Evolution in a Toxic World

How Life Responds to Chemical Threats

By Emily Monosson

ISLAND PRESS

Copyright © 2012 Emily Monosson
All rights reserved.
ISBN: 978-1-59726-977-3

Contents

About Island Press,
Title Page,
Copyright Page,
PREFACE,
ACKNOWLEDGMENTS,
Chapter 1 – An Introduction,
PART 1 – Element,
Chapter 2 – Shining a Light on Earth’s Oldest Toxic Threat?,
Chapter 3 – When Life Gives You Oxygen, Respire,
Chapter 4 – Metal Planet,
PART 2 – Plant and Animal,
Chapter 5 – It Takes Two (or More) for the Cancer Tango,
Chapter 6 – Chemical Warfare,
Chapter 7 – Sensing Chemicals,
Chapter 8 – Coordinated Defense,
PART 3 – Human,
Chapter 9 – Toxic Evolution,
Chapter 10 – Toxic Overload?,
APPENDIX: FIVE RECENT ADDITIONS TO THE CHEMICAL HANDBOOK OF LIFE,
NOTES,
SELECTED BIBLIOGRAPHY,
INDEX,
Island Press Board of Directors,

CHAPTER 1

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 life on Earth. Looking through an evolutionary lens, toxicologists might consider how chemicals, many of them “new” to life, affect not only embryonic or fetal development, but also the development of the toxic response. How might such exposures influence development of a body’s response to chemicals? Are there examples of comparable changes (e.g., natural yet sudden shifts in the chemical environment) in the evolutionary record? Might this help us identify responses or physiological systems most sensitive to such changes? What happens to chemicals that mimic or resemble naturally occurring chemicals—hormone mimics, for example, or nutrients? And how do we predict which chemicals will act as mimics? By considering the evolution of a body’s response to harmful amounts and combinations of chemicals, toxicologists might better predict, and possibly prevent, the harm caused by today’s novel challenges.

Nature’s Toxicants

Throughout time, chemicals with some potential to be toxic have been both a necessity and a bane to all living things. The chemical world in which life evolved was a world where atmospheric oxygen rose from fractions of a percent to over 20%, ultraviolet light once intense and deadly now filters through a tenuous shroud of ozone, and metals, like the Cheshire cat, bounced back and forth between bioavailable and inaccessible. And these chemicals influenced not only the evolution of toxic defense but also the basic mechanisms of everyday life. There are more than one hundred known elements, which can occur in a virtually unlimited number of combinations—some naturally and some with human aid. Living things must separate the essential (or nutritional) from the nonessential while they sequester or dispose of the toxic. Sometimes, it is simply a matter of “the dose makes the poison.” This has been the motto of toxicology, shorthand for the dose-response relationships that were first described by the sixteenth-century Swiss alchemist and physician Paracelsus, and it has (for better or worse) been committed to memory by new toxicologists for decades. Nutrition and toxicology are often part of the same continuum, and one of life’s earliest challenges may well have been maintaining nontoxic concentrations of those chemicals—essential minerals and others—necessary for basic functions. Vitamins, including A and D for example, are both necessary, yet toxic in high concentrations. And while essential metals such as zinc and copper each have their own toxic tipping point, it is plausible that the process of natural selection eventually optimized the body’s response to these chemicals. That is, potential harm is reduced, benefits are maximized, and trade-offs between benefits and costs are optimized. This process requires fine-tuning of all aspects of toxic defense: selective absorption, excretion, detoxification, and storage. Placing this process in an evolutionary context may provide valuable insights into a species’ response to common and essential dietary chemicals and to chemicals that closely resemble these chemical compounds—nutritional mimics capable of bypassing exclusion and detoxification mechanisms.

Optimization of essential minerals highlights an important evolutionary principle. Evolutionary change results from a combination of environmental selection pressures. In this case, the availability of zinc influences a heritable trait, the production of a zinc-containing enzyme, and affects proteins that sequester zinc and influences their role in essential biological functions. The earth’s chemical history and the changing availability of elements have dramatically influenced life’s ability to defend against an overload of naturally occurring chemicals, and it may even explain why some chemicals have a greater potential for toxicity than do others. The prevalence of water-soluble chemicals in seawater (carbon, nitrogen, hydrogen, oxygen, and others) at the dawn of life likely explains why some chemicals are more harmful than are others. And chemicals that were possibly more widely available before the rise in oxygen, like nickel or even cadmium, may have been used at first by early life but replaced, or displaced, as environmental conditions changed. Optimization, however, cannot prepare life for major changes in environmental conditions. A useless metal may become more readily available, taking the place of an essential metal; concentrations of an essential metal may become too high; or chemicals that are relatively new to life may flood into the environment because of human activity.

While not all chemicals are essential, all chemicals have the potential to cause toxicity and all living things—whether a single-celled bacterium, sea anemone, or human—must maintain chemical balance (homeostasis) in an ever-changing environment. At the very least, maintenance requires absorption of beneficial chemicals; exclusion, transformation, and excretion of harmful chemicals; and, for multicellular beings, the ability to sort vital intercellular chemical signals from the chemical noise. For complex animals that change drastically from embryo to adult and whose nutritional needs vary, maintaining balance can place different requirements on different cells and organs at different times throughout development. Throughout the course of evolution, these mechanisms have been modified by reproductive strategies, life history, sex, age, co-occurring chemicals, nutritional status, temperature, the presence of certain other chemicals, and many other factors. From cell membranes to placentas, membrane pumps to complex organs, sensory neurons to brains, and single proteins to complex enzyme systems, life has evolved the ability to maintain some degree of balance. In animals that are more complex, the endocrine system, with its interconnected web of chemical messengers and receptors, is central to the maintenance of homeostasis; it is also highly susceptible to chemical-induced disruptions—a feature that toxicologists have just begun to appreciate over the past couple of decades. Yet in all species, no matter how simple or complex, the underlying cause of toxicity is the same: the defensive network becomes overwhelmed. The better we understand how the defensive network works, the better we will be able to predict when it will fail—and evolution can help us get there.

Evolutionary History of Toxicology

Before we begin our exploration, it may help to consider the other end of this equation and its evolution—toxicology, the ancient science of poisons and poisoning, and the modern science we rely on for protection today. We know that humans have a long history of exploiting mineral resources (e.g., zinc, lead, mercury, and arsenic) and suffering the consequences. Perhaps foreshadowing our society’s reliance on a host of industrial chemicals, the Romans were said to be addicted to lead. They were also aware of its darker side. The god Saturn shares his ancient symbol with lead, and “saturnine” refers to a melancholy, sullen disposition—one often associated with lead poisoning. Though Rome’s aristocrats limited their own exposures, leaving the mining to slaves and the smelting to those in the provinces, they continued to drink water provided by lead-lined pipes and to sprinkle the sweet-tasting metal into their wine and on their food. Some attribute the fall of Rome partially to massive lead poisoning—the first known example of large-scale harm caused by a chemical loosed from the earth’s crust by humans. It is also one of the first known examples of human-influenced environmental contamination.

Human reliance on metals increased both the quest to find and extract more raw materials and the incidence of illnesses associated with exposure to toxic chemicals. Some of the first documented cases of toxicity can be found in literature dating back centuries and includes the effects of lead in miners, mercury madness in hatters, silicosis in stone workers, and cancer of the scrotum in chimney sweeps. Generally, limited populations were exposed through their occupations, rather than through large-scale releases of chemicals, but observations of these exposures planted the seeds for one of the older branches of the field, occupational toxicology.

With the chemical/industrial revolution of the mid-nineteenth century came the environmental release and redistribution of historic amounts of naturally occurring and synthetic chemicals. On the heels of this chemical explosion emerged the organized science of toxicology, devoted to characterizing life’s response to chemicals for the purposes of regulation, management, and exploitation. Seeking relatively quick, inexpensive, and standardized testing techniques, toxicology became a field known for its reliance on high doses, single chemicals, lethality assays, and other relatively insensitive animal-intensive techniques. This approach encouraged characterizing toxic responses as discrete or unique to one physiological system or another—the brain, the liver, or the kidney, for example—in standardized test species. Though there is no doubt we are better off today than we were even ten or twenty years ago thanks to traditional toxicity testing, there are upward of one hundred thousand industrial chemicals currently in commerce, only a small fraction of which have ever crossed the threshold of a toxicology laboratory, or have been sufficiently tested. The science of toxicity testing and its application has quickly fallen behind the chemical reality.

Over the years, advances in analytical techniques without simultaneous advances in the underlying theory of toxicology has left scientists, regulators, and managers scrambling to make sense of an ever-increasing avalanche of data. This is true even for what were once considered well-characterized chemicals. While improved sensitivity of analytical chemistry alerts us to smaller and smaller concentrations of chemicals in water, soil, blood, urine, and breast milk, molecular genetics allows us to observe altered genetic expression as tens or thousands of genes are turned on and off in response to small amounts of chemicals. And toxicologists, managers, and regulators are faced with nagging questions: What does it mean? At what point is a chemical’s effect adverse? What does it mean to be exposed to parts per billion or trillion or less of chemicals like PCBs, atrazine, mercury, or plasticizers—either individually or, more realistically, in combination? And how do we interpret the reports that some chemicals typically classified as toxic in large amounts behave differently in very small amounts? Hormesis, the stimulatory response to very low doses of a chemical or physical agent, was once questioned but is now increasingly accepted as normal. So at what point is the boundary crossed between an adverse effect and physiological balance, or homeostasis? Would a deeper understanding of the nature of these systems, provided through an evolutionary perspective, help to define the boundary (if one exists) between what is toxic and what is not? Would looking back into life’s past help make sense of today’s data?

(Continues…)Excerpted from Evolution in a Toxic World by Emily Monosson. Copyright © 2012 Emily Monosson. Excerpted by permission of ISLAND PRESS.
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