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On the pivotal role of dose for particle toxicology and risk assessment: exposure is a poor surrogate for delivered dose

O. Schmid,F. Cassee

Published 2017 in Particle and Fibre Toxicology

ABSTRACT

Introduction There is still concern regarding potential health effects of nano-sized and nano-structured materials (NMs). Since reliable risk assessment is essential for sustained societal acceptance, there has been substantial funding for toxicological studies in the past decades. Albeit a wealth of data has been published since, the relevance of those data for risk assessment can be questioned. This is particularily the case for data from studies that focused on inhalation as the route of exposure. The derivation of exposure limits for NMs is still an elusive issue, although some regulatory measures have been undertaken e.g. for inhalation of carbon nanotubes at the workplace [1]. Today, one of the main obstacles for risk assessment of nanoand micronsized particles and fibres is not the lack of toxicological data, but a shortage of data meeting all of the criteria for use in risk assessment. One of the most important criteria is accurate dosimetry. While most studies provide accurate data on particle exposure concentration, i.e. mass of particles per volume air (μg/ m) or – for in vitro submerged cell-based assays – per volume cell culture medium (μg/cm), the pivotal role of dose delivered to the site of exposure (e.g. lung epithelium (in vivo) or lung cell culture (in vitro)) has been widely overlooked. This is especially the case in but not limited to studies with in vitro cell systems [2, 3]. In addition, the choice of consistent and relevant dose metrics (e.g. mass, volume, surface area, number) has also been identified as one of the key issues for limited applicability of toxicological data for risk assessment [4]. While this is beyond the scope of this editorial, we mention that current results indicate that – in addition to mass, the traditionally used metric – at least one more dose metric should be used such as surface area, volume or number, depending on the type of NM [5–7]. This editorial highlights the fundamental role of delivered particle dose (sometimes also referred to as internal dose) for translation of toxicological dose-response data into risk assessment and exposure limits. The concept of delivered dose is of overarching significance for any type of particle exposure scenario. For simplicity we are focusing on poorly soluble particles (PSP) and models for respiratory toxicity assessment, i.e. inhalation exposure for in vivo studies and cell culture exposure under submerged or air-liquid interface conditions.

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