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Chemical Mixtures (chemical + mixture)
Selected AbstractsCumulative effects of in utero administration of mixtures of reproductive toxicants that disrupt common target tissues via diverse mechanisms of toxicityINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2010C. V. Rider Summary Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act required the US Environmental Protection Agency to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures of chemicals to elucidate mechanisms of joint action at the systemic level with the goal of providing a framework for assessing the cumulative effects of reproductive toxicants. Previous mixture studies conducted with antiandrogenic chemicals are reviewed briefly and two new studies are described. In all binary mixture studies, rats were dosed during pregnancy with chemicals, singly or in pairs, at dosage levels equivalent to approximately one-half of the ED50 for hypospadias or epididymal agenesis. The binary mixtures included androgen receptor (AR) antagonists (vinclozolin plus procymidone), phthalate esters [di(n-butyl) phthalate (DBP) plus benzyl n-butyl phthalate (BBP) and diethyl hexyl phthalate (DEHP) plus DBP], a phthalate ester plus an AR antagonist (DBP plus procymidone), a mixed mechanism androgen signalling disruptor (linuron) plus BBP, and two chemicals which disrupt epididymal differentiation through entirely different toxicity pathways: DBP (AR pathway) plus 2,3,7,8 TCDD (AhR pathway). We also conducted multi-component mixture studies combining several ,antiandrogens'. In the first study, seven chemicals (four pesticides and three phthalates) that elicit antiandrogenic effects at two different sites in the androgen signalling pathway (i.e. AR antagonist or inhibition of androgen synthesis) were combined. In the second study, three additional phthalates were added to make a 10 chemical mixture. In both the binary mixture studies and the multi-component mixture studies, chemicals that targeted male reproductive tract development displayed cumulative effects that exceeded predictions based on a response-addition model and most often were in accordance with predictions based on dose-addition models. In summary, our results indicate that compounds that act by disparate mechanisms of toxicity to disrupt the dynamic interactions among the interconnected signalling pathways in differentiating tissues produce cumulative dose-additive effects, regardless of the mechanism or mode of action of the individual mixture component. [source] Computational economy improvements in PRISMINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 9 2003Shaheen R. Tonse The Piecewise Reusable Implementation of Solution Mapping (PRISM) procedure is applied to reactive flow simulations of (9-species) H2 + air combustion. PRISM takes the solution of the chemical kinetic ordinary differential equation system and parameterizes it with quadratic polynomials. To increase the accuracy, the parameterization is done piecewise, by dividing the multidimensional chemical composition space into hypercubes and constructing polynomials for each hypercube on demand. The polynomial coefficients are stored for subsequent repeated reuse. Initial cost of polynomial construction is expensive, but it recouped as the hypercube is reused, hence computational gain depends on the degree of hypercube reuse. We present two methods that help us to identify hypercubes that will ultimately have high reuse, this being accomplished before the expense of constructing polynomials has been incurred. One method utilizes the rate of movement of the chemical trajectory to estimate the number of steps the trajectory would make through the hypercube. The other method defers polynomial construction until a preset threshold of reuse has been met; an empirical method which, nevertheless, produces a substantial gain. The methods are tested on a 0-D chemical mixture and reactive flow 1-D and 2-D simulations of selected laminar and turbulent H2 + air flames. The computational performance of PRISM is improved by a factor of about 2 for both methods. © 2003 Wiley Periodicals, Inc., Int J Chem Kinet 35: 438,452, 2003 [source] Factors affecting the degradation of pharmaceuticals in agricultural soils,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2009Sara C. Monteiro Abstract Pharmaceuticals may be released to the soil environment through the application of biosolids to land. To understand those factors affecting the persistence of pharmaceuticals in the soil environment, the present study was performed to assess the effects of soil type, the presence of biosolids, and the impact of chemical mixture interactions on the degradation of three pharmaceuticals: naproxen, carbamazepine, and fluoxetine. Single-compound studies showed that naproxen degraded in a range of soils with half-lives ranging from 3.1 to 6.9 d and in biosolids with a half-life of 10.2 d. No relationships were observed between degradation rate and soil physicochemical properties and soil bioactivity. For naproxen, addition of biosolids to soils reduced the degradation rate observed in the soil-only studies, with half-lives in the soil-biosolid systems ranging from 3.9 to 15.1 d. Carbamazepine and fluoxetine were found to be persistent in soils, biosolids, and soil-biosolid mixtures. When degradation was assessed using a mixture of the three study compounds and the sulfonamide antibiotic sulfamethazine, the degradation behavior of fluoxetine and carbamazepine was similar to that observed in the single compound studies (i.e., no degradation). However, the degradation rate of naproxen in soils, biosolids, and soil-biosolid systems spiked with the mixture was significantly slower than in the single-compound studies. As degradation studies for risk assessment purposes are performed using single substances in soil-only studies, it is possible that current risk assessment procedures will underestimate environmental impacts. Further work is therefore warranted on a larger range of substances, soils, biosolid types, and chemical mixtures to better understand the fate of pharmaceuticals in terrestrial systems. [source] Nonnutrient anthropogenic chemicals in seagrass ecosystems: Fate and effectsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2009Michael A. Lewis Abstract Impacts of human-related chemicals, either alone or in combination with other stressors, are important to understand to prevent and reverse continuing worldwide seagrass declines. This review summarizes reported concentrations of anthropogenic chemicals in grass bed,associated surface waters, sediments, and plant tissues and phytotoxic concentrations. Fate information in seagrass-rooted sediments and overlying water is most available for trace metals. Toxicity results in aqueous exposures are available for at least 13 species and a variety of trace metals, pesticides, and petrochemicals. In contrast, results for chemical mixtures and chemicals in sediment matrices are uncommon. Contaminant bioaccumulation information is available for at least 23 species. The effects of plant age, tissue type, and time of collection have been commonly reported but not biological significance of the chemical residues. Experimental conditions have varied considerably in seagrass contaminant research and interspecific differences in chemical residues and chemical tolerances are common, which limits generalizations and extrapolations among species and chemicals. The few reported risk assessments have been usually local and limited to a few single chemicals and species representative of the south Australian and Mediterranean floras. Media-specific information describing exposure concentrations, toxic effect levels, and critical body burdens of common near-shore contaminants is needed for most species to support integrated risk assessments at multiple geographical scales and to evaluate the ability of numerical effects-based criteria to protect these marine angiosperms at risk. [source] Hormesis: Why it is important to toxicology and toxicologists,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2008Edward J. Calabrese Abstract This article provides a comprehensive review of hormesis, a dose-response concept that is characterized by a low-dose stimulation and a high-dose inhibition. The article traces the historical foundations of hormesis, its quantitative features and mechanistic foundations, and its risk assessment implications. The article indicates that the hormetic dose response is the most fundamental dose response, significantly outcompeting other leading dose-response models in large-scale, head-to-head evaluations. The hormetic dose response is highly generalizable, being independent of biological model, endpoint measured, chemical class, and interindividual variability. Hormesis also provides a framework for the study and assessment of chemical mixtures, incorporating the concept of additivity and synergism. Because the hormetic biphasic dose response represents a general pattern of biological responsiveness, it is expected that it will become progressively more significant within toxicological evaluation and risk assessment practices as well as have numerous biomedical applications. [source] Examining the single and interactive effects of three insecticides on amphibian metamorphosis,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2008Michelle D. Boone Abstract Although aquatic communities frequently are exposed to a number of pesticides, the effects of chemical mixtures are not well understood. In two separate studies, I examined how insecticide mixtures influenced the likelihood of unpredictable, nonadditive effects on American toad (Bufo americanus) and green frog (Rana clamitans) tadpoles reared in outdoor aquatic communities. I exposed tadpoles to single or multiple insecticides at approximately half the reported median lethal concentrations using insecticides that were either acetylcholinesterase inhibitors (carbaryl or malathion) or a sodium-channel disruptor (permethrin). I found that combinations of insecticides with the same mode of action were more likely to have nonadditive effects on amphibian metamorphosis compared with those having different modes of action. Additionally, in one study, a commercial formulation of permethrin led to near-complete elimination of American toads, suggesting that this formulation could have adverse effects on aquatic communities. Many community studies exploring the ecological effects of expected environmental concentrations of pesticides have suggested that indirect effects in the food web, rather than direct effects on individual physiology, have the largest effect on amphibians. The present study indicates that direct effects of pesticides may become particularly important when insecticides with the same mode of action are present in the environment. [source] Development and validation of a 2,000-gene microarray for the fathead minnow (Pimephales promelas)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2007Patrick Larkin Abstract Gene microarrays provide the field of ecotoxicology new tools to identify mechanisms of action of chemicals and chemical mixtures. Herein we describe the development and application of a 2,000-gene oligonucleotide microarray for the fathead minnow Pimephales promelas, a species commonly used in ecological risk assessments in North America. The microarrays were developed from various cDNA and subtraction libraries that we constructed. Consistency and reproducibility of the microarrays were documented by examining multiple technical replicates. To test application of the fathead minnow microarrays, gene expression profiles of fish exposed to 17,-estradiol, a well-characterized estrogen receptor (ER) agonist, were examined. For these experiments, adult male fathead minnows were exposed for 24 h to waterborne 17,-estradiol (40 or 100 ng/L) in a flow-through system, and gene expression in liver samples was characterized. Seventy-one genes were identified as differentially regulated by estradiol exposure. Examination of the gene ontology designations of these genes revealed patterns consistent with estradiol's expected mechanisms of action and also provided novel insights as to molecular effects of the estrogen. Our studies indicate the feasibility and utility of microarrays as a basis for understanding biological responses to chemical exposure in a model ecotoxicology test species. [source] Comparative sediment quality guideline performance for predicting sediment toxicity in Southern California, USAENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2005Doris E. Vidal Abstract Several types of sediment quality guidelines (SQGs) are used by multiple agencies in southern California (USA) to interpret sediment chemistry data, yet little information is available to identify the best approaches to use. The objective of this study was to evaluate the predictive ability of five SQGs to predict the presence and absence of sediment toxicity in coastal southern California: the effects range-median quotient (ERMq), consensus moderate effect concentration (consensus MEC), mean sediment quality guideline quotient (SQGQ1), apparent effects threshold (AET), and equilibrium partitioning (EqP) for organics. Large differences in predictive ability among the SQGs were obtained when each approach was applied to the same southern California data set. Sediment quality guidelines that performed well in identifying nontoxic samples were not necessarily the best predictors of toxicity. In general, the mean ERMq, SQGQ1q, and consensus MECq approaches had a better overall predictive ability than the AET and EqP for organics approaches. In addition to evaluating the predictive ability of SQGs addressing chemical mixtures, the effect of an individual SQG value (DDT) was also evaluated for the mean ERMq with and without DDT. The mean ERMq without DDT had a better ability to predict toxic samples than the mean ERMq with DDT. Similarities in discriminatory ability between different approaches, variations in accuracy among SQG values for some chemicals, and the presence of complex mixtures of contaminants in most samples underscore the need to apply SQGs in combination, such as the mean quotient. Management objectives and SQG predictive ability using regional data should be determined beforehand so that the most appropriate SQG approach and critical values can be identified for specific applications. [source] Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysisENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2005Martijs J. Jonker Abstract In ecotoxicology, the state of the art for effect assessment of chemical mixtures is through multiple dose,response analysis of single compounds and their combinations. Investigating whether such data deviate from the reference models of concentration addition and/or independent action to identify overall synergism or antagonism is becoming routine. However, recent data show that more complex deviation patterns, such as dose ratio,dependent deviation and dose level,dependent deviation, need to be addressed. For concentration addition, methods to detect such deviation patterns exist, but they are stand-alone methods developed separately in literature, and conclusions derived from these analyses are therefore difficult to compare. For independent action, hardly any methods to detect such deviations from this reference model exist. This paper describes how these well-established mixture toxicity principles have been incorporated in a coherent data analysis procedure enabling detection and quantification of dose level,and dose ratio,specific synergism or antagonism from both the concentration addition and the independent action models. Significance testing of which deviation pattern describes the data best is carried out through maximum likelihood analysis. This analysis procedure is demonstrated through various data sets, and its applicability and limitations in mixture research are discussed. [source] Dynamic reduction of a CH4/air chemical mechanism appropriate for investigating vortex,flame interactionsINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 4 2007Shaheen R. Tonse This paper describes two methods, piecewise reusable implementation of solution mapping (PRISM) and dynamic steady-state approximation (DYSSA), in which chemistry is reduced dynamically to reduce the computational burden in combustion simulations. Each method utilizes the large range in species timescales to reduce the dimensionality to the number of species with slow timescales. The methods are applied within a framework that uses hypercubes to partition multidimensional chemical composition space, where each chemical species concentration, plus temperature, is represented by an axis in space. The dimensionality of the problem is reduced uniquely in each hypercube, but the dimensionality of chemical composition space is not reduced. The dimensionality reduction is dynamic and is different for different hypercubes, thereby escaping the restrictions of global methods in which reductions must be valid for all chemical mixtures. PRISM constructs polynomial equations in each hypercube, replacing the chemical kinetic ordinary differential equation (ODE) system with a set of quadratic polynomials with terms related to the number of species with slow timescales. Earlier versions of PRISM were applied to smaller chemical mechanisms and used all chemical species concentrations as terms. DYSSA is a dynamic treatment of the steady-state approximation and uses the fast,slow timescale separation to determine the set of steady-state species in each hypercube. A reduced number of chemical kinetic ODEs are integrated rather than the original full set. PRISM and DYSSA are evaluated for simulations of a pair of counterrotating vortices interacting with a premixed CH4/air laminar flame. DYSSA is sufficiently accurate for use in combustion simulations, and when relative errors are less than 1.0%, speedups on the order of 3 are observed. PRISM does not perform as well as DYSSA with respect to accuracy and efficiency. Although the polynomial evaluation that replaces the ODE solver is sufficiently fast, polynomials are not reused sufficiently to enable their construction cost to be recovered. © 2007 Wiley Periodicals, Inc. 39: 204,220, 2007 [source] Modeling the solid,liquid equilibrium in pharmaceutical-solvent mixtures: Systems with complex hydrogen bonding behaviorAICHE JOURNAL, Issue 3 2009Ioannis Tsivintzelis Abstract A methodology is suggested for modeling the phase equilibria of complex chemical mixtures with an equation of state (EoS) for the case where only limited experimental data exist. The complex hydrogen bonding behavior is explicitly accounted for and the corresponding parameters are adopted from simpler molecules of similar chemical structure and/or are fitted to Hansen's partial solubility parameters. The methodology is applied to modeling the solubility of three pharmaceuticals, namely acetanilide, phenacetin, and paracetamol, using the nonrandom hydrogen bonding (NRHB) EoS. In all cases, accurate correlations were obtained. The prediction ability of the approach was evaluated against predictions from the COSMO-RS model. A thorough discussion is made for the appropriate modeling of solid solubility considering the effect of the difference of the heat capacities of the solute in liquid and solid state, ,Cp = Cpl , Cps, in the determination of solid chemical potential and, also, of the polymorphism of drugs. © 2009 American Institute of Chemical Engineers AIChE J, 2009 [source] Interactive effects of cadmium and all- trans -retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice,BIRTH DEFECTS RESEARCH, Issue 1 2006Grace S. Lee Abstract BACKGROUND Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13- cis -retinoic acid and all- trans -retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated. METHODS Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects. RESULTS When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive. CONCLUSIONS The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||