Intentional Human Dosing Studies for EPA Regulatory Purposes Scientific and Ethical Issues (2004) / Chapter Skim
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Appendix A: Values and Limitations of Animal Toxicity Data
Appendix A: Values and Limitations of Animal Toxicity Data
Pages 159-167
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From page 159... ...
Knowledge of chemical toxicity can be gained from several types of human studies. Intentional dosing studies of humans typically involve acute or short-term administration of low to moderate doses of drugs, vaccines, cosmetics, food additives, pesticides, or occupational or environmental agents.
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From page 160... ...
The intentional human dosing studies with pesticides reviewed by this committee involved low doses that produce no effects or minimal, reversible changes in sensitive biomarkers, albeit in one study the effect was sufficiently large to warrant termination of the study. Although epidemiological investigations of exposed populations may identify associations of adverse effects and chemical exposures and support inferences of cause and effect, epidemiological data are nonetheless usually limited by inadequate characterization of exposures and by an inability to recognize or control confounding factors (Dourson et al., 2001)
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From page 161... ...
The most definitive study to date of interspecies concordance involved an International Life Sciences Institute-sponsored review of data supplied by 12 pharmaceutical companies (Olson et al., 2000)
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From page 162... ...
The Olson study described other reports of poor correspondence between animal data and human toxicities severe enough to lead to market withdrawal of drugs. Many of these cases apparently involved idiosyncratic reactions that occurred with a very low incidence in patient populations, a phenomenon that reflects the pronounced influence of exogenous and endogenous factors on interindividual responses.
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From page 163... ...
This disparity has been attributed to very efficient conjugation of the major reactive metabolite by mice. Interspecies extrapolations on the basis of body surface area and comparative metabolism studies with primary hepatocytes of mice, rats, and humans indicate that the susceptibility of humans to a number of compounds resembles that of rats (Hengstler et al., 1999)
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From page 164... ...
FDA (2002) has published a draft guidance document that describes a strategy recommended for deriving safe starting doses of therapeutic agents for clinical trials with healthy research participants.
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From page 165... ...
Validated models allow one to simulate the human exposure conditions that will produce a target organ dose equivalent to that previously found to be associated with toxicity in the test animal. This so-called HED approach has been used successfully for a number of chemicals including, among others, methylene chloride (Andersen et al., 1991)
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From page 166... ...
1998. Application of a hybrid computa tional fluid dynamics and physiologically based inhalation model for interspecies do simetry extrapolation of acidic vapors in the upper airways.
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From page 167... ...
1996. Variability in biological exposure indices using physiologically-based pharmacokinetic modeling and Monte Carlo simulation.
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