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Assessment of Biochemical and Behavioral Effects of Carbaryl and Methomyl in Brown-Norway Rats from Preweaning to Sensecence
Citation:
Moser, V. C., P. Phillips, AND Kathy Mcdaniel. Assessment of Biochemical and Behavioral Effects of Carbaryl and Methomyl in Brown-Norway Rats from Preweaning to Sensecence. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 331:1-13, (2015).
Impact/Purpose:
Age is considered an important determinant of susceptibility in the general population. Each major life stage (from neonates to aging adults) is characterized by differences in behaviors influencing exposure patterns (e.g., Cohen Hubal et al., 2000; Lawrie, 1998) and in physiology impacting pharmacokinetic parameters (e.g, Clewell et al., 2004; Kinirons and O'Mahony, 2004; Makri et al., 2004; Saghir et al., 2012). Taken together, these factors play a major role in determining age-specific threats to health. The bulk of this literature, however, focuses on the young end of the lifespan, but aging also produces many changes (e.g., Shi and Klotz, 2011; Weinert and Timiras, 2003). Increased susceptibility at any age could be evident as a greater sensitivity to environmental chemicals and/or slower (perhaps incomplete) recovery from acute effects. These differences can be due to toxicokinetic factors that impact tissue levels, and/or toxicodynamic factors that influence the ensuing response. A better understanding of how pesticide exposures are modulated by these age-dependent factors could inform risk decisions for populations representing all life stages.
Description:
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-l0/dose or time) ranging from adolescence to senescence (1, 4, 12, 24 mo). Carbaryl was administered orally at 3, 7.5, 15, or 22.5 mg/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, 2.5 mg/kg) and time-course (1.25 mg/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. Acetylchloinesterase 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.
