sons between mice and primates. The tests of the toxicant susceptibility of developmental components of mouse mutants will greatly guide research in humans.

2.5. Quantitative risk assessment: low-dose effects of toxicants and chemical mixtures should be better detected and characterized.

Risk assessors need data on toxicant effects covering a wide range of doses. A chemical might affect a variety of development processes at high doses but only one critically sensitive pathway at low doses, making that single pathway the most relevant for overall risk assessment. Studies of model systems—such as Drosophila, C. elegans, zebrafish, and the mouse—could provide quantitative information to improve understanding of such dose distinctions and their basis.

In risk assessment, animal test results obtained at high doses of a toxicant and with a small population of animals are frequently used to estimate the consequences of low doses in large populations. Furthermore, when a group of animals is exposed to the lowest dose of toxicant for which there is an effect, the individuals of the group usually respond in a heterogeneous way. Thus, there are many uncertainties about extrapolation to low doses. Basic questions to be explored in this area include the following: (1) What is the shape of the dose-response curve for developmental toxicants at low, environmentally relevant doses? (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? (3) Do the low-dose responders represent variants with genetic susceptibility? and (4) Is there an inescapable nongenetic variability to development?

2.5.1. Low-dose cellular responses revealed through the molecular-stress and checkpoint pathways.

Some developmental toxicants might act primarily by interfering with basic cellular reproduction (e.g., DNA synthesis or mitosis). The conceptus might be more sensitive than the adult because it has a higher frequency of cell division (and fewer cells are in a nondividing differentiated state). Dose effects might be nonlinear. High doses of a toxicant might cause so much cell death that local development is impaired, but low doses might cause so little cell death that cell proliferation by the unaffected cells can restore the population and development is not detectably abnormal. At even lower doses, the various molecular-stress and checkpoint pathways might protect individual cells so that none dies, and development is completely normal. Nonetheless, the activation of the recovery pathways might be detected as an indicator of effect in this low-dose range. The committee recommends that these toxicants be explored over a range of doses, to detemine whether responses can be found in doses too low to cause developmental defects and to reveal the capacity of the conceptus for recovery.

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