TOXICOGENOMIC TECHNOLOGIES AND RISK ASSESSMENT OF ENVIRONMENTAL CARCINOGENS

A Workshop Summary



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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary TOXICOGENOMIC TECHNOLOGIES AND RISK ASSESSMENT OF ENVIRONMENTAL CARCINOGENS A Workshop Summary

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary Summary of the Workshop INTRODUCTION Toxicogenomics is a discipline that has developed with recent advances in toxicology, molecular genetics, and cell biology and holds promise for advancing the scientific basis of risk assessment and other fields of science. To consider the potential contributions of toxicogenomics in risk assessment, the National Research Council convened a 1-day workshop titled “How Toxicogenomics Technologies Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals,” on December 15, 2003, at the request of the standing National Research Council Committee on Emerging Issues and Data on Environmental Contaminants. This standing committee, which is sponsored by the National Institute of Environmental Health Sciences (NIEHS), provides a forum on toxicogenomics and other emerging issues. The Committee on How Toxicogenomics Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals was formed to plan the workshop and summarize its highlights. This summary covers the presentations and discussion at the workshop and background on risk assessment; it is not a primer on either risk assessment or toxicogenomics. The objective of the workshop was not to evaluate the promise of toxicogenomic technologies but rather to highlight eventual possible toxicogenomic uses of data in risk assessment. These highlights can serve as a basis for discussing what can be realistically expected of

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary toxicogenomics and for discussing policy challenges associated with the use of the data. The workshop focused on cancer risk assessment for several reasons: cancer risk assessments are numerous, the many scientific uncertainties lead to controversies on this topic, and there is much scientific research involving toxicogenomics in the field of carcinogenesis. The workshop dealt specifically with cancer risk assessment of environmental exposure to chemicals,1 based on the committee’s understanding of applicable frameworks. Risk assessment is a set of methods, applied in regulatory and other settings, for estimating the likelihood that exposure to hazardous agents, including chemicals, will harm people or the environment. Many public-health decisions in environmental, occupational, and consumer protection are based on risk assessments of chemicals. Risk assessment is conducted in several steps: hazard identification, the characterization of intrinsic toxic properties of a chemical or the nature of the hazard; the quantitative relationship between exposure and effects, the dose-response assessment; and assessment of potential exposures of human populations to the chemical of concern. A final step is risk characterization, which “combines the assessment of exposure and response under various exposure conditions to estimate the probability of specific harm to an exposed individual or population” (NRC 1994). The first three steps of risk assessment are described in this report; the probabilistic approach of risk characterization was not a focus of the workshop or of this report. Risk assessments are frequently criticized for their dependence on default values used to deal with uncertainties in the absence of relevant data (NRC 1994). The task of risk assessors is difficult because they are often charged with protecting the public health without adequate scientific understanding of the fundamental causes of cancer and other diseases associated with chemical exposures. New scientific discoveries or technologies that might resolve crucial data gaps and data inconsistencies have the potential to improve risk assessment by providing additional data on toxic effects, increasing understanding of mechanisms and modes of action, and enhancing the reliability of dose response extrapolation. Toxicogenomics encompasses technologies that enable scientists to measure genetic-sequence variation (genomics), gene transcription (tran- 1   The term environmental exposure was used to convey the idea of exposure that is not deliberate and controlled, in contrast, for example, with pharmaceutical exposure. The concepts discussed are also relevant to occupational exposure to chemicals.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary scriptomics), protein expression (proteomics), and metabolite profiles (metabolomics) in response to chemicals and other stressors. Those “-omics” technologies hold promise for obtaining new information relevant to the scientific requirements of risk assessment. However, exactly how toxicogenomic findings will be incorporated into the regulatory process may not be clear for some time,2 even the general concepts of how toxicogenomics might be incorporated into risk assessment may be unclear to toxicologists and other biologists not working directly in risk assessment, and some risk assessors may not be sufficiently familiar with toxicogenomics to see its eventual impact on their work. In an attempt to bridge that gap and to provide an opportunity for scientists interested in regulatory issues and scientists interested in genomics to discuss the intersection of their interests, the workshop included scientists with expertise in “-omics” technologies, as well as experts in toxicology, risk assessment, epidemiology, and public health. The workshop began with an overview of how scientific information generally informs risk assessment and an overview of the types of data gaps that make regulatory risk assessments challenging and controversial. It then moved to presentations on types of toxicogenomic studies, focusing largely on studies of gene expression. Next, two case studies were presented to illustrate the nature and extent of challenges in carcinogen risk assessment and to foster discussion of the potential contribution of toxicogenomic technologies to improving cancer risk assessment. The workshop concluded with a discussion of types of research that might be undertaken to move the field forward. The workshop agenda is included as Appendix A, and biographical sketches of speakers and planning-committee members are presented in Appendix B. Audiofiles and PowerPoint files for most of the presentations are available at http://dels.nas.edu/emergissues. CANCER RISK ASSESSMENT Government agencies charged with the protection of the public health, such as the U.S. Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA), are required to review, quantify, and ultimately regulate chemicals in a manner that will protect and 2   EPA has produced an interim policy on genomics that discusses genomics data and its possible use in risk assessment and for regulatory purposes (EPA 2002).

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary enhance the public health and the environment. Since the early 1980s, in the United States and increasingly worldwide, regulatory analyses are conducted with an evaluation framework called risk assessment. To understand how toxicogenomics may enhance risk-assessment, it is necessary to understand how risk assessment is generally conducted. This section provides a general discussion of regulatory risk assessment related to cancer risks, as understood by the committee, but it does not consider specific risk assessment protocols (which are often disagreed upon). Further details about the risk-assessment process can be found in such references as EPA's 1986 Guidelines for Carcinogen Risk Assessment, EPA’s 2003 Draft Final Guidelines for Carcinogen Risk Assessment, an EPA staff paper titled “An Examination of EPA Risk Assessment Principles and Practices,” the National Research Council’s Risk Assessment in the Federal Government: Managing the Process (also known as the Red Book), and the National Research Council’s Science and Judgment in Risk Assessment (EPA 1986, 2003, 2004; NRC 1983, 1994). The goal of a risk assessment is to obtain a reasonable estimate of the likelihood of harm associated with exposure to a toxic chemical on the basis of 1) the hazard (the nature of the chemical), 2) the relationship between dose and effects, and 3) potential exposure. The risk characterization itself combines information on exposure and response assessments (NRC 1994). The calculations and analyses provide risk assessors a quantitative basis for health and environmental regulatory standards and guidelines. Current Approaches to Risk Assessment Hazard Identification: Qualitative Determination of Whether the Chemical Causes Cancer Cancer risk assessments have both qualitative and quantitative components. The key qualitative determination is of whether a chemical has the property of inducing cancer in test animals or in exposed human populations. That determination is based on human data (as from epidemiologic or clinical studies) and experimental data (from in vitro or animal studies). When possible, regulators look beyond empirical tumor data and epidemiologic studies of cancer incidence or prevalence to what EPA refers to as mode-of-action (MOA) data (EPA 2003). MOA data comprise chemical and biologic information on key cellular and bio-

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary chemical events that are thought to lead to the tumor end point.3 (How toxicogenomics may contribute to risk assessment with MOA data is described later.) EPA describes the degree of certainty that a chemical may be carcinogenic to humans as outlined in Box 1. The analysis requires considerable scientific judgment and uses several criteria: the quality of the evidence reviewed, the consistency of findings in experimental animals, and, if available, information on effects in humans. Consistently positive findings of well-conducted epidemiologic studies offer the strongest evidence of human cancer risk, and the few chemicals on which there is such information are considered proven human carcinogens. Lacking that information (and it is lacking for most chemicals of regulatory concern), a conclusion that a chemical acts as a carcinogen and may pose a carcinogenic risk to humans can be supported by consistent findings of well-conducted animal studies, especially studies in more than one species, and by an indication that the number of tumors increases with dose (EPA 2003). Evaluation of Dose-Response Relationship: Quantitative Determination of Carcinogenic Potency After the qualitative classification of carcinogenic potential, risk assessors work on the quantitative component of the risk-assessment framework to calculate a carcinogenic potency factor for the chemical. The potency factor indicates the extent to which cancer incidence increases with dose or exposure (the dose-response relationship). The dose-response relationship is evaluated by modeling the empirical data (see Figure 1, where x’s indicate observed data). Because only rarely is a dose-response analysis based on epidemiologic studies, data from animal bioassays are generally used to model this relationship in the observable 3   According to EPA, “understanding an agent’s ‘mode of action’ means understanding the general sequence of events by which it causes effects on cell growth control that result in cancer. ‘Mode of action’ is used rather than ‘mechanism of action,’ which is a term that implies complete knowledge of the steps of carcinogenesis at the molecular level, a level of understanding that currently does not exist for any agent” (EPA 1999, 2003). MOA data may also be referred to as nontumor data, conveying that they are not empirical data on the number of tumors produced.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary BOX 1 EPA’s Standard Descriptors for Expressing Conclusions About the Weight of Evidence of Human Carcinogenic Potential Different conclusions may apply to a single agent if carcinogenicity is dose or route dependent. This text is from EPA’s 2003 Draft Final Guidelines for Carcinogen Risk Assessment (EPA 2003, pages 2-40 to 2-43): “Carcinogenic to Humans” This descriptor is appropriate when there is convincing epidemiologic evidence of a causal association between human exposure and cancer. Exceptionally, this descriptor is equally appropriate with a lesser weight of epidemiologic evidence that is strengthened by other lines of evidence. It can be used when all of the following conditions are met: a) there is strong evidence of an association between human exposure and either cancer or the key precursor events of the agent’s mode of action but not enough for a causal association, and b) there is extensive evidence of carcinogenicity in animals, and c) the mode(s) of carcinogenic action and associated key precursor events have been identified in animals, and d) the key precursor events that precede the cancer response in animals are anticipated to occur in humans and progress to tumors, based on available biological information. “Likely To Be Carcinogenic to Humans” This descriptor is appropriate when the weight of the evidence is adequate to demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the descriptor “carcinogenic to humans.” Adequate evidence consistent with this descriptor covers a broad spectrum. Although the term “likely” can have a probabilistic connotation in other contexts, its use as a weight of evidence descriptor does not correspond to a quantifiable probability. This is because the data that support cancer assessments generally are not suitable for numerical calculations of the probability that an agent is a carcinogen. The weight of evidence descriptor “likely to be carcinogenic to humans” may be taken loosely to imply that an agent is more likely than not—but is not certain—to cause cancer in humans. “Suggestive Evidence of Carcinogenic Potential” This descriptor of the database is appropriate when the weight of evidence is suggestive of carcinogenicity; a concern for potential carcinogenic effects in humans is raised, but the data are judged not sufficient for a stronger conclusion. This descriptor covers a spectrum of evidence associated with varying levels of concern for

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary carcinogenicity, ranging from a positive result in the only study on an agent to a single positive result in an extensive database that includes negative studies in other species. Depending on the extent of the database, additional studies may or may not provide further insights. Some examples include: a marginal increase in tumors observed only in a single animal or human study; a slight increase in a tumor with a high background rate in that sex and strain; a statistically significant increase at one dose only but no significant response at the other doses or trend overall; or evidence of a response in a study whose power, design, or conduct limits the ability to draw a confident conclusion. “Inadequate Information to Assess Carcinogenic Potential” This descriptor of the database is appropriate when available data are judged inadequate for applying one of the other descriptors. Additional studies generally would be expected to provide further insights. Some examples include: little or no pertinent information. conflicting evidence, that is, some studies provide evidence of carcinogenicity but other studies of equal quality in the same sex and strain are negative. "Not Likely To Be Carcinogenic to Humans” This descriptor is appropriate when the available data are considered robust for deciding that there is no basis for human hazard concern. The judgment may be based on animal evidence that demonstrates lack of carcinogenic effect in well-designed and well-conducted studies in at least two appropriate animal species (in the absence of other animal or human data suggesting a potential for cancer effects), extensive experimental evidence showing that the only carcinogenic effects observed in animals are not relevant to humans, convincing evidence that carcinogenic effects are not likely by a particular exposure route, or convincing evidence that carcinogenic effects are not likely below a defined dose range.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary range. Typically, tumor incidence measured in 18- to 24-month animal (rodent) bioassays4 is used. The reliance on animal bioassays has long raised concerns. First, the use of animal bioassays to determine human risk is complicated by uncertainties in the interspecies extrapolation between rodents and humans and even between mice and rats—the traditional two species used in bioassays for cancer-hazard characterizations may have different responses to a given chemical. Second, relatively high doses are usually used in bioassays5—sometimes several hundred times those expected in environmental situations—and clearly are not optimal for understanding effects at more environmentally relevant doses. Excess doses are used largely for statistical reasons. It is not possible to detect either the presence or absence of a significant increase in tumor rate reliably unless the tumor rate is very high, which requires a high exposure.6 As a result, there are rarely experimental data in the range of exposures that are of concern to risk assessors, and the relationship between dose and response must be extrapolated from study doses down to doses relevant to the general population rather than determined observationally. The dashed curve in Figure 1a illustrates a linear model of extrapolation, and the dashed curve of Figure 1b illustrates an alternative, nonlinear, or threshold dose-response model. The risk assessors’ determination of which model shape appropriately conveys the relationship between dose and response for a particular chemical can be controversial. Whenever possible, risk assessors evaluate MOA information to draw a conclusion about the most likely shape and interpretation of the dose-response relationship. MOA information may provide insight into the relevant underlying biologic processes important to the specific chemical (such as pharmacokinetics and cellular mechanisms of response). More specific information about how typical and conventional MOA information fits into a risk assessment is described below. 4   In environmental toxicology, the term bioassay is often used to describe 18- to 24-month rodent studies. 5   The standard animal bioassay uses the so-called maximal tolerated dose (MTD) as the high dose. Toxicologists aim to use the highest chronic dose that the test animals can tolerate without exhibiting frank toxicity that might compromise long-term survival. Lower doses are fractions of the MTD; the lowest dose is intended to identify a dose that produces no toxic effects under the conditions of the study—a no-observed-adverse-effects level (NOAEL). 6   This is because expense typically limits the number of bioassays to 50-60 animals of each sex per dose, including controls.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary FIGURE 1 Presentation of data with (a) linear and (b) threshold dose-response curve extrapolation.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary earlier by Greer and Moore, workshop participants identified several types of toxicogenomic inquiries that might be particularly useful for the two chemicals and others about which there are similar uncertainties. The purpose of this exercise was not to determine how uncertainties regarding the specific chemicals could be resolved but to illustrate how toxicogenomics might be useful in resolving uncertainties about chemicals in general. Species Differences and Gaining a Better Understanding of Mode of Action Species differences in response to a chemical are critical for both 1,3-butadiene and arsenic. Workshop participants thought that such differences presented a prime opportunity for toxicogenomic experimentation. As explained above, there are large differences in how rats and mice react to 1,3-butadiene and great uncertainty as to which species is more relevant to humans. Patterns of gene-expression changes in target tissues (such as lung, bladder, and skin) of rats and mice could be compared to determine whether the differential sensitivity in tumor incidence is mirrored in unique patterns of gene-expression changes in the two species. The patterns could then be compared with those in humans. A comparison of the three species—two known to be quite distinct in their tumor response—could help to determine whether humans more closely resemble rats than mice in sensitivity to 1,3-butadiene, as is currently hypothesized. Such work might also confirm the proposed MOA or provide evidence of alternative MOAs. In the case of arsenic, humans appear to be more sensitive to carcinogenic effects than laboratory animals are, but there is no biologic understanding of that. Although there are a number of hypotheses, the MOAs involved in the tumors seen in humans are not known. Patterns of gene-expression changes in rats, mice, and humans exposed to arsenic could be compared to identify the changes in humans that are not seen in the animal models. That would provide a starting point for toxicologists to begin studying the MOA of the chemical in humans and perhaps to identify potential key events that contribute to the specific cancer sensitivity. In addition, arsenic offers a unique opportunity to use genomic information to explore which biologic responses that are not tumors themselves are potentially critical to tumor formation. Because arsenic does not cause cancer in laboratory animals, it would be enlightening to use

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary the response patterns in microarray experiments to identify gene changes that are not precancerous in animals. Such changes could be cataloged for later study of effects of unknown chemicals. In another approach for improving the understanding of MOAs, participants discussed opportunities to study gene-expression profiles in human populations before and after arsenic exposure. Drinking water is the primary route of arsenic exposure, and this allows accurate exposure measurements. In the United States, populations are exposed to a wide range of arsenic concentrations because only some drinking-water supplies are being upgraded to remove arsenic. Populations that use the latter supplies could be followed to detect changes in gene-expression patterns or proteins before and after arsenic exposure is reduced. The genes and proteins whose expression reverses with decreased arsenic exposure could be indicators of cellular processes involved in arsenic’s effects. Differences Between Male and Female Responses The differential sensitivity of males and females to 1,3-butadiene is poorly understood. Like differences between species, sex differences could be studied by comparing gene-expression changes. Toxicity of Metabolic Products Differences in gene-expression patterns between inorganic parent and methylated forms of arsenic could be compared to shed light on whether methylation is an activation or detoxification mechanism in humans. Similarly, other organic and inorganic forms of arsenic could be compared to understand their relative toxicities. In the case of 1,3-butadiene, the gene-expression pattern of the parent compound could be compared with that of the key metabolites to challenge or add weight to the hypothesis that 1,2:3,4-diepoxybutane is the most potent and important 1,3-butadiene metabolite. Dose-Response Relationship Gene-expression experiments conducted over a continuum from high to realistic (low) doses of both chemicals might allow researchers to distinguish adaptive responses that are not indicative of toxicity or car-

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary cinogenicity from responses that signal precancer and other adverse responses. Gene-expression changes could be measured over a range of doses that would include exposures of the general population and in the workplace. Once particular types of responses are identified, experiments could indicate whether threshold exposures to either compound exist. Coexposure to Other Chemicals Few, if any, conventional toxicologic experiments have been conducted to study the effects of coexposure to chemicals that commonly occur in occupational or environmental settings. Yet many chemicals are known to co-occur with a few other toxicologically relevant substances, such as tobacco smoke. 1,3-Butadiene and styrene coexposure is common in the workplace and has complicated the interpretation of several epidemiologic studies of occupational exposure. Microarray experiments with coexposure to 1,3-butadiene and styrene would be particularly important if they helped to tease out the effects of coexposure to styrene on toxicity of 1,3-butadiene at the cellular level. It would also be helpful to examine the effects of coexposure to 1,3-butadiene and gasoline components, such as benzene, xylene, and toluene. Whether smoking potentiates arsenic toxicity is a key question in epidemiologic studies. It is particularly difficult to answer because of the lack of animal models of arsenic carcinogenicity. However, microarray experiments with human tissues might be able to elucidate the effect of confounders, such as smoking, on cancer outcomes of exposure to arsenic. Individual Variability in Susceptibility Individual human variability in metabolizing enzymes could be compared. Studies that compare traditional toxic end points in animals with different metabolic enzymes (some of which mimic human polymorphisms) could reveal information about the effects of human variability. Similarly, studies with human cells that express different metabolizing enzymes could be useful. For arsenic in particular, the effects of genotype on gene expression could be studied in humans directly because the target tissues of interest—skin, lung, and bladder—yield cells that can be obtained noninvasively.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary MOVING FORWARD The evaluation of chemicals in risk assessment has progressed from empirical pathologic assessment of tumors to the incorporation of biochemical and cellular information about how chemicals exert their toxic effects. Risk assessment now attempts to include information about a chemical’s MOA and encourages the consideration of a wide variety of data. But despite the advances in risk assessment, data gaps and uncertainties in connection even with well-studied chemicals complicate risk-assessment efforts. For the field of toxicogenomics to deliver on its potential, it will be important to identify the types of specific data gaps and inconsistencies of greatest importance to the risk-assessment process and to set research priorities accordingly. Achieving that goal may be hampered by the general unfamiliarity of many toxicogenomic researchers with the risk-assessment framework and the key technical issues of controversy underlying regulatory decisions on individual compounds. Similarly, some risk assessors may be unfamiliar with the rapidly developing world of toxicogenomics and thus lack the insight to understand what toxicogenomic research could deliver in the short and long term. In the final session of the workshop, participants considered the presentations and discussions, brought up new ideas, and highlighted topics that are advancing rapidly. There was no consensus process, nor were the ideas fully developed. But the following paragraphs provide some insight into how research relevant to risk assessment might move forward in the coming years. Screening of Chemicals The paucity of data on the possible carcinogenicity of many chemicals invites contributions from toxicogenomic research. Risk assessors must either defer action or make decisions on poorly tested or untested compounds by using structure-activity relationship (SAR) models to infer likely effects. Some workshop participants expressed enthusiasm for using gene-expression patterns to supplement current SARs, and several believed that such experiments could be accomplished in a relatively short period. “Training sets” could be developed by looking at the geneexpression patterns generated by chemicals that have relatively well-known adverse effects. Researchers could develop testable hypotheses

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary about gene-expression patterns by using the training sets and use the training sets to test the hypotheses against other, less well-understood chemicals. One participant noted that researchers have already tested what they have learned with some chemicals on chemicals whose effects are somewhat understood. Using blind tests, they have successfully used patterns of gene expression to predict the biology of unknown chemicals. Individual Sensitivity One participant suggested that a simple way to start investigating individual sensitivity is to compare how various types of mice respond to given toxicants; for example, transgenic or mutant mice that have polymorphisms in particular genes could be compared with wild-type mice. The results might explain how polymorphisms influence heterogeneity of response. Enhancements in consistency of results from different microarray systems would improve that kind of experiment, as they would improve other types of experiments also described here, by decreasing artificial variability (variability not related to biologic differences). At present, there may be too much variability to develop insight into polymorphism influence on response. At a minimum, it would be necessary to sift through a lot of artificial variability to develop insights. Better Understanding of a Chemical’s Mode of Action One view is that for toxicogenomics to contribute substantially to risk assessment, links between gene expression and disease or other adverse outcomes must be established—a process sometimes referred to as phenotypic anchoring. Even without those linkages, analysis of gene-expression changes can provide clues about which biologic pathways may be involved in the MOA of a toxic chemical. Workshop participants noted the importance of conducting toxicogenomic studies over ranges of dose and time. The concern that the MOA of a chemical may be dose- or time-dependent is a key issue in regulatory risk assessment. Master Switches In discussing the value of information on preneoplastic changes for both cancer biologists and public-health officials, participants noted the

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary merits of focusing research attention on the effects of chemicals on master switches in a cell. Master switches are thought to consist of a relatively few loci important for cancer. Thus, rather than looking at thousands of potential gene interactions, investigations of effects on cell circuitry and gene-gene interactions relevant to suspected master switches could have high priority. Some participants suggested that it might be valuable to study gene interactions related to master switches during key stages of development while keeping an eye on the responses of the entire genome. Study of Preneoplastic Changes Some participants suggested that researchers set priorities among studies of signatures of preneoplastic changes, pointing out that the few key events involved in preneoplastic changes might narrow the search for the highest-priority signatures. Specifically, it might be valuable to look at gene-expression patterns that correlate with the detection of known preclinical markers, that is, intermediate end points that have been validated as predictive of the disease before the disease manifests. One participant pointed out the value of looking at transcriptional profiling prospectively in people known to have been exposed to a compound to see whether there are early markers that will prove predictive of development of disease. Such markers would be particularly valuable if they enable invasive procedures to be replaced with procedures using surrogate cells or surrogate tissue to study chemical MOAs. CONCLUSION This workshop provided a forum for discussion of some of the ways that toxicogenomics might eventually contribute to improving the science of risk assessment. The discussion allowed different communities of experts, including those conducting “-omics” work and those working in the policy arena, to see where their fields might intersect in the future. The workshop provided a baseline of shared understanding or future discussions on, for example, the scientifically appropriate use of toxicogenomic data in risk assessment and the nonscientific challenges involved in using such information.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary REFERENCES Albertini, R., H. Clewell, M.W. Himmelstein, E. Morinello, S. Olin, J. Preston, L. Scarano, M.T. Smith, J. Swenberg, R. Tice, and C. Travis. 2003. The use of non-tumor data in cancer risk assessment: Reflections on butadiene, vinyl chloride, and benzene. Regul. Toxicol. Pharmacol. 37(1):105-132. Breitkreutz, B.J., C.S. Stark, and M. Tyers. 2003. Osprey: A network visualization system. Genome Biology 4(3): R22. Bus, J.S., and J.A. Popp. 1987. Perspectives on the mechanism of action of the splenic toxicity of aniline and structurally-related compounds. Food Chem. Toxicol. 25(8):619-626. CancerWEB Project. 2005. Online Medical Dictionary. Definition of Adduct [Online]. Available: http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=adduct [accessed April 25, 2005]. EDF (Environmental Defense Fund). 1997. Toxic Ignorance: The Continuing Absence of Basic Health Testing for Top-Selling Chemicals in the United States. Environmental Defense Fund, Washington, DC [Online]. Available: http://www.environmentaldefense.org/documents/243_toxicignorance.pdf [accessed Feb. 23, 2005]. EGE (Ethylene Glycol Ethers Panel). 2004. IARC Finds Inadequate Evidence of Carcinogenicity in Humans and Limited Evidence of Carcinogenicity in Animals for Two Glycol Ethers. June 2004 [Online]. Available: http://www.egep.org/glycol_ethers_update.htm [accessed Nov. 10, 2004]. EPA (U.S. Environmental Protection Agency). 1986. Guidelines for Carcinogen Risk Assessment. EPA/630/R-00/004. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1991. Alpha-2u-globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. EPA/625/3-91/019F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 1997. Guiding Principles for Monte Carlo Analysis. EPA/630/R-97/001. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [Online]. Available: http://www.epa.gov/ncea/raf/montecar.pdf [accessed Nov. 5, 2004]. EPA (U.S. Environmental Protection Agency). 1998a. Health Risk Assessment of 1,3-Butadiene. External Review Draft. EPA/600/P-98/001A. NCEA-W-0267. National Center for Environmental As-

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary sessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC [Online]. Available: http://www.epa.gov/ncea/pdfs/but/butadiene.pdf [accessed Nov. 9, 2004]. EPA (U.S. Environmental Protection Agency). 1998b. Arsenic, Inorganic. CASRN 7440-38-2. Integrated Risk Information System (IRIS) [Online]. Available: http://www.epa.gov/iris/subst/0278.htm [accessed Feb. 24, 2005]. EPA (U.S. Environmental Protection Agency). 1999. Guidelines for Carcinogen Risk Assessment. Review Draft. NCEA-F-0644. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [Online]. Available: http://www.epa.gov/ncea/raf/pdfs/cancer_gls.pdf [accessed Nov. 5, 2004]. EPA (U.S. Environmental Protection Agency). 2002. Interim Policy on Genomics. Science Policy Council. U.S. Environmental Protection Agency. Washington, DC [Online]. Available: http://www.epa.gov/osa/spc/htm/genomics.pdf [accessed April 13, 2005]. EPA (U.S. Environmental Protection Agency). 2003. Draft Final Guidelines for Carcinogen Risk Assessment (External Review Draft, February 2003). EPA/630/P-03/001A. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [Online]. Available: http://www.epa.gov/ncea/raf/cancer2003.htm [accessed Nov. 5, 2004]. EPA (U.S. Environmental Protection Agency). 2004. An Examination of EPA Risk Assessment Principles and Practices. Staff Paper Prepared for the U.S. Environmental Protection Agency by Members of the Risk Assessment Task Force. EPA/100/B-04/001. Office of the Science Advisor, U.S. Environmental Protection Agency , Washington, DC [Online]. Available: http://www.epa.gov/osa/ratf-final.pdf [accessed Nov. 5, 2004]. GAO (U.S. General Accounting Office). 1994. Toxic Substances Control Act: Preliminary Observations on Legislative Changes to Make TSCA More Effective: Statement of Peter F. Guerrero, Director, Environmental Protection Issues, Resources, Community, and Economic Development Division, before the Subcommittee on Toxic Substances, Research, and Development, Committee on Public Works, U.S. Senate. GAO/T-RCED-94-263. Washington, DC: U.S. General Accounting Office. Hamadeh, H.K., P.R. Bushel, S. Jayadev, O. DiSorbo, L. Bennett, L. Li, R. Tennant, R. Stoll, J.C. Barrett, R.S. Paules, K. Blanchard, and C.A. Afshari. 2002a. Prediction of compound signature

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary using high density gene expression profiling. Toxicol. Sci. 67(2):232-240. Hamadeh, H.K., P.R. Bushel, S. Jayadev, K. Martin, O. DiSorbo, S. Sieber, L. Bennett, R. Tennant, R. Stoll, J.C. Barrett, K. Blanchard, R.S. Paules, and C.A. Afshari. 2002b. Gene expression analysis reveals chemical-specific profiles. Toxicol. Sci. 67(2):219-231. Hodges, L.C., J.D. Cook, E.K. Lobenhofer, L. Leping, L. Bennett, P.R. Bushel, C.M. Aldaz, C.A. Afshari, and C.L. Walker. 2003. Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells. Mol. Cancer Res. 1:300-311. Haseman, J.K., and A.M. Lockhart. 1993. Correlations between chemically related site-specific carcinogenic effects in long-term studies in rats and mice. Environ. Health Perspect. 101(1):50-54. IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Vols. 1–42, Supplement 7. Lyon, France: IARC Press. IARC (International Agency for Research on Cancer). 1997. Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. IARC Monographs on the Evaluation on Carcinogenic Risk to Humans Vol. 69. Lyon, France: IARC Press. IARC (International Agency for Research on Cancer). 1999. Some Chemicals that Cause Renal or Urinary Bladder Tumors in Rodents, and Some Other Substances IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 73 (13–20 October 1998) [Online]. Available: http://www-cie.iarc.fr/htdocs/announcements/vol73.htm [accessed Nov. 15, 2004]. Johnson, C.D., Y. Balagurunathan, M.G. Tadesse, M.H. Falahatpisheh, M. Brun, M.K. Walker, E.R. Dougherty, and K.S. Ramos. 2004. Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon receptor. Environ. Health Perspect. 112(4):403-412. Kier, L.D., R. Neft, L. Tang, R. Suizu, T. Cook, K. Onsurez, K. Tiegler, Y. Sakai, M. Ortiz, T. Nolan, U. Sankar, and A.P. Li. 2004. Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro. Mutat. Res. 549(1-2):101-113.

OCR for page 1
Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary Loffredo, C.A., H.V. Aposhian, M.E. Cebrian, H. Yamauchi, and E.K. Silbergeld. 2003. Variability in human metabolism of arsenic. Environ. Res. 92(2):85-91. Mah, N., A. Thelin, T. Lu, S. Nikolaus, T. Kühbacher, Y. Gurbuz, H. Eickhoff, G. Klöppel, H. Lehrach, B. Mellgård, C. M. Costello, and S. Schreiber. 2004. A comparison of oligonucleotide and cDNA-based microarray systems. Physiol. Genomics 16:361-370. Marnell, L.L., G.G. Garcia-Vargas, U.K. Chowdhury, R.A. Zakharyan, B. Walsh, M.D. Avram, M.J. Kopplin, M.E. Cebrián, E.K. Silbergeld, and H.V. Aposhian. 2003. Polymorphisms in the human monomethylarsonic acid (MMAV) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem. Res. Toxicol. 16(12):1507-1513. NIEHS (National Institute of Environmental Health Sciences). 2003. Polymorphism and Genes, Haplotype. Environmental Genome Project [Online]. Available: http://www.niehs.nih.gov/envgenom/haplotyp.htm [accessed Nov. 9, 2004]. NIH (National Institutes of Health). 2005. Talking Glossary. Definition of Polymorphism. National Human Genome Research Institute, National Institutes of Health [Online]. Available: http://www.genome.gov/glossary.cfm?key=polymorphism [accessed Feb. 25, 2005]. Norppa, H., A. Hirvonen, H. Jarventaus, M. Uuskula, G. Tasa, A. Ojajarvi, and M. Sorsa. 1995. Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes. Carcinogenesis 16(6):1261-1264. NRC (National Research Council). 1983. Risk Assessment in the Federal Government: Managing the Process. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Science and Judgment in Risk Assessment. Washington, DC: National Academy Press. NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: National Academy Press. Silbergeld, E.K. 2003. Facilitative mechanisms of lead as a carcinogen. Mutat. Res. 533(1-2):121-133. Spencer, P.J., J.W. Crissman, W.T. Stott, R.A. Corley, F.S. Cieszlak, A.M. Schumann, and J.F. Hardisty. 2002. Propylene glycol monomethyl ether (PGME): Inhalation toxicity and carcinogenicity

OCR for page 1
Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary in Fischer 344 rats and B6C3F1 mice. Toxicol. Pathol. 30(5):570-579. Thomas, D.J., S.B. Waters, and M. Styblo. 2004. Elucidating the path-way for arsenic methylation. Toxicol. Appl. Pharmacol. 198(3): 319-326.