Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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8 A Multilevel Approach to Improving Risk Assessment for Developmental Toxicity
8 A Multilevel Approach to Improving Risk Assessment for Developmental Toxicity
Pages 196-219
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From page 196... ...
. · Second, research advances can be made that would increase our ability to reliably extrapolate from test results from model test animals to humans and to all members of the heterogeneous human population.
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From page 197... ...
As mechanisms are better understood for certain chemicals, can the effects of related chemicals be better predicted? THE MULTIDISCIPLINARY, MULTILEVEL, INTERACTIVE APPROACH The committee will outline in the remainder of this chapter a multidisciplinary, multilevel, interactive approach in which recent and future advances in developmental biology and genomics can be integrated with developmental toxicology to improve risk assessment for human developmental defects.
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From page 198... ...
All levels are designed to provide information useful for human developmental toxicity risk assessments.
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From page 199... ...
Toxicity Assessment in Model Systems Information levels 1 and 2 of model systems in Table 8-1A generally involve relatively inexpensive and fast characterizations of chemicals and developmental effects. They should provide valuable information about which developmental pathways (signaling pathways and transcriptional regulatory circuits)
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202 Cq o .s o ·_4 an Cq o x C)
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From page 203... ...
Information levels 1 and 2 make use of model systems of far less complexity than humans. The results from these specialized cell assays and model organisms would be useful to organize chemicals according to their effects (e.g., to reveal chemicals that bind to the same protein e.g., a nuclear-hormone receptor or interfere with the same conserved cell signaling pathway)
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From page 204... ...
· relative potency information for chemicals evaluated in the same assays, · information about the activity of chemical mixtures, and · some quantitative information across assay end points for estimating relative potency across chemical classes. When coupled with estimates of actual or impending human exposure, such assay information would be useful in prioritizing chemicals for in vivo assessments at information levels 2 and 3.
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From page 205... ...
Compounds that do not show effects in these assays would still need testing at other levels of assessment if human exposure or environmental release is likely. At this information level, false positives are preferable to false negatives, and high sensitivity is preferable to low sensitivity (see discussions on how to use such information to strategize test applications by Lave and Omenn 1986~.
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From page 206... ...
General toxicity caused by a chemical can be distinguished from specific effects on development in the animals by evaluating general lethality, growth, and developmental effects versus specific effects on the particular locally sensitized pathway of development. An argument against the use of these model organisms is that the amount of information relevant to chemical effects on human organogenesis will be small, because the organs of model organisms, such as the fruit fly and nematode, differ substantially from those of humans.
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From page 207... ...
At information level 2, the fruit fly organ can be used for assaying for chemical effects on conserved signaling pathways and gene regulation. In addition, some fruit fly organs are now thought to have deep evolutionary similarities to particular vertebrate organs, including human organs, in their combination of pathways and circuits.
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From page 208... ...
Chemicals that alter signaling pathways, molecular-stress pathways, or checkpoint pathways in assays at information levels 1 and 2 would be scrutinized at level 3 to ascertain in vivo mammalian effects. Test animals would likely be the mouse and rat.
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significant clues for human risk assessment (e.g., analyzing differences between test animals and humans)
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Assessment of Toxicity, Susceptibility, and Chemical Exposure in Human Populations The committee believes that the quality and the accessibility of human epidemiological information need re-examination, in light of its present and increasing relevance for developmental toxicity risk assessment. The committee considered ways to link data from human surveillance studies with data from in vitro studies and in vivo animal studies and discussed how new biomarkers of exposure and susceptibility in humans could be linked more effectively with new biomarkers of effect, in order to improve the assessment of human risk for developmental toxicity.
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Some prospective post-surveillance followup studies have been directed by pharmaceutical companies evaluating post-marketing impacts of drugs. The committee suggests that the data from pharmaceutical company studies be made available and that the existing efforts to track human developmental outcomes be better characterized and recognized.
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From page 212... ...
Human populations are expected to contain a large number of sequence polymorphisms (e.g., single nucleotide polymorphisms occur at least at 1 in 500 bases, recent estimates being as high as 1 in 25 bases) ; therefore, population samples cannot be selected only on the basis of a shared sequence difference.
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From page 213... ...
As evident from the extensive discussions of conserved cell signaling pathways and genetic regulatory circuits, the committee suggests that polymorphisms in components of these pathways and circuits be tracked for the following reasons: . The pathways and circuits are used widely in embryonic development.
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From page 214... ...
Database of Human Biomarkers This domain would provide the best information on human exposure to chemicals and on human susceptibility to developmental effects from chemical exposure. Biomarkers of exposure indicate the actual level of a chemical in the individual (e.g., lead concentrations in blood or dentine in children; organophosphate metabolites in urine)
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From page 215... ...
susceptibility are less advanced but might include polymorphisms of genes encoding components of signaling pathways, genetic regulatory circuits, or molecular-stress pathways. Biomarkers of effect might include indicators of early activation of molecular-stress pathways or signaling pathway inhibition (e.g., due to exposure of a person to environmental chemicals and pharmaceuticals)
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From page 216... ...
The Importance of Linking Databases The committee's multidisciplinary, multilevel, interactive approach to improving risk assessment assumes that the recent research advances in development and genomics have the potential, not yet realized, to improve cross-species extrapolations and cross-assay extrapolations and to ascertain the developmental targets of toxicants. Although more relevant information will become available for human risk assessment, a significant challenge facing risk assessors who want to use this information is the informatics problem.
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From page 217... ...
In both cases, profiles of gene expression changes can be determined for tissues with specific developmental defects and for affected tissues after toxicant exposure.
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From page 218... ...
Catalogs of phenotypes of mouse null mutants for individual genes in the heterozygous and homozygous states, and in combination with other gene disruption, will be useful for comparison with phenotypes of human birth defects in order to gain inferences about what is affected in human development. The level 2 and 3 model system assays for developmental defects will draw from these genomic databases and contribute to them.
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From page 219... ...
SUMMARY The committee has developed a multilevel, multidisciplinary, interactive approach for improving risk assessment for developmental toxicity. Model animal systems and human epidemiological studies are shown to be valuable sources of information for risk assessment, and it is emphasized that the multilevel approach is not a tiered approach.
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