Selection of the Most Suitable Source Analogue for 2,3-Benzofluorene Using Read-Across Methodology to Support Derivation of Human Health Toxicity Values
Background and Purpose: Chemical hazard assessments derive human health toxicity values for use in the Superfund Program. Toxicity values are derived from a review of the relevant scientific literature using U.S. EPA methods, sources of data, and guidance for value derivation. In some instances, no useful human or animal toxicity data are available for the chemical under evaluation and read-across assessments are attempted. 2,3-Benzofluorene is a polycyclic aromatic hydrocarbon (PAH). Although not produced commercially, 2,3-benzofluorene is formed during the incomplete combustion or pyrolysis of organic matter such as wood and fuel. PAHs, including 2,3-benzofluorene, are also generated as byproducts of industrial processes, such as coal and petroleum refining, and the production of iron, steel, and aluminum. The chemical hazard assessment of 2,3-benzofluorene evaluated the feasibility of deriving provisional oral and inhalation toxicity values.
Methods: Literature searches were conducted to identify studies relevant to the derivation of provisional toxicity values for 2,3-benzofluorene. Repeated-dose, short-term, subchronic, chronic, and reproductive/ developmental toxicity studies were considered relevant study designs to determine if data were suitable for derivation of provisional toxicity values using traditional methods. Because adequate data were not located, an alternative analogue approach was used to identify candidate analogues that could be used to derive screening-level oral or inhalation toxicity values. Structural analogues were initially identified using automated screening tools (e.g., ChemID Plus, CompTox Chemicals Dashboard, OECD Toolbox) and then refined by an experienced chemist based on known or expected structure-toxicity relationships, reactivity, and metabolic pathways. Metabolic analogues (metabolites and metabolic precursors) were identified from metabolism simulators and targeted literature searches. Toxicity/mechanistic/mode-of-action (MOA) analogues were identified from in vivo toxicity data and in vitro mechanistic data (e.g., bioactivity data) for 2,3-benzofluorene. The availability of toxicity values from authoritative sources was determined for the candidate analogues. Candidate analogues with available toxicity values were evaluated across three similarity domains (structural/physicochemical, metabolic/toxicokinetic, and toxicodynamic/MOA) to determine the most suitable source analogue for 2,3-benzofluorene.
Conclusions: Fluorene was selected as the source analogue for the derivation of screening oral toxicity values for 2,3¿benzoflourene. The adoption of oral points-of-departure (PODs) for fluorene to support the development of screening p-RfDs for 2,3-benzofluorene is reasonably expected to be protective of effects resulting from oral exposure to 2,3-benzofluorene.