Utility of life stage-specific chemical risk assessments based on New Approach Methodologies (NAMs).

The safety assessments for chemicals targeted for use or expected to be exposed to specific life stages, including infancy, childhood, pregnancy and lactation, and geriatrics, need to account for extrapolation of data from healthy adults to these populations to assess their human health risk. However, often adequate and relevant toxicity or pharmacokinetic (PK) data of chemicals in specific life stages are not available. For such chemicals, New Approach Methodologies (NAMs), such as physiologically based pharmacokinetic (PBPK) modeling, biologically based dose response (BBDR) modeling, in vitro to in vivo extrapolation (IVIVE), etc. can be used to understand the variability of exposure and effects of chemicals in specific life stages and assess their associated risk. A life stage specific PBPK model incorporates the physiological and biochemical changes associated with each life stage and simulates their impact on the absorption, distribution, metabolism, and elimination (ADME) of these chemicals. In our review, we summarize the parameterization of life stage models based on New Approach Methodologies (NAMs) and discuss case studies that highlight the utility of a life stage based PBPK modeling for risk assessment. In addition, we discuss the utility of artificial intelligence (AI)/machine learning (ML) and other computational models, such as those based on in vitro data, as tools for estimation of relevant physiological or physicochemical parameters and selection of model. We also discuss existing gaps in the available toxicological datasets and current challenges that need to be overcome to expand the utility of NAMs for life stage-specific chemical risk assessment.

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science.

A physiologically-based pharmacokinetic (PBPK) model represents the structural components of the body with physiologically relevant compartments connected via blood flow rates described by mathematical equations to determine drug disposition. PBPK models are used in the pharmaceutical sector for drug development, precision medicine, and the chemical industry to predict safe levels of exposure during the registration of chemical substances. However, one area of application where PBPK models have been scarcely used is forensic science. In this review, we give an overview of PBPK models successfully developed for several illicit drugs and environmental chemicals that could be applied for forensic interpretation, highlighting the gaps, uncertainties, and limitations.