Background and Purpose: Fiber dimension, durability/dissolution, and biopersistence are critical factors for the risk of fibrogenesis and carcinogenesis. In the modern era, to reduce, refine, and replace animals in toxicology research, the application of in vitro test methods is paramount for hazard evaluation and designing SVFs for safe use. A proposed framework for application of next generation NAMs was developed through consideration of fiber AOPs. Methods: AOP frameworks following the conceptual model of the Organization for Economic Co-operation and Development (OECD) were developed through a systematic evaluation of available molecular and cellular initiating events, which lead to key events and key event relationships in the development of fiber-induced fibrogenesis and carcinogenesis. AOP framework development included consideration of fiber physicochemical properties, respiratory deposition and clearance patterns, biosolubility, and biopersistence, as well as cellular, organ, and organism responses. Available in vitro bioassays and methods gaps were evaluated for their purpose in informing hazard along the AOP network. Data on SVF biosolubility, biopersistence, and in vitro/in vivo health effects were integrated in the fiber AOP framework for consideration of NAMs needs for SVF hazard assessment. Results: Available data support that fiber AOPs begin with fiber physicochemical characteristics which influence fiber exposure and biosolublity and subsequent key initiating events are dependent on fiber biopersistence and reactivity. Key cellular events of pathogenic fibers include oxidative stress, chronic inflammation, and epithelial/fibroblast proliferation and differentiation, which ultimately lead to hyperplasia, metaplasia, and fibrosis/tumor formation. Available in vitro models (e.g., single-, multi-cellular, organ system) provide promising NAMs tools to evaluate these intermediate key events. However, data on SVFs demonstrate that in vitro biosolubility is a reasonable predictor for downstream events of in vivo biopersistence and biological effects. In vitro SVF fiber dissolution rates greater than 100 ng/cm2/hr (glass fibers in pH 7 and stone fibers in pH 4.5) and in vivo SVF fiber clearance half-life less than 40 or 50 days were not associated with fibrosis or tumors in animals. Long (fiber lengths >20 µm) biodurable and biopersistent fibers exceeding these fiber dissolution and clearance thresholds may pose a risk of fibrosis and cancer. Conclusions: In vitro fiber dissolution assays provide a promising avenue and potentially powerful tool to predict in vivo SVF fiber biopersistence, hazard, and health risk. NAMs for fibers (including SVFs) may involve a multi-factor in vitro approach leveraging in vitro dissolution data in complement with cellular- and tissue- based in vitro assays to predict health risk.