Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes

Abstract

BackgroundA diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the ‘gold standard’ for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance.MethodsGene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical-chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT.ResultsSimilar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0–30.4 μg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0–27.1 μg/mouse).ConclusionsThe results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0125-9) contains supplementary material, which is available to authorized users.

Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury

“…It is important to note that our objective was to evaluate the impact of HA functionalization on nanotube-induced pathology and for that reason we opted to use an effective dose for pulmonary toxicity end points (especially fibrosis). 40 Moreover, our in vitro doses of 25–50 μ g/mL (5–10 μ g/cm 2 ) are comparable with mouse exposure doses previously reported in the literature. 10,25,34 …”

Mechanisms of carbon nanotube‐induced pulmonary fibrosis: a physicochemical characteristic perspective

“…Interestingly, a rod-like MWCNT treatment via oropharyngeal aspiration results in a more Th2 response as indicated via mucous cell metaplasia and/or eosinophilia 31,34 . M2 macrophages produce Th2 cytokines, like IL-4, IL-5, and IL-13 which drive the adaptive immune response and are upregulated in bleomycin-induced fibrosis 105 . IL-17 is also upregulated in bleomycin treated lungs which can down-regulate the Th1 response and drive production of growth factors, like TGF-β1, and result in excess collagen deposition into the ECM and decreased collagen metabolism thereby disrupting homeostasis 105 .…”

Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice

“…But their increased production has also increased the potential risk of human exposure [1;2]. It is well established in rodent models that pulmonary exposure to MWCNTs through inhalation, instillation or aspiration is associated with lung inflammation, genotoxicity, fibrosis and granuloma formation [3–14]. In addition, pulmonary exposure to MWCNTs may increase the risk of developing cardiovascular diseases (CVD) [15].…”