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PubMed1987

A QSAR study of the acute toxicity of some industrial organic chemicals to goldfish. Narcosis, electrophile and proelectrophile mechanisms.

1. A baseline toxicity QSAR model was derived for the 24-h LC50 to the goldfish, Carassius auratus. 2. The QSAR-predicted LC50 values for six epoxide derivatives were 2.8-985 times greater than measured. The excess toxicity of these epoxides and other compounds was ascribed to an electrophile molecular mechanism involving SN2 reaction with sulphydryl and other neucleophile groups present in enzymes and other biological macromolecules. 3. The excess toxicities of allyl alcohol and pentaerythritol triallyl ether were interpreted in terms of proelectrophile mechanisms. For the latter compound, this involves a monooxygenase-mediated free radical proton abstraction to a stable allyl radical. The allyl-free radical can undergo enzymic free radical hydroxylation to afford the corresponding acetal, which on decomposition yields the Michael acceptor electrophile acrolein.

Animals↗
PubMed2002

Biocomplexity: the post-genome challenge in ecotoxicology.

There are four crucial challenges for the environmental toxicologists in the next decade: (1) understanding the mechanisms of molecular and subcellular interactions with pollutant chemicals, including genomic and proteomic aspects; (2) the development of predictive simulation models of toxic effects on complex cellular and physiological processes; (3) linking molecular, cellular and patho-physiological 'endpoints' with higher level ecological consequences; and (4) precautionary anticipation of possible harmful impacts of novel developments in industrial processes, including biotechnology and nanotechnology. One of the major difficulties in ecotoxicology is to link harmful effects of chemical pollutants in individual animals and plants with the ecological consequences. Consequently, this obstacle has resulted in a 'knowledge-gap' for those seeking to develop policies for sustainable use of resources and environmental protection. The overall problem is: how to develop effective procedures for environmental/ecological impact and risk assessment? However, the use of diagnostic 'clinical-type' tests or 'biomarkers' has started to provide information on the health-status of populations based on relatively small samples of individuals. Also, biomarkers can now be used to begin to link processes of molecular and cellular damage through to the higher levels (i.e. prognostic capability), where they can result in reduced performance and reproductive success. Research effort to meet this challenge must be inter-disciplinary in character, since the key questions mainly involve complex interfacial problems. These include effects of physico-chemical speciation on uptake and toxicity, the toxicity of complex mixtures; and linking the impact of pollutants through the various hierarchical levels of biological organisation to ecosystem and human health. Finally, the development and use of process-based computational simulation models (i.e. 'virtual' cells, organs and animals), illustrated using an endosomal/lysosomal uptake and cell injury model, will facilitate the development of a predictive capacity for estimating risk associated with the possibility of future environmental events.

Animals↗
PubMed1997

Dopamine neurotoxicity in cortical neurons.

Dopamine (DA), at concentrations greater than 100 microM, has previously been demonstrated to be toxic to mesencephalic, striatal and dorsal root ganglion cell cultures. Pharmacological experiments suggest that DA also may play a role in the cortical neurotoxicity caused by systemic administration of N-methyl-D-aspartate receptor antagonists such as phencyclidine and MK-801. In this study, the potential toxicity of DA in primary cortical cell cultures was determined in vitro. Using calcein and ethidium homodimer fluorescence as a marker for live and dead cells, respectively, we observed that a 24 h treatment with 10-100 microM DA produced a concentration-dependent increase in the number of ethidium homodimer-labelled cells. The cell death induced by 10 microM DA was dramatically reduced by co-administration of either superoxide dismutase and catalase or deferoxamine mesylate, an iron chelator. To verify this observation, the effects of 10 microM DA on the release of cytoplasmic lactate dehydrogenase (LDH) was measured. DA increased LDH release in a manner that was inhibited by both superoxide dismutase/catalase and deferoxamine. Nomifensine potentiated the effect of DA on LDH release, suggesting a protective role for DA uptake in this system. On the other hand, neither D1 nor D2 antagonists were able to prevent DA-induced LDH release. These data suggest that relatively low concentrations of DA can be injurious to cortical neurons through a mechanism that likely involves DA autooxidation and the formation of reactive oxygen species such as superoxide anion and hydroxyl radical. This mechanism may be important in the toxic effects of psychomotor stimulants such as amphetamine. However, the failure of DA receptor antagonists to affect DA-induced injury argues that the effect of DA on cortical neurons in culture does not model the toxic effect of phencyclidine and MK-801 observed in vivo.

Animals↗
PubMed2000

Hepatocyte growth factor in renal failure: promise and reality.

Can science discover some secrets of Greek mythology? In the case of Prometheus, we can now suppose that his amazing hepatic regeneration was caused by a peptide growth factor called hepatocyte growth factor (HGF). Increasing evidence indicates that HGF acts as a multifunctional cytokine on different cell types. This review addresses the molecular mechanisms that are responsible for the pleiotropic effects of HGF. HGF binds with high affinity to its specific tyrosine kinase receptor c-met, thereby stimulating not only cell proliferation and differentiation, but also cell migration and tumorigenesis. The three fundamental principles of medicine-prevention, diagnosis, and therapy-may be benefited by the rational use of HGF. In renal tubular cells, HGF induces mitogenic and morphogenetic responses. In animal models of toxic or ischemic acute renal failure, HGF acts in a renotropic and nephroprotective manner. HGF expression is rapidly up-regulated in the remnant kidney of nephrectomized rats, inducing compensatory growth. In a mouse model of chronic renal disease, HGF inhibits the progression of tubulointerstitial fibrosis and kidney dysfunction. Increased HGF mRNA transcripts were detected in mesenchymal and tubular epithelial cells of rejecting kidney. In transplanted patients, elevated HGF levels may indicate renal rejection. When HGF is considered as a therapeutic agent in human medicine, for example, to stimulate kidney regeneration after acute injury, strategies need to be developed to stimulate cell regeneration and differentiation without an induction of tumorigenesis.

Acute Kidney Injury↗
PubMed2006

Bioavailability and toxicity of heavy metals in the presence of natural organic matter.

The effect of humic acids (HA) on the toxicity of copper, zinc and lead was investigated in this study, using the photobacterium Vibrio fischeri (Microtox test) as a test organism. The metal species and the complexation capacity of HA were predicted using model WinHumicV for speciation modeling. The toxicities of copper and lead were generally comparable, while the toxicity of zinc was lower than the ones of the other two method. The toxicity of copper decreased with the addition of HA, while the toxicity of zinc remained almost constant. The complexation of Zn with HA was low. Thus the presence of HA did not significantly influence the toxicity of Zn. For Cu and Zn, the free metal ion species showed to be basically responsible for the toxicity of these metals, while for Pb the chlorocomplexes and Pb-HA complexes contributed to the toxicity of Pb, indicating that the toxicity of heavy metals depends not only on the free metal ion species concentration but on different metal species that may be bioavailable.

Aliivibrio fischeri↗
PubMed2003

QSAR modeling with the electrotopological state indices: predicting the toxicity of organic chemicals.

A quantitative structure-activity relationship model, based on the atom-type electrotopological state (E-state) indices, for the prediction of toxicity to fathead minnow for a diverse set of 140 organic chemicals is presented. Multiple linear regression and artificial neural network techniques were employed in the modeling of experimental toxicity (-logLC(50)) values ranging from 0.85 to 6.09. For the training set of 130 organic compounds a linear regression model with r(2)=0.84 and s=0.36 was obtained with 14 atom-type E-state indices. For the test set of 10 compounds, the corresponding statistics were r(2)=0.83 and s=0.47, respectively. Neural networks gave a significant improvement using the same set of parameters, and the standard deviations were s=0.31 for the training set and s=0.30 for the test set when an artificial neural network with five neurons in the hidden layer was used. The results clearly show that accurate models can be rapidly calculated for the prediction of toxicity for a diverse set of organic chemicals using easily calculated parameters.

Animals↗
PubMed1992

Pre-clinical toxicity of IL-4: a model for studying protein therapeutics.

The purpose of this presentation was to review issues and findings in the pre-clinical development and evaluation of recombinant human protein therapeutics. Since human cytokines and lymphokines are endogenous proteins, their pre-clinical development and evaluation would seem straightforward and their toxicities minimal. Unfortunately, the pre-clinical development of this class of agents has been problematic and confounding. Some of the clinical toxicities and pharmacodynamics have been predicted by the pre-clinical evaluation and others have not. Some molecules are species specific which limits species selection for pre-clinical evaluation. Other confounding issues include: route of exposure, synergy of toxicity with other lymphokines, length of study design, immunogenicity, predictiveness of pre-clinical evaluation and iatrogenic toxicities. An approach used by SWPRD in the evaluation of this class of molecules was discussed. Insight gained during the pre-clinical and clinical development of these molecules should simplify the further development of protein therapeutics that follow. Specific studies with recombinant human interleukin-4 (rhuIL-4) were reviewed in detail as part of a pre-clinical safety evaluation. Native IL-4 has properties that exemplify many of the immune recognition-induced lymphokines and is produced principally by activated T-lymphocytes CD4+. It is a co-factor in B-cell proliferation and enhances ex vivo B-cell expansion and is believed to be a candidate for the treatment of refractory cancer based on this immune enhancement ability. rhuIL-4 is a 15,400 molecular weight cytokine produced in a yeast expression system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Biodegradation of high 4-chlorophenol concentrations in a discontinuous reactor fed with an optimally controlled influent flow rate.

This work presents the results of the application of an optimally controlled influent flow rate strategy to biodegrade, in a discontinuous reactor, high concentrations of 4-chlorophenol used as toxic compound model. The influent is fed into the reactor in such a way as to obtain the maximal degradation rate, thus avoiding the inhibition of the microorganisms. The optimal strategy was able to manage increments of toxic concentrations in the influent up to 7,000 mg 4CP/L without any problem. It was shown not only that higher concentrations of toxic could be treated, but also that a reduction in degradation time (around 52%) and in the supplied air volume was obtained.

Bacteria, Anaerobic↗
PubMedDate not supplied

QSAR model for predicting pesticide aquatic toxicity.

A hierarchical QSAR approach was applied for the prediction of acute aquatic toxicity. Chemical structures were encoded into molecular descriptors by an automated, seamless procedure available within the OpenMolGRID system. Finally, various linear and nonlinear regression techniques were used to obtain stable and thoroughly validated QSARs. The final model was developed by a counterpropagation neural network coupled with genetic algorithms for variable selection. The proposed QSAR is consistent with McFarland's principle for biological activity and makes use of seven molecular descriptors, namely HACA-2, HOMO-LUMO energy gap, Kier and Hall index, HA dependent HDSA-1, BETA polarizability, FHBCA fractional HBSA, and LogP. The model was extensively tested by the test set (R2= 0.79), the y-scrambling test, and sensitivity/stability tests.

Algorithms↗
PubMed2006

Toxic acute liver failure treatment by isolated hepatocytes allotransplantation in experimental.

Acute liver failure treatment nowadays is a common problem in modern hepatology, despite of well studied pathogenesis and treatment modalities, lethality of the disease is still high, and in 21 century in the world's best clinics it accounts to 70-80%. For uptake of isolated hepatocytes we uses the fermental-mechanical method modified by Korukhov (1983) for the treatment of acute liver failure by hepatocyte allotransplantation and to stimulate liver reparative regeneration processes, which gives a chance to liver for the function restoration by replacement of injured hepatocytes with transplanted liver cells. We provide experiments on 45 white laboratory Vistar line rats (150-200gr) which were kept on standard environment, animals were divided into three equal groups: I group (n=20) was served as a control group, in which we provide acute liver failure modelling, by toxic agent (carbontetrachloride CCL4 ) treatment by naso-gastric tube, After acute liver failure modelling, in the II group (n=20) of animals we were conducting liver cell transplantation, III group (n=5) animals were served as donors for isolated hepatocyte uptake. Cell ultrastructure element proliferation clearly seen by morphological evaluation and animals which have acute liver failure had a chance for survival and it may be concluded that our proposed method can be the curative treatment method of acute liver failure in experiment.

Animals↗
PubMed2001

A model for absorption of low-volatile toxicants by the airway mucosa.

Inhaled chemical toxicants can damage the lungs during two phases: (1) the first-pass phase, in which toxicants are initially absorbed through the air/blood barrier, or (2) the circulation-transport phase, in which toxicants are transported back through the lungs with the circulating blood. While respiratory-tract dosimetry for inhaled toxicants is relatively easy to evaluate for the circulation-transport phase, it is more problematic for the first-pass phase and can involve higher local concentrations of toxicants. This article describes a respiratory-tract dosimetry model that simulates both the rate of absorption and the local concentration of low-volatile organic toxicants in the airway mucosa. The model simulates the non-steady-state diffusion of organic solutes from the air interface through the epithelium and into the capillary bed below. Cellular tissues are described as a heterogeneous, two-phase medium, with a minor lipid phase dispersed in a major aqueous phase. Results show that the lipid-phase/aqueous-phase partition coefficient, PC(L/A), is a critical factor in determining the rate of absorption of solutes in the airway mucosa. For a PC(L/A) in the range 1 to 100, absorption is limited by blood flow and occurs with typical half-times from about 1 to 10 min. As PC(L/A) increases above 100, absorption is gradually limited by the rate of diffusion through the air/blood barrier, and absorption half-times increase to hours. Over the same range, the concentration gradient in the mucosa changes from almost uniform to more nonuniform, and the site-of-entry epithelium becomes more selectively exposed. As a result, with increasing PC(L/A), protoxicants of lower reactivities can still be activated in significant quantities in the airway epithelium and thus act as site-of-entry toxicants. The presented results are important for understanding exposure/target-dose relationships of chemical carcinogens and for conducting reliable risk assessments.

Absorption↗
PubMed2006

Evaluation of two novel peptide safety markers for exocrine pancreatic toxicity.

Current markers of exocrine pancreatic toxicity have historically been poor indicators for both early diagnosis of disease and prediction of disease severity. Recently we identified two peptide markers (RA1609 and RT2864) of pancreatic toxicity that are target organ specific. In order to evaluate sensitivity of these markers versus current standard tests for pancreatic damage (i.e., lipase), we measured amylase and lipase, as well as RA1609 and RT2864 marker levels, in serum from rats treated with four doses (50-200 mg/kg) of the model pancreatic toxicant cyanohydroxybutene (CHB). In addition, to determine whether these peptide markers could detect pancreatic injury induced by different toxicants and in different species, we measured RA1609 and RT2864 marker levels in rats treated with the pancreatic toxicant caerulein, and in mice treated with CHB. RA1609 and RT2864 peptide markers proved to be more sensitive than amylase or lipase in detecting pancreatic damage, especially at an early time point (8 h) following CHB administration. The peptide markers also accurately predicted pancreatic injury induced by caerulein in rats. These markers were sensitive in detecting very mild pancreatic damage following CHB administration in mice, which are less susceptible to CHB-induced pancreatic toxicity. In addition, a species comparison of the RA1609 albumin fragment sequence indicated that cleavage of albumin from pancreatic proteases produces a similar fragment marker in several species, including humans. To determine whether the comparable human albumin fragment could be detected in sera from pancreatitis patients, we analyzed sera from normal individuals and from patients with diabetes, vasculitis, pancreatic cancer, and pancreatitis. It was found that markers corresponding to the fragments found in rat serum (RA1609 and RT2864) were present in human serum, and changes in these were indicative of and specific to pancreatitis. In conclusion, the RA1609 and RT2864 peptides are sensitive indicators of exocrine pancreatic damage that may be useful as safety markers for general pancreatic toxicity in multiple species.

Acute Disease↗
PubMed1979

Hazards from chemicals: scientific questions and conflicts of interest.

All substances are toxic when the dose is large enough. In order to regulate the use of chemicals, we need to measure the level at which toxic effects are found. Epidemiological evidence suggests that present levels of chemical use do not lead to widespread harmful contamination of the human environment. For chemicals, most of the problems of toxicity are found in the workplace, while the population at large gets most of its toxic effects from voluntary exposure to substances such as tobacco smoke and ethanol. The prevention and control of toxic effects depends on a series of steps. This begins with measurement of toxicity in model systems, such as laboratory animals, and the estimation of the likely exposure of workers or consumers. Reliable extrapolation of information gathered from animals to the diverse and biochemically differing human population depends on understanding mechanisms of toxic effects. The toxic effect and mechanisms of action of substances such as carbon tetrachloride or paracetamol have been extensively investigated, and our ability to predict toxicity or develop antidotes to poisoning has had some success, but epidemiology is still an essential part of assessment of toxic effects of new chemicals. The example of phenobarbitone shows how animal experiments may well lead to conclusions which do not apply to man. After measurement of toxicity and assessment of likely hazards in use comes the final evaluation of the use of a chemical. This depends not only on its toxicity, but also on its usefulness. The direct effects on health may be small in comparison with the indirect advantageous effects which a useful substance such as vinyl chloride may bring. The assessment of risks and benefits of new chemicals can be partly removed from a political style of discourse, but the evaluation of the relative weight to be attached to these risks and benefits is inescapably political. The scientific contribution must be to allow the debate to take place in the light of maximum clarity of information about the consequences of use of chemicals.

Acetaminophen↗
PubMed2001

Description and evaluation of a short-term reproduction test with the fathead minnow (Pimephales promelas).

Due to the time and expense associated with full life-cycle testing, most current toxicity tests with fish do not explicitly consider reproductive output as an endpoint but, rather, focus on early life-stage survival and development. However, some classes of chemicals could adversely impact reproduction at concentrations below those that affect development. Further, estimates of the effects of toxic compounds on reproductive output can be critical to the ecological risk assessment process. In this manuscript, we describe a short-term reproduction test with the fathead minnow (Pimephales promelas) and evaluate the test using two model reproductive toxicants, methoxychlor (an estrogenic compound) and methyltestosterone (an androgenic chemical). The test is initiated with reproductively mature animals and is comprised of a pre-exposure phase of 14 to 21 d, followed by a chemical exposure of up to 21 d. During and at completion of the test, several endpoints related to reproductive fitness and endocrine function are assessed. Both chemicals evaluated in our study caused a significant decrease in fecundity of the fish at nominal concentrations of 5.0 micrograms/L (methoxychlor) and 0.2 mg/L (methyltestosterone). Methoxychlor decreased plasma concentrations of one or more steroids (testosterone, 11-ketotestosterone, beta-estradiol) in both sexes and caused a significant induction of plasma vitellogenin in males, a response consistent with activation of the estrogen receptor by the pesticide (or its metabolites). Methyltestosterone decreased plasma concentrations of sex steroids and adversely affected gonadal status (as evaluated by relative weight and histopathology) in both sexes. The androgenic nature of methyltestosterone was clearly expressed as masculinization of exposed females via formation of nuptial tubercles, structures normally present only in reproductively active males. The chemical also caused a significant induction of plasma vitellogenin in both males and females; this unexpected estrogenic response was most likely due to aromatization of the androgen to a form capable of binding to the estrogen receptor. These studies demonstrate the utility of this short-term assay for identifying chemicals that exert reproductive toxicity through alterations in endocrine systems controlled by estrogens and androgens.

Animals↗
PubMed1992

[Effects of zinc overdose on the viscera and tissue pathomorphology].

This investigation included two toxic animal models of zinc: acute and subacute. In the subacute model, ultrastructural changes occurred and zinc content of the liver and kidney increased when the concentration of serum zinc was not obviously changed. In the acute model, the functions of the liver, kidney and cell immunity were impaired, and marked ultrastructural changes noted. The results showed that long-term use of zinc or overdose is dangerous, although zinc is considered of lower toxicity as compared to other heavy metal elements. It is suggested that zinc should be used carefully in children.

Animals↗
PubMed2004

A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug.

Aims were to observe pharmacokinetics, pharmacodynamics, and toxicity for constructing a Sino-pegylated liposomal platform. Human hepatocarcinoma cells (Bel7402) and murine hepatocarcinoma cells (H(22)) were used for the cytotoxicity assay and the in vivo solid xenograft tumor model in mice, respectively. Pharmacokinetic results in mice showed that the pegylated liposomal doxorubicin markedly prolonged the blood circulation of doxorubicin. Elimination half-time (T(1/2,gamma)) of pegylated, regular liposomal doxorubicin and free doxorubicin were 46.09 +/- 14.44, 26.04 +/- 3.34, and 23.72 +/- 5.13 h, respectively. The area under the concentration-time curves (AUC(0- infinity )) (h. microg/g) of the pegylated and regular liposomal doxorubicin were 6.8- and 2.6-fold higher than that of free doxorubicin, respectively. Cytotoxicity and antitumor activity in vivo indicated that activity of the pegylated liposomal doxorubicin was higher than that of the regular or the free one, respectively. After two weeks of tail intravenous injection of the pegylated liposomal doxorubicin at a single dose of 10 mg/kg, no significant damage was observed in gastric, intestinal mucosa, and heart muscle, but pronounced damages were found in the control group after dosing free doxorubicin. The results demonstrate that the pegylated liposomes improve the efficacy of toxics and reduce the toxicity, therefore providing favorable evidence for building a pegylated liposomal platform.

Animals↗
PubMed2005

Effect of chemical speciation on toxicity of mercury to Escherichia coli biofilms and planktonic cells.

While it is known that microbial uptake of mercury (Hg) by planktonic cultures is influenced by the extracellular speciation of mercury in aquatic systems, Hg uptake in biofilm cultures is understudied. We compared the importance of Hg(II) speciation in toxicity to both planktonic and biofilm cultures of the Gram-negative bacterium Escherichia coli 055. Variable chloride chemistry experiments were carried out to modify mercury speciation. Biofilms were observed to be more resistant to Hg than planktonic cells. In both planktonic and biofilm cultures, the toxicity of Hg increased and then decreased along the chloride gradient. The percent reduction in cell viability was linearly related to the concentration of HgCl2(0) when Hg-chloro complexes dominated the speciation, consistent with a passive diffusion model. However, toxicity to both planktonic cells and biofilms at low salinities could not be explained by passive diffusion alone, which suggests that microbial uptake of Hg in both planktonic cells and biofilms may occur by both passive diffusion of neutral species and facilitated uptake. The relationship between toxicity and chloride concentration was similar in the presence and absence of a biofilm, indicating that the presence of the biofilm does not drastically change the relative availability of the dominant mercury species.

Biofilms↗
PubMed2006

Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study.

INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998-2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04-4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes.

Adult↗