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BEHAVIOR OF HEAVY METALS

IN HUMAN URINE AND BLOOD
FOLLOWING CALCIUM
DISODIUM ETHYLENEDIAMINE
TETRAACETATE INJECTION:
OBSERVATIONS IN METAL
WORKERS
Fumihiro Sata Shunichi Araki Katsuyuki Murata Hiroshi
Aono
Published online: 30 Nov 2010.

To cite this article: Fumihiro Sata Shunichi Araki Katsuyuki Murata Hiroshi Aono
(1998) BEHAVIOR OF HEAVY METALS IN HUMAN URINE AND BLOOD FOLLOWING CALCIUM
DISODIUM ETHYLENEDIAMINE TETRAACETATE INJECTION: OBSERVATIONS IN METAL
WORKERS, Journal of Toxicology and Environmental Health, Part A: Current Issues, 54:3,
167-178, DOI: 10.1080/009841098158881

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 BEHAVIOR OF HEAVY METALS IN HUMAN URINE
AND BLOOD FOLLOWING CALCIUM DISODIUM
ETHYLENEDIAMINE TETRAACETATE INJECTION:
OBSERVATIONS IN METAL WORKERS

Fumihiro Sata, Shunichi Araki, Katsuyuki Murata

Department of Public Health, Faculty of Medicine, University
of Tokyo, Tokyo, Japan

Hiroshi Aono
Department of Public Health and Hygiene, Medical College
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of Oita, Oita, Japan

To evaluate the effects of calcium disodium ethylenediamine tetraacetate ( CaEDTA) on

the behavior of 8 heavy metals in human urine and blood, CaEDTA was administered
for 1 h by intravenous injection to 18 male metal foundry workers, whose blood lead
concentrations ( PbB) were between 16 and 59 ( mean 34) µg/ dl. Significant increases
were found in urinary excretion of manganese, chromium, lead, zinc, and copper after
the start of CaEDTA injection. Urinary chromium excretion reached a maximal level
within 1 h after the start of injection, while urinary manganese, lead, and zinc excretion
reached their highest concentrations between 1 and 2 h. Urinary copper excretion
reached the highest level between 2 and 4 h. The rapid increases in urinary excretion of
five metals were different from the “circadian rhythms,” which are the normal, daily
variations in renal glomerular filtration, reabsorption, and excretory mechanisms. Plasma
lead concentrations were highest 1.5 h after the start of the 1-h injection, while plasma
zinc concentration became lowest 5 h after the start of CaEDTA injection. Data suggest
that manganese and chromium absorbed in human tissues might be mobilized by
CaEDTA.

The use of the chelating agent calcium disodium ethylenediamine

tetraacetate (CaEDTA) for the treatment of occupational and environmen-
tal lead poisoning has been established (Rieders et al., 1955; Chisolm,
1974). One of the target sites associated with lead poisoning is bone,
where this heavy metal is deposited (Teisinger et al., 1969). With current
technology a noninvasive procedure of x-ray fluorescence has enabled
investigators to measure human bone lead levels with accuracy (Tell et
al., 1992). Although chelation therapy has been utilized to remove lead
from bones with some success, difficulties still exist with this treatment
regime (Chisolm, 1990; Kosnett, 1992). Uncontrolled CaEDTA therapy in

Received 3 June 1997; sent for revision 23 July 1997; accepted 22 October 1997.
The present study was partly supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, and Culture in Japan.
Address correspondence to Prof. Shunichi Araki, Department of Public Health, Faculty of
Medicine, University of Tokyo, Tokyo 113-0033, Japan.

167

Journal of Toxicology and Environmental Health, Part A, 54:167–178, 1998

Copyright © 1998 Taylor & Francis
0098-4108/98 $12.00 + .00
 168 F. SATA ET AL.

lead-poisoned patients was found to produce nephrotoxicity (Foreman et

al., 1956), central nervous system disturbances (Porru & Alessio, 1996),
and no improvement in clinical outcome (Kosnett, 1992). Hence, there
are limitations or drawbacks of CaEDTA as an effective treatment for lead
poisoning.
The behavior of lead, zinc, and copper in urine, plasma, and erythro-
cytes following intravenous administration of CaEDTA in lead workers has
been investigated (Araki et al. 1984; Aono & Araki, 1984; Ishihara et al.,
1984). Urinary lead excretion (PbU) and plasma lead concentrations
(PbP) were found to increase after intravenous injection of CaEDTA with-
out any alterations in the lead concentration in either erythrocytes (PbE)
or whole blood (PbB) (Araki et al., 1984). These findings suggested that
PbU might be mobilized for the most part from tissues other than periph-
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eral blood. In contrast, PbB levels correlated closely with the mobiliza-
tion yield of lead obtained from urine of lead-exposed workers treated
with CaEDTA (Alessio et al., 1979, 1981; Brangstrup-Hansen et al., 1981;
Araki et al., 1986), suggesting that PbB levels may reflect the body burden
of chelatable metal in exposed workers. As more than 90% of PbB exists
in the erythrocytes, PbE may serve as a more reliable index of the lead
body burden than PbP. The x-ray fluorescence method indicated that
chelatable lead mainly reflected the blood and soft-tissue lead pool,
which is only partly derived from skeletal sources. It is important to note
that skeletal lead content comprises the largest component of the total
body burden (Tell et al., 1992). CaEDTA was found to produce a higher
mobilization rate of lead into urine, followed by substantial conversion of
nonche latable to chelatable lead (Aono & Araki, 1984; Araki et al.
1983b). In contrast, plasma zinc concentrations (ZnP) decreased rapidly
and were followed by a gradual rise in the erythrocyte zinc concentration
(ZnE) 5 h after CaEDTA injection (Araki et al., 1984). These observations
suggested that chelatable zinc might be mobilized mainly from the plasma
into the urine shortly after CaEDTA injection. The depleted ZnP was,
however, largely replenished by movement of zinc from other tissues dur-
ing the 24-h period following the injection (Araki et al., 1984). Copper
was observed to be mobilized into urine without any changes in its con-
centration in either plasma (CuP) or erythrocytes (CuE) after CaEDTA
injection (Aono & Araki, 1984). CaEDTA inhibited the activity of a cop-
per-dependent enzyme, dopamine b -hydroxylase (DBH), in the serum (De
Paris & Caroldi, 1994).
Although the effect of CaEDTA therapy on lead, zinc, and copper has
been studied to a greater extent, the behavior of manganese, chromium,
cadmium, mercury, and tin in urine, plasma, and erythrocytes following
CaEDTA injection remains unknown. Tin was included in these studies as
this metal was present in the occupational setting. In Japan, only CaEDTA
has been approved for use as a chelating agent in lead-exposed workers.
Although it is important to examine the behavior of these metals in healthy
 BEHAVIOR OF HEAVY METALS BY CaEDTA 169

people without occupational exposure to lead and to whom CaEDTA

can be administered, this is not practical or ethical. In the present study,
the effects of CaEDTA were examined on the behavior in human urine
and blood of these heavy metals to which humans were occupationally
exposed.

MATERIALS AND METHODS

Subjects
The 18 subjects, aged 23 to 57 (mean 45) yr, were male gun-metal
foundry workers employed at a metal factory for 1–18 (mean 10) yr. Gun
metal was composed of lead (5%), zinc (5%), copper (85%), and tin (5%).
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Prior to the start of chelation therapy the PbB content of most of the
workers exceeded 40 µg/dl. CaEDTA treatment was initiated and the PbB
concentrations in the final stages of therapy ranged from 16 to 59 (mean
34) µg/dl. None of the subjects displayed renal dysfunction, as evidenced
by a lack of albuminuria and glucosuria. The procedure was fully explained
to all subjects, and this study was conducted with their informed consent.
Collection and Analysis of Urine and Blood Samples
Following collection of urine samples for 24 h prior to CaEDTA,
which served as control, CaEDTA was administered by intravenous injec-
tion to each subject in a dosage of 20 mg/kg body weight in 250 ml of
5% glucose solutions from 9 to 10 am. Urine samples were then collected
during a 24-h period divided into 6 periods after initiation of CaEDTA
injection as follows: (1) 0–1 h, (2) 1–2 h, (3) 2–4 h, (4) 4–6 h, (5) 6–12 h,
and (6) 12–24 h. Blood samples were collected just before and 1.5, 5, 12,
and 24 h after the start of CaEDTA injection, using heparin as an anti-
coagulant. Plastic bottles soaked in pure nitric acid solution overnight
were used for urine samples and disposable vacuum tubes for blood sam-
ples.
Analytical methods, lower limits of detection, and reproducibility of
analysis for all substances except for the case of tin have been reported
previously (Araki et al., 1986; Araki & Aono, 1986; Aono & Araki, 1988).
The methods used to measure urinary excretion and plasma, erythrocyte,
and whole blood for each metal are summarized in Table 1. PbB, PbE,
and PbU were measured by atomic absorption spectrophotometry (AAS)
after wet ashing, chelation by sodium diethyl dithiocarbamate (DDTC),
and extraction in water saturated methyl isobutyl ketone (MIBK); PbP was
measured by the method of De Silva (1981). Plasma, erythrocyte, and uri-
nary mercury concentrations (HgP, HgE, and HgU) were determined by
the method of Magos (1971) and Magos and Clarkson (1972). Plasma and
erythrocyte concentrations of cadmium (CdP, CdE) and copper (CuP, CuE)
were measured by flameless AAS after deproteinization by trichloroacetic
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TABLE 1. Methods used to measure urinary excretion, plasma, erythrocyte, and whole blood concentrations for eight metals

Urine Plasma Erythrocyte Whole blood

Manganese Wet ashing, chelation by DDTC,
extract to MIBK and AAS
Chromium Wet ashing, chelation by DDTC,
extract to MIBK and AAS
Lead Wet ashing, chelation by DDTC,
extract to MIBK and AAS
Deproteinization by TCA and
flameless AAS using the standard
addition technique
Deproteinization by TCA and
flameless AAS using the standard
addition technique
De Silva (1981)
Deproteinization by TCA and —
flameless AAS using the standard
addition technique
Deproteinization by TCA and —
flameless AAS using the standard
addition technique
Wet ashing, chelation by DDTC, Wet ashing, chelation
extract to MIBK and AAS by DDTC, extract
to MIBK and AAS

170
Zinc Deproteinization by TCA and Deproteinization by TCA and Wet ashing and AAS —
AAS AAS
Copper Wet ashing, chelation by DDTC, Deproteinization by TCA and Deproteinization by TCA and —
extract to MIBK and AAS flameless AAS flameless AAS
Cadmium Subramanian et al. (1982) Deproteinization by TCA and Deproteinization by TCA and —
flameless AAS flameless AAS
Mercury Magos (1971) Magos (1971) Magos (1971) —
Magos and Clarkson (1972) Magos and Clarkson (1972) Magos and Clarkson (1972)
Tin Hydride generation technique Hydride generation technique Hydride generation technique —
with subsequent AAS with subsequent AAS with subsequent AAS

Note. Abbreviations: AAS, atomic absorption spectrophotometry; DDTC, sodium diethyl dithiocarbamate; MIBK, methyl isobutyl ketone; and TCA,
trichloroacetic acid.
 BEHAVIOR OF HEAVY METALS BY CaEDTA 171

acid (TCA). Urinary cadmium (CdU) was determined by the method of

Subramanian et al. (1983). Plasma and erythrocyte concentrations of
manganese (MnP, MnE) and chromium (CrP, CrE) were measured by
flameless AAS using the standard addition technique after deproteiniza-
tion with TCA. Urinary manganese (MnU), chromium (CrU), and copper
(CuU) concentrations were measured by AAS after wet ashing, chelation
by DDTC, and extraction with MIBK. Plasma (ZnP) and urinary (ZnU)
zinc concentrations were measured by AAS after deproteinization by
TCA; ZnE was determined by AAS after wet ashing. Plasma (SnP), erythro-
cyte (SnE), and urinary (SnU) tin concentrations were measured by the
hydride generation technique with subsequent AAS. Lower limits of
detection for SnP, SnE, and SnU were 5, 5, and 3 µg/L, respectively. The
reproducibility of analysis, when expressed by a coefficient of variation,
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was 4.3% for SnP, 3.8% for SnE, and 5.0% for SnU.
Statistical Analysis
Differences in levels of heavy metals in urine, plasma, and erythro-
cytes between different time periods before and after the start of CaEDTA
injection were tested by Morrison’s multiple significance test, which is
most appropriate for a repeated-measurements experiment (Morrison,
1990). All analyses were performed with the Statistical Package for the
Biosciences (SPBS, Uni-Science Co., Tokyo) or SPSS for Macintosh (SPSS,
Inc., Chicago).

RESULTS
The urinary excretions of manganese, chromium, lead, zinc, copper,
cadmium, mercury, and tin following CaEDTA injection for various time
periods are shown in Table 2. Urinary excretion of manganese, chromium,
lead, zinc, and copper increased significantly after the start of CaEDTA
injection (Figure 1). CrU reached a maximal level within 1 h after the
start of the injection. The highest urinary levels of MnU, PbU, and ZnU
occurred between 1 and 2 h, while CuU reached its maximum between 2
and 4 h. The urinary excretion of cadmium, mercury, and tin did not alter
significantly following CaEDTA injection. PbP increased significantly fol-
lowing CaEDTA injection (Figure 2), with PbP concentrations being great-
est at 1.5 h. In contrast, zinc levels fell to the greatest extent 5 h after
CaEDTA administration. It is worthwhile to note that there were no
marked changes in the plasma and erythrocyte concentrations of all other
metals examined in this study.

DISCUSSION AND CONCLUSIONS

The behavior of certain heavy metals in human urine and blood
excluding lead and zinc following CaEDTA injection still remains un-
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TABLE 2. Urinary excretion of heavy metals before and after the start of 1-h CaEDTA injection in 18 metal workers

Before After CaEDTA

CaEDTA, _______________________________________________________________________
Heavy metals –24 to 0 h 0–1 h 0–2 h 0–4 h 0–6 h 0–24 h

Manganese (µg/h) 0.26 ± 0.14 2.18 ± 1.18 (10.7) 2.42 ± 1.01 (23.3) 2.39 ± 1.03 (46.6) 2.05 ± 0.89 (59.7) 0.86 ± 0.38 (100)
Chromium (µg/h) 0.38 ± 0.11 1.60 ± 0.82 (13.9) 1.58 ± 0.68 (27.8) 1.18 ± 0.53 (40.9) 0.99 ± 0.39 (51.3) 0.48 ± 0.17 (100)
Lead (µg/h) 3.5 ± 1.2 129 ± 50 (9.3) 149 ± 50 (21.4) 136 ± 54 (38.6) 118 ± 42 (50.7) 58 ± 20 (100)

172
Zinc (mg/h) 0.05 ± 0.02 1.90 ± 0.67 (14.6) 2.10 ± 0.45 (32.3) 1.95 ± 0.40 (60.0) 1.72 ± 0.39 (79.2) 0.54 ± 0.12 (100)
Copper (µg/h) 0.76 ± 0.14 1.26 ± 0.46 (4.8) 1.59 ± 0.37 (11.9) 1.95 ± 0.52 (29.0) 1.77 ± 0.54 (39.4) 1.12 ± 0.40 (100)
Cadmium (µg/h) 0.38 ± 0.27 1.19 ± 1.93 (6.1) 1.57 ± 2.33 (15.7) 1.72 ± 2.59 (34.8) 1.57 ± 2.20 (47.5) 0.82 ± 1.36 (100)
Mercury (µg/h) 0.27 ± 0.15 0.69 ± 0.50 (12.3) 0.59 ± 0.41 (21.0) 0.46 ± 0.27 (31.6) 0.37 ± 0.19 (38.6) 0.22 ± 0.11 (100)
Tin (µg/h) 2.1 ± 0.6 4.9 ± 4.6 (8.9) 4.4 ± 3.4 (16.1) 4.1 ± 2.3 (28.6) 3.7 ± 1.8 (39.3) 2.3 ± 1.0 (100)

Note. Each excretion period is expressed as mean ± standard deviation, and ratio (%) of accumulated excretion during each time period for 24-h
excretion after the start of CaEDTA injection is shown in parentheses.
 BEHAVIOR OF HEAVY METALS BY CaEDTA 173
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FIGURE 1. Urinary excretion of manganese, chromium, lead, zinc, and copper before and after the
start of 1-h CaEDTA injection in 18 metal workers for varying collection periods (mean ± standard
deviation). The v — V and v —| indicate significant differences at p < .05 and p < .01, respectively.
 174 F. SATA ET AL.
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FIGURE 2. Plasma lead and zinc concentrations before and after the start of 1-h CaEDTA injection in
18 metal workers (mean ± standard deviation). The v –| indicates significant differences at p < .01.
 BEHAVIOR OF HEAVY METALS BY CaEDTA 175

known. In the present study urinary excretion of manganese and that of

chromium were observed to increase significantly after the start of intra-
venous injection of CaEDTA. In addition, PbP rose significantly, while
ZnP levels were decreased, as shown previously (Araki et al., 1984). As
the changes in cadmium, mercury, and tin were not marked, data for
these metals in urine and blood were not included. Further due to the
quantity of blood obtained, only the plasma and erythrocyte data for
these metals could be detected.
Aono and Araki (1988) defined normal, daily renal function mecha-
nistically as circadian with respected to fluctuations in the urinary ex-
cretion of heavy metals with (1) the rhythm of glomerular filtration [creati-
nine (Cn) rhythm], (2) the rhythms of reabsorption by the distal tubule and
collecting duct [urinary flow (UF) rhythm], and (3) complex type of renal
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excretory mechanism. The rhythms in MnU, CrU, and CuU depend on

the Cn rhythm, while the rhythms in PbU, HgU, CdU, and ZnU were
considered as reflecting complex renal excretory mechanisms. The alter-
ations of spontaneo us excretion of these metals were gradual within
twofold daily timed collection periods of excretion (Aono & Araki, 1988).
In contrast, the alterations produced by CaEDTA were so sudden and
sharp as to often exceed 10-fold daily excretion. Thus these rapid increases
in MnU, CrU, PbU, ZnU, and CuU after the CaEDTA injection were
apparently different from the circadian-like normal fluctuations in metal
excretion.
There have been a few studies describing CaEDTA chelation of man-
ganese in the literature. Ibim et al. (1992) reported that CaEDTA treatment
in dogs decreased manganese levels in hair and zinc levels in hair, duo-
denum, and skin, while there was an increase in copper levels in kidney
associated with increased MnU, ZnU, and CuU. They suggested that sus-
tained urinary loss of manganese, zinc, and copper was probably asso-
ciated, in part, with mobilization and redistribution of these essential ele-
ments from storage (bone) tissues as well as soft tissues. De Paris and
Caroldi (1994) reported that CaEDTA injection increased MnU, PbU,
ZnU, but not CuU in lead workers. In addition, CaEDTA reduced the
activity of serum DBH, a copper-dependent enzyme. Kaur et al. (1984)
observed that CaEDTA lowered the manganese levels in kidney, spleen, and
brain of manganese poisoned rats. Manganese is more potent than other
transition metal ions stimulating dopamine auto-oxidation. Nachtman et al.
(1987) reported that addition of CaEDTA produced 80% decrease in man-
ganese-stimulated dopamine auto-oxidation. The mechanism of daily
MnU excretion is not known well. Greger et al. (1990) found that MnU
losses were not correlated with consumption of manganese, other miner-
als, or foods from specific categories in human male subjects.
Studies of CaEDTA chelation of chromium have been very rare as
CaEDTA seems unable to chelate chromium in the body. Banner et al.
(1986) reported that CaEDTA was able to produce an increase in CrU in
rats intoxicated with potassium dichromate but it was not as potent as N-
 176 F. SATA ET AL.

acetylcysteine (NAC). Pharmacokinetic studies of chromium have sug-

gested that chromium(VI) or chromium(III) clearance followed at least a
two-compartment model comprising a rapid phase and a slower phase
(Anderson et al., 1993). There are two notable disadvantages in urine sam-
ples with chromium: (1) Due to the rapid urinary excretion of chromium it
is not stored in tissues within the body, and (2) urinary chromium levels
cannot provide a basis for distinguishing between chromium(VI) and
chromium(III) because all chromium(VI) is reduced to chromium(III) in vivo
(Anderson et al., 1993). Chromium is also associated with glucose home-
ostasis. Morris et al. (1992) reported that there could be transient changes
in uptake and binding chromium by insulin-sensitive tissues.
Although CaEDTA seems to be a reliable and safe chelating agent
among those currently available, there exist some limitations to its use in
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the treatment of metal poisoning. A major drawback of CaEDTA is the

accompaniment of enormous urinary loss of zinc (Chisolm, 1990; Porru
& Alessio, 1996). It is possible that much of the toxicity of CaEDTA is
associated with the mobilization of zinc (Chisolm, 1990). However, it
should be noted that treatment with CaEDTA in therapeutic doses has not
produced any nephrotoxic effect in patients with normal renal function
and even in patients with preexisting renal disease (Araki et al., 1983a;
Wedeen et al., 1983). The prolonged or excessive dosage of CaEDTA
should be avoided. It has been reported that longer periods of continuous
administration at higher dose were nephrotoxic and were associated with
fatalities due to renal failure (Foreman et al., 1956). The redistribution of
lead should be taken into account in the treatment of CaEDTA, especially
in children. It has been reported that the treatment of CaEDTA does not
produce any net reduction in brain lead concentrations (Chisolm, 1990).
Cases of lead colic and worsening of the central nervous system signs and
symptoms have been described following inappropriate timing of the
administration of high dosages of CaEDTA (Porru & Alessio, 1996). Un-
fortunately, there is little evidence that chelation therapy improves the
clinical outcome of intoxicated patients (Kosnett, 1992). Data indicated
that manganese and chromium in addition to lead are mobilized from tis-
sues by CaEDTA in occupationally exposed workers.

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