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PubMed1998

A toxicity reduction evaluation for an oily waste treatment plant exhibiting episodic effluent toxicity.

A Toxicity Reduction Evaluation (TRE) was conducted on the oily wastewater treatment plant (Plant) at a Naval Fuel Depot. The Plant treats ship and ballast wastes, berm water from fuel storage areas and wastes generated in the fuel reclamation plant utilizing physical/chemical treatment processes. In the first period of the project (Period I), the TRE included chemical characterization of the plant wastewaters, monitoring the final effluent for acute toxicity and a thorough evaluation of each treatment process and Plant operating procedures. Toxicity Identification Evaluation (TIE) procedures were performed as part of the overall TRE to characterize and identify possible sources of toxicity. Several difficulties were encountered because the effluent was saline, test organisms were marine species and toxicity was sporadic and unpredictable. The treatability approach utilizing enhancements, improved housekeeping, and operational changes produced substantial reductions in the acute toxicity of the final effluent. In the second period (Period II), additional acute toxicity testing and chemical characterization were performed through the Plant to assess the long-term effects of major unit process improvements for the removal of toxicity. The TIE procedures were also modified for saline wastewaters to focus on suspected class of toxicants such as surfactants. The TRE was successful in reducing acute toxicity of the final effluent through process improvements and operational modifications. The results indicated that the cause of toxicity was most likely due to combination of pollutants (matrix effect) rather than a single pollutant.

Animals↗

PubMed1995

Bacillus thuringiensis protoxin: location of toxic border and requirement of non-toxic domain for high-level in vivo production of active toxin.

Insecticidal crystal proteins, or protoxins, of Bacillus thuringiensis are composed of two domains, an amino-terminal half essential for toxicity, and a carboxy-terminal half with an as yet unassigned function. To define the boundary of the two domains, sequential termination codons were introduced from the 3'-end of the DNA sequence encoding the toxic domain of the 1155-residue cry1A(b) gene product. The mutated and the intact genes were placed under the control of the Escherichia coli inducible promoter PrecA, and toxicity of the cell extracts was determined using silkworm larvae. Under non-induced conditions, in which the gene products accumulated to a limited degree, mutations encoding 606 amino acid residues or more were toxic, whereas those encoding 605 residues or less were non-toxic. Comparison of the toxicities and the levels of the toxic proteins suggested that the mutant proteins had comparable activity to that of the intact protoxin. Furthermore, the non-toxic protein seemed to be unstable in the extracts. To investigate the roles of the non-toxic domain, the mutant proteins were overproduced in both E. coli and B. thuringiensis. The intact and the mutated genes carrying natural promoters were introduced into acrystalliferous B. thuringiensis. Upon induction of PrecA in E. coli, and upon sporulation in B. thuringiensis, there was a large accumulation of gene products which formed inclusion bodies. The inclusion bodies of the intact protoxin were active, whereas those of the mutant proteins were inactive. Inclusion bodies of the intact protein could be solubilized in alkali, whereas the mutant inclusion bodies were insoluble. Since solubilization under alkaline conditions in the insect midgut is considered to be the first step of toxic action, the non-toxic domain is required to direct the synthesis of inclusion bodies as an active soluble form.

Amino Acid Sequence↗

PubMed2001

Acute toxicity of (chloro-)catechols and (chloro-)catechol-copper combinations in Escherichia coli corresponds to their membrane toxicity in vitro.

(Chloro-)catechols are toxic for bacteria and higher organisms, but the mode of action is not yet clearly understood. We have compared the acute toxicity of different chlorinated catechols to Escherichia coli with membrane toxic effects, namely narcosis and uncoupling that we have determined in an in vitro assay. In vitro membrane toxicity was quantified by measuring the accelerated decay of the membrane potential of chromatophores isolated from Rhodobacter sphaeroides. Both acute and membrane toxicity increased with increasing degree of chlorination. Analysis of dose-response curves, pH dependence, and estimated membrane concentrations gave a consistent picture of the mechanisms of membrane toxicity: At pH 7, the higher-chlorinated catechols acted as uncouplers of oxidative and photophosphorylation, and the lower-chlorinated catechols and catechol acted as narcotics. In the case of 3,5-dichlorocatechol and 4-monochlorocatechol at pH 8.8, both mechanisms appeared to contribute to the overall toxicity. Copper exhibited a diverging effect on the toxicity of catechols and of (chloro-)catechols to E. coli. Whereas the presence of copper increased the toxicity of catechol and 4-monochlorocatechol, the toxicity of 3,5-dichlorocatechol, 3,4,5-trichlorocatechol, and tetrachlorocatechol decreased. Again, the results obtained with in vitro assays agreed with the acute toxicity observed in E. coli: The presence of copper accelerated decay of the membrane potential of catechol and 4-monochlorocatechol; however, the effect was reversed by copper in experiments with 3,5-dichlorocatechol, 3,4,5-trichlorocatechol, and tetrachlorocatechol. We have proposed a mechanistic model to explain the diverging effects of copper on the uncoupling activities of the different catechols.

Catechols↗

PubMed2006

Aquatic toxicity of nine aircraft deicer and anti-icer formulations and relative toxicity of additive package ingredients alkylphenol ethoxylates and 4,5-methyl-1H-henzotriazoles.

Characterization of the effects of aircraft deicer and anti-icer fluid (ADAF) runoff on aquatic organisms in receiving streams is a complex issue because the identities of numerous toxic additives are proprietary and not publicly available. Most potentially toxic and endocrine disrupting effects caused by ADAF are due to the numerous additive package ingredients which vary among manufacturers and types of ADAF formulation. Toxicity investigations of nine ADAF formulations indicate that endpoint concentrations for formulations of different manufacturers are widely variable. Type IV ADAF (anti-icers) are more toxic than Type I (deicers) for the four organisms tested (Vibrio fischeri, Pimephales promelas, Ceriodaphnia dubia, and Selenastrum capricornutum). Acute toxicity endpoint concentrations ranged from 347 to 7700 mg/L as ADAF for Type IV and from 1550 to 45,100 mg/L for Type I formulations. Chronic endpoint concentrations ranged from 70 to 1300 mg/L for Type IV and from 37 to 18,400 mg/L for Type I formulations. Alkylphenol ethoxylates and tolyltriazoles are two known classes of additives. Nonylphenol, nonylphenol ethoxylates, octylphenol, octylphenol ethoxylates, and 4,5-methyl-1H-benzotriazoles were quantified in the nine ADAF formulations, and toxicity tests were conducted with nonylphenol ethoxylates and 4,5-methyl-1H-benzotriazoles. Toxicity units computed for glycol and these additives, with respect to toxicity of the ADAF formulations, indicate that a portion of ADAF toxicity can be explained by the known additives and glycols, but much of the toxicity is due to unidentified additives.

Aircraft↗

PubMed2003

Quantitative assessment of natural toxicity in sponges: toxicity bioassay versus compound quantification.

Microtox assay was used to assess the natural toxicity of two sponges, Dysidea avara and Ircinia variabilis. The activity of crude extracts and major metabolites were compared. Methanol extract of D. avara was more toxic than that of acetone and was as toxic as pure avarol, thus suggesting that the toxicity of the sponge was mainly due to this metabolite. We also quantified palinurin, the major metabolite of I. variabilis, in specimens from several habitats. With the same methanol extracts used for palinurin quantification, we ran the Microtox assay and found a positive significant regression between toxicity and concentration of this metabolite. Pure palinurin was tested at the same concentration present in the extract, and the toxicity recorded was higher than that of the methanol extract. As with avarol from D. avara, palinurin is the main secondary metabolite that confers toxicity to I. variabilis. The results confirm that the standardized Microtox assay is an accurate and reproducible tool for assessing the toxicity of crude extracts and pure metabolites of marine organisms. These results also suggest that methanol is more suitable than acetone for the detection of species toxicity by Microtox. The method is faster and easier to perform than chemical quantification even when the sponge chemistry is known, and is appropriate for studies on variation in natural toxicity over a range of environmental conditions.

Animals↗

PubMed2006

Discriminating toxicant classes by mode of action. 1. (Eco)toxicity profiles.

BACKGROUND AND SCOPE: Predictive toxicology, particularly quantitative structure-activity relationships (QSARs), require classification of chemicals by mode of action (MOA). MOA is, however, not a constant property of a compound but it varies between species and may change with concentration and duration of exposure. A battery of MOA-specific in-vitro and low-complexity assays, featuring biomolecular targets for major classes of environmental pollutants, provides characteristic responses for (1.) classification of chemicals by MOA, (2.) identification of (eco)toxicity profiles of chemicals, (3.) identification of chemicals with specific MOAs, (4.) indication of most sensitive species, (5.) identification of chemicals that are outliers in QSARs and (6.) selection of appropriate QSARs for predictions. METHODS: Chemicals covering nine distinct modes of toxic action (non-polar non-specific toxicants (n=14), polar non-specific toxicants (n=18), uncouplers of oxidative phosphorylation (n=25), inhibitors of photosynthesis (n=15), inhibitors of acetylcholinesterase (n=14), inhibitors of respiration (n=3), thiol-alkylating agents (n=9), reactives (irritants) (n=8), estrogen receptor agonists (n=9)) were tested for cytotoxicity in the neutralred assay, oxygen consumption in isolated mitochondria, oxygen production in algae, inhibition of AChE, reaction with GSH and activity in the yeast estrogen receptor assay. Data on in-vivo aquatic toxicity (LC50, EC50) towards fish, daphnids, algae and bacteria were collected from the literature for reasons of comparison and reference scaling. RESULTS AND DISCUSSION: In the MOA-specific in-vitro test battery, most test chemicals are specifically active at low concentrations, though multiple effects do occur. Graphical and statistical evaluation of the individual classes versus MOA 1 (non-polar non-specific toxicants) identifies interactions related to predominant MOA. Discriminant analyses (DA) on subsets of the data revealed correct classifications between 70% (in-vivo data) and >90% (in-vitro data). Functional similarity of chemical substances is defined in terms of their (eco)toxicity profiles. Within each MOA class, the compounds share some properties related to the rate-limiting interactions, e.g., steric fit to the target site and/or reactivity with target biomolecules, revealing a specific pattern (fingerprint) of characteristic effects. CONCLUSION: The successful discrimination of toxicant classes by MOA is based on comprehensive characterization of test chemicals' properties related to interactions with target sites. The suite of aquatic in-vivo tests using fish, daphnids, algae and bacteria covers most acute effects, whilst long-term (latent) impacts are generally neglected. With the MOA-specific in-vitro test battery such distinctions are futile, because it focuses on isolated targets, i.e. it indicates the possible targets of a chemical regardless of the timescale of effects. The data analysis indicates that the in-vitro battery covers most effects in vivo and moreover provides additional aspects of the compounds' MOA. RECOMMENDATION AND PERSPECTIVE: Translating in-vitro effects to in-vivo toxicity requires combining physiological and chemical knowledge about underlying processes. Comparison of the specific in-vitro effects of a compound with the respective sensitivities of aquatic organisms indicates particularly sensitive species. Classifications of toxicants by MOA based on physicochemical descriptors provides insight to interactions and directs to mechanistic QSARs.

Animals↗

PubMed2004

The role of maternal toxicity in lovastatin-induced developmental toxicity.

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.

Abnormalities, Drug-Induced↗

PubMed1996

Evaluation of effluent toxicity and ambient toxicity in a polluted lowland river.

The impact of an industrial effluent containing high loads of calcium, cadmium, lead chloride and sulphate, on a river ecosystem was assessed using a combination of an effluent toxicity test, an ambient toxicity test and an ecological survey. Only this combination of techniques made it possible to discriminate between the effects of the discharge and those of the background pollution. Each of the individual techniques detected essential effects which the other failed to reveal. With the physical and chemical measurements, important increases of several components were measured at all sampling sites downstream of the discharge. With the ecological survey, however, no large changes in water quality could be determined at the sampling sites, due to the high degree of pollution present upstream of the discharge. Reproduction of Daphnia magna, exposed to sublethal effluent dilutions, was followed over two generations. The offspring of the first generation were shown to have an increased sensitivity to the effluent, compared to the first generation that was born from previously unexposed mothers. Besides the toxicity of the effluent, the acute and chronic toxicity of its main component, CaCl(2), was also determined. The results of the CaCl(2)-tests and toxicity data from literature for the suspected toxicants were transformed to Toxic Units (TU). Using the sum of the TUs we investigated the possibility of predicting effluent toxicity to Daphnia magna. Effluent toxicity was under-estimated by calculating the sum of the TUs of the individual components. Dilution of the effluent to a level at which the measured toxicant concentrations comply with European regulations still showed significant effects on Daphnia reproduction.

Journal Article↗

PubMed2002

Derivation of a toxicity-based model to predict how water chemistry influences silver toxicity to invertebrates.

The effect of altering water chemistry on acute silver toxicity to three invertebrate species, two Daphnids, Daphnia magna and Daphnia pulex, as well as an amphipod Gammarus pulex was assessed. In addition, the physiological basis of Ag(I) toxicity to G. pulex was examined. Daphnia magna and D. pulex were more sensitive than G. pulex and 48 h LC(50) values in synthetic ion poor water were 0.47, 0.65 and 2.1 microg Ag(I) l(-1), respectively. Increasing water [Cl(-)] reduced Ag(I) toxicity in all species, and increasing water [Ca(2+)] from 50 to 1,500 microM reduced Ag(I) toxicity in G. pulex. Whole body Na(+) content, but not K(+) or Ca(2+) was significantly reduced in G. pulex exposed to 6 microg Ag(I) l(-1) for 24 h, but there was no inhibition of whole body Na(+)/K(+)-ATPase activity. Both increasing water [Cl(-)] and [Ca(2+)] reduced this Ag(I)-induced Na(+) loss. For D. magna, the presence of 10 mg l(-1) humic acid or 0.5 microM 3-mercaptoproprionic acid (3-MPA) increased the 48 h LC(50) values by 5.9 and 58.5-fold, respectively, and for D. pulex the presence of 1 microM thiosulfate increased the 48 h LC(50) value by four-fold. The D. magna toxicity data generated from this study were used to derive a Daphnia biotic ligand model (BLM). Analysis of the measured LC(50) values vs. the predicted LC(50) values for toxicity data from the present and published results where water Cl(-), Ca(2+), Na(+) or humic acid were varied showed that 91% of the measured toxicity data fell within a factor of two of the predicted LC(50) values. However, the daphnid BLM could not accurately predict G. pulex toxicity. Additionally, the Daphnia BLM was under-protective in the presence of the organic thiols 3-MPA or thiosulphate and predicted an increase in the LC(50) value of 114- and 74-fold, respectively. The Daphnia toxicity based BLM derived from the present data set is successful in predicting Daphnia toxicity in laboratory data sets in the absence of sulfur containing compounds, but shows its limitations when applied to waters containing organic thiols or thiosulphate.

Amphipoda↗

PubMed2001

Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor- alpha versus toxicity after melphalan alone.

AIMS: To determine whether the addition of high-dose tumour necrosis factor-alpha (TNF alpha) to isolated limb perfusion (ILP) with melphalan increases acute regional tissue toxicity compared to ILP with melphalan alone. METHODS: A retrospective, multivariate analysis of toxicity after normothermic (37--38 degrees C) and 'mild' hyperthermic (38--40 degrees C) ILPs for melanoma was undertaken. Normothermic ILP with melphalan was performed in 294 patients (70.8%), 'mild' hyperthermic ILP with melphalan in 71 patients (17.1%) and 'mild' hyperthermic ILP with melphalan combined with TNF alpha in 50 patients (12.0%). Toxicity was nil or mild (grades I--II according to Wieberdink et al.) in 339 patients (81.7%), and more severe acute regional toxicity (grades III--V) developed in 76 patients (18.3%). A stepwise logistic regression procedure was performed for the multivariate analysis of prognostic factors for more severe toxicity. RESULTS: On univariate analysis, 'mild' hyperthermic ILP with melphalan plus TNF alpha significantly increased the incidence of more severe acute regional toxicity compared to normothermic and 'mild' hyperthermic ILP with melphalan alone (36% vs 16% and 17%; P=0.0038). However, after ILP using TNF alpha no grade IV (compartment compression syndrome) or grade V (toxicity necessitating amputation) reactions were seen. Significantly more severe toxicity was seen after ILPs performed between 1991 and 1994 compared with earlier ILPs (33%vs 14%P=0.0001). Also, women had a higher risk of more severe toxicity than men (22% vs 7%; P=0.0007). After multivariate analysis, prognostic factors which remained significant were: sex (P=0.0013) and either ILP schedule (P=0.013) or treatment period (P=0.0003). CONCLUSIONS: Regional toxicity after 'mild' hyperthermic ILP with melphalan and TNF alpha was significantly increased compared to ILP with melphalan alone. This may be caused by increased thermal enhancement of melphalan due to the higher tissue temperatures (39--40 degrees C) at which the melphalan in the TNF alpha-ILPs was administered or by an interaction between high-dose TNF alpha and melphalan.

Adult↗

PubMed1980

Toxicities and description of some toxaphene fractions: isolation and identification of a highly toxic component.

Toxaphene was separated into 13 fractions and the toxicity of each fraction was determined. The acute toxicities (LD50) to houseflies (topical in acetone) ranged from 21 to greater than 246 mg/kg (toxaphene LD50 = 33 mg/kg) and the relative toxicities ranged from 0.6 to greater than 7.5. A similar pattern was found in mice when the toxicities of several fractions were determined. The acute toxicities (LD50, ip injection in dimethyl sulfoxide) in mice ranged from 20 to 67 mg/kg (toxaphene LD50 = 33 mg/kg) for the fractions tested. The most toxic fraction was further separated into six subfractions and their toxicities (housefly LD50) were found to range from 10 to 74 mg/kg. The most toxic subfraction appeared to be an almost pure compound and was purified for further identification. It was found to be identical to a previously reported highly toxic C10H10Cl8 mixture of predominantly two components. The components were reported to be 2,2,5-endo,6-exo, 8,8,9,10-octachlorobornane and 2,2,5-endo,6-exo,8,9,9,10-octachlorobornane. This highly toxic mixture has now been isolated independently by three research teams using different separation schemes.

Animals↗

PubMed2003

The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

BACKGROUND: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM: To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN: Retrospective analysis of prospectively collected data METHODS: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. RESULTS: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. DISCUSSION: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.

Analysis of Variance↗

PubMed2004

Agonist-induced internalization of leukotriene B(4) receptor 1 requires G-protein-coupled receptor kinase 2 but not arrestins.

The leukotriene B(4) (LTB(4)) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB(4) stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB(4), BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail-truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB(4), suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type-specific signaling in response to LTB(4), depending on GRK expression levels.

Animals↗

PubMed1978

[Mechanism of methamphetamine toxicity in grouped mice and the effects of centrally acting drugs on its toxicity (author's transl)].

The mortality of ddK mice treated with 40 mg/kg i.p. of methamphetamine (MA) was 85% in grouped conditions (10 mice in a cage) and 3% in individually isolated conditions. This mortality was not altered by the social environments even when other mice in the cage were not treated with MA. The mortality of mice individually isolated in cages with transparent walls was significantly higher than that of completely isolated mice. Almost all neuroleptics dose-dependently antagonized the MA toxicity in grouped mice, in small doses. The antagonizing activity of clozapine was somewhat weak, and sulpiride potentiated MA toxicity. Phentolamine and propranolol antagonized the MA toxicity at higher doses than neuroleptics. Reserpine and tetrabenazine previously given to mice remarkably antagonized the MA toxicity. H44/68 (a tyrosine hydroxylase inhibitor) had a considerable effect in antagonizing the MA toxicity, but diethyldithiocarbamate, U-14, 624 and FLA 63 (dopamine-beta-hydroxylase inhibitors) prevented the MA toxicity to a lesser extent than did H44/68. Apomorphine had no effect on the MA toxicity. The present data show that the MA toxicity in grouped mice (the increase in mortality) was enhanced by the presence of other mice, and suggest that the norepinephrine neurons play an important role in promoting the MA toxicity. Neuroleptics antagonize MA toxicity probably by blocking alpha-receptors in the central nervous system.

Adrenergic alpha-Antagonists↗

PubMed2000

Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism?

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.

Animals↗

PubMed2004

Use of zeolite for removing ammonia and ammonia-caused toxicity in marine toxicity identification evaluations.

Ammonia occurs in marine waters including effluents, receiving waters, and sediment interstitial waters. At sufficiently high concentrations, ammonia can be toxic to aquatic species. Toxicity identification evaluation (TIE) methods provide researchers with tools for identifying aquatic toxicants. For identifying ammonia toxicity, there are several possible methods including pH alteration and volatilization, Ulva lactuca addition, microbial degradation, and zeolite addition. Zeolite addition has been used successfully in freshwater systems to decrease ammonia concentrations and toxicity for several decades. However, zeolite in marine systems has been used less because ions in the seawater interfere with zeolite's ability to adsorb ammonia. The objective of this study was to develop a zeolite method for removing ammonia from marine waters. To accomplish this objective, we performed a series of zeolite slurry and column chromatography studies to determine uptake rate and capacity and to evaluate the effects of salinity and pH on ammonia removal. We also assessed the interaction of zeolite with several toxic metals. Success of the methods was also evaluated by measuring toxicity to two marine species: the mysid Americamysis bahia and the amphipod Ampelisca abdita. Column chromatography proved to be effective at removing a wide range of ammonia concentrations under several experimental conditions. Conversely, the slurry method was inconsistent and variable in its overall performance in removing ammonia and cannot be recommended. The metals copper, lead, and zinc were removed by zeolite in both the slurry and column treatments. The zeolite column was successful in removing ammonia toxicity for both the mysid and the amphipod, whereas the slurry was less effective. This study demonstrated that zeolite column chromatography is a useful tool for conducting marine water TIEs to decrease ammonia concentrations and characterize toxicity.

Adsorption↗

PubMed2002

A comparison of five rapid direct toxicity assessment methods to determine toxicity of pollutants to activated sludge.

Five rapid direct toxicity assessment methods were used in three European partner countries to determine the toxicity of single toxicants, mixed toxicants and real industrial wastes. The final aim was to protect microbial degradation of organic wastes in biological treatment processes and hence enhance the quality of treated effluents to be discharged to the environment. Nitrification inhibition, Respirometry, Adenosine triphosphate luminescence and Enzyme inhibition were tested utilising activated sludge as the testing matrix. The Vibrio fischeri toxicity test was used as a surrogate to compare the various microbial bioassays. The IC50 (toxicant concentration eliciting a 50% inhibitory effect) was determined for a number of pollutants including single toxicants Cd, Cr, Cu, Zn, 3,5-dichlorophenol, toluene and linear alkylbenzenesulphonate (LAS); a standard mixture of metals and LAS; a standard mixture of organics and LAS, and 16 industrial effluents. The V. fischeri bioassay was also chosen in order to assess quality control of toxicant preparation during testing in the different laboratories of the partner countries. Comparisons of sensitivity, cost of implementation, cost per test, relevance, and ease of use were made. The most sensitive bioassays were V. fischeri and Nitrification inhibition, however, this depended in the main on the pollutant and mixtures tested. It is recommended that during assessment of wastewater toxicity a suite of tests be used rather than reliance on one particular test.

Adenosine Triphosphate↗

PubMed2001

Predicting the joint algal toxicity of multi-component s-triazine mixtures at low-effect concentrations of individual toxicants.

Herbicidal s-triazines are widespread contaminants of surface waters. They are highly toxic to algae and other primary producers in aquatic systems. This results from their specific interference with photosynthetic electron transport. Risk assessment for aquatic biota has to consider situations of simultaneous exposure to various of these toxicants. In tests with freshwater algae we predicted and determined the toxicity of multiple mixtures of 18 different s-triazines. The toxicity parameter was the inhibition of reproduction of Scenedesmus vacuolatus. Concentration-response analyses were performed for single toxicants and for mixtures containing all 18 s-triazines in two different concentration ratios. Experiments were designed to allow a valid statistical description of the entire concentration-response relationships, including the low concentration range down to EC1. Observed effects and effect concentrations of mixtures were compared to predictions of mixture toxicity. Predictions were calculated from the concentration-response functions of individual s-triazines by applying the concepts of concentration addition and independent action (response addition) alternatively. Predictions based on independent action tend to underestimate the overall toxicity of s-triazine mixtures. In contrast, the concept of concentration addition provides highly accurate predictions of s-triazine mixture toxicity, irrespective of the effect level under consideration and the concentration ratio of the mixture components. This also holds true when the mixture components are present in concentrations below their individual NOEC values. Concentrations statistically estimated to elicit non-significant effects of only 1% still contribute to the overall toxicity. When present in a multi-component mixture they can co-operate to give a severe joint effect. Applicability of the findings obtained with s-triazines to mixtures of other contaminants in aquatic systems and consequences for risk assessment procedures are discussed.

Chlorophyta↗