RESUMO
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 0.01 or 0.1 mg paraquat dichloride/kg bw, plasma PQ concentration-time profiles were dose-proportional. Excretion up to 48 h (predominantly urinary) was 82.9%, with ca. 10% remaining unexcreted. In vitro blood binding was similar across Cynomolgus monkeys, humans and rat. Our PBPK model for the rat, mouse and dog, employing a single set of PQ-specific parameters, was scaled to Cynomolgus monkeys and well represented the measured plasma concentration-time profiles over 14 days. Addition of a cartilage compartment to the model better captured the percent remaining in the monkeys at 48 h, whilst having negligible effect on model predictions for the other species. The PBPK model performed well for all four species, demonstrating there is little difference in PQ kinetics between non-primates and primates enabling a more confident extrapolation to humans. Scaling of the PBPK model to humans, with addition of a human-specific dermal submodel based on in vitro human dermal absorption data, provides a valuable tool that could be employed in defining internal dosimetry to complement human health risk assessments.
Assuntos
Herbicidas/farmacocinética , Modelos Biológicos , Paraquat/farmacocinética , Animais , Simulação por Computador , Herbicidas/administração & dosagem , Herbicidas/sangue , Herbicidas/toxicidade , Humanos , Infusões Intravenosas , Eliminação Intestinal , Macaca fascicularis , Paraquat/administração & dosagem , Paraquat/sangue , Paraquat/toxicidade , Ratos , Eliminação Renal , Medição de Risco , Absorção Cutânea , Especificidade da Espécie , Distribuição Tecidual , ToxicocinéticaRESUMO
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. Simulations with this preliminary model were then used to identify key data gaps and to design a new blood binding study to reduce uncertainty in critical aspects of the model. The new data provided evidence to support the model structure, and its predictive performance was then assessed against dog and rat datasets not used in model development. The PQ-specific model parameters are the same for all three species, with only the physiological parameters varying between species. This consistency across species provides a strong basis for extrapolation to other species, as demonstrated here for the dog. The model enables a wide range of PQ data to be linked together to provide a broad understanding of PQ pharmacokinetics in rodents and the dog, showing that the key aspects of PQ kinetics in these species are understood and adequately encapsulated within the model.
Assuntos
Herbicidas/farmacocinética , Modelos Biológicos , Paraquat/farmacocinética , Animais , Simulação por Computador , Cães , Herbicidas/sangue , Herbicidas/toxicidade , Eliminação Intestinal , Camundongos , Paraquat/sangue , Paraquat/toxicidade , Ligação Proteica , Ratos , Eliminação Renal , Medição de Risco , Especificidade da Espécie , Distribuição Tecidual , ToxicocinéticaRESUMO
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. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Guanidina/análogos & derivados , Inseticidas/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Guanidina/toxicidade , Guanidinas/toxicidade , Humanos , Imidazóis/toxicidade , Insetos/efeitos dos fármacos , Neonicotinoides , Nitrocompostos/toxicidade , Oxazinas/toxicidade , Piridinas/toxicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Nicotínicos/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Medição de Risco , Tiametoxam , Tiazinas/toxicidade , Tiazóis/toxicidade , Estados Unidos , United States Environmental Protection AgencyRESUMO
Male and female C57BL/6J mice were administered diquat dibromide (DQâBr2) 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. Achieved dose levels at 62.5 ppm were 6.4 and 7.6 mg DQ (ion)/kg bw/day for males and females, respectively. A separate group of mice was administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ip as a positive control. The comparative effects of DQ and MPTP on the substantia nigra pars compacta (SNpc) and/or striatum were assessed using neurochemical, neuropathological and stereological endpoints. Morphological and stereological assessments were performed by investigators who were "blinded" to dose group. DQ had no effect on striatal dopamine concentration or dopamine turnover. There was no evidence of neuronal degeneration, astrocytic or microglial activation, or a reduction in the number of tyrosine hydroxylase positive (TH(+)) neurons in the SNpc or neuronal processes in the striatum of DQ-treated mice. These results are consistent with the rapid clearance of DQ from the brain following a single dose of radiolabeled DQ. In contrast, MPTP-treated mice exhibited decreased striatal dopamine concentration, reduced numbers of TH(+) neurons in the SNpc, and neuropathological changes, including neuronal necrosis, as well as astrocytic and microglial activation in the striatum and SNpc.
Assuntos
Encéfalo/efeitos dos fármacos , Diquat/toxicidade , Herbicidas/toxicidade , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Dieta , Diquat/sangue , Diquat/farmacocinética , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Herbicidas/sangue , Herbicidas/farmacocinética , Ácido Homovanílico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Testes de Toxicidade SubcrônicaRESUMO
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. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators 'blinded' to the origin of the tissue. Neither dose of PQ·Cl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH(+)) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH(+) neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQ·Cl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Herbicidas/toxicidade , Paraquat/toxicidade , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Feminino , Herbicidas/administração & dosagem , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Paraquat/administração & dosagem , Fatores Sexuais , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
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. Incorporating these tools into the study plan for a new agrochemical or drug during development offers a promising alternative to the traditional need to conduct later, specialized MOA studies after the results of chronic bioassays are known.
Assuntos
Anilidas/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Fígado/efeitos dos fármacos , Receptor de Pregnano X/genética , Pirazóis/toxicidade , Receptores Citoplasmáticos e Nucleares/genética , Ativação Transcricional/efeitos dos fármacos , Anilidas/sangue , Animais , Receptor Constitutivo de Androstano , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos Endogâmicos , Cultura Primária de Células , Pirazóis/sangue , Ratos Wistar , Especificidade da Espécie , Toxicogenética , ToxicocinéticaRESUMO
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). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
Assuntos
Carcinógenos , Glicina/análogos & derivados , Hipoglicemiantes/toxicidade , Oxazóis/toxicidade , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Glicina/farmacocinética , Glicina/toxicidade , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Neoplasias/patologia , Oxazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , UrináliseRESUMO
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. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Intoxicação por MPTP/patologia , Microglia/efeitos dos fármacos , Paraquat/toxicidade , Parte Compacta da Substância Negra/citologia , Animais , Peso Corporal/efeitos dos fármacos , Contagem de Células , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/patologia , Parte Compacta da Substância Negra/patologia , Análise de Sobrevida , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
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. PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum. There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc). There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH(+)) neurons. There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays. Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168 h after 1, 2 or 3 doses of PQ. In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 10mg/kg/dose×4 doses, 2 h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing. The number of TH(+) neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum. MPTP-mediated cell death was not attributed to apoptosis. MPTP activated microglia and astrocytes within 4 h of the last dose, reaching a peak within 48 h. The microglial response ended by 96 h in the SNpc, but the astrocytic response continued through 168 h in the striatum. These results bring into question previous published stereological studies that report loss of TH(+) neurons in the SNpc of PQ-treated mice. This study also suggests that even if the reduction in TH(+) neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum.