Schaumberg DA, Mendes F, Balaram M, Dana MR, Sparrow D, Hu H. Accumulated Lead Exposure and Risk of Age-Related Cataract in Men. JAMA. 2004;292(22):2750-2754. doi:10.1001/jama.292.22.2750
Author Affiliations: Division of Preventive
Medicine (Dr Schaumberg), Channing Laboratory (Dr Hu), Brigham and Women's
Hospital, Schepens Eye Research Institute, Department of Ophthalmology, Harvard
Medical School (Drs Schaumberg, Mendes, Balaram, and Dana), Department of
Epidemiology (Dr Schaumberg), Department of Environmental Health (Dr Hu),
Harvard School of Public Health, The Normative Aging Study, Department of
Veterans Affairs (Dr Sparrow), Harvard School of Public Health, Boston, Mass.
Context Low-level lead exposure may increase the risk for a number of chronic
age-related diseases. Several studies have documented the presence of lead
in lenses with cataract. The intrusion of lead into the lens may alter lens
redox status and cause protein conformational changes that decrease lens transparency.
Objective To determine the relationship of cumulative lead exposure with the development
Design, Setting, and Participants Tibial (cortical) and patellar (trabecular) bone lead levels were measured
by K x-ray fluorescence between 1991 and 1999 in a subset of participants
in the Normative Aging Study (NAS), a Boston-based longitudinal study of aging
in men. Among the first 795 NAS participants to have bone lead levels measured,
we reviewed eye examination data (collected routinely every 3-5 years) for
the period after the bone lead measurements were taken. We limited the population
to men aged 60 years and older who had sufficient eye examination information
available (n = 642). Blood lead levels were also measured.
Main Outcome Measures Cataract assessment was done while masked to the lead level results.
A participant was considered to have cataract if there was documentation for
either eye of cataract surgery or a cataract graded clinically as 3+ or higher
on a 4-point scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were
calculated as estimates of the magnitude and significance of the relationship
of lead exposure with cataract, in logistic regression models.
Results The mean age of the study participants was 69 years and cataract was
identified in 122 men. The age-adjusted OR (95% CI) for cataract for men in
the highest vs lowest quintile of tibia lead level was 2.68 (1.31-5.50). Further
adjustment for pack-years of cigarette smoking, diabetes, blood lead levels,
and intake of vitamin C, vitamin E, and carotenoids resulted in an OR of 3.19
(95% CI, 1.48-6.90). For patella lead level, there was an increased risk of
cataract in the highest vs lowest quintile (OR, 1.88; 95% CI, 0.88-4.02),
but the trend was not significant (P = .16). Blood
lead levels, more indicative of short-term exposure levels, were not significantly
associated with cataract (OR, 0.89; 95% CI, 0.46-1.72; P = .73).
Conclusions These epidemiological data suggest that accumulated lead exposure, such
as that commonly experienced by adults in the United States, may be an important
unrecognized risk factor for cataract. This research suggests that reduction
of lead exposure could help decrease the global burden of cataract.
Although lead toxicity in humans has been recognized for centuries,
the 20th century has left a legacy of unprecedented lead levels spread throughout
the environment. Lead continues to pose a significant public health problem
in spite of substantial reductions in lead exposure in the United States in
the recent past. Moreover, exposure has not been totally eliminated and most
adults continue to have substantial body burdens of lead.1
Much of the lead taken into the body is incorporated into bone where
it constantly interchanges with other tissues.2 Recent
studies suggest that accumulated lead exposure is related to several chronic
disorders of aging including hypertension and cognitive decline,1 disorders
that have been associated with oxidative stress.3,4 Several
lines of evidence suggest that accumulated lead exposure could also increase
the risk of another oxidative-stress–related disorder of aging, age-related
cataract—the leading cause of blindness and visual impairment worldwide.5 In the present study, the first we are aware of to
investigate this hypothesis, we tested whether bone lead levels measured in
both the tibia and patella were associated with age-related cataract in an
ongoing study of men from the United States who were drawn from the general
population surrounding Boston.
Participants were drawn from the Normative Aging Study (NAS), a longitudinal
study of 2 280 healthy male volunteers, begun in Boston in the 1960s.6 At the time of their initial enrollment, all NAS participants
were free of heart disease, hypertension, diabetes mellitus, cancer, peptic
ulcer, gout, recurrent asthma, bronchitis, or sinusitis. Study participants
were predominantly white, and ranged in age from 48 to 93 years at the time
of bone lead measurement. Every 3 to 5 years, participants underwent an extensive
physical examination that included a standard ocular evaluation, not always
including a dilated fundus examination, with notation of any abnormalities
in the lens, optic nerve, and macula. Beginning in 1991 and continuing through
1999, NAS participants were invited to undergo bone and blood lead measurements.2,7 At the time the present study was initiated,
795 (68%) of the 1 171 NAS participants who were still being monitored
had completed bone lead measurements. The main reason for nonparticipation
in the bone lead measurements was the inconvenience of returning to the bone
lead laboratory on a separate day from the regular NAS follow-up examination.
In an earlier analysis, no important differences were detected between NAS
participants who did and did not have bone lead measurements taken.8 Because we were interested in occurrence of age-related
cataract, we limited our analysis to men who were at least 60 years of age
at the time of measurement (n = 663), and had at least one eye examination
available during the period spanning the year prior to bone lead measurement
and the time of this study in 2002 (n = 642).
K x-ray fluorescence9,10 was
used to measure bone lead levels. Bone lead levels were measured at both the
midtibial shaft and the patella. These 2 sites were chosen to represent the
2 main bony compartments: trabecular bone (patella) and cortical bone (tibia).
Since trabecular bone has a higher turnover rate as compared with cortical
bone, the amount of lead in trabecular bone reflects more recent exposure
than the amount present in cortical bone.10 Bone
lead measurements were recorded on a continuous scale in units of μg/g.
Standard eye evaluations including a complete history, documentation
of medication use, visual acuity measurement, biomicroscopy, tonometry, and
ophthalmoscopy were performed and recorded at each routine NAS study visit.
These examinations were generally performed by staff optometrists at the NAS
examination facility. Thus, during the course of the study, several clinicians
evaluated study participants but possible inter-rater differences were not
investigated. For the present study, standardized forms were established for
extraction of eye disease data from NAS study records. Without knowledge of
the participants’ bone lead results, we reviewed medical records for
diagnoses and severity of cataract, and occurrence of cataract extraction
between 1986 and 2002. Lens status was assessed by biomicroscopy and a participant
was considered to have cataract if there was documentation for either eye
of cataract surgery or a cataract (of any subtype), graded clinically as 3+
or higher on a 4-point scale, diagnosed either after or within 1 year prior
to bone lead measurement.
In all analyses performed using version 8 of the SAS System (Cary, NC),
we classified individuals rather than eyes, because the same examiner made
assessments at the same time for both eyes of each participant, and consequently,
classification of the 2 eyes was not independent. We examined relationships
for categories of tibia and patella bone lead formed using quintile cutpoints.
We determined the mean levels (or percentages) of baseline characteristics
according to quintiles of bone lead levels, and assessed the significance
of a linear trend using linear regression models for the continuous variables,
and the Mantel-Haenszel χ2 test for trend for dichotomous
variables. We determined the odds ratio (OR) and 95% confidence interval (CI)
for occurrence of cataract using logistic regression models. The P value of significance was <.05. In initial analyses, we obtained
age- and smoking-adjusted OR of cataract by quintile of bone lead level (separately
for tibia or patella). We extended these models to control for other possible
risk factors including history of diabetes mellitus (yes vs no), vitamin C,
carotenoids, and/or vitamin E intake, all as assessed at the time of bone
lead measurement. Using interaction terms in regression models, we explored
whether diabetes or cigarette smoking modified the effect of bone lead level
on cataract risk.
Finally, we calculated the age-adjusted attributable fraction in the
population as a measure of the amount of cataract associated with lead exposure.
Since relative risks of cataract were elevated in each of the top 4 quintiles
of tibia lead, relative to the first with a significant linear trend, we determined
the attributable fraction associated with tibia lead above the 20th percentile
(ie, considering 80% of the population to be exposed).11
The mean age of study subjects was 69 years (range, 60-93). The concentration
of tibia lead ranged from 0 to 126 μg/g (median, 20 μg/g), while patella
lead ranged from 0 to 165 μg/g (median, 29 μg/g). The correlation
of tibia and patella lead levels was 0.68. Blood lead levels ranged from 0
to 35 μg/dL (median, 5 μg/dL), and were moderately correlated with
both tibia (r = 0.31) and patella (r = 0.39) lead levels. Older age (P<.001),
higher blood lead levels (P<.001), a greater number
of pack-years of cigarette smoking (P<.001), and
a history of diabetes (P = .03), were related to
higher concentrations of tibia lead (Table 1).
Older age (P<.001), higher blood lead levels (P<.001), and a greater number of pack-years of cigarette
smoking (P<.001), were also associated with higher
patella lead levels.
We identified 122 cases of cataract among the 642 study participants
aged 60 years and older, who had bone lead measurements and sufficient eye
examination data. In univariate analyses, both tibia (P for trend <.001) and patella (P for trend = .02)
lead were associated with an increased risk of cataract. After controlling
for age, tibia lead level remained a significant predictor of cataract (OR
for highest vs lowest quintile, 2.68; 95% CI, 1.31-5.50; P for trend = .03). Additional control for pack-years of
cigarette smoking, blood lead levels, diabetes, and dietary intake of vitamin
C, vitamin E, and carotenoids did not alter this association (OR, 3.19; 95%
CI, 1.48-6.90; Table 2). In contrast,
there was no significant association of patella lead level with cataract after
controlling for age. The age-adjusted OR (95% CI) contrasting the highest
vs the lowest quintile of patella lead level was 1.44 (0.75-2.78; P for trend = .43). Additional control for other risk factors
did not alter this null finding for the trend (P =
.16), although the OR for the top quintile of patella lead level increased
to 1.88 (95% CI, 0.88-4.02).
In contrast to the findings of significant associations between bone
lead levels and cataract, the risk of cataract was not different across categories
of blood lead levels (P = .67), which were available
in 630 men. After controlling for age, the OR (95% CI) contrasting the top
vs bottom quintile of blood lead level was 0.88 (0.47-1.64). This finding
did not change after controlling for additional risk factors (OR, 0.89; 95%
CI, 0.46-1.72; Table 3).
Since tibia lead level was related to both cigarette smoking and diabetes,
2 prominent cataract risk factors, we examined whether there was any evidence
that these risk factors might modify the associations between tibia lead level
and cataract. In these models, there was no significant interaction of tibia
lead level with either diabetes (P for interaction = .93),
or cigarette smoking (P for interaction = .25).
Finally, after controlling for age, the attributable fraction of cataract
in this population associated with lead exposure was 42%.
Although much progress has been made to limit lead exposure in the United
States and other industrialized countries, primarily through the elimination
of leaded gasoline and workplace exposures, most adults have already accumulated
a substantial body burden of lead.1 Moreover,
generalized low lead exposure along with pockets of higher exposure remain
commonplace, including in the United States where more than 80% of homes built
before 1980 are contaminated by lead-based paint and/or leaded water pipes.12 Results of the present study suggest that cumulative
lead exposure is a risk factor for cataract, which accounts for more than
40% of all cases of blindness worldwide.5 There
was a greater than 2.5-fold increased risk of cataract in men with the highest
levels of lead in the tibia, compared with men with the lowest tibia lead
levels. The estimated attributable fraction of cataract in this population
resulting from lead exposure was 42%. However, as expected, there was no association
between blood lead levels and risk of cataract in these men.
Since blood lead levels are indicative only of recent exposures,2,10 they are not likely to be very relevant
to the development of age-related eye diseases, which take many years to develop.
Approximately 95% of the total body burden of lead is present in the skeleton
and, consequently, measurement of bone lead levels can provide an integrated
picture of more long-term exposure. Lead stored in cortical bone has a biological
half-life of more than 10 years, and lead from trabecular bone has a half-life
of 1 to 5 years.13,14 Lead is
continuously mobilized from the skeleton, circulates in plasma at very low
levels that are difficult to measure, and is made available for interactions
with other tissues. Thus, bone lead levels are thought to be indicative not
only of the magnitude of the cumulative exogenous exposure, but also of exposure
from endogenous sources.2,10 Indeed,
bone lead measured by K x-ray fluorescence has recently been found to be a
better biomarker of lead dose than blood lead in terms of predicting several
chronic toxicity outcomes such as hypertension, decreased cognitive function,
and electrocardiographic conduction disturbances in adults.7,8,15- 20
We are interested in studying the relationship between lead exposure
and cataractogenesis because lead can disrupt lens redox status, the maintenance
of which is necessary to maintain lens clarity,21 and
conversely, cataract appears to be the result of accumulated oxidative damage
to lens epithelial cells.22 Furthermore, lead
adversely affects glutathione metabolism in the lens23 and
increases the amount of protein-bound glutathione and cysteine. Malondialdehyde,
a major lipid peroxidation product, is also increased in the lens following
lead exposure.21 Lead can interfere with the
calcium homeostasis of various tissues, and normal calcium homeostasis is
essential to the maintenance of lens clarity.24
In animal studies, lead accumulated in a time- and concentration-dependent
manner in the lenses of exposed rabbits.25 More
importantly, several studies have now shown that lead may be present at higher
levels in human cataractous lenses as compared with clear lenses.23,26- 29 Further,
lens lead levels were inversely correlated with lens levels of the antioxidant
zinc, and the intrusion of lead into the lens caused protein conformational
changes that affected lens transparency.27
The NAS is an ongoing cohort study with high-quality data. However,
ocular photographs were not taken and standardized cataract grading schemes
were not used. Although some misclassification may result from our use of
medical records to determine cataract status, it is unlikely that any misclassification
would be differential with respect to bone lead levels; and, thus, the expected
bias would be in the direction of a null finding. Furthermore, our use of
cataract surgery or a relatively severe grade of cataract should have further
minimized disease misclassification. Nonetheless, we were not able to examine
risk as it might be related to specific types of cataract, which may have
different etiologies,30 or the risk among younger
individuals (<60 years of age) as the more severe cataracts we examined
were virtually nonexistent in this subgroup. Confounding by unmeasured risk
factors such as sunlight exposure and use of steroid medications is an improbable
explanation of our findings, since these exposures are unlikely to be strongly
correlated with bone lead levels. Although we controlled as rigorously as
possible for cigarette smoking, using pack-years of exposure, residual confounding
by cigarette smoking is theoretically possible since lead can be present in
cigarette smoke.31 NAS participants are fairly
representative of similarly aged men in Massachusetts, with similar rates
of smoking and alcohol consumption; although they tended to be slightly better
educated, and with a slightly higher median income than men of comparable
age in the general population of the United States.32
Prevention of age-related cataract remains an important public health
goal. Expenditures for cataract surgery comprise the largest single line item
in the Medicare budget.33 In addition to the
obvious problems of reduced vision, visual disability such as that produced
by cataract can have a deleterious impact on risk of falls, fractures, quality
of life, and possibly even mortality.34- 38 Lead
has been spread throughout the environment, primarily through leaded gasoline
and lead paint, and nearly every adult in the United States has accumulated
some degree of lead in the skeleton. Moreover, lead exposure in many developing
countries, where the cataract burden is even greater, continues to be high.39- 41
These are, to our knowledge, the first data suggesting that accumulated
lead exposure, such as that commonly experienced by adults in the United States,
may be an important, unrecognized risk factor for cataract. This research
suggests that reduction of lead exposure could help decrease the global burden
Corresponding Author: Debra A. Schaumberg,
ScD, MPH, Brigham and Women’s Hospital Division of Preventive Medicine,
900 Commonwealth Ave, East Boston, MA 02215-1204 (firstname.lastname@example.org).
Author Contributions: Dr Schaumberg had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Schaumberg, Hu.
Acquisition of data: Schaumberg, Mendes, Balaram,
Dana, Sparrow, Hu.
Analysis and interpretation of data: Schaumberg,
Drafting of the manuscript: Schaumberg, Dana,
Critical revision of the manuscript for important
intellectual content: Schaumberg, Mendes, Balaram, Sparrow, Hu.
Statistical analysis: Schaumberg, Sparrow.
Obtained funding: Schaumberg, Hu.
Administrative, technical, or material support:
Schaumberg, Dana, Hu.
Study supervision: Schaumberg, Dana, Hu.
Funding/Support: This work was supported by
Fight for Sight (GA20020) and NIEHS (ES 05257-06A1, P42-ES05947, 2 P30 ES00002).
The Normative Aging Study is supported by the cooperative studies program/ERIC,
Department of Veterans Affairs, and is a component of the Massachusetts Veterans
Epidemiology Research and Information Center (MAVERIC). Men were evaluated
for bone lead with support from National Institutes of Health (NIH) grant
NCRR GCRC M01RR02635. The K x-ray fluorescence instrument was developed by
ABIOMED, Inc, with support from NIH grant SBIR 2R44 ES03918-02.
Role of the Sponsor: This study was wholly
designed, conducted, analyzed, and reported by the authors without any input
from industrial sponsors.