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PubMed2001

Application of a sigmapolycyclic aromatic hydrocarbon model and a logistic regression model to sediment toxicity data based on a species-specific, water-only LC50 toxic unit for Hyalella azteca.

Two models, a sigmapolycyclic aromatic hydrocarbon (PAH) model based on equilibrium partitioning theory and a logistic-regression model, were developed and evaluated to predict sediment-associated PAH toxicity to Hyalella azteca. A sigmaPAH model was applied to freshwater sediments. This study is the first attempt to use a sigmaPAH model based on water-only, median lethal concentration (LC50) toxic unit (TU) values for sediment-associated PAH mixtures and its application to freshwater sediments. To predict the toxicity (i.e., mortality) from contaminated sediments to H. azteca, an interstitial water TU, calculated as the ambient interstitial water concentration divided by the water-only LC50 in which the interstitial water concentrations were predicted by equilibrium partitioning theory, was used. Assuming additive toxicity for PAH, the sum of TUs was calculated to predict the total toxicity of PAH mixtures in sediments. The sigmaPAH model was developed from 10- and 14-d H. azteca water-only LC50 values. To obtain estimates of LC50 values for a wide range of PAHs, a quantitative structure-activity relationship (QSAR) model (log LC50 - log Kow) with a constant slope was derived using the time-variable LC50 values for four PAH congeners. The logistic-regression model was derived to assess the concentration-response relationship for field sediments, which showed that 1.3 (0.6-3.9) TU were required for a 50% probability that a sediment was toxic. The logistic-regression model reflects both the effects of co-occurring contaminants (i.e., nonmeasured PAH and unknown pollutants) and the overestimation of exposure to sediment-associated PAH. An apparent site-specific bioavailability limitation of sediment-associated PAH was found for a site contaminated by creosote. At this site, no toxic samples were less than 3.9 TU. Finally, the predictability of the sigmaPAH model can be affected by species-specific responses (Hyalella vs Rhepoxynius); chemical specific (PAH vs DDT in H. azteca) biases, which are not incorporated in the equilibrium partitioning model; and the uncertainty from site-specific effects (creosote vs other sources of PAH contamination) on the bioavailability of sediment-associated PAH mixtures.

Animals↗
PubMed1992

NTP technical report on the toxicity studies of Toxicity Studies of Antimony Potassium Tartrate (CAS No. 28300-74-5) in F344/N Rats And B6C3F1 Mice (Drinking Water and Intraperitoneal Injection Studies).

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an anti-schistosomal drug. APT was efficacious in humans only if administered intravenously at a near-lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested a possible association between APT treatment and bladder cancer, prechronic toxicity studies were initiated with APT to select a route of administration and appropriate doses in the event chronic studies were needed. To determine the most appropriate route for longer-term studies, toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice that were administered APT in drinking water or by i.p. injection for 14 or 16 days. The animals were assigned to dose groups, 5/sex/species. Drinking water doses, estimated by water consumption, were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice; i.p. doses were 0, 1.5, 3, 6, 11, or 22 mg/kg in rats and 0, 6, 13, 25, 50, or 100 mg/kg in mice. APT was poorly absorbed and relatively nontoxic when given orally. There was no mortality or histopathological lesions in rats or mice receiving doses of APT as high as 168 or 273 mg/kg, respectively. One mouse in the highest dose group (407 mg/kg) died, and there were treatment-related lesions in the liver and forestomach of most mice in this dose group. In contrast, i.p. administration of the drug was much more toxic, resulting in the deaths of rats administered 22 mg/kg; kidney and liver lesions were found in these rats. In mice, i.p. administration of APT caused deaths and liver lesions at dose levels one-fourth of those that caused similar effects by oral administration. All male and female mice injected with 100 mg/kg APT died; half of the female mice given 50 mg/kg APT died; additional deaths occurred with doses as low as 6 mg/kg. Hepatocellular necrosis and inflammation of the liver capsule were present in both sexes of mice in the 50 mg/kg dose groups. As a result of these findings, an i.p. dose regimen was selected for subsequent studies. Groups of ten male and female F344/N rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, or 24 mg/kg doses of APT 3 times per week for 13 weeks by i.p. injection. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality and reduction in body weight. Four male rats in the 24 mg/kg dose died; body weights in both sexes of rats from this dose group and in male rats from the 12 mg/kg dose group were 10-20% below controls. No clinical signs of toxicity in the mice, nor gross or microscopic lesions, could be attributed to APT. Increased concentrations of antimony, considered to be dose-related, were detected in the blood, liver, kidney, spleen, and heart of rats, and in the liver and spleen of mice. In rats, hepatocellular degeneration and necrosis were associated with dose-related elevations in activities of the liver-specific serum enzymes, sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the i.p. route would be suitable for chronic studies. Hepatotoxicity in rats occurred in dose groups where there was little evidence of renal toxicity and no cardiac toxicity; thus, serial measurement of liver-specific serum enzyme activities may be useful to monitor the presence and progression of hepatocellular degeneration in longer-term exposures. Synonyms: APT; Tartar emetic; tartrated antimony; tartarized antimony; potassium antimonyltartrate; Bis [μ-[2,3-dihydroxy- butanedioato(4-)-O1, O2:O3, O4]]-diantimonate dipotassium trihydrate (stereoisomer).

Journal Article↗
PubMed1995

Preclinical toxicity of liposome-incorporated annamycin: selective bone marrow toxicity with lack of cardiotoxicity.

Annamycin (Ann) is a new lipophilic anthracycline antibiotic with a marked ability to circumvent typical multidrug resistance both in vitro and in vivo. Because of its high affinity for lipid membranes and very low solubility in water, Ann has been prepared in a submicron liposome formulation (L-Ann) that is currently being investigated in a Phase I clinical study. We studied the preclinical toxicity of L-Ann in mice and beagle dogs and compared it with that of free Ann in suspension and the parent compound doxorubicin (Dox). In mice, free Ann was about twice as toxic as Dox (LD50 after a single i.v. bolus administration, 8.8 versus 19.9 mg/kg; P < 0.01). The liposomal carrier reduced Ann toxicity by 2-fold (LD50, 15.74 mg/kg for L-Ann versus 8.8 mg/kg for free Ann; P < 0.01). Granulocytopenia was the main toxicity of Ann, either free or liposome incorporated, and was much more profound than with an equitoxic dose of Dox as assessed by blood counts and pathological studies. In chronic mouse studies, L-Ann was remarkably less cardiotoxic than Dox. Cumulative toxicity with the weekly administration of a given fraction of the subacute LD10 was markedly higher with Dox than with L-Ann as assessed by body weight and mortality studies. L-Ann also had less vesicant toxicity than Dox after intradermal administration in mice. Beagle dogs tolerated the mouse-equivalent LD10 dose of L-Ann (1.4 mg/kg) with no side effects, changes in the hematological and biochemical blood parameters, or pathological changes. Our results indicate that: (a) L-Ann is more selectively myelotoxic than Dox and is noncardiotoxic; (b) the liposome carrier plays a major role in the favorable toxicity profile of L-Ann; and (c) the standard one-tenth of the LD10 should be a safe starting dose for Phase I clinical trials with L-Ann in humans.

Animals↗
PubMed1994

A new in vitro toxicity test based on the response to toxic substances in solutions of mitochondria from beef heart.

A simple, rapid and inexpensive in vitro method which may be used as a biological sensor for the valuation of toxicity of chemical compounds in water is proposed. The method utilizes the response of the respiratory chain of beef heart mitochondria to a wide range of toxic substances. By means of simple voltametric measurements, the method not only gives an indication of toxicity in water but, by using different substrates of the respiratory chain and exploiting some features of the toxic substances, it also allows selective detection of some toxic substance or groups of substances. Since the method reproduces the standard "rainbow trout" test, it may also be proposed as a screening test to precede whole bioorganisms bioassays or as a method to assess the presence of certain toxic substances in water.

Adenosine Triphosphate↗
PubMed2002

Apparent toxicity resulting from the sequestering of nutrient trace metals during standard Selenastrum capricornutum toxicity tests.

The water accommodated fractions (WAFs) of aqueous mixtures of three lubricant additives showed significant apparent toxicity to the freshwater alga, Selenastrum capricornutum, and experiments were conducted to investigate the hypothesis that toxicity resulted from the removal of one or more essential nutrients from the test medium by the lubricant additives. Algal growth effects were noted at ashless dispersant A concentrations as low as 0.5 x mg l(-1) and growth was completely inhibited at 100 mg x l(-1). Algal cells transferred from the 100 mg x l(-1) WAF of ashless dispersant A to fresh medium at the end of a standard 96-h toxicity test resumed growing at a rate similar to growth in undosed algal medium, indicating that the effect was algistatic rather than algicidal. Fortifying the iron (Fe) and disodium ethylenediaminetetraacetic acid (EDTA) concentrations of the WAF with 200% of the concentrations used in the formulation of algal medium after 24 h of exposure caused a resumption of algal growth at a rate comparable to the control growth, and a resulting EL50 value above 100 mg x l(-1). Similar effects were observed when the two other lubricant additives were tested at WAF concentrations that completely inhibited algal growth during standard toxicity tests: fortification of a 50 mg x l(-1) WAF of ZnDTP with 1000% of the Fe and EDTA used in the formulation of algal medium caused a resumption of growth at a rate statistically identical to the control growth, and the fortification of a 2800 mg x l(-1) WAF of ashless dispersant B with 700% of the entire complement of nutrients used in the formulation of algal medium caused a resumption of growth at a rate comparable to the control. The indirect toxic effect of these lubricant additives to algae results from the sequestration of one or more nutrient metals essential for algal growth. Standard algal toxicity tests with these lubricant additives may, therefore, have little environmental relevance because the complex chemistry of natural waters differs greatly from the nutrient limited algal medium, and the sequestration effect observed in these static tests could be absent under real world conditions.

Chlorophyta↗
PubMedDate not supplied

Toxicological characterisation of sludge from sewage treatment plants using toxicity identification evaluation protocols based on in vitro toxicity tests.

The ecotoxicological characterisation of complex mixtures, such as sludge from sewage treatment plants, is complex. Toxicity identification evaluation (TIE) protocols, developed by the United States Environmental Protection Agency (US EPA); to identify toxic pollutants in complex effluents, are useful tools in this context; to solve the difficulties in assessing unknown organic pollutants by analytical methods, the usefulness of bioassays to detect the relevant (toxic) organic compounds present in complex samples, and the possibilities of in vitro cytotoxicity tests as screening tools, offers a profitable combination. The sludge obtained from a sewage treatment plant was extracted by acetonitrile using a microwave extractor and fractionated in an HPLC system. The toxicity of every fraction was assayed using a RTG-2 cytotoxicty test, based on the fibroblastic RTG-2 fish cell line (ATCC, CCL N. 55). At exponential growth, three endpoints, beta-galactosidase activity, culture viability assayed by the neutral red assay (NR) and inhibition of growth rate using the FRAME KB protein assay (KBP), were used. By plotting the toxicity of each fraction vs elution time, the corresponding "toxicograms" were built. The UV and fluorescence chromatograms are compared to the three toxicograms (one for each toxicity endpoint).

Animal Testing Alternatives↗
PubMedDate not supplied

Structural features of toxic chemicals for specific toxicity.

We have studied the structural features of toxic chemicals from the RTECS database associated with specific toxicity. The frameworks, functional groups, and structure patterns of molecules are taken into account. Potential active frameworks, groups, and structure patterns for specific toxicity are gained by computational chemistry approaches. These structural features of toxic chemicals will be helpful in understanding activities of toxic chemicals and useful in predicting the toxicity of chemicals, especially in the early stage of drug design.

Database Management Systems↗
PubMed2003

Toxicity of heavy metals using sperm cell and embryo toxicity bioassays with Paracentrotus lividus (Echinodermata: Echinoidea): comparisons with exposure concentrations in the Lagoon of Venice, Italy.

Sperm cell and embryo toxicity tests using the Mediterranean sea urchin Paracentrotus lividus Lmk were performed to assess the toxicity of As3+, Cd2+, Cr3+, Ni2+, Pb2+, Cu2+, Zn2+, and Hg2+. The aim of this study was to improve information about the comparative sensitivity of sea urchin bioassays to the heavy metals, which are an important cause of contamination in the ecosystem of the Lagoon of Venice. Considering the data in mM/L, the order of toxicity is Hg2+ > Cu2+ > Zn2+ > As3+ > or = Cr3+ > or = Cd2+ > or = Pb2+ > or = Ni2+ for the sperm cell test and Hg2+ > or = Pb2+ > Cu2+ > Zn2+ > Cd2+ > Ni2+ > As3+ > or = Cr3+ for the embryo test. New toxicity data for metals expressed as median effective concentration (EC50) and no-observed-effect concentration (NOEC) are reported for the Mediterranean species. Accurate observations of embryotoxic effects at increasing metal concentrations were done, detecting some different behaviors in metal toxicity. Toxicity data compared with water column and pore-water concentrations recorded in the Lagoon of Venice (Italy) demonstrate the potential ability of bioassays using sea urchin to detect important contaminants in this ecosystem.

Abnormalities, Drug-Induced↗
PubMed1999

An integrated process for the production of toxic catechols from toxic phenols based on a designer biocatalyst.

We describe the biocatalytic production of 3-phenylcatechol from 2-phenylphenol with the whole cell biocatalyst Escherichia coli JM101 (pHBP461). The recombinant produces 2-hydroxybiphenyl 3-monooxygenase, an enzyme from Pseudomonas azelaica HBP1. This enzyme introduces a hydroxyl-group at the C3-position of a variety of 2-substituted phenols, such as 2-phenylphenol. This permits the biocatalytic production of 3-substituted catechols, which are difficult to synthesize chemically. Both 2-phenylphenol and 3-phenylcatechol are highly toxic to E. coli. The toxic effects of 2-phenylphenol were minimized by feeding this substrate to the reactor at a rate slightly below the maximum biooxidation rate. As a result, the substrate concentration in the reactor remained below toxic levels during the bioconversion. The toxic product formed was removed by continuous adsorption on the solid resin Amberlite XAD-4. To this end the reaction mixture, containing the biocatalyst, was pumped continuously through an external loop with a fluidized bed of the resin. This resin efficiently and quantitatively adsorbed both 3-phenylcatechol and the remaining trace amounts of 2-phenylphenol. Consequently, the concentrations of these compounds were kept at subtoxic levels (below 100 mg L-1) and gram amounts of 3-phenylcatechol were produced with space-time yields of up to 0.39 g L-1 h-1. The product was recovered from the resin by acidic methanol elution and purified by recrystallization from n-hexane resulting in overall yields exceeding 59%. The optimized system served as a surprisingly simple and efficient integrated process, that allows the bioconversion of toxic substrates to toxic products with whole cell biocatalysts.

Adsorption↗
PubMed2003

[Special features of intensive care of toxic shock syndrome. Review and case report of a TSST-1 associated toxic-shock syndrome with adult respiratory distress syndrome and multiple organ failure from a staphylococcal panaritium].

Toxic-shock-syndrome (TSS) is an acute febrile, exanthematous illness caused by toxins such as toxic-shock-syndrome-toxine-1 (TSST-1) and other endotoxines from staphylococcus aureus with an incidence of 0,5 per 100.000 inhabitants. Patients with menstrual toxic-shock-syndrome (menstrual-TSS) usually have TSS associated with menstruation and use of a vaginal device such as tampons. Other patients with non-menstrual toxic-shock-syndrome (non-menstrual-TSS) have a focus of staphylococcal infection such as a surgical wound infection or soft tissue abscess. TSS usually presents with fever, pharyngitis, diarrhoea, vomiting, myalgia and may progress rapidly (within hours) to signs of hypovolaemic hypotension and shock. In some cases TSS is associated with multisystem failure including shock, renal failure, myocardial failure and adult respiratory distress syndrome. In its acute phase the diagnosis of TSS is often uncertain because of its initial symptoms are non-specific and numerous conditions need to be considered in the differential diagnosis. But obviously less incidence, the signs and symptoms of toxic-shock-syndrome should be recognised early to permit successful therapy. The site of infection should be adequately drained and treated with antimicrobial therapy. Possible complications including ARDS and myocardial failure require a thorough understanding of its underlying pathophysiology to ensure appropriate intensive-care treatment. Only if appropriate therapy is instituted as early as possible, most of patients will be able to survive their toxic-shock-syndrome. In other cases TSS can be a rapidly progressive and perhaps lethal ending disease because of possible multiple organe failure such as ARDS.

Adolescent↗
PubMed1995

Olfactory toxicity of diethyldithiocarbamate (DDTC) and disulfiram and the protective effect of DDTC against the olfactory toxicity of dichlobenil.

Disulfiram and its breakdown product diethyldithiocarbamate (DDTC) have been investigated for their potential to protect against chemically-induced toxicity and carcinogenesis because of their inhibitory effects on cytochrome P450 2E1. We used DDTC in order to examine the role that cytochrome P450 2E1 plays in the bioactivation of beta,beta'-iminodipropionitrile (IDPN) and 2,6-dichlorobenzonitrile (dichlobenil), resulting in site-specific olfactory lesions in the Long-Evans rat and C57B1 mouse. DDTC and disulfiram themselves produced olfactory mucosal lesions in the rat, whereas DDTC protected against the olfactory toxic effects of dichlobenil in the mouse. A dose-response study revealed that approximately twice the dose of DDTC was required in mice to cause the same olfactory toxic effects seen in the rat. A study to determine the catalytic activity of P450 2E1 by p-nitrophenol (PNP) hydroxylation indicated that the Long-Evans rat nasal mucosa is 2.4 times more active than the C57B1 mouse, which may account for the greater susceptibility of the rat to the olfactory toxic effects of DDTC. PNP hydroxylation assays confirmed that DDTC decreased P450 2E1 activity in both the rat and mouse liver and nasal mucosa. Whereas the results of the mouse study strengthen the hypothesis that dichlobenil is bioactivated to a toxic metabolite by cytochrome P450 2E1 in the C57B1 mouse, rats pretreated with a marginally toxic dose of DDTC prior to the administration of IDPN displayed olfactory mucosal damage, indicating that an alternative or additional pathway may be operative in the metabolism of IDPN and/or DDTC.

Analysis of Variance↗
PubMed1990

Cryoprotectant toxicity and cryoprotectant toxicity reduction: in search of molecular mechanisms.

Cryoprotectant toxicity is a fundamental obstacle to the full potential of artificial cryoprotection, yet it remains in general a poorly understood phenomenon. Unfortunately, most relevant biochemical studies to date have not met the basic criteria required for demonstrating mechanisms of toxicity. A model biochemical study of cryoprotectant toxicity was that of Baxter and Lathe, which demonstrated that alteration of a specific enzyme (fructose diphosphatase, or FDPase) was the cause of impaired glycolysis after treatment with and removal of dimethyl sulfoxide (D). FDPase alteration by D was reported to be preventable by the simultaneous presence of amides. This protection could be due to a "counteracting solute" effect similar to that employed by nature, but we find no meaningful correlation between the general protein stabilizing or destabilizing tendency of the cryoprotectant medium and its toxicity. Baxter and Lathe postulated that the effect of D arises from hydrogen bonding between D and the epsilon amino groups of surface lysine residues on FDPase, and it was found that molecules which resembled this group could block the alteration induced by D, presumably by competing with lysine residues for association with D. However, we find that the interaction between D and lysine in the presence of water is actually thermochemically repulsive, and that the presence of formamide does not affect the interaction between D and lysine, implying no useful complex formation between formamide and D. We were also unable to demonstrate that the blocking compounds consistently reduce toxicity when added to D rather than substituting for D, contrary to predictions based on complex formation between blocking compounds and D. In summary, it seems that present concepts of cryoprotectant toxicity are in need of serious revision.

Amides↗
PubMed1985

Ethyl acrylate-induced gastric toxicity. II. Structure-toxicity relationships and mechanism.

Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).

Acrylates↗