Toxicogenomics

COVER Toxicogenomics STORY A scientific revolution is underway that is already affecting environmental, safety, and health regulatory policy and could dramatically change it within the next decade or so. It is not too soon for EPA as well as other affected agencies to begin the policy evolution necessary to keep up with the new technology

LYNN L. BERGESON, LISA M. CAMPBELL, and RICHARD P. BOZOF

oxicogenomics — an emerging ter screening of industrial chemicals and al- science that studies the interaction lowing safer drugs to get to market faster; between peoples’ genes, toxic • Individuals who have been exposed to chemicals in the environment, and chemicals, improving health intervention disease — has the potential to measures, improving epidemiological studies, Trevolutionize risk assessments and the regu- and affecting toxic tort litigation; and latory actions that rely on them, as well as • Individuals who may be unusually sus- to greatly advance the fields of toxicology ceptible to environmental stressors, including and environmental health. Its use for risk chemicals, enabling or requiring their expo- assessment could alter dramatically how sure to be reduced or that their health be moni- safety margins are calculated and how ex- tored more closely, particularly in a workplace posures are assessed, as well as premarket setting. safety testing of chemicals, evaluations of The Environmental Protection Agency and new drugs, and a host of other issues — all other regulatory agencies are considering of which in turn raise countless legal and toxicogenomics in various contexts. In No- ethical issues. vember, for example, representatives from the The legal issues range from the implica- Department of Energy, Occupational Safety tions of toxicogenomics information on ad- and Health Administration, National Institute verse information reporting requirements of Occupational Safety and Health, and EPA under the federal pesticide and chemical participated in a National Academy of Sci- substances laws, to their effect on workplace ences symposium entitled “Toxicogenomics: safety standards and the rights of individual The ‘New Biology’ Revolution in Environ- employees, to their use — and potential mis- mental Health Sciences.” Each federal agency use — in toxic tort actions. Toxicogenomics acknowledged the significance of genomic data and their use also raise a plethora of data. Given the significant issues and deep ethical issues — many of which involve core and wide-ranging impacts this technology privacy rights. The debate and resolution of may have, which they acknowledge — and these issues will affect regulation and liti- the fact that they are already using gation — and individuals — in fundamen- toxicogenomics data — the agencies are not tal ways for years to come. as aggressive as they should be in adopting These controversies should not obscure policies governing toxicogenomics and pre- the numerous potential benefits of paring to integrate it into their decisionmak- toxicogenomics, many of which are highly ing where warranted. significant. First and foremost, toxico- In particular, EPA’s Interim Policy on genomics can help explain the mechanisms Genomics does not go nearly far enough. Pre- by which chemicals cause toxicity, improv- pared last June by the agency’s Science Policy ing our understanding of disease. In a regu- Council, it appropriately acknowledges the latory setting, toxicogenomics can produce significance of toxicogenomics, but leaves a number of desirable results. For example, unexpressed the critical need for EPA to de- it can help identify: velop a comprehensive policy framework to •The toxic effects of pollutants and govern the use of this rapidly growing tech- manufactured chemicals and drugs in hu- nology and expedite its inclusion in risk as- mans, reducing exposure risks through bet- sessment and other agency science as appro-

priate. In the interim policy, EPA indeed states potentially be followed by other agencies — that toxicogenomics will “have an enormous ignores the crosscutting nature of these bur- impact on our ability to assess the risks from geoning applications and invites inconsis- exposures to stressors and ultimately to im- tency and potential confusion. EPA in particu- prove our risk assessments.” However, the lar should, given that risk assessment is its life- agency cautions that the technology is evolv- blood and the foundation for many of its regu- ing, that the relationships between gene ex- latory decisions, be in the forefront of devel- pression (the proteins the gene produces) and oping a framework to govern how this infor- adverse health effects are at present unclear, mation should be factored into its policies. and that for assessment purposes EPA will Lynn L. Bergeson and Lisa consider genomics information on a case-by- M. Campbell are founding case basis. Thus, the policy recognizes, but he sensitive and controversial shareholders of Bergeson does not address, the need to investigate how issues raised by the use of & Campbell, P.C., and information from this technology may be used toxicogenomics data — which are Richard P. Bozof is Of in risk assessments or the need to provide outlined below — require that guidance on the ethical, legal, and social im- such a framework be developed Counsel to the firm. plications of such use. early and, given the profound ethical and le- Located in Washington, T D.C., the firm Other agencies that will be much affected gal issues at stake, through a transparent, pub- by toxicogenomics — OSHA and the Food and lic process. As a practical matter, the horse is concentrates on chemical, Drug Administration in particular — appear already out of the barn — these data are being medical device, and also not to be moving forward as aggressively provided to EPA under the Voluntary diagnostic product as they should be. Neither Children’s Chemical Evalu- approval and regulation, OSHA nor FDA has adopted ation Program, its Endocrine and associated business a policy on toxicogenomics. EPA’s Interim Disrupter Screening Pro- issues. NIOSH, which is within gram, and other programs. OSHA, is using genomics in- Genomics Policy EPA will consider them, and formation, and FDA has ini- it should not do so without tiated toxicogenomics re- recognizes, but such a framework. The search projects that promise agency has convened pub- to improve the effectiveness does not address, lic advisory committees un- of therapeutic drugs and re- the need to der the Federal Advisory duce their risks. But neither Committee Act for issues of agency appears to have de- investigate how less significance, and it veloped a formal framework should do so here promptly. to anticipate and address this technology In short, with its revolu- many of the issues concern- may be used in tionary potential advan- ing toxico-genomics that are tages, toxicogenomics can- pertinent to its mission. risk assesments or not be relegated to a “wait Given the dramatic and and see” approach by EPA far-reaching benefits of the need to and other agencies who rely toxicogenomics informa- on risk assessments. More tion, the similarly dramatic provide guidance needs to be done now to en- effects that it can have on on other uses sure the expeditious and op- risk assessment and its con- timal use of this technology sequences, and the many in a manner that is scientifi- important legal and ethical issues its use cally, legally, and ethically sound. Given their raises, EPA’s interim policy — and the respective charges, EPA and other agencies backseat position taken by other agencies whose work will be most affected should take whose mandates also will be dramatically af- a strong lead in identifying and resolving the fected by these issues — needs to be much significant issues that toxicogenomics raises. bolder. A scientific revolution is underway EPA in particular is well-suited to assume a that is already affecting environmental, safety, leadership role in developing an interagency and health regulatory policy and could dra- framework, including, at a minimum, OSHA, matically change it within the next decade — FDA, the National Institute of Environmental and it is not too soon to begin the policy evo- Health Sciences, and the Centers for Disease lution necessary to keep up with the chang- Control and Prevention, for how, when, and in ing science. The cautious case-by-case ap- what circumstances toxicogenomics informa- proach stated in EPA’s policy — one that may tion will be considered for regulatory pur-

A Powerful Tool With Great Promise For Risk Assessments

s expressed in our recently minnows as an indicator of exposure genomics technology be applied to issued Interim Policy on to estrogen. This would help exam- decisions about the risk a chemical AGenomics, we at the Envi- ine the quality of water in streams may pose to humans and wildlife. ronmental Protection Agency believe and identify endocrine disrupters. We are concerned not only about “that genomics will have an enor- An important goal for the agency what these tests are telling us, but mous impact on our ability to assess is to use genomics to provide data we must also focus on the quality of the risk from exposure to stressors for the modeling of toxicological the tests themselves. There needs to and ultimately improve our risk as- pathways for single chemicals or be a concerted effort among all the sessments.” EPA’s position, gener- classes of chemicals. We believe that regulatory agencies and the regu- ated by many across the agency un- defining specific biological indica- lated public to address the reproduc- der the auspices of EPA’s tors for the various steps ibility of the tests, the quality of data, Science Policy Council, in the pathway will help and when any of the genetic changes recognizes the promise of identify a set of key seen truly indicate an adverse effect. this rapidly evolving sci- events for specific chemi- Before we can effectively use ence. It also provides cals that are tied to ad- genomics information in agency risk some focus on where EPA verse outcomes (e.g., de- assessments, these quality issues would like to expand in velopment of tumors, re- need to be resolved. EPA is working utilizing these new tools. productive effects, etc). with its partners to advance efforts As biotech and phar- Such key events can then to address the quality issues. maceutical interests race Paul Gilman be used for predicting The agency’s interim policy rec- to unlock the potential of toxicity and potentially ognizes the promises of the genomic-related drug therapies, the adverse health outcomes for chemi- genomics revolution, but also real- regulatory agencies are also moving cals of unknown or untested toxic- izes its current limitations for regu- ahead with many genomics-related ity. As part of its pilot use of “com- latory decisions. So while EPA en- initiatives but with more measured putational toxicology,” the agency is courages and supports continued steps. EPA’s initial research initia- looking at techniques to assist in the genomics research as a powerful tool tives are focusing on using genomics program for identifying and assess- for understanding the molecular to identify, and ultimately solve, ing endocrine disruptors. basis of toxicity and developing human and environmental prob- A major, if not almost overwhelm- biomarkers of exposure, effects, and lems. This use of the technology will ing, characteristic of genomics is the susceptibility, genomics data alone help us to build the assurance that generation of massive amounts of are currently insufficient as a basis the tools provide appropriate infor- data. This huge new body of infor- for risk assessment and decisions. mation to support regulatory actions mation will need to be analyzed to However, genomics information is and decisions. discern what pieces will be most use- useful in a weight-of-the-evidence We are developing genomics tools ful to support our myriad regulatory approach for human health and eco- to examine the possible toxicity of responsibilities. This task will re- logical risk assessments on a case-by- chemicals and other stressors that quire development and application case basis at this time. For example, may impinge on human and ecologi- of new approaches in the emerging EPA has identified genomic informa- cal health and to monitor stressors field of bioinformation. tion in the scientific literature and that may harm the environment. We Because of the explosive genera- has used it as part of some risk as- are also leveraging our capabilities tion of genomics data, regulatory sessments for well studied chemicals and resources with our many federal agencies are faced with the basic such as dioxin. As EPA gains experi- partners, industry, and other orga- questions of, What does this all mean, ence in assessing the quality, accu- nizations to advance techniques to What do these data tell us? Before we racy, reproducibility, and relevance examine these stressors. For ex- can extrapolate the results of of genomics information, it will re- ample, EPA is developing a new gen- genomics tests to possible human and examine and, if appropriate, refine eration of microbial water quality in- ecological health outcomes, we must the interim policy and issue more dicators using genomics to assess, in resolve many underlying biology specific guidance to its program and real time, whether exposure to or questions as well as data quality is- regional offices on how genomics consumption of a given source of sues. Importantly, we need to under- information can be used in regula- water is safe. stand how a chemical or other stres- tory actions and decisions. Another major initiative is to de- sor affects a gene or its expression of Paul Gilman, Ph.D., is Assistant velop biological indicators in senti- proteins and whether those changes Administrator for EPA’s Office of Re- nel species that are prevalent in the are tied to a particular adverse out- search and Development and the environment. For example, we are come or not. Only after we under- agency’s Science Advisor. The Interim looking for changes in gene expres- stand these relationships can the in- Policy on Genomics is available at sion of particular proteins in fathead formation from the application of www.epa.gov/osp/spc/genomics.htm

poses given the concrete, substantial, and chemicals be tested, but potentially many overarching effect on its regulatory work that more endpoints will be assessed. Vast toxicogenomics risk assessments and other amounts of data can be generated with uses may well have. Representatives from the toxicogenomics, and the new science of European Union and other foreign govern- bioinformatics is being developed to analyze ments should be invited as observers, as the the data, using sophisticated computational global view should be recognized as well. and statistical methods. This is the reason why toxicogenomics will profoundly affect risk assessment, and the oxicogenomics is based on newly results of those assessments, for chemicals developed methods of measuring in the regulatory arena, in the workplace, and “gene expression” — the series of in the courts. Toxicogenomics will provide biochemical steps resulting in and information that could significantly expand including the production of a spe- the scope of issues that must be considered Tcific protein by a specific gene. As a result of as individual chemicals are regulated and the the Human Genome Project, we now know potential liabilities the entire human genetic makeup in consid- faced by those manufac- erable detail. And we are rapidly learning turing and selling those how specific chemicals may alter the man- chemicals and products ner and extent to which genes produce pro- made with them. This Its use for risk teins or the biochemical precursors of pro- information will in- assessment teins — hence, toxicogenomics. While the clude: cases in which we can show a one-to-one cor- • Explaining mecha- could alter respondence between a chemical and a pro- nisms of toxicity of vari- tein will be rare, with advances in, and inte- ous chemicals and other dramatically gration of toxicogenomic methods, we will environmental stres- soon be able to narrow dramatically the mar- sors; how safety gin of error over current methods of evalu- • Developing gene margins are ating toxic effects of chemicals in humans as expression profiles that well as dramatically widening the number permit grouping or clas- calculated of chemicals that can be evaluated for toxic- sifying of chemicals ac- ity. We may also be able to calibrate with a cording to profile pat- and exposures much greater degree of refinement the terns indicative of spe- are assessed “dose” level at which certain effects occur. cific toxic responses (or As Laura Lane and Leslie Pray write in components of such re- the magazine The Scientist, “The new field is sponses) and that may based on the premise that tumors, disease, permit or assist in toxicological characteriza- and other physical responses to toxic chemi- tion of compounds with unknown character- cals find their origins in gene expression, istics; which depends on the environment — •Allowing for screening of chemicals that chemical or otherwise. Determining how are likely to pose significant toxic effects; genes respond to a toxicant, then, could be a • Assisting in designing chemical or stres- direct measure of toxicity. It’s faster, cheaper, sor exposure studies; and more accurate than animal testing, which • Identifying subgroups of humans that often takes years to perform; examining gene are genetically susceptible to specific chemi- expression takes only days or months.” Ac- cals and drugs and elucidating mechanisms cording to the authors, that’s welcome news, of susceptibility; and given that there are 80,000 substances used • Developing gene expression “signa- in commerce, such as drugs, food additives, tures” or “biomarkers” that will provide a cosmetics, and chemicals, of which relatively basis for identifying agents and doses to few have been tested with present methods. which individuals or populations have been Toxicogenomics can provide information, exposed and for early detection of diseases many believe, on endpoints such as carcino- induced by such agents. genicity, liver damage potential, heart prob- Toxicogenomics potentially will provide lems, neurotoxicity, immunotoxicity, repro- many public health benefits. The refinements ductive and developmental toxicity, and oth- in the risk assessment process and the fast ers. With the greater efficiency of toxico- screening for toxicological effects of a large genomics, however, not only will many more number of chemicals are the most obvious.

EPA Is Right To Be Cautious; Utility Is Limited By Many Factors

enomics is a rapidly ex- potentially valuable in screening and environmental factors conspire panding field of molecular chemicals for deleterious effects and to move a healthy individual to a dis- Gbiology that has captured prioritizing for further testing. eased state. In such cases, as Profes- the attention of the public and Third, it could assist in elucidating sor Judith Miller has reasoned, “ge- policymakers. Can environmental the exposure-response continuum netics loads the gun, but environ- professionals take advantage of this by revealing in greater detail how a ment pulls the trigger.” In other new knowledge to improve the compound acts to disrupt DNA or words, to begin to reduce the bur- public’s health and reduce chronic RNA or alter protein synthesis. den imposed by chronic disease we disease? In the short term, genomics is need to know both what our genes According to EPA, genomics is likely to make its greatest impact in can do and what environmental fac- the study of all of the genes of a cell, screening and prioritization. Be- tors we confront. or tissue, at a DNA, RNA, and pro- cause genomics testing can be done The genomics revolution is testa- tein level. The agency is- rapidly and in batches, ment to our massive investment to sued its Interim Policy on many compounds can be understanding what loads the gun. Genomics in June, no tested in a short period of Regrettably, we have devoted far doubt in response to re- time. Once specific and fewer scientific resources to under- quests from scientists characteristic patterns of standing what pulls the trigger. Our and risk assessors who gene expression are asso- federal science and public health were wondering how the ciated with genetic dam- agencies should invest parallel re- agency is planning to in- age and a disease signa- sources in the study of environmen- corporate genomics data ture, rapid screening will tal factors. Otherwise, our genomic into its decisionmaking. Paul A. Locke be a reality. lexicon will be no more than an en- EPA’s policy acknowl- For the near future, cyclopedia without an index. edges the promise of the new tech- genomics will be less useful for de- Twenty-first century exposure sci- nology, encourages the use of coding population susceptibilities ence, such as the biomonitoring data genomics information, but adopts and mechanisms of action. We sim- contained in the National Exposure a “go slow” approach. The agency ply do not have a full understand- Report produced by the Centers for has agreed to review genomics data ing of what the gene alterations re- Disease Control’s National Center on a case-by-case basis, and refine ally mean. While screening can be for Environmental Health, should be its interim policy as it gains more done with incomplete knowledge, greatly expanded and linked to experience. more precise applications of ge- emerging genomic information. The EPA is right to be cautious. nomic data will require a richer un- CDC has also initiated a nationwide Genomics is a new field, and its so- derstanding of the data. health tracking network that will phisticated methodologies are at The utility of genomics is limited help us understand the linkages present running ahead of our abil- by several factors, and EPA seems to among environmental factors and ity to interpret the information they recognize implicitly these limita- chronic diseases. produce. We have a long way to go tions. First off, genomics only pro- Finally, although EPA’s genomics before we are able to incorporate vides information about diseases policy does not explicitly say so, en- genomics routinely in environmen- that alter gene function. But more couraging humane science is an- tal decisionmaking. And if we do importantly, where it can be useful, other reason for employing this new not begin serious efforts to collect genomics provides information technology. Genomics has the po- information about environmental about only a portion of the exposure- tential to reduce the number of ani- factors — exposure to chemicals to-response puzzle. It is focused on mals needed for laboratory testing, and radiation, diet, lifestyle and be- the changes that occur in DNA, by replacing tests that use animals havior — we may never be able to RNA, and protein synthesis, but can- with genomics procedures that are unlock the promise that genomics not detect the environmental factors animal-free. Given the number of holds. and chain of events that caused these new and existing compounds that As EPA’s policy points out, changes. In rare cases, genetics has have not been evaluated for toxic- genomics has the potential to be uncovered genes, such as those as- ity, and the public’s dual desire to useful in at least three areas. First, sociated with Huntington’s disease know more about these compounds it can help identify those persons or phenylketonuria, that are suffi- but also to reduce the preventable in a population who have been im- cient by themselves to cause disease. loss of animal life and animal pain pacted by environmental factors. In the case of most chronic diseases and suffering, genomics fills an im- These individuals will show mo- and conditions of interest to public portant role. lecular changes, through DNA, health professionals — asthma, birth Dr. Paul A. Locke is Deputy Direc- RNA, or protein alterations, that defects, cancers, and pulmonary dis- tor and General Counsel at Trust for can be measured. Second, it can be eases — complex arrays of genetic America’s Health in Washington, D.C.

But other public health benefits will result. rizing EPA to restrict or ban the manufacture Toxicogenomics may allow for the identifi- of chemicals that are believed to present an cation of exposed individuals both in the “unreasonable risk of injury to health or the workplace and among the general public to environment,” the Federal Insecticide, Fun- particular chemicals through biomarkers, gicide, and Rodenticide Act’s “unreasonable which may allow health intervention mea- adverse effects” standard used in making sures, such as increased health monitoring, pesticide registration determinations, and the preventive treatments, and preventive mea- Clean Air Act’s requirement to establish pri- sures against further exposures. Further, the mary national ambient air quality standards technology may facilitate the detection and with an “adequate margin of safety” and to therefore the taking of preventive measures take into account health thresholds with an for the protection of highly susceptible indi- “ample margin of safety” in regulating haz- viduals both in the workplace and among the ardous air pollutants. general public. For example, identification of Quantitative risk assessments of chemicals highly susceptible individuals to potential under these statutes and programs often re- toxic effects of certain consumer products quire extrapolation from animal data alone, may lead to measures that reduce the expo- or animal data combined with incomplete sures of such individuals. In addition, human data. In general, when extrapolating toxicogenomics likely will provide informa- risks from such data, uncertainty factors are tion on mechanism of action that in turn may employed to take into lead to the development of more effective account the incomplete- medical treatments or intervention measures ness of information. for prevention of progression of disease pro- The approach for es- cesses initiated by exposure to chemicals or timating non-cancer hu- Changes are other toxicants. man risks from animal in store for Further, toxicogenomics may allow for the studies that generally is use of highly useful, but potentially toxic, utilized by EPA, as well premarket drugs while reducing the risks by identify- as by other regulatory ing hypersusceptible individuals to whom agencies, is exemplified safety testing the drug should not be administered. Other by the methodology de- potential benefits with regard to the use of scribed in the agency’s of therapeutic drugs or with regard to medical Integrated Risk Infor- manufactured treatments also have been identified. For ex- mation System. Under ample, toxicogenomics methods may be use- the most basic approach chemicals and ful in predicting drug responsiveness in in- included in this meth- dividual cancer patients and in identifying odology, the level of ex- evaluations of useful combination therapies. Toxicoge- posure at which a toxic new drugs nomic methods could also potentially be effect of concern is not used to measure a key parameter determin- expected to be observed ing the usefulness of a drug — the therapeu- in humans is typically tic index, which is a measure of the median determined in two steps. First, the “no ob- toxic dose of a drug to the drug’s median servable adverse effect level” (or other com- effective dose — by providing data on both parable dose-response benchmark) is deter- toxic and beneficial effects of a drug. mined from animal studies. The NOAEL is then divided by a 100-fold uncertainty fac- tor. This UF is actually composed of two uantitative methods of esti- separate 10-fold UFs, one to account for the mating human risks posed by uncertainty in extrapolating from animals to chemicals are utilized in a humans and a second to account for varia- wide spectrum of environ- tion in sensitivities within the human popu- mental and other public lation. A number of studies have shown that Qhealth laws to determine how these UFs are generally “conservative,” chemicals to which persons may be exposed which means they lean in the direction of pro- should be regulated. Examples include as- tecting health. certaining risks under standards established Toxicogenomics can support significantly by a number of environmental protection reduced UFs without jeopardizing health. laws administered by EPA, such as the Toxic Toxicogenomics may accomplish such refine- Substances Control Act’s provisions autho- ments by providing more data on the mecha-

nism of a chemical’s toxicity, which in turn cant-specific biomarkers may make it pos- will increase the accuracy of extrapolation sible to identify chemicals and the dose to between animals and humans. As noted which individuals or populations may be above, toxicogenomics could also be used exposed. Toxicogenomics thus may prove to to identify specific factors that make some be an extremely useful tool in refining the humans more susceptible to a chemical. exposure assessment component of risk as- Such information could help refine and re- sessment. How toxicogenomics information duce the UF used to ac- is used to refine an exposure assessment — count for differences in and the parameters on its use for that pur- susceptibility among dif- pose — must be framed now given the many Toxicogenomics ferent humans in the potential consequences of exposure assess- population. EPA’s In- ments that newly identify chemicals as rais- will provide terim Policy on ing human health issues. Refined Genomics states that toxicogenomics-based exposure assessments information genomics holds promise will not only have clear regulatory conse- to identify variability quences, but will also impact significantly the that could and susceptibilities in in- resolution of toxic tort liability and the de- significantly dividuals from exposed velopment of workplace standards. populations or among For the most part, the risk posed by a expand the different species, thus chemical requires a battery of tests to deter- concurring with the view mine what adverse effects may be caused by scope of issues that toxicogenomics may the chemical after acute (short-term), sub- that must be provide a basis for reduc- acute or subchronic (medium-term), and ing the UFs. chronic exposures. In addition, different considered ... Toxicogenomics also types of tests are necessary to evaluate cer- might enable regulators tain types of adverse effects, such as repro- to bypass traditional risk ductive or developmental toxicity, carcino- assessment approaches genicity, or neurotoxicity. Where relevant in some instances by allowing for identifica- human data, such as epidemiological stud- tion of sensitive individuals by means of a ies, do not exist, as is frequently the case, toxicogenomics test rather than use of broad laboratory animal tests, often involving a brush UFs to account for intraspecies vari- large number of test animals, are required. ability. Whether such an approach would be FIFRA, TSCA, and the Federal Food, Drug feasible legally will likely be the subject of and Cosmetic Act, among other statutes, re- much debate on a wide variety of issues rang- quire a variety of tests before a product may ing from those related to an individual’s right be marketed or as a condition of continued to privacy to those concerning the feasibility marketing of the product. Under TSCA Sec- of implementing regulatory controls of a tion 4, for example, EPA may require chemi- chemical on such a basis and the potential cal manufacturers to test existing chemicals liabilities if better information is later devel- either through a test rule or an enforceable oped. consent agreement with manufacturers, and Risk assessments required under various under Section 5 the agency may restrict or environmental, product, and public health ban the manufacture or use of new chemi- regulatory programs generally must evalu- cals for which Premanufacture Notices have ate not only the levels of exposure at which been submitted pending development of humans may be at risk to the toxic effects of new toxicology data. Another example is the chemicals, but also which segments of the FFDCA, which requires new drugs to go population are exposed and the magnitude through a series of extensive and expensive of any such exposures. For example, in evalu- tests, beginning with animal toxicology test- ating whether pesticides pose “unreasonable ing. adverse effects on the environment [includ- Toxicogenomics technology could dra- ing humans]” under FIFRA, it is necessary matically impact these and similar testing to relate estimated exposures resulting from requirements, as well as chemical production the use of pesticides to the levels of expo- and drug development, in a number of ways. sure at which pesticides may cause toxic ef- First, by providing a quick screening method fects in humans. of identifying highly toxic chemicals or other The National Center for Toxicogenomics, products early in the investigative stages, established within NIEHS, believes that toxi- toxicogenomics may provide manufacturers

with valuable information in deciding ing requirements of Section 8(e). These offi- whether to proceed with product develop- cials said at the same meeting that whether ment before conducting more expensive toxi- a pattern of gene response should be cological tests on experimental animals. Sec- deemed an adverse effect will be deter- ond, the technology may provide EPA a valu- mined after a consensus is reached in the able means of prioritizing for further testing broader scientific community on this issue. the many chemicals for which there are in- Toxicogenomics could also affect various sufficient toxicological data. Third, it may aspects of toxic torts litigation, including the provide highly useful information in deter- establishment of causation, theories of liabil- mining whether and what testing should be ity, and certification of classes in class actions. required for new chemicals for which PMNs The implications for establishing causation are submitted. Fourth, because of informa- are perhaps the most prominent. Since the tion which might be provided concerning landmark 1993 Supreme Court decision mechanism of action and similarity of gene Daubert v. Merrell Dow Pharmaceuticals, which expression profiles to other chemicals with redefined the standards for admissibility of well-established toxicological information, expert scientific evidence and the court’s role toxicogenomics may reduce or eliminate the as “gatekeeper” for the screening of such traditional types of toxicological tests that evidence, there has been a growing trend in might otherwise be required for new or ex- court rulings to require human evidence to isting chemicals or may reduce the number establish causation in toxic torts action. More of animals needed to conduct a particular specifically, in toxic tort actions many courts test. Further, toxicogenomics, by raising a red have ruled that causation can only be estab- flag about the potential toxicity of a chemi- lished by epidemiological studies that dem- cal, may actually increase the degree of test- onstrate the substance in question resulted ing that otherwise might be required, if the in a doubling or more of the risk of the dis- toxicogenomics data are insufficiently pre- ease or injury for which the plaintiff seeks dictive. relief. The theory behind these rulings is that only such evidence is suffi- number of statutes regulating ciently reliable to show ... as hundreds chemical products require that the plaintiff’s illness manufacturers and others to more likely than not re- of new report information on adverse sulted from the exposure effects associated with chemi- to the substance. Many chemicals are Acals. For example, TSCA Section 8(e) requires courts therefore have regulated and any person who manufactures, processes, or ruled that causation can- distributes a chemical substance and who not be established by ani- firms face the obtains information which reasonably sup- mal data alone or by epi- ports the conclusion that such substance pre- demiological studies that liabilities of sents a “substantial risk of injury to health show less than a dou- or the environment” to inform EPA of such bling of risk. manufacturing information. Agency guidelines implement- Data generated from and selling ing this provision indicate that sources of toxicogenomics may fa- substantial risk information include, among cilitate the establishment them other things, controlled studies, epidemio- of causation in toxic tort logical studies, environmental monitoring cases in several ways. studies, and clinical studies. First, as discussed above, Toxicogenomics data that either establish it is anticipated that this technology will be that a chemical poses certain adverse toxico- able to show whether an individual is highly logical risks or that demonstrate significant susceptible to the toxic effects of a particular human exposures to chemicals of known tox- chemical. If it can be shown that the plaintiff icity may be subject to these and similar re- is highly susceptible to the effects of the sub- porting requirements, at least after the tech- stance on which the action is based, courts nology is further advanced and validated. In that generally apply the doubling of risk rule a recent meeting at which EPA announced may allow recovery even if the epidemiologi- its new interim policy, officials indicated that cal data show a relative risk of less than two. they were looking into whether toxico- Further, application of toxicogenomic tech- genomics data would be subject to the report- niques may identify biomarkers that provide

both qualitative and quantitative evidence s toxicogenomics develops and of the plaintiff’s exposure to the substance provides an increased ability to in question and therefore help establish the determine increased suscepti- required showing of specific causation. In bility of individuals to the toxic addition, data generated by toxicogenomics effects of chemicals, many legal, technology combined with animal data and Apolicy, and ethical issues concerning the other non-epidemiological data possibly rights and obligations of employers and may be sufficient to establish causation even employees in the workplace will arise. At in courts that generally present, the legal framework at the federal adhere to the epidemio- level for addressing these issues is composed logical evidence rulings. largely of the Occupational Safety and Health Toxicogenomics For example, if a gene ex- Act and the Americans with Disabilities Act. pression profile for the The OSH Act regulates toxic substances can support substance in question primarily through standards established shows a “fingerprint” under Section 6(b)(5) and the general duty reduced very similar to that of an- clause in Section 5(a)(1). Section 6(b)(5) pro- other chemical shown by vides that OSHA shall set standards concern- “uncertainty epidemiological evi- ing toxic materials which adequately assure factors” dence to cause the dis- that “to the extent feasible . . . no employee ease suffered by the will suffer material impairment of health or without plaintiff, such informa- functional capacity.” The general duty clause tion by itself or in con- requires that each employer furnish employ- jeopardizing junction with other data, ees with employment and a place of employ- human such as animal toxicol- ment “which are free from recognized haz- ogy data, may suffice to ards that are causing or are likely to cause health ... establish causation. death or serious physical harm.” Citations A number of other is- may be issued for violations of the general sues may be raised by the duty clause, however, only with regard to availability of toxicoge- hazards that specific standards promulgated nomics technology with respect to toxic torts under the OSH Act are not intended to ad- liability, including: dress. • Whether a demonstration of wide varia- Leading experts in occupational health tion in genetic susceptibility among a group law and other commentators have expressed of plaintiffs by toxicogenomics technology the view that occupational standards estab- would preclude certification of a class pur- lished under Section 6(b)(5) and other OSHA suant to Federal Rule of Civil Procedure 23 provisions largely apply to average workers on the grounds of differences in issues con- and that the statute is not intended to pro- cerning causation; tect highly susceptible individuals to the • Whether the ready availability of same degree as the normal or average toxicogenomic techniques to determine sus- worker. The Supreme Court has held that ceptibility to a manufacturer’s product im- standards under Section 6(b)(5) “must be poses a duty to ascertain whether any sig- addressed to ‘significant risks’ of material nificant groups are hypersusceptible to the health impairment.” The Court has deter- product and to provide an adequate warn- mined further that, provided the “significant ing targeted at such groups; risk” threshold requirement has been met, the • Whether a defendant would be permit- standard must be “feasible” based on eco- ted to request a determination of potential nomic and technological considerations, but hypersusceptibility in a plaintiff through cannot be based on a balancing of costs and toxicogenomic techniques and whether such benefits. This case law makes uncertain the a determination would provide a defense, extent to which OSHA may establish Section particularly if the hypersensitivity is rare 6(b)(5) standards to protect hypersusceptible among the general population; and employees. Both the significant risk and the • Whether the availability of toxico- feasibility criteria, however, indicate that a genomics technology to ascertain standard typically cannot provide for an ab- biomarkers of exposure to a hazardous sub- solutely safe workplace, given that genetic stance would impose a duty on an employer and other factors can make for a very wide to test or offer to test potentially exposed range of susceptibility among workers. employees. Moreover, OSHA in fact generally has not

made special provision for susceptible work- dicated by the 1991 Supreme Court decision ers in setting permissible exposure levels in UAW v. Johnson Controls, Inc., which held under Section 6(b). that an employer’s practice of excluding all The Supreme Court has held, however, fertile women, but not fertile men, from jobs that OSHA could require monitoring and involving lead exposure constituted sex- medical testing for employees exposed to based discrimination against women prohib- levels below the standard and “in this way ited by Title VII of the Civil Rights Act of . . . could ensure that workers who were un- 1964. Other issues concerning removal of usually susceptible . . . could be removed unusually susceptible employees from haz- from exposure before they had suffered any ardous working conditions include the de- permanent damage.” OSHA in fact has is- gree of hypersusceptibility that should be sued a substantial number of standards that required for such actions and the question do require medical examinations and moni- of who should bear the costs of such actions. toring, but OSHA generally has not required Alternatively, should toxicogenomics data be specific tests. made available free of cost to the employees A number of questions arise as to how and the decisions of how to use that infor- toxicogenomic technology as it evolves could mation be left to them? or should be utilized under OSHA. One is- Other issues that might arise if employers sue is whether and to what extent employ- conduct toxicogenomics tests on employees ers should be required to test their employ- include how employers can be prevented ees for hypersusceptibility. Questions of the from misusing such data and from unfairly reliability of the tests and how they should discriminating against hypersusceptible be interpreted likely will be an issue in de- employees, how employee confidentiality termining whether the tests should be re- and privacy should be best protected, to quired. Another issue is how the tests should whom toxicogenomics data should be made be utilized. It could be impractical to require available, and what obligations and assump- employers to lower exposure levels to the lev- tions of risk should be els necessary to protect the most susceptible made by employees pro- employees, particularly where the incidence vided with such data. of hypersusceptible individuals is very low. The Americans with ... by providing Moreover, the question remains as to what Disabilities Act addresses other steps should be taken to protect many aspects of discrimi- more data on hypersusceptible individuals. According to nation in the workplace a leading expert in the field, it is unclear based on disability. To be a chemical’s whether employers are required under the subject to the protections toxicity, general duty clause to protect workers they of the ADA, a person know are hypersusceptible. At the same time, must be a “qualified indi- increasing the as discussed above, the Supreme Court has vidual with a disability.” indicated that standards may provide for While the Equal Employ- accuracy of removal of unusually susceptible individu- ment Opportunity Com- als from workplace areas with concentrations mission in 1995 had is- extrapolating of hazardous substances below specified lim- sued an interpretation from animal its based on test results, and some OSHA that an employer that dis- standards in fact provide for such a proce- criminates against an in- data dure under limited circumstances. Neverthe- dividual based on a pre- less, it is possible that amendment of the OSH dictive genetic test would Act may be a necessary and appropriate step be in violation of the to afford adequate protection of ADA, the interpretation of the term “dis- hypersusceptible workers. If added protec- abled” in recent Supreme Court holdings in- tions are required, a host of questions arises dicates that it is unlikely that a genetically as to how such protections should be imple- susceptible person who is not actually dis- mented. For example, should employers gen- abled by illness would be covered by the pro- erally be required to remove hypersuscept- tections of the ADA. For example, in Sutton ible employees from conditions that might v. United Air Lines, Inc., the Court held that be dangerous, and if so, how and under what “[a] ‘disability’ exists [under the ADA] only circumstances? Caution must be exercised as where an impairment ‘substantially limits’ a to how unusually sensitive individuals may major life activity, not where it ‘might,’ be excluded from working conditions, as in- ‘could,’ or ‘would’ be substantially limiting

if mitigating measures were not taken.” Ac- applied in the next few years. EPA should cordingly, a “person whose physical or men- be at the forefront of addressing those issues, tal impairment is corrected by medication or through a public process that involves stake- other measures does not have an impairment holders in a meaningful manner, in coordi- that presently ‘substantially limits’ a major nation with NIH. life activity.” Some believe that given the cur- This importance of addressing ELSI issues rent interpretations of the law, new legisla- in the context of toxicogenomics is under- tion will be introduced, scored by the fact that such issues are far- with the stated purpose reaching and raise privacy issues of consti- of ensuring that employ- tutional importance. Genetics information, In toxic torts ers do not discriminate for example, provides insights into many in- on the basis of the results timate aspects not only of a particular indi- litigation, of toxicogenomic tests in- vidual but also that individual’s relatives. dicating hypersuscepti- Such information may concern not only caustion may bility in employees or po- health susceptibility, but also possibly behav- tential employees. ioral predispositions, issues of parentage, be easier to and reproductive options. The information prove than contained in a person’s DNA can constitute he ethical, the most personal and private information under the legal, and so- about an individual. The availability and fu- cial ramifica- ture development of genomics and current tions of re- toxicogenomics methods also can make “doubling search into de- DNA samples a ticking time bomb which in cipheringT the human ge- the future might release sensitive private in- of risk” rule ... nome were recognized formation about the individual. Some fear by the federal agencies that if such information is not sufficiently involved in the Human safeguarded, harm may result from the un- Genome Project — the fair use of the information by employers, in- National Human Genome Research Insti- surers, and others. tute within the National Institutes of Other key ELSI issues that have been iden- Health and the Department of Energy. In tified in connection with human genomics 1990, those agencies established a program and toxicogenomic issues include: to evaluate the ethical, legal, and social im- • How should unauthorized access to ge- plications of human genetics research, netic samples contributed by individuals be known as the ELSI Program. Considerable prevented? research and analysis has been conducted • How should the privacy and confiden- under this program. Much also has been tiality of genetic information about an indi- written about ethical issues concerning re- vidual generated by toxicogenomics meth- search and application of human genomics odologies be protected? technology by commentators in academia • How should safeguards be imple- and by other outside observers. The issues, mented to restrict access to databanks con- however, which are extremely complex, taining toxicogenomics data concerning in- have evolved and have been viewed in ever dividuals? changing contexts as the human genomics • How should toxicogenomics data be technology has progressed and as new so- evaluated for accuracy, reliability, and util- cial and policy considerations and perspec- ity and how should use of such data be regu- tives have come to light. Many of the is- lated or restricted if it does not meet suffi- sues, therefore, remain controversial and cient standards? How should uncertainties unresolved. about susceptibility be dealt with where sus- While there is considerable overlap be- ceptibility to the disease in question is linked tween ELSI issues concerning the Human to multiple genes and/or multiple gene-en- Genome Project, and those concerning vironment interactions? toxicogenomics methods and applications, • How should the potential for psycho- the latter brings a plethora of new issues that logical impacts on persons tested be taken are to be addressed within the ELSI program. into account, particularly where testing may Experts in the ELSI field have expressed the provide information about hypersusceptibil- view that ELSI issues could profoundly af- ity for which preventive or treatment mea- fect the manner in which toxicogenomics is sures are not available?

• Should there in fact be restrictions or rent diagnosis of illness shall not be consid- conditions on testing individuals for hyper- ered a preexisting condition. This legislation susceptibility to diseases long before it is an- applies largely to insurance coverage for ticipated that effective medical interventions persons who change jobs. It does not, how- will be available? ever, regulate new insurance premiums, • How should potential for stigmatization which may be set at high levels based on of individuals or definable groups, such as genetic susceptibility. ethnic groups or races which show hyper- While not all of these issues may directly susceptibility, be minimized? What protec- affect the risk assessment procedures of EPA tions are necessary to prevent discrimination or other regulatory agencies, they are part of against individual or minority groups that the public dialogue that may either directly show hypersusceptibility? or indirectly affect how toxicogenomics in- • How should informed consent prin- formation is used for EPA and other agen- ciples be applied before subjecting individu- cies for regulatory purposes. als to toxicogenomics tests? What matters concerning risks and benefits should be ex- plained, and by whom, before toxico- oxicogenomics is an emerging genomics tests are applied to individuals? science that has the potential to • How should decisions be made on change dramatically the way risks who should have access to toxicogenomics are assessed. It will drive count- data concerning individuals and who less issues affecting the regulation should make the decision to disclose such Tof chemical products in the marketplace and data and to whom? For example, should in the workplace. Risk assessments and their employers have the right of access to pro- effect on regulation will be shaped dramati- tect hypersusceptible employees? Should cally in coming years by the decisions that the decision to supply such data be left will be made with regard to how and when with the employee? Even if the employee toxicogenomics informa- decides to be tested and provide the em- tion can be used. More- ployer with hypersusceptibility data, what over, the individual pri- restrictions should be placed on the vacy rights at stake — is- ... perhaps employer’s use and dissemination of such sues that have long been data? the subject of passionate hypersusceptibility • What protective measures should be debate — will make the provided to prevent misuse of toxicogenomics debate can be shown in toxicogenomics data, including discrimina- high profile and public; the plaintiff, or tion, by employers, insurance companies, care will be needed to en- schools, and government? sure that sound science is specific • What additional protections are needed not lost in these debates. to protect individuals seeking health insur- Because toxicogenomics “biomarkers” ance from discrimination by insurance com- information will affect panies based on toxicogenomics data? To dramatically the risk as- of exposure to what extent should insurance companies of- sessments that EPA must the chemical fering other types of insurance, such as life constantly make and re- insurance, have the right to require appli- fine to fulfill its statutory may be found cants to submit toxicogenomics tests? duties, the agency must Federal law addresses genetic discrimi- take action now to de- nation by providers of health insurance to velop a comprehensive a limited degree in the Health Insurance policy framework for considering those data. Portability and Accountability Act of 1996. That framework should be developed This law, however, applies only to em- through an open and transparent public pro- ployer-based and commercially issued cess that solicits and considers the views of group health insurance. No federal law af- all stakeholders on issues that will have far- fords similar protections to private indi- reaching effects for many years to come. viduals who seek health insurance . Among Other agencies that base regulatory action on other things, HIPAA limits exclusions for risk assessments similarly should also act ex- preexisting conditions in group health plans peditiously in developing a policy frame- to 12 months and expressly provides that work for utilizing toxicogenomics informa- genetic information in the absence of a cur- tion. •

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