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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↗
PubMed1994

Responses of Gammarus pulex (Amphipoda, Crustacea) to metalliferous effluents: identification of toxic components and the importance of interpopulation variation.

This study was designed to evaluate the ability of an in-situ bioassay to assess the impact of complex effluents on freshwaters and to identify toxic components. Reductions in the feeding rate of Gammarus pulex proved to be a sensitive indicator of the impact of metalliferous effluents on receiving water quality. The effluents contained a mixture of five potentially toxic metals. By combining information on feeding rates with bioaccumulation data, two metals, iron and manganese, were identified as the probable toxic agents. Laboratory experiments validated the conclusions reached from the field study and confirmed that iron was a major toxicant. The sensitivities of Gammarus pulex from a metal-contaminated site and a clean site were compared during both the field and laboratory studies. Interpopulation differences in the response of G. pulex to toxicants were detected in the field study but not in the laboratory experiments. Possible reasons for this are discussed.

Journal Article↗
PubMedDate not supplied

Acute toxicity of aluminium chloride, acephate, and their coexposure in male Wistar rat.

Exposures to environmental pollutants are often not limited to a single chemical. Probabilities of exposure to two or more compounds are high. As information on toxic interactions between metal and pesticide are lacking, the present study was undertaken to find the toxic effect of a mixture of a metal and a pesticide. Aluminium, a common metal compound, and acephate, an organophosphorous pesticide, are two widely used chemicals known for their neurotoxic effects. To assess the toxic interaction of aluminium and acephate, acute toxicity study of aluminium chloride, acephate, and their combination was made. Male Wistar albino rats were dosed orally in a increasing geometric progressive doses of aluminium chloride, acephate, and their combination (1 part aluminium:1 part acephate) in distilled water. The median lethal oral dose of aluminium chloride, acephate, and their combination was found to be 3630 +/- 400, 2851 269, and 4074 +/- 388 mg/kg body weight respectively. Log dose-response curve revealed the acute toxic effects of combination of metal and pesticide to be reduced, suggesting antagonistic action. Antagonistic action of the combination of compounds shows that aluminium reduced the toxic effect of organophosphorous pesticide acephate. It is of clinical interest to further explore the antagonistic action and determine whether aluminium could be used to reduce the toxic effect produced by organophosphorous pesticides.

Algorithms↗
PubMed1993

[Cytochromes P450: toxicologic importance of determination of levels].

Drug-metabolizing enzymes, especially cytochrome P450-dependent monooxygenases, are involved in the metabolic activation of the majority of xenobiotics and in the production of oxygen radicals. The most significant are cytochromes P450IA1 and IA2, but also P450IIB, IIE and IIIA are involved. Various classes of xenobiotics induce levels of distinct P450 forms. Their key position in the expression of toxic, mutagenic, carcinogenic and other adverse effects of reactive metabolites and oxygen radicals allows us: 1. to estimate the tetrachlorodibenzo-p-dioxin-like toxicity in both environmental mixtures and individual contaminants by the measurement of induction of P450IA1; 2. to monitor the contamination of ecosystems by the measurement of P450 induction in selected species; 3. to determine toxicity potentials of drugs, agrochemicals, industrial contaminants and other xenobiotics by the measurement of P450IA, IIB, IIE, IIIA and/or IVA levels in model systems.

Animals↗
PubMed1987

A new approach for using short-term tests to screen complex mixtures.

This paper suggests a framework for developing parsimonious batteries of rapid, inexpensive biological assays which provide quantifiable estimates of human risk. The framework for the statistical design is tier testing. The framework develops an unusual perspective for using chemical spiking to evaluate the toxicity of a complex mixture to a battery of bioassays. This framework allows immediate evaluation of hazardous wastes and identifies important problems to provide focus for basic research.

Animals↗
PubMed2002

Pesticide toxicity assessment using an electrochemical biosensor with Pseudomonas putida and a bioluminescence inhibition assay with Vibrio fischeri.

Two different toxicity tests, an electrochemical biosensor Cellsense and a bioluminescence inhibition assay ToxAlert were performed in order to establish and compare the acute toxicity responses of different types of raw and spiked water for a selected group of pesticides. The selected compounds were endosulfan, chlorfenvinphos, dimethoate, fenamiphos, ametryn, deltamethrin and alpha-cypermethrin; all of them are used in large quantities for agricultural purposes. In the first step, the study of the toxicity responses for each individual pesticide with Milli-Q water was carried out. Next, the toxic responses of different mixtures of these pesticides in different water matrices, i.e., Milli-Q water, surface water, groundwater and wastewater were studied in order to evaluate (i) device advantages and limitations for the toxicity evaluation of real environmental samples, (ii) antagonistic or synergistic effects and (iii) the influence of the water matrices. The survey of pesticides in real samples was carried out using a combined method involving both chemical analysis and toxicity bioassays. Chemical analysis involved the use of solid-phase micro-extraction (SPME) followed by gas chromatography with electron capture detection (GC/ECD) or thermoionic specific detection (GC/TSD) with mass spectrometric confirmation (GC/MS).

Biosensing Techniques↗
PubMedDate not supplied

In vitro toxicological methods for environmental health testing.

Increasing public interest in environmental health issues has created a demand for alternatives to using animals for assessing the toxic effects of chemical mixtures on humans. This review focuses on applications of in vitro toxicological screening methods developed for human health biomonitoring using cultured clonal cell lines, which have the which have the following advantages: genetic variation between samples and experiments is minimal; the cultivation of cell lines is rapid and consistent conditions for culture are easily maintained; most of the phenotypic variation that is encountered with use of cell donors is eliminated; and radiolabeled precursors can be used for labeling and quantifying protein and DNA. We describe the current state of development of in vitro toxicity testing methods, present detailed procedures for the test methods optimized in our laboratory, and compare these techniques with other approaches. Toxicity testing using cell lines provides a mechanism to quantify the risks associated with environmental exposure to chemical mixtures.

Animal Testing Alternatives↗
PubMed2003

Pesticide degradation in a 'biobed' composting substrate.

Pesticides play an important role in the success of modern farming and food production. However, the release of pesticides to the environment arising from non-approved use, poor practice, illegal operations or misuse is increasingly recognised as contributing to water contamination. Biobeds appear to offer a cost-effective method for treating pesticide-contaminated waste. This study was performed to determine whether biobeds can degrade relatively complex pesticide mixtures when applied repeatedly. A pesticide mixture containing isoproturon, pendimethalin, chlorpyrifos, chlorothalonil, epoxiconazole and dimethoate was incubated in biomix and topsoil at concentrations to simulate pesticide disposal. Although the data suggest that interactions between pesticides are possible, the effects were of less significance in biomix than in topsoil. The same mixture was applied on three occasions at 30-day intervals. Degradation was significantly quicker in biomix than in topsoil. The rate of degradation, however, decreased with each additional treatment, possibly due to the toxicity of the pesticide mixture to the microbial community. Incubations with chlorothalonil and pendimethalin carried out in sterile and non-sterile biomix indicated that degradation, rather than irreversible adsorption to the matrix, was the main mechanism responsible for the reduction in recovered residues. Results from these experiments suggest that biobeds offer a viable means of treating pesticide waste.

Biodegradation, Environmental↗
PubMed1986

Toxic response of hamster embryo cells on exposure to mixtures of Ni2+ and benzo(a)pyrene.

Exposure of hamster embryo cells (HEC) to mixtures of benzo(a) pyrene and soluble Ni2+ neutral salts elicits additive responses in the enhanced nucleoside excretion assay. Ni2+ shows no significant excretion response until concentrations near 10 microM are reached. Addition of 0.4 micromolar benzo(a)pyrene and 30 microM, or 325 microM Ni2+ to HEC cultures results in total excretion equal to the sum of excretions induced by the individual chemicals. These observations suggest that excretion of pyrimidines may be a useful measure of biological dosimetry.

Animals↗
PubMed2006

Organic pollutant removal versus toxicity reduction in industrial wastewater treatment: the example of wastewater from fluorescent whitening agent production.

Industrial wastewater treatment in the chemical industry aims at eliminating organic contaminants, as these pollutants may be persistent and ecotoxic. In a case study performed in collaboration with the chemical industry, we investigated the removal of a fluorescent whitening agent and its side products in the wastewater-treatment system. Adsorption to activated carbon and biological treatment were simulated in laboratory tests. Algae toxicity tests were performed to quantify the toxicity of the wastewater mixture and of single components. The contaminants identified accounted for up to 82% of the wastewater's total organic carbon (TOC). Adsorption to activated carbon eliminated the TOC and the single contaminants only slightly. Nevertheless, the toxicity of the wastewater decreased by 40%. In contrast, biological treatment reduced the TOC by up to 80%, and the whole effluent toxicity increased. These results indicate that new ecotoxic metabolites were formed during the biological treatment. They also illustrate that mere reduction of the TOC in the wastewater-treatment system is not sufficient for ensuring a reduction of environmental impact. Therefore, simultaneously conducting TOC measurements and toxicity tests, as demonstrated in the current work, is recommended.

Adsorption↗
PubMed2000

Mixtures and interactions.

Drinking water can be considered as a complex mixture that consists of tens, hundreds or thousands of chemicals of which the composition is qualitatively and quantitatively not fully known. From a public health point of view it is most relevant to answer the question of whether chemicals in drinking water interact in a way that results in an increased overall response as compared to the sum of the responses to the individual chemicals in the mixture, or indeed in an effect that is simply a summation of the expected effects of the individual chemicals. Present methods for risk assessment of mixtures rely heavily on some form of additivity model, unless data are adequate for a direct risk assessment of the mixture of concern in its entirety. The "dose-addition" concept ("simple similar action") is the most common approach to risk assessment of mixtures and it is applicable over the whole range of exposure levels from low non-toxic to toxic levels when all chemicals in the mixture act in a similar way. However, in toxicity studies at environmentally relevant exposure scenarios the mixtures that meet such conditions are the exception rather than the rule. In that case the "effect addition" model has to be followed assuming "independent joint action". For these compounds now experimental data have indicated that the results at low exposure levels are probably difficult to predict based on response additivity found at higher dose levels. Thus, although the additivity models are mathematically simple, they require assumptions about the mechanisms of action and the high-to-low dose extrapolation. Therefore, theoretical considerations in risk assessment of chemical mixtures should be verified by simple case studies. Up till now, the number of environmentally relevant mixtures to which a direct risk assessment has been devoted is limited. Even if toxicity data on individual compounds are available, we are still facing the immense problem of extrapolation of findings obtained at relatively high exposure concentration in laboratory animals to man being exposed to (much) lower concentrations. Therefore the prioritization of compounds for further research and the extrapolation to low doses should be considered as key issues in the assessment of possible health risks from exposure to chemical mixtures such as drinking water.

Drug Interactions↗
PubMed2000

Effects of arsenic, cadmium, chromium, and lead on gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells.

Toxic metals occur naturally at low concentrations throughout the environment, but are found in higher concentrations at many of the hazardous waste sites on the EPA Superfund list. As part of the Agency for Toxic Substances and Disease Registry (ATSDR) mandate to evaluate the toxicity of metals and mixtures, we chose four of the high-priority metal pollutants from ATSDR's HAZDAT list, including arsenic, cadmium, chromium, and lead, to test in a commercially developed assay system, CAT-Tox(L) (Xenometrix). This assay employs a battery of recombinant HepG2 cell lines to test the transcriptional activation capacity of xenobiotics in any of 13 different signal transduction pathways. Our specific aims were to identify metal-responsive promoters and determine whether the pattern of gene expression changed with a mixture of metals. Humic acid was used in all assays as a carrier to help solubilize the metals and, in all cases, the cells were exposed to the humic acid-metal mixture for 48 h. Humic acid alone, at 50-100 microM, showed moderate activation of the XRE promoter, but little other notable activity. As(V), at doses of 50-250 microM, produced a complex profile of activity showing significant dose-dependent induction of the hMTIIA, GST Ya, HSP70, FOS, XRE, NFkappaBRE, GADD153, p53RE, and CRE promoters. Pb(II) showed dose-related induction of the GST Ya, XRE, hMTIIA, GRP78, and CYP IA1 promoters at doses in the range of 12-100 microM. Cd(II), at 1.25-15 microM, yielded significant dose-dependent induction of hMTIIA, XRE, CYP IA1, GST Ya, HSP70, NFkappaBRE, and FOS. Whereas Cr(III) yielded small, though significant inductions of the CRE, FOS, GADD153, and XRE promoters only at the highest dose (750 microM), Cr(VI) produced significant dose-related inductions of the p53RE, FOS, NFkappaBRE, XRE, GADD45, HSP70, and CRE promoters at much lower doses, in the range of 5-10 microM. Assays testing serial dilutions of a mixture comprising 7.5 microM Cd(II), 750 microM Cr(III), and 100 microM Pb(II) (the combination of metals most frequently found at National Priority List sites) showed significant dose-dependent induction of the hMTIIA promoter, but failed to show dose-related induction of any other promoter and showed no evidence of synergistic activation of gene expression by the metals in this mixture. Our results thus show metal activation of gene expression through several previously unreported signal transduction pathways, including As(V) induction of GST Ya, FOS, XRE, NFkBRE, GADD153, p53RE, and CRE; Pb(II) induction of GST Ya, XRE, Cyp IA1, and GADD153; Cd(II) induction of NFkBRE, Cyp IA1, XRE, and GST Ya; and Cr(VI) induction of p53RE, XRE, GADD45, HSP70, and CRE promoters, and thus suggest new insights into the biochemical mechanisms of toxicity and carcinogenicity of metals. It is also an important finding that no evidence of synergistic activity was detected with the mixture of Cd(II), Cr(III), and Pb(II) tested in these assays.

Arsenic↗
PubMed2002

The use of in vitro methods for hazard characterisation of chemicals.

The usual starting points for hazard characterisation are No Observed Adverse Effect Levels (NOAELs)/benchmark doses for threshold effects and risk-specific doses/unit risks for non-threshold effects. In vitro studies are in general of no use in identifying these doses. However, based in part on in vitro investigations toxic equivalency factors have been developed for selected halogenated organic PCDD/PCDF/PCB congeners. Such factors can be used to determine the total toxic equivalent doses of mixtures of these contaminants. Studies with paracetamol illustrate that in vitro systems may help in the identification of the most sensitive species and strain. In vitro methods have been successfully used to studying qualitative and quantitative species differences in the toxicity of agents such as peroxisome proliferators and dichloromethane. Investigations with a number of chemicals show that in vitro systems are excellent models for characterisation of the mode of action of chemicals, but in vitro findings need to be validated in vivo. Experiments with bis(tri-n-butyltin)oxide illustrate that in vitro systems may aid in the extrapolation from high to low dose and from experimental animals to humans. In addition, in vitro approaches can be used to obtain useful information on the disposition of xenobiotics. It is concluded that if sufficient in vivo mechanistic information is available, in vitro studies using sub-cellular fractions/cells/tissue from animals and humans may significantly aid in the hazard characterisation of chemicals.

Animals↗
PubMed1991

CFC replacements: safety testing, approval for use in metered dose inhalers.

HFA-134a and HFA-227 (chlorine free hydrofluoro-alkanes) are at present in extensive nonclinical safety testing sponsored by two joint research consortia (IPACT-I, IPACT-II) of companies interested in metered dose inhalers (MDI). The rationale for toxicity testing of these CFC replacements is to predict safety of their use as drug propellants in MDI. Frequency of use, intervals and systemic exposure levels are key parameters. Intact animals and in-vitro systems repeatedly exposed to multiples of patient doses, under conditions comparable to human administration should not show adverse reactions. With an emphasis different from non-U.S. Health Authorities, the U.S. FDA insists on proof of toxic effects which may require excessive doses. This principle is questioned for essentially inert gases such as CFCs and HFA-134a and HFA-227 which only through the effects of oxygen deprivation at unreasonably high concentrations of the inhaled propellant/air mixture indirectly cause mild toxic effects in animals. Provided that no intrinsic toxic effects will be detected, chances are good that these CFC replacements will eventually be approved. In view of the estimated 5-year testing time frame and the risks involved, CFCs should remain available for MDI for some time in the future.

Administration, Inhalation↗
PubMed2002

Interactions between a polycyclic aromatic hydrocarbon mixture and the microbial communities in a natural freshwater sediment.

The toxicity of a polycyclic aromatic hydrocarbon (PAH) mixture was assessed on the indigenous microbial communities of a natural freshwater sediment. The fate and effects of the PAH mixture (phenanthrene, fluoranthene and benzo(k)fluoranthene) were studied over 28 days. Bacterial communities were described by bacterial counts (total bacteria and viable bacteria), and by some hydrolytic enzyme activities (beta-glucosidase and leucine-aminopeptidase), PAH concentrations were measured in the overlying waters and in the sediments. No effect of PAH was detected at 30 mg/kg for all bacterial parameters. At 300 mg/kg, the quantity of total bacteria and the proportion of viable bacteria markedly decreased, compared to the control (0 mg PAH/kg). At 300 mg/kg, an increase of the beta-glucosidase activity and a decrease of the leucine-aminopeptidase activity were observed. For all treatments, the benzo(k)fluoranthene concentration in the sediment was stable over 28 days whereas, in the same time, only 3-6% of the initial concentrations of phenanthrene and fluoranthene remained. This study shows that (1) PAH induce perturbations of sediment microbial communities in terms of density and metabolism (but not always as an inhibition), (2) indigenous bacteria of sediments might be used for toxicity assessment of specific organic pollutants, (3) native microorganisms of sediment seem to have a high capacity for PAH degradation, depending on the physico-chemical properties and the bioavailability of the substance encountered.

Bacteria↗
PubMedDate not supplied

The use of a genetically engineered Pseudomonas species (Shk1) as a bioluminescent reporter for heavy metal toxicity screening in wastewater treatment plant influent.

Heavy metals are known to be inhibitory and toxic to the activated-sludge microbial community in biological wastewater treatment plants. Toxicity screening of aqueous mixtures of these heavy metal ions in plant influent could use both chemical and biological methods. As a biological method, luminescent bacterial bioreporters offer the advantages of a simple test procedure and rapid response. Current biologically based methods for screening aqueous streams for toxicity are labor-intensive, inaccurate, or difficult to use in continuous monitoring applications. In the present study, a system was developed that is simple and easily automated. This system is based on the bacterium Shk1, a genetically engineered bioluminescent Pseudomonad whose parent strain was originally isolated from activated sludge. Compared with other bioluminescence-based systems (specifically, the Microtox assay), the system of the present study more accurately reflects the effects of the toxicity of common metal ions on activated-sludge respirometry without being overly sensitive to typical constituents of wastewater. The use of Shk1 as a bioluminescent reporter for heavy metal toxicity testing for the application of wastewater treatment influent toxicity screening is presented in this study.

Biological Assay↗