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

International audienceTo 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 x min BD and 300 ppm x min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm x min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe

The ethics of human volunteer studies involving experimental exposure to pesticides: unanswered dilemmas

The controversy about the use of data from human volunteer studies involving experimental exposure to pesticides as part of regulatory risk assessment has been widely discussed, but the complex and interrelated scientific and ethical issues remain largely unresolved. This discussion paper, generated by authors who comprised a workgroup of the ICOH Scientific Committee on Rural Health, reviews the use of human experimental studies in regulatory risk assessment for pesticides with a view to advancing the debate as to when, if ever, such studies might be ethically justifiable. The discussion is based on three elements: (a) a review of discussion papers on the topic of human testing of pesticides and the positions adopted by regulatory agencies in developed countries; (b) an analysis of published and unpublished studies involving human testing with pesticides, both in the peer-reviewed literature and in the JMPR database; and (c) application of an ethical analysis to the problem. The paper identifies areas of agreement which include general principles that may provide a starting point on which to base criteria for judgements as to the ethical acceptability of such studies. However, the paper also highlights ongoing unresolved differences of opinion inherent in ethical analysis of contentious issues, which we propose should form a starting point for further debate and the development of guidelines to achieve better resolution of this matter.<br/