MEDICINE, SCIENCE AND SOCIETY Comparative Toxicology, Environmental Health and National Productivity JOSHUA LEDERBERG, Ph.D., M.D. oxicology, as a branch of forensic medicine, has Tioen a stepchild of pharmacology. Few would have attributed it great scientific depth or national impor- tance. Since World War I, however, toxicology has permeated national policy choices that influence our entire economy and culture. This process gained mo- mentum with concerns about food additives and pre- scription drugs, and was accelerated by anxieties oc- casioned by pesticides and nuclear power. Legislative and administrative actions, that would take volumes to summarize, now regulate every aspect of industrial and technologic activity in the name of environmental health: a reaction to decades of neglect and to the rec- ognition that the atmosphere, oceans and water supplies are all too finite a sink for the absorption of the by- products of massive industrial growth. These policies have become prime movers in corporate investment in new plants, in the location of job and housing opportu- nities and, thereby, of our urban populations, in our fundamental energy choices and, thereby, in our eco- nomic and military position in world affairs. Globally, concerns about toxic side-effects of contraceptives complicate the crucially important effort to contain world population growth. Few would disagree that our concerns and anxieties about environmental hazards have outstripped the scientific base for them. Too often we must rely upon unabated suspicion and fear, rather than confirmed harm to human health, as a basis for cautionary and preventive actions. This approach can hardly be faulted for exceptional threats, but our accumulated investment in environmental precautions—including the oppor- tunity costs of foregone initiatives and the dampening of an otherwise exuberant technological imperative— may by now match the considerable part of our gross national product that we expend for health services. This has occasioned an ill-guided debate about the “cast-effectiveness of government regulation.” This debate evades the specific questions: which elements of a complex public policy are most susceptible to mo- deration? Which require still further stringency? Which are the routes of political accommodation? This is not the place to elaborate on the politics or the economics of choice under uncertainty. Most socially significant choices intersect with national crossfires of ideology and interest. Yet it is plain that the public in- terest is poorly served indeed by the continued uncer- tainty as to the gravity of environmental threats to health. Speculations abound that occupational hazards account for as much as 20 percent, or less than 1 percent, of future expected cancer. These generate very different priorities and demands for investment in cautionary controls. Misallocations of such investments, on either side of the true optimum, gravely affect not only our economic welfare but also the credibility of our political mechanisms, and finally the public health itself. Perhaps intimidated by the political dimensions of these issues, medical scientists have not, in general, given proportionate attention to the development of predictive toxicology [1] as a scientific discipline. The scientific dimensions of public and preventive health are altogether undernourished in our academic insti- tutions. The schools denominated for public health have fostered public administration and epidemiologically oriented work more than experimental studies that might establish the scientific foundations for their ac- cepted goals. Pharmacology has had its own identity problems in relating fundamental biochemistry and physiology to clinical affairs. The schools of medicine have been just that: namely, are intellectually and or- ganizationally centered on research and education pertinent to the practice of medicine, the care of indi- vidual patients. This focus has become the more cate- goric with the drying up of venture-oriented funding for the medical institutions and their absolute reliance today on revenues derived from the care of patients. Third party payers, including government, are if anything more assiduous than individual patients in demanding From the Rockefeller University, New York, NY. Requests for reprints should be addressed to Dr. Joshua Lederberg, ‘he Rockefeller University, York Avenue at 66th Street, New York, NY 10021. January 1981 The American Journal of Medicine Volume 70 9 MEDICINE SCIENCE AND SOCIETY—LEDERBERG accountability that health care revenues not be “di- verted” to health research and training, nor even ta preventive measures. Whilst the medical schools still remain the site of the richest scientific insight into dis- ease processes, their students who might be interested in environmental health science {as also for clinical research) face innumerable counterincentives towards careers in the practice specialties. Basic scientists, on the other hand, have many capti- vating challenges in their quest for fundamental knowledge of cellular processes—knowledge that in truth is the indispensable prerequisite for more than half-way approaches to either therapy or prevention. Half-sclutions to therapeutic problems (like kidney di- alysis or cardiac transplants} are notorious for the cost- burdens and moral dilemmas they pose in our struggle to exploit the best available death-averting technologies [2]. They bear some analogy to the exquisitely sensitive technologies of picomolar analytic chemistry and of genetic toxicology which reveal potential threats from environmental molecules but fall short of a compre- hensive assessment of quantitative risk to exposed man. The myriad of questions raised in the conflicts be- tween regulatory and industrial interests (to oversim- plify a complex multipolar tangle) has indeed motivated a large investment in toxicologic studies. Much of this is mandated for industry by the Toxic Substances Control Act and other legislation for which food, drug and pesticides regulation was the forerunner. Most of our major chemical, petroleum and related industria! corporations are enlarging or establishing formal toxi- cologic laboratory efforts. For the most part, however, these are necessarily concentrated on meeting the stated, routine procedural testing requirements which their own new products (or byproducts} must meet for regulatory approval. In similar fashion, the government has allocated $70 million in the fiscal year 1980 for a National Toxicology Program of testing a large array of substances already established in industrial usage. A few academic centers, and the cooperative not-for-profit Chemical Industry Institute for Toxicology are begin- ning new assaults on fundamental issues of risk as- sessment and on the underlying method and logic of predictive toxicolagy. Without these, we may persevere in shadow boxing—at enormous direct and indirect cost—whiice even graver hazards remain to be properly identified, assessed and controlled. The staffing even of the more empirically oriented efforts has already created a crisis in skillpower that our present institutions are iJ]-equipped to meet, whether from a doctrinal or a fiscal perspective. The national interest and shared sense of urgency about a rational predictive toxicology is not yet matched by the evident funding, whether from public or corporate sources, that would be needed for both the training and the funda- mental investigation that the situation demands. The other side of the coin is the relative poverty, from the 10 January 1981 The American Journal of Medicine academic side, of the conceptual framework whereby predictive toxicology would challenge the basic scientist while also responding to the needs of contemporary technologic advancement and applied public health. A paradox is that most formal toxicology stops just where exciting scientific inquiry would begin: namely, at the discovery of a “side-effect,” an unanticipated toxic action. From a regulatory perspective, this is ordinarily the quietus on any further investment in a substance: far cheaper to move to another candidate molecule for technologic development. If the agent is already in wide use, legal and administrative recourse is more likely to be effective in rebutting a suspicious finding and the imposition of regulatory sanctions than is scientific argument in a forum that is ill-experienced at the ex- trapolation of risk from one species or setting to another. In consequence, there has been little motivation for continued investigation of substances that have become controversial—a norm that precisely contradicts the custom of the natural sciences. Much, if not most, of the laboratory information on disparate toxicity is buried in the unpublished, sometimes proprietary, reports of industrial laboratories. It is unfortunate that predictive toxicology tends to be viewed solely as applied technology. Let us recast it as an aspect of comparative biology. On the one hand, a scientifically sound framework of risk assessment, of the extrapolation from other species’ responses to human vulnerability, is of crucial importance to our national economic productivity in its most meaningful and urgent aspects: the use of our edge in technologic innovation to sustain our standard of living and our capability of peaceful influence in world affairs and global devel- opment. On the other, comparative toxicology could exemplify the most powerful enduring traditions in the history of biological science. The very concept of a “biology’’—as Aristotle would have taught, though the term dates only to 1802—is founded on a comparative examination of instances of life, the search for the unifving principles that ratio- nalize dealing with the organic world as a coherent discipline. In 1628, William Harvey [3] complained that “those persons do wrong who ... content themselves with looking inside one animal only, namely man—and that one dead. In this way they merely attempt a uni- versal syllogism on the basis of a particular proposition (like those who think they can construct a science of politics after exploration of a single form of government, or have a knowledge of agriculture through investigation of one character of a single field.}.” From these beginnings of biology, comparative studies have served in turn to (4) establish a basis for systematic description and classification [4]; (2) support general- izations of function, e.g., the circulation, and (3) elicit and substantiate evolutionary theory. We might designate these as the Linnaean, Harvevan and Darwinian strands, the main tissue of general biologic theory. More recently, comparative biology can serve to (4) bolster Volume 70 understanding of human nature by contrast with other primates and lower animals; (5) furnish practical tools for dissecting metabolic pathways [5,6]; (6) found ra- tional chemotherapy based on differences in metabolic pathways, allowing specific toxicity for a parasite, sparing the hos: [7]; and (7] assess environmental toxic hazards to our own species. The most opprobrious approach to environmental health policy would be to insist on actual injury to human subjects as the primary index of environmental hazard. The alternative is an assessment of toxic risks based on a robust theory that enables the prediction of responses in man from those seen in laboratory animals and in in vitro test systems. Such a theory requires the best that modern cell and molecular biology can offer, and more. Its most provocative points of departure will be the analysis of unexpected differences in response (by species, but also by such factors as dosage rate, sex, age and supervening environmental factors), which in turn may be the most cogent approaches to the under- standing of mechanisms of toxic action. Indeed, toxic substances have furnished some of the most specific reagents used in the experimental laboratory today for the unravelling of complex biologic phenomena. In turn, the comparative biology of toxic effects is a way of cancelling out much of the biologic complexity shared by two genotypes but differing in an observed response. MEDICINE SCIENCE AND SOCIFTY—LEDERBERG This powerful differential method resembles the can- celling of matching terms in complex algebraic ex- pressions, allowing attention to be focussed on the re- sidual differences. In toxicology, as has long been ex- ploited in physiology and biochemistry, it can be a powerlul approach to mechanistic insight, as well as an imperative for the avoidance of human exposure. The basic biologic sciences have generated untold human benefit through the development of therapeutic applications used in medicine. These fruits may even be overtaken by the rationalization of policy choices for managing the environment in the interest of optimizing human health and welfare. REFERENCES 1. Boyd EM: Predictive toxicometrics. Baltimore: Williams & Wilkin, 1972. 2. Thomas L: The technology of medicine. In: The Lives of a Cell. New York: Viking, 1974; 31-36. 3. Harvey W: Mavement of the heart and blood in animals. transl. by K. |. Franklin. Oxford: Blackwell, 1957; 44. 4. Eldredge N. Cracralt J: Phylogenetic patterns and the evolu- tionary process; method and theory in comparative biology. New York: Columbia University Press. 1980. 5. Beadle GW: Genes and chemical reactions in Neurospara. Les Prix Nabel, 1958. 6. ‘Tatum EL: A case study in biological research. Les Prix Nobel, 1958. 7. Albert A. Selective toxicity, 5th ed. Landon: Chapman & Hall, 1973. Reprinted from the January issue of The American Journal of Medicine. A Yorke Medical Journal. Published by Technical Publishing Company, A Division of Dun-Donnelley Publishing Corporation, A Dun & Bradstreet Co., 666 Fifth Avenue, New York, N.Y. 10103. Copyright 1981. All rights reserved. Printed in the U.S.A.