Environmental medicine: where are we and where do we go from here? (you can't navigate from lost).

As many of us do, I found myself in the waiting room of a U.S. senator keeping an appointment with a staff person to express my opinion on the importance of the work of the National Institute of Environmental Health Sciences (NIEHS) to the nation's public health and to the world's view of global environmental impact on human health. This was a trip I made as often as I could afford and one that I found generally useful and gratifying. At the end of my intonations on what has been achieved, what we now know, and the emerging technologies that will help us protect our health from environmental threat, the staff person looked at me intently and asked, "So what is the next big problem?" As the overwhelming nature of the problem before us seeped into my consciousness, I nearly froze. Nearly, but not quite. Without the hesitation that might have been more suited to the occasion, I blurted out "Air!" Then, after a few seconds reflection and in a more subdued tone, I added, "Well, water too. Air and water." I then proceeded to explain my meaning to a busy staff person whose attention had already moved to her next big and important problem. I could not shake the implications of that exchange from my mind. We have come so far with water in terms of remediation, in terms of knowing the health effects we are trying to protect ourselves from (such as the profound birth defects first raised to public consciousness when discovered in flogs in Minnesota), the role of farm runoff, what we can expect from wetlands, and how to make synthetic wetlands. In the moment I had to respond, it seemed as if all the work on water was done.

Meanwhile, a greater understanding of the problems associated with air was still needed but perhaps not far off. We were confronted with a burgeoning epidemic of asthma that perhaps represents only a sentinel of respiratory disorders that are on the rise in our population. We have no doubt made tremendous strides in our approach to air quality and even gained ground on the public's understanding of why it is important to continue this effort. Direct understanding of risk and mechanism seemed a daunting challenge. It still is. We now know there is a connection between particulate matter in the air, mostly from coal-fired power plants, and mortality great distances from the site of air pollution sources (Bateson and Schwartz 2004; Pope et al. 2002; Schwartz 2004). We can begin to envision ways to establish mechanistic links between particulates and asthma, and design methods for looking at complex chemical mixtures in the air and what to do about them, but we have still only scratched the surface of a global problem. Ultimately, we breathe and share the same atmosphere and the universal desire for unrestrained development. A need to improve living conditions is shared by everyone, but how to do that without doing more harm than good is not so clear. More of our body is exposed to the environment through the lung than through any other tissue in terms of surface area, volume of environmental exposure, and duration of exposure (basically every minute of our lives)-hence my enthusiastic, if concerned, claim that the air is next really big environmental health issue. But then environmental health impacts from water are not resolved either. Most recently the mercury contamination in our fish tells us the magnitude of threats from water and also reminds us that we can hardly separate air and water when considering the environmental impact on our health.

All this made me wonder where is medicine in the cause for understanding what in the environment hurts our health and how. Did medicine ever have an important role? Certainly medical scientists did and continue to, although one colleague once said to me that all this environmental stuff is just fringe science! Where did such an attitude come from? Is it widely shared? What would it take to convince the broader scientific community of the relevance and importance of environmental health science?

Environmental medicine is one of the oldest of medical practices in the modern era. That is, once the profession began to give up on the Greek notion of humors causing disease, physicians immediately began to look at what people were exposed to as an explanation for their health-related problems. Ramazini and later Percivall Port formally discussed occupational health based on the notion that so much time is spent at work that large exposure problems were per force work related. Giovanni Battista Morgagni, the great Italian anatomist, collated a prodigious clinical experience in the Seats and Causes of Disease in 1761 when he was 79 years of age (Morgagni 1769). Morgagni is largely credited with the origin of the concept of clinical pathological correlation where the presentation of a patient is described along with the patient's clinical signs and symptoms. The end of the case is usually the death of the patient and the pathological anatomy of the process (i.e., the autopsy findings are presented and used to explain the clinical course and outcome). Morgagni's five books published as expository letters to unnamed or fictional correspondents set the standard for this method of description that has been a mainstay of clinical medical teaching ever since. A common theme throughout these volumes is early and succinct description of the patient's occupation: "There was at Bologna a nun" (book II, letter XVI, 43), "A public professor of law at Bologna" (book I, letter IV, 4), another "was addicted to a sedentary life ... as nobleman generally are" (book I, letter IV, 2), "A robust young man, who had been us'd to live on board gallies" (book II, letter XXVI, 11], and "A strumpet of eight-and-twenty years of age" (book II, letter XXVI, 13).

Pott in his Chirurgical Works (Pott 1775) described the scrotal tumors that occur in chimney sweeps and ascribed the cancers to exposures sustained in the course of their work. At the time of his writing in 1775, he recognized the efforts of Ramazini, a contemporary and friend of Morgagni, in describing diseases that resulted from on-the-job exposure. Port writes, citing Ramazini: "[E]very body is acquainted with the disorders to which painters, plummers, glaziers, workers in white lead are liable" (Figure 1).

[FIGURE 1 OMITTED]

Occupational health has been an important part of medical education in the United States from the earliest days, usually within schools of public health. But even though we all are willing to recognize that exposures to environmental toxicants are not restricted to the workplace, this notion still has the dominant place in our medical schools, where the training for environmental medicine is restricted primarily to occupation exposure. However, when we think of environmental medicine, we must think about the effects that things we have done to our environment have had on our own health. Human alteration by contamination is the source of a great disease burden. Understanding that burden in order to do something about it is an imperative. Addressing these challenges takes will and perseverance. They are part of a new environmental medicine, one that must be proactive in finding the mechanisms of problems related to the environment and engaged directly in the invention of approaches to deal with them.

For example, despite the well-known health effects of lead exposure, in this country one-fourth of children younger than 6 years have elevated blood lead levels (Bernard and McGeehin 2003). Environmental medicine's new role includes trying to ameliorate effects of exposures that result in these lead levels. First, altering the household environment and then reducing blood lead levels in exposed children with effective chelation therapy (Ettinger et al. 2002) were tried. Both approaches are known to reduce lead in exposed children, but has the health outcome after the exposure improved? As it turns out, probably not (Dietrich et al. 2004). Chelation is a powerful therapeutic intervention with its own health effects, and therefore avoiding its use where no clear benefit can be expected is an important result of research efforts.

Many American workers are exposed to powerful pesticides in the course of their jobs, and the exposure is not just limited to them; it also includes their families. Because these chemicals are effective by virtue of their toxicity, it is not unreasonable to be concerned that human exposure may have important consequences to human health. The new environmental medicine is looking into this by accumulating data on nearly 100,000 workers and family members and documenting their exposure (Samanic et al. 2004). These individuals will be followed for many years to determine the risk of cancer, autoimmune disease, neurodegenerative disorders, diabetes, reproductive disorders, and respiratory diseases. Similar efforts are under way with populations in other parts of the world with particularly serious toxic exposures, such as the Ukraine (Monaghan et al. 2001) and China (Venners et al. 2004).

Not all environmental sources of disease are man-made of course. Radon is an odorless and colorless gas that is naturally occurring and is known to cause lung cancer and other health problems. Its removal, or at least attempted remediation, can cost thousands of dollars per household. So the cost of exposure needs to be addressed in the context of true risk of exposure. It is the role of environmental medicine to determine the true risk as it actually occurs in households. Otherwise we may face a conflict of interest by relying on the very people who stand to make a lot of money removing the radon to assess the risk. We now know from Norwegian studies that mean household radon levels can result in nearly 900 lives lost because of lung cancer (Steinbuch et al. 1999). But this result is highly sensitive to radon exposure distribution and may be peculiar to the Norwegian situation. A much more refined search of households in radon risk areas would be tremendous undertaking but of obvious importance to making rational policy decisions. Increasingly, the role of environmental medicine is to generate the data that can bridge to policy and action, a truly translational approach. This approach is already under way in a study of several thousand lung cancer patients and controls to assess the role of household radon exposure. These studies ongoing at the NIEHS will be combined with several others in different parts of the country to increase the power of the analysis, including a large group of uranium miners who are occupationally exposed to radon. So far, studies of this sort have shown that radon is not associated with acute myeloid leukemia, despite anecdotal evidence that it was (Steinbuch et al. 1999).

Environmental medicine is closely related to toxicology, and in the 21st century the scientists and clinicians in these fields must work together to ensure that mechanistic research, high-throughput analysis, and complex network analysis of RNA and protein reactions result in the best information possible to bring about an improvement in public health. Toxicology as a discipline needs to think in terms of public health and become very focused on what we now need to know to better define public health. A central player in this effort should be the National Toxicology Program (NTP). This program was authorized by Congress in 1978 as an interagency effort comprising the toxicology efforts from the NIEHS, the Centers for Disease Control and Prevention's National Institute for Occupational Safety and Health, and the Food and Drug Administration's National Center for Toxicological Research. The National Cancer Institute participates in an advisory capacity. As part of the Department of Health and Human Services, the NTP was</p> <pre> to coordinate toxicological testing programs within the Department, strengthen the science base in toxicology; develop and validate improved testing methods; and provide information about potentially toxic chemicals to health regulatory and research agencies, the scientific and medical communities, and the public. (NTP 2005) </pre> <p>This critically important activity is a national imperative, as there are more than 80,000 registered chemicals with more entering commercial use every day. The toxicological effects of these contaminants are largely unknown, and the NTP's overall mission is to learn the role of these compounds in our health. The NTP could be a springboard for the coordination of interests and activities of clinicians that deal with the effects of toxic exposures and the scientists that try to understand which chemicals are dangerous and why.

In the coming years molecular genetics of development will prove to be a fruitful domain of the new environmental medicine. An emphasis on the genetic pathways in the context of toxic exposure is critical to developing a sense of where toxic exposure may make contact with critical signal transduction pathways that regulate pattern formation. These pathways when mis-regulated cause cancer or serious birth defects and are responsible for a major human disease burden. Important advances could be made if toxicology were on the minds of the hypothesis-driven scientists bringing precepts of toxicology to the genetics and the biochemistry of development. Ideally there could be a one-to-one partnership of developmental geneticists and toxicologists. Critical to this vision is the expansion of high-throughput technologies including microarray gene expression profiling and proteomics in terms of both high-throughput protein interaction techniques and mass spectra mining for protein identification. Transcription factor network analysis will be an area of critical importance in the future, as transcription factors are an important way toxic exposures are translated into disease. High-throughput knockout mouse models are now a reality with the use of saturation mutagenesis and yeast screens (Zan et al. 2003). This technology will allow the rapid development of model systems useful in the study of toxic exposure, and I believe it is an approach that needs to be promoted. Pathways such as Sonic hedgehog/Patched/Gli (Villavicencio et al. 2000; Walterhouse et al. 1999) and Notch/delta (Park et al. 2003) are central to the normal specification of fate during pattern formation as the body plan develops after fertilization. The National Academy of Sciences has argued that relatively few genetic pathways such as these two explain all pattern formation. Thus, establishing the role of environmental exposure on poor pregnancy outcome, birth defects, and childhood cancers should be completely tractable, and importantly ameliorating effects of exposure is a realistic goal.

The role of diethylstilbestrol [DES) in malformation of the reproductive tract in children of mothers treated during pregnancy has come to a molecular explanation in terms of these signal transduction pathways. David Sassoon and his colleagues observed that female reproductive tract abnormalities in Wnt7a (a gene important in early development) knockout mice were very much like those after DES exposure in pregnant dams (Sassoon 1999). Experiments designed to elucidate a possible relationship revealed that DES acting through the estrogen receptor is inhibiting Wnt7a and that this in turn results in a failure to maintain Wnt5a (another member of the Wnt gene family) and Hox10 and Hox11 (genes for transcription factors critical in early development). DES exposure results in decreased Wnt7a exposure, and there is a critical period of sensitivity for this effect. The mediation of DES exposure through the estrogen receptor is one of a class of important environmental exposures known as endocrine disruptors that have been increasingly understood in recent years (Markey et al. 2002; McLachlan 2001), Because compounds that mimic endocrine signals, especially estrogen, are widely present in the environment, we must understand the molecular mechanisms of their effects on human health and strive to ameliorate them. Disruption of signal transduction pathways can occur in other ways. Phytoalkaloids like cyclopamine are present in a range of plants and result in severe birth defects of offspring when pregnant animals are exposed to them. This occurs as a result of down-regulation of the Sonic hedgehog/patched/Gli pathway. Alcohol also attenuates normal developmental signals from this pathway, and this effect explains some of the features of fetal alcohol syndrome (Ahlgren et al. 2002).

Emerging opportunities to expand the reach and effect of environmental medicine are rolling out of the expansion of high-throughput technologies. This has generated a critical need for useful and relational database platforms, particularly for gene expression profiling and proteomics (Karpinets et al. 2004; Waters et al. 2003a, 2003b). These will provide the access and information of the type that genomics benefited from with the GenBank system (http://www.ncbi.nlm.nih.gov/ Genbank/index.html). As genome software tools become more and more robust, the value of "data mining" in both discovery and application is increasing dramatically. A current example is the use of existing genome sequences to suggest candidate single nucleotide polymorphisms. This candidate approach yields important differences between strains and individuals after validation. Clinicians and scientists in environmental medicine will need to be aware of and make use of these tools.

RNA editing, transport, and protein binding are becoming an increasingly well-understood important part of human disease. The new environmental clinician must be aware of developments in the molecular regulation of gene activity by mechanisms including exon skipping, splicing silencers, and translational regulation because they are all potential targets of environmental exposure.

The interface of water margins, people, and oceans or lakes is critical to our health and to our ecology. The Great Lakes, for example, represents about 20% of the world's flesh water, affecting 38 million people [Copeland, 1996). Several federal agencies are charged with responsibility for this critical aspect of our health. These include National Oceanic and Atmospheric Administration and the National Institutes of Health (NIH) through the NIEHS. Through important initiatives such as the Marine and Fresh Water Biomedical Sciences Centers Program, the NIH is providing a platform for research into the most important of our emerging coastal water problems. As the wetlands ecology degrades, what happens to the quality of species there that are eaten by many people? According to the U.S. Environmental Protection Agency (2005), nearly all the commercial fish and shellfish catch along Atlantic and Gulf coasts depend on wetlands for survival. In estuarial regions, loss of filtering capacity with ecological degradation directly affects the health of ocean species that we eat. The use of "constructed wetlands" to remediate both wastewater and possibly pesticides in industrial farm operations (pigs, cows, etc.) is just developing and needs to be explored further. We still have only rudimentary knowledge of environmental human health effects of toxic algae blooms that adversely affect human health.

There are many areas of emerging science that could be very important to human health. Environmental medicine must act as an advocate for the generation of data in these arenas and be aware of their consequences. For example, biotransport, especially amino acid transport, into cells has received very little attention from the environmental health sciences community. Yet these coupled energy-dependent transporters provide important targets of environmental disruption. The underlying mechanisms of action of these transporters are being revealed by genetics and biochemistry. Other biotransport issues include trafficking transcription factors, nuclear import and export, heavy metal transport, solute gradient systems, and metabolic transporters (e.g., glucose transporters). Advances will be made as high-throughput technologies are applied to the question of toxicological disruption of transport process.

Other fields include biophotonics and phototoxicity. Surely exposure to light is also among the most common of environmental exposures. One might presume it to be a completely safe exposure to which humans are fully adapted. This is, however, unlikely to be true. We are well aware of the dangerous effects of excessive exposure to high-energy ultraviolet (UV) radiation, for example. In the future a broad definition of photobiology can open an important horizon on phototoxicity. For example, current focus on UV C and even UV B may be misguided in terms of exposure dose. Quantitatively, short-wavelength blue is a much more important exposure at the cell population most at risk (basal layers of skin). In terms of quantity of light delivered to the basal layers, high-energy UV is not that important; very little makes it to the earth's surface. Moreover, relatively little UV irradiation makes it through the outer layers of the skin (and, because outer skin cells are postmitotic, represents little problem). Longer wavelength UV and short wavelength blue light are quantitatively more of a problem. We know that very brief exposures in blue and long UV initiate apoptosis very quickly (in a matter of seconds) (Hockberger 2000; Hockberger et al. 1999). What are the second messengers of this process? What is the role of activated oxygen species in mediating toxic outcome of exposure? It seems likely that phototoxicity is mediated in part by disruption of protein-protein interactions. These types of molecular injuries could powerfully disrupt signal transduction pathways. Studies of the emission and detection of electromagnetic radiation by cells can become a new important area of toxicology research. New areas of research suggested by or aided by biophotonics are arising at a rapid pace. These include functional imaging and multiphoton laser scanning microscopy to allow live cell imaging over time.

The new environmental medicine should also consider food sources. Amazingly little research that is hypothesis driven and in the public domain exists to address the impact of genetically modified organisms in the food supply, This is an environmental issue of high impact globally and should be directly involved in toxicology concerns.

The role of the environment in infectious disease is an important emerging area of concern for the new environmental medicine. For example, changes in widespread land use can drive the emergence of infectious disease outbreaks and modify the outcomes and transmission of these diseases (Patz et al. 2004). An example of this is agricultural runoff, which is becoming an increasingly important source of human infectious disease and is commonly underappreciated (Spencer and Guan 2004).

Knowing the problem is one thing; doing something about it is another. The importance of developing translational research programs in environmental health is obvious. Large projects beyond the scope of individual labs or medical centers will require cooperative partnerships with national labs, particularly the NIH in the United States. But beyond drug trials using extant paradigms, what should be next in the realm of treating environmental exposure? Phase II detoxification metabolism is a potential therapeutic target in toxic exposures. Environmental medicine needs to explore the role of enhanced detoxification to leverage what is learned about polymorphic susceptibility genes. That is, the explosion of genomic data will lead to a rapid increase in our understanding of the genes that with some polymorphic states or haplotypes will result in greater or lesser susceptibility to environmental exposures. With respect to metabolism of xenobiotics, it is not just metabolism to electrophilic species or so-called phase I metabolism resulting in toxicity, but also detoxification genes or so-called phase II metabolism that can be expected to yield important modulating polymorphisms. The initial exposure to most toxic substances results in activation of cytochrome P450 (CYP) enzymes that attempt to produce water-soluble compounds capable of excretion by redox reactions (phase I metabolism). The intermediate metabolites are strongly electrophilic and therefore potentially dangerous as a result of their reactivity with many cellular constituents including DNA and proteins. In phase II metabolism detoxification of redox products occurs. One of the most significant of these reactions is the conjugation of electrophiles to glutathione. The glutathione S-transferases (GSTs) are responsible for these reactions (Boucher and Iannaccone 1995; Connelly et al. 1993; Suzuki et al. 1996), So if one were to exploit metabolism of dangerous compounds to ameliorate the risk of exposure, one might decrease phase I by inhibiting the CYP proteins or genes. Alternatively, one might increase glutathione or the activity of the 6STs to increase detoxification of electrophiles once they are induced. The phase I enzymes would be hard to manipulate because of a wide variation in substrate specificity and relative paucity of broadly effective inhibitors. The best example of the first type of inhibition is clarithromycin (used in treating Helicobacter) that is a potent specific inhibitor of CYP3A enzymes (Ushiama et al. 2002). Known CYP3A substrates include not only benzodiazepines but also testosterone and estrogen.

It may be that a better approach would be to boost the GST activities or glutathione stores or both. Kahweol and cafestol increase metabolic activity of GST of many different classes (alpha, mu, pi, and theta) and in several organs in the rat (Huber et al. 2002). This activation is protective against phenylimidazopyridine (PhIP) mutagenesis and aflatoxin carcinogenesis in the colon in the rat. Importantly, the generation of increased GSZ activity in one organ site can provide protection throughout the body. Herbs, including Evodia rutaecarpa, induce GST and UDP-glucuronosyltransferase (but also CYP and 7-ethoxyresorufin-O-deethylase) in mice (Ueng et al. 2002). There are a number of human approaches to this, some in the public domain and some in early trials with proprietary protection. 0ltipraz, a chemoprotective drug originally developed as an antishistosomal agent, in humans reduces the excretion of oxidative metabolites of aflatoxin by enhanced formation of aflatoxin-glutathione conjugates (Kwak et al. 2001). Similar approaches have been used for chemoprotection after therapy for cancer. The GST gene promoters are available for manipulation genetically, and this is an important opportunity for therapeutic targets. Several drugs are in proof-of-principle or efficacy/safety stages in humans because of what we have learned over the past three decades about the isoforms of the enzymes relevant to the metabolism of xenobiotics. Genome research particularly from the Environmental Genome Project will reveal more enzyme polymorphisms related to decreased risk of toxic exposure, and these will open the door to new therapeutic targets. I can imagine a time that we could modulate detoxifying enzymes as prophylaxis in cleanup workers or others with at risk genotypes.

The role of the NIEHS in this ambitious agenda cannot be overstated and the importance of Ken 0lden's leadership for more than a decade in keeping the NIEHS vibrant and central is clear. Ken Olden is the third director of the NIEHS, and his leadership in that role has had a major impact on the way we perceive environmental medicine. His legacy is big science and understanding what can be done at a national lab that cannot be done in a university. He was responsible very early in his tenure for promoting interagency cooperation and initiatives. These were creative and innovative, often ahead of the curve, like the Ecology of Infectious Diseases initiative. This initiative acquired funding from the National Science Foundation and the NIH through the Fogarty International Center; the National Institute of Allergy and Infectious Diseases, the NIEHS and other federal agencies participated in the program, including the National Aeronautics and Space Adminstration, the U.S. Department of Agriculture, and the U.S. Geological Survey. He supported and promoted interventional epidemiology and molecular epidemiology, two important new trends in population-based research. He was responsible for the reorganization of the NTP. He understood the importance of the Superfund to the public health and led substantial growth of the Superfund Basic Research Program. This critical program has grown to a sophisticated suite of basic research projects, conferences, and a separate training system (the Worker Education and Training Program) that feeds to the heart of remediation of dangerous toxic sites throughout the nation and indeed the world. The program added important supplemental grant support to study the environmental health effects of the 2001 World Trade Center catastrophe. A measure of its success was the recent congressional decision to establish independent, stable funding for the program. The Environmental Genome Project began under Dr. Olden's leadership, and he fostered the growth of the National Center for Toxicogenomics as a steadfast supporter of high-throughput technologies. Dr. Olden was a champion of the NIEHS journal Environmental Health Perspectives and, especially the journal's role in educating the world while providing a forum for the best science in the field. He developed a clear mission statement for the NIEHS and a new responsiveness to the public interest. Because of these achievements, the institute is moving forward in a brave and robust fashion regardless of political climate.

So the next big problems in environmental health science are air and water-and all other aspects of our environment. But the problem goes deeper: the real next problem is recognition and development of a plan among the next generation of physicians to take advantage of our newly acquired knowledge to push forward the envelope of diagnosis and treatment for the next generation of medical scientists. From all that is happening, it should be clear that my colleague's notion that this grand effort represents fringe science is just wrong and is not widely shared. The effort is grand because as the NIEHS reminds us "the environment is your health."

SUMMARY

Environmental medicine has a long and important history. Although largely in the domain of schools of public health or occupational medicine, the reach of this endeavor goes beyond the borders of occupationally related diseases. The efforts of environmental medicine in the future will build on recent successes in interventional epidemiology, molecular epidemiology, developmental genetics, and molecular mechanisms of toxicity. As we confront increasing global environmental challenges, including health problems related to air- and water-based exposure to toxic agents, environmental medicine will need to be steadfast in its determination to understand mechanisms of disease. The goals of environmental medicine must include prevention as well as safe remediation and translational therapeutic intervention in human populations after exposures. The leadership of the National Institute of Environmental Health Sciences (NIEHS) has been crucial to the continuing promotion and obtainment of these goals. Under the visionary directorship of Ken Olden, the NIEHS has initiated programs of lasting importance and far-reaching benefits to the public's health. doi: 10.1289/ehp.7752 available via http://dx.do.org/

NOTES

Address correspondence to P.M. Iannaccone, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Children's Memorial Institute Research Center, 2300 Children's Plaza (MC 204), Chicago, IL 60614-3394 USA. Telephone: [phone]. Fax: [phone]. E-mail: [e-mail]

The author declares he has no competing financial interests.

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Philip Iannaccone is the George M. Eisenberg professor at the Northwestern University Feinberg School of Medicine and deputy director for Basic Research at Children's Memorial Research Center in Chicago, Illinois. His research includes investigation of the genetics and biochemistry of transcription factors in normal development and disease states. The fundamental research aims at determining the role of environmental disruption on abnormal development and cancer. His lab has pioneered methods to establish the kinetics of generation of organ parenchyma using mosaic pattern analysis.