American Journal of Epidemiology Advance Access published February 17, 2013

American Journal of Epidemiology

The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of DOI: 10.1093/aje/kws279
Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Original Contribution

High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins,

and the Risk of Age-related Cataract: A Population-based Prospective Cohort
Study of Men

Jinjin Zheng Selin, Susanne Rautiainen, Birgitta Ejdervik Lindblad, Ralf Morgenstern, and
Alicja Wolk*
* Correspondence to Dr. Alicja Wolk, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden
(e-mail: Alicja.Wolk@ki.se).

Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016

Initially submitted March 14, 2012; accepted for publication May 22, 2012.

We examined the associations of high-dose supplements of vitamins C and E and low-dose multivitamins with
the risk of age-related cataract among 31,120 Swedish men, aged 4579 years, in a population-based prospec-
tive cohort. Dietary supplement use was assessed from a questionnaire at baseline in 1998. During follow-up
(January 1998December 2006), 2,963 incident age-related cataract cases were identified. The multivariable-
adjusted hazard ratio for men using vitamin C supplements only was 1.21 (95% confidence interval (CI): 1.04,
1.41) in a comparison with that of nonsupplement users. The hazard ratio for long-term vitamin C users (10
years before baseline) was 1.36 (95% CI: 1.02, 1.81). The risk of cataract with vitamin C use was stronger
among older men (>65 years) (hazard ratio = 1.92, 95% CI: 1.41, 2.60) and corticosteroid users (hazard
ratio = 2.11, 95% CI: 1.48, 3.02). The hazard ratio for vitamin E use only was 1.59 (95% CI: 1.12, 2.26). Use of
multivitamins only or multiple supplements in addition to vitamin C or E was not associated with cataract risk.
These results suggest that the use of high-dose (but not low-dose) single vitamin C or E supplements may
increase the risk of age-related cataract. The risk may be even higher among older men, corticosteroid users,
and long-term users.

ascorbic acid; cataract; dietary supplements; oxidative stress; vitamin E

Abbreviations: CI, confidence interval; HR, hazard ratio.

Vitamin C and E supplement use has not shown protec-
tive effects in prevention of chronic diseases in large long-
term randomized controlled trials (1, 2). On the contrary,
studies have reported potential harmful effects of high-dose
antioxidant supplements, such as increased risk of mortality
(3, 4), heart failure (5), and some cancer types (68).
The etiology of age-related cataract is multifactorial, in-
cluding oxidative damage of the lens (9). Antioxidants may
protect the lens against oxidative stress (10). However, the
effects of antioxidant supplements on cataract risk in ran-
domized controlled trials (1118) and results from observa-
tional studies (1926) have been inconsistent. Interestingly,
in vitro and animal studies show that high doses of vita-
mins C and E have prooxidative properties and increase
oxidative stress in the lens (2731). Indeed, we have recently
observed in a prospective study of women that the use of
high-dose vitamin C supplements (but not multivitamins
with low-dose vitamin C) was associated with increased risk
of age-related cataract extraction (19).
The use of dietary supplements is widespread in many
countries. It is therefore of public health importance to in-
vestigate the association of antioxidant supplements with
risk of cataract, especially if single, high-dose supplements
are associated with cataract risk differently from low-dose
(Recommended Daily Intake) supplements. We examined if
high-dose vitamin C and E supplements and low-dose mul-
tivitamins are associated with the risk of age-related cata-
ract in men, as well as whether the associations varied by

1
2 Selin et al.
reactive oxygen speciesgenerating factors, such as age,
smoking, abdominal obesity, hypertension, and corticoste-
roid use.
MATERIALS AND METHODS
Study population
The Cohort of Swedish Men was established in the late
fall of 1997 to study major chronic diseases including age-
related cataract. A questionnaire regarding diet and lifestyle
factors, including questions on dietary supplement use,
diet, age, smoking status, waist circumference, educational
level, medical history (including diagnoses of diabetes and
hypertension), corticosteroid use, and alcohol intake, was
sent out to all men, aged 4579 years, living in central
Sweden (rebro and Vstmanlands counties), and 48,850
(49%) men answered.
In this study, we excluded men with missing or errone-
ous personal identity number (n = 205), who sent a blank
questionnaire (n = 92), who died before January 1, 1998
(n = 55), and with a previous cancer diagnosis other than
nonmelanoma skin cancer (n = 2,592). We also excluded
men with cataract diagnosis or extraction before baseline
(n = 923), men with cardiovascular disease or diabetes
before baseline to avoid potential changes in dietary habits
and use of dietary supplements (n = 7,929), men with
missing information on supplement use (n = 1,506), and
those using supplements not including vitamin C, vitamin
E, or multivitamins (n = 4,428).
Cancer diagnosis was identied through the Swedish Na-
tional Cancer Register. History of cardiovascular disease
(myocardial infarction, angina pectoris, heart failure, and
stroke) was obtained through linkage with the National In-
patient and Outpatient Registers at the Swedish National
Board of Health and Welfare. Diabetes history was identi-
ed through the National Outpatient Register, National Dia-
betes Register, and self-reported data.
A total of 31,120 men were included in the analysis.
Assessment of dietary supplement use and diet
The questionnaire from 1997 inquired about dietary sup-
plement use starting with a general question: Do you use
vitamin, mineral, or other supplements? with 3 prespeci-
ed responses (no, regular use, and occasional use). This
question was followed by more specic questions with pre-
specied types of supplements and open answers about fre-
quency and duration of use. Men that reported regular or
occasional use were considered as supplement users. Dura-
tion of vitamin C, vitamin E, and multivitamin use was in-
quired by open-ended questions. Long-term and short-term
users were dened as men that reported use 10 and <10
years before baseline, respectively. The most commonly
used dose of vitamin C and vitamin E as single supple-
ments was estimated to be 1,000 mg and 100 mg, re-
spectively (32, 33), and multivitamins were estimated to
contain 60 mg of vitamin C and 9 mg of vitamin E
(doses close to the Recommended Daily Intake) (32).
Intakes of vitamin C and vitamin E from diet were as-
sessed by a 96-item food frequency questionnaire at base-
line with questions on how often, on average, during the
past year the men had consumed different food items.
Intakes of vitamins C and E were estimated by multiplying
the frequency of consumption of different food items by
the nutrient composition of those items obtained from the
Swedish National Food Agency (34) and adjusted for
energy intake by using the residual method (35).
Ascertainment of cases and follow-up
Between January 1, 1998, and December 31, 2006, we
identied 2,963 incident cataract cases (dened as men
with cataract diagnosis and/or cataract extraction). Cataract
diagnoses and extractions were ascertained by linkage to
the National Outpatient and Inpatient Registers at the Na-
tional Board of Health and Welfare and to the Swedish
Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016
National Day-Surgery Register (International Classica-
tion of Diseases, Tenth Revision, code H25 and operation
codes designated CJC, CJD, CJE, and CJG). To comple-
ment the preceding data, we also matched against local cat-
aract extraction registers at both public and private clinics
in the study area. Among the men with both cataract diag-
nosis and extraction in this study, 83% got the extraction
within 1 year after diagnosis. Cataracts that were considered
to be congenital or secondary to ocular trauma, intraocular
inammation, or previous intraocular surgery were excluded.
On the basis of the Swedish National Cataract Register,
most men had a preoperative visual acuity in the cataract-
containing eye of less than 20/40 Snellen equivalents,
which corresponds to difculties in driving. The mean pre-
operative visual acuity in the cataract-containing eye was
20/70 Snellen equivalents during the study period, which
corresponds to difculties in reading the newspaper. Ap-
proximately one-fourth of the men were legally blind
(visual acuity of 20/200 Snellen equivalents) (36).
The Regional Ethical Board at Karolinska Institutet
(Stockholm, Sweden) approved this study, and completion
of the questionnaire was considered to imply informed
consent to participate in this study.
Statistical analysis
All men were followed from January 1, 1998, until the
date of cataract diagnosis, cataract extraction, date of death
(through linkage to the Swedish Death Register), or the end
of follow-up (December 31, 2006), whichever came rst.
The men were categorized into nonsupplement users
and 1) users of vitamin C only, vitamin E only, or multivi-
tamins only (including both regular and occasional users),
not using other vitamin or mineral supplements, and 2)
users of multiple supplements in addition to vitamin C or
vitamin E. We estimated hazard ratios with 95% condence
intervals (37) using the Cox proportional hazards model
and the PHREG procedure in SAS, version 9.2, software
(SAS Institute, Inc., Cary, North Carolina). The rst multi-
variable model was adjusted for age, smoking, abdominal
obesity, educational level, history of hypertension, cortico-
steroid use, alcohol intake, and fruit and vegetable intake.
 Vitamin Supplements and Cataract Risk 3

The second model was further adjusted for physical activity
and self-reported health. Missing values for any of the po-
tential confounders were treated as a separate category in
the model. The proportional hazard assumption was tested
by including the product of vitamin C, vitamin E, and mul-
tivitamin use and the natural logarithm of time in the
models, and we did not nd evidence of violation of this
assumption. The rst 4 years of follow-up were excluded to
evaluate potential risk of reversed causality. We used the
Cox proportional hazards model to analyze the association
between duration of vitamin C and multivitamin use and
cataract risk. The difference between the observed risk esti-
mates for long-term and short-term use and cataract was
tested with the Wald test. Because of few cases, long-term
vitamin E use was not examined. To evaluate the effect of
misclassication of self-reported supplement use on our
risk estimates, we performed correction analyses, using the
episens command in Stata, version 11, software (StataCorp
RESULTS
During an average follow-up of 8.4 years (259,949
person-years), we identied 2,963 cases of age-related cata-
ract (among those 744 men with only diagnosis). The mean
age in the cohort was 58.3 years (standard deviation: 9.2),
the mean waist circumference was 95.4 cm (standard devia-
tion: 10.1), and 24.5% were current smokers. Among the
men, 5.3% reported vitamin C use only; 0.5%, vitamin E
use only; and 11.3%, multivitamin use only.
Baseline characteristics of the study population by
dietary supplement use are described in Table 1. The age-
and multivariable-adjusted hazard ratios for dietary supple-
ment use and age-related cataract are presented in Table 2.
In the multivariable analysis, vitamin C supplement use
only was associated with 21% (95% condence interval
(CI): 4, 41) increased risk of cataract compared with non
supplement use. Vitamin E use only was associated with

Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016

LP, College Station, Texas) (38). Assumptions of sensitiv-
ity and specicity of 0.7 and 0.9 for vitamin C, 0.8 and
0.99 for vitamin E, and 0.7 and 0.98 for multivitamin use,
respectively, were based on results from our previous vali-
dation study of men living in central Sweden (33).
We performed stratied analyses to examine if the risk
between vitamin C use and cataract differed by reactive
oxygen speciesgenerating factors (age, smoking, abdomi-
nal obesity, history of hypertension, and corticosteroid
use), as well as dietary intakes of vitamin C and vitamin
E. The attributable proportion of risk due to interaction (in
excess of the additive effects between the 2 exposures of
interest) was calculated with 95% condence interval (39,
40). Multiplicative interaction tests were also performed by
the likelihood test. All P values shown are 2 sided, and we
considered P < 0.05 as statistically signicant.
59% (95% CI: 12, 126) increased risk of cataract. Multivi-
tamin use only was not statistically signicantly associated
with cataract risk. Additional adjustments for health status
and healthy behavior as physical activity did not change
the results. When the rst 4 years of follow-up were ex-
cluded, similar results were obtained for users of vitamin C
(hazard ratio (HR) = 1.28, 95% CI: 1.07, 1.53), vitamin E
(HR = 1.62, 95% CI: 1.06, 2.48), and multivitamins
(HR = 0.90, 95% CI: 0.78, 1.04). The hazard ratios corrected
for measurement error in self-reported use of supplements
were 3.0 for vitamin C, 3.2 for vitamin E, and 1.1 for
multivitamins.
The multivariable-adjusted hazard ratios for men who
took multiple supplements (one or more other supplements)
in addition to vitamin C (276 cases) or vitamin E (169
cases) were 1.06 (95% CI: 0.93, 1.20) and 1.02 (95% CI:

Table 1. Baseline Characteristicsa of the Men in the Cohort of Swedish Men, 19982006

Dietary Supplement Use

No Supplement Use Vitamin C Vitamin E Multivitamins
Variables
(n = 22,015) Onlyb (n = 1,652) Onlyb (n = 144) Onlyb (n = 3,532)
Mean (SD) % Mean (SD) % Mean (SD) % Mean (SD) %

Age, years 57.8 (9.0) 58.6 (9.4) 62.9 (9.4) 58.9 (9.7)
Current smoking 25.8 21.1 19.0 21.5
c
Abdominal obesity 46.4 45.8 43.0 43.6
Education >12 years 16.9 19.1 13.2 25.7
History of hypertension 17.6 18.6 21.4 16.8
Corticosteroid use 8.2 9.2 12.2 9.2
Alcohol intake, g/day 14.8 (20.7) 13.5 (15.1) 12.5 (12.0) 14.5 (28.8)
Diet
Fruits and vegetables, g/day 375.6 (235.8) 414.9 (246.7) 437.3 (246.3) 426.8 (245.5)
Vitamin C, mg/day 105.2 (52.8) 110.6 (54.6) 113.8 (56.4) 112.9 (55.1)
Vitamin E, mg/day 8.8 (1.5) 9.0 (1.5) 8.9 (1.6) 9.0 (1.5)

Abbreviation: SD, standard deviation.

a
All variables, except age, were directly standardized to the age distribution of the entire study cohort.
b
No reported use of other vitamin or mineral supplements.
c
Defined as waist circumference 94 cm.
4 Selin et al.

Table 2. Age- and Multivariable-adjusted Hazard Ratios for Dietary Supplement Use and Risk of Age-related Cataract in the Cohort of
Swedish Men, 19982006

Multivariable Multivariable
Dietary Total No. of No. of Age Adjusted
Person-Years Adjusted 1a Adjusted 2b
Supplement Use Subjects Cases
HR 95% CI HR 95% CI HR 95% CI

No supplement use 22,015 1,937 184,911 1.00 Referent 1.00 Referent 1.00 Referent
Vitamin C onlyc 1,652 188 13,660 1.21 1.04, 1.40 1.21 1.04, 1.41 1.21 1.04, 1.41
Vitamin E onlyc 144 32 1,138 1.68 1.18, 2.39 1.59 1.12, 2.26 1.57 1.10, 2.22
Multivitamins onlyc 3,532 345 29,311 0.97 0.87, 1.09 0.96 0.86, 1.08 0.96 0.85, 1.07

Abbreviations: CI, confidence interval; HR, hazard ratio.

a
Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), and fruit and vegetable intake (g/day, continuous).
b
Adjusted for the same covariates as multivariable model 1 and additionally for physical activity (metabolic equivalent hours/day, quartiles)
and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
c
No reported use of other vitamin or mineral supplements.

Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016

0.87, 1.20), respectively, in a comparison with non
supplement users.
Long-term vitamin C use only (10 years before base-
line) compared with nonsupplement use was associated
with 36% (95% CI: 2%, 81%) increased risk of cataract
(Table 3). The difference between the observed risk esti-
mates for long-term vitamin C users and short-term users
was not statistically signicant (P = 0.71). Multivitamin use
only 10 or <10 years before baseline was not associated
with cataract risk.
Furthermore, we examined if the association between
vitamin C use and risk of cataract was modied by putative
reactive oxygen speciesgenerating factors (age, smoking,
abdominal obesity, history of hypertension, and corticoste-
roid use). We observed a stronger positive association for
vitamin C use among older men ( >65 years) and cortico-
steroid users (Table 4). The attributable proportion due to
interaction on the additive scale was borderline statistically
signicant for age and statistically signicant for corticoste-
roid use. However, the multiplicative interaction was not
statistically signicant for age (P = 0.23) or corticosteroid
use (P = 0.17). Interaction between the other reactive
oxygen speciesgenerating factors and vitamin C use was
not statistically signicant on either the additive (all 95%

Table 3. Age- and Multivariable-adjusted Hazard Ratios for Duration of Dietary Supplement Use and Risk of Age-related Cataract in the
Cohort of Swedish Men, 19982006

Duration of Dietary Total No. of No. of Age Adjusted Multivariable Adjusteda

Person-Years
Supplement Use Subjects Cases HR 95% CI HR 95% CI

No supplement use 22,015 1,937 184,911 1.00 Referent 1.00 Referent

Vitamin C onlyb
<10 years before baseline 521 56 4,355 1.28 0.98, 1.66 1.26 0.97, 1.65
10 years before baseline 420 48 3,458 1.34 1.01, 1.79 1.36 1.02, 1.81
Vitamin E onlyb
<10 years before baseline 71 16 559 N/Ac N/Ac
10 years before baseline 14 4 114 N/Ac N/Ac
b
Multivitamins only
<10 years before baseline 1,212 102 10,185 0.99 0.81, 1.21 0.97 0.80, 1.19
10 years before baseline 657 65 5,418 0.94 0.73, 1.20 0.94 0.73, 1.21

Abbreviations: CI, confidence interval; HR, hazard ratio; N/A, not available.
a
Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), fruit and vegetable intakes (g/day, continuous), physical activity
(metabolic equivalent hours/day, quartiles), and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
b
No reported use of other vitamin or mineral supplements.
c
Not available because of too few cases.
 Vitamin Supplements and Cataract Risk 5

Table 4. Multivariable-adjusted Hazard Ratios for Vitamin C Supplement Use and Risk of Age-related Cataract by Subgroups of Age and
Corticosteroid Usea in the Cohort of Swedish Men, 19982006

No Supplement Use (n = 22,015) Vitamin C Only (n = 1,652)b Attributable

Total No. of
Subgroups No. of No. of Proportion 95% CI
Subjects HR d
95% CI HR d
95% CI
Cases Cases due to Interactionc

Age, years
65 18,311 804 1.00 Referent 63 1.07 0.83, 1.38
>65 5,356 1,133 1.48 1.14, 1.91 125 1.92 1.41, 2.60 0.19 0.01, 0.40
Corticosteroid
usee
Never 16,270 1,283 1.00 Referent 123 1.18 0.98, 1.42
users
Ever users 1,942 239 1.33 1.16, 1.53 31 2.11 1.48, 3.02 0.29 0.01, 0.56

Abbreviations: CI, confidence interval; HR, hazard ratio.

a
A total of 7,453 men (out of 31,120 men) using other supplements than vitamin C only were excluded.
b
No reported use of other vitamin or mineral supplements.
c
The attributable proportion of risk due to interaction (in excess of the additive effects between the 2 exposures) and the corresponding 95%

Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016

confidence interval.
d
Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), fruit and vegetable intakes (g/day, continuous), physical activity
(metabolic equivalent hours/day, quartiles), and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
e
Of 23,667 men, there were 5,455 men with missing information on corticosteroid use.

CIs for interaction including 0) or the multiplicative (all Ps
for interaction > 0.8) scale. There were too few cases to
examine if the association between vitamin E use and cata-
ract risk was stronger with long-term use or among men
with reactive oxygen speciesgenerating factors.
Compared with that for nonsupplement users, the multi-
variable-adjusted hazard ratio for vitamin C only supple-
ment users with low vitamin C intake from diet (< median,
96.9 mg/day) was 1.30 (95% CI: 1.06, 1.58), and for high
vitamin C intake from diet ( median), the hazard ratio
was 1.12 (95% CI: 0.90, 1.40) (P for interaction = 0.32).
Among vitamin E only supplement users with low vitamin
E intake from diet (< median, 8.8 mg/day), the hazard ratio
for cataract was 1.70 (95% CI: 1.09, 2.65), and for high
vitamin E intake ( median), the hazard ratio was 1.38
(95% CI: 0.78, 2.44) (P for interaction = 0.56). Vitamin C
or vitamin E from diet ( median compared with < median)
was not associated with cataract risk; the hazard ratios were
1.04 (95% CI: 0.95, 1.13) and 1.00 (95% CI: 0.92, 1.08),
respectively.
DISCUSSION
In this large, prospective, population-based cohort of
men, we observed that those who used high-dose vitamin C
or vitamin E supplements (but not low-dose multivitamins)
had a statistically signicant increased risk of age-related
cataract. The positive association between vitamin C use
and risk of cataract was even stronger among those with
higher oxidative stress because of older age and corticoste-
roid use and among long-term users. The limited number
of vitamin E users only did not allow us to evaluate the
associations for long-term vitamin E use and associations
between vitamin E use and factors associated with in-
creased reactive oxygen species levels.
Our results are in agreement with our previous prospec-
tive observations in 24,593 women (2,497 cataracts), where
the use of high-dose vitamin C supplements (but not low-
dose multivitamins) was associated with increased risk of
cataract extraction (HR = 1.25, 95% CI: 1.05, 1.50), espe-
cially among older women (HR = 1.74, 95% CI: 1.24,
2.46) and corticosteroid users (HR = 1.97, 95% CI: 1.35,
2.88) (19). The present results are partly in line with a re-
cently published randomized controlled trial (8 years dura-
tion) that reported for high-dose vitamin C supplements
(500 mg) a nonsignicant increased risk of cataract among
obese (body mass index: 30) and smoking men (11).
However, no effect was reported for high-dose vitamin E
supplements (268 mg) in that study (11). Vitamin C and/or
vitamin E use was associated with nonsignicant increased
risk of cataract in men (26). Other prospective studies of
vitamin C use observed statistically signicant increased
risk of cortical opacities among older women using vitamin
C for >10 years (21) and a nonsignicant increased risk of
cataract extraction among women aged 60 years (20). No
association of cataract risk was reported in some random-
ized controlled trials testing vitamin E use only (50402 mg
daily or alternate days) (1113, 15) or high-dose vitamin C
and vitamin E use combined with other constituents (1416),
as well as in some observational studies of vitamin C and
vitamin E use (20, 21, 23). In contrast, one randomized con-
trolled trial testing daily high-dose vitamin C (750 mg),
vitamin E (268 mg), and -carotene (15 mg) supplements
combined for 3 years reported a small deceleration of cata-
ract progression (17), and another randomized controlled
trial examining multivitamin/mineral supplements with
6 Selin et al.
relatively low doses of vitamin C (180 mg/day) and vitamin
E (40 mg/day) reported decreased risk of nuclear cataracts
only among participants aged 65 years (18). Prospective
studies have also observed decreased risk for nuclear (22,
24) and cortical cataracts among women aged <60 years (21)
and for long-term users (25). Multivitamin use was not asso-
ciated with cataract risk in some prospective studies (20, 21)
and randomized controlled trials (14, 18), whereas others ob-
served a decreased risk of cataract (23, 25, 26) and some
cataract subtypes (18, 22, 24).
Several factors may contribute to the differences between
our results and those of other studies. First, the outcomes
differed, as some studies investigated the risk of cataract
diagnosis or extraction (1115, 18), while others examined
the change in lens opacication (16, 17). Second, the dose
of supplements used differed. Third, the randomized con-
trolled trials were based on populations with different base-
line nutritional status and were ongoing for shorter periods
(36 years), except for 2 studies (89 years) (11, 12).
However, the populations in these 2 studies were based on
physicians and nurses, who are generally more health con-
scious and well nourished: Only 3%4% among the physi-
cians were current smokers (11), compared with 24% of the
men in this study. In another randomized controlled trial,
malnutrition was common at baseline (18).
Although vitamin C and vitamin E have been proposed,
because of antioxidant properties, to decrease the risk of
cataract (10, 41), in vitro and animal studies using large
doses of vitamin C and vitamin E have shown their pro-
oxidative effects, such as enhancing the toxic effect of hy-
drogen peroxide in glutathione-depleted lens epithelial cells
(42). High vitamin C concentrations may disturb oxidation-
reduction homeostasis of the lens and promote cataracto-
genesis (43), for example, by increasing glycation of lens
proteins (2830) and generating superoxide (31). The
plasma vitamin C concentration is suggested to reach a
plateau by intake of 200 mg of vitamin C/day (44).
However, vitamin C concentrations in the lens are from 50-
to 60-fold higher than in plasma, and a linear relation
between dietary intake and lens concentrations has been re-
ported (44). This suggests that oversupplementation may
lead to an even higher vitamin C accumulation in the lens
and result in a prooxidative state. High vitamin E concen-
trations may also disturb oxidation-reduction homeostasis
of the lens, by inducing lipid peroxidation (45) and inhibit-
ing glutathione S-transferase (27). Moreover, vitamin E
supplements containing only -tocopherol may also reduce
other natural forms of vitamin E (46). Studies have shown
2-fold higher vitamin E concentrations in cataract lenses
compared with noncataract lenses (47), and high plasma
vitamin E concentrations have been associated with in-
creased risk of all types of cataracts, but this was not ob-
served for vitamin C (48).
Our observation that the increased risk of cataract was
attenuated and not statistically signicant for users of multi-
ple supplements in addition to vitamin C or vitamin E
could be because the use of other supplements may lessen
the increased risk associated with use of vitamin C or
vitamin E only. These results resemble the results from a
recently published large randomized controlled trial exam-
ining the effect of vitamin E and selenium supplements
(taken separately or together) on the risk of prostate cancer
(7). The risk was increased in the groups receiving only
vitamin E (HR = 1.17, 95% CI: 1.004, 1.36) or selenium
(HR = 1.09, 95% CI: 0.93, 1.27), but in the group receiving
vitamin E and selenium together, the risk was attenuated
(HR = 1.05, 95% CI: 0.89, 1.22) (7).
The biological mechanisms behind the observed statisti-
cally signicant interaction between vitamin C use and corti-
costeroid use may involve an inammatory mechanism (49).
Corticosteroid use is a known risk factor for cataract (50)
and has also been associated with increased reactive oxygen
species production (51). Furthermore, use of corticosteroids
may indicate an underlying illness associated with increased
oxidative stress and inammation. Oxidative stress associated
with aging may also explain the higher risk estimates for cat-
aract among men aged >65 years using vitamin C.
Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016
There are several strengths of this study. First, the large,
population-based, prospective design includes many cases
of cataract. Second, we had information on both cataract
diagnosis and extraction. Third, the validity of the self-
reported supplement use data, as assessed by sensitivity
and specicity, was relatively high, which allowed us to
correct for misclassication bias of the exposure.
There are also some limitations of this study. The possi-
bility of outcome misclassication exists because lens
opacities can occur without symptoms. This may lead to
underestimation of the association. Because of the lack of
standardized eye examinations in the cohort, we did not
have information on cataract subtypes or grade of lens
opacity and could therefore not examine whether the asso-
ciation was restricted to a certain subtype. As we did not
have information on the exact doses of supplements used
in this study, we used an estimation of the most commonly
used doses in Sweden (32, 33). One could speculate that
our results may be affected inasmuch as men using supple-
ments may be more health conscious and seek medical
help earlier. However, multivitamin use was not associated
with increased cataract risk. By excluding the rst 4 years
of follow-up, we found that the risk estimates remained
similar, which contradicts the notion that the association is
due to reversed causality. After adjustments for health
status and health behaviorrelated factors, such as fruit and
vegetable intakes, education, and physical activity, similar
results were obtained. Moreover, everyone has the same
access to cataract extractions ( patient charge of <$50/
surgery) in the Swedish health-care system.
In conclusion, the use of high-dose vitamin C or vitamin
E supplements (but not low-dose multivitamins or vitamins
C and E together with other supplements) may be associated
with increased risk of age-related cataract among men. The
risk for cataract with vitamin C use may be even higher
among those with potentially higher oxidative stress and
among long-term users. In the broader context of accumulat-
ing evidence from other recent studies also showing poten-
tially harmful effects of high-dose antioxidant supplements,
our results further underscore the need to consider use of
unregulated supplements with caution.

ACKNOWLEDGMENTS
Author afliations: Division of Nutritional Epidemiology,
Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden (Jinjin Zheng Selin, Susanne Rautiainen,
Birgitta Ejdervik Lindblad, and Alicja Wolk); Division of
Biochemical Toxicology, Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden (Ralf Morgenstern);
Division of Preventive Medicine, Brigham and Womens
Hospital and Harvard Medical School, Boston, Massachusetts
(Susanne Rautiainen); Department of Ophthalmology, rebro
University Hospital, rebro, Sweden (Birgitta Ejdervik Lind-
blad); and School of Health and Medical Sciences, rebro
University, rebro, Sweden (Birgitta Ejdervik Lindblad).
This work was supported by research grants from the
Swedish Council for Working Life and Social Research (Dnr.
2010-1064) and the Swedish Research Council/Committee for
Infrastructure (Dnr. 2008-5947), Stockholm, Sweden.
Conict of interest: none declared.
REFERENCES
1. Lin J, Cook NR, Albert C, et al. Vitamins C and E and beta
carotene supplementation and cancer risk: a randomized
controlled trial. J Natl Cancer Inst. 2009;101(1):1423.
2. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C
in the prevention of cardiovascular disease in men: the
Physicians Health Study II randomized controlled trial.
JAMA. 2008;300(18):21232133.
3. Mursu J, Robien K, Harnack LJ, et al. Dietary supplements
and mortality rate in older women: the Iowa Womens Health
Study. Arch Intern Med. 2011;171(18):16251633.
4. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in
randomized trials of antioxidant supplements for primary and
secondary prevention: systematic review and meta-analysis.
JAMA. 2007;297(8):842857.
5. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin
E supplementation on cardiovascular events and cancer: a
randomized controlled trial. JAMA. 2005;293(11):13381347.
6. The effect of vitamin E and beta carotene on the incidence of
lung cancer and other cancers in male smokers. The Alpha-
Tocopherol, Beta Carotene Cancer Prevention Study Group.
N Engl J Med. 1994;330(15):10291035.
7. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E
and the risk of prostate cancer: the Selenium and Vitamin E
Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):
15491556.
8. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors
for lung cancer and for intervention effects in CARET, the
Beta-Carotene and Retinol Efcacy Trial. J Natl Cancer Inst.
1996;88(21):15501559.
9. Shichi H. Cataract formation and prevention. Expert Opin
Investig Drugs. 2004;13(6):691701.
10. Lou MF. Redox regulation in the lens. Prog Retin Eye Res.
2003;22(5):657682.
11. Christen WG, Glynn RJ, Sesso HD, et al. Age-related cataract
in a randomized trial of vitamins E and C in men. Arch
Ophthalmol-Chic. 2010;128(11):13971405.
12. Christen WG, Glynn RJ, Chew EY, et al. Vitamin E and age-
related cataract in a randomized trial of women.
Ophthalmology. 2008;115(5):822829.
Vitamin Supplements and Cataract Risk 7
13. McNeil JJ, Robman L, Tikellis G, et al. Vitamin E
supplementation and cataract: randomized controlled trial.
Ophthalmology. 2004;111(1):7584.
14. AREDS Study. A randomized, placebo-controlled, clinical
trial of high-dose supplementation with vitamins C and E and
beta carotene for age-related cataract and vision loss: AREDS
report no. 9. Arch Ophthalmol. 2001;119(10):14391452.
15. Teikari JM, Rautalahti M, Haukka J, et al. Incidence of
cataract operations in Finnish male smokers unaffected by
alpha tocopherol or beta carotene supplements. J Epidemiol
Community Health. 1998;52(7):468472.
16. Gritz DC, Srinivasan M, Smith SD, et al. The Antioxidants in
Prevention of Cataracts Study: effects of antioxidant
supplements on cataract progression in South India. Br
J Ophthalmol. 2006;90(7):847851.
17. Chylack LT Jr, Brown NP, Bron A, et al. The Roche
European American Cataract Trial (REACT): a randomized
clinical trial to investigate the efcacy of an oral antioxidant
micronutrient mixture to slow progression of age-related
cataract. Ophthalmic Epidemiol. 2002;9(1):4980.
Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016
18. Sperduto RD, Hu TS, Milton RC, et al. The Linxian cataract
studies. Two nutrition intervention trials. Arch Ophthalmol.
1993;111(9):12461253.
19. Rautiainen S, Lindblad BE, Morgenstern R, et al. Vitamin C
supplements and the risk of age-related cataract: a population-
based prospective cohort study in women. Am J Clin Nutr.
2010;91(2):487493.
20. Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective
study of vitamin supplement intake and cataract extraction
among U.S. women. Epidemiology. 1999;10(6):679684.
21. Taylor A, Jacques PF, Chylack LT Jr, et al. Long-term intake
of vitamins and carotenoids and odds of early age-related
cortical and posterior subcapsular lens opacities. Am J Clin
Nutr. 2002;75(3):540549.
22. Jacques PF, Chylack LT Jr, Hankinson SE, et al. Long-term
nutrient intake and early age-related nuclear lens opacities.
Arch Ophthalmol. 2001;119(7):10091019.
23. Klein BE, Knudtson MD, Lee KE, et al. Supplements and
age-related eye conditions: the Beaver Dam Eye Study.
Ophthalmology. 2008;115(7):12031208.
24. Leske MC, Chylack LT Jr, He Q, et al. Antioxidant vitamins
and nuclear opacities: the longitudinal study of cataract.
Ophthalmology. 1998;105(5):831836.
25. Mares-Perlman JA, Lyle BJ, Klein R, et al. Vitamin
supplement use and incident cataracts in a population-based
study. Arch Ophthalmol. 2000;118(11):15561563.
26. Seddon JM, Christen WG, Manson JE, et al. The use of
vitamin supplements and the risk of cataract among US male
physicians. Am J Public Health. 1994;84(5):788792.
27. van Haaften RI, Haenen GR, van Bladeren PJ, et al. Inhibition
of various glutathione S-transferase isoenzymes by RRR-
alpha-tocopherol. Toxicol In Vitro. 2003;17(3):245251.
28. Cheng R, Lin B, Lee KW, et al. Similarity of the yellow
chromophores isolated from human cataracts with those from
ascorbic acid-modied calf lens proteins: evidence for
ascorbic acid glycation during cataract formation. Biochim
Biophys Acta. 2001;1537(1):1426.
29. Cheng R, Feng Q, Ortwerth BJ. LC-MS display of the total
modied amino acids in cataract lens proteins and in lens
proteins glycated by ascorbic acid in vitro. Biochim Biophys
Acta. 2006;1762(5):533543.
30. Linetsky M, Shipova E, Cheng R, et al. Glycation by
ascorbic acid oxidation products leads to the aggregation
of lens proteins. Biochim Biophys Acta. 2008;1782(1):2234.
31. Linetsky M, James HL, Ortwerth BJ. Spontaneous generation
of superoxide anion by human lens proteins and by calf lens
8 Selin et al.
proteins ascorbylated in vitro. Exp Eye Res. 1999;69(2):
239248.
32. Holmquist C, Larsson S, Wolk A, et al. Multivitamin
supplements are inversely associated with risk of myocardial
infarction in men and womenStockholm Heart
Epidemiology Program (SHEEP). J Nutr. 2003;133(8):
26502654.
33. Messerer M, Wolk A. Sensitivity and specicity of self-
reported use of dietary supplements. Eur J Clin Nutr. 2004;
58(12):16691671.
34. Bergstrom L, Kylberg E, Hagman U, et al. The food
composition database KOST: the National Administrations
Information system for nutritive values of food. Var Foda.
1991;43:439447.
35. Willett W, Stampfer MJ. Total energy-intakeimplications
for epidemiologic analyses. Am J Epidemiol. 1986;124(1):
1727.
36. Nationella Kataraktregistret [in Swedish]. Karlskrona, Sweden:
Eye-Net Sweden; 2008. (http://www.cataractreg.com/
Cataract_Sve/forstasida.htm). (Accessed November 1, 2011).
37. Cox DR. Regression models and life tables (with discussion).
J R Stat Soc (B). 1972;34(2):187220.
38. Orsini N, Bellocco R, Bottai M, et al. A tool for deterministic
and probabilistic sensitivity analysis of epidemiologic studies.
Stata J. 2008;8(1):2948.
39. Assmann SF, Hosmer DW, Lemeshow S, et al. Condence
intervals for measures of interaction. Epidemiology. 1996;
7(3):286290.
40. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
41. Chiu CJ, Taylor A. Nutritional antioxidants and age-related
cataract and maculopathy. Exp Eye Res. 2007;84(2):229245.
42. Shang F, Lu M, Dudek E, et al. Vitamin C and vitamin E
restore the resistance of GSH-depleted lens cells to H2O2.
Free Radic Biol Med. 2003;34(5):521530.
43. Truscott RJ. Age-related nuclear cataract-oxidation is the key.
Exp Eye Res. 2005;80(5):709725.
44. Taylor A, Jacques PF, Nowell T, et al. Vitamin C in human
and guinea pig aqueous, lens and plasma in relation to intake.
Curr Eye Res. 1997;16(9):857864.
45. Bowry VW, Stocker R. Tocopherol-mediated peroxidation
the prooxidant effect of vitamin-E on the radical-initiated
oxidation of human low-density-lipoprotein. J Am Chem Soc.
1993;115(14):60296044.
46. Huang HY, Appel LJ. Supplementation of diets with alpha-
tocopherol reduces serum concentrations of gamma- and
delta-tocopherol in humans. J Nutr. 2003;133(10):
31373140.
47. Krepler K, Schmid R. Alpha-tocopherol in plasma, red blood
cells and lenses with and without cataract. Am J Ophthalmol.
2005;139(2):266270.
48. Ferrigno L, Aldigeri R, Rosmini F, et al. Associations
Downloaded from http://aje.oxfordjournals.org/ by guest on September 17, 2016
between plasma levels of vitamins and cataract in the Italian-
American Clinical Trial of Nutritional Supplements and Age-
Related Cataract (CTNS): CTNS Report #2. Ophthalmic
Epidemiol. 2005;12(2):7180.
49. Schaumberg DA, Ridker PM, Glynn RJ, et al. High levels of
plasma C-reactive protein and future risk of age-related
cataract. Ann Epidemiol. 1999;9(3):166171.
50. Cumming RG, Mitchell P. Inhaled corticosteroids and
cataract: prevalence, prevention and management. Drug Saf.
1999;20(1):7784.
51. Urban RC Jr, Cotlier E. Corticosteroid-induced cataracts. Surv
Ophthalmol. 1986;31(2):102110.