PUBLIC HEALTH AND THE EYE

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1 SURVEY OF OPHTHALMOLOGY VOLUME 39. NUMBER 4. JANUARY-FEBRUARY 1995 PUBLIC HEALTH AND THE EYE JOHANNA SEDDON AND DONALD FONG, EDITORS Epidemiology of Risk Factors for Age-Related Cataract SHEILA K. WEST, PhD., AND CHARLES T. VALMADRID, MD, MPH Dana Center for Preventive Ophthalmology, Wilmer Eye Institute, The Johns Hopkins Unive~:~ity, Baltimore, Maryland Abstract. Epidemiologic studies on risk factors for cataract have progressed significantly over the last decade. Age-related cataract is a multifactorial disease, and different risk factors seem to play a role for different cataract types. Cortical and posterior subcapsular cataracts appear to be most closely related to environmental stresses such as ultraviolet exposure, diabetes, and drug ingestion. Nuclear cataracts appear to be associated with smoking. Alcohol use seems to be associated with all cataract types. Consistent evidence also suggests that the prevalence of all cataract types is lower among those with higher education. Most of the current data support a role for antioxidants associated with decreased rates of all cataract types, but further studies are needed. More data are needed to establish the association, if any, of diarrhea, blood pressure, and use of allopurinol and phenothiazines with senile cataracts. (Surv Ophthalmol 39: , 1995) Key words, age-related cataract 9 alcohol 9 allopurinol 9 antioxidants aspirin 9 cataract ~ diabetes 9 diarrhea 9 education 9 epidemiology gender 9 phenothiazines 9 risk factors 9 smoking 9 steroids 9 ultraviolet radiation O Cataract is the leading cause of blindness worldwide, accounting for half of the world's blind population.~l In the developing world, the prevalence is believed to be greater and the onset at earlier ages, making the social and medical costs of blindness from cataract highly disproportional in areas of the world that can ill afford them.~19 Currently, the sole treatment is surgical extraction of the involved lens. In the United States, the economic impact of cataract surgery alone is estimated to be over $3.4 billion per year. ~3 Although surgery is effective, preventing or delaying the development of cataract remains the preferred approach to confront the global cataract problem. Should a factor be found to delay cataract onset by ten years, the number of cataract operations is estimated to decrease by 45%. 65 However, the development of preventive programs requires sound epidemiologic investigations into the risk and protective factors involved in cataractogenesis. The last major review of the cataract epidemiology 7~ was published in Since then, a number of epidemiologic studies on risk factors associated with cataract development have been done. These were supported by the growing technical developments in the objective identification and grading of various types of lens opacities. The purpose of this review is to provide an update of the current knowledge of the various factors associated with senile cataracts. These include education, gender, smoking, alcohol, blood pressure, ultraviolet radiation exposure, diabetes, diarrhea, nutritional factors, and cer- 323

2 324 Surv Ophthahnol 39 (4) January-February 1995 WEST, VALMADRID tain medications. Assessment of Cataract The lens, the biconvex crystalline structure behind the iris, constitutes part of the refracting mechanism of the eye. Lens transparency is regulated by physical and chemical processes, the disturbance of which may result in lens damage and opacification. The term "cataract" has been broadly used to mean any opacity or loss of transparency of the lens. Lens opacities are the earliest visible changes in cataractogenesis. Typically, cataracts are defined as lens opacities associated with some degree of visual impairment. Senile, or age-related cataracts, are the most common type of cataracts. For epidemiologic studies, they may be classified, according to anatomic location, into nuclear, cortical, posterior subcapsular (PSC), or mixed types. In advanced or hypermature cataract, the whole lens may become opaque. Rigorous epidemiological investigations into risk factors for age-related cataract have been enhanced by the development of reliable and valid methods to assess the presence and severity of lens opacities. Differentiation of the morphologic types is important, as risk factors appear to be different for each senile cataract type. Important characteristics of any assessment scheme are the validity and reproducibility of the technique. At least four systems have been developed to classif~ and grade lens opacities. These include the grading system developed at the Wilmer Ophthalmological Institute of the Johns Hopkins University] ~ the Oxford Clinical Cataract Classification and Grading System, I~176 the Lens Opacity Classification System (LOCS), TM and the Wisconsin system. 6~ These involve photographic documentation of the lens, using standard camera and flash settings, with interpretation of the lens photographs by trained graders. One study has shown an overlap in the grades assigned to photographs according to each system, which is expected because each system varies primarily according to the standard photographs used.l~ Nuclear cataracts can be documented by slitlamp photography and graded by assigning ordinal scores according to the degree ofopacification based on standard color photographs2 'j~' 60,J22 Cortical and PSC opacities can be documented by retroillumination photography and graded according to the percentage area of the lens obscured by the opacity or categorized based on standard photographs. In recent years, a number of cataract identifi- cation and classification systems and devices have been developed, tested and used in research settings. Since many of the systems are similar, the amalgamation of one common system, which would permit comparisons across studies, would be useful. Risks Factors for Cataracts SOCIAL AND PERSONAL FACTORS Education The association between education and cataract was initially suggested by prevalence studies carried out in populations. In the Framingham Eye Study, 5~ Kahn et al noted significantly higher cataract rates among females age years and males are years who had seventh grade education or less. In an age-adjusted analysis of data from a survey done in Punjab, India, cataract rates of high school graduates were compared with those having no formal education. 14 The group with no formal education had significantly higher prevalence rates of cataract. Using data from the National Health and Nutrition Examination Survey (NHANES), Hiller et al also found an association of cataract with fewer years spent in school, 45 and a subsequent analysis showed a nearly two-fold increased risk for cortical cataracts in those with less than nine grades of education compared to those with college education. 46 Other variables could confound the association of educational status with cataracts. For example, in the study done in Punjab, India, multivariate analyses included dietary factors, and education was not independently related to cataracts. ~ However, other studies which included a number of potential risk factors still showed education to be significantly associated with cataract. A case-control study done in India reported lower cataract rates for all cataract types with a "2- level increase" of educational status, independent of personal, dietary, and environmental factors. 8~ A matched case-control study of PSC opacity patients who underwent cataract extraction s also found a two-fold increased risk in those with less than high school education, adjusting for ultraviolet-b exposure, steroid use, eye color, and diabetes. A case-control study, done in Italy, likewise found low (less than high school) education to be associated with all types of cataract, independent of gender, sunlight exposure, and antioxidative enzyme levels. 5~ Another case-control study, done in Boston, similarly documented the relationship of education with all cataract types, correcting for the effects of personal, occu-

3 RISK FACTORS FOR AGE-RELATED CATARACT 325 pational, nutritional, medical and environmental factors. TM Thus, data from different case-control investigations in diverse populations consistently showed low education as significantly associated with any senile cataract type. There is no obvious biological link between low education and cataractogenesis. Confounding factors, such as different dietary patterns or different job exposures to sunlight, did not explain the association in several studies. ~'5~ The association appears to be independent, and deserves further investigation into likely explanatory factors. Gender Combined evidence from three populationbased, cross-sectional studies has suggested a small, excess risk of cataract among women A follow-up study of data from the NHANES suggested that such an excess risk for women is specific to cortical cataracts. 46 Two case-control studies that controlled for a number of potential cataractogenic risk factors have also reported that women are at increased risk for cortical cataracts only. ~~176 In a population-based prevalence survey in Beaver Dam, Wisconsin, women had more cortical opacities compared to men within similar age groups. 29 Interestingly, a protective effect for nuclear opacities with current use of postmenopausal estrogens was reported in the Beaver Dam study. 63 Older age at menopause was associated with decreased risk of cortical opacities, suggesting hormonal influences in cataractogenesis. Smoking An increased risk of lens opacities associated with smoking has now been shown in eight studies. ~7"~~ West et al showed that, in a group of white male fishermen, the cumulative dose of cigarettes smoked was related to nuclear but not to cortical opacities.l2~ Furthermore, the risk of nuclear opacities decreased in those who stopped smoking for 10 years. A similar doseresponse finding was seen in the analysis of crosssectional data from 1029 volunteers from a range of social and occupational backgrounds working in or around LondonY It documented a significant association of past heavy smoking and an even greater association of current heavy smoking with nuclear opacities. Similar results have also been found in case-control, TM cross-sectional, 59 and prospective ~7':~7 studies. Christen et al, in a prospective study of male physicians, found an increased risk for PSC opacities as well. Iv A dose response relationship of increasing pack-years and prevalence of PSC opacities was found for men, and, although not significant, for women in the Beaver Dam study. 59 Two clinic based, case-control studies did not find an association between smoking and senile cataract types. 5~176 In the India study, "smokes" referred to cigarettes and other tobacco products common in the subcontinent. The comparability of these types of cigarette to cigarettes smoked in the U.S. and London studies is unknown. The lack of association between smoking and nuclear opacities was also evident in the Italian case-control study. 5~ This finding is difficult to interpret, as the case control study in Boston used similar methodologies and did find an association. TM The mechanisms by which inhaled smoke might cause cataractogenesis are currently being explored by biochemists. Cigarette smoke contains substances known to impair antioxidant defense mechanisms, and substances which are directly capable of altering lens proteins. 4'-' Consistent findings across several different studies strengthens the role of cigarette smoking as a risk factor for nuclear opacities and possibly for PSC opacities. Currently, 26% of the USA population smoke, suggesting that as much as 20% of the cataract cases are attributable to smoking in the USA. ~ Alcohol Several studies have found an association between regular alcohol consumption and cataract. In a 1980 case-control study of surgical patients, Clayton et al reported that cataract patients were more likely to be heavy drinkers than controls, z~ In a later report, the same group showed a "Jshaped relationship," with higher risks among total abstainers and heavy drinkers compared to occasional drinkers. 22 The J-shape suggested a protective effect of light drinking, or possible misclassification of nondrinkers. In a clinicbased case-control study of 300 cases and 609 controls in Oxfordshire, England, heavy beer drinking was associated with a two-fold increased risk of cataract. 4~'4'-' In a case-control study of surgical PSC cataract cases, Mufioz et al demonstrated a similar J-shaped relationship with alcohol use, and showed that users who consume more than one drink per day have a four-fold increased risk of PSC cataract compared to controls, adjusting for other potential confounders. ~ The same group recently found an increased risk of all types of lens opacities associated with consuming more than a drink a day, in a cross-sectional survey of white male fishermen. ~'-' A cross-sectional survey of 4926 adults

4 326 Surv Ophthahnol 39 (4) January-l:ebruary 1995 WEST, VALMADRID age 43 to 86 in Wisconsin found an association of heavy drinking with severe nuclear, cortical and PSC opacities. ~ The mechanism by which alcohol use could result in cataracts is not clear. Harding has suggested that the risk may be the result of alcohol conversion to acetaldehyde, which can react with lens proteins) ~ Alcohol use may well be an important risk factor for lens opacities because of the prevalence of drinking in most societies. Blood Pressure/Hypertension In the Framingham Eye Study, systolic blood pressure was found to be significantly higher in those with cataract compared with noncataract subjects in the same age and sex groups. 55 In the National Health and Nutrition Examination Survey (NHANES), although cataract was significantly associated with systolic pressures of at least 160 mm Hg after adjusting for age and sex, the relationship disappeared after controlling for race, education, diabetes, residence and ultraviolet-b exposure. 45 A number of clinic-based casecontrol studies have shown varied results: senile cataracts were found to be associated with hypertension, J.;:_,0:_,~. J05 negatively associated with hypotension, ~5 or not associated with blood pressure at all. 7'~'~4 The association of blood pressure with specific types of cataracts have shown variable results. Using the data from the NHANES, Hiller et al showed a two-fold increased risk for having PSC cataract in those with systolic blood pressure of 160 mm Hg compared to those with 120 mm Hg. 46 In the India-US Case-Control Study, Mohart et al documented an increase in the risk for nuclear and mixed cataracts for each 20 mm Hg increase in systolic blood pressure:" It remains unclear why blood pressure might potentially affect cataract development. Some researchers suggested a role for antihypertensive medications, 4:5'2~ such as diuretics, j~'6~ particularly thiazide diuretics '-'~ and furosemide, 1~ as possible risk factors. In light of these equivocal findings, more studies that examine the independent effects of blood pressure and use of antihypertensive medications are warranted. It may be possible that blood pressure is a surrogate for the cataractogenic effects of certain anti-hypertensive medications, or that commonly related factors, such as diabetes, race and education, are responsible for the relationship. However, it is difficult to separate the effect of hypertension, particularly severe hypertension, with antihypertensive drug use. Experimental studies on animals may pro- vide better biological models ti)r assessing tile role of blood pressure in cataractogenesis. For example, an investigation on genetically hypertensive, salt-sensitive rats showed that cataract could be prevented by both acute and chronic dietary sodium restriction, suggesting a stronger role for extracellular fluid volmne status, more than that of sustained arterial hypertension, in cataract development. :~~ ULTRAVIOLET RADIATION Lens opacification has been linked to ocular exposure to ultraviolet radiation, particularly ultraviolet B (UV-B). The lens is known to absorb UV-B and UV-A. Change in lens clarity has been linked in animal experiments with short-term, high intensity exposure and chronic exposure to UV_B. ~7 The question of whether long-term, chronic exposure to UV-B in sunlight might increase the risk of cataract in humans has been addressed in several epidemiologic studies. These studies are basically of two types: ecologic prevalence studies, and prevalence or case-control studies which attempt some measures of personal dosimetry. For example, early studies noted that cataract occurred more frequently in tropical or sunny regions where exposure to solar radiation, including ultraviolet light, might be high, compared to more temperate climates. 43:~4:25 Hollows and Moran developed five climatic zones of increasing ambient UV-B radiation in Australia, and examined 64,307 Aborigines for the prevalence of cataract. 47 They showed a dose-response relationship of increasing prevalence of cataract with increasing levels of ultraviolet B radiation. In Nepal, Brilliant et al found a positive correlation between cataract prevalence and average daily sunlight hours in a national survey. 9 Nepalese living in sites with a daily average of 12 hours of sun exposure had a prevalence of cataract nearly four times as high as those living in sites with seven hours of exposure. In the United States, Hiller et al used data from the National Health and Nutrition Examination survey to study a similar ecologic association. The data from over 10,000 eye examinations in 35 geographic locations suggested that individuals living in areas with higher total annual sunshine hours had a higher prevalence of cataract, 45 especially cortical cataract. 46 However, in all of these studies, individual exposure, especially ocular exposure, was not measured. Ambient levels of sunlight was the proxy for an individual's actual level of exposure. This approach is not valid for populations where occupation and

5 RISK FACTORS FOR AGE-RELATED CATARACT 327 leisure time may be spent indoors and where modifiers of ocular exposure, such as glasses and hats, are commonly used. Such modifiers of exposure have considerable impact on personal ocular doses of UV-B. 9~ Such variables are not simply confounders in a predictive model, but must modify actual doses of UV-B. In subsequent studies, attempts were made to develop more detailed models of personal exposure to sunlight. In a study of 838 Chesapeake Bay watermen, a cumulative, personal, ocular dose of UV-B was calculated based on job history, glasses and hat use, and field measurements relating ambient exposure to ocular doses. 91 The resulting range of ocular exposure to UV-B in these fishermen was wide, due not just to the amount of ambient exposure, but the variation in glasses and hat use. An increased risk of cortical cataracts was associated with increasing personal UV-B exposure, and no association was found with UV-B and nuclear opacity. I~ Using the same model for personal ocular UV-B dosimetry, Bochow found an increased risk of PSC opacities with increasing exposure to UV-B in a case-control study of surgical cataract patients. ~ Other studies used less detailed personal exposure measurements, but had similar findings. A case-control study showed that the risk for cortical or PSC opacities was slightly increased in persons with moderate and high sunlight exposures. '23 A study of 160 cataract surgery patients matched by age and gender with 160 noncataract controls failed to document any relationship between a history of sunlight exposure and the presence of surgical cataracts; ~~ however, the type of cataract was not specified and the methodology for selection of the cases would have resulted in few cortical opacities. In the Beaver Dam study, an increased risk of severe cortical opacities was associated with average ambient ultraviolet-b radiation at the place of residence. ~" Protective factors for ocular exposure were modeled as independent variables, rather than absolute modifiers of exposure. Interestingly, no association was found for women, who had more cortical opacities than men in this population, The women in the Beaver Dam study showed little dispersion in the residential exposure history, and an association may have been difficult to detect with such low levels. Nevertheless, the women had more opacities, illustrating again the multifactorial origins of cataracts. In summary, current epidemiologic evidence seems to support a role for sunlight exposure in the development of cortical and PSC cataracts. Much concern has been raised over the potential increase in cataracts associated with increased UV-B radiation in connection with the ozone hole. However, we do not have sufficient data on the range of ocular exposure in human populations to determine the magnitude of any increase in risk of age-related cataracts. Further work in this area is clearly warranted. There are other data on cataract and other types of radiation, such as x-ray exposure, microwave and infrared exposure, which will not be reviewed in this summary. DIABETES Diabetes is a well-recognized risk factor for cataracts. Biochemical studies of cataractous lenses in those with diabetes and galactosemia, known as "sugar cataracts," showed abnormalities in the levels of electrolytes, glutathione, glucose or galactose. 54 Formation of sugar alcohols from either glucose or galactose by the enzyme aldose reductase can lead to hyperosmotic effects in the lens such as lens fiber swelling, vacuole formation, and opacification. 54'5" A number of epidemiologic studies have reported a positive association between cataract and diabetes. The association of increasing blood sugar level with cataract was observed in the Framingham Eye Study. 5~ Several clinic-based studies also supported the finding of diabetes as a risk factor for cataract. ~ ~~ 5A0.44 However, subsequent analyses of population-based data from the Framingham Eye Study and NHANES showed a three- to four-fold excess risk of senile cataracts among diabetic individuals less than 65 years old, but the risk did not persist for those over 65 years of age in the Framingham data? 1 Data from a population-based study of diabetics in South Central Wisconsin have identified important characteristics of diabetic patients that were associated with cataract. 61 For younger-onset diabetics, the most important factor was increasing duration of diabetes; for older-onset diabetics, it was age at the time of the survey. In a population-based study in Israel of individuals years old who underwent concurrent oral glucose tolerance test and ophthahnoscopy, glucose intolerance was associated with a six-fold excess risk of senile cataract among women. ~ An association was also seen between cataract and increased level ofglycosylated hemoglobin (HbA1), independent of the effect of glucose tolerance, among women. While these data imply that cataract risk is associated with poorer control of diabetes, none of these associations was seen in men. In studies where type of opacity was docu-

6 328 Surv Ophthalmol 39 (4) January-February 1995 WEST, VALMADRID mented, cortical, TM PSC, *'4<> and mixed-corticaland-psc TM cataracts have been the types associated with diabetes. Such consistency of resuhs across various epidemiologic studies highlights the need for regular lens examination in patients with diabetes. DIARRHEA Harding has proposed that frequent episodes of diarrhea may be related to cataractogenesis and may account for the excess prevalence in some developing countries) s Four intermediate events have been suggested to explain the role of diarrhea in the development of cataract: malnutrition secondary to malabsorption of nutrients; relative alkalosis from administration of rehydrating fluids with bicarbonate; dehydration-induced osmotic disturbance between the lens and the aqueous humor; and increased levels of urea and ammonium cyanate which may denature lens proteins by the process of carbamylation) ~ Six case-control studies have examined the relationship of severe diarrhea and increased risk of cataract, with discordant results. Two casecontrol, clinic-based studies done in Madhya Pradesh, v7 and Orissa, TM India have suggested a three- to four-fold increase in the risk for cataract for those with remembered episodes of lifethreatening dehydration crises, severe enough to render the patient bedridden for at least three days. However, these findings were not replicated in two other epidemiologic investigations done in India. Using a less stringent definition of diarrhea (confinement to bed for one day), the India-US Case-Control Study found no associations with cataracts. ~~ Also, a village-based casecontrol study in Southern India showed no association between severe diarrhea and risk of cataract) Furthermore, an observational study done in Matlab, Bangladesh, revealed that diarrhea from all causes was not significantly associated with cataract, although it was difficult to determine how cataract was defined in the study. 57 The case-control study in Oxfordshire found a marginally significant excess risk of cataract with reported severe diarrhea, but a significant risk in the subgroup aged 70 and older. "~' Adjustments for the other possible confounding factors also found in the study were not done. Considering the potential public health importance of diarrhea as a risk factor, as well as the biologically plausible role of dehydration in cataractogenesis, further research to clarify this association is needed. Prospective studies involving closer follow-up of groups of patients who suffered from acute life-threatening diarrhea may provide more convincing evidence. Moreover, studies that examine the cumulative effect of milder, chronic dehydration episodes in cataractogenesis:' may also add to the current understanding of this issue. ANTIOXIDANTS Early studies, largely animal experiments, initially suggested a possible role of nutritional status in cataract fbrmation. Various factors such as caloric and nutrient intake and blood levels of protein, amino acids, carbohydrates, vitamins and minerals have been implicated. ~o.~j But their relevance to human cataractogenesis remains uncertain because of the extreme nature of the experimental procedures used and the important dissimilarities between humans and animals. ]o_9 Of all the dietary factors studied thus far, antioxidant nutrients have received the most attention in cataract research involving humans. Cataract may result from inadequate mechanisms to protect lens enzymes, proteins, and membranes from oxidative stress. Activated oxygen species - hydrogen peroxide, superoxide anion, singlet oxygen, and hydroxyl free radicals - may be involved in oxidative reactions due to external insults such as exposure to radiation It therefore follows that elevated amounts in the lens of substances with antioxidant properties such as enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and vitamins (carotenoids, riboflavin, ascorbic acid, and alpha-tocopherol) may protect against such insults. J.~:~.l J6 There have been ten published epidemiologic studies that investigated the association between some form of lens opacities and some measure of antioxidant status. :~6'5~ The findings are quite conflicting even though eight studies documented a protective effect of high levels of some antioxidants. The use of some form of vitamin supplementation was associated with a protective effect against cataract in four studies. A clinic-based case-control study in Canada indicated a decrease in the risk of cataracts of at least 45% in those with past intake of supplementary vitamins C, E or both. 89 In a case-control study in Boston of different lens opacity types, regular intake (at least once a week for at least one year) of multivitamins decreased the risk of cortical, nuclear, PSC and mixed opacities. TM An analysis of prospective data on over 50,000 nurses in the United States found that the risk of cataract extraction was 45% lower in women who used vitamin

7 RISK FACTORS FOR AGE-RELATED CATARACT 329 C supplements for at least 10 years, but no association was seen with multivitamin use. 3~ In a report of the prevalence of clinically determined lens opacities in persons aged 45 to 74 enrolled in a nutritional intervention trial in China, vitamin/mineral supplements were associated with a decreased prevalence of nuclear opacitiesj ~ Riboflavin plus niacin was associated with a 44% reduction in the prevalence of nuclear opacities. Two other studies have found no protective effect of multivitamin use. 5~ A case-control study done in Italy, 5~ using nutritional intake measures similar to the case-control study of lens opacity types done in Boston, 7~ did not find any association with use of multivitamins nor with any individual nutrients. 5~ A study involving 660 persons aged 40 and older in Baltimore found no association of multivitamin use with senile lens opacity types.l~r Associations with specific antioxidants are quite conflicting. The case-control study of lens opacity types done in Boston found that high nutritional intake, as assessed by a food frequency questionnaire, of vitamins A and C and of vitamins B2 and E was significantly associated with lowered risk for nuclear and cortical cataracts, respectively. 7~ In the prospective study of nurses, intake of total vitamin A (but not necessarily [3- carotene) was associated with a 39% lower risk of cataract extraction? 6 Jacques et al found a decreased risk of cortical opacities associated with increasing carotinoid levels. ~ However, vitamin A intake, plasma vitamin A, and serum retinol were not found to be associated with cataracts in four other studies. 5~ Blood levels of alpha-tocopherol, 64'''7 past intake of vitamin E, TM or prior vitamin E supplement use 89 has been associated with a decreased risk of nuclear opacities, 7~ cortical opacities, 7~ or cataract or cataract extraction. 64'89 Other studies did not find any protective effect. :~s'5~ Ascorbic acid or vitamin C is known to be a potent antioxidant, with lens levels many fold higher than plasma levels. ~0~ High serum vitamin C level was found to be associated with a protective effect of PSC opacity, 5' and dietary intake of vitamin C with nuclear opacity. TM Vitamin C supplement use decreased the risk fbr cataract extraction in two other studies. :~'s'~ Other investigations did not corroborate with these findings, 5~''~~ and one case-control study, done in India, showed that high serum vitamin C increased the risk of mixed (nuclear and PSC) cataracts, so An index of antioxidant status, which combines various measures of antioxidant vitamins and erythrocyte enzymes, were created and examined by several investigators. Mthough two studies did not show a protective effect, ~~ four studies documented that high antioxidant index scores were protective for all types of cataract , s0 For a number of reasons, it is difficult to summarize the epidemiologic evidence that antioxidants are protective against cataracts. The conflicting findings could be due to several factors. First, very different populations were enrolled in these studies, with different nutritional requirements and ranges of homogeneity in their diets. Most data analyses rank the study groups into antioxidant categories of high, medium, and low, based on their own data base. If there is considerable homogeneity in the diets as might be true for India or Italy, any differences between high and low levels could be difficult to detect. As few studies report the levels that qualified as "high" or "low" for the antioxidants, we cannot determine if this explanation is reasonable. Second, there is no model describing the relationship ofantioxidant status to cataractogenesis that would tell us, for example, if a threshold of deprivation is necessary before an increased risk is observed, or if a protective effect is not seen until greater than a certain level is achieved. Such a model requires basic data on specific levels of nutrients, which are not published in most of these studies. The lack of such data also makes it difficult to put the public health significance of any findings into perspective. Finally, we must recognize the imprecision of surrogate measures for lens antioxidant status. Dietary intake may not reflect physical antioxidant status, which is likely affected by cofactors, such as smoking. There is a need to assess the interaction of oxidative stressors and antioxidant status in cataractogenesis. Moreover, a finding of low antioxidant status associated with increased risk of cataract does not necessarily mean that supplementation will decrease that risk. Homeostatic processes may mitigate any effect of supplementation on lens status. Animal or human surgical cataract studies on the effect of supplementation on antioxidant status in the lens is needed before clinical trials are justified. At present, vitamin supplementation is being promoted for the prevention or treatment of cataract; such claims are misleading and unproven. DRUGS Steroids In 1960 Black et al documented a highly significant association between the occurrence of

8 330 Surv Ophthahnol 39 (4)January-February 1995 WEST, VALMADRID PSC cataract and intake of oral corticosteroids among rheumatoid arthritis patients. 7 Since then, a number of earlier papers have confirmed the cataractogenic role of steroids '-'s':~4'83'84'h~4 in patients with rheumatoid arthritis, asthma, pemphigus, nephrosis, lupus, as well as in patients on massive steroid doses tor immunosuppression after renal transplantation. 4~ PSC cataract is the hallmark, "starting as a fine granular and vacuolated opacity at the posterior pole of the lens. ''7"~ Several reports in the literature have indicated the more frequent occurrence of PSC opacities with high doses (more than 15 mg prednisone or equivalent per day) and prolonged use (more than one year) ofcorticosteroids. 7:~'lj:~ In a clinic-based case-control study in Oxfordshire, consumption of steroids for as little as four months emerged as a significant risk factor for cataract. 41 Other epidemiologic studies that examined senile cataract types ~'5~176 have also confirmed the role of steroids in the development of PSC opacities. Given the widespread use of corticosteroids and their association with PSC cataracts, ophthalmologists must be aware of a patient's medication history and recognize the distinguishing features of PSC cataracts) ~3 Aspirin and Other Analgesics Acetylsalicylic acid or aspirin, or its active component, salicylate, was proposed as protective against cataract formation because it inhibits aldose reductase activity and lowers plasma tryptophan levels. 24'26'27'97 With the observation of increased levels of plasma tryptophan and more aldose reductase activity of the lens in patients with cataracts, aspirin and other nonsteroidal antiinflammatory agents were hypothesized to delay, if not prevent, cataractogenesis. 26'97 Salicylate competes with tryptophan for a common albumin binding site in the plasma, resulting in decreased levels of bound and total tryptophan.'~"~ Findings fi'om studies in human populations are mixed. In patients with rheumatoid arthritis, Cotlier observed that cataracts were less common among those taking aspirin. 27 In a subsequent study of diabetic and nondiabetic patients, aspirin appeared to reduce cataract formation in both groups and particularly among the nondiabetics with osteoarthritis, in whom a delay in cataract appearance of about 10 years was suggested. 2~ A case-control study in India showed an increased risk of PSC and mixed cataracts in those who used less than one tablet of aspirin per month compared to those who used more.~~ A case-control study in Oxfbrdshire supported the role of "aspirin-like analgesics" in reducing the risk for cataract extraction, although aspirin alone was not fbund to signifcantly affect the risk. 41 A subsequent analysis showed that intake of aspirin, paracetamol and ibuprofen, alone or in combination, was associated with at least 30~ decrease in the risk for cataract extraction) '~ While these studies suggest a protective effect for aspirin or similar compounds, the majority of human research has failed to find any effect of aspirin. Two population-based observational studies 96'v-'1 and one among diabetics 62 showed no association of aspirin intake with decreased cataract prevalence. Two case-control studies of multiple cataract risk factors done in Boston and Italy found no protective effect of aspirin or similar medications for arthritis. 3~176 Two prospective studies involving large cohorts of nurses 35 and elderly residents of a retirement community ~5 failed to find any relationship of cataract with aspirin use. Furthermore, three randomized trials of aspirin for cardiovascular disease found no evidence of a protective effect for cataracts. Trials of aspirin use among British 86 and American 95 male physicians showed no significant reduction in cataract risk in those on aspirin versus those on placebo. Another trial involved the randomization of 2435 patients into groups taking placebo and aspirin at doses of 300 mg and 1200 mg daily. ~2 The prevalence of cataract did not differ between the groups after an examination from one to five years after randomization. Similarly, analysis of data from a randomized trial of aspirin among patients with nonproliferative and early proliferative diabetic retinopathy showed no evidence that aspirin use decreased the risk of cataract extraction. ~6 The trials do not address the issue of a protective effect of higher doses of aspirin, or use for prolonged periods. Nevertheless, since recently conducted observational studies and randomized controlled trials have failed to confirm any benefit of aspirin at reasonable doses, recommending its use to prevent cataracts appears unjustified. Allopurinol Allopurinol, an antihyperuricemic agent, has been commonly used in treating gout. Scattered reports on the possible association between longterm ingestion of the drug and premature development of PSC cataract led investigators to conduct experimental studies of animal lenses and in vitro studies of human cadaver lenses. 74'92 Early animal experiments failed to document that prolonged high-dose intake of allopurinol could

9 RISK FACTORS FOR AGE-RELATED CATARACT 331 produce cataract, TM and showed conflicting evidence that allopurinol could act as a photosensitizer to light-induced damage caused by ultraviolet radiation. 69'92 Lerman et al reported that cataractous lenses from persons on the drug for more two years exhibited the characteristic allopurinol-photobinding effect, a result not seen in normal lenses from those on the drug for the same duration. 68 The authors suggest that chronic allopurinol intake, per se, does not necessarily result in cataract formation unless it has been retained within the lens, thereby enhancing the potential for photochemical insults. 66-6s Data from epidemiological studies on allopurinol are difficult to interpret because of small numbers or lack of information about long-term ingestion. Jick and Brandt reported no association of cataracts with allopurinol, based on two studies: an analysis of patients with first-discharge diagnosis of cataract and their age- and sex-matched hospital controls, and an analysis of concurrent exposure to allopurinol of patients in a medical cooperative health plan admitted from 1977 to 1981 for cataract extraction)'~ However, the exposure measure was not sensitive to long term allopurinol use (intake "of at least once per week for at least one month" during the past three months for the matched case-control analysis and "one or more prescriptions for allopurinol in a given year" for the health plan study). Marks et al evaluated the development of cataract in only 70 geriatric health screening program participants exposed to allopurinol and found no excess cataracts. 7~ Clair et al analyzed the presence of cataract among allopurinol users identified from hospital pharmacy records, but allopurinol exposure was not clearly defined and the exact duration of exposure was not available on at least one-fourth of the 51 users of the drug. ~~ Furthermore, the power of the study was relatively small to detect differences in risk estimates. Liu et al reported a series of 53 patients attending a gout clinic in London with at least 18 months of allopurinol ingestion, v2 Different lens changes, from thinning of the anterior clear zone of the lens to anterior subcapsular opacities, were reported in some patients. However, no comparison group was included. Leske et al found an association between use of "at least once a week for at least one month" of" "gout medications" and mixed cataracts. TM However, exposure to allopurinol was not specifically reported. Well-designed investigations specifically for allopurinol are currently needed to assess any independent effect of chronic allopurinol inges- tion on cataract development. Phenothiazines In 1965 the occurrence of ocular pigmentation and lens opacity in patients on high-dose phenothiazine drugs, particularly chlorpromazine, was reported in several papers. :~'~:~'~8 Phenothiazine has been thought to cause pigmentation by virtue of its ability to combine with melanin and form a photosensitive product.l~~ It is also postulated that this process might accelerate any predisposition to lens opacification from environmental insults such as solar radiation. A study involving schizophrenic patients showed an association between severity or grade of lenticular pigmentation and equivalent dose of phenothiazinc intake.~l~ Epidemiologic research on the role of phenothiazines in cataractogenesis is limited. A casecontrol study done in North Carolina found a two-fold increased risk of cataract in those with history of tranquilizer use, although the types of tranquilizers and cataracts were not characterized. 2:~ A health maintenance organizationbased, nonconcurrent prospective study that controlled for steroid use and diabetes documented at least three-fold increased risk for cataract extraction among current and past (two to five years prior to extraction) users of two groups of tranquilizers: "antipsychotic phenothiazine drugs" (chlorpromazine, thioridazine, trifluoperazine, perphenazine, fluphenazine) and "other phenothiazine drugs" (chlorperazine, prochlorperazine, promethazine, trimeprazine)? ~ Given the paucity and limitations of available epidemiologic data, more studies, such as those characterizing the specific types of senile cataracts and phenothiazines, are needed to verify any association. Conclusion Clearly, age-related cataract is a multifactorial disease, and different risk factors appear to play a role for different cataract types. Cortical and PSC cataracts seem to be most closely associated with environmental stresses such as ultraviolet exposure, diabetes, alcohol and other drug ingestion. Nuclear cataracts appear to be associated with smoking. Consistent evidence also suggests that the prevalence of all cataract types is higher among those with lower education and among heavy drinkers of alcohol. There is likely a protective effect of antioxidants against cataract, but the precise antioxidant and the role of supplementation is not clear. Given the serious public health burden from

10 332 Surv Ophthalmol 39 (4) January-February 1995 WEST, VALMADRID cataracts, further epidemiological investigations to elucidate the interactive role of these and other factors in cataractogenesis are needed. Such data will provide a sound basis for developing effective public health programs aimed at preventing or delaying the onset of cataracts. References 1. Augusteyn RC: Protein modification in cataract: possible oxidative mechanisms, in Duncan G (ed): Mechanisms of Cataract Fo~'mation in the Human Lens. London, Academic Press, 1981, pp Bailey IL, Bullimore MA, Raasch TW, Taylor HR: Clinical grading and the effects of scaling. Invest Ophthalmol Vis Sci 32: , BarsaJA, NewtonJC, SaundersJC: Lenticular and corneal opacities during phenothiazine therapy. 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A~rh Ophthalmol 105: , West SK, Rosenthal F, Newland HS, Taylor HR: Use of photographic techniques to grade nuclear cataracts, h:- vest Ophthalmol Vis Sci 29:73-77, Zigler JS Jr, (;ousey JD: Singlet oxygen as a possible 1actor in human senile nuclear cataract development. Curr Eve Res 3:59-65, Zigman S: Photochemical mechanisms in cataract flumation, in Duncan G (ed): Mechanisms o/'calaract F(mnalion m the Human Let,s. London, Academic Press I nc Ltd, 1981, pp Zigman S, Datiles M, Torczynski E: Sunlight and human cataracts. Invest Ophthalmol Vis Sci 18: , 1979 We are grateful for the comments of Drs. Oliver D. Schein and Harry A. Quigley. Dr. SheBa West is a Research to Prevent Blindness Senior Scientific Investigator. This work was supported by NIH Grant P01 AG Reprint address: Dr. SheBa West, Dana Center for Preventive Ophthahnology, Wilmer Room 116, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD