Evaluation of Physiologically Based Models of Pregnancy and Lactation for Their Application in Children's Health Risk Assessments

In today's scientific and regulatory climates, an increased emphasis is placed on the potential health impacts for children exposed either in utero or by nursing to drugs of abuse, pharmaceuticals, and industrial or consumer chemicals. As a result, there is a renewed interest in the development and application of biologically based computational models that can be used to predict the dosimetry (or ultimately response) in a developing embryo, fetus, or newborn. However, fundamental differences between animal and human development can create many unique challenges. For example, unlike models designed for adults, biologically based models of pre- and postnatal development must deal with rapidly changing growth dynamics (maternal, embryonic, fetal, and neonatal), changes in the state of differentiation of developing tissues, uniquely expressed or uniquely functioning signal transduction or enzymatic pathways, and unusual routes of exposure (e.g., maternal-mediated placental transfer and lactation). In cases where these challenges are overcome or addressed, biological modeling will likely prove useful in assessments geared toward children's health, given the contributions that this approach has already made in cancer and non-cancer human health risk assessments. Therefore, the purpose of this review is to critically evaluate the current state of the art in physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) modeling of the developing embryo, fetus, or neonate and to recommend potential steps that could be taken to improve their use in children's health risk assessments. The intent was not to recommend improvements to individual models per se, but to identify areas of research that could move the entire field forward. This analysis includes a brief summary of current risk assessment practices for developmental toxicity, with an overview of developmental biology as it relates to species-specific dosimetry. This summary should provide a general context for understanding the tension that exists in modeling between describing biological processes in exquisite detail vs. the simplifications that are necessary due to lack of data (or through a sensitivity analysis, determined to be of little impact) to develop individual PBPK or PD models. For each of the previously published models covered in this review, a description of the underlying assumptions and model structures as well as the data and methods used in model development and validation are highlighted. Although several of the models attempted to describe target tissues in the developing embryo, fetus, or neonate of laboratory animals, extrapolations to humans were largely limited to maternal blood or milk concentrations. Future areas of research therefore are recommended to extend the already significant progress that has been made in this field and perhaps address many of the technical, policy, and ethical issues surrounding various approaches for decreasing the uncertainty in extrapolating from animal models to human pregnancies or neonatal exposures.