Integration of paraquat pharmacokinetic data across species using PBPK modelling.

Paraquat dichloride (PQ) is a non-selective herbicide which has been the subject of numerous toxicology studies over more than 50 years. This paper describes the development of a physiologically-based pharmacokinetic (PBPK) model of PQ kinetics for the rat, mouse and dog, firstly to aid the interpretation of studies in which no kinetic measurements were made, and secondly to enable the future extension of the model to humans. Existing pharmacokinetic data were used to develop a model for the rat and mouse.

Paraquat pharmacokinetics in primates and extrapolation to humans.

By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated into a single physiologically based pharmacokinetic (PBPK) model that enables more confident extrapolation to humans. Because available data suggested there might be differences in PQ kinetics between primates and non-primates, a radiolabelled study was conducted to characterize pharmacokinetics and excretion in Cynomolgus monkeys. Following single intravenous doses of 0.

Sedaxane-Use of Nuclear Receptor Transactivation Assays, Toxicogenomics, and Toxicokinetics as Part of a Mode of Action Framework for Rodent Liver Tumors.

Experimental data demonstrate a mode of action (MOA) for liver tumors in male rats and mice treated with sedaxane that starts with activation of CAR, followed by altered expression of CAR-responsive genes, increased cell proliferation, and eventually clonal expansion of preneoplastic cells, leading to the development of altered foci and tumors. This MOA is nonrelevant to human risk assessments. Methods and results in the MOA work for sedaxane illustrate promising directions that future MOA studies may be able to employ, in the spirit of "Tox21" and reduction of in vivo animal use: (1) currently available in vitro CAR and PXR reporter assays demonstrated that sedaxane is a direct CAR activator in mice and rats, and a weak PXR activator in rats; (2) mouse liver microarray results compared with a published CAR biomarker signature (based on 83 genes) showed a clear, statistical match, and a lack of correlation to similar biomarker signatures for AhR, PPARα, and STAT5B; (3) Ki67 immunohistochemistry and zonal image analysis showed significant increases in this marker of cell proliferation in mouse liver, without the need to dose a DNA labeling agent; and (4) toxicokinetic analysis of Cmax levels of sedaxane in blood showed a marked species difference between mice and rats that helps to explain differences in sensitivity to sedaxane.

Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice.

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment.

Dietary administration of diquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.

Male and female C57BL/6J mice were administered diquat dibromide (DQ∙Br2) in their diets at concentrations of 0 (control), 12.5 and 62.5 ppm for 13 weeks to assess the potential effects of DQ on the nigrostriatal dopaminergic system.

A critical review of neonicotinoid insecticides for developmental neurotoxicity.

A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses.

Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.

Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc.

Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice.

The pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25 mg/kg/week. Approximately 0.3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks.

Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar.

The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day).

Effects of doxylamine succinate on thyroid hormone balance and enzyme induction in mice.

The effects of doxylamine (as the succinate salt) on microsomal enzyme activity and serum thyroid hormone levels were examined in B6C3F1 mice following dietary exposure for 7 or 15 days (0, 40, 375, 750, or 1500 ppm in diet, expressed as free base doxylamine). In addition, the hepatic P450 enzyme inducer sodium phenobarbital (375 ppm, expressed as free acid phenobarbital) was used as a positive control for CYP2B induction. Exposure of mice to doxylamine produced dose-related increases in liver weight at both time points.

Effect of lead exposure on patterns of food intake in weanling rats.

The reduction in growth resulting from lead (PB) exposure in weanling rats is consistent with a lowering of the biological set-point for food intake. In this study the effects of lead on the patterns of food intake were examined. For 10 days (from ages 26 to 36 days), female rats were provided with drinking water containing 250 ppm lead as the acetate (n = 6) or equivalent acetate as sodium acetate (n = 6).

The effects of chlordane exposure during pre- and postnatal periods at environmentally relevant levels on sex steroid-mediated behaviors and functions in the rat.

Technical chlordane is a mixture of four main isomers (i.e., heptachlor, cis-chlordane, trans-chlordane, and trans-non-achlor) found in meat and dairy products as well as in indoor air of houses treated for termites.

Reversibility of lead-induced depression of growth.

The overall objective of this investigation was to determine whether the growth-depressive effects of lead (Pb) are reversible. The animal model used was the female weanling rat. In Study 1, one group of animals was exposed to Pb for 10 days, a second group was exposed for an additional 21 days, and a third group of animals served as controls.

Differential effects of triethyllead on synaptosomal [3H]dopamine vs. [3H]acetylcholine and [3H]gamma-aminobutyric acid release.

In vitro exposure to tetraethyllead (Et4Pb, 10 microM) did not alter the release of [3H] dopamine (DA), [3H]acetylcholine (ACh), or [3H]gamma-aminobutyric acid (GABA) from superfused synaptosomes isolated from rat brain striatum, hippocampus, and cortex, respectively. On the other hand, a concentration-dependent increase in the spontaneous release of these transmitters was observed following exposure to triethyllead (Et3Pb, 0.1-10 microM).

Lead exposure lowers the set point for food consumption and growth in weanling rats.

Lead (Pb) depresses growth in infants and young children. Our earlier studies using a weanling rat model of Pb exposure suggest that this Pb effect is due to depression of appetite. In the present study we examined whether this depression of appetite is consistent with a down-regulation of the appetite "set point" as described using dietary manipulations following either lesions of certain hypothalamic regions or 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.

Effects of inorganic mercury on [3H]dopamine release and calcium homeostasis in rat striatal synaptosomes.

Inorganic mercury (Hg2+) in vitro increases spontaneous transmitter release from nerve terminals. The mechanisms of action are not well understood but may involve alterations in intraterminal Ca2+ dynamics. In this study we describe actions of Hg2+ in vitro on isolated mammalian CNS striatal nerve terminals (synaptosomes).

Effects of methylmercury on neurotransmitter release from rat brain synaptosomes.

Although the effects of methylmercury (MeHg) at the neuromuscular junction have been well characterized, similar studies employing CNS preparations and transmitters have been limited. We found that MeHg (0.5-5.

Effects of mercuric chloride on [3H]dopamine release from rat brain striatal synaptosomes.

Electrophysiological studies employing amphibian neuromuscular preparations have shown that mercuric chloride (HgCl2) in vitro increases both spontaneous and evoked neurotransmitter release. The present study examines the effect of HgCl2 on the release of [3H]dopamine from synaptosomes prepared from mammalian brain tissue. Mercuric chloride (3-10 microM) produces a concentration-dependent increase in spontaneous [3H]dopamine release from "purified" rat striatal synaptosomes, in both the presence and absence of extra-synaptosomal calcium.

Calcium efflux and neurotransmitter release from rat hippocampal synaptosomes exposed to lead.

The results of several studies, employing various tissue preparations, have demonstrated that in vitro Pb exposure has similar effects on the release of several different transmitter substances. Pb has been observed to attenuate depolarization-evoked release and increase spontaneous (depolarization-independent) release. The current study confirms that Pb in vitro increases the spontaneous release of [3H]acetylcholine (ACh) from superfused synaptosomes prepared from rat hippocampus.

Calcium transport, thiol status, and hepatotoxicity following N-nitrosodimethylamine exposure in mice.

The hepatotoxicant N-nitrosodimethylamine (NDMA) is presumed to exert toxicity through reactive metabolites. NDMA is similar in this respect to numerous other hepatotoxicants, for which hepatotoxicity is also associated with a rapid depletion of soluble and/or protein thiols, and an inhibition of calcium transport systems. We examined the hypothesis that hepatotoxicity for NDMA is preceded by thiol depletion and/or inhibition of calcium transport in isolated liver subcellular fractions.

Differential effects of inorganic lead and delta-aminolevulinic acid in vitro on synaptosomal gamma-aminobutyric acid release.

Several studies have shown that inorganic lead added in vitro does not alter gamma-aminobutyric acid (GABA) release from rat brain synaptosomes. The decrease in GABA release observed following chronic neonatal in vivo lead exposure has been proposed to be an indirect effect mediated by the increase in delta-aminolevulinic acid (ALA) accompanying chronic lead exposure. In the present study the effect of both lead and ALA in vitro on several aspects of [3H]GABA release from superfused rat cortical synaptosomes are examined.

Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes.

The effect of inorganic lead in vitro in several aspects of [3H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec.

A superfusion apparatus for the examination of neurotransmitter release from synaptosomes.

A superfusion apparatus for examining the release of neurotransmitter from synaptosomes is described. The apparatus provides for accurate temperature control, rapid switching and continuous gassing of superfusing buffers, short (i.e.