Heavy Metal Concentrations in Human Eyes
JAY C. ERIE, MD, JOHN A. BUTZ, BA, JONATHAN A. GOOD, BS, ELIZABETH A. ERIE, BA,
MARY F. BURRITT PHD, AND J. DOUGLAS CAMERON, MD
● PURPOSE: To measure the concentration of toxic heavy
metals in the fluids and tissues of human eyes.
● DESIGN: Laboratory investigation.
● METHODS: Thirty autopsy eyes of 16 subjects were
dissected to obtain the aqueous, vitreous, lens, ciliary
body, retina, and retinal pigment epithelium/choroid.
Concentrations of lead, cadmium, mercury, and thallium
in ocular tissues, ocular fluids, and blood were determined using an inductively coupled plasma-mass spectrometer and expressed as ng/g. Heavy metal
concentrations in ocular tissues were compared using a
paired t test.
● RESULTS: Lead and cadmium were found in all of the
pigmented ocular tissues studied, concentrating to the
greatest extent in the retinal pigment epithelium/choroid
(mean, 432 ⴞ 485 ng/g and 2,358 ⴞ 1,522 ng/g).
Cadmium was found in the retina in all eyes (mean,
1,072 ⴞ 489 ng/g) whereas lead was found in the retina
in 9 (30%) of 30 eyes (mean, 53 ⴞ 54 ng/g). Trace
concentrations of lead and cadmium were detected in the
vitreous (mean, 0.5 ⴞ 1.0 ng/dl and 19 ⴞ 29 ng/dl), lens
(mean, 13 ⴞ 18 ng/g and 20 ⴞ 18 ng/g), and blood
(mean, 0.5 ⴞ 1.2 ␮g/dl and 3.1 ⴞ 4.1 ␮g/l) but were not
detected in the aqueous. Mercury and thallium were not
detected in any ocular tissues or fluids or in the blood.
● CONCLUSIONS: Lead and cadmium accumulate in human ocular tissues, particularly in the retinal pigment
epithelium and choroid. The potential ocular toxicity of
these heavy metals and their possible role in eye disease
requires further study. (Am J Ophthalmol 2005;139:
888 – 893. © 2005 by Elsevier Inc. All rights reserved.)
H
METHODS
UMAN CELLS EMPLOY METALS, SUCH AS COPPER,
zinc, and iron, to control significant metabolic
and signaling functions making them essential for
life. Other metals can be potentially toxic such as the
heavy metals: lead, cadmium, mercury, and thallium. Lead,
Accepted for publication Dec 3, 2004.
From the Department of Ophthalmology (J.C.E., J.D.C., E.A.E.) and
Metals Laboratory (J.A.B., J.A.G, M.F.B) Mayo Clinic and Mayo Clinic
College of Medicine, Rochester, Minnesota.
Supported by Research to Prevent Blindness, New York, New York and
the Mayo Foundation, Rochester, Minnesota.
Inquiries to Jay C. Erie, MD, Mayo College of Medicine, 200 1st Street
SW, Rochester, MN 55905; fax: 507-284-4612; e-mail:
erie.jay@mayo.edu
888
in particular, is a neurotoxin that has been linked to visual
deterioration,1 central and peripheral nervous system disorders,2 renal dysfunction,3 and hypertensive cardiovascular disease.4 Cadmium toxicity has been associated with
renal disease, hypertension, and an increased prevalence of
cardiovascular disease.5
Heavy metals are ubiquitous pollutants that have permanently contaminated air, water, and soil. The toxic
effect of heavy metals usually involves an interaction
between the heavy metal ion and the specific target
protein, resulting in a change in protein structure and
function.6 Cells involved in the transport of trace metals
are particularly susceptible to toxicity. The retinal pigment
epithelium is a metal-chelating tissue that is capable of
binding essential and toxic heavy metals because of the
high affinity of metals to melanin in retinal pigment
epithelium melanosomes.7,8 Recently, Eichenbaum and
Zheng9 showed that the retina and choroid can accumulate the heavy metal, lead.
Blood and urine samples reflect the amount of metals
circulating at the time of sampling and do not represent
the cumulative degree of exposure. Tissue biopsies for
elemental analysis can aid in identifying the accumulation
of metals from chronic exposure.10,11 At present, data on
heavy metal concentrations and distribution in human
eyes are limited.7,9 The purpose of our study was to measure
the concentrations and establish a reference range of toxic
heavy metals (lead, cadmium, mercury, and thallium) in
the fluids and tissues of eyes.
©
2005 BY
● SAMPLE COLLECTION: Eye tissue and blood were collected at the time of autopsy according to a protocol
reviewed and approved by the Mayo Foundation Institutional Review Board. This study was a laboratory investigation. Thirty eyes from 16 subjects (10 men, 6 women)
aged 62 to 94 years (mean, 78 ⫾ 9 years) were prospectively analyzed. In two randomly selected subjects, one eye
was dissected and sent for metal analysis and the fellow eye
was dissected and sent for histologic examination. All
subjects were Caucasian. Based on autopsy findings, eye
dissection findings, and review of medical history, subjects
were excluded if they had previous ocular trauma, intraoc-
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/05/$30.00
doi:10.1016/j.ajo.2004.12.007
TABLE 1. Eye Concentrations of Lead and Cadmium
Lead
Dry Weight (ng/g)
Aqueous
Vitreous
Lens
Ciliary body
RPE/Choroid
Retina
Cadmium
Wet Weight (ng/g or ng/dL)*
Dry Weight (ng/g)
Wet Weight (ng/g or ng/dL)*
Mean ⫾ SD
Range
Mean ⫾ SD
Range
Mean ⫾ SD
Range
Mean ⫾ SD
Range
13 ⫾ 18
321 ⫾ 127
432 ⫾ 485
53 ⫾ 54
0–97
127–464
29–2,165
0–172
0
0.5 ⫾ 1.0
4⫾4
73 ⫾ 70
82 ⫾ 109
5⫾7
0
0.0–3.5
0–13
27–175
6–378
0–27
20 ⫾ 18
1,012 ⫾ 1,464
2,358 ⫾ 1,522
1,072 ⫾ 489
0–50
220–3,495
407–4,846
130–1,624
0
21 ⫾ 34
5⫾5
109 ⫾ 70
298 ⫾ 165
82 ⫾ 60
0
0–123
0–16
53–201
74–731
5–212
* ⫽ Units for aqueous and vitreous are expressed as ng/dL wet weight only. Units for lens, ciliary body, RPE/choroid, and retina are
expressed as ng/g for dry and wet weight; n ⫽ 16 (30 eyes) for vitreous, RPE/choroid, and retina; n ⫽ 8 (9 eyes) for ciliary body and lens; n
⫽ 5 (5 eyes) for aqueous.
ular tumor, glaucoma, diabetes mellitus, exudative macular
degeneration, corneas suitable for corneal transplantation,
or any systemic disease or occupation likely to cause
aberration in metal content. Eyes with macular drusen
were included. All samples were collected, refrigerated,
and processed within 11 hours after death (5.9 ⫾ 3.6
hours).
Aqueous aspirates were obtained through a clear cornea
stab incision with a 30-gauge needle on a tuberculin
syringe. The anterior segment was dissected from the
posterior segment using a scissors and a fine-toothed
forceps. The crystalline lens, if present, and the ciliary
body were detached and removed separately. In some cases,
the anterior segment was used for glaucoma research and
the aqueous, lens, and ciliary body were not available.
Vitreous aspirates from all specimens were collected with
an 18-gauge needle in an “open-sky” fashion. The retina
and choroid complex were isolated and removed separately
using a fine-toothed forceps and scissors. The entire dissection procedure was completed within 15 minutes. All
samples were placed in separate labeled, acid-washed,
metal-free plastic containers (Sarstedt Inc., Newton,
North Carolina, USA) for transport to the metals laboratory. Blood was obtained from the femoral vein directly
into a metal-free EDTA tube.
The cause of death of the subjects were as follows: six
acute myocardial/cardiac arrest, three acute respiratory
distress, two pancreatic cancer, one trauma, one lymphoma, one leukemia, one pneumonia, one perforated
bowel. Occupations included: five housewives, four farmers, two office workers, two teachers, one attorney, one
construction worker, and one telephone operator.
● FRESH TISSUE PREPARATION AND DIGESTION:
Each
tissue was placed into a preweighed Teflon digestion tube.
The sample was weighed to determine a wet weight (grams)
and then dried at 95 C overnight. The sample was then
reweighed the next day to determine the dry weight (grams).
Concentrated trace metals grade nitric acid (0.5 ml) was
VOL. 139, NO. 5
added to the digest tube. The tube was placed in a Teflon
heating mantel, and the sample was digested at 95 C for
approximately 1 hour until all tissue material has been
dissolved. 3.5 milliliters of reagent grade water was added to
each tube. This digest mixture was then thoroughly vortexed.
Two deviations from this procedure were considered acceptable: (1) aqueous, vitreous, and blood were processed strictly
on a wet weight basis, and (2) the amount of acid and water
used for the digestion was sometimes adjusted for extremely
small weights or incomplete digestions.
● MASS SPECTROMETRY ANALYSIS:
All four elements
(lead, cadmium, mercury, and thallium) were analyzed simultaneously on a PE/SCIEX Elan 6100 inductively coupled
plasma-mass spectrometer (Perkin Elmer Life & Analytical
Sciences, Shelton, Connecticut, USA). Aqueous acidic calibrating standards were diluted with an aqueous acidic diluent
(2% hydrochloric acid, 2.5% tertiary butanol, and 1 ␮g/l
gold) containing three internal standards (bismuth, gallium,
and rhodium). Blanks, quality control specimens, and digested samples were also diluted in an identical manner. All
samples were vortexed and aspirated into a pneumatic nebulizer. The resulting aerosol was directed to the hot plasma
discharge by a flow of argon. Instrumentation response was
defined by the linear relationship of analyte concentration vs
ion counts (analyte ion count/internal standard ion count).
Analyte concentrations were derived by reading the ion
count ratio for each mass of interest. The concentration of
the digest was used to calculate the concentration of metal in
the tissue as a dry and wet weight and expressed as ng/g.
Subsequent analysis and discussion is based on tissue concentrations as a dry weight, as this avoids potential errors
attributable to tissue hydration and allows for future comparisons with formalin-fixed (that is, partially dehydrated)
concentrations.10
● TISSUE ANALYSIS AND ASSAY TECHNIQUE:
The assay
used to quantitate metal concentrations in the tissue
digests is routinely employed to perform the same analysis
HEAVY METAL CONCENTRATIONS
IN
HUMAN EYES
889
TABLE 2. Cadmium and Lead Concentrations (mean ⫾ SD, ␮g/g) in Smokers vs Non-smokers
Cadmium
RPE/Choroid
Retina
Lead
Smoker*
Non-smoker†
P‡
Smoker*
Non-smoker†
P‡
4,029 ⫾ 1,819
1,498 ⫾ 528
1,652 ⫾ 845
932 ⫾ 423
.004
.002
367 ⫾ 210
39 ⫾ 39
286 ⫾ 196
49 ⫾ 63
.56
.62
*n ⫽ 5 subjects (9 eyes).
†
n ⫽ 10 subjects (19 eyes); the smoking status of 1 subject (two eyes) was unknown, and these eyes were excluded from analysis.
‡
2-sample t-test.
above the normal adult range (⬍5 ␮g/l); 2 of the 3 subjects
were smokers. No subjects had detectable blood levels of
mercury and thallium.
Table 1 shows the concentrations and reference ranges
for lead and cadmium in the fluids and tissues of fresh
autopsy human eyes. No mercury or thallium was detected
in any of the ocular tissues or fluids. Cadmium and lead
were found in all of the pigmented ocular tissues (e.g.,
retinal pigment epithelium/choroid, ciliary body) studied
but concentrated to the greatest extent in the retinal
pigment epithelium/choroid (mean, 2,389 ⫾ 1592 ng/g
and 439 ⫾ 507 ng/g, dry weight; n ⫽ 16). Retinal pigment
epithelium/choroid cadmium concentrations were fivefold
greater than retinal pigment epithelium/choroid lead concentrations (P ⬍ .0001). Cadmium was found in the retina
of all 30 eyes (mean, 1,113 ⫾ 486 ng/g, dry weight, n ⫽
16), whereas lead was found in the retina in 9 (30%) of 30
eyes (mean, 59 ⫾ 75 ng/g, dry weight, n ⫽ 16) at a
concentration 18-fold less than cadmium (P ⬍ .0001).
Retinal pigment epithelium/choroid cadmium concentrations were twofold greater than retina cadmium concentrations (P ⫽ .0002), whereas retinal pigment epithelium/
choroid lead concentrations were sevenfold greater than
retina lead concentrations (P ⬍ .0001).
Five subjects were smokers, 10 were nonsmokers, and 1
was unknown. Cadmium concentrations in the retinal
pigment epithelium/choroid and retina were greater in
smokers than in nonsmokers (P ⫽ .004, P ⫽ .002,
respectively; Table 2). Blood cadmium concentrations
were not significantly different in smokers (3.7 ⫾ 6.1 ␮g/l,
n ⫽ 5) when compared with nonsmokers (2.4 ⫾ 3.1 ␮g/l,
n ⫽ 10, P ⫽ .38). There was no difference in lead
concentrations in the retinal pigment epithelium/choroid
and retina in smokers when compared with nonsmokers (P
⫽ .56, P ⫽ .62, respectively; Table 2).
Retina and retinal pigment epithelium/choroid cadmium concentrations in the right eye correlated with
concentrations in the left eye (P ⬍ .001). Similarly, retinal
pigment epithelium/choroid lead concentrations in the
right eye correlated with concentrations in the left eye (P
⬍ .001). Retina lead concentrations did not correlate
between eyes (P ⫽ .92; Figure 1).
The two eyes randomly selected for histologic examination (hematoxylin-eosin and periodic acid/Schiff) showed
on blood, urine, and digests of hair and nails. As such, it is
validated to perform with less than a 20% coefficient of
variation on both an intra- and inter-assay basis at the
lowest level of each calibration curve. These values in ␮g/l
are 10, 5, 0.2, and 1 for thallium, lead, cadmium, and
mercury, respectively. Additionally, for the purposes of this
study, the precision for lead was examined at a significantly
lower level because of the concentration of lead in the
tissue digests.
A lead calibration curve ranging from 0.01 to 0.50 ␮g/dl
was prepared with each analytical run and demonstrated
an r2 of 0.999 or better. To demonstrate analytical precision for lead, 17 tissue digests were analyzed 6 times over
the course of 5 separate analytical runs. The CV of these
analyses ranged from a low of 1.6% on a sample with a
concentration of 0.219 ng/dl to a high of 35.9% on a
sample with a concentration of 0.037 ng/dl. Seventy-three
percent of samples with a lead concentration ⬎0.219 ng/dl
had a CV ⬍15%. In the typical sample with a CV above
10%, the results increased with each measurement. This
suggests that the variation in the results is primarily
attributable to contamination and highlights the significant challenge of sample handling in trace metals analysis.
● DATA ANALYSIS:
Heavy metal concentrations from
two eyes of the same subject were averaged and treated as
one observation (total number of observations equals 16).
Tissue heavy metal concentrations, as a dry weight, were
compared using a paired t test when data were distributed
normally or Wilcoxon rank-sum tests if they were not.
Lead and cadmium concentrations in smokers and nonsmokers were compared using a 2-sample t test. Correlations between right and left eyes were examined by using
Pearson Product Moment analysis. The level of significance was P ⬍ .05.
RESULTS
MEAN BLOOD LEAD AND CADMIUM LEVELS AT THE TIME OF
death were 0.5 ⫾ 1.2 ␮g/dl (range, 0 – 4 ␮g/dl) and 3.1 ⫾
4.1 ␮g/l (range, 0.2–14.6 ␮g/l). All 16 subjects had blood
lead levels within the normal adult range (⬍20 ␮g/dl).
Three (19%) of 16 subjects had blood cadmium levels
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AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY 2005
FIGURE 1. Correlations of heavy metal concentrations (ng/g, dry weight) between left and right eyes for retina cadmium (Top left),
retina lead (Bottom left), retinal pigment epithelium/choroid cadmium (Top right), and retinal pigment epithelium/choroid lead
(Bottom right).
that the dissected retina contained only neural retina and
the dissected uvea contained both retinal pigment epithelium and choroid.
DISCUSSION
THIS INVESTIGATION DEMONSTRATES THAT THE HEAVY
metals, lead and cadmium, accumulate in the tissues of
adult human eyes, concentrating to the greatest extent
in the retinal pigment epithelium and choroid. The
pigmented tissues of the eye, such as the retinal pigment
epithelium, choroid, iris, and ciliary body, have a high
affinity for metal ions.8 Melanin within the pigment
granules binds metal ions.11 Metal ions are bound by
melanosomes according to atomic weight and volume
(e.g., the percentage binding of calcium 30%, zinc 37%,
lead 62%, iron 65%, and mercury 72%).8 Metals such as
zinc, copper, calcium, manganese, molybdenum, and
iron are found in ocular melanosomes, particularly
within the retinal pigment epithelium.8,12–14 Heavy
metals can effectively compete for the same binding
sites as other metal ions15 and have the capacity to
replace previously bound metals and alter ocular metal
concentrations.16,17 Once bound, heavy metals are not
VOL. 139, NO. 5
easily amenable to displacement.18 Ulschafer and coworkers,7 using metal x-ray spectra, showed that aluminum, mercury, and selenium were sometimes present in
retinal pigment epithelium melanosomes; energy spectra
for lead and cadmium were not presented. Eichenbaum
and Zheng9 found measurable concentrations of lead in
the choroid and retina; cadmium was not analyzed.
Does the accumulation of lead and cadmium in ocular
tissues provoke toxic injury? Neither lead or cadmium
has any demonstrated beneficial effect, and both metals
generally disrupt cellular biochemistry.6 Neurotoxicity
from lead19 and cadmium20 exposure is of concern,
especially because lead at even very low concentrations
can have profoundly detrimental neurologic effects21
Low-level lead exposure produces scotopic vision deterioration and rod and bipolar apoptotic cell death.1,22,23
In rabbits, lead poisoning causes swelling of the retinal
pigment epithelium,24 which leads to degeneration of
the photoreceptors.25 Visual loss in humans after systemic lead poisoning is usually related to encephalopathy and optic neuropathy, because of the toxic effect of
lead on the brain and optic nerve. Recent evidence,
however, indicates that lead and cadmium can exert
oxidative stress by producing reactive oxygen species
that result in lipid peroxidation, DNA damage, and
HEAVY METAL CONCENTRATIONS
IN
HUMAN EYES
891
depletion of cell antioxidant defense systems.19,26 Oxidative stress and free radical damage is thought to play
a significant role in age-related macular degeneration.27
The metal ion, iron, has recently been implicated in
retinal degeneration through iron-mediated oxidative
damage.28 Whether the accumulation of lead and cadmium in the retinal pigment epithelium/choroid or
retina could reach a concentration necessary to cause
retinal pigment epithelium and photoreceptor damage
requires additional study.
Lead and cadmium were found in all of the pigmented
ocular tissues (e.g., retinal pigment epithelium/choroid,
ciliary body) that we studied. The importance of melanin
binding of heavy metals in pigmented ocular tissues is
unclear. Melanin may confer tissue protection by acting as
a filter or detoxicant for heavy metals from the adjacent
neural retina and photoreceptor cells.7,9 Similar to the
retinal pigment epithelium, the choroid plexus of the brain
sequesters lead, acting as a defensive barrier to prevent
entry of toxic elements into the brain.29 Conversely,
melanin binding of heavy metals throughout the life of an
individual produces a local reservoir of potentially toxic
elements that ultimately could reach a concentration that
is destructive to the retinal pigment epithelium and
adjacent retina. For example, chronic exposure to chloroquine and phenothiazine derivatives, which have an affinity for melanin, can result in degeneration of pigment cells
or adjacent photoreceptors.30,31
In our study, lead and cadmium concentrations in the
retinal pigment epithelium/choroid were significantly
higher than concentrations in the retina. Because heavy
metals have a high affinity for sulfhydryl groups in melanin, one would expect higher heavy metal concentrations
in the pigmented retinal pigment epithelium and choroid
than in the neural retina. In contrast, Eichenbaum and
Zheng,9 reported higher lead concentrations in the retina
than in the choroid. These authors, however, did not
screen for blood lead levels, so it is not known if their
subjects had systemic lead intoxication. Additionally, they
used older atomic absorption spectrophotometry that is
approximately 50-fold less sensitive to lead detection than
the mass spectrometer used in our study. Finally, they
mistakenly attributed retina lead levels to the accumulation of lead ions in retinal pigment epithelium melanosomes. Many studies,24,32 as well as our histologic
examination, show that the neural retina separates from
the retinal pigment epithelium at death and that retinal
pigment epithelium cells are included with the choroid not
the neural retina.
How lead and cadmium avoid the blood-retinal barrier
and gain entry to the neural retina is not entirely clear.
Investigators have shown that lead and cadmium can enter
various cells through calcium channels33 or avoid the
blood-brain barrier by retrograde axonal transport.34 Additionally, potential defects or gaps in the blood-retinal
barrier could represent sites for metal ion transport or
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AMERICAN JOURNAL
leakage into the retina. For comparison, retina cadmium
levels in our study (1,072 ⫾ 489 ng/g) are 20-fold higher
than published normal brain cadmium levels (38 to 57
ng/g).10 Retina lead levels (53 ⫾ 54 ng/g), by contrast, are
similar to published normal brain lead levels (0 –100
ng/g).10,35
Lead and cadmium are industrial pollutants that cause
permanent contamination of air, dust, and soil. These
heavy metals are released into the environment from fossil
fuel power plants, mining and smelting of metal ores, trash
incineration, and combustion of leaded gasoline. Human
exposure to these metals is inevitable. Lead and cadmium
enter the blood from either the lung or intestine and clear
the blood rapidly in approximately 30 days.36 By contrast,
lead and cadmium reside in target organs with very long
half-lives, accumulate in the body over time, and increase
in concentration with age.5,19,21 Therefore, tissue metal
concentrations reflect cumulative exposure, whereas blood
concentrations reflect recent exposure.10,37 In our study,
blood lead and cadmium concentrations in all subjects
were well below alert levels, indicating no recent elevated
exposure. Lead and cadmium concentrations in the ocular
fluids (e.g., vitreous and aqueous) were similarly very low
or not detectable. Tissue concentrations of lead and
cadmium were considerably higher, suggesting that the
ocular tissue heavy metal concentrations in these subjects
reflect accumulation from chronic exposure rather than
recently elevated doses.
No previous studies have examined cadmium concentrations in the choroid and retina of human eyes. We
found cadmium in the retinal pigment epithelium/choroid
and retina of all the subjects studied. Similarly, cadmium
primarily accumulates in the uvea of rabbit eyes.38 In our
study, retinal pigment epithelium/choroid and retina cadmium concentrations were significantly greater in smokers
than in nonsmokers. Others have shown that smokers
have higher cadmium body burdens than nonsmokers of
similar ages.39 Tobacco plants are a bioaccumulator of
cadmium, and cigarette smoke is a significant source of
cadmium,40 with 50% of inhaled cadmium absorbed into
systemic circulation.39 Blood cadmium can then reach the
uvea and be deposited in the choroid and adjacent retinal
pigment epithelium.
In summary, lead and cadmium are toxic heavy metals
that accumulate in the retinal pigment epithelium and
choroid, ciliary body, and the retina of humans at concentrations greater than found in the blood or in the fluids of
the eye. The potential ocular toxicity of these heavy
metals and their possible role in diseases of the retina and
choroid requires further study.
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Biosketch
Jay C. Erie, MD is a comprehensive ophthalmologist and an assistant professor of Ophthalmology at Mayo Clinic and
Mayo College of Medicine, Rochester, Minnesota, USA.
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