of tita-
nium per drop of water (Johansson et al., 1975).
X-Ray fluorescence has been used widely for
the determination of titanium in air, water, and
biological samples; the detection limit for titanium in
air is 0.011 μg/m3 at a sensitivity of 0.01 μg/m3 (Kalbasi
et al., 1995 ).
Neutron activation analysis has been employed
for the determination of titanium in air, while spark
source mass spectrography has been used for the anal-
ysis of water, food, and biological samples. Gravimet-
ric filter weight is the most common method employed
for determining titanium and titanium dioxide as par-
ticulate matter in air (NIOSH, 1980, 1994b,c); spectro-
scopic methods are most commonly used for detecting
the metal associated with particulates in air (NIOSH,
1994d).
3  PRODUCTION AND USES
3.1 Production
Titanium is one of the most common components in
the Earth’s crust (ninth in abundance, 0.6% by mass); it
occurs in a number of minerals as well as in living sys-
tems and natural bodies of water. Among the various
mined titanium minerals, ilmenite is of great commer-
cial significance. The world production of ilmenite in
2002 (including leucoxene) and rutile were c. 5.64 mil-
lion tons and c. 0.35 million tons, respectively (Index
Mundi, 2014). The recovery of titanium from second-
ary sources probably does not exceed 1% of the total
production. Two main production processes are used
for preparing commercial titanium dioxide pigments:
the sulfate and chloride processes.
3.2 Uses
Titanium metal finds an extensive number of appli-
cations in the aircraft and spacecraft industries because
of its very high tensile strength, light weight, and
extraordinary corrosion resistance, as well as its abil-
ity to withstand extreme temperatures. When used for
these purposes, titanium is usually used in the form of
alloys, which are stronger and more resistant against
corrosion than is the metal itself. Because of its resis-
tance to corrosion and its chemical inertness, titanium
is used widely in the chemical industry, for example,
as tubing and for the lining of vessels used in the pro-
duction of nitric acid and acetaldehyde. Its resistance
to corrosion means that titanium is useful also in the
paper pulp industry. Titanium is the newest metallic
biomaterial among the most popular metallic alloys
(Niinomi, 2002). Titanium and its alloys continue to
receive much attention in medical and dental fields
because of the balance between their excellent mechan-
ical properties and corrosion resistance; they are used
 57 Titanium
mainly for implant devices that replace failed hard
tissue, for example, artificial hip or knee joints, bone
plates, and dental implants. Titanium and its alloys are
also used in dental products, such as crowns, bridges,
and dentures.
Titanium dioxide (TiO2) is the most common tita-
nium compound; it constitutes almost 95% of all tita-
nium consumed. Titanium dioxide is the most common
white synthetic pigment used in the paint industry. It
has many favorable properties: ready availability, a
comparatively cheap price, extreme whiteness and
brightness, and a high index of refraction. Based on
these characteristics, titanium dioxide is used exten-
sively as a white pigment in paints, lacquers, enamels,
paper coatings, and plastics. Because of its effective-
ness as a sunscreen toward short-wave ultraviolet
radiation, titanium oxide is included within a variety
of drugs and cosmetics. It is also used as a color addi-
tive in confections, dairy products, and bread flours as
a replacement flour-bleaching agent. Titanium diox-
ide serves as a clouding agent incorporated into dry
beverage mixes, and is used in tobacco wrappings and
tobacco substitutes. Titanium dioxide is also used in
the pharmaceutical industry as a constituent of tablets.
Titania nanoparticle (TNP) is a nanomaterial widely
used in applications such as photocell coating, photo-
catalysts, cosmetics, and sunscreen products and addi-
tives (Hu et al., 2010).
Titanium tetrachloride (TiCl4) is another commer-
cially important titanium derivative that is used as an
intermediate in the production of titanium metal and
titanium pigments, and as a component and catalyst in
the chemical industry. Titanium chloride (TiCl3), which
is prepared by the reduction of titanium tetrachloride,
serves as a coloring agent and as a catalyst in various
chemical processes.
4  ENVIRONMENTAL LEVELS
AND EXPOSURES
4.1  General Environment
4.1.1  Food and Daily Intake
Titanium is poorly absorbed by plants and animals
and is retained to only a limited extent. High levels
of titanium in food products can be detected, how-
ever, when soil is contaminated by fly ash fallout or
titanium-containing sewage residues (used as fertil-
izers), and when titanium dioxide is used as a food
whitener. High concentrations of titanium in certain
types of cheese result from the addition of titanium
dioxide as a whitener and an aging accelerator. Food,
which is considered to be the most important source of
1289
exposure to titanium, contributes more than 99% of the
daily intake of the element. There is no relevant toler-
able intake for titanium against which to compare esti-
mated dietary intake (JFSSG, 2000). Typical diets may
contain c. 0.3-0.5 mg titanium (Schroeder et al., 1963;
Poole and ­Johnston, 1969; Tipton et al., 1969).
4.1.2  Water, Soil, and Ambient Air
It has been reported that titanium concentrations
range from 2 to 107 μg/L in freshwater in Canada and
the USA ( Durum and Haffty, 1961) and 0.5 to 15 μg/L
(mostly around 2 μg/L) in drinking water in the USA
(Durfor, 1963). Titanium concentrations in seawater
are mostly around 0.6-1 μg/L, but values up to 9 μg/L
have been reported (Bowen, 1966; Ishibashi, 1966;
­Silvey, 1967).
The titanium content of soil generally ranges from
0.3 to 6%, with high levels found in the vicinity of
power plants because of the combustion of coal (Klein
and Russell, 1973).
Titanium concentrations in the atmosphere are com-
paratively low. However, some investigation showed
that ambient air titanium concentrations have recently
shown a significant increase in some areas in the USA
(Spengler et al., 2011). Annual average concentrations
in urban air are mostly below 0.1 μg/m3, and are lower
still in rural air (EPA, 1973). Air concentrations up to
0.5 μg/m3 have been reported in urban and industrial-
ized areas (JESC, 1971; EPA, 1973; Giauque et al., 1974).
The daily intake from urban air is c. 1-5 μg; it is likely
to be less than 1 μg in rural areas (Schroeder et al., 1963;
Woolrich, 1973). Compared with the amount of tita-
nium absorbed from food, the intake of titanium from
the air is negligible: under most conditions, it is less
than 1% to the total daily intake. Their widespread
usage results in the release of a large amount of TNPs
into the environment (Lee et al., 2010, Tsuji et al., 2006).
4.2  Working Environment
Occupational exposure to titanium occurs princi-
pally in the form of dust; inhalation is the most com-
mon route of exposure. High exposure levels have been
reported from mining, from the production of the metal,
and from the production and processing of titanium
dioxide, carbide, and hydride. T ­ypical dusty opera-
tions include the crushing, grinding, m
­ ixing, and siev-
ing of rutile concentrates. High exposure to titanium
compounds in the air has also been reported from the
manual handling, screening, and p­ ackaging of titanium
hydride powder (Skurko and Brahnova, 1973). Expo-
sure to fumes and vapors occurs in the handling of tita-
nium tetrachloride. Exposure to titanium tetrachloride
1290 Taiyi Jin and Maths Berlin
may also occur in the reduction process, where workers
are exposed to titanium tetrachloride and titanium oxy-
chloride vapors and to titanium ­dioxide particulates
(Garabrant et al., 1987). Exposure may occur at any
stage during the mining of ores and the preparation of
titanium dioxide, and in any industries in which the
powder is stored and used. The American Conference
of Governmental I­ ndustrial Hygienists (ACGIH, 2005)
suggested a threshold limit value/time-weighted aver-
age for TiO2 (CAS No. 13463-67-7) of 10 mg/m3.
5 KINETICS
An important property of titanium is that, on expo-
sure to air or various liquids, it rapidly develops a
layer of oxide, which reduces its reactivity (Olmedo
et al., 2003).
5.1 Absorption
Titanium nanoparticles may be taken up via the
nasal route (Wang et al., 2008) and after oral intake
(Wang et al., 2007). A number of studies have indi-
cated that titanium is mainly absorbed through inges-
tion, but different conclusions have been drawn as to
the extent. One study undertaken by Schroeder et al.
(1964) found that titanium levels in the organs of mice
given potassium titanium oxalate at a concentration
of 5 mg/L in their drinking water during their entire
life span were five times higher than those observed
in control animals. Translocation of TiO2 (rutile) par-
ticles to intestinal-tract-associated tissues and other
organs was observed in rats administered 12.5 mg/
kg/day TiO2 by gavage for 10 days (Jani et al., 1994). In
another study using mice, a very low degree of absorp-
tion from the gastrointestinal tract was observed: the
whole-body count of experimental animals given 44Ti
intragastrically did not exceed the background level
after 24 hours (Thomas and Archuleta, 1980). Blood
titanium levels were found to increase following oral
administration of TiO2 (anatase) to human volunteers
(Böckmann et al., 2000).
There is much data to indicate that titanium is
absorbed poorly from the gastrointestinal tract in
human beings. It is likely that transferrin may act as
a specific carrier of titanium ions and thus play a cen-
tral role during the transporting and biodistribution
of soluble titanium species throughout the organism
(Ishiwata et al., 1991). Titanium concentrations found
generally in urine (c. 10 μg/L) suggest an absorption of
less than 5%, assuming a daily intake of at least 300 μg.
Although this estimate agrees with that reported by
Schroeder et al. (1963), it may be erroneous because
other possible routes of excretion, especially intestinal,
were not been taken into consideration.
The deposition of titanium dioxide dust in the lungs
of rats is similar to that observed for other particles
(Ferin et al., 1983). Titanium dioxide is found in the
lymphocytes and regional nodes in the lungs, indi-
cating that a slow rate of removal occurs by this pro-
cess. Clearance is also significantly decreased, or even
ceases, at high exposure over a period of time because
of overload (Bermudez et al., 2002, 2004). It is suggested
that small amounts of titanium dioxide can enter the
general circulation from the lungs (Lee et al., 1985). The
absorption and transference of titanium to the liver and
spleen in rats exposed to 10 mg/m3 titanium tetrachlo-
ride aerosol for 6 hours per day, 5 days per week, for 2
years, have been reported (Lee et al., 1986).
5.2 Distribution
Several transport mechanisms have been described
for titanium, including systemic dissemination by the
vascular system in solution or as particles (Meachin
and Williams, 1973; Edel et al., 1985; Merritt and Brown,
1995) and lymphatic dissemination as free particles or
as phagocytosed particles within macrophages (Bianco
et al., 1996).
Titanium concentrations of 2-9 mg/kg wet weight
were found in the parenchymatous organs—such as
the heart, lungs, spleen, liver, and kidneys—of mice
that had been given titanium oxalate in their drinking
water at a level of 5 mg/L throughout their life. The
concentrations were similar to those observed in wild
mice, but were five times higher than the concentra-
tions found in untreated animals (Schroeder et al.,
1964). Six hours after titanium dioxide was adminis-
tered to rats through intravenous injection at 250 mg/
kg body weight, the highest concentration appeared in
the liver; after 24 hours, the highest concentration was
detected in the celiac lymph nodes, which filter the
lymph from the liver (Huggins and Froehlich, 1966).
In the general population, titanium has been
detected in various parenchymatous organs, with the
highest concentrations consistently being found in the
lungs (Hamilton et al., 1972/1973), probably as a result
of inhalation of titanium-containing dust particles. Ter-
aoka (1980) reported even higher concentrations in the
hilar lymph nodes than in the lungs. Lung concentra-
tions in coal miners, have been reported to be several
times those found in the general population (Crable
et al., 1967, 1968). Titanium was demonstrated in the
lymphatic systems of three workers engaged in the pro-
cessing of titanium dioxide pigments (Elo et al., 1972).
 57 Titanium
5.3  Biological Half-Time
There is still an insufficient amount of data for
estimating the biological half-time of titanium in
humans or animals. The International Commission
on Radiological Protection calculated a half-life of 320
days (ICRP, 1959). Although the half-life in mice was
reported to be 640 days, the authors speculated that
in humans the half-life might be even longer (Thomas
and Archuleta, 1980).
5.4 Excretion
Titanium taken orally remains mostly unabsorbed
and is eliminated in the feces. In humans, the excre-
tion rate of titanium is c. 10 μg/L urine (Schroeder
et al., 1963). Tipton et al. (1966) reported, however,
urinary excretion rates as high as 0.41 and 0.46 mg/
day (30-day mean), respectively, in two adults. The
mechanism of excretion and the possible amount
of titanium excreted by the intestinal route remain
unknown.
6  LEVELS IN TISSUES AND BIOLOGICAL
FLUIDS
It has been reported that the blood concentration
of titanium ranges from 0.03 to 0.15 mg/kg (Hamilton
et al., 1972/1973). Titanium concentrations of 0.8 mg/
kg wet weight in the brain, 1.3 mg/kg in the kidney
cortex, 1.3 mg/kg in the liver, 3.7 mg/kg in the lungs,
and 0.2 mg/kg in muscle have been reported (­Hamilton
et al., 1972/1973).
Titanium tends to accumulate with age in lung tis-
sue, but not in other organs (Schroeder et al., 1964).
Titanium concentrations of 33 mg/kg dry weight in
the lungs and 150 mg/kg in hilar lymph nodes have
been reported (Teraoka, 1980). No analytical methods
have been described for the measurement of titanium
dioxide in urine.
It has been observed that serum titanium concen-
trations were c. 50 times greater, due to abrasion and
wear of the titanium base material, in patients with
failed patellar components of titanium-based joint
implants (average concentration of serum titanium
135.57 ng/mL ) when compared with those of a con-
trol group. There were, however, no significant differ-
ences in the levels of urinary titanium. Elevated serum
titanium may, therefore, serve as a marker of failed
patellar components in subjects who have undergone
total knee replacements with titanium alloy bearings
(Jacobs et al., 1999).
1291
7  EFFECTS AND DOSE-RESPONSE
RELATIONSHIPS
No evidence exists that titanium is an essential ele-
ment for humans or other animals.
7.1  Local Effects and Dose-Response
Relationships
7.1.1 Animals
7.1.1.1 Lungs
The effects of inhalation or endotracheal instillation
of TiO2 particles have been studied in rats, mice, rab-
bits (Dale, 1973), and hamsters. At levels of exposure
causing little accumulation of particles in the lungs
and with an effective clearance of deposited particles,
no effects were found on the viability of alveolar mac-
rophages (Maatta and Arstila, 1975), nor any stimu-
lation of fibroblasts (Heppleston, 1971). At heavier
exposure, causing an overload of the rat lung clear-
ance function and with accumulation of particles in the
lungs, an inflammatory response was induced, with
increased numbers of neutrophils and fibrosis. The
lung clearance of TiO2 particles is less efficient in rats
and mice than in hamsters (Hext et al., 2005). Thus, rat
lungs are overloaded at lower particle loads than are
the lungs of other tested animals; they also exhibit a
more pronounced tendency to undergo inflammatory
and fibrogenic reactions. Lee et al. (1986) found that
exposure to 250 mg/m3 pigment-grade TiO2 particles
for 1 year caused retention of Ti-particles in the alveoli
and alveolar ducts, and impaired clearance with pro-
gressive tissue changes. Similar observations were
made in studies designed to compare the development
and possible progression of the lung responses of rats,
mice, and hamsters exposed to a range of concentra-
tions of pigment-grade TiO2 and ultrafine-grade TiO2
particles over a period of 90 days, with subsequent
retention of some exposed animals for up to 1 year.
The ultrafine particles appeared to be more toxic than
the pigment-grade particles when measured in terms
of mg TiO2/m3; when the lung burden was measured
in terms of the total particle surface area, however, a
better correlation existed between the lung load and
the histopathological response and the inflammatory
reaction, in terms of an increased number of neutro-
phils in the lung lavage liquid (Baggs et al., 1997; Ber-
mudez et al., 2002, 2004; Hext et al., 2002). Watanabe
et al. (2002) compared the in vitro toxicities of particu-
late and fibrous titanium dioxide samples toward rat
alveolar macrophages and found that the fibrous mate-
rial was more toxic than the particles.
1292 Taiyi Jin and Maths Berlin
The endotracheal administration of 50 mg (in 1 mL
saline) of titanium carbide, boride, or nitride caused
mild fibroses in the lungs of rats (Brahnova, 1969;
Brahnova and Samsonov, 1970); the administration
of 50 mg of titanium hydride to rats led to a weak
fibrogenic effect 6 and 12 months later (Brahnova and
Skurko, 1972).
The ability of titanium fibers to cause fibrosis is
determined by their dimensions. Dose-related fibrosis
was found in inhalation studies of rats, hamsters, and
guinea pigs when using potassium octatitanate fibers
with an average length of 6.7 μm and a diameter of
0.2 μm that were administered for 6 hours daily for 3
months in doses ranging from 2.9 to 41.8 × 106 fibers/L.
The fibrosis was registered 15-24 months after treatment
(Lee et al., 1981). Similarly, dose-related fibrosis was
observed in rats after the administration of man-made
titanium phosphate fibers with lengths of 10-20 μm and
diameters of 0.2-0.3 μm (Gross et al., 1977).
Administration of a total dose of 75 mg barium tita-
nate, given in three weekly doses as a 5% suspension,
through endotracheal instillation, did not produce any
fibrotic changes in guinea pigs for up to 12 months
(Pratt et al., 1953). Inhalation of titanium hydride for
16 months, however, produced weak fibrogenic effects
(Skurko and Brahnova, 1973).
TNPs have been shown to induce pulmonary dam-
age and inflammation (Lee et al., 2009; Chen et al., 2006).
TNPs have recently been used as a model for studying
nanoparticle toxicity (for further details see Chapter 4,
“Toxicity of Metal and Metal Oxide Nanoparticles”).
7.1.1.2  Other Sites and Implants
Studies on rats given single intraperitoneal injec-
tions of 25 mg titanium dioxide (Sethi et al., 1973) or an
intravenous injection of 250 mg/kg body weight (Hug-
gins and Froehlich, 1966) indicated that the compound
is biologically inert.
Most medical reports on titanium in the early
1980s focused on whether titanium alloys were suit-
able implantation materials (e.g. Schroeder et al., 1981;
­Brunette et al., 1983; Kallus and Hensten-Pettersen,
1983; Kasemo, 1983). The general inertness of titanium
has been convincingly demonstrated in several stud-
ies. The lack of irritation, the good degree of wound
healing, and the encapsulation of the metal by fibrous
tissues after the implantation of titanium metal in dogs
all suggest that soft tissue has a high tolerance for tita-
nium metal (Shpak and Margolin, 1971).
7.1.2 Humans
7.1.2.1 Lungs
Elo et al. (1972) studied lung specimens from three
factory workers exposed for 9 years to the titanium
dioxide pigments during processing; they found
deposits in the pulmonary interstitium, along with cell
destruction and slight fibrosis. Clearance of titanium
dioxide through the lymphatic system was demon-
strated by the identification of particles in the lymph
nodes. A subsequent report (Maatta and Arstila, 1975)
revealed the presence of aluminum and silica in the
macrophages, in addition to titanium particles. It was
suggested that the simultaneous exposure to silica
compounds was responsible for the fibrotic changes,
rather than exposure to titanium dioxide itself. Clinical
and epidemiological studies have generally confirmed
the experimentally demonstrated lack of fibrogenicity
of titanium dioxide. Through an autopsy study, exten-
sive titanium dioxide deposits were discovered in two
heavily exposed workers, but fibrosis was not detected
(Ophus et al., 1979).
There are several epidemiological studies describing
the effects of titanium dioxide. Studies on men exposed
to titanium dioxide for prolonged periods did not
reveal any signs of clinical or radiological abnormality.
A study of 136 workers exposed to ilmenite and rutile
in Sri Lanka did not find any significant difference in
the incidence of radiological lesions of the chest com-
pared with that of the general population (Uragoda
and Pinto, 1972). A study of 207 workers engaged in
the production of titanium dioxide from ilmenite, with
an exposure time of 20 years for 90% of the workers,
found that in 47% of the subjects the obstruction was
discovered by spirometry, which the authors suggested
may have been caused by irritant effects associated
with the sulfate process; no fibrotic effects attributable
to the titanium dioxide exposure were noted, however
(Daum et al., 1977). Chen and Fayerweather (1988)
studied the rate of mortality among 1576 male employ-
ees who had been exposed to TiO2 for more than 1 year
in two TiO2-producing plants in the USA. The mortal-
ity of the members of the group was monitored from
1935 to 1983. No excess mortality from nonmalignant
respiratory disease was observed. Some members of
part of the group (336 workers) were examined with
X-rays; no cases of fibrosis were detected. A European
multicenter epidemiological study monitored workers
employed in 11 plants producing TiO2 in six European
countries. Mortality over a 30-year period from non-
malignant respirator disease was less than expected
(Boffetta et al., 2004). A similar multicenter study in the
USA monitored 4241 workers exposed in TiO2-manu-
facturing plants. A mortality follow-up study, covering
40 years, did not reveal any adverse effects related to
TiO2 exposure (Fryzek et al., 2003).
Acute (short-term) exposure of humans to titanium
tetrachloride may result in marked congestion of the
mucous membranes of the pharynx, vocal cords, and
trachea, as well as stenosis (constriction) of the larynx,
 57 Titanium
trachea, and upper bronchi. Workers producing tita-
nium tetrachloride have developed hyperemia and
thinning of the mucosa of the respiratory tract, as well
as bronchitis, possibly because of the production of
hydrochloric acid upon the rapid hydrolysis of tita-
nium tetrachloride by water (EPA, 1985). Chronic inha-
lation exposure may produce upper respiratory tract
irritation, chronic bronchitis, coughing, bronchocon-
striction, wheezing, chemical pneumonitis, and pul-
monary edema in humans. Pleural diseases of workers
involved in titanium metal production have been
linked with their chronic (long-term) occupational
exposure to titanium tetrachloride. This finding sug-
gests that chronic exposure to titanium tetrachloride
may result in restrictive pulmonary changes (ATSDR,
1997). There are no conclusive epidemiological studies
on the risks of TNP exposure.
7.1.2.2  Other Sites and Implants
Titanium is widely used as an implant material in
orthopedics, oral surgery, and neurosurgery because it
exhibits high biocompatibility (Williams and Adams,
1976; Schroeder et al., 1981). It has been shown in vitro
that titanium particles can suppress osteogenic dif-
ferentiation in human bone marrow, stroma-derived
mesenchymal stem cells; bone marrow cells became
apoptotic and their numbers decreased, while, at the
same time, the levels of tumor suppressor proteins
increased (Wang et al., 2003).
The in vitro cytotoxicity of titanium particles toward
human neutrophils is dependent upon their size: the
smaller the size, the greater the toxicity (Kumazawa
et al., 2002). Titanium and its oxides may not be as inert
and biocompatible as was once believed. Further stud-
ies are necessary to demonstrate the adverse effects of
titanium and its oxides.
Titanium tetrachloride is highly irritating to the skin,
eyes, and mucous membranes in humans; indeed, it
may result in surface skin burns, while acute exposure
may also damage the cornea. Conjunctivitis and kera-
titis have been discovered after contact with titanium
tetrachloride (Mogilevskaja, 1983).
7.2  Systemic Effects and Dose-Response
Relationships
7.2.1 Animals
Recent scientific evidence indicates that titanium, or
its corrosion by-products, may cause harmful reactions
after traveling through the circulatory or lymphatic
system. These harmful reactions usually take place in
the blood, fibrotic tissue, and osteogenic cells.
In a comparative study of metallic biomaterials toxic-
ity assessing histochemical and immunohistochemical
1293
changes, the spleens of mice were observed to display
irregular features within the capsule and medulla
(depletion of T4 and B cells) after subcutaneous
administration of a titanium solution (0.4 mg/mL)
every 72 hours over a period of 30 days. Such altera-
tions in the functioning of T4 and B cells may indicate
reduced functioning of the immune system (Ferreira
et al., 2003).
Rats administered with titanium dioxide at
25-250 mg/kg body weight through parenteral injec-
tions (Huggins and Froehlich, 1966; Sethi et al., 1973)
did not exhibit any special changes other than those
that could be expected from the injection of inert
particles. Liver dystrophy was reported in rats after
the endotracheal administration of 50 mg titanium
nitride, boride, or carbide (Brahnova and Samsonov,
1970; Brahnova, 1969). The administration of titanium
hydride dust through endotracheal instillation had
similar effects (Skurko and Brahnova, 1973). More-
over, swelling of the tubular epithelium in the kidneys
occurred after administration of the nitride, whereas
dystrophic changes were detected in the kidneys and
hearts of test animals after absorption of the hydride.
7.2.2 Humans
Adverse effects have not been found from the
small amounts of titanium occasionally released from
implants into adjacent tissues (Lyell, 1979; Brun and
Hunziker, 1980), but yellow nail syndrome was found
in five subjects with titanium implants who had high
levels of titanium in their nails (up to 120 μg/g). Each of
these subjects had undergone dental restoration using
gold. The authors suggested that the high difference in
redox potential between titanium and gold caused the
migration of titanium into the tissues (Berglund and
Carlmark, 2011).
There are no available data on the possible dose-
response or dose-effect relationships related to the
systemic changes caused by titanium compounds in
human subjects.
Although titanium dioxide is regarded to be biolog-
ically inert, based on experimental as well as clinical
and epidemiological studies (Stokinger, 1981; WHO,
1982), systemic side effects have been reported in
patients taking drugs in the form of tablets contain-
ing titanium oxide. The symptoms ceased when the
active substance was delivered in tablets lacking tita-
nium dioxide (Berglund and Carlmark, 2011). Several
metals, including titanium, may impair the immune
response and cytokine release, suggesting that patients
who experience extensive exposure to these metals
may develop immune dysfunction (Wang et al., 1996).
No significant information is available to demon-
strate cardiovascular, gastrointestinal, hepatic, renal,
1294 Taiyi Jin and Maths Berlin
endocrine, and immunological effects of titanium tet-
rachloride (ATSDR, 1997).
7.3  Mutagenicity, Carcinogenicity,
Teratogenicity, and Effects on Reproduction
7.3.1 Animals
Various titanium compounds have been tested
using the rec-assay with Bacillus subtilis (Kada et al.,
1980). The following compounds produced negative
results: titanium trichloride, tetrachloride, boride,
carbide, fluoride, and dioxide. Titanium tetrachloride
has also been regarded as nonmutagenic (Kanematsu
et al., 1980; Ogawa et al., 1987). Bronchoalveolar lavage
(BAL) cells from rats instilled endotracheally with TiO2
particles, however, induced Hrpt gene mutations in rat
alveolar cells in vitro. Mutagenesis could be prevented
by the addition of catalase, suggesting that free o
­ xygen
radicals maybe mediate the process (Driscoll et al.,
1997). In a study of exposure to TiO2 particles through
inhalation, rats exposed to 250 mg/m3 developed lung
adenomas and keratinizing squamous metaplasia, sug-
gestive of squamous cell carcinoma (Lee et al., 1985,
1986). Endotracheal instillation of a high dose of TiO2
particles in female rats caused an increased incidence
of malignant lung tumors (IARC, 2006). Other rodents,
such as mice and hamsters, that had been endotrache-
ally instilled with TiO2 particles did not exhibit any
increases in the incidence of tumors. The International
Agency for Research on Cancer (IARC) has listed tita-
nium dioxide in Group 2b, indicating that there is suf-
ficient evidence from experimental animals to suggest
its carcinogenicity.
It is commonly believed that titanium belongs
to a group of metals that display low carcinogenic-
ity (­Sunderman, 1978). There is no evidence that
TiO2-coated mica produced either toxicological or
carcinogenic effects when fed to Fischer 344 rats at
­ ACGIH (American Conference of Governmental Industrial Hygien-
dietary concentrations as high as 5.0% (Bernard et al.,
1990). The organic compound titanocene is carcinogenic
in rats and mice when suspended in trioctanoin and
administered by intramuscular injection monthly: fibro-
sarcomas occurred at the injection sites and h­ epatomas
and malignant lymphomas of the spleen developed in
the animals (Furst and Haro, 1969; Furst, 1971).
Metallocene dichlorides, (C5H5)2MCl2, where M
is titanium, vanadium, molybdenum, or niobium,
displayed cancerostatic activity against the Ehrlich
ascites tumor system in mice. Treatment with such
compounds led to total curing. Survival times without
tumor manifestation were longer in animals treated
intraperitoneally with titanocene dihalides at doses
ranging from 10 to 240 mg/kg body weight than they
were in control animals (Köpf-Maier et al., 1980; Köpf-
Maier and Krahl, 1981).
In reproduction studies, an adverse effect was dis-
covered in rats exposed to soluble titanate (5 mg/L)
in drinking water (Schroeder and Mitchener, 1971;
Köpf-Maier and Erkenswick, 1984). Each group was
followed through three generations. A significant
reduction occurred in the number of animals surviving
up to the third generation, and showed a progressive
reduction in the male:female ratio. Controls continued
to breed for four generations at the normal rate.
TNPs were reported to induce cellular apoptosis
and necrosis (Vamanu et al. 2008). Several in vitro
mammalian studies showed that TNPs can have dif-
ferent adverse effects on mammalian cells, including
increased production of reactive oxygen species and
cytokine levels, reduction of cell viability and prolif-
eration, and induction of apoptosis and genotoxicity
(Iavicoli et al., 2011). The underlying mechanisms of
the toxic effects of TNPs are associated with inflam-
mation and include fibrosis, oxidative stress, and DNA
damage (Iavicoli et al., 2012). (See also Chapter 4.)
7.3.2 Humans
Several epidemiological mortality studies suggest
that TiO2 dust exerts no carcinogenic effect on human
lungs (Fayerweather et al., 1992; Boffetta et al., 2001,
2004; Fryzek et al., 2003); these studies all considered
cancer mortality. No studies have revealed an increase
in cancer mortality related to TiO2 exposure. According
to the IARC, “there is inadequate evidence in humans
for the carcinogenicity of titanium oxide” and TiO2 is
classified as “possibly carcinogenic to humans, Group
2B” (IARC, 2006, 2010).
References
ists), 2005. TLVs and BEIs for Chemical Substances and Physical
Agents. ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry), 1997. Tox-
icological profile for titanium tetrachloride. Department of Health
and Human Services, Public Health Service, Atlanta, GA, U.S.A.
Baggs, R.B., Ferin, J., Oberdorster, G., 1997. Vet. Pathol. 34, 593–597.
Berglund, F., Carlmark, B., 2011. Biol. Trace Elem. Res. 143, 1–7.
Bermudez, E., Mangum, J.B., Asgharian, B., et al., 2002. Tox. Sci. 70,
86–97.
Bermudez, E., Mangum, J.B., Wong, B.A., et al., 2004. Tox. Sci. 77,
347–357.
Bernard, B.K., Osheroff, M.R., Hofmann, A., Mennear, J.H., 1990. J.
Toxicol. Environ. Health 29, 417–429.
Bianco, P., Ducheyne, P., Cuekler, J.M., 1996. Biomaterials 17, 1937.
Böckmann, J., Lahl, H., Eckert, T., et al., 2000. Int. J. Pharm. 105,
157–168.
Boffetta, P., Gaborieau, V., Nadon, L., et al., 2001. Scand. J. Work En-
viron. Health 27, 227–232.
 57 Titanium
Boffetta, P., Soutar, A., Cherrie, J.W., et al., 2004. Cancer Causes Con-
trol 15, 697–706.
Bowen, H.J.M., 1966. Trace Elements in Biochemistry. Academic
Press, London, p. 206.
Brahnova, I.T., 1969. Gig. Tr. Prof. Zabol. 13, 26–31.
Brahnova, I.T., Skurko, G.A., 1972. Gig. Sanit. 37, 36–39.
Brahnova, I.T., Samsonov, G.V., 1970. Gig. Tr. Prof. Zabol. 14, 48–50.
Brun, R., Hunziker, N., 1980. Contact Dermatitis 6, 212–213.
Brunette, D.M., Kenner, G.S., Gould, T.R., 1983. J. Dent. Res. 62,
1045–1048.
Chen, H.W., Su, S.F., Chien, C.T., et al., 2006. FASEB J 20, 2393.
Chen, J.L., Fayerweather, W.E., 1988. J. Occup. Med. 30, 937–942.
Crable, J.V., Keenan, R.G., Wolowicz, F.R., et al., 1967. Am. Ind. Hyg.
Assoc. J. 28, 8–12.
Crable, J.V., Keenan, R.G., Kinser, R.E., et al., 1968. Am. Ind. Hyg.
Assoc. J. 29, 106–110.
Dale, K., 1973. Scand. J. Respir. Dis. 54, 168–184.
Daum, S., Anderson, H.A., Lilis, R., et al., 1977. Proc. R. Soc. Med.
70, 31–32.
Driscoll, K.E., Deyo, L.C., Carter, J.M., et al., 1997. Carcinogenesis18,
423–430.
Durfor, C.N., 1963. Quoted in: WHO (1982) “Environmental Health
Criteria, 24.”. Titanium. World Health Organization, Geneva.
Durum, W.H., Haffty, J., 1961. US Geol. Surv. Circ. 445, 1–11.
Edel, J., Marafante, E., Sabbioni, E., 1985. Human Toxicol. 4, 177–185.
Elo, R., Maatta, K., Uksila, E., et al., 1972. Arch. Pathol. 94, 417–424.
EPA (U.S. Environmental Protection Agency), 1973. Air Quality Data
for Metals, 1968 and 1969, from “the National Air Surveillance
Networks, Publication No. APTD-1467,” pp. 13/1-13/13. U.S.
Environmental Protection Agency.
EPA, 1985. (CASRN:7750-45-0): EPA Chemical Profiles. Environmen-
tal Protection Agency, Washington, DC, U.S.A.
Fayerweather, W.E., Karns, M.E., Gilby, P.G., et al., 1992. J. Occup.
Med. 34, 164–169.
Ferin, J., Mercer, T.T., Leach, L.J., 1983. Env. Res. 31, 148–151.
Ferreira, M.E., De Lourdes Pereira, M., Garcia e Costa, F., et al., 2003.
Trace Elem. Med. Bi01 17, 45–49.
Fryzek, J.P., Chadda, B., Marano, D., et al., 2003. J. Occup. Environ.
Med. 45, 400–409.
Furst, A., 1971. Geol. Soc. Am. Mem. 123, 109–110.
Furst, A., Haro, R.T., 1969. Prog. Exp. Tumor Res. 12, 102–133.
Garabrant, D.H., Fine, L.J., Oliver, C., et al., 1987. Scand. J. Work En-
viron. Health 13, 47–51.
Giauque, R.D., Goda, L.Y., Brown, N.E., 1974. Environ. Sci. Technol.
8, 436–441.
Gross, P., Kociba, R., Sparschv, G.L., et al., 1977. Arch. Pathol. Lab.
Med. 101, 360–367.
Hamilton, E.I., Minski, M.J., Cleary, J.J., 1972/1973. Sci. Total Envi-
ron. 1, 341–374.
Heppleston, A.G., 1971. In: Walton, W.H. (Ed.), Inhaled Particles and
Vapours, III. Unwin Brothers Ltd., United Kingdom, pp. 357–369.
Hext, P.M., Warheit, D.B., Mangum, J., et al., 2002. Ann. Occup. Hyg.
46 (Suppl. 1), 191–196.
Hext, P.M., Tomenson, J.A., Thompson, P., 2005. Ann. Occup. Hyg.
49, 461–472.
HHS (U. S. Department of Health and Human Services), 1993. Haz-
ardous Substances Data (HSDB. Online database) National Toxi-
cology Information Program. National L Medicine, Bethesda, MD.
Hu, R., Gong, X., Duan, Y., Li, N., Che, Y., Cui, Y., Zhou, M., Liu, C.,
Wang, H., Hong, F., 2010. Biomaterials 31 (31), 8043–8050.
Huggins, C.B., Froehlich, J.P., 1966. J. Exp. Med. 124, 1099–1106.
IARC, 2006. IARC Monograph on the Evaluation of Carcinogenic
Risks to Humans. p. 98.
IARC, 2010. IARC Monographs on the Evaluation of Carcinogenic Risks
to Humans, Carbon Black, Titanium Dioxide and Talc, vol. 93, .
1295
Iavicoli, I., Leso, V., Fontana, L., et al., 2011. Eur. Rev. Med. Pharma-
col. Sci. 15, 481–508.
Iavicoli, I., Leso, V., Bergamaschi, A., 2012. J. Nanomater. vol 2012.
Article ID 964381.
ICRP (International Commission on Radiological Protection), 1959.
Health Phys. 3, 1–380.
Mundi, Index, 2014. Titanium: World Production Of Mineral Concen-
trates, By Country. http://www.indexmundi.com/en/commoditi
es/minerals/titanium/titanium_t15.html (accessed 24.01.14).
Ishibashi, M., 1966. Chem. Abstr. 71, 84417T.
Ishiwata, K., Ido, T., Monma, M., et al., 1991. Int. J. Rad. Appl. In-
strum. 42, 707–712.
Jacobs, J.J., Silverton, C., Hallab, N.J., et al., 1999. Clin. Orthop. Re.
Res., 173–180.
Jani, P.U., McCarthy, D.E., Florence, A.T., 1994. Pharmazie 55,
140–143.
JESC (Japan Environmental Sanitation Centre), 1971. Air Pollut.
Abstr. 9.
JFSSG (Joint Food Safety and Standards Group), 2000. Food Surveil-
lance Information Sheet No. 199.
Johansson, T.B., van Grieken, R.E., Nelson, J.W., et al., 1975. Anal.
Chem. 47, 855–860.
Kada, T., Hirano, K., Shirasu, Y., 1980. Chem. Murat. 6, 149–173.
Kalbasi, M., Peryea, F.J., Lindsay, W.L., et al., 1995. Soil Sci. Soc. Am.
59, 1274.
Kallus, T., Hensten-Pettersen, A., 1983. J. Biomed. Mater. Res. 17,
741–756.
Kanematsu, N., Hara, M., Kada, T., 1980. Mutat. Res. 77, 109–116.
Kasemo, B., 1983. J. Prosthet. Dent. 49, 832–837.
Klein, D.H., Russell, P., 1973. Environ. Sci. Technol. 7, 357–359.
Köpf-Maier, P., Krahl, D., 1981. Naturwissenschaften 68, 273–274.
Köpf-Maier, P., Hesse, B., Kopf, H.U., 1980. J. Cancer Res. Clin.
­Oncol. 96, 43–51.
Köpf-Maier, P., Erkenswick, P., 1984. Toxicology 33, 171–181.
Kumazawa, R., Watari, F., Takashi, Y., et al., 2002. Biomaterials 23,
3757–3764.
Lee J., Mahendra S., Alvarez P.J.J., ACS Nano (2010). 4(7):3580–90.
Lee, K., Yang, Y.S., Kwon, S.J., et al., 2009. Toxicol. Lett. 189, S186.
Lee, K.P., Barras, C.E., Griffith, F.D., et al., 1981. Am. J. Pathol. 102,
314–323.
Lee, K.P., Trochimowicz, H.J., Reinhardt, C.F., 1985. Exp. Mol. Pathol.
142, 331–343.
Lee, K.P., Kelly, D.P., Schneider, P.W., et al., 1986. Toxicol. Appl. Phar-
macol. 83, 30–45.
Lomer, M.C.E., Thompson, R.P.H., Commisson, J., et al., 2000. Ana-
lyst 125, 2339–2343.
Lyell, A., 1979. Int. J. Dermatol. 18, 805–807.
Maatta, K., Arstila, A.U., 1975. Lab. Invest. 33, 342–346.
Meachin, G., Williams, D.F., 1973. J. Biomed. Mater. Res. 7, 555.
Merritt, K., Brown, S.A., 1995. J. Biomed. Mater. Res. 29, 1175–1178.
Mogilevskaja, O.J., 1983. In: Encyclopedia of Occupational Health and
Safety, 3rd ed. International Labour Office, Geneva, pp. 2179–2181.
Niinomi, M., 2002. Metallurgical Mater. Trans. A 33, 477.
NIOSH (National Institute for Occupational Safety and Health).
(1980) Health Hazard Evaluation Report No. HE-79-17-751 at
RMI Metals Reduction Plant, Ashtabula, OH. Cincinnati, OH:
National Institute for Occupational Safety and Health, Hazard
Evaluations and Technical Assistance Branch, Division of Sur-
veillance, Hazard Evaluation and Field Studies. NTIS/PB82-
103243.
NIOSH, 1994a. Methods 8310. Metals in Urine. In: NIOSH Manual
of Analytical Methods, fourth ed. National Institute for Occupa-
tional Safety and Health. Centers for Disease Control and Pre-
vention. Public Health Service. U.S. Department of Health and
Human Services.
1296 Taiyi Jin and Maths Berlin
NIOSH, 1994b. Methods 0500. Particulates Not Otherwise Regulat-
ed, Total. In: NIOSH Manual of Analytical Methods, fourth ed.
National Institute for Occupational Safety and Health. Centers
for Disease Control and Prevention. Public Health Service. U.S.
Department of Health and Human Services.
NIOSH, 1994c. Methods 0600. Particulates Not Otherwise Regulat-
ed, Respirable. In: NIOSH Manual of Analytical Methods, fourth
ed. National Institute for Occupational Safety and Health. Cen-
ters for Disease Control and Prevention. Public Health Service.
U.S. Department of Health and Human Services.
NIOSH, 1994d. Methods 7300. Elements by ICP. In: NIOSH Manual
of Analytical Methods, fourth ed. National Institute for Occupa-
tional Safety and Health. Centers for Disease Control and Pre-
vention. Public Health Service. U.S. Department of Health and
Human Services.
Ogawa, H.I., Tusruta, S., Niuitani, Y., et al., 1987. Jpn. J. Genet. 62,
159–162.
Olmedo, A.G., Tasat, D., Guglielmotti, M.B., et al., 2003. J. Mater. Sci.:
Mater. Med. 14, 1099–1103.
Ophus, E.M., Rode, L., Gylseth, B., et al., 1979. Scand. J. Work Envi-
ron. Health 5, 290–296.
Poole, K.W., Johnston, D.R., 1969. US Clearinghouse for Federal Sci-
entific and Technical Information. Springfield, IL.
Pratt, P.C., Bailey, D., Delahant, A.B., et al., 1953. Arch. Ind. Hyg. Oc-
cup. Med. 8, 109–117.
Schroeder, A., van der Zypen, E., Stich, H., et al., 1981. J. Maxillofac.
Surg. 9, 15–25.
Schroeder, H.A., Balassa, J.J., Tipton, I.H., 1963. J. Chronic Dis. 16, 55–69.
Schroeder, H.A., Balassa, J.J., Vinton Jr, V.H., 1964. J. Nutr. 83, 239–250.
Schroeder, H.A., Mitchener, M., 1971. Arch. Environ. Health 23,
102–106.
Sethi, S., Hilscher, W., Flasbeck, R., 1973. Zentrabl. Bakteriol. Para-
sitenkd. Infektionskr. Hyg. Abt. 1, Orig. Reihe B157, 131–144.
Shpak, G.E., Margolin, S.E., 1971. Skh. Biol. 6, 567–569.
Silvey, W.D., 1967. US Geol. Surv. Water Supply Pap. 1535-L, LI-L25.
Skurko, G.A., Brahnova, I.T., 1973. Poroshk. Metall. 13, 100–102.
Spengler, J., Lwebuga-Mukasa, J., Vallarino, J., et al., 2011. Res. Rep.
Health Eff. Inst. 15, 5–132.
Stokinger, H.E., 1981. Patty’s Industrial Hygiene and Toxicology, vol.
2A, John Wiley & Sons, New York, pp. 1968–1981.
Sunderman, F.W., 1978. Fed. Proc. 37, 40–46.
Teraoka, H., 1980. Arch. Environ. Health 36, 155–164.
Thomas, R.G., Archuleta, R.F., 1980. Toxicol. Lett. 6, 115–118.
Tipton, I.H., Stewart, P.L., Martin, P.G., 1966. Health Phys. 12,
1683–1689.
Tipton, I.H., Stewart, P.L., Dickson, J., 1969. Health Phys. 16, 455–462.
Tsuji, J.S., Maynard, A.D., Howard, P.C., James, J.T., Lam, C., W ­ arheit,
D.B., Santamaria, A.B., 2006. Toxicol. Sci. 89, 42.
Uragoda, C.G., Pinto, M.R.M., 1972. Med. J. Aust. 1, 167–169.
Vamanu, C.I., Cimpan, M.R., Ho, P.J.1, et al., 2008. Toxicol. In Vitro
22, 1689–1696.
Wang, J., Zhou, G., Chen, C., et al., 2007. Tox. Lett. 168, 176–185.
Wang, J., Liu, Y., Jiao, F., et al., 2008. Toxicology 254, 82–90.
Wang, J.Y., Tsukayama, D.T., Wicklund, B.H., et al., 1996. J. Biomed.
Mater. Res. 32, 655–661.
Wang, M.L., Tuli, R., Manner, P.A., et al., 2003. Orthop. Res. 21, 697–707.
Watanabe, M., Okada, M., Kudo, Y., et al., 2002. J. Toxicol. Environ.
Health A 65, 1047–1060.
WHO (World Health Organization), 1982. Environmental Health
Criteria 24. Titanium. World Health Organization, Geneva.
Williams, D.F., Adams, D., 1976. J. Clin. Pathol. 29, 657–661.
Woolrich, P.F., 1973. Am. Ind. Hyg. Assoc. J. 34, 217–226.