Biopersistence of man-made vitreous fibres (MMVF) / synthetic vitreous fibres (SVF): advancing from animal models to acellular testing

Abstract

The field of fibre toxicology highlights a significant connection between the physicochemical properties of fibres-such as diameter, length, and durability-and their toxicity when inhaled. Among these properties, durability, particularly in terms of biopersistence and retention time in the lungs, is crucial in determining chronic toxicity. This understanding of fibre biopersistence is especially relevant to the regulation and safety assessment of Man-Made Vitreous Fibres (MMVF), also referred to in North American literature as Synthetic Vitreous Fibres (SVF). Despite its importance, current practices rely heavily on in vivo testing methods for evaluating biopersistence, which conflicts with the movement towards reducing animal testing and utilising new approach methodologies (NAMs) for hazard and risk assessment. In vitro assessments of biodurability have long been employed by the research community and industry alike to investigate the persistence of fibres in the lung, offering an alternative to reduce animal testing to evaluate this critical mediator of fibre toxicity. Here, we explore recent developments in acellular in vitro biodurability approaches for assessing fibre durability in the lung, addressing the variations and key challenges associated with using these methods to determine the safety of bio-soluble MMVF.

Keywords: Biopersistence; Fibres; Regulatory assessment; Respiratory toxicity; Safety; Synthetic vitreous fibres.

Fig. 1

Categories of fibres and sub-classification of Man-Made Vitreous Fibres/ Synthetic Vitreous Fibres

Fig. 2

Length-weighted fibre diameter distribution of glass wool product as an example MMVF. This graph has been kindly provided by JH using unpublished data

Fig. 3

Modification of partial dissolution rate in vivo (S) as a function of the alumina/silica ratio. The partial dissolution rate (S) was derived from in vivo K_dis for a range of fibre compositions by Eastes et al. [48]. Blue data points and trendlines have a weight ratio of Al₂O₃/ SiO₂ of < 0.3, while the orange data points and trendlines have a weight ratio of Al₂O₃/ SiO₂ of > 0.3

Fig. 4

Graphical representation of an alveolus showing the various environments a depositing MMVF may encounter in the distal lung

Fig. 5

Diagram of typical acellular dissolution analysis apparatus. (A) Static dissolution using bulk suspension of MMVFs in simulant media (e.g. Gamble’s solution) with or without continuous stirring. (B) Static dissolution using MMVFs immobilised between filters inside a dissolution chamber submerged in simulant media. (C) USP Apparatus 4 (USP-4) consists of containers, called “cells”, in which the MMVFs are placed between a red bead and a filter, through which a fluid flows in a closed loop or open loop configuration. (D) Continuous flow through (CFT) method whereby MMVFs are held between two filters within a flow cassette through which the simulating solution flows via a pump circulating the fluid in a closed loop or open loop configuration. (E) Single-fibre dissolution system used to observe by microscopy the dissolution of fibres mounted across the path of the fluid in a CFT system (left: cross section of the cell, right: planar view of the cell).