Joseph C. Street

Alteration of induced cellular and humoral immune responses by pesticides and chemicals of environmental concern: quantitative studies of immunosuppression by DDT, aroclor 1254, carbaryl, carbofuran, and methylparathion.

Abstract Dose-dependent, immunosuppressive effects of continued dietary treatment of rabbits with DDT, Aroclor 1254, carbaryl, carbofuran, and methylparathion were studied. The animals were given a diet containing graded amounts of chemicals for 4 wk and challenged with sheep red blood cells and Freunds adjuvant. The testing followed for an additional 4 wk while the animals were maintained on the same diets as before. The most sensitive indication of immunosuppression was based on evaluation of lymphatic organs, primarily those dependent on thymus-derived lymphocytes. The chemical treatments resulted in a decreased count of plasma cells in popliteal lymph nodes (except with carbaryl), reduction of germinal centers in the spleen, and increasing atrophy of thymus cortex. These responses were generally scaled to increasing levels of the compounds tested. Hemolysin and hemagglutinin titers were not significantly affected by any of the chemical treatments nor were consistent trends observed. The antigen-induced increase in serum γ-globulin was consistently decreased with DDT, Aroclor, carbaryl, and carbofuran treatments, but only carbaryl produced significant changes (at 10 days postantigen). DDT groups showed significantly higher preantigen γ-globulin values which were less evident following antigen challenge. Skin sensitivity to tuberculin was decreased (except with carbaryl) but generally only at high dosages of the test chemicals. None of the compounds showed any effect on growth, food consumption, leucocyte count, or on organ to body weight ratios for liver, kidney, spleen, and adrenal, except for slight liver enlargement caused by Aroclor 1254.

DDT Antagonism to Dieldrin Storage in Adipose Tissue of Rats.

Storage of dieldrin in the adipose tissue of female rats was markedly depressed when DDT and dieldrin were fed simultaneously. The amount of dieldrin present in the tissues of rats fed 1 and 10 parts of dieldrin per million was significantly reduced by the addition of 5 ppm DDT to the feed. The addition of 50 ppm DDT to the feed caused a 15-fold reduction in the amount of dieldrin stored in rats fed 1 ppm dieldrin, and a 6-fold reduction in rats fed 10 ppm dieldrin. This antagonistic effect of DDT suggests that the criteria used in predicting the pharmacological effects of combined residues of related insecticides need some revision.

Ascorbic acid deficiency and induction of hepatic microsomal hydroxylative enzymes by organochlorine pesticides.

Abstract Hepatic microsomal hydroxylative enzyme systems, O -demethylation of p -nitroanisole and hydroxylation of aniline, were induced by dietary dieldrin and to a lesser extent by DDT and lindane in guinea pigs. However, liver weights were not consistently increased nor were microsomal protein concentrations elevated. Ascorbic acid deficiency impaired the induction by dieldrin as early as 2 days on deficient diet. As scurvy developed through stages of normal weight gains, depressed gains and finally hemorrhagic lesions, the impairment became consistently lower during the period of depressed weight gains due to the accompanying decline in basal enzyme activity. Sex had no effect on either induction by dieldrin or its impairment in ascorbic acid deficiency. Maintenance of induction was related to dietary levels rather than hepatic concentrations of the vitamin and required higher dietary levels of ascorbic acid than scurvy prevention.

Drug Effects on Dieldrin Storage in Rat Tissue

SummarySelected drugs were tested for effectiveness in reducing dieldrin retention by rats. Female rats were fed diets treated to contain 1 ppm dieldrin. The drugs were administered as feed additives or by i.p. injections. The rats were sacrificed after 10 days of treatment and abdominal adipose tissue was analyzed for dieldrin using electron capture gas chromatography.Heptabarbital (40 and 225 mg/kg rat/day), aminopyrine (75 and 350 mg/kg rat/day), tolbutamide (60 and 290 mg/kg rat/day), and phenylbutazone (90 mg/kg rat/day) were effective as feed additives in reducing tissue dieldrin. Heptabarbital was the most effective and reduced the concentration of tissue dieldrin by 80 per cent at the higher dose level. In comparison, DDT (4 mg/kg rat/day) effected a 72 per cent reduction. A contrast with DDT was also observed in trials with i.p. administration of drugs and DDT. In those trials, the duration of the DDT action was apparently greater than that of the drugs.We suggest that suitable drugs might be used to reduce insecticide accumulation in the tissues of animals and man, and for treatment of individuals after over exposure to insecticides.

Stimulation of dieldrin metabolism by DDT

Abstract The excretion of polar metabolites of dieldrin by DDT-treated female rats greatly exceeded that by rats given only dieldrin- 14 C. Increased metabolite excretion was observed in both feces and urine, the relative increase being greater in the urinary products. The chromatographic properties of the major urinary dieldrin metabolite in DDT-stimulated rats did not match those of trans -dihydroxydihydroaldrin, the principal urinary metabolite in the rabbit.

Organochlorine insecticide interactions affecting residue storage in rainbow trout

SummaryThree dose levels each of dieldrin (0 mg, 0.04 mg, 0.2 mg), DDT (0 mg, 0.2 mg, 1.0 mg), and methoxychlor (0 mg, 0.6 mg, 3.0 mg) were used in a 33 completely randomized factorial design. All 27 possible compound and dose combinations were used in the study. Six fish were used per treatment. The fish were individually given doses of insecticidesper os in corn oil enclosed in gelatin capsules. The fish were dosed on alternate days, seven doses in all. On the fifteenth day, the fish were killed and the fat body analyzed for lipid content and residual insecticides.Tissue storage of DDT and DDE increased when DDT and dieldrin were fed in combination. The same response had been noted in rats but was of much greater magnitude in fish. Dieldrin storage was reduced by the presence of either DDT or methoxychlor. The effect of methoxychlor was more pronounced than that of DDT. The effect of DDT on tissue dieldrin reduction is much less in fish than in rats. Feeding of DDT with methoxychlor resulted in decreased methoxychlor storage. The influence of dieldrin on increasing tissue methoxychlor was highly significant (P<.01) when fish were given doses of 3.0 mg methoxychlor. Insecticide interactions occur in fish, but large differences in these responses exist between fish and rats.

Identification of products arising from the metabolism of cis- and trans-chlordane in rat liver microsomes in vitro: Outline of a possible metabolic pathway

Abstract The metabolism of pure cis- and trans-chlordane was studied in vitro. Microsomal preparations from the livers of male rats induced with cis- or trans-chlordane in feed for 10 days were used to metabolize the pure compound corresponding to the inducer. Subsequent extraction, column fractionation, and combined gas chromatography-mass spectroscopy resulted in the characterization of four compounds not previously reported from an in vitro system. In addition to the substrate, trans-chlordane extracts contained species with the following molecular weights and empirical formulas: m e 370, C10H5Cl7, heptachlor; m e 352, C10H6OCl6, a hydroxylated chlordene; and m e 422, C10H6OCl8, a hydroxylated chlordane. Dichlorochlordene, oxychlordane, and 1-chloro-2-hydroxy-dihydrochlordene were also present. With the exception of the hydroxychlordane, cis-chlordane extracts contained all of the metabolites found in the trans incubates. Additionally, a fully saturated compound, m e 372, C10H7Cl7, a dihydroheptachlor, was present. The 1,2-trans-dihydrodiol of heptachlor found in previous in vitro incubates of cis-chlordane was not present in this extract. This information has been incorporated into a proposed route for the biotransformation of the chlordanes that offers an explanation for the observed differences in the metabolism of cis and trans isomers. The pathway is based on the reductive dechlorination of the chlordanes through dihydroheptachlor to dihydrochlordene. Parallel pathways of hydroxylation, desaturation, and epoxide formation arise at each of these species and at chlordane itself.

DDT intoxication in rainbow trout as affected by dieldrin

Abstract Rainbow trout were dosed po with 5 mg DDT alone and in combination with 0.04 mg or 0.20 mg dieldrin on alternate days, 4 treatments in all. Fish were also pretreated on 4 alternate days with 0.20 mg dieldrin per dose followed by 4 alternate day treatments of 5 mg DDT per dose. The presence of dieldrin resulted in reduced mortality from DDT intoxication. The time until death after demonstrating signs of intoxication was also much longer in fish receiving dieldrin in addition to DDT than in those receiving DDT only. DDT increased with time in adipose tissue, but the lethal brain levels of DDT were nearly constant. It was observed that rainbow trout die at a much lower brain level of DDT than reported for rats or birds.

Microsomal activation of chlordane isomers to derivatives that irreversibly interact with cellular macromolecules.

Incubation of 14C-labeled cis and trans isomers of chlordane with cofactor-fortified mouse hepatic microsomes resulted in binding of insecticide-derived material to endogenous protein and RNA and to added DNA. The microsomes were prepared from male C57BL/6J mice. Chlordane is known to cause hepatocellular carcinoma in a similar strain. The highest concentrations of radioactive material bound to protein, followed by RNA and DNA. The cis isomer produced greater amounts of bound radioactivity, while binding from trans-chlordane was slight and, in the case of DNA, not detectable. Investigation of the effect of microsomal enzyme induction by chlordane isomers and phenobarbital on the yield of bound, chlordane-derived material gave mixed results. Generally, use of induced microsomes increased binding to protein and DNA and had no effect on binding to RNA. The inducers caused increased mixed-function oxidase activity, cytochrome P-450 content, and epoxide hydratase activity in experimental microsomes. Omission of the NADPH generating system from microsomal preparations had a variable effect on binding. Inhibition of epoxide hydratase reduced cis-chlordane-related binding to DNA to unmeasurable levels.

Pharmacokinetics of dicamba isomers applied dermally to rats

Abstract The pharmacokinetic profile of the herbicide dicamba (3,6-dichloro-2-methoxybenzoic acid) and its isomer (3,5-dichloro-2-methoxybenzoic acid) present in dicamba formulation was examined in rats given single dermal applications of 100 mg/kg of dicamba, 20 mg/kg of the isomer, or their combination at those rates. The concentration of the isomer in blood increased up to 9 hr following application and then declined slowly. The rate of clearance of dicamba from the blood greatly exceeded that of the isomer and was apparently of first order for both. The rate constants for first-order elimination ( k e ) were 1.7 and 0.19 hr −1 for dicamba and the isomer, respectively. The rates of absorption of the two chemicals through the skin as determined by urinary excretion was 0.0029 hr −1 for dicamba and 0.0012 hr −1 for the isomer. Urinary excretion of the original dose was 16.5% for dicamba and 7.5% for the isomer. Following the combined application, the kinetics of uptake and clearance was similar to that determined for each chemical administered alone.