Use of a chemical probe to increase safety for human volunteers in toxicokinetic studies

Risk Analysis : an Official Publication of the Society for Risk Analysis
Céline Brochot, Frédéric Y Bois

Abstract

To avoid interspecies extrapolation in toxicokinetics and drug development, it is convenient to directly develop human data. In that case, exposure dose should pose null or negligible risk to the exposed individual, but still be sufficiently high to allow quantification. We propose to reduce the dose received by human volunteers during exposure, and to compensate for loss of information by exposing the same volunteers to a nontoxic agent. This method was applied to develop 1,3-butadiene (BD) exposure protocols for humans. To study the potential of such a procedure, we worked with simulated data. Three exposure times (20, 10, and 5 minutes) and four exposure concentrations (2, 1, 0.8, and 0.5 ppm) were used to define 12 inhalation exposure scenarios for BD. Isoflurane was used as a probe, with simulated exposure of 20 subjects to 20 ppm isoflurane during 15 minutes. Isoflurane or BD-exhaled air concentrations were supposed to be measured 10 times. A three-compartment physiological toxicokinetic model was used to jointly describe BD and isoflurane data. For each subject, BD data were analyzed, in a Bayesian framework, either alone or together with the isoflurane data. The precision of BD metabolic rate constant or fraction metabo...Continue Reading

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Citations

Jan 24, 2016·Toxicology and Applied Pharmacology·Marie-Emilie WilleminCéline Brochot
Jun 11, 2009·Risk Analysis : an Official Publication of the Society for Risk Analysis·Alexandre Roger Raymond Péry, Frederic Yves Bois

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