Data derived Extrapolation Factors for developmental toxicity: A preliminary research case study with...

Guidelines of the United States Environmental Protection Agency (EPA, 1991) and the International Programme on Chemical Safety (IPCS, 2005) suggest two different default positions for dosimetric extrapolation from experimental animals to humans when the dosimetry of the critical effect is not known. The default position of EPA (1991) for developmental toxicity is to use peak concentration (or Cmax) for this dosimetric extrapolation. In contrast, IPCS (2005, page 39) states its default position for dosimetric choice in the absence of data is to use the area under the curve (or AUC). The choice of the appropriate dose metric is important in the development of either a Chemical Specific Adjustment Factor (CSAF) of IPCS (2005) or a Data Derived Extrapolation Factor (DDEF) of EPA (2014). This research shows the derivation of a DDEF for developmental toxicity for perfluorooctanoate (PFOA), a chemical of current interest. Here, identification of the appropriate dosimetric adjustment from a review of developmental effects identified by EPA (2016) is attempted. Although some of these effects appear to be related to Cmax, most appear to be related to the average concentration or its AUC, but only during the critical period of development for a particular effect. A comparison was made of kinetic data from PFOA exposure in mice with newly available and carefully monitored kinetic data in humans after up to 36 weeks of PFOA exposure in a phase 1 clinical trial by Elcombe et al. (2013). Using the average concentration during the various exposure windows of concern, the DDEF for PFOA was determined to be 1.3 or 14. These values are significantly different than comparable extrapolations by several other authorities based on differences in PFOA half-life among species. Although current population exposures to PFOA are generally much lower than both the experimental animal data and the clinical human study, the development of these DDEFs is consistent with current guidelines of both EPA (2014) and IPCS (2005).