An Introduction

The best way to envisage the situation is as follows: the environment presents challenges to living species, to which the latter may respond by adaptive genetic changes.

Theodosius Dobzhansky

All of life is chemical. But not all chemicals are compatible with life. Since their earliest origins, cells have excluded, transformed, and excreted chemicals. But sometimes a cell's defenses fail and a chemical causes damage: an organ malfunctions, a fetus is deformed, an animal dies. Toxicology is the study of these adverse effects and the protective measures that life has evolved throughout its nearly four-billion-year history. It is a science with deep evolutionary roots, and we have much to gain by better understanding the evolutionary process—whether it is how insects continually outwit pesticides, or why highly conserved metal-binding proteins interfere with the treatment of cancer. While the former, and similar cases of adaptation, have captured the attention of toxicologists and scientists interested in rapid evolutionary changes, less attention has been paid to the evolution of the detoxification systems in general. For the past century, toxicologists have studied these systems, harnessing new knowledge for chemical management and regulation. We know a great deal about how any one system responds to chemicals, yet the training of toxicologists and the application of toxicology seldom includes consideration of evolutionary principles. Through the study of evolution, other sciences have begun to glean insights about the genesis of disease, or why some populations can consume milk and others cannot, or how wildlife management might be improved. But as ecologists, immunologists, nutritionists, and medical scientists plumb the genesis of the interactions, mechanisms, and responses relevant to their fields, toxicologists are just beginning to dip their toes in the earth's Archean waters.

Writing about the importance of turning on this "light of evolution," Theodosius Dobzhansky observed, "Without that light [biology] becomes a pile of sundry facts—some of them interesting or curious, but making no meaningful picture as a whole." The word "biology" could easily be replaced with "toxicology" or any other science focused on the diversity of life and its relationship with the earth. Nearly thirty years after Dobzhansky's famous quote, an editorial in the journal Science proclaimed that "evolution is now widely perceived and appreciated as the organizing principle in all levels of life," while adding that the evolutionary principle is so pervasive and penetrating that it may, in a sense, be taken for granted. And we do. Although toxicologists depend on animal and cellular models, assuming common structures and functions across the broad spectrum of life, only a handful have delved into any kind of evolutionary analysis.

The toxicology of drug and chemical metabolism provides a very relevant example of how an evolutionary perspective has helped advanced the science. In the 1980s, toxicologists joked that to be published, all you needed to do was identify yet another species with a form of cytochrome P450 enzyme responsive to PCBs and dioxins (now referred to as CYP1A1). Most often the objective was to identify fish and wildlife species suitable for the monitoring of chemical contaminants. Evolution was rarely mentioned, despite the raft of papers identifying this enzyme in an astounding diversity of species, at least until the latter part of the decade. We now know the CYP system is highly conserved, and this is of critical importance for understanding the evolutionary underpinnings of herbicide and insecticide resistance in plants and insects and organochlorine resistance in fish, and for predicting potentially toxic food and drug combinations in some individuals.

The aim of this book then is to venture into the evolutionary history of life's response to chemical toxicants. It gathers the work of those toxicologists who have already begun looking back, and integrates their findings with relevant work by geologists, biochemists, microbiologists, physiologists, evolutionary biologists, and others. Turning the light of evolution toward toxicology, we will explore an exemplary set of defensive responses. Some, including DNA repair and antioxidants, likely appeared at the dawn of life, conserved (in most species) for more than three billion years. Others, like the p53 tumor suppressor protein, are unique to eukaryotic life. And still other protective measures blossomed only after terrestrial plant and animal life surfaced at the water's edge. Throughout this book, I refer to the network of defensive responses, for lack of a better term, as "toxic defense." Revealing these responses' evolutionary roots offers a new perspective on life's ability to handle naturally occurring chemicals, as well as today's toxic synthetic and industrial chemicals.

A recent commentary explaining how physicians might incorporate evolution into medicine suggested that rather than considering the human body as the "optimally functioning" outcome of evolution, and disease as an abnormal failure, they should think of diseases as "expected and true responses to novel environmental challenges and conditions that were not present fifty thousand years ago or even fifty years ago." In other words, doctors should examine how our bodies, as the products of an ancient and ongoing evolutionary process, might face new, and perhaps very different, challenges. In light of evolution, biomedical researchers are now asking questions that might seem antithetical to medicine: Has the modern-day reduction in parasite infestation and intestinal worms in many human populations led to increases in asthma, autoimmune diseases, and allergies? How useful are responses like cough, fever, and diarrhea, and when do they become a threat rather than a benefit? What is the relationship between the physiology of starvation, obesity, and diabetes? "Simply put," write Randolph Nesse and coauthors in the journal Science, "... training in evolutionary thinking can help both biomedical researchers and clinicians ask useful questions that they might not otherwise pose." The same could be said for researchers and practitioners of toxicology.

There is no question that we have dramatically changed much of the world's chemistry, both globally and locally. Contaminants including mercury, organochlorines, polybrominated compounds, and a host of other chemicals used in plastics, pesticides, waterproof clothing, nonstick pans, and other consumer items are now readily available to...