title: Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: a case study.
abstract: There is currently no standard paradigm for hazard and human risk assessment of environmental metabolites for agrochemicals. Using an actual case study, solutions to challenges faced are described and used to propose a generic concept to address risk posed by metabolites to human safety. A novel approach - built on the foundation of predicted human exposures to metabolites in various compartments (such as food and water), the threshold of toxicological concern (TTC) and the concept of comparative toxicity - was developed for environmental metabolites of a new chemical, sulfoxaflor (X11422208). The ultimate aim was to address the human safety of the metabolites with the minimum number of in vivo studies, while at the same time, ensuring that human safety would be considered addressed on a global regulatory scale. The third component, comparative toxicity, was primarily designed to determine whether the metabolites had the same or similar toxicity profiles to their parent molecule, and also to one another. The ultimate goal was to establish whether the metabolites had the potential to cause key effects - such as cancer and developmental toxicity, based on mode-of-action (MoA) studies - and to develop a relative potency factor (RPF) compared to the parent molecule. Collectively, the work presented here describes the toxicology programme developed for sulfoxaflor and its metabolites, and how it might be used to address similar future challenges aimed at determining the relevance of the metabolites from a human hazard and risk perspective. Sulfoxaflor produced eight environmental metabolites at varying concentrations in various compartments - soil, water, crops and livestock. The MoA for the primary effects of the parent molecule were elucidated in detail and a series of in silico, in vitro, and/or in vivo experiments were conducted on the environmental metabolites to assess relative potency of their toxicity profiles when compared to the parent. The primary metabolite, X11719474 found in soil, crops and, potentially, at low concentrations, in groundwater, was the most extensively studied, with genetic, acute, short-term rat and dog, rodent reproductive and developmental toxicity studies, and MoA studies conducted. These data supported that the toxicity profile for X11719474 was limited to liver effects via the same MoA as the parent and, overall, X11719474 was significantly less toxic than parent. Subsequently, the comparative toxicology programme was extended to cover all metabolites of sulfoxaflor. Based on structure (i.e., similarity of metabolite structures to one another), toxic effects in comparison with parent (i.e., consistency of the toxicity profiles and confidence in terms of ability to read across), residue compartment (e.g., crop, soil, water) and predicted level of exposure, fewer studies were required for establishing safety of these metabolites compared to X11719474. For example, for some metabolites with very low predicted environmental concentrations only genotoxicity testing was required. For some metabolites with low predicted concentrations, for example only present in liver, a TTC approach was utilized. This strategy of comparative assessment utilizing MoA data, relative potency, hazard characterization, read-across, predicted exposure and TTC provided a robust database, which minimized animal use, comprehensively assessed the hazard and human risk presented by these metabolites.
authors.affiliation: Dow AgroSciences LLC, Oxfordshire, UK. Electronic address: cterry@dow.com.
authors.forename: C
authors.initials: C
authors.lastname: Terry
authors.affiliation: Dow AgroSciences LLC, Indianapolis, Indiana, United States.
authors.forename: R J
authors.initials: RJ
authors.lastname: Rasoulpour
authors.affiliation: Dow AgroSciences LLC, Oxfordshire, UK.
authors.forename: S
authors.initials: S
authors.lastname: Knowles
authors.affiliation: Dow AgroSciences LLC, Oxfordshire, UK.
authors.forename: R
authors.initials: R
authors.lastname: Billington
mesh_terms: D016573:Agrochemicals / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D004285:Dogs; D004785:Environmental Pollutants / Q000378:metabolism* / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment / Q000379:methods
chemical_list: D016573:Agrochemicals; D004785:Environmental Pollutants
keywords: Agrochemical; Groundwater; Hazard; Metabolites; Pesticide; Plant protection products; Relative potency; Risk assessment; TTC; Threshold of toxicological concern