TOXICOLOGY AND APPLIED PHARMACOLOGY

ARTICLE NO.

141, 145158 (1996)

0271

Absorption and Elimination of Trivalent and Hexavalent Chromium in

Humans Following Ingestion of a Bolus Dose in Drinking Water
B. D. KERGER,* D. J. PAUSTENBACH, G. E. CORBETT,*

AND

B. L. FINLEY

*McLaren/HartChemRisk, 16755 Von Karman Avenue, Irvine, California 92606; and McLaren/HartChemRisk,
1135 Atlantic Avenue, Alameda, California 94501
Received February 21, 1996; accepted June 29, 1996

Absorption and Elimination of Trivalent and Hexavalent Chromium in Humans Following Ingestion of a Bolus Dose in Drinking
Water. KERGER, B. D., PAUSTENBACH, D. J., CORBETT, G. E., AND
FINLEY, B. L. (1996). Toxicol. Appl. Pharmacol. 141, 145158.
These studies investigate the magnitude and valence state of
chromium absorbed following plausible drinking water exposures
to chromium(VI). Four adult male volunteers ingested a single
dose of 5 mg Cr (in 0.5 liters deionized water) in three chromium
mixtures: (1) Cr(III) chloride (CrCl3), (2) potassium dichromate
reduced with orange juice (Cr(III)-OJ); and (3) potassium dichromate [Cr(VI)]. Blood and urine chromium levels were followed
for 13 days prior to and up to 12 days after ingestion. The three
mixtures showed quite different pharmacokinetic patterns. CrCl3
was poorly absorbed (estimated 0.13% bioavailability) and rapidly
eliminated in urine (excretion half-life, 10 hr), whereas Cr(III)OJ was absorbed more efficiently (0.60% bioavailability) but more
slowly (half-life, 17 hr), and Cr(VI) had the highest bioavailability (6.9%) and the longest half-life (39 hr). All three chromium
mixtures caused temporary elevations in red blood cell (RBC) and
plasma chromium concentrations, but the magnitude and duration
of elevation showed a clear trend (Cr(VI) Cr(III)-OJ CrCl3).
The data suggest that nearly all the ingested Cr(VI) was reduced
to Cr(III) before entering the bloodstream based on comparison
to RBC and plasma chromium patterns in animals exposed to
high doses of Cr(VI). These findings support our prior work which
suggests that water-soluble organic complexes of Cr(III) formed
during the reduction of Cr(VI) in vivo explain the patterns of
blood uptake and urinary excretion in humans at drinking water
concentrations of 10 mg/liter or less. q 1996 Academic Press, Inc.

Many studies have examined the pharmacokinetics of hexavalent chromium using radiolabeled compounds or total
chromium measurements, but definitive information on the
process of Cr(VI) reduction in vivo is not available. Hexavalent chromium [Cr(VI)] is much more toxic than trivalent
forms [Cr(III)] (OFlaherty, 1993, 1994; Anderson, 1994)
and is readily reduced to Cr(III) by organic materials in
many exogenous and endogenous media (De Flora et al.,
1987; De Flora and Wetterhahn, 1989; Kerger et al., 1996b).
The United States Environmental Protection Agency

(USEPA) and other groups have concluded that low doses of

Cr(VI) ingested orally are readily reduced prior to systemic
uptake (USEPA, 1991). A recent study in our laboratory
indicated that ingestion of low doses of Cr(VI) results in a
pattern of chromium distribution and excretion consistent
with absorption as water-soluble Cr(III) organic complexes
(Kerger et al., 1996a). The current study was designed to
examine differences in absorption and elimination of ionic
and organic complex forms of chromium to further elucidate
the process of Cr(VI) reduction in humans.
Urinary excretion of total chromium has been used for
decades as a biomonitoring tool to evaluate exposure to chromium compounds in occupational settings (Gylseth et al.,
1977; Lindberg and Vesterberg, 1983a,b; Mutti et al., 1985;
Minoia and Cavalleri, 1988). A recent study by Finley et al.
(1996) showed that significant increases in urinary chromium concentrations were observed in human volunteers
who ingested gelatin capsules containing the USEPA oral
reference dose of 0.005 mg Cr(VI)/kg-day (Finley et al.,
1996). Although comparison of urinary chromium concentrations to the administered dose provides an estimate of
the amount of chromium systemically absorbed, it does not
provide an indication of the valence state in which it was
absorbed. There are organic complex forms of nontoxic trivalent chromium that are fairly well absorbed, e.g., chromium from Brewers yeast is absorbed 10 to 25% orally
(Mertz, 1975). Therefore, elevated urinary chromium levels
can be misleading if interpreted as a biomarker for Cr(VI)
exposure and/or toxicity.
The concentration of total chromium in red blood cells
(RBCs) is a more specific biomarker for characterizing recent exposure to Cr(VI) (Lewalter et al., 1985; Korallus,
1986b). Hexavalent chromium compounds that enter the
bloodstream are actively transported into RBCs via sulfate
anion channels (Ottenwaelder and Wiegand, 1988; Wiegand
et al., 1988) (Fig. 1). Once inside the RBC, the Cr(VI) is
rapidly reduced to unstable intermediates (i.e., short-lived
Cr(V) and Cr(IV) species) which become bound to hemoglobin and other intracellular proteins (Gray and Sterling, 1950;

145

AID

TOX 7948

6h12$$$301

10-08-96 09:15:40

0041-008X/96 $18.00
Copyright q 1996 by Academic Press, Inc.
All rights of reproduction in any form reserved.

toxas

AP: Tox

146

KERGER ET AL.

Lewalter et al., 1985; Ottenwaelder and Wiegand, 1988;

Wiegand et al., 1988; Coogan et al., 1991; Miksche et al.,
1994), resulting in increased total chromium levels that remain elevated in the RBC fraction of blood for several
weeks. Animal studies have demonstrated this distinctive
elevation in RBC chromium concentrations following intratracheal or intravenous exposures to Cr(VI), also reporting
that concurrent plasma chromium concentrations drop off in
a matter of days (Gray and Sterling, 1950; Weber, 1983;
Edel and Sabbioni, 1985; Wiegand et al., 1988). Therefore,
the demonstrated pattern for Cr(VI) uptake into the blood is
one in which RBC and plasma chromium levels rise rapidly
and concurrently to a peak, and then RBC chromium levels
remain consistently elevated for weeks while plasma chromium levels return rapidly to background.
In contrast to Cr(VI), Cr(III) in the bloodstream can become associated with RBCs and plasma in a more rapidly
reversible manner (Gray and Sterling, 1950; Wiegand et al.,
1988) and its distribution and excretion characteristics are
highly dependent on the chemical form(s) administered and/
or formed in vivo (Mertz, 1975; Gonzalez-Vergara et al.,
1981; Edel and Sabbioni, 1985; Lewalter et al., 1985; Kortenkamp and Beyersmann, 1987). Consequently, the observation of RBC and plasma chromium concentrations over
time can give specific insights as to the magnitude of Cr(VI)
versus Cr(III) uptake and distribution in the body and is
useful to help identify in vivo thresholds for Cr(VI) reduction
and detoxification.
Several studies have shown that there are many sources
of high-capacity reducing agents within fluids and tissues of
the body that can severely limit the possibility that Cr(VI)
will reach organs outside the stomach following ingestion
of plausible drinking water levels. In this and other recent
studies, we have assumed that plausible drinking water concentrations of Cr(VI) are below 10 mg/liter based on the
occurrence of bright yellow coloring in the range 15 mg/
liter (Kerger et al., 1996b). We recently showed that several
common beverages (e.g., coffee, tea, orange juice, powdered
drink mixes) that might be mixed with drinking water can
readily reduce all the Cr(VI) at concentrations of at least 8
mg Cr(VI)/liter (Chute et al., 1996; Kerger et al., 1996b).
Hexavalent chromium can be rapidly and completely reduced to trivalent chromium at low pH upon contact with a
variety of organic substrates (e.g., glutathione, amino acids,
ascorbate, citrate), and/or in the presence of certain metals
and other reducing environments commonly found in body
tissues and fluids. For example, a high capacity for reduction
of Cr(VI) has been demonstrated in the gastric juice of the
stomach, accounting for the reduction of perhaps more than
80 mg of Cr(VI) per day to Cr(III) (Donaldson and Barreras,
1966; De Flora et al., 1987; De Flora, 1996). A somewhat
lower reduction capacity has been identified for saliva, gas-

AID

TOX 7948

6h12$$$302

10-08-96 09:15:40

trointestinal bacteria, and blood plasma (Korallus et al.,

1984; Petrilli and De Flora, 1988; De Flora et al., 1989;
Capellmann and Bolt, 1992), which also may reduce milligram quantities of ingested Cr(VI). Further, red blood cell
lysates have a substantial and regenerable capacity to reduce
100 mg of Cr(VI) based on the hematocrit of an average
adult (De Flora and Wetterhahn, 1989; De Flora, 1996). And
finally, essentially all tissues possess a similar high capacity
to reduce Cr(VI) to Cr(III), especially the liver, which is
responsible for first pass effect biotransformations of
many chemicals (Sipes and Gandolfi, 1991). Therefore,
many potential barriers exist to limit the uptake and distribution of Cr(VI) following oral exposure.
Based on available data, the acute and chronic hazard
following oral ingestion of low doses of Cr(VI) in humans
(e.g., less than 10 mg/day) should be minimized by the reduction potential of the gastrointestinal system and other
organs/tissues. For example, MacKenzie et al. (1958)
showed that rats exposed for 1 year to 25 mg Cr(VI)/liter
in drinking water (2.4 mg/kg-day) did not exhibit frank signs
of oral or gastrointestinal tissue irritation or other adverse
health effects (MacKenzie et al., 1958). The USEPA 10day health advisory for total chromium in drinking water
(USEPA, 1996) is equivalent to 0.14 mg/kg-day (incorporating a 100-fold safety factor), which is based on a 60-day rat
study of drinking water at up to 134 mg Cr(VI)/liter (14.4
mg Cr(VI)/kg-day) showing no adverse effects (Gross and
Heller, 1946). The adult (70 kg) equivalent to the USEPA
10-day health advisory corresponds to a safe daily dose of
9.8 mg Cr(VI) per day. This amount falls well below the
daily reduction capacity for the human stomach (De Flora
et al., 1987; De Flora, 1996).
The purpose of this study was to examine the pharmacokinetics following single bolus oral exposure to low doses of
Cr(VI) and two forms of Cr(III) via drinking water. Urine
was collected for the duration of the experiment (pre- and
postdosing) and blood was collected (RBCs and plasma) at
specified times before and after dosing for analysis of each
for total chromium. The specific objectives of this study
were to (a) measure total urinary excretion of chromium as
a direct measure of absorption, (b) determine to what degree
the reduction of Cr(VI) in orange juice (i.e., formation of
Cr(III)-organic complexes) changes the blood uptake and
excretion patterns as compared to CrCl3 and Cr(VI), (c) determine to what extent the three mixtures affect chromium
content in RBCs and plasma (biomarkers of exposure), and
(d) determine the bioavailability and half-life of urinary excretion in humans for each mixture.
METHODS
Absorption and elimination rates were evaluated after ingestion of
single doses of three different chromium compounds: (1) chromic (III)

toxas

AP: Tox

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

chloride, (2) potassium dichromate reduced completely to Cr(III) in orange juice and diluted in water, and (3) potassium dichromate in water.
Each of these experiments was conducted 30 to 60 days apart. In each
experiment, 5 mg chromium was ingested in 0.5 liters of deionized water
(0.5 liters of 10.0 ppm Cr), with the entire dose being swallowed by
each volunteer within 2 min.
Human Use Committee
A Human Use Committee composed of three board-certified occupational
physicians and one board-certified toxicologist (each was a university faculty member) reviewed the study protocol prior to initiation. The committee
concluded that the study design was adequate to satisfy the objectives and
that the doses would not pose a health risk to the participants. The committee
concluded that the participants were properly informed of the reported
adverse health effects associated with exposure to chromium.
Description of Human Volunteers
Eight volunteers were included in the single dose experiments, including
seven healthy, male, Caucasian volunteers (ages 2166) weighing 160
220 pounds and one healthy, female, Caucasian (age 28, 135 pounds). Each
had formal college training in toxicology. Prior to participation in the study,
all individuals completed a consent form, as well as a questionnaire regarding basic physiological and medical information. No medical conditions
that would preclude participation in the study were reported. For the study
wherein potassium dichromate [Cr(VI)] was ingested, only those having
received graduate-level training in toxicology participated since we wanted
to ensure that informed consent was obtained.
Preparation of Cr(VI) Drinking Water
Potassium dichromate (K2Cr2O7) was used as the source of soluble
Cr(VI), and chromic trichloride was used as the source of soluble Cr(III).
The Cr(VI) mixture was prepared for each participant by pipetting an aliquot
from a 1000 mg/liter standard solution (Fluka Chemical Corp., Ronkonkoma, NY) into a 0.5-liter volume of deionized water. The Cr(VI)orange
juice solution was prepared by adding the same aliquot to approximately
300 ml of single strength orange juice from concentrate that had been
strained of pulp solids prior to mixing. This solution was then brought to
a 0.5-liter volume using deionized water. The chromic trichloride solution
in deionized water1 was prepared from a 1000 mg/liter stock solution prepared from the 99% pure solid (J. T. Baker & Co., Phillipsburgh, NJ). All
drinking water samples were assayed for both Cr(VI) and total chromium
concentrations at MBT Environmental Laboratories (Rancho Cordova, CA)
using EPA Methods 218.6 and 7196, respectively, prior to ingestion by the
volunteers. Water containing 10.0 mg Cr(VI)/liter (ppm) was noted to have
a bright yellow color.
Record Keeping and Dosing Regimens
Diet was not controlled in this study. The participants followed their
normal food and liquid intake practices with the exception that they were
prohibited from ingesting vitamin supplements containing vitamin C or
chromium. Because many foods contain varying amounts of chromium, a

1
A chromic trichloride plus orange juice group was not studied here
because the orange juice was intended to mimic the in vivo reduction process
of gastric juices/contents. There is limited evidence that high doses of
ascorbate (60 mg/kg) in guinea pigs may alter the disposition of zinc, iron,
and manganese (Seaborn et al., 1994); however, the relevance of these
findings to the relatively small amount of ascorbate remaining after Cr(VI)
reduction in orange juice in the current study is unclear.

AID

TOX 7948

6h12$$$302

10-08-96 09:15:40

147

detailed log of each participants beverage, food, and dietary supplement

intake was maintained throughout the duration of the study. The participants
also recorded any physical activity (exercise) other than normal daily activity which might affect urinary creatinine measurements.
Each urine void was collected and assayed separately throughout the
study, which resulted in the analysis of nearly 1000 samples for these
studies. Blood samples were collected at prescribed times as shown in Figs.
3, 5, and 7. The three different forms of chromium were ingested at a
concentration of 10.0 mg Cr/liter in a total volume of 0.5 liters.
Collection of Urine Samples
In all three experiments, urine voids were collected starting from Day 1
(beginning with the first morning void) through the last day of study (including the last void before bedtime or until midnight). Each sample was collected in a separate, labeled 500-ml polyethylene container. Labels provided
the following information: study participant number, study day, number of
void for the day (no. 1 for the first void of the day and all others numbered
consecutively), and date and time of collection. Samples were stored at
refrigerator temperatures until packed for shipment. All urine samples were
delivered overnight via Federal Express in coolers containing ice packs and
a copy of the chain-of-custody forms to the National Medical Services
(NMS) Laboratory (Willow Grove, PA).
Collection of Blood Samples
The participants were assigned (according to their geographic location)
to a medical clinic which collected the blood samples for analysis. In all
three phases of the study, blood samples were drawn, centrifuged, and
pooled for analysis of plasma and RBCs at designated intervals. The vials
used in the blood draw were glass vacutainer tubes with royal blue tops
(made by BectonDickinson or Sherwood Medical) which contained an
ethylenediamine tetra-acetate (EDTA) anticoagulant and were guaranteed
to have a low metals content. The negligible concentration of Cr in the
vials was validated through separate testing (contribution, 0.4 mg Cr/liter;
see Paustenbach et al., 1996). The plasma and RBC samples were sent to
NMS Laboratories via overnight delivery and were analyzed for chromium
content within 48 hr of collection. Three other analytical issues regarding
blood collection and chromium analyses were investigated in preliminary
studies (data not shown). First, it was determined that the vacutainer needles
used for venipuncture did not add measurable chromium to the blood (0.1
mg/liter; see Paustenbach et al., 1996). Second, we investigated whether
EDTA could influence Cr(VI) reduction or total chromium concentration
by examining these parameters in blood serum (no anticoagulant) with and
without the EDTA at relevant concentrations. No effects were found in
these experiments, but it cannot be excluded based on our data whether
EDTA has some consistent influence on the distribution of chromium between RBC and plasma. Third, we performed identical studies where background and elevated blood samples were collected and analyzed for chromium when sent to the laboratory (a) not centrifuged or separated into RBC
and plasma or (b) centrifuged immediately after collection and placed in
separate plasma and RBC fraction containers. Again, no influence on chromium concentration or RBC/plasma distribution was associated with these
variables.
Prior to and following ingestion of the chromium solution in each experiment, each volunteer had clinical screening tests performed, including a
complete blood count, clinical chemistries (SMA-20), and urinalysis. The
purpose of these clinical tests was to identify any significant changes in
these parameters that might have been due to exposure.
Laboratory Methods and Quality Control: Total Chromium Analyses
Urine analyses. All urine samples were analyzed for total chromium,
total urine volume, specific gravity, and creatinine at NMS Laboratories.

toxas

AP: Tox

148

KERGER ET AL.

An Atago Uricon-N urine specific gravity refractometer (NSG Precision

Cells, Farmingdale, NY) was used to determine urine specific gravities.
An alkaline picrate procedure (Instrumentation Laboratory Monarch 2000,
Instrumentation Laboratory, Lexington, MA) was used to measure urinary
creatinine. Urinary creatinine was used to correct for urine volume differences between samples due to variable fluid intakes by the participants.
The concentration of total chromium was determined using a PE-4100 ZL
graphite furnace atomic absorption spectrometer (AAS) according to EPA
Method 218.2 as modified by Paustenbach et al. (1996). The limit of detection was 0.5 mg Cr/liter urine. The concentrations of total chromium in the
samples were then obtained from a calibration curve of total chromium in
urine. Laboratory results were expressed in mg/liter of urine and mg/g creatinine. Chromium excretion expressed relative to creatinine excretion is a
means of compensating for interindividual fluctuation in hydration and
activity level as creatinine follows a relatively constant basal level of daily
excretion.
Laboratory quality assurance and quality control consisted of laboratory
spikes, laboratory controls (e.g., duplicate samples), and water blanks. Laboratory controls were obtained from Bio-Rad Laboratories for total chromium
and creatinine. Calibration curves were prepared daily by testing a spiked
sample in the matrix and controls were run after every 10 samples. All
results were found to be within acceptable quality control limits for the
assay (within 10 to 15% of defined standards).
Blood analyses. All plasma and red blood cell samples were analyzed
at NMS Laboratories in general accordance with EPA Method 218.2 using
a PE-4100 ZL graphite furnace AAS (Paustenbach et al., 1996). The limit
of detection was 0.3 to 0.5 mg Cr/liter for plasma samples and 2 mg Cr/
liter for RBC samples.
Laboratory quality assurance and quality control included laboratory
blanks and laboratory controls. The laboratory equipment was calibrated
on a daily basis using plasma samples spiked with known chromium concentrations and UTAK serum with known background chromium levels. All
results were found to be within acceptable quality control limits for the
assay (within 10 to 15% of defined standards).
Calculation of Urinary Excretion Rates
The half-life of chromium excreted in the urine was calculated by examining the total cumulative chromium excretion (in the urine) versus time
throughout the study period. At each time-point (i), the instantaneous rate
of chromium excretion was calculated by determining the slope of the total
cumulative excretion curve at that time-point [y (Ai/1 0 Ai01)/(ti/1 0
ti01)]. The instantaneous rate of excretion was then plotted versus median
time of void (tmedian ti01 / (ti/1 0 ti01)/2) and the resulting relationship
was fit using a monoexponential decay function of the form y A0 1 exp
(0k 1 t). The resulting k represented the rate of chromium excretion in the
urine and was used to represent the overall rate of chromium excretion
from the body. The half-life was then calculated using the relationship t12
0.693/k.
The bioavailability of chromium (or percentage of dose absorbed) was
calculated as the cumulative amount of chromium that was excreted between
the time when the dosing began (for each dosing segment) and when the
rate of chromium excretion reached background rates, divided by the total
dose ingested.

RESULTS

In this study, we examined in separate experiments the

absorption (first 2 hr) and elimination (up to 14 days) pharmacokinetics of three different chromium compounds: (1)
chromic (III) chloride (CrCl3 ; conducted in May 1995), (2)
potassium dichromate reduced to Cr(III) in orange juice

AID

TOX 7948

6h12$$$302

10-08-96 09:15:40

(Cr(III)-OJ; conducted in July 1995); and (3) potassium dichromate (Cr(VI); conducted in August 1995). In each study,
three or four volunteers ingested 0.5 liters of 10 ppm chromium solution (i.e., 5 mg Cr), which was consumed within
a 2-min period in the morning between 9:00 and 12:00 to
simulate high-dose ingestion on an empty stomach. One volunteer (H4) was common to all experiments.
The single dose studies were designed to obtain kinetic
information on the acute time course of chromium uptake
into the blood and excretion in urine. Blood and urine chromium levels were followed for 13 days prior to and up to
12 days after the single dose ingestion.
Urinary Excretion
Data on the time course and magnitude of urinary excretion following single dose administration of the three chromium mixtures are presented in Table 1 and Figures 2, 4,
and 6. The ingestion of 5 mg of the various forms of chromium resulted in differential uptake and urinary excretion
that was highly mixture-dependent.
Ingestion of chromic chloride resulted in the lowest percentage absorption corresponding to an average bioavailability of only 0.13% (range for all 4 subjects, 4.0 to 12 mg Cr
or 0.08 to 0.24%) as shown in Fig. 2 and Table 1. Following
administration of chromic chloride, total urinary excretion of
chromium was clearly elevated above prestudy background
levels on the first 3 days following exposure. During the
first 3 days, the volunteers excreted 7082% of the total
chromium measured in urine within 7 days. Peak concentrations in individual voids averaged 8.9 mg Cr/g creatinine
(range, 4.0 to 13 mg Cr/g creatinine). The calculated average
urinary excretion half-life for this mixture is approximately
10.3 hr (range, 4.8 to 15.4).
Administration of potassium dichromate [Cr(VI)] reduced in orange juice (presumably to Cr(III)-organic complexes and Cr(III) ions) resulted in a significantly higher
apparent uptake than chromic chloride, corresponding to
an average bioavailability of 0.60% (range for all four
subjects, 15.5 to 41.0 mg Cr or 0.31 to 0.82%) as shown
in Fig. 4 and Table 1. This mixture produced an elevated
urinary chromium for 4 to 5 days. Within the first 3 days
the volunteers excreted 90 to 96% of the total chromium
measured in urine. Peak urine chromium concentrations
averaged 24 mg Cr/g creatinine (range, 18 to 36 mg Cr/g
creatinine). The calculated urinary elimination half-life
for Cr(III) formed in orange juice averaged 15 hr (range,
10.1 to 19), which is considerably longer than that observed for Cr(III) chloride (10.3 hr).
Ingestion of potassium dichromate [Cr(VI)] resulted in
apparently higher and more variable uptake compared to the
other mixtures, corresponding to an average bioavailability
of 6.9% of the administered dose (range for all four subjects

toxas

AP: Tox

AID

TOX 7948

6h12$$7948

10-08-96 09:15:40

toxas

AP: Tox
0.13 { 0.04%
(6.3 { 1.9)

0.09%
(4.5)

0.08%
(4.0)

0.09%
(4.5)
0.24%
(12)

10 { 2.2

15

9.6

11

4.8

Elimination
half-lifeb
(hr)

24 { 4.3

18

18

36

23

Peak
(mg Cr/g creat.)

0.60 { 0.11%
(30.1 { 5.5)

0.31%
(15.5)

0.71%
(35.5)
0.82%
(41.0)
0.57%
(28.5)

Bioavailabilityb
[% of dose absorbed
(mg Cr in urine)]

15 { 4.0

19

17

10

13

Elimination
half-lifeb
(hr)

Potassium dichromate reduced in OJ

209 { 128

77

143

585

29

Peak
(mg Cr/g creat.)

6.9 { 3.7
(343 { 186)

2.4%
(120)

6.4%
(320)

1.2%
(57.5)
17.5%
(875)

Bioavailabilityb
[% of dose absorbed
(mg Cr in Urine)]

Potassium dichromate

39 { 1.7

37

36

43

41

Elimination
half-lifeb
(hr)

a
Mean background total urinary excretion of chromium for the eight volunteers ranged from 0.3 to 1.5 mg/day. For nondetects, 12 the detection limit was used. No background adjustments
were made to postdose urinary excretion values.
b
Bioavailability and elimination half-life calculations are described under Methods.

8.9 { 2.0

H10

Average {
standard error

13

H9

H8

H6
4.0

H5

H7

11

7.4

H4

H1

Subject

Peak
(mg Cr/g creat.)

Bioavailabilityb
[% of dose absorbed
(mg Cr in urine)]

Chromic chloride

TABLE 1
Urinary Excretion of Chromium in Human Volunteers Following a Single Bolus Dose (0.5 Liters at 10 mg Cr/Liter) as Potassium Dichromate,
Potassium Dichromate Reduced to Cr(III) in Orange Juice, or Chromic Chloride in Watera

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

149

150

KERGER ET AL.

the predose levels in most subjects for at least 4 hr after

administration. Peak plasma concentrations of chromium averaged 2.8 mg/liter (range, 1.3 to 3.7). In at least three of
the four volunteers, plasma chromium concentrations appeared to remain elevated for 12 days after administration,
although clotting of samples during this time span in subject

FIG. 1. Cr(VI) and Cr(III) uptake in red blood cells. This schematic
depicts how Cr(VI) readily enters the red blood cell, where it is reduced
to short-lived reactive intermediates [Cr(V), Cr(IV)] and bound to hemoglobin (Hb) and soluble ligands (L) such as glutathione and amino acids.
Essentially complete binding of intracellular Cr(VI) to hemoglobin occurs
because 30% of red blood cell mass is hemoglobin. The hemoglobinbound Cr complexes remain part of the red blood cell for its entire life
span. Conversely, water-soluble chromium(III) moves across the cell membrane via much slower diffusion and perhaps other processes related to the
chemical structure of the attached ligands.

at 10 mg Cr(VI)/liter, 57.5 to 875 mg Cr or 1.2 to 17.5%)

as shown in Fig. 6 and Table 1. The distribution of results
for total chromium excretion was much broader in this experiment compared to our other experiments where Cr(III) and
Cr(III)OJ were consumed. Volunteer H5 appeared to be an
atypical person or high absorber of Cr(VI) via ingestion.
Volunteer H5 exhibited five-fold higher urinary chromium
excretion within 4 days and a seven-fold higher peak chromium concentration in urine compared to the average for
the other three participants. For the four volunteers ingesting
this mixture, approximately 76 to 82% of the 14-day total
for chromium in urine was excreted within the first 4 days,
with peak concentrations averaging 209 mg Cr/g creatinine
(range, 29 to 585 mg Cr/g creatinine; Table 1). The average
urinary excretion half-life was calculated to be 39.3 hr
(range, 3641).
Chromium Concentrations in Plasma
Following single dose administration of 10 ppm Cr(III) as
chromic chloride (Fig. 3), plasma chromium concentrations
peaked within 90 min and remained elevated slightly above

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

FIG. 2. The excretion of chromium in urine of 4 volunteers ingesting

0.5 liter of 10 mg Cr(III)/liter within 2 min. The time of ingestion was
between 9:00 and 9:30 AM on Day 2. The elimination half-lives for volunteers (A) H1, (B) H4, (C) H7, and (D) H9 were 4.8, 11.3, 9.6, and 15.4 hr,
respectively. The mean (plus 1 standard error) background values for H1,
H4, H7, and H9 are 2.0, 0.6, 1.7, and 0.3 mg/day.

toxas

AP: Tox

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

151

FIG. 3. Daily (A) plasma and (B) RBC chromium concentrations in 4 volunteers ingesting bolus dose of 0.5 liter of 10 mg Cr(III)/liter in 2 min.
Peak blood chromium measurements from the dose day were used for Day 2 values. Mean RBC and plasma background (plus 1 standard error) of all
volunteers from measurements taken prior to dosing are represented by the dotted lines BR and BP , respectively. Data points are connected using a
smoothed-curve function. Clotting of blood samples from volunteer H7 following the dose day led to an incomplete dataset.

H7 led to an incomplete dataset regarding changes in blood

levels. These trends seem to compare well with the urinary
chromium excretion data for this mixture.
Administration of potassium dichromate [Cr(VI)] reduced to
Cr(III) in orange juice resulted in a lesser elevation of chromium concentrations in plasma compared to chromium chloride (Fig. 5), with an average chromium concentration of 2.2
mg/liter (range, 1.92.5). Peak plasma levels occurred between
90 and 240 min after the dose except for volunteer H8 whose
peak occurred within 15 min. The concentration of chromium
in plasma remained elevated slightly above predose background
concentrations in at least two of the volunteers for 1 to 2 days
after the dose. The trend of generally lower plasma chromium
concentrations did not seem to agree with the urine data when

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

compared to Cr(III) chloride dosing, since the magnitude of

urinary excretion was on average three-fold higher for the orange juice mixture while plasma concentrations were lower.
Single dose administration of 10 mg Cr(VI)/liter resulted
in temporary elevations in the concentration of chromium in
plasma in all volunteers (Fig. 7). Peak plasma concentrations
occurred and reached an apparent plateau for all subjects
within 90 min after dosing, with an average concentration
of 26 mg Cr/liter (range, 5.1 to 57). All subjects except
H5 returned to their historical background range for plasma
chromium content by the end of this monitoring period.
These trends in plasma chromium concentration are consistent with those observed for concurrent measurements of
RBC and urinary chromium content.

toxas

AP: Tox

152

KERGER ET AL.

Chromium Concentration in RBCs

In all four volunteers, the concentration of chromium in
RBCs (Fig. 3) was clearly elevated following administration
of the Cr(III) chloride mixture, with the peak concentrations
averaging 7.5 mg/liter (range, 5.1 to 14). Peak RBC chromium levels occurred at the 15-min time point for one volunteer, and at 120 and 240 min in the other two people. At
least two of the volunteers had RBC values for chromium
that returned to nondetectable levels 2 days after ingesting
the chromium.
Administration of potassium dichromate reduced in orange juice also resulted in brief elevations in the concentration of chromium in RBC in all volunteers (Fig. 5), with the
peak concentration averaging 5.5 mg/liter (range, 5.1 to 6.1).
Peak RBC chromium levels appeared to rise quickly, within
15 min after the dose for three of four volunteers. Subject
H5 showed an unusual trend of no elevation until a transient
peak was observed at 90 min, followed by a return to nondetectable levels. Similarly, while the other three volunteers
returned to low or nondetectable RBC chromium levels 1
2 days after the dose, there seemed to be a rise and plateau of
RBC chromium levels in subject H5 in the 5 days following
administration of this mixture.
The trends of temporary elevation in chromium concentrations observed for RBCs (Fig. 7) were consistent in timing
and magnitude with those in plasma and urine following the
single dose ingestion of 10 mg Cr(VI)/liter. In the acute time
course measurements, a relatively rapid rise and plateau in
RBC chromium concentrations was observed in all volunteers within 15 to 60 min, with the peak concentration on
the day of dosing averaging 17.6 mg/liter (range, 13.5 to
24). All volunteers except H4 exhibited plasma chromium
concentrations similar to or exceeding concurrent RBC levels for at least 3 days postdose. Subject H5 showed a trend
of considerably increased RBC chromium levels (up to 36
mg/liter) in the 3 days following the dose, and his plasma
levels remained higher than concurrent RBC values for at
least 12 days. RBC chromium levels in subject H4 returned
to predose background levels within 1 day after administration, while H10 returned to predose background levels only
after about 5 days and volunteers H5 and H8 still had apparently elevated RBC chromium content at 1214 days postdose.

FIG. 4. The excretion of chromium in urine of 4 volunteers ingesting

0.5 liter of 10 mg Cr(VI)OJ/liter within 2 min. The time of ingestion was
between 9:00 and 11:00 AM on Day 2. The elimination half-lives for volunteers (A) H4, (B) H5, (C) H6, and (D) H8 were 12.7, 10.1, 16.8, and 27.1
hr, respectively. The mean (plus 1 standard error) background values for
H4, H5, H6, and H8 are 1.7, 0.7, 0.5, and 0.3 mg/day. Study days in which
urine was not sampled are indicated by NS.

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

toxas

AP: Tox

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

153

FIG. 5. Daily (A) plasma and (B) RBC chromium concentrations in 4 volunteers ingesting bolus dose of 0.5 liter of 10 mg Cr(VI)OJ/liter in 2
min. Peak blood chromium measurements from the dose day were used for Day 2 values. Mean RBC and plasma background (plus 1 standard error) of
all volunteers from measurements taken prior to dosing are represented by the dotted lines BR and BP , respectively. Data points are connected using a
smoothed-curve function.

DISCUSSION

These findings indicate that volunteers ingesting soluble

chromate at 10 mg Cr(VI)/liter in drinking water have a
pattern of blood uptake and urinary excretion consistent with
primary uptake and distribution in the trivalent state. Our
data suggest that Cr(VI) uptake is generally quite low at
these concentrations (average, 6.9%) but that interindividual
variation in gastrointestinal reduction and/or ingestion of
Cr(VI) during fasting conditions may strongly influence uptake. In most of our volunteers, the absence of substantial
and sustained elevations in RBC chromium content in the
weeks following Cr(VI) ingestion suggests that the hexava-

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

lent chromium is probably reduced rapidly to trivalent chromium prior to RBC uptake and systemic distribution. However, one of the four volunteers exposed to 10 mg Cr(VI)/
liter exhibited an elevation in both plasma and RBC chromium that was sustained above background levels for at
least 12 days. The sustained elevation of chromium in both
RBCs and plasma seems consistent with two plausible explanations: (1) the observations reflect tissue loading with
Cr(III) in organically complexed forms that are slowly excreted and in equilibrium between RBC and plasma compartments, or (2) some small fraction of the Cr(VI) escaped
reduction in the plasma and was then rapidly sequestered
and reduced within the RBC fraction of blood. In either

toxas

AP: Tox

154

KERGER ET AL.

case, we cannot exclude the fact that Cr(VI) may have been
absorbed in minute amounts that are below the detection
limits of the methods used here.
We believe that these findings more strongly support the
conclusion that Cr(VI) ingestion at these doses resulted in
increased chromium uptake in the form of Cr(III) complexes
that induced a tissue loading effect in some individuals at
10 mg/liter. First, these results are not consistent with intravenous or intratracheal Cr(VI) exposures in animals which
demonstrate that chromium levels in plasma do not remain
consistently elevated as do RBCs (Gray and Sterling, 1950;
Weber, 1983; Edel and Sabbioni, 1985; Wiegand et al.,
1988). Concurrently and almost equally elevated RBC and
plasma levels observed in the current study may indicate an
equilibrium process with Cr(III). Second, previous studies
show in vivo formation (Ronai, 1969; Sanderson, 1976; Levis et al., 1978; Edel and Sabbioni, 1985) and enhanced
uptake of chromium (III) organic complexes (Mertz, 1969,
1975; Mertz and Roginski, 1971; Gonzalez-Vergara et al.,
1981; Edel and Sabbioni, 1985; Kortenkamp and Beyersmann, 1987; Gargas et al., 1994); the process of Cr(VI)
reduction in vivo likely involves formation of trivalent chromium complexes that are more readily absorbed than inorganic Cr(III) forms. Third, systemic uptake of Cr(VI) as
organic Cr(III) complexes is also consistent with the longer
observed half-life for urinary excretion of chromium. Fourth,
in a previous study we found no detectable Cr(VI) (1 to
2 ppb) in plasma or urine in volunteers who ingested up
to 10 mg Cr(VI)/liter, even during the rapid uptake and
distribution phases (Kerger et al., 1996a). And finally, none
of the volunteers exhibited signs or symptoms or gastrointestinal irritation or any clinical indications of toxicity to the
kidney, liver, or blood.
Our data are consistent with published pharmacokinetic
models of Cr(III) behavior in mammals. Aitio et al. (1988)
have suggested that the half-life of chromium in humans is
based on distribution and elimination rates of chromium
from three separate compartments: the fast elimination compartment (t12 7 hr), the moderate elimination compartment
(t12 15 days), and the slow elimination compartment (t12
3 years) (Aitio et al., 1988). Lim et al. (1983) reported a
similar compartment model, suggesting chromium half-lives
of 0.5 to 12 hr in blood (fast compartment), 1 to 14 days in
storage organs like the liver and spleen (medium), and 3 to
12 months in other solid tissues (slow compartment) (Lim
et al., 1983). Our data for CrCl3 appear to be consistent with
the fast compartment elimination (half-life, 10 hr), while the
data for Cr(III)OJ (half-life, 15 hr) and Cr(VI) in water
FIG. 6. The excretion of chromium in urine of 4 volunteers ingesting
0.5 liter of 10 mg Cr(VI)/liter within 2 min. The elimination half-lives
for volunteers (A) H4, (B) H5, (C) H8, and (D) H10 were 41, 43, 36,
and 37 hr, respectively. The mean (plus 1 standard error) background
values for volunteers H4, H5, H8, and H10 are 0.6, 0.7, 0.3, and 0.3

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

mg/day, respectively. Ingestion occurred on Day 2, between the hours of

9:30 AM and 12:00 PM. Study days in which urine was not sampled are
indicated by NS.

toxas

AP: Tox

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

155

FIG. 7. Daily (A) plasma and (B) RBC chromium concentrations in 4 volunteers ingesting 0.5 liter of 10 mg Cr(VI)/liter (bolus dose). Peak blood
chromium measurements from the dose day were used for Day 2 values. Mean RBC and plasma background (plus 1 standard error) of all volunteers
from measurements taken prior to dosing are represented by the dotted lines BR and BP , respectively. Data points are connected using a smoothed-curve
function.

(half-life, 39 hr) may represent a combination of the fast

and moderate elimination compartments.
The distinctly different urinary excretion half-life values
for the three chromium mixtures examined in the current
study could be explained by their tendency to form Cr(III)
organic complexes that are distributed differently and excreted more slowly than inorganic (i.e., ionic) Cr(III) compounds. For example, Anderson et al. (1996) reported significantly greater proportions of chromium accumulated in
the liver of rats following subchronic administration of
Cr(III) picolinate compared to Cr(III) chloride (Anderson et
al., 1996). Consistent with our studies, Anderson et al.
(1996) found no evidence of organ damage or toxicity in

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

the animals fed either form of Cr(III). We showed in the

current study that Cr(III) organic complexes (formed by adding Cr(VI) to orange juice) were orally absorbed about four
times more readily and exhibited a urinary excretion halflife almost double that observed for ingestion of Cr(III) trichloride. This evidence suggests that Cr(VI) intake can result
in the formation of Cr(III) organic complexes in the upper
digestive tract fluids and tissues, resulting in enhanced uptake into the blood and proportionately greater urinary excretion as observed in the current study.
The biological reasons for the unusually high absorption
of chromium by volunteer H5, and the prevalence of these
persons in the background population, have not been charac-

toxas

AP: Tox

156

KERGER ET AL.

terized. Volunteer H5 reported ingesting no food for several

hours before and after ingesting the Cr(VI) dose, providing
fasting-like conditions. The small amount of gastric juice
present in the stomach during fasting periods is probably
overwhelmed by a 0.5-liter bolus dose of 10 mg Cr(VI)/liter
(De Flora et al., 1987). It is possible that this bolus exposure
resulted in absorption of Cr(VI) into the epithelial lining of
the upper gastrointestinal tract of volunteer H5, and perhaps
all of the participants. Reduction of Cr(VI) primarily in the
epithelial tissues (and perhaps some fraction in the blood)
may lead to the formation of bioavailable Cr(III) complexes
which are absorbed and excreted in the observed pattern in
the current study.
Many investigators have shown that if hexavalent chromium enters the blood, it is taken up by transport through
sulfate anion channels and becomes covalently bound to
protein (e.g., hemoglobin) inside RBCs for essentially the
entire life span of the cell (Langard et al., 1978; Lewalter
et al., 1985; Korallus, 1986a,b; Ottenwaelder and Wiegand,
1988; Wiegand et al., 1988; Coogan et al., 1991; Miksche
et al., 1994). In contrast, certain forms of soluble Cr(III)
(i.e., both inorganic salts and organic complexes) enter the
RBC but do not become bound to intracellular substrates like
hemoglobin (Gray and Sterling, 1950; Mertz, 1969, 1975;
Gonzalez-Vergara et al., 1981; Edel and Sabbioni, 1985;
Lewalter et al., 1985; Kortenkamp and Beyersmann, 1987;
Ottenwaelder and Wiegand, 1988). These Cr(III) compounds
are consequently mobile and subject to equilibrium forces
acting across the cell membrane, and/or alternative uptake
mechanisms controlled by the ligands of the Cr(III) complex.
Based on these studies and recent data developed in our
laboratory we postulate that the understanding of the pharmacokinetics of certain organic Cr(III) complexes is probably central to defining the fate of Cr(VI) at low doses in
vivo.
The findings of this study may have important mechanistic
implications applying to the detoxification of Cr(VI) at plausible concentrations in drinking water (i.e., 10 mg/liter).
While small but apparently sustained increases of total chromium in plasma and RBC were observed in one of the four
volunteers ingesting 10.0 mg Cr(VI)/liter, these increases
were always similar for plasma and RBC. This suggests an
equilibrium in the concentration of Cr(III) between the cellular and noncellular compartments of the blood and is consistent with the kinetic behavior of absorbed Cr(III) but not
Cr(VI). It seems plausible that the reactivity of Cr(VI) might
enhance the rate of stable complex formation in certain microenvironments in vivo. Cr(VI) is likely converted to certain
bioavailable Cr(III) complexes in gastric juices/contents and
may also form such complexes within the lining fluids and
epithelial cells of the upper gastrointestinal tract. It is interesting to note that compared to CrCl3 , Cr(VI) reduced in

AID

TOX 7948

6h12$$$303

10-08-96 09:15:40

orange juice exhibited a fourfold higher bioavailability but

distinctly lower peak and residual plasma concentrations of
chromium. This observation could represent the formation
of highly soluble chromium complexes (e.g., with ascorbate
or sulfhydryl protein ligands) that were rapidly cleared from
plasma via tissue uptake and/or kidney filtration. Based on
observations in guinea pigs, Seaborn et al. suggested that
chromium(III) ingestion may attenuate ascorbate metabolism
by protecting it from oxidation (Seaborn et al., 1994). Bioavailable Cr(III) complexes may be formed less readily following ingestion of ionic Cr(III) because of its lower solubility and tissue permeability. It is also possible that a small
fraction of the dose was absorbed into the blood as Cr(VI),
where it encountered a multitude of reducing agents and
potential complexation ligands that produced a variety of
chromium complexes with different pharmacokinetic characteristics. However, it seems unlikely that the reducing capacity of the blood was overwhelmed at the absorbed doses
indicated in the current study.
CONCLUSIONS

In conclusion, this study demonstrates that oral administration of Cr(VI) at low doses in drinking water results in a
pharmacokinetic profile in blood and urine that is consistent
with predominant reduction of Cr(VI) in the stomach and
small intestine followed by systemic uptake, distribution,
and excretion as Cr(III) organic complexes. Administration
of both Cr(VI) and Cr(III) at or below 10 mg Cr/liter can
cause temporary elevations in RBC and plasma chromium
levels, with more extended excretion times probably influenced by Cr(VI) reduction, binding to organic ligands, and
distribution to different pharmacokinetic storage compartments compared to inorganic Cr(III). This pharmacokinetic
mechanism of Cr(VI) reduction via the oral route helps to
explain why subchronic and chronic drinking water administration at relatively high concentrations (e.g., 11 to 140 mg
Cr(VI)/liter) did not demonstrate appreciable toxicity in animals (Gross and Heller, 1946; MacKenzie et al., 1958; Anwar et al., 1961; Borneff et al., 1968).
REFERENCES
Aitio, A., Javisalo, J., Kiilunen, M., Kalliomaki, P. L., and Kalliomaki, K.
(1988). Chromium. In Biological Monitoring of Toxic Metals (T. W.
Clarkson, L. Friberg, G. F. Nordberg, and D. R. Sager, Eds.), pp. 369
382. Plenum, New York.
Anderson, R. A. (1994). Nutritional and toxicologic aspects of chromium
intake: An overview. In Risk Assessment of Essential Elements (W. Mertz,
C. O. Abernathy, and S. S. Olin, Eds.), pp. 187195. International Life
Sciences Institute, Washington, DC.
Anderson, R. A., Bryden, N. A., and Polansky, M. M. (1996). Lack of
toxicity of chromium chloride and chromium picolinate. Fundam. Appl.
Toxicol. 30, 299. [Abstract]

toxas

AP: Tox

PHARMACOKINETICS OF CHROMIUM (III) AND (VI)

Anwar, R. A., Langham, F. F., and Hoppert, C. A. (1961). Chronic toxicity
studies, 3: Chronic toxicity of cadmium and chromium in dogs. Arch.
Environ. 3, 456460.
Borneff, J., Engelhardt, K., Griem, W., Kunte, H., and Reichert, J. (1968).
Kanzerogene substanzen in wasser und boden (German). Arch. Hyg.
Bakteriol. 152 (1), 4553.
Capellmann, M., and Bolt, H. M. (1992). Chromium(VI) reducing capacity
of ascorbic acid and of human plasma in vitro. Arch. Toxicol. 66, 45
50.
Chute, S. M., Overman, S. K., Kerger, B. D., Finley, B. L., and Paustenbach, D. J. (1996). The Cr(VI) reductive capacity of household beverages:
Implications for risk assessment. Fundam. Appl. Toxicol. 30, 7. [Abstract]
Coogan, T., Squibb, K. S., Motz, J., Kinney, P. L., and Costa, M. (1991).
Distribution of chromium within cells of the blood. Toxicol. Appl. Pharmacol. 108, 157166.
De Flora, S. (1996). Letter to author. January.
De Flora, S., Badolati, G. S., Serra, D., Picciotto, A., Magnolia, M. R., and
Savarino, V. (1987). Circadian reduction of chromium in the gastric
environment. Mutat. Res. 192, 169174.
De Flora, S., Serra, D., Camoirano, A., and Zanacch, P. (1989). Metabolic
reduction of chromium as related to its carcinogenic properties. Biol.
Trace Elem. Res. 21, 179187.
De Flora, S., and Wetterhahn, K. E. (1989). Mechanisms of chromium
metabolism and genotoxicity. Life Chem. Rep. 7, 169244.
Donaldson, R. M., Jr., and Barreras, R. F. (1966). Intestinal absorption of
trace quantities of chromium. J. Lab. Clin. Med. 68, 484493.
Edel, J., and Sabbioni, E. (1985). Pathways of Cr(III) and Cr(VI) in the rat
after intratracheal administration. Hum. Toxicol. 4, 409416.
Finley, B. L., Scott, P. K., Norton, R. L., Gargas, M. L., and Paustenbach,
D. J. (1996). Urinary chromium concentrations in humans following ingestion of safe doses of hexavalent and trivalent chromium: Implications
for biomonitoring. Submitted for publication.
Gargas, M. L., Norton, R. L., Paustenbach, D. J., and Finley, B. L. (1994).
Urinary excretion of chromium by humans following ingestion of chromium picolinate: Implications for biomonitoring. Drug. Metab. Dispos.
22, 522529.
Gonzalez-Vergara, E., De Gonzalez, B. C., Hegenauer, J., and Saltman, P.
(1981). Chromium coordination compounds of pyridoxal and nicotinic
acid: synthesis, absorption and metabolism. Israel J. Chem. 21, 1822.
Gray, S. J., and Sterling, K. (1950). The tagging of red cells and plasma
proteins with radioactive chromium. J. Clin. Invest. 29, 16041613.
Gross, W. G., and Heller, V. G. (1946). Chromates in animal nutrition. J.
Ind. Hyg. Toxicol. 28, 5256.
Gylseth, B., Gundersen, N., and Langard, S. (1977). Evaluation of chromium exposure based on a simplified method for urinary chromium determination. Scand. J. Work Environ. Health 3, 2831.
Kerger, B. D., Finley, B. L., Corbett, G. E., Dodge, D. G., and Paustenbach,
D. J. (1996a). Ingestion of chromium (VI) in drinking water by human
volunteers: Absorption, distribution and excretion of single and repeated
doses. J. Toxicol. Environ. Health, in press.
Kerger, B. D., Richter, R. O., Chute, S. M., Dodge, D. G., Overman, S. K.,
Liang, J., Finley, B. L., and Paustenbach, D. J. (1996b). Refined exposure
assessment for ingestion of tapwater contaminated with hexavalent chromium: Consideration of exogenous and endogenous reducing agents. J.
Exp. Anal. Environ. Epidemiol. 6, 163179.
Korallus, U. (1986a). Biological activity of chromium(VI)- against chromium (III)- compounds: New aspects of biological monitoring. In Chromium Symposium 1986: An Update, May 2021. Arlington, VA. [Abstract]

AID

TOX 7948

6h12$$$304

10-08-96 09:15:40

157

Korallus, U. (1986b). Chromium compounds: Occupational health, toxicological and biological monitoring aspects. Toxicol. Environ. Chem. 12,
4759.
Korallus, U., Harzdorf, C., and Lewalter, J. (1984). Experimental bases for
ascorbic acid therapy of poisoning by hexavalent chromium compounds.
Int. Arch. Occup. Environ. Health 53, 247256.
Kortenkamp, A., and Beyersmann, D. (1987). Uptake of chromium(III)
complexes by erythrocytes. Toxicol. Environ. Chem. 14, 2332.
Langard, S., Gundersen, N., Tsalev, D. L., and Gylseth, B. (1978). Whole
blood chromium level and chromium excretion in the rat after zinc chromate inhalation. Acta Pharmacol. Toxicol. 42, 142149.
Levis, A. G., Bianchi, V., Tamino, G., and Pegoraro, B. (1978). Cytotoxic
effects of hexavalent and trivalent chromium on mammalian cells in
vitro. Br. J. Cancer 37, 386396.
Lewalter, J., Korallus, U., Harzdorf, C., and Weidemann, H. (1985). Chromium bond detection in isolated erythrocytes: A new principle of biological monitoring of exposure to hexavalent chromium. Int. Arch. Occup.
Environ. Health 55, 305318.
Lim, T. H., Sargent, T., III, and Kusubov, N. (1983). Kinetics of trace
element chromium(III) in the body. Am. J. Physiol. 244 (4), R445-R454.
Lindberg, E., and Vesterberg, O. (1983a). Monitoring exposure to chromic
acid in chromeplating by measuring chromium in urine. Scand. J. Work
Environ. Health 9, 333340.
Lindberg, E., and Vesterberg, O. (1983b). Urinary excretion of proteins in
chromeplaters, exchromeplaters and referents. Scand. J. Work Environ.
Health 9, 505510.
MacKenzie, R., Byerrum, U., Decker, C., Hoppert, C., and Langham, F.
(1958). Chronic toxicity studies: Hexavalent and trivalent chromium administered in drinking water. Arch. Ind. Health 18, 232234.
Mertz, W. (1969). Chromium occurrence and function in biological systems.
Physiol. Rev. 49, 163239.
Mertz, W. (1975). Effects and metabolism of glucose tolerance factor. Nutr.
Rev. 33(5), 129135.
Mertz, W., and Roginski, E. E. (1971). Chromium metabolism: The glucose
tolerance factor. In Newer Trace Elements in Nutrition (W. Mertz and
W. E. Cornatzer, Eds.). Dekker, New York.
Miksche, L., Lewalter, J., and Korallus, U. (1994). Determination of chromium in erythrocytes: A new principle for biological monitoring in chromium (VI) exposed workers. In Proceedings of the DOE Symposium on
Biomarkers. February, San Diego, CA.
Minoia, C., and Cavalleri, A. (1988). Chromium in urine, serum and red
blood cells in the biological monitoring of workers exposed to different
chromium valency states. Sci. Total Environ. 71, 323327.
Mutti, A., Pedroni, C., Arfini, G., Franchini, I., Minoia, C., Micoli, G.,
and Baldi, C. (1985). Biological monitoring of occupational exposure to
different chromium compounds at various valency states. In Carcinogenic
and Mutagenic Metal Compounds Environmental and Analytical Chemistry and Biological Effects (M. E., R. W. Frei, W. Hardi, and C. Schlatter,
Eds.), pp. 119125. Gordon & Breach, London.
OFlaherty, E. (1993). A pharmacokinetic model for chromium. Toxicol.
Lett. 68, 145158.
OFlaherty, E. (1994). Comparison of reference dose with estimated safe
and adequate daily dietary intake from chromium. In Risk Assessment of
Essential Elements (W. Mertz, C. O. Abernathy, and S. S. Olin, Eds.).
ILSI Press, Washington, DC.
Ottenwaelder, H., and Wiegand, H. J. (1988). Uptake of 51Cr(VI) by human
erythrocytes: Evidence for a carrier-mediated transport mechanism. Sci.
Total Environ. 71, 561566.
Paustenbach, D. J., Throop, L., Fritch, D., McDougal, M., Overman, S. K.,

toxas

AP: Tox

158

KERGER ET AL.

and Kerger, B. D. (1996). Validation of a rapid assessment method for

measuring total chromium in human blood. In review.
Petrilli, F. L., and De Flora, S. (1988). Metabolic reduction of chromium
as a threshold mechanism limiting its in-vivo activity. Sci. Total Environ.
71(3), 357364.
Ronai, P. M. (1969). The elution of 51Cr from labelled leukocytesA new
theory. Blood 33(3), 408413.
Sanderson, C. J. (1976). The uptake and retention of chromium by cells.
Transplantation 21, 526529.
Seaborn, C. D., Cheng, N., Adeleye, B., Owens, F., and Stoecker, B. J.
(1994). Chromium and chronic ascorbic acid depletion effects on tissue
ascorbate, manganese, and 14C retention from 14C-ascorbate in guinea
pigs. Biol. Trace Elem. Res. 41, 279294.
Sipes, J. G., and Gandolfi, A. J. (1991). Biotransformation of toxicants. In
Casarett and Doulls Toxicology: The Basic Science of Poisons (M. O.
Amdur, J. Doull, and C. D. Klassen, Eds.). Pergamon, New York.

AID

TOX 7948

6h12$$$304

10-08-96 09:15:40

USEPA (1991). National primary drinking water regulations-synthetic organic chemicals and inorganic chemicals; monitoring for unregulated
contaminants; national primary drinking water regulations implementation; national secondary drinking water regulations. Fed. Regist. 56,
35263597.
USEPA (1996). Chromium. Washington, D.C.: Integrated Risk Information
System (IRIS). Office of Health and Environmental Assessment, U.S.
Environmental Protection Agency. Down-loaded from National Library
of Medicine on-line service, January 25.
Weber, H. (1983). Long-term study of the distribution of soluble chromate51 in the rat after a single intratracheal administration. J. Toxicol. Environ. Health 11, 749764.
Wiegand, H. J., Ottenwalder, H., and Bolt, H. M. (1988). Recent advances
in biological monitoring of hexavalent chromium compounds. Sci. Total
Environ. 71, 309315.

toxas

AP: Tox