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188 THE LIFE SCIENCES able to feed herself. A few hundred acres of new wheat were planted in 1964. By 1968, more than 20 million acres were under cultivation and plans called for 40 million acres in 1970. Withal, this represents only a fraction of India's farmland and is but a start. The new wheats and rices emerged from painstaking crossbreeding with available strains to provide seeds that carry the most advantageous char- acteristics and with new mutants, each being examined for new useful properties. These new grains demand careful nurture. Designed to resist lodging, they also require and can make maximum use of fertilizers and water. They must be planted at the optimum moment and carefully tended. And, as in American agriculture, if the "revolution" is to be sustained, it will be essential that in these regions there be a continuing program of plant breeding to replace current strains as they fall victim to infection or pests. The revolution began 30 years ago, when the Rockefeller Foundation sponsored a program to improve wheat and maize in Mexico. Through these efforts, the average yield per acre of wheat had been increased more than threefold by 1964. In 1959, the Rockefeller and Ford Foundations decided on a similar effort with rice, the staple food in the Orient. To this end, they established an International Rice Research Institute in the Philip- pines. The successful new rice varieties were bred there, drawing on the background of genetic information that had been accumulated in this coun- try and Mexico. Success of the new varieties depends on packaging selected seed, fertilizer, and pesticides so that the farmer has these essential inputs at planting time. Perhaps the most significant aspect of this "green revolu- tion" is that traditional farmers have been shown what can be done and are thus receptive to the further changes necessary to extend and stabilize these advances. There is no better illustration of the contribution of biological science to human welfare. MAN AND HIS ENVIRONMENT Science is applied to human affairs through an increasingly complex net- work of technologies. Each new technology finds acceptance if, for example, it solves a problem, eases a burden, enriches life, assures the food supply, or facilitates communication and transportation. But each such bene- ficial technology must be examined for its potential social cost. In this connection scientists must be particularly wary of threats to the public health, to the fertility of the soil, to the quality of air and water, and to the security of renewable resources.

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BIOLOGY IN THE SERVICE OF MAN 189 Perhaps 500,000 distinct chemical entities and mixtures are in current use and hundreds more are added annually. Each must be considered for its effects on the biosphere, particularly on man himself-effects that may be acute, dramatic, and self-apparent or extremely slow, difficult to detect, and even indirect. For these reasons an increasing force of trained scien- tists is engaged in these activities. The level and pace of such activity are patently insufficient to the national need. Such agencies as the Food and Drug Administration and the Fish and Wildlife Service are seriously under- staffed relative to national needs. Let us consider only a few pertinent problems typical of this large and disparate field of concern. Water Supplies Although it may not long be true, most American communities may still boast a supply of biologically safe water for domestic purposes. The char- acter of the situation is such that potential hazards must be avoided from the beginning rather than removed after their introduction. The life scientist must be aware of these hazards, establish appropriate monitoring pro- cedures, be aware of indications in the community of failure of controls, and establish reasonable standards. Avoidance of improper metals is now a long-established practice, as are a variety of procedures designed to minimize the presence of pathogenic bacteria. That human disease can be transmitted through the water supply has been known in a qualitative way throughout history. Yet specific under- standing of its role in disease transmission goes back only to the past cen- tury, with investigations of the spread of cholera and typhoid fever. Co- operative work by engineers, biologists, chemists, and physicians on the organisms responsible for such diseases and on development of methods for their control was so successful that these infectious diseases have been virtually eradicated from developed countries in which adequate treatment and sanitary control of water supplies are maintained. Water can be freed of pathogenic microbial agents by (1 ) protection of water sources against initial contamination; (2) removal of organisms by filtration, adsorption, or similar physical means; and (3) chemical destruc- tion of the organisms. All three approaches have been put under stress by increasing population density and demand for water. Because of these factors, coupled with a concurrent increase in sources of contamination i.e., human and animal wastes completely uncontaminated primary sources of water are becoming difficult to find. As knowledge of the factors that affect the survival of waterborne patho- gens and their sensitivity to various forms of water treatment increases, new

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190 THE LIFE SCIENCES ~. ., methods of water management may well emerge. Research is needed to provide sanitary engineers with a rational rather than empirical basis for the design of facilities for collection, treatment, and distribution of water. It has become apparent in recent years that traditional control measures are inadequate to prevent the spread of certain viral diseases that may be waterborne. Epidemics of infectious hepatitis have been known to be caused by water contamination. A most dramatic example was the 1956 epidemic in Delhi, India, where nearly 30,000 cases of hepatitis resulted from a temporarily contaminated water supply. There are now about 50 documented instances of similar, although much smaller, waterborne out- breaks of this disease, several in the United States. Because the hepatitis virus has only recently been identified and no animal other than man is known to be sensitive to this virus, thus precluding an animal model of the disease, there has until now been little opportunity to engage in the neces- sary studies. Other viruses are assumed to be waterborne but have not been shown to transmit disease. With the possible exception of the polio virus, con- firming epidemiological patterns have not yet been established. New tech- niques are required to gain definitive information about the health hazard these viruses present and the necessity for measures to remove them from communal water supplies. Increasingly, water authorities must be aware of chemical contamination at the source, particularly by materials entering through groundwater or washed from the air by rain. Such materials do not announce themselves; one must be aware of the problem, perform appropriate analyses, establish standards, and, when feasible, institute procedures for removal of offending chemicals. Such actions may be taken on the general principle that no contaminants are acceptable, but there is greater conviction and urgency when the biological effects of a given contaminant are known. Most note- worthy, perhaps, are the various agricultural chemicals insecticides, herbi- cides, and fertilizers. The soil burden of nondegradable insecticides is already such that they will be leached and present in communal waters for years to come. Current levels are such that no general risk is known to exist. Similar considerations apply to the herbicides. Although its tera ~, togenic activity has resulted in a ban, 2,4~5-T concentrations in communal water supplies are trivial. The problems presented by fertilizers and non- degradable detergents are somewhat more serious. Nitrate from fertilizers, leached from manure piles or from sewage-disposal plants, occasions methemoglobinemia (the iron of hemoglobin is oxidized to the ferric state, Fe:+, in which condition it is useless for internal oxygen transport). Sig- nificant levels of methemoglobin caused by such contamination have been detected in various populations. No known deaths have resulted, and, in

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BIOLOGY IN THE SERVICE OF MAN 191 almost all such cases, it has been possible to trace the contamination and act accordingly. These incidents serve to point up the need for intelligent, biologically sophisticated management of water supplies. Air The intensities of air pollutants in American cities today may be no greater than they were 25 years ago, except for a few areas such as Los Angeles or New York on bad days. But techniques for measuring the levels of chemicals or particulate matter in the air, then as now, were less than ade- quate. The most significant change in this quarter-century is that the American people are beginning to demand a higher level of quality in the environment. Levels of air pollution are difficult to measure, but new, sophisticated instrumentation is being developed. The body of knowledge concerning the biological effects of known pollutants is increasing but is unconvincing. Experience has shown that, when meteorological conditions heighten the concentration of atmospheric pollutants, individuals suffering from chronic lung disease and perhaps those with cardiac disorders may have serious reactions. Such episodes have no observable effect other than discomfort in the average, healthy member of the population, the indi- vidual of most concern to environmental biologists trying to evaluate the potential for serious consequences of long-term low levels of exposure. The most evident aspect of acute episodes of air pollution thus far is the increase in airborne sulfur dioxide and other sulfur-containing products from the combustion of coal and fuel oils. Normally less than 0.1 part per million (ppm ), concentrations during prolonged inversions may rise to 0.5 ppm or more. Such concentrations are harmful to the most susceptible individuals and discomforting, for the remainder. The fact that no evident illness is occasioned in healthy members of the population should not lead to a false sense of security. Effects not detectable by current procedures are not necessarily absent. In a few cases, toxic effects of pollutants have been documented. Beryllium, for example, is known to have produced serious disease downwind of beryllium-processing plants. Pollutants of well-established biological significance, e.g., carbon monoxide and dead, are being added to the atmosphere in immense quantities, primarily from automobile exhausts. It is clear that all urban dwellers, because of the relatively high atmos- pheric concentrations of carbon monoxide, carry significant amounts of carboxyhemoglobin but not in sufficient quantity to limit physiological function. In episodes of striking increase, the consequence is an additional pumping burden on the heart, of no account in normal persons but perhaps sufficient to lead to serious crisis in those with incipient cardiac failure.

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192 THE LIFE SCIENCES From epidemiological studies, the connection between cigarettes and lung cancer, heart disease, emphysema, and other diseases is now known. The carcinogenic action of cigarette smoke has been confirmed experi- mentally in animals, although specific chemical toxins have yet to be identified. Inhalation of smoke by rodents does not cause neoplasia; however, painting the tar of cigarette smoke on their skin is highly carcino- genic. There is a possibility that smoke contains agents that are not in themselves capable of producing cancer but that promote the growth of tumors by somehow interacting with otherwise innocuous doses of car- cinogens. The causal relationship to cardiac disease is not understood. Nicotine does increase the oxygen requirement of the heart, while carbon dioxide from the smoke reduces the available oxygen supply, but these effects seem too small to account for known effects. Attempts to separate the effects of cigarette smoke from those of more general air pollution indicate a much higher correlation between smoking and disease than be- tween community pollution and disease. It seems quite conceivable that a combination of cigarette smoking and general air pollution accounts for the higher statistical incidence of disease in the smoking population. The necessity for monitoring the quality of air will not be lessened. New technologies will pose new hazards, and existing technologies will be used on larger scales. Thus, it is anticipated that combustion of fossil fuels for generation of electricity will quadruple by the end of the century, while that for transportation will double. Thus the potential gain from use of more efficient, less polluting automobiles may be totally offset by the in- creased level of use, a phenomenon demonstrated in the Los Angeles area. Food and Drugs Mounting concern with the effects of myriad chemicals in the environment has brought under closer scrutiny the agents that are deliberately added to food. Approximately 1,700 food additives are in use in the United States, and an equal number of additional materials go into animal feed and packaging materials. Each agent is subject to regulation by the Food and Drug Administration, which issues specific requirements to define closely the allowable concentrations of some agents and maintains a list of others that are "Generally Regarded As Safe" (the GRAS list). The safety of many of these materials that have enjoyed long tenure on the GRAS list is predi- cated on limited examinations performed years ago and on their long and seemingly innocuous usage by the public. Safety is no longer easily assumed, nor is it a simple concept. When cyclamates noncaloric sweeteners were first introduced in the early

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BIOLOGY IN THE SERVICE OF MAN 1950's, their use was limited to individuals who used them to sweeten coffee or tea. A decade later, the diet-soft-drink era came into being, fol- lowed by a mushrooming of the diet-food industry. The very fact that cyclamates were then consumed by many people in substantial amounts generated concern. Experiments voluntarily conducted by a pharmaceutical house revealed bladder tumors in a group of mice that had been fed vast doses of cyclamate over their entire life-spans (the equivalent of several thousand sweetened cups of coffee per day for many. Although there was no evidence of similar effects in human beings despite the huge scale of the human "experiment," according to the Delaney amendment to the Pure Food and Drug Act of 1958, any agent in food that causes cancer in any species, regardless of dose, must be banned. Cyclamates, therefore, were ordered removed from ordinary foods. But this points up major difficulties. Where is the rational limit? How shall one balance the beneficial effects of voluntary caloric restrictions and avoidance of obesity bv millions of Americans against the very remote chance of tumors in a few? By any seemingly reasonable standard, cycla- mates had been adequately screened for toxicity until an almost absurd experiment was undertaken. It is noteworthy that, among the group of animals at half the tumor-producing level in the diet, absolutely no lesions were encountered! Quite conceivably, an equivalently rigorous and exten- sive review of the GRAS list will yield some similar experiences. When there is available a substitute that, by the same yardsticks, is innocuous, the course is clear. But when there is no substitute? This dilemma risk versus benefit, and not necessarily to the same individuals characterizes most major decisions concerning the environment. The difficulty cannot readily be mitigated, but certainly each such decision should rest on thor- ough understanding of the biological implications. It cannot be assumed that toxicological data are adequate for many of the familiar chemical entities in the environment, let alone the scores of new ones. It was only 25 years ago that investigators learned of the effect of nitrate on hemoglobin. Recognition that cadmium in low concentrations in water may have adverse physiological effects and that some water sup- plies occasionally carry appreciable quantities of this element is even more recent. A Public Health Service standard for an allowable limit of cadmium was not set until 1962. The task of the toxicologist is complicated by the fact that what is usually required is an analysis not of the acute effects of large doses but of the effects of very small doses accumulated gradually, of variability of response within a large population, and of the effects of other environmental variables and of disease. If there is evidence that a toxic compound accumulates in the body and that no tolerance develops to it or that its effects are ~. ~, , 193

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THE LIFE SCIENCES irreversible, that agent is more menacing than one that can be detoxified or readily excreted or whose effects are reversed when it is removed from the environment. The interaction of chemicals is often difficult to determine. The inter- action of trace amounts, difficult enough in themselves to detect, compounds the difficulty, but can be of critical importance. A few years ago, it was found that when malathion and EPN (ethyl nitrophenyl benzytriphospho- nate), both organophosphate insecticides, are fed together to experimental animals, the toxic effects are considerably greater than the sum of the toxicities of both chemicals. In consequence, the Food and Drug Ad- ministration issued a regulation requiring that each new organophosphate be tested jointly with every organophosphate already approved before the new insecticide is cleared for sale. The pyramiding of tests that this would engender is apparent. Relief came when the basis of this hazardous inter- action was elucidated, thus permitting use of simpler means for predictin dangerous combinations. Both of these insecticides are toxic because they inhibit cholinesterase, an enzyme essential to normal functioning of the neuromuscular system. Alone, malathion is only mildly toxic to mammals because it is itself de- stroyed by another group of enzymes, the aliesterases, before it can render extensive damage to cholinesterase. The aliesterases, however, are inhibited by EPN, thus opening the way for the total toxic effect of the malathion that accumulates. Understanding of the underlying mechanisms in this situation has permitted direct measurement of the effects of new pesticides by testing them against appropriate enzyme systems, offering a rational approach to the design of new pesticides. The need to overcome similar problems in testing procedures and to acquire the ability to predict adequately what will occur in given situations is evident. Toxicologists, aware of their own limitations and responsible for protecting the public health, would have to lean on crude and cumber- some procedures to avoid any uncertainty about the safety of products they stamp with approval. But even excessive caution cannot guarantee safety if the substance of fundamental biological knowledge is inadequate. Re- sults of extensive testing on animals may not be applicable to man. Thalid- omide only rarely deforms unborn rats though it consistently deforms human beings. Relatively early identification of the effects of this com- pound in man must be attributed to the fact that it results in a deformity that is so rarely seen ordinarily that the problem was readily evident. Phocomelia, an anomaly in which the limbs fail to develop, is so rare a congenital abnormality that it immediately aroused suspicions of some environmental agent when the deformity began to appear in a relatively