JOURNAL OF APPLIED TOXICOLOGY, VOL.

13(3), 217-224 (1993)

REVIEW

The Toxicology of Chromium with Respect to its

Chemical Speciation: a Review

Sidney A. Katz
Rutgers University, Camden, NJ 08102-1205, USA

Harry Salem
Chemical Research Development. and Engineering Centre. Toxicology Division, Aberdeen Proving Ground. M D
21010-5423. USA

Key words: chromium; toxicology; review

The properties of trivalent and hexavalent chromium are reviewed with respect to acute and chronic oral
toxicity, dermal toxicity, systemic toxicity, toxicokinetics, cytotoxicity, genotoxicity and carcinogenicity. The
hexavalent chromium compounds appear to be 10-100 times more toxic than the trivalent chromium
compounds when both are administered by the oral route. Dermal irritancy and allergy are more frequently
caused by contact with soluble hexavalent chromium compounds. The cytotoxicity of soluble and insoluble
hexavalent chromium compounds to fibroblasts is 100-1000 times greater than that demonstrated by trivalent
chromium compounds. In short-term tests, the hexavalent chromium compounds demonstrated genotoxic
effects four times more frequently than did the trivalent chromium compounds. Carcinogenicity appears to
be associated with the inhalation of the less soluble/insoluble hexavalent chromium compounds. The toxicology
of chromium does not reside with the elemental form. It varies greatly among a wide variety of very different
chromium compounds. Oxidation state and solubility are particularly important factors in considering the
toxicity of chromium with respect to its chemical speciation.

According to Beyersmann,‘ direct DNA damage is

INTRODUCTION
The toxicities of many chromium compounds have
been established both with epidemiological studiesl
and with animal studies.’ Oxidation state is a critical
factor often overlooked in evaluating the activities of
chromium compounds in such studies. Hexavalent
chromium compounds are, in general, more toxic
than are the trivalent chromium compounds. This
observation is frequently attributed to the stronger
oxidizing power and the higher membrane transport
of the former. Tissue damage, irritative lesions of the
skin and respiratory tract and cell-mediated allergic
reactions caused by exposure to hexavalent chromium
are well documented.’ Some hexavalent chromium
compounds also induce tumors in rodents at the
site of injection. Of the chromium carcinogens, the
insoluble hexavalent chromium compounds appear to
be the most potent in experimental animals. In contrast,
soluble and insoluble trivalent chromium compounds
are usually not active as carcinogens. Cytotoxic and
genotoxic events within the cell appear to involve the
reduction of hexavalent chromium to the trivalent
state after penetration of the cell. Popper and WoldrichJ
proposed that the cytotoxicity of chromates to pneumo-
cytes was caused by oxygen radicals possibly formed
during an oxidative process, and Susa et al.s found
that the cytotoxicity of chromates to HeLa cells
(originating from human cervical carcinoma) was
decreased when hexavalent chromium was reduced to
the trivalent state with biologically occurring thiols.
Chromate genotoxicity may involve two mechanisms.
caused by an intermediate pentavalent chromium
species, and trivalent chromium, the end-product
from the biological reduction of chromates, causes
DNA-protein cross-links. Bronzetti and coworker^^.^
appear to favor a genotoxic mechanism involving the
induction of DNA breaks by the oxidizing activity of
hexavalent chromium and the subsequent binding of
the resulting trivalent chromium.
Since biological reductions usually involve only one
or, at most, two electrons, intermediate pentavalent
and tetravalent chromium species are involved in the
reduction to the trivalent state. The lability of these
intermediate species facilitates the attachment of bio-
ligands during the reduction process. This sometimes
stabilizes some of these intermediate oxidation states.
In addition to its classification as a toxic element,
some compounds of chromium are essential micronutri-
ents.” Dietary deficiency of chromium has been associ-
ated with impaired growth and fertility, a diabetic-
like state connected to impaired glucose tolerance,
hyperinsulinemia, hypercholesterolemia and enhanced
atherogenesis. Human chromium deficiency has been
indisputably proved in protein-calorie malnutrition and
in patients receiving total parenteral nutrition (TPN)
devoid of chromium supplements. The symptoms of
chromium deficiency were alleviated by supplementing
the TPN solution with 12 kg of chromium(II1) chlor-
ide. Following such supplementation. the blood
glucose level dropped from 450 to 150 mg dl-’ for
an accident victim receiving TPN. In experimental
animals, chromium deficiency decreased their life-
spans. I I

0260-437X/93/030217-0N$OY .OO Received 23 September I992

0 1993 by John Wiley & Sons. Ltd. Accepred (revised) 10 December I992
218 S. A . KATZ A N D H . SALEM

Table 1. Standard reduction potentials" Table 2. Solubilities of hexavalent chromium compounds at

20-30°C
Half-cell reaction Change
Solubility
Cr,O:- + H,O + 2 e- -+ 2Cr02- + 2 H+ 0.55 VI to v Compound (mol kg - l water) K,,"
Cr,O:- + 6 H ' + 4 e + 2Cr0, + 3 H,O 0.95 VI to IV
Cr,O:- + 14H' + 6e-+2Cr3+ + 7H,O 1.38 VI to 111 (NH,),CrO, 2.4
Cr0:- + 4 H' + e - + CrO, + 2H,O 1.34 v to IV (NH,),Cr,07 1.4
CrOz- + 8 H + + 2 e - - + C r 3 + +4H,O 1.72 v to 111 Li,CrO, 8.7
CrO, + 4 Hi + e -+ Cr3+ + 2 H,O 2.10 IV to 111 Li,Cr,O, 5.7
Cr3+ + e- + Cr2' -0.42 111 to II Na,CrO, 5.2
Cr3+ + 3 e- + Cr -0.74 Ill to 0 Na,Cr,0,~2H20 9.7
Cr2+ + 2 e- -+ Cr -0.90 II to 0 K,CrO, 3.3
Cr0:- + 4 H,O + 3 e - -+ [Cr(OH),l- + 4 OH -0.72 VI to 111 KzCrzO7 0.44
Cr0:- + 4 H,O + 3 e - -+ Cr(OH), + 5 OH - -0.11 VI to 111 Rb,CrO, 2.6
[Cr(OH),]- + 3 e -+ Cr + 4 OH- -1.33 111 to 0 R b,Cr,O, 0.15
Cr(OH), + 3 e- -+ Cr + 3 OH -1.33 111 to 0 Cs,CrO, 2.2
MgCr04.7H,0 5.2
CaCrO,.PH,O 0.83
CaCrO, 0.00071
That chromium is both a chemical carcinogen and SrCrO, 0.0059 2.2 x 10.-5-
an essential micronutrient appears to be paradoxical. BaCrO, 0.000017 1.8 x 10-lo
PbCrO, 0.00000018 b
Resolution of the paradox lies with the chemical
Ag,CrO, 0.0000060
speciation of the chromium. The essentiality of chro- 0.000019
AgzCrz07
mium is associated with the glucose tolerance factor, TI,CrO, 0.000038
a complex of trivalent chromium. The carcinogenicity HgzCrO, Very slightly soluble 2.0 x
of chromium, on the other hand, appears to reside HgCrO, Slightly soluble
with some of the hexavalent chromium compounds HgCrzO, Insolubled
of limited solubility. Soluble hexavalent chromium CoCrO, Insoluble
compounds are rapidly taken up via the sulfate trans- CuCrO, 3.6 x
port systems of cells and are subsequently reduced CuCr,O,. 2H,O Very soluble
intracellularly to trivalent chromium. Whether the ZnCrO, Insoluble
ZnCr,07.3H,0 Soluble
resulting trivalent chromium or the pentavalentketra-
valent intermediate is the ultimate carcinogen has not " T h e K,, for SrCrO, is the product of the equilibrium molar
been resolved. These possibilities as they relate to concentrations of the strontium ion and of the chromate ion
chemical form and solubility must be considered in at a constant temperature, usually 298 K, i.e. K,, = [Sr2+l
the toxicology of chromium. [CrO:-]. The other K,, values are similarly defined.
Reported values range from 2.8 x l o - " t o 1.8 x lo-',
Reported values range from 9.0 x 10 l 2 t o 1.1 x
Soluble, molarity of saturated solution > 1 x 10 l ; insoluble,
CHEMICAL AND PHYSICAL PROPERTIES molarity of saturated solution < 1 x

Elemental chromium was first prepared and charac-

terized by Louis Vanquelin in 1793. Its name reflects
the many colors of its compounds. In compounds,
chromium demonstrates oxidation numbers +2, + 3,
+4, +5 and +6. Of these, the compounds of trivalent
chromium are the most stable and most abundant.
The hexavalent chromium compounds are well known
as laboratory reagents and as manufacturing inter-
mediates. The standard potentials for the
oxidation-reduction equilibria among the valence states
are summarized in Table 1.
The ground-state electron configuration for the
chromium atom is 1s' 2s2ph 3s23ph3d' 4s2. The com-
pounds of divalent chromium are usually blue and
they demonstrate basic properties. Trivalent chromium
compounds range from purple to green in color and
are amphoteric. The hexavalent chromium compounds
demonstrate acidic properties and their colors range
from yellow to orange.
The acid anhydride C r 0 3 and acid chloride CrO2CI2,
and a wide variety of metal chromates MCrO, and
metal dichromates MCr207. are typical hexavalent
chromium compounds. The chromate-dichromate
equilibrium was evaluated by Cresser and Hargitt'? as
2 HCrO; e Cr20$- + H 2 0
K,, = [Cr20$-]/[HCr0;]2 = 33
and Neuss and Rieman', have evaluated the acid
functions
H,CrO, e H + + HCr0; K , , = 1.8 X lo-'
HCrO; e H f + Cr0;- Kn2= 3.2 X
The solubility equilibria of hexavalent chromium com-
pounds are complex and highly pH dependent. Rep-
resentative solubility data from the reference
handbooks's-'x are summarized in Table 2.
The trivalent state of chromium is the most thermo-
dynamically stable, and many compounds of trivalent
chromium have been prepared and characterized. The
high stability of the half-filled tZg level of the d3
configuration in octahedral geometry is responsible for
the kinetic inertness of many of these compounds.
The violet hexaquo chromium(II1) ion, [ C T ( H ~ O ) ~ ] ~ + ,
is virtually inert to water exchange. Its exchange constant
is only 3.5 X s-I, which is equivalent to a half-life
 CHROMIUM TOXICOLOGY WITH RESPECT TO CHEMICAL SPECIATlON
Table 3. Solubilities of trivalent chromium compounds at
20-30°C
Solubility
Compound (mol kg water) KSP
Cr(CH30C00)3.H 2 0 Soluble
IC~(H~O)E.ICI~ 2.2
[Cr(H,O)CI,]CI .2H20 2.2
CdOH), 1.2 X 10
Cr(NO,),. 9H20 5.2
CrPO, 2.4 x 10-23
CrK(SO,),. 12H20 0.44
CrJSO,),. 18H20 3.1
of > 2 days. While aqueous solutions containing the
aquo complexes of trivalent chromium ([Cr(H20)l3+or
[Cr(H,O), (OH)]' are violet, those containing the
+
chloro [CrCI]'+ ... [CrClJ- and sulfato [Cr(SO,)]'
.. . [Cr(SO,),]'- complexes are green. The hexa-aquo
complex of trivalent chromium exhibits a pK of 4.
Heating, aging or raising the pH of aqueous solutions
of trivalent chromium compounds frequently causes
hydrolysis followed by OH bridging to form polymeric
species of limited solubility. The amphoterism of trivalent
chromium is responsible for the resolubilization of these
polymers at very high pH. Simple inorganic complexes
of trivalent chromium are only slightly soluble in the
pH 4-12 range, but some complexes of trivalent chro-
mium with 'bio-ligands' are soluble at physiological pH.
The solubilities of some trivalent chromium compounds
are presented in Table 3."''
Most divalent chromium compounds are vulnerable
to air oxidation. Consequently, they are unstable in
all but the most anaerobic systems. The pentavalent and
tetravalent chromium compounds are also unstable.
Electron precession resonance (EPR) spectroscopy
has shown stabilization of the pentavalent complexes
formed from the reduction of hexavalent chromium
with various biological thiols prior to DNA binding. I 9
Tetravalent chromium is stable as the dioxide CrO,
and it has found wide use as magnetic recording tape.
TOXICOLOGY
Acute oral toxicity
The NIOSH Registry"' data on the acute oral toxicity
of trivalent chromium compounds range from 1900 to
3300 mg kg-l body weight. By comparison, the
for sodium chromate, a hexavalent compound, is
reported to be 5G1.50 mg kg-' body weight. Hexaval-
ent chromium appears to be 10-100 times more toxic
than the trivalent chromium compounds by the oral
route of acute exposure. Acute oral toxicity data
reported for some chromium compounds in the rat
are presented in Table 4.
Samitz*' reported that the gastric intubation of 1 ml
of a 0.24 M potassium dichromate solution (equivalent
to 130 mg of hexavalent chromium per kilogram body
weight) was lethal to all rats tested, while doses of up
to 5 ml of a 0.48 M chromium (111) chloride hexahydrate
219
Table 4. Oral acute toxicity of some chromium compounds
in the rat'"
ID50
Compound mg mmol
Cr kg-' Cr kg - '
CrCI,.6H20, chromium(ll1) chloride 1870 7.0
Cr(CH,CO,),.H,O, chromium(ll1) acetate" 11260 46
28 Cr(N03),.9H,0, chromium(ll1) nitrate 3250 8.1
CrO,, chromium(V1)oxide 80-114 0.80-1.1
Na,CrO,, sodium chromate(V1) 52 0.32
Na,Cr207, sodium dichromate(V1) 51 0.39
K,Cr20,, potassium dichromate(V1) 57 0.39
(NH,),Cr207, ammonium dichromate(V1) 54 0.43
a Minimal bioavailability because of stability of this complex.
solution (equivalent to 650 mg of trivalent chromium
per kilogram body weight) caused no toxic effects. He
further reported that of 28 rats receiving the lethal dose
of hexavalent chromium followed by 4 ml of an ascorbic
acid antidote (20% w/v aqueous solution) within 2 h, 26
survived. The antidote probably reduced the hexavalent
chromium to a less toxic trivalent form. Samitz et d.'*
reported that the gross autopsy findings for rats that
received the lethal dose of hexavalent chromium were
diffuse hemorrhage, gastritis and enteritis, and that
sacrificed control rats and rats intubated with trivalent
chromium showed no gross pathology. Spectrographic
analysis showed elevated chromium concentrations in
the kidneys, livers, lungs and spleens of the rats that
received the lethal doses of hexavalent chromium relative
to control rats, rats intubated with trivalent chromium
and rats intubated with hexavalent chromium to which
the ascorbic acid antidote was promptly administered.
Chronic oral toxicity
MacKenzie et ~ 1 . ' have
~ evaluated the chronic toxicity
of chromium compounds. They reported that rats that
received either trivalent CrCI, or hexavalent K2Cr20,
at concentrations up to 0.025 mg m1-I in drinking
water for a 1-year period showed no significant adverse
effects. The rats that received the 0.025 mg ml-'
K2Cr207showed a 20% reduction in water consump-
tion. Schroeder et ~ 1 reported
. ~ no ~ adverse effects in
male and female rats during lifetime exposure to 5 ppm
(0.005 mg ml-I) chromium acetate in drinking water.
Bread baked with 1-5% (10-50 mg g-l) chromium(II1)
oxide was fed to rats for 5 days a week for 2 years.
This chronic feeding exposure was correlated with
dose-dependent decreases in the weights of livers and
spleens and with a possible increase in the frequency of
mammary fibrosarc~mas.'~ The incidence of mammary
fibrosarcomas was 7/180 (3.9%) in the exposed animals
versus 31120 (2.5%) in the control group. The low
chronic oral toxicity of trivalent chromium compounds
may be related to the low bioavailability of trivalent
chromium from the compounds investigated.
Dermal toxicity
Irritative dermatitis. High incidences of skin ulcer-
ation and nasal septum perforation were frequent
220 S. A . KATZ AND H . SALEM
consequences of occupational exposure to hexavalent
chromium compounds in some industrial facilities for
tanning, electroplating and chromate production.22
The chrome ulcer generally occurred on exposed areas
of the workers' bodies in contact with vapors, fumes
andlor dusts containing hexavalent chromium. The
nasal septum was frequently involved. The lesions
were multiple or single and typically crusted and
painless. After removal of the tenuous crust, a punched-
out ulcer of 2-5 mm diameter with a thickened,
indurated and undermined border appeared. The
center was deep and the base was covered with
exudate. The ulcers of the nasal septum were often
present without the workers being aware of them.
When subjected to continued exposure or trauma,
chrome ulcers sometimes extended to the underlying
tissues and became very painful. The chrome ulcers
were slow to heal and left atrophic scars on the skin
and perforations of the nasal septum.
Chrome ulcers were produced with hexavalent
0.34 M K2Cr207 on the depilated and abraded mid-
dorsa of guinea pigs." No ulcers were produced with
trivalent 1.0 M Cr2(S04), in the depilated and abraded
control animals. Additional experiments using 0.34 M
K2S04 and 0.34 M K2Cr04 ruled out non-specific
osmotic and pH factors from the ulcerogenic process.
Allergic contact dermatitis. The preponderance of
the initial literature on contact allergy to chromium is
directed towards the hexavalent form. Several of
the original investigators of chromate
maintained that the trivalent form was not active in
the elicitation of the allergic response. Fregert and
R ~ r s m a n , ~ +however,
~' have observed positive epider- chromium reaching the kidneys was developed from this
mal tests with high concentrations of trivalent salts
(0.5 M CrCI3.6H2O and 0.1 M Cr2(S04)3)and C ~ h e n , ~ liver was less toxic than the original sodium dichromate
found that all of his 44 chromate-sensitive subjects
responded positively to intradermal testing with a
0.25% (9.4 X lo-,) solution of CrCI,, a trivalent
compound. Samitz and Shrager3' reported that 5 %
(0.125 M) C T ( N O ~ ) 5% ~ , (0.187 M) CrCI, and 5%
(0.0735 M) Cr2(S04), produced positive reactions on
intact skin only occasionally, and that positive reactions single doses to rats of Na2Cr04, ZnCrOj and PbCr04,
to these trivalent chromium compounds were more
frequent when the epidermis was stripped away with
tape prior to testing. Valer and R a e ~however,
, ~ ~ were
unable to confirm that promoting penetration of
trivalent chromium compounds into the skin of chro-
mate-sensitive subjects enhanced the provocation of
allergic reactions, and they suggested that the other
investigators may have been misled by irritant reactions
from the high concentrations and low pH of the
trivalent chromium salts. These divergent results make
difficult the identification of the species of chromium
responsible for the allergic contact dermatitis.
Systemic toxicity
Hexavalent chromium compounds are more toxic than
are the compounds of trivalent chromium. Kidney
effects are the primary result of exposures to chromium
compounds.
The initial toxic signs of ingesting hexavalent chro-
mium compounds by humans are abdominal pain,
vomiting, diarrhea and intestinal bleeding.3s These
are followed by renal failure resulting from tubular
necrosis.36 Hepatic failure secondary to primary hepa-
tocellular damage, encephalopathy, methaemoglobin-
aemia and hemolysis are frequent complication^.'^
Aggressive dialysis appears to be the best therapy for
chromate ingestion,3x and the administration of ascorbic
acid (see earlier section on acute oral toxicity) has been
recommended to reduce the highly toxic hexavalent
chromium to the less toxic trivalent form.39.40
Rats that received subcutaneous injections of
20 mg kg-' sodium chromate showed damage to the
kidney epithelium within 2 4 h.4*Rabbits were injected
intraperitoneally daily for 3 weeks with 2 mg Cr kg-'
either from Cr(N03), or from K2Cr207.42Sacrifice
and necropsy after this time showed marked congestion
in the kidneys of the rabbits injected with trivalent
Cr(N03),. The kidneys of the rabbits injected with the
hexavalent K2Cr207also showed marked congestion, in
addition to thickening in the walls of the small blood
vessels. Glomerular tufts were shrunken in some places
while proliferation of endothelial cells obliterating the
Bowman space were seen in others. There was necrosis
and epithelial desquamation of the convoluted tubules.
Gregus and Klaassen4, have shown that the highest
concentrations of radiotracer chromium administered to
the rat by intravenous injection of chromium(II1) chloride
were in the kidneys. The relative distributions of chro-
mium from (hexavalent) sodium dichromate between
kidney and liver, however, was shown to depend upon
the route of administration, i.e. intraperitoneal injection
favored accumulation in the liver while subcutaneous
injection favored accumulation in the kidney.44A hypoth-
esis relating nephrotoxicity to the chemical form of the
observation: chromium that was biotransformed in the
to renal structure and function.
The chromium from chromates intratracheally
administered to rats is also capable of damaging
kidneys and livers. Bragt and van D ~ r a found"~ that
the concentrations of chromium in the kidneys and
livers reflected the solubilities of the compounds after
having equivalent hexavalent chromium contents. The
more soluble the compounds, the greater the accumu-
lations in these organs. Similarly, Salem and Katz4"
reported increased chromium concentrations in the
kidneys and livers of rats that received Whetlerite, a
material containing both soluble and insoluble hexaval-
ent chromium and insoluble trivalent chromium, by
intratracheal administration.
Toxicokinetics
hop kin^^^ reported a biphasic urinary elimination
pattern for SICr administered to rats as single intra-
venous doses of CrCI, containing either 0.1 or 0.01 pg
of chromium. Mertz et ~ 1 . " reported~ a triphasic
elimination pattern based on the whole body counting
of "Cr in rats that received single doses of
chromium(II1) chloride by intravenous injection. The
half-times for the three components of the elimination
pattern were 0.5, 5.9 and 83.4 days, respectively.
Sayato et ~ 1 compared
. ~ ~the urinary elimination of
chromium from rats injected with S*Cr-labeledsodium
 CHROMIUM TOXICOLOGY WITH RESPECT TO CHEMICAL SPECIATION
chromate and rats injected with "Cr-labeled
chromium(II1) chloride. They found that the "Cr from
the hexavalent compound was excreted more rapidly
than the "Cr from the trivalent compound. The
respective half-times that they reported were 22.24
and 91.79 days. Yamaguchi et d."' also found that the
urinary excretion of chromium from rats injected with
hexavalent chromium from potassium dichromate was
more rapid than that from rats injected with trivalent
chromium from chromium(II1) nitrate.
Bragt and van Dura" reported biphasic elimination
patterns based on whole body counting of 51Cr in
rats that received intratracheal doses of slCr-labeled
chromates. The half-times for the fast phase and slow
phase elimination of chromium from sodium chromate
(a soluble hexavalent chromium salt) were 5.0 and
71.1 days, respectively. For lead chromate (an insoluble
hexavalent chromium compound), the corresponding
half-times were 1.9 and 94.8 days.
Bragt and van Dura" also reported that the clearance
of "Cr from the blood was biphasic. The half-times
for the fast phases of blood clearance were 4.6 and
2.4 days for the rats that received the Na,"CrO, and
the Pb"CCrO,, respectively.
The biphasic blood clearance patterns and the bi-
/multiphasic urinary excretion patterns for chromium
suggest the existence of several slow-releasing storage
compartments. The distribution of chromium to/from
these compartments is complicated by the possibility
of different transport mechanisms for hexavalent and
trivalent chromium, and the potential for reduction of
the former to the latter. Nearly SO years ago, Gray and
Sterling" described the selective affinities of hexavalent
and trivalent chromium for red cells and plasma proteins,
respectively, and have subsequently investi-
gated the nature of the chromium-protein interactions.
Chromium appears to be mainly bound to transferrin,
and, to a lesser extent, to albumin. It is quite clear that
some of the compartments to/from which chromium is
distributed include kidney, liver, spleen and bone, but
the proposed pathways and kinetic models require
additional refinement^.^^.^^.^',^^
Cytotoxicity
The cytotoxicity of soluble (s) and insoluble (i) hexaval-
ent and trivalent chromium compounds has been
evaluted using diploid human fibroblastic cells derived
from foreskins." The hexavalent chromium compounds
were found to be 1000 times more toxic to these cells
than were the trivalent chromium compounds. All six
of the hexavalent chromium compounds studied-
CaCrO,(s), Na,CrO,(s), Cr03(s), CaCr,O,(s),
K2Cr20,(s) and PbCrO,(i)-caused cytotoxicity in
the 0.1-1.0 pM concentration range. The average
concentrations of these hexavalent chromium com-
pounds that allowed 50% cell survival was 0.5 p M .
The four trivalent chromium compounds studied-
CrCI3. 6H,O(s), Cr,O,(i), CrC13(i) and Cr2S3(i)-
induced dose-dependent cytotoxicity over a wider
concentration range of 10-500 p M . The average SO%
survival concentration was 50 kM. Some typical results
from the work of Biedermann and Landolphs6 are
summarized in Table 5.
Sodium chromate demonstrates a threshold concen-
22 1
Table 5. Cytotoxicity of Cr(V1) and Cr(II1) compounds
Cr(VI) as K,Cr,O, Cr(lll) as CrCI,.GH,O
CLM YO lethality PM YO lethality
0.05 16 2.5 25
0.1 50 5.0 13
0.2 92 10.0 25
tration of ca. 2.5 p M above which it becomes highly
toxic to mouse peritoneal macrophages in a concen-
tration-dependent manner.57 The viability of these
macrophages was not affected by chromate concen-
trations of 1.25 and 2.5 p M during a 28-day exposure,
but only a small fraction of these cells survived more
than 2 days of exposure to 5 pM sodium chromate.
In 10 pM sodium chromate, almost all of the cells
detached within 3 days. This dependency of cytotoxicity
on dose has also been demonstrated with Syrian
hamster embryo cells and chromates of calcium,
strontium, zinc and lead.sx
It is interesting to note that SLCr-releaseassays have
been developed to assess cytotoxicities of mineral
dust ,sy ursodeoxy-cholic acid,@'"mouse splenocytes'l
and sera from human rheumatoid arthritis patients.(j*
In each case, the target cells were labeled with sodium
radiochromate (Na2"Cr04), at concentrations well
below those producing cytotoxic effects. It follows,
therefore, that a threshold similar to that mentioned
above must exist for each of these target cells.
Genotoxicity
DeFlora et af.h3have reviewed approximately 650 results
reported in the literature with 32 chromium compounds
assayed in 130 short-term tests using different targets
and/or genetic end points. The large majority of the
positive results were obtained with hexavalent chromium
compounds. Trivalent chromium compounds, although
more reactive than the hexavalent chromium compounds
with purified nucleic acids, did not induce genotoxic
effects in the majority of the studies conducted with
intact cells. With few exceptions, solutions of hexavalent
chromium compounds were consistently positive in cellu-
lar systems. Almost 400 out of 450 results showed that
soluble hexavalent chromium compounds are mutagenic
in bacteria. In addition, the soluble hexavalent chromium
compounds induced a broad range of genetic effects
in yeasts and in insects. Soluble trivalent chromium
compounds were inactive in cellular systems, but they
produced a variety of genetic effects in acellular or
subcellular targets.
The frequency of positive results with hexavalent
chromium compounds was related to their solubilities
and, hence, to their bioavailabilities to the target
cells. Although soluble trivalent chromium compounds
appear to be capable of producing genetic effects when
directly challenged with purified nucleic acids or with
subcellular targets, this potential genotoxicity is lost
in cellular systems. The results obtained with these
genotoxic tests are summarized in Table 6.
222 S. A . KATZ AND H . SALEM
Table 6. Summary of results obtained with hexavalent and
trivalent chromium compounds in genotoxic tests63
Cr(VI) Cr(lll)
compounds compounds
% Positive 88.2 23.0
% Negative 8.5 67.5
Total tests 450 209
Carcinogenicity
Epidemiological studies in the USAhJ.65 and in the
UK66.67from more than a quarter of a century ago
confirmed even earlier German findingshHon the excess
risk of lung cancer associated with exposure to some
hexavalent chromium compounds in some occupational
and industrial settings. Continuing epidemiological
studies in the USA,hythe UK,70.71Germany,72 Italy7'
and Japan7J confirmed that the increased risk of
bronchial cancer was associated with exposure to
chromium-containing compounds. Specific identifi-
cation of the causative agent or agents with epidemiol-
ogical studies, however, has not been successful.
Consequently, the carcinogenic potential of various
chromium compounds was evaluated from studies using
laboratory animals.
Glaser et reported three lung tumors (one
adenocarcinoma and two adenomas) in 20 rats exposed
for 78 weeks (7 days per week, 22 h per day), to a
sodium dichromate aerosol containing 100 p g hexa-
valent chromium m-3. Primary lung tumors were not
found in 40 control rats, nor were lung tumors found
in rats exposed to sodium dichromate aerosols containing
25 or 50 pg soluble hexavalent chromium m-3.
Soluble hexavalent and trivalent chromium com-
pounds were not tumorigenic in laboratory animals
after intratracheal, intrabronchial and intrapleural
implantation and instillation, or intramuscular and
intravenous The intrabronchial, intratra-
cheal and intrapleural implantation or instillation of
calcium chromate and lead chromate, on the other
hand, clearly demonstrated the carcinogenicity of these
less soluble/insoluble hexavalent chromium com-
p o u n d ~ . ~ ~ Intramuscular
.~',~~) implantation of strontium
chromate7hand intrabronchial implantation of stainless-
steel mesh pellets containing lead chromate7' also
produced tumors in experimental animals.
Inhalation studies have not unequivocally confirmed
the carcinogenicity of the less soluble/insoluble hexaval-
ent chromium compounds in laboratory animals. Nette-
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