Mutation Research, 239 (1990) 163-179

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Elsevier MUTREV 07289

INTERNATIONAL COMMISSION FOR PROTECTION AGAINST ENVIRONMENTAL MUTAGENS AND CARCINOGENS

ICPEMC Working Paper 7 / 1 / 2 S h a r e d risk factors for c a n c e r a n d atherosclerosis - a r e v i e w of the e p i d e m i o l o g i c a l e v i d e n c e Eva Stottrup Hansen Institute of Community Health, University of Odense (Denmark)

(Received 17 May 1990)

Keywords: Arsenic; Correlation; Dioxin; Hereditable diseases; Ionizing radiation; Occupational mortality; Polycyclic aromatic

hydrocarbons; Somatic mutation; Smoking; Vinyl chloride monomer

Summary This paper reviews the epidemiological literature of relevance for the hypothesis that somatic mutation is involved in the formation of the atherosclerotic plaque. Assuming that somatic mutations are involved in atherogenesis, one would expect at least some of the risk factors for cancer and for atherosclerosis to be identical. Therefore, the review covers the correlated occurrence of cancer and atherosclerotic disease. Special interest is given to populations at high risk of cancer, including subpopulations with certain genetic diseases, and populations exposed to certain carcinogenic environmental agents including ionizing radiation, vinyl chloride monomer (VCM), arsenic, tobacco, and various industrial combustion effluents containing polycyclic aromatic hydrocarbons (PAHs). Exposure to combustion effluents from burning of tobacco or fuel is associated with an increased risk of cancer and atherosclerotic disease. Combustion effluents constitute a complex mixture of potentially hazardous agents, however, and the observed correlation of cancer and atherosclerosis among exposed persons cannot be unambiguously interpreted as evidence of a common etiology of the two groups of diseases. For ionizing radiation, arsenic, and VCM there is suggestive evidence that these agents possess an atherogenic effect beside their well-known carcinogenic properties. Both arsenic and VCM seem to have a specific affinity to the vascular bed causing various lesions including angiosarcomas and atherosclerotic plaques. Regarding ionizing radiation, the atherogenic effects seem to be localized to heavily irradiated fields. Beside the carcinogenic and atherogenic effects, exposure to arsenic, VCM, and ionizing radiation brings about an increase in the incidence of mutations and chromosomal aberrations. A theory involving somatic mutation in the pathogenesis of the atherosclerotic plaque could be consistent with the observed biological effects of ionizing radiation,

Correspondence: Dr. J.D. Jansen, Medical Biological Laboratory TNO, P.O. Box 45, 2280 AA Rijswijk (The Netherlands). ICPEMC is affiliated with the International Association of Environmental Mutagen Societies (IAEMS).and the Institut de la Vie. 0165-1110/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

164 arsenic, and VCM. The scant data from families with certain inherited diseases may also be consistent with an involvement of the genome in the pathogenesis of atherosclerosis. In conclusion, there is strong epidemiological evidence that several factors associated with an increased risk of cancer are also associated with an increased risk of atherosclerosis.

Introduction

F r o m the results of epidemiological and experimental studies it has been inferred that a number of environmental agents play an etiologic role in the development of malignant neoplasms. Most, if not all carcinomas seem to be of monoclonal origin, indicating that the crucial steps in the malignant transformation involve the genome of a single cell. Accordingly, the prevailing theory for carcinogenesis is the somatic mutation theory. As to atherosclerosis, epidemiological studies have pointed out an association with the level of serum cholesterol, the ratio of high-density versus lowdensity lipoproteins, and with life-style phenomena such as cigarette smoking, physical inactivity and dietary habits. Various theories have been proposed for the pathogenesis of atherosclerosis, for example that it could be a response to intravascular injury. The discovery that the cells of the atherosclerotic plaque are monotypic led the Benditts to propose that plaques may be regarded as monoclonal benign neoplasms of the artery wall. According to the monoclonal theory, plaques and carcinomas may share important pathogenetic features, including the occurrence of one or more mutational events (Benditt et al., 1973). If this theory holds, it implies that at least some mutagens should be expected to exert both an atherogenic and a carcinogenic effect, and that populations at high risk of cancer may also experience a high risk of atherosclerosis-related diseases. The major part of this paper concentrates on the morbidity or mortality pattern in populations at high risk of cancer, including persons with certain genetic constitutions, and persons exposed to certain environmental mutagenic or carcinogenic agents. Investigations of possible correlations between national rates of cancer and atherosclerotic diseases are not reviewed. On the other hand, such

correlations are considered for well-defined subpopulations exposed to specific risk factors for cancer. The review also covers studies of the possible correlation of cancer and atherosclerosis at the individual level, because such correlations may reflect a common cause for the two groups of diseases. Considerations on methodological issues

Epidemiology is tailor-made to point out risk factors of relevance to human beings. For instance, the epidemiologically based knowledge of the effects of tobacco smoking is of great value for preventive purposes. However, being unable to manipulate exposure in an experimental way, epidemiology is badly equipped to investigate the agent-specific etiology and the basic pathogenetic features of a disease. Referring again to the effects of tobacco smoking, it is beyond any doubt that cigarette smoke constitutes a strong atherogen and a powerful carcinogen as well (Department of Health, Education, and Welfare, 1979; Department of Health and H u m a n Services, 1982, 1983). It is impossible, however, on this basis to claim that the specific carcinogenic and atherogenic substances in the smoke are identical. As a matter of fact, high-dose exposure to a single chemical substance is a rare thing in h u m a n life. Sometimes, however, mono-exposure to specific carcinogens has occurred in industry, in therapeutic medical practice and in relation to man-made disasters including acts of war.

Co-occurrence of diseases That two diseases tend to occur together means that the probability of finding both diseases in one individual exceeds the product of the probabilities of finding each one of the diseases, all other risk factors for the diagnosis of each of the two diseases being equal.

165 If two diseases tend to occur together, i.e., in the same individual, this may reflect that the two diseases have some etiologic factor(s) in common. Such factors could be either external, for example an environmental chemical, or internal, for example a genetically determined susceptibility for both of the diseases in question. A positive correlation between two diseases may, however, also reflect a correlated occurrence of some of the risk factors for the diseases in question. Or the observed correlation may reflect some type of interdependence of the diseases: for example one of the diseases may further the development or the diagnosis of the other disease, or the two diseases may in fact constitute different manifestations of the same disease process. If the diseases interact biologically, or form part of a single syndrome, the correlation will appear in any study. When looking for a possible c o m m o n etiology of two diseases, a serious draw-back is that a causal factor is likely to remain undetected, unless it has a strong effect, is prevalent in the studied population, and is the predominant causal factor for the diseases in question in that population. Apart from tobacco smoking, exposures that are associated with a high risk of cancer are usually not prevalent in the population at large.

Diagnostic validity Studying the correlation of diseases, it is important to consider the contents of the diagnostic entities and the appropriateness of the diagnostic procedures. The typical clinical course of cancer is relatively uniform compared to the variety of manifestations typical of atherosclerosis. Malignant neoplasms constitute a rather well-defined group of diseases that is not subject to extensive misclassification. The following considerations on diagnostic validity therefore mainly concern atherosclerotic diseases. The extension and severity of atherosclerotic disease may be minutely recorded at autopsy. In clinical practice, however, the diagnosis of atherosclerotic disease is always prompted by the occurrence of signs of organ ischemia. Ischemia typically occurs in association with severe atherosclerosis, but there is no general relationship

between the clinical diagnosis and the pathoanatomical appearance of the relevant arteries. Typically, atherosclerosis develops silently over an extensive period of time and signs of organ ischemia often have an insidious onset. Depending on the affected organ, ischemic episodes cause more or less dramatic symptoms. The duration of subclinical disease will therefore tend to vary considerably depending on the localization and severity of the atherosclerotic lesions. For instance, an initial episode of amaurosis fugax is likely to lead to immediate consultation of a medical professional. On the other hand, incipient intermittent claudication may remain undiagnosed for a long period of time. Yet another problem is that organ ischemia may not only be produced by atherosclerotic lesions, but also by acute vasoconstriction, for instance in response to epinephrine release or due to exposure to nicotine. Ischemic symptoms may also develop because of general hypoxia, for example due to a high level of carboxy-hemoglobin occurring in relation to carbon monoxide exposure. It is likely that most cases of acute organ ischemia have both a precipitating vasoconstrictive and an underlying atherosclerotic component. Population surveys may include some measurements of the prevalence of ischemic symptoms from various organs. If the participation rate is high, and the diagnostic procedures are extensive and of high quality, such surveys may provide good estimates of the prevalence of atherosclerotic disease in the studied population. It is important to recognize, however, that persons with a long disease duration (i.e., less severe cases) will be overrepresented among the prevalent cases. The more severe cases that experience a short fatal course of disease will be available as "prevalent cases" for a short period of time only. Thus, selection by severity of ischemic disease is likely to bias the inference that m a y be drawn from a prevalence study. By the same token, competing causes of death may cause a selection bias in a prevalence study. As an example of the latter, heavy smokers will be expected to be underrepresented among aged persons with angina pectoris, because heavy smokers have been eliminated from the population at a lower age by death from myocardial infarction, non-syphilitic aorta aneu-

166 rism, lung cancer, chronic bronchitis, and other tobacco-related diseases.

Mortality studies Most epidemiological studies on atherosclerosis-related diseases use rather hard endpoints, such as fatal myocardial infarction or fatal cerebral ischemia. Although the probability of death from for instance coronary heart disease is closely related to the extension and severity of atherosclerosis (Strong et al., 1968), mortality studies are rather insensitive for the study of atherosclerosis-related diseases, because non-fatal disease will not be noticed. Another feature of the mortality study that may detract from its sensitivity is that it usually derives the diagnostic data from death certificates. Autopsy studies have revealed that diagnostic misclassification occurs in about one third of death certificates (Heasman, 1962; Britton, 1974; Asn~es, 1984). In particular, acute myocardial infarction and ischemic heart disease are overdiagnosed at the expense of other vascular diseases, lung diseases, and certain malignant neoplasms. Non-differential overascertainment of a particular diagnosis, for example ischemic heart disease, reduces the chances of detecting a real difference when two (or more) populations are compared in terms of the mortality or incidence of the disease in question (Hansen et al., 1989).

Problems of occupational epidemiology Almost all of the studies of atherosclerosis-related diseases in relation to occupation are mortality studies in which the occupational group in question has been compared with the general population. Atherosclerosis-related diseases typically have a protracted course and the symptoms may often be disabling. It is unlikely that a person suffering from say ischemic heart disease will apply for a physically demanding job, and if currently employed in such a job, the person will tend to quit it as the symptoms become aggravated. The resulting health-based selection of the active work force brings about a 'healthy-worker effect', the phenomenon that the observed mortality in an occupational cohort may be considerably lower than the 'expected' mortality as calculated from the

death rates of the general population (McMichael, 1976). The selection against persons suffering from ischemic heart disease and other atherosclerosisrelated diseases can be anticipated to be very effective for the majority of blue-collar workers. Thus, the prevalence of severe atherosclerosis is likely to be much lower in the occupationally active part of the population, especially among blue-collar workers, than among unemployed and retired persons (Hernberg, 1984). At the same time, blue-collar workers are more likely than the average population to be exposed to mutagens and carcinogens in the work place. Due to the health-based selection of exposed occupational groups, a possible relationship between occupational carcinogens and atherosclerotic disease is likely to go undetected. Accordingly, a standardized mortality ratio (SMR) equal to 100% for ischemic heart disease may indicate a considerably increased risk for the occupational group in question. Furthermore, epidemiological studies of chronic diseases in relation to occupational agents are often hampered by a low sensitivity and even rather strong effects may remain undetected. One reason for this may be a biologically determined time lag between exposure and disease. Other reasons are the defective assessment of occupational exposure, the facts that workers are typically exposed to a mixture of environmental agents, that the composition of this mixture is often not well determined, and that an individual worker's exposure is likely to change over time along with job changes, variations in output and means of production, work procedures, and job duties. In particular when studying health effects of long-term exposures, these features make it difficult to define relevant plus and minus exposure categories for comparison in terms of health outcome. In occupational epidemiology, the studied exposure contrast is typically weaker than anticipated due to 'dilution' of the plus-exposure category and possible 'contamination' of the non-exposure category (Hansen et al., 1989). Studies of cancer and studies of atherosclerotic diseases are likely to suffer equally from low sensitivity. The negative bias produced by health-based selection, on the other hand, is anticipated to be

167 much stronger for atherosclerotic diseases than for cancer, because of the difference in the typical course and duration of the two groups of diseases. Genetic disorders

Families with certain hereditary diseases associated with a high risk of cancer attract particular interest. Epidemiologic studies of the morbidity patterns in such populations may add important information about possible pathogenic pathways for the development of atherosclerosis. An increased risk of malignant lymphoproliferative disease is seen in persons suffering from ataxia telangiectasia (Spector et al., 1982), an autosomal recessive syndrome that is associated with a deficient repair of potentially lethal chromosomal damage after T- or X-ray exposure (Cox, 1982). Among obligatory ataxia telangiectasia heterozygotes, an increased mortality has been found for ischemic heart disease as well as for cancer (Swift et al., 1983, 1987; Swift, 1985). The background for these observations and for the manifestations typical of ataxia telangiectasia is not understood. Persons homozygous for the xeroderma pigmentosum gene experience an extremely high risk of basal and squamous cell carcinomas of the skin. The disease is associated with a defective repair of UV-induced D N A breaks (Robbins et al., 1974) combined with a reduced natural killer cell activity (Norris et al., 1989). An increased incidence of non-melanoma skin cancer has also been found among blood relatives of the homozygous probands (Swift et al., 1979). It is interesting that the lymphocytes of persons with atherosclerosis have been reported to display a lower intensity of D N A repair after UV irradiation than those of healthy subjects of the same age (Dil'man et al., 1981). Regarding polyposis coli, an autopsy study of the prevalence of adenomatous polyps and atherosclerosis (Stemmermann et al., 1986) has indicated a positive association between singular as well as multiple benign polyps of the colon and the degree of atherosclerosis. N o conclusions can be drawn from the limited amount of data on the prevalence of atherosclerosis among persons affected with ataxia telangiectasia, xeroderma pigmentosum, or polyposis coli.

D o cancer and atherosclerosis tend to occur together?

It is necessary to devote some effort to the multitude of studies of 'syntropy', that is the occurrence of cancer and severe atherosclerosis in the same individual. Most of these studies of co-occurrence have used cross-sectional outcome data, mainly from autopsies. Only a few follow-up studies of cancer incidence among atherosclerotics are available. Observed correlations, positive or negative, between diseases can only be interpreted in terms of correlated or identical risk factors if all other risk factors for the diseases and for their diagnosis are equal. However, it is often difficult to ensure that the results are not invalidated by extraneous factors. For m a n y years, for example, the findings in autopsy studies have been interpreted as indicative of a negative association between cancer and atherosclerosis, i.e., that individuals with malignant neoplasms in general have less atherosclerosis than individuals without cancer (Schneider, 1936; Wanscher et al., 1951; Juhl, 1955; Chomette et al., 1968). However, the findings at autopsy cannot be extrapolated to the living population, because the composition of any autopsy series is influenced both by selection by death and by selection by autopsy among the deceased persons. For example, most cancer cases in an autopsy series are likely to have died because of their cancer, whereas it is likely that most of the persons in a non-cancer autopsy series have died from diseases related to atherosclerosis. As a consequence, one would expect a much higher prevalence of severe atherosclerosis among non-cancer autopsies than among cancer autopsies. The prevalence of atherosclerosis in the live population has been estimated from autopsy series of 'healthy' persons dying from accidents. The prevalence and severity of atherosclerosis as determined at autopsy did not differ significantly between this type of reference series and the series of cancer cases (Parrish, 1961; Giertsen, 1966; Lange, 1967; Hempel et al., 1968). In other autopsy studies, comparisons have been made between a cancer series and a series of non-cancer cases dying from causes assumed to be unrelated to the severity of atherosclerosis (Juhl, 1957; Montenegro

168 et al., 1968; Sternby, 1973, 1976). With one exception (Juhl, 1957), these studies demonstrated no difference between the cancer and the comparison series with respect to extension or severity of the atherosclerotic lesions. In particular, a huge international autopsy study, the International Atherosclerosis Project, has consistently shown no difference between deaths from cancers unrelated to tobacco consumption and deaths from external causes in terms of extension and severity of atherosclerosis as measured by a standardized blinded method (Montenegro et al., 1968). As regards specific cancer sites, several autopsy studies have demonstrated an excess prevalence of severe atherosclerosis in persons with bronchial carcinoma compared with persons dying from external causes or from brain tumors (Abdelhamid et al., 1967; Hempel et al., 1968; McGill et al., 1968). Similar results have been obtained by comparison of a bronchial carcinoma series with a stomach cancer series (Burkhardt, 1959), and with a broader autopsy series excluding deaths due to cardiovascular disease and other diseases related to atherosclerosis (Sternby, 1973, 1976). In addition, the Swedish study indicated that women dying from ovarian or m a m m a r y cancer have less severe atherosclerosis than women dying from causes thought to be unrelated to atherosclerosis (Sternby, 1973, 1976). Biological explanations for this observation are conceivable. However, confounding by smoking habits is another possible explanation, in particular for m a m m a r y cancer, for which a positive social gradient is well recognized as opposed to a negative social gradient of cigarette smoking in the Scandinavian countries. The Swedish data furthermore indicated an excess severity of atherosclerosis among males with prostatic cancer (Sternby, 1973). However, the data originated from the University Hospital of Lund, where there has been an excessively high frequency of notified prostatic carcinomas incidentally diagnosed at autopsy because of a particular autopsy routine. Accordingly, the report points out that the majority of the prostatic cancers had not been diagnosed prior to autopsy and that most of the persons with that cancer had not died of it (Sternby, 1973). It is likely that the majority of the prostatic cancer cases in the Swedish autopsy series represent a random sample of the total number of

deaths in males - an assumption which may explain the high prevalence of atherosclerosis among the prostatic cancer cases as compared with persons who had died from causes anticipated to be unrelated to the severity of atherosclerosis. The prevalence of atherosclerosis among live persons has been estimated from the presence of calcified atheroma as visualized by radiography of the abdominal aorta. Comparing a series of patients with carcinoma with a series of control patients, aortic calcifications were recorded about twice as often in the control group as in the carcinoma group (Elkeles, 1959). The criteria for inclusion in the control series were not specified, but it is likely that all of the control persons were non-cancer patients. Hospital controls are not a random sample of the total population and in particular, persons with atherosclerotic disease are likely to be overrepresented. In a later study, the same author, using the same method, investigated the prevalence of atherosclerosis in a stomach cancer series, a gastric ulcer series, and a control series (Elkeles, 1970). The prevalence of atherosclerosis was much lower in the cancer series than in the gastric ulcer series. This finding may reflect the fact that cigarette smoking is an important risk factor for both gastric ulcer and atherosclerosis. Furthermore, because of the u r b a n - r u r a l gradient of stomach cancer it is likely that persons from rural areas were overrepresented among the cancer cases. In general, people from rural areas have smoked fewer cigarettes and would therefore be expected to have less atherosclerosis than the population on average. A few follow-up studies on cancer mortality and morbidity among atherosclerotic persons are available. A 3-year follow-up study involving comparison of atherosclerotic and non-atherosclerotic persons, who had been hospitalized for symptoms of peripheral occlusive vascular disease, indicated a relative risk around 3 for cancer death among atherosclerotic males aged 50-64 years (Huismans et al., 1972). In a similar study, persons with intermittent claudication were divided into two groups depending on the results of plethysmography. The two groups were compared in terms of morbidity and mortality over the subsequent 10 years. This study revealed a relative risk of 6.1 for tobacco-related malignant neoplasms among 4 0 -

169 54-year-old males with peripheral atherosclerosis. For males aged 55-69 years, the corresponding relative risk was 2.9 (K~iller~5, 1981). The Framingham study has indicated an increased risk of cancer among males with clinically diagnosed coronary heart disease as compared to males without this diagnosis (unstandardized relative risk estimated to be 2.3) (Kannel et al., 1970). To conclude, the various types of studies of co-occurrence are consistent regarding the observation that tobacco-related cancers and severe atherosclerosis tend to occur in the same individual, indicating that tobacco smoking adds both to the cancer risk and to the risk of severe atherosclerosis. This is concordant with current knowledge.

Tobacco smoking It is beyond any doubt that cigarette smoking contributes considerably to the mortality from coronary heart disease and other vascular diseases (Department of Health, Education, and Welfare, 1979; Department of Health and Human Services, 1983). It also seems superfluous to mention that cigarette smoke acts as a strong carcinogen with several target organs such as the oral cavity, the esophagus, the pancreas, the respiratory system, and the bladder (Department of Health, Education, and Welfare, 1979; Department of Health and H u m a n Services, 1982). Regarding the development of atherosclerosis, one particular constituent of tobacco smoke, carbon monoxide, has previously received intense interest, as animal experiments seemed to indicate an atherogenic effect. However, refinement of the experimental routines (e.g., blind readings) has resulted in dissimilar findings, and today there seems to be consensus that apart from a slight increase in serum cholesterol induced by hypoxia, carbon monoxide has no bearing on the development of atherosclerosis (Gori, 1979; Weir et al., 1982). As regards the epidemiologic data on smoking and atherosclerosis, the evidence is most consistent for cigarette smoking. According to several huge studies (Hammond et al., 1958; Doll et al., 1964, 1976; Best, 1966; Keys et al., 1966; Shapiro, 1969; Rogot et al., 1980; Higenbottam et al.,

1982; Carstensen et al., 1987), cigarette smoking is strongly associated with mortality from ischemic heart disease and other circulatory diseases, including non-syphilitic aorta aneurysm and arteriosclerosis. A clear-cut dose-response pattern has been demonstrated for ischemic heart disease and non-syphilitic aorta aneurysm. Ischemic heart disease is by far the most important single cause of death in relation to cigarette smoking. According to estimates from several investigators, 30-40% of the U.S. deaths from ischemic heart disease can be attributed to cigarette smoking (Department of Health and Human Services, 1983). In general, the relative death rate of smokers compared with never-smokers is higher in the younger age groups than in the older ones (Doll et al., 1976; Carstensen et al., 1987). However, the 'background' mortality from ischemic heart disease increases dramatically with age (Doll et al., 1976) and if the two risk factors, smoking and age, are less interactive than assumed by a multiplicative model, the relative rate for smokers should decrease with increasing age. Actually, Doll and Peto's mortality data on ischemic heart disease (Doll et al., 1976) indicate a combined effect of age and smoking which is between that predicted by an additive and a multiplicative model. People who quit smoking continue to have an excess mortality from ischemic heart disease (Doll et al., 1976; Rogot et al., 1980; Carstensen et al., 1987). The mortality pattern for ex-smokers shows interesting differences for age groups. According to the 20-year follow-up of male British doctors (Doll et al., 1976), the ischemic heart disease mortality rate of ex-smokers aged 30-45 years decreased rapidly after smoking was stopped and within the first 10 years after stopping the death rate stabilized at a level which was only a little above that of never-smokers. For the age groups 55-64 years and 65 + years, respectively, the pattern was less clearcut, but in general the exsmokers' death rate lay between that of current smokers and that of never-smokers. The difference in mortality between ex-smokers and neversmokers tended to decrease slightly with increasing number of years since smoking was stopped. (The rate difference is here assumed to be the most appropriate parameter in relation to exsmokers, because there is no current exposure

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(smoking) to interact with either age or calendar time.) The decrease in rate difference with increasing number of tobacco-free years may simply reflect a dose-response relationship. For persons aged 55-64 years for example, those who up smoking 15 or more years ago are likely to have consumed a much smaller cumulated dose than those who have gave up smoking within the last 5 years. The observed mortality patterns for ex-smokers seem to indicate that permanent atherosclerotic changes in the coronary arteries are of great importance for fatal cardiac ischemia in older smokers including ex-smokers. The rapid and lasting decrease in mortality from ischemic heart disease seen in the younger group of ex-smokers indicates that a major part of the cardiac deaths a m o n g younger smokers is caused by acute vasoconstriction, most likely due to nicotine. The observation by pathologists that severe atheroscleros]s occurs more often in persons who have died from tobacco-related cancers than in persons who have died from extraneous causes (mentioned previously in this paper) further corroborates the evidence that tobacco smoke plays a part in the etiology of atherosclerosis. Quite another type of evidence for the effects of tobacco smoke on human vessels comes from a series of studies in which smoking mothers were compared with never-smoking mothers in terms of ultrastructural changes of the umbilical artery and vein, and of the placental villi (Asmussen et al., 1975; Asmussen, 1977, 1978, 1979, 1980). The studies included only normal pregnancies, deliveries and children. All readings were completed without knowledge of the smoking history. The results unambiguously indicated that maternal tobacco smoking during pregnancy is associated with severe damage to the fetal vessel wall. In the studied parts of the fetal cardiovascular system, maternal tobacco smoking was strongly associated with marked alterations of the two inner layers of the vessel wall, the intima and the media. The lesions consisted of intimal leakage, widening of the basement membrane, a loss of tight intercellular junctions of the endothelial cells, and media myocyte proliferation and migration. The changes found in smokers appeared to be dose-related. A few non-smoker cases displayed the same type of

alterations, although to a much lighter degree than did most of the smokers. The husbands of all these women were smokers. The ultrastructural alterations were never found in non-smoking mothers married to non-smoking men. The author states that the lesions seen in the umbilical artery and vein and in the placental villi of smoking mothers are identical to those seen in animal studies of early atherosclerotic lesions. This is consistent with the observation of a much higher prevalence of calcifications in the placentas of smoking mothers than in those of non-smoking mothers, as determined by detailed gross examination without knowledge of the mother's smoking habits (Christianson, 1979). It is beyond doubt that tobacco smoke is an important etiologic factor for the development of atherosclerosis in man. Tobacco smoke, however, is a complex mixture of numerous chemical substances, and the particulate matter in the smoke may even act as a carrier of radon daughters emitted from the ground or from building materials. We do not know which specific agents in tobacco smoke are to blame for the development of atherosclerosis or of carcinomas. Regarding the latter, we would expect mutagens, premutagens, or ionizing radiation to play a central part. Assuming a somatic mutational theory for the formation of the atherosclerotic plaque, the agents responsible for cancer and atherosclerosis would be expected to be almost identical. However, agent-specific inferences regarding the health effects of tobacco smoking cannot be drawn from the epidemiologic data.

Occupational exposures In several instances, the recognition of an 'occupational cancer' has subsequently led to the identification of specific carcinogenic agents in the work environment. As regards occupational exposures associated with atherosclerosis, it is well established that workers exposed to nitroglycerine, nitroglycol, and carbon disulfide suffer an increased cardiovascular morbidity and mortality (Hogstedt, 1980; Nurminen et al., 1985). A concomitantly increased mortality from malignant neoplasms and ischemic heart disease has been reported for workers exposed to arsenic

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(Lee et al., 1969; Axelson et al., 1978; Welch et al., 1982), beryllium (Wagoner et al., 1980), vinyl chloride monomer (Byren et al., 1976; Molina et al., 1981; Greiser et al., 1982), and ethylene oxide (Hogstedt et al., 1969). A similar mortality or morbidity pattern has been observed in several occupational groups exposed to combustion effluents, including certain categories of foundry workers (Koskela et al., 1976), chimney sweeps (Hansen, 1983, 1984; Gustavsson et al., 1987), workers exposed to diesel exhaust (Bofetta et al., 1988), thermoelectric power plant workers (Forastiere et al., 1988), waste incinerator workers (Gustavsson, 1989) and asphalt workers (Hansen, 1989). Reportedly, also rubber workers (Holmberg et al., 1983) and auto mechanics (Hansen, 1989) display a mortality pattern of excess mortality from cancer as well as ischemic heart disease. The cancer site most frequently reported to be associated with atherosclerotic disease is the respiratory tract, but malignant neoplasms of the digestive organs, the urogenital organs, and of hematopoietic tissue have also been found in excess in occupational groups which display an increased risk of circulatory diseases. Regarding occupational exposures, arsenic, vinyl chloride monomer, and combustion effluents are the ones for which the evidence is most consistent as regards a possible etiologic role in the development of cancer and atherosclerosis. The specific agents arsenic and vinyl chloride monomer are separately discussed later in this paper.

Combustion effluents Occupational exposure to various combustion effluents from coal, oil, wood, etc., has been reported to be associated with both cancer a n d circulatory diseases more often than any other occupational exposure. However, combustion effluents constitute a complex mixture including various metals, polycyclic aromatic hydrocarbons (PAH) with known carcinogenic properties, and a huge number of other compounds for only a few of which the chemical structure is known. Regarding the carcinogenic PAHs, a promoting effect on the development of atherosclerosis has been demonstrated in animal experiments (White et al., 1943; Albert et al., 1977; Bond et al., 1981; Penn et al., 1981). The carcinogenic PAHs are

premutagens that need metabolic activation to become mutagenic. The activating enzyme system is arylhydrocarbon hydroxylase, which is present in most human tissues including the arteries. It is interesting that atherosclerosis-susceptible and atherosclerosis-resistant animal species differ with regard to the presence/absence of arylhydrocarbon hydroxylase activity in the aorta (Hogg et al., 1982). These observations are consistent with a mutation theory of plaque formation, involving carcinogenic PAHs as initiators. Dioxin (TCDD)

The population of Seveso (Italy) was exposed to the chlorinated biphenyl 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after an explosion in a nearby chemical plant on July 10, 1976. A followup study of the persons exposed at that incident has revealed an increased mortality from ischemic heart disease, cerebrovascular diseases, and certain malignant neoplasms (Bertazzi, 1988). Vietnam veterans constitute another group who may have been exposed to T C D D . A recent survey from the CDC (Centers for Disease Control, Vietnam experience study, 1988), in which Vietnam veterans were compared with non-Vietnam veterans, indicated a slightly elevated prevalence of impaired peripheral circulation and of electrocardiographic signs of ischemia among t h e Vietnam veterans. 1.9% of the Vietnam veterans had a post-discharge health history including chloracne, whereas the corresponding percentage for nonVietnam veterans was 0.3, indicating a difference in past exposure to TCDD. T C D D is a potent enzyme inducer and raised -/-glutamyl transpeptidase activity and lipid abnormalities have been recorded in dioxin-exposed subjects (International Agency for Research on Cancer, 1977; Walker et al., 1979). Reportedly, occupationally exposed workers with chloracne display a consistent pattern of elevated serum cholesterol and reduced high-density lipoprotein (Walker et al., 1979), indicating a higher than average risk of ischemic heart disease. Similar abnormalities have been obtained in animal assays (Zinkl et al., 1973; McConnel et al., 1978; Swift et al., 1981). Experimental data indicate that exposure to T C D D causes a pronounced increase in

172 the serum level of very-low-density lipoprotein (Swift et al., 1981). It seems likely that the observed association between T C D D and ischemic heart disease reflects a non-mutagenic mechanism which involves enzyme induction and subsequent abnormalities of lipid metabolism.

Ionizing radiation Ionizing radiation is one of the most thoroughly investigated and documented carcinogenic agents. However, this agent has had and still has a widespread therapeutic application, mainly in the treatment of malignant neoplasms. Among the untoward long-term effects of therapeutic radiation is the development of a 'postirradiation atherosclerosis' which resembles atherosclerosis histologically. Reports in the literature mention severe atherosclerosis of the carotid arteries, coronary arteries, thoracic aorta, subclavian artery, axillary artery, abdominal aorta, mesenteric artery, renal artery, iliac artery, femoral artery, popliteal artery, hypogastric artery, and the intracranial arteries (Prentice, 1965; Stewart et al., 1967; Savlov et al., 1969; Glick, 1972; Hayward, 1972; Huff, 1972; Benson, 1973; Huvos et al., 1973; Levinson et al., 1973; St. Louis et al., 1974; Leigl, 1975; Painter et al., 1975; Rogers, 1976; Eisenberg et al., 1978; Nylander et al., 1978; Silverberg et al., 1978; Brosius et al., 1981; Lawson, 1985; Dunsmore et al., 1986; Amemiya et al., 1987; Hupp et al., 1987; Loftus et al., 1987; Werner et al., 1988). Only in a few of the reported cases had the anti-neoplastic treatment included chemotherapeutic drugs. Silverberg and co-workers' study of patients with atherosclerotic occlusive disease in neck vessels (Silverberg et al., 1978) indicated that radiation-induced atherosclerosis represents a separate clinical entity: the patients with radiation-induced atherosclerosis experienced carotid occlusion at a significantly younger age than the control patients, and were less likely to have associated coronary or peripheral vascular disease, indicating that some other factor, presumably radiation, had accelerated the process of atherosclerosis within the field of irradiation. These findings are consistent with most of the numerous case reports of occlusive atherosclerotic lesions after therapeutic

radiation: that the patients were relatively young and that most of them did not have angiographic or clinical signs of generalized vascular disease. Furthermore, several of the patients had never smoked, and hypercholesterolemia or other serum lipid abnormalities were not notably frequent among them. The persons with occlusive postirradiation atherosclerosis typically had severe atherosclerosis localized segmentally in one or a few arteries within the irradiated region, whereas the rest of the affected artery was free from disease. Furthermore, the stenoses were often 'abnormally' localized with regard to the typical predilection sites of atherosclerotic lesions of the artery in question. Reportedly, the atherosclerotic lesions seen after radiation cannot be distinguished patho-anatomically from the ordinary age-dependent atherosclerosis, except for their Focalized character and the atypical predilection sites mentioned above. Occlusive symptoms may occur several decades after the radiation treatment, but as short a lag time as 15 months to 2 years has been reported (Stewart et al., 1967; Savlov et al., 1969; Nylander et al., 1978; Silverberg et al., 1978; Lawson, 1985). The lag time from irradiation to occlusive atherosclerosis seems to depend on the field of irradiation. For the above-mentioned cases the median lag time was around 8 years. Only a few follow-up studies of persons receiving therapeutic irradiation have been performed, and all of these except one have been mortality studies. It has been pointed out previously in this paper that mortality studies are rather insensitive for the study of atherosclerosis-related diseases, partly because of the low reliability of death certificate diagnoses, partly because non-fatal manifestations of disease will not be noticed. Studies of patients given X-ray treatment for ankylosing spondylitis have indicated an increased mortality from cancers as well as from other diseases (Brown et al., 1965; Smith et al., 1982), including cerebrovascular and other circulatory diseases (Brown et al., 1965). However, the clinical features of ankylosing spondylitis may include aortitis, and an increased mortality from cerebrovascular and other circulatory diseases has been reported even for ankylosing spondylitis patients not given X-ray therapy (Smith et al., 1977; Rad-

173 ford et al., 1977). The excess mortality from circulatory diseases has been found to be of the same order of magnitude for irradiated and non-irradiated ankylosing spondylitis patients. A follow-up study of 957 patients with Hodgkin's disease, of whom 678 had had irradiation to the heart in the treatment for Hodgkin's disease, showed that in the irradiated group the mortality from coronary heart disease was 1.5 times that of the group that had not received irradiation to the heart (95% confidence interval: 0.59-3.7) (Boivin et al., 1982). In a historical cohort study, 910 patients surviving at least 5 years after cervical irradiation for malignant neoplasms were followed with regard to incidence of stroke (Elerding et al., 1981). Within the period of follow-up, 63 persons had a stroke whereas the expected number of strokes was 38. A survey of 118 of these 910 patients showed that 25% of these persons had carotid lesions as diagnosed by non-invasive methods (symptoms, carotid phonoangiogram, and oculoplethysmography). The 118 patients had received therapeutic radiation 5-21 years prior to the survey. The authors recommended that 5-year survivors of cervical irradiation, because of their high risk, should undergo routine non-invasive examinations to detect occult carotid disease (Elerding et al., 1981). A mortality study in British radiologists (Brown et al., 1958) did not indicate an increased mortality. However, a similar study in U.S. radiologists compared with other medical specialists (Seltser et al., 1965) reported an increased mortality not only from cancer but also from cardiovascular-renal diseases and from other non-neoplastic diseases. So far, the studies of the mortality of A-bomb survivors have indicated no increase in the mortality from non-cancer diseases (Kato et al., 1982). For deaths occurring from 1950 through 1978, no dose-response pattern has been demonstrated for diseases of the circulatory system. The mortality studies of A-bomb survivors, radiologists, and patients receiving therapeutic radiation do not show a consistent pattern with regard to atherosclerosis-related diseases. However, mortality studies are rather insensitive for studying the possible association between ionizing radiation and the development of atherosclerosis.

Accordingly, there is no real discrepancy between the inconclusive mortality data and the numerous case reports of arterial occlusion due to postirradiation atherosclerosis. Regarding the latter, the observation of localized 'premature' severe atherosclerosis in an area that was irradiated some years previously is suggestive, particularly as the arteries on either side of the irradiated area are typically observed to be free of atherosclerosis and as the typical patient has no evidence of severe atherosclerosis elsewhere. It seems to be warranted to adopt the term 'post-irradiation atherosclerosis' as an indication that ionizing radiation is one of several etiologic factors for atherosclerosis. Whether this effect of radiation involves a mutational mechanism or not cannot be judged from the epidemiological and clinical data. In fact, several other pathogenic pathways have been proposed, including (i) changes in permeability of the vessel wall to serum lipids as the result of radiation damage to the endothelium, ground substance, and internal elastic membrane leading to the deposition of lipids in the vessel wall, (ii) impairment of healing and (iii) infarcts of the vessel wall due to peri-arterial fibrosis and subsequent occlusion of the vasa vasorum. It is also possible that the atherogenic effect of therapeutic irradiation is mediated by somatic mutations. The antineoplastic doses of ionizing radiation are in a range that induces a significant increase in the in vivo mutant frequency in circulating lymphocytes (Messing et al., 1985). The cell-killing effects of ionizing radiation may also be thought to promote the growth of monoclonal plaques by stimulating the division of surviving artery wall myocytes, including such cells that have already been initiated or transformed to plaque cells. Vinyl chloride m o n o m e r

The reporting of three cases of angiosarcoma of the liver in one polyvinyl chloride (PVC) manufacturing plant (Creech et al., 1974) led to the recognition of the carcinogenic properties of vinyl chloride monomer (VCM). Hepatic angiosarcoma is otherwise extremely rare, but seems to be induced by VCM, arsenic, and Thorotrast (Popper et al., 1978). The vascular bed seems to be a target organ

174

for VCM (and for arsenic as well). Not only does VCM cause malignant transformation of endothelial cells leading to angiosarcomas, it also impedes peripheral circulation and causes Raynaud's phenomenon, acroosteolysis, telangiectasis, and other capillary abnormalities (Dodson et al., 1971; Holmberg et al., 1974, 1976; Selikoff et al., 1975; Maricq et al., 1976). The clastogenic properties of VCM are reflected by the finding of a dose-dependent excess of chromosomal aberrations among exposed workers (Heath et al., 1977; Purchase et al., 1978). Studies on occupational mortality have consistently shown an increased cancer risk among workers exposed to VCM. In some instances, an excess mortality from circulatory diseases has also been demonstrated (Byren et al., 1976; Molina et al., 1981; Greiser et al., 1982). In all of these studies, the mortality of the total population was used as standard of reference. The 'expected' mortality of the VCM workers (used for comparison with the actually observed mortality) has therefore been considerably overestimated (cf. the 'healthy-worker effect'). The observed excess mortality from circulatory diseases is remarkable, and is likely to be underestimated.

1969; Axelson et al., 1978; Welch et al., 1982). Peripheral vascular disease has been described in relation to chronic arsenic intoxication (Butzengeiger, 1940; Chen et al., 1988). In particular, exposure to high-arsenic artesian well water has been shown to be associated with a high risk of peripheral arteriosclerosis leading to gangrene (black-foot disease), and a high mortality from cardiovascular diseases (Chen et al., 1988). Electrocardiographic abnormalities have also been reported (Glazener, 1968). A dose-response relationship has been demonstrated for respiratory cancer (Lee et al., 1969; Axelson et al., 1978; Welch et al., 1982; J~irup et al., 1989) and for cardiovascular diseases (Axelson et al., 1978; Welch et al., 1982). For the latter diagnostic group, the most pertinent dose proxy seemed to be peak exposure, whereas for respiratory cancer, the time-weighted average exposure appeared to be more appropriate. These observations might be consistent with a somatic mutation theory for atherogenesis as well as for carcinogenesis provided that only one 'hit' is needed to initiate the formation of an atherosclerotic plaque, and that two or more 'hits' are needed for the initiation of a malignant neoplasm.

Arsenic Conclusions

A carcinogenic effect of arsenic has been repeatedly demonstrated in epidemiological investigations (Hill et al., 1948; Braun, 1958; Pinto et al., 1963; Fiertz, 1965; Lee et al., 1969; Kuratsune et al., 1974; Ott et al., 1974; Axelson et al., 1978; Pinto, 1978; Mabuchi et al., 1979; Enterline et al., 1980; Wall, 1980; Cuzick et al., 1982; Enterline et al., 1982; Welch et al., 1982; Chen et al., 1988; J~irup et al., 1989), whereas most animal experiments have failed to show such an effect. In humans, exposure to arsenic has been shown to be associated with increased frequency of chromosomal aberrations (Petres et al., 1970, 1977; Nordenson et al., 1978, 1979, 1982) and of sisterchromatid exchange (Burgdorf et al., 1977). In vitro investigations have indicated that arsenic interacts with DNA-repair mechanisms (Jung et al., 1970; Rossman et al., 1977). Increased mortality from lung cancer and from ischemic heart disease has been reported for copper smelter workers exposed to arsenic (Lee et al.,

The epidemiological literature indicates that certain carcinogenic agents may exert an atherogenic effect as well. The numerous studies on smokers' mortality combined with the unanimous findings in autopsy studies leave no doubt that cigarette smoke has a pronounced atherogenic potency. Studies on occupational mortality seem to indicate a similar feature as regards exposure to combustion effluents in the working environment, as this exposure tends to be associated with an increased mortality from cardiovascular diseases and from malignant neoplasms. However, the epidemiological studies of exposure to combustion products cannot single out specific atherogenic or carcinogenic agents in the smoke or fume. Epidemiological studies of atherosclerosis-related diseases in relation to exposure to a single carcinogenic agent are relatively rare, as mono-exposure is a rarity in human life. As regards chem-

175 ical c a r c i n o g e n s a n d m u t a g e n s , an i n c r e a s e d mortality from cancer and atherosclerosis-related d i s e a s e s h a s b e e n r e p o r t e d for p o p u l a t i o n s exp o s e d to arsenic, b e r y l l i u m , v i n y l c h l o r i d e m o n o mer, ethylene oxide and dioxin. Regarding ionizing radiation, the established clinical concept of a 'post-irradiation atherosclerosis' s e e m s to b e j u s t i f i e d b y t h e s p e c i f i c c l i n i c a l f e a t u r e s of this d i a g n o s t i c e n t i t y t h a t has b e e n d o c u m e n t e d in a c o n s i d e r a b l e n u m b e r o f c a s e reports. The apparently 'negative' findings with r e g a r d to t h e m o r t a l i t y f r o m a t h e r o s c l e r o s i s - r e l a t e d diseases among A-bomb survivors do not detract f r o m the c r e d i b i l i t y o f t h e c l i n i c i a n s ' e x p e r i e n c e that therapeutic radiation may bring about premature, l o c a l i z e d a t h e r o s c l e r o s i s . A s t r i k i n g l i k e n e s s s e e m s to exist b e t w e e n arsenic, v i n y l c h l o r i d e m o n o m e r a n d i o n i z i n g r a d i a t i o n ( i n c l u d i n g T h o r o t r a s t ) in t e r m s o f several biological effects including chromosomal aberrations, m a l i g n a n t n e o p l a s m s l o c a t e d in s p e c i f i c ' t a r g e t o r g a n s ' s u c h as t h e v a s c u l a r b e d a n d t h e liver, a n d v a r i o u s m a n i f e s t a t i o n s of c i r c u l a t o r y disease. It is h a r d to i m a g i n e a c o m m o n m o d e o f a c t i o n o f all t h r e e agents. H o w e v e r , t h e y m a y all p l a y a p a r t in t h e s a m e p a t h o g e n i c p r o c e s s l e a d i n g to s o m a t i c m u t a t i o n , for e x a m p l e e i t h e r d i r e c t l y b y c a u s i n g c h r o m o s o m a l b r e a k a g e or i n d i r e c t l y b y influencing the DNA-repair mechanisms. The fact t h a t all t h r e e a g e n t s c a u s e c a n c e r a n d also s e e m to c a u s e a t h e r o s c l e r o t i c d i s e a s e s m a k e s it t e m p t i n g to propose a significant similarity of the basic pathog e n i c p r o c e s s e s for at l e a s t s o m e s u b g r o u p s o f t h e s e t w o g r o u p s o f diseases.

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