Toxicokinetics, dose–response, and risk assessment of nanomaterials: Methodology, challenges, and future perspectives

Abstract

The rapid growth of nanomaterial applications has raised safety concerns for human health. A number of studies have been conducted to assess the toxicokinetics, toxicology, dose–response, and risk assessment of different nanomaterials using in vitro and in vivo animal and human models. However, current studies cannot meet the demand for efficient assessment of toxicokinetics, dose–response relationships, or the toxicological risk arising from the rapidly increasing number of newly synthesized nanomaterials. In this article, we review the methods for conducting toxicokinetics, hazard identification, dose–response, exposure, and risk assessment studies of nanomaterials, identify the knowledge gaps, and discuss the challenges remaining. We provide the rationale behind the appropriate design of nanomaterial plasma toxicokinetic and tissue distribution studies, including caveats on the interpretation and correlation of in vitro and in vivo toxicology studies. The potential of using physiologically based pharmacokinetic (PBPK) models to extrapolate toxicokinetic and toxicity findings from in vitro to in vivo and from animals to humans is discussed, and the knowledge gaps of PBPK modeling for nanomaterials are identified. While challenges still exist, there has been progress in the toxicokinetics, hazard identification, and risk assessment of nanomaterials in the past two decades. Recent advancements in the field are highlighted with relevant examples. We also share latest guidelines as well as our perspectives on future studies needed to characterize the toxicokinetics, toxicity, and dose–response relationship in support of nanomaterial risk assessment.This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

Meta-Analysis of Nanoparticle Distribution in Tumors and Major Organs in Tumor-Bearing Mice

“…The number of NPs in the blood was assumed to be approximately equal to that in the plasma or serum. In the blood or plasma, the formation of biomolecular coronas will substantially affect the PK profile of NPs . In previous studies, the changes in targeting capabilities of NPs were reported to be impacted by the physicochemical properties, such as NP surface modification.…”

Integration of In Vitro and In Vivo Models to Predict Cellular and Tissue Dosimetry of Nanomaterials Using Physiologically Based Pharmacokinetic Modeling

“…Recent rapid advancements in nanotechnology have enabled efficient synthesis of nanomaterials (NMs) or nanoparticles (NPs) with a variety of physicochemical properties for several different applications, such as consumer products, industrial, and medical applications. − As the usage of NMs increases, human exposure to these materials inevitably intensifies. The effect of NM exposure on human health could be diagnostic, therapeutic, or detrimental depending on the NM itself (usually related to its physicochemical properties), the drug that the NM carries, the external exposure dose, frequency and duration, the internal dose at the target organ and cells, as well as the sensitivity of the species, organs, and cells. − Many animal studies have shown that overexposure to NMs can cause adverse effects on different organ systems, such as the lungs, liver, and blood. − A few human studies have also associated accidental or occupational exposure to NMs with adverse effects. − The increasingly widespread use of NMs and the reported toxicity data have caused concern on the potential risk of NMs and raised a need to develop strategies to properly assess the risk of NMs.…”

“…Multiple studies have attempted to develop methods for risk assessment of different NMs, including titanium dioxide, gold, and silver NPs. ,− However, existing methods/models are limited to a certain type of NMs, and some of the models have not been adequately validated due to a lack of in vitro or in vivo data. High variations in the type and physicochemical properties of NMs, the type of target cells, and the number of cells in the body, as well as the route of exposure, create an impossible task to perform risk assessment of different NMs using conventional animal toxicity data-based approaches.…”

“…Differences in Physiologically Based Pharmacokinetic Modeling between Small Molecules and Nanoparticles a Usually the same as small molecules in mass per unit volume, but some studies showed that the dose metrics of particle number or surface area may be more appropriate for certain toxicity end points, such as lung inflammation 4. Absorption Approaches to simulate extravascular absorption for small molecules are well established.Depending on the administration route and availability of data, it could be a simple firstorder linear absorption or a more complex mechanistic model, such as the advanced compartmental absorption and transit model for oral absorption.…”

“…The effect of NM exposure on human health could be diagnostic, therapeutic, or detrimental depending on the NM itself (usually related to its physicochemical properties), the drug that the NM carries, the external exposure dose, frequency and duration, the internal dose at the target organ and cells, as well as the sensitivity of the species, organs, and cells. 4 − 6 Many animal studies have shown that overexposure to NMs can cause adverse effects on different organ systems, such as the lungs, liver, and blood. 6 − 8 A few human studies have also associated accidental or occupational exposure to NMs with adverse effects.…”