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PubMed2001

Neurotoxicological outcomes of perinatal heptachlor exposure in the rat.

The developing nervous system has been identified as a potential target of pesticide exposure. Heptachlor is a cyclodiene pesticide that was widely used for many years, and for which inadvertent exposure to children and fetuses took place in the early 1980s; yet little is known regarding the developmental neurotoxicity of it and other cyclodienes. The aim of this study was to determine whether perinatal heptachlor exposure results in persistent alterations in nervous system function. Pregnant Sprague-Dawley dams were dosed from gestational day (GD) 12 to postnatal day (PND) 7, whereupon the rat pups were dosed directly until PND 21 (group A) or PND 42 (group B). Dose levels were 0, 0.03, 0.3, or 3 mg/kg/day, po. There were no dose-related effects on maternal weight, litter size, or pup growth. GABA(A) receptor binding (using [(35)S] tert-butylbicyclophosphorothionate; TBPS) and GABA-stimulated Cl- flux were evaluated in control and high-dose brain tissues taken on PND 7, 21, and 43. The B(max) values for [(35)S]-TBPS binding in brainstem, but not cortex, were decreased in female rats across all ages tested. There were no such changes in male rats, nor were K(D) values altered in either tissue or gender. GABA-stimulated Cl- flux was decreased in female cortex synaptoneurosomes only on PND 21. The ontogeny of the righting response (PND 2-5) was delayed in the high-dose females. All subsequent testing took place a week to months after dosing ceased. The functional observational battery (FOB) showed treatment-related, but not necessarily dose-related, changes in different aspects of the rat's reactivity and activity levels. Group-A rats also showed altered within-session habituation of motor activity. There were no heptachlor-related differences in motor activity following challenge with a range of chlordiazepoxide doses. Cognitive assessments were conducted in both groups of rats. There were no statistically significant differences among treatment groups in a one-trial passive avoidance test, although there was a trend toward less learning. In group B, rats (both sexes), heptachlor altered spatial learning in the Morris water maze during two weeks of daily training (2 trials/day). On probe trials, heptachlor-treated rats did not show significant preference for the correct quadrant (all dose groups in males, high dose in females). These rats did not show alterations on subsequent working-memory training (where the platform position was relearned each day). Thus, perinatal exposure to heptachlor produced neurochemical and persistent neurobehavioral changes, including alterations in spatial learning and memory.

Animals↗
PubMedDate not supplied

Differential regulation of the major cyclin-dependent kinases, cdk2 and cdc2, during cell cycle progression in human lymphocytes exposed to heptachlor.

Heptachlor, a chlorinated hydrocarbon insecticide, has been considered an environmental contaminant with potential adverse health effects. Exposure to heptachlor may impair immune functions including the inhibition of leukocyte chemotaxis, which causes defects in host defense mechanisms. This study addresses the effects of heptachlor on the cell cycle progression of human lymphocytes. It has been found that addition of heptachlor to cultured lymphocytic cells prevents the cells from progression into the S phase of the cell cycle, with a concomitant accumulation of cells in G1 phase. An accompanying decrease (deactivation) in cyclin-dependent kinase cdk2 and dephosphorylation (activation) of cdc2 was observed. The altered cell cycle progression may trigger the cell's apoptotic potential, as indicated by the reduced amount of Bcl-2 synthesized inside heptachlor-treated cells. The interference of cell cycle progression by heptachlor was also seen with chlordane and toxaphene, two other chlorinated hydrocarbon insecticides.

Apoptosis↗
PubMed2004

Gestational and lactational exposure to heptachlor does not alter reproductive system development in rats.

Like other organochlorine insecticides, heptachlor is lipophilic and accumulates in fatty tissues. Earlier studies suggested that in utero exposure to heptachlor decreased fertility in the offspring; neonatal exposure to the closely related insecticide chlordane reportedly delayed puberty and disrupted estrous cycling in females. We hypothesized that in utero and lactational exposure to heptachlor would disrupt the development of the reproductive system in males and females, resulting in altered timing of puberty and abnormal gonadal histology and reproductive hormone levels. Timed pregnant Sprague-Dawley rats were treated by oral gavage with heptachlor in corn oil at doses of 0.5 and 5.0 mg/kg or an equivalent volume of corn oil alone daily from gestational day 8 through post-natal day (PND) 21, the day of weaning (n = 7-8/group). Litters were standardized to 4 males and 4 females on the day of birth. Two of the dams in the 5.0 mg/kg/d group died. Pups in the highest dose group weighed significantly less than those in the other 2 groups on PND 0. All but 1 litter of the 5.0 mg/kg/d group died within the first 4 post-natal days. Age at eye opening was delayed with increasing heptachlor dose. There was no effect of treatment on pup weight gain in the surviving litters, on anogenital distance, age at puberty, nipple retention past the infantile period in males, estrous cycling, serum sex steroid concentrations, reproductive organ weights, or testicular or ovarian histology. These results suggest that heptachlor exposure during gestation and lactation does not disrupt development of the reproductive system in rats.

Animals↗
PubMed1977

Bioassay of heptachlor for possible carcinogenicity.

A bioassay of technical-grade heptachlor for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered low or high concentrations of the heptachlor for 80 weeks, then observed for 30 weeks. Doses for females were first increased, but because of toxic effects the doses were then reduced twice for both male and female rats during the remaining course of the tests. Time-weighted average doses used for the male rats were 38.9 and 77.9 ppm; for the females, 25.7 and 51.3 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups combined with 50 untreated male and 50 untreated female rats from similar bioassays of five other compounds. All surviving rats were killed at 110-111 weeks. Groups of 50 mice of each sex were administered the test material at low or high concentrations for 80 weeks, then observed for 10 weeks. The low- and high-dose groups were tested at different calendar times, but a concurrent control group was started with each. Because of toxic effects, doses were reduced once for the males at 17-18 weeks after the initiation of tests; twice for the females, at 17 and 30 weeks, after the initiation of tests. The time-weighted average doses used for the male mice were 6.1 and 13.8 ppm; for the females, 9 and 18 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 90 untreated male and 70 untreated female mice from similar bioassays of five other compounds. All surviving mice were killed at 90-91 weeks. The effects of heptachlor on body weights and other clinical signs in rats and mice indicated that the dosages used were near the maximum permissible. This was evident in that average body weights of rats treated with high doses were consistently lower than those of untreated controls, while body weights of low-dose rats were unaffected. Body weights of mice given either high or low doses showed little or no differences from those of control mice; however, other adverse clinical signs were found in high-dose mice, predominantly in the females. The effects of heptachlor on survival rates indicated that mortality was dose-related for both female rats and female mice, but not for males of either species. However, a substantial proportion of all groups of animals survived to an age at which tumors could be expected to appear. In mice, hepatocellular carcinoma showed a highly significant dose-related trend in both males (matched controls 5/19, low dose 11/46, high dose 34/47, P=0.001) and females (control 2/10, low dose 3/47, high dose 30/42, P<0.0001). When pooled controls were used for the comparison, the significance of the trend in males increased to P<0.0001. Comparably high levels of significance were attained when the data were subjected to life-table adjustment. No other tumors were found in mice in sufficient numbers to justify analysis. In marked contrast to the findings observed in mice, no hepatic tumors were observed in rats administered heptachlor. There was significant statistical evidence for the induction of proliferative lesions of follicular cells of the thyroid in treated female rats, but this finding was discounted because the rates of incidence were comparatively low and are known to be variable in control rat populations. It is concluded that under the conditions of this bioassay, heptachlor is carcinogenic for the liver in mice.

Journal Article↗
PubMed1999

Heptachlor alters expression and function of dopamine transporters.

Epidemiological data support a relationship between pesticide exposure and Parkinson's disease; however, no experimental evidence has been provided to support this association. Here we report that subchronic administration of the organochlorine insecticide heptachlor (0, 3, 6, 9, or 12 mg/kg given 3 times over a 2 week period) leads to a pronounced increase in both the plasma membrane transport of dopamine and the expression of the plasma membrane dopamine transporter (DAT), as well as the vesicular monoamine transporter (VMAT2) in the striatum of C57BL mice. To address possible mechanisms of increased DAT and VMAT2 expression, we performed transport studies in cell lines expressing the human forms of either DAT or VMAT2. In a DAT expressing cell line, acute treatment with the putative toxic species of heptachlor, heptachlor epoxide, did not alter plasma membrane dopamine uptake. In a VMAT2 expressing cell line, heptachlor epoxide significantly inhibited vesicular uptake of dopamine (45% reduction at 10 microM). Since DAT has been proposed to be the molecular gateway for dopaminergic toxins, such as the parkinsonism-inducing neurotoxin MPP, and VMAT2 has been proposed to protect cells from MPP and other toxins by sequestering the toxin into vesicles, the combined effects of heptachlor could increase the susceptibility of the nigrostriatal dopamine system to neurodegeneration. We further propose that altered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease.

Animals↗
PubMed2002

Alteration of thrombine-signaling mechanism by heptachlor in human platelets.

Heptachlor is a persistent organochlorine insecticide that has been detected in human tissues and fluids. The ability of heptachlor to interfere with platelet phosphoinositides metabolism and related signaling events stimulated by thrombin was evaluated. In vitro incubations with a concentration range of 1-100 microM heptachlor, prior to platelets activation, were performed. Experiments showed that 10 microM increased protein Kinase C (PKC) activity and phosphatidylinositolbiphosphate and phosphatidic acid phosphorylation. Simultaneously phosphatidylcholine and phosphatidylethanolamine breakdown were prevented. Similar effects were observed with HC 1 microM. However, heptachlor 100 microM increased phosphatidylinositolbiphosphate phosphorylation but reduced serine/threonine kinases activity. We propose that signal transduction steps downstream phospholipase C (PLC) are unphysiologically activated by heptachlor and facilitated by the increase in phosphatidylinositolbiphosphate, the substrate for PLC activity, thus producing an accumulation of phosphatidic acid. The elevated level of this compound itself or the transient increase in diacylglycerol produced may cause calcium mobilization and the activation of PKC. In contrast with the alterations observed in phospholipids and protein phosphorylation, no changes in aggregation properties were observed.

Blood Platelets↗
PubMed1992

Exposure of applicators and residents to chlordane and heptachlor when used for subterranean termite control.

Research was conducted to assess dermal and respiratory exposure to applicators from chlordane and heptachlor used for subterranean termite control and exposure to residents of treated homes. Dermal exposure of 29 applicators was evaluated by using gauze pads attached to outer and inner clothing at selected body regions. Respiratory exposure of applicators was monitored with personnel-type air samplers worn during application periods. Air samplers were equipped with polyurethane foam plugs to trap airborne chlordane and heptachlor. Exposure of residents was measured by sampling ambient air of 19 homes treated with the termiticides. Electric air samplers equipped with foam plugs were used to monitor ambient air from the basement, the kitchen, and one bedroom at: 24 h prior to termiticide application, during application, and post-application at 24 h, 1 wk, and monthly for 6 mo. Applicator dermal exposure was estimated based on exposure rates to each body region. Respiratory exposure was estimated based on termiticide concentrations in the air and on the ventilation rate of a person doing light work. Residents' exposure was estimated based on the amount of termiticide present in ambient air. Results indicated that applicator exposure rates to chlordane and heptachlor were 2.54 and 1.88 micrograms/kg/h, respectively. Residents were exposed to less than 0.69 and 2.86 micrograms/m3 of chlordane and heptachlor, respectively. During this research, the application of termiticide containing chlordane and heptachlor posed minimal risk in terms of acute exposure to either the applicators or the residents of the treated homes.

Air Pollution, Indoor↗
PubMedDate not supplied

Subacute toxicity of dietary heptachlor to mink (Mustela vison).

Mink were fed diets that contained 0, 12.5, 25, 50, or 100 mg/kg active ingredient heptachlor (as technical grade formulation) for 28 days followed by a 7-day observation period to determine the toxicity of this insecticide to mink. Diets that contained 25 mg/kg, or more, heptachlor resulted in a significant decrease in feed consumption, while 50 mg/kg, or more, heptachlor caused a significant reduction in body weights. Mortality (37.5%) occurred only in the group fed 100 mg/kg heptachlor. The dead mink showed neurological signs of toxicity prior to death. Animals fed 100 mg/kg heptachlor also had reduced relative weights of the spleen and kidney and increased relative weight of the adrenal glands when necropsied at the time of death or at the termination of the study.

Animals↗
PubMed1993

The reproductive effects of dietary heptachlor in mink (Mustela vison).

Adult female mink were fed diets containing 0 (control), 6.25, 12.5, and 25 ppm (micrograms/g) technical grade heptachlor prior to and throughout the reproductive period (181 days) to evaluate the effects of heptachlor consumption on reproduction and offspring viability and to assess the extent of placental and mammary transfer of heptachlor epoxide to mink offspring. Feeding 12.5 and 25 ppm resulted in significant reductions in feed consumption and body weights of female mink. Mortality was 0, 8, 67, and 100% for the control, 6.25, 12.5, and 25 ppm groups, respectively. All females in the 25 ppm group died within 88 days. Mink fed the two higher heptachlor diets displayed clinical signs indicative of central nervous system involvement just prior to death. Females were mated with males on the same dietary treatments. Whelping success rates were 67, 83, 27, and 0% for the control, 6.25, 12.5, and 25 ppm groups, respectively. High mortality in the 12.5 and 25 ppm groups accounted for the lack of reproductive success. Gestation length, litter size and birth weight of kits were not significantly affected by adult female consumption of 6.25 ppm heptachlor while kits helped by females on the 12.5 ppm diet weighed significantly less than control kits at birth. Survival of kits in the 12.5 ppm group from birth to three weeks of age was also adversely affected. At three and six weeks of age, kit body weights in both the 6.25 and 12.5 ppm groups were significantly less than body weights in control kits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Induction of differentiation in human myeloblastic leukemia ML-1 cells by heptachlor, a chlorinated hydrocarbon insecticide.

Effects of heptachlor, an organochlorine pesticide, on human myeloblastic leukemia ML-1 cells were determined. Similar to 12-O-tetradecanoylphorbol-13-acetate (TPA), a known tumor promoter, heptachlor induced cell adherence and formation of extended cytoplasmic pseudopodia in ML-1 cells. The growth of ML-1 was slightly stimulated by low concentrations (less than 30 nM) of heptachlor. A dose-responsive cell death was also observed when ML-1 cells were treated with heptachlor at concentrations greater than 80 microM. Examination by light microscopy of the cells treated with 80 microM heptachlor revealed a gradual appearance of differentiation characteristics in the culture. On Day 3 of the treatment, 41% of the cells remained unchanged as ML-1, 39% of the cells showed changes and apparent cell differentiation, and 20% of the cells were induced to differentiate to monocyte- or macrophage-like cell type. Electron microscopy also revealed cellular differentiation and the presence of monocyte- and macrophage-like cell types (22%) was confirmed by positive esterase staining.

Acute Disease↗
PubMed2006

The pesticide heptachlor affects steroid hormone secretion in isolated follicular and luteal cells of rat.

Heptachlor, a chlorinated hydrocarbon pesticide, suppresses the production of progesterone and estradiol in the female rat in vivo or in isolated ovaries in vitro. In this study the effect of heptachlor on steroid hormone production by isolated rat luteal and follicular cells, in the presence of two precursor hormones was investigated. Ovaries were isolated from anesthetized mature normocyclic virgin rats (3 to 4 months old), under sterile conditions. Corpora lutea and follicles were microscopically dissected out and separately enzymatically dispersed with collagenase at 37 degrees C. Viable cells collected after centrifugation were used at a concentration of approximately 2.5 x 10(5) cells/10 mL. Both luteal and follicular cell preparations were separately incubated overnight (15 h) at 37 degrees C in the presence of pregnenolone (P5) and androstenedione (A4) at a concentration of 6.0 nmol/L each, and heptachlor at either 0.12 microg/mL (low dose) or 1.20 microg/mL (high dose) (test cells) or in the absence of heptachlor (control cells). At the end of the incubations, progesterone and estradiol 17beta levels were analyzed in the incubation media. The results indicate that heptachlor significantly suppressed the production of both progesterone and estradiol in both cell types in a dose related manner even in the presence of A4 and P5 as precursor hormones (P<0.05).

Androstenedione↗
PubMed2005

Perinatal heptachlor exposure increases expression of presynaptic dopaminergic markers in mouse striatum.

Although banned in the 1970s, significant levels of the organochlorine pesticide heptachlor are still present in the environment raising concern over potential human exposure. In particular, organochlorine pesticides have been linked to an increased risk of Parkinson's disease. Studies from our laboratory and others have demonstrated that exposure of laboratory animals to heptachlor alters the levels and function of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for the dopaminergic neurotoxin MPTP. In this study, we examined the effects of developmental exposure to heptachlor on DAT, and other key components of the dopaminergic system, including the vesicular monoamine transporter 2 (VMAT2), tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC). Female C57BL/6J mice received 0 or 3mg/kg heptachlor in peanut butter every 3 days for 2 weeks prior to breeding and throughout gestation and lactation until the offspring were weaned on postnatal day (PND) 21. On postnatal day 28, DAT, VMAT2, and TH levels were increased by 100, 70, and 30%, respectively, with no change in AADC levels or total dopamine levels. The ratio of DAT:VMAT2 was increased 29%. Since an increase in the DAT:VMAT2 ratio appears to predict susceptibility of brain regions to Parkinson's disease (PD) and results in increased toxicity of MPTP, these results suggest that alterations of the dopaminergic system by developmental heptachlor exposure may increase the susceptibility of dopamine neurons to toxic insult.

Animals↗
PubMed1997

In vitro production of testosterone and plasma levels of luteinising hormone, testosterone and cortisol in male rats treated with heptachlor.

Male rats were divided into six groups of five rats each. Rats were injected subcutaneously with different concentrations of heptachlor for 2 weeks. Heptachlor at all doses significantly suppressed plasma testosterone levels (P < 0.05). Plasma luteinizing hormone (LH) (P < 0.01) and cortisol (P < 0.02) levels were significantly elevated in heptachlor-treated rats as compared to corn oil-treated controls. LH and testosterone levels showed strong correlation (r = 0.69, P < 0.05). The testes in rats treated with 25 mg/kg body weight of heptachlor showed some pathological changes. We conclude that heptachlor causes adverse effects on several male reproductive parameters in rats.

Animals↗
PubMed1990

Blocking actions of heptachlor at an insect central nervous system GABA receptor.

The actions of the polychlorocycloalkane insecticide heptachlor, and its epoxide metabolite, were examined on GABA receptors in insects and vertebrates. Electrophysiological experiments on the cell body of the cockroach (Periplaneta americana) fast coxal depressor motor neuron (Df), and GABA-activated 36Cl- uptake experiments on microsacs prepared from cockroach ventral nerve cords showed that both heptachlor and heptachlor epoxide blocked functional GABA receptors. The block appeared to be non-competitive and was voltage-independent over the membrane potential range -75 mV to -110 mV. There was no significant difference between the potencies of heptachlor and heptachlor epoxide in the functional assays for insect GABA receptors. Both compounds inhibited [35S]-t-butylbicyclophosphorothionate [( 35S]TBPS) binding in insects and vertebrates. The findings provide further evidence for block of an insect GABA receptor/Cl- channel by the cyclodiene class of polychlorocycloalkanes, and reveal differences in the insecticide-[35S]TBPS binding site interactions of insects and vertebrates.

Animals↗
PubMed2005

Mortality and cancer incidence among children and adolescents in Hawaii 20 years after a heptachlor contamination episode.

In 1982, dairy products were recalled from all stores on Oahu, Hawaii, after heptachlor epoxide was detected in milk at concentrations exceeding the federal action level. At the time, an increase in human exposure to heptachlor in children was detected, but no evidence of serious health effects was observed. In an ecologic study design, this report compares mortality and cancer incidence rates of children and adolescents born from 1980 to 1982 to rates of children born before and after the heptachlor episode. Children born from 1980 to 1982 on Oahu were considered to be the exposed population, whereas children born during the same time on the other Hawaiian islands and all children born before 1980 and after 1982 constituted the unexposed population. Poisson regression was used to compare rates by age group, year, birth cohort, and place of residence. Death rates among children born from 1980 to 1982 were consistent with the overall declining mortality trend in children; the rates were consistently lower on Oahu than on the other islands. In agreement with the national trend, cancer incidence rates increased slightly in Hawaii during the last 25 years. Across all ages, cancer risk did not differ significantly between children born between 1980 and 1982 and those born during earlier and later years. However, a slightly higher occurrence of cancer for the heptachlor-exposed cohort when they were 15-19 years old deserves continued observation in the future. Overall, this report found no indication of higher mortality or cancer incidence among children born during the heptachlor contamination period.

Adolescent↗
PubMed1989

Rapid [14C]heptachlor clearance from body stores of ovines: ingested mineral oil and parenteral trans-stilbene oxide lack effects.

Recently we reported elimination of radioactivity from [14C]heptachlor from body stores of lactating ovines, mainly into excreta rather than milk, contrasting sharply with bovines. To further assess heptachlor metabolism and clearance by ovines, 12 fine-wool wether lambs (41 +/- 3 kg) housed in metabolism stalls were fed pelleted alfalfa hay (96%) plus molasses (3%) ad libitum and were dosed i.p. once with [14C]heptachlor (1.643 mg/kg body wt; sp. act. = .89 microCi/mg). Feces and urine were collected separately and quantitatively. Light mineral oil was mixed with feed (5 g/100 g) of six lambs and trans-stilbene oxide, an inducer of biotransformational enzymes, was administered i.p. (4 g/hd initially; 2 g/hd daily thereafter) through 20 d to three lambs given each mineral oil treatment, in 2 x 2 factorial arrangement. Feces, urine, blood, bile and body tissues were assayed for total 14C activity. Radioactivity (heptachlor and [or] metabolites) eliminated into excreta during 21 d amounted to 34 to 36% of dose administered, of which 67% appeared in urine and 33% in feces. Biological half-time for elimination into excreta was 11.3 d [Kel = -.061/d], similar to 11.7 d we reported for lactating ewes. Clearance from blood had T1/2 = 14 d. Neither mineral oil nor trans-stilbene oxide altered rate or route of 14C activity excreted or concentrations of 14C activity in blood. Results confirmed that ovines eliminate heptachlor much more rapidly than bovines.

Animals↗
PubMed1995

Detection of DNA adducts in declining hop plants grown on fields formerly treated with heptachlor, a persistent insecticide.

Hop decline was observed in Alsace, eastern France, in reparcelled sugar beet fields formerly abundantly treated with an insecticide, heptachlor. Leaves were collected from 'declining hops' grown in an heptachlor-contaminated area and from 'healthy hops' grown in a soil not contaminated by heptachlor. These two samples came from hop vines treated with other usual pesticides. 'Control' hop leaves came from soil neither treated with pesticide nor contaminated with heptachlor. Hypermodified nucleotides (DNA adducts) were detected using the (32)P-postlabelling method. No detectable DNA adducts were found in the 'control' specimen, whereas eight adducts were detected in the 'healthy hops' specimen, probably due to the usual pesticide treatment. However, 16 adducts, nine of which were new adducts, could be detected in the 'declining hops' specimen. It may therefore be supposed that the presence of these hypermodified nucleotides perturbs gene expression and so contributes to the hop decline. In addition, to confirm the genotoxicity of heptachlor, it is shown that it induces DNA adducts in bean-cell suspension culture as well. Finally, it is proposed, in the case of alternate cultures scheduled in fields which were formerly treated with pesticides, adapted to other cultures, that particular attention should be given to the history of the soils.

Journal Article↗
PubMed1984

Enhanced total body clearance of heptachlor from rats by trans-stilbeneoxide.

The effect of the phase II enzyme inducer, trans-stilbeneoxide (TSO; 400 mg/kg i.p. on 4 consecutive days), on the clearance of intravenously given [14C]heptachlor (2 mg/kg) was investigated in male Sprague-Dawley rats. TSO or vehicle treatment was started 4 days before (group I), immediately after (group II), or 4 days following (group III) heptachlor injection. Rats were sacrificed 6 days after the last TSO or vehicle dosage. In all 3 groups TSO increased cumulative excretion of heptachlor derived material in feces significantly (P less than 0.01) but had no effect on total urinary excretion. Pretreatment (group I) of rats with TSO resulted in elevated fecal excretion of 14C already on the first day after dosing with heptachlor, whereas the effect of the treatment was not apparent in group II and III rats until after 2 days and reached its maximum 3 days after the start of TSO administration. At termination, tissue radioactivity was significantly (P less than 0.05) lower in fat, kidney, brain, skin, heart and muscle, but not in serum, erythrocytes (group II and III), liver (group II and III), and spleen of TSO treated rats as compared to controls. The body burden calculated from the sum of 14C remaining in tissues was reduced to about 27% of control values. The toxicity of TSO may preclude it from considerations as a useful therapeutic agent in the treatment of chlorinated cyclodiene insecticide-exposed individuals. However, this experiment further emphasizes the importance of pharmacokinetic considerations when examining interactions in the disposition of xenobiotics.

Animals↗