Human and Experimental Toxicology
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Skin irritation testing in man for hazard assessment — evaluation of four patch systems 1 The limitations of the Draize rabbit skin irritation test for hazard evaluation for man are widely documented. Nevertheless it remains the prescribed method for deter mining acute skin irritation hazard. 2 While the use of human testing for risk assessment of irritants is well established, the use of predictive testing in man for hazard identification has not been explored widely, and this is the object of the research programme. 3 The experiment described in this report evaluates the sensitivity of four patch testing systems (Finn chamber, Hill Top patch, Van der Bend chamber, and Webril patch) using a total of six irritant substances. 4 Following preliminary range-finding experiments, test materials were applied to the upper outer arm for up to 4 h. Assessments were performed immediately after patch removal and at 1, 24, 48 and 72 h. 5 Webril and Hill Top patches generated the greatest lev els of response, although responses with Finn and Van der Bend were observed. Hill Top patches are recom mended for future development work. 6 The use of very small preliminary panels to predict the effects in larger panels using different volunteers was only of limited value as each volunteer was found to have different irritant thresholds.
Human and Experimental Toxicology - Tập 14 Số 9 - Trang 729-734 - 1995
Relationship of dose intensity to the induction of palmar-plantar erythrodysesthia by pegylated liposomal doxorubicin in dogs 1 The multiple dose pharmacokinetics of pegylated liposomal doxorubicin (PL-DOX), known as DOXIL® (US) and CAELYX® (EU), was characterized in dogs and a pharmacokinetic/pharmacodynamic model to identify a relationship between drug exposure and the probability of observing treatment-related palmarplantar erythrodysesthesia (PPE) was developed. 2 Twenty dogs were assigned to PL-DOX groups (2/sex/ group) that received intravenous PL-DOX doses of 0.5 mg/kg q1, 2, or 4 weeks; 1.0 mg/kg q2weeks; or 1.5 mg/kg q4weeks for 12 weeks. Blood was collected for HPLC analysis of doxorubicin concentration pre-dose and periodically up to 120 h after dosing three times during treatment. 3 Plasma drug concentration was modeled using iterative 2-stage analysis. Dermal lesions (PPE) were scored twice weekly for six regions of each dog using a 0-6 severity scale; maximum severity was 36. PPE score data were modeled using an approach in which the% probability of PPE was related to a hypothetical effect site by a series of Hill-type functions. 4 Pharmacokinetics were best modeled as a one-compartment open model. Vss (ml/kg), CLt (ml/hr/kg) and half-life (h) were 44.1, 1.39 and 23.1, respectively. Cmax increased linearly with dose. CLt decreased with repeated doses. 5 A two-compartment pharmacodynamic model, which correctly predicted 97% of the observed lesion severity, was developed to establish the relationship of lesion severity to dose intensity (a measure of drug exposure incorporating the effect of both dose level and dosing frequency, which can be expressed in units of mg/kg/week). The model demonstrated that maximal PPE was positively correlated with dose intensity, the major factor that affects the incidence and severity of dermal lesions. 6 The model can be used to predict acceptable dose intensities in humans utilizing body surface area conversion factors and comparative AUCs for dogs and humans. It predicts that a dose intensity of 10-12.5 mg/m2 of PL-DOX will be well tolerated in patients. The results of recent clinical studies are consistent with this prediction.
Human and Experimental Toxicology - Tập 18 Số 1 - Trang 17-26 - 1999
Lipid peroxidation as a possible secondary mechanism of sterigmatocystin toxicity Sterigmatocystin (Stg), a major secondary metabolite of Aspergillus versicolor and A. nidulans, is the precursor of aflatoxin B1 In this study, male albino rats were treated with Stg-contaminated diet for 30 days, resulting in reduced levels of glutathione, ascorbic acid, and tocopherol. The activity of catalase in liver was reduced, whereas an increase in the activities of superoxide dismutase and glutathione peroxidase was observed. The levels of cytochrome P450 , cytochrome b 5, cyto-chrome b 5 reductase, cytochrome c reductase, hydroxyl radical, and hydrogen peroxide formation significantly increased in the Stg-treated rat liver microsomes. Hepatic parenchymal cell injury, necrosis, and Kupffer cells proliferation were noticed in histological sections of liver from animals treated with Stg. Overall results suggest that generation of free radicals imposes depletion of antioxidants. This led to enhanced lipid peroxidation. The observed elevation of hepatic thiobarbituric acid reactive substances appears to originate mainly from the damaged Kupffer cells. As a result, elevated levels of serum marker enzymes were also observed.
Human and Experimental Toxicology - Tập 20 Số 8 - Trang 398-403 - 2001
Karyomegaly of tubular cells as early stage marker of the nephrotoxicity induced by ochratoxin A in rats Cases of karyomegaly were described by Sclare30 and by Mihatch31 in patients affected with tubular-interstitial nephropathy. The Karyomegalic cells showed enlarged nuclei with accumulation of genetic material. No aetiology was suggested. Our study of rats experimentally intoxicated by ochratoxin A, a well-known nephrotoxic compound, indicates the presence of karyomegaly with alteration of the tubular tissue. In control animals no karyomegalic cells were detected. These observations suggest that karyomegaly with megacytosis may be caused by the nephrotoxic ochratoxin A in the kidney. In addition abnormal mitosis together with karyomegalic cells were observed at an earlier stage of the intoxication (30 days) suggesting possible regeneration if the OTA insults are stopped. After 90 days of treatment, the degeneration increased and only karyomegalic and apoptotic-like cells were observed indicating that the regeneration no longer occurs and that the degeneration becomes irreversible.
Human and Experimental Toxicology - Tập 18 Số 6 - Trang 410-415 - 1999
Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood–testis barrier via mTOR signaling pathway Doxorubicin (DOX) is an anthracycline derivative antibiotic that still frequently used in the treatment of solid tumors and hematological malignancies. The clinical use of DOX is largely restricted due to acute and chronic renal, cardiac, hematological, and testicular toxicities. Previous studies have indicated that oxidative stress, lipid peroxidation, and apoptosis in germ cells are the main factors in DOX-induced testicular toxicity, but the entire molecular mechanisms that responsible for DOX-induced testicular damage are not yet fully understood. Fluvastatin is a cholesterol-lowering agent that acts by inhibiting hydroxylmethyl glutaryl coenzyme A, the key enzyme for cholesterol biosynthesis. In addition to its cholesterol-lowering effect, fluvastatin showed an antioxidant effect by cleaning hydroxyl and superoxide radicals and this drug could have a protective effect by acting on the mammalian target of rapamycin (mTOR) signal pathway in testicular damage caused by obesity. This study aimed to investigate the possible protective and therapeutic effects of fluvastatin on the DOX-induced testicular toxicity model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction analyses. The present study indicates that fluvastatin may have a protective and therapeutic effect by removing reactive oxygen species and by regulating the mTOR, connexin 43, and matrix metalloproteinase 9 protein and messenger ribonucleic acid expressions, which play an important role in regulating the blood–testis barrier. On the other hand, the use of fluvastatin as a protective/prophylactic agent was found to be more effective than the use of this drug for treatment. In light of this information, fluvastatin may be a candidate agent that can be used to prevent testicular toxicity observed in men receiving DOX treatment.
Human and Experimental Toxicology - Tập 38 Số 12 - Trang 1329-1343 - 2019
Thymoquinone is a protective agent that reduces the negative effects of doxorubicin in rat testis Background: Doxorubicin (DOX) is used for treatment of many cancer types. Thymoquinone (THQ) is a powerful antioxidant agent used for reducing side effects of several drugs. The aim of this study is to determine possible therapeutic effects of THQ on doxorubicin-induced testicular toxicity in rats. Methods: Rats were divided into five groups ( n = 8): control, THQ, olive oil, DOX (a single dose of 15 mg/kg intraperitoneally (i.p.) on seventh day of the experiment), and DOX + THQ (10 mg/kg THQ per day and 15 mg/kg DOX i.p. on seventh day). Animals were euthanized, and testis tissues were evaluated histopathologically. Caspase 3 and HSP90 immunostaining were performed to determine the expression levels of these proteins among groups. Terminal deoxynucleotidyl transferase 2′-deoxyuridine, 5′-triphosphate nick-end labeling method was used for evaluation of apoptotic index. Moreover, serum testosterone levels and total antioxidant status (TAS) and total oxidant status (TOS) in testicular tissue were measured by ELISA assay. Results: The DOX group had histopathological deterioration compared to the control group. There was an increase in apoptotic index, caspase 3 and HSP90 expressions in the DOX group. While TAS level of the DOX group decreased, TOS level increased when compared with the other groups. Serum testosterone levels in the DOX group decreased compared to the control group. However, there was improvement in testicular tissue in DOX + THQ group compared to the DOX group. There was a decrease in apoptotic index, caspase 3, and HSP90 expressions in DOX + THQ group compared to the DOX group. Testosterone level of DOX + THQ significantly increased compared to the DOX group. Conclusion: We suggest that THQ can be used as a protective agent to reduce the toxic effects of DOX.
Human and Experimental Toxicology - Tập 39 Số 10 - Trang 1364-1373 - 2020
Effects of DMSO on gene expression in human and rat hepatocytes Dimethyl sulfoxide (DMSO) is a very common organic solvent used for dissolving lipophilic substances, for example for in vitro cell-based assays. At the same time, DMSO is known to be cytotoxic at high concentrations. Therefore, it is important to define threshold concentrations of DMSO for cells but relevant data at the molecular level are very limited. We have focused on conducting microarray analyses of human and rat hepatocytes treated with more than 100 chemicals in attempts to identify candidate biomarker genes. In the present study, the effects of DMSO on gene expression and cytotoxicity were assessed in human cryopreserved hepatocytes and rat primary cultured hepatocytes. A cytotoxicity test with lactate dehydrogenase (LDH) activity demonstrated DMSO to be noncytotoxic up to a concentration of 2% (v/v) in both cases and there were only few effects on the gene expression profiles up to 0.5% (v/v). The observed differences from controls were considered to be of little toxicological importance, but still need to be taken into account in interpretation of findings when DMSO is used at high concentration.
Human and Experimental Toxicology - Tập 30 Số 10 - Trang 1701-1709 - 2011
Nuclear factor erythroid 2-related factor 2 rescues the oxidative stress induced by di-<i>N</i>-butylphthalate in testicular Leydig cells Aim: This study aimed to determine whether nuclear factor erythroid 2-related factor 2 antagonized the oxidative stress induced by di- N-butylphthalate (DBP) in testicular Leydig cells. Methods: Mouse TM3 testicular Leydig cells were treated with Nrf2 knockdown (KD) or overexpression in the presence and absence of DBP. Oxidative profiles were examined. Nrf2 target antioxidant genes were studied, and the effects of Nrf2 inducer sulphoraphane (SFN) were tested. Results: DBP induced intracellular oxidative stress to a similar extent with Nrf2 KD. Expression and protein levels of Nrf2 were increased together with its target genes, namely heme oxygenase 1, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 and peroxiredoxin 6, following DBP stimulation. Use of SFN not only restored the intracellular oxidative toxicity but also cell proliferation and testosterone secretion in response to DBP. Conclusion: Increased Nrf2 activity, for example, by SFN can effectively antagonize the oxidative stress in testicular Leydig cells caused by DBP.
Human and Experimental Toxicology - Tập 34 Số 2 - Trang 145-152 - 2015
Glucose uptake through translocation and activation of GLUT4 in PI3K/Akt signaling pathway by asiatic acid in diabetic rats In this study, we examined the in vivo effect and the mechanism of asiatic acid (AA) on glucose uptake in an insulin target skeletal muscle. Diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, and lipid hydroperoxides, decreased levels of insulin and antioxidants, and impairment in insulin-signaling proteins such as insulin receptor (IR), insulin receptor substrate (IRS)-1/2, phosphoinositide 3-kinase (PI3K), Akt, and glucose transporter 4 (GLUT4) proteins. Oral treatment with AA (20 mg/kg body weight) showed near-normalized levels of plasma glucose, lipid peroxidation products, and antioxidants and improved insulin, IR, IRS-1/2, PI3K, Akt, and GLUT4 proteins. These findings suggest that AA improves glucose response by increasing GLUT4 in skeletal muscle through Akt and antioxidant defense in plasma and it also improves glucose homeostasis.
Human and Experimental Toxicology - Tập 34 Số 9 - Trang 884-893 - 2015
Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning 1 In vitro studies with human erythrocyte acetylcholin esterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazi non and other OPs is characterized by slow sponta neous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly sus ceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 μg/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.
Human and Experimental Toxicology - Tập 16 Số 8 - Trang 466-472 - 1997
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