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PubMed1995

Chemical mixtures: current risk assessment methodologies and future directions.

Some of the most challenging problems that toxicologists confront are determining how biological effects of components in a complex mixture may interact, determining how these interactions affect the overall toxicity of the mixture, and determining how to incorporate this information into risk assessments of chemical mixtures. There has been considerable effort in this area since the publication of the U.S. Environmental Protection Agency's guidelines for risk assessment of chemical mixtures in 1986. This paper reviews the terminology used to describe chemical interactions and the methodologies that have been developed for conducting risk assessments of chemical mixtures. Particular attention is directed towards an examination of the applicability and validity of the methods for the assessment of risk posed by exposure to environmentally relevant concentrations of chemical mixtures. Limited, yet compelling, data are reviewed that suggest that for noncancer endpoints, adverse effects are unlikely to occur when the individual components in the mixture are present at levels well below their respective thresholds. Synergistic or antagonistic effects, not readily predicted from the mechanisms of action of the individual components, are possible when the mixture components are present at levels equal to or above their individual thresholds. Finally, synergistic carcinogenic effects have been observed in animal studies of mixtures, even at relatively low doses.

Animals↗
PubMed2006

Acute toxicity of pyrithione antifouling biocides and joint toxicity with copper to red sea bream (Pagrus major) and toy shrimp (Heptacarpus futilirostris).

We evaluated the median lethal concentrations (LC50s) of the pyrithione (PT) antifoulants copper pyrithione (CuPT) and zinc pyrithione (ZnPT) to a teleost, red sea bream (Pagrus major), and a crustacean, toy shrimp (Heptacarpusfutilirostris). The 96-h LC50 values of CuPT and ZnPT, on the basis of actual concentrations, were 9.3 and 98.2 R.g/L, respectively, for red sea bream and 2.5 and 120 microg/L, respectively, for toy shrimp. Histological observations revealed that the secondary lamellae of the gill filaments of the experimental fish were heavily damaged after exposure to the PTs, suggesting that fatal hypoxemia was one cause of death. Because CuPT and ZnPT are usually used in combination with Cu, we also estimated the joint toxicities of the PTs with Cu using the LC50 values of the PTs and those of Cu (84.4 and 113 microg/L for red sea bream and toy shrimp, respectively). The results suggested that the joint toxicity of the ZnPT and Cu mixture is more than the additive toxicities of CuPT and Cu, especially in toy shrimp. The enhancement of toxicity in the mixture was inferred to be caused by conversion of ZnPT to the more toxic CuPT in the presence of Cu.

Animals↗
PubMed1987

Reduction of vincristine toxicity by Cronassial.

A mixture of gangliosides (Cronassial) protects against the chronic but not the acute lethal toxicity of vincristine in mice and affords some protection against the acute lethal toxicity of vincristine in chicks. The protective effect of Cronassial appears to be greatest near the LD50 of vincristine and then diminishes as the dose of vincristine increases further. Cronassial does not, however, reduce the vincristine antitumour activity, so that the net effect is an improvement in the vincristine therapeutic index. Clinical trials are underway to examine the effect of the combination on the development of neurotoxicity in cancer patients.

Animals↗
PubMed2004

Evaluation of the reproductive and developmental toxicity of the D-003, a mixture of long-chain fatty acids, in rats and rabbits.

D-003 is a mixture of long-chain fatty acids isolated and purified from sugar cane wax with cholesterol-lowering properties. D-003 given orally (500 and 1000 mg/kg/day) to female rats for 15 days prior to mating, through mating and gestation to day 21 of lactation and male rats for 4 weeks prior and during mating did not induce toxic effects on reproduction. There were no significant reductions in the number of animals that conceived, in the numbers of pups born to those that did conceive, in the numbers of pups that survived until weaning, and in their body weights at weaning. Drug-treated and control groups' offspring were comparable in growth, physical and behavioral development, spontaneous activity and reproductive performance. Pregnant New Zealand rabbits were given D-003 as oral doses of 500 and 1000 mg/kg/day on days 6 through 18 of gestation without any evidence of embryotoxicity or teratogenicity. The no-observed-effect dose in these two experimental studies was 1000 mg/kg/day. After assessment of the potential of high doses of D-003 to act on developing embryo and reproduction process, no evidence supports the conclusion that D-003 is a reproductive and developmental toxicant/teratogen.

Animals↗
PubMed2003

Assessing the impact of triazine herbicides on organophosphate insecticide toxicity to the earthworm Eisenia fetida.

A standard Organization for Economic Cooperation and Development (OECD) filter paper test was used to assess the acute toxicity of chlorpyrifos, atrazine, cyanazine, and simazine to the earthworm Eisenia fetida. Acute toxicity of chlorpyrifos was also determined in combination with the three-triazine herbicides. Surprisingly, atrazine and cyanazine caused mortality at concentrations lower than chlorpyrifos. Atrazine and cyanazine also increased the toxicity of chlorpyrifos 7.9- and 2.2-fold, respectively. However, simazine caused no toxicity to the worms and did not affect chlorpyrifos toxicity in binary mixture experiments. Possible mechanisms for the greater-than-additive toxicity for the binary combinations of atrazine and cyanazine with chlorpyrifos were investigated, including changes in uptake and biotransformation rates of chlorpyrifos in the presence of atrazine. Uptake of chlorpyrifos into the worms decreased slightly when atrazine was present in the system, therefore eliminating increased uptake as a possible explanation for the increased toxicity. Body residue analysis of worms indicated increased metabolite formation, suggesting the greater-than-additive response may be due to increased biotransformation to more toxic oxon metabolites.

Animals↗
PubMed1988

Comparative toxicity of Bacillus thuringiensis var. israelensis crystal proteins in vivo and in vitro.

Bacillus thuringiensis var. israelensis crystal proteins were purified by FPLC on a Mono Q column to yield 130, 65, 28, 53, 30-35 and 25 kDa proteins. All the purified proteins killed Aedes aegypti larvae after citrate precipitation, but the 65 kDa protein was the most toxic. A precipitated mixture of 27 and 130 kDa proteins was almost as toxic as solubilized crystals. In assays against a range of insect cell lines, the activated form (25 kDa) of the 27 kDa protein was generally cytotoxic with the lowest LC50 values in vitro. By contrast, the activated forms of the 130 kDa and 65 kDa protoxins (53 kDa and 30-35 kDa proteins, respectively) were much more specific than the 25 kDa protein in their action on dipteran cells, and each showed a unique toxicity profile which, in the case of the 130 kDa preparation, was restricted to Anopheles and Culex cell lines.

Aedes↗
PubMed2005

Effects of pharmaceuticals on Daphnia survival, growth, and reproduction.

Pharmaceuticals have been globally detected in surface waters, and the ecological impacts of these biologically-active, ubiquitous chemicals are largely unknown. To evaluate the aquatic toxicity of individual pharmaceuticals and mixtures, we performed single species laboratory toxicity tests with Daphnia magna, a common freshwater zooplankton. We conducted acute (6-day) and chronic (30-day) exposure pharmaceutical bioassays and evaluated survivorship and morphology of adults and neonates, adult length, resting egg production, brood size (fecundity), and the proportion of male broods produced (sex ratio). In general, exposure to a single pharmaceutical in the 1-100 microg/l range yielded no apparent effects on the normal life processes of Daphnia. However, chronic fluoxetine exposure (36 microg/l) significantly increased Daphnia fecundity, and acute clofibric acid exposure (10 microg/l) significantly increased sex ratio. A mixture of fluoxetine (36 microg/l) and clofibric acid (100 microg/l) caused significant mortality; the same fluoxetine concentration mixed with 10 microg/l clofibric acid resulted in significant deformities, including malformed carapaces and swimming setae. Mixtures of three to five antibiotics (total antibiotic concentration 30-500 microg/l) elicited changes in Daphnia sex ratio. We conclude: (1) individual and mixtures of pharmaceuticals affect normal development and reproduction of Daphnia magna, (2) aquatic toxicity of pharmaceutical mixtures can be unpredictable and complex compared to individual pharmaceutical effects, and (3) timing and duration of pharmaceutical exposure influence aquatic toxicity.

Animals↗
PubMed2005

Combined toxicity of copper and phenol derivatives to Daphnia magna: effect of complexation reaction.

The complexation of Cu with phenol was investigated in aqueous solution to find the changes in toxicity toward Daphnia magna in mixtures of copper and phenol derivatives and determine an appropriate prediction model for the toxicity of these mixtures. In the titration experiment, the results showed that phenol played an important role in the remarkable reduction of the Cu(2+) concentration, due to its complexation with Cu, with the subsequent reduction in the toxicity of aqueous mixtures containing both Cu and phenol. As a result, it was clearly demonstrated that Cu-phenol formed a non-toxic complex toward D. magna as the mortality declined, despite the addition of phenol to a fixed Cu concentration. Meanwhile, prediction of the combined toxicity for binary mixtures of Cu and 11 phenol derivatives more accurately followed an independent action model (p = 0.143, df = 124, and t = -1.475 in t-test) than an effect summation model (p approximately 0, df = 134, and t = 7.528 in t-test) due to the dissimilar modes of action and the complexation reactions between Cu and each of the phenolic compounds. Consequently, this study supports the importance of considering complexation reactions in assessing the combined toxicity for the formulation of water quality in mixtures of heavy metals and organic compounds, and in these cases, an independent action model was found to be appropriate.

Animals↗
PubMed2006

The role of inflammatory mediators in the synergistic toxicity of ozone and 1-nitronaphthalene in rat airways.

Ambient air is polluted with a mixture of pulmonary toxicants. Previous studies indicate that prior exposure to atmospheric oxidant pollutants such as ozone may significantly alter the response to other pollutants, such as 1-nitronaphthalene (1-NN) . 1-NN, a component of the particulate exhaust from diesel engines, has been found at low concentrations in ambient air. Using a metabolomic approach, we investigated inflammatory responses in arachidonic and linoleic acid biochemical cascades (35 metabolites) and the expression of 19 cytokines/chemokines at three time points (2, 6, and 24 hr) following exposure to 1-NN with and without prior long-term O3 exposure. Long-term O3 exposure is associated with biochemical changes that have been shown to render the lung resistant to further O3 exposure. This study indicates that airways of O3-tolerant rats exhibited a low level of chronic inflammation, rendering the lungs more susceptible to other environmental pollutants such as 1-NN. Specifically, a 12.5-mg/kg dose of 1-NN to O3-tolerant rats produced significantly higher levels of cysteinyl-leukotrienes in bronchiolar lavage fluid even when compared to a 50-mg/kg dose of 1-NN in rats exposed to filtered air. Collectively, these results indicate that the combination of exposures as encountered in polluted ambient air are considerably more injurious to the lung than would be anticipated from previous studies employing single exposures. The observed synergism between O3 and 1-NN may be causally related to a shift in a T-helper 1 to T-helper 2 immune response in the airways.

Administration, Inhalation↗
PubMed1994

Toxicity of an anthraquinone violet dye mixture following inhalation exposure, intratracheal instillation, or gavage.

Anthraquinone dyes are utilized by the military in colored-smoke grenades. During production, workers in munitions plants may be exposed to fugitive emissions of these dyes or mixtures thereof. The effects of a prototype violet dye mixture (VDM) consisting of Disperse Red 11 (DR11), [1,4-diamino-2-methoxy-anthraquinone] and Disperse Blue 3 (DB3) [1-methylamino-4-hydroxyethylamino-anthraquinone] on F344 male and female rats have been investigated. Acute 1-day inhalation exposures (6 hr) to VDM were conducted at 1000, 300, 100, 70, 40, and 10 mg/m3, with an additional exposure to 40 mg/m3 6 hr/day for 5 days; 4.22 +/- 2.1 microns (MMAD +/- delta g). Lung burdens of dye, general histopathology, and/or liver function were evaluated at 0, 3, and 7 days postexposure. Unexpected lethality due to severe liver damage was observed with acute exposures of > or = 300 mg/m3 and in the 5-day 40 mg/m3 exposures. Centrilobular degeneration and necrosis of liver cells was concentration-dependent with inhalation of VDM > or = 40 mg/m3. In addition, nasal olfactory epithelium exhibited degeneration and necrosis with acute exposures > or = 10 mg/m3. Lung instillations at 250, 500, and 1000 micrograms of the VDM revealed no lung or liver toxicity. Because per os exposure due to preening was suspected as a major exposure route, a gavage study with the VDM and its two component dyes DR11 and DB3 (800 mg/kg) was undertaken. One day following gavage with DR11 or DB3, serum enzymes indicative of liver toxicity (LDH, SGPT, SDH, and ICDH) were slightly elevated (1-6x control). However, rats gavaged with VDM had serum enzyme levels 10-100x control by Day 1 after gavage, indicating acute liver toxicity. Activities of liver enzymes involved in xenobiotic and glutathione metabolism were also acutely affected. All of the dyes caused various degrees of induction of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and nonprotein sulfhydryls. The enzymes involved in xenobiotic metabolism (glutathione S-transferase, NADPH cytochrome-c reductase, and P450) were also elevated by the two component dyes, in contrast to their significant depression with VDM treatment. The similarity between the liver and olfactory epithelium effects of these compounds and the lack of pulmonary tissue effects is not fully understood, but the interaction of the individual dyes as VDM emphasizes the need to assess chemicals such as the anthraquinones as their likely-to-be-encountered mixtures.

Administration, Inhalation↗
PubMed2005

Oxidative DNA damage from potassium bromate exposure in Long-Evans rats is not enhanced by a mixture of drinking water disinfection by-products.

Public drinking water treated with chemical disinfectants contains a complex mixture of disinfection by-products (DBPs) for which the relative toxicity of the mixtures needs to be characterized to accurately assess risk. Potassium bromate (KBrO(3)) is a by-product from ozonation of high-bromide surface water for production of drinking water and is a rodent carcinogen that produces thyroid, mesothelial, and renal tumors. The proposed mechanism of KBrO(3) renal carcinogenesis involves the formation of 8-oxoguanine (8-oxoG), a promutagenic base lesion in DNA typically removed through base excision repair (BER). In this study, male Long-Evans rats were exposed via drinking water to carcinogenic concentrations of KBrO(3) (0.4 g/L), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (0.07 g/L), chloroform (1.8 g/L), bromodichloromethane (0.7 g/L), or a mixture of all these chemicals at the same concentrations for 3 weeks. Half of one kidney was processed for microscopic examination, and the remaining kidney was frozen for isolation of genomic DNA. Levels of 8-oxoG were measured using HPLC with electrochemical detection in DNA samples incubated with formamidopyrimidine-DNA glycosylase. Aldehydic lesions (e.g. abasic sites) in DNA samples were quantitated using an aldehyde-reactive probe slot-blot assay. Treatment with KBrO(3) produced a measurable increase of 8-oxoG in the kidney, and this effect was greater than that produced by treatment with the DBP mixture. No other single chemical treatment caused measurable increases of 8-oxoG. The mixture effect on the amount of 8-oxoG observed in this study suggests an interaction between chemicals that reduced the generation of oxidative DNA damage. No increases in abasic sites were observed with treatment, but a decrease was apparent in the rats treated with the DBP mixture. These data are consistent with previous studies where chronic exposure to this chemical mixture in drinking water resulted in a less than additive carcinogenic response in Tsc2 mutant Long-Evans rats.

Animals↗
PubMed1975

Influence of mixtures of taurocholate, fatty acids, and monolein on the toxic effects of deoxycholate in rat jejunum in vivo.

The influence of mixtures of taurocholate (TC), oleic acid (OA), caprylic acid (CA), and monolein (MO) on the toxic effects of deoxycholate (DC) in rat jejunum have been investigated using both a closed loop and perfusion technique. DC induced net secretion of water and electrolytes, inhibited glucose transport and transmural potential difference (PD), and inactivated mucosal "total" and (Na+ -K+)-adenosine triphosphatase. Secretion was reversed to absorption when the instilled or perfused solutions were composed of mixtures of DC, TC and OA; substitution of MO or CA for OA produced a similar effect. DC-induced inhibition of PD, glucose absorption, and mucosal adenosine triphosphatase activity was abolished when DC was mixed with TC and OA. Oleic acid emulsions had no effect on secretion induced by DC. Absorption of DC was inhibited from mixed micellar solutions (TC, OA, DC) but not from pure micellar solutions (TC, DC). These results indicate that the presence of taurocholate and fatty acids or monolein within the intestinal lumen markedly modify a number of the toxic effects of DC on jejunal function. The clinical effects of DC on intestinal function in man may therefore depend on the relative concentrations of other bile salts and lipids within the intestinal lumen.

Adenosine Triphosphatases↗
PubMed2005

Resolution of liver fibrosis in chronic CCl4 administration in the rat after discontinuation of treatment: effect of silymarin, silibinin, colchicine and trimethylcolchicinic acid.

The purpose of this work was to obtain a suitable model of fibrosis, in which spontaneous reversion was minimal, to study the ability of silymarin, silibinin, colchicine and trimethylcolchicinic acid (TMCA) to reverse it. Reversal of liver fibrosis was studied in male Wistar rats after one, two or three months of CCl(4) administration (0.4 g/kg intraperitoneally, three times per week), by discontinuation of the toxin for 2 months. Silymarin (50 mg/kg), silibinin (50 mg/kg), colchicine (10 microg/rat) and trimethylcolchicinic acid (100 microg/rat) were administered daily, by gavage, after 3 months of CCl(4) administration. Collagen content was determined by measuring hydroxyproline in liver samples; glycogen, was determined utilizing the anthrone reagent; Mallory's trichromic stains of liver sections were performed. The best scheme of treatment was obtained when CCl(4) was administered during three months (collagen increased 6 times). Discontinuation of the toxin for two months produced a significant but relative small reduction of fibrosis (collagen was still 4.5 times over control). Colchicine, TMCA, silymarin or silibinin treatment showed no significant fibrolitic effect. This scheme of treatment may be an excellent tool to study the ability of drugs to reverse fibrosis. The hepatoprotective properties of silymarin, silibinin, colchicine and trimethylcolchinic acid may be irrelevant to reverse established cirrhosis.

Alanine Transaminase↗
PubMed2006

Inhibition of CYP6B1-mediated detoxification of xanthotoxin by plant allelochemicals in the black swallowtail (Papilio polyxenes).

The structural and biosynthetic diversity of allelochemicals in plants is thought to arise from selection for additive toxicity as a consequence of toxin mixture or for enhanced toxicity as a result of synergism. In order to understand how insects cope with this type of plant defense, we tested the effects of some allelochemicals in host plants of the black swallowtail Papilio polyxenes on the xanthotoxin-metabolic activity of CYP6B1, the principal enzyme responsible for the detoxification of furanocoumarins in this caterpillar. Additionally, the effects of some synthetic compounds not normally encountered by P. polyxenes on CYP6B1 were tested. These studies demonstrate that the integrity of furanocoumarin structure is important for competitive binding to the active site of CYP6B1, even though the carbonyl group on the pyranone ring apparently does not affect its inhibitory capacity, as in the case of furanochromones. Angular furanocoumarins are generally less phototoxic to many organisms than linear furanocoumarins due to their reduced capacity for cross-linking DNA strands, yet they are more toxic than linear furanocoumarins to black swallowtail larvae. This enhanced toxicity in vivo may be due to the ability of angular furanocoumarins to bind to the active site of CYP6B1 without being rapidly metabolized. This binding reduces the availability of CYP6B1 to metabolize other linear furanocoumarins. The structure-activity relationships for methylenedioxyphenyl compounds, flavonoids, imidazole, and imidazole derivatives are also discussed in light of their capacity to inhibit the xanthotoxin-metabolic activity of CYP6B1.

Animals↗