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ABSTRACT:Deltamethrin (DLM) is a relatively potent and widely used pyrethroid insecticide. Inefficient detoxification has been proposed to be the primary reason for the greater sensitivity of immature rats to the acute neurotoxicity of DLM. The objective of this study was to test this hypothesis by characterizing the age dependence of DLM metabolism in vitro, as well as toxic signs and blood levels of the neurotoxic parent compound following administration of 10

The toxicity of carbon tetrachloride (CCl 4 ) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl 4 was rhythmic and coincided in time with maximum susceptibility to CCl 4 hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl 4 metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl 4 /kg at 2-to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl 4 near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of 14 CCl 4 /metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl 4 . Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl 4 . Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl 4 -induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl 4 . These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl 4 chronotoxicity in rats.Many physiological and biochemical processes in laboratory animals and humans have been found to vary rhythmically over a 24-h period (i.e., to exhibit a circadian or diurnal rhythm). Rhythms are considered as sequences of biological events, repeating themselves in the same order and at the same intervals. Temporal differences in drug action and toxicity have been recognized for over 50 years in humans and in laboratory animals. A number of cyclic physiological processes can affect the absorption, distribution, metabolism, and elimination of drugs and other chemicals (Labrecque and Belanger, 1991).The chronotoxicity of solvents and other industrial chemicals has received relatively little attention. Volatile organic compounds (VOCs) are a class of solvents to which many people are exposed occupationally and environmentally. Early studies of chloroform (Lavigne et al., 1983), carbon tetrachloride (CCl 4 ) (Harris and Anders, 1980;Bruckner et al., 1984), and 1,1-dichloroethylene (Jaeger et al., 1973) revealed circadian rhythms in susceptibility of rats to liver damage by the chemicals. Some of the investigators speculated that periods of enhanced susceptibility might be due to cyclic increases in metabolic activation of the VOCs. Tempora...

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The objective of this research was to examine the time- and dose- dependent disturbances in the hypothalamic-pituitary-thyroid (HPT) axis of adult male rats administered a potent coplanar (non-ortho) PCB, 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Adult male Sprague-Dawley rats were administered a single oral bolus dose of 0, 7.5, 75, or 275 microg PCB 126/kg bw dissolved in corn oil. The rats were sacrificed periodically over 22 days. The 7.5-microg/kg dose induced hepatic ethoxyresorufin-O-deethylation EROD activity, but no changes were observed in hepatic uridine diphosphate glucuronyl transferases (UDPGTs) activity or serum TSH, T4, or fT4 concentrations. The two highest doses caused a modest decline in weight gain, induced hepatic EROD and UDPGT activities, increased serum TSH concentrations, and decreased serum T4 and fT4 concentrations. The amount of thyroxine glucuronide formed daily (pM/mg protein) increased linearly with the area-under-the-concentration-curve (AUCC) for PCB 126 in liver (microg/kg/day) and then slowed at the 275-microg/kg PCB 126 dose. Perturbations in the HPT axis were nonlinear with respect to PCB 126 dosing. As expected, an inverse relationship between the AUCC for serum T4 (microg/dl/day) and the AUCC for serum TSH (ng/dl/day) was observed; however, the relationship was highly nonlinear. These data support a mode of action for PCB 126 involving induction of hepatic UDPGTs by the aryl hydrocarbon receptor AhR. However, the dose-response characteristics of the HPT axis are nonlinear and complex, requiring sophisticated tools, such as PBPK models, to characterize dose response.

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