Showing papers on "Toxicity published in 2007"

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

Abstract: Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexaBDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers.

Drug-Induced Liver Injury

Abstract: Drug-induced liver injury is a frequent cause of hepatic dysfunction Reliably establishing whether the liver disease was caused by a drug requires the exclusion of other plausible causes and the search for a clinical drug signature The drug signature consists of the pattern of liver test abnormality, the duration of latency to symptomatic presentation, the presence or absence of immune-mediated hypersensitivity and the response to drug withdrawal Determination of causality also includes an evaluation of individual susceptibility to drug-induced liver injury This susceptibility is governed by both genetic and environmental factors Components of the drug signature in conjunction with certain risk factors have been incorporated into formal scoring systems that are predictive of the likelihood of drug-induced liver injury The most validated scoring system is the Roussel-Uclaf causality assessment method, which nonetheless retains certain imperfections Mitigating the potential for drug-induced liver injury is achieved by the identification of toxicity signals during clinical trials and the monitoring of liver tests in clinical practice There are three signals of liver toxicity in clinical trials: (i) a statistically significant doubling (or more) in the incidence of serum alanine aminotransferase (ALT) elevation >3 x the upper limit of normal (ULN); (ii) any incidence of serum ALT elevation >8-10 x ULN; and (iii) any incidence of serum ALT elevation >3 x ULN accompanied by a serum bilirubin elevation >2 x ULN Monitoring of liver tests in clinical practice has shown unconvincing efficacy, but where a benefit-risk analysis would favour continued therapy, monthly monitoring may have some benefit compared with no monitoring at all With rare exception, treatment of drug-induced liver injury is principally supportive Drug toxicity is the most common cause of acute liver failure, defined as a prolonged prothrombin time (international normalised ratio > or =15) and any degree of mental alteration occurring <26 weeks after the onset of illness in a patient without pre-existing cirrhosis A patient who meets these criteria must be evaluated for liver transplantation The pathogenesis of drug-induced liver injury can be examined on the basis of the two principal patterns of injury The hepatocellular pattern is characterised by a predominant rise in the level of transaminases and results from the demise of hepatocytes by means of either apoptosis or necrosis The cholestatic pattern is characterised by a predominant rise of the serum alkaline phosphatase level and usually results from injury to the bile ductular cells either directly by the drug or its metabolite, or indirectly by an adaptive immune response

Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity.

Abstract: Purpose: Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Experimental Design: Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Results: Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity ( P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity ( P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Conclusion: Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition.

Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin‐based chemotherapy for colorectal liver metastases

Abstract: BACKGROUND. The current study evaluated the effect of bevacizumab added to fluoropyrimidine-plus-oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology. METHODS. A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated. RESULTS. Bevacizumab-containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX-only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had <25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P < .01). CONCLUSIONS. In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM. Cancer 2007. © 2007 American Cancer Society.

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Abstract: The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-γ in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17–18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.

effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers.

Abstract: The inhibition of hepatic uptake transporters, such as OATP1B1, on the pharmacokinetics of atorvastatin is unknown. Here, we investigate the effect of a model hepatic transporter inhibitor, rifampin, on the kinetics of atorvastatin and its metabolites in humans. The inhibitory effect of a single rifampin dose on atorvastatin kinetics was studied in 11 healthy volunteers in a randomized, crossover study. Each subject received two 40-mg doses of atorvastatin, one on study day 1 and one on study day 8, separated by 1 week. One intravenous 30-min infusion of 600 mg rifampin was administered to each subject on either study day 1 or study day 8. Plasma concentrations of atorvastatin and metabolites were above the limits of quantitation for up to 24 h after dosing. Rifampin significantly increased the total area under the plasma concentration-time curve (AUC) of atorvastatin acid by 6.8+/-2.4-fold and that of 2-hydroxy-atorvastatin acid and 4-hydroxy-atorvastatin acid by 6.8+/-2.5- and 3.9+/-2.4-fold, respectively. The AUC values of the lactone forms of atorvastatin, 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin, were also significantly increased, but to a lower extent. An intravenous dose of rifampin substantially increased the plasma concentrations of atorvastatin and its acid and lactone metabolites. The data confirm that OATP1B transporters represent the major hepatic uptake systems for atorvastatin and its active metabolites. Inhibition of hepatic uptake may have consequences for efficacy and toxicity of drugs like atorvastatin that are mainly eliminated by the hepatobiliary system.

Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease

Abstract: Parkinson's disease (PD) has been linked to mitochondrial dysfunction and pesticide exposure. The pesticide rotenone (ROT) inhibits complex I and reproduces features of PD in animal models, suggesting that environmental agents that inhibit complex I may contribute to PD. We have previously demonstrated that ROT toxicity is dependent upon complex I inhibition and that oxidative stress is the primary mechanism of toxicity. In this study, we examined the in vitro toxicity and mechanism of action of several putative complex I inhibitors that are commonly used as pesticides. The rank order of toxicity of pesticides to neuroblastoma cells was pyridaben > rotenone > fenpyroximate > fenazaquin > tebunfenpyrad. A similar order of potency was observed for reduction of ATP levels and competition for (3)H-dihydrorotenone (DHR) binding to complex I, with the exception of pyridaben (PYR). Neuroblastoma cells stably expressing the ROT-insensitive NADH dehydrogenase of Saccharomyces cerevisiae (NDI1) were resistant to these pesticides, demonstrating the requirement of complex I inhibition for toxicity. We further found that PYR was a more potent inhibitor of mitochondrial respiration and caused more oxidative damage than ROT. The oxidative damage could be attenuated by NDI1 or by the antioxidants alpha-tocopherol and coenzyme Q(10). PYR was also highly toxic to midbrain organotypic slices. These data demonstrate that, in addition to ROT, several commercially used pesticides directly inhibit complex I, cause oxidative damage, and suggest that further study is warranted into environmental agents that inhibit complex I for their potential role in PD.

Comparative pulmonary toxicity assessments of C60 water suspensions in rats: few differences in fullerene toxicity in vivo in contrast to in vitro profiles.

Abstract: It has previously been reported that the in vitro cytotoxic effects of water-soluble fullerene species are a sensitive function of their surface derivatization status. In a recent study, it was reported that doses of an aggregated form of underivatized C60, termed nano-C60, were 3−4 orders of magnitude more toxic to human dermal fibroblasts, lung epithelial cells, and normal human astrocytes when compared to identical exposures of these cell types to a fully derivatized, highly water-soluble derivative, C60(OH)24. Accordingly, the aim of this study was to test and validate these in vitro findings by comparing the in vivo pulmonary toxicity effects in rats of intratracheally instilled nano-C60 and C60(OH)24. In two combined studies, groups of rats were instilled with doses of either 0.2, 0.4, 1.5, or 3.0 mg/kg of nano-C60, C60(OH)24, or α-quartz particle types using Milli-Q water as the vehicle. Subsequently, the lungs of vehicle and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fl...

The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction.

Abstract: Mercury, cadmium, and other heavy metals have a high affinity for sulfhydryl (-SH) groups, inactivating numerous enzymatic reactions, amino acids, and sulfur-containing antioxidants (NAC, ALA, GSH), with subsequent decreased oxidant defense and increased oxidative stress. Both bind to metallothionein and substitute for zinc, copper, and other trace metals reducing the effectiveness of metalloenzymes. Mercury induces mitochondrial dysfunction with reduction in ATP, depletion of glutathione, and increased lipid peroxidation; increased oxidative stress is common. Selenium antagonizes mercury toxicity. The overall vascular effects of mercury include oxidative stress, inflammation, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, immune dysfunction, and mitochondrial dysfunction. The clinical consequences of mercury toxicity include hypertension, CHD, MI, increased carotid IMT and obstruction, CVA, generalized atherosclerosis, and renal dysfunction with proteinuria. Pathological, biochemical, and functional medicine correlations are significant and logical. Mercury diminishes the protective effect of fish and omega-3 fatty acids. Mercury, cadmium, and other heavy metals inactivate COMT, which increases serum and urinary epinephrine, norepinephrine, and dopamine. This effect will increase blood pressure and may be a clinical clue to heavy metal toxicity. Cadmium concentrates in the kidney, particularly inducing proteinuria and renal dysfunction; it is associated with hypertension, but less so with CHD. Renal cadmium reduces CYP4A11 and PPARs, which may be related to hypertension, sodium retention, glucose intolerance, dyslipidemia, and zinc deficiency. Dietary calcium may mitigate some of the toxicity of cadmium. Heavy metal toxicity, especially mercury and cadmium, should be evaluated in any patient with hypertension, CHD, or other vascular disease. Specific testing for acute and chronic toxicity and total body burden using hair, toenail, urine, serum, etc. with baseline and provoked evaluation should be done.

Surgical applications of cyanoacrylate adhesives: a review of toxicity.

Abstract: Cyanoacrylate (CA) and its homologues have a variety of medical and commercial applications as biological adhesives and sealants. Homologues of CA are being widely promoted in surgery as a tissue adhesive to replace traditional suturing techniques. Potential benefits of using CA adhesives include better cosmetic results, more rapid wound closure, and perhaps most significantly, the potential for significant reductions in percutaneous injuries from suture needles, which would in turn also reduce the risk of transmission of infectious diseases. Nevertheless, certain concerns have been raised regarding the potential toxicity of CA within patients, as well as among health professionals who are occupationally exposed when using CA compounds. Reported toxicity of CA in the workplace may result in dermatological, allergic and respiratory conditions. To help reduce the occupational burden, therefore, medical staff using CA adhesives should avoid direct contact with the compound and use appropriate personal protective measures at all times. Maintaining higher levels of humidity, optimizing room ventilation and using special air conditioning filters in surgical suites and operating theatres may also be useful in minimizing the exposure to volatile CA adhesives.

The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale.

Abstract: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.

Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma.

Abstract: Purpose To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma. Patients and Methods One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease. Results Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall c...

Acute toxicity studies and determination of median lethal dose

Abstract: Whenever an investigator administers a chemical substance to a biological system, different types of interactions can occur and a series of dose-related responses result. In most cases these responses are desired and useful, but there are a number of other effects which are not advantageous. These may or may not be harmful to the patients. The types of toxicity tests which are routinely performed by pharmaceutical manufactures in the investigation of a new drug involve acute, sub-acute and chronic toxicity. Acute toxicity is involved in estimation of LD 50 (the dose which has proved to be lethal (causing death) to 50% of the tested group of animals). Determination of acute oral toxicity is usually an initial screening step in the assessment and evaluation of the toxic characteristics of all compounds. This article reviews the methods so far utilized for the determination of median lethal dose (LD 50 ) and the new changes which could be made. This has to go through the entire process of validation with different categories of substances before its final acceptance by regulatory bodies.

Developmental toxicity in zebrafish (Danio rerio) embryos after exposure to manufactured nanomaterials: buckminsterfullerene aggregates (nC60) and fullerol.

Abstract: The present paper summarizes, to our knowledge, the first study regarding the developmental toxicity of stable buckminsterfullerene aggregates suspended in water (nC60) using zebrafish (Danio rerio) as a vertebrate model. Zebrafish embryo survival, hatching rate, heartbeat, and pericardial edema were noted and described within 96 h of exposure. Fullerol (a hydroxylated C60 derivative, C60(OH)16-18) at 50 mg/L did not exert toxicity to zebrafish embryos. In contrast, nC60 at 1.5 mg/L delayed zebrafish embryo and larval development, decreased survival and hatching rates, and caused pericardial edema. Toxicity was mitigated by adding an antioxidant (glutathione), which suggests that a free radical-induced mechanism or another form of oxidative stress played a role in developmental toxicity.

Antibiotics for local delivery systems cause skeletal cell toxicity in vitro.

Abstract: Antibiotic concentrations associated with antibiotic bone cements may cause skeletal cell toxicity and prevent fracture healing. We investigated toxicity effects of dose and treatment time after exposure to three antibiotics commonly used in orthopaedic local drug delivery systems. We hypothesized a threshold exists for toxicity of osteoblasts and chondrocytes after treatment with ciprofloxacin, vancomycin, or tobramycin. To test this hypothesis, we first determined whether treatment with antibiotics caused differences in cellular morphology. Cells exposed to ciprofloxacin showed considerable changes in spread, cell membrane, and extensions. We next asked what dosage of antibiotic would cause reductions in osteoblast and chondrocyte cell numbers. Ciprofloxacin at a dose greater than 100 microg/mL and vancomycin and tobramycin at doses greater than 2000 microg/mL severely decreased cellular proliferation. Finally, we questioned whether observed decreases in cell numbers were the result of increased cellular toxicity or senescence. Released lactate dehydrogenase ratios were severely increased in osteoblasts. These data suggest the balance between the targeted microbicidal effects and host cellular toxicity is critical for skeletal cell survival and function.