Grouping of orally ingested silica nanomaterials via use of an integrated approach to testing and assessment to streamline risk assessment

Abstract

Background Nanomaterials can exist in different nanoforms (NFs). Their grouping may be supported by the formulation of hypotheses which can be interrogated via integrated approaches to testing and assessment (IATA). IATAs are decision trees that guide the user through tiered testing strategies (TTS) to collect the required evidence needed to accept or reject a grouping hypothesis. In the present paper, we investigated the applicability of IATAs for ingested NFs using a case study that includes different silicon dioxide, SiO2 NFs. Two oral grouping hypotheses addressing local and systemic toxicity were identified relevant for the grouping of these NFs and verified through the application of oral IATAs. Following different Tier 1 and/or Tier 2 in vitro methods of the TTS (i.e., in vitro dissolution, barrier integrity and inflammation assays), we generated the NF datasets. Furthermore, similarity algorithms (e.g., Bayesian method and Cluster analysis) were utilized to identify similarities among the NFs and establish a provisional group(s). The grouping based on Tier 1 and/or Tier 2 testing was analyzed in relation to available Tier 3 in vivo data in order to verify if the read-across was possible and therefore support a grouping decision. Results The measurement of the dissolution rate of the silica NFs in the oro-gastrointestinal tract and in the lysosome identified them as gradually dissolving and biopersistent NFs. For the local toxicity to intestinal epithelium (e.g. cytotoxicity, membrane integrity and inflammation), the biological results of the gastrointestinal tract models indicate that all of the silica NFs were similar with respect to the lack of local toxicity and, therefore, belong to the same group; in vivo data (although limited) confirmed the lack of local toxicity of NFs. For systemic toxicity, Tier 1 data did not identify similarity across the NFs, with results across different decision nodes being inconsistent in providing homogeneous group(s). Moreover, the available Tier 3 in vivo data were also insufficient to support decisions based upon the obtained in vitro results and relating to the toxicity of the tested NFs. Conclusions The information generated by the tested oral IATAs can be effectively used for similarity assessment to support a grouping decision upon the application of a hypothesis related to toxicity in the gastrointestinal tract. The IATAs facilitated a structured data analysis and, by means of the expert’s interpretation, supported read-across with the available in vivo data. The IATAs also supported the users in decision making, for example, reducing the testing when the grouping was well supported by the evidence and/or moving forward to advanced testing (e.g., the use of more suitable cellular models or chronic exposure) to improve the confidence level of the data and obtain more focused information.

Critical aspects in dissolution testing of nanomaterials in the oro-gastrointestinal tract: the relevance of juice composition for hazard identification and grouping

“…Therefore, we recognize “complete” juices (inorganics + enzymes + other organics, Type 1 formulation) as the preferable option in dissolution tests. We also stress the importance and the use of ‘complete juice’ for mechanistic studies on substances of gradual dissolution, 12,55 where the chemical nature of the released ion is well known to be toxic ( i.e. copper ion).…”

“…8,[18][19][20]22 In order to simulate the digestion process, a modied version of the in vitro dissolution test described by our recent work was followed. 2,12,[18][19][20] Here, the overall volume of the process was scaled down three-fold to increase its practicality. NM110 was dispersed in MilliQ water at a concentration of 2.56 mg mL −1 , The suspension was sonicated using a Bandelin Sonopuls Ultrasonic Homogenizers HD 2200, equipped with a 3 mm probe (BANDELIN electronic GmbH & Co. KG; Berlin, Germany).…”

“…9 Extrinsic parameters relevant to dissolution kinetics are the physical chemical (PC) properties of the NMs, which can be applied to group NFs of a NM with similar properties. 2,3,[10][11][12][13][14] Currently, different in vitro methods are available to measure dissolution, in static or dynamic mode (e.g., ow-through and continuous ow), as described by the ISO/TR 19057. 5 The molecular composition of the simulated juices usually varies in regard to the extent of prediction of in vivo conditions when a toxicity assessment is required.…”

“…Extrinsic parameters relevant to dissolution kinetics are the physical chemical (PC) properties of the NMs, which can be applied to group NFs of a NM with similar properties. 2,3,10–14…”

Similarity of multicomponent nanomaterials in a safer-by-design context: the case of core–shell quantum dots

“…The method has been successfully applied by Tsiliki et al for grouping NMs under different scenarios 10 and different grouping hypotheses. 7,39,40 The main difference between the BF approach and the previously presented approach is that based on the given data (in this case a dose–response data matrix for a pair of MCNMs), it estimates the function that best describes them across a range of both observed and unobserved data points, and at the same time can incorporate the assumption of similarity. In fact, the BF compares the model of similarity against the model of dissimilarity; if the resulting BF is a high value, then the two MCNMs are considered to be similar, otherwise dissimilar.…”