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Acute toxicity, in vitro metabolism and structure-toxicity relationship of aliphatic mononitriles were examined in mice pretreated with carbon tetrachloride (CCl4). The LD50 in mice pretreated with CCl4 (LD50-CCl4) was increased in most nitriles compared to that in untreated animals (LD50-cont.) with different degrees among compounds. Microsomal metabolism of nitriles to CN- was completely inhibited when microsomes were prepared from livers of mice pretreated with CCl4. Log (1/LD50-CCl4) was a linear function of partition coefficient, log P, i.e., log (1/LD50-CCl4) = -0.371 log P-0.152, and the equation was statistically significant (P less than 0.01), provided aceto- and 3-hydroxypropionitrile were omitted from the analysis. These two compounds seem to be different from the others in exerting the biological effect.  相似文献   

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Toxicity data for 200 substituted benzenes tested in the two-day Tetrahymena pyriformis population growth impairment assay representing the neutral narcosis, polar narcosis, respiratory uncoupling, and weak and strong electrophilic mechanisms of toxic action were evaluated. A quantitative structure-toxicity model correlating toxic potency [log(IGC(50)(-)(1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log K(ow)) and electrophilic reactivity quantified by the molecular orbital parameter, maximum superdelocalizability (S(max)), was developed. This model [log(IGC(50)(-)(1)) = 0.50(log K(ow)) + 9.85(S(max)) - 3.47; n = 197, r(2) = 0.816, s = 0.34, F = 429, Pr > F = 0.0001] allows for the prediction of acute potency without the a priori identification of the mechanism of action. The examination of residuals reveals that neutral narcotics with high volatility (e.g., methyl- and chloro-substituted benzenes) and highly reactive fluoro- and nitro-containing derivatives are fitted poorly. A comparison of observed (obs) and predicted (pred) toxicities on the additional set of derivatives [log(obs IGC(50)(-)(1)) = 1.05[log(pred IGC(50)(-)(1))] + 0.02; n = 20, r(2) = 0.979, s = 0.13, F = 825, Pr > F = 0.0001] validated the model as a good predictor of toxicity regardless of the mechanism of toxic action.  相似文献   

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Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).  相似文献   

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The teratogenicities and the lethalities of hydantoin (H), ethotoin (E), mephenytoin (M), phenytoin (P), and phenacemide (PA) were examined in the CD-1 mouse. The outcome of pregnancy was observed following single daily ip administrations on Days 8, 9, and 10 using at least three dose levels for each compound. For comparison, a limited number of dose groups were run on Days 11, 12, and 13. Adult lethality was estimated using female nonpregnant animals following the same 3-day dosing schedule. Dose-response (D-R) relationships were examined by probit analysis. The lethal potency of the compounds varied from an LD50 of 53.7 mmol/kg/day for H to 0.32 mmol/kg/day for P. Slopes of the lethality D-R lines were not significantly different for E, M, and P. There was a strong correlation (R2 = 0.94) between the LD50s of the five compounds and their octanol-water partition coefficients (log P). H, E, P, and PA were teratogenic over both treatment schedules while M showed no evidence of dose-related increases in malformations and was embryolethal only at maternally lethal doses. All compounds reduced fetal weights, over both dose schedules. Malformation profiles were similar for H, E, P, and PA, most commonly skeletal and cardiovascular anomalies, exencephaly, and cleft palate for Days 8, 9, and 10 and cleft palate and cardiovascular defects for Days 11, 12, and 13. Teratogenic potency varied from a tD05 (dose required to induce 5% malformations, Days 8, 9, 10 data) of 30.2 mmol/kg/day for H to 0.17 mmol/kg/day for P. For each compound, the slope of the teratogenicity D-R was different from their lethality slope; however, there were no significant differences between the teratogenicity slopes of H, E, and P. Again, there was a correlation between tD05 and log P (R2 = 0.89) for H, E, P, and PA. The relative teratogenic index (RTI = LD01tD05) was calculated as an indicator of teratogenic hazard. The compounds can be ranked in order of increasing hazard: mephenytoin, <0.9; hydantoin, 1.27; ethotoin, 1.39; phenytoin, 1.62; phenacemide; 3.32. These data suggest a common mechanism of teratogenicity for the closed-ring hydantoins, H, E, and P, and of lethality for the substituted hydantoins E, M, and P. Lethal and teratogenic potencies seem to be determined primarily by lipid solubility but the physiochemical properties which determine relative teratogenic hazard have yet to be identified.  相似文献   

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Many 2,6,7-trioxabicyclo[2.2.2]octanes with P, PO, PS, CH or C-alkyl substituents in the 1-position and C2H5, n-C3H7, i-C3H7, n-C4H9, or other substituents at the 4-position act at very low intraperitoneal dosages to produce convulsive seizures and death in mice. The signs of poisoning, probably resulting from stimulation of the central nervous system, resemble those of 2,6-dithia-1,3,5,7-tetrazatricyclo[3.3.1.13,7]decane-2,2,6,6-tetroxide and 1-(p-chlorophenyl)-2,8,9-trioxa-5-aza-1-silabicyclo[3.3.3]undecane, which are of similar toxicity to 4-isopropyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane and its 1-oxide and 1-sulfide derivatives. It appears likely that toxicants of several of the chemical classes represented within the 67 compounds that were studied act at the same site in the central nervous system without having a requirement for metabolic activation. Synthesis procedures are reported here for many of these toxic materials. The findings of this study are relevant to the hazards associated with certain intermediates used in coordination chemistry and organic synthesis and with the combustion products of some flame retardants in the presence of certain polyols.  相似文献   

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Endocrine-disrupting chemicals (EDCs) are known for their ever-looming persistent negative effects on the environment and public health. A remarkable array of mechanistic evidence suggests EDCs exposure is hazardous, but no approved paradigm exists for integrating it into a global context of EDCs-related risks. It is challenging to address such issues just via human effort; studies involving extensive environmental monitoring over extended periods of time are often time-consuming and laborious. To better comprehend and predict the wide variety of possible negative consequences associated with EDCs, a computational framework might be useful for addressing EDCS-linked environmental concerns by implementing green predictive approaches. To cover the existing research gap, a computational framework was deployed in the current work to elucidate the possible toxic risks and hazards of seven EDCs (Estrone, 17β-estradiol, 17 α -ethinylestradiol, Bisphenol A, Triclosan, 4-Nonylphenol diethoxylate, and 4-Octylphenol) exploiting Toxtree, and ECOSAR program, and its possible catalytic exploration by exploiting docking analyses. Predicted hazard results exhibited Class 1 (easily biodegradable chemical), and Class 2 (persistent chemical), even observed alerts for protein and DNA bindings. Likewise, predicted aquatic toxicity was estimated by exploiting different model systems. The far lowest Fish LC50 (96H) concentration was measured for 4-Octylphenol (0.11 mg L?1). Similarly, 4-Nonylphenol diethoxylate was measured for the lowest Daphnid LC50 (48H) concentration 0.21 (mg L?1). Likewise, a considerably lowest EC50 in Green algae (96H) was measured for 4-Octylphenol (0.01 mg L?1). In an attempt to predictive biodegradation of EDCs, A set of three oxidoreductases i.e. Dye type peroxidase (DyP), versatile peroxidase (VP), and laccase (LAC) were exploited for enzyme-EDCs docking. The far lowest binding affinity was measured for the LAC-4-Nonylphenol diethoxylate complex with a binding score of ?9.194 (kcal mol-1). The findings reported herein revealed the severe toxicological risk posed by EDCs, which could be reduced with the use of oxidoreductases. The theoretical basis of enzymes-EDCs interaction endorsed the sufficient binding affinity, which could be implemented in green sustainable degradation design in combination with a real-time assay to regulate the existing environmental issues.  相似文献   

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In poisoning animals with various aliphatic series haloid-hydrocarbons (LK99 and LD99) free cysteine was found to be a group antidote in rats poisoned with monohaloid-hydrocarbons. It was established that the therapeutic activity of cystein depends not on the nature of haloid and double bonds, but on the number of the haloid atoms in a molecule, the length, ramification and nature of the radical. A good durative action are shown by such cystein derivatives as acetyl-cysteine, glutathione and cystein salts. In poisoning with haloid-alkyls dithiol antidotes (unithiol, mecaptide, BAL) and other drugs proved ineffective.  相似文献   

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The effect of modification of amino groups on RTX-III induced lethality in mice has been studied. The toxicity was not affected by guanidination of one or two lysine residues with O-methylisourea, but guanidination of three or four lysine residues decreased lethality two-fold. Acetylation of the N-terminal amino group with [3H]acetic anhydride caused a 12-fold decrease of lethality. The toxin containing acetylated Lys-4 or one of three C-terminal lysine residues had half the lethal potency of the native RTX-III. Diacetylated derivatives were 30- to 35-fold less toxic than the native toxin. By circular dichroism, it was shown that modification of one or two amino groups did not affect the secondary structure of the toxin. We conclude that protonated amino groups are essential for neurotoxicity.  相似文献   

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Biodegradation of each primary alcohol from methanol (C1. OH) to 1-dodecanol (1–C12. OH) was manometrically measured as a function of alcohol concentration. The study employed resting cells prepared from the growth of a mixed microbial culture on the respective alcohol substrate. Biodegradation rates at each alcohol concentration were calculated in terms of μmol oxygen consumed/μg cell protein/h. Maximum biodegradation rates of all alcohols were correlated with the concentrations of respective alcohols. Gaussian curves were obtained for all alcohols, except 1-undecanol and 1-dodecanol. From the rate inhibition data, concentrations that reduced maximum observed biodegradation rates by 50% (experimental EC50) were statistically derived for 10 alcohols (C1. OH to 1-C10. OH). The logarithms of 1-octanol/water partition coefficients (Log P) and EC50 values of these alcohols were correlated. This relationship was parabolic and defined by the polynomial regression equation: Log EC50 (mol/L) = –0.88 (Log P) + 0.07 (Log P)2–0.23. This equation was used for predicting EC50 values of 19 narcotic industrial chemicals based on their Log P values. Experimental EC50 values of these test chemicals were derived in the same manner as described for alcohols. The EC50 values were compared for each test chemical by taking a ratio of predicted to experimental EC50 (mol/L). The mean value of these ratios was 1.16 ± 0.35. The logarithms of microbial respirometric EC50 and fathead minnow acute toxicity (96-h LC50) values of 7 primary alcohols were correlated. This relationship was linear and defined by the exponential equation: LC50 (mg/L) = 0.0001 (EC50 mg/L)1.76. This equation was used for predicting LC50 values of 12 narcotic chemicals. Predicted and experimental (from literature) LC50 values of each chemical were compared by appropriately taking a ratio. The average of these ratios was about 1.2.  相似文献   

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The objectives of this study were to (i) develop quantitative structure-property relationships (QSPRs) for blood:air partition coefficients (Pb:a), tissue:air partition coefficients (Pt:a), and hepatic clearance (CLh) and (ii) conduct interspecies extrapolations of the pharmacokinetics of low molecular weight volatile organic chemicals (VOCs) by incorporating the above QSPRs within a physiologically based pharmacokinetic (PBPK) modeling framework. Pb:a and Pt:a were predicted using the following algorithm: FnlxPo:a+FwxPw:a+f(b)xFpxPp:a, where Fnl=content of neutral lipid equivalents in biological matrix, Fw=content of water equivalents in biological matrix, Fp=protein content of blood and tissues, Po:a=vegetable oil:air partition coefficient, Pw:a=water:air partition coefficient, f(b)=fraction of total protein involved in the partitioning process, and Pp:a=protein:air partition coefficient. CLh was estimated as follows: Qlx[(CLintxC(P4502E1)xVl)/(Ql+CLintxC(P4502E1)xVl)], where CLint=intrinsic clearance normalized for P450 2E1 content, Ql=blood flow to the liver, C(P4502E1)=hepatic concentration of P450 2E1 in the species of interest, and Vl=volume of liver. QSPRs relating molecular fragments of 46 VOCs and parameters required for estimating Pb:a, Pt:a, and CLh (namely, Po:a, Pw:a, Pp:a, and CLint) were established using a group contribution method (f(i)xCi, where f=frequency of occurrence of the group i in a given molecule and Ci=contribution of the group i to Po:a, Pw:a, Pp:a, or CLint). Values of group contributions were determined by multilinear regression of experimental data. The species specific parameters required for solving the above algorithms were obtained from the literature. These algorithms, once incorporated into a multispecies PBPK modeling framework, enabled extrapolation of the kinetics of chemicals across species. The inhalation pharmacokinetics of dichloromethane and toluene as well as two de novo compounds (1,2,4-trimethyl benzene and ethyl benzene) were extrapolated from rat to human, using the present modeling methodology. This study has demonstrated that it is possible to extrapolate the pharmacokinetic behavior of chemicals from rats to humans on the basis of QSPRs and species specific physiological information.  相似文献   

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