Lack of human relevance for procymidone’s developmental toxicity attributable to species difference in its kinetics and metabolism

Abstract

The agricultural fungicide procymidone can cause external genitalia abnormalities in rats but not monkeys or rabbits. To investigate the relevance of developmental findings in rats to humans, we conducted in vitro plasma protein binding studies, in vitro metabolism (biotransformation) studies using liver S9 fractions and hepatocytes, and in vivo metabolism and excretion studies using chimeric mice with humanized hepatocytes. On the basis of these results, we concluded that the metabolic and excretion profiles of procymidone in humans are similar to those in monkeys and rabbits but differ from those in rats. From the findings of this and previous studies, we judge the developmental toxicity potential of procymidone to be very low in humans.

Suspect screening and targeted analyses: Two complementary approaches to characterize human exposure to pesticides

“…Although data on the urinary excretion of pesticides are generally available in rodents, they have not or have only rarely been described in humans. For example, several authors have highlighted important differences in the metabolic pathways for procymidone between species, including humans using in vitro models and/or chimeric mice with humanized hepatocytes (Abe et al 2018;Tomigahara et al 2018). Carboxylated-procymidone was found to be a major urinary endproduct in rats.…”

Researches on the evaluation of pesticide safety in humans using a pharmacokinetic approach

“…pared among species, higher exposure (i.e., AUC and C max ) was observed in rats and rat chimeric mice whereas the exposure was rather low in rabbits, monkeys, and human chimeric mice for both procymidone and its hydroxylated metabolite. In the previous articles on procymidone metabolism in intact rats, 5) delayed T max and higher exposure to the hydroxylated metabolite were caused by the entero-hepatic circulation of its glucuronide.…”

“…14 C-Labeled procymidone was orally administered to the chimeric mice and other laboratory animals, and the plasma concentrations of procymidone and its metabolites were measured. 5,6) The pharmacokinetic parameters of chimeric mice and other laboratory animals are summarized in Table 1. When the parameters are com-Fig.…”

Toxicity of procymidone to Bombyx mori based on physiological and transcriptomic analysis

“…Procymidone is often used on many crops in China including tomato (Cai et al, 2020; H. Li, et al, 2020; T. T. Li et al, 2020), wheat (Zhou et al, 2020), and mulberry tree (Wei et al, 2016) due to its wide spectrum and high efficiency. A number of studies have shown that procymidone had toxicity to organisms (Abe et al, 2018; Lai et al, 2021; Tarui et al, 2018; Tomigahara et al; 2018, Y. Wu et al, 2018, A. Wu et al, 2021). For instance, procymidone exposure could lead to scoliosis and pericardial edema, and decreased ATPase activity in larval zebrafish (Y. Wu et al, 2018).…”