Int. J. Hyg. Environ. Health 206, 263 ± 267 (2003)¹ Urban & Fischer Verlaghttp://www.urbanfischer.de/journals/intjhyg

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Christopher Schonwalder, Kenneth Olden

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Received July 19, 2002 ¥Revision received August 20, 2002 ¥Accepted August 21, 2002

��������Over the past half century, environmental health research has branched from a descriptive,observational process into one of hypothesis driven and mechanistically based science.Nevertheless, the meaning of observed effects of exposures in experimental systems to humanpublic health remains elusive. Recent advances in genetics and ∫omics™ hold great promise tofurther our abilities to assess potential human health effects and to manage exposuresproperly. But the comfort of 100% certainty will not be available in the foreseeable future,leaving us with the challenge of designing relevant experiments and test systems upon whichto base ∫logical™ policy in risk management.

Key words: Environmental health ± human health risk ± toxicology ± epidemiology ± genetics± public health ± toxicogenomics ± molecular mechanisms

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The future of environmental health research will bemarked by better understanding of human riskthrough integration of the scientific disciplines;toxicology, epidemiology, genetics, and publichealth. Each contributes new knowledge to the issueof untoward health effects due to environmentalexposures. But proper action to prevent diseasedepends on an understanding of the completespectrum of exposure, effects and their clinicalsignificance, and population outcomes.The beginning of the new century marked the 30th

birthday of the US EPA, an agency charged with theawesome task of responding the American public'sconcerns about the environment. Like other inter-national health agencies throughout the world,

those in positions of public trust want answers totheir peoples' primary question about environ-mental health: ™Are there things out there whichwillmakeme sick; things I can not see or control, butwhich are unwanted by-products of the technologieswhich benefit me and the country's economy? Am I,as an individual, taking an unwarranted and un-wanted risk of becoming ill due to exposures toenvironmental agents?∫ Citizens have asked theirgovernments to set up systems to respond to theseconcerns. But to do so, government regulators needboth data (information) and understanding (knowl-edge).The field of environmental health sciences has the

responsibility to provide the means for our society,through its representatives, to make ™knowledge-able∫ choices based on fact and reasoned logicregarding exposures. The recent exercise in the US

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Corresponding author: Christopher Schonwalder, Ph.D., Director of International Programs, National Institute ofEnvironmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709 ± 2233, USA. Phone: ��919541 4794, E-mail: schonwalder@niehs.nih.gov

on dioxin risk assessment demonstrated a criticalneed for more basic understanding. Because it is notpossible to go through such an analysis with everychemical, new research must provide clues andindications to strengthen risk assessment and guidefuture studies. Through research, the risk assessmentprocess will be mademore efficient.We have come along way, but we have a long way to go.

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Paracelsus declared the bedrock of toxicology in the16th century: ™The dosemakes the poison∫. That is aprinciple simple to state, but difficult to apply inpolicy because, as is often said, ™the devil is in thedetails∫. But the solution is likewise in the details,and it is the pursuit of these elusive details that hasdefined the field throughout its short history.Medieval toxicology was focused upon finding

better ways to dispose of ones enemies. The searchwas for more efficient, effective and clandestineways to ™do him in∫.We havemoved beyond that asa society. The conversion of the old Pine BluffsArsenal, a factory for implements of chemicalwarfare, to the National Center for ToxicologicalResearch (NCTR) is symbolic of that movement.The first concerns ofmodern humanhealth related

to toxicology came from three developments thatbrought together biology and chemistry: (1) Con-cerns about the safety of the human food supply,including food additives: Public attention wasbrought about by the publication of Upton Sinclair's™The Jungle∫ (1981). In response, the Food, Drugand Cosmetics laws were passed and revised oftenover the last 75 years to express societal concernsover toxic effects, especially chronic ones that werenot easy to control by personal choice. (2) Thewidespread use of pesticides to control insect vectorsof disease and to reduce losses of agriculturalproducts to insects: Public attention was arousesby Rachel Carson's ™Silent Spring∫ (1962). Pesticideregistration and controls began being written intolaw. (3) The demands upon the pharmaceuticalindustry to demonstrate the safety of new drugs:New attention on the regulatory clearance of drugswas paid after the Thalidomide scare of the early1960's. To develop and get approval for humantesting of drugs, companies needed to know whichtoxicities to look for in clinical trials. This requiredmore thorough animal testing and exacting humanprotocols.The environmentalmovement of the 60's stemmed

from concern that the chemical technologies of the

40's and 50's might be harmful to human health.Legislation controlling toxic chemicals resulted andspread worldwide. In the 60's and 70's, risk assess-ments were primarily done based on descriptivetoxicology comprised of dose and blood levelmeasurements plotted against observed effects suchas enzyme activities or organ function tests. Somemechanistic understanding was available, such aswith organophosphate insecticides, but most regu-lated exposure levels were based upon observedbiochemical, functional ormorphological endpointsmodified by a safety factor.In the early 70's with the passage of the US Toxic

Substances Control Act, there was great concernabout the availability of scientists to deal with issuesof toxic substances through research and testing.Where would they be trained? How should they betrained? The US Congress charged the NationalInstitute of EnvironmentalHealth Sciences (NIEHS)with the task of developing and supporting newtraining programs (NIEHS web site: www.nih.niehs.gov). We did that and played a major role inthe establishment of the field as an independentscience. Through workshops and program solicita-tions NIEHS increased its funding for Ph.D. andpost-doc programs almost fourfold in five years.Initial programs were mostly in departments ofpharmacology, pathology, and epidemiology; butthese laid the groundwork for the future develop-ment of departments that included toxicology andenvironmental health in their titles.At the endof thatperiod we were producing trained environmentalhealth sciences researchers at a rate of about 100 peryear, a rate that continues todayIn the 1980's, there was still not enough data and

understanding to do risk assessment by other thandefault assumptions, andworst cases scenarios wereused to ™err on the side of safety∫. The value ofmechanistic data was recognized, although it wasnot widely used. The difference between variabilityin biological experiments (a normal attribute whichcan be dealt with using statistical methods) anduncertainty (a lack of understanding) was realized.The uncertainty was the basis for the continuing useof default assumptions. Most risk assessments dealtwith cancer, with its foundation in the programs ofthe USNational Toxicology Program (established in1978) and its predecessor NCI bioassay program.In the 1990's we came to the realization that the

uncertainty in risk assessments can be very costly,either in terms of unnecessarily strict regulations orin terms of health consequences, disease treatmentcosts, and lost productivity from underestimating ornot being aware of health hazards to humans. Wehave come to appreciate thewisdomof the statement

264 C. Schonwalder, K. Olden

by Leon Golberg, (the first president of CIIT), that™The mechanism will make you free∫. And todaymechanistic information has been used by regula-tory agencies to a limited extent with expectationsthat greater use is on the horizon.Understanding mechanisms is the first step to

understanding risk because it will: (1) Determine therelevance of bioassay data to humans. (2) Provideclues to the development of validated short termscreens such as functional toxicity screens usingtissue culture, genetically altered models for cancerand other endpoints, and receptor based screens. (3)Give power to predictive models based on chemicalstructure. (4) Provide the basis for prevention andintervention strategies. (5) Give clues to design ofproductive and informative research projects.

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We have come a long way. One indication of this isseen in the presentations at scientific society meet-ings where rather than the descriptive papers of the70's, topics presented today are on pharmacody-namics, pharmacokinetics and mechanisms in riskassessment with emphases on gene-environmentinteractions.Another indication of progress is seen in compar-

ing the tables of contents of the 1983 NAS ™RedBook∫ with the 1993 version, ™Science and Judg-ment in Risk Assessment∫. The 1983 publicationoutlined the now famous risk assessment ™para-digm∫ and endorsed the use of ™inference guide-lines∫ (i.e. default assumptions). It also described thedifficulties in cancer risk assessment due to uncer-tainties about thresholds and the mathematicalmodels used to extrapolate down to low doses.That was all! The 1993 version includes 12 chaptersdevoted to the nuances of risk assessment, howscientific information is used in risk assessment, theimportance of understanding and considering bio-logical differences between and among species, theneed to understand aggregate exposures to multipleagents, and the need to develop and use tieredapproaches to defining data and research needs.Next year, in 2003, we will be ready for a newupdate, further delineating how to use science in theassessment of risk.The practical side of the future of environmental

health research is that we will need to be muchmoredirect in dealing with uncertainty. It is not thepublic's tendency to think of science as beinguncertain ... but our science contains uncertaintiesbecause of the mix of biological variation and the

difficulty in connecting cause and effect. This isespecially true when dealing with latency andchronic exposures. And what has been causing somuch political turmoil is the mixing of uncertainscience with value judgments. Science should not beused as a tool of advocacy. But scientists must beadvocates for the advancement of the knowledgeneeded to reduce these uncertainties.To use the US as an example; when $200 to $400

billion per year are being spent for compliance, andmost of this for environmental and health compli-ance, it only makes sense to assure that we arecontrolling the right things to the right levels.According to the US Office of Technology Assess-ment (OTA), only about $520 million was spent in1995 on research related to health risks. This isobviously not a proper balance. About 15% of theUS Gross Domestic Product is spent on health care,and the biomedical research costs to learn how toavoid these expenses will have an extremely highreturn on investment. And it is not right to use as aparameter of risk a calculated ™one in a hundredthousand∫ or ™one in a million∫ deaths as accept-able, because the major cost in terms of both moneyand human suffering is in disease, not death.So the greatest challenge in the field of environ-

mental health is to prevent diseases rather than tocure them. We must find potential causes of diseaseand avoid exposing people to levels that might bringabout the diseases. Interestingly, this often removesour ability to complete the scientific process ofverification of results. Ifwe believe an exposure to beahazard,we shouldnot allow the™Experiment∫ (theexposure) to happen. We cannot complete theexperiment to prove the theoretical conclusion thatwe prevented disease (at least not in humans)!This is why it is so important to keep this mix of

data, theories and perspectives foremost in ourminds. We will always be discussing exposure andhealth effect issues with incomplete knowledge, andwe should accept that. But rather than have that factparalyze us in incessant argument (™paralysis byanalysis∫), we must bring together parties from allperspectives to agree on what additional knowledgewouldbemost valuable in narrowing theperspectivegap. The limits ofwhat science can deliver need to bedescribed. Then appropriate actions can be chosenknowing the role of uncertainty in the choiceprocess. In the end, it is a subjective judgment, likehow much insurance to buy.Lynn Goldman, a recent head of the US EPA office

of pesticides and toxic substances stated unequivo-cally ™The last thing we want to do is to put ourlimited resources into protecting people from thingsthat are harmless∫ (Science, 21 April 1995). This is

Environmental health 265

the truth, andwhat the field of environmental healthneeds to focus on in the 21st century is the concept of™value added∫.What will research provide to gain abetter perspective on issues of human health? Andwhat percentage of our effort should be invested in™Sharpening the Saw∫ (term from Steven Covey™The 7 Habits of Highly Effective People∫)? By thiswe are referring to the less focused curiosity drivenresearch, which provides understanding of theunderlying principles of the operation of life'ssystems. And how far can science and rationalthought go in understanding life's secrets? Surelythere are parts of life thatwill be forever unknowablethrough the tools of logic and analysis.Several areas are ripe for investigation and appro-

priate for investing resources. They beg for thedevelopment of partnership within and amongscientific disciplines. These areas can provide the™value added∫ in our understanding of how humansystems respond to xenobiotic chemicals.

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Modern molecular biology has been the key tounderstanding genetic control over cell growth andproliferative processes. By understanding how envi-ronmental agents influence these processes andwhich genes are most likely to be affected, we willbe able to begin to predict toxicities on the basis ofchemical structure. Furthermore, understandingmolecular mechanisms will allow the developmentof prevention and interventionmethods. Gene-arraytechnology will be developed to monitor precursormolecular events involved in the initiation of diseaseand to elicit uniquepatterns of gene response to toxicagent exposures. This understanding will allowrapid, inexpensive and early risk assessment fornew chemicals and drugs not yet on the market.

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Human epidemiological investigation has the ad-vantage of dealing directly with humans in theirnatural surroundings. It can assess the courses andcharacteristics of disease. It can give clues tosusceptibility. It can provide the foundation fordisease prevention and control activities and guidefuture basic research. But there are weaknesses, notleast of all being issues of exposure estimation andcause/effect determinations. Developments in mo-lecular biologywill soonprovide techniques to boostthe ability of human population studies to separate

real risks from noise and confounding factors. Here,current exposures can be assessed and exposure-disease cause-effect learned. This is real world afterthe fact epidemiology that might be seen as the leasttheoretical of all. Opportunities for such studiesmust be capitalized upon. Differences in exposurescenarios and in genetics between people in devel-oped and developing countries alike present tremen-dous investigative opportunities. The NIEHS isworking diligently with the NIH Fogarty Interna-tionalCenter to develop and support such programs.

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We need a better understanding of genes responsiblefor programmed senescence and cell death and howenvironmental agents that target organ systemsinfluence these. We need to better understand repairprocesses in response to spontaneous or inducedlesions. The development and use of transgenicanimals is an exciting area and has just started toshow its utility. The role of protein messengers andreceptors has opened entirely new concepts intoxicology. It not only brings toxicological investi-gation to a new level of complexity, but also holdsgreat potential to predict toxicities. Binding toreceptors of known function can be a powerfulpredictive tool. Systems to measure binding can bedeveloped as screens for toxic effects.

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Descriptive toxicology can be used as a screen formore sophisticated studies based on pharmacoki-netic models to describe the true tissue doses of thetoxic metabolites. Adding mechanistic understand-ing refines the estimate of risk. Transgenic animalsand cellular systems sensitive to known toxic effectscan be developed. The challenge, as in all science, ofcourse, is to know what the data mean. In biology,that understanding comes from experiments de-signed to elucidate how various levels of exposurewill affect human populations. This is the publichealth relevance of all our work, made morecomplicated by differing susceptibilities of individ-uals at different life stages.

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In real life, as Einstein said, ™Our theories determinewhat we measure∫. So even the most unbiased ofexperiments will have some perspective built into

266 C. Schonwalder, K. Olden

them. But this is OK as long as our observations canremain unbiased. It is the nature of toxicologicalexperiments to detect the unexpected. Educatedobservation of these events often leads to break-throughs in understanding which are much morevaluable than if the experiment had gone as planned.Everyone who has worked in a scientific laboratoryhas seen this happen. In the human populationrealm, we must redouble our efforts to understandthe relationships between environmental exposures,lifestyle choices, economics, and health outcomes.We must spread the ™center of mass∫ of scientificinquiry from its sole location in the developedworldand assure that scientific inquiry can take place inareas of opportunity worldwide. This is good publicpolicy, as relevance is critical to action.So the challenges to investigators in this field are

numerous and not just scientific. It is critical thatthose closest to the science do not retreat from theheat of the political battles and that they ™hangtough∫ when being forced to explain that science isnot yet ready to unambiguously answer the ques-tions being posed. We know that 50% understand-ing is more than twice as good as 25% understand-ing. Therefore as the field of environmental healthemerges from its infancy, let us keep a stronghandonthe helm so that the winds of ignorance do not blow

us off course. We must stand firm in the realizationthat we have come a long way and we are makingreal progress. Scientific input is critical, because ifworking scientists don't define the goals for the field,someone (like those who hold the purse strings) willdo it for us. If we don't demonstrate how environ-mental health research relates to real life humanhealth and that the knowledge generated has a realvalue, those who don't understand will interpretthings for us. If we don't engage in activities thatbring together the varied factions in this field towork for commonknowledge,wewill all suffer fromthe battle. Victories of presumptions over fact areshort lived and swinging pendulumsmake very littleprogress. To ask for definitive 100%certain answerswith today's understanding is to ask to be deceived.But the 21st century will reveal many answers andmany surprises.

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Carson, R.: Silent Spring. Houghton, Mifflin, Boston(1962)

Sinclair, U.: The Jungle. Bantam Books (1981)

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