tized pathways and reporter-gene constructs), and more information is obtained with them than with standard animals. In this way, the levels are connected to each other and kept relevant to risk assessment.

1.4.3. Molecular-stress and checkpoint pathways.

Other assays should be directed toward the detection and characterization of cellular responses to chemicals by way of these defense pathways. Approximately 10 of these conserved pathways are now known. Their activation might be relevant to detecting the effects of broadly acting toxicants on maternal and embryonic cells—that is, toxicants such as antimitotic agents or inhibitors of replication, transcription, or translation—that interact with many targets in many cells.

Research remains to be done to connect the damaging effects of toxicants on cells to the disruption of particular steps of development. The connection could be established with level 2 organisms genetically sensitized in one or more of their molecular-stress and checkpoint pathways in a particular organ. The established connection might provide leads for level 3 tests with mice.

Recommendation 2. The committee recommends investigating how the new information about development and developmental toxicity can address the uncertainties in quantitative and qualitative risk assessment.

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. They are costly in time and resources, and, therefore, only a small percentage of the more than 80,000 chemicals in commercial use (or the even larger number—about 6 million—of natural products) can be tested. Rodent-test end points are frequently limited to effects on growth, organogenesis, and viability of the conceptus and do not include functional, molecular, or cellular effects, nor do they include early developmental losses. The relevancy of animal toxicity outcomes for humans is often questioned, as is the significance of high dose animal exposure conditions for human exposures. Hence, risk assessors must often resort to large default corrections when extrapolating animal results to define safe exposure concentrations for humans. The validity of the extrapolation of particular test results from animals to humans is itself usually not assessed.

The committee envisions that research directions included in the informational framework established in Chapter 8 will address various existing limits on the data available to risk assessors and have the potential to provide the scientific basis to reduce the magnitude of or replace defaults using mechanism-based extrapolation approaches.



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