Association between Blood Lead Levels and Age-Related Macular Degeneration
Association between Blood Lead Levels and Age-Related Macular Degeneration
Ho Sik Hwang 0 1
Seung Bum Lee 0 1
Donghyun Jee 0 1
0 1 Department of Ophthalmology, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University , Chuncheon, Korea, 2 Seoul St. Mary's Eye Hospital , Suwon , Korea , 3 Department of Ophthalmology and Visual Science, St. Vincent's Hospital, College of Medicine, Catholic University of Korea , Suwon , Korea
1 Editor: Demetrios Vavvas, Massachusetts Eye & Ear Infirmary, Harvard Medical School , UNITED STATES
Data Availability Statement: Data are available from
the Korea Center for Chronic Disease and Control
Institutional Data Access / Ethics Committee for
researchers who meet the criteria for access to
confidential data. We obtained the data set from the
Korea Center for Chronic Disease and Control, which
owns the data. Readers can send requests for data to
Tel:82-43-719-7466 or Email:
(Division of Health and Nutrition Survey, KCDC) or
Osong Health Technology Administration Complex,
187 Osongsaengmyeong2(i)-ro, Osong-eup,
Heungduk-gu, Cheongju-si, Chungcheongbuk-do,
Korea 363-700 (Tel: +82-43-719-7464,63 E-mail:
To investigate the association between blood lead levels and prevalence of age-related
macular degeneration (AMD).
A nationwide population-based cross-sectional study included 4,933 subjects aged over 40
years who participated in the 2008–2012 Korean National Health and Nutrition Examination
Survey, and for whom fundus photographs were available. All participants underwent a
standardized interview, evaluation of blood lead concentration, and a comprehensive
ophthalmic examination. Digital fundus photographs (45°) were taken of both eyes under
physiological mydriasis. All fundus photographs were graded using an international classification
and grading system.
Mean blood lead levels were 3.15 μg/dL in men and 2.27 μg/dL in women (P < 0.001). After
adjusting for potential confounders including age, gender, smoking status, total cholesterol
levels, triglyceride levels, heart problems and strokes, the adjusted odds ratio (OR) in
women for any AMD was 1.86 (95% Confidence Interval [CI], 1.03–3.36) and for early AMD
was 1.92 (95% CI, 1.06–3.48), for those in the highest quintile of lead level compared with
the lowest quintile. In men, however, blood lead level was not significantly associated with
Blood lead levels were higher in men, but were only associated with AMD in women.
Increased levels of blood lead may be involved in the pathogenesis of AMD development in
Funding: This study was supported by the fund of
Ajou Pharm (5-2013-D0383-00002) from Catholic
Medical Center Research Foundation in the program
year of 2012.
Competing Interests: The authors have declared
that no competing interests exist.
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly in
industrialized countries . Although the precise etiology of the condition remains unclear,
AMD is known to be a multifactorial disease, involving interactions between genetic and
environmental factors . Established risk factors include age and smoking [1, 3]. Other potential
factors include cardiovascular disease, dietary oxidant intake, and sunlight exposure, all of which
have been inconsistently associated with prevalence of AMD [4–7]. We previously reported that
AMD is associated with age, hypertension, and male gender in a representative Korean
population [8, 9]. Recently, increasing evidence has suggested that trace metals may play a role in the
pathogenesis of AMD [10–12]. For example, we reported that blood cadmium levels were
positively associated with prevalence of AMD in a representative Korean population .
Lead is a non-essential metal that is toxic to human tissue at very low concentrations 
and is ranked second most toxic substance in the hazardous substances list by the Agency for
Toxicity and Disease Registry . The body burden of lead increases with age, despite efforts
to reduce exposure to the metal. The principal sources of lead are paints, water, food, dust, soil,
kitchen utensils, and leaded gasoline. Most cases of lead poisoning are attributable to oral
ingestion and absorption through the gut . Most ingested lead accumulates in specific
target tissues including blood, soft tissues, and bone, where it has a very long half-life .
Chronic lead exposure can adversely affect the central nervous, renal, cardiovascular,
reproductive, and hematological systems, and can trigger cognitive decline [18–22]. Lead can
promote aging by increasing oxidative stress and stimulating production of inflammatory
cytokines . In the eye, increased lead exposure is associated with the development of
agerelated cataracts in men  and low-tension glaucoma in women . The retina is
particularly susceptible to oxidative stress because of its elevated oxygen tension, high polyunsaturated
lipid content, and high level of exposure to light. Very low concentrations of lead can cause
detrimental effects to the retina [16, 26–28]. A recent study of 30 autopsy eyes found that lead
accumulates in the retinal pigment epithelium (RPE) and choroid . Moreover, excess lead
was found in the neural retinas of donor eyes with AMD , suggesting that lead
accumulation may be associated with the development of AMD. However, most previous studies involve
experimental animal studies or case–control studies on human autopsy eyes. Epidemiological
studies investigating an association between lead and AMD are limited, and show conflicting
results. A recent study examined 5390 participants in the U.S. National Health and Nutrition
Examination Survey (NHANES), 2005–2008, and found no association between blood lead
levels and AMD . Conversely, the Korean NHANES, 2008–2011, showed a significant
association between lead levels and AMD . There is increasing evidence that the detrimental
health effects of toxic metals differ in prevalence, or manifest differently, between men and
women . Experimental studies suggest that females are more susceptible to the
immunotoxic effects of lead [33, 34], thus indiscrimination of blood lead levels by gender could bias the
association between lead levels and AMD . Therefore, we evaluated the effect of blood lead
levels on AMD prevalence, and additionally analyzed potential effect modification, using data
collected from a population-based epidemiological study.
Subjects and Methods
The present study used data from the Korean National Health and Nutrition Examination
Survey (KNHANES). This is an ongoing, nationwide, population-based, cross-sectional survey of
nationally representative Korean participants, conducted by the Division of Chronic Disease
Surveillance, Korean Center for Disease Control and Prevention. The survey consists of a
health interview, a nutritional survey, and a health examination. Details on the study design
and methods have been reported previously [36, 37]. Briefly, the KNHANES adopted a rolling
sampling design which is a stratified, complex, multistage, probability cluster survey with
proportional allocation based on the National Census Registry for the non-institutional civilian
population of Korea. Data from the fourth (KNHANES IV, 2008–2009) and fifth (KNHANES
V, 2010–2012) surveys were used to investigate the association between blood lead levels and
AMD. In the current study, 11,159 individuals whose blood lead levels were measured were
selected. Of these, 5,718 who were aged under 40 years, and 508 who did not undergo retinal
fundus examinations were excluded. Thus, 4,933 participants aged 40 years or older were
included in the analysis (Fig 1). All participants were informed of the aims of the study, and all
gave written informed consent. The study design followed the tenets of the Declaration of
Helsinki for biomedical research, and was approved by the Institutional Review Board of the
Catholic University of Korea in Seoul, Korea.
Digital fundus images were taken under physiological mydriasis using a digital fundus camera
(TRC-NW6S; Topcon, Tokyo, Japan). For each participant, a 45° digital retinal image centered
on the fovea was taken of each eye (two images per subject). Each fundus photograph was
graded twice [38, 39]. Preliminary grading was done at the scene of photography by a trained
ophthalmologist, using the International Age-related Maculopathy Epidemiological Study
Group grading system . Detailed grading was performed later by 9 retina specialists
experienced in grading early and late AMD, who were masked to the patients' characteristics and
entrusted by the Korean Ophthalmologic Society (KOS). Final grading was based on the
detailed grading, and any discrepancies between the preliminary and detailed grading were
resolved by 1 reading specialist. The inter-rater reliability for AMD grading between the
preliminary and detailed grading in right and left eyes was 90.2% and 90.7% in 2008, 92.4% and
93.3% in 2009, 94.1% and 95.0% in 2010, 96.2% and 96.6% in 2011 and 96.0% and 96.2% in
2012, (available at: https://knhanes.cdc.go.kr/knhanes/sub04/sub04_03_02.do?classType ¼8).
Early-AMD was defined by the presence of soft, indistinct, or reticular drusen; any type of
drusen plus hyper- or hypo-pigmentary changes to the RPE in the macula; or by the presence
of soft drusen without late-AMD signs in the macula [38, 39]. Late-AMD was defined by the
presence of one of the following lesions: detachment of the RPE or neurosensory retina,
hemorrhages in the subretinal or sub-RPE space, disciform scar, or geographic atrophy as a discrete
depigmented area with visible choroidal vessels [38, 39]. For subjects with AMD lesions in only
one eye, or asymmetric AMD lesions in both eyes, the worst eye was considered.
Demographic information was obtained from health interview data. Height was measured
using a wall-mounted measuring scale, and weight was measured using calibrated electronic
scales. Body mass index (BMI) values were calculated as follows: weight (kg)/height (m)2.
Subjects were assigned to age bands of 10 years. Smoking status was self-reported as current
smoker, past-smoker, and never-smoker. Alcohol use was self-reported as ever-drinker or
never-drinker, wherein never-drinker represented people who had never consumed alcohol
during their entire life.
Blood samples were collected after 10–12 h of fasting. Levels of fasting glucose, hemoglobin
A1c, total cholesterol, and triglycerides were measured using a Hitachi automatic analyzer
(model 7600, Hitachi, Tokyo, Japan). Blood lead levels were determined by graphite furnace
atomic absorption spectrophotometry (SpectrAA-800; Varian, Australia). Detection limit was
approximately 0.12 μg/L. Details of the lead analysis method have been reported previously
Fig 1. Flow diagram showing selection of study participants.
[41–43]. All blood analyses were performed in the Neodin Medical Institute, a laboratory
certified by the Korean Ministry of Health and Welfare. For internal quality assurance and control,
commercial standard reference materials were obtained from Bio-Rad (Lyphocheck Whole
Blood Metals Control; Hercules, CA). The coefficients of variation were 0.95–4.83% upon
analysis of reference samples. In terms of external quality control, the Neodin Medical Institute has
passed the German External Quality Assessment Scheme operated by Friedrick Alexander
University. The Scheme assesses the reliability of measurement of low concentrations of chemicals.
The Neodin Medical Institute is also certified by the Korean Ministry of Labor as a laboratory
competent in the analysis of specific chemicals.
Blood pressure was measured in a sitting position with a sphygmomanometer. After three
measurements at 5-min intervals, the average of the second and third measurements was
included in the analysis. Diabetes mellitus was defined by a fasting blood glucose level of 126
mg/dL or if the individual was taking anti-glycemic medication. Hypertension was defined by a
systolic blood pressure of 140 mmHg, diastolic blood pressure 90 mmHg, or if the
individual was taking anti-hypertensive medication. Heart problems were defined as a history of
myocardial infarction, and/or angina, and stroke was self-reported.
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS)
version 18.0 software (SPSS; IBM Corp, Armonk, NY, USA). Strata, sampling units, and
sampling weights were used to obtain unbiased point estimates and robust linearized standard
errors. Participant characteristics are presented as means and standard errors for continuous
variables, percentages and standard errors for categorical variables, and are presented in
relation to the presence of AMD. Analysis of variance (ANOVA) or chi-squared testing was used,
as appropriate, to compare demographic characteristics.
To evaluate the effect of blood lead level on AMD prevalence, lead levels were grouped into
quintiles . Simple and multiple logistic regression analyses were used to explore
associations between blood lead level and AMD. After calculation of crude odds ratios (Model 1), we
adjusted for age, gender, and other confounders that have been established as AMD risk factors
in previous studies, including smoking status, hypertension, lipid profiles, and cardiovascular
disease (Model 2) [3, 6, 8]. We evaluated an effect modification by gender by including
interaction terms lead and gender in model 2. Blood lead levels were dichotomized at the median
concentrations and adjusted odds ratios for low and high lead levels were calculated for each
stratum of gender. We also performed separate regression models stratified by gender. All
variables in logistic regression analyses were examined in terms of multicollinearity, and only
variables with variance inflation factors of less than 10 were used. All P-values were two-tailed, and
P < 0.05 was considered to indicate statistical significance.
Of 5,441 eligible subjects aged over 40 years for whom blood lead levels were available, the
fundus (both eyes) was examined in 4,933 (90.6%) subjects. Reasons for the absence of fundus
photographs were as follows: small pupils (42.3%), cataracts (26.7%), poor cooperation (7.1%),
refusal (4.8%), corneal opacity (4.4%), and miscellaneous (14.3%). Thus, 4,933 subjects were
included in our final analysis and their demographic characteristics are summarized by AMD
status in Table 1. Subjects with AMD were more likely to be older (P < 0.001), to be
neverdrinkers (P<0.001), and to have higher systolic blood pressure (P = 0.031) and hypertension
(P < 0.001) compared to those without AMD.
Demographic and clinical characteristics per quintile blood lead level are shown in Table 2.
Subjects with higher blood lead levels were more likely to be male (P for trend, <0.001), older
(P for trend <0.001) and smokers (P for trend, <0.001), and to have high systolic blood
pressure (P for trend, <0.001), high diastolic blood pressure (P for trend, <0.001), total cholesterol
(p < 0.001), triglyceride (p < 0.001) and hypertension (P for trend, <0.001).
Mean blood lead levels were 3.15 μg/dL (95% CI, 3.05–3.25 μg/dL) in men and 2.27 μg/dL
(95% CI, 2.22–2.31 μg/dL) in women (P < 0.001). In women, mean blood lead levels in subjects
with AMD (2.41 μg/dL; 95% CI, 2.27–2.55) was significantly higher than those without AMD
(2.23 μg/dL; 95% CI, 2.18–2.27; P = 0.013). However, there was no statistically significant
difference in blood lead levels between men with and without AMD (3.30 μg/dL; 95% CI, 3.07–
3.52 versus 3.07 μg/dL; 95% CI, 3.00–3.15, P = 0.069). The prevalence of AMD by quintile of
blood lead levels showed a non-linear pattern (Fig 2). The prevalence of AMD increased in the
upper 20% of blood lead levels and decreased in the lower 20% of blood levels. However, the
prevalence of AMD did not show a significant change in the middle 60% (quintiles 3, 4, and 5)
of blood levels.
The association between blood lead levels and any type of AMD is shown in Table 3. In
women, the adjusted OR for any AMD after adjusting for potential confounders was 1.86 (95%
CI, 1.03–3.36) among those in the highest blood lead quintile compared with those in the
Data are expressed as weighted means or weighted frequency (%) with standard errors.
*P < 0.05
Pa values compared patients with any AMD and without AMD.
Pb value compared patients with and without fundus photograph available.
lowest quintile (P for trend = 0.164). In men, however, we found no significant association
between blood lead quintile and AMD (Fig 3). The adjusted OR for early AMD in women was
1.92 (95% CI, 1.06–3.48) among those in the highest quintile compared with those in the lowest
quintile, but this was without significant linear trend (P for trend = 0.159), whereas in men
there was no significant association (Table 4). Late AMD was not significantly associated with
blood lead level in either gender (Table 5). Using a Wald test for coefficient of interaction term
to evaluate effect modification, we found a marginally significant interaction between lead level
and any AMD by gender (P for interaction = 0.082, Table 6), and between the lead level and
late AMD by gender (P for interaction = 0.071, Table 6).
Our study found that the risk of any AMD and early AMD was significantly increased in
women with high blood lead levels compared with those in the lowest quintile of blood lead
Table 2. Demographic and clinical characteristics by quintile blood lead category among representative Korean adults aged 40 years or older
included in the study.
Fig 2. The prevalence of any AMD by quintile of blood lead level, stratified by gender.
Fig 3. The odds ratio of any AMD by quintile of blood lead level, stratified by gender.
levels. However, in men there was no significant increased risk of AMD associated with high
lead blood levels. Blood lead levels were higher in men (3.15 μg/L) than in women (2.27 μg/L,
P < 0.001).
We found that higher blood lead levels were significantly associated with decreasing odds of
AMD in women, after adjusting for potential confounders. The present study found that the
trend analysis for OR did not show a significant ascending trend in AMD as blood lead
quintiles per increase. This indicates the possibility of a poor dose-response relationship between
blood lead levels and AMD, even though the risk of AMD development is significantly higher
in those with high blood lead levels than in those with lower blood lead levels. A recent study
using U.S. NHANES data showed no correlation between blood lead levels and AMD . The
mean blood lead level in the Korean population studied (2.71 μg/L) was 64.2% higher than
those in the U.S. population studied (1.65 μg/L). This suggests that environmental lead
exposure may be greater in Korea than in the U.S.A. For example, the regulation of lead use in paint
was not instigated in Korea until 1998, while this regulation has been established in the U.S.A
since 1978. Another study using Korea NHANES data showed a significant positive association
between lead levels and AMD . However, the present study differs from that study in
several aspects. First, our study stratified data by gender, while Park et al. showed overall
association only. Second, the present study performed logistic regression analysis using raw data,
while the previous study used logarithmic transformed data. Finally, the sample size in our
study was 4,933 subjects, which is 21.6% larger than in the previous study (3,865 subjects).
Potential biochemical mechanisms of lead-induced predisposition to AMD include
oxidative stress and inflammation . The presence of lead in human tissues causes the production
P for interaction
N with/without AMD
N with/without AMD
1.28 (0.71, 2.30)
1.28 (0.71, 2.30)
2.20 (0.20, 24.38)
1.55 (0.85, 2.83)
1.61 (1.01, 2.57)
1.47 (0.81, 2.68)
9.89 (1.15, 84.8)
5.14 (0.41, 64.13)
of inflammatory cytokines, and increases oxidative stress levels, causing oxidative damage to
retinal cells. Lead can increase the production of reactive oxygen species such as the hydroxyl
radical, superoxide radical, and hydrogen peroxide. Lead exposure results in lipid peroxidation,
DNA damage, and depletion of cell antioxidant defense systems. For example, lead has a high
affinity for the sulfhydryl group (SH), and binds to the SH group of glutathione (GSH) which
is major cellular antioxidant. Furthermore, oxidative stress and inflammation have been related
to the pathogenesis of AMD .
In women, the risk of any and early AMD was 1.86- and 1.92-fold higher, respectively, for
those in the highest blood lead quintile compared with those in the lowest. However, in men,
no significant association between blood lead levels and AMD was shown. A recent study of 98
primary open angle glaucoma patients and 215 controls showed that lead accumulation levels
in hair were significantly higher in the female glaucoma patient group compared to the control
group, but not between the male groups . In the present study, blood lead levels were
higher in men than in women. One possible explanation is that as men have higher
hematocrits, and lead binds to erythrocytes, this leads to a rise in blood lead levels [47, 48]. Another
possible explanation is a gender-related difference in lead metabolism. More than 90% of lead
in the body localizes to bone, with an average half-life of 10 years. The release of lead from
bone into the blood is slower in premenopausal women than in men , and hormone
replacement therapy in women may reduce lead release from bone into the blood . In
addition, pregnancy increases mobilization of lead from the maternal skeleton . It is well
accepted that blood lead levels in women reflect hereditary factors to a considerable extent
(about 40%), while in men they mainly (more than 95%) reflect environmental exposure .
Therefore, we propose that blood lead levels are influenced by different factors in men and
women. The finding that blood lead levels were higher in men, but were only associated with
AMD in women is intriguing, particularly taking into account women's lower blood lead levels
compared to men. This may reflect a gender difference in the uptake and metabolism of lead,
as well as decreased sensitivity to lead in men or increased sensitivity in women. Further studies
are needed to identify the factors responsible for this difference, and especially to elucidate the
biological mechanisms of lead absorption and regulation thereof by each gender.
Potential confounders included in this analysis were age, smoking status, hypertension
status, total cholesterol levels, triglyceride levels, heart problems and stroke. However, alcohol
consumption was not included in the final analysis as a confounder for two reasons. First,
alcohol consumption was not associated with AMD after adjusting for gender and age. This was
addressed in our previous published article reporting the prevalence and associated factors of
AMD in Korea using the same KNHANES data as the present study . Second, most studies
examining factors associated with AMD have found that alcohol is not associated with AMD.
[6, 53–55] Thus, we did not include alcohol consumption in the regression analysis. Instead,
we presented alcohol consumption according to AMD status and lead levels.
The major strength of our present study is the relatively large number of participants
(n = 4,933) and the study design (a systemic, stratified, multistage, clustered, random sampling
method). Another strength is the rigorous quality control of ophthalmic examinations of the
fundus and measurement of blood lead levels in KNHANES participants. However, our study
has several limitations. First, occupational lead exposure was not recorded. It would have been
useful to know whether subjects had been, or were currently involved in smelting, welding,
mixing of ceramic glazes, or battery manufacture. However, KNHANES data do not include
occupational information. Second, lead exposure status was evaluated only by the
measurement of lead levels in blood samples, not in bone or soft-tissue samples. Thus, measurements
may not accurately reflect chronic exposure status. However, blood lead level is a good
indication of lead body burden in populations with low level environmental exposure [41, 43, 56–58].
Thirdly, KNHANES participants who were ineligible for the present study due to non-gradable
fundus photographs, were older than participants who did meet inclusion criteria. Since the
older population are more likely to have AMD, this may impact our results. Finally, our study
was cross sectional in design, therefore it is difficult to infer causality. However, we report an
association between blood lead levels and AMD based on existing evidence of the effect of lead
on AMD development. Such a differential pattern of blood lead level is unlikely to be caused by
In conclusion, the present study provides population-based epidemiological data on the
association of blood lead levels with AMD in a representative Korean population. We found
that blood lead levels were higher in men but were associated with AMD only in women. This
result implies a possible gender difference in the uptake and metabolism of lead, as well as a
potential gender difference in sensitivity to lead. In addition, blood lead levels in the Korean
population were much higher than those in the U.S. population. Further studies are required to
evaluate factors that may be responsible for these gender differences, and to elucidate the
biological mechanisms of lead metabolism by gender.
The authors thank the Epidemiological Survey Committee of the Korean Ophthalmological
Society for conducting examinations on KNHANES subjects and for supplying the data used
This study was supported by the fund of Ajou Pharm (5-2013-D0383-00002) from Catholic
Medical Center Research Foundation in the program year of 2012.
Wrote the paper: HSH DJ.
Conceived and designed the experiments: HSH DJ. Performed the experiments: HSH SBL DJ.
Analyzed the data: HSH SBL DJ. Contributed reagents/materials/analysis tools: HSH SBL DJ.
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