Data derived extrapolation factors (DDEFs) for rat to human interspecies extrapolation for the HPPD inhibitor mesotrione

Abstract

In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a “data-derived” adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of ∼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.