Annals New York Academy of Sciences, 1978 , pp 203-219.
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
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).
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.
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.
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:  at the experimental level, where Schroeder's findings have been replicated and extended to other metals (54);  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  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).
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.
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).
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%).
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).
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)
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.
1.KOBAYASHI, J. 1957. On geographical relationship between the chemical nature of river water and death rate from apoplexy. Ber. Ohara Inst. Landwirtsch. Biol.. Okayama Univ. 11: 12-21.
2.CRAWFORD, M. D. 1972. Hardness of drinking-water and cardiovascular disease. Proc. Nutr. Soc. 31(3): 347-353.
3.MASIRONI, R. 1973. Water quality, trace elements, and cardiovascular disease. WHO Chronicle, 1973. 27: 534-538.
4.PUNSAR, S. 1973. Cardiovascular mortality and quality of drinking water. An evaluation of the literature from an epidemiological point of view. Work Environ. Health 10: 107-125.
5.NERI, L. C., D. HEWITT & G. B. SCHREIBER. 1974. Can Epidemiology elucidate the water story. Am. J. Epidemiol. 99: 75.
6.HARNISH, R. A. 1975. Water Hardness and Cardiovascular disease. Mimeographed article.
7. Müller, G. 1974. Problems of Epidemiological evaluation of Water Contents. Schriftenr. Ver. Wasser Boden Lufthyg. Berlin-Dahlem. Stuttgart, 1973. 40: 39-52.
8.NERI, L. C. & D. HEWITT. 1975. Review and implication of ongoing and projected research outside the European Communities, Hardness of Drinking Water and Public Health: Proceedings of the European Scientific Colloquim, Luxembourg. : 443-466. Pergamon Press. New York.
9.SHARRETT, A. R. & M. FEINLEIB. 1975. Water Constituents and Trace Elements in Relation to Cardiovascular Disease. Prev. Med. 4: 20-36.
10.CRAWFORD, M. D., M. J. GARDNER & J. N. MORRIS. 1968. Mortality and hardness of local water-supplies. Lancet i: 827-831.
11.LOWE, C. R., C. J. ROBERTS & S. LLOYD. 1971. Malformations of central nervous system and softness of local water supplies. Br. Med. J. 2: 357-361.
12.CRAWFORD, M. D., M. J. GARDNER & P. A. SEDGWICK. 1972. Infant mortality and hardness of local water supplies. Lancet i: 988-992.
13.ELWOOD, J. M. 1977. Anenchephalus and Drinking Water. Am. J. Epidemiol. 105: 460-467.
14.SPIERS, P. S., S. G. WRIGHT & D. G. SIEGEL. 1974. Infant Mortality and Water Hardness in the United States. Pediatrics 54(3): 317-9.
15.STOCKS, P. 1970. Incidence of Congenital Malformations in the Regions of England and Wales. Br. J. Prev. Soc. Med. 24: 67-77.
16.SAUER, H. I. 1974. Relationship between trace element content of the drinking water and chronic diseases, observed effects of trace metals in drinking water on human health. Presented at the 16th Water Quality Conference, University of Illinois, Urbana on February 12, 1974.
17.NERI, L. C., J. S. MANDEL & D. HEWITT. 1972. Relation between mortality and water hardness in Canada. Lancet i: 931-934.
18.ANDERSON, T. W., W. H. LERICHE & J. S. McKAY. 1969. Sudden death and ischemic heart disease. New Engl. J. Med. 280: 805-807.
19.NERI, L. C., D. HEWITT & J. S. MANDEL. 1971. Risk of sudden death in soft water areas. Am. J. Epidemiol 94: 101-104.
20.SCHROEDER, H. A. 1967. Cadmium, chromium, and cardiovascular disease. Circulation 35: 570-82.
21.SCHROEDER, H. A. & H. W. VINTON, JR. 1962. Hypertensioninduced in rats by small doses of cadmium. Am. J. Physiol. 202: 515-518.
22. SCHROEDER, H. A. 1965. Cadmium as a factor in hypertension. J. Chronic Dis.18: 647-656.
23. NERI, L. C., H. L. JOHANSEN & F. D. F. TALBOT. 1977. The chemical content of Canadian drinking water related to cardiovascular health. Department of Epidemiology, University of Ottawa and Health and Welfare, Canada.
24. SCHROEDER, H. A. 1966. Municipal drinking water and cardiovascular death rates. JAMA 1952: 81-85.
25. CRAWFORD, M. D. & T. CRAWFORD. 1969. Lead content of bones in a soft and hard water area. Lancet I: 699-701.
26. CRAWFORD, M. D. & D. G. CLAYTON. 1973. Lead in bones and drinking water in towns with hard and soft water. Br. Med. J. 2: 21-23.
27. JOOSSENS, J. V. 1973. Salt and Hypertension: Water Hardness and Cardiovascular Death Rate, Triangle (Engl Ed) 12(1): 9-16.
28. MORTON, W. E. 1971. Hypertension and drinking water constituents in Colorado. Am. J. Public Health 61: 1371-1378.
29. FOULGER, J. H. 1943. Medical control of industrial exposure to toxic chemicals. Ind. Med. 12: 214-225.
30. SYMANSKI, H. 1952. Schwere gesundheitsschadigungen dutch befufliche nitroglykoleinwirkung. Arch. Hyg. Bakteriol 136: 139-158.
31. FORSSMAN, S., N. MASRELIEZ, G. JOHANSSON, et al. 1958. Untersuchungen des gesundheitszustandes von nitroarbeitem bei drei schwedischen sprengstof. fabriken. Arch. Gewerkepathol. Gewerbehyg. 16: 157-177.
32. SAKADO, A. 1962. A clinical study on nitroglycol poisoning. Jpn. J. Ind. Health 4: 583. (English summary, article in Japanese).
33. EINERT, C., W. ADAMS, R. CROTHERS, et al. 1963. Exposure to mixtures of nitroglycerin and ethylene. glycol dinitrate. Am. Ind. Hyg. Assoc. J. 24: 435-447.
34. Report of Second Meeting of Investigators on Trace Elements in Relation to Cardiovascular Disease (WHO/IEAE Joint Research Programme). Vienna (IAEA) 19-23 February 1973, and Geneva (WHO) 2-6 April 1973. World Health Org. CVD/73.4.
35.STITT, F. W., M. D. CRAWFORD, D. G. CLAYTON & J. N. MORRIS. 1973. Clinical and biochemical indicators of cardiovascular disease among men living in hard and soft water areas. Lancet i: 122-126.
36.ELWOOD, P. C., D. BAINTON, F. MOORE, D. F. DAVIES, E. J. WAKLEY, M. LANGMAN & P. SWEETNAM. 1971. Cardiovascular Surveys in areas with different water supplies. Br. Med. J. 2: 362-363.
37.CRAWFORD, M. D. & J. N. MORRIS. 1967. Lead in Drinking Water. Lancet ii: 1087-1088.
38.CRAWFORD, T. & M. D. CRAWFORD. 1967. Prevalence and pathological changes of ischemic heart disease in a hard-water and in a soft-water area. Lancet i: 229-232.
39.BEEVERS, D. G., E. ERSKINE, M. ROBERTSON, A. D. BEATTIE, B. C. CAMPBELL, A.GOLDBERG & M. R. MOORE. 1976. Blood Lead and Hypertension. Lancet ii: 1-3.
40.LANGFORD, H. G., R. L. WATSON & B. H. DOUGLAS. 1968. Factors affecting blood pressure in population groups. Trans. Assoc. Am. Physicians 81: 135-146.
41.KEMPER, W. 1944. Treatment of Kidney Disease and Hypertensive Vascular Disease with Rice Diet. N. C. Med. J. 5: 125-133.
42.MENEELY, G. R. 1967. The Experimental Epidemiology of Sodium Chloride Toxicity in the Rat. In The Epidemiology of Hypertension. J. Stamber, R. Stamier, T. N. Pullman, Eds. : 240. Grune & Stratton. New York & London.
43.SHAPER, A. G., P. J. LEONARD, K. W. JONES & M. E. JONES. 1969. Environmental effects on the body build, blood pressure and blood chemistry of nomadic warriors serving in the army in Kenya. Afr. Med. J. 46: 282-286.
44. SAKAKI, N. 1964. The relation of salt intake to hypertension in the Japanese. Geriatrics 19: 735-744.
45. STEINBACH, M., M. CONSTANTINEANU & P. NARNAGEA. 1975. Relationship between the genetic and the ecologic factors in the determination of high blood pressure. Rev. Roum. Med. 13(4): 261-263.
46.FODOR, J. G., A. C. ABEOTT & I. E. RUSTED. 1973. An epidemiological study of hypertension in Newfoundland. Can. Med. Assoc. J. 108: 1365-13,68.
47. FODOR, I. G. & I. E. RUSTED. Salt and Hypertension. Paper presented at the American Heart Assoc. Meeting, February 1976, New Orleans.
48. SCHROEDER, H. A. 1960. Relation between mortality from cardiovascular disease and treated water supplies: variations in states and 163 largest municipalities of the United States. JAMA 172: 1902-1908.
49. LEWIS, M. 1974. Letter: Softened Water. JAMA 228(8): 978.
50. PERRY, H. M. 1973. Minerals in cardiovascular disease. J. Am. Dietetic Assoc. 62: 631-637.
51.PERRY, H. M., JR. & E. F. PERRY. 1974. Possible relationships between the physical environment and human hypertension: cadmium and hard water. Prev. Med. 3: 344-352.
52.PERRY, H. M., G. S. THIND & E. F. PERRY. 1976. The Biology of cadmium Med. Clin. North Am. 60(4): 759-69.
53.PERRY, H. M., JR., M. W. ERLANGER & E. F. PERRY. 1974. Prevention of cadmium-induced hypertension by selenium,.,zinc, and hard water. 8th Annual Conference on Trace Substances in Environmental Health, Columbia, Mo.
54.THIND, G. S. 1972. Role of cadmium in human and experimental hypertension. J.Air Pollut. Control Assoc. 22(No.4): 267-270.
55.LENER, J. B. 1971. Cadmium and hypertension. Lancet i: 970.
56.THIND, G. S. & O. M. FISCHER. 1974. Relationship of plasma zinc to human hypertension. Clin. Sci. Mol. Med. 46: 137-141.
57.VOORS, A W., M. S. SHUMAN & P. N. GALLAGHER. 1972. Zinc and cadmium; autopsy levels for cardiovascular disease in geographical context. 6th Annual Conference on Trace . Substances in Environmental Health.-Columbia, Mo.
58.BIERENBAUM, M. L., A. I. FLEISCHMAN, J. DUNN & J. ARNOLD. 1975. Possible toxic water factor in coronary heart disease. Lancet I: 1008-1010.
59.SHARRETT, A. R. & M. FEINLEIB. 1975. Possible toxic water factor in coronary heart disease. Lancet ii: 76.
60.CARROLL, R. E. 1966. The relationship of cadmium in the air to cardiovascular disease death rates. JAMA 198: 267-269.
61.TSUCHIYA, K. 1967. Proteinuria of workers exposed to cadmium fumes. Arch. Environ. Health 14: 876-880.
62.HAMMER, D. I., J. F. FINKLEA, J. P. CREASON, S. H. SANDIFER, J. E. KEIL, L. E. PRIESTER & J. F. STARA. 1971. Cadmium exposure and human health effects. In Trace Substances in Environmental Health V. D. D. Hemphill, Ed. : 269-283. University of Missouri Press. Columbia, Mo.
63. Blood Pressure of Adults by Race and Area, United States 1960-62. Vital and Health Statistics Series 11 No. 5. U.S. Dept. of Health Education and Welfare.
64. Hypertension and Hypertensive Heart Disease in Adults, United States 1960-62. Vital and Health Statistics Series 11, No. 13. U.S. Dept. of Health Education and Welfare.
65. Muss, D. L. 1962. Relation between water quality and deaths from cardiovascular disease. J. Am. Water Works Assoc. 54(11): 1371-1378.
66. STÖFFN, D. 1974. Environmental lead and the heart. J. Mol. Cell Cardiol. 6: 285-90.
67. MOORE, M. R., P. A. MEREDITH, A. GOLDBERG, K. E. CARR, P. G. TONER & T.D. V. LAWRIE. 1975. Cardiac effects of lead in drinking water of rats. Clin. Sci. Mol. Med. 49: 337-341.
68. NERI, L. C., D. HEWITT, G. B. SCHREIBER, T. W. ANDERSON, J. S. MANDEL & A. ZDROJEWSKY. 1975. Health aspects of hard and soft water. J. Am. Water Works Assoc. 67(8): 403-409.
69. SIX, K. M. & R. A. GOYER. 1973. Experimental enhancement of lead toxicity by low dietary calcium. J. Lab. Clin. Med. 76: 933-942.
70. HARTUNG, R. 1973. The biological effects of heavy metal pollutants in water. In Proceedings of a Conference on the Role of Metal Ions in Biological Systems, November 20-21, 1972 Argonne, Illinois. Plenum Press. New York.
71. SCHROEDER, H. A. 1965. The biological trace elements. J. Chronic Dis. 18: 217-228.
72. SCHROEDER, H. A. & L. A. KRAEMER. 1974. Cardiovascular mortality, municipal water and corrosion. Arch. Environ. Health 28: 303-311.
73. NERI, L. C. 1970. The relationship between water hardness and cardiovascular mortality (The Canadian Experience). Thesis, University of Toronto. Toronto, Ont., Canada.
74. SCHROEDER, H. A. 1966. Municipal drinking water and cardiovascular death rates. JAMA 195(2): 81-85.
75. SAUER, H. I., D. W. PARKE & M. L. NEILL. 1970. Associations between drinking water and death rates. In Trace Substances in Environmental Health IV. D.D. Hemphill, Ed. : 318. University of Missouri Press. Columbia, Mo.
76. CRAWFORD, M. D., M. J. GARDNER & J. N. MORRIS. 1968. Mortality and hardness of local water-supplies. Lancet i: 827-831.
77. LEWIS, G. P., W. J. JUSKO, L. L. COUGHLIN & S. HARTZ. 1972. Cadmium accumulation in man: influence of smoking occupation, alcoholic habit and disease. J. Chronic Dis. 25: 717-726.
78. MASIRONI, R. 1970. Cardiovascular mortality in relation to radioactivity and hardness of local water supplies in the U.S.A. Bull. WHO 43: 687-697.
79. MASIRONI, R., S. R. KOIRTYOHANN, J. O. PIERCE & R. G. SCHAMSCHULA. 1976. Calcium content of river water, trace element concentrations in toenails, and blood pressure in village populations in New Guinea. Sci. Total Environ. 6: 41-53.
80.SEELIG, M. S. & H. A. HEGGTVEIT. 1974. Magnesium interrelationships in Ischemic Heart Disease: A review. Am. J. Clin. Nutr. 27: 59-79.
81. SZELENYI, I. 1973. Magnesium and its significance in Cardiovascular and Gastro-Intestinal disorders. World Rev. Nutr. Diet. 17: 189-224.
82.MARIER, J. R. 1976. Some current thoughts on magnesium with particular emphasis on the water-factor and cardiac disorders. Mimeographed monograph.
83.ISERI, L. T., J. FREED & A. R. BURES. 1975. Magnesium deficiency and cardiac disorders. Am. J. Med. 58: 837-846.
84.BAJUSZ, E. 1965. In Nutritional Aspects of Cardiovascular Disease. : 129-131. Crosby Lockwood. London.
85.HEROUX, O., D. W. PETER & H. A. HEGGTVEIT. 1973. Potentiation of cold induced cardiac lesions in white rats resulting from chronic dietary magnesium insufficiency. In First International Symposium on Magnesium Deficit in Human Pathology. J. Durlach, Ed.: 337, 341. Springer-Verlag.
86.SHUSTVOL, N. S. & A. A. BERESTOV. 1973. The effects of potassium chloride and magnesium chloride in electrocardiographic and morphologic changes in ischemic necrosis of the myocardium. Patol. Fiziol. Eksp. Ter. 17; 19-23.
87.MALVIEL-SHAPIRO, B. 1958. Further observations on parenteral magnesium sulphate therapy in coronary heart disease. S. Afr. Med. J. 32: 1211-1214.
88.PARSONS, R. S., T. L. BUTLER & E. P. SELLARS. 1960. Coronary artery disease. Med. Proc. 6: 479-481.
89.THURNHERR, A. & J. KOCH. 1962. Versuch einer Kausaltherapie der Arteriosclerose mit einer Kombination von Hyaluronidase und Magnesium. Schweiz. Med. Wochenschr. 92: 949-956.
90.SEELIG, M. S. 1964. The requirements of magnesium by the normal adult. Am.J Clin. Nutr. 14: 242-290.
91.MARIER, J. R. 1968. The importance of dietary magnesium with particular reference to humans. Vitalst. Zivilisationskr. 13: 144-149.
92.SCHROEDER, H. A. 1971. Losses of vitamins and trace metals resulting from processing and preservation of food. Am. J. Clin. Nutr. 24: 562-573.
93.BROWN, J. O. & 18 others. 1970. Nutritional and epidemiologic features related to heart disease. World Rev. Nutr. Diet. 12: 1-43.
94.ANDERSON, T. W., L. C. NERI, C. B. SCHREIBER, F. D. F. TALBOT & A. ZDROJEWSKI. 1975. Ischemic heart disease, water hardness and myocardial magnesium. Can. Med. Assoc: J. 113L 188-203.
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