Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens A Workshop Summary (2005) / Chapter Skim
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Summary of the Workshop
Summary of the Workshop
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TOXICOGENOMIC TECHNOLOGIES AND RISK ASSESSMENT OF ENVIRONMENTAL CARCINOGENS A Workshop Summary
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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.
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Many publichealth 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.
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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.
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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.
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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.
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It can be used when all of the following conditions are met: a) there is strong evidence of an association be tween human exposure and either cancer or the key precursor events of the agent's mode of action but not enough for a causal as sociation, and b)
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The judgment may be based on · animal evidence that demonstrates lack of carcinogenic ef fect 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 car cinogenic 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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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)
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Toxicogenomics and Risk Assessment of Environmental Carcinogens 11 (a) Linear Dose-Response Curve (b)
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Role of Mode-of-Action Data7 James Bus, of the Dow Chemical Company, provided an overview on the types of conventional (nontoxicogenomic) MOA information in 7MOA data are sometimes referred to as nontumor data because they are not empirical data on tumors.
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The improved understanding can contribute to improved risks assessments in two fundamental ways: it may facilitate the qualitative categorization of a chemical's potential human cancer risks based on nonhuman data, and it may guide the selection of models used as quantitative elements of the dose-response relationship. Qualitatively, risk assessors have used MOA data to draw conclusions on the strength of evidence to support inferences of human cancer risk from animal data.
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Risk assessors evaluate those complex possibilities before concluding that the carcinogenic risk of a chemical is due to only one particular MOA. Because of the complexities and uncertainties associated with cancer and the lack of data, it may not be simple for some scientific information to be used in a qualitative assessment of a chemical's carcinogenicity or a quantitative assessment of its potency.8 That should come as no surprise inasmuch as many of the studies contributing to the basic understanding of cancer causation are in cutting-edge fields of biologic research and are insufficient to challenge existing default assumptions used in risk assessments of specific chemicals.
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Critical Data Needs in Conventional Risk Assessment John Moore, of Hollyhouse Consulting, and Linda Greer, of the Natural Resources Defense Council, led discussions about what they viewed as the most crucial information gaps and inconsistencies (that is, where study results may seem to provide conflicting information) that complicate cancer risk assessments (see Box 2)
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Insufficiencies and Uncertainties in Human Data, Including Exposure Levels For cancer risk assessment, human data, such as results of epidemiologic studies, are the most sought-after data; use of such data eliminates the uncertainties in extrapolating effects from other animals to humans. EPA's cancer guidelines indicate that human data are used whenever possible in carcinogenicity evaluations (EPA 2003)
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Relevance of Animal Data to Humans Even chemicals that have been tested in standard animal bioassays may pose difficulties in interpretation for risk assessment. Tumors in laboratory animals are not always predictive of cancer in humans, and questions about the relevance of animal data to humans (interspecies extrapolation)
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She did not focus on cancer alone, but she thought that the lack of exposure data obtained at different life stages was a limitation in risk-assessment datasets. Standard animal bioassays begin dosing in early adulthood (for example, when rodents are 6- to 8-weeks-old)
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The inability to study 1,3-butadiene exposure alone creates uncertainties in the hazard assessment of this chemical. In addition to the difficulties in distinguishing the effects of individual chemicals, datasets may fail to detect the role of chemical interactions in increasing cancer risk (Silbergeld 2003)
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Toxicogenomic Techniques Toxicogenomic researchers profile transcriptional responses by using DNA microarrays, sometimes referred to as gene chips, which are glass slides or membrane filters to which thousands of unique DNA "target" sequences are affixed. After exposure of a sample (such as tissue, cells, or an animal)
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Usually scientists arbitrarily select a two-fold change in expression as upregulation or downregulation. The red-green "heat map" shown in Figure 2 is an example of the type of analysis commonly used to illustrate patterns of gene expression observed in microarray experiments.
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22 Toxicogenomics and Risk Assessment of Environmental Carcinogens FIGURE 2 The red-green heat map, an example of the type of analysis commonly used to illustrate patterns of gene expression observed in microarray experiments. The heat map illustrates the expression pattern of genes upregulated (red)
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Mechanistic Insight In addition to the possibility of using signature patterns of gene expression to assess similarities among chemicals and to predict adverse effect outcomes, toxicogenomic experiments can generate insight into the biologic mechanisms by which a compound causes an adverse effect. Understanding a chemical's mechanisms may contribute to the MOA components of risk analysis.
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pyrene and its ability to activate aryl hydrocarbon receptor (Ahr) signaling and cause oxidative stress.
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. These data come from experiments in which Ramos and colleagues sought to identify associations between the expression patterns of individual genes regulated by ligands of the aryl hydrocarbon receptor (Ahr)
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Presentations by Walker and Ramos and further discussion from workshop participants identified some topics through which toxicogenomics might contribute to risk assessment: · New ways of screening untested compounds. · Providing more accurate information on human exposure levels.
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to cancer or precancer conditions even when the full biology underlying the gene-expression pattern was not understood. For example, if a signature correlated with an increase in liver damage, the empirical linkage would be valuable information -- a biomarker -- even if the underlying biologic mechanism of liver damage were not understood.13 Although pattern-recognition experiments may hold considerable promise, technical problems limit their usefulness at present.
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Human Exposure Levels The diverse "-omics" technologies underpinning toxicogenomics could be used to quantify and integrate human exposures -- a key problem in epidemiologic investigations -- and perhaps even to quantify cumulative exposure over time. Although every person presumably has unique characteristics with respect to dose-response manifestation, toxicogenomic data could be used to classify individuals, local communities, and larger populations more accurately with respect to exposure status.
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Dose-Response Relationships The dose-response relationship is the core quantitative component of a regulatory risk assessment. Toxicogenomic techniques might be useful in elucidating different responses at different doses and differences due to changes in frequency and duration of exposure.
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At least one workshop participant thought that toxicogenomics could improve the quantitation of exposure including exposure to multiple chemicals. In addition, the high-data producing capability of gene
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Human Variability As understanding of polymorphisms improves, toxicogenomic technologies hold promise for the identification of susceptible people. Just as in conventional animal bioassays that use outbred strains in which not every exposed animal develops tumors in response to a carcinogen, not every person exposed to a carcinogen develops cancer.
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Presenters interpreted information on 1,3-butadiene and arsenic risk assessments to provide background for discussing toxicogenomic applications. The highlights of their presentations are discussed here.
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Ramos highlighted several key findings in the 1,3-butadiene literature that create uncertainties in characterizing and quantifying the human cancer risk posed by exposure to 1,3-butadiene: · Animal bioassay data. Mice are more sensitive than rats in 1,3-butadiene bioassays, apparently because mice form reactive epoxides more readily than rats.
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However, exposure conditions are not well quantified, and it has not been possible to eliminate or control for possible styrene confounding in epidemiologic studies. · Variability in individual susceptibility.
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The differential toxicity and carcinogenicity of the forms are not well understood. The National Research Council's arsenic risk assessment is based primarily on epidemiologic studies in Taiwan, Chile, and Utah (NRC 1999, 2001)
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Although extensive human exposure data are available, a lack of understanding of the cancer MOA in humans, coupled with a lack of an animal model of cancer, has complicated EPA's estimate of the carcinogenic potency of arsenic. The difficulties in quantifying exposure in epidemiologic studies and the possibility of confounding factors that also lead to cancer complicate the arsenic risk evaluation further.
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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.
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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.
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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.
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But despite the advances in risk assessment, data gaps and uncertainties in connection even with well-studied chemicals complicate riskassessment 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.
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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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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.
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2003. The use of non-tumor data in cancer risk assessment: Reflections on butadiene, vinyl chloride, and benzene.
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2003. Draft Final Guide lines for Carcinogen Risk Assessment (External Review Draft, Feb ruary 2003)
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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.
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2002. Propylene glycol monomethyl ether (PGME)
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Toxicogenomics and Risk Assessment of Environmental Carcinogens 47 in Fischer 344 rats and B6C3F1 mice. Toxicol.
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