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Use of a Chemical Probe to Increase Safety for Human Volunteers in Toxicokinetic Studies

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  • 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 metabolized was increased, and bias reduced, when BD and probe data were considered jointly. An exposure to 10 ppm × min BD and 300 ppm × min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm × min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe.

Suggested Citation

  • Céline Brochot & Frédéric Y. Bois, 2005. "Use of a Chemical Probe to Increase Safety for Human Volunteers in Toxicokinetic Studies," Risk Analysis, John Wiley & Sons, vol. 25(6), pages 1559-1571, December.
  • Handle: RePEc:wly:riskan:v:25:y:2005:i:6:p:1559-1571
    DOI: 10.1111/j.1539-6924.2005.00682.x
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    References listed on IDEAS

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    1. Bois, Frederic Y. & Maszle, Don R., 1997. "MCSim: A Monte Carlo Simulation Program," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 2(i09).
    2. Karen H. Watanabe & Frédéric Y. Bois, 1996. "Interspecies Extrapolation of Physiological Pharmacokinetic Parameter Distributions," Risk Analysis, John Wiley & Sons, vol. 16(6), pages 741-754, December.
    3. Maura Mezzetti & Joseph G. Ibrahim & Frédéric Y. Bois & Louise M. Ryan & Long Ngo & Thomas J. Smith, 2003. "A Bayesian compartmental model for the evaluation of 1,3‐butadiene metabolism," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 52(3), pages 291-305, July.
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    Cited by:

    1. Alexandre Roger Raymond Péry & Frederic Yves Bois, 2009. "Stochasticity in Physiologically Based Kinetics Models: Implications for Cancer Risk Assessment," Risk Analysis, John Wiley & Sons, vol. 29(8), pages 1182-1191, August.

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