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Query: UMLS:C0155339 (Brown)
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Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensitivity differences across the life span. Tissue (brain, plasma, liver) levels of the N-methyl carbamate carbaryl, and its metabolite 1-naphthol, were determined and related to brain and RBC cholinesterase (ChE) inhibition in the same animals. Dose-response (3, 7.5, 15, or 22.5 mg/kg, 40-45 min postdosing) and time course (3 or 15 mg/kg at 30, 60, 120, or 240 min postdosing) of acute effects of carbaryl (oral gavage) in preweanling (postnatal day [PND] 18) and adult male Brown Norway rats from adolescence to senescence (1, 4, 12, 24 mo) were compared. At all ages there were dose-related increases in carbaryl and 1-naphthol in the dose-response study, and the time-course study showed highest carbaryl levels at 30 min postdosing. There were, however, age-related differences in that the 1- and 4-mo rats showed the lowest levels of carbaryl and 1-naphthol, and PND18 and 24-mo rats had similar, higher levels. The fastest clearance (shortest half-lives) was observed in 1- and 4-mo rats. Carbaryl levels were generally higher than 1-naphthol in brain and plasma, but in liver, 1-naphthol levels were similar to or greater than carbaryl. Brain ChE inhibition closely tracked brain carbaryl concentrations regardless of the time after dosing, but there was more variability in the relationship between RBC ChE and plasma carbaryl levels. Within-subject analyses suggested somewhat more brain ChE inhibition at lower carbaryl levels only in the PND18 rats. These findings may reflect maturation followed by decline in kinetic factors over the life span.
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PMID:Carbaryl and 1-naphthol tissue levels and related cholinesterase inhibition in male Brown Norway rats from preweaning to senescence. 2427 16

Factors impacting life stage-specific sensitivity to chemicals include toxicokinetic and toxicodynamic changes. To evaluate age-related differences in the biochemical and behavioral impacts of two typical N-methyl carbamate pesticides, we systematically compared their dose-response and time-course in preweanling (postnatal day, PND, 18) and adult male Brown Norway rats (n=9-10/dose or time) ranging from adolescence to senescence (1, 4, 12, 24 mo). Carbaryl was administered orally at 3, 7.5, 15, or 22.5mg/kg and data were collected at 40 min after dosing, or else given at 3 or 15 mg/kg and data collected at 30, 60, 120, and 240 min. Methomyl was studied only in adult and senescent rat (4, 12, 24 mo) in terms of dose-response (0.25. 0.6, 1.25, 2.5mg/kg) and time-course (1.25mg/kg at 30, 60, 120, 240 min). Motor activity as well as brain and erythrocyte (RBC) cholinesterase (ChE) activity were measured in the same animals. In the carbaryl dose-response, PND18 rats were the most sensitive to the brain ChE-inhibiting effects of carbaryl, but 12- and 24-mo rats showed more motor activity depression even at similar levels of brain ChE inhibition. We have previously reported that brain ChE inhibition, but not motor activity effects, closely tracked carbaryl tissue levels. There were no age-related differences in methomyl-induced ChE inhibition across doses, but greater motor activity depression was again observed in the 12- and 24-mo rats. Carbaryl time-course data showed that motor activity depression reached a maximum later, and recovered slower, in the 12- and 24-mo rats compared to the younger ages; slowest recovery and maximal effects were seen in the 24-mo rats. Acetylcholinesterase sensitivity (concentration-inhibition curves) was measured in vitro using control tissues from each age. Inhibitory concentrations of carbaryl were somewhat lower in PND18, 12-, and 24-mo tissues compared to 1- and 4-mo, but there were no differences with methomyl-treated tissues. Thus, in the dose-response and time-course, there were dissociations between brain ChE inhibition and the magnitude as well as recovery of motor activity changes. The explanation for this dissociation is unclear, and is likely due to early development followed by aging-related decline in both kinetic parameters and neurological responsiveness.
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PMID:Assessment of biochemical and behavioral effects of carbaryl and methomyl in Brown-Norway rats from preweaning to senescence. 2570 86