Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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9 Conclusions and Recommendations
9 Conclusions and Recommendations
Pages 220-244
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From page 220... ...
Several reasons for this limited understanding should be cited: · Development is complicated. Only recently have developmental processes and molecular components been elucidated.
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From page 221... ...
The analysis of mechanisms of toxicity requires advanced interdisciplinary information and approaches of the kind that have only recently become available. In considering hypothesized mechanisms, the committee discussed the different scopes and levels of understanding implied by the term "mechanism," as used by different researchers in biochemistry, molecular biology, genetics, developmental biology, toxicology, and epidemiology.
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From page 222... ...
derived from it) with specific molecular components of cellular or developmental processes in the conceptus or with maternal or extraembryonic components of processes supporting development.
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From page 223... ...
, built upon advances in genetics, cell biology, molecular biology, and biochemistry. Developmental processes have been illuminated for the first time in a number of animals at the level of identification of molecular components and their activities, especially of the signaling pathways and genetic regulatory circuits of these processes.
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From page 224... ...
Although not anticipated at the outset, the information from these model organisms proved to be extensively transferable to mammals, because molecular components and many developmental processes are deeply conserved across animal phyla. In particular, development in diverse animals, including mammals, depends on cell-cell signaling at all stages before cytodifferentiation, and this signaling involves repeated use of the same 10 intercellular signaling pathways.
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From page 225... ...
among test animals, and a deliberate effort to control the differences, would reduce and rationalize the wide range of responses of test animals to a toxicant. An understanding of human polymorphisms of molecular components of toxicokinetic and toxicodynamic importance would allow better estimation of safe exposures of individuals over the whole range of human susceptibility to a toxicant.
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From page 226... ...
The committee concludes that recent advances in the fields of developmental biology and genomics provide unprecedented opportunities to understand the molecular mechanisms of action of toxicants, the differences in the developmental responses of test animals and humans to toxicants, the extrapolation of highdose effects to low-dose effects, and the differences in the individual human susceptibility effects of toxicants on development. These advances can lead to improved animal tests for toxicants, improved extrapolation of animal results to humans, and through the means of better data, improved risk assessment.
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From page 227... ...
, and fit the altered function into the effects on a developmental process, the abnormal operation of which leads to a structural or functional defect. The committee recommends that model organisms be used extensively to access this level of analysis so that researchers can benefit from genetic tractability, experimental convenience, and a background of information about molecular components and developmental processes.
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From page 228... ...
Approximately 10 kinds of signaling pathways are repeatedly used at all times and places of development before cytodifferentiation (i.e., during cleavage, gastrulation, neurulation, and organogenesis)
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From page 229... ...
Further arguments for emphasizing these components as potential targets are the following: · When signaling is interrupted in mutant animals, development is affected, with specific effects depending on the component that is inactivated. · A few toxicants currently are known to affect signaling in mammals, such as cyclopamine (the Hedgehog signaling pathway; Chapter 4)
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From page 230... ...
. Thus, the committee's hypothesis, namely, that signaling pathways and the associated genetic regulatory circuits are critical molecular points of susceptibility of development to toxicants, has not been proved.
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As noted above, there are many steps in absorption, distribution, metabolism, and excretion that determine whether the conceptus will be exposed to a toxicant. The molecular components of absorption, distribution, and excretion are not well known, but those of metabolism, the DMEs, have been extensively elucidated in recent years.
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From page 232... ...
in cattle was possible once it was realized that mouse mutants of some components of the Hedgehog signaling pathway are also cyclopic; once the basic developmental studies showed the importance of sonic Hedgehog signal for inhibiting eye development in the ventral midline of the prospective diencephalon, leaving bilateral eye development, the mechanism of the cyclopamine-induced birth-defect became better understood. Scrutiny of the developmental defects of mutants of developmental components in genetically favorable model organisms, and the scrutiny of toxicantcaused developmental defects, might provide informative parallels.
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From page 233... ...
If a toxicant affects cellular activities, setting off molecular-stress and checkpoint pathways, and causes cell death, comparison mutants could be generated and analyzed to understand the consequences for development. The committee recommends basic research on toxicant-affected developmental processes in well-understood model organisms.
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From page 234... ...
Although signaling pathways and genetic regulatory circuits are particularly attractive for study, there is little information on their genetic differences at this time compared with that on DMEs. However, many mouse mutants in genes encoding such components show developmental defects similar to those in humans, and a few human polymorphisms of components are known to correlate with disease (e.g., Patched mutations and a predisposition to basalcell carcinoma)
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From page 235... ...
In general, the connection made between mutational alterations in developmental components and chemical induced developmental defects should be strong. A further determination to be made is how much of the apparent specificity of the outcome of a toxicant-induced developmental defect is due to the specificity of the toxicant and how much is due to the particular genetic background of the exposed animal.
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From page 236... ...
There are two domains of information. One contains results from model systems and model-animal tests of toxicant effects on development and of genetic alterations affecting toxicant susceptibility.
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From page 237... ...
Other assays of toxicants should be used to focus on their effects on developmental processes, particularly on the intercellular signaling pathways and genetic regulatory circuits, which operate repeatedly and pervasively in the development of animals of all phyla. Some assays can be done at level 1, since many signaling components have been identified and their genes isolated.
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From page 238... ...
The committee believes that the new information and approaches of developmental biology and genomics will be useful in improving the quantitative as well as qualitative components of risk assessment. As they are currently designed, the rodent tests for developmental toxicity are limited in their capacity to provide mechanistic information.
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2.3. Quantitative risk assessment: the toxicokinetic differences of test animals and humans should be characterized to improve extrapolations.
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The differences in development of various organisms mostly reflect differences in the time, place, order, and combinations of use of conserved developmental components, such as those of the signaling pathways and genetic regulatory circuits. The committee's recommendation to make more use of nonmammalian model animals in developmental toxicology is based on the recognition of the conservation, although with the caveat that the scoring of toxicant effects is done in these animals at the molecular level of conserved components, and not at the diversified tissue and organ levels, which are obviously not conserved across phyla.
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From page 241... ...
(2) Can the increased attention on key cell-signaling pathways and genetic-regulatory circuits identify biomarkers useful for defining low-dose responses caused by developmental toxicants?
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Does the heterogeneous response of a population of test animals to toxicants give a detectable effect that reflects genetic heterogeneity? To determine the role of genetic differences, various mouse strains can be produced with limiting levels of activity of particular developmental components, and these strains can be tested for their sensitivity to a standard set of toxicants representing a variety of suspected mechanisms of action.
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From page 243... ...
Recommendation 3. To improve the interdisciplinary advances in developmental toxicology, the committee recommends that the databases of developmental toxicology, developmental biology, and genomics be better linked on the Internet and that multidisciplinary outreach programs be establishedfor the effective exchange of information and techniques related to the analysis of developmental defects and to the assessment of toxicity for risk assessment.
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From page 244... ...
For the successful application of this report's findings, the committee believes that multidisciplinary educational and research programs must be conducted. Programs, such as workshops and professional meetings, should be organized so that researchers of developmental toxicology, developmental biology, genomics, medical genetics, epidemiology, and biostatistics can come together to exchange new insights, approaches, and techniques related to the analysis of developmental defects and to risk assessment.
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