Drinking water and cardiovascular disease

PERGAMON

Food and Chemical

“g$gy

40 (2002) 13 I l-1325

Toxicology

www.elsevier.com

locateifoodchemtox

Review

Drinking water and cardiovascular M-P. Sauvant”.

Accepted

disease

D. Pepin

I2 January

2002

Abstract A link between cardiovascular disease (CVD) mortality and the hardness of drinking water (DW) is suggested by about 30 epidemiological studies performed worldwide in the general population since 1957. This review examines the main ecological studies, case-control studies and cohort studies, published between 1960 and 2000. Attention is paid to the problem of interpretation of this typical result of environmental epidemiology. Some studies focused on the role played by inorganic elements known as DW contaminants (mainly. As, Pb) and above all on the role of the magnesium content of DW and its cardioprotective effects. To date. it would be impossible to understand this environmental findings without large intervention studies performed in well-controlled public health programs. \c 2002 Elsevier Science Ltd. All rights reserved. K~~,l,o~ls;Drinking

w-ater; Cardiovascular

disease; Environmental

epidemiology:

1. Introduction Cardiovascular disease (CVD) is among the main causes of mortality and morbidity in the industrialised countries (Thorn, 1993; Kuulasmaa et al., 2000). For many years, research focused on the identification of the main risk factors of CVD, such as hypertensive disease (HD), dyslipidemia, smoking, alcohol abuse, dietary habits and physical inactivity (Hornstra et al., 1998; Wilson, 1999). Although these classical factors contribute significantly to the development of atherosclerotic lesions, they did not entirely explain the worldwide variability of CVD mortality. In order to better understand the determinants of CVD, particular attention has recently be given to environmental factors, such as weather, air pollution and especially the chemical quality of drinking water (DW) (Gyllerup et al., 1991a,b; Taylor, 1996; Lonn and Yusuf, 1999; Wilson, 1999). Abhw~~iations: AMI, acute myocardial infarction; CHD. coronary heart disease; CVD. cardiovascular disease; DW, drinking water: ECG, electrocardiogram; ICD, international classification of diseases; IHD, ischaemic heart disease; HT, hypertensive disease; OR. odds ratio; RR, relative risk; SMR, standardised mortality ratio. * Corresponding author. Tel.: + 33-4-73-17-80-56; fax: +33-4-7328-84-55. E-mailuddrrs.~; m-pierre.sauvant@u-clermontl .fr (M-P. Sauvant). 027x-691 5/02,‘$ - see front matter PII: SO27X-6915(02)0008l-9

Risk assessment:

Magnesium;

Inorganic

elements

The relationship between the cardiovascular mortality and the mineral content of DW was first described by Kobayashi (1957) in Japan and by Schroeder (1960) in the United States. Since that time, about 30 studies have been performed worldwide and most described an inverse relationship between the mortality rates from CVD and the hardness-or the magnesium content-of the drinking water. Furthermore, the interpretation of this association must be performed with some caution, and with special attention to the design of the studies and to the methodological aspects, which often did not allow a cause-and-effect relationship to be demonstrated. First, the relationship between CVD and the DW has been evaluated by population-based ecological studies (Table 1). Studies performed with a cohort design (Table 2) or with a case-control design (Table 3) are less numerous. Although some biases and confounding factors are frequently present in these studies, the main ecological studies, cohort studies and case-control studies have been considered and critically examined for this review. They have been selected from the Medline database (1960-2000), by using the keyword search terms “drinking water” and “cardiovascular disease”. Although these studies differ in type, their period, the measurements and the parameters researched in DW, most of them have highlighted a significant negative

(I: 2002 Elsevier Science Ltd. All rights reserved

Death rates for hypertensive heart diseases (ICD codes:440- 442). arteriosclerotic heart diseases (420) and cerebrovascular diseases (330 334)

(1966)

88 Cities of the USA 1960 White men, 45564 years

and eqxci;tlly and (ICD codes. obtained from registration

Schroeder

Death rates from CVD coronary heart diseases cerebrovascular diseases 330-334 and 410468). certified causes of death

Death rates. according to the ICD codes 330-334.400~4 16.430~ 422. 430447 and 450~ 468

X3 County boroughs of England and Wales 1948, I954 Men 4 women. 3574 years old

33 Swedish towns with more than 25,000 inhabitants 1951,196O Men + women. 25-14 years old

(1061)

Biorck et al. (1965)

Morrts et al.

mortality

compounds

of drmking

Hardness Conductance Calcium Magnesium Sodium Potassium Silicon Sulfates Bicarbonates Dissolved solid\ Chloride Traces elements (Ba. Cu. L.I. Mn. Sr. V. b-radioactrvtty

Hardness

Calcium

Temporary hardness (carbonated) Permanent hardness (non-carbonated) Calcium

PH Conductance

Silica Calcium Magnesium Bicarbonate Sulfate Fluoride Dissolved solids Hardness

Parameters of drinking water associated with CVD mortality or morbidity

and or \ome other chemical

Age-adjusted death rates from CHD (ICD codes: 330-334. 400-468 and 420)

(1960)

of cardiovascular

disease (CVD) and the hardnca\

163 Largest municipalities of USA 19491’1951 White men. 45-64 years old

cardiovascular

Schroeder

between Measures

a rclationshtp

Area, period and population

studies invc\tigating

Authors

Table I Ecologrcal

Race sex Age

Potential cont;~undcrx considered

water (DW)

et al. (1974)

( 1974)

Pocock ct al. (1980)

Elwood

et al.

Mortality rates and standardised mortality ratio (SMR) from CVD (specially, from stroke and ischaemtc heart disease)

253 Towns in England. Wales and Scotland 1969/1973 Men + women. 35-74 years old

Age- and sex-adjusted death rates for six causes of CVD mortality : hypertension (HT, as main cause of death), heart disease and HT, stroke, stroke and HT, myocardial infarction, ischaemic heart disease

Mortality rates from three CVD: cerebrovascular lesions (ICD,330-334), arteriosclerosis and degenerative heart disease (ICD, 420-423), other diseases of the circulatory system(ICD, 410-468)

Death rates from CVD, specially coronary heart diseases (data of the National Register)

Mortality rates from ischaemic heart diseases

ages

communities, of different Burbank and

mortaht)

to the

of cardiovascular

Death rates, according ICD codes 420 422

Measures

48 Local-authority areas in South Wales 1973 Men + women, 35-64 years old

Three Los Angeles supplied by water hardness (Reseda, Downey) 1969/1970 Men + women. all

Residents of the 5 16 Canadian municipalities 1950/1952 and 1960/1962 Men, more than 35 years old

(I 972)

Neri et al.

Alwright

61 County boroughs of England and Wales, with a population of 80,000 or over at the 1961 census 1958/1964 Men + women, 45-74 years old

et al. (1968)

Crawford

._~~

Three Swedish towns (Maim& Gbteberg, Stockholm) 1951!‘1960 Men + women, 45-64 years. old

_~~

Area, period and population

and Westet

I (c~w~tinurcl)

Bostrom (1967)

Authors

Table

Total hardness Carbonate hardness Calcium Nitrate Silica Conductivity

Calcium Magnesium Manganese Lead

Hardness

Hardness Calcium Total solids

Calcium .Trace elements (As. <‘r. (‘s. Cu, Fe. Rb, Sb. Zn) for female mortality ([CD-9, 422) and for male mortality (ICD-9, 420 and 422)

Parameters of drinking water abaociated with CVD mortality or morbidity

Air pollution Socm-economtc iI/ 15) Blood groups

~‘limate t,rctors

Race Income Socio-economic status Stability in the area

Sex, age and residence place Local indices of socioeconomic status, size of community, median mcome occupation, climatic ‘itres’i. temperature

Social index. demographic and geographic indices for each town (latitude, temperature. air pollution)

Potential confounders considered

~~~

(1993)

et al. (1992)

Nerbrand

Hall and jungncr

et al.

( 199 I )

et al. (1991)

(1991)

Rylandcr

Gyllerup

Flaten and Bolviken

~~~

AlIthOE

Hardness Calcium Carbonates Sulphates Fluoride

Hardness

Mortality rates obtained from the Official Vital Statistics of Sweden for lschaemic Heart Diseases (ICD, codes 410~414) and for Stroke (ICD. codes 432438)

Study of the CVD morhiciit~ (from ischaemic heart disease (ICD. codes:41 1414) and hypertensive disease (410). defined by the number of hospital discharge diagnoses per 100.000 inhabitants/year for acute myocardial infarction (AMI)

76 Communities in seven counties in Sweden I969/ 1983 Men I women. 45 -74 years old

Population from seven municipalities. counting for 15%of the populatron in Sweden 1984 1985 Men f women. all ages

Hardness Calcium Magnesium

Hardness

Mortality index after standardisation for age groups. for the Ischaemic Heart Diseases (ICD codes 41W14) and Cerebrovascular Diseases (ICD codes 430-438)

Mortality data obtained from the Cause of Death Register and indirectly standardised against the country (SMR) for the ICD, code 410

259 Administrative units in Sweden 1975’1984 Men. 40-64 years old

/iw /HI1

ott[l~

Parameters of drinking water associated with CVD mortality or morbidity

27 Swedish municipalities. counting 809.655 inhabitants 1969’1978 Men + women. all age<

Mortality data. provided by the Central Bureau of Statistics of Norway and age-adjusted, sex-specific municipal mortality rates from CVD (ICD8. codes 390 458)

97 (of the 454) Norwegian municipalities. characterised by a stability of the quality of drinking water. on the period of study and countmg 2.246,389 inhabitants 1974/1983 Men + women, all ages

Area. period and population

Procedures of hai-dening or softening the drinking vvatei- over the period of study Smokmg habtts Physical activity Stress Food intake

Potential confoundci-\ considered

Sauvant

et al.

( 1999)

and Pepin (2000)

Maheswaran

Yang et al. (1996)

of cardiova\culai-

mortality

hospitalization services]

Determination of the expected numbers of deaths from Acute Myocardial infarction (ICD, codes 4 IO) and ischaemic heart disease (ICD, codes 4 I O&414). standardised for age, sex and socio-economic indicator and comparison to the observed deaths, by log linear Poisson regression model

Determination of the SMR of the Diseases of the CV System (ICD codes 3904.58) according to the death data obtained from the National Service of Medical Statistics of France

52 Cantons of the French departement Puy de Dome. corresponding to 307.358 women and 29 1,135 men 198881992 Men + women. all ages

Death data obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health Determination of the Standardised Mortality Ratio (SMR) of the lschaemic Heart Diseases (ICD, codes 410-414)

Health

obtainedfrom

and Public

[Data

Registration of all deaths from sudden cardiac deaths and coronary artery diseases, i.e. 32 cases (23 men and nine women), aged 66.3 &9 years (44;93)

Measures

13794 Enumeration districts. corresponding to a resident population of I, 124,623 men and 1,372.036 women. aged 45 years or more 1990/l 992

227 Municipalities of Taiwan 1981 90 Men + women, all ages

Survey of the population of the Media Valle del Serchio (Tuscany, Italy) (35,000 inhabitants), supplied with a very soft drinking water, from January 1992 to January 19%

Bernardi

et al. (1995)

Arca, period and population

Authors

Hardness

Hardness 9.6% excess of coronary deaths. in areas with soft water (< 75 mg CaCO& compared with areas with hardwater ( z 150 mg CaC03/l)

Hardness Incidence of sudden cardiac deaths in this area = 9/ 10,000 vs 6,/ 10.000 in Italy and 5i10,OOO in Europe

Parameters of drinking water associated with CVD mortality or morbidity

Population

density

Socioeconomic deprivation (described by the Carstairs score)

Age Sex

Urbanisation index, taking into accounl I9 variables such as population density. age composition, mobility. economic activity, family income, education level, environmental and health service-related facilities

Potential confounders considered

relationship between CVD mortality and DW hardness: the cardioprotective role of hard water is specially noteworthy for water showing a high Mg:Ca ratio. The methodological features and the main results of these studies are briefly presented in the Tables I 3. Thus. the purpose of this review is to summarise this knowledge and to highlight the contribution of the main components of DW in the development of CVD.

2. Drinking history

water and cardiovascular

disease: an old

2.1. T/w ecological studies The methodological features and the main results of the ecological studies are summarised in Table 1. Most of these first studies have been performed in the period 1960-1980, with an ecological design, using mortality data from national registers and geographical areas defined from administrative basis as units of analysis. These ecological studies (Schroeder, 1966, 1960; Morris et al., 1961; Biorck et al., 1965; Bostrom and Wester. 1967; Crawford et al., 1968; Neri et al., 1972; Allwright et al., 1974; Elwood et al.. 1974; Pocock et al.. 1980) have been performed at various geographical levels, as well as states, counties, major cities of a state or a county, as populations or communities selected geographically. There are some important shortfalls in these studies. in that they are performed with average values of DW parameters (total hardness, calcium and/or magnesium contents), which could induce considerable non-differential classification. Moreover, the chronology of the events, such as the “exposure to the DW risk factor” and the “CVD mortality”, is not always respected. Often, the mineral content of DW is determined at the time of the study (i.e. after the time of the CVD events): thus, the results could not strictly represent the quality of water that the persons have actually ingested before their death. confounding factors have often been Moreover. neglected, although they can greatly modify the magnitude of the association. For instance, Morris et al. (1961) observed in a study conducted in South Wales. that the DW hardness effect has been considerably reduced after the adjustment for climatic and socioeconomic factors. In Canada, Neri et al. (1972) observed that the more significant relationship between CVD and DW was observed with the premature deaths. rather with the mortality rates of elderly persons. In a 48 local authority areas in south Wales, Elwood et al. ( 1974) showed that the CVD mortality can be explained by Ca. Mn, Mg and Pb; calcium explained about 18% of the variance in CVD mortality and Mn, Mg, Pb improved the regression to about 22%. tinlike most

studies. .Allwrlghl et al. ( 19’74) did not tind ;I ~~~n~~stcn~ association betLveen death from heart disease and hartinesa of DW. in \\ ork including three communitlez mached for age. sex, race, income, socio-economic \tatuy and stability in the area of Los Angeles. These ccological studies allowed some specific description. but not a causal relationship, to bc stated. Moreover. in most ecological studies. the association between DW hardness or Mg content and cardiovascular mortality is described a\ well for the coronaropathies and ischnemic heart diseases. as for the cerebrovascular diseases. Rylander et al. ( 199 1) obser\,ed a significant relationship only for coronary disease. and not for stroke ‘These results can bc easily explained by the fact that most studies have tested the association of DW paramctcrs with the mortality from all causes of deficient), 01‘the circulatory system or inversely with only one specific cause of death; this approach is strictly linked to the collecting process of mortality data. based on the death certificate. Moreover, ischaemic heart disease and cerebrovascular disease can result from similar physiopathological abnormalities. linked to the role of magnesium deficiency in the atherosclerotic process (Saris et al.. 2000). In view of these elements. it is impossible to establish a possible difference of mortality between coronary disease and ccrebrovascular disease in relation to DW parameters. Furthermore. the critical analysis of ecological studies is difficult. because information on their methodological design is not always well recorded. Sometimes the geographical units are too large and too heterogeneous to be regarded as valid entities: thus the association is so slight that it could have occurred by chance. Concurrently. the contribution of each DW compound to the CVD has been also widely reviewed (Punsar. 1971; Neri ct al.. 1974: Huel et al.. 197X: Comstock. 1979, 1980). and two theories have been proposed to explain the relationship between the CVD mortality and DW. The first stated on the protective role played by calcium and especially magnesium content of DW, on the cardiovascular system (Karppanen, 1984. 19X6: Marie,, 1986): the second is r&ted to the cardiovascular toxic efTccts of inorganic elements leached from the pipes into soft acidic water (Mansironi, 1969). In most geographical studies. the relationship between CVD mortality and DW hardness was tested by simple regression analysis. without taking into consideration the potential confounding factors. Pocock et al. (1980) described a negative non-linear relationship between CVD mortality and DW hardness. After adjustment for other risk factors of CVD mortality in soft-water areas was ( (25 mg CaC03/1), the risk of CVD mortality estimated to be IO-15% higher than that in hard-water areas ( > 170 mg CaCOr:l). These relevant results, based on rigorous methodology. allowed an excess of

White and black people (men and women) from Kansas City (Missouri. USA), supplied with soft water (-cases / II = 260 subjects) and from Kansas City (Kansas. USA). supplied with hardwater ( 2 controls II = 760 subjects) 1969 197 1

et al. (1975)

Hierenbaum

County boroughs of England and Wales (n - 72) Study of the variatton of CVD mortality between the two periods 1958-1964 and 1948-1954, according to the change of water hardness in the included towns Men + women, 45-74 years old, living in six towns with the softer water (-cases) and in sic towns with the harder water ( controls)

Population of a very soft-water area (Glasgow) and of a very hard-water area (London) Cases = 86 deaths from unexpectedly IHD in Glasgow Controls = 90 deaths from accident in London Date not mentioned Men, 30-69 years old

the relationship

Middle-aged malt CIVIIservants, aged 40-65 yeara old USA 1968 1970 Cases = 244 patients with CVD hvmg in a hard-water area Controls = 245 patients with CVD living in a soft-water area

et al. (1971)

( !‘K)

status investigating

Area. population. case-control definition and period of study

based on exposure

Stitt et al. (1973)

Crawford

ClJU ford ‘liid C‘r‘,\\ i\,i-d

Authors

Table 2 Cohort studies and studies

rates from CVD

01 cardiac lesions tn two series of medicolegal

and/or

CVD defined by clinical examination. detailed medical history and biological parameters

C‘VD defined by biologlcal and clinical exammation (specially, ECG, vital capacity and forced expiratory. blood pressure. cholestcrolemia) and bq questionnaire in a country-wide study of leisure activity and health

Death

Comparison comparable necropsies

of cardiovascular

CVD and the hardness

Measures mortality

between

compounds

of DW

Higher CVD mortality observed m the hard-water area. and associated with arterial hypertension Description of a difference of serum levels in both groups for sodium, potassium. lithium. calcium. magnesium. chrome. copper. fine and cadmium

Higher slgniticant values of blood pressure, cholcsterolemia. heart-rate in the group living in the
Decreased mortality from CVD (-10%) in the men and women populations living in the towns with the harder water and increased mortality from CVD in the towns with the softer water

C’oncluston suggesting that the mineral content of the arteries is related to the mineral content of the drinking water

Parameters of drinking watrl associated with CVD mortality or morbidity

some other chemical parameters

in

Groups matched for age, \cx. length of residence C‘omparable for marital
Length of residence the area Occupation

Matching

2 !;:

CVD risk in soft-water areas to be quantili4 Sllorc over, Pocock et al. (19X2) observed that an inct-ease 111 hardness of I .09 mmol C’aC.‘Oi~l gives an estimated 3.9”/(, reduction of CVD mortality. They concluded that the CVD mortality excess in ;I soft-water area t ‘- 0.05 mmoll). compared with a hard-water area ( > 3.0 mmol CaCO,Il) may be of the order of IO’%. Pococh et al. (1982) discussed this methodological problem and they analysed the best strategy that may be provided to compare disease-specific mortality rates. For these ,1nc1 the authors, the multivariate statistical techniques spatial patterns are the most relevant techniques. l.ater. such an approach has been adopted by Morin et al. (1985) (multivariate ANCOVA model, with a step-down procedure). by Gyllerup et al. ( 1991 b) (weighted regression, with proportional weights to the population \ize of the Swedish municipalities and to the inverse of distances between towns). by Nerbrand et al. (1992) (logistic regression and multivariate regression analysis with a stepwise procedure) and by Yang et al. (1996) (weighted regression with the reciprocal values of the estimated variance of the standardised mortality ratios (SMRs), that is Wi =exp”obs). However, Pocock ct al. (1982) concluded that unweighted regression is rnore appropriate than fully weighted regression when the mortality rates or SMRs are based on substantial numbers of deaths. Recently, Maheswaran ct al. ( 1999) used log linear Poisson regression models, with adjustment for potential confounders (age, sex. socio-economic deprivation) at the level of enumeration district. to test the association between magnesium concentrations in DW supplies and mortality from acute rnyocardial infarction (AMI) or ischaemic heart disease (IHD). in a very large population in north-west England. Although these authors detected a marginally significant association of both Mg and Ca concentrations and IHD mortality, these did not persist after adjustment for geographical trends; thus. they concluded that Mg is not the key DW factor in relation to mortality from heart disease. These results must be examined with caution because this work was based on a small-area geographical study, tn which the range of Mg concentrations are limited; in such a study. the ecological fallacy cannot be ruled out. In the last decade, significant progress in cpidemiological methodology (Morgenstern and Thomas. 1993: Prentice and Thomas. 1993; Rothman, 1993) has again stimulated the research on the relationship between CVD and DW. with ecological studies performed on very large populations liv,ing in specific geographical areas (Flaten and Bolviken, I99 1; Gyllerup et al.. 199 1b; Rylander et al.. 1991: Nerbrand et al.. 1992; Hall and Jungner, 1993: Bernardi et al., 1995; Yang et al., 1996; Sauvant and Pepin. 2000). Moreover, an ecological study performed in Sweden has allowed a significant association between CVD morbidity and DW hardness to be stated (Hall and Jungner. 1991).

studies investigating

CVD and the hardness

Death rates for AMI. calculated by using the mortality register data

Death from AM1 registered by the National Central Bureau of Statistics

17 municipalities of southern Sweden Cases = 854 men died from AMI, between the ages 50 and 69 years during the period 1982-1989 Controls = 989 men of the same age, died from cancer in the same area over the same period

I6 municipalities in southern Sweden Cases = 378 women died from AMI between the ages of 50 and 69 years Controls = 1368 women died from cancer and with similar age

RubenowitL et al. (1999)

Death registered by the National Office of Statistics of Taiwan

Prevalence of hypertension (HT) and death rates from CVD (ICD, codes 390-459)

CVD defined by clinical examination and by tilledin questionnaire

Rubcnoui~~ et .d. (1996)

60 localities of Spain Group I (srudyqf HTA and mugne.vium): 1245 cases and 4160 controls Group 2 (study of HTA md iodine): 938 cases and 2964 controls

South-eastern region of Fmland Cases = acute myocardial infarction (AMI) (n = 50) vs hospital controls matched (n = 50) Men, 3g-64 years old

some other chemical

MeaPureq of cardiovascular

and/or

252 municipalities of Taiwan Cases = 17, I33 subjects who died from cerebrovascular diseases (ICD, codes 430438) Controls = 17.133 subjects who died from other causes (excluded other diseases of the circulatory system (ICD, codes 401429 and 440.458) 19X9-1993 Men + women, SO-69 years old

et al. (1990)

between

Area, population. case-control definition and period of study

a relationship

Yang (1998)

Gimeno-Ortiz

~____~ ~~~ ~~ Luoma et al. (19X3)

Authors

Table 3 Case-control mortality

compounds

Definition of an inverse relationship between the mortality rate and the levrlc of Mg and Ca in DW If Mg> IO mg:l tvs ~2.5 mg Me/l): OR-O.70 (IC9s”,,,-10.50: 0.99], If Ca > 70 mg:l (vs x 28 mg Gail): OR = 0.66 (IC,,j., ~ [0.47; 0 941)

Magnesium: OR = 0.65 (I&,,,, = [0.50: 0.841)

Definition of a significant and dose-effect protection by magnesium intake from drinking water on the risk of cerebra vascular diseases: If Mg concentration ranked between 7.4 and 13.4 mg’l: OR = 0.75 (IC& = [0.65; 0.851) If Mg concentration over 13.5 mg/l: OR = 0.60 (Icss%:, = [OS? 0.701)

Significant relationship between prevalence of HT and DW, especially with: low hardness: OR = 2.24 (K&Y/. = [ I .97; 2.551). low magnesium level: OR = 3.61 (IC9C”,”= [3.17$0X]). high iodine level: OR = I .25 (IC& = [l.OE; 1.451).

Parameters of drinking water associated with CVD mortality or morbidity ~._______ Relative risk for the assotxttion between AMI and: Magnesium: RR ~4.4 Fluoride: RR = 3.0

of DW parameters

Groups pair-matched by sex, year of birth. and year of death

Pupulallon palr-matched for
Matching

g %. 2 4

a

a

3

3. Cohort studies and the studies based on exposure status

studies. the main l'ea~urcs rat As for the ecological methodology and results of the cohort studies and ot the studies based on exposure status are presented in Table 2. First, some significant relationship between CVD mortality or morbidity and the hardness of DW have been shown by a few studies based on exposure status in England and Wales (Crawford and Crawford. 1967; Crawford et al.. 1971). Finland (Schwartz et al., 1977) and the USA (Stitt et al.. 1973; Bierenbaum et al.. 1975). Although the registration of confounding factors is better performed in these studies. these geographical mortality studies also remained difficult to interpret. because generally factors that can act on CVD mortality (i.e. dietary habits, smoking) were not always analysed and the amount of ingested DW was not detailed. This last point can induce significant non-differential misclassification. Moreover, the spatial pattern was generally not used in the statistical analysis and the contiguity of geographic units is neglected. From these studies it is impossible to exclude the possibility that lifestyle factors. diet or socio-economic status or other unidentified factors would explain observed CVD mortality. Furthermore, the comparison of the results of these studies is difficult, because they did not use the same classification for “soft” and “hard” water; also, there were considerable variations in the cut-off levels used for the definition of DW hardness. However, these results have greatly influenced the strategy of investigation used in later studies.

4. Case-control

studies

The methodology and the summarized results of the case-control studies are shown in Table 3. These studies, based on the outcome status (Luoma et al., 1983; Gimeno-Ortiz et al., 1990: Yang, 1998; Rubenowitz et al., 1996, 1999, 2000) are not numerous, but they observed that the lower CVD mortality or morbidity rates are associated with areas with hard water and the higher mortality rates with areas with soft water. Some significant and dose-dependent protection by magnesium intake from DW has been observed on the risk of cerebrovascular disease in a very large population in Taiwan (Yang. 1998). A similarly graded relationship was described in Sweden, and also with mortality data from AMI (Rubenowitz et al.. 1999) and morbidity from subjects surviving of AMI (Rubenowitz et al., 2000). This last study is of great interest. because it addresses the issue of dietary sources of Ca and Mg, which might act as confounding factors. This methodological feature allows the strength of the association between DW parameters and cardiovascular mortality to be studied more precisely.

Moreover, the relative risk, in most studies estimating the relationship between CVD mortality and the Mg content in DW, clustered around 1.6 (ranging from 1.4 to 7.8) and the attributable risk ranged from 33 to 87% (Marx and Neutra, 1997). These results agreed with those of Nerbrand’s et al. (1992) who estimated by multivariate analysis that the water factor accounted for 41% of the variation in the mortality from IHD and for 14% of the variation in the mortality from stroke over the 76 communities studied in Sweden. In etiological epidemiology. a causal association is only recognised if several criteria are observed. The first one is consistency. This has been observed for DW and CVD; the relationship has been independently described in different studies performed in different areas, at different times and with different populations. However, the specificity (i.e. a given exposure induces a specific kind of disease) is not evident, relating to the fact that CVD is a multifactorial disease. The strength of the association, measured by the values of the relative risk (RR) or the odds ratio (OR), is also an important criterion. In the published studies (Table 3). when the calculation of these ratios was performed, the values obtained were moderate or weak. but statistically significant. The biological plausibility is also used in the assessment of causality. The most relevant theories lie in the expected beneficial effect of the principal constituents of DW hardness (i.e. calcium and especially, magnesium), for which a insufficient uptake can partly be explained by the consumption of a soft water and/or the protective effect of other trace elements present in hard water (i.e. selenium, lithium, silicium, zinc, vanadium) (Eisenberg. 1992; Rylander, 1996; Marx and Neutra. 1997). Inversely. the cardiovascular toxicological effects of inorganic DW pollutants leached from the water supply system are less mentioned (Houtman, 1996). All these points are in favour of the causal hypothesis.

5. Role of drinking water in the cardiovascular outline of physiopathological theories 5. I. l@ects of’mclgnesium di.reax2.r

tkficiency

disease:

in cardiovascular

Magnesium deficiency accelerates the development of atherosclerosis and the induction of thrombocyte aggregation, and consequently it is described as a risk factor for AMI, and for cerebrovascular disease (Altura and Altura, 199.5; Saris et al., 2000). Magnesium is known as a protective agent against soft tissue calcification (especially, for myocytes) and its role in acute AM1 has been well documented (Eisenberg, 1992; Durlach and Bara, 2000). As long ago as 1973, Chipperfield and Chipperfield (1973) showed that heart muscle from subjects who died

suddenly from coronary thrombosis or myocardial degeneration contained significantly smaller concentrations of magnesium than heart muscle from subjects who died from other causes. It is suggested that these results may be related to the high death rate from CVD in soft-water areas. The role of DW magnesium was then mentioned by Karppanen and co-workers (1978, 1984) following a study performed in Finland among middle-aged men. This point has been confirmed by Marier and Neri (1985), who described a significant correlation between ischaemic heart diseases and the dietary Ca:Mg ratio. In 1989, a geographical variation in the incidence of AMI-associated myocyte calcification has been made by Bloom and Peric-Golia (1989), from autopsy reports of subjects living in Salt Lake City, USA (i.e. an area with a low AM1 death rate and a high level of Mg in DW) and in Washington (i.e. an area with a high AM1 death rate and a low level of Mg in DW). Different ecological studies reported significant correlation coefficients between the rates of CVD mortality and the concentration of the main constituents of DW hardness. namely magnesium and calcium (Table 4). Nevertheless. the strength of this association must be interpreted cautiously. because the design of these studies did not allow a spurious relationship and a true (causal) association to be characterised. In the casecontrol studies. a dose-effect relationship has been observed between the amount of DW magnesium and the mortality ratio (Table 3). Moreover. Rylander et al. (1991) found that changes in low magnesium levels in DW induced significant differences in the incidence of CVD mortality in Sweden. It is true that the contribution of magnesium in water to the total intake is weak, compared to the amount ingested in food. However, the speciation of Mg could explain its high bioavailability from water, rather from food (Durlach et al., 1985; Theophanides et al., 1990; Marx and Neutra, 1997; Durlach and Bara, 2000). Because of these results, the Mg supplementation of DW has been suggested in order to prevent CVD (Eisenberg, 1992; Hall and Jungner. 1993). Furthermore, controlled clinical studies are still required to understand the role of Mg brought by the DW in human cardiovascular diseases and to draw definitive conclusions.

6. Toxicological drinking water

effects of inorganic

contaminants

of

For many years, the relationship between the CVD mortality and the exposure to environmental trace elements has been mentioned, but it has been studied less than those with bulk DW elements. As early as 1960, Schroeder suggested that there was something beneficial to the outcome of CVD in hard water. and/or there was

C‘orrelatlon

coefficients

Reference5

Schroeder

a significant

relationship

between mortality

from CVD and the hardness

Significant (PcO.05) correlation coefficients(r) determined following chemical parameters of drinking Natcr

of DW

between the CVD mortality

Hardness

C‘dlclLlm

-0.29

~-0.27

-0.30

-0.231

-0.3%

Magnesium

(1960)

Morris et al. (1961)

Schroeder

showmg

( 1966)

and the

Other parameters Silica: -0. I XX HIcarbonates: ~-0 31 Sulphatrb: -0.‘2 Fluoride: 0.207 Dissolved solids- -0.22 C‘onducti\It\: 0 207

-0.43 to -0.54 (according to sex- and age-groups) -0.411

S1lrca: --(I.?40 Bicarbonatea:

0.337 Sulfatcs~-0 2.54 Chloride: -0 2S I Sodium: -0.2611 Potassium: -0 457 Dissolved ~hda: -0.302 C‘trnducti\ It)_ 0 434

Crawford

et al. (1968)

Neri et al. (I 972) Pocock et al. (1980)

Rylander

et al. (1991)

Hall and Jungner Yang et al. (1996)

(1991)

-0.30 to -0.70 (according to sex- and age-groups) -0.40 -0.67

-0.367 to -0.602 (according to sex- and age-groups) -0.57 (men) -0.65 (women) -0.20

some adverse factor in soft water. In 1966, Schroeder described significant negative correlation between death rates from arteriosclerotic heart diseases, in white males aged 45-64 years, and some minor constituents of DW (i.e. vanadium, barium, copper, strontium, lithium and manganese). The meaning of such associations was, and is still, unclear. Similar investigations have been performed by Bostrom and Wester (1967), who concluded that no significant amounts of DW trace elements (arsenic, chromium, copper, iron, antimony and zinc) derived from water pipes could contribute to the mortality from IHD and cerebrovascular diseases. After Mansironi’s report (1969). special attention has been given to inorganic elements (such as arsenic. cobalt, copper, chromium, manganese, zinc, selenium. cadmium and lead), which could be described as aquatic pollutants. In fact, it is now well known that soft and acidic water can attack the pipes through which it runs, and thus the DW can be contaminated by these inorganic elements, leached out from the pipes. Recently, the roles of some inorganic trace elements in cardiovascular diseases have been reviewed by Houtman (1996) and by Ramos et al. (1996). The cardiovascular effects associated to each element have been documented, but the dose-response relationship

-0.71

Not signifiant

-0.67

Not significant

PO.323 to -0.515

-0.143

Sihca: Aj.58 NItrates: -0.6X ConductiLity: --0.63

to -0.618

observed between the CVD and the long-term exposure to such inorganic elements remains to be elucidated. Most of the recent studies focused mainly on the effects of arsenic (Engel and Smith, 1994; Chen et al.. 1996; Abernathy et al., 1999; Lewis et al., 1999; Tchounwou et al., 1999; Viraraghavan et al., 1999; Hertz-Picciotto et al., 2000; Ryan et al., 2000), and lead (Pirkkle et al., 1985; Pocock et al., 1988; Staessen et al.. 1994; Schwartz, 1995; Ryan et al.. 2000), which have been involved by experimental investigations and by epidemiological studies to the hypertensive disease and to the development of the arterial plaques of atheroma in IHD and cerebrovascular diseases.

7. Conclusion

and requirements

In the past, epidemiological studies have provided important help to identify the main risk factors of the CVD, which have a multifactorial aetiology. Recently, Hornstra et al. (1998) highlighted that only about 50% of the incidence of CVD can be explained by the major risk factors, namely dyslipidemia, hypertensive disease, tobacco, obesity, lack of exercise. In this context, great attention is now given to nutritional and environmental

factors. Moreover, the epidemiology of chemical contaminants of DW is concurrently maturing, with the toxicological evaluation of the DW pollutants (Houtman, 1996; Calderon, 2000; Van Leeuwen, 2000). The negative association worldwide, noted between CVD mortality and DW hardness, is a typical finding of environmental epidemiology. This relationship has been mainly investigated by ecological studies, rather than by case-control or cohort studies. This fact can be explained by the easier feasibility of ecological studies, which are based on aggregated data, generally collected for the national death registration and for the official survey of water quality. Furthermore, these studies allow a specific situation to be described. but they do not entitle a causal relationship to be stated and the specific role of DW in CVD to be quantified. Moreover, in such studies the main problem is to determine whether the correlations found between CVD mortality and DW hardness are likely to represent cause and effect, or whether they merely reflect other factors with which both water and mortality are associated. To date, the relationship between DW and CVD mortality is defined as an indirect relationship and its causality is still not but there are many potential arguments in proven, favour. The studies highlighting a relationship between CVD mortality and DW are too numerous and too often repeated to only be considered as the result of a methodological artefact. However, the main mechanistic explanation of this relationship is based on the effect of magnesium deficiency on cardiac function. Further research is needed to identify which bulk and/or trace elements could be implicated in the pathogenesis of CVD (especially, hypertensive disease, coronary heart disease or cerebrovascular disease). To date, this relationship has not been judged sufficiently clear-cut to justify any preventive action, such as the adjustment of the hardness of the DW supplied to the populations with CVD risk. Future research must be performed in this way to explain the water factor. Furthermore, it is difficult to individualise the DW factor among many patterns which are specifically linked to the studied populations and to the geographical areas. Only intervention studies. integrating all the cardiovascular risk factors, could help to identify the attributable risk of DW in the multifactorial CVD.

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I 9.