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PubMed1980

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

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

Animals↗
PubMed1994

Statistical analysis of joint toxicity in biological growth experiments.

The authors formulate a model for the analysis of designed biological growth experiments where a mixture of toxicants is applied to biological target organisms. The purpose of such experiments is to assess the toxicity of the mixture in comparison with the toxicity observed when the toxicants are applied individually to the organisms. The analysis is based on a random differential equation describing the growth of the organisms. This model yields a natural measure of interaction between toxicants and the hypothesis of independent action from a mixture of toxicants can be tested. The proposed model is applied on data from an experiment where inhibition of the growth of the bacteria Pseudomonas fluorescens caused by different mixtures of pentachlorophenol and aniline was studied.

Aniline Compounds↗
PubMed1987

CNS oxygen toxicity in oxygen-inert gas mixtures.

Central nervous system oxygen toxicity in hyperbaric oxygen-inert gas mixtures was studied by exposing male rats to various gas mixtures having the same oxygen partial pressure and varying pressures of inert gases. The duration of the latent period until the appearance of electrical discharges in the electroencephalogram was used as the criterion for the sensitivity to CNS oxygen toxicity. Two hundred and twenty rats with chronically implanted cortical electrodes were subjected to a single exposure to 1 of 11 different gas mixtures at ambient pressures ranging from 5 to 10 ATA. All gas mixtures had a constant oxygen partial pressure of 5 ATA and varying pressures of inert gas (helium or nitrogen). The duration of the latent period was found to be significantly different in the 11 experimental groups (P less than 0.001). While increasing the inert gas pressure, the latency gradually shortened, reaching the lowest values in mixtures of 5 ATA oxygen and 3 ATA of either inert gas. On further increase in the inert gas pressure up to a total ambient pressure of 10 ATA, the latency returned to control (pure 5 ATA oxygen) values. No difference was found between nitrogen and helium of equal partial pressures. These findings suggest that the risk of CNS oxygen toxicity in gas mixtures is not determined solely by the PO2, and even a relatively low pressure of inert gas can contribute to the imminence of hyperbaric-oxygen-induced seizures.

Animals↗
PubMed1993

Evaluation of the role of reactive oxygen species in the interactive toxicity of carbide-cobalt mixtures on macrophages in culture.

The lung toxicity of a carbide-cobalt mixture is more important than that of each individual component; the mechanism of this interaction is not understood. The capacity of cobalt metal particles alone and mixed with different carbides to generate hydroxyl radicals was examined with the deoxyribose assay. In a chemical system, cobalt ions and cobalt metal particles (Co) were found to catalyse the degradation of deoxyribose in the presence of hydrogen peroxide. Carbides were able to directly oxidize deoxyribose, but their respective activities did not support such a mechanism to explain the carbide-cobalt interactive toxicity, since there was no direct relationship between deoxyribose degradation ability and cytotoxicity toward macrophages. Tungsten, niobium, titanium and chromium carbides (interactive carbides) were only weak oxidants and conversely molybdenum, vanadium and silicon carbides (non-interactive carbides) were the most potent ones. The ability of cobalt metal to produce hydroxyl radicals in the presence of hydrogen peroxide was not increased by tungsten carbide. The role of reactive radical formation in the toxicity of these particles was further assessed in a macrophage culture model. Catalase (4000 U/ml), superoxide dismutase (300 U/ml), sodium azide (1 mM), sodium benzoate, mannitol, taurine and methionine (all 20 mM) were all unable to protect against the cytotoxic effects of cobalt ions and cobalt metal alone or mixed with tungsten carbide. In conclusion, no evidence was found that production of reactive oxygen species contributes to the elective toxicity of carbide-cobalt mixtures.

Animals↗
PubMed2003

Six interaction profiles for simple mixtures.

The Agency for Toxic Substances and Disease Registry (ATSDR) has a program for chemical mixtures that encompasses research on chemical mixtures toxicity, health risk assessment, and development of innovative computational methods. ATSDR prepared a guidance document that instructs users on how to conduct health risk assessment on chemical mixtures (Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures). ATSDR also developed six interaction profiles for chemical mixtures. Two profiles were developed for persistent environmental chemicals that are often found in contaminated fish and also can be detected in human breast milk. The mixture included chlorinated dibenzo-p-dioxins, hexachlorobenzene, dichlorodiphenyl dichloroethane, methyl mercury, and polychlorinated biphenyls. Two profiles each were developed for mixtures of metals and mixtures of volatile organic chemicals (VOCs) that are frequently found at hazardous waste sites. The two metal profiles dealt with (a) lead, manganese, zinc, and copper; and (b) arsenic, cadmium, chromium, and lead; the two VOCs mixtures dealt with (a) 1,1,1-trichloroethane, 1,1-dichloroethane, trichloroethylene, and tetrachloroethylene; and (b) benzene, ethylbenzene, toluene, and xylenes (BTEX). Weight-of-evidence methodology was used to assess the joint toxic action for most of the mixtures. Physiologically based pharmacokinetic modeling was used for BTEX. In most cases, a target-organ toxicity dose modification of the hazard index approach is recommended for conducting exposure-based assessments of noncancer health hazards.

Animals↗
PubMed2003

Bioaccumulation and critical body residue of PAHs in the amphipod, Diporeia spp: additional evidence to support toxicity additivity for PAH mixtures.

Polycyclic aromatic hydrocarbons (PAHs) are considered to act additively when exposed as congener mixtures. Additive internal concentrations at the site of toxic action is the basis for recent efforts to establish a sum PAH guideline for sediment-associated PAH toxicity. This study determined the toxicity of several PAH congeners on a body residue basis in Diporeia spp. These values were compared to the previously established LR(50) value for a PAH mixture based on the molar sum of PAH congeners and demonstrated similar LR(50) values for individual PAH. These results support the contention that the PAH act at the same molar concentration whether present as individual compounds or in mixture. Aqueous exposures were conducted for 28 d, and the water was exchanged daily to maintain the exposure concentration. The concentration in the exposures declined by an average of 22% between water exchanges across all compounds, and ranged from 11% to 32%. The toxicokinetics were determined using both time-weighted-average (TWA) and time-variable water concentrations and were not statistically different between the two source functions. Toxicity was determined for both mortality and immobility (failure to swim on prodding) and on both a TWA water concentration and a body residue basis. The LC(50) values ranged from 1757 microg l(-1) for naphthalene after 10 d exposure to 79.1 microg l(-1) for pyrene after 28 d exposure, and the EC(50) ranged from 1587 microg l(-1) for naphthalene after 10 d exposure to 38.2 microg l(-1) for pyrene after 28 d exposure. The LR(50) values for all congeners at all lengths of exposure were essentially constant and averaged 7.5+/-2.6 micromol g(-1), while the ER(50) for immobility averaged 2.6+/-0.6 micromol g(-1). The bioconcentration factor declined with increasing exposure concentration and was driven primarily by a lower uptake rate with increasing dose, while the elimination remained essentially constant for each compound.

Amphipoda↗
PubMed2005

A simple hydrophobicity-based approach to predict the toxicity of unknown organic micropollutant mixtures in marine water.

In this study, we propose a simple hydrophobicity-based approach to predict the toxicity of mixtures of marine organic micropollutants. Fifty mixtures were chosen, comprising individual chemicals randomly chosen from three halogenated benzenes, three phenols, two petroleum hydrocarbons, three polychlorinated biphenyls (PCBs), four organochlorine pesticides (OCPs) and two herbicides, with the intention of simulating the mixtures of organic micropollutants that may exist in some marine waters. The hydrophobicity of the mixtures was quantified by measuring the C(18)-Empore(TM) disk/water partition coefficients (K(MD)). A K(MD)-based approach was proposed to describe their toxicity to Photobacterium phosphoreum, and the application of this approach to another 10 related mixtures proved its predictive capability, as indicated by the consistency between the predicted and observed toxicities (r(2)=0.905, SE=0.101, and F=76.325 at P<0.001). This predictive capability convinces us that the K(MD)-based approach provides a general approach to predicting the toxicity of mixtures of organic micropollutants in marine water.

Hydrophobic and Hydrophilic Interactions↗
PubMed1995

The number of components in a mixture determines whether synergistic and antagonistic or additive toxicity predominate: the funnel hypothesis.

A new hypothesis, the funnel hypothesis, was derived to explain the variation in toxicity of equitoxic multicomponent mixtures of nonspecific toxicants (narcotics). The variation is explained in terms of the volumes associated with solute-solute and solute-solvent interactions. The hypothesis predicts that as the number of components in a mixture increases, the range of deviation from toxic additivity decreases. It also predicts that the toxicity of mixtures measured using biological endpoints that require high toxicant concentrations will deviate more from toxic additivity than endpoints that require low concentrations. Aquatic toxicity data for equitoxic mixtures of narcotic toxicants to a range of aquatic organisms compiled from the literature support the predictions of the funnel hypothesis.

Data Collection↗
PubMed2003

Toxicity of a complex mixture of atmospherically transported pesticides to Ceriodaphnia dubia.

The presence of several anthropogenic chemicals has been documented in the atmosphere of the Canadian prairies. The deposition of these chemicals as a mixture is of importance since little is known of the combined effects of these chemicals on aquatic organisms. This study was designed to evaluate the acute and chronic toxicity of a complex mixture of nine atmospherically transported pesticides to Ceriodaphnia dubia. The nine selected pesticides (bromoxynil, dicamba, 2,4-D, MCPA, triallate, trifluralin, pentachlorophenol, lindane, and 4,4'-DDT) were detected in appreciable quantities in dry atmospheric deposits. The concentration of each pesticide in the mixture was based on maximum measured daily dry deposition rates for central Canada, except for pentachlorophenol, which was estimated based on atmospheric concentrations. The 48-h LC50 estimate for C. dubia exposed to the pesticide mixture was 174.60 microg L(-1) (340 times the measured total dry deposition concentration). The estimated NOEC and LOEC for both survival and reproduction, as determined in the 7-d chronic toxicity test, were 51.3 (100 times) and 154 microg/L(-1) (300 times), respectively. A basic risk assessment, using the toxic unit approach, suggested that the toxicity of the pesticide mixture was mainly due to 4,4'-DDT. Overall, this atmospherically transported complex mixture of pesticides appears to pose a negligible toxicological risk to non-target aquatic invertebrates such as zooplankton.

Air Pollutants↗
PubMed2005

Increased toxicity to Ceriodaphnia dubia in mixtures of atrazine and diazinon at environmentally realistic concentrations.

The acute toxicity of diazinon in combination with atrazine concentrations of 5, 10, 20, and 40 microg/L was evaluated using Ceriodaphnia dubia. Atrazine concentrations as low as 5 microg/L in combination with diazinon significantly increased toxicity to C. dubia compared to diazinon alone. Atrazine and diazinon residues within water samples collected from 65 subbasins throughout Denton, Texas, USA were used to assess the environmental relevance of pesticide concentrations. A geographical information system was used to examine the relationship between subbasin land uses and pesticide concentrations. Significant correlations were observed between in situ atrazine and diazinon concentrations and some subbasin land uses. Atrazine was significantly (P < 0.05) correlated to diazinon during some months. Of the 276 samples collected, 39% exceeded our experimentally derived diazinon LC(50) value, and 39% exceeded our minimum atrazine concentration of 5.0 microg/L. Results indicate the potential for increased toxicity from mixtures of compounds at environmentally realistic concentrations.

Animals↗
PubMed2006

Toxicity of jet fuel aliphatic and aromatic hydrocarbon mixtures on human epidermal keratinocytes: evaluation based on in vitro cytotoxicity and interleukin-8 release.

Jet fuels are complex mixtures of aliphatic (ALI) and aromatic (ARO) hydrocarbons that vary significantly in individual cytotoxicity and proinflammatory activity in human epidermal keratinocytes (HEK). In order to delineate the toxicological interactions among individual hydrocarbons in a mixture and their contributions to cutaneous toxicity, nine ALI and five ARO hydrocarbons were each divided into five (high/medium/low cytotoxic and strong/weak IL-8 induction) groups and intra/inter-mixed to assess for their mixture effects on HEK mortality and IL-8 release. Addition of single hydrocarbon to JP-8 fuel was also evaluated for their changes in fuel dermatotoxicity. The results indicated that when hydrocarbons were mixed, HEK mortality and IL-8 release were not all predictable by their individual ability affecting these two parameters. The lowest HEK mortality (7%) and the highest IL-8 production were induced with mixtures including high cytotoxic and weak IL-8 inductive ARO hydrocarbons. Antagonistic reactions not consistently correlated with ALI carbon chain length and ARO structure were evident and carried different weight in the overall mixture toxicities. Single addition of benzene, toluene, xylene or ethylbenzene for up to tenfold in JP-8 did not increase HEK mortality while single addition of ALI hydrocarbons exhibited dose-related differential response in IL-8. In an all ALI environment, no single hydrocarbon is the dominating factor in the determination of HEK cytotoxicity while deletion of hexadecane resulted in a 2.5-fold increase in IL-8 production. Overall, decane, undecane and dodecane were the major hydrocarbons associated with high cytotoxicity while tetradecane, pentadecane and hexadecane were those which had the greatest buffering effect attenuating dermatotoxicity. The mixture effects must be considered when evaluating jet fuel toxicity to HEK.

Aviation↗
PubMed2006

Laboratory investigation of the toxicity and interaction of pesticide mixtures in Daphnia magna.

The probabilistic ecological risk assessment-toxic equivalent (PERA-TE) combination approach is a relatively new risk assessment approach used to assess the toxicity and interaction of chemical mixtures. The validity and effectiveness of the PERA-TE combination approach has been tested previously in field microcosm studies using pesticide mixtures. The related laboratory studies described here, using Daphnia magna, were conducted to verify the conclusions made regarding the toxicity and interaction of the mixtures tested in the microcosms. Two types of pesticide mixture were assessed: the first consisted of pesticides with similar modes of action (chlorpyrifos, diazinon, and azinphos-methyl; OP mixture), and the second consisted of pesticides with different modes of action (chlorpyrifos, endosulfan, and trifluralin; CET mixture). Similar to the field studies, PERA-TE mixtures with a predetermined effect assessment criterion (10th centile of acute toxicity effects distributions) and proportional ratio (89:11 for binary mixture and 80:10:10 for ternary mixtures) were tested. Further assessment of the (PERA-) TE approach was achieved by altering the effect assessment criterion (to EC/LC(50) point estimates) and the proportional ratio of the pesticides in the mixture (to 50:25:25). Generally, but with some exceptions, basing mixtures on species-specific effect criteria and/or changing the proportional ratio of pesticides in the mixture redistributed the concentration of pesticides in the mixture to produce an equitoxic response. The ability to produce these equitoxic responses supported the conclusions drawn from the field studies: The pesticide toxicity in the OP and CET PERA-TE mixtures were effectively additive. Furthermore, it is shown that these alternative (PERA-) TE mixtures would be suitable to confirm or reject the interaction of chemicals in a PERA-TE mixture.

Animals↗
PubMedDate not supplied

Mixture risk assessment: a case study of Monsanto experiences.

Monsanto employs several pragmatic approaches for evaluating the toxicity of mixtures. These approaches are similar to those recommended by many national and international agencies. When conducting hazard and risk assessments, priority is always given to using data collected directly on the mixture of concern. To provide an example of the first tier of evaluation, actual data on acute respiratory irritation studies on mixtures were evaluated to determine whether the principle of additivity was applicable to the mixture evaluated. If actual data on the mixture are unavailable, extrapolation across similar mixtures is considered. Because many formulations are quite similar in composition, the toxicity data from one mixture can be extended to a closely related mixture in a scientifically justifiable manner. An example of a family of products where such extrapolations have been made is presented to exemplify this second approach. Lastly, if data on similar mixtures are unavailable, data on component fractions are used to predict the toxicity of the mixture. In this third approach, process knowledge and scientific judgement are used to determine how the known toxicological properties of the individual fractions affect toxicity of the mixture. Three examples of plant effluents where toxicological data on fractions were used to predict the toxicity of the mixture are discussed. The results of the analysis are used to discuss the predictive value of each of the above mentioned toxicological approaches for evaluating chemical mixtures.

Adipates↗
PubMed2005

Toxicity assessment of pesticide mixtures typical of the Sacramento-San Joaquin Delta using Chironomus tentans.

This study examined the effects of nine commonly detected pesticides in the Sacramento-San Joaquin Delta on the aquatic midge Chironomus tentans. Pesticides were chosen from a variety of chemical classes including organophosphate (OP) insecticides as well as triazine, triazinone, and substituted urea herbicides. Both single toxicant and binary mixture bioassays were performed. In addition, midges were pre-exposed to DDE at environmentally relevant concentrations and then challenged by exposing them to chlorpyrifos or diazinon in single-toxicant acute bioassays. Results indicate that most of the binary mixtures elicited additive responses in C. tentans, whereas OP insecticides in combination with various herbicides caused greater-than-additive responses. Pre-exposures with DDE did not have a significant impact on subsequent OP challenges at DDE concentrations of 0.2, 2, and 20 microg/kg. This study represents an important first step in understanding the interactions among various pesticides commonly detected throughout the Delta.

Animals↗
PubMedDate not supplied

Quantifying the toxic and mutagenic activity of complex mixtures with Salmonella typhimurium.

The toxicity and mutagenicity of 11 compounds individually and in mixtures were quantified in Salmonella typhimurium strains TA98, TA100, and TA1537 by a modification of the Ames spot test. The distance (millimeters) from the center of the petri dish to the bacterial growth front represented the toxic response. When mutagenicity occurred, the distance from the inner radius to the outer radius of the mutagenic growth represented the mutagenic response. Multiple regression analysis was used to quantify the toxicity and mutagenicity of individual compounds in the mixtures. The results indicate that the effects of compounds in mixtures are generally additive.

Azaserine↗
PubMed1989

Toxicity of complex waste mixtures: a comparison of observed and predicted lethality.

The ability to predict the biological effect of complex waste mixtures from chemical characterization data was examined by comparing observed mortality to that predicted by a mathematical additivity model with literature LD50 values for the chemicals identified in the mixtures. Male F344 rats were exposed by gavage to 1 of 10 samples of complex industrial waste. Seven of the 10 waste samples caused death within 24 h of administration at dosages ranging from 1 to 5 ml/kg body weight. Two of the 7 lethal waste samples produced 100% mortality at a dosage of 2.5 ml/kg; another 2 waste samples produced 100% mortality at 5 ml/kg. The partial chemical analysis, although providing more extensive information on chemical composition than might normally be available for most complex waste mixtures, was not sufficient to distinguish lethal from nonlethal waste samples or to indicate lethal potency. Possible explanations for the apparent inability to predict readily lethality from the chemical characterization data include the possible inappropriateness of an additivity model due to the presence of interactions, such as synergism or antagonism; the kinetics of chemical absorption, distribution, and elimination, which may be affected by administration of the chemical in a complex matrix; and the presence of unidentified chemicals in the mixture that may have contributed to the observed toxicity.

Animals↗
PubMed2004

Toxicity of metals and metal mixtures: analysis of concentration and time dependence for zinc and copper.

The toxic effects of heavy metals, zinc and copper, in unary and binary solutions were studied using the Microtox acute toxicity test which relies upon the attenuation of light intensity emitted by Vibrio fischeri. The toxic effect Gamma (ratio of the light intensity lost at time t to the light intensity remaining at time t) of zinc could be related to its concentration [X] by a two-parameter equation Gamma=a(1-exp(-b[X])), where parameter a was a function of time and b equal to 0.88L/mg. The toxic effect of zinc asymptotically approached a maximum with respect of to concentration at all times. The toxic effect of copper was fundamentally different from that of zinc, and increased exponentially with concentration without any limiting maximum value. It could also be described by a two-parameter equation, however, the equation had the form Gamma=aexp(b[X]), where parameter a was a constant and b a function of time. The different functional dependencies (of the toxic effect on the metal concentration) of zinc and copper indicate that different toxicity/inhibition mechanisms were possibly responsible for the attenuation of light intensity for the two metals. The toxic effects of binary mixtures were substantially higher than those expected on the basis of additivity of individual metals. No simple correlations were obtained that could relate the toxic effect of binary mixture to those of individual metals. A better understanding of metal-microbe interactions is needed for achieving predictive capability for toxic effect of mixtures.

Aliivibrio fischeri↗
PubMed2006

Measurement of un-ionized ammonia in complex mixtures.

The toxicity of un-ionized ammonia, NH3 (aq), in anaerobic digestion of high-nitrogen wastes has been researched extensively. Previous estimates of NH3 (aq) concentration have relied on a simple speciation approach, based only on the acid dissociation constant and the sample pH and total ammonia concentration. The distinction between concentration and chemical activity has generally not been made, despite the potential for resulting errors in the calculation of NH3 (aq) concentration, and the greater applicability of activity to toxicity work. The currently accepted approach for estimating NH3 (aq) concentration is based on assumptions that are not valid in digested animal manure or other concentrated wastes. This work presents an approach for directly measuring NH3 (aq) activity in complex mixtures using gaseous/aqueous equilibrium across microporous tubing. Application of this approach to anaerobic digester samples confirms that the currently accepted approach is not accurate; it overestimated NH3 (aq) activity in unaltered samples by 45-200%. Previous work on the toxicity of ammonia to methanogenesis has probably overestimated the tolerance of consortia to NH3 (aq), due to overestimation of concentrations. The method introduced here is expected to be useful in a range of research on ammonia toxicity and volatilization.

Ammonia↗