Quantitative structure-activity relationship of DDT analogs

A quantitative structure-activity relationship (QSAR) has been carried out for Phormia regina toxicity by a set of 24 p,p′-disubstituted analogs of DDT. The toxicity data are from the extensive studies of R. L. Metcalf. Preliminary examination of the data indicated that toxicity was parabolically related to molar refractivity, MR, of the ring substituents. This enabled parabolic regression to be evaluated. Multiple regression analysis relating toxicity and the substituent constants MR, Taft steric parameter (E_s), hydrophobicity (π), and polar effect (σ) showed that MR dominated the regression equations. The implication of these physicochemical properties in the interaction of DDT analogs with the receptor site is discussed.     

Insecticidal activity and microsomal metabolism of biooxidizable lindane analogs

The insecticidal activity of lindane analogs, in which some chlorine atoms were replaced by other groups susceptible to microsomal oxidative metabolism, was determined against mosquitos, house flies, and German cockroaches. When tested with a synergist, piperonyl butoxide, one of the methylthio analogs was as active as lindane, whereas several others were also highly active. By examining the ratio of synergized and unsynergized LD₅₀ values (synergistic ratio value), the highly insecticidal methylthio, methoxy, and methyl analogs appear to undergo metabolic detoxication effectively in house flies. By means of in vitro metabolism experiments using microsomal fraction from house fly abdomen, the methoxy, ethoxy, and methylthio analogs were shown to be metabolized rapidly at similar rates. The synergized insecticidal activities of these compounds against various insect species relate linearly with each other, suggesting that the oxidative degradation is inhibited by the synergist to a similar extent and that the transport process to the site of action is not a limiting factor in determining the relative insecticidal activity.     

Anaerobic metabolism of DDT analogs by pigeon liver preparations

The amounts of p,p′-DDT and of five other trichloroethane derivatives decreased upon incubation under anaerobic conditions with 12,000g × 30 min pigeon liver supernatant fraction. The addition of an exogenous NADPH-generating system sometimes, but not invariably, increased the rate of metabolism. Only one hexane-soluble metabolite was detected in the postincubation reaction medium of each of the six trichloroethane derivatives. After isolation by tlc the six metabolites were shown by mass spectrometry to have molecular weights 34 units less than their parent compounds. Comparison of the isotope patterns in the spectra of each substrate and its metabolite reveals that in each case the metabolism involves the loss of a chlorine atom. From these data it is concluded that several substituted trichloroethanes undergo reductive dechlorination when they are incubated with liver preparations in an atomosphere of nitrogen. Two dichloroethane derivatives, tested in a similar manner, were unchanged and were recovered quantitatively. Mass spectrometric and chromatographic data of reactants and products are recorded.     

The effects of DDT and its analogs upon lecithin and other monolayers

The effect of DDT, 11 analogs, dieldrin, and lindane was studied on the pressure-area curves obtained by compressing monolayers of lecithin. The minimum cross-sectional area of lecithin and the compounds was measured by photography of models. All compounds shifted the pressure area curves in a direction and to an amount that suggested they formed 1:1 complexes with lecithin, and the complex had the cross-sectional area of the compound. DDT did not complex with cholesterol monolayers. Both DDT and DDMU formed complexes with phospholipids from Torpedo electroplax which resembled those with lecithin. The lack of difference in effects on monolayers between physiologically active and inactive analogs indicated that the monolayer effects did not explain the physiological action of DDT.     

The structure-activity relationship of DDT analogs in crayfish giant axons

The effects of 14 DDT analogs on the resting and action potentials of the crayfish giant axon were investigated using the intracellular microelectrode technique. These analogs can be classified into three groups, excitatory, blocking, and dualist. An excitatory analog tends to increase the excitability of the axonal membrane, and has hydrophobic side chains on the para positions whose optimal size equals that of the ethoxy group. A blocking analog suppresses the action potential without affecting the resting potential, and has hydrophilic side chains capable of forming hydrogen bonds. A dualist has both excitatory and blocking actions, and the latter may be related to restriction in rotation imposed by the grouping on the benzylic carbon. However, the dividing lines between these categories are not sharp, the compounds tending to fall along a spectrum between pure excitatory and pure blocking activity.     

The effects of DDT analogs upon potassium conductance in synthetic membranes

The effects of p,p′-DDT and 13 analogs were studied upon the K⁺ conductance which valinomycin induces in a lecithin-octane bilayer. Eight compounds decreased conductance, 4 relatively polar analogs increased conductance, and one had no effect. A partial correlation of these variations with physiological effects upon cockroach nerve and crayfish giant axon was found. Evidence was presented that the effect on the bilayer was due to an effect of the compounds on the fluidity of the membrane's interior rather than a direct interaction with the valinomycin.     

The effect of DDT and its analogs on the fragility of human erythrocytes

The antihemolytic actions of DDT and eight analogs were examined with human erythrocytes. Apparent aqueous concentrations to produce 60% of control hemolysis ranged from 3.7 × 10^?4 to 2.4 × 10^?6M, with DDT being one of the least active. No correlation was found between antihemolytic potency and neurotoxicity, and it was concluded that the findings did not illuminate the toxic or neural actions of these compounds.     

The sensitivity of mitochondrial Mg2+ ATPase to DDT and analogs at different temperatures

Oligomycin-sensitive (O-S) Mg²⁺ ATPase from American cockroach muscle was more sensitive to DDT, TDE, methoxychlor, and DDE at cool temperatures than at warm temperature, thus showing a negative temperature effect. In contrast, inhibition by acaricides dicofol, chlorfenethol, and Plictran shows a positive temperature effect. Oxidative phosphorylation in a mitochondrial preparation from cockroach coxal muscle was reduced by DDT, but the reduction was greater at a higher temperature (32°C) than at a cooler temperature (22°C). In addition, Na⁺K⁺ ATPase from cockroach nerve cord showed a positive temperature effect with DDT. The inhibition by DDT was much less on Na⁺K⁺ ATPase than on O-S Mg²⁺ ATPase. The negative temperature effect by DDT and analogs on O-S Mg²⁺ ATPase parallels toxicity effects on insects and fish as reported by numerous researchers. The results provide further evidence for this energy-regulating enzyme being a critical component in the biological action of DDT.     

The effect of some DDT and methoxychlor analogs on temperature selection and lethality in brook trout fingerlings

The effects of several DDT and methoxychlor analogs on trout fingerling temperature selection and lethality were investigated. The molecular requirements for lethality and alteration of temperature selection were different. Only p, p′-DDT, p, p′-DDD, and p, p′-methoxychlor were toxic in the range 10–50 ppb used. All the compounds tested, except DDE-type analogs, altered temperature selection. The effect of p, p′-methoxychlor on temperature selection progressively decreased until normal values were obtained 5 days after exposure. The effect of p, p′-DDT was still pronounced 9 days after exposure.     

In vitro effects of DDT analogs on trout brain Mg2+-ATPases: Inhibition kinetics

A continuous in vitro steady-state assay procedure was used to investigate the dependence of trout brain mitochondrial Mg²⁺-stimulated adenosinetriphosphatase specific activity on temperature and substrate concentration. The inhibition of enzyme activity by DDT was independent of substrate concentration. DDT and several analogs caused increases in the experimental activation energy and frequency factor of the enzyme-catalyzed reaction, which gave rise to a negative temperature coefficient of inhibition. It is suggested that DDT and other highly lipophilic compounds have the potential to allosterically affect membrane-bound enzymes by simply becoming a major lipoid component of the membranes.     

In vitro effects of DDT analogs on trout brain Mg2+-ATPases: I. Specificity and physiological significance

A continuous steady-state assay procedure was used to investigate the effects of DDT and several analogs on the in vitro Mg²⁺-stimulated adenosinetriphosphatase of a trout brain mitochondrial fraction. Pharmacological dissection of the enzyme with oligomycin, dicyclohexyl-carbodiimide, and azide failed to yield a fraction specifically sensitive to the organochlorines. At 25°C, low doses of DDT (≤1.35 μmol/mg of protein) stimulated enzyme activity, while methoxychlor was stimulatory at all doses. Higher doses of DDT and of several analogs caused only 45.5% or less inhibition at 25°C, but inhibition increased at lower temperatures. The physiological significance of these effects is discussed.     

Comparative metabolism of six ethoxychlor analogs and DDT in DDT-resistant and susceptible strains of the house fly Musca domestica L

The metabolic fate of six ³H-ring-substituted ethoxychlor analogs with altered aliphatic moieties and [¹⁴C]p,p′-DDT was investigated in susceptible and DDT-resistant strains of the house fly Musca domestica Linnaeus. The chloroalkane analogs, dichloroethane, chloropropane, and dichloropropane were primarily metabolized to the corresponding dehydrochlorinated products. This pathway was relatively more prominent in the resistant strain than in the susceptible strain. Biotransformation and detoxication of the isobutane, nitropropane, and neopentane derivatives was through microsomal oxidation (O-deethylation) of aryl ethoxy degradophores, and oxidation of the aliphatic moieties to produce the corresponding benzophenones, with no substantial differences between the resistant and susceptible strain. There was a strong correlation between the Taft ($\text{σ}{}^1$) values for the altered aliphatic moieties of chloroalkane analogs and their rate of dehydrochlorination in both the strains. These results suggest the importance of altered aliphatic moieties in developing resistance-proof DDT derivatives.     

Kinetics of sodium channel modification as the basis for the variation in the nerve membrane effects of pyrethroids and DDT analogs

The effects of a wide range of pyrethroids and DDT analogs on the membrane potential and membrane sodium currents were studied in crayfish giant axons. Compounds differed greatly in their ability to produce depolarizing afterpotentials, repetitive firing, and membrane depolarization. The differences observed at the membrane potential level could be explained by differences in the kinetics with which the insecticides interact with the nerve membrane sodium channel. The compounds containing a cyano group at the α position retain sodium channels in a modified open state persistently, depolarize the membrane, and block the action potential without causing repetitive firing. The pyrethroids without an α-cyano group and DDT analogs retain sodium channels in a modified open state only transiently, cause large depolarizing afterpotentials, and evoke repetitive firing with minimal effect on the resting potential. The effects of the phenoxybenzyl pyrethroids were found to be intermediate between these two extremes suggesting that a continuous variation exists in kinetics with which pyrethroids and DDT analogs modify sodium channels. It was not necessary to assume a second site of action to account for the variability observed. The implications of these results to the construction of quantitative structure-activity relationships is discussed.     

Residues of DDT in cottonseed after spraying with DDT and torbidan

DDT at 1.12 and 2.24 kg/ha a.i. and Torbidan at 5 and 10 litre formulation/ha (1 and 2 kg DDT/ha) were sprayed five times on cotton over a period of 15 weeks. Seeds from the first pick of the crop were found to contain as residues pp′-DDT and pp′-DDE [1,1-dichloro-2,2-di- (4-chlorophenyl)ethylene]. The highest residue level (0.783 parts/10⁶) was found in seeds from Torbidan 10 litre/ha treatment.     

Insecticidal activity of N-arylalkylbenzhydrolpiperidines

Benzhydrolpiperidine (BZP) insecticides represent a novel class of chemistry. Their specificity and efficacy as well as their low mammalian toxicity give them excellent potential for commercialization. Several N-arylalkylbenzhydrolpiperidines were tested for activity against a variety of insects in the laboratory and greenhouse. These tests were used to select compounds for field trials and determine rates of application for field tests. The BZP compounds have good activity against Lepidoptera, with modest Coleoptera activity. They are toxic by oral administration and have about 100-fold lower activity by topical exposure. A methyl carbamate BZP, F4265, was the most active compound, with LC50 values of 6 mg litre(-1) or less for most Lepidopteran species tested. F4265 was active in a variety of field trials at 112-224gAI ha(-1). Whole-plant testing methods conducted in the greenhouse were effective in determining field test rates.     

Effects of reducing DDT usage on total DDT storage in humans

Agricultural uses of the insecticide DDT were cancelled by the U.S. Environmental Protection Agency December 31, 1972. However, the domestic use of DDT had begun to decline before this action. Beginning July 1969, residues of DDT and its metabolites were measured in human adipose tissue collected through an annual national survey. Levels of total DDT equivalent residues in human adipose have decreased slightly, but the frequencies of finding DDT or its metabolites have remained high. The most marked decline in residue concentration has been found in the youngest age group (0-14 years). Approximately 80 percent of the total DDT equivalent found in this survey was DDE. These data show that the reduction of the agricultural uses of DDT has decreased human exposure to and storage of this chemical.     

苯甲酰脲类化合物的合成及杀虫活性

对2-氨基-5-芳基-1,3,4- 口 恶 二唑的合成进行了深入研究,找到了一种基于HBr-H2O2 体系的绿色合成新方法,并以此为中间体,合成了18个未见报道的苯甲酰脲类目标化合物,所有化合物均通过核磁共振、高分辨质谱、红外光谱的分析鉴定。生物活性测试结果表明,在500 mg/L浓度下该系列目标化合物均未表现出显著的杀虫活性。     

DDT and inflammatory responses: 1. Influenza infection in mice fed DDT

Mice fed casein diets containing 100 and 200 ppm DDT for 20 days failed to exhibit any signs of DDT intoxication or an impairment of growth. When the mice were infected with influenza A₂ virus, the resulting disease was more severe in the DDT-fed groups as evidenced by increased inflammatory lung oedema and mortality rates. While DDT failed to affect viral replication in the lungs, the increased lung inflammatory oedema was evaluated in relationship to lung histamine content. Following the infection the lung histamine levels decreased; control group 30%; 100 ppm DDT 57%; and 200 ppm DDT 69%. The results indicate that DDT increases release of histamine that accelerates the inflammatory reaction and thus contributes to the mortality caused by influenza. The results suggest that DDT residues stored in tissues can affect inflammatory responses induced by infectious agents.