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The Lanthanides, Rare Earth Elements

Willard H. Wells, Jr., Ph.D., CIH and Vickie L. Wells, MS, CIH

1.0 Common Lanthanide Compounds crystallization techniques have been developed that result in
the availability of pure (99.99%) materials.
The names, synonyms, CAS Numbers molecular weights and
All the lanthanides are silvery white, very reactive metals
formulae of some of the more common lanthanide com-
with high melting points. Their þ3 ion reduction electrode
pounds are provided in Table 21.1. The atomic number,
potentials are very similar. The metals react slowly with cold
weight and relative abundance of the elements is provided
water, but rapidly with acids to produce hydrogen, but not
in Table 21.2.
readily with concentrated H2SO4. The metals are active
reducing agents, ignite in air, and are pyrophoric on filing
(mixed metals). They react with halogens, carbon, silicon,
1.1 Chemical and Physical Properties
nitrogen, and sulfur at elevated temperatures. Reaction with
The chemical and physical properties of the lanthanides are hydrogen produces salt-like hydrides. The metals also
given in Table 21.3. The unique characteristic of the chem- absorb hydrogen without reacting, forming interstitial
istry of the lanthanides is their similarity. The defining 4f hydrides of the approximate composition M(1):H(2.8).
electrons are deep within the lanthanide atoms and are The metals react with oxygen to yield oxides of the general
shielded from the environment around the atom by their formula M2O3 (except cerium, which yields CeO2). The
outer 6s and 5d electrons. Thus the f electrons do not cause M2O3 oxides react with water to form insoluble hydroxides,
strong variations in chemical properties. This is in contrast to M(OH)3, which are not amphoteric (i.e., capable of reacting
the wide variation in the properties shown by the transition chemically as either an acid or base). Insoluble carbonates,
metals, whose defining outer d electrons project from the M2(CO3)3, may be produced by the reaction of carbon
atoms and ions and interact with surrounding materials. dioxide with the oxides or hydroxides. The sulfates, nitrates,
All the lanthanides form ions in the characteristic group and chlorates of the þ3 ions are soluble in water; the
IIIB oxidation state of þ3. Some of the elements exhibit other phosphates, fluorides, and oxalates are insoluble. The pre-
oxidation states, but they are less stable. There is evidence cipitation of these elements as oxalates serves as the basis of
that the elements with, half-filled, and filled 4f orbital shell an analytical determination. Generally, the compounds are
ions have very stable configurations; thus La (empty), Gd paramagnetic and highly colored. Lanthanides alloy with
(half-filled), and Lu (filled) form only þ3 ions. The most almost all metals. It is convenient to group the rare earths
stable þ2 and þ4 ions are Eu2þ, Yb2þ, Ce4þ, and Tb4þ. The into two broad classes based on their properties and occur-
ceric ion, Ce4þ, is a good oxidizer. rence as the “light” or cerium group, and the “heavy” or
The elements occur together in nature in large part due to yttrium group. The cerium group includes La, Ce, Pr, Nd,
their chemical similarity. The exception is promethium, Sm, Eu, and Gd. The yttrium group includes Y, Tb, Dy, Ho,
which is radioactive and probably occurs naturally only in Er, Tm, Yb, and Lu. The cerium-group metals are soft;
trace amounts, if at all. The elements are extremely difficult however, hardness increases with atomic number. Oxide-
to separate. Modern ion-exchange and repeated fractional free metals are malleable, but oxide inclusions reduce this

Patty’s Toxicology, Sixth Edition. Volume 1, Edited by Eula Bingham and Barbara Cohrssen.
 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.


Table 21.1. Common Lanthanide Compounds, their CAS Numbers, Synonyms, Molecular Weights and Formulae
Compound CAS Number Synonyms Molecular Weight Molecular Formula
Scandium Chloride [10361-84-9] NA 151.31 ScCl3
Lanthanum Oxide [1312-81-8] Dilanthanum oxide, dilanthanum trioxide, 325.09 La2O3
lanthana, lanthania (La2O3), lanthanum
sesquioxide, lanthanum trioxide, lanthanum
(þ3) oxide, lanthanum(III) oxide
Lanthanum Nitrate [10099-59-9] NA 324.94 La(NO3)3
Cerium [7440-45-1] NA 140.12 Ce
Neodymium [7440-00-8] NA 144.24 Nd
Neodymium Oxide [1313-97-9] Dineodymium trioxide, neodymia, neodymium 336.48 Nd2O3
sesquioxide, neodymium trioxide,
neodymium (þ3) oxide, neodymium(III)
Samarium Oxide [12060-58-1] Disamarium trioxide, samaria, samarium 348.72 Sm2O3
sesquioxide, samarium trioxide, samarium
(þ3) oxide, samarium(III) oxide
Europium Oxide [1308-96-9] Dieuropium trioxide, europia, europium 351.92 Eu2O3
sesquioxide, europium trioxide, europium
(þ3) oxide, europium(III) oxide
Gadolinium [7440-54-2] NA 157.25 Gd
Gadolinium Oxide [12064-62-9] Digadolinium trioxide, gadolinia, gadolinium 362.50 Gd2O3
sesquioxide, gadolinium trioxide,
gadolinium (þ3) oxide, gadolinium(III)
Terbium Trinitrate [10043-27-3] Terbium (þ3) nitrate; nitric acid, terbium (þ3) 344.95 Tb (NO3)3
Dysprosium Oxide [1308-87-8] Didysprosium trioxide, dysprosium 373.00 Dy2O3
sesquioxide, dysprosia, dysprosium (þ3)
oxide, dysprosium(III) oxide
Erbium Trioxide [12061-16-4] Dierbium trioxide, erbia, erbium sesquioxide, 382.52 Er2(O3)3
erbium (þ3) oxide, erbium(III) oxide
Ytterbium [7440-64-4] NA 173.04 Yb
Yttrium [7440-65-5] Yttrium-89 88.91 Y

property. The metals are good heat conductors and moderate water molecules. Many of the biological properties of the
electrical conductors. lanthanides are a function of their similarity to calcium (3).
The lanthanides exhibit a prominent characteristic termed The chlorides, nitrates, and sulfates of lanthanides are
“lanthanide contraction.” From La to Lu, the radius of soluble whereas their carbonates, phosphates, and hydro-
lanthanide ions (þ3) decreases as the atomic number xides are insoluble. These solubility differences among ionic
increases. This characteristic is due to the attraction of 4f forms of the lanthanides also seem to influence their meta-
orbital electrons by the increasing positive charge of the bolic fate in biological systems. In general, the toxicity of the
nucleus with increasing atomic number. A decrease in basic- lanthanides decreases as the atomic number increases,
ity and increase in solubility are also associated with increas- probably because of the greater solubility and ionic stability
ing atomic number. These physiochemical qualities seem to of the heavier lanthanide ions (2).
correlate with distribution in tissues; the larger lighter and The lanthanide salts precipitate readily at physiological
less soluble ions tend to deposit in the liver, and the smaller, pH range because their isoelectric point is pH ,7. Lantha-
heavier, more soluble ions tend to deposit in bone. The ionic num and other rare earths form insoluble complexes with
size of the lanthanides is similar to Ca2þ, and as such nucleic acids (4, 5). The stability of lanthanide complexes
lanthanides have been used as Ca2þ probes in physiological with EDTA has been determined at 20 C and at an ionic
and biochemical studies. Lanthanides, especially La, have strength of m ¼ 0.1 (4, 5).
been shown to be calcium antagonists, as well as elements Most of the lanthanide ions are luminescent, either fluo-
that produce tissue calcification (1, 2). The lanthanides have a rescent (e.g., PrIII, NdIII, HoIII, ErIII, and YbIII,) or phospho-
higher charge than Ca2þ, so they have a higher affinity for rescent (e.g., orange SmIII, red EuIII, GdIII, which emits in the
Ca2þ sites on biological molecules, and a stronger binding to UV, green TbIII, yellow DyIII, and blue TmIII). Their emission

Table 21.2. Atomic Numbers, Weights, and Concentrations of the stable compounds only in the þ3 oxidation state. It has 11
Lanthanides, Cadmium, and Lead Included for Reference known isotopes, only one of which occurs in nature.
Atomic Atomic Earth’s Yttrium is very similar to scandium. It is also an active
Element No. Weight Crust (ppm) metal. The oxide of yttrium, Y2O3, is a white powder,
insoluble in water but soluble in acids. In its compounds,
Scandium (Sc) 21 44.9559 5–6
yttrium displays only þ3 oxidation state.
Yttrium (Y) 39 88.9059 28–70
Cadmium (Cd) 48 112.41 0.1–0.2
Lanthanum (La) 57 138.9055 5–18 1.2 Production and Use
Cerium (Ce) 58 140.12 46
Praseodymium (Pr) 59 140.9077 6 Although many minerals contain rare earths, only three
Neodymium (Nd) 60 144.24 24 contain sufficient percentages to be of widespread commer-
Promethium (Pm) 61 145 4.5  1020 cial value. (1) Monazite, an orthophosphate primarily of the
Samarium (Sm) 62 150.4 6 light, or cerium group; (2) bastnaesite, a fluorocarbonate of
Europium (Eu) 63 151.96 1 the cerium group; and (3) xenotime, an orthophosphate of the
Gadolinium (Gd) 64 157.3 6 heavy, or yttrium, group. The average rare earth content in
Terbium (Tb) 65 158.9254 0.9
these minerals is shown in Table 21.4. Other minerals,
Dysprosium (Dy) 66 162.50 4
including allanite, cerite, gadolinite, and euxenite, contain
Holmium (Ho) 67 164.9304 1
Erbium (Er) 68 167.26 2 extractable quantities of rare earths but are not in widespread
Thulium (Tm) 69 168.9342 0.2 commercial use.
Ytterbium (Yb) 70 173.04 3 The most important sources of monazite are placer and
Lutetium (Lu) 71 174.97 0.8 marine beach deposits in the form of heavy mineral sands
Lead (Pb) 82 207.2 1.6  103 found in Australia, Brazil, China, India, South Africa, and the
United States (Florida and the Carolinas). The most signifi-
cant bastnaesite deposits are found in Palabora, South Africa;
colors cover the entire spectrum from UV to visible and near- Paotou, Inner Mongolia in the People’s Republic of China;
infrared ranges (6). and at Mountain Pass San Bernadino County, California
Relatively little is known about the chemistry of scandium, (USA) (7). In California, Molycorp, Inc. operated this
even though it is not particularly rare. Its chemistry resembles mine through 2002 when the mine was shut down for
that of aluminum in many ways. The metal reacts vigorously economic reasons. Through most of the first decade of the
with water to liberate hydrogen when its oxide coating is twenty-first century, China has provided about 95% of the
removed. Like Al2O3, the oxide Sc2O3 is insoluble in water, world’s rare earths from mines in Inner Mongolia and in
but because of the larger size of the Sc3þ ion, Sc2O3 is basic Southern China. (8). Xenotime is also found in placer and
rather than amphoteric. Like aluminum, scandium forms beach deposits with commercial quantities extracted with

Table 21.3. Physical and Chemical Characteristics of the Lanthanides

Element Atomic No. Electronic Configuration Atomic Weight Melting Point ( C) Density Radius of RE3þ (A)a
Scandium (Sc) 21 3d14s2 44.9559 1541 2.989 0.83
Yttrium (Y) 39 4d15s2 88.9059 1552 4.472 1.06
Lanthanum (La) 57 5d16s2 138.9055 921 6.146 1.22
Cerium (Ce) 58 4f26s2 140.12 798 6.162 1.18
Praseodymium (Pr) 59 4f36s2 140.9077 931 6.769 1.16
Neodymium (Nd) 60 4f46s2 144.24 1016 7.007 1.15
Promethium (Pm) 61 4f56s2 145 1168 7.264
Samarium (Sm) 62 4f66s2 150.4 1072 7.54 1.13
Europium (Eu) 63 4f76s2 151.96 817 5.24 1.13
Gadolinium (Gd) 64 4f75d16s2 157.3 1313 7.868 1.11
Terbium (Tb) 65 4f96s2 158.9254 1357 8.253 1.09
Dysprosium (Dy) 66 4f106s2 162.50 1410 8.556 1.07
Holmium (Ho) 67 4f116s2 164.9304 1740 8.799 1.05
Erbium (Er) 68 4f126s2 167.26 1522 9.006 1.04
Thulium (Tm) 69 4f136s2 168.9342 1525 9.318 1.04
Ytterbium (Yb) 70 4f146s2 173.04 824 6.959 1.00
Lutetium (Lu) 71 4f145d16s2 174.97 1663 9.849 0.99
Radius of rare earth (þ3) in angstroms.

Table 21.4. Average Rare Earth Content of the Major Ore Minerals ide digestion followed by treatment with hydrochloric acid.
(in Percent) The process involves cracking the ore, removing the thorium,
Element Monazite Bastnaesite Xenotime and separating the lanthanides. The latter process is more
commonly used because it has the advantage of recovering
La 23 32
the phosphate as the useful by-product, trisodium phosphate,
Ce 46 92 50 98.7 10.6
and yielding rare earth chlorides, which are a useful inter-
Pr 5 4
Nd 18 13 mediate in further processing (9).
Sm 2.3 0.5 1.2 The Molycorp method for bastnaesite processing is to
Eu 0.7 4.7 0.1 0.75 0.01 4.8 calcine the ore after concentration by flotation. It is then
Gd 1.7 0.15 3.6 attacked by hydrochloric acid to solubilize most of the
Tb 0.16 1.0 trivalent rare earths as chlorides. The residue containing
Dy 0.5 7.5 the tetravalent components is filtered for recovery and con-
Ho 0.09 2.0 tains 65–80% cerium oxide. This fraction, after further
Er 0.13 0.9 Almost 6.2 84.6 calcination, can be used directly as a glass polishing com-
absent pound. The rare earth chloride fraction is used for processing
Tm 0.01 1.27
into specific applications. Xenotime, also an orthophosphate,
Yb 0.06 6.0
is usually treated by the sulfuric acid method described for
Lu 0.006 0.63
Y 2 2 60.0 monazite to yield the rare earth yttrium group (9).
Th 10 0.5 Separation of the individual lanthanides and yttrium is
difficult because their identical external electron shell con-
figuration gives them very similar chemical properties. The
development of ion-exchange and liquid–liquid extraction
placer tin deposits in Southeast Asia, and from the monazite techniques allows separation processes to take advantage of
deposits in the U.S. Carolinas and Florida. The production of their substantial difference in ionic sizes that result from their
these yttrium-group xenotime ores is considerably less than lanthanide contraction property. Kaczmarek describes the
that of monazite or bastnaesite. overall separation strategy as a combination of the following
When a mining project is initiated the potential products procedures: (1) fractional crystallization of amorphous salts,
are divided into principal products and by-products. For (2) selective oxidation or reduction, and (3) basicity differ-
example, the principle product of a lead mine is lead, but ences, including (a) ion exchange and (b) solvent extraction.
smaller amounts of zinc may also be produced as by-product. All of these procedures, with the exception of oxidation or
Most production of REEs is as a by-product of other mining reduction, are fractional, and require repeated steps to obtain
activities. Table 21.5 shows production of rare earth mines in desired purities. Selective oxidation is used to obtain rela-
2009. Processing of minerals to common metals such as iron, tively pure quantities of the þ2 valent metals europium and
lead, or zinc is usually done using a narrow set of common, samarium, both of which have significant commercial
well-developed smelting technologies. For the rare earths, applications (10).
each ore has different characteristics and specialized tech- Scandium has only a few commercial uses because it is
niques must be developed to extract pure metals. For this difficult to process. It is found as a minor element in many
reason, while the elements are common, purification is minerals but there is only one, thortveitite, which contains
difficult and expensive (8). significant concentrations. This mineral is a silicate that was
Monazite is processed in one of two ways depending on the found in granite pegmatite in southern Norway. A similar
desired product: a sulfuric acid digestion or a sodium hydrox- mineral, befanamite, has been found in Madagascar (11).

Table 21.5. Production of Rare Earth Element Mines in 2009

2009 Output (Metric
Country Mine Tons Total RE Oxides) Primary Product By-product
Brazil Buena Norte 650 Ilmenite concentrate Monazite concentrate
China Bayon Obo 55,000 Iron ore Bastanasite concentrate
Sichuan 10,000 Bastanasite concentrate
South China 45,000 Rare earth elements
India Heavy mineral sands 2,700 Ilmenite concentrate Monazite concentrate
Malaysia Ipoh sand plant 380 Cassiterite concentrate Xenotime concentrate
Russia Lovezero 2,500 Loparite concentrate Rare earth elements chloride
Source: USGS Mineral Commodity Summaries (2010) in Ref. (8).

Scandium is most widely used by the lighting industry in the storage containers that have significant weight and pressure
manufacture of “metal halide” lamps. The use of scandium advantages over gas or liquid hydrogen storage containers.
iodide in these lamps produces a nearly perfect spectral Lanthanide chemicals are used in carbon-arc lighting
match to natural daylight (12). It is also used as an alloy applications. Lanthanide-cored carbons are indispensable
agent in aluminum baseball bats. to the motion picture industry, in both studio lighting and
Yttrium is used as an alloying agent in specialty stainless in theater projection. U.S. Army, Navy, and Coast Guard
steels that require high resistance to corrosion at temperature searchlights also use these lanthanide-cored carbons.
extremes. These alloys have been used in the nuclear indus- Another lighting application is in their use in incandescent
try, as the base metal for catalytic converters for automobile gas mantles. A small cotton sock which has been saturated
exhaust systems, and as protective coating on turbine engine with a salt solution of La2O3 and ZrO2 is raised in tempera-
blades. As an alloying agent with titanium, it improves ture in the hottest part of a flame until the metals give off
ductility and ease of fabrication. It improves the strength visible light radiation. The salt mixture and surface area of
of magnesium castings when used in combination with the mantle substrate are optimized to give off the most light in
zirconium. The conductivity of aluminum transmission the visible range. Later versions of this mantle, which contain
lines is improved by as much as 50% with as little as thorium oxide to improve spectral characteristics, are still in
100 ppm of yttrium in the alloy. In the electronics industry, use today.
yttrium is used as the matrix of europium-activated red The lanthanides are used widely in the chemical industry
phosphors that give the red hue in color television as process materials and as catalysts. Lanthanum is largely
tubes (12, 13). used as a component of zeolite catalysts for cracking crude
At one time, the only commercial use of the rare earths was petroleum into gasoline and other light-petroleum fractions.
as misch metal, an alloy consisting principally of cerium This catalytic property is also used in some catalytic con-
(47%), neodymium (19%), and lanthanum (27%), plus other verters for automobile exhaust systems. Lanthanides are also
rare earths. It is pyrophoric (catching fire in air) when finely used as a reagent and as a phosphor in fluorescent lamps.
divided and is used to make cigarette-lighter flints. Com- Gadolinium is used in X-ray film emulsions to intensify
mercial usage of the rare earths continues to expand as exposed images, which allows lower exposure doses.
quantities of pure materials become more economically Neodymium is used as the dopant in YAG (yttrium aluminum
available and with technical innovations that take advantage garnet) lasers. Nano fabrication techniques are being
of newly discovered properties and applications. Their use in widely employed to improve the dispersion of REEs within
industry falls into five general categories: (1) metallurgical, Al2O3 and YAG matrices for solid-state laser materials.
(2) lighting and chemical catalysis, (3) glass and ceramics, Manufacturing techniques include chemical vapor deposi-
(4) phosphors and electronics, and (5) pharmaceuticals. An tion and liquid–solid gel ion implantation (16).
extensive reference regarding the technology and uses of Cerium oxide and some forms of specially prepared
lanthanides is found in the Handbook on the Physics and lanthanide oxides are widely used in the polishing of specta-
Chemistry of Rare Earths, which in 2011 included 41annual cle and optical instrument lenses and in the surface prepara-
volumes (14). tion of mirror glass, gemstones, and other glass specialties.
The most common and known use of lanthanides is in the This polishing process is dependent on both the abrasive
form of mixed lanthanide metal (misch metal) and cerium nature and high melting temperature of the oxide.
metal. These metals are used in lighter flints, magnesium Lanthanum increases the refractive index of glass and is
alloys, and some of the ferrous alloys. Cerium in the pure used in manufacturing high quality lenses and in the manu-
state is not very pyrophoric, but when slightly oxidized or facture of fiber-optic glass. Cerium is added to glass to
alloyed with iron, it becomes readily pyrophoric. Cerium decolorize and to provide UV light absorption characteristics
flashes at 150–180 C. Misch metal, containing cerium, without adding color to the glass. Neodymium, praseodym-
becomes pyrophoric on filing and for this reason is used ium, and erbium oxides are used in art glass to produce
for lighter flints (15). In metallurgy, the lanthanides Ce, La, specific colors. When neodymium is used, it provides a
Nd, and Pr have been added to iron to improve the strength delicate pink tint with violet reflections. The color varies
and ductility of cast-iron products by the removal of oxygen with glass thickness, concentration of neodymium, and
and sulfur, and by controlling the formation of graphite source of illumination. The color shifts from light pink in
crystals. These metals have been added to steel to improve thin sections to a blue-violet in thicker pieces in a process
forming characteristics for cold-stamping applications. In called dichroism, which is used in art glasses and for special
higher concentration alloys they are used to form specialty filters. Higher concentrations of neodymium are used to
stainless steels. Samarium is alloyed with cobalt in a 1:5 ratio produce welding glasses that protect against the yellow
to make strong permanent magnets. Samarium and europium flame color. Praseodymium gives a green color to glass
are used in nuclear reactor control rods. Lanthanum is alloyed similar to chrome glasses. Erbium produces a pale pink
with nickel in 1:4 and 1:5 ratios to form solid-state hydrogen that cannot be obtained by other means.

In the electronics industry, europium finds its greatest use used for drug screening processes and to contribute to the
as the material that produces the vivid red in color television clarification of biological systems (22).
screens. This is due to its narrow emission spectrum, which As pharmaceuticals, the lanthanides have found applica-
peaks near 620 nm. Bubble domain memory materials for the tions as therapeutic agents. Samarium-153 ethylenedi-
computer industry are made on a gadolinium gallium garnet aminetetramethylene phosphoric acid ([153 Sm] EDTMP) is
(GGG) substrate. PLZT electrooptical devices are made from injected as a radiopharmaceutical to combine with metastatic
a ceramic material composed of lead, lanthanum, zirconium, bone cancer lesions to reduce pain resulting from skeletal
and titanium. An example application is an electric welding carcinoma (23). There is considerable research being con-
helmet. When an arc is struck, sensors detect the intense light ducted to develop lanthanide anticancer agents with an
and remove voltage from the PLZT shutter to instantly emphasis on lanthanide coordination complexes, which pro-
darken the viewing lens. When the arc is stopped, the shutter vide a broader spectrum of antitumor activity. The dominant
reactivates and eliminates the necessity of raising and low- pharmacological applications of lanthanides are as agents in
ering the helmet; thus the mask can be kept in the down radioimmunotherapy and photodynamic therapy (24).
position, eliminating the possibility of eye burns from adja- Cerium nitrate is being used as an adjunct to silver sulfadia-
cent welding operations emission (17). Oxygen sensors, first zine cream for the topical treatment of burn wounds, partic-
used in automobile exhaust systems to minimize hydrocar- ularly in situations where surgical intervention is not feasible.
bon and carbon monoxide emissions, contain zirconium in a Cerium helps to prevent postburn sepsis and systemic inflam-
yttrium oxide stabilization medium. Several lanthanides are matory response by fixing burn toxins (25). Lanthanum
components of crystals that have been reported to demon- carbonate (Fosrenol) is approved for the treatment of hyper-
strate superconductivity. phosphatemia in renal dialysis patients. Mottexafin gadolin-
Lanthanide ion complexes are being studied in the devel- ium is being investigated for treatment of brain metastases in
opment of new materials for light-emitting diodes (LEDs), nonsmall cell lung cancer. The lutetium texaphyrin (a lan-
and Ln(III)-ion based LEDs have become increasingly thanide complex) has been investigated as a photoactivated
common (18). agent for the treatment of artherosclerotic plaque in coronary
The highly emissive Y2O3EuIII material is the origin of artery disease, and for treatment of age-related macular
phosphors for cathode-ray tubes and fluorescent lamps. degeneration. In addition the lanthanides have been investi-
Lanthanide luminescence is also being evaluated for use gated for the treatment of liver toxicity and rheumatoid
in telecommunication, lighting, electroluminescent devices, arthritis (3).
bioanalytical sensors, and bioimaging (19). Gadolinium, as gadopentetate dimeglumine, is used as a
Research is being conducted on fluorescent lanthanide magnetic resonance imaging (MRI) contrast enhancing
complexes to develop probes to determine enzymatic activity agent, which represented the first approved application of
and allow real-time monitoring of enzyme kinetics (20). In this technique in the United States (26). While gadolinium
addition, lanthanide probes are being developed for cellular (III) remains the dominant starting material for contrast agent
applications. The probes are intended to be targeted to design, other lanthanide ions are being increasingly investi-
specific organelles in order to allow direct observation of gated as alternations to gadolinium(III) within laboratory
changes in these regions (21). S. Mizukami et al. have conditions (27).
developed novel luminogenic lanthanide probes for detecting Current usage of rare earth elements in these various
protease activity. These lanthanide-based probes could be applications is summarized in Table 21.6.

Table 21.6. Usage of Rare Earth Elements (% by Application)

Application La Ce Pr Nd Sm Eu Gd Tb Dy Y Other
Magnets — — 23.4 69.4 — — 2 0.2 5 — —
Battery alloys 50 33.4 3.3 10 3.3 — — — — — —
Metal alloys 26 52 5.5 16.5 — — — — — — —
Auto catalysts 5 90 2 3 — — — — — — —
Petroleum refining 90 10 — — — — — — — — —
Polishing compounds 31.5 65 3.5 — — — — — — — —
Glass additives 24 66 1 3 — — — — — 2 4
Phosphors 8.5 11 — — — 4.9 1.8 4.6 — 69.2 —
Ceramics 17 12 6 12 — — — — — 53 —
Other 19 39 4 15 2 — 1 — — 19 —
Source: Lynas Corporation (2010) in Ref. (8).

1.3 Exposure Assessment abraded skin. They also act as calcium agonists and impact a
variety of enzymatic functions. Rare earth chlorides and
Characteristically, the analytic methodology of the lantha-
oxides have been proven to cause bronchitis, pneumonitis,
nides has progressed through the quantitative estimation by
and granulomatous lesions in animals. However, there is no
the arc spectrographic method, using a diffraction grating of
evidence that they cause pneumoconiosis or chronic pulmo-
sufficient dispersion to separate the complex spectra of the
nary reactions in animals or are carcinogenic.
lanthanides (28), followed by flame photometry (29), and
As discussed in detail in Section 1.4.2, rare earths have
finally atomic absorption spectrometry (AAS) using nitrous
been shown to act as an anticoagulants in humans. However,
oxide–acetylene flame (30). Yttrium, by this method for the
the side effects are too severe for these agents to be used
determination in air, has a range of 0.529–2.211 mg/m3 with a
clinically. More importantly, a number of case studies dem-
precision of 0.054, and a sensitivity of 10 mg (at 2 mg/mL for
onstrate that exposure to rare earths can cause pneumoconi-
1% absorption) in 5 mL final volume. Interferences of alumi-
osis in humans.
num, potassium, and H3PO4, which cause depression of
absorbance, can be overcome by the addition of NaCl to
samples and standards. Lamps are presently available (Per- 1.4.1 Experimental Studies
kinElmer) for all lanthanides except cerium and lutetium (15).
Early research investigations on the biological and medical
Most lamps require the nitrous oxide–acetylene flame.
aspects of the lanthanides are recorded through 1955 in the
With regard to yttrium, the only one of the rare earths that
proceedings of a conference sponsored by the Medical
is regulated, the preferred NIOSH method (7300) involves
Division of the Oak Ridge Institute of Nuclear Studies (34).
collection on a particulate filter and acid digestion. Analysis
This evidence, which was later confirmed through extensive
is carried out by inductively coupled plasma spectroscopy (31).
investigations of Haley and coworkers (35–40) and Graca
The three favored methods for determination of lantha-
et al. (41), was that the toxicity of the lanthanides, including
nides from biological specimens are neutron activation anal-
yttrium, is low orally and high parenterally and varies greatly
ysis (NAA), high pressure liquid chromatography (HPLC),
according to the associated nonmetallic component.
and inductively coupled plasma–mass spectrometry
Under the general title of pharmacology and toxicology
(ICP–MS). Chiba et al. evaluated the comparability of
of the lanthanides, Haley and coworkers studied 11 of the
these three methods by injecting mice with the chloride
lanthanides (Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, Tm, Yb, and
compounds of Y, La, Ce, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er,
Lu). These investigations included acute intraperitoneal and
or Yb at a dose of 25 mg/kg body weight (bw) and sacrificing
oral toxicity of the chlorides in mice; chronic (12 week) oral
the animals after 20 h. Element ratios between the methods
toxicity in rats; determinations of ocular and dermal irrita-
were calculated to compare results. The ratios for HPLC/
tion, and effects on isolated ileum in rabbits, and pharmaco-
ICP–MS ranged from 0.91 to 1.17; those for the NAA/
logical effects consisting of electrocardiographic changes
ICP–MS, 0.76 to 1.33. The better agreement between the
and changes in acetylcholine, epinephrine, and histamine and
former comparison was attributed to similarity of sample
effects on vagal stimulation.
preparation, rather than any deficiency between the methods.
Because separation and purification procedures before the
The authors concluded that the results obtained by the three
1950s yielded impure lanthanides, with resulting question-
methods agreed well within acceptable limits (32).
able toxicity data, only data obtained on lanthanides since the
Allain et al. (33) used ICP–MS to determine the back-
institution of newer purification methods are included. Data
ground concentrations of rare earths in the plasma and urine
supplied by Haley and coworkers were obtained on lantha-
from healthy male volunteers from France. The concentra-
nides of 98 or 99% minimal purity and those by Graca
tions of La, Ce, Gd, Tb, and Yb (the ions selected for analysis)
et al. (41) on lanthanides from Ames, Iowa Laboratories,
were all ,0.3 mg/L, except for one urine that contained
where the newer purification procedures originated. Thus the
cerium at 1.5 mg/L. The authors indicate that their data are
rat intraperitoneal (IP) LD50 of 99% pure LaCl3, determined
in agreement with general data about rare trace elements in
by Kyker and Cress (42) to be 187 mg compound/kg, was
biological samples.
about half that reported by Cochran et al. (43) some years
previously (350 mg/kg). The corresponding LD50 value for
YCl3 was 100 mg/kg, compared with 450 mg/kg according to
1.4 Toxic Effects
Cochran et al. As pointed out by Kyker and also by Graca
As discussed in detail in Section 1.4.1, rare earths have been et al. (41), however, precise acute toxicity determinations of
shown to have both acute and chronic toxic effects in animals. the lanthanides are difficult because of their protein-precipi-
Specifically, rare earths prevent blood coagulation and tating capacity and the unusually great influence of the
adversely impact reproduction and development. Further, nonmetallic components. Toxicity values could be greatly
they are toxic to the gastrointestinal tract (GI), liver, kidney, modified, therefore, according to concentration and rate of
spleen, and lung tissues. They are irritating to the eye and to the injected dose; animal strain differences may be another

factor. Hart et al. (44) reported that when lanthanum and Hirano and Suzuki (2) reviewed the mortality data for ionic
yttrium were administered to humans and animals, the uptake and chelated forms of rare earths administered orally, IP, and
of lanthanum and yttrium by the tissues varied according IV. They concluded that the median lethal dose (LD50)
to the form administered, that is, whether ionized or as an indicated the rare earths were not highly toxic for oral or
EDTA complex. IP administration. However, they questioned the validity of
establishing LD50 values for intravenous (IV) administration. Acute Toxicity. The acute toxic response has been They reported that the percent mortality peaked at
determined in laboratory animals for the lanthanides by IP, 20–40 mg Pr(NO3)3/kg bw following IV injection in both
IV, and oral routes as nitrates, chlorides, oxides, and chlor- mice and rats of both sexes; however, the lethality then
ide–citrate complexes. Bruce et al. (45), reporting on all the decreased as the dose increased. They postulated that the
lanthanides except lanthanum and promethium, found that colloid formation of ionic rare earths in blood at higher doses
for mice the approximate IP LD50 values of the nitrates of rare earth chlorides or nitrates might be responsible for the
ranged from 225 to 480 mg compound/kg bw; for rats, the bell-shaped dose–response curve. More study is needed to
values ranged from 210 to 335 mg/kg. Oddly, the most and test this hypothesis.
least toxic lanthanides for the mouse, Tb and Er, did not Uniform signs and symptoms of acute poisoning reported
correspond to the most and least toxic for the rat (Eu and Lu), by Haley et al. were ataxia, writhing, slightly labored and
although administered by the same route, indicating differing depressed respiration, arched back, stretching of limbs on
metabolism for these elements in the two species. There were walking, and lacrimation, all starting within 24 h and,
other discrepancies (Gd, Dy, and Ho), but generally the depending on the lanthanide, peaking between 48 and
degree of toxicities was parallel in the two species. 72 h. Gadolinium and samarium differed in that peak mor-
As expected, toxicity by the IV route was far greater, tality was delayed until the fourth or fifth day. Graca
ranging from 49.6 to 77.2 mg/kg for the male rat for the five et al. (47), while observing the effect on heart rate, blood
lanthanides tested (Ce, Pr, Nd, Sm, Er), with a surprising pressure, and respiration in 135 dogs, administered 100 mg
increase in toxicity for the female rat (from 4.3 to 35.8 mg/ compound/kg in 10 mg/kg doses at 10 min intervals and
kg). Again, the relative toxic degree was not always parallel found that the only specific effects were increases in pro-
in the two sexes, although cerium proved the most toxic for thrombin and coagulation times. Cardiovascular collapse and
both sexes. Toxicities for IV and IP routes showed no respiratory paralysis were considered by both investigators to
relationship among the lanthanides tested (45). be the cause of death.
Typical of polyvalent metals with their protein-
precipitating potential and consequent poor absorption Chronic and Subchronic Toxicity. Studies on the
from the GI tract, the oral toxicity of the nitrates was of a toxicity and safety of a mixture of rare earth metal nitrates Ce,
different order of magnitude, with LD50 values ranging from La, Nd, Pr, and Sm used in agricultural operations were
2750 to 4200 mg/kg, 10 or more times that of the IP route. reported (46). Subchronic and chronic toxicity studies were
With the exception of the elements Eu, Gd, and Tb, for which done at different doses in monkeys (100 mg/kg) and rats (200
the oral LD50 values were greater than 5000 mg/kg, the and 1800 mg/kg); biochemical and histopathological exami-
nitrates roughly exhibited an increase in toxicity with nation of tissues showed no abnormal or specific pathological
increasing atomic weight (45). changes. In chronic feeding studies with rats, the incidence of
All the oxides of the lanthanides were tolerated by female benign and malignant tumors in the test groups was lower
rats at 1000 mg/kg (33). Haley and coworkers (35–40) tested than that in the control. Rat fetuses did not show any
the toxicity of the chlorides of the lanthanides, all except teratogenicity when the dams were orally fed up to
those of La, Ce, Pm, Eu, and Y, and found the IP LD50 values 330 mg/kg of this nitrate mixture. Ames mutagenicity tests
to range from 315 to 600 mg compound/kg; lutetium was the were negative at 50 mg/kg. The investigators (47) concluded
most and praseodymium and neodymium the least toxic, that an oral dose of 60 mg/kg should be considered as a no-
showing that with acute exposures the chlorides are about effect level with an allowable dietary intake of 0.6 mg/kg.
half as toxic as the nitrates. As with the nitrates, the chlorides’ Spencer et al. studied gadolinium chloride (GD) toxicity in
oral LD50 levels were of a different order, ranging from 7.5 to male and female Sprague–Dawley rats. Rats were given a
22.5 times lower than those by the IP route. Although a rough single intravenous injection of gadolinium chloride solution
parallelism existed between IP toxicity and increasing at dosages of 0, 0.07, 0.14, and 0.35 mmol/kg. Half the rats
atomic weight, no corresponding parallelism was found were necropsied 48 postdose, and the remaining rats were
for the oral route. necropsied 15 days postdose. Major lesions related to gado-
Ji and Cui (46) studied a mixture of rare earth metal nitrates linium chloride toxicity consisted of mineral deposits in the
Ce, La, Nd, Pr, and Sm. They reported that in mice, rats, and capillary beds (particularly lung and kidney), enlarged,
guinea pigs, the oral LD50 ranged from 1397 to 1876 mg/kg. mineral-containing Kupffer cells of the liver and splenic
They concluded that absorption from the GI tract was low. marcophages, necrosis in liver and spleen followed by

dystrophic mineralization and granulomatous inflammation, Cerium and praseodymium produced hepatoxic effects and
mineralization of gastric mucosa without necrosis followed increased serum alanine aminotransferase (ALT) and aspar-
by mucous cell hyperplasia, decreased platelet numbers and tate aminotransferase (AST) levels. Nakamura et al. hypoth-
increased PT and APTT (48). esized that lanthanide chlorides might be categorized into
three groups according to their ionic radii (light lanthanides, Pharmacokinetics, Metabolism, and Mechan- Y and medium lanthanides, and heavy lanthanides) and from
isms. The distribution of all 15 lanthanides has been deter- their behavior, that is, distribution pattern, Ca accumulating
mined (34, 49) from their radioisotopes in a dozen tissues and action and hepatotoxicity (50).
body sites of rats for periods of 1–256 days for the longer- Hirano and Suzuki (2) summarized inhalation studies that
lived isotopes, following oral or intramuscular (IM) injection showed that significant amounts of inhaled CeCl3, Ce(OH)3,
as citrate complexes. In general, absorption from parenteral and Y (chemical form unknown) were translocated to the
injection was relatively complete in 4 days (,6.5% unab- skeleton or liver in rats or hamsters. They also reported a half-
sorbed), whereas absorption from the GI tract of the four life of 140 days for inhaled Ce(OH)3.
lanthanides 144 Ce , 152;154 Eu , 160 Tb , and 170 Tm was less Berthezene et al. (26) evaluated the safety aspects and
than 1% of the administered dose. The low parenteral absorp- pharmacokinetics of aerosolized gadopentetate dimeglu-
tion of 140 La (22.5% unabsorbed in 4 days) was attributed to mine in Sprague–Dawley rats. They determined that pulmo-
its low solubility at body pH and, in general, to the amount of nary clearance of aerosolized gadopentetate dimeglumine
stable carrier administered (49). had a half-life of 2.16 h. They also determined that material
The skeleton was the most important site of deposition for was excreted via the kidneys and renal elimination was
all lanthanides, particularly the heavy ones; deposition ran- complete in 30 h. No acute hemodynamic effect, histological
ged from 62% for gadolinium to 90% of the administered change, or induction of edema was demonstrated. Thus they
dose for lutetium. The skeleton was, however, initially a concluded that inhalation is well tolerated. In reviewing these
secondary site of deposition for the light lanthanides, whose data, Hirano and Suzuki (2) concluded that gadopentetate
major deposition site was the liver, ranging from 67% for dimeglumine was stable in the alveolar space and was hardly
lanthanum to 45% for samarium of the administered dose. taken up by macrophages because of limited release of ionic
For the transition lanthanides (Eu and Gd), deposition was Gd from the complex.
nearly equal in liver and skeleton (4). Galle et al. (51) exposed male Wistar rats to submicrom-
The kidney, which initially contained a greater concentra- eter aerosols generated from a 1% solution of cerium chloride
tion than any other soft tissue for the light and heavy (CeCl3), chromium chloride (CrCl3), uranyl nitrate
lanthanides (1.6 and 0.9%/g), decreased in all cases to [UO2(NO3)26H2O], and aluminum chloride (AlCl3). Rats
very low levels at 8 months (4). were exposed to a concentration of 10–30 mg/cm3 for 5 h/day
In the blood, lanthanide levels, even at day 1, never for 5 days. The ultrastructure of the cells in lung sections was
exceeded 0.02%/mL, and steadily decreased thereafter to examined using a Philips EM 300 microscope. The intracel-
unmeasurable amounts. Initial levels in muscle were about lular localization of the elements was determined using an
the same as in blood, but those in the skin were 3–4 times electron probe Camebax Camerca microanalyzer equipped
greater. The GI tract showed concentrations about 10 times with thallium acid phthalate (TAP), pentaerythritol (PET),
those of blood and muscle initially, but concentrations were and lithium fluoride (LiF) crystals. A specially adapted
still measurable 8 months later for the lighter lanthanides, for electron microscope allowed the analysis of intracellular
which the GI tract is the main excretory route. Concentrations organelles. The study showed that inhaled cerium chloride
in the spleen depend on the route of administration. By IM accumulated in alveolar and tissue macrophages and alveolar
injection they are low (,0.5%/g wet tissue); but by vein, they walls. They attributed the mechanism involved to the high
are high if administered as halides or nitrates, from which acid phosphatase activity of lysosomes and considered it as
colloids form to be deposited in the reticuloendothelial an in vivo Gomori reaction. They postulated that in the lung
system (4). macrophage this mechanism of intralysosomal concentration
Nakamura et al. investigated the difference in behavior and precipitation may prevent the diffusion of the toxic
among the chlorides of seven REEs (Y, Ce, Pr, Eu, Dy, Yb, elements through the alveolar membrane.
and Lu) by intravenous administration to rats. They found Hirano et al. (52) investigated the metabolic behavior and
that lanthanide ions are cleared from the blood within the first pulmonary toxicity of intratracheally administered yttrium
day, but remain much longer in the organs. The percentages chloride (YCl3). Yttrium chloride solution was intratrache-
of europium and dysprosium in the liver reach the maximum ally instilled in male Wistar rats at doses of 10, 20, 50, 100,
between 8 and 48 h after administration, and then decrease and 200 mg Y/rat. The time-course and dose-related changes
gradually, while the concentration of praseodymium remains in distribution of Y between lung tissue and bronchoalveolar
high. Changes in Ca concentrations in the liver, spleen and lavage fluid (BALF) and pulmonary inflammatory responses
lungs were in accordance with those of the lanthanides. were investigated. It was determined that the pulmonary

clearance of Y was very slow, with an estimated half-life of heavier lanthanides are excreted primarily in the urine, and
168 days. Yttrium content in the supernatant of BALF did not those in the middle of the series by both routes, about
exceed 5 mg Y/lung, even at a dose of 200 mg Y/rat. equally (55).
Hirano et al. concluded that the alveolar surface fluid could Dean et al. (56) concluded that intravenously administered
retain at most 5 mg Y. Yttrium content in the pellet of BALF gadolinium chloride (GdCl3) forms insoluble carbonate and
changed with the number of macrophages retrieved in BALF. phosphate precipitates in the blood, which are taken up by the
Transmission electron microscopy and X-ray microanalysis reticuloendothelial system. Barnhart et al. (57) also found
suggested that Y was localized in lysosomes of alveolar and that intravenously injected GdCl3 was found primarily in the
interstitial macrophages and in basement membranes. No liver and spleen. Further, they demonstrated that it accumu-
detectable amount of Y was accumulated in the liver. Renal Y lated rapidly, reaching 72% of the injected dose in 2 h. They
content increased with time, but only 0.1% of the initial dose also found that Gd-DPTA was quickly accumulated in the
was accumulated in the kidney, even at 162 days. kidney and excreted in urine, with only 2% of the injected
Suzuki et al. (53) investigated the distribution and health dose remaining after 2 h.
effects of lanthanum chloride (LaCl3) intratracheally The metabolism and toxicity of IV injected yttrium chlo-
instilled in rats. Lanthanum chloride solution was intratra- ride (YCl3) in male Wistar rats was studied by Hirano
cheally instilled in male Wistar rats at doses of 0.5, 1, 10, 20, et al. (58). They concluded that IV injected YCl3 resulted
50, 100, and 200 mg La/rat. The distribution of La among in the dose-dependent formation of colloidal material in
tissues revealed that the metal remains mostly in the lung blood plasma. The collodial plasma Y was accumulated
with a biological half-life of 244 days. The subcellular predominantly in phagocytic cells in the liver and spleen.
localization by transmission electron microscopy with an The liver Y was cleared slowly with a half-life of 144 days.
X-ray microanalyzer indicated that La localizes in macro- Hirano and Suzuki (2) concluded that chelated rare earths
phages as high electron-dense granular inclusions in lyso- are excreted mainly via the urine after a transient accumula-
somes and cytoplasm and on the cell surface and basement tion in the kidney and that their whole-body half-lives are
membranes of type I pneumocytes among lung cells. La was several hours. Rare-earth chlorides are taken up by the liver
not detectable in any femur samples, and was detected and spleen, and those rare earths are not easily excreted.
marginally in liver and kidney samples. La was detected A study of the subcellular distribution in rat liver after IV
at high concentration in the pulmonary hilum lymph node administration of representative lanthanides, Ce, Pm, Tb, Ho,
samples, which the authors interpreted as suggesting that La Yb, and Y revealed that in females the largest amounts of
is transferred from the lung through the lymph nodes. 144
Ce and 169 Yb were in the microsomal fraction; in males,
Yoneda et al. (54) investigated the effects of gadolinium in the supernatant for 144 Ce and in the mitochondria and
chloride on rat lung. They performed the study in the same supernatant for 169 Yb . The nuclear fraction was lowest for
manner as those Hirano et al. performed for yttrium chloride both isotopes in male and female rats (15).
and Suzuki et al. performed for lanthanum chloride. GdCl3 The complexing capacity of the lanthanides, particularly
solution was intratracheally instilled at doses of 10, 20, 50, with proteins, is unquestionably the basis for their charac-
and 100 mg Gd/rat. The results were quite similar to those teristic distribution and excretion pattern, varied toxicity by
obtained with yttrium chloride and lanthanum chloride. Gd in different routes according to compound type, and lack of
the lung tissue decreased very slowly with a biological half- mobility from an injection site. This property is, in turn, a
life of 136 days at a dose of 50 mg Gd/rat. Gd content in the consequence of their high ionic charge, tri- or tetravalence.
supernatant of bronchoalveolar lavage fluid did not exceed Lanthanum, for example, forms insoluble complexes with
5 mg Gd/BALF even at a dose of 100 mg Gd/rat. These results nucleic acids in a physiological pH range (59–62). This has
suggest that intratracheally instilled Gd can be retained in been useful in analyzing and purifying nucleic acids and for
epithelial lining fluid only to a limited extent as soluble electron-stain chromatin fibrils. Similarly, all salts of lantha-
forms, and is deposited in the lung tissue probably in num, praseodymium, neodymium, and samarium precipitate
insoluble forms that are metabolized very slowly. They fibrinogen at concentrations of 0.01–1%. Higher salt con-
also found that Gd caused a rapid and selective infiltration centrations partially resolve the precipitates, and the chlor-
of serum calcium before acute lung toxicity. ides of praseodymium, neodymium, and samarium
Hirano and Suzuki (2) postulated that the differences in the completely resolve them. Human serum proteins are incom-
extrapulmonary translocation of rare earths between the pletely precipitated at 0.25–0.7% lanthanide salt and dissolve
intratracheal instillation and inhalation studies may be due at concentrations .1.5% (63). Bamann (64), however,
to absorption of rare earths from the upper airways or GI tract believed that the well-studied anticoagulant action of the
after being transported through the esophagus. lanthanides on blood is mediated through their capacity to act
Excretion of the lanthanides is both urinary and fecal, as phosphate acceptors and indirectly reduce prothrombin
depending on their position in the series; light lanthanides are content of blood. The reasons for these actions are open to
excreted in the feces following accumulation in the liver. The other interpretations.

Due to the similarity to calcium, Ln3þ blocks both voltage- Chronic (12 week) oral toxicity to male and female rats at
and receptor-operated calcium channels. The Ln3þ ion can dietary levels of 0.01, 0.1, and 1% of lanthanide chloride
block the Naþ/Ca2þ synaptic plasma membrane exchange, uniformly had no influence on growth or hematological
and inhibit skeletal, smooth and cardiac muscle contraction variables. At autopsy, tissues of eight internal organs showed
by blocking the Ca2þ-ATPase in the sarcoplasmic reticulum no histological changes at the 0.01 or 0.1% levels; but some,
of muscle. The Ln3þ ion acts by blocking the face of the gadolinium, terbium, thulium, and ytterbium, showed non-
calcium channel. Lanthanides can inhibit or activate cal- specific liver damage (perinuclear vacuolization and granular
cium-dependent enzymes. Examples of enzymes inhibited cytoplasm) at 1%. Hutcheson et al. (67) evaluated the possi-
by Ln3þ include Staphylococcal nuclease, the family of ble toxic effects of scandium, lanthanum, samarium, euro-
cytochrome P450 xenobiotic metabolizing enzymes, and pium, dysprosium, terbium, thulium, and ytterbium oxides
enzymes involved in blood clotting. Enzymes stimulated on growth, general development, reproduction, and lactation.
by Ln3þ include trypsin and acetylcholinesterase. The Mice were fed different doses of these compounds for three
lanthanides can substitute for calcium and other metal generations. The amount of elements fed were 0, 1, 10, 100,
ions in proteins. The Ln3þ will interact with other cal- and 1000 times the use amount. The use amounts were (in
cium-binding proteins and will bind to the calcium-binding ppm) Sc, 0.12; La, 0.40; Sm, 0.80; Eu, 0.036; Tb, 1.20; Dy,
protein calmodulin, and cause polymerization of collagen 1.20; Tm, 0.08; and Tb, 0.12. The used amount was one-fifth
and G. actin (2). of the concentration required for activation analysis. Mortal-
ity and morbidity were negligible. No consistent growth rate Reproductive and Developmental. A single IP changes were observed. The number of mice born showed no
injection of lanthanum chloride (44 mg La/kg) into pregnant significant differences among treatment groups. Survival,
mice reduced the number of successful pregnancies and the growth rate, hematology, morphological development, mat-
average litter size. The most susceptible periods of pregnancy uration, reproduction, and lactational performance were
were preimplantation (days 4 and 6) and near-term period comparable in mice fed the different levels of metal oxides
(days 14 and 16). Injection of lanthanum during the preim- to those mice fed the basal diet.
plantation period resulted in a cessation of pregnancy in Rat fetuses did not show any teratogenicity when the dams
24–43% of females, and injection during near-term period were orally fed up to 330 mg/kg of a mixture of rare earth
produced the cessation of pregnancy in 36–46% of the nitrates (46).
females. The average litter size after injection of lanthanum
during preimplantation or near-term periods was reduced to Carcinogenesis. Scant investigative attention has
about 75% of the average litter size in the control animals. No been given to the neoplastic potential of the stable isotopes of
external malformations were observed among fetuses, but the the lanthanides. According to the National Cancer Institute
exposure of single-cell stage embryos to lanthanum chloride survey of compounds for carcinogenic activity for
in vitro resulted in an increase in the fraction of embryos 1970–1971, only gadolinium and ytterbium have been inves-
developing into blastocysts (65). tigated, and only sporadic testing has been done on some of
Pregnant female mice received either a single subcutane- the radioisotopes of lanthanum and cerium or their admix-
ous dose of cerium citrate (80 mg Ce/kg) or an equivalent (in tures with other lanthanide radioisotopes.
citrate) dose of sodium citrate on day 7 or 12 of gestation or Subcutaneous implantation of 118 CFW male and female
on day 2 postpartum. To separate effects of prenatal and mice with 200 mg each of gadolinium and ytterbium metal
postnatal exposure, a cross-fostering design was employed. pellets by Ball et al. (68) resulted in a variety of neoplastic
The weight and gross activity of the neonates were assessed growths, 12 carcinomas at implant sites with pulmonary
on day 8 or 13 postpartum. Open-field behavioral parameters, metastases in four, and 24 additional neoplasm, 16 of
accelerating rotarod performance, and passive avoidance which, in female implanted mice, were diagnosed as mam-
learning were assessed on days 60–65 postpartum. Maternal mary carcinomas, 9/30 (30%) from gadolinium and 7/28
offspring retrieval latency was measured on day 3 postpar- (25%) from ytterbium. By comparison, sham-implanted
tum. Analyses revealed that neonatal weight was reduced female CFW mice developed 44 and 40% mammary cancers
both in offspring exposed to cerium in utero and in the from gadolinium and ytterbium, respectively. Similarly,
offspring of mothers receiving cerium during lactation. whereas sham-implanted female mice developed 25% bron-
Cerium also appeared to affect maternal–offspring interac- chial adenomas, only 7% developed the same tumor from
tion: pups exposed prenatally to cerium were retrieved in gadolinium; 25% of ytterbium controls developed the tumors
less time than control pups. Except for an increased fre- versus 14% ytterbium-implanted. Occasional tumors at other
quency of rearings in the open field of adult offspring sites—hemangiomas of the liver, ovarian, salivary, and vul-
exposed to cerium in utero, cerium exposure had no apparent var adenoma, and malignant lymphoma—were too few in
effect on behavioral parameters, either in neonatal or adult number in either group to permit comparison. They were
offspring (66). about equal in incidence in both treated and in controls. These

data indicate that both gadolinium and ytterbium are antitu- the transport and release of synaptic transmitters and block
mor agents of mild degree in a species (CFW mice) that has a some membrane receptors, for example, GABA and gluta-
high spontaneous incidence of mammary carcinomas and mate receptors. Many lanthanides enhance GABA response
bronchial adenomas in females and hemangiomas and lym- (prolongation of the opening time of the chloride channel)
phomas in males. and this effect varies in inverse proportion to the radius of the
In chronic feeding studies with rats, the incidence of hydrated ion (72).
tumors and malignant tumors in test groups was lower Palasz and Czekaj report that La3þ interact with the
than that in the control groups (46). Using radioisotopic monoamine and Naþ-binding sites of neurons, thus inhibit-
mixtures of 140 La and other lanthanides, investigators in ing the binding of Ca2þto the synaptosome membrane and
the former Soviet Union found a 2% incidence of lympho- the functioning of membrane proteins that transport such
sarcomas in rats at 500 rad to bone marrow and 350 rad to the neuromediators as epinephrine, serotonin, and dopamine (72).
GI tract in 320–640 days (69). Other Soviet investigators The La3þion, long known to antagonize calcium binding in
reported five bronchogenic or alveolar lung carcinomas in heart muscle, inhibits the calcium influx requirement for the
rabbits and rats intratracheally injected with 25 mCi colloidal human neutrophil chemotaxis, thus inactivating the contrac-
CeF3 (70). Magnusson (71) found five squamous cell tile chemotactic process (74). In a related manner, if sialic
carcinomas with two metastases among 23 rats inhaling acid is removed from cultured heart cells, lanthanum, nor-
an average of 170 mCi/kg; tests with 144 Ce by other inves- mally restricted to cell surfaces, can now enter the cell and
tigators were negative. Hirano and Suzuki (2) concluded that displace more than 80% of the cellular calcium, thus dem-
rare earths have not been found to be carcinogenic in animals. onstrating a specific role of cell surface constituents in the
From these reports, it can be concluded that at least certain control of calcium exchangeability in the heart (75).
stable lanthanide isotopes have, if anything, mild antitumor In vitro, rare earth chlorides (EuCl3, DyCl3, HoCl3, and
activity, and that certain radioisotopic forms are mildly ErCl3) dose-dependently decrease the tonus and contractility
carcinogenic. of rabbit ileum in response to acetylcholine or nicotine (40).
Kostova reviewed recent advances in developing lantha- Triggle and Triggle (76) demonstrated that lanthanide
nide anticancer agents with an emphasis on lanthanide cations strongly inhibit the phasic and tonic component of
coordination complexes. A number of coumarins and their the response to muscarine agonist cis-2-methyl-4-dimethy-
lanthanide complexes have demonstrated antiproliferative laminomethyl-3-dioxolane methiodide (CD) in guinea pig
activity on various cancer cell lines. Terbium has been shown ileal longitudinal smooth muscle. They found that lanthanide
to enhance the cytotoxicity of cisplatin, possibly by increas- cations also inhibited the responses evoked by high Kþ, but
ing accumulation of drug in cisplatin-resistant cells. She here the effect was mainly on the phasic response, and the
concluded that there are a number of results indicating that tonic component was merely delayed. Other members of the
Ln compounds might be developed into future drugs (24). lanthanide series, with the exception of cerium, were more
S. Fricker reports that the texaphyrins (lanthanide com- effective than lanthanum in their ability to inhibit the CD
plexes) have progressed to clinical trials. Gadolinium tex- response. Thulium (Tm3þ) was the most effective. They
aphyrin has entered clinical trials for the treatment of brain concluded that lanthanide cations combine with membrane
metastases of nonsmall cell lung cancer (3). sites specifically involved in Ca2þ translocation during exci-
tation–contraction coupling. Genetic and Related Cellular Effects Studies. Swamy et al. (77) evaluated the effect of La3þ and Tm3þ
Lanthanides have ionic radii similar to that of calcium, on the mechanical responses of rat vas deferens and found
which enables them to compete with calcium ions. Ln3þ that they inhibited the noradrenaline and Kþ-induced
blocks both voltage- and receptor-operated calcium chan- responses; complete inhibition was obtained at approxi-
nels. Trivalent lanthanide ions, especially La3þ and mately 103 M Ln3þ. La3þ and Tm3þ were equally effective
Gd3þblock different calcium channels in human and animal in inhibiting noradrenaline and Kþ responses. The phasic and
cells (72). The Ln3þ ions themselves are unable to cross cell tonic components of the noradrenaline response were equally
membranes, but act by blocking the face of the calcium sensitive to lanthanide cations, but the phasic component of
channel (3). the Kþ response was more sensitive than the tonic compo-
Lanthanides can affect numerous enzymes. Dy3þ and nent. They theorized that the action of Ln3þ in the rat vas
La3þ block Ca2þ-ATPase and Mg2þ-ATPase, while Eu3þ deferens are mediated through some kind of membrane
and Tb3þ inhibit calcineurin (72). Blocking Ca2þ-ATPase stabilization rather than via a specific Ca2þ-binding site,
inhibits skeletal, smooth and cardiac muscle contraction. as postulated for the Ln3þ action in guinea pig ileal longitu-
Calcium-dependent enzymes can be inhibited or activated dinal muscle.
by lanthanides (3). Ghosh et al. (78) reported that administering a single IP
In neurons, La3þ, Gd3þ, and Lu3þ, can directly trigger the dose of 250 mg/kg bw of lanthanum chloride and neodymium
release of neurotransmitters (73). Lanthanide ions regulate chloride to chicks reduced the activity of certain enzymes

bound to the erythrocyte membranes. Specifically they conspicuous polymorphonuclear cell infiltration was
reported that activities of acetylcholinesterase, NADH dehy- observed in the gastric and duodenal lamina propria and
drogenase, Mg2þ-ATPase, and p-nitrophenyl phosphatase submucosa, especially in those areas adjacent to the necrotic
were reduced. Membrane bound glycosidases were also zones.
reduced. They also found that cholesterol and phospholipid Spencer et al. showed that intravenous administration of
residues were reduced, but the ratio of cholesterol to phos- gadolinium chloride in rats resulted in mineralization of
pholipid remained constant. In addition, they reported that gastric mucosa without necrosis (48).
membrane sulfhydral groups were also significantly inhibited.
In summarizing enzymatic and cellular effects, Hirano and Kidney. Hirano and Suzuki (2) summarized the
Suzuki (2) reported that IP administration of LaCl3 to chicks work of Endre et al. (81) and reported that perfusing rat
decreased lipid peroxides and the contents of sulfhydryl kidney for 30 min with a solution containing 3–5.5 mM of
groups while increasing the activities of glutathion peroxi- chelated Dy reduced urinary concentrating ability and
dase, glutathione reductase, glutathione-S-transferase, and increased renal vascular resistance.
catalase in bone marrow. In addition, there was a marked Salonpaa et al. (82) investigated the effects of liver-dam-
depression in the activities of neural Ca2þ-ATPase, Mg2þ- aging doses of cerium chloride (2 mg/kg) on the expression of
ATPase, and cholinesterase. They concluded that the depres- Cyp2a-4 and Cyp2a-5 in the liver and kidney, which differ in
sion of these enzymes may be related to inhibitory effects of the regulation of the Cyp2a-4/5 gene complex. A dose of
La3þon binding of Ca2þ to brain synaptosomal membrane. 2 mg/kg cerium was administered IV to adult male DBA/2
Yajima et al. (79) reported forming adenosine 30 50 -cyclic (D2) and C57BL/6N (B6) mice. In D2 mice they found that
monophosphate (cAMP) from adenosine triphosphate at pH COH activity peaked 4.4-fold over the control value at 4 days
8 and 50 C using lanthanide ions. Pr3þ and La3þ were after treatment, and then returned to the normal level. The
reported as being the most active. The authors concluded activities of 7-ethoxyresorufin O-deethylase (EROD) and
that lanthanide ions can function as the catalytic center of testosterone 15a-hydroxylase were unchanged during the
artificial adenylate cyclase. first 2 days, and then showed a slight reduction, coinciding
Hirano and Suzuki (2) summarizing the work of with the increase in COH activity at days 3 and 4 after
Komiyama et al., reported that rare earth ions hydrolyze treatment. A comparable change was not seen in B6 mice.
RNA dinucleoside monophates and phosphatidylinositol in Northern blot analysis showed seven- and sixfold increases in
vitro under physiological conditions. They also reported that the level of Cyp2a-4/5 mRNA in the kidneys of D2 mice at 6 h
Ce4þ hydrolyzes cAMP under physiological conditions. and 1 day after the cerium injection. No increases occurred in
the mRNA levels in the kidneys of B6 mice. Other: Neurological, Pulmonary, Skin Maulik et al. (83) found that administering a single acute
Sensitization dose of lanthanum chloride to chicks altered the level of
enzymes of the antioxidant defense system of the renal cortex Eye. Only terbium produced detectable damage fractions. There was significant decrease in the activities of
to the cornea and iris after instillation of 0.1 mL of a 1:1 glucose-6-phosphate dehydrogenase, glutathione reductase,
solution of the chloride into the rabbit eye, showing a maximal glutathione peroxidase, and catalase of kidney epithelial
irritation index immediately; healing required 18 days. Sev- cells. Glutathione and total thiol contents were decreased
eral of the lanthanides produced multiple 1 mm-diameter while lipoperoxidative reactions in the kidney cortex was
conjunctival ulcers, particularly lutetium, praseodymium, significantly enhanced. They concluded that amelioration of
neodymium, thulium, ytterbium, and erbium (35–40). lanthanum toxicity by methionine supplementation may be
In rabbits, a topical application of a suspension of due to the methionine serving as a precursors of glutathione.
500 mg/mL produced mild irritation of the skin and eye Spencer et al. showed that gadolinium chloride adminis-
mucosa (46). tered intravenously to rats resulted in mineral deposition in
the capillary beds, particularly, in the lung and kidney (48). Gastrointestinal tract. Haley and coworkers
reported pharmacological effects uniformly had a depressing Liver. Intravenous injection of the “light” lantha-
effect on blood flow and pressure, intestinal tonus, and nides (cerium) produced fatty infiltration in the livers of
contractility of rabbit ileum (35–40). rats (84), characterized by an increase in neutral fat esters;
Stineman et al. (80) orally administered doses of 1000 and total hepatic cholesterol and phospholipid levels were
1163 mg Ce/kg bw to mice. At both doses, gastritis and unchanged. Cerium was associated almost wholly with
enteritis were evident in all animals. The stomach and the the acid-soluble fraction of the liver, and not with the
duodenum manifested focal hemorrhages and necrosis of the lipid. The action of cerium was sex-based because it appeared
mucosa. Homogenous conglomerates of eosinophilic sub- most pronounced in females; testosterone-treated and
stances were found within the necrotic mucosa. In addition, ovariectomized females showed marked reduction in the

response. Neither choline nor methionine exerted a protec- Salonpaa et al. (82) summarized the enzymatic activities in
tive effect against cerium. Injection of CeCl3 caused fatty mouse liver and kidney, which are as follows.
liver in female rats, but not in male rats (71); the reason for Coumarin 7-hydroxylase (COH) is activity catalyzed by
this limitation remains unknown (2). the Cyp2a-5 gene product (P450COH) in mice. Cyp2a-4
Stineman et al. (80) found that subcutaneous administra- mediates the 15a-hydroxylation of testosterone and some
tion of Ce at a dose of 173 mg Ce/kg bw caused focal necrosis other steroids in the mouse liver and kidney. Cyp2a-5 is
in the liver of mice. Regenerative changes characterized by a predominantly expressed in the liver, while Cyp2a-4 is the
moderate number of mitotic figures in the hepatocytes were main component in the kidney. Mouse hepatic Cyp2a-5
also observed. expression is often increased in conditions in which other
Electron microscopic examination of the liver by P450 isoforms are repressed.
Magnusson (71) showed changes in both the mitochondria This is helpful in understanding the impact of cerium on
and endoplasmic reticulum (ER). The mitochondria were the liver, as discussed below.
enlarged, and changes in the ground substance and cristae When CeCl3 was IV injected into two strains of mice at
were seen chiefly in female rats treated with cerium. Changes doses of 0.5, 1.0, and 2.0 mg/kg, coumarin 7-hydroxylase
in the endoplasmic reticulum were manifested as a dilatation was increased in a dose-dependent manner in DBA/2 (D2)
of the cisternae and a loss of ribosome; similar changes animals after 24 h, whereas no change was seen in C57BL/6N
occurred with all the lanthanides tested in female as well as (B6) animals. A significant increase in all other enzymes
male rats. Associated with these changes was a lowering of studied (cytochrome P450, ethoxycoumarin O-deethylase,
the blood glucose level during the first 3 or 4 days; the lowest and 7-ethoxyresorufin O-deethylase) was seen in D2 mice
levels occurred in female rats injected with cerium. injected with the highest dose of cerium. In B6 mice at 72 h
Hirano and Suzuki (2) reported that dilation, disorganiza- cerium increased COH activity, as well as other enzymes, in a
tion, and degranulation of rough endoplasmic reticulum and dose-dependent manner. In D2 mice the increase was seen
proliferation of smooth endoplasmic reticulum occurred only after the two lower doses; the highest dose caused severe
following the IV injection of CeCl3 in rats. They concluded morphological changes in the liver structure and a clear
that the liver is the primary target organ of IV injected CeCl3. decrease in COH and other activities. This demonstrated
Magnusson (71) reported that IV injection of rare earth that an IV dose of 2 mg/kg caused severe disintegration of the
chlorides (YCl3, TbCl3, HoCl3, and YbCl3), except CeCl3, liver tissue in D2 mice. The changes consist of diffuse
caused focal necrosis with calcium deposition in rats. panlobular necrosis, disintegration of nuclei, cytoplasmic
Hirano et al. (58) administered yttrium chloride solution accumulation of fat droplets, and sinusoid congestion. These
to male Wistar rats at doses of 0.1, 0.2, 0.5, 1, and 2 mg Y/rat changes do not occur in the B6 mice at the same dose level.
to evaluate its metabolism and toxicity. They showed that The differences are not due to unequal tissue distribution of
some plasma calcium was translocated to the collodial cerium in the two mouse strains (86).
material and plasma calcium concentration was increased Salonpaa et al. (82) investigated the effects of liver-
transiently following injection of YCl3. The authors theo- damaging doses of cerium chloride (2 mg/kg) on the expres-
rized that the increase in calcium concentration was due to sion of Cyp2a-4 and Cyp2a-5 in the liver and kidney, which
resorption of bone. At doses of 1 mg Y/rat, the calcium differ in the regulation of the Cyp2a-4/5 gene complex. A
content of the liver increased over 10-fold. Gross observation dose of 2 mg/kg cerium was administered IV to adult male
of the tissues indicated there were white blotchy necroses DBA/2 (D2) and C57BL/6N (B6) mice. As described above,
centriportally in the liver. Examination by transmission Arvela et al. (86) had demonstrated that this dose resulted in
electron microscopy (TEM) equipped with an X-ray micro- severe liver damage in D2 mice, but not in B6 mice.
analyzer (XMA) revealed that calcium was deposited focally Salonpaa et al. found that in D2 mice COH activity in
in the necrotic sites of the liver. As well as calcium deposi- the liver was increased 3.2-fold 2 days after cerium was
tion, the study indicated that at a dose of 1 mg Y/rat, 75% of administered, and 3 and 4 days after cerium treatment, there
the dose was accumulated in the liver at 7 h postinjection. The was a dramatic decrease, to about 10% of the control value,
authors concluded that the liver is one of the primary target in COH activity. Testosterone 15a-hydroxylase activity
organs of intravenously injected YCl3. was steadily decreased by cerium, and also the Cyp1a-1-
At the enzyme level, Cochran et al. (43) found that mediated 7-ethoxyresorufin O-deethylase activity was
lanthanum stimulated the activity of the succinic dehydro- substantially decreased after a slight initial increase. The
genase system, as did aluminum, a trivalent element; but both sharp decrease in enzymatic activity coincided with
lanthanum and yttrium inhibited adenosine triphosphatase the occurrence of overt liver damage. In the B6 mice,
activity at 103 M. Horecke et al. (85) had previously shown there was only a 1.7-fold increase in COH activity 2 days
that, like polyvalent aluminum and chromium, certain after treatment. Further, no sharp decrease in the enzyme
lanthanides had a promoting effect on the succinic dehydro- activities comparable to those in the D2 mice took place in
genase–cytochrome oxidase system. the B6 mice.

Northern blot analysis showed a 21-fold increase in the of the rare earths by the hepatocytes, resulting in reduced
hepatic Cyp2a-4/5 mRNA in the D2 mice at day 2, whereas hepatic injury.
no increase occurred in the B6 mice. A polymerase chain- Spencer et al. reported that intravenously administered
reaction-mediated analysis method utilizing a unique PstI gadolinium chloride accumulates in Kupffer cells, inhibits
restriction site in the Cyp2a-5 cDNAwas used to differentiate their phagocytic ability, and leads to cell death (48).
between the highly homologous Cyp2a-4 and Cyp2a-5 Gadolinium chloride (GD) has been shown to accumulate
mRNAs. Cerium was found to increase the amount of hepatic in Kupffer cells, and Kupffer cells produce the septic
Cyp2a-4 and Cyp2a-5 mRNA only in the D2 mice. This study response mediators, tumor necrosis factor, and prostaglandin
showed that administration of a liver-damaging dose of E2(PGE2). Roland et al. studied the secretory response to
cerium causes an increase in the expression of Cyp2a-4/5 lipopolysaccharide (LPS) by Kupffer cells isolated from rats
in the liver of D2 mice, but not B6 mice. Salonpaa et al. injected with saline or GD 2 days before Kupffer cell isola-
concluded that the Cyp2a-4/5 complex is regulated in a tion. They found that treatment with GD significantly
different way in D2 and B6 mice, and that some association reduced PGE2 release, and significantly enhanced release
exists between the development of liver damage and COH of tumor necrosis factor. They also studied the effects of
induction. In reviewing these data, Hirano and Suzuki (2) GD on calcium flux in Kupffer cells and determined that
concluded that hepatic injury caused by IV injection of CeCl3 GD inhibited calcium flux and calcium-dependent PGE2
seemed to reduce P450 content and P450-related enzyme synthesis. They concluded that this may explain the previ-
activities in rats and mice. ously reported ability of GD to prevent the mortality of
Palasz and Czekaj summarized data showing that GdCl3 endotoxemia (88).
decreases the total cytochrome P450 content of hepatic Ferreira et al. investigated the effects of gadolinium
microsomes and cytochrome P450-dependent monooxygen- chloride on rat liver oxygen uptake and content of mitochon-
ase activities, and contributes to the reduction of liver injury drial cytochromes. They concluded that gadolinium chloride
caused by certain toxicants including ethanol, CCl4 and induced a reversible decrease in liver oxygen consumption
acetominophen. They concluded that the protective effect that seems to be due to a diminution in the content of
of gadolinium is cytochrome P450 dependent. They pro- mitochondrial cytochromes c1 and c (89).
posed that the possible mechanisms by which gadolinium Ruttinger et al. studied the hepatic microcirculation of rats
ions inhibit cytochrome P450 include stimulation of tumor pretreated with either gadolinium chloride (10 mg/kg) or
necrosis factor (TNF) and IL-6 release from Kupffer cells, saline. The animals treated with gadolinium chloride showed
and inhibition of the release of cytokines that maintain the a significantly lower phagocytic activity of Kupffer cells, and
constitutive expression of cytochrome P450 (72). a pronounced increase of serum cytokine activity. The
Other lanthanides also have a protective effect on liver cells. hepatic microvascular perfusion was characterized by a
Barriault et al. demonstrated that hepatic damage induced by moderate increase in the number of nonperfused sinusoids
phalloidin was significantly decreased by pretreatment with accompanied by a reduction in bile flow. They concluded that
zymosan and Pr(NO3), and that liver cell proliferation was hepatic alterations following Kupffer cell blockade with
increased. They concluded that agents which stimulate or gadolinium chloride may be the consequence of cytokine
depress reticuloendothelial system can protect mice against release as a response to the phagocytic challenge of gadolin-
phalloidin-induced hepatotoxicity and mortality (87). ium chloride aggregates (90).
Hirano and Suzuki (2) also reported that IV injection of Hirano and Suzuki (2) summarized data reporting a wide
Pr(NO3)3 in rats decreased serum very low density lipopro- variety of hepatic biochemical changes following IV injec-
tein (VLDL) and high density lipoprotein (HDL). They tion of rare earth chlorides and nitrates. This information is
theorized that the decrease could be due to decreased hepatic summarized in Table 21.7 (58, 71, 82, 86, 91–99). Hirano
secretions of these lipoproteins. Hirano and Suzaki (2) noted and Suzuki concluded that, with the exception of the effect
that the effect of IV injected Pr(NO3)3 on serum glutamic– on RNA polymerase activity, the rare earths consistently
oxaloacetic and glutamic–pyruvic transaminase activities increased hepatic triglyceride levels and increased leakage of
was dose-dependent. Enzymatic activity increased signifi- hepatic enzymes into the blood.
cantly at doses of 20 mg/kg bw, indicating hepatic injury, Basu et al. (99) administered lanthanum chloride IP to
but decreased at doses above this level. Hirano et al. (44) chicks. They found that lanthanum chloride markedly altered
had previously shown that increasing the dose of YCl3 the antioxidant defense system of the liver. In treated animals
significantly increased the formation of collodial rare earths they observed significant elevation of lipid peroxidation
in blood. Thus, Hirano and Suzuki (2) postulated that the IV with concomitant depression in the activities of glutathione
injected Pr(NO3)3 was taken up by Kupffer cells, rather than reductase, and glutathione peroxidase and the levels of
by hepatocytes, at doses higher than a maximum lethality. reduced and oxidized glutathione. L-Cysteine hydrochloride
They further concluded that the uptake of collodial rare supplementation in treated animals could partially prevent
earths by the Kupffer cells may have reduced the uptake the alterations produced by toxic doses of lanthanum.

Table 21.7. Hepatic and Liver-Associated Biochemical Changes Following IV Injection of Rare Earth (2) a
Effect Compound Dose Animal References
CeCl3, Ce(NO3)3 2–10 Ck/kg
La(NO3)3 3–10 mg La/kg
s-GOT, s-GPT" YCL3 1 mg Y/rat Rat 44, 70, 71
3–40 mg Pr(NO3)3/kg Rat, mouse 71–73
s-GOT, s-GPT" Pr(NO3)3
s-SDH" La(NO3)3 3–10 mg RE/kg Rat 71
CeCl3 1.5–3 mg Ce/kg
PrCl3 3 mg Pr/kg
LaCl3 0.75 mg La/kg
YCl3 9 mg Y/kg
TbCl3 35 mg Tb/kg
HoCl3 40 mg Ho/kg
s-OCT" YbCl3 60 mg Yb/kg Rat 57, 74
s-FFA" Pr(NO3)3 10 mg Pr(NO3)3/kg Rat 75
s-VLD, s-HDL# Pr(NO3)3 10 mg Pr(NO3)3/kg Rat 76
Triglyceride (liver)" CeCl3 10 mg CeCl3/kg Rat 77
7 mg Pr/kg
10–20 mg
Triglyceride (liver)" Pr(NO3)3 Pr(NO3)3/kg Rat, mouse 71, 73, 75
ATP# CeCl3 10 mg CeCl3/kg Rat 77
P450, AH, AD# Pr(NO3)3 7 mg Pr/kg Rat 71
COH, EROD, Cyp2a-4/5-mRNA"# 2 mg CeCl3/kg
CeCl3 0.5–2 mg Ce/kg Mouse 66, 70
RNA polymerase I# Nd(NO3)3 35 mmol/kg Rat 78
RNA polymerase II" Er(NO3)3 35 mmol/kg Rat 78
RNA polymerase II# Sm(NO3)3 35 mmol/kg Rat 78
LPO" LaCl3 250 mg LaCl3/kg Chick (lip) 79
GR# LaCl3 250 mg LaCl3/kg Chick (lip) 79
These studies indicate that cerium, and possibly other rare earths, are hepatotoxic agents.

Spencer et al. showed that intravenous administration of fluorides, 17% C) had a less severe reaction. The most
gadolinium chloride in rats resulted in necrosis to the liver prominent feature was a cellular eosinophilia, and although
and spleen (48). most of the dust was trapped within focal atelectatic areas, no
substantial chronic cellular reaction or fibrosis occurred Lung. Chronic inhalation of mixtures of lantha- around these deposits (68).
nides high in fluorides (65% fluorides, 10% oxides, 31% C), Ball and Van Gelder (101) exposed mice to gadolinium
with a calculated particle size of 1–2 mm, by guinea pigs at oxide aerosol for 20–120 days to evaluate the chronic effects
massive concentrations of 200–300 million particles per of the exposure. They found that there was a trend toward
cubic foot daily for 3 years showed histological changes shorter lifespans in exposed mice. Further, they observed an
consisting of focal hypertrophic emphysema, regional accumulation of macrophages in the lung, with focal areas of
bronchiolar stricturing, and subacute chemical bronchitis. interstitial thickening around macrophages, particularly for
Although pigment was focally retained, no fibrosis or gran- mice exposed for 120 days. Some macrophages containing
ulomatosis developed (100). By comparison, guinea pigs gadolinium oxide were undergoing degeneration, evidenced
exposed to the high oxide mixture (26.4% oxide, 39.6% by pyknosis and karyolysis. There was little tendency toward

pulmonary fibrosis, but there was calcification in the region in rats. Both compounds were shown to cause pneumonitis
of the alveolar basement membrane and elastic laminae of and acute inflammation in lung tissue.
small pulmonary vessels. In a study that paralleled those of Hirano et al. (52) and
The rare earth metals cerium, lanthanum, and neodymium Suzuki et al. (53), Yoneda et al. (54) investigated the effects
were each evaluated in an in vitro cytotoxicity assay system of gadonlinium chloride when intratracheally instilled in rat
using adult male rat pulmonary alveolar macrophages (102). lung. As described more fully in Section Yoneda et al.
Both the soluble chlorides and the insoluble metal oxides found that pulmonary clearance of Gd was slow, with an
were studied. For comparison purposes, the cytotoxicities of estimated biological half-life of 136 days. They found that
cadmium chloride and cadmium oxide were also quantified calcium content in BALF increased more rapidly than did
in this test system. In general, regardless of the cytotoxicity other toxicological indices such as LDH activity, protein
parameter measured, that is, cell viability, lysosomal enzyme content, and inflammatory cell counts. Gd also showed acute
leakage, or changes in cell surface morphology, cadmium lung toxicity. Their findings were very similar to those for
was more toxic to these cells than were the rare earth metals. YCl3 and LaCl3. Thus it is clear that, in animals, inhalation or
Of the rare earth metals studied, only lanthanum chloride intratracheal exposure to rare earths causes acute pneumoni-
(LC50 ¼ 52 mM), cerium chloride (LC50 ¼ 29 mM), and neo- tis and inflammation in lung tissue.
dymium oxide (LC50 ¼ 101 mM) displayed significant cyto- Spencer et al. showed that gadolinium chloride adminis-
toxicity in this test system. Cadmium chloride exhibited an tered intravenously to rats resulted in mineral deposition in
LC50 value of 28 mM, whereas the LC50 value for cadmium the capillary beds, particularly in the lung and kidney (48).
oxide was 15 mM. These findings support the conclusions of
Haley (1) that rare earth metal fumes should be considered as Skin. Of the 11 lanthanides tested by Haley et al.,
cytotoxic to lung tissue. only erbium produced irritation to the intact rabbit skin;
As discussed in detail in Section, Hirano et al. (52) however, all uniformly and severely irritated abraded skin,
investigated the metabolic behavior and pulmonary toxicity producing within a day erythema and edema (maximum
of intratracheally administered yttrium chloride in male score), with scars 25–35 mm in diameter and complete
Wistar rats. Examination of the lung tissue showed that healing only after 45 days, according to the Draize procedure.
rats developed granulomatous lesions. Yttrium was observed Skin reactions to intradermal injection of seven lanthanides
as black, granular inclusions in alveolar macrophages. (Pr, Nd, Eu, Dy, Ho, Er, and Lu) as the chlorides into guinea
Transmission electron microscopy and X-ray microanalysis pigs resulted in the formation of nodules 2 mm in diameter,
suggested that Y was localized in lysosomes of alveolar and which contained crystalline deposits (103). These deposits,
interstitial macrophages, and basement membranes. resulting from 0.05 to 5 mg lanthanide administration, con-
Comparative dose–effect profiles of lactate dehydrogenase tained calcium (but no iron) and were surrounded by histio-
activity in BALF supernatant revealed that 1 mol of YCl3 is cytes and foreign-body giant cells with fibroblasts and
equivalent to about 0.33 mol of cadmium compounds and granulation tissue extending into the area. No decrease in
about 3 mol of zinc oxide in the potency for acute pulmonary nodule size or indication of any resorption of the crystalline
toxicity. On the basis of this study, Suzuki et al. (53) con- deposit occurred within the 45 day observation period (35–40).
cluded that Y showed acute toxicity comparable to copper In rabbits, a topical application of a suspension of
when the metal was administered intratracheally. 500 mg/mL produced mild irritation of the skin and eye
Suzuki et al. (53) investigated the distribution and health mucosa (46).
effects of lanthanum chloride (LaCl3) intratracheally instilled
in male Wistar rats. This study is discussed in more detail in Spleen. Stineman et al. (80) observed hypertro-
Section and parallels the study described above. The phy, reticuloendothelial hyperplasia, and hyperactive lym-
authors used lactate dehydrogenase (LDH), b-glucuronidase phoid follicles in the spleens of mice who had been treated
activities, and P content in the supernatant fraction of BALF as with cerium, either orally or subcutaneously. As summarized
indices for cell lysis, secretion of lysosomal enzymes, and by Hirano and Suzuki (2), Marciniak and Baltrukiewicz (94)
surfactant content, respectively. This represented acute reported that in mice LaCl3 and CeCl3 increased vascular
inflammatory responses in the bronchoalveolar tissues. permeability of the spleen.
They found that LDH and b-glucuronidase activities Yttrium chloride solution was administered IV to male
increased significantly at doses higher than 1 mg/rat. P content Wistar rats at doses of 0.1, 0.2, 0.5, 1, and 2 mg Y/rat to
increased significantly at doses of 0.5 mg/rat. Using LDH evaluate its metabolism and toxicity. The study demonstrated
activity as an indicator of acute toxicity, the authors compared that some plasma calcium was translocated to the collodial
La and Y. At a dose of 10 mg metal/rat, both Y and La induced material and plasma calcium concentration was increased
1.8-fold increases in LDH activity. Thus, the authors con- transiently following injection of YCl3. The authors theo-
cluded that La and Y showed comparable acute pulmonary rized that the increase in calcium concentration was due to
toxicity when their chloride salts were intratracheally instilled resorption of bone. At doses of 1 mg Y/rat, the calcium

content of the spleen increased over 100-fold. Gross obser- Waring and Watling (105) reported the case of a movie
vation of the tissues indicated the presence of white blotchy projectionist with approximately 25 years of occupational
necroses in the spleen. Examination by transmission electron exposure to carbon-arc-lamp fumes. The carbon-arc deposits
microscopy equipped with an X-ray microanalyzer revealed were visible in histological sections as small granules within
that calcium was deposited focally in the necrotic sites of the macrophages of the tracheobronchial lymph nodes and
spleen. In addition to calcium deposition, the study indicated hepatic Kupffer cells. Electron microprobe analysis by
that at a dose of 1 mg Y/rat, 20% of the dose was accumulated energy-dispersive analysis of X rays showed the granules
in the spleen at 7 h postinjection. The authors concluded that were composed of the rare earth elements cerium, lanthanum,
the spleen is one of the primary target organs of IV injected and neodymium, which are the major constituents of carbon-
YCl3 (58). arc rods. Tissue concentrations, as determined by inductively
Spencer et al. showed that intravenous administration of coupled plasma spectroscopy, were approximately 250–2000
gadolinium chloride in rats resulted in necrosis to the liver times those of unexposed controls, and there was evidence of
and spleen. (48). their redistribution throughout the reticuloendothelial sys-
tem. There were no respiratory symptoms or radiographic or
histological pulmonary changes attributable to the progres-
1.4.2 Human Experience
sive accumulation of the rare earth elements; as such, the General Information. The pulmonary toxicity of patient cannot be considered to have suffered from pneumo-
inhaled lanthanides has been the subject of debate. The coniosis. However, the authors reviewed 21 published cases
relative contributions of radioactive versus stable elements of rare earth pneumoconiosis, mainly in photoengravers
in the development of lanthanide-associated progressive pul- exposed to carbon-arc fumes, and concluded that rare
monary interstitial fibrosis has been questioned. Haley (1) earth oxides are not innocuous dusts.
examined the epidemiological and experimental data and McDonald et al. (106) described a case of rare earth
concluded that significant pathogenic potential of inhaled pneumoconiosis in a 68 year old male patient with a 35
lanthanides exists and is related to the type and physicochem- year history of optical lens grinding, which is associated with
ical form of the material inhaled and also to the dose and exposure to cerium oxide. The patient had ceased working as
duration of exposure. Although contamination of the dust of a lens grinder 13 years prior to seeking medical treatment.
lanthanides with radioactive materials may accelerate and The patient initially presented with progressive dyspnea.
enhance the pathological response, depending on the form Chest X rays revealed an interstitial lung pattern that was
and dose of radioactivity encountered, there is little evidence consistent with fibrosis. Open-lung biopsy showed interstitial
to suggest that the level of radioactive contamination of fibrosis histologically indistinguishable from usual intersti-
occupationally encountered lanthanide dusts is sufficient to tial pneumonitis. Numerous birefringent particulates were
be included as a risk factor for pulmonary disease. Haley (1) observed in the interstitium using polarized light microscopy.
concluded that the pulmonary syndrome induced by stable Scanning electron microscopy with energy-dispersive X-ray
rare earths includes progressive pulmonary fibrosis and analysis demonstrated numerous particulate deposits in the
should not be referred to as “benign pneumoconiosis.” lung, the majority of which contained cerium alone or in
Hirano and Suzuki (2) concluded that chronic exposure to combination with other elements. This case supports Haley’s
rare earth dusts probably causes pneumoconiosis in humans. conclusion (1) that stable rare earths cause pneumoconiosis.
J. Pairon et al. described the case of a 58 year old patient Clinical Cases. A case of rare earth pneumoconi- previously exposed to asbestos and rare earth dusts. He
osis was described by Sabbioni et al. (104). A man working in had worked as a plumber and roofer from 1935 to 1959.
a lithographic laboratory as a photoengraver and exposed to Then he had been employed in a crystal manufacture as a
the smoke of cored carbon-arc lamps over a period of 46 smelter (1959–1963), polisher (1963–1967), truck driver
years developed an interstitial pneumoconiosis. Neutron (1967–1975), and a painter (1976–1980). He also reported
activation analysis of eight rare earths (La, Ce, Nd, Sm, extraprofessional activities as a movie projectionist between
Eu, Tb, Yb, and Lu) in lung and lymph node biopsies showed 1951 and 1964. He had a history of smoking, but had not
an abnormally high amount of these elements in comparison smoked in 8 years. The patient was first seen in 1980 for
to the corresponding values from 11 autopsied unexposed recent onset of dyspnea. For diagnostic purposes, mineral-
subjects. The estimated radiological dose due to the inhala- ogical analysis was performed in bronchoalveolar lavage
tion of natural thorium, as calculated from NAA of thorium fluid and lung tissue. No significant retention of asbestos was
in the biopsies, tends to exclude the effect of ionizing demonstrated in lung tissue. Particles containing cerium,
radiation in the pathogenesis of lung fibrosis. The findings lanthanum, and phosphorus were identified in alveolar
strongly suggest that a relationship exists between the macrophages in bronchoalveolar lavage fluid, and cerium
pneumoconiosis diagnosed and the occupational exposure containing particles accounted for 70% of the particles
to rare earth dusts. observed in the lung tissue. Ultrastructural analysis of

lung tissue revealed the presence of particles containing lanthanum in lung tissue among smelter workers as com-
cerium and phosphorus in interstitial macrophages and elas- pared to controls. Of the smelters, nearly 33% died from
tic fibers. This study demonstrates the biopersistence of rare malignancies (approximately 10% of these from respiratory
earth particles in the respiratory tract, both in alveolar and cancer) and approximately 45% from cardiovascular disease.
interstitial spaces. The study confirmed that inhaled cerium In the control group nearly 80% died from cardiovascular
oxide-containing particles can be metabolized in humans, diseases, but no malignancies were present. In lung tissues
leading to the formation of insoluble cerium phosphate (107). the lanthanum did not decline with time after exposure had
ended, indicating a long biologic half-life. The causes of Acute toxicity. Considerable study has been con- death could not be related to any single factor (109).
ducted in the past on the anticoagulant action of the lantha- Samarium-153 ethylenediaminetetramethylene phospho-
nides on blood for the prevention of thrombosis. Neodymium nic acid (EDTMP) was developed as a radiopharmaceutical
salts injected IV in total dosages of 250–500 mg have been to treat metastatic bone cancer pain. In this study 2 mCi of
reported to prolong the coagulation time of human [153 Sm ]EDTMP was injected IV into five male patients.
blood (103) for 6 h; no ill effects were noted, but oral or The study showed that the chelate was cleared rapidly, with
subcutaneous administration was without anticoagulant only 5.17% of the activity remaining at 2 h postinjection and
effect. Beaser et al. (108), after having confirmed in rabbits 2.09% of the activity remaining at 4 h postinjection. The
the innocuousness of small anticoagulant doses of neodym- complex clears through the kidneys, and approximately 50%
ium (10 mg/kg), critically evaluated the anticoagulant effects of the injected dose is excreted into the urine in 8 h (23).
of neodymium, lanthanum, and cerium in 18 patients with Chelates such as Gd(DTPA), which is used as an NMR
single and repeated daily doses of 3–12.5 mg/kg. All contrast agent, is rapidly cleared with a plasma half-life of
the lanthanides tested increased the clotting time of 20 min, and within 3 h over 80% is excreted in urine (3).
blood to the point of incoagulability, which persisted in
diminishing degree for 8 h. The toxic reactions of chills, Epidemiology Studies. Weifang et al. (110) com-
fever, headache, muscle pains, abdominal cramps, hemo- pared the incidence of arteriosclerosis in individuals living in
globinemia, and hemoglobinuria were such as to exclude three different regions of China. The three regions were
the use of lanthanides as anticoagulant agents. Determina- described as areas A, B, and C. In areas A and B, the soil
tion of blood levels of neodymium showed that it was still contains 40–90% exchange-state rare earth elements (REEs)
present in considerable amounts during decline of the and there were numerous places where rare earths were
anticoagulant effect. Neodymium was not found in the mined. In area A the concentration of REE in drinking
urine of the treated patients, despite repeated analysis; water averaged 1.9 mg/L water. In area B the concentration
available evidence suggested removal by the reticuloendo- of REE in drinking water averaged 47.0 mg/L water. In area
thelial system of the liver and spleen. Local thrombophle- C, the soil contained less than 25% REE and there were no
bitis was observed in humans, and also reported in dogs, mining locations. In area C the concentration of REE in
after injection of the lanthanide chloride. Hemoglobinemia drinking water averaged only 0.92 mg/L water. The authors
was unexpected; it had not been seen previously in animals calculated the daily REE intake for each of the areas.
and does not occur when the lanthanides are added to blood Villagers in area A were estimated to take in 16 times
in vitro. These findings provide guideposts in the medical more REE than area C villagers. Area B villagers were
control of exposures to lanthanides. Blood serum hemo- estimated to take in 45 times more REE than area C villagers.
globin values would be the most sensitive indicator; values Villagers aged 25–45 years with no history of angina or
of 9% would indicate overexposure. Initial appearance of hypertension were selected from each geographic area. They
or repeated headache, malaise, chills and fever, and nausea were examined using an ophthalmofunduscope, and the
would be indicative symptoms. extent of arteriosclerosis was determined. The arteriosclero-
sis of the fundus aculi was graded according to Scheie’s Chronic and subchronic toxicity. As discussed in method. The authors reported a significantly higher number
Section, Haley (1, 35–40) and Hirano and Suzuki (2) of arteriosclerotic villagers in areas A and B than in area C.
concluded that chronic exposure to rare earth dusts probably As all the villagers were poor and did not have access to a
causes pneumoconiosis in humans. high lipid diet, which is a known risk factor for arterioscle-
rosis, the authors postulated that intake of REE could be Pharmacokinetics, metabolism, and mechanics. responsible for the increased incidence of arteriosclerosis.
Lung, liver, and kidney tissue concentrations of lanthanum
from 66 deceased copper smelter workers have been com- Yttrium. Although yttrium (see the first sections
pared with 14 controls. Samples were taken in connection for each compounds for CAS number, etc.) reacts chemically
with ordinary autopsies at the local hospital. Neutron activa- in a manner similar to La and is included with the lanthanides,
tion analysis was used. There was a twofold increase of early studies indicated that toxicologically it might differ

sufficiently to single it out from the lanthanides. The yttrium Soviet Union publication (111) that Y2O3, on intratracheal
citrate–chloride complex was reported by Graca et al. (41), administration, resulted in severe lung damage (15). The
for example, to be the most acutely toxic to both guinea pigs ACGIH (113) also cites a study by Tebrock and Machle (114)
and mice by the intraperitoneal route of all the lanthanides in which exposure to a mixture of yttrium, europium,
(with LD50 values of 42 and 78 mg/kg, respectively, com- and vanadate produced irritation to the eyes and respiratory
pared with a close member in the series, cerium, with tract as a result of vanadium content, but the concentration
respective LD50 values of 82 and 150 mg/kg). Further, in a of yttrium was 1.4 mg/m3. The OSHA PEL is also
comparative investigation of the oxides of yttrium, cerium, 1 mg/m3 (115).
and neodymium in rats intratracheally administered at a dose No standards have been recommended for any of the other
of 50 mg (0.222, 0.152, and 0.148 mM, respectively), Y2O3 lanthanides because either suitable data for setting a stan-
showed the most pronounced changes in the lung of the three dard, such as inhalation studies, or studies on individual
oxides tested (111). At 8 months, in the lung tissue in which lanthanides are lacking (15). However, because of the accu-
Y2O3 was present, characteristic granulomatous nodules mulating evidence of induction of fibrosis with the lantha-
developed, consisting of crystalline deposits of the oxide nides and their expanding use, the exposure should probably
and cellular elements. Nodules in the peribronchial tissue be limited to 1 mg/m3.
compressed and deformed several bronchi; the surrounding
lung areas were emphysematous, the interalveolar walls were
1.6 Studies on Environmental Impact
thin and sclerotic, and the alveolar cavities dilated. In con-
trast, Ce2O3 did not elicit serious changes, and produced Volokh et al. (116) reported on a study of REO pollution from
neither diffuse nor nodular fibrotic processes. Although a phosphorus fertilizer production facility in Russia. They
Nd2O3 granulomas resembled those induced by Y2O3, studied air-pollution sediment that fell on soil or snow,
their further development differed. Their characteristic uptake into agricultural plants, and human uptake as indi-
was a very poor formation of connective-tissue fibers, cated by hair samples from plant operators and local resi-
which were extremely weak around the granulomas, and dents. Samples were analyzed using X-ray fluorescence and
sclerosis of the interalveolar walls was only moderate. It was neutron activation analysis. Results are reported for Sc, Cr,
concluded that, regardless of the similarity of their chemical As, Se, Br, Sb, La, Ce, Sm, and Eu. They concluded that these
and physical properties, Y2O3 exhibited specific toxicologic elements were emitted from the plant in the form of a
actions that were the most severe of the three oxides studied. phosphogypsum dust with a diameter of 8 mm. Abnormally
A still further toxicological difference is the lesser degree high concentrations were measured in soil and snow within
of skeletal deposition. Yttrium chloride, YCl3, administered 1 km of the plant and extended up to a radius of 8 km that was
to rats IP on alternate days, for as many as 83 injections influenced by prevailing wind direction. Apples, beets, pota-
totaling 936 mg, did not accumulate large amounts of yttrium toes, and carrots showed an increased storage of ytterbium
in femoral bone (112). Yttrium never exceeded 330 ppm of and europium. Hair samples of plant employees demon-
bone ash, and after it had been deposited to the extent of strated storage of Sm, La, and Ce. Resident children’s hair
150–200 ppm (corresponding to about 50 mg injected YCl3), stored La, Sm, and Ce, but in lesser amounts than did the hair
further accumulation proceeded at a very slow rate. With age, of plant workers. No values from a representative control
the ratio of yttrium concentration in spongy to compact bone group were provided for comparison, nor were any expres-
approached 1. By comparison, skeletal deposition amounted sions regarding toxicity or adverse effects presented.
to 20% for lanthanum, ranging to 70% for lutetium (Lu). Taylor reviewed literature pertaining to rare earth elements
Conversely, Hirano and Suzuki et al. (52–54) more in soil and plant systems. The review covers REEs in primary
recently studied the effects of yttrium chloride, lanthanum and secondary soil minerals, concentrations in surface soils,
chloride, and gadolinium chloride when intratracheally factors influencing adsorption, solubility and transport in
instilled in rat lung. The toxicities and action mechanisms soils, including weathering and transformation or rare earth
of all three compounds were similar, which does not support minerals, and vertical distribution in soil profiles. He also
the previous conclusion that Y differs toxicologically from reviewed and discussed concentration, distribution and local-
the other lanthanides. ization of REEs in plants and plant organs, soil–plant rela-
tionships and interactions, effects on plant growth and crop
production and their importance in plant physiology and
1.5 Standards, Regulations, or Guidelines of Exposure
biochemistry. In reviewing environmental considerations, he
ATLV (threshold level value) of 5 mg/m3 was recommended stated that in China widespread use of REEs in agriculture
by the ACGIH TLV Committee in 1960 for yttrium, the only has been observed as a potential environmental problem, but
correlative member of the lanthanides for which a limit has that the amounts applied annually as seed dressings or spray
been set. This limit was revised downward to 1 mg/m3 in on growing crops are small compared to the total amounts
1964 when the ACGIH TLV Committee learned from a present in soil. He noted that REEs supplied as fertilizers are

much more soluble and reactive than the average soil pool. Applications of Rare Earth Elements, American Chemical
He concluded that the use of REEs in Chinese agriculture Society, Washington, DC, 1981, pp. 167–175.
does not seem to be of great environmental concern at 13. J. R. McColl and F. C. Palilla, Use of rare earths in television
currently recommended application levels. He noted that and cathode ray phosphors. In K. A. Gschneidner, ed.,
REEs used as catalysts in petroleum-cracking and their Industrial Applications of Rare Earth Elements, American
products in oil-fired power plants and oil refineries are Chemical Society, Washington, DC, 1981, pp. 177–193.
other sources of REE pollution. This type of pollution has 14. K. A. Gschneidner Jr. and L. Eyring, eds., Handbook on the
resulted in marine sediments on the coast of California being Physics and Chemistry of Rare Earths, Vols. 1–41, Elsevier,
Amsterdam, 2011.
polluted by REEs. He postulated this type of pollution may be
present in other parts of the world as well. He reviewed a 2004 15. H. E. Stokinger, In G. Clayton and F. Clayton, eds., Patty’s
Industrial Hygiene and Toxicology, 3rd ed., Vol. 2A, Wiley,
study by Taylor which showed that atmospheric deposition of
New York, 1981, pp. 1493–2060.
all REEs over southern Sweden decreased by a factor
16. M. Veith, New synthetic routes to nano-composites with
between 2.5 and 2.8 between 1972/1975 and 1997/2000.
ceramic particles, using lanthanide compounds, J. Sol Gel
He concluded that REE pollution is unlikely to cause any Sci. Technol. 46, 291–298 (2008).
large scale environmental problems in the near future (117).
17. G. H. Haertling, PLZT electrooptic ceramics and devices.
In K. A. Gschneidner, ed., Industrial Applications of Rare
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