In Vivo Inhalation Toxicity Screening Methods for Manufactured Nanomaterials

Information on possible toxic effects of nanomaterials is essential to ensure occupational and consumer safety. As regards human exposure to nanomaterials, inhalation is recognized as an exposure route of potential concern, especially in the occupational context, but also for consumers. Generally, comprehensive regulatory toxicity testing for the hazard and risk assessment of an inhalable chemical encompasses a dose range finding inhalation study using rats followed by a rat 28-day and 90-day inhalation toxicity study (OECD TG 412 and 413). However, performing such inhalation toxicity tests is time-consuming, cost-intensive, and can require up to 160 animals per study. Given the increasing number of products containing nanomaterials entering the market and the multitude of different variants of the same nanomaterial, the fulfillment of all information requirements for every single variant of a given nanomaterial is impractical and undesirable for economic reasons, and it further stands in contradiction to the internationally accepted 3Rs principle to replace, reduce, and refine animal testing. On the other hand, in vivo inhalation toxicity tests cannot yet be replaced by in vitro methods. Taking into account the specific purpose of the investigation, both the short-term inhalation study (STIS) and the intratracheal instillation (IT) study are suitable in vivo screening methods that allow identifying if nanomaterials that reach the lung elicit signs of inflammation. These screening methods allow reducing and refining animal testing as compared to the 28-day and 90-day inhalation toxicity studies. IT studies are useful to obtain initial information on pulmonary effects elicited by nanomaterials, e.g., during product development and as an initial step for hazard identification, but R. Landsiedel (*) Experimental Toxicology and Ecology, BASF SE, Ludwigshafen am Rhein, Germany e-mail: robert.landsiedel@basf.com M. Gamo National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan A. Hirose Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Kawasaki, Japan