Clinical Toxicology, 37(2), 173–194 (1999) Chromium Donald G. Barceloux Topanga, California ABSTRACT Chromium occurs primarily in the trivalent state (III), which is the most stable form, or in the hexavalent state (VI), which is a strong oxidizing agent. Elemen- tal chromium (0) does not occur naturally on earth. Trivalent chromium (III) is an essential trace metal necessary for the formation of glucose tolerance fac- tor and for the metabolism of insulin. Commercial applications of chromium compounds include tanning (III), corrosion inhibition, plating, glassware-clean- ing solutions, wood preservatives (VI), manufacture of safety matches, metal finishing (VI), and the production of pigments (III, VI). Hexavalent chromium (VI) contaminated local soil when chromium waste slag was part of the fill material present in residential, public, and industrial areas. In some urban areas, about two-thirds of the chromium in air results from the emission of hexavalent chromium from fossil fuel combustion and steel production. The remaining chromium in air is the trivalent form. The residence time of chro- mium in air is ,10 days, depending on the particle size. Trivalent compounds generally have low toxicity and the gastrointestinal tract poorly absorbs these compounds. Hexavalent chromium is a skin and mucous membrane irritant and some of these hexavalent compounds are strong corrosive agents. Hexavalent chromium compounds also produce an allergic contact dermatitis characterized by eczema. Sensitivity to trivalent compounds is much less frequent, but some workers may react to high concentrations of these compounds. Hexavalent chromium is recognized by the International Agency for Research on Cancer and by the US Toxicology Program as a pulmo- nary carcinogen. The increased risk of lung cancer occurs primarily in workers exposed to hexavalent chromium dust during the refining of chromite ore and the production of chromate pigments. Although individual studies suggest the possibility of an excess incidence of cancer at sites outside the lung, the results from these studies are inconsistent. Correspondence: Dr. Donald Barceloux, PO Box 1750, Topanga, CA 90290. Tel/Fax: 310/455-2752; E-mail: [email protected]173 Copyright 1999 by Marcel Dekker, Inc. www.dekker.com Clinical Toxicology Downloaded from informahealthcare.com by North Carolina State University on 10/05/12 For personal use only.
Transcript
Clinical Toxicology, 37(2), 173–194 (1999)
Chromium
Donald G. Barceloux
Topanga, California
ABSTRACT
Chromium occurs primarily in the trivalent state (III), which is the most stableform, or in the hexavalent state (VI), which is a strong oxidizing agent. Elemen-tal chromium (0) does not occur naturally on earth. Trivalent chromium (III)is an essential trace metal necessary for the formation of glucose tolerance fac-tor and for the metabolism of insulin. Commercial applications of chromiumcompounds include tanning (III), corrosion inhibition, plating, glassware-clean-ing solutions, wood preservatives (VI), manufacture of safety matches, metalfinishing (VI), and the production of pigments (III, VI). Hexavalent chromium(VI) contaminated local soil when chromium waste slag was part of the fillmaterial present in residential, public, and industrial areas. In some urbanareas, about two-thirds of the chromium in air results from the emission ofhexavalent chromium from fossil fuel combustion and steel production. Theremaining chromium in air is the trivalent form. The residence time of chro-mium in air is ,10 days, depending on the particle size.
Trivalent compounds generally have low toxicity and the gastrointestinaltract poorly absorbs these compounds. Hexavalent chromium is a skin andmucous membrane irritant and some of these hexavalent compounds are strongcorrosive agents. Hexavalent chromium compounds also produce an allergiccontact dermatitis characterized by eczema. Sensitivity to trivalent compoundsis much less frequent, but some workers may react to high concentrations ofthese compounds. Hexavalent chromium is recognized by the InternationalAgency for Research on Cancer and by the US Toxicology Program as a pulmo-nary carcinogen. The increased risk of lung cancer occurs primarily in workersexposed to hexavalent chromium dust during the refining of chromite ore andthe production of chromate pigments. Although individual studies suggest thepossibility of an excess incidence of cancer at sites outside the lung, the resultsfrom these studies are inconsistent.
Correspondence: Dr. Donald Barceloux, PO Box 1750, Topanga, CA 90290. Tel/Fax: 310/455-2752; E-mail: [email protected]
173
Copyright 1999 by Marcel Dekker, Inc. www.dekker.com
In 1798, Vaquelin discovered the element chromiumin the mineral crocoite (PbCrO4). Chromium is the sixthmost abundant element in the earth’s crust. This metalalways occurs in combination with other elements, dis-playing a wide variety of colors. Only meterorites containfree chromium and most chromium appears in chromiteore, which contains iron and oxygen.1 Exposure to chro-mium compounds occurs primarily in the occupationalsetting where chromium commonly is used in the follow-ing 3 basic industries: chemical, metallurgical, and re-fractory (heat-resistant). The carcinogenesis of hexava-lent chromium compounds was recognized first in the late19th century when nasal tumors were described in Scot-tish chrome pigment workers.2 Case reports in the 1930sfocused attention on the incidence of lung cancer inchromate workers, and lung cancer in German chromateworkers was accepted as a work-related disease in 1936.3
Since 1961, there has been no mining of chromite ore inthe US and the US became totally dependent on foreignsource of chromium in 1985.4
In the 1960s and 1970s, chromium-containing slagwas a substantial component of landfills in a variety ofresidential and commercial settings in Hudson County,New Jersey. Health concerns about exposure to this soilwere based on experience with workers exposed to chro-mium. Epidemiological studies of chromate workers in-dicate an increased risk of death from lung cancer inworkers exposed to hexavalent (61) chromium com-pounds.5,6 Hexavalent chromium compounds are bothskin and pulmonary sensitizers, producing a generalizedirritation of the conjunctiva and mucous membranes, na-sal perforations,7 and a contact dermatitis (e.g., Blackjackdisease in card players exposed to chromium in greenfelt).8 Trivalent chromium is an essential trace metal nec-essary for the formation of glucose tolerance factor andfor the metabolism of insulin.
PHYSICAL AND CHEMICALPROPERTIES
Table 1 lists the identifying characteristics of chro-mium and chromium compounds. Although the oxidationstates of chromium range from 2II to 1VI, the importantvalences are 0, II, III, and VI. Elemental chromium (0)does not occur naturally on earth. Most chromium com-pounds exist as halides, oxides or sulfides. The divalent(chromous) state is a strong reductant and this form ofchromium rapidly decomposes in air or water to form the
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Chromium 175
Tab
le1
Iden
tify
ing
Fac
tors
for
Chr
omiu
man
dC
hrom
ium
Com
poun
ds
CA
SN
IOSH
Che
mic
alR
egis
try
RT
EC
SO
ther
Nam
esV
alen
ceF
orm
ula
Num
ber
Num
ber
Chr
omiu
mC
hrom
e0
Cr
7440
-47-
3G
B42
0000
0C
hrom
ium
acet
ate,
Ace
ticac
id,
chro
miu
msa
lt,hy
drat
e;ch
rom
ic1
3C
r(C
H3C
OO
) 3⋅H
2O25
013-
82-5
AG
3050
000
mon
ohyd
rate
acet
ate,
hydr
ate
Chr
omiu
mni
trat
e,N
itric
acid
,ch
rom
ium
salt,
nona
hydr
ate;
chro
-1
3C
r(N
O3)
3⋅9
H2O
7789
-02-
8G
B63
0000
0no
nahy
drat
em
ium
nitr
ate,
nona
hydr
ate
Chr
omiu
mch
lori
deC
hrom
ium
tric
hlor
ide,
C17
7295
13
CrC
l 310
025-
73-7
GB
5425
000
Chr
omiu
mch
lori
deH
exaa
qua-
chro
miu
mch
lori
de1
3C
r(C
l)3
⋅6H
2O10
060-
12-5
GB
5450
000
hexa
hydr
ate
Ferr
ochr
omite
Chr
omite
13
FeC
r 2O
413
08-3
1-2
GB
4000
000
Chr
omiu
mox
ide
Chr
omiu
mse
squi
oxid
e,di
chro
miu
mtr
ioxi
de1
3C
r 2O
313
08-3
8-9
GB
6475
000
Chr
omiu
mph
osph
ate
Chr
omiu
mor
thop
hosp
hate
;ph
osph
oric
acid
,1
3C
rPO
477
89-0
4-0
GB
6840
000
chro
miu
msa
lt;A
mau
don’
sG
reen
Chr
omiu
msu
lfat
eSu
lfur
icac
id,
chro
miu
msa
lt;C
hrom
itan
B1
3C
r 2(S
O4)
310
101-
53-8
GB
7200
000
Sodi
umch
rom
ite1
3N
aCrO
212
314-
42-0
Chr
omiu
mox
ide
Chr
omiu
mdi
oxid
e1
4C
rO2
1201
8-01
-8A
mm
oniu
mdi
chro
mat
eC
hrom
icac
id,
diam
mon
ium
salt
16
(NH
4)2C
r 2O
777
89-0
9-5
HX
7650
000
Cal
cium
chro
mat
eC
hrom
icac
id,
calc
ium
salt;
Cal
cium
Chr
ome
16
CaC
rO4
1376
5-19
-0G
B27
5000
0Y
ello
wC
hrom
ium
trio
xide
Chr
omic
acid
,ch
rom
ican
hydr
ide
16
CrO
313
33-8
2-0
GB
6650
000
Lea
dch
rom
ate
Chr
omic
acid
,le
adsa
lt1
6Pb
CrO
477
58-9
7-6
GB
2975
000
Pota
ssiu
mch
rom
ate
Chr
omic
acid
,di
pota
ssiu
msa
lt1
6K
2CrO
477
89-0
0-6
GB
2940
000
Pota
ssiu
mdi
chro
mat
eC
hrom
icac
id,
dipo
tass
ium
salt
16
K2C
r 2O
777
78-5
0-9
HX
7680
000
Sodi
umch
rom
ate
Chr
omic
acid
,di
sodi
umsa
lt,C
asw
ell
No.
757
16
Na 2
CrO
477
75-1
1-3
GB
2955
000
Sodi
umdi
chro
mat
e,C
hrom
icac
id,
diso
dium
salt;
dihy
drat
e1
6N
a 2C
r 2O
7⋅2
H2O
7789
-12-
0H
X77
5000
0di
hydr
ate
Stro
ntiu
mch
rom
ate
Chr
omic
acid
,st
ront
ium
salt
16
SrC
rO4
7789
-06-
2G
B32
9000
0Z
inc
chro
mat
eC
hrom
icac
id,
zinc
salt
16
ZnC
rO4
1353
0-65
-9G
B32
9000
0
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pted
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e12
,ta
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3-1.
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176 Barceloux
relatively inert chromic (trivalent) compound. The hexa-valent (chromate) form is the second most stable chro-mium compound and is a strong oxidizing agent, espe-cially in acid media. The hexavalent compounds usuallyexist as oxides or as oxohalides. The reduction of dichro-mates to trivalent chromium increases with decreasingpH. Chromate (Cr (VI)) occurs only rarely in nature inthe mineral, crocoite (PbCrO4); therefore, most chromateresults from man-made production. Cr (IV) and Cr (V)compounds are relatively unstable and occur infrequentlyin nature.
Table 2 lists the physical properties of various chro-mium compounds. As indicated in Table 2, trivalentchromium compounds are poorly soluble in water at pHranging from 4–11 except for the acetate, chloride (hexa-hydrate), and nitrate salts. In alkaline media, trivalentchromium easily oxidizes to hexavalent chromium.Hexavalent chromium compounds (e.g., chromic acid,chromic trioxide, ammonium salt, sodium, or potassiumalkali metal salts) are soluble in water. Generally, dichro-mates are more soluble than the corresponding chro-mate.9 Although hexavalent chromium compounds tra-verse cell membranes well and are reduced to trivalentcompounds intracellularly, there is no direct evidencethat biological systems can convert trivalent compoundsto hexavalent compounds.10 The pH of chromium com-pounds range from 0.5 (chromic acid) to 13 (ammoniumdichromate). Trivalent chromium sulfate is a corrosivesubstance that reacts with tissue proteins to liberate up to6 moles of hydrogen ion per mole of chromium sulfate.11
EXPOSURE
Production Processes
Chromite (trivalent) ore is the major source of chro-mium, and even the highest grade of ore (FeOCr2O3) con-tains slightly more than 50% chromic oxide. Productionof chromium involves the reduction of chromite ore withaluminum, carbon, or silicon followed by purification.The roasting of chromite ore with soda ash produces so-dium chromate and dichromate. The latter two com-pounds are the starting mixtures for most other chromiumcompounds.
Uses
Commercial applications include tanning (III), corro-sion inhibition, plating, glassware-cleaning solutions,wood preservatives (VI), safety match manufacture,metal finishing (VI), and pigments (III, VI). The primary
users of chromium compounds are chemical, metallurgi-cal, and refractory industries. Chromium applications inthe metallurgical industry include ferrochromium inter-mediates for stainless steels, cast irons, and nonferrousalloys.12 In concentrations ranging from 11–30% chro-mium, the inclusion of chromium in alloys increaseshardness and resistance to corrosion. There are two typesof chrome plating: (1) decorative plating, where the basemetal (e.g., nickel) receives a thin layer (0.5–1 µ) ofchromium, and (2) hard plating, where the layer is muchthicker (5–10 µ) and more corrosion resistant. The highmelting point of chromium and its resistance to acid andalkali are ideal characteristics in the refractory industry.Chromium is a component of chrome and chrome-mag-nesite castables, chrome-magnesite firebricks in furnaces,and granular chromite in various heat-resistant applica-tions. In the chemical industry, the use of chromium pri-marily involves its application as a pigment (green, or-ange, red, yellow). Sufficient water soluble chromatesleach from zinc potassium chromate in primer paints toproduce allergic reactions. These levels of chromates aremuch higher than the concentration (0.0002–0.0008%)of water-soluble chromates in cement.13 Although thecommercial applications of natural isotopes (50Cr, 52Cr,53Cr, 54Cr) are limited, the artificial, radioactive isotope51Cr is commonly used in biomedicine.
Sources
Most chromium released into the environment resultsfrom human activities at stationary point sources. Com-bustion and the processing of ore discharge primarily tri-valent chromium into the environment as chromium ox-ide; however, small amounts of hexavalent chromiumdoes appear in fly-ash of coal-fired power plants14 andfrom chromate manufacturing sites. The highest exposureto hexavalent chromium occurs during chromate pro-duction, ferrochrome and chrome pigment production,chrome plating, and stainless steel welding.12
The composition of welding fumes is complex andvaries depending on the type of welding and the composi-tion of the metal, fluxes, and electrodes as well as thepresence of oxygen and air contaminants.15 Stainless steelis an alloy of iron, nickel, and chromium while mild steelis an alloy of iron, carbon, and silicon. Consequently,fumes from the welding of stainless steel, but not ofmild steel, contains Cr (VI) and smaller amounts ofnickel.16 In a study of stainless steel welders, the meanplasma concentration of chromium in welders using themanual metal arc process was significantly higher com-pared with the plasma chromium concentrations of weld-
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Chromium 177
Tab
le2
Phy
sica
lP
rope
rtie
sof
Chr
omiu
man
dC
hrom
ium
Com
poun
ds
Mol
ecul
arM
elti
ngD
ensi
tyW
ater
Wei
ght
Col
orP
oint
,°C
g/m
3So
lubi
lity
Chr
omiu
m51
.996
Stee
l-gr
ay18
577.
2(2
8°C
)In
solu
ble
Chr
omiu
mac
etat
e,m
onoh
ydra
te24
7.15
Gra
y-gr
een,
blui
sh-g
reen
No
data
No
data
Solu
ble
Chr
omiu
mni
trat
e,no
nahy
drat
e40
0.15
Purp
leor
viol
et60
No
data
Solu
ble
Chr
omiu
mch
lori
de15
8.36
Vio
let
orpu
rple
Abo
ut11
502.
76(1
5°C
)Sl
ight
lyso
lubl
eC
hrom
ium
chlo
ride
hexa
hydr
ate
266.
45V
iole
t83
1.76
58.5
g/dL
@(2
5°C
)Fe
rroc
hrom
ite22
3.84
Bro
wn-
blac
kN
oda
ta4.
97(2
0°C
)In
solu
ble
Chr
omiu
mox
ide
151.
99G
reen
2266
5.21
Inso
lubl
eC
hrom
ium
phos
phat
e14
6.97
Gra
y-br
own
orbl
ack
.18
002.
94@
(32.
5°C
)In
solu
ble
Chr
omiu
msu
lfat
e39
2.16
Vio
let
orre
dN
oda
ta3.
012
Inso
lubl
eSo
dium
chro
mite
106.
98N
oda
taN
oda
taN
oda
taN
oda
taC
hrom
ium
oxid
e83
.99
Bro
wn-
blac
k30
0(d
ecom
pose
s)N
oda
taIn
solu
ble
Am
mon
ium
dich
rom
ate
252.
06O
rang
e17
0(d
ecom
pose
s)2.
15@
(25°
C)
Solu
ble
Cal
cium
chro
mat
e15
6.07
Yel
low
No
data
No
data
2.23
g/dL
Chr
omiu
mtr
ioxi
de99
.99
Red
196
2.7
@(2
5°C
)So
lubl
eL
ead
chro
mat
e32
3.18
Yel
low
844
6.12
@(1
5°C
)5.
8µg
/dL
Pota
ssiu
mch
rom
ate
194.
2Y
ello
w96
8.3
2.73
2@
(18°
C)
Solu
ble
Pota
ssiu
mdi
chro
mat
e29
4.18
Red
398
2.67
6@
(25°
C)
Solu
ble
Sodi
umch
rom
ate
161.
97Y
ello
w79
22.
71–2
.736
Solu
ble
Sodi
umdi
chro
mat
e,di
hydr
ate
298.
0R
ed35
6.7
2.52
@(1
3°C
)So
lubl
eSt
ront
ium
chro
mat
e20
3.61
Yel
low
No
data
3.89
5@
(15°
C)
Slig
htly
solu
ble
Zin
cch
rom
ate
181.
37L
emon
-yel
low
No
data
3.40
Inso
lubl
e
Ada
pted
from
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e12
,ta
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178 Barceloux
ers using metal inert gas and tungsten inert gas pro-cesses.17
Air
Typical concentrations in rural areas of the US are,0.01 µg Cr/m3 while concentrations in urban areas av-erage 0.01–0.03 µg Cr/m3.18 Stationary fuel combustionaccounted for slightly less than half of the total emissionsof chromium to the air in Los Angeles between 1976–1980; releases from metal industries accounted for 26–45%.19 The US EPA estimates that 64% of total atmo-spheric chromium results from the emission of hexava-lent chromium from fossil fuel combustion and steel pro-duction, while 32% results from the release of trivalentchromium from chemical manufacture, chrome plating,cooling towers, and metal production.20
Soil
Chromium levels vary widely in soil depending on thecomposition of parent rocks. A collection of US soil sam-ples revealed concentrations ranging from 1–2,000 mgCr/kg with a geometric mean of 37 mg Cr/kg.12 Deposi-tion of commercial products containing chromium ac-counts for a majority of the chromium in soil and veryhigh concentrations of chromium in soil may result fromthe deposition of these commercial products in areas suchas landfills.21 Most chromium in soil occurs as insolubletrivalent salts (oxide, carbonate).
Water
The concentration in US drinking water averages 0.4–8.0 µg Cr/L with a mean value (1.8 µg Cr/L), which isabout 6-fold higher than the mean chromium level in seawater.22 The current US EPA maximum contaminantlevel (MCL) is 50 µg Cr/L. The concentrations in USrivers range from ,1–30 µg Cr/L with a median of about10 µg Cr/L.23 Chromium in the aquatic phase appears ineither solubilized solution or suspended particles. Solublechromium accounts for a small amount of the total chro-mium in water as both hexavalent and trivalent chro-mium. The major source of chromium in aquatic systemsis domestic wastewater effluents. Less important sourcesof chromium in aquatic systems include the followingsources in the order of importance: metal manufacturing,ocean dumping of sewage, chemical manufacturing, pro-cessing of nonferrous metals, and atmospheric fallout.21
Food
Trivalent chromium is an essential nutrient and insuf-ficient dietary intake of chromium produces a disease
similar to adult-onset diabetes and cardiovascular dis-ease.24 The recommended daily intake for adults is 50–200 µg Cr.25 Studies of the US diet indicate that theamount of chromium ranges from 25–224 µg Cr/d witha mean between 60–79 µg Cr/d.26,27 However, little dataare available on the bioavailability of these chromiumcompounds. The reported daily intake of chromium fromthe diet has decreased over the last few decades as a resultof improved instrumentation and reduction in contamina-tion from sources such as stainless steel containers.28 Astudy of 32 volunteers indicated that the average dailydiet of most people ranges from 10–40 µg Cr and that thebioavailability of dietary chromium was dose dependent,ranging from 2% at 10 µg Cr/d to 0.5% at 40 µg Cr/d.24
Foods high in chromium include green beans, broccoli,high-bran breakfast cereals, and some brands of beerand wine.29 Frozen or canned vegetables, canned fruits,chicken eggs, seafood, and meat may contain up to 200µg Cr/kg.30 Concentrations in tobacco range from 0.24–14.6 mg Cr/kg, but the valence and amount of chromiumabsorbed into the body as a result of smoking is notknown.
ENVIRONMENTAL FATE
Air
Chromium particles in air possess mass median diam-eters of approximately 1 µm.31 Removal of chromiumfrom the atmosphere occurs primarily by dry depositionand, to a lesser extent, by wet deposition. Based on thesize of chromium particles, the expected residence timein the air is ,10 days. Chromium compounds do not vol-atilize from water.
Soil
The fate of chromium in soil depends on the redoxpotential and the pH of the soil. For example, the pres-ence of low levels of organic matter, oxygen, manganesedioxide, moisture, and brush fires facilitate the conver-sion of the trivalent form to the hexavalent form.32 Inmost soils, chromium occurs primarily in the trivalentstate. Chromium is not very mobile in soil because mostof the chromium exists as the insoluble oxide (Cr2O3 ⋅nH2O). Soluble hexavalent and trivalent chromium com-pounds are more mobile in the soil, but organic mattereventually reduces the hexavalent form to insoluble chro-mic (trivalent) oxide. Plants do not easily transport chro-mium from the soil to the above ground parts of theplants.22
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Chromium 179
Water
Most of the aqueous chromium ultimately deposits inthe sediment.12 Soluble chromium accounts for a verysmall percentage of the total chromium in water, and par-ticles (iron oxide, clay, organic) suspended in water ab-sorb most chromium. The valence state of chromium inwater depends on the pH and the redox potential in theaquifer. Cr (VI) predominates under high oxidation con-ditions, such as shallow groundwater with pH 6–8, whiletrivalent chromium predominates under reducing condi-tions, typical of the more acidic conditions in deepgroundwater.
DOSE-EFFECT
Acute Ingestion
The toxicity of a hexavalent chromium compound de-pends both on its oxidizing and on its corrosive proper-ties. An average lethal dose is approximately 1–3 g Cr(VI) compound. Other than chromium sulfate, trivalentchromium compounds are relatively nontoxic.
Trivalent Chromium
Trivalent compounds generally have low toxicity. Innutritional studies, no signs of toxicity occurred follow-ing the ingestion of up to 1 mg trivalent chromium/d.33
An exception is the corrosive, chromium sulfate. A 41-year-old woman, who ingested 48 g chromium sulfate,developed a hemorrhagic gastroenteritis, pancreatitis,and intractable cardiogenic shock.11 Postmortem exami-nation demonstrated an erosive gastroenteritis of the en-tire gut, hemorrhagic pancreatitis, pulmonary congestion,and peritonitis.
The US EPA reference dose (RfD) for trivalent chro-mium is 1 mg/kg/d based on a chronic animal study, inwhich the NOAEL was based on administering 5%chromic trioxide (C2O3) in the diet of rats.34 For hexa-valent chromium, the RfD is 5 µg/kg/d based on a 1-yeardrinking water study in Sprague-Dawley rats.35
Hexavalent Chromium
Chromic Acid
A 44-year-old man died 1 month after the ingestionof an estimated 4.1 mg H2CrO7 (hexavalent chromicacid)/kg.36 The ingestion of chromic acid 125 mL by a33-year-old electroplating worker was associated with re-fractory hypotension, acute renal tubular necrosis, and
hepatic failure.37 No concentration of chromic acid wasreported, but electroplating fluid usually contains 20–40% chromic acid. He died 2 days after ingestion. Withthe use of dialysis, patients have survived the reportedingestion of 5–15 g chromic acid.38,39
Dichromate
A 15-year-old girl ingested a few grains of potassiumdichromate. She then vomited, became unconscious, anddied in 12 hours. The initial blood sample contained35,000 µg Cr/L.40 A 17-year-old male died after the re-ported ingestion of 29 mg Cr (VI)/kg (i.e., about 2 g).41
An 18-year-old man ingested approximately 5 g of potas-sium dichromate by history.41 On admission, he was hy-potensive and cyanotic (22% methemoglobinemia) andshortly thereafter a coagulopathy, hemorrhage, and a car-diac arrest occurred. The initial blood chromium levelwas 58,000 µg/L.
Some case reports suggest that the lethal dose of hexa-valent chromium may be somewhat lower (0.5–0.8 g).A 14-year-old boy developed an acute gastroenteritisand toxic hepatitis with renal failure, leading to anuriaand death 8 days after ingesting 7.5 mg Cr (VI)/kg bodyweight.42 The use of dimercaprol (BAL), ascorbic acid,exchange transfusion, and peritoneal dialysis did not alterhis clinical course. Postmortem examination demon-strated extensive liver and kidney damage along withhigh tissue concentrations of chromium.
Survival has been reported after large ingestions ofhexavalent chromium. A 20-year-old man ingested about45 g of a powder containing 70% K2Cr2O7 (31.5 g potas-sium dichromate).43 He immediately developed gastroin-testinal symptoms (vomiting, hematemesis, diarrhea) andhypotension. He recovered after a prolonged hospitalcourse that included hepatorenal failure and gastrointesti-nal bleeding.
Skin
Trivalent chromium has not been associated with der-matitis, whereas exposure to hexavalent chromium pro-duces both a primary irritant dermatitis and a type IVhypersensitivity reaction. The risk of sensitization to hex-avalent chromium depends on the duration and amountof exposure. A substantial decrease in the number of sen-sitized cement workers occurred after the concentrationof water-soluble chromate (VI) declined to ,2 µg Cr(VI)/g (ppm) cement.44 Based on patch testing, the re-lease of ,0.3 µg leachable chromates/cm2 should beassociated with minimal sensitization of workers exposedto hexavalent chromium.45
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Risk Assessment46
Incidental ingestion is the most important route of ex-posure to trivalent chromium unless people consume gar-den vegetables grown in chromium-contaminated soil.Trivalent chromium possesses negligible risk because ofits low inherent toxicity and low bioavailability.47 Thedata on dose–response relationships for chromium com-pounds are very limited and the use of reference dose fortrivalent data based on data for hexavalent chromiummay lead to highly inaccurate assessments of risk.48 Riskanalysis of soil contaminated with hexavalent chromiumindicates that soil concentrations in the range of 130–450ppm Cr provide adequate protection against the develop-ment of allergic contact dermatitis, respiratory cancer,and systemic toxicity.49
Cancer
Hexavalent chromium is a lung carcinogen that alsopossesses the ability to induce allergic reactions in theskin and in the lungs. Workers (e.g., chromate andchromate pigment production) exposed to hexavalentchromium developed an increased risk of lung cancer,whereas no increased risk of lung cancer was detected inworkers in the ferrochromium industry where exposureto trivalent chromium occurs.50 Using the multistage ex-trapolation method, the US EPA calculated an inhalationunit risk for exposure to hexavalent chromium of 0.012per (µg Cr/m3).51 This value correlates to an upper 95%confidence limit of 1:1,000,000 for an air concentrationof 8 3 10–5 µg Cr/m3. The inhalation of Cr (VI)-contami-nated dust is a carcinogenic hazard, but oral or dermalexposure to hexavalent chromium probably does not pro-duce lung cancer. For persons living on residential prop-erties, the estimated risk of lung cancer is ,1:1,000,000when the concentration of total chromium in the soil is,180 mg Cr/kg (ppm) soil.
The body possesses mechanisms in the lung and thestomach to reduce hexavalent chromium to the less toxictrivalent chromium. Thus, at low levels of exposure tohexavalent chromium, the body has the potential to re-duce Cr (VI) to Cr (III) before the former compound caninteract with DNA. Current evidence, including the de-cline in the incidence of lung cancer in chromate workersafter reduction in Cr (VI) levels, suggests that a thresholdfor the carcinogenic potential of hexavalent chromium inhumans may exist.52
TOXICOKINETICS
Absorption of chromium occurs from the gastrointes-tinal tract and from the lungs. Urinary excretion may take
more than 14 days. The toxicity of chromium compoundsis apparently related to the powerful oxidizing action ofthe hexavalent compound, which the acid milieu of thestomach converts to the less toxic trivalent form. Chro-mium is stored in all body tissues. The kidney excretesabout 60% of the absorbed chromate dose within 8 hoursof ingestion. Elimination also occurs via the intestine.38
Small amounts of chromium are excreted in breast milk.53
Absorption
Inhalation
The exact bioavailability of respirable chromium par-ticles (0.2–10 µm) is not known, but the lung probablyabsorbs soluble chromium compounds well. The actualamount of absorption of chromium into the blood de-pends on a number of factors, including oxidation state,size, solubility, and the phagocytic activity of alveolarmacrophages. In most cases, hexavalent compounds aremore easily absorbed through the lungs compared withtrivalent compounds, in part because of the relativelygreater ease with which hexavalent chromium com-pounds traverse biological membranes. Animal studiessuggest that the lungs absorb about 53–85% of respirablehexavalent chromium particles (,5 µm) and approxi-mately 5–30% of respirable trivalent chromium parti-cles.12
Ingestion
The absorption of chromium compounds from the gutis poor and averages about 0.5–2%. Based on the renalexcretion of chromium, volunteers absorbed about 0.4%of a dose of Cr (III) chloride.54 In doses present in thenormal diet, the stomach reduces hexavalent chromiumto trivalent chromium, which accounts for the poor bio-availability of hexavalent chromium.55 In a study of adultvolunteers given a single 10 mg dose of Cr (VI) in drink-ing water, endogenous reducing agent within the uppergastrointestinal tract and the blood reduced virtually all(.99.7%) of the ingested dose of Cr (VI) to Cr (III) priorto absorption into the blood.56 Consequently, large dosesof hexavalent chromium are required to bypass the reduc-ing capacity of the stomach and to enter the blood intoxicologically significant amounts.
Dermal
Both hexavalent chromium and trivalent chromiumpenetrate skin to a very limited extent, except followingmassive exposure that produces burns.57 Both potassiumdichromate (VI)58 and chromium chloride (III) penetratedhuman skin,59 but chromium sulfate did not traverse ex-
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cised intact epidermis of humans. The rates of absorptionof sodium chromate (VI) from occluded patches on vol-unteers were concentration-dependent. One study dem-onstrated the following absorptive rates for Cr (VI): 1.1µg Cr (VI)/cm2/h for a 0.01 M solution, 6.4 µg Cr (VI)/cm2/h for a 0.1 M solution, and 10 µg Cr (VI)/cm2/h fora 0.2 M solution.60
Distribution
The body reduces most of the hexavalent chromiumthat enters the body and, thus, trivalent chromium ac-counts for the vast majority of total chromium in thebody. After absorption, trivalent chromium binds totransferrin in plasma and distributes widely throughoutthe body. Little penetration of Cr (III) into erythrocytesoccurs. In contrast, hexavalent chromium rapidly pene-trates red cells, where it binds to the β-chain of hemoglo-bin.61 Within the erythrocyte, hexavalent chromium re-duces to trivalent chromium. With the exception of thelungs, the concentration of chromium in all other tissuesdecreases with age.62 A study of autopsies of smelterworkers revealed higher concentrations of total chro-mium in the lungs of the workers compared with controls,but the concentration of chromium in the liver and thekidneys was similar to controls.63 The excess concentra-tions of chromium in the lungs decreased as the periodbetween death and retirement lengthened. Following in-gestion, chromium concentrates in white blood cells andthe liver, and the kidney and brain contain lower concen-trations of chromium than the leukocytes and the liver.42,64
Elimination
The kidney rapidly excretes most of the absorbedchromium with little retention of chromium in tissues.Healthy adults, who received 30–100 µg Cr/d in theirdiet, excreted a daily average of 2–10 µg Cr/L urine.65
The urinary half-life of hexavalent chromium rangesfrom 15–41 h.56,66 Erythrocytes release chromium slowlyand kinetic studies suggest the possibility of limited re-lease of chromium from a slow compartment (t1/2 5months–few years).67,68 Biliary excretion accounts forabout 10% of the elimination of chromium with smalleramounts of chromium appearing in hair,69 milk, nails, andsweat.
Pregnancy and Lactation
Hexavalent chromium traverses the placenta, and themaximum level of chromium is present at birth in mosttissues with the exception of the lungs.70 Most samples
of breast milk from lactating women on regular diets con-tained ,0.4 µg Cr/L with a mean of about 0.3 µg/L.53
PATHOPHYSIOLOGY
Mechanism of Action
Trivalent chromium is an essential trace metal neces-sary for the normal metabolism of cholesterol, fat, andglucose. Although trivalent chromium has the potentialto form complexes with proteins and nucleic acids, hexa-valent chromium must first be converted to the trivalentstate before it combines with nucleic acids and proteins.12
Trivalent chromium forms tight bonds with oxygen- andsulfur-containing ligands and some chromium complexeswith histidine and cysteine are relatively inert because ofthese tight bonds.71 Trivalent chromium potentiates theaction of insulin, probably through a glutathione-likecomplex composed of niacin, trivalent chromium, andamino acids.72 Chromium deficiencies in the diet produceelevated circulating insulin concentrations, hyperglyce-mia, hypercholesterolemia, elevated body fat, decreasedsperm counts, reduced fertility, and a shortened life span.
Mechanism of Toxicity
Hexavalent chromium is a skin and mucous mem-brane irritant as well as a powerful oxidizing agent. Somechromium compounds (chromic acid, ammonium or po-tassium dichromate,73 chromium sulfate) are strong cor-rosives. Hexavalent chromium, and to a much lesser ex-tent, trivalent chromium are sensitizing agents capable ofproducing an allergic dermatitis. The primary risk factorsfor the development of chromium sensitization are priorirritation of the skin and the concentration of chromiumpresent at the surface of the skin. Co-exposure to othermetals (cobalt, nickel) is not a prerequisite for the devel-opment of chromium sensitization, although sensitizationto these metals may occur in the same individual.
The production of oxidative DNA damage may be theunderlying basis for the genotoxicity of hexavalent chro-mium compounds.2 However, the exact mechanism bywhich hexavalent chromium produces toxicity is notknown. Intracellular chemical intermediates (Cr (V), car-bon-based radicals) formed during the reduction of Cr(VI) to Cr (III) probably cause the genotoxicity associ-ated with hexavalent chromium.74 The major defenseagainst the action of hexavalent chromium in the lungsand the stomach is the reduction of hexavalent chromiumto trivalent chromium via an NADPH-dependent mecha-nism involving ascorbate. Animal studies indicate thatglutathione plays an important role in the reduction of
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hexavalent chromium in erythrocytes and also providessome reducing capacity in the lungs.75
Pathological Changes
Lung
Hexavalent chromium is a strong pulmonary irritantthat produces hyperemia,76 ulceration, and other inflam-matory changes in the mucosa of the respiratory tract fol-lowing inhalation. Additionally, hexavalent chromiumcompounds are pulmonary sensitizers that cause bron-chospasm and anaphylactoid reactions in sensitizedworkers.77 Trivalent chromium is a milder pulmonary ir-ritant compared with hexavalent chromium. Although tri-valent chromium is not a good sensitizer, exposure to tri-valent chromium may cause occupational asthma.78
Hexavalent chromium compounds are recognized hu-man carcinogens. Although all pathological types of lungcancer occur following exposure to hexavalent chro-mium, small-cell carcinomas, and to a lesser extent,poorly differentiated cancers predominate in postmor-tem investigations of chromium workers dying of lungcancer.79
Kidney
The acute ingestion of large amounts of hexavalentchromium produces acute tubular necrosis, marked inter-stitial changes, and renal failure.36,80 The association ofrenal tubular dysfunction with exposure of workers tohexavalent chromium compounds is equivocal, but thereis no apparent association of renal dysfunction with expo-sure to trivalent or metallic chromium. The glomeruliusually remain intact.81
Liver
Hepatic necrosis occurs after the acute ingestion ofvery large quantities of hexavalent chromium.42 Postmor-tem analysis of a patient who died of hepatorenal failure26 hours after receiving a purgative containing high lev-els of hexavalent chromium demonstrated that the chro-mium concentration in the liver was 20 times higher thanother tissues.82 Based on clinical reports, the dose ofhexavalent chromium required to produce renal toxicityis less than the dose necessary to produce hepatic ne-crosis.39,83
A study of 5 workers in the chrome plating industryassociated histological changes (lymphocytic and histio-cytic infiltrates, hyperplasia of Kupffer’s cells, necrosis)in the liver with exposure to hexavalent chromium.84
However, most epidemiological studies of workers have
not detected an increased incidence of liver damage.85 In-halation studies in rats have not confirmed the hepatotox-icity of hexavalent chromium at subacute doses of 0.4mg sodium dichromate for up to 90 days86 or at chronicdoses of 0.1 mg sodium dichromate.87
CLINICAL RESPONSE
Acute Systemic Toxicity
Acute chromic acid ingestion causes an acute gastro-enteritis with yellow-green vomitus or hematemesis, he-patic necrosis, gastrointestinal hemorrhage, and acutetubular necrosis with renal failure.38,39 An intravenouschromic acid exposure resulted in nausea, vomiting, darkred urine, loose reddish stool, and renal failure, whichrequired temporary hemodialysis.83 Additionally, the in-gestion of large doses hexavalent chromium causes ver-tigo, thirst, abdominal pain, bloody diarrhea, and in se-vere cases, coma and death. A hepatorenal syndrome,43
severe coagulopathy,41 or intravascular hemolysis88 mayoccur. If the patient survives the initial phase of shock,hepatic and renal failure may still develop within 1–2days. Occasionally, renal dysfunction may persist afterrecovery from the acute overdose of hexavalent chro-mium.82
Skin
Chromic acid is a corrosive that produces inflamma-tion and ulceration of the skin. Trivalent chromium gen-erally does not cause skin ulcers unless converted to thehexavalent form.89 The exception is chromium sulfate,which may produce a severe hemorrhagic gastroenteritisfollowing ingestion. Skin ulcers (chrome holes) developslowly in exposed areas of the body following exposureto hexavalent chromium, particularly in areas of the skinwhere there is a loss of integrity of the dermis. Thesepainless ulcers are usually well circumscribed with tena-cious crusts and healing often results in scarring.90 In ad-dition, chromic acid burns can cause systemic toxicityfollowing even relatively small burns. External burns of10% of the total body surface caused by chromic acidwere fatal in 1 case, whereas a 20% burn produced he-patic damage, acute renal failure, and a normochromicand normocytic anemia in another.91
Immunological Reactions
In addition to irritating effects, chromium compoundsproduce an allergic contact dermatitis characterized by
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Chromium 183
an acute or chronic eczema. Chromium sensitivity is aclassic delayed-type (class IV) hypersensitivity reaction.A lag phase of 14 days is necessary for sensitized, anti-gen-specific T-cells to form in the lymphatic system andpercolate into the skin. Subsequent dermal exposure tochromium releases cytokines and cytotoxic T-cells,which produce dermal inflammation. Although the con-centration of chromium in cement is small (,0.2%),chromium sensitivity is the most common type of sensi-tivity in cement workers. As many as 8–9% of cementworkers have positive patch tests for hexavalent chro-mium compounds, even though the incidence of allergicdermatitis is much less.92 A study of volunteers from areferral clinic indicated that sensitivity to chromates (VI)in that population averaged 1.7%,93 but the actual inci-dence for patients with normal skin and normal sensitiv-ity probably is much less (0.1%). The range of sensitivityto chromates in workers exposed to potassium chromatewhile handling automobile parts was much higher(24%).94 Sensitivity to trivalent chromium compounds israre compared with sensitivity to hexavalent chromiumcompounds, but patch testing indicates that some workerswith chromate sensitivity do react to high concentrationsof trivalent chromium compounds.95 Among constructionworkers, hexavalent chromate in cement is the most com-mon cause of allergic contact dermatitis. Over the lastseveral decades, the prevalence of allergic contact derma-titis in cement workers decreased as a result of the reduc-tion of hexavalent chromate in cement.96
Case reports have associated the development of occu-pational asthma in chromium-sensitized workers with thefollowing type of exposures: chromic acid vapors,77,97
metal plating with chromium,78 chromate spray paint,98
zinc chromate primer paint,97 and Cr (VI) fumes fromstainless steel welding.99 Inhalational challenges of chro-mates in chromium-sensitized workers produced angi-oedema, erythema, pruritus, cough, wheezing, and bron-chospasm.100
Chronic Toxicity
Chromate dusts cause conjunctivitis, lacrimation, noseand throat irritation, rhinitis, epistaxis, ulceration or per-foration of the nasal septum,85,101,102 and contact dermatitisdepending on the concentration of chromium.103 A smallexcess of deaths (SMR 5 143) due to chronic obstructivepulmonary disease was detected in chromate workerswhose employment began before 1945,104 but there wasno direct correlation between the presence of chromatesand the development of chronic obstructive pulmonarydisease in ferrochromium workers.105 Older studies of
chromate workers associated heavy exposure to chro-mates with sinusitis, laryngitis, nasal polyps, and bron-chitis.106,107
Mortality and morbidity studies of workers in the pro-duction of chromium compounds have not demonstratedan excess prevalence of liver disease.6 Studies of renalfunction in chrome platers suggest the possibility that ex-posure to hexavalent chromium concentrations in excessof Cr (VI) 4 µg/m3 produce renal tubular dysfunction asmanifest by increased urinary excretion of β2 microglob-ulin.108 However, no increase in urinary β2 microglobulinappeared in ex-chrome platers who worked .1 year inchrome plating plants.109 Other epidemiological studieson chrome platers110 and stainless steel welders111 havenot confirmed the association between renal tubular dys-function and exposure to hexavalent chromium. In addi-tion, occupational exposure to trivalent chromium in aferroalloy metallurgy plant112 and metallic chromium inan alloy steel plant113 has not been associated with renaleffects.
Carcinogenicity
Lung
The International Agency for Research on Cancer(IARC) and the US Toxicology Program recognize hexa-valent chromium as a known human carcinogen. Basedon positive responses in assays for genotoxicity, hexa-valent chromium is the most potent genotoxic chro-mium compound.2 The solubility of these hexavalentcompounds is a significant risk factor with the moder-ately soluble compounds (e.g., strontium and zinc chro-mates) associated with the greatest risk of developinglung cancer. The increased risk of lung cancer is associ-ated with the inhalation of hexavalent chromium in theoccupational setting, primarily in populations of workersrefining chromite ore or producing chromate pigments.114
Studies of end-users of chromate (e.g., painting opera-tions using chromate pigments) do not demonstrate astrong association between exposure to chromium com-pounds and the development of lung cancer.115 In the gen-eral population, no excess of tumors occurred in personsfrom areas with high concentrations of chromium pollu-tion.116 An increased incidence of lung cancer occurredin workers exposed to hexavalent chromium in chromateproduction (adjusted SMR 5 197)104 and in chromiumpigment production.5 The approximate 30–40% increasein the incidence of lung cancer in welders does correlatewell with exposure to hexavalent chromium, and a studyof welders demonstrated little difference in the rates oflung cancer between stainless steel welders (chromium,
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nickel exposure) and mild steel welders (no chromium,nickel exposure).117 Squamous- and small-cell carcino-mas are the predominant cell type with the developmentof small-cell carcinomas occurring after more intense ex-posures over shorter periods of time compared with theappearance of squamous-cell carcinomas.2 In general,water-soluble chromates (sodium and potassium chro-mate, dichromates) are more potent carcinogens than lesssoluble chromate compounds with the exception of cal-cium and zinc chromates.118
The risk of lung cancer following exposure to hexava-lent chromium increases with the duration of exposure,particularly after 30 years of exposure.119 The mean la-tency period ranges from 13–30 years, although a fewcases have appeared following 5 years of exposure tochromates.120 In the 1950s and 1960s, process modifica-tions (i.e., elimination of calcium chromate by changingto lime-free processes) and improved environmental con-trols reduced exposure to chromium compounds. A meta-analysis of cancer studies post-modification did not dem-onstrate a statistically significant excess of lung cancer;however, the combined studies lacked sufficient statisti-cal power to exclude a moderate increase in the risk oflung cancer.121 An etiological research study of 398 chro-mate workers at a new facility, where ,99% of the per-sonal breathing zone samples were ,50 µg Cr (VI)/m3,did not demonstrate increased mortality.122 The numberof subjects was small and the follow-up period was rela-tively short (15 years). The risk of cancer from dermalor oral exposures to hexavalent chromium compounds isnot well documented. Hexavalent compounds, for whichthere is evidence in animal studies for carcinogenicity,include the following: barium chromate, calcium chro-mate, chromium trioxide, lead chromate, sodium dichro-mate, and strontium chromate.
Non-Pulmonary Sites
A review of the carcinogenicity of hexavalent chro-mium indicated that there is suggestive evidence of anincreased risk of cancer in nonpulmonary sites (bone,stomach, prostate, genital, renal, bladder, blood [lympho-mas, Hodgkin’s, leukemia]).123 However, the evidencecited for this conclusion primarily involved mortalitystudies, many of which demonstrated nonsignificant in-creases in the SMR. Furthermore, the author failed to dis-cuss the inherent weakness of mortality studies (selectionbias, accuracy of exposure data, confounding) and thelack of well-designed cohort studies to support the devel-opment of cancer at sites distant from the sites of admin-istration. For example, most of the studies cited for stom-
ach cancer contained small numbers of observed casesand nonsignificant increases in the SMR.124,125 Althoughindividual studies suggest the possibility of an excess in-cidence of cancer at sites outside the lungs (nose, gastro-intestinal tract), results from these studies are inconsis-tent.104,126 For example, the previous relationship betweensinonasal cancer and chromates was complicated by co-exposure to sawdust.127 A review of the chromium dataindicated that heterogeneity of reporting and reportingbias precluded the use of meta-analysis to determine theincidence of cancer at sites outside the lung.121
Elemental and Trivalent Chromium
Based on animal studies, there is inadequate evidenceof carcinogenicity for metallic Cr (0) and for some Cr(III) compounds (chromic oxide, chromium acetate).There is no direct evidence that trivalent chromium is acarcinogen and epidemiological studies of workers ex-posed to trivalent chromium in the ferrochromium indus-try did not reveal an increased incidence of cancer.128 Inexperimental studies, Cr (III) compounds produce ge-netic changes only in acellular or in subcellular systems.Trivalent chromium compounds exhibit no genetic activ-ity in cellular systems, probably because these com-pounds do not cross cell membranes.129
Reproductive Abnormalities
Reproductive data in humans are limited. A study of30 tungsten inert gas stainless steel welders exposed tolow concentrations of hexavalent chromium did not re-veal serious effects on spermatogenesis.130 Histologicalstudies of rats exposed to Cr (VI) 15.5 mg/m3 for 2 yearsdid not demonstrate pathological changes in the sex or-gans.131 Large oral doses (Cr (VI) 57 mg/kg/d) of potas-sium dichromate in drinking water caused severe devel-opmental and fetal toxicity in rats including increasedpost-implantation loss, decreased cranial ossification, anddecreased fetal weight.132
LABORATORY
SI Units
1 µmol 5 52 µg Cr1 µg Cr 5 0.019 µmol 5 19 nmol
Analytical Methods
The ubiquitous presence of chromium in laboratoriesand the low sensitivity of most methods require careful
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handling of the sample in the laboratory. Some plasticcontainers contain significant amounts of leachable chro-mium, and therefore special acid-washed specimen con-tainers are necessary. Stainless steel utensils, scalpels, ortrays should not be used to collect tissue specimens foranalysis of chromium levels. Generally, available tech-niques do not separate trivalent chromium from hexa-valent chromium. Graphite furnace atomic absorptionspectrometry is the most common method used to deter-mine chromium concentrations in biological samples, butappropriate background correction methods are neces-sary to insure accuracy.133
Concentrations in Humans
Blood
Plasma chromium levels reflect recent exposure bothto hexavalent and to trivalent chromium, whereas intra-cellular chromium concentrations reflect the burden ofhexavalent chromium because only hexavalent chro-mium penetrates red blood cells. Consequently, concen-trations of chromium in erythrocytes indicate the extentof exposure to hexavalent chromium during the lifetimeof the red blood cell. Low concentrations of chromium inred blood cells imply that the concentration of hexavalentchromium did not significantly exceed the plasma reduc-ing capacity for Cr (VI). Chromium studies in a patientwith acute dichromate (VI) poisoning indicated that theconcentration of hexavalent chromium in erythrocytesexceeded the plasma chromium concentrations by 4- to6-fold and therefore the whole blood chromium wouldbe approximately 2–3 times higher than the plasmachromium.82 Serum concentrations for individuals inthe general population with no occupational exposureto chromium are between 1–3 nmol/L (0.052–0.156(µg/L).134 Whole blood concentrations of 2–3 mg Cr/Lare lethal.
Urine
Urine chromium concentrations reflect absorption ofchromium primarily over the last 1–2 days. Although tri-valent chromium does contribute somewhat to the totalchromium concentration, substantial portions of the totalchromium result from the reduction of hexavalent chro-mium. Most analytical methods do not distinguish be-tween trivalent and hexavalent chromium. Typically,urine concentrations are ,10 µg Cr/L for patients withnormal exposures to chromium compounds. The upper95% reference limit in Finnish subjects without occupa-tional exposure to chromium was 0.52 µg (0.01 µmol)
Cr/L.135 In a study (National Health and Nutrition Exami-nation Survey [NHANES III]) of the US population, the95 percentile concentration was 0.7 µg Cr/L as mea-sured by inductively coupled argon plasma mass spec-trometry.136 The mean concentration in the urine of non-exposed workers was 0.11 6 0.04 µg Cr/g creatinine.137
Substantial individual variation in urine chromiumconcentrations occurs between individuals as a result ofvariations in the reductive capacity for hexavalent chro-mium.138 Consequently, in a selected population of‘‘strong reducers,’’ relatively high urine chromium con-centrations may reflect more efficient elimination pro-cesses rather than a higher risk of toxicity. In chromeplaters exposed to much higher chromium levels com-pared with the general population, the rapid initial phaseof the renal elimination of chromium is followed by aslow phase characterized by an elimination half-life ofabout 1 month.139
Hair
The use of hair analysis in the occupational settingis complicated by the difficulty distinguishing chromiumbound to the hair after absorption from chromium depos-ited via external sources. Chromium concentrations inhair are up to 1000 times higher than the concentrationsin serum. One study of tannery workers indicated thatchromium hair concentrations were an index to exposureto trivalent chromium.140
Ancillary Tests
In general, the evaluation of a patient exposed to largedoses of chromium should include a urinalysis and CBCas well as assessment of liver and kidney function. Con-centrations of chromium in the blood and urine documentthe extent of absorbed chromium when collected within 2days of exposure and analyzed as discussed above. Somehexavalent chromium compounds are strong oxidizersand therefore methemoglobinemia potentially may de-velop. Following exposure to high ambient air concentra-tions of chromium, the evaluation should include a chestX–ray (pulmonary edema, infiltrates) and pulmonaryfunction tests. Testing the urine for low molecular weightproteins (β2 microglobulin, retinol binding protein) helpsdetect subtle changes in renal proximal tubule functionof subjects exposed to low concentrations of chromium,but the significance of any elevations of these biomarkersas predictors of chronic renal dysfunction remains un-clear.
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HEALTH SURVEILLANCE
Medical Monitoring
Medical surveillance of workers exposed to hexava-lent chromium involves a pre-placement and annualphysical examination that includes the following: (1)comprehensive work and smoking history, (2) potentialconditions that would be exacerbated by exposure tochromium (skin and pulmonary sensitization, skin or mu-cous membrane diseases, kidney disease), and (3) evi-dence of dermatitis, mucous membrane irritation, orchrome ulcers. Routine laboratory tests include urinaly-sis, chest X-ray, and kidney function tests. Although an-
Table 3
Respirator Selection Guide for Protection Against Noncarcinogenic Cr (VI)
Multiples of TWA Limit Respirator Type
Less than or equal to 103 Half-mask respirator with replaceable high efficiency filter(s).or
Type C supplied-air respirator, demand type (negative pressure), withhalf-mask facepiece.
Less than or equal to 103 Full facepiece respirator with replaceable high efficiency filter(s).or
Type C supplied-air respirator, demand type (negative pressure), withfull facepiece.
orSelf-contained breathing apparatus in demand mode (negative pressure),
with full facepiece.Less than or equal to 2003 Powered air-purifying (positive pressure) respirator with high efficiency
filter(s).Greater than 2003 Self-contained breathing apparatus with positive pressure in full face-
piece.or
Combination supplied-air respirator, pressure-demand type, with auxiliaryself-contained air supply.
Emergency (no concentra- Self-contained breathing apparatus with positive pressure in full face-tion limit) piece.
orCombination supplied-air respirator, pressure-demand type, with auxiliary
self-contained air supply.Evacuation or escape Self-contained breathing apparatus in demand or pressure-demand mode
(no concentration limit) (negative or positive pressure).or
Gas mask, Type N, with high efficiency filter, and mouthpiece respiratorwith high efficiency filter(s).
Note: A high efficiency filter is defined as a filter having an efficiency of at least 99.97% against 0.3 µm DOP (Dioctyl Phthalate).From NIOSH Recommended Standard for occupational exposure to chromium (VI), USHEW 1979.
nual chest x-rays are recommended after the age of 40,a study of chromate workers did not detect a significantimprovement in 5-year survival of workers in the screen-ing program.141 Table 3 lists the respiratory protection re-quired for protection against high levels of hexavalentchromium.
Biological Monitoring
Table 4 lists the recommendations and standards forexposure to chromium, including the recommendationsof the American Conference of Governmental and Indus-trial Hygienists (ACGIH) for biological monitoring. Nor-
50 µg/m3 15-minute ceiling limit for noncarcinogenic Cr (VI)salts
OSHA Air-Workplace 100 µg/m3 Regulation: PEL‡ for chromic acid and chromates(ceiling)
500 µg/m3 PEL‡ for soluble chromic salts (8-hour TWA†)1000 µg/m3 PEL for chromium metal and insoluble salts
(8-hour TWA†)EPA Air-Environment N/A Under review
Drinking-Water 50 µg/L Regulation: current MCL§ for total chromium;proposed MCL is 100 µg/L
*ACGIH: American Coference of Governmental Industrial Hygienists; NIOSH: National Institute for Occupational Safety and Health;OSHA: Occupational Safety and Health Administration; EPA: Environmental Protection Agency. †TWA (Time-Weighted Average):time-weighted average concentration for a normal workday and 40-hour workweek to which nearly all workers may be repeatedlyexposed. ‡PEL (Permissible Exposure Limit): an allowable exposure level in workplace air. §MCL (Maximum Contaminant Level):enforceable standard for drinking water. Reprinted with permission from reference 4, table 1 with updates per ACGIH 1998.
mal chromium concentrations in workers must be inter-preted cautiously because of the low sensitivity of currentmethods and the ubiquity of chromium in laboratories.After several weeks of exposure to water soluble hexava-lent chromium, the end-of-shift, end-of-workweek uri-nary chromium concentration should not exceed 30 µgCr/g creatinine and the increase during a shift should notexceed 10 µg Cr/g creatinine.142 In a study of 16 workersfrom an aircraft construction factory using hexavalentchromium adhesives, the exposure to airborne chro-mium was low (0.2–1.5 µg Cr/m3).137 The correspondingamount to chromium in the urine also was low (0.16–7.74 µg Cr/g creatinine). Urine chromium concentrationsbetween 10–40 µg Cr/L correlate with external exposureto Cr (VI) 100 µg/m3.143 Confounding factors for in-
creased urinary chromium include beer drinking, diabe-tes, occupational exposure to chromium, chromium sup-plementation, prostheses with chromium-containingalloys,144,145 and exercise; however, these factors do notaffect the concentration of chromium in erythrocytes.146
The concentrations of chromium in the erythrocytemay be a selective indicator of exposure to hexavalentchromium because Cr (VI) is preferentially deposited inthe red blood cell for its lifetime (110 days).147 AlthoughCr (III) does not easily penetrate the erythrocyte, Cr (VI)is reduced in the erythrocyte to Cr (III).148 Insufficientdata are available presently to correlate the developmentof lung cancer with the ratio of plasma and erythrocytechromium concentrations. Substantial differences in theability of individuals to reduce chromium in plasma com-
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plicate the interpretation of chromium concentrations inerythrocytes. Individuals, who reduce Cr (VI) quickly,have relatively high urinary chromium levels and rela-tively low blood chromium levels compared with slowreducers.
A study of welders exposed to chromium and nickeldemonstrated a statistically significant increase in the rateof DNA single-strand breakage and in the sister chroma-tid exchange frequencies when compared with unexposedcontrols.149 However, there was no significant correlationbetween these measures and the results of the urine chro-mium or nickel concentrations. Almost all of the urinesamples for the biological monitoring of these workerswere below the current Biological Exposure Indices rec-ommended by the ACGIH.
TREATMENT
Treatment is symptomatic. The efficacy of BAL, he-modialysis, and exchange transfusion has not been estab-lished.
First Aid
Dilution is the preferred first aid measure for the in-gestion of hexavalent chromium compounds because ofthe corrosive properties of hexavalent compounds. Tri-valent chromium compounds are less toxic and are notcorrosive. Therefore, syrup of ipecac would be appro-priate only for very large ingestions of the trivalent com-pound that present within 1 hour of ingestion. Dermalexposure to chromic acid requires careful decontamina-tion with copious amounts of saline. Systemic toxicitymay result from relatively small burns (1%) even afterdecontamination.
Chromic acid produces severe injury to the corneacharacterized by infiltration, vascularization, and opaci-fication. Following instillation of chromic acid in the eye,the eye should immediately be irrigated copiously withsaline for at least 15–20 minutes or until the pH normal-izes in the conjunctival sac. Subsequently, the eye shouldbe evaluated by slit lamp examination to determine theextent of injury.
Gut Decontamination
Patients who ingest large doses of hexavalent chro-mium usually vomit profusely. Syrup of ipecac is not rec-ommended for hexavalent compounds because of their
strong oxidizing properties. If the patient presents within1–2 hours of ingestion, the careful insertion of a soft tubeis appropriate in order to aspirate and to lavage the stom-ach. Insufficient data are available to recommend the useof lavage with magnesium hydroxide. Although ascorbicacid reduces the more soluble chromium compounds(hexavalent) to the relatively poorly soluble ones (triva-lent) in vitro,150 there are no data on the effectiveness ofascorbic acid to reduce the absorption of chromium (VI)when administered following lavage. Activated charcoalprobably does not bind chromates well.
Chelation
No adequate chelation measures are available. N-acetylcysteine (NAC) is a potential antioxidant based onanimal studies,151 but human data are inadequate to evalu-ate the effectiveness of this regimen.
Antidotes
There are no antidotes.
Enhancement of Elimination
Exchange transfusion may reduce serum chromiumconcentrations,152 but data are not available to confirmthat these measures alter clinical outcome. A double-volume exchange transfusion removed only 3.77 mgchromium and 3 hours of hemodialysis removed only0.17 mg chromium from a child, who had ingested anestimated 1 g ammonium dichromate.153 Hemodialysis isprimarily a supportive modality rather than a method toenhance elimination.154 Studies in dogs indicate that char-coal hemoperfusion removes only 1% of the estimateddose of chromium (VI) following an acute dichromatepoisoning.155 Peritoneal dialysis does not effectively re-move chromium from the blood. After 19 peritoneal dial-ysis runs, the clearance of chromium from the blood wasabout 24 mg/d in a child, who died after ingesting potas-sium chromate, despite a reduction in the serum chro-mium from 580 to 30 mg/dL.142
Supportive Care
General
Endoscopy may be necessary to evaluate the extentof esophageal and gastric burns. Renal failure generallyoccurs within 1–2 days of exposure and patients hospital-ized for serious ingestions of chromates should be moni-
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tored for the development of renal failure. Supportivecare includes the monitoring of renal and hepatic functionas well as the correction of any fluid or electrolyte imbal-ance. Alkalinization of the urine may be necessary if he-molysis develops. Liver transplantation is an option whensevere hepatocellular necrosis results from the ingestionof potassium dichromate.156
Ascorbic Acid
The intravenous administration of large doses (3 gascorbic acid over 30–60 minutes) has been recom-mended for the reduction of chromate-induced renal tox-icity based on uncontrolled, in vitro studies, which indi-cate that ascorbic acid reduces hexavalent chromium tothe less toxic trivalent form.157 Subsequent animal studiesindicated that large parenteral doses (0.5–5 g/kg) ofascorbic acid prevented renal toxicity only when adminis-tered within 1–2 hours following the administration ofchromate.158,159 In these studies, the later administrationof ascorbic acid was associated either with no effect orwith increased nephrotoxicity. There are no clinical stud-ies to support the use of ascorbic acid after the ingestionof Cr (VI) compounds or to determine the potential com-plication (e.g., oxaluria) of this therapy. A 24-month-oldchild recovered from the ingestion of up to 50 mL 10%sodium dichromate (initial serum chromium 210 (g/L)without the development of renal toxicity.160 Supportivecare included the daily administration of ascorbic acid(1 g via nasogastric tube) as well as peritoneal dialysisand British Anti-Lewisite (BAL) therapy. A 49-year-oldworker received burns over 40% of his body from contactwith hot chromic acid (25% sulfuric acid).161 Despite theuse of 5 g ascorbic acid per day beginning on the day ofinjury, the patient developed anuria on the 2nd day anddied on the 6th day.
Skin
The topical application of 1% aluminum acetate wetdressings is an anecdotal treatment for chrome ulcersalong with topical ascorbic acid. An animal study demon-strated that the application of 10% ascorbic acid within30 minutes of the initiation of chrome ulcers significantlyreduced the healing times of these ulcers.162 This non-blinded study did not use statistical analysis to comparetreatment times with controls. There are also case reports,which associate the use of a 10% ascorbic acid as a pre-ventive cream with the resolution of chromate-induceddermatitis over a period of several months,163,164,165 butthere are no clinical studies that compare the healing
rate of chromate-induced dermatitis with controls (noascorbic acid).
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