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PubMed2003

Water quality objectives for mixtures of toxic chemicals: problems and perspectives.

The need to develop water quality objectives not only for single substances but also for mixtures of chemicals seems evident. For that purpose, the conceptual basis could be the use of the two existing biometric models: concentration addition (CA) and independent action (IA), which is also called response addition. Both may allow calculation of the toxicity of mixtures of chemicals with similar modes of action (CA) or dissimilar modes of action (IA), respectively. The joint research project Prediction and Assessment of the Aquatic Toxicity of Mixtures of Chemicals (PREDICT) within the framework of the IVth Environment and Climate Programme of the European Commission, provided the opportunity to address (a) chemometric and QSAR criteria to classify substances as supposedly similarly or dissimilarly acting; (b) the predictive values of both models for the toxicity of mixtures at low, statistically nonsignificant effect concentrations of the individual components; and (c) the predictability of mixture toxicity at higher levels of biological complexity. In this article, the general outline, methodological approach, and some preliminary findings of PREDICT are presented. A procedure for classifying chemicals in relation to their structural and toxicological similarities has been developed. The predictive capabilities of CA and IA models have been demonstrated for single species and, to some extent, for multispecies testing. The role of very low effect concentrations in multiple mixtures has been evaluated. Problems and perspectives concerning the development of water quality objectives for mixtures are discussed.

Animals↗
PubMed2006

Defining the toxic mode of action of ester sulphonates using the joint toxicity of mixtures.

Previously we have presented aquatic toxicity data for the class of anionic surfactant ester sulphonates (ES) to Daphnia magna. We now present toxicity data for binary mixtures of ES substances with reference substances of known mode of action. Using a toxic unit (TU) approach, data indicated that ES substances exhibit concentration addition with linear alkylbenzene sulphonate (LAS) and phenols and response addition with alcohols. This suggests that ES behave with a similar mode of action to phenol and LAS which are known polar narcotics and with a dissimilar mode of action to alcohols which are known baseline narcotics.

Alcohols↗
PubMed2005

Influence of hydroxypropylcyclodextrins on the toxicity of mixtures.

We studied the influence of hydroxypropylcyclodextrins (HPCDs) on the toxicity of some mixtures. Using the Photobacterium phosphoreum toxicity test, the joint toxicological effect for Mixture I (containing p-nitrobenzaldehyde and 1-nitronaphthalene) and Mixture II (containing p-nitrobenzaldehyde and malononitrile) were determined in water and in aqueous solutions of HPCDs. The results indicate that, although the toxicological joint effect for Mixture I (simple addition) differs from that of Mixture II (synergism), alpha- and beta-HPCD can significantly reduce the toxicity of the test compounds, whereas gamma-HPCD has only a slight effect. Explanations for these observations are given that invoke the molecular structure of the individual chemicals as well as the structures of HPCDs. This provides information to assist the application of HPCDs in remediation of environmental pollution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMedDate not supplied

Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action.

The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. In a 4-wk feeding study, lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene and d-limonene, each affecting renal proximal tubular cells but through different modes of action, were administered simultaneously at their individual lowest-observed-nephrotoxic-effect level (LONEL), no-observed-nephrotoxic-effect level (NONEL) and NONEL/4. Combined exposure at the LONEL resulted in increased growth depression and increased renal toxicity in male but not in female rats. Co-exposure at the NONEL produced only weak signs of toxicity (slightly retarded growth and increased renal weight), and rats co-exposed at the NONEL/4 did not show any treatment-related changes. The absence of an obviously increased hazard on combined exposure at the NONEL suggested absence of synergism and probably also of additivity. In a subsequent study the additivity assumption (dose addition) was tested, using the similarly acting nephrotoxicants tetrachloroethylene, trichloroethylene, hexachloro-1,3-butadiene and 1,1,2-trichloro-3,3,3-trifluoropropene. The compounds were given to female rats by daily oral gavage for 32 days either alone, at the LONEL and NONEL (= LONEL/4), or in combinations of four (at the NONEL and LONEL/2) or three (at the LONEL/3). Relative kidney weight was increased on exposure to the individual compounds at their LONEL and, to about the same extent, on combined exposure at the NONEL or the LONEL/3. As assessed by this endpoint, the renal toxicity of the mixtures corresponded to the effect expected on the basis of the additivity assumption. The other endpoints were not (or hardly) affected on combined exposure.

Administration, Oral↗
PubMed1997

A proposed approach to study the toxicology of complex mixtures of petroleum products: the integrated use of QSAR, lumping analysis and PBPK/PD modeling.

Mixture toxicity is a topic that has become a matter of concern during the last two decades. One of the major problems with assessing the toxicity of mixtures and the associated human and environmental risk is the large number of possible mixtures, as well as the fact that the actual mixture effect for a given set of constituents might strongly depend on the actual composition of the mixture, i.e., the ratios of the constituent, as well as their nature. This paper presents a possible approach to describe and thereby better understand the pharmacokinetics and dynamics of complex mixtures by combining quantitative structure-activity relationships to predict needed parameters, lumping to reduce the complexity of the problem, and physiologically based pharmacokinetic/pharmacodynamic modeling to integrate all this information into a complete toxicological description of the mixture. It is our hope that by presenting this conceptual approach we might be able to stimulate some criticisms and discussions in the toxicology community regarding this complex and yet very important area of research.

Animals↗
PubMedDate not supplied

Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology.

In the analysis of combined effects two reference concepts are currently considered as equally valid for the assessment of mixture toxicities: these are LOEWE additivity (concentration addition) and BLISS independence (response addition) (Greco et al., 1995). The aim of this study of 137 binary mixtures of pesticides and surfactants using an algal biotest was to find rational procedures for the assessment of mixture toxicities in the aquatic environment. By introducing an index on prediction quality the quantitative relationships between predicted and observed effects are evaluated for each concept. It is shown that LOEWE additivity leads to good predictions of mixture toxicities for most combinations, whereas BLISS independence tends to underestimate mixture toxicities. By this it is reaffirmed that there is a solid basis for forthcoming regulatory activities on mixtures of chemicals.

Animals↗
PubMed1990

Toxicity of mixtures of parathion, toxaphene and/or 2,4-D in mice.

The toxicity of the mixtures of parathion (PA), toxaphene (TOX) and/or 2,4-dichlorophenoxyacetic acid (2,4-D) was studied in ICR male mice (21-24 g) by oral intubation, in corn oil, daily for up to 14 days. On Day 15, the exposure was discontinued, and animals were monitored for an additional period of 7 days for the possible reversibility of the toxicity. The body weight gain decreased with the mixtures, as well as with the individual agricultural chemicals (ACs), during the 14-day period. The cholinesterase (ChE) activity in the serum and brain was inhibited in the animals of the groups of PA (1-10 mg kg-1) and PA (5 mg kg-1)-containing mixtures. TOX (50-200 mg kg-1) caused initial inhibitory effects of 20-65% on the serum ChE (Day 1) before producing increases of 53-64% in the enzyme activity by Day 15, with little effects on the brain ChE levels. 2,4-D (50-200 mg kg-1) resulted in significantly elevated levels of the serum ChE, with substantial decreased in the brain ChE activity. The serum glutamic pyruvic transaminase level was up (38-630%) in TOX (50 mg kg-1), 2,4-D (50 mg kg-1) or their mixture group. No pathological changes at the light microscopic level in the brain and liver were noticed. TOX and TOX-containing mixtures significantly increased the liver/body weight ratio and decreased the pentobarbital (60 mg kg-1, i.p., in saline)-induced sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

2,4-Dichlorophenoxyacetic Acid↗
PubMed2004

[Quantitative structure-activity relationships and joint toxicity of substituted biphenyls].

The single toxicities (24h-EC50) and mixture toxicities of 18 substituted biphenyls to Daphnia magna were tested. Quantitative structure-activity relationships (QSARs) were developed from the single toxicities. Octanol-water partition coefficient (IgK(ow)) model, theoretical linear solvation energy relationship (TLSER) model and quantum chemistry parameter model were built for these compounds. It was found that the quantum chemistry parameter model had a good predictive capability. The study of mixture toxicities of substituted biphenyls showed that the joint toxicity mechanism was concentration addition. Half effective concentrations of mixtures (EC50mix) were predicted according to concentration addition. The predicted and observed values coincided rather well.

Animals↗
PubMed2006

Assessment of the toxicity of mixtures of copper, 9,10-phenanthrenequinone, and phenanthrene to Daphnia magna: evidence for a reactive oxygen mechanism.

Polycyclic aromatic hydrocarbons and their derivatives are ubiquitous environmental contaminants. They are commonly present in complex mixtures with other contaminants, such as metals. The toxicities of phenanthrene (PHE) and 9,10-phenanthrenequinone (PHQ) with or without Cu were determined using Daphnia magna. Copper was the most toxic among the three chemicals tested, followed by PHQ and then PHE, with 48-h median effective concentrations (EC50s) of 0.96, 1.72, and 5.33 microM, respectively. Copper at 0.31 microM, or approximately the 5% effective concentration, decreased the EC50 of PHQ from 1.72 to 0.28 microM. Likewise, PHQ at 1.2 microM, or approximately the 10% effective concentration, significantly lowered the EC50 of Cu from 0.96 to 0.30 microM. This synergistic effect was not observed, however, in mixtures of Cu and PHE based on the response addition model. Assimilation of Cu wasfound to be similar with or without PHQ at increasing external concentrations of Cu, indicating that the increased toxicity of their mixtures is physiologically based. The ability of Cu plus PHQ to generate reactive oxygen species (ROS) was measured as well. Copper alone caused elevated ROS levels at a low concentration (0.63 microM). With PHQ present, however, this elevation in ROS occurred at an even lower Cu level (0.31 microM). Possible attenuation effects of ascorbic acid (vitamin C) on toxicity and ROS production induced by Cu, PHQ, and their mixtures were then examined. Ascorbic acid protected against Cu and Cu-plus-PHQ mixture-mediated toxicity but did not affect PHQ toxicity. Ascorbic acid also lowered ROS levels in the presence of Cu and Cu plus PHQ. We conclude that there exist potential toxic interactions between metals and modified PAHs and that these interactions can involve ROS formation.

Animals↗
PubMed1989

Toxicity of mixtures of trichloroethylene, tetrachloroethylene and 1,1,1-trichloroethane: similarity of in vitro to in vivo responses.

The toxicities of various combinations of trichloroethylene (TRI), tetrachloroethylene (TET) and 1,1,1-trichloroethane (TCE) were examined in suspensions of rat hepatocytes and in vivo. For each pair and for the three solvents together, an interactive toxicity was demonstrated in vitro, as determined by release of potassium ion and cytoplasmic enzymes. A similar pattern of response was found after administration to the intact rat for increases in plasma alanine aminotransferase and sorbitol dehydrogenase, both indices of hepatotoxicity. Plasma urea levels were significantly elevated on exposure to the three chemicals together. Thus a remarkably similar pattern of toxicity was found in vitro and in vivo, which supports the possible use of hepatocyte suspensions as a screening procedure for toxicity of mixtures.

Alanine Transaminase↗
PubMed2006

Analysis of the interaction of phytoestrogens and synthetic chemicals: an in vitro/in vivo comparison.

In the evaluation of chemical mixture toxicity, it is desirable to develop an evaluation paradigm which incorporates some critical attributes of real world exposures, particularly low dose levels, larger numbers of chemicals, and chemicals from synthetic and natural sources. This study evaluated the impact of low level exposure to a mixture of six synthetic chemicals (SC) under conditions of co-exposure to various levels of plant-derived phytoestrogen (PE) compounds. Estrogenic activity was evaluated using an in vitro human estrogen receptor (ER) transcriptional activation assay and an in vivo immature rat uterotrophic assay. Initially, dose-response curves were characterized for each of the six SCs (methoxyclor, o,p-DDT, octylphenol, bisphenol A, beta-hexachlorocyclohexane, 2,3-bis(4-hydroxyphenyl)-propionitrile) in each of the assays. The six SCs were then combined at equipotent ratios and tested at 5-6 dose levels spanning from very low, sub-threshold levels, to a dose in which every chemical in the mixture was at its individual estrogenic response threshold. The SC mixtures also were tested in the absence or presence of 5-6 different levels of PEs, for a total of 36 (in vitro) or 25 (in vivo) treatment groups. Both in vitro and in vivo, low concentrations of the SC mixture failed to increase estrogenic responses relative to those induced by PEs alone. However, significant increases in response occurred when each chemical in the SC mixture was near or above its individual response threshold. In vitro, interactions between high-doses of SCs and PEs were greater than additive, whereas mixtures of SCs in the absence of PEs interacted in a less than additive fashion. In vivo, the SC and PE mixture responses were consistent with additivity. These data illustrate a novel approach for incorporating key attributes of real world exposures in chemical mixture toxicity assessments, and suggest that chemical mixture toxicity is likely to be of concern only when the mixture components are near or above their individual response thresholds. However, these data suggest that extrapolation from in vitro assays to in vivo mixture effects should be approached with caution.

Animals↗
PubMed1997

Bioprotection of microbial communities from toxic phenol mixtures by a genetically designed pseudomonad.

Pseudomonas sp. B13 SN45RE is a genetically engineered microorganism (GEM) that is able to simultaneously degrade mixtures of chloro- and methylaromatics ordinarily toxic for microbial communities via a designed novel ortho-cleavage pathway. The utility of the GEM was investigated in a laboratory scale sewage plant fed with mixtures of either 4-chlorophenol and 4-methyphenol or 3-chlorophenol and 4-methylphenol. In the model system the GEM significantly increased the rate and extent of degradation of the phenol mixtures. In the absence of the GEM, shock loads of the phenol mixtures (1 mM of each compound) reduced the numbers of culturable bacteria by three orders of magnitude, completely eliminated protozoa and metazoa, and caused a drastic decrease in oxygen consumption, whereas the presence of the GEM protected the indigenous microbial community and assured continued functioning of the sewage plant.

Biodegradation, Environmental↗
PubMed1998

Modeling acute and chronic toxicity of nonpolar narcotic chemicals and mixtures to Ceriodaphnia dubia.

The response of the daphnid Ceriodaphnia dubia to six widely used industrial chemicals acting through nonpolar narcosis and a mixture was determined. Toxicological effect levels were based on reasonably steady-state, measured concentrations. Reproductive IC50S were 149 microM benzene, 82 microM trichloroethylene, 35 microM toluene, 31 microM ethylbenzene, 26 microM m-xylene, and 4 microM tetrachloroethylene. A QSAR describing 2-day LC50S as a function of log Kow accounted for 90.97% of the variation in response across chemical. A similar QSAR for chronic effects on reproduction accounted for 78.92%. Mixtures of benzene, trichloroethylene, and toluene had effects at concentrations below their individual LOELs. Observed effects of 20/24 mixtures tested fell within the 95% prediction interval for a concentration-addition model of joint action derived from tests with individual components. However, the observed response differed significantly from the predictive relationship. In general, the predictive relationship overestimated mixture toxicity. Fitted relationships reduced observed error by as much as 82% compared to the predictive model.

Animals↗
PubMed2005

Biochemical responses of the aquatic higher plant Lemna gibba to a mixture of copper and 1,2-dihydroxyanthraquinone: synergistic toxicity via reactive oxygen species.

Metals and polycyclic aromatic hydrocarbons (PAHs) are known to be toxic to plants. Because metals and PAHs often are cocontaminants in the environment, plants can be subjected to damage caused by their combined effects. We recently found that copper and an oxygenated PAH (1,2-dihydroxyanthraquinone [1,2-dhATQ]) synergistically are toxic to plants. This synergistic toxicity was linked indirectly to production of reactive oxygen species (ROS). In this study, plant growth, chlorophyll pigments, protein accumulation, and ROS production were chosen as endpoints to assess the mechanism of toxicity of copper and 1,2-dhATQ to Lemna gibba in more detail. Because copper and PAHs can generate ROS, we assayed for specific antioxidant enzymes: Superoxide dismutase (SOD), glutathione reductase (GR), and ascorbate peroxidase (APX). Copper treatment at a concentration that did not cause growth inhibition resulted in upregulation of Mn SOD, Cu-Zn SOD, and APX. At a level that moderately was toxic to plants, 1,2-dhATQ did not alter significantly the levels of these antioxidant enzymes. However, a synergistically toxic mixture of copper plus 1,2-dhATQ upregulated Cu-Zn SOD, Mn SOD, and GR, although APX activity was downregulated. When plants were treated with the ROS scavenger dimethyl thiourea (DMTU), enhanced toxicity and formation of ROS caused by the mixture both were diminished substantially. However, 1,2-dhATQ toxicity was not affected significantly by DMTU. Based on this study, the toxicity caused by the mixture of copper plus 1,2-dhATQ directly can be connected to elevated levels of ROS.

Anthraquinones↗
PubMed1985

Joint toxicity of mixtures of groups of organic aquatic pollutants to the guppy (Poecilia reticulata).

In this study acute lethal concentrations (LC50) to the guppy (Poecilia reticulata) were determined for mixtures of 4 groups of aquatic pollutants. The groups were composed of 11 nonreactive, nonionized organic chemicals, 11 chloroanilines, 11 chlorophenols, and 9 reactive organic halides. Earlier studies indicated that the joint toxicity within each of these groups was concentration additive, probably because of a similar mode of action. The joint toxicity of combinations of one representative from each group showed a high variance, but generally tended to be partially additive to concentration additive. This high variance is probably caused by the low number of compounds in these mixtures. Experiments with mixtures of whole groups gave more accurate results. The toxicity of a mixture of the first three groups, containing 33 well-known aquatic pollutants, was almost completely concentration additive. Concentrations of 0.04 of the individual LC50 values contributed to the toxicity of this mixture.

Aniline Compounds↗
PubMed1999

Interaction between phenanthrene and zinc in their toxicity to the sheepshead minnow (Cyprinodon variegatus).

Many contaminated sites contain a variety of toxicants. Risk assessment and the development of water quality criteria therefore require information on the interactive effects among toxicants in such mixtures. Interactions between metals are relatively well studied, but little is known about interactions between metals and hydrocarbons. This study investigated the interaction between phenanthrene and zinc in the sheepshead minnow Cyprinodon variegatus. Interaction studies were performed with 7-day-old minnows in 96-h bioassays with zinc and phenanthrene at a fixed ratio and with varying proportions of zinc and phenanthrene. Mixture toxicity was quantified with the toxic unit, additive index, and excess function methods. All three methods generally indicated an antagonistic interaction between phenanthrene and zinc, though the results also provide some evidence for a synergistic interaction at low toxicant levels or at specific phenanthrene-to-zinc ratios. Short-term uptake experiments were conducted to determine if the strong antagonistic interaction observed when zinc and phenanthrene were present at 50% of their LC50 values was due to effects of zinc and phenanthrene on each other's uptake. Significantly less 65Zn uptake occurred in the presence of phenanthrene than in its absence. In contrast, zinc did not appear to affect the uptake of 14C-phenanthrene.http://link. springer-ny.com/link/service/journals/00244/bibs/37n2p251.++ +html

Animals↗
PubMed2004

Pharmaceuticals in the aquatic environment--a comparison of risk assessment strategies.

The growing concern over the release of pharmaceutically active compounds and personal care products into the environment has prompted the introduction of risk assessment guidelines in both the European Union by the European Medicines Evaluation Agency (EMEA) and in the United States by the Food and Drug Administration (FDA), details of which are presented herein. Both employ a similar tiered system that compares the predicted environmental concentrations (PEC) with the worst-case no effect concentrations estimated from standard toxicity assays. These approaches are compared and contrasted. Results demonstrate room for improvement in areas such as the use of threshold values to trigger investigations, chronic and mechanism specific toxicity screening and mixture toxicity for which possible solutions are proposed.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2006

Effect of hardness on acute toxicity of metal mixtures using Daphnia magna: prediction of acid mine drainage toxicity.

In this study, the effect of hardness on the combined outcome of metal mixtures was investigated using Daphnia magna. The toxic unit (TU) was calculated using modified LC(50) values based on the hardness (i.e., LC(50-soft) and LC(50-hard)). From a bioassay test, the degree of sensitivity to hardness on the toxicity changes was in the order: Cd<Cu<Zn<Pb, with 25, 66, 77 and 88% decreases in the LC(50) values, respectively, when the hard test solution was replaced with a soft test solution. In mixture toxicity tests, the difference in the test solution hardness was found to clearly cause different toxicities, as determined by the TU calculated by the LC(50-hard), using the toxicity of a standard culture medium as the reference. That is, approximately four to five times higher toxicity was observed in soft (i.e., 44+/-4 mg/L as CaCO(3)) rather than hard water (i.e., 150+/-10mg/L as CaCO(3)) test solutions. In the tests where the modified reference toxicity values (i.e., LC(50-soft) and LC(50-hard) for soft and hard test solution, respectively) obtained from the individual metal toxicity tests with different hardness were used to calculate the TU, the results showed very similar D. magna toxicities to those of the TU from the mixture of soft and hard test solutions, regardless of the hardness. According to the toxicity results of the mixture, the aquatic toxic effects of the acid mine drainage (AMD) collected from mine areas that contained metal mixtures were investigated using Daphnia magna and the modified LC(50) value of the TU hardness function calculated for varying solution hardness. The results of the biological WET test closely matched our overall prediction, with significant correlation, having a p-value of 0.513 in one way ANOVA test (n=19). Therefore, this study revealed that the predicted toxicity of the metal mixture agreed well with the biological toxicity test when the modified LC(50) value was employed as the basis of hardness in the TU calculation.

Acids↗