Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment

Abstract

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Keywords: Dose selection; KMD; Toxicokinetics; Weight of evidence.

Fig. 1.

Simulated administered dose versus area under the curve (AUC) of plasma concentration of a hypothetical chemical and its metabolite, assuming (A) either first-order or saturable metabolism of the hypothetical chemical or (B) either first-order or saturable oral absorption of the hypothetical chemical.

Fig. 2.

Blood area under the curve (AUC) for a florpyrauxifen-benzyl acid metabolite vs. florpyrauxifen-benzyl intake from a 90-day study in rats. Individual AUC data plotted on a log-log scale for males and females. Data indicate saturation of absorption above 100 mg/kg/day.

Fig. 3.

Blood concentration of a fenpicoxamid metabolite vs. fenpicoxamid intake from a 90-day study in mice. Individual animal data plotted on a log-log scale. Data indicate saturation of absorption with increasing dose administered. Doses converted from ppm to mg/kg/day with dose group averages for males: 33, 161, 361, and 1000 mg/kg/day; and females: 46, 275, 470, and 995 mg/kg/day.

Fig. 4.

Plasma concentration (ug/g) vs. sulfoxaflor intake in mg/kg bw/day from a 90-day dietary study in mice. Individual animal data plotted on a log-log scale for males and females. Data indicate saturation of clearance with increasing dose administered in males and saturation of absorption with increasing dose administered in females.

Fig. 5.

The high dose in mg/kg/bw (mkd) used in a 90-day study, the high dose selected in the chronic/oncogenicity studies with the NOAELs as compared to the acceptable daily intake (ADI) and estimated human dietary exposures for florpyrauxifen-benzyl, fenpicoxamid, and sulfoxaflor. ADI and estimated human exposure data form EFSA conclusions (EFSA, 2014; EFSA, 2018a; EFSA, 2018b).