New molecular and instrumental techniques have made available many markers of cellular damage that can be evaluated in multiple tissues in vivo at low cost without compromising the normal conduct of in vivo toxicity evaluations, and without the need for substitution of new species or strains of animals. These techniques include (1) the activation of stress genes that respond to general classes of toxic agents and cellular damage at doses below those that cause frank toxicity; (2) electrophoretic methods for the detection of DNA strand breakage due to DNA degradation resulting from cell death or genotoxic damage; (3) the use of fluorescent chromosome-specific DNA probes that allow evaluation of stable chromosomal rearrangements, chromosomal breaks, and aneuploidy in laboratory animals; and (4) endogenous and exogenous (transgenic) reporter genes for the evaluation of in vivo gene mutation. Additionally, powerful new analytical techniques such as accelerator mass spectrometry make possible ultrasensitive measurements of metabolite binding to specific macromolecular targets and permit pharmacokinetics studies at very low doses. Often, identical or analogous endpoints can be measured in cellular models, in laboratory animals, and in humans, an approach that allows in vitro screening for product development, in vivo hazard identification, and early risk assessments in animal models and direct risk assessment in humans. These new in vivo techniques will greatly enhance our ability to extrapolate laboratory data to human health risk.
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