Case analysis of kinetics investigations in toxicity studies of pesticides to identify the nonlinearity of internal exposure and the influences of nonlinearity on the toxicological interpretation of pesticide residue.

Abstract The nonlinearity of internal exposure to 8 pesticides was investigated in toxicity studies using kinetics to identify nonlinearity visually and to investigate the influence of nonlinearity on toxicological evaluation. Data were obtained from risk assessment reports published by the Food Safety Commission (FSCJ). Nonlinearity was defined using 2 indicators: the lowest visual inflection point (LVIP) and the second lowest visual inflection point (SVIP) of kinetics by drawing a linear distribution chart. The area under the curve and 24-h urine concentrations were stable parameters used to identify the LVIP/SVIP. The sampling timing affected the blood concentrations, and the LVIP/SVIP was detected for 6 pesticides using the parent compounds or their metabolites as analytes. The subproportional nonlinearity was significant for these pesticides. The LVIP/SVIP values were consistent in the same species up to a 1-year period, but the values showed species-specific differences in several compounds. In all compounds found to be nonlinear, apical outcomes were observed at the SVIP or above. The presence of nonlinearity was recognized by the FSCJ. The recognition influenced their judgment of no-observed-adverse-effect levels (NOAELs) for carcinogenicity or health-based guidance values, indicating the importance of appropriate kinetics to identify the nonlinearity for toxicological evaluation of pesticide residue.