Quarterly Reviews of Biophysics II, 4 (1978), pp. 429-437 Printed in Great Britain
Environmental intoxicants and their fundamental interactions J. EISINGER AND W. E. BLUMBERG Bell Laboratories, Murray Hill, N. J. 07974 The biological sciences are and should be responsive to the needs of medicine: thus the deficiency diseases (e.g. beri-beri and scurvy) stimulated the search for vitamins, just as contagious diseases fathered immunology and the study of antibiotics. It has been said that we live in the era of environmental disease, which suggests that an important fraction of human disease in technological societies is induced by environmental conditions, including some which are more commonly referred to as life styles. While this assessment requires further amplification (see below), it is clear that the sheer number and variety of potentially dangerous environmental agents has become so great that a better understanding of their fundamental interactions with the living system is clearly needed. As of the end of 1977, the American Chemical Society's Chemical Abstract Service contained over four million entities, and it is estimated that there are about 63000 chemicals in common usage. The toxicity of only a very small number of these has been investigated. Environmental intoxicants may be defined as materials (or radiations) in our environment (e.g. air, water, food) which are inimical to human health. This definition ignores the somewhat arbitrary division into naturally occurring and man-made intoxicants since some of the former are extremely toxic and some of the latter may afford protection against certain diseases. The important issue in identifying an environmental intoxicant is whether it interferes with the normal processes of a cell at levels of exposure encountered in the environment. It is the identification of such agents which is the most important, as well as the most difficult, task of the environmental physician. While the collection of papersf offered in this issue of the Quarterly t These papers are based on talks presented at the joint meeting of the Biophysical Society and the American Physical Society in Washington, D.C., in March 1978, as a 'Symposium on the Fundamental Interactions of Environmental Intoxicants'. We are grateful to Dr I. J. Selikoff for many stimulating talks and for contributing to the symposium which inspired this collection of papers. 27
o.RB-11
430
J. EISINGER AND W. E. BLUMBERG
Review of Biophysics deals with only a small fraction of the intoxicants which surround us, it is our hope that they will serve to illustrate the wide spectrum of such agents affecting the living system in a variety of ways. Included are papers which discuss biochemical interactions as well as interactions between light and crystalline matter with cell components. Other papers deal with the degradability of toxins and with the biological defenses of cells and indeed of man. To lend perspective to the contributions in this issue, it may be useful to make some general remarks about diseases of environmental origin and their role in an industrial society. Environmental diseases have attained their primary importance today only because the most serious health hazards of what Fernand Braudel (1974) has called the biological ancien regime have been largely eliminated by public health legislation and such medical triumphs as smallpox vaccination and antibiotics. Even so, one can only make a case for the majority of disease having environmental causes if one includes among the causes such voluntarily administered ones as cigarette smoking, injudicious eating, and excessive drinking (Kristein, Arnold & Wynder, 1977). Nevertheless, the great public concern about environmental pollution and disease (particularly cancer) has awakened among scientists a new interest in xenobiotics (molecules foreign to life) and in their modes of action. Apart from the new biochemical insights which this has led to, this field has considerable practical importance, if for no other reason than because our environment has been stocked for generations to come with molecules that were essentially non-existent during evolutionary times and because organisms have in many cases been found to have extreme sensitivities and unpredictable responses to them. The manifestations of adverse environments can be roughly divided into two groups. The first deals with widely distributed environmental conditions which generally have a low incidence of disease. The health problems associated with them have origins which are notoriously difficult to trace and are often unrecognized. The second kind of manifestation is what might be called environmental health disasters which result from heavy exposure to a toxic environment of a geographically (or otherwise) well-defined population. We would like to offer a few examples and comments on both of these environmental problems.
Environmental intoxicants
431
The widely distributed conditions - environmental pandemics - include some to which exposure is voluntary but closely related to the life styles of our society, such as cigarette smoking and rich diets. The first in particular have been studied extensively, and there exists strong evidence that it greatly increases the risk of disease. In spite of the wide publicity which these findings have received, cigarette consumption in the U.S. has not been reduced, and attempts to achieve this by public education alone have failed. Involuntary pandemics are caused by the wide distribution of such well-known carcinogens as polycyclic aromatic hydrocarbons (PAH), which usually result from the incomplete combustion of organic matter. These pollutants were present at low levels in the environment during evolutionary times and, as discussed elsewhere in this volume (Blumberg, 1978), man has developed enzyme systems to modify these xenobiotics in order to facilitate their excretion. It is clear however that the levels of PAH in our environment have been rising steadily along with their commercial production and exceed the ' natural' level, which is primarily due to forest fires, by more than an order of magnitude (see Fig. 1). Similarly the level of inorganic lead in our environment is some orders of magnitude greater than in the pre-industrial period (Eisinger, 1978). It is very difficult to estimate how much disease can be traced to such pollutants, but there is little doubt that it is a considerable amount. Another much studied industrial pollutant is asbestos, which has been shown to cause lung cancer and mesothelioma, a cancer of the lining of the chest cavity, at quite low levels of exposure (Langer, 1978). It is thus a danger to the general population since asbestos was and is widely used in insulation and many other applications so that exposure to asbestos fibres is virtually unavoidable in industrial societies. An interesting aspect of asbestos is the long latency period (20-30 years) between exposure and the first manifestation of disease. Such long delays present a challenging puzzle to the physiologist and greatly complicate the task of the environmental epidemiologist, who relies on surveys of heavily, usually professionally, exposed populations (e.g. insulation or shipyard workers in the case of asbestos) to give warning to the general population (Selikoff & Lee, 1978). By no means are all environmental intoxicants pollutants: Aflatoxin is an example (Rodricks, 1978) of one which is endemic to a wide variety of foods in vast areas of the world and is of natural origin. 27-2
432
J. EISINGER AND W. E. BLUMBERG 1-0
1850
1970
Fig. i. Total unsubstituted polycyclic aromatic hydrocarbon (PAH) production, relative to the 1970 level, calculated as a function of time by Hites, Leflamme & Farrington (1977).
Aflatoxins are among the most potent carcinogens in animals and are the major cause of cancer of the liver in man in certain parts of the world (Stoloff, 1977). They are metabolites of moulds which under suitable climatic conditions infest many foodcrops and stored foodstuffs (some examples from reference (Langer, 1978) are given in Table 1). The best known aflatoxin contamination is that of peanuts, and in 1969 the U.S. Food and Drug Administration imposed a maximum level of 20 parts per billion (ppb) on peanut products. It has now become clear however that corn and other grains can also be hosts to aflatoxin producing moulds and that grains appear to constitute the most important source of these toxins in the United States (Rodricks, 1978). Our food of course contains innumerable other natural substances whose toxicity, or indeed chemical structure, has never been studied. For example, about 200 compounds are present in the white potato Solanum tuberosum in readily detectable concentrations (Crampton & Charlesworth, 1975). Another naturally occurring intoxicant has recently been discovered, albeit not positively identified, in Turkey. It has been known for a long time that the inhabitants of the village Karain in Anatolia (whose name means 'abdominal pain' in a Turkish dialect) are peculiarly liable to develop a certain kind of chest disease. This has now been
Environmental intoxicants TABLE
433
1. Occurrence of aflatoxin in peanut and corn products Percentage of samples contaminated
Peanut products U.S.A. and Canada Thailand Uganda Philippines Corn and corn products U.S.A. corn belt U.S.A. southeast Thailand Uganda Philippines
Aflatoxin B r (ppb)
19
1
54 19
470 70
88
130
25 41
35 40
97
Environmental intoxicants and their fundamental interactions J. EISINGER AND W. E. BLUMBERG Bell Laboratories, Murray Hill, N. J. 07974 The biological sciences are and should be responsive to the needs of medicine: thus the deficiency diseases (e.g. beri-beri and scurvy) stimulated the search for vitamins, just as contagious diseases fathered immunology and the study of antibiotics. It has been said that we live in the era of environmental disease, which suggests that an important fraction of human disease in technological societies is induced by environmental conditions, including some which are more commonly referred to as life styles. While this assessment requires further amplification (see below), it is clear that the sheer number and variety of potentially dangerous environmental agents has become so great that a better understanding of their fundamental interactions with the living system is clearly needed. As of the end of 1977, the American Chemical Society's Chemical Abstract Service contained over four million entities, and it is estimated that there are about 63000 chemicals in common usage. The toxicity of only a very small number of these has been investigated. Environmental intoxicants may be defined as materials (or radiations) in our environment (e.g. air, water, food) which are inimical to human health. This definition ignores the somewhat arbitrary division into naturally occurring and man-made intoxicants since some of the former are extremely toxic and some of the latter may afford protection against certain diseases. The important issue in identifying an environmental intoxicant is whether it interferes with the normal processes of a cell at levels of exposure encountered in the environment. It is the identification of such agents which is the most important, as well as the most difficult, task of the environmental physician. While the collection of papersf offered in this issue of the Quarterly t These papers are based on talks presented at the joint meeting of the Biophysical Society and the American Physical Society in Washington, D.C., in March 1978, as a 'Symposium on the Fundamental Interactions of Environmental Intoxicants'. We are grateful to Dr I. J. Selikoff for many stimulating talks and for contributing to the symposium which inspired this collection of papers. 27
o.RB-11
430
J. EISINGER AND W. E. BLUMBERG
Review of Biophysics deals with only a small fraction of the intoxicants which surround us, it is our hope that they will serve to illustrate the wide spectrum of such agents affecting the living system in a variety of ways. Included are papers which discuss biochemical interactions as well as interactions between light and crystalline matter with cell components. Other papers deal with the degradability of toxins and with the biological defenses of cells and indeed of man. To lend perspective to the contributions in this issue, it may be useful to make some general remarks about diseases of environmental origin and their role in an industrial society. Environmental diseases have attained their primary importance today only because the most serious health hazards of what Fernand Braudel (1974) has called the biological ancien regime have been largely eliminated by public health legislation and such medical triumphs as smallpox vaccination and antibiotics. Even so, one can only make a case for the majority of disease having environmental causes if one includes among the causes such voluntarily administered ones as cigarette smoking, injudicious eating, and excessive drinking (Kristein, Arnold & Wynder, 1977). Nevertheless, the great public concern about environmental pollution and disease (particularly cancer) has awakened among scientists a new interest in xenobiotics (molecules foreign to life) and in their modes of action. Apart from the new biochemical insights which this has led to, this field has considerable practical importance, if for no other reason than because our environment has been stocked for generations to come with molecules that were essentially non-existent during evolutionary times and because organisms have in many cases been found to have extreme sensitivities and unpredictable responses to them. The manifestations of adverse environments can be roughly divided into two groups. The first deals with widely distributed environmental conditions which generally have a low incidence of disease. The health problems associated with them have origins which are notoriously difficult to trace and are often unrecognized. The second kind of manifestation is what might be called environmental health disasters which result from heavy exposure to a toxic environment of a geographically (or otherwise) well-defined population. We would like to offer a few examples and comments on both of these environmental problems.
Environmental intoxicants
431
The widely distributed conditions - environmental pandemics - include some to which exposure is voluntary but closely related to the life styles of our society, such as cigarette smoking and rich diets. The first in particular have been studied extensively, and there exists strong evidence that it greatly increases the risk of disease. In spite of the wide publicity which these findings have received, cigarette consumption in the U.S. has not been reduced, and attempts to achieve this by public education alone have failed. Involuntary pandemics are caused by the wide distribution of such well-known carcinogens as polycyclic aromatic hydrocarbons (PAH), which usually result from the incomplete combustion of organic matter. These pollutants were present at low levels in the environment during evolutionary times and, as discussed elsewhere in this volume (Blumberg, 1978), man has developed enzyme systems to modify these xenobiotics in order to facilitate their excretion. It is clear however that the levels of PAH in our environment have been rising steadily along with their commercial production and exceed the ' natural' level, which is primarily due to forest fires, by more than an order of magnitude (see Fig. 1). Similarly the level of inorganic lead in our environment is some orders of magnitude greater than in the pre-industrial period (Eisinger, 1978). It is very difficult to estimate how much disease can be traced to such pollutants, but there is little doubt that it is a considerable amount. Another much studied industrial pollutant is asbestos, which has been shown to cause lung cancer and mesothelioma, a cancer of the lining of the chest cavity, at quite low levels of exposure (Langer, 1978). It is thus a danger to the general population since asbestos was and is widely used in insulation and many other applications so that exposure to asbestos fibres is virtually unavoidable in industrial societies. An interesting aspect of asbestos is the long latency period (20-30 years) between exposure and the first manifestation of disease. Such long delays present a challenging puzzle to the physiologist and greatly complicate the task of the environmental epidemiologist, who relies on surveys of heavily, usually professionally, exposed populations (e.g. insulation or shipyard workers in the case of asbestos) to give warning to the general population (Selikoff & Lee, 1978). By no means are all environmental intoxicants pollutants: Aflatoxin is an example (Rodricks, 1978) of one which is endemic to a wide variety of foods in vast areas of the world and is of natural origin. 27-2
432
J. EISINGER AND W. E. BLUMBERG 1-0
1850
1970
Fig. i. Total unsubstituted polycyclic aromatic hydrocarbon (PAH) production, relative to the 1970 level, calculated as a function of time by Hites, Leflamme & Farrington (1977).
Aflatoxins are among the most potent carcinogens in animals and are the major cause of cancer of the liver in man in certain parts of the world (Stoloff, 1977). They are metabolites of moulds which under suitable climatic conditions infest many foodcrops and stored foodstuffs (some examples from reference (Langer, 1978) are given in Table 1). The best known aflatoxin contamination is that of peanuts, and in 1969 the U.S. Food and Drug Administration imposed a maximum level of 20 parts per billion (ppb) on peanut products. It has now become clear however that corn and other grains can also be hosts to aflatoxin producing moulds and that grains appear to constitute the most important source of these toxins in the United States (Rodricks, 1978). Our food of course contains innumerable other natural substances whose toxicity, or indeed chemical structure, has never been studied. For example, about 200 compounds are present in the white potato Solanum tuberosum in readily detectable concentrations (Crampton & Charlesworth, 1975). Another naturally occurring intoxicant has recently been discovered, albeit not positively identified, in Turkey. It has been known for a long time that the inhabitants of the village Karain in Anatolia (whose name means 'abdominal pain' in a Turkish dialect) are peculiarly liable to develop a certain kind of chest disease. This has now been
Environmental intoxicants TABLE
433
1. Occurrence of aflatoxin in peanut and corn products Percentage of samples contaminated
Peanut products U.S.A. and Canada Thailand Uganda Philippines Corn and corn products U.S.A. corn belt U.S.A. southeast Thailand Uganda Philippines
Aflatoxin B r (ppb)
19
1
54 19
470 70
88
130
25 41
35 40
97
