PREVENTIVE

MEDICINE

4, 20-36 (1975)

Water Constituents and Trace Elements Relation to Cardiovascular Diseases

in

A. RICHEY SHARRETT AND MANNING FEINLEIB Epidemiology Branch, Division of Heart and Vascular Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland 20014 Significant inverse correlations between the hardness of drinking water and local cardiovascular mortality rates are found consistently in major national studies and less consistently within smaller regions. A number of bulk and trace constituents of finished water at the treatment plant show correlations with mortality of equal but not greater magnitude to the correlations of hardness with mortality. Little is known about these relationships with tap water, but levels of several trace metals of biological significance are known to vary markedly within water distribution systems and are probably related to types of pipe and the corrosiveness of the water supplied. Tap water studies and studies of localities within smaller regions are recommended to disentangle the association of water quality and health from the associations of both to other regionally distributed factors. Rainfall is one such factor which may influence the content of both drinking water and soil and thus human mineral intake. A number of other environmental and social factors seem unlikely to be intermediaries from the results of several multivariate studies.

Inverse correlations between the hardness of drinking water and local cardiovascular mortality rates have been discovered and confirmed in the United States (65,70) Canada (54) and in England and Wales (1150). A current commentary on the subject cites 49 studies from 9 countries relating regional differences in cardiovascular disease (CVD) to constituents of drinking water but finds the data inadequate to discriminate between basic hypotheses (55). The question remains open as to whether the bulk or the various trace elements usually found in hard water are protective or whether something in soft water is harmful. The correlations may mean only that water quality is an index of something else, a factor not transmitted through drinking water. Although it has been estimated that the maximum attainable mortality reduction from optimal conditioning of drinking water is at most 15%, the absolute number of potentially preventable deaths is large, so that recent meetings of investigators have given strong endorsement to continuing research in this area (44,88). The present report attempts to summarize and illustrate the complexity of studies of this question and of the related issue of the role of trace metals in the occurrence of CVD. The most suggestive areas are highlighted as deserving priority for future studies. WATER HARDNESS

Hardness is not a specific constituent of water but a complex characteristic measured by titration with a chelating agent and often expressed as calcium carbonate equivalent. Schroeder’s 1960 investigations were the first reports of cor20 Copyright

@ 1975 by Academic

Press, Inc. All rights of reproductmn

in any form reserved.

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CVD

relations between water hardness and cardiovascular mortality (65,66). Using data by the U.S. Geological Survey on finished water supplies in 13 15 U.S. cities to calculate average state values and age-adjusted death rates for whites by state, he found negative correlations for all-cause and cardiovascular rates-lower death rates in states with hard water. The correlation with noncardiovascular diseases taken as a group was small and not significant. Within the cardiovascular category there were strong relationships to water hardness for arteriosclerotic heart disease (ASHD) (r = -.5) and hypertensive heart disease (r = -.6), and less of a relationship for stroke deaths (r = -.3). However, relationships were not confined to cardiovascular diseases: hardness was positively correlated with deaths from accidents and congenital malformations and negatively with malignancies. The negative correlation of hardness to coronary death rates was not as high when 163 large cities were studied as it was with data for entire states, despite the fact that in the city analysis water values more closely represent the exposure of the population at risk than in the state analysis. Correlations found in the major studies of public water supplies are shown in Table I. The above study used water data published in 1952 and deaths from the 1949-195 1 period. Using the same water data and 1960 mortality figures, Schroeder again found correlations for states between hardness and ASHD (Y = -.5) and hypertensive heart disease (r = -.4) to be significant and stronger than that for stroke (v = -.25) (70). Using 1962 water data and 1960 mortality data for 88 large cities, he found a correlation for ASHD of -.4. Again the city data showed a weaker correlation than the state data. Other authors using United States mortality data have confirmed the negative correlations with water hardness. McCabe using 1949- 195 1 mortality in 135 central county areas found not only the expected negative relationships between mineralization of city water and heart diseases and negative correlations with malignancies and cirrhosis and positive correlations with accidents TABLE I CORRELATION BETWEEN MORTALITY AND HARDNESS OF FINISHED PUBLIC DRINKING WATER”

Author, year published Schroeder, 1%0 Schroeder, 1966 Saner, 1970 Morris, 1961 Crawford, 1968 Bitirck, 1965 Lindeman, 1964 Mulcahy, 1966 Morton, 1971 Neri, 1972

GCOgraphiCd

unit studied States, USA Metropolitan areas, USA States, USA Metropolitan areas, USA Metropolitan state economic areas, USA County boroughs, UK County boroughs, UK Towns, Sweden Counties, Oklahoma Urban areas, Ireland Counties, Colorado Provinces, Canada Municipalities, Canada

ArtFXiosclerotic heart disease -48’” - .29** -.51** -.41** -.32** -.39** -.52** -.I6 .03 -.22 -.12 -.61 -.08

All cardiovascular disease -.34*

NO”-CdiW

vascular diseases

Malignant neoplasms

All causes

-.53**

-.lO

-.32*

-.38’S

-.31** -.54** -.65**

-.I9 -.35**

-.23* -.12 - .22

- .09

- .26*

- .25* -.39** -.55** .06 - .22

-.66* - .14**

- .87** -.16**

- .25

- .42** - .56** -.19 -.17 -.I8 -.22 - .69* - .09*

n One asterisk indicates the correlation coefficient is significant at the .05 level. Two asterisks indicates significance at the .Ol level.

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and congenital malformation deaths, as Schroeder had found, but also a significant positive correlation with strokes (41), which contrasts with Schroeder’s finding, and other significant correlations with stomach ulcer, diseases of infancy, and gastritis. The plethora of significant findings (all of the above greater than + or -.6) cast doubt in his mind on the specificity of any of the relationships. Sauer used 1960 water and mortality data for 95 U.S. metropolitan areas and found a greater negative correlation for coronary disease than any other category of cardiovascular disease (63). The relationship with hypertensive heart disease was less marked than in Schroeder’s earlier data. Again a negative correlation with malignant deaths shows that the correlations are not entirely specific to cardiovascular diseases. Masironi correlated state 1960 mortality to river water analyses and found a significant negative correlation for hypertensive heart disease, a smaller negative correlation for ASHD and a nonsignificant positive correlation for noncardiovascular diseases (40). The most extensive investigation of the water hardness story has been in England and Wales by a team with the Medical Research Council. Morris first reported analyses of mortality in 1948-1954 among 83 county boroughs (50). Correlation with all cardiovascular disease was of the order of -5 for both males and females, both in the 45-64 and 65-74 age groups. But here the relationship was stronger with cerebrovascular disease than with hypertensive or coronary heart disease. Cancer again showed a significant negative correlation, but only for females. Bronchitis also was more frequent in soft water areas. These observations were repeated using death data in 1958- 1964 in the 61 largest county boroughs (1 I), resulting in even larger negative correlations for the cardiovascular disease categories than before. Now, however, the negative correlation of noncardiovascular deaths with hardness was significant, with bronchitis and cancer both contributing to this relationship. In a subsequent study five towns which increased the hardness of their water between 1900 and 1955 by 50 parts per million or more had more favorable cardiovascular trends between 195 l- 196 1 than six towns which decreased hardness, and the 72 towns with constant water were intermediate (13). Stocks has used the most recent mortality data for the British county boroughs (1958 1967) and found little if any relationship between cardiovascular mortality and water hardness (77). Stroke mortality appeared to be highest in towns with hardness between 150 and 200 ppm, as did hypertensive heart disease deaths. Correlations were not reported, but ASHD deaths were only slightly less frequent in the hard water categories which Stocks used to classify the data. These results are in substantial disagreement with other studies of the same county boroughs. Results are presented as proportionate mortality ratios instead of standardized or agespecific rates, and it is not known whether this is the reason or whether the past relationships no longer hold with new data. The major findings from the U.S. and U.K. are in substantial agreement, but cardiovascular death rates for white males are about 40% higher in extreme soft water than in extreme hard water areas in the U.K., and only 15% higher in the U.S. Cerebrovascular disease shows strong negative correlations with hardness in the U.K. and weak negative correlations in U.S. data (McCabe’s

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data showed a significant positive correlation). Arteriosclerotic and hypertensive heart disease mortality show consistently negative and usually significant correlations in most age-sex groups in both countries. There are negative correlations of borderline significance with cancer in both countries, but the U.S. and U.K. data for other noncardiovascular categories are completely different. Noncardiovascular diseases as a group correlate negatively with hardness in U.K. data at significant levels but this correlation is absent in the U.S. Bronchitis and cancer, both negatively correlated, seem to be the factors explaining the noncardiovascular relationship in the U.K. In the U.S. a variety of significant positive correlations and a few negative ones have been found which have no counterparts in England. The differences here support the hypothesis of a factor in water which is specific for cardiovascular diseases. This hypothesis has been tested in several other areas of more limited geographic extent, with mixed results. In 34 of the largest Swedish towns hardness showed weak negative correlations to cardiovascular diseases in both sexes, significant only for stroke in females and for “other degenerative heart disease” (7th ICD no. 422) in females and young males (6). This ICD category was similarly related to hardness in U.K. data, but the finding is of uncertain significance because of lack of diagnostic specificity and changing fashions in the use of this category. In Oklahoma counties hardness was unrelated to cardiovascular diseases as a group (39). There were no significant cardiovascular results, and ASHD mortality was slightly higher in hard water counties. The value of this test is limited by the fact that the few counties which had soft water were all clustered in the southeastern portion of the state. Mulcahy showed negative correlations for all cardiovascular categories in 28 Irish urban areas (52). There was no apparent relationship between atherosclerotic lesions at autopsy and hardness in the water of 14 cities in the International Atherosclerosis Project (78), but these cities on four continents differ from each other in many ways other than in drinking water. Among the South American cities in this study hard water cities had lower hypertensive heart disease mortality (40). In Colorado the relation between hardness and ASHD mortality depended on the classification of areas (51); if counties were grouped by altitude the correlation was -5, classified by river basin, i-.6, unclassified -.l. Comstock analyzed water consumed at home by ASHD decedents and population-based controls and found the difference in hardness insignificant and in the wrong direction, i.e., decedents drank harder water (9). His cases were 189 middle-aged white males from Washington County, Maryland, an area with a pattern of water hardness favorably dispersed for a test of this hypothesis. Finally, Neri has looked at the relationship in Canadian provinces and municipalities and found negative correlations as in the other nationwide studies (54). Both stroke and ASHD show negative correlations, whether the unit of study is municipalities or whole provinces. Non-cardiovascular diseases as a unit, however, also consistently show higher rates in soft water areas. The correlation between hardness and ASHD among 9 provinces was -.61. Among the 516 municipalities it was only -.OS. However, as the authors point out, at the

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level of cities, correlation of death rates with any imputed factor has a theoretical upper limit well below that for provinces because of the instability of such rates in small areas. On the other hand, 516 cities as a sample is in reality a much smaller sample of truly independent units, and spurious significant correlations should be expected when the assumption of independence is not met. Neri also makes the point that if relationships are more clearly seen in regional comparisons than in small area comparisons it may be that the factor responsible has a truly regional distribution and has little effect on mortality differences between small areas. Furthermore, to isolate small area effects, it is not enough to look at small area correlations. One must simultaneously control for region effects. Within regions, Neri found small area correlations to support the hardness hypothesis in Ontario, where there was the widest spread of water hardness, and in Quebec, but not in the other provinces. The average correlation for ASHD weighted by provinces was -. 14, larger than the -.08 found when the city data for all provinces is pooled, and is significant. Differences in the hardness of drinking water do not explain the differences in atherosclerosis rates in 14 cities in the Atherosclerosis Project, or the differences in cardiovascular disease among counties in Oklahoma or Colorado. ASHD decedents in Washington County, Maryland did not drink softer water than controls. However, differences among cities in Sweden, Ireland, and the United States and Canada and among County boroughs in Britain and states in the United States and Provinces in Canada are related to water hardness. The strongest relationship is among the county boroughs of England and Wales, but it is not known to what extent this correlation is dependent upon broader regional differences. In Canada the negative slope of regression of mortality on water hardness is steeper for provinces than for municipalities (54). The expectation of the regression coefficient, unlike that of the correlation coefficient is not lower for small areas than for regions, so the reduction of the slope when small areas are considered is evidence that the factor indexed by water hardness may be regionally distributed, according to Neri. This question has been raised but not answered in U.S. investigations. Schroeder found larger correlations for states than cities generally, but this is expected with the variability of local rates. High coronary mortality and soft water both have a distribution along seacoasts in the United States (22), and when states are divided into inland and seacoast categories, Schroeder’s state correlations become insignificant (17). Hypertensive heart disease correlations survived this analysis however (70). The fact that raw water correlations have proved as strong or stronger in U.S. data than correlations with finished drinking water may support the view that water hardness is more representative of something in the geochemical environment than something found in a glass of drinking water (40,63). The lack of findings in Comstock’s paper would support this view further. If the factor indexed by water is regionally distributed, however, the way to discover it may be by searching for geochemical maps which are congruent with cardiovascular mortality maps rather than by explaining the variance in small area mortality. This is more akin to the estimation of the regression of mortality on a component of water than to testing the significance of correlations, and, of

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course, regression would make data from the above studies of areas of diverse size more directly comparable. WATER CONSTITUENTS

The question of a specific etiological factor in water has been raised in all major studies. Calcium and magnesium, the major constituents of the hardness in water, seemed unlikely factors because water is not the major contributor to human intake for these ions (29). Schroeder initially expected the hardness correlation would be positive instead of negative (65) on the basis of Kobayashi’s work. Kobayashi found that areas in Japan with high apoplexy rates were served by river water with high sulfate/carbonate ratios (35). Schroeder, who analyzed the Japanese data and reported that all heart disease correlated better to SO&O, than did cerebral hemorrhage, must have expected that hard water, which is usually correlated positively with sulfate, would correlate positively with disease. But the correlation was negative, and SO&O, was uncorrelated in Schroeder’s data and hardness in Kobayashi’s (67). In Canada and the United States both calcium and magnesium related to cardiovascular mortality in the same way that hardness did. Both correlated highly with total hardness, .94 for calcium and .92 for magnesium (63) and with each other, .79 (63) .85 (84). The negative correlations to cardiovascular mortality in North American data are about equally strong for calcium and magnesium (54,55,63,65,7 1,74). However, in England and Wales only calcium had a strong negative correlation to mortality, and magnesium content showed little suggestion of an effect (11,50). When the U.S., U.K. and Japanese differences first emerged, Schroeder speculated that the factor common to them all may be the corrosiveness of water to pipes (65). Soft water tends to be acid, and the Japanese waters with high SO&O, ratios had remarkably low pH. Hard water usually has high conductance and total dissolved solids, a high content of sodium, potassium, bicarbonate, sulfate, and silica, and high radioactivity levels. These characteristics, and sodium, and the other bulk constituents have all shown negative correlations with cardiovascular mortality in various studies (6,40,63,65,70,74). Of course the sodium findings in these geographic studies give no evidence regarding possible effects of drinking water in the very few areas with sodium content as high as 250 mg/liter on individuals with sodium restricted diets. In untreated river water in the United States hardness is highly correlated with higher levels of trace metals (40). Positive correlations to hardness greater than .90 are found for cadmium, chromium, cobalt, molybdenum, nickel, and vanadium. Zinc correlates with hardness at .90, lead .87, manganese .65, iron .30, and copper .21. Not surprisingly, the levels of all these metals in raw water correlated negatively with cardiovascular disease death rates by state within the United States, except copper, which showed slight positive correlations (40). The levels of correlation were higher for HHD than for ASHD and ranged from about --.5 to -.2 (for HHD). The strength of the correlations was in rough correspondence to the correlations with hardness.

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Spectrographic analyses for trace elements in finished water at treatment plants sampled before entering the distribution system were performed by Durfor and Becker with the U.S. Geological Survey (19) and have become the basis for a number of U.S. reports. Among the trace metals studied by Masironi in raw water, vanadium showed the strongest correlations in these reports on finished water. Schroeder showed vanadium levels correlated -.34 with ASHD in white males in 88 cities (70). Sauer reported similar results (64), and Voors, using substantially the same data, showed correlations of this magnitude, independent of calcium and magnesium, for all four race-sex groups in 99 cities (84). In Schroeder’s recent paper, vanadium showed relationships with both coronary and stroke death rates that were more consistent across age, race, and sex groups than were those of any other trace metal (74). This should be interpreted cautiously because only 22 cities had detectable vanadium levels in Durfor and Becker’s report. But the geographic pattern of vanadium in city water is broadly scattered, similar to the pattern for vanadium in soil reported by Schacklette (75), so that the association of vanadium with mortality cannot be explained away by other obvious associations. Copper and molybdenum also showed correlations to cardiovascular disease in the same direction for finished water as for raw water: copper positive (63,70,74) and molybdenum negative (74). But manganese (70,74) and zinc (84) were positively correlated in finished water analyses, at borderline levels of significance and opposite in sign to the relationships in raw water. Chromium (74,84), iron (74), lead (63,74), and nickel (74) show weak or inconsistent correlations in finished water analyses. Cadmium was undetected by the methods used in Durfor and Becker’s report, and none of these studies give correlations for it or for cobalt. Lithium, which Masironi did not analyze in raw water, now emerges in treated water as a strong negative correlate of cardiovascular mortality (7,63,70,74,84). Using partial correlations, Voors found the effect of lithium, as well as vanadium, to be independent of calcium or magnesium. However, lithium correlations did not persist after partial correlation analysis in Canadian data (5% The above reports using Durfor and Becker data still do not evaluate drinking water as consumed, although finished water at the treatment plant comes closer to this than does raw river water and may be a valid measure for elements which are not affected by pipes. Finished water at the plant of the 25 cities with the highest ASHD death rates compared with the 25 cities with the lowest rates was softer and had less lithium and vanadium (71). Little is known about tap water concentrations of the metals which may be affected by pipes, but McCabe presents values from 2595 distribution samples from 969 public water supply systems in 8 U.S. Standard Metropolitan Statistical Areas and the entire state of Vermont (42). Zinc and copper are found in higher concentration in acid tap water than alkaline probably because of leaching from galvanized and copper pipes. The high copper levels are mostly in waters with low specific conductance (soft waters) but zinc levels may be high also in high conductance waters. Iron and manganese are found at higher levels in acid tap waters of low conductance than in hard alkaline water, but hard alkaline water may also have high levels, presumably from the water source. Lead and

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cadmium in tap water does not seem to have any certain relationship to conductivity or pH. Chromium is most often found in tap water with high conductivity and neutral pH. Neri in a study of tap water from 575 Canadian communities found essentially the same results: copper at higher levels in soft water samples; chromium, in hard water samples; and cadmium and zinc, at equivalent levels in both hard and soft water (55). Lead was at highest concentration in very soft water but was often found at appreciable levels in all other hardness ranges. Crawford reported on tap water samples from 15 towns in Britain which were at the extremes of the water hardness distribution (11). Manganese was consistently higher in soft water and vanadium in hard, as in U.S. data. But copper, though it was found in acid, low conductance tap water in North America, was usually at higher levels in hard water towns in England and Wales. Chromium, molybdenum, and nickel levels were not different in hard and soft water samples. If hard water at the treatment plant protects against cardiovascular disease, these are the best clues we have about its trace element content as consumed. One would expect that the hardness, calcium, magnesium, lithium, and vanadium values of finished water change little in its passage to the tap. But the levels of copper, iron, lead and zinc seem to be affected as much by the distribution system as by the source, and only tap water studies can give relevant data for them. The distribution system should affect tap water most when the water is corrosive. In Crawford’s study of tap water from 15 towns, the levels of cadmium, iron, lead, and zinc which might be expected to leach from pipes, were as high in hard water as soft and copper was higher in hard water. However, lead in bone in medicolegal autopsies and in tap water left standing overnight was considerably higher in soft water towns than hard water towns (12,15), and this indicates that soft water in England and Wales may be more corrosive than their study of the 15 towns indicated. Crawford notes that until recently over 90% of the homes in large industrial towns in Britain had lead pipes. It could well be that corrosive water in areas with different plumbing could have different health effects. Cadmium could be the problem in areas with galvanized and copper pipes. In his recent paper Schroeder employs a form of the Langelier index of corrosiveness, based on hardness, alkalinity, carbonates, and pH, and finds it correlates better than hardness does to ASHD (74). The appropriate index of corrosiveness in public water may depend on the particular corroded metals of interest, but certainly further research on such indices in epidemiological studies is indicated. If hard water contains beneficial trace elements, vanadium and lithium and possibly chromium are candidates. If soft water contains harmful metals, there are a number of possibilities. Cadmium and lead are known toxins which can be leached from pipes. Copper correlated positively with cardiovascular diseases and, in North America, was found more often in soft water. This is also true for manganese and zinc, though it would seem unlikely that these have direct harmful physiological effects. The toxicity of a number of trace metals to aquatic animals is increased in soft water because low calcium increases their absorption (30,68). The discussion of possible etiological agents in drinking water is incomplete

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without mentioning that Morton found that nitrate levels correlated positively with hypertension prevalence and mortality in Colorado (5 1). The effect seemed to be largely confined to counties in one river basin and could, therefore have other explanations, but the data are plausible because of other data on workers in nitrate industries. Neri suggests that the first responsibility of investigators may be to distinguish between the hypothesis that water exerts its effect through an agent contained in it and the hypothesis that water is just an index of the general geochemical environment (55). The search for the agent in water should be undertaken with the knowledge that this prior question is not yet answered. CONFOUNDING

FACTORS

In recent years controversy has arisen in Britain as to whether the observed associations between drinking water and cardiovascular disease may be secondary. Crawford examined correlations of water calcium with over sixty social and environmental indices (11). The associations with social indices were small, but there was a correlation of .42 with average temperature. Multiple regression analysis, with cardiovascular mortality studied in relation to water calcium, rainfall, latitude, air pollution, and a derived social factor score showed independent contributions by rainfall, latitude, and water calcium, but the standardized regression coefficients were not as large for calcium as for rainfall and latitude (25). Similar work on 116 U.S. metropolitan areas by Dudley showed that hardness was a significant contributor but less so than were climate variables, particularly a comfort index derived from temperature and humidity (18). When cities were divided according to mean annual temperature, drinking water (as might be expected) had the most effect in the warmest areas; climate, in the areas with temperature extremes. Dudley’s climate index showed that hot humid areas had the highest mortality; hot dry, the lowest. But of course in the United States, the Southeast is humid and has soft water and the Plains are dry and have hard water. Roberts correlated coronary mortality with rainfall and water hardness in the areas studied by Gardner plus fifty local-authority areas in South Wales (61). Here again, rainfall and hardness were negatively correlated. Partial correlation of hardness and mortality eliminating the effect of rainfall was -.21 for England and -.25 for Wales, not significant. The authors argued that it is probable that the water hardness association with mortality is “entirely dependent on the association of hardness with rainfall.” Crawford objected to this conclusion based on partial correlations and points out that the Wales data are unstable due to the small size of the local areas, and that additional variability is introduced by Roberts’ use of standardized mortality ratios in England instead of specific rates (14). West analyzed the interrelationships of rainfall, temperature, and water variables in the county boroughs used by Gardner and found that the effect of temperature was the least dependent on other associations (86). The conclusion again was that the association of hardness and mortality was secondary to associations with climate. Sauer, however, using a step up multiple correlation technique for cardiovascular diseases in U.S. cities found water magnesium or dissolved solids to be more important than precipitation or temperature (64). What has not been

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discussed is that high rainfall and soft water, both of which seem to contribute to cardiovascular mortality, may be synergistic. High rainfall reduces both the calcium content of soils and its content of a number of associated trace elements. This may be seen both in the low magnesium and potassium content in soils in the eastern parts of the United States and in low zinc levels along the Atlantic and Gulf coasts (75). The low levels of lithium in city water in northwestern states and along the Atlantic Coast suggests a relationship between rainfall and lithium content of natural aquifers. Persons living in soft water, rainy areas may be exposed to similar trace element intake from both drinking water and local animal and vegetable foodstuffs. That water hardness has an effect independent of climate is suggested by the report of Crawford’s group that towns which changed the hardness of their drinking water had predicted changes in mortality (13). But if rain and soft water are synergistic, it may be inappropriate to try to decide between Neri’s alternatives of water being an etiologic agent or merely an index of a regional factor (55). It could be both. CLINICAL

AND PATHOLOGICAL

FACTORS

Crawford compared the pathology in Glasgow, which has very soft drinking water, and London, with hard water (10). In the soft water area accident victims had more myocardial scarring but less coronary atherosclerosis. Myocardial infarction deaths also had less coronary disease than in hard water areas. This led the authors to speculate that soft water may somehow sensitize the myocardium to minor degrees of ischemia. The pathogenesis may relate to calcium and magnesium. Among young accident victims, with little coronary disease in either city, coronary artery levels of calcium and magnesium were lower in Glasgow, where the drinking water is also low in these ions. Calcium and magnesium were also low in bone in Glasgow compared with London (12), as was magnesium in serum (5). Serum calcium and magnesium were both significantly lower in Winston-Salem (soft water) than in Omaha (hard water) in the latter study. And finally, myocardial magnesium was lower in Canadian soft water cities compared with hard water cities in recent reports (3,56). Both ions have essential roles in myocardial physiology. They would not explain the associations of water hardness with stroke. Anderson found that coroner certified myocardial infarction death rates were lower in hard than soft water areas of Ontario (2). This was not true for infarctions not certified by coroners. They reasoned that hard water ions may protect against sudden arrhythmic deaths but not affect atherosclerosis. Peterson replicated the design of Anderson’s study in Washington State (58). Using coroner certification he was unable to replicate the findings, but if he switched the index of sudden death to whether or not the case was dead on arrival, hardness again seemed to protect against sudden death. However, as Neri pointed out, the findings were weakened by the fact that noncardiovascular diseases appeared to be similarly affected (53). Neri found Anderson’s pattern in several Canadian provinces, but not in others. Bierenbaum compared serum lipid values in London and Glasgow and in

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Omaha and Winston-Salem (5). In each case cholesterol and triglycerides were higher in the hard water area. A higher dietary fat intake in the hard water areas explained the difference, but the data agree with the above papers in suggesting that the water effect is not by way of an influence on lipids. Elwood was unable to find differences in blood clotting or fibrinolysis between hard and soft water towns (2 1). Stitt however, found significantly higher cholesterol in soft water towns than hard water towns among British male civil servants (76). More consistent results were seen in the comparisons of pulse rate and blood pressure, where most of the 6 soft water towns had higher levels than any of the 6 hard water towns. Thus, there are several possible mechanisms to explain the relationship of drinking water to cardiovascular disease. TRACE

METALS

The following metals with suspected cardiovascular effects are suggested by the water studies either because they are found in hard water and are negatively correlated with mortality, or because they can be found in excessive amounts in corrosive tap water. Cadmium in water has not been correlated to disease because data on its occurrence in drinking water is lacking. When detected in U.S. municipal and surface waters, its concentration is known to be low, averaging 8 or 9 pg/liter in U.S. cities (36,80). In U.S. surface water, detection is most frequent in the Northeast (20). Levels in water as high as the U.S. Drinking Water Standard, 10 pglliter, would be an appreciable source of daily intake because of high retention of absorbed cadmium (24). Such levels occur in soft tap water exposed to copper or galvanized pipes (72), and have been found in tap water in a number of Canadian communities (56). Cadmium in air was highly correlated to cardiovascular mortality in 28 U.S. cities studied by Carroll (8), but not significantly correlated in 77 cities studied by Hunt (32). Significant correlations between cardiovascular mortality and cadmium content of pasteurized milk supplies in U.S. cities was shown by Pinkerton to be secondary to population density (59). Schroeder produced hypertension in rats (and Thind in rabbits and dogs (81)) by long-term feeding of small doses of cadmium. He reported high renal cadmium in human hypertension deaths compared with accident deaths and high urinary cadmium in hypertensive patients compared with controls (69). Subsequent reports on renal cadmium are inconsistent (37,38,48,85), and reports on urinary cadmium do not show differences associated with blood pressure (43, 45,79). Hammer et al. showed higher blood pressure in workers exposed to high levels of cadmium dust, but there was no consistent difference between the groups with intermediate and low exposure (28). The subject has recently been reviewed by Thind (81) and Perry (57). Chromium in the U.S. is positively correlated with the hardness of raw water and in North America (but not in the U.K.) in tap water it is associated with hardness and high conductance. Schroeder makes a strong case for a beneficial cardiovascular effect of chromium (73). He reports that dietary chromium deficiency in rats produces elevated serum glucose and cholesterol levels

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and the deposition of aortic lipid plaques. His data show low levels in human tissues from the U.S. compared with other countries and low aortic chromium in arteriosclerotic deaths compared with accident deaths. He suggests that atherosclerosis in developed countries may be related to reduced chromium intake from the use of refined sugar and flour. Mertz reports the use of chromic salts in 150 microgram daily doses to correct abnormal glucose tolerance (46). Chromium would seem a good candidate for further study. Copper has a weak positive correlation with hardness in U.S. raw water. The tap water samples in North America with the highest concentrations of copper are soft (56) or are acid and have low conductivity (42). But in tap water samples in the U.K. copper levels were somewhat higher in hard water towns than soft water towns. In any case, soft water left standing in copper pipes can accumulate over 1 part per million (7 l), which may represent a sizeable fraction of daily ingestion. Despite the existence of homeostatic mechanisms for copper, human tissue concentrations of copper apparently are significantly influenced by drinking water, copper levels in liver being higher in soft water cities (71). In both raw and finished water copper correlated positively with cardiovascular mortality. Kanabrocki found elevated serum copper (33) and Morgan found elevated hepatic copper (49) in patients who had myocardial infarction. Hypertensive patients, whether or not on antihypertensive medication, were seen to have significantly higher 24-hour urinary copper (43). But elevated serum copper was reported to be transitory after myocardial infarction in a small series from India, with levels down to normal range within three weeks, and perhaps lower thereafter (34). Wester showed low levels in myocardium and all layers of the coronary artery in a small series of myocardial infarction patients compared with controls (87). A possible protective function of lithium and vanadium is suggested by the water studies. Both are found predominantly in hard water and are negatively correlated to cardiovascular mortality. These negative correlations were seen to persist and remain significant after controlling for calcium and magnesium (84). Their biological functions are obscure. Voors argues that the therapeutic use of lithium in manic states indicates that it may have a specific influence on catecholamines and the coronary prone behavior pattern (83). Vanadium is probably an essential trace element in human nutrition (47) and has been reported to inhibit hepatic cholesterol synthesis (16). Zinc is ubiquitous in human tissues and has an essential role in DNA and protein synthesis as well as in several enzyme systems. In the U.S. in untreated river water zinc is found at highest concentrations in hard water, but in tap water it may also be found in water with low conductance, particularly if acid, probably because of pipe corrosion, However, zinc tissue levels may be lower in persons from soft water areas, for example the North Carolina Coastal Plains (8.5), where zinc-poor leached soils predominate (75). Correlations between zinc in finished water and cardiovascular mortality are positive but weak, but adequate zinc levels in water are of hypothetical importance in view of the growing suspicion that American diets can supply insufficient amounts of zinc (23,47,62). Sandstead has expressed the view that the condition of impaired wound

32

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healing which is reported to be responsive to zinc supplements is due to zinc deficiency (62). Recent double-blind trials of zinc in treatment of chronic venous leg ulcers show improved epithelialization rates, a significant difference in patients with low serum zinc before treatment (26,27). If Henzel’s reports of improved collateralization in ischemic limbs with zinc therapy could be confirmed (31), this process would be seen to be related to atherosclerosis. Cadmium and zinc are antagonistic in biological systems (23). Exposure to cadmium seems to lead to proportional zinc and cadmium deposition in the kidney (60). Schroeder reports that zinc chelate reverses cadmium hypertension in rats (72). In hypertensive patients recent reports have not found altered levels of urinary zinc (43) or plasma zinc (82). In an autopsy survey Voors found high renal cadmium/zinc ratios in atherosclerotic cases compared with controls (85). In hypertensive cases, the renal cadmium/zinc ratio was also high, but not significant. CONCLUSIONS

The negative correlation of the hardness of public drinking water with cardiovascular mortality is consistent in large national studies. Whether or not this association is due to any constituent of drinking water is still unknown. The fact that the association seems stronger in U.S. and Canadian data when studied by region than when studied by smaller local areas indicates that there may be regional variables affecting mortality rates which are associated with, but not contained in, hard or soft water. The relative weakness of the association between mortality and water hardness in studies confined to a single state, province, or small country may be due to sampling variation or the curtailed range of values for water hardness, but may indicate that drinking water itself is not a potent factor. To control for regional factors, more work needs to be done within small areas which have a wide range of water hardness. More emphasis needs to be placed on estimation of effects and placing confidence limits around the estimates rather than on determining the degree of correlation. Maps of mortality rates and of the independent variable being considered are more useful than coefficients of correlation for showing the consistency of the relationship and generating hypotheses. Cities which change their water may provide “natural experiments” which should be studied. However, attribution of any subsequent changes in mortality rates specifically to changes in the water must be conditioned by changes in other factors that may occur in these cities. Regionally distributed variables which are consistently associated with water hardness are very likely not associated by chance. For example, in both Britain and North America soft city water is associated with rainfall. This needs further investigation, not only to see if effects of water persist after statistically controlling for rainfall, but to clarify the interrelationships of rain, drinking water, and soil chemistry to human nutrition. On the other hand, the fact that water hardness has a regional pattern invites nongeochemical hypotheses as well. Presumably a number of factors differentiate life along the American Coasts from that in the Western Plains. Cardiovascular mortality does not have a simple relationship to social class, and

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socioeconomic variables have not explained away the water associations, but the search should continue for nongeochemical determinants of regional mortality differences. The evidence that calcium and magnesium levels in tissues vary with the hardness of city water is suggestive. A review of the biochemistry of these ions is beyond the scope of this paper, but work should certainly be encouraged to define further the relationship of the levels of these ions in water to their levels in tissues and the effect of these tissue differences to cardiovascular disease. Despite the apparent importance of both essential and toxic trace metals, work has scarcely begun on their epidemiology in water. Data which has been used do not attempt to define typical levels for trace metals at each city. Most values reported are for spot samples, but trace metals in city water are known to have wide day-to-day and seasonal variation (1,4). With these limited data the trace metals most strongly implicated in the water studies are lithium and vanadium. Others discussed in this view are of interest because of their associations with hardness or corrosiveness of water and their probable physiological functions. Corrosiveness certainly affects exposure to trace metals at the tap, and its use as an index in epidemiological studies is advisable. Study of corrodable trace metals in representative tissues in cities with varying corrosiveness of water may be fruitful. Finally, more work is needed on tap water, though these are the most difficult studies to conduct. Knowledge is needed both on the actual trace metal content of tap water and on the relationships to risk factors and clinical disease. REFERENCES 1. Andelman, J. B., and Shapiro, M. A. Changes in trace element concentrations in water treatment and distribution systems, in “Trace Substances in Environmental Health VI” (D. D. Hemphill, Ed.), p. 87. University of Missouri Press, Columbia, 1972. 2. Anderson, T. W., LeRiche, W. H., and MacKay, J. S. Sudden death and ischemic heart disease. New Engl. J. Med. 280, 805-807 (1969). 3. Anderson, T. W., Hewitt, D., Neri, L. C., Schreiber, G., and Talbot, F. Water hardness and magnesium in heart muscle. Lancet 2, 1390-1391 (1973). 4. Barnett. P. R., Skougstad, M. W., and Miller, K. J. Chemical characterization of a public water supply. J. Amer. Waler Works Ass. 61, 61-67 (1969). 5. Bierenbaum, M. L., Fleischman, A. I., Dunn, J. P., Hayton, T., Pattison, D. C., and Watson, P. B. Serum parameters in hard and soft water communities. Amer. J. Pub/. He&h 63, 169-73 (1973). 6. Biiirck, G., Bostriim, H., and Widstrom, A. On the relationship between water hardness and death rate in cardiovascular diseases. Acta Med. Stand. 178, 239-252 (1965). 7. Blachly, P. H. Lithium content of drinking water and ischemic heart disease. New Engl. J. Med. 281, h82 (1969). 8. Carroll, R. E. The relationship of cadmium in the air to cardiovascular disease death rates. J. Amer. Med. Ass. 198, 267-269 (1966). 9. Comstock, G. W. Fatal arteriosclerotic heart disease, water hardness at home, and socioeconomic characteristics. Amer. ./. Epidemiol. 94, l-10 (1971). 10. Crawford, T., and Crawford, M. D. Prevalence and pathological changes of ischaemic heartdisease in a hard-water and in a soft-water area. Lance? 1, 229-232 (1967). 11. Crawford, M. D., Gardner, M. J., and Morris, J. N. Mortality and hardness of local watersupplies. Lancet 1, 827-83 1 (1968). 12. Crawford, M. D., and Crawford, T. Lead content of bones in a soft and a hard water area. Lancer 1, 699-701 (1969).

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37. Lener, J., and Bibr, B. Cadmium and hypertension. Lancet 1,970 (1971). 38. Lewis, G. P., Jusko, W. J., and Coughlin, L. L. Cadmium accumulation in man: Influence of smoking, occupation, alcoholic habit and disease. J. Chron. Dis. 25, 7 17-726 (1972). 39. Lindeman, R. D., and Assenzo, J. R. Correlations between water hardness and cardiovascular deaths in Oklahoma counties. Amer. J. Pub/. Healrh 54, 1071-1077 (1964). 40. Masironi, R. Cardiovascular mortality in relation to radioactivity and hardness of local water supplies in the USA. Bull. WHO 43, 687-697 (1970). 41. McCabe, L. J. The correlation of drinking water quality and vascular disease, Paper presented at the Conference on Cardiovascular Disease Epidemiology. Chicago, February 3, 1963. 42. McCabe, L. J. Metal levels found in distribution samples. Presented at the Seminar on Corrosion By Soft Water, American Water Works Association, Washington, D.C., June 21, 1970. 43. McKenzie, J. M., and Kay, D. L. Urinary excretion of cadmium, zinc and copper in normotensive and hypertensive women. N. 2. Med. J. 78, 68-70 (1973). 44. Medical Research Council. “Report and recommendations,” Conference on Trace Elements and Disease in Man, London, July 6, 1970. 45. Mertz, Von D. P., Koschnick, R., and Wilk, G. Renale Ausscheidungsbedingungen von Cadmium beim normotensiven und hypertensiven Menschen. Z. K/in. Chem. K/in. Biochrm. 10, 21-24 (1972). 46. Mertz, W. Chromium occurrence and function in biological systems. Physiol. Rev. 49, 165-239 (1969). 47. Mertz, W. Human requirements: Basic and optimal. Ann. N.Y. Acad. Sci. 199, 191-201 (1972). 48. Morgan, J. M. “Normal” lead and cadmium content of the human kidney. Arch. Environ. Health 24, 364-368 (1972). 49. Morgan, J. M. Tissue copper and lead content in ischemic heart disease. Arch. Environ. Health 25, 26-28 (1972). 50. Morris, J. N., Crawford, M. D., and Heady, J. A. Hardness of local water-supplies and mortality from cardiovascular disease in the county boroughs of England and Wales. Lancer 1, 860-862 (1961). 5 1. Morton, W. E. Hypertension and drinking water constituents in Colorado. Amer. J. Publ. Health 61, 1371-1378 (1971). 52. Mulcahy, R, The influence of water hardness and rainfall on cardiovascular and cerebrovascular mortality in Ireland. J. Irish Med: Ass. 59, 14-15 (1966). 53. Neri, L. C., Hewitt, D., and Mandel, J. S. Risk of sudden death in soft water areas. Amer. J. Epidemiol. 94, 101-104 (1971). 54. Neri, L.. C., Mandel, J. S., and Hewitt, D. Relation between mortality and water hardness in Canada. Lnncet 1, 931-934 (1972). 55. Neri, L.. C., Hewitt, D., and Schreiber, G. B. Can epidemiology elucidate the water story? Amer. J. Epidemiol. 99, 75-88 (1974). 56. Neri, L.. C., Hewitt, D., Schreiber, G. B., and Mandel, J. S. Is there a water factor: A case for magnesium. Presented at the Seventh International Water Quality Symposium, April 23-24, 1974, Washington, DC. 57. Perry, H. M. Minerals in cardiovascular disease. J. Amer. Diet. Ass. 62, 631-637 (1973). 58. Peterson, D. R., Thompson, D. J., and Nam, J. Water hardness, arteriosclerotic heart disease and sudden death. Amer. J. Epidemiol. 92, 90-93 (1970). 59. Pinkerton, C., Creason, J. P., Shy, C. M., Hammer, D. I., Buechley, R. W., and Murthy, G. K. Cadmium content of milk and cardiovascular disease mortality, in “Trace Substances in Environmental Health V” (D. D. Hemphill, Ed.), p. 285. University of Missouri Press, Columbia, 1971. 60. Piscator, M., and Lind, B. Cadmium, zinc, copper, and lead in human renal cortex. Arch. Environ. Health 24, 426-43 1 (1972). 61. Roberts, C. J., and Lloyd, S. Association between mortality from ischemic heart-disease and rainfall in South Wales and in the county boroughs of England and Wales. Lancer 1, 109 l-1093 (1972). 62. Sandstead, H. H. Zinc nutrition in the United States. Amer. J. Clin. Nutr. 26, 125 l-1260 (1973). 63. Sauer, H. I., Parke, D. W., and Neill, M. L. Associations between drinking water and death

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74. Schroeder, H. A., and Kraemer, L. A. Cardiovascular mortality, municipal water, and corrosion. Arch. Environ. Health 28, 303-3 11 (1974). 75. Shacklette, H. T. A U.S. Geological Survey study of elements in soils and other surflcial materials in the United States, in “Trace Substances in Environmental Health IV” (D. D. Hemphill, Ed.), p. 35. University of Missouri Press, Columbia, 1970. 76. Stitt, F. W., Crawford, M. D., Clayton, D. G., and Morris, J. N. Clinical and biochemical indicators of cardiovascular disease among men living in hard and soft water areas. Lancet 1, 122-126 (1973). 77. Stocks, P. Mortality from cancer and cardiovascular diseases in the county boroughs of England and Wales classified according to the sources and hardness of their water supplies, 1958-67. J. Hyg. (Land.) 71, 237-252 (1973). 78. Strong, J. P., Correa, P., and Solberg, L. A. Water hardness and atherosclerosis. Lab. Invest. 18,

160-162 (1968). 79. Szadkowski, Von D., Schaller, K.-H., and Lehnert, G. Renale Cadmiumausscheidung, Lebensalter und arterieller Blutdruck. Z. K/in. Biochem. 8, 551-552 (1969). 80. Taylor, F. B. Significance of trace elements in public finished water supplies. J. Amer. Water Works Ass. 55, 619-623 (1963). 8 1. Thind, G. S. Role of cadmium in human and experimental hypertension. ./. Air Pollution Control Ass. 22, 267-270 (1972). 82. Thind, G. S., and Fischer, G. M. Relationship of plasma zinc to human hypertension. C&r. Sci. Mol. Med. 46, 137-141 (1974). 83. Voors, A. W. Does lithium depletion cause atherosclerotic heart-disease? Lancet 2, 1337-1339 (1969). 84. Voors, A. W. Minerals in the municipal water and atherosclerotic heart death. Amer. J. Epi& miol. 93, 259-266 (197 1). 85. Voors, A. W., Shuman, M. S., and Gallagher, P. N. Zinc and cadmium autopsy ]eve]s diovascular disease in geographical context, in “Trace Subances in Environmental

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