Paper number 0062 -- Revised 1995
G.C.D.: Energy and Resources Group Building T-4, Room 100 University of California Berkeley, California 94720
P.R.E.: Center for Conservation Biology Stanford University Stanford, California 94305
Although improvements in human health represent a crucial aspect of development worldwide, many trends associated with development and global change appear to be reducing health security. In this article, we define the human epidemiological environment and describe key biophysical, economic, sociocultural, and political factors that shape it. The potential impact upon the epidemiological environment of aspects of both development and global change are then examined: the influences of human population size, mobility, geographic distribution, and nutritional status; modernization; loss of indigenous medicinal knowledge; microbial evolution of antibiotic resistance; land conversion and biodiversity loss; agricultural intensification; stratospheric ozone depletion; and climate change. Human vulnerability to infectious disease is often strongly and deleteriously influenced by ongoing, intensifying changes in these factors. An unprecedented level of communication and cooperation between experts, institutions, and nations is required to respond to the increasing threat of epidemic disease, which points to a promising area for enhanced interdisciplinary collaboration.
When one comes into a city to which he is a stranger, he ought to consider its situation, how it lies as to the winds and the rising of the sun; for its influence is not the same whether it lies to the north or to the south, to the rising or to the setting sun. These things one ought to consider most attentively, and concerning the waters which the inhabitants use, whether they be marshy and soft, or hard and running from elevated and rocky situations, and then if saltish and unfit for cooking; and the ground, whether it be naked and deficient in water, or wooded and well-watered, and whether it lies in a hollow, confined situation or is elevated and cold...
From these things he must proceed to investigate everything else. For if one knows all these things well, ... he cannot miss knowing, when he comes into a strange city, either the diseases peculiar to the place or the particular nature of the common diseases, or commit mistakes, as is likely to be the case provided one had not previously considered these matters. And in particular, as the season and year advances, he can tell what epidemic disease will attack the city, ... and what each individual will be in danger of experiencing from the change of regimen. -- Hippocrates, On Airs, Waters, and Places, cat 400 B.C. (quoted in Garrett 1994, p. 234).
Good health is such an integral part of human well-being that, in many languages, everyday greetings and meal-time toasts are synonymous with best wishes for it. In English, the very word "salutation" is derived from the Latin salutare or salus, which refer to health and safety. People have always been wary of being unexpectedly stricken by disease.
Although the loss of good health is inherently unpredictable, human behavior at the individual and societal levels profoundly influences the incidence of disease. This has been understood since ancient times and, indeed, the same fundamental factors that determined human vulnerability to disease early on remain paramount today. The rates and scales over which these factors now operate are unprecedented, however, greatly disrupting the epidemiological environment and opening new opportunities for disease agents.
The epidemiological environment consists of the conditions and processes, both biophysical and social, that influence the interaction between human beings and disease agents. It encompasses a complex of interrelated factors, including:
* the parasites that are actually or potentially pathogenic to Homo sapiens, defined broadly to include subcellular, unicellular, and multicellular organisms such as prions , viruses, bacteria, fungi, protozoa, helminths, and arthropods; ( Whether these proteins could be considered organisms and, indeed, whether they exist at all is a matter of debate that extends beyond the bounds of this article (see Prusiner 1995).)
* biophysical determinants of the reproductive success of such parasites, including conditions such as temperature and moisture, availability of and transmittancy to vectors and hosts, the evolution of virulence, and coevolution of human immunity and parasites' resistance to the immune system and other human defensive measures;
* social determinants of the reproductive success of such parasites, including the frequency and nature of interpersonal contact, travel and migration patterns, access to health care and information, pharmaceutical markets, urbanization, poverty, public health policy, medical training, funding of medical research, and political leadership.
These factors span virtually the entire human environment. Nonetheless, their nexus is little appreciated because the pathogenic actors in it are largely invisible -- out of sight, out of mind (Ornstein and Ehrlich, 1989). Few people are aware that each human being encloses billions of microorganisms and is surrounded by trillions more. Some of these organisms play key roles in keeping people alive; others represent lethal threats. The two kinds do not have to be very different. Some strains of Escherichia coli, common bacteria that live in the human large intestine, are helpful in synthesizing vitamins that are essential to people. Other strains may cause lethal disease.
Recent and projected future changes in the epidemiological environment pose a major threat to health security, which is presently manifesting itself in a variety of ways (Ehrlich and Ehrlich, 1970, pp. 148-151; 1972, pp. 181-184; Ehrlich et al., 1977, pp. 606-609; Leaf, 1989). Old diseases such as malaria (e.g., Pearce, 1995), tuberculosis (Bloom and Murray, 1992; Brown, 1992), bubonic plague (Altman, 1994; Burns, 1994), and cholera (Glass et al., 1992) are resurgent; the new epidemic of AIDS is creating formidable public health problems; some strains of old bacterial enemies may be becoming more deadly (Nowak, 1994); "miracle" drugs are losing their potency; and a variety of nasty viruses such as Ebola appear to be lurking in the wings (e.g., MacKenzie, 1995; Morell, 1995; Altmann, 1995). Malaria was once thought to be on the way toward eradication (Garrett, 1994, p. 31), yet now there are between 300 and 500 million cases annually, resulting in as many as 2.7 million deaths (Nussenzweig and Long, 1994).
These problems mark the second major round in a coevolutionary (Ehrlich and Raven, 1965) battle between Homo sapiens and its parasitic enemies. The first began with the agricultural revolution, some 10,000 years ago. This led to the development of towns and cities where human populations grew to a size and density at which they could sustain epidemics of diseases such as measles, smallpox, flu, cholera, and polio (Black, 1966, 1975). It also led to concentrations of human and animal wastes ideal for the propagation of protozoan and helminth parasites (Inhorn and Brown, 1990).
After World War II, many believed that the first round was ending in victory for humanity with the defeat of microbial pathogens through the use of sanitation, water purification, vaccination, antibiotics, and pesticides. Indeed, in 1969 U.S. Surgeon General William H. Stewart testified before Congress that it was time to "close the book on infectious disease" (Fisher, 1994); like most physicians of his day, he was deeply ignorant of the nature of the epidemiological environment.
As the human population has increased to unprecedented size, it has dramatically changed this vast, tumultuous, little understood world. Some of these alterations have been to our benefit; many are already clearly deleterious and promise to become more so in the future. Alterations in the epidemiological environment have been little examined, and do not fit into the heuristic framework by which other aspects of human activity and the environment have been explored (Ehrlich and Holdren, 1971; Holdren and Ehrlich, 1974; Ehrlich and Ehrlich, 1990).
In our view, in no aspect of the human environment are the economic costs of environmental deterioration clearer, of greater importance to those concerned with development, or more threatening to the human future. Consider the warning of the late Howard Temin, who received the Nobel Prize for his discovery of retroviruses (which include HIV): "...it is not surprising that a major new epidemic has accompanied the dramatic post-World War II social changes -- the greater urbanization and enormous population increases in Africa, the rise of freer lifestyles in North America and Europe, and the growth of jet travel everywhere. If anything, the surprise might be that there has been only one major new epidemic" (Temin, 1989, p. 1).
In this paper, we examine the impact on this hidden environment of both development and global change. These two aspects of the increase in scale of the human enterprise are so tightly interrelated as to make any classification of their elements quite arbitrary. We have structured our inquiry around three categories of changes: (i) those in biophysical and social characteristics of the human population; (ii) those in human tactics and strategies for controlling disease; and (iii) dramatic alterations of the biophysical environment, collectively referred to as "global change" (Lovejoy, 1993), that for the most part represent unintended consequences of the first category.
For successful establishment in a host population, a parasite must achieve a basic reproductive rate of greater than one (Macdonald 1952, May and Anderson, 1979). In general, this means that each infected individual, on average, infects more than one other individual. This, in turn, means that a threshold or critical community size is necessary for the perpetuation of most epidemic diseases. The precise threshold for disease establishment is determined by complex characteristics of both the parasite and the host, such as whether transmission is direct or mediated through a vector and/or animal reservoirs; seasonality in transmission; incubation, latent, and infectious periods of the host; the existence and duration of acquired host immunity; reproductive requirements of the parasite; and so on (Anderson and May 1991).
The bottom line is that human population size and density are key variables in epidemiology, influencing the rate of introduction of new parasites into the population, their chances of becoming established, the rate of their spread, the evolution of their virulence, and the capacity of human cultural evolution to defend against them. Paleolithic groups were probably relatively free of virulent epidemic disease (Cohen, 1989; Inhorn and Brown, 1990). It was not until a critical community size was reached in early agricultural societies that parasites previously confined to nonhuman animals were able to exploit Homo sapiens. Examples of such diseases include smallpox, influenza, and measles, which are thought to have evolved from monkey pox, avian flu, and rinderpest or canine distemper, respectively (Fenner et al., 1974). Measles apparently could not get a foothold in human populations until there were aggregations of about 200,000 to 500,000 people (Bartlett, 1957; Black, 1966).
Today's 5.7 billion people represent a brand new environment for pathogens and potential pathogens (Mitchison, 1993). It is the densest population the world has ever seen, and it contains large numbers of immune-compromised people due primarily to malnourishment, the presence of immunosuppressive pollutants in the environment (Ross et al., 1992; Repetto, 1992; Colborn et al., 1996) and, increasingly, to AIDS. That vulnerable portion of the population makes an especially favorable environment for the evolution of virulence in viruses, bacteria, and fungi that in the past were viewed as benign (e.g., Sternberg, 1994; Georgopapadakou and Walsh, 1994). For a parasite, evolving host specificity to humans would amount to winning the biggest jackpot in history.
It is not clear, at present, how HIV-1 (the virus that causes the most serious form of AIDS) first entered the human population, but one possibility is that it was the result of a transfer by a vector (e.g., a mosquito or tick) from another primate. Such events are thought to occur very rarely (Humphery-Smith et al., 1993), but increased human numbers make more probable such "jumps" from other species.
Moreover, population growth is accompanied by large families, which increase the vulnerability of populations by presenting arrays of immune-similar individuals. As viruses colonize individuals in such families sequentially, they may evolve greater virulence, as was the case in rural Senegal where the case fatality rate was higher in children who caught the measles from relatives than among those that contracted the disease from nonrelatives (Garenne and Aaby, 1990). Immune-similarity of individuals may also have contributed to the near extinction over recent centuries of native Americans and their cultures (Roberts, 1989). Black (1992, 1994) has argued that the decimation of these populations by disease was due not just to a lack of immunological experience that made them highly susceptible, but also to a relative lack of genetic variability tracing to their rapid expansion after the genetic "bottleneck" of the trans-Bering invasion. Sadly, the genetic mixing through immigration that might protect isolated cultures would probably simultaneously destroy them (Black, 1994).
The movement of people has always been an important mode of spread of disease. The legacy of merchants, explorers, and conquistadores extends far beyond that assessed by most historians (McNeill, 1976). European sailors brought smallpox, measles, and swine flu to the New World; the first epidemics of leprosy in Europe followed the expansion of the Roman Empire; the black death of fourteenth-century Europe made its way from central Asia via the Silk Road; and cholera was carried unwittingly by traders and armies into Europe from India in the early 1800s. As we write, world health authorities are declaring states of emergency in Central America, and port cities throughout Latin America are on alert, due to the rapid spread of dengue fever (New York Times, 1995; UPI, 1995).
The spread of epidemics is clearly greatly facilitated by the development of high-speed modern transport systems. In recent years, indices of the amount of international travel were highly associated with the spread of AIDS (Darrow et al., 1986). Steamships alone made it possible to transport bubonic plague to all major ports in the world at the end of the last century, something that could not have occurred earlier because all of the susceptible passengers on plague-infested, slow-moving sailing ships would generally have died before the ships reached ports (McNeill, 1976). People carrying dengue fever on airplanes have represented an important mode of its recent spread (Monath, 1993). Rapid transportation helps the spread of antibiotic-resistant strains of bacterial pathogens (Tauxe et al., 1990).
Modern high-speed transport also plays a role in the distribution of recreational drugs; large supplies produced in the "golden triangle" of southeast Asia or the mountains of South a flow easily into rich and poor nations around the world. Almost everywhere, sharing of needles by addicts contributes to the propagation of infectious diseases. The problem is especially serious because narcotic addicts are often immune-compromised, making their bodies ideal environments for the multiplication of numerous pathogens (e.g., Cherubin, 1971; Levine and Sobel, 1991).
Modern transport also helps to move animals that are potential vectors or disease reservoirs around the world, which combined with projected climate change could further degrade the epidemiological environment (Soule, 1995; Dobson and Carper, 1992). In Uganda a century ago an agricultural officer introduced the shrub Lantana camera for use as an ornamental hedge. The Lantana provided excellent moist habitat for tsetse flies, and an increase in sleeping sickness followed. Perhaps the most spectacular recent case of the transfer of a dangerous vector was the moving from Asia to the United States of a mosquito (Anopheles albopictus; the Asian tiger mosquito) capable of transmitting dengue. The mosquito larvae apparently survived a ship journey in water collected in old tires (Craven et al., 1988; Monath, 1993). Soon after its introduction, A. albopictus was found to be carrying another potentially dangerous virus, that of La Crosse encephalitis (Francy et al., 1990; Henig, 1995). The usual vector of this disease is a woodland mosquito that relatively rarely bites human beings. George Craig of Notre Dame, perhaps America's greatest authority on mosquitoes, considers the combination of that virus and the aggressive tiger mosquito especially worrying (Henig, 1995). Dengue has returned to Mexico just south of the border of the United States (Rohter, 1995), from where the tiger mosquito could move it north into areas in which its normal vector cannot survive the cold winters.
Modern transportation systems certainly improve the epidemiological environment by making it relatively easy to move food to the hungry and medical personnel, drugs, and vaccines to the ill. But even here they are a two-edged sword, because they are susceptible to disruption during epidemics by fear and by the disease itself (Ehrlich and Ehrlich, 1970; p. 150). Truck drivers and pilots are generally loath to enter plague areas.
As nations develop, they are characterized by relatively larger urban populations (Gizewski and Homer-Dixon, 1995). This can improve access to health care, food, and clean water. For example, in urban areas of poor nations, a minimum of 170 million people do not have access to clean drinking water, but an estimated 855 million lack that access in rural areas (World Bank, 1992). About 35 percent of the population of developing nations (1.5 billion people) now live in cities, so this suggests that the water-supply element in the epidemiological environment has been somewhat improved by urbanization, even among the poor. Only some 15 percent of urbanites in poor countries may suffer bad drinking water, while over a quarter of the 3 billion who live in the countryside do. (These data may overstate the quality of drinking water in many cities in developing countries, however; much depends on such things as what is meant by "a minimum of 170 million people" and interpretation of the statement that "many of those who officially have access still drink polluted water"; World Bank, 1992, p. 47).
Urbanization does not have only positive effects on the epidemiological environment, however (e.g., Morse, 1991). Cities above all bring large numbers of people into intimate contact. In 1950 only New York, London, and Shanghai had populations of over 10 million. By the start of the 21st century, 23 cities will have surpassed that number, and more than half of all human beings are projected to be city dwellers by 2010 (United Nations, 1987). This sudden concentration of humanity would greatly facilitate disease transmission even if all urbanites were well fed and supplied with clean water, adequate shelter, and access to health care. But that is hardly the case, and it will be difficult to achieve given the tremendous rate of growth in demand for such resources and services.
In poor countries, urban inhabitants very often lack clean water and adequate sanitation. In Uganda, unskilled urban workers often spend 10 percent of their income on small quantities of poor-quality water (Bradley, 1993b). Yet even poor quality water can be important for use in washing to restrict the direct fecal oral transmission of diseases (Bradley, 1993b).
A problem afflicting cities in rich and poor nations alike is the lack of control of disease reservoirs (e.g., rodents) and vectors (e.g., mosquitoes). Rats, for example, are all too common in New York and other cities in the United States. Urbanization has contributed to the great spread of dengue fever (Anonymous, 1995c) by bringing large numbers of people into close association with the household mosquito Aedes aegypti, the vector of the causative virus (Monath, 1993). A. aegypti breeds in water standing in containers, and everything from coke bottles to old tires that can hold small pools help support it in third-world slums.
The anonymity associated with large-scale movement and urbanization is associated with behavior that tends to be suppressed in small communities. In both rich and poor nations, urban conditions may promote drug use, prostitution, and greater sexual promiscuity in general, especially among homosexual men (Symons, 1978, although time-series data on this point are lacking). Interestingly, for diseases transmitted sexually or through the sharing of needles, lack of acquired immunity in recovered hosts permits persistence in low-density populations. In such cases, a principal criterion for persistence is a threshold average number of partners, rather than a general threshold host density (Anderson and May 1991; Thrall et al., 1993).
The increase in density that inevitably accompanies population growth is now thought by some (Ewald, 1994) to increase the virulence of certain parasites, such as those that cause dysenteries and influenza, which do not depend on vectors for transmission (and thus whose spread is slowed if hosts are immobilized by illness). Important evidence for this comes from the record of the increased virulence of such diseases during crowding of troops in wartime -- indeed it has been suggested that the mysterious increase in virulence that made the 1918-19 flu epidemic the worst ever was due to the evolution of higher virulence in the hideous trench conditions on the western front (Ewald, 1994).
Finally, another feature of urban (and suburban) areas that causes deterioration in the epidemiological environment is the increased "air tightness" of buildings (in the name of energy efficiency) and air conditioning (and, incidentally, the reduced rate of airflow in the cabins of modern jet airliners, also in the name of energy efficiency). All three factors tend to keep people breathing the same recirculated air, making the transmission of airborne pathogens all the easier (Tolchin, 1993), especially if the systems are not operating optimally (Moser, et al., 1979). In addition, at least one emerging bacterium has adapted itself beautifully to air-conditioning systems: Legionella pneumophila, the causative agent of often-fatal Legionnaire's disease (Hudson, 1979; Lederberg et al., 1992).
Overpopulation and concomitant urban crowding also appear to exacerbate the conditions for crime, war, and other forms of social disruption that degrade the epidemiological environment, although the connections are complex and disputed (see, e.g., Percival and Homer-Dixon, 1995). For instance, the economic and social deterioration in the former Soviet Union has led to a decline in nutrition, a shattering of the public health system, higher mortality (especially in males), and, among other things, epidemics of diptheria (Stone, 1993; Maurice, 1995). Globally, it appears that the development of urban infrastructure, including public heath facilities, is retarded by violence (Gizewski and Homer-Dixon, 1995).
In short, urban centers may be considered "ecosystem[s] that can amplify infectious diseases" (De Cock and McCormick, 1988) or, more bluntly, "graveyards of mankind" (J. Cairns, unpublished, quoted in Garrett 1994).
Suburbanization has also greatly altered the epidemiological environment, especially in the United States. It clearly helped improve the epidemiological environment of those who could flee the cities, while perhaps worsening it for those, mostly people of color and the elderly, forced to stay behind with a diminishing tax base and decaying health-care delivery system.
But other problems have overtaken some suburbanites as a result of large-scale ecosystem alteration. The first stage was the massive clearing of eastern forests, with the removal of both large trees and top predators such as wolves and mountain lions. Many of farms for which the clearing was done were then reclaimed by second growth, and this in turn was fragmented by suburbs. The result is a habitat matrix that is ideal for deer, which often are also protected from hunting, and some small rodents, especially the white-footed mouse (Peromyscus leucopus). Deer and small mammals in turn support the tick, Ixodes scapularis (=dammini, Oliver et al., 1993) which transmits the spirochaete (Borrelia burgdorferi) that causes Lyme disease from its natural reservoir in the mouse to human beings (Lastavica et al., 1989; Barbour and Fish, 1993). Large concentrations of deer support dense adult tick populations (the deer do not serve as important reservoirs of the spirochaete) and young ticks acquire the spirochaetes from smaller animals. In the past 15 years Lyme disease has become the most common arthropod-borne infection in the United States (Lederberg et al., 1992). Babesiosis, a sometimes-fatal disease similar to malaria, can be transmitted in the same manner as Lyme, and sometimes people are infected with both. So can an emerging, sometimes deadly tick-borne disease, ehrlichiosis, caused by the rickettsia Ehrlichia chafeensis (Adler, 1994).
Although undernutrition is declining globally, in both relative and absolute terms, roughly 1 billion people still do not have diets sufficient to support normal daily activity, and nearly 500 million are essentially slowly starving to death (summary of data in Uvin, 1994). Hunger, however, is rarely the proximate cause of mortality; rather, the Grim Reaper usually makes his appearance in the guise of disease. Approximately 10 million people die of "hunger-related disease" annually (Dumont and Rosier, 1969, pp. 34-35; WHO, 1987; WRI, 1987, pp. 18-19; UNICEF, 1992).
A synergistic interaction between undernutrition and infection is well established (e.g., Smythe et al., 1971; Beisel, 1984; Harrison and Waterlow, 1990; Ellner and Neu, 1992). Infections enhance the need for nutrients (by increasing a person's metabolic rate through fever), while simultaneously diminishing their supply (through reduced appetite, lower absorption by the gastrointestinal tract, loss through faeces, and direct loss in the gut; Beisel, 1984; see also the excellent summary in Dasgupta, 1993, on. 405-408). This synergism is especially apparent in young children: both mortality and morbidity are critically determined by a child's nutritional status, as measured by a weight-for-height ratio (Chandra 1983). Interestingly, the synergism is not universal; in fact, undernourishment may actually confer a survival advantage in some cases, although this remains speculative (see Dasgupta, 1993, p. 407). Overnutrition, epidemic in some developed countries, may impair immune function as well (e.g., Chandra, 1981).
Death rates from many diseases were lowered dramatically in today's developed nations long before antibiotics or other effective medical interventions were available (McKeown, 1979). This was accomplished largely with improved nutrition, housing less vulnerable to vermin, cleaner drinking water, improved isolation from human fecal contamination, and soap (e.g., McKeown, 1979; McKeown et al., 1972; 1974). Improvement of water supplies traces back to Dr. John Snow's work on cholera (1855). A rough estimate of the positive health impacts of providing those who now lack it with access to safe drinking water and adequate sanitation would be the annual prevention of 2 million deaths from diarrhea in children under five, and having 200 million fewer cases of diarrheal illness, 300 million fewer people infected with roundworms, 150 million fewer infected with schistosomes, and 2 million fewer infected with guinea worm (World Bank, 1992).
Interestingly, however, the general improvement of sanitation carries a risk. By causing the prevalence of relatively benign diseases to decline, such improvements might enhance the chances of more virulent parasites to invade. This appears to have been the case of herpes simplex virus 1 (HSV-1), the cause of "cold sores" or "fever blisters," which declined in developed countries due to improved personal hygiene. Unfortunately, however, the relatively benign HSV-1 may provide some protection against the development of genital herpes (caused by HSV-2), which is now an epidemic sexually transmitted disease (STD). Improved public health conditions call for careful surveillance of populations that become increasingly immunologically naive.
The level of health care generally rises with modernization and development. This is apparent in several indicators, such as the proportion of physicians in a population (World Bank, 1993). In sub-Saharan Africa, for example, there are about .12 doctors for every 1000 people; in India, .41; in China, 1.37; in the United States, 2.38, and in Switzerland, 1.59. In the same areas, hospital beds per 1000 population were 1.1, 0.7, 2.6, 5.3, and 11.0, respectively. Another index of overall health care is the percentage of children immunized against measles -- 52, 77, 96, 80, and 90 in those areas, respectively. Infant mortality rates (per thousand live births) and life expectancies (in years) are perhaps the best indices of health, and the quality and availability of health care are factors in those statistics (adequacy of food supplies and quality of water supply are others). Infant mortality and life expectancy respectively in sub-Saharan Africa are 95/52; India, 74/60; China, 44/69; U.S., 8/76; and Switzerland, 5.6/78 (Population Reference Bureau, 1995).
Since roughly 1930, the medical system has made a positive contribution to public health. While there clearly is no perfect correlation between standard economic measures of development and the quality of health care, it seems fair to say that modernization of the health-care system mostly improves the epidemiological environment. Development, by bringing medical care to billions of people, has saved innumerable lives through immunization, use of antibiotics, surgery, and so on.
Nonetheless, physicians and hospitals can also have negative effects on the epidemiological environment by helping to spread pathogens. This problem can be particularly acute in developing nations; at the extreme, it can be devastating, as when a poorly prepared mission hospital in Zaire served as a focus for the spread of Ebola virus in a situation where simple sterilization would have greatly limited the propagation of the disease (Garrett, 1994). In rich nations as well, the rate of nosocomial infections (those acquired in hospitals) remains about 5 or 6 percent. That amounts to 2 million infections per year in the United States, 6 million excess days of hospital stay, some 20,000 direct deaths, as well as contributions to perhaps 40-60,000 additional deaths (Last, 1987). Many of these deaths can now be traced to drug-resistant bacteria.
A classic example of iatrogenic disease (induced by medical treatment) is blackwater fever, whose victims were overcome with fever, urinated dark fluid, and often died. It took decades to discover the cause: in the vast majority of cases it was overuse of quinine to treat malaria (Manson-Bahr and Apted, 1982).
Even medical "miracles" can have negative impacts on the epidemiological environment. Transfusions, transplants, and deliberate immune-suppression in connection with transplants provides new ways for pathogens to move from person to person or (in the rare cases of transplant from other animals) species to species, while adding to the immune-compromised population. Hepatitis B and HIV have been widely spread through blood transfusions. Today HIV is being spread extensively that way in India, where a quarter of all HIV-positive individuals in West Bengal are blood donors, and where up to half of all blood in banks is infected with hepatitis B (Anonymous, 1995a). The rare prion of Creutzfeldt-Jakob disease has occasionally been transmitted by corneal transplants (Miller, 1989).
Urbanization, modernization, and other forces have led to the supplanting of indigenous medical systems by western medicine, in the process leaving a great unmet need for health care. Ratios of physicians to population as high as one to more than 10,000 or 15,000 in the world's poorest countries leave no doubt that most people do not get medical treatment from trained professionals (Fischer 1994). According to the World Health Organization, over 80 percent of people rely for their primary health care on tradition plant medicines (Dobson, 1985).
Meanwhile, traditional medicinal knowledge is rapidly disappearing with cultural change and declining access, in both urban and rural areas, to sources of natural medicinal products. It is estimated that, in the Amazon Basin alone, one indigenous culture goes extinct annually (Dobson, 1985). The principal natural sources, upon whose extracts many modern pharmaceuticals are based, are plants (Farnsworth, 1988; Eisner and Meinwald, 1995). Most villages in the world are no longer surrounded by the natural habitat that formerly served as a medicine cupboard, supporting a diversity of medicinal plants, animals, and microorganisms. In many regions of the world, bodies of folk knowledge that have been honed for thousands of years are disappearing at an alarming rate.
In the absence of traditional medicine, the role of doctor in most developing nations is played either by the local pharmacist or by the sick individual and his or her relatives themselves. Antibiotics and other powerful drugs are readily available without proper diagnosis and prescription, through pharmacies and black markets (Levy, 1992). This tragic situation is made worse by its sinister consequences, microbial evolution of resistance to antibiotics.
As Nobel Laureate Joshua Lederberg said, "The survival of the human species is not a preordained evolutionary program. Abundant sources of genetic variation exist for viruses to learn new tricks, not necessarily confined to what happens routinely, or even frequently." (quoted in Garrett, 1995, p. 6). The current crisis in antibiotic resistance is severe enough to lead another expert to question whether or not humanity is entering a "post antimicrobial era" (Cohen, 1992). The primary source of the crisis is overuse of antibiotics, not just for treating human disease, but also as a feed supplement to speed the growth of animals being raised for slaughter (Neu, 1992; Fisher, 1994).
Viruses, bacteria, fungi, and their human and non-human hosts are engaged, neck-and-neck, in a coevolutionary race, perpetually trying to devour, outcompete, or otherwise defeat each other (Ehrlich and Raven, 1965; Anderson and May, 1979; Ehrlich, 1986, May, 1993). Bacteria had billions of years of experience using antibiotics to battle each other, fungi, and other microbes before Homo sapiens evolved. It is no wonder that they show signs of defeating our antibiotic weapons a mere half-century after they were first deployed on a large scale (Anonymous, 1995b). Indeed, some evolutionists and medical professionals have been very concerned about the evolutionary consequences of antibiotic misuse, going all the way back to Alexander Fleming himself (e.g., Ehrlich and Holm, 1963; Lappe, 1982; Slater, 1989; Cohen, 1992; Levy, 1992; Neu, 1992; Russell, 1993).
Bacteria have such rapid life cycles, extraordinary abilities to swap genetic material (e.g., Davies, 1994; see also Conway et al., 1991 on the malarial parasite), and intrinsic mechanisms of resistance derived from their evolutionary experience (Nikaido, 1994) that the surprise really is that they did not all become resistant to our puny efforts sooner. The oft-heard lament that no antibiotics have been found that control viruses would be humorous if it were not so tragic. Viruses, especially RNA viruses (such as HIV) reproduce and mutate even more rapidly than bacteria, and could be expected to evolve resistance even faster.
Human beings, on the other hand, are condemned by their long generation times (decades rather than minutes as in microorganisms) to evolve genetic responses very slowly. But they have a capacity for cultural evolution that can be much more rapid, and that gives Homo sapiens the best chance of staying even or getting ahead in the coevolutionary race (e.g., Alland, 1970; Inhorn and Brown, 1990).
Regrettably, human behavior with respect to the use of antibiotics has been maladaptive since the start. These "miracle drugs" are routinely misused in anticipation of or in response to all manner of possible illnesses, without deterring whether an antibiotic could even be effective (Lappe, 1982; Levy, 1992; Fisher, 1994). Even when taken to cure infections against which they are effective, they are often taken for far too short a period (due to ignorance and/or poverty), thereby killing off the most susceptible bacteria while promoting those that are resistant.
In developed nations, widespread ignorance of evolutionary implications among medical professionals, false or misleading information distributed by drug companies, inner-city poverty, and the determination of misinformed patients to get antibiotics by any means necessary have played major roles in the rapid evolution of antibiotic resistance. In developing nations, the principal factors at work include the inaccessibility of professional health care, inability to afford the necessary full course of antibiotic treatment, and the casual availability of antibiotics through pharmacies and black markets. Poor health policy, in general, is responsible in both regions of the world (Lappe, 1982; Levy, 1992; Fisher, 1994; Erlich, 1995).
The particular case of a well-to-do Argentinian businessman is indicative of what is going on worldwide. This energetic individual led a busy life and did not like to be held back by colds or other minor illnesses. Although he respected the advice of his physician, for convenience he usually simply treated himself with readily available drugs sold at the local pharmacy. On one occasion, however, he developed a cough and fever that would not go away, although he tried to treat it with several different antibiotics. To make a long story short, he eventually saw his doctor and was sent immediately to the United States for treatment of acute leukemia, which can be caused by the antibiotic chloramphenicol. Although the leukemia treatment went well, the patient became infected with a strain of Escherichia cold from his own intestinal tract that was resistant to eight different antibiotics -- a level of resistance never seen before by his doctors in the U.S. He died of massive infection in a matter of a few weeks, succumbing to a usually beneficial bacterium turned lethal due to his excessive self-treatment with antibiotics (Levy, 1992).
Such multiply resistant bacterial strains can easily be passed on to other people in hospitals or otherwise spread rapidly. For example, public health officials have been able to trace the initial source of penicillin-resistant bacteria causing gonorrhea, now found worldwide, to brothels in Southeast Asia (Levy, 1992).
Back in 1950, few, if any staphylococci exhibited antibiotic resistance. Yet by 1960, about 80 percent of the strains of staph showed resistance to penicillin, tetracycline, and chloramphenicol. At the St. Joseph Hospital in Paris, levels of resistance were up to 14 times higher than reported in the United States. By 1980, penicillin was only effective against 10 percent of the varieties of staph that it used to control (Lappe, 1982). A similar story has unfolded in the case of most pathogenic bacteria (Levy, 1992). Most recently, bacteria have developed a complex strategy for protecting themselves from vancomycin -- the "last ditch" antibiotic for use agains enterococci (Lipsitch, 1995). The fear now is that staph will acquire the resistance via plasmid transfer from enterococci.
Overuse of antimalarial drugs has had similar grim consequences, leading eventually to strains of the most lethal malaria species, Plasmodium falciparum, that were resistant to virtually all drugs (Looareesuwan et al., 1992; Ter Kuile et al., 1993; Gay et al., 1994). Resistant malaria has led, among other things, to increased AIDS transmission through the use of transfusions to save children from death from chloroquine-resistant Plasmodium falciparum (Bloland, et al., 1993; Lackritz et al., 1992). Sadly, there are now signs that the schistosomes (the blood flukes that cause Bilharzia) are becoming resistant to praziquantel, the most important drug used to treat the disease. Since some 200 million people are affected by the disease, and some 200,000 die annually, this is bad news indeed (Brown, 1994).
Another very serious problem has developed in connection with the intensification of animal agriculture: the massive use of antibiotics in farm animals. More than half of the antibiotics produced in the United States -- in the vicinity of 8000 tons -- are fed annually to livestock alone, mostly in sub-therapeutic doses which are ideal for the development of resistance (Lappe, 1982; Holmberg et al., 1984; Fisher, 1994; Levy, 1984, 1992; Wuethrich, 1994). Transmission of antibiotic-resistant bacteria from livestock to humans can occur through routes hardly imagined earlier. In 1991 in Massachusetts an outbreak of a dangerous strain of Escherichia cold (0157:H7) was traced to contaminated apple cider; the cider was made from apples from trees that had been fertilized with livestock manure. Subsequently, this strain of E. cold has been blamed for 6,000 food poisonings, sometimes lethal in small children, each year in the United States (Garrett, 1994).
Moreover, antibiotics are given not just to domestic livestock, but also to honeybees, fish, family pets, and even to plants and trees (Levy, 1992). For example, various palms are injected with oxytetracycline to delay or prevent "lethal yellowing," and chrysanthemum cuttings are placed directly into an antibiotic solution to deter disease. Streptomycin is one of the two most commonly used antibiotics on plants. Streptomycin resistance is now among the most prevalent resistances found in bacterial strains associated with humans, possibly tracing to its widespread use on plants. Although the use of streptomycin in humans is now rare (because of its toxicity), streptomycin resistance generally occurs in conjunction with resistance to other antibiotics that are important in human therapy.
Homo sapiens has been very successful in developing industrial societies, although it has been very unsuccessful at spreading the benefits of development equitably (Ehrlich et al., 1995). But successful development has allowed the scale of human enterprise to become so large that humanity is now a global force -- rivalling natural processes in its ability to modify climate, change landscapes, mobilize minerals, and so forth (SCEP, 1970; Turner et al., 1990). As a result, the entire biosphere is being altered in a process generally known as "global change."
In many people's minds, "global change" is virtually synonymous with global warming and climate change. But it includes much more than changes in the balance of gases in the atmosphere. The growth of the human population to unprecedented size is itself an aspect of global change. The modification of every square centimeter of Earth's surface by human activities is an aspect of global change. So is the extent of land degradation, which now afflicts over 40 percent of Earth's terrestrial vegetated surface and has caused the loss of about 10 percent of the potential direct instrumental value of productive land (Daily, 1995). And, perhaps least appreciated of all, alteration of the epidemiological environment is an aspect of global change (Epstein, 1992).
The threat of "emergent viruses" -- such as HIV, Ebola, Marburg, and Lassa -- traces not just to the recent dramatic increase in human population size. Rather, it is that increase, coupled with mass migration into areas only marginally suited, at best, to intensive agriculture and dense human habitation, that so increases the chances for eruption of a "new" disease. Larger and larger human populations, pushed into contact with animal reservoirs of disease, both increase the odds that a pathogen will invade human populations and that the disease will become endemic. In small populations, diseases would more likely quietly die out as death and immunity exhausted the supply of susceptible individuals.
Population growth has been especially rapid in Africa, which had only about 275 million people in 1960, now has 720 million, and may double that population size by 2025. Africa is the homeland of humanity, and our closest living relatives, the old-world monkeys and apes, are abundant there. Evolutionarily, these are the animals most likely to be harboring parasites, such as Marburg virus, that are capable of infecting Homo sapiens (Smith et al., 1967; Kissling et al., 1968).
Forest clearance is one of the commonest land-use changes wrought by Homo sapiens, usually occurring in connection with agriculture, and it may exert positive or negative effects on the epidemiological environment. On the positive side (at least from an epidemiological viewpoint), it can reduce contact of human populations with forest-dwelling disease sources or reservoirs, including primates which are among the most likely sources of emergent viruses.
On the negative side, forest clearance can bring the Haemogogus mosquitoes that transmit yellow fever among animal reservoirs in forest canopy into contact with human beings. That can start yellow fever epidemics, with the disease being propagated in the human population by the domestic mosquito vector, Aedes aegypti (Brom, 1977). In Brazil, the most effective Amazonian vector of malaria is Anopheles darling), a species of the forest and forest edge. It makes malaria a major hazard for farmers attempting to colonize the area (Bradley, 1993b). Clearing primary forest in Tanzania has caused expansion of malaria by increasing temperatures and creating sunny breeding sites for the vector Anopheles gambiae. Forest clearance in Latin America has exacerbated problems with leishmaniasis by increasing populations of both its mammalian reservoirs and sandfly vectors (Sutherst, 1993).
Land degradation, including deforestation and desertification, also exerts a great impact on the epidemiological environment by contributing to malnutrition (e.g., Dasgupta, 1993; Daily, 1995; Ehrlich et al., 1995). In addition, it may promote fungal diseases such as coccidioidomycosis (valley fever), which is contracted by breathing spore-laden dust (Sternberg, 1994).
Land conversion for agricultural purposes is the paramount direct cause of the ongoing mass extinction episode. As a matter of convenience, biodiversity loss is usually quantified in terms of the rate of loss of species diversity. A conservative estimate of the global rate of species loss is one extinction per hour (Wilson, 1992), which exceeds by at least four orders of magnitude the rate of evolution of novel species (Lawson and May, 1995).
It is important to remember, however that biodiversity refers to the diversity of life at all levels of organization -- from the subcellular to the ecosystem level. Dramatic as the rate of species loss is, the relevant rate here -- that of the loss of population diversity -- is still orders of magnitude higher (Daily and Ehrlich, 1995; unpublished analysis). The benefits that biodiversity supplies to humanity are delivered through populations of species (Daily and Ehrlich 1995; Daily, 1996). In the extreme, the preservation of just one population of each of Earth's species in a zoo or park would do humanity little good, since most people would not have access to it.
Moreover, the diversity of populations is important for human health. Different populations of the same species may produce different types or quantities of defensive chemicals (potential pharmaceutical or pesticide compounds; e.g., Dolinger et al., 1973). For example, the development of penicillin as a therapeutic antibiotic took a full 15 years after Alexander Fleming's famous discovery of it in common bread mold. This was in part because scientists had great difficulty producing, extracting, and purifying needed quantities of it. In 1940, from 500 litres of broth culture scientists were not even able to extract one-fourth of what was later established as a single day's treatment of pneumococcal pneumonia. Yet, by 1944 production capabilities had improved so tremendously that all seriously injured British and American troops could be treated. One key to this improvement was the discovery, after a worldwide search, of a variant of Fleming's mold that produced more penicillin than the original (Dowling, 1977). Thus, population diversity in the mold Penicillium notatum helped in saving many lives.
Least appreciated is the impact of destroying not other life forms themselves, but their interactions. For it is in these interactions that many clues to the discovery of new pharmaceuticals lie. It is hard to appraise a weapon of war, or even recognize its existence, without observing it in use. The discovery of penicillin by Fleming occurred largely by accident when, upon returning from a weekend vacation, he noticed that the mold that had contaminated one of his bacterial cultures was actually killing the bacteria (Levy, 1992). That is, Fleming saw the aftermath of the war being waged on his laboratory plates. Only then did he realize that penicillin is a mold's weapon of war and that humans might be able to wield it to great advantage, too.
The magnitude of this problem is difficult to overestimate. A recent study has shown that 118 out of 150 top prescription drugs are based on chemical compounds from other organisms, three quarters of them from plants. In the U.S. nine of the ten top prescription drugs are based on natural plant compounds (Dobson, 1995). Yet only slightly more than a thousand of some 365,000 plant species have even been preliminarily screened for medicinal compounds. It is impossible to know what opportunities for pharmaceutical discovery are forever lost with the destruction of biodiversity -- but the loss is akin to emptying our armory.
Recent intensification of agriculture has had manifold effects on the epidemiological environment. Expansion of food supplies has had an enormous positive effect (even if temporary; Ehrlich et al., 1995), but there have been negative effects as well. Broadcast spraying of synthetic organic insecticides against crop pests has induced resistance not only in insects that attack our food supplies, but also in vectors of disease. This problem was first foreseen by Rachel Carson (1962). Agricultural spraying, especially on cotton and rice, has contributed greatly to the evolution of pesticide resistance in the Anopheles mosquitoes that transmit malaria and thus to the resurgence of that disease (World Health Organization, 1976; Chapin and Wasserstrom, 1981; Ehrlich, 1986; Georghiou, 1990). "In effect, throughout southern India, the recrudescence of malaria now represents a social cost of growing high-yielding rice -- just as elsewhere in India and Central America it represents a social cost of producing cotton" (Chapin and Wasserstrom, 1981, p. 184).
The switch from subsistence agriculture to cash-cropping of rice in the Demerara river estuary of Guyana caused a related and similarly widely manifested deterioration of the epidemiological environment. Flooded rice fields were ideal breeding grounds for the local Anopheles vectors, while mechanization reduced local populations of domestic animals, the preferred source for the Anopheles's blood meals. The enlarged population of vectors concentrated on Homo sapiens, and the result was a malaria epidemic (Desowitz, 1981). In Honduras, agricultural intensification and associated forest fragmentation has led to the concentration of disease vectors and reservoirs in periurban "misery belts", where the incidence of malaria, leishmaniasis, dengue fever, and Chagas' disease has increased dramatically (Almendras et al., 1993). Rodents, in particular, are important consumers of agricultural crops and players in the life cycle of many groups of diseases, including bacterial and viral haemorrhagic fevers, tick-borne encephalitides, Venezuelan equine encephalitis, the hantaviruses, typhus, and spirochaetal and parasitic diseases. Agricultural intensification typically promotes rodent populations through the removal of predators and other natural enemies while supplementing their food supply (Epstein and Chikwenhere, 1994).
Increases of bilharzia (schistosomaisis) with the introduction of irrigation following the construction of the Aswan, Volta Lake (Ghana), and other dams are another example (Ehrlich and Ehrlich, 1970; Mobarak, 1982; Bradley, 1993b). So was the epidemic of Rift Valley Fever that ravaged people in the Aswan area in 1977 (Meegan, 1978). In the first case, perennial irrigation and large impoundment lakes made possible by the dams proved ideal breeding grounds for snails that served as intermediate hosts for the blood flukes that cause bilharzia (Ehrlich at al., 1977). Thus incidence of bilharzia in the population along the Nile between Cairo and Aswan increased from 5 percent before the dam to 35 percent after (Van der Schalie, 1974). In the second, the mosquito vector (Aedes pseudoscutellaris) of a virus causing a hemorrhagic disease similar to yellow fever built up huge population sizes in newly irrigated fields. That, possibly linked to the evolution of increased virulence in the virus (Davies et al., 1981; Monath, 1993) caused a nasty epidemic which killed hundreds of people and sickened hundreds of thousands.
Water management schemes can either encourage or discourage the simuliid (blackfly) vectors of onchocerciasis (river blindness). A dam may destroy the rapids required by blackfly larvae, and substitute bilharzia (which is easier to treat) for onchocerciasis (Bradley, 1993b).
Intensification of agriculture in the Pampas of Argentina led to the introduction of herbicides after World War II to fight weeds that competed with maize production. The resultant change in the grass flora favored a mouse, Calomys musculinus, which was the natural reservoir of the Junin virus, the cause of Argentine hemorrhagic fever. The disease was described in 1953 and is still expanding its range (Johnson, 1993). Another viral disease, Oropouche fever, emerged following the agricultural colonization of the Amazon and the planting of cacao as a cash crop. The latter makes excellent breeding conditions for the vector, a biting gnat, Culicoides parasnsis (Monath, 1993). In contrast, a shift from cattle raising to subsistence agriculture encouraged another small mouse, Calomys callosus, in eastern Bolivia, which was the reservoir of the Machupo virus. The latter invaded the human population causing Bolivian hemorraghic fever. The cautionary point is this: any major land-use change is likely to alter the epidemiological environment in ways that are often difficult to predict.
Ducks, other waterfowl, and shorebirds (Webster, 1993) are major reservoirs of influenza viruses, and some flu pandemics are thought to have their origin in integrated pig-duck farming in China (Morse, 1993). Pigs can function as "mixing vessels" for new flu strains able to infect human beings; an agricultural system that puts the reservoir and the mixing vessels in intimate contact seems bound to degrade the epidemiological environment. The pig-duck system, in place in China for several centuries and now being intensified, constitutes a natural laboratory for generating new flu strains (Scholtissek and Naylor, 1988) as viruses move back and forth between human beings and swine and swine and ducks (Webster, 1993). It might have been responsible for the catastrophic 1918-1919 pandemic, possibly the worst single disease catastrophe ever to afflict humanity in terms of numbers of lives lost in a short period of time (Kiple, 1993). Even though many strains of flu that infect birds are genetically attenuated in primate systems (e.g., Murphy, 1993), such an event could transpire again (Webster, 1993).
Ozone depletion may also play a role in reducing food supplies and in directly suppressing immune responses (e.g., Jones and Wigley, 1989; McCalley and Cassel, 1990; Jeevan and Kripke, 1993). We hope that the steps being taken to restore the ozone layer will be sufficient to cancel this possible deleterious effect (e.g., Benedick, 1991).
The likelihood of human-induced, rapid climatic warming is becoming increasingly clear. The possible magnitude of the change over the next century could be as large as the change from 18,000 years ago, when there was a mile of ice over New York, to today. The regional consequences of global warming are, at present, impossible to predict in detail. It is almost certain, however, that such change will alter the geographic distributions of pathogens, reservoirs, and vectors; the competitive and predator-prey interactions among them; and the probability of disease transmission (Smith and Tirpak, 1988; Weihe and Mertens, 1991; Bradley, 1993a).
Many tropical diseases, whose distributions are now restricted by climate, may move into the temperate zones (Haines, 1990; Shope, 1991; Sutherst, 1993) where the majority of human beings live. Such diseases kill 15-20 million people annually at present (Gibbons, 1992). Recent modelling efforts indicate, for instance, that malaria could extend its range by tens of millions of square kilometers (Martin and Lefebvre, 1995; Pearce, 1995). This is supported by extensive empirical information on the coupling of malaria outbreaks and climatic fluctuations, particularly those associated with the El Nino-Southern oscillation (Bouma et al. 1994). In addition, detailed analysis of the 1987 resurgence of malaria incidence in Rwanda revealed that temperature and rainfall explained 80 percent of the variance in monthly malaria incidence (Loevinsohn, 1994). Climate change appears to have played a role in India's recent bout with bubonic plague as well (e.g., Epstein, 1994). This should not lead one to conclude that devastating epidemics of now-tropical diseases are inevitable concomitants of global warming. Rather, it should lead to the conclusion that such epidemics are possible, should be guarded against, and could be better anticipated by careful monitoring of climatic changes, especially at the latitudinal and attitudinal limits of diseases (Gillett, 1974; Rogers and Packer, 1993).
A more general lesson pertinent to the impacts of both development and global change on the epidemiological environment is that any large-scale change in an ecosystem can greatly affect the health of human beings involved in that ecosystem. Drainage of swamps, screening of houses, and general improvements in sanitation and nutrition had yellow fever and malaria on the retreat in the southern U.S. and malaria receeding from southern Europe long before the etiologies of those diseases were understood. On the other hand, an unusual weather sequence, not clearly associated with any human activity, caused major changes in the ecosystems of the southwestern United States in 1992 and 1993. Exceptionally wet weather broke a six-year drought in the spring of 1992 and caused superabundant production of pinyon-pine nuts, which in turn led to an outbreak of deer mice (Peromyscus maniculatus). The abundant urine and feces of those mice carried a previously unidentified strain of hantavirus, which caused an outbreak of often-fatal respiratory disease in 1993, especially among those on Navajo reservations (Nichol et al., 1993; Hughes et al., 1993).
Alterations of marine ecosystems accompanying climatic change may also cause unpleasant changes in the epidemiological environment (Epstein, 1992; Epstein et al., 1993). We can only guess what warmer climate and rising sea level might mean to the strains of Vibrio cholera e that live in the bays and estuaries of the Gulf Coast of the United States that serve as a reservoir for cholera (Shope, 1991).
Important as those changes may be, it is likely that the impact of climate change on agricultural production will constitute its most important influence on the epidemiological environment. Rapid climatic change could very much reduce humanity's ability to keep food supplies up with expanding populations (Daily and Ehrlich, 1990; Ehrlich et al., 1995). More widespread malnutrition would increase the proportion of the population that is immune compromised, further worsening our position in the coevolutionary race against pathogens.
There is increasing evidence that the epidemiological environment has played a major role in shaping human history -- for example, allowing the easy conquest of the western hemisphere by Europeans and preventing a similar sequence of events in Africa (McNeill, 1976, 1993). If humanity does not exercise more caution, diseases could reassert their historic influence. The AIDS situation in Central African nations may already be so bad that population growth there will be reversed by AIDS mortality itself (Anderson et al., 1991). But one always must be aware that direct mortality caused by a pathogen now may only be the tip of the iceberg. Social breakdown has accompanied epidemics in the past, and our limited experience with more recent ones gives little reason to expect human behavior to be different (e.g., Hudson, 1979). In highly centralized modern societies, starvation could quickly follow plague if the latter led to disruption of transport systems.
At the very least' disease is costly in economic terms, and problems with the epidemiological environment retard development processes which already face great difficulties. For example, preventing deformity in India's 645,000 lepers would have increased the nation's 1985 GNP by some $130 million, equivalent to about 10 percent of the external aid the nation received at that time. Yet leprosy amounted to less than 1 percent of India's disease burden (World Bank, 1993). The global burden of disease, defined as the present value of the future stream of disability-free life lost as a result of death, disease, or injury, is already huge. For 1990 it was estimated at 1,362,000,000 disability adjusted life years (DALYs), 259 DALYs per thousand in the population, or the equivalent of 42 million infant deaths. Any substantial increase in the disease burden of the global population would be an economic as well as a human catastrophe.
It is easy to underestimate the danger of such a catastrophe (Hudson, 1979). One could conceivably be caused simply by an increase in the virulence of a common pathogen. Webster (1993) describes a flu virus in chickens that suddenly became highly lethal in Pennsylvania in 1983 -- wiping out all the chickens in some rearing facilities. "The Agriculture Department used the standard methods of eradication, killing the infected chickens and the exposed neighboring birds and burying the carcasses. But we can't help asking ourselves what we would have done if this virus had occurred in humans. We can't dig holes and bury all the people in the world" (p. 41). Webster goes on to point out that when he tried the anti-viral drug amantadine on chickens infected with the virus, the highly mutable virus (Palese, 1993) became resistant within a week. "Battery" chicken rearing facilities should be an ideal environment for evolving highly lethal strains of diseases not transmitted by vectors (Ewald, 1994), and (as we have pointed out -- Daily et al., 1994) many people seem determined to move humanity into a condition parallel to that of battery chickens.
It has long been recognized that a fundamental problem in health care in developing countries is that "curative care is emphasized while prevention and early treatment are neglected" (World Bank, 1980, p. 7). That remains a critical problem, but not just in poor nations. While much attention is paid in rich nations to prevention of cancer (but not enough to suppress smoking, its most important known cause), support of efforts to prevent infectious disease is actually declining in the United States and perhaps elsewhere.
There are few barriers today between rich and poor to stop the spread of epidemic disease. That Ebola, Marburg, Lassa fever and a host of other "emergent" viruses have not yet become established outside Africa may be primarily a matter of luck. There has been no such luck with HIV. Similarly, the evidence is abundant that pathogens evolving resistance to the weapons humanity develops to counter them can share that ability with other pathogen populations globally (Tauxe et al., 1990; Cohen, 1992).
The situation with tuberculosis (TB), the global leader among infectious diseases in causing death (almost 3 million annually, mostly in Asia and Africa), is alarming (Bloom and Murray, 1992; Brown, 1992). Drug-resistant strains are emerging that threaten to make it impossible to control the disease; a third of New York City's cases in 1991 were resistant to one or more drugs, and the fatality rate of those infected with strains resistant to two or more major antibiotics is 40-60 percent, roughly that of untreated cases (Bloom and Murray, 1992). TB is resurgent for a number of reasons in addition to drug resistance. It is a "sentinal disease" for AIDS because a large portion (about one-third -- Brown, 1995) of the human population is infected by Mycobacterium tuberculosis asymptomatically, and TB commonly becomes patent when the immune system is depressed (the annual risk of infected people developing the disease if they are HIV positive is roughly the same as the lifetime risk if they are not coinfected with HIV). TB is primarily spread via droplets released in speaking and coughing. Increased crowding, poverty, HIV infection, drug resistance, the difficulties of doing research on the causitive organism, and a decline of public health services (Bloom and Murray, 1992) make it one of the major threats to health in both rich and poor nations.
It therefore is in the interest of both rich and poor to start altering the epidemiological environment to give Homo sapiens as much of an edge as possible in its coevolutionary race with pathogens. Some steps are obvious:
First and foremost, the medical community, decision makers, and the general public must, as far as possible, be made aware of the evolutionary and ecological dimensions of the human health situation. In the short run, that requires media cooperation, but in the long run it means much more attention should be paid to evolution and ecology in schools -- especially in medical schools. Unless there is general understanding of the perpetual ability of microorganisms to evolve in response to human biological and cultural evolution, people will continue to seek "magic bullet" cures for infectious diseases. That is a strategy usually doomed to eventual failure and it could potentially be a recipe for catastrophe. Humanity will win its coevolutionary race with some pathogens (the best example is the smallpox virus), continue it with others, and enter into new races with emerging pathogens. What must be avoided is losing races.
Physicians by instinct and training focus on the health of individuals; they must learn to pay more attention to the health of whole societies and to deal with the difficult conflicts of interest that often arise between the two. One physician, Jeffrey Fisher (1994), recommends that physicians be required to take periodic recertification exams in which they are tested on antibiotic knowledge. If antibiotics had been used more judiciously over the past few decades, there doubtless would have been more deaths from bacterial infections misdiagnosed as viral, and fewer deaths from allergic reactions to antibiotics. But a small net increase in deaths would probably have been a reasonable price to pay to avoid the present situation, which portends a return to the pre-antibiotic era and much higher death rates.
Public education is essential as well. Public pressure in the United States and elsewhere has led to the stigmatization of AIDS victims on one hand and (at least in the U.S.) the treatment of the HIV pandemic as a civil rights rather than a public health issue. Certainly there should be heavy penalties for revealing publicly that an individual has AIDS, but AIDS testing of all blood and making medical personnel alert to seropositive patients is essential. Lack of data is a major reason that it is extremely difficult to predict the course of the AIDS epidemic (e.g., Chin, 1995). In general, much greater emphasis should be placed on interdicting the spread of pathogens rather than, as has been the case since World War II, treating people after infection.
If humanity is to mount a coordinated ecological-evolutionary response to infectious disease, it must have the infrastructure necessary to implement it. We think this means strengthening the Centers for Disease Control in the United States and similar institutions in other nations, and finding ways to minimize bureaucratic delays and turf wars within them and within the global coordinating body, presumably the World Health Organization.
The steps required on the front lines cannot be exhaustively listed here, but some of the more obvious include:
1. Redoubling efforts to halt the growth of the human population and eventually reduce it to an optimum size (Daily et al., 1994). This is a very basic step, since overpopulation makes substantial, diverse contributions to the degradation of the epidemiological environment, in addition to degrading other aspects of Earth's carrying capacity (Daily and Ehrlich, 1992).
2. Establishing early warning networks (including comprehensive monitoring and reporting systems) and expert response teams to improve the chances of promptly detecting and limiting potential viral epidemics (Henderson, 1993) and sharing information on drug resistance (Gibbons, 1992b). At the moment policies seem to be moving backwards. Overconfidence, leading to funding cuts at federal, state, and local levels, for example, has compromised infectious disease surveillance in the United States (Barbour and Fish, 1993; Altman, 1994; Berkelman et al., 1994).
3. Encouraging governments to develop well-funded and well administered national vaccination programs (e.g., Bloom, 1994; Fisher, 1994). Vaccines are the cheapest, most efficient method of disease prevention (World Bank, 1993).
4. Finding workable methods of encouraging governments and pharmaceutical companies to put more effort into vaccine research (Cohen, 1994), to maintain a high level of preparedness for producing vaccines, and to develop drugs for dealing with tropical diseases and drug-resistant strains of all pathogens. The situation today is not encouraging. Even in the United States, government funding of research on antibiotics is inadequate (e.g., Culotta, 1994). At present, pharmaceutical houses are not anxious to do work on either vaccines or new antibiotics (Gibbons, 1992a, b) for economic reasons. With the possible exception of Mycobacteriumterium tuberculosis, resistance problems are still most serious in developing nations -- in rich countries, physicians usually can still find (at a price) an antibiotic that still works (see, however, Altman, 1995).
The numbers tell the story. It costs a company about $200 million to bring a new drug to market, and the drug will not make a profit if it is of use primarily in poor countries (Gibbons, 1992b). Japan spends over $400 per person annually on drugs, and Germany and the United States about $200 each. The world average is about $40, but very poor countries spend much less -- Kenya only $4 per person, India $3, Bangladesh $2, and Mozambique $2 (Ballance et al., 1992). Contrast these expenditures with the need for $13 per treatment to deal effectively with a standard case of TB (Brown, 1995) or the $25,000 worth of antibiotics that had to be prescribed for one physician who was infected by a multidrug-resistant strain of the TB Mycobacterium (Brown, 1992b).
A vaccine for malaria could restore to health the roughly 5 percent of the human population currently afflicted with that debilitating disease. The overall economic gains would be enormous, creating a vaccine is clearly feasible (Nussenzweig and Long, 1994), and effective control might be achieved at levels of vaccination much lower than previously expected (recent work suggests that malaria transmissibility, a primary determinant in effective levels of vaccination, may be much lower than inferred earlier; Gupta et al., 1994). But whether success can be had at an acceptable price (which might involve the costs of continuous vaccine modification to keep up with rapidly evolving plasmodia) is an open question. On top of the problem of ability to pay for drugs and vaccines is an extremely serious one of liability of drug companies. Fear of gigantic awards by juries dampens the enthusiasm of pharmaceutical houses for producing novel products likely to become the subject of law suites.
How well cultural evolution, mediated by molecular biologists, can keep us with the biological evolution of resistance in bacteria, fungi, and protozoa is an open question -- unless we choose to lose the coevolutionary race by failing to devote adequate resources to it. The screening of microorganisms, plants, and animals for new antibiotics should be accelerated. So should research on "rational drug design" in which understanding of the modes of acquiring resistance is used to create or modify drugs to counter it (e.g., Taylor, 1993; Travis, 1994; Spratt, 1994; Amabile-Cuevas et al., 1995) as well as other novel ways to eliminate or slow the spread of resistance.
5. Developing global strategies of highly targeted and minimal antibiotic and pesticide use, and the imposition of moratoria, to slow the development of resistance and thus extend the life of some of our most potent antimicrobial and antivector weapons (e.g., Gerding et al., 1991; Haley et al., 1985; Amabile-Cuevas et al., 1995). All nations should move to restrict unsupervised access of people to antibiotics. In addition, the U.S. and all other nations should follow Europe's and ban all antibiotic use in animal feed (Levy, 1992). Indeed, it would be very beneficial for human health if grain-feeding of animals were greatly reduced, since the damage done by saturated fats in the diets of the rich is becoming increasingly clear.
Basically the principles of integrated pest management (IPM; e.g., Flint and van den Bosch, 1981) should be extended to all enemies of Homo sapiens. In essence, IPM consists of using a variable mix of measures tailored to specific situations and modified as needed. IPM requires more knowledge and better management than traditional "magic bullet" approaches to pest control, but can be more successful in the long run and produces fewer negative side effects. For example, used in place of massive spraying of DDT and other pesticides in rice and cotton agriculture, IPM can help reduce problems of insecticide resistance in malaria vectors (Chapin and Wasserstrom, 1981). Indeed, today the scientific community is recommending what is basically IPM as the strategy for dealing with resurgent malaria (Oaks et al., 1991). One promising method of controlling malaria involves engineering and disseminating strains of Anophel es that disable malaria parasites (Aldhous, 1993). Some Anopheles species might be controlled in that manner, and others by habitat modification and judicious use of pesticides when necessary (e.g., Oaks et al., 1991; Collins and Besansky, 1994). In conjunction with such vector control, increased sceening and bed nets, improved treatment of severe cases (Miller et al., 1994), and a moderately successful vaccination program might eliminate malaria as a public health problem. IPM techniques show great promise for controlling many parasitic diseases (Kolberg, 1994), but research programs in parasitology to develop the needed techniques are in jeopardy from the current financial drought (Aldhous, 1994).
Much more research is also needed on such topics as the relationship of drug resistance to virulence and the impacts of the use of antibiotics against resistant strains on the competitors of those strains. The entire topic of the evolution of virulence and transmissibility is just beginning to be explored (e.g., Anderson and May, 1979; Dwyer et al., 1990; Johnson, 1986; Lenski, 1988; Read and Harvey, 1993; Herre, 1993; Ewald, 1988; 1994) and remains controversial (e.g., Bull and Levin, 1994), although there can be little question that virulence (or benignness) is often an evolved strategy of a pathogen, although in some cases it is almost certainly evolutionarily neutral (or close to it). More research on virulence and transmissibility is required at levels ranging from mathematical modeling of demographic and evolutionary dynamics of diseases to investigation of the molecular mechanisms of pathogenicity.
Why, for example, should pneumonic plague be so much more deadly than bubonic (Mee, 1990) if Ewald's view of the evolution of virulence is correct? This is but one of the enduring mysteries about this disease (McEvedy, 1988). Might HIV evolve towards droplet transmissibility, and if so would it still cause AIDS (Ehrlich and Ehrlich, 1990, pp. 147-148)? What are the chances that viruses such as Ebola and Marburgvirus might evolve the ability to be transmitted by mosquitoes, ticks, or other arthropods to end-run the transmission handicap of being so virulent (Ewald, 1994)? If they did become arboviruses, would that prevent a predicted evolution toward lower virulence? Why are helminth parasites so readily able to evade or modulate the immunological defenses of human beings (Maizels et al., 1993)?
6. Instituting worldwide campaigns designed both the slow the spread and control the virulence of pathogens (e.g., Ewald, 1994), especially those that are generally not vector-borne. The prototypical campaign, already in place in some areas, are campaigns against AIDS to promote condom use and lessen the number of sexual contacts. In China and elsewhere, integrated aquaculture systems should be modified to isolate waterfowl from swine, in order to reduce the chances of evolution of novel flu strains (Scholtissek and Naylor, 1988).
7. Instituting worldwide campaigns to emphasize limiting the number of sexual partners, and to increase the use of condoms and spermicides. Such changes would both to lower the incidence of STDs and encourage the evolution of reduced virulence in them (Ewald, 1994). Special attention should be paid to methods that can be adopted by women (e.g., Rosenberg and Gollub, 1992; Rosenberg et al., 1992; Rosenberg et al., 1993), which should tie in neatly to related methods of improving the epidemiological environment by limiting human population growth (Ehrlich et al., 1995).
8. Designing cheap, disposable syringes that self-destruct after one use for distribution to intravenous drug abusers (while supporting programs to prevent such abused.
9. Upgrading facilities in hospitals worldwide so that, for instance, no health worker is required to reuse an unsterilized syringe. It is imperative that the frequency of nosocomial infections be sharply reduced.
10. Making massive efforts worldwide, after decades of talk, to provide adequate diets, pathogen-free drinking water and sound sanitary facilities to everyone.
11. Providing international aid for the upgrading of hospital buildings and dwellings in poor nations so that access of arthropod vectors and rodents to infected persons is greatly restricted. Screened homes will be more effective (both epidemiologically and economically) against many serious vector-borne diseases than bed-nets, antibiotics, or (in some cases) vaccination. They are difficult defenses for vectors to evolve around, and they are not heavily dependent on the behavior of susceptible human beings for their effectiveness.
12. Persuading the leadership of both developed and developing countries that infectious disease prevention and treatment must have higher funding priority. Providing aid to poor countries is essential. It has been estimated that the expenditure of the required $13 per patient on tuberculosis could save more than a million people per year over the next decade (Brown, 1995; Economist, 1995).
The last few steps are so basic that it seems almost foolish to reiterate them here. They are classic "no regrets" strategies that humane people have long recommended without knowledge of potentially serious degradation of the global epidemiological environment. Well-educated people in developed countries will realize that such steps are in their own immediate self interest. But they will not be simple to take in the face of continued expansion of the human enterprise in general and population growth in particular.
There is no question that improved water supplies and sanitation still have great potential for improving the epidemiological environment; there is a question of how long such improvement can be continued. It is likely that the quality of water supplies is already declining in developed countries. Half a century ago surface water could safely be consumed in most sparsely inhabited areas of the United States. Now Giardia presents a threat almost everywhere. Pathogens are becoming increasingly resistant to chlorine (Russell, 1993; Levy, 1992; Nikaido, 1994), and disease episodes traceable to treated but still contaminated municipal supplies seem to be on the rise. In 1993 the Natural Resources Defense Council estimated that nearly a million Americans were getting sick annually and some 900 dying because of drinking water contamination (see summary in Garrett, 1994, pp. 428-430). A spread of chlorine resistance would be a global public health disaster, since there seem to be no economically viable substitutes on the horizon, and increasing doses of chlorine would add more carcinogens to the water supply via the chemical reactions of the chlorine with contaminants in the water.
This nexus of tasks amounts to an unprecedented opportunity for interdisciplinary cooperation. Important social and economic issues regarding the efficient allocation of funds among alternative disease-control strategies remain little analyzed. At the most basic level, for example, how would the benefits of concentrating spending on slowing population growth or improving the water supply compare to benefits derived through better funding of other public health measures, such as improving a population's nutritional status, its female educational status, or its access to maternal health care? These gruesome tradeoffs are made all the time, but often without consideration of impacts on the epidemiological environment, or analysis of the nexus of interactions among possible interventions. Other key issues, such as the economics of the complex of benefits and costs (especially negative externalities) associated with the evolution of antibiotic resistance, remain largely unaddressed by economists. Doing the required analyses, and implementation of the recommendations enumerated above, represent a gigantic challenge to physicians, ecologists, epidemiologists, economists, pharmacologists, molecular biologists, chemists, sanitary engineers, political scientists, sociologists, and all others professionally involved in the maintenance of public health.
Recently, the eminent historian of disease, William H. McNeill stated: "The possibility of really drastic epidemiological disaster bringing a halt to the modern surge of human population seems to me something we all should take very seriously... [In very short time], we have doubled in number. A marvelous target for any organism that can adapt itself to invading us" (1993, p. 33-34). We agree, although a worldwide epidemic would be a most undesirable and inhumane way to end the population explosion. But ending that explosion humanely is a step that is absolutely necessary (but not sufficient -- Ehrlich and Ehrlich, 1990) if the health of our life-support systems and of ourselves is to be preserved. Simultaneously, we should be taking all the other steps listed above to improve the epidemiological environment. To solve all of these problems, it is essential that equity of opportunity between sexes, races, region, religions, and nations be increased (Ehrlich et al., 1995). That is something that is in the vital interest of both the rich and the poor.
We thank Angela Kalmer for substantial help in searching the literature. Alan Campbell, Anne H. Ehrlich, and Donald Kennedy (Department of Biological Sciences, Stanford), Stanley Falkow (Department of Microbiology and Immunology, Stanford), Peter Bing, MD (Los Angeles), and Charles Daily, MD (San Rafael) were kind enough to read and criticize the manuscript. This work has been supported in part by a grants from the W. Alton Jones, Winslow, and Heinz Foundations and the generosity of Peter and Helen Bing.
Adler, T. (1994), 'Tick threats: new diseases brought to you by your neighborhood ticks', Science News 146, 44-45.
Aldhous, P. (1993), 'Malaria: focus on mosquito genes', Science 261, 546-547.
Aldhous, P. (1994), 'Fighting parasites on a shoestring', Science 264, 1857-1859.
Alland, J., A. (1970), Adaptation in Cultural Evolution: An Approach to Medical Anthropology, Columbia University Press, New York.
Almendares, J., et al. (1993), 'Critical regions, a profile of Honduras', The Lancet 342, 1400-1402.
Altman, L. K. (1994a), 'Infectious disease on the rebound in the U.S., a report says', New York Times, 10 May, B7.
Altman, L. K. (1994b), 'Lesson of plague: beware of 'vanquished' diseases', New York Times, 27 September, 1.
Altman, L. K. (1995a), 'No one can say why virus striking Zaire is so deadly', New York Times, 13 May, 1.
Altman, L. K. (1995b), 'As TB surges, drug producers face criticism', New York Times, 18 September,
Amabile-Cuevas, C. F. and M. E. Chicurel (1993), 'Horizontal gene transfer', Scientific American 81, 332-341.
Anderson, R. M. and R. M. May (1979), 'The population biology of infectious diseases. Part I', Nature 280, 3611-367.
Anderson, R. M., et al. (1991), 'The spread of HIV-1 in Africa: sexual contact patterns and the predicted demographic impact of AIDS', Nature 352, 581-587.
Anderson, R. M. and R. M. May (1992), Infectious Diseases of Humans, Oxford University Press, Oxford.
Anderson, J. F. and L. A. Magnarelli (1994), 'Lyme Disease', American Entomologist 1994, 217-227. Anonymous (1995a), 'Bad blood', New Scientist, 1988, 29 July, 11.
Anonymous (1995b), 'Sharp rise in drug-resistant bacteria', New York Times, 25 August,
Anonymous (1995c), 'Fear of an epidemic rises in Central America' New York Times, 26 August,
Ballance, R., et al. (1992), The World's Pharmaceutical Industries: An International Perspective on Innovation, Competition, and Policy, Edward Elgar, Aldershot, UK.
Barbour, A. G. and D. Fish (1993), 'The biological and social phenomenon of Lyme disease', Science 260, 1610-1616.
Bartlett, M. S. (1957), 'Measles periodicity and community size', J. Royal Statistical Society A120, 48-70.
Bartlett, M. S. (1960), 'The critical community size for measles in the United States', Journal of the Royal Statistical Society 123, 37-44.
Beisel, W. R. (1984),.'Nutrition, infection, specific immune responses, and nonspecific host defenses: a complex interaction. R. W. Watson ed., Nutrition, Disease Resistance, and Immune Function, New York, Marcel Dekker, 21-30.
Benedick, R. E. (1991), Ozone Diplomacy: New Directions in Safeguarding the Planet, Harvard University Press, Cambridge, MA.
Berkelman, R. L., et al. (1994), 'Infectious disease surveillance: a crumbling foundation', Science 264, 368-370.
Black, F. L. (1966), 'Measles endemicity in insular populations: critical community size and its implications.', Journal of Theoretical Biology 11, 207-211.
Black, F. L. (1975), 'Infectious diseases in primitive societies', Science 187, 515-518.
Black, F. L. (1992), 'Why did they die?', Science 258, 1739-1740.
Black, F. L. (1994), 'An explanation of high death rates among New World peoples when in contact with Old World diseases.', Perspectives in Biology and Medicine 37, 292-307.
Bloland, P. B., et al. (1993), 'Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa', Journal of Infectious Diseases 167, 932-937.
Bloom, B. R. and C. L. Murray (1992), 'Tuberculosis: commentary on a reemergent killer', Science 257, 1055-1064.
Bouma, M. J., et al. (1994), 'Climate change and periodic epidemic malaria', The Lancet 343, 1440.
Bradley, D. J. (1993a), 'Human tropical diseases in a changing environment', J. V. Lake, G. R. Bock and K. Ackrill ea., Environmental Change and Human Health, Chichester, Wiley, 146-162.
Bradley, D. J. (1993b), 'Environmental and health problems of developing countries', J. V. Lake, G. R. Bock and K. Ackrill ea., Environmental Change and Human Health, Chichester, Wiley, 234-244.
Brown, A. W. A. (1977), 'Yellow fever, dengue and dengue haemorrhagic fever', G. M. Howe ea., A World Geography of Human Diseases, London, Academic Press, 271-317.
Brown, P. (1992), 'The return of the big killer', New Scientist, 10 October, 30-37.
Brown, P. (1994), 'Deadly worm may be turning drug-resistant', New Scientist, 12 November, 4.
Brown, P. (1995), 'Millions dies as TB warning is ignored', New Scientist, 25 March, 4.
Bull, J. J. and B. R. Levin (1994), 'Parasites on the move', Science 265, 1469-1470.
Burns, J. F. (1994), 'Plague cases are confirmed in regions across India', New York Times, 28 September,
Carson, R. (1962), Silent Spring, Houghton Mifflin, Boston.
Chandra, R. K. (1981), 'Immunodeficiency in undernutrition and overnutrition', Nutrition Reviews 39, 225-231.
Chandra, R. (1983), 'Nutrition, immunity, and infection: present knowledge and future directions', Lancet 1, 688-691.
Chapin, G. and R. Wasserstrom (1981), 'Agricultural production and malaria resurgence in Central America and India', Nature 293, 181-185.
Cherubin, C. E. (1971), 'Infectious disease problems of narcotic addicts', Archives of Internal Medicine 128, 309-313.
Chin, J. (1995), 'Scenarios for the AIDS epidemic in Asia', February,
Cohen, M. N. (1989), Health and the Rise of Civilization, Yale University Press, New Haven.
Cohen, M. L. (1992), 'Epidemiology of drug resistance: implications for a post-antimicrobial era', Science 257, 1050-1055.
Cohen, J. (1994), 'Bumps on the vaccine road', Science 265, 13711373.
Colborn, T., et al. (1996), Our Stolen Future, Dutton, New York.
Collins, F. H. and N. J. Besansky (1994), 'Vector biology and the control of malaria in Africa', Science 264,
Conway, D. J., et al. (1991), 'The epidemiology of multiple-clone Plasmodium falciparum infections in Gambian patients', Parasitology 103, 1-6.
Corey, L. and P. G. Spear (1986), 'Infections with Herpes Simplex viruses', New England Journal of Medicine 314, 686-691.
Craven, R. B., et al. (1988), 'Importation of Aedes albopictus (Skuse) and other exotic mosquito species into the United States in used tires from Asia', Journal of the American Mosquito Control Association 4, 138-142.
Culotta, E. (1994), 'Funding crunch hobbles antibiotic resistance research', Science 264, 362-363.
Daily, G. C. and P. R. Ehrlich (1990), 'An exploratory model of the impact of rapid climate change on the world food situation', Proceedings of the Royal Society of London, B 2241, 232-244.
Daily, G. C. and P. R. Ehrlich (1992), 'Population, sustainability, and Earth's carrying capacity', Bioscience 42, 761-771.
Daily, G. C., et al. (1994), 'Optimum human population size', Population and Environment 15, 469-475.
Daily, G. C. (1995), 'Restoring value to the world's degraded lands', Science 269, 350-354.
Daily, G. C. and P. R. Ehrlich (1995), 'Population extinction and the biodiversity crisis', C. A. Perrings, K.-G. Maler, C. Folke, C. S. Holling and B.-O. Jansson ea., Biodiversity Conservation, Dordrecht, Kluwer Academic Publishers,
Daily, G. C. (ed) (1996), Ecosystem Services: Their Nature and Value, Island Press, Washington, DC.
Darrow, W. W., et al. (1986), 'The social origins of AIDS: social change, sexual behavior, and disease trends', D. A. Feldman and T. M. Johnson ea., The Social Dimensions of AIDS: Method and Theory, New York, Praeger, 95-107
Dasgupta, P. (1993), An Inquiry into Well-being and Destitution, Clarendon Press, Oxford.
Davies, F. G., et al. (1981), 'Rainfall and epizootic Rift Valley fever', Bulletin of the World Health Organization 63, 941943.
Davies, J. (1994), 'Inactivation of antibiotics and the dissemination of resistance genes', Science 264, 375-382.
De Cock, K. M. and J. B. McCormick (1988), 'HIV infection in Zaire', New England Journal of Medicine 319, 309.
Desowitz, R. (1981), Tapeworms and Jewish Grandmothers, Norton, New York.
Dobson, A. (1995), 'Biodiversity and human health', Trends in Ecology and Evolution 10, 390-391.
Dobson, A. P. and R. Carper (1992), 'Global warming and potential changes in host-parasite and disease-vector relationships', R. L. Peters ea., Global Warming and Biodiversity, New Haven, Yale University Press,
Dolinger, P., et al. (1973), 'Alkaloid and predation patterns in Colorado lupine populations', Oecologia 13, 191-204.
Dowling, H. F. (1977), Fighting Infection, Harvard University Press, Cambridge, MA.
Dumont, R. and B. Rosier (1969), The Hungry Future, Praeger, New York.
Dwyer, G., et al. (1990), 'A simulation model of the population dynamics and evolution of myxomatosis', Ecological Monographs 60, 423-447.
Economist (1995), 'Disease fights back', Economist, 20 May, 15-16.
Ehrlich, P. R. and R. W. Holm (1963), The Process of Evolution, McGraw-Hill, New York.
Ehrlich, P. R. and P. H. Raven (1965), 'Butterflies and plants: a study in convolution', Evolution 18, 586-608.
Ehrlich, P. R. and A. H. Ehrlich (1970), Population, Resources, Environment: Issues in Human Ecology, W.H. Freeman, San Francisco .
Ehrlich, P. R. and J. P. Holdren (1971), 'Impact of population growth', Science 171, 1212-1217.
Ehrlich, P. R. and A. H. Ehrlich (1972), Population, Resources, Environment: Issues in Human Ecology. Second Edition, W.H. Freeman, San Francisco.
Ehrlich, P. R., et al. (1977), Ecoscience: Population, Resources, Environment, W.H. Freeman and Company, San Francisco.
Ehrlich, P. R. (1986), The Machinery of Nature, Simon and Schuster, New York.
Ehrlich, P. R. and A. H. Ehrlich (1990), The Population Explosion, Simon and Schuster, New York.
Ehrlich, P. R., et al. (1995)-, The Stork and the Plow: The Equity Answer to the Human Dilemma, Putnam, New York.
Eisner, T. and J. Meinwald (1995), 'Proceedings of the colloquium on chemical ecology', Proceedings of the National Academy of Sciences, USA 92, 1-82.
Ellner, P. D. and H. C. Neu (1992), Understanding Infectious Disease, Mosby-Year Book, St. Louis, MO.
Epstein, P. R. (1 1167-1168. 1992a), 'Cholera and the environment', Lancet 339,
Epstein, P. R. (1992b), 'Commentary: pestilence and poverty -historical transitions and the great pandemics', American Journal of Preventive Medicine 8, 263-265.
Epstein, P. R., et al. (1993), 'Marine ecosystems', Lancet 342, 1216-1219.
Epstein, P. R. (1994), 'Climate change played a role in India's plague', New York Times, 13 November, 3.
Epstein, P. R. and G. P. Chickwenhere (1994), 'Environmental factors in disease surveillance', The Lancet 343, 1440-1441.
Ewald, P. W. (1988), 'Cultural vectors, virulence, and the emergence of evolutionary epidemiology', Oxford Surveys of Evolutionary Biology 5, 215-245.
Ewald, P. W. (1994), Evolution of Infectious Disease, Oxford University Press, Oxford.
Farnsworth, N. R. (1988), 'Screening plants for new medicines', E. O. Wilson ea., Biodiversity, Washington, DC, National Academy Press, 83-97.
Fenner, F., et al. (1974), The Biology of Animal Viruses, Academic Press, New York.
Fisher, J. A. (1994), The Plague Makers, Simon and Schuster, New York.
Flint, M. L. and R. van den Bosch (1981), Introduction to Integrated Pest Management, Plenum, New York.
Fogarty, D. G., et al. (1994), 'In-vitro resistance of Plasmodium falciparum to qinghaosu derivatives in West Africa', The Lancet 343, 850-851.
Francy, D. B., et al. (1990), 'A new arbovirus from Aedes albopictus, an Asian mosquito established in the United States', Science 250, 1738-1740.
Garenne, M. and P. Aaby (1990), 'Pattern of exposure and measles mortality in Senegal', Journal of Infectious Diseases 161, 1088-1094.
Garrett, L. (1994), The Coming Plague: Newly Emerging Diseases in a World out of Balance, Farrar, Straus and Giroux, New York.
Gay, F., et al. (1994), 'In-vitro resistance of Plasmodium falciparum to qinghaosu derivatives in West Africa', Lancet 343, 850-851.
Georghiou, G. P. (1990), 'The effect of agrochemicals on vector populations', R. T. Roush and B. E. Tabashnik ea., Pesticide Resistance in Arthropods, New York, Chapman and Hall, 183-202.
Georgopapadakou, N. H. and T. J. Walsh (1994), 'Human mycoses:drugs and targets for emerging pathogens', Science 264, 371-373.
Gerding, D. N., et al. (1991), 'Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital', Anitmicrobial Agents and Chemotherapy 35, 1284-1290.
Gibbons, A. (1992a), 'Researchers fret over neglect of 600 million patients', Science 256, 1135. Gibbons, A. (1992b), 'Exploring new strategies to fight drugresistant microbes', Science 257, 1036-1038.
Gillett, J. D. (1974), 'Direct and indirect influences of temperature on the transmission of parasites from insects to man', A. E. R. Taylor and R. Muller ea., The Effects of Meteorological Factors upon Parasites, Symposia of the British Society for Parasitology, 12, 79-95.
Gizewski, P. and T. Homer-Dixon (1995), Urban Growth and Violence: Will the Future Resemble the Past, American Association for the Advancement of Science, Washington, DC.
Glass, R. I., et al. (1992), 'Epidemic cholera in the Americas', Science 256, 1524-1525.
Gupta, S., et al. (1994), 'Antigenic diversity and the transmission dynamics of Plasmodium falciparum', Science 263, 961963.
Haines, A. (1990), 'Global warming: the implications for health', J. Legget ea., Global Warming: The Greenpeace Report, Oxford, Oxford University Press, 149-162.
Haley, R. W., et al. (1985), 'The efficacy of infection surveillance and control programs in preventing nosocomial infections in U.S. hospitals', American Journal of Epidemiology 121, 182-205.
Harrison, G. A. and J. C. Waterlow (ed) (1990), Diet and Disease in Traditional Developing Societies, Cambridge University Press, Cambridge.
Henderson, D. A. (1993), 'Surveillance systems and intergovernmental cooperation', S. S. Morse ea., Emerging Viruses, New York, Oxford, 283-289.
Henig, R. M. (1995), 'The new mosquito menace', New York Times, 13 September,
Herre, E. A. (1993), 'Population structure and the evolution of virulence in nematode parasites of fig wasps', Science 259, 1442-1445.
Holdren, J. P. and P. R. Ehrlich (1974), 'Human population and the global environment', American Scientist 62, 282-292.
Holmberg, S. D., et al. (1984), 'Drug-resistant Salmonella from animals fed antimicrobials', New England Journal of Medicine 311, 617-622.
Hudson, R. P. (1979), 'Lessons from Legionnaires disease', Annals of Internal Medicine 90, 704-707.
Hughes, J. M., et al. (1993), 'Hantavirus pulmonary syndrome: an emerging infectious disease', Science 262, 850-851.
Humphry-Smith, I., et al. (1993), 'Evaluation of mechanical transmission of HIV by the African soft tick, Ornithodoros moubata', AIDS 7, 341-347.
Inhorn, M. C. and P. J. Brown (1990), 'The anthropology of infectious disease', Annual Review of Anthropology 19,
Johnson, R. B. (19861, 'Human disease and the evolution of pathogen virulence', Journal of Theoretical Biology 122, 19-24.
Jeevan, A. and M. L. Kripke (1993), 'Ozone depletion and the immune system.', Lancet 342, 1159-1160.
Jones, R. and T. Wigley (ed) (1989), Ozone Depletion: Health and Environmental Consequences, Wiley, New York.
Johnson, K. M. (1993), 'Emerging viruses in context: an overview of viral hemorrhagic fevers', S. S. Morse ea., Emerging Viruses, New York, Oxford,
Kipple, K. F. (ed) (1993), The Cambridge World History of Human Disease, Cambridge University Press, Cambridge.
Kissling, R. E., et al. (1968), 'Agent of disease contracted from green monkeys', Science 160, 888-890.
Kolberg, R. (1994), 'Finding 'sustainable' ways to prevent parasitic diseases', Science 264, 1859-1861.
Lappe, M. (1982), Germs that won't die., Anchor Press, Garden City, N.Y.
Last, J. M. (1987), Public Health and Human Ecology, Appleton and Lange, Norwalk, Connecticut.
Lastavica, C. C., et al. (1989), 'Rapid emergence of a focal epidemic of Lyme disease in coastal Massachusetts', New England Journal of Medicine 320, 133-137.
Lawton, J. and R. May (1995), Extinction Rates, Oxford University Press, Oxford.
Leaf, A. (1989), 'Potential health effects of global climatic and environmental changes', New England Journal of Medicine 321, 1577-1583.
Lederberg, J., et al. (ed) (1992), Emerging Infections: Microbial Threats to Health in the United States, National Academy Press, Washington, D.C.
Lenski, R. E. (1988), 'Evolution of plague virulence', Nature 334, 473-474.
Levine, D. P. and J. D. Sobel (1991), Infections in Intravenous Drug Abusers, Oxford University Press, Oxford.
Levins, R., et al. (1994), 'The emergence of new diseases', American Scientist 82, 52-58.
Levy, S. B. (1984), 'Playing antibiotic pool: time to tally the score', New England Journal of Medicine 311, 617-622.
Levy, S. B. (1992a), The Antibiotic Paradox, Plenum, New York.
Levy, S. B. (1992b), 'Active efflux mechanisms for antimicrobial resistance', Antimicrobial Agents and Chemotherapy 36, 695703.
Lipsitch, M. (1995), 'Fears growing over bacteria resistant to antibiotics', New York Times, 12 September,
Loevinsohn, M. E. (1994), 'Climatic warming and increased malaria incidence in Rwanda', The Lancet 343, 714-718.
Looareesuwan, S., et al. (1992), 'Randomized trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria', Lancet 339, 821-824.
Lovejoy, T. E. (1993), 'Global change and epidemiology: nasty synergies', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 261-268.
MacDonald, G. (1952), 'The analysis of equilibrium in malaria', Tropical Diseases Bulletin 47, 907-915.
MacKenzie, D. (1995), 'Can we afford not to track deadly viruses?', New Scientist, 20 May, 4.
Maizels, R. M., et al. (1993), 'Immunological modulation and evasion by helminth parasites in human populations', Nature 365, 797-805.
Manson-Bahr, P. E. C. and F. I. C. Apted (1982), Manson's Tropical Diseases, Balliere Tindall, London.
Martin, P. H. and M. G. Lefebvre (1995), 'Malaria and climate: sensitivity of malaria potential transmission to climate', Ambio 24, 200-207.
Maurice, J. (1995), 'Russian chaos breeds diphtheria outbreak', Science 267, 1416-1417.
May, R. M. and R. M. Anderson (1979), 'The population biology of infectious diseases. Part II', Nature 280, 455-461.
May, R. M. (1993), 'Ecology and evolution of host-virus associations', S. S. Morse ea., Emerging Viruses, New York, Oxford, 58-68.
McCally, M. and C. Cassell (1990), 'Medical responsibility and the global environment', Annals of Internal Medicine 113, 467473.
McEvedy, C. (1988), 'The Bubonic Plague', Scientific American, February, 118-123.
McKeown, T., et al. (1972), 'An interpretation of the modern rise of population in Europe', Population Studies 26, 345-382.
McKeown, T., et al. (1974), 'An interpretation of the decline of mortality in England and Wales during the twentieth century', Population Studies 29, 391-422.
McKeown, T. (1979), The Role of Medicine: Dream, Mirage, or Nemesis?, Princeton University Press, Princeton.
McKeown, T. (1988), The Origins of Human Disease, Blackwell, Oxford.
McNeill, W. H. (1976), Plagues and Peoples, Doubleday, Garden City, N.Y.
McNeill, W. H. (1993), 'Patterns of disease emergence in history' S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 29-36.
Mee, C. L., Jr. (1990), 'How a mysterious disease laid low Europe's masses', Smithsonian, February, 67-79.
Meegan, J. M. (1978), 'Rift valley fever in Egypt: an overview of the epizootic in 1977 and 1978', Controversies in Epidemiology and Biostatistics 3, 100-113.
Miller, J. F., et al. (1989), 'Coordinate regulation and sensory transduction in the control of bacterial virulence', Science 243, 916-922.
Miller, J. A. (1989), 'Diseases for our future', Bioscience 39, 509-517.
Miller, L. H., et al. 1878-1883. (1994), 'Malaria pathogenesis', Science 264,
Mitchison, A. (1993), 144. 'Will we survive?', Scientific American 136
Mobarak, A. B. (1982), 'The schistosomiasis problem in Egypt', American Journal of Tropical Medicine and Hygiene 31, 87-91.
Monath, T. P. (1993), 'Arthropod-borne viruses', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press,
Morell, V. (1995), 'Chimpanzee outbreak heats up search for Ebola origin', Science 268, 974-975.
Morse, S. S. (1991), 'Emerging viruses: defining the rules for viral traffic', Perspectives in Biology and Medicine 34, 387409.
Morse, S. S. (1993), 'Examining the origins of emerging viruses', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 10-28.
Moser, M. R., et al. (1979), 'Aircraft transmission of influenza A', American Journal of Epidemiology 110, 1.
Murphy, B. (1993), 'Factors restraining emergence of new influenza viruses', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 234-240.
Neu, H. C. (1992), 'The crisis in antibiotic resistance', Science 257, 1066-1077.
Nibert, M. L., et al. (1991), 'Mechanisms of viral pathogenesis', Journal of Clinical Investigation 88, 727-734.
Nichol, S. T., et al. (1993), 'Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness', Science 262, 914-917.
Nikaido, H. (1994), 'Prevention of drug access to bacterial targets: permiability barriers and active efflux', Science 264, 382-388.
Nowak, R. (1994), 'Flesh-eating bacteria: not new, but still worrisome', Science 264, 1665.
Nussenzweig, R. S. and C. A. Long (1994), 'Malaria vaccines: multiple targets', Science 265, 1381-1383.
Oaks, S. C., Jr., et al. (ed) (1991), Malaria: obstacles and opportunities, National Academy Press, Washington, D.C.
Oliver, J. H., et al. (1993), 'Conspecificity of the ticks Ixodes scapularis and I. dammini (Acari: Ixodidae).', Journal of Medical Entomology 30, 54-63.
Ornstein, R. and P. R. Ehrlich (1989), New World/New Mind: Moving Towards Conscious Evolution, Doubleday, New York.
Palese, P. (1993), 'Evolution of influenza and RNA viruses', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 226-233.
Pearce, F. (1995), 'Global alert over malaria', New Scientist, 13 May, 4-5.
Percival, V. and T. Homer-Dixon (1995), Environmental Scarcity and Violent Conflict: The Case of Rwanda, American Association for the Advancement of Science, Washington, DC.
Population Reference Bureau (1995), World Population Data Sheet, Population Reference Bureau, Washington, D.C.
Prusiner, S. B. (1995), 'The prion diseases', Scientific American, January, 48-57.
Read, A. F. and P. H. Harvey (1993), 'The evolution of virulence', Nature 362, 500-501.
Repetto, R. (1992), 'Policy Implications of Possible Effects of Pesticides on the Immune System',
Roberts, L. (1989), 'Disease and death in the New World', Science 246, 1245-1247.
Rogers, D. J. and M. J. Packer (1993), 'Vector-borne diseases, models, and global change', Lancet 342, 1282-1285.
Rohter, L. (1995), 'U.S. may be threatened by epidemic of dengue', New York Times International, 23 September, 5.
Rosenberg, M. J. and E. L. Gollub (1992), 'Commentary: methods women can use that may prevent sexually transmitted disease, including HIV', American Journal of Public Health 82, 14731478.
Rosenberg, M. J., et al. (1992), 'Barrier contraceptives and sexually transmitted diseases in women: a comparison of female dependent methods and condoms', American Journal of Public Health 82, 669-674.
Rosenberg, M. J. and K. K. Holmes (1993), 'Virucides in prevention of HIV infection', Sexually Transmitted Diseases 20, 41-44.
Ross, P. S., et al. (1992), 'Antibodies to phocine distemper virus in Canadian seals', Veterinary Record 130, 514-516.
Russell, A. D. (1993), 'Microbial cell walls and resistance of bacteria and fungi to antibiotics and biocides', Journal of Infectious Diseases 168, 1339-1340.
SCEP (Study of Critical EnvironmentaI Problems) (1970), Man's Impact on the Global Environment, MIT Press, Cambridge.
Scholtissek, C. and E. Naylor (1988), 'Fish farming and influenza pandemics', Nature 331, 215.
Shope, R. (1991), 'Global climate change and infectious diseases', Environmental Health Perspectives 96, 171-174.
Slater, A. J. (1989), 'Antibiotic resistance in the tropics. 3. Medical responsibilities of the pharmaceutical industry with respect to use of antibiotics in the tropics', Transactions of the Royal Society of Tropical Medicine and Hygiene 83, 4548.
Smith, C. E. G., et al. (1967), 'Fatal human disease from vervet monkeys', Lancet 2, 1119-1121.
Smith, J. B. and D. A. Tirpak (ed) (1988), The Potential Effects of Global Climate Change on the United States, United States Environmental Protection Agency, Washington, D.C.
Smythe, P. M., et al. (1971), 'Thymolymphatic deficiency and depression of cell-mediated immunity in protein-calorie malnutrition', Lancet 2, 939-943.
Snow, J. (1855), On the Mode of Transmission of Cholera, Churchill, London .
Soule, M. (1995), 'Health implications of global warming and the onslaught of alien species', Wild Earth 5, 56-61.
Spika, J. S., et al. (1987), 'Chloramphenicol-resistant Salmonella newport traced through hamburger to dairy farms', New England Journal of Medicine 316, 565-570.
Spratt, B. G. (1994), 'Resistance to antibiotics mediated by target alterations', Science 264, 388-393.
Sternberg, S. (1994), 'The emerging fungal threat', Science 266, 1632-1634.
Stone, R. (1993), 'Resurging infectious diseases in Russia', Science 261, 415.
Sutherst, R. W. (1993), 'Arthropods as disease vectors in a changing environment', J. V. Lake, G. R. Bock and K. Ackrill ea., Environmental Change and Human Health, New York, Wiley, 124139
Symons, D. (1978), The Evolution of Human Sexuality, Oxford University Press, Oxford.
Tauxe, R. V., et al. (1990), 'Antimicrobial resistance of Shigella isolated in the USA: the importance of international travelers', Journal of Infectious Diseases 162, 1107-1111.
Taylor, G. (1993), 'A rational attack on influenza', Nature 363, 401-402.
Temin, H. M. (1989), 'Is HIV unique or merely different?', Journal of Acquired Immune Deficiency Syndromes 2, 1-9.
Ter Kuile, F. O., et al. (1993), 'Halfantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria', Lancet 341, 1044-1049.
Thrall, P. H., et al. (1993), 'Host and pathogen coexistence in sexually transmitted and vector-borne diseases characterized by frequency-dependent disease transmission', American Naturalist 142, 543-552.
Tolchin, M. (1993), 'Exposures to tuberculosis on planes are investigated', New York Times,
Travis, J. (1994), 'Reviving the antibiotic miracle', Science 264, 360-362.
UNICEF (1992), State of the World's Children 1992, United Nations, New York.
United Nations (1987), The Prospects of World Urbanization, Revised as of 1984-85, United Nations, New York.
United Press International (1995), 'Peru officials declare dengue alert', 27 August,
Uvin, P. (1994), The International Organization of Hunger, Kegan Paul, London.
Van der Schalie, H. (1974), 'Aswan dam revisited', Environment 16, 237-242.
Webster, R. G. (1993), 'Influenza', S. S. Morse ea., Emerging Viruses, New York, Oxford University Press, 37-45.
Weihe, W. H. and R. Mertens (1991), 'Human well-being, diseases and climate', J. Jager and H. L. Ferguson ea., Climate Change: Science, Impacts and Policy, Cambridge, Cambridge University Press, 345-359
Williams, G. C. and R. M. Neese (1991), 'The dawn of Darwinian medicine', The Quarterly Review of Biology 66, 1-22.
Wilson, E. O. (1992), The Diversity of Life, Harvard University Press, Cambridge.
World Bank (1980), Health Sector Policy Paper, World Bank, Washington, D.C.
World Bank (1992), World Development Report 1992: Development and the Environment, Oxford University Press, Oxford.
World Bank (1993), World Development Report 1993: Investing in Health, Oxford University Press, Oxford.
World Bank (1994), World Development Report 1994: Infrastructure for Development, Oxford University Press, Oxford.
World Health Organization (1976), 'Resistance of Vectors and Reservoirs of Disease to Pesticides', Technical Report 585.
World Health Organization (1987), International Health News, September.
World Resources Institute (1987), World Resources 1987, Basic Books, New York.
Wuethrich, B. (1994), 'Migrating genes could spread resistance', New Scientist, 15 October, 9.
Zulueta, J. d. (1987), 'Changes in the geographical distribution of malaria throughout history', Parasitologia 29, 193-205.