Non-linear model analysis of the relationship between cholinesterase activity in rats exposed to 2, 2-dichlorovinyl dimethylphosphate (dichlorvos) and its metabolite concentrations in urine

• Published in: Toxicology (Amsterdam) Vol. 450; p. 152679
• Main Authors: Sato, Hirotaka, Ito, Yuki, Hanai, Chinami, Nishimura, Masaya, Ueyama, Jun, Kamijima, Michihiro
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.02.2021
• Subjects: Animals; Benchmark dose; Brain - drug effects; Brain - metabolism; Cholinesterase Inhibitors - toxicity; Cholinesterases - metabolism; Dichlorvos; Dichlorvos - toxicity; Gas chromatography-mass spectrometry; Guidance value; Male; Nonlinear Dynamics; Organophosphate pesticide; Organophosphorus Compounds - urine; Random Allocation; Rats; Rats, Wistar; Urinary metabolite; LOD; AChE; ChE; GC–MS; BBB; DDVP; BMR; DMP; Organophosphate pesticide; Urinary metabolite; IS; Gas chromatography-mass spectrometry; Guidance value; LOQ; OPs; LOAEL; NOAEL; BMD; Dichlorvos; DAPs; Benchmark dose
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2021.152679

•Urinary organophosphate metabolites have no health-based guidance values.•Dimethylphosphate (DMP) was quantified in urine of dichlorvos-administered rats.•Cholinesterase (ChE) activities in red blood cells, plasma, and brain were measured.•DMP concentrations in urine equivalent to 20 % ChE inhibitions were estimated.•A novel guidance value for urinary metabolite of dichlorvos was suggested. Urinary dialkylphosphates (DAPs) are measured to assess exposure to organophosphorus pesticides (OPs), but they are common metabolites of OPs and not specific indices for individual agents. Biomonitoring (BM) of urinary DAPs has been widely adopted as an assessment of individual exposure in general environments, however, guidance values for DAPs based on health effects have yet to be established. The present study aimed to clarify the relationship between the amount of urinary dimethylphosphate (DMP), a metabolite of dichlorvos (DDVP), and the inhibition of cholinesterase (ChE) activity in rats exposed to DDVP. The relationship was analyzed using a nonlinear model analysis, and the excretion level of urinary DMP equivalent to ChE 20 % inhibition (EL20) and the lower limit of the 95 % confidence interval of EL20 (ELL20) were estimated. EL20 and ELL20 (mg/24 h urine) of brain, erythrocyte, and plasma ChE activities after 10-day administration of DDVP were 0.21 and 0.15, 0.11 and 0.06, and 0.23 and 0.09, respectively. Extrapolating ELL20 of the brain ChE to humans, the range of 24 h urinary DMP concentration according to the 20 % inhibition of cholinesterase activity was estimated to be 20.5–30.8 mg/l. In conclusion, the amount of urinary DMP as ELL20 for DDVP exposure was identified and could probably be used as a novel index for the assessment of risk from OP exposure. Further studies are needed to clarify the ELL20 s derived from OPs other than DDVP, for informing efforts to establish guidance values of urinary OP metabolites that should prevent neurotoxicity.