Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

Abstract

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

“…The extension of the dosing period during the lactation period raised several issues, specifically in the areas of pharmacokinetic/toxicokinetic data needs, behavioral testing, and neuropathologic evaluation. Overall, the working group agreed that the current DNT test protocol was based upon solid scientific principles and experience, that there were opportunities to revise and improve some aspects of the U.S. EPA guideline study, and that further research would be valuable in providing the scientific basis for development of TG 426 ( Cory-Slechta et al 2001 ; Dorman et al 2001 ; Garman et al 2001 ; OECD 2003 ). Further considerations of methodologic issues related to the conduct of the DNT study include an ILSI workshop on the direct dosing of preweaning mammals.…”

“…Diverse groups have advocated increased testing for DNT ( Andersen et al 2000 ; Grandjean and Landrigan 2006 ; NRC 1992 , 1993 ; Nelson 1986 ; Office of Technology Assessment 1990 ; Stein et al 2002 ; Vorhees 1986 ). There have also been calls to include evaluations of end points not currently assessed, such as social behavior ( Cory-Slechta et al 2001 ), pharmacokinetics and neurochemistry ( Andersen et al 2000 ; Dorman et al 2001 ), and changes during senescence ( Cory-Slechta et al 2001 ). In addition, there have been criticisms of the complexity of the study, accompanied by calls for deleting some test components from the protocol ( Li 2005 ) or using screening approaches that incorporate DNT testing into other testing protocols ( Cooper et al 2006 ; Ladics et al 2005 ).…”

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

“…Additionally, they can result in methodological and scientific uncertainties. This includes the challenges in extrapolation of findings from rats to humans that result from timing differences in brain development, toxicokinetics, and inherent difficulties in the use of non-homologous functional tests (Tsuji and Crofton, 2012;Dorman et al, 2001;Kaufmann, 2003). For these reasons, DNT has been regarded as an area in need of the development of alternative methods in order to establish a timeand cost-efficient predictive testing strategy.…”

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

“…However, presently practiced animal tests for DNT are problematic in several ways: (i) they are ethically questionable, since for testing one substance about 140 dams and 1,000 juveniles are required; (ii) they last up to 12 months for the testing of one compound; (iii) they are very expensive (up to € 1,000,000/substance) and (iv) their predictivity for protection of the human brain is questionable. This uncertain transferability of animal experiments to humans (iv) is in part due to a lack of information on pharmaco-/toxicodynamics of the developing brain of rodents compared to humans (Dorman et al, 2001, Kaufmann, 2003. It is therefore essential to utilize alternative test methods in regulatory toxicology, which are able to predict DNT of compounds in a shorter time, less expensive and based on humanspecific toxicity pathways (Crofton et al, 2011).…”