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Annals New York Academy of Sciences, 1978 , pp 203-219.


WATER HARDNESS AND CARDIOVASCULAR MORTALITY

Luciano C. Neri

Department of Epidemiology and Community Medicine
University of Ottawa
Ottawa, Ontario, Canada

Helen L. Johansen

Bureau of Epidemiology
Laboratory Center for Disease Control, Health and Welfare
Ottawa, Ontario, Canada


Ever since Kobayashi (1) in 1957, noted a parallel between the geographic distribution of the acidity of water in Japanese rivers and the distribution of what was then one of the major causes of mortality in Japan, apoplexy, an increasing number of investigators all over the world have attempted to elucidate and confirm a geographic relationship between quality of drinking water and mortality, particularly from cardiovascular causes. The now voluminous literature in this field has been subject to several comprehensive reviews (2-9).

As remarkable as the geographic diversity of these studies is the great diversity of the hypotheses that have been favored by different investigators, both as regards the identity of the water-borne factor to which they impute a good or bad influence, and as regards the nature of the disease or pathologic process induced. Recently (5), we expressed regret at the lack of any emerging consensus among those who have contributed to the literature over the last 15 years, and at the failure of most studies to yield evidence capable of discriminating among any of 64 major classes of explanatory hypotheses that need to be considered. Kobayashi did not refer to any category other than apoplexy, but ecological studies, from Schroeder on, have usually tried several cause-specific death rates as dependent variables.

Thus, even though most investigators continue to refer to the hazard of residing in soft-water areas as if it related specifically to cardiovascular disease, support for this view has been progressively weakened by the admission of a bronchitis effect (10) and by the suggestion that there is also an infant mortality effect in England, Wales (11, 12) and possibly Canada, (13) though not in the United States (14). Stocks (15) showed that whatever may be the environmental or genetic factor responsible for regional mortality patterns of cardiovascular disease in the United Kingdom, it would appear to have a pronounced effect also on the incidence of congenital malformation of the central nervous system, and to a lesser extent this would apply to nephritis and carcinoma of the stomach. In the United States, Sauer (16) found as strong a negative correlation of hardness with malignant neoplasm as with cardiovascular deaths. Canadian statistics (17) show that more than half the excess mortality in soft-water areas is certified to noncardiovascular causes of death.

Uncertainty as to the real effect of the water factor has lead some investigators to discriminate between various components of cardiovascular mortality in the hope of identifying a more specific association. For example, in Ontario, coronary deaths were subdivided into coroner- and noncoroner-certified deaths (18). It was reported that water effects related specifically to the former, which were taken to represent sudden deaths. The interpretation offered was that a mechanism of increased susceptibility to lethal arrhythmias was operating in soft-water areas. Although the use of coroner certification as a proxy for suddenness of death has been challenged (19), the proposed mechanism is still of interest, especially if it can be extended into the domain of deaths certified to non-cardiovascular disease. Likewise, the suggestion, originally made by Schroeder (20), whereby the mode of action of soft water was through an increased risk of hypertension, is promising to the extent that it can be applied across the board, not merely within the small fraction of deaths in which hypertension is certified as an underlying or contributing cause.

Schroeder's theory of cadmium-induced hypertension as the missing link in the water story was based on four considerations:
1. Cadmium induction of hypertension in rats (21);
2. The finding of higher cadmium concentration in human subjects who died of hypertension (22);
3. The theoretical availability of cadmium from pipes through corrosive action of soft water (20);
(I use the word "theoretical" because Schroeder did not have as we now have in Canada any widely-based survey data on cadmium in relation to softness.)
4. The relationship between soft water and cardiovascular mortality (21), and thence to hypertension.

This is no doubt a very attractive theory that has support from laboratory, experimental and clinical evidence. However, epidemiologic support has been slow in forthcoming. An alternative hypothesis, still attributing increased mortality to increased frequency of hypertension in soft-water areas, has been proposed by Crawford. Initially, she postulated a protective effect of calcium against lead absorption in soft-water areas (25, 26), and later a more complex mechanism involving the ratio of magnesium plus calcium to sodium (2). A similar theory was proposed by Joossens (27), who nominated sodium as the noxious element, with calcium exerting the protective action. Nitrates in drinking water, hitherto considered related only to methemoglobinemia, have also been implicated in an increased frequency of hypertension and its complications.

I will discuss these four postulated water-borne hypertensive agents in turn.

Morton (TABLE 1) reported that the Republican River counties in east central Colorado, which have the hardest water, have the highest level of nitrates, the highest hypertensive death rates and the highest prevalence of hypertension among draft registrants (28). He speculated that since organic nitrates have been associated with increased risk of diastolic hypertension in explosives workers (29-33), regions with more intensive agriculture and greater use of nitrogen fertilizers may experience an increase in hypertension risk. However, Sauer pointed out (34) that cardiovascular death rates are generally low in Colorado, and that if one sums the four cardiovascular causes of death offered by Morton, the mortality on the Republican River counties becomes the lowest.


TABLE 1
NO3 2- CONCENTRATION VERSUS AGE-ADJUSTED MORTALITY RATES
(1959-61) AND PREVALENCE OF HYPERTENSION IN SELECTIVE SERVICE
REGISTRANTS (1957-64)*
-----------------------------------------------------------------
                            Mortality/100,000
                                    Four
                     Hyper-     Cardiovas-  Prevalence/
River Basin  N032- **   tension   cular Causes   1000
----------------------------------------------------------------
Republican R. 13.7         57         340       16.0
Platte R.      3.0         24         371        8.5
Arkansas R.    1.9         26         358        8.4
Rio Grande R.  1.0         31         343        4.4
San Juan R.    0.6         18         357        7.8
Colorado R.    0.4         25         365        5.8
-----------------------------------------------------------------

 *  Data from: W. E. Morton, 1971. (28)
** Population weighted mean values in ppm for countries grouped
by river basin.

The strongest epidemiologic support implicating the mechanism of hypertension in the water story comes from Stitt, in the United Kingdom. He reported (35) on a sample of 244 civil servants living in six hard-water localities and as many living in six localities with soft water. FIGURE 1 summarizes the results of these observations. It can be seen that not only are both systolic and diastolic blood pressures higher in the soft-water areas but that, particularly for diastolic, and quite noticeably for systolic blood pressure, there is a divergence of mean pressure with increasing age. The localities under study were chosen to represent a contrast between high mortality in areas having soft water and low mortality in areas having hard water (FIGURE 2). This leaves us with some uncertainty as to the generality of an association between water quality and blood pressure. Larger cohorts presently being studied in the United Kingdom may enable the investigators to confirm their findings. It seems, however, to be in conflict with the observations of Elwood in Wales (36), where similar-sized random samples from the population of hard- and soft-water areas were also examined, and no significant differences in mean blood pressures were found (see TABLE 2).

Hardness Figure 1

Hardness Figure 2

Hardness Table 2

Stitt did not propose a specific mechanism to explain his findings; however, the British group was then advocating the theory of a protective effect from calcium against plumbosolvency in soft waters (37). The origin of this theory comes from a large autopsy study conducted by Crawford and Crawford (38) in Glasgow and in London. They found that in Glasgow (very soft water) there was a significant excess of lead in the bones of both accidental and myocardial deaths (26). Additionally, they found:
1. Accidental deaths in Glasgow had higher prevalence of healed infarcts, more atheroma and lumen stenosis;
2. Ischemic heart disease sudden deaths in Glasgow had less extensive atheroma and lumen stenosis than in London.
They suggested that the findings in both cities indicated an increased susceptibility of the myocardium in soft-water areas.

Further support for the possible involvement of lead comes from Beevers et al (39). They examined the blood and tap-water lead levels of 135 pairs of age-sex-matcbed hypertensive and normotensive subjects. TABLE 3 shows their findings: significant excess of persons with high blood lead levels among hypertensives; and, among normotensives, a significant positive correlation between blood lead and tap-water lead concentrations.

Hardness Table 3

A protective effect of calcium has also been related to the water story by Langford and Watson (40) who proposed that a low calcium intake may accentuate the hypertensive effect of sodium. The relationship between sodium and high blood pressure has been confirmed by clinical and experimental studies for the past 30 years. Clinical observations made as early as 1944 by Kemper (41) indicate that a low sodium diet was helping hypertensive patients. Experimentally, Meneely (42) demonstrated that rats could be made hypertensive by feeding them large amounts of sodium chloride. Joossens (27) in 1973 showed that there are populations in which blood pressure does not increase with age and that these are primitive populations that use no salt in their diets. Shaper (43) observed rapid rises in blood pressure in young Samburis, used to eating without salt, when they were given 15 grams of salt a day during military service. A converse phenomenon was reported by Sakaki (44) in Japan who noted that by reducing salt intake in children taking school meals, their blood pressure declined progressively.

Epidemiologic confirmation of the possible influence of salt in drinking waters come from Steinbach et al (45). When the village of Juilovka was found to have one of the highest prevalence levels of hypertension in the world [45%], they searched for an environmental factor and found that the water contained a concentration of sodium 26 times greater than in Bucharest and in the nearby village in the Gurghiu Valley. Fodor (46, 47) observed that the rate of hypertension among Newfoundland fishing villagers was much higher than in mainland Canada and that the consumption of salt, particularly salt-preserved food, was also very high. He was unable to demonstrate a difference in salt consumption between hyper-and normotensive subjects, but he drew attention to the fact that essential elements such as magnesium, calcium, potassium, and zinc were very much below minimum requirements; the possibility of a protective effect from anions was again raised. The increased tendency in industrialized countries to soften water supplies, mostly in order to prevent scaling or poor detergent action, illustrates the possible public health importance of sodium. Schroeder (48) indicated the extent to which this municipal softening bid progressed when he found that 2.5 times as many urban municipalities (16.5%) softened their water in 1952 as compared to 1932. In defense of sodium, it has been pointed out that water softening only increases the amount of sodium ions that will be available in the form of carbonate or bicarbonate (49) rather than chloride, which is the chemical form implicated in hypertension. Certainly evidence such as that offered by Joossens in FIGURE 3 is highly suggestive of an effect of sodium chloride. In Canada, we have attempted to study the effect of domestic water softeners. Two very large case-control studies have been completed and will be reported shortly. These studies involve a total of about 20,000 households, and they are both prospective and retrospective in design.

Hardness Figure 3

For none of the above-mentioned elements, however, is the evidence of a hypertensive effect from water as cogent as it is in the case of cadmium. This evidence has been recently reviewed by Perry, (50-52) and particular interest attached to his observation that the hypertensive effect of cadmium in rats was inhibited when hard water was used as the vehicle for administration of the metal (53). Since publication of the initial hypothesis by Schroeder and collaborators, Support has been forthcoming: [1] at the experimental level, where Schroeder's findings have been replicated and extended to other metals (54); [2] at the clinical (autopsy level) where evidence of increased cadmium or cadmium to zinc ratio in kidneys of hypertensives has been confirmed in most studies (50, 54, 55) (some of which tie low zinc concentrations more to renal damage than to essential hypertension) (56), and [3] in part, at least, at the ecological level, studying the association between cadmium in drinking waters and prevalence of hypertension (57).

Bierenbaum (58) studied an apparent reversal of the usual water story in Kansas City, where higher mortality from cardiovascular disease was noted in the Kansas (hard water) part as compared to the Missouri (soft water) part. Both Kansas and Missouri components of the city derive their municipal water supply from the same source. However, in Missouri the water is softened to less than one-half the original value. TABLE 4 summarizes the findings, which have been held to suggest that the differences in systolic and diastolic pressure found in their case-control series might be explained by differences in cadmium concentration, both in the drinking water and in the sera of individuals involved. These data, however, have certain puzzling features, some of which have been commented on, by Sharrett and Feinleib (59).

Hardness Table 4

Inconsistent with the cadmium theory is the fact that cadmium workers have never been shown to suffer excess hypertension (60-62).

We have not been able to obtain data on prevalence of hypertension in smaller geographic units of the United States than the three used by the National Health Survey (63, 64). FIGURE 4 shows how these relate to the map of state average water hardness prepared by Muss (65) on the basis of weighted municipal values. The findings are far from clear: one could expect, on the basis of hardness, that the lowest prevalence ofhypertension would occur in the west and the highest in the northeast. TABLE 5 indicates that south has the lowest and northeast the highest mean blood pressures, yet these regions are indistinguishable in terms of their weigted average hardness. The next column shows the actual prevalence of definite hypertension and its deviation from an expectation based on age and sex composition of the white population of the areas involved. Here the west has the largest deficit as predicted. However, as great a difference is found between south and northeast, and this is not fully explainable in terms of water hardness.

Hardness Figure 4


TABLE 5

WATER HARDNESS, PREVALENCE OF HYPERTENSION, AND MEAN SYSTOLIC
BLOOD PRESSURE FOR WHITE ADULTS, U.S. NATIONAL HEALTH SURVEY,
1960-62
-----------------------------------------------------------------

                                           Rate of Definite
                                         Hypertension
                                                Difference
    Weighted Mean  Mean Systolic                  from
Region     Hardness*  Blood Pressure    Actual      Expected
---------------------------------------------------------------
North East     78          132.6          16.8         +2.60
South          76          127.6          12.8          -.04
West          147          130.5          12.2         -2.40
----------------------------------------------------------------

* Calculated from data of H.A.Schroeder, 1960. (48)

What does all this add up to?

From an epidemiologic point of view we are mainly interested to see whether any of the appealing mechanisms proposed can be considered the explanation of the water story, rather than speculating whether the agents proposed are capable of exerting a hypertensive effect at the clinical level. In this context, I would like to propose to you some criteria for judging their plausibility.

1. The first essential requisite for an agent to be considered compatible with the water story as we know it, is that its concentration in water supplies must follow the geographic distribution of water hardness.

2. Its postulated effect, whether in terms of prevalence or mortality, has to be consistent with the geographic variation in mortality, including mortality attributed to cardiovascular disease.

3. Its concentration in drinking waters must be sufficient to exert the postulated effect.

It follows from the third criterion that the intake from water should be critical in relation to the adequacy or deficiency of intake from other sources. In judging this adequacy or deficiency, it must be borne in mind that the chemical state in which some elements may be found in water, could make it more or less important than the simple arithmetic of food intake and water intake suggests. It is not clear that any of the substances so far discussed meet all these criteria. Nitrates have not been implicated in epidemiologic data from anywhere outside of Colorado. Against lead militates the fact that the reports implicating its association have been limited to England and that its cardiotoxicity and/or hypertensive effect, at usual levels of intake, have not been well demonstrated either in animals or in humans (66-67). Its concentration has been found to vary little between hard and soft waters (68), but its supposed interrelation with calcium may make this unimportant (69-71). Except perhaps in the Bulgarian case, sodium intake from water, even from softened waters, is too little as compared to other sources (72). In Canada, the higher sodium concentrations are found in the prairie provinces where mortality is lowest, and in fact, sodium correlates negatively with mortality (73). The same observation has been made by Schroeder (74) and by Sauer (75) in the United States where the substance having the strongest correlation with mortality was indeed sodium, but the correlations were negative.

Cadmium is detectable in only a small percentage of municipal waters (14% of those sampled in Canada), and its concentration in these source waters does not correlate with hardness. The same is true in the United Kingdom (76). At the point of use, cadmium may as Schroeder speculated, and as Canadian data weakly confirm, be more abundant in very soft water (8). Even so, cadmium intake from drinking waters does not seem substantial, particularly if we consider the amount that can be absorbed in other ways, such as smoking (71).

Hence, if cadmium is to be cast for a role in the water story, it will probably have to be in terms of postulated interaction with some other element that is more abundant in hard than in soft waters. (It is not clear whether zinc meets this description.) Epidemiologically the effects on health determined by a magnesium:cadmium or a calcium:cadmium ratio would be indistinguishable from a situation in which concentrations of the bulk elements alone determined the geographic variation in risk. Certainly hardness as such, or calcium or magnesium alone, can be shown, in various bodies of data, to be related in a striking way to cardiovascular disease in general and to hypertension in particular.

For example Masironi reported a study comparing the mortality of residents in four United States river basins, two with hard and two with soft water, found the death rates from hypertensive heart disease to be 17% to 70% (see TABLE 6) higher in the soft-water basin (78). Also from Masironi, we have a report relating the mean systolic pressure in New Guinea villages along the Wogupmeri River to calcium concentration (see FIGURE 5). As calcium in the river water (which is drunk directly by the villagers) declines from 8 to 3 ppm, the mean pressure rises from about 97 to 110 mmHg (79).

Hardness Figure 5


TABLE 6
DEATH RATES FROM HYPERTENSIVE HEART DISEASE(HHD)IN FOUR RIVER
BASINS, TWO WITH SOFT WATER AND TWO WITH HARD WATER *
-----------------------------------------------------------------

                            Water Hardness        Death Rates
River Basin                                    (per 100,000)
-----------------------------------------------------------------

 Ohio River                      soft                 39.7
 Columbia River                  soft                 33.3
 Missouri River                  hard                 28.3
 Colorado River                  hard                 23.3
 ----------------------------------------------------------------
 * Data from: R. Masironi, 1970.(78)


The relationship between water hardness and mortality in Canada is summarized in TABLE 7 in terms of the decrement of death rate corresponding to an increment of hardness from 0 to 350 ppm (roughly the difference between some parts of Newfoundland or British Columbia and Saskatchewan/Alberta). As has already been stressed, more than half of this mortality "effect" is expressed in noncardiovascular categories (-91.9/-157.5 = 58%).

Hardness Table 7

For the interest of this audience, I will draw attention to the fact that the largest proportionate decrease (-23%) occurs in the category with the closest affinity to hypertension. However, rather than pursuing the hypothesis of a hypertensive effect as the underlying mechanism of the water factor, in Canada we are systematically examining the idea of an agent, present in hard-water areas, protective against premature death, perhaps especially against sudden deaths. Magnesium appears to be a more likely agent of such a protective effect than calcium or any of the 15 elements whose concentration we have surveyed in waters from the kitchen tap of 526 Canadian localities (68). The hypothesis is also in accord with the known behavior of magnesium, as reviewed in recent publication (80-83). Of interest in this context is the experimental evidence indicating the adequacy of supplementary magnesium as a protection against cardiotoxic substances (84) and against stress such as cold (85). This effect has been confirmed by rat experiments in Russia (86) where the yield, the extent and the rate of involution of cardiac necrosis have been measured. Support may also be found in human studies (87-89).

Hardness Table 8

TABLE 8 indicates that magnesium intake from hard waters may be substantial. The average North American diet is of doubtful adequacy in this respect (90-92) as exemplified in the findings of Brown et al. concerning the Boston brothers of men, who remained in Ireland (93). Thus the 50 mg or more which may be received from water by residents in areas where water is hard may become critical especially in circumstances in which such requirements are raised by a stressful situation, such as an episode of arrhythmia.

Supporting evidence also comes from our recently reported autopsy study (94) in which concentration of elements in the myocardium (and in the diaphragm and pectoralis as control muscles), was studied in residents of hard and soft water areas in Ontario who died either of myocardial infarction or accidents. Of the seven elements studied, magnesium was the only one to show a pattern of differences completely consistent with the role of "factor X" in the water story, by being:

1. More abundant in hard than in soft water areas as well as unaffected by the distribution system (TABLE 9).

2. More abundant in the myocardium of hard water residents than of soft water residents (TABLE 10).

3. More abundant in the myocardium of healthy subjects than of those with fatal heart disease.

4. Lastly its concentration in the kitchen tap waters surveyed yields the strongest association with mortality from all causes both in Ontario and in Canada (TABLE 11).


TABLE 9
RELATIONSHIP BETWEEN MINERAL CONTENT OF PRIMARY AND TAP WATERS
*----------------------------------------------------------------

                   Mean Concentration     Correlation between
                       (ppm)              Measurement on
            Primary            Tap      Primary and on
           Water            Water       Tap Water
----------------------------------------------------------------

 Magnesium        10.62            10.15         0.951
 Calcium          33.73            34.20         0.739
 Cadmium           0.0005           0.0004       0.054
 Zinc              0.18             0.32         0.184
----------------------------------------------------------------

 After L. C. Neri et at., 1975.(23)


Hardness Table 10

Hardness Table 11

ACKNOWLEDGMENTS

We are very grateful to our colleague Prof. D. Hewitt, University of Toronto, for his many useful suggestions and for reviewing the manuscript and to Dr. H. M. Perry, Jr., Washington University and Dr. J. Marier of the N.R.C. for suggesting the addition of the section on magnesium.

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