Chemical hazard assessment of fluorene in the provisional peer-reviewed toxicity value (PPRTV) program
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CHEMICAL HAZARD ASSESSMENT OF FLUORENE IN THE PROVISIONAL PEER-REVIEWED TOXICITY VALUE (PPRTV) PROGRAM
Background and Purpose: Provisional Peer-Reviewed Toxicity Value (PPRTV) assessments derive toxicity values for chemicals of interest in support of the U.S. EPA’s Superfund Program. The PPRTV assessment for fluorene evaluated the feasibility of deriving subchronic and chronic provisional reference doses (p-RfDs) and reference concentrations (p-RfCs) when values were not available from the Integrated Risk Information System (IRIS).
Methods: Literature searches were conducted to identify studies relevant to the derivation of provisional toxicity values for fluorene. Repeated-dose, short-term, subchronic, chronic, and reproductive/developmental toxicity studies were evaluated to determine if data were suitable for derivation of a subchronic p-RfD and subchronic or chronic p-RfCs using chemical-specific data. Structural analogues were initially identified using automated screening tools and then reviewed by an experienced chemist to refine the candidate pool 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. Toxicodynamic analogues were identified from in vivo toxicity data for fluorene and in vitro mechanistic data (e.g., bioactivity data). Availability of toxicity assessments from reliable sources (U.S. EPA IRIS and PPRTV assessments, Agency for Toxic Substances and Disease Registry [ATSDR], and California Environmental Protection Agency [CalEPA]) was determined for candidate analogues.
Results: The database of relevant studies for derivation of an oral subchronic p-RfD was limited to a published 60-day gavage study that evaluated behavioral endpoints in rats, an unpublished 13-week study that evaluated a comprehensive set of endpoints in mice, and two subchronic-to-chronic studies in rats with substantial limitations. The 60-day and 13-week studies provided dose-response data adequate for toxicity value derivation. The no-observed-adverse-effect level human equivalent dose (NOAEL[HED]) of 0.24 mg/kg-day for increased liver weight from the 60-day study was selected as the point of departure (POD). The subchronic p-RfD of 0.0008 mg/kg-day was derived by applying a composite uncertainty factor of 300 (reflecting an interspecies uncertainty factor [UFA] of 3, an intraspecies uncertainty factor [UFH] of 10, and a database uncertainty factor [UFD] of 10) to the POD. The database of inhalation studies was limited to a 14-day study that evaluated behavioral effects in rats. No subchronic or chronic toxicity studies were identified, which precluded the derivation of p-RfC values using chemical-specifc data. A read across evaluation was performed to determine if screening-level p-RfCs values could be derived. Twenty candidate analogues (7 structural, 12 metabolic, and 1 toxicodynamic) were identified. However, since none of the candidates had an inhalation toxicity assessment available, no screening-level pRfCs were derived.
Conclusions: The subchronic p-RfD value of 0.0008 mg/kg-day derived in the 2023 PPRTV assessment of fluorene was used to update the Office of Land and Emergency Management’s (OLEM’s)Regional Screening Level (RSL) tables and will support remediation at Superfund sites. Without the availability of adequate chemical-specific data for inhalation exposure to fluorene or suitable analogues with reliable toxicity assessments, the derivation of subchronic and chronic p-RfCs was not feasible.
The views expressed are those of the authors and do not necessarily reflect the views and policies of the US EPA.