Using 21st Century Science to Improve Risk-Related Evaluations (2017) / Chapter Skim
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7 Interpretation and Integration of Data and Evidence for Risk-Based Decision-Making
7 Interpretation and Integration of Data and Evidence for Risk-Based Decision-Making
Pages 117-138
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From page 117... ...
risk assessment and to integrate the findings with results of traditional whole-animal assays and epidemiological DATA INTERPRETATION AND studies. Approaches will also be needed to analyze and in- KEY INFERENCES tegrate different 21st century data streams and ultimately to use them as the basis of inferences about, for example, Interpreting data and drawing evidence-based inferchemical hazard, dose–response relationships, and groups ences are essential elements in making risk-based decithat are at higher risk than the general population.
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Are exposures of the young or elderly of greater concern? Figure 7-1 illustrates the sufficient-component-cause concept and shows that the same outcome can result from To set the context for the discussion of inference and more than one causal complex or mechanism; each "pie" data interpretation to address the above questions, the has multiple components and generally involves the joint committee begins by considering a useful causal model action of multiple components.
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is using the characand drawing inferences for risk assessment on the basis of teristics as a way to organize mechanistic data relevant 21st century data. It can be used to interpret mechanistic to agent-specific evaluations of carcinogenicity (IARC data for addressing the four critical questions above.
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or modulation of endogenous ligands (including hormones) Causes immortalization Inhibition of senescence, cell transformation Alters cell proliferation, cell death, or nutrient supply Increased proliferation, decreased apoptosis, changes in growth factors, energetics and signaling pathways related to cellular replication or cell cycle a Any characteristic could interact with any other (such as oxidative stress, DNA damage, and chronic inflammation)
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ternal to or in an agency. The causal-guidance topics provided in Box 7-3 can be adapted to guide expert judgments in establish Linking Agents to Pathway Perturbations ing causal links between chemical exposure and pathway perturbations on the basis of broad, systematic consider For drawing conclusions about whether a substance ation of the evidence from the published literature and contributes to disease by perturbing various pathways or government databases.
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Another consideration of consistency in the context of 21st century data is related to outcomes that have been linked to suites of chemicals tested in assays that evaluate the same perturbations. Do chemicals that affect similar pathways and mechanisms lead to related outcomes and provide consistent results?
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and between data domains, and tools for such integration and the possible implicit biological assumptions needed Assessing Dose–Response Relationships for their use are discussed later in this chapter. Chapter 5 and the case studies described in the ap- Characterizing Human Variability pendixes show how some of the various 21st century data and Sensitive Populations might be used in understanding dose–response relationships for developing a quantitative characterization of People differ in their responses to chemical exposures, risks posed by different exposures.
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humans. As described in Chapter 2, environmental chemical expo TABLE 7-2 Examples of Inferences or Assumptions Needed to Use 21st Century Data in Various Analyses Analysis That Involves Dose–Response Considerations Examples of Inferences or Assumptions Needed Read-across: health reference values • Sufficiency of chemical similarities for read-across on the basis, for example, derived from structurally or biologically of biological, chemical-structure, metabolic, or mechanistic similarities similar anchor chemicals • Comparison of chemical activity on the basis, for example, of pharmacokinetics and biological activity in assays Toxicogenomic screening to determine • Generalizability of results to susceptible and general human populations whether environmental exposures are of • Consequence or importance of toxicogenomic effects seen at exposures negligible concern or otherwise greater than environmental exposures • Sufficiency of procedure to filter and analyze genomics data; assumptions as to which pathway-related indicators are important Extrapolation of effect or benchmark doses • Sufficiency of understanding about human pharmacokinetic and in vitro to human exposures to establish pharmacodynamic variability health reference valuesa • Generalizability of results to susceptible and general human populations.
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ability in a single pathway. The chapter also describes how genetically diverse panels of inbred mice strains can be APPROACHES FOR EVALUATING AND used to explore variability and how various studies that INTEGRATING DATA AND EVIDENCE use such strains have been able to identify genetic factors associated with liver injury from acetaminophen (Harrill et The volume and complexity of 21st century data pose al.
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integrating data from various studies, datasets, and data To illustrate one of the statistical issues, the winner's streams are described, and some suggestions are provided curse correction, consider an in vitro assay that is used to for their use with 21st century data. The committee notes measure chemicals in a class for a particular activity, such that recent reports of the National Research Council and as binding to the estrogen receptor alpha.
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. Shrinkage and winner's curse correction: Measurement error can affect output from multiple assays or condi tions in such a way that the measured outcome values are more varied than the underlying true variation.
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The report Review of EPA's In tegrated Risk Information System (IRIS) Process (NRC Systematic Review 2014)
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Similarly, their application to 21st and from related studies. Some examples of prior elicicentury data streams is expected to be uncommon given tation in environmental risk assessment are provided in the heterogeneity of the data and the need to integrate data Wolfson et al.
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For several agents on which there are few mends that guided expert judgment be the approach used or no human data to assess carcinogenicity, complemen- in the near term to integrate diverse data streams for drawtary experimental animal data and mechanistic data have ing causal conclusions. Guided expert judgment is not as been used to support an overall conclusion that a chemical easily applied to other elements of the risk-assessment is carcinogenic in humans.
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For each of the 10 characteristics, the evidence can be labeled strong, moderate, weak, or insufficient to evaluate. The mechanistic evidence is then integrated with the evidence from other data streams to support conclusions about carcinogenicity.
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As discussed in Chapter 5, that biological pathways and approaches that acknowledge report laid out the iconic four steps in risk assessment: that stressors from multiple sources can contribute to a hazard identification, dose–response assessment, expo- single disease and that a single stressor can lead to multisure assessment, and risk characterization. The report ple adverse outcomes.
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Recommendation: The committee sees no immediate Advancing the Use of Data on Disease Components alternative to the use of guided expert judgment as the ba and Mechanisms in Risk Assessment sis of judgment and recommends its continued use for the time being. Expert judgment should be guided and cali Challenge: Data generated from tools that probe brated in interpreting data on pathways and mechanisms.
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PBPK sponse estimates to human populations. Uncertainties are model of trichloroethylene kinetics.
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. tection Agency Endocrine Disruptor Screening Program IARC (International Agency for Research on Cancer)
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and Some Bayesian estimation of pharmacokinetic and pharmacody Organochlorine Insecticides. IARC Monographs on the namic parameters in a mode-of- action-based cancer risk Evaluation of Carcinogenic Risks to Humans Vol.
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2014. Systematic review and evidence inte ia Chemical Spill: 5-Day Rat Toxicogenomic Studies, gration for literature-based environmental health science June 2016 NTP Update [online]
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2016. A Bayesian belief network systematic review methodology: A rigorous and transpar approach for assessing uncertainty in conceptual site mod- ent method for translating environmental health science els at contaminated sites.
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