• Toxicological Research
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• v.12 no.2
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• pp.231-236
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• 1996

The toxicity of the mixture of diazinon, toxaphene(TOX) and/or endrin was studied in ICR male mice(18-22 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 pesticides, during the 14-day period. TOX and TOX containing mixtures significantly increased the liver/body weight ratio. The serum glutamic pyruvic transaminase level increased at 23~374% in diazinon, TOX, and endrin or their mixture group. The cholinesterase(ChE) activity in the serum and brain was inhibited in the animals of the group of diazinon(5, 10 mg/kg) and diazinon(5 mg/kg) containing mixtures. TOX(40, 80 mg/kg) caused initial inhibitory effects on the serum ChE Day 1. but there is little effects on the brain ChE levels. endrin(5,10 mg/kg) results in significantly elevated levels of the serum ChE, with substantial decreases in the brain ChE activity. TOX and TOX containing mixtures decreased the pentobarbital(60 mg /kg, ip., in saline) induced sleep. The effects produced by this pesticides singly, as well as by their mixtures, appeared to be reversible in nature. The toxic effects exhibited by the mixtures of diazinon(5 mf/kg), TOX(40 mg/kg), and /or endrin(5 mg/kg) were found to be the resultant of the effect showed by their components individually.

• Bulletin of the Korean Chemical Society
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• v.35 no.12
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• pp.3637-3641
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• 2014

In this study, we analyzed the toxicity of mixtures of dimethylformamide (DMF) and methyl ethyl ketone (MEK) or DMF and toluene (TOL) and predicted their toxicity using quantitative structure-activity relationships (QSAR). A QSAR model for single substances and mixtures was analyzed using multiple linear regression (MLR) by taking into account the statistical parameters between the observed and predicted $EC_{50}$. After preprocessing, the best subsets of descriptors in the learning methods were determined using a 5-fold cross-validation method. Significant differences in physico-chemical properties such as boiling point (BP), specific gravity (SG), Reid vapor pressure (rVP), flash point (FP), low explosion limit (LEL), and octanol/water partition coefficient (Pow) were observed between the single substances and the mixtures. The $EC_{50}$ of the mixture of DMF and TOL was significantly lower than that of DMF. The mixture toxicity was directly related to the mixing ratio of TOL and MEK (MLR $EC_{50}$ equation = $1.76997-1.12249{\times}TOL+1.21045{\times}MEK$), as well as to SG, VP, and LEL (MLR equation $EC_{50}=15.44388-19.84549{\times}SG+0.05091{\times}VP+1.85846{\times}LEL$). These results show that QSAR-based models can be used to quantitatively predict the toxicity of mixtures used in manufacturing industries.

• Toxicological Research
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• v.20 no.3
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• pp.281-292
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• 2004

The purpose of this study was to assess the single and 5 week oral dose toxicity of calcitriol and alendronate combination (1 : 10,000) treatment for osteoporosis or Paget's disease in male and female rats. In single dose oral toxicity study, the values of $LD_{50}$ of calcitriol and alendronate mixture were 750.075 mg/kg in male rats and 775.0775 mg/kg in female rats, respectively. Body weight and food consumption were continuously increased after adminstration of calcitriol and alendronate mixtures, and there was no significant changes in body weight and food consumption in all groups. In five-week oral toxicity study of calcitriol and alendronate mixture at a dose of 0.2 $\mu\textrm{g}$ + 2 mg, 1 $\mu\textrm{g}$ + 10 mg, 5 $\mu\textrm{g}$ + 50 mg and 25 $\mu\textrm{g}$ + 250 mg, respectively, there was no mortality, abnormal behavior and appearance in all groups throughout the administration period (5 weeks) and recovery period (2 weeks). Dose-dependent changes in parameters of urinalysis and hematological analysis were not observed in male and female rats treated with calcitriol and alendronate mixtures. All the values of the parameters appeared to be in the normal range. These data indicate that both calcitriol and alendronate are drugs having low toxicity in rats. NOAEL of calcitriol and alendronate mixtures were 50.005 mg/kg in 5-week oral toxicity.

• Proceedings of the Korean Environmental Health Society Conference
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• 2003.06a
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• pp.158-161
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• 2003

Toxicity evaluations of 3-tert-butyl-, 2-isopropyl-, 3-isopropyl- and 4-propyl-phenol and their binary mixtures were performed with the Microtox$\^$(R) / assay and compared to invertebrates and fish. The single chemical, 4-isopropylphenol, exhibited the greatest relative toxicity to the Microtox organism (Vibrio fischeri). The relative electrophilicity (LUMO) of the phenols, in contrast to the lipophilicity (Log P), was strongly correlated with toxicity to V fischeri (r$^2$=0.96, p<0.01). In contrast, relative electrophilicity alone could not explain variances in toxicity of the phenols to Ceriodaphnia dubia. Results suggest that electrophilicity in conjunction with lipophilicity provide better correlation with toxicity to C. dubia and Pimephales promelas. Microtox results from the binary mixture toxicity tests of selected phenolics indicate a mechanism of interaction governed by suppression/antagonism.

• Toxicological Research
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• v.32 no.4
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• pp.337-343
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• 2016

We determined the toxicity of mixtures of ethyl acetate (EA), isopropyl alcohol (IPA), methyl ethyl ketone (MEK), toluene (TOL) and xylene (XYL) with half-maximal effective concentration ($EC_{50}$) values obtained using human hepatocytes cells. According to these data, quantitative property-activity relationships (QPAR) models were successfully proposed to predict the toxicity of mixtures by multiple linear regressions (MLR). The leave-one-out cross validation method was used to find the best subsets of descriptors in the learning methods. Significant differences in physico-chemical properties such as boiling point (BP), specific gravity (SG), Reid vapor pressure (rVP) and flash point (FP) were observed between the single substances and the mixtures. The $EC_{50}$ of the mixture of EA and IPA was significantly lower than that of contained TOL and XYL. The mixture toxicity was related to the mixing ratio of MEK, TOL and XYL (MLR equation $EC_{50}=3.3081-2.5018{\times}TOL-3.2595{\times}XYL-12.6596{\times}MEK{\times}XYL$), as well as to BP, SG, VP and FP (MLR equation $EC_{50}=1.3424+6.2250{\times}FP-7.1198{\times}SG{\times}FP-0.03013{\times}rVP{\times}FP$). These results suggest that QPAR-based models could accurately predict the toxicity of polar and nonpolar mixtures used in rotogravure printing industries.

• Toxicological Research
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• v.30 no.3
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• pp.199-204
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• 2014

The aim of this research was to improve our understanding of human toxicity due to exposure to DMF, MEK, or TOL individually as compared to exposure to DMF-MEK or DMF-TOL mixtures, by comparing $EC_{50}$ values as well as the morphological changes in HepG2 cells treated with these substances. We found that there was marked cell necrosis in the groups treated with mixtures than in those treated with the compounds alone, and that the amount of cell death and the $EC_{50}$ value were more dependent on MEK and TOL than on DMF. Moreover, analysis of the changes in effective concentration curves revealed that MEK had an antagonistic effect on the human toxicity of DMF, whereas TOL had a synergistic effect. Accordingly, these results suggest that in workplaces involved in the manufacture of synthetic leather, mixtures of DMF and TOL should be avoided as much as possible in order to minimize environmental toxicity and protect the health of the workers.

• Journal of Korean Society on Water Environment
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• v.30 no.4
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• pp.403-408
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• 2014

The toxicity of heavy metals (Zn, Pb) and diesel, in single and binary solution was investigated using the photobacterium Vibrio fischeri (Microtox test) as a test organism. In this experiment, the concentration of water soluble fraction of diesel was based on the total petroleum hydrocarbon (TPH). The toxicity of each single compound showed the following $EC_{50}$ (15min): Zn 1.90 mg/L, Pb 0.31 mg/L, TPH 2.09 mg/L. The observed toxicity of binary mixtures increased, depending on the concentration of the mixed substance. The effects were defined as synergistic, antagonistic, or additive, in accordance with the sign of difference between the predicted and observed toxicity at binary mixtures. The interactive effects between zinc and lead were synergistic, on the other hand, antagonistic and additive effects were found in each metal and TPH mixtures on the bioluminescence of V. fischeri.

• Journal of Environmental Health Sciences
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• v.49 no.2
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• pp.89-98
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• 2023

Background: Organophosphorus flame retardants (OPFRs) are a group of chemical substances used in building materials and plastic products to suppress or mitigate the combustion of materials. Although OPFRs are generally used in mixed form, information on their mixture toxicity is quite scarce. Objectives: This study aims to elucidate the toxicity and determine the types of interaction (e.g., synergistic, additive, and antagonistic effect) of OPFRs mixtures. Methods: Nine organophosphorus flame retardants, including TEHP (tris(2-ethylhexyl) phosphate) and TDCPP (tris(1,3-dichloro-2-propyl) phosphate), were selected based on indoor dust measurement data in South Korea. Nine OPFRs were exposed to the luminescent bacteria Aliivibrio fischeri for 30 minutes and the human hepatocyte cell line HepG2 for 48 hours. Chemicals with significant toxicity were only used for mixture toxicity tests in HepG2. In addition, the observed EC_x values were compared with the predicted toxicity values in the CA (concentration addition) prediction model, and the MDR (model deviation ratio) was calculated to determine the type of interaction. Results: Only four chemicals showed significant toxicity in the luminescent bacteria assays. However, EC₅₀ values were derived for seven out of nine OPFRs in the HepG2 assays. In the HepG2 assays, the highest to lowest EC₅₀ were in the order of the molecular weight of the target chemicals. In the further mixture tests, most binary mixtures show additive interactions except for the two combinations that have TPhP (triphenyl phosphate), i.e., TPhP and TDCPP, and TPhP and TBOEP (tris(2-butoxyethyl) phosphate). Conclusions: Our data shows OPFR mixtures usually have additivity; however, more research is needed to find out the reason for the synergistic effect of TPhP. Also, the mixture experimental dataset can be used as a training and validation set for developing the mixture toxicity prediction model as a further step.

• Journal of Environmental Health Sciences
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• v.50 no.3
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• pp.201-211
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• 2024

Background: Organic ultraviolet (UV) filters are widely used in sunscreen products and have been identified as an emerging contaminant. Organic UV filters co-exist with multiple components, but their mixture toxicity remains largely unknown. Objectives: We investigated the toxicity of single and binary mixtures of commonly used UV-filters using the human adrenocarcinoma (H295R) cell line. Methods: After exposure to non-cytotoxic concentrations of avobenzone (AVO), homosalate (HS), octisalate (OS), octinoxate (OMC), and octocrylene (OC), the levels of testosterone (T) and 17β-estradiol (E2) were measured. The median effective concentration (EC₅₀) values for the E2 of the individual substances were used to determine the mixture effect of four binary combinations: OMC+AVB, OMC+HS, OMC+OS, and OMC+OC. The synergistic, additive, and antagonistic effects of the mixture were determined by calculating toxic units (TU). To examine the mechanism of mixture toxicity, eight genes involved in steroidogenesis were analyzed using the real-time polymerase chain reaction. Results: The significant increase in E2 in H295R cells exposed to AVO, HS, OS, OMC, and OC suggest an estrogenic effect of the tested UV-filters. A significant decrease in T was observed in cells exposed to HS and OS. EC₅₀ values for E2 increase were 105 nM for AVO, 110 nM for HS, 120 nM for OS, 55 nM for OMC, and 80 nM for OC. Both binary mixtures consisting of OMC+HS and OMC+OS have synergistic effects. Conclusions: Our results showed that five types of UV-filter substances increase E2 in H295R cells. We examined the mixture toxicity in terms of increased estrogenicity and confirmed that E2 significantly increased when OMC was mixed with a salicylate-based UV-filters. These findings highlight the importance of determining the impact of UV filter mixtures.

• Journal of Korean Society on Water Environment
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• v.33 no.5
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• pp.556-562
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• 2017

Heavy metals in water systems are being managed on the concentration-based guidelines in Korea. However, various chemicals present in water can interact with heavy metals affecting their toxicity. Such interactions are not considered in the concentration-based guidelines. This study investigated the effect of hardness and coexisting heavy metals on heavy metal toxicity to emphasize the importance of having the effect-based guidelines together with the concentration-based guidelines in water management. The toxic effects of Cd, Zn, or mixtures of Cd and Zn were studied with Daphnia magna as a test species following the standard test method at different hardness conditions (100, 200, and $300mg\;L^{-1}$ as $CaCO_3$). The toxicities of single metal solutions and mixtures showed a decreasing trend with increasing hardness, and this can be attributed to the competition between heavy metals and cations such as calcium ions ($Ca^{2+}$) that cause hardness. The predicted toxicities of the heavy metal mixtures from the single metal toxicity deviated from the measured toxicities, and the predicted toxic effects tend to be greater than the measured toxic effects suggesting that Cd and Zn are in competition. This shows the limitations of using predicted toxic effects and the needs for further studies on mixture toxicities. Overall, this study shows that the management of heavy metals in waters needs to employ the effect-based guidelines together with the concentration-based guidelines.