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Contrary to expectations hexadecane had no significant effect on the body clearance of heptachlor in rats. However, phase II enzyme induction altered the kinetics of heptachlor dramatically, reducing its half-life by about 3-fold. The reduction of half-life was reflected in correspondingly lowered adipose tissue and blood levels.
A variety of enzymes and other proteins are produced by organisms in response to xenobiotic exposures. Cytochrome P450s (CYP) are one of the major phase I-type classes of detoxification enzymes found in terrestrial and aquatic organisms ranging from bacteria to vertebrates. One of the primary functions of stress proteins (HSPs) is to aid in the recovery of damaged proteins by chaperoning their refolding. These and other biomarkers of xenobiotic exposure and resulting effects have not been studied in crustacean larvae. This information is of potential importance for environmental management and risk assessment. In this work, we have given Homarus americanus larvae single 24 h exposures to the cyclodiene pesticide heptachlor, a known environmental endocrine disruptor (EDC) on different days of the 1st larval instar. We followed these larvae during the first larval stage for effects on timing of ecdysis to 2nd stage, ecdysteroid molting hormone titers, and alterations in the levels of cytochrome P450 CYP45 and HSP70 proteins. Delays in ecdysis were correlated with alterations in ecdysteroid levels. This result provides clues that this pesticide may function as an environmental endocrine disruptor in crustaceans. CYP45 and HSP70 levels were significantly elevated for several days following heptachlor exposure. The elevation in HSP70 was prolonged depending on the day of pesticide exposure and this was directly related to the increase in mortality. These results demonstrate the utility of these measurements as potential biomarkers in crustacean larval developmental toxicology and EDC effects research.
The 1980-1982 milk supply contamination on the island of Oahu, Hawaii, by the insecticide heptachlor offered an opportunity to investigate the possible human teratogenicity of this organochlorine. An analysis of incidence rates for 23 major congenital malformations, derived from hospital-generated data collected by the Birth Defects Monitoring Program of the Centers for Disease Control, failed to show any remarkable rate increase on Oahu in 1981-1983, based on comparisons with the rates for previous time periods on this island and with the rates for two unexposed populations (the other Hawaiian islands and the total U.S.). A rise in the rates of cardiovascular malformations and hip dislocation was apparent but antedated the exposure. These results suggest that no major rate increase for malformations recognized at birth resulted from the heptachlor contamination on Oahu. However, misclassification of exposure status in this study may have obscured a more moderate effect.
The cyclodiene pesticides endosulfan, chlordane and heptachlor have been reported to be non-genotoxic rodent hepatocarcinogens. These three compounds and several metabolites of endosulfan (endosulfan sulfate, endosulfan ether and endosulfan lactone) were examined for their effects on gap junctional intercellular communication (GJIC) in primary cultured male F344 rat hepatocytes and B6C3F1 mouse hepatocytes. GJIC was evaluated by Lucifer Yellow CH dye-coupling. Endosulfan and endosulfan sulfate inhibited rat and mouse hepatocyte GJIC in a dose-responsive manner (50-200 microM) after 4 h treatment. Endosulfan ether inhibited rat hepatocyte GJIC only at 200 microM and had no effect on mouse hepatocytes. Endosulfan lactone did not affect rat or mouse hepatocyte GJIC. Chlordane and heptachlor inhibited both mouse and rat hepatocyte GJIC at concentrations of 50-200 microM. The inhibition of GJIC by the cyclodienes showed similar dose-response relationships and kinetics of onset of inhibition and reversibility for both mouse and rat hepatocytes. Concomitant treatment of the cells with inhibitors of cytochrome P450 monooxygenases (SKF-525A, piperonyl butoxide or carbon monoxide) did not alter the inhibition of GJIC by the cyclodienes, suggesting that cytochrome P450 metabolism was not involved in the inhibitory mechanism. Dibutyryl cyclic AMP (0.5 mM), however, decreased the inhibition of GJIC by the cyclodienes and may indicate that these compounds inhibit intercellular communication through a cAMP-dependent process. The inhibition of mouse and rat hepatocyte GJIC by the cyclodienes correlated with previous reports indicating that these compounds are non-genotoxic rodent liver carcinogens.
A retrospective mortality study has been carried out on workers employed in the manufacture of chlordane and heptachlor between 1946 and 1976. The study group was comprised of 1403 white males who worked for more than three months at either of the two plants in the United States now producing these compounds. Information on deaths among terminated employees was obtained from the Social Security Administration and supplemented by information collected by another investigator by individual follow-up. There were 113 deaths observed in the group, compared to 157 expected, giving a standardized mortality ratio (SMR) of 72. There was no overall excess of deaths from cancer, even among workers followed twenty or more years after entry into the occupation. There was one death from liver cancer. An excess of deaths from lung cancer (12 observed, 9.0 expected) was not statistically significant and was not distributed by duration of exposure or of latency in any pattern suggesting an etiologic role for chlordane-heptachlor exposure. Although diseases of the circulatory system as a whole showed fewer deaths than expected (SMR 83), there was a statistically significant excess of deaths from cerebrovascular disease (17 observed, 9.3 expected). This excess was not related to duration of exposure or latency and occurred exclusively after termination of employment.
Exposure of the cyclodiene insecticide heptachlor at 1/8 and 1/4 LD50 to male and female albino rats before mating affected fertility in both sexes. A decrease in implantations, serum oestrogen and progesterone levels and increase in resorptions in the females was observed. However, no histological changes were observed except for few atretic follicles in the treated females. In males, a dose-dependent significant decrease in the sperm count and coagulating gland fructose levels was observed, with marginal degeneration of seminiferous tubules. These results are indicative of the prenatal toxicity of heptachlor in male and female rats.
The relationships between the gross appearance, histologic types, and cytochemical characteristics of hepatocellular neoplasms were studied in B6C3F1 mice given the liver carcinogen diethylnitrosamine either alone or followed by the organochlorine pesticides, 4,4'-dichlorodiphenyltrichloroethane, chlordane, or heptachlor as promoting agents. Hepatocellular neoplasms were categorized according to their cytoplasmic staining properties with hematoxylin and eosin. Acidophilic neoplasms more often displayed increased activity of alkaline phosphatase than did basophilic neoplasms. The activities of glucose-6-phosphatase and adenosine triphosphatase were decreased in both acidophilic and basophilic neoplasms. There was no difference in the activities of these enzymes or gamma-glutamyltranspeptidase between adenomas and carcinomas, although most neoplasms did not display gamma-glutamyltranspeptidase. Chlordane or heptachlor exposure increased the alkaline phosphatase activity in neoplastic cells, but not that of other enzymes. The majority of neoplasms displayed a deficiency of iron accumulation. The macroscopic appearance of neoplasms was closely related to their cytoplasmic staining properties and cytochemical characteristics.
Intramuscular administration of two doses: 0.50 LD50 (14.70 mg/kg b w) and 0.75 LD50 (22.30 mg/kg b w) of heptachlor in Rattus norvegicus for 14 days induced significant hypocalcemia without altering serum inorganic phosphate value. Parathyroid chief cells of the experimental rats exhibited degranulation, vacuolation, loss of secretory granules and lipid droplets, reduction in chromatin, and degenerative changes in endoplasmic reticulum and cristae of the mitochondria. Not much of histological and ultrastructural changes could be seen in C cells of the heptachlor treated rats.
Lethal dieldrin concentrations were found in the brains of dead gray bats (Myotis grisescens) collected during 1976 and 1977 beneath a maternity roost in a Missouri cave. In addition, residues of heptachlor epoxide, oxychlordane, cis-chlordane, and trans-nonachlor increased significantly in both brains and carcasses of bats collected during 1977. These increases appear to reflect a switch by local farmers from aldrin, dieldrin's parent compound, to heptachlor for the control of cutworms. They also constitute an additional threat to this colony of this endangered bat species.
Broiler chickens were fed heptachlor in concentrations of 0, 0.01, 0.03, 0.1, and 0.3 mg/kg of the ration for the first 8 weeks of life. There were no adverse effects on health or performance. Residue concentrations in adipose tissue increased rapidly for 1 to 2 weeks and then tended to plateau at concentrations about five times greater than those in the rations. Birds exposed only during the 7th week of life stored 25% as much residue as did the chickens exposed in the 1st week, but the former also ate only 63% as much feed. Fat extracted from liver and muscle contained more residue than did fat extracted from adipose tissue. The ratio of the concentration of heptachlor to its epoxide metabolite was higher in muscle fat than in heptic or abdominal fat. Residue concentrations depleted by about half in the first 4 weeks after cessation of exposure.
In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interaction. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.
Adult female mink previously fed diets containing 0 (control) and 6.25 mg heptachlor/kg diet for 181 days were fed either the same control diet ad libitum (AL) or the control diet containing 10% mineral oil and restricted by 45% of ad libitum intake (MO/R) for 21 days to determine the efficacy of the latter treatment in enhancing the elimination of heptachlor epoxide (HE) from mink. Kit mink (2-3 months of age) whelped by dams of the control and 6.25 mg/kg groups were also fed the MO/R or AL diets for 21 days. Daily consumption (g/kg bw/day) of the AL diet by kit mink was significantly greater than consumption of the same diet by the adult females. Body weights of the control adults and the control and 6.25 mg/kg kits were significantly reduced by feeding the MO/R diet. Two adults from the control group and one adult from the 6.25 mg/kg group fed the MO/R diet died during the 21-day period. No mortalities occurred in kit mink fed either diet. Administration of the MO/R diet caused a significant reduction in body fat of the control adults and kits, but not in the 6.25 mg/kg adults and kits. Decreases in body fat of the MO/R groups were not associated with greater elimination of HE when compared to the AL groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Given the suspected effects of estrogens on breast cancer, xenoestrogenic insecticides may be a risk factor. Studies of the weak xenoestrogen, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), have failed to demonstrate a causal relationship, though another estrogenic organochlorine insecticide, dieldrin, belonging to the cyclodiene family, has recently been linked to breast cancer. Other cyclodienes such as heptachlor epoxide (HE) and oxychlordane (OC) present in breast tissue have not been evaluated as rigorously, presumably due to their lower concentration and lower recovery using solvent extraction procedures. We used sparging extraction coupled with gas chromatography to determine the levels of HE, OC, and DDE in adipose tissue within breast biopsies in a series of 34 women evaluated for breast abnormality. Of the three insecticides tested, only HE (p=0.007) was positively associated with prevalence of breast cancer in the biopsies. In rapid, non-genomic studies using isolated human leukocytes, flow cytometric methods were used to measure HE-induced oxidants and DNA damage. These studies indicated that HE, at concentrations similar to those in breast biopsies, induced an inverted-U increase in intracellular oxidants and DNA strand breaks [both blocked by specific nitric oxide- (NO-) synthesis blockade withL: -NMMA] in human polymorphonuclear leukocytes (PMNs). HE-treated PMNs also induced damage to surrounding lymphocytes in mixed-leukocyte incubations (also inhibited by NO blockade). The HE-induced changes in NO were inhibited by 17beta-estradiol-(17beta-E2) receptor antagonists and were mimicked by similar concentrations of 17beta-E2. The addition of tumor necrosis factor-alpha (TNF-alpha) increased intracellular oxidants and DNA damage and shifted the responses to lower HE concentrations. This study, along with others, suggests that HE-induced NO production may contribute to initiation, promotion, and progression of cancer.
The effects of the organochlorine (OC) liver tumor promoter heptachlor epoxide (HE) and a related non-tumor promoting OC, delta-hexachlorocyclohexane (delta-HCH), on the dynamics of intracellular calcium (Ca2+) were investigated in mouse 1c1c7 hepatoma cells. HE induced a non-capacitative, Ca2+ entry-like phenomenon, which was transient and concentration-dependent with 10 and 50 microM HE. The plasma membrane Ca2+ channel blocker SKF-96365 antagonized this HE-induced Ca2+ entry. delta-HCH failed to induce Ca2+ entry, rather it antagonized the HE-induced Ca2+ entry. Both HE and delta-HCH induced Ca2+ release from endoplasmic reticulum (ER) at treatment concentrations as low as 10 microM; at 50 microM, the former induced 5x as much Ca2+ release as the latter. The HE-induced Ca2+ release from the ER was antagonized using the IP3 receptor/channel blocker xestospongin C, suggesting that HE induces ER Ca2+ release through the IP3 receptor/channel pore. These results show that the effect of HE on cellular Ca2+ mimics that of mitogens such as epidermal and hepatocyte growth factors. They also provide insight into the similarities and differences between tumorigenic and non-tumorigenic OCs, in terms of the mechanisms and the extent of the [Ca2+]i increased by these agents.
One approach to the toxicological evaluation of chemical mixtures is to construct full dose-response curves for each compound in the presence of a range of doses of each of the other compounds, i.e., a factorial design. This study was undertaken as part of an interdisciplinary project to evaluate a mixture of three environmental pollutants. A full-factorial design was undertaken to determine the neurobehavioral consequences of short-term repeated exposure to five dose levels each of three chemicals, in order to characterize potential two- and three-way interactions. Adult female F344 rats received (p.o.) for 10 days either one of five doses of trichloroethylene, di(2-ethylhexyl)phthalate, or heptachlor, or else one of all possible chemical combinations. Neurobehavioral evaluations were conducted using motor activity and an abbreviated functional observational battery. Response-surface analysis was applied to each of the endpoints. Hypotheses were tested based on the estimated model parameters; of primary interest was the overall test for interaction among the three chemicals. In addition, an abbreviated design was created by fitting only a subset of the data to the model. In general, significant overall interactions that deviated from response additivity were detected for most endpoints (11 of 14). All of the interactions on the neurobehavioral endpoints showed either antagonism, or else an interaction that could not be fully characterized. Often the results of the abbreviated dataset analysis were not the same as for the full-factorial design. This study was extremely intensive, in terms of the number of rats and time required for conduct of the study as well as the data analysis. These results underscore the need for more economical approaches to evaluate the toxic effects of mixtures of chemicals.
The organochlorine pesticides chlordane and heptachlor were evaluated for their genotoxicity and epigenetic membrane effects. Both compounds were non-genotoxic in the ARLHGPRT mutagenesis assay in which the genotoxic carcinogens 7, 12-dimethylbenz[a]anthracene and benzo[a]pyrene induced significant increases in mutant incidence. The pesticides both markedly inhibited intercellular communication between cultured liver cells, a property demonstrated by many tumor promoting agents, whereas benzo[a]pyrene did not produce this epigenetic effect.
A neonate with a cerebral gliosarcoma was found to have chromosome abnormalities in tissue culture of the tumor, but normal karyotyping of peripheral blood. Similarities to and differences from chromosome abnormalities found in other human gliomas are noted. Unusual exposure of the child to heptachlor during prenatal development and the neonatal period suggests the need for further studies on the role of toxins in oncogenesis.
Silica (350 m(2) g(-1)) was chemically modified with Cp2ZrCl2 and (nBuCp)2ZrCl2 by grafting. Hybrid silica bearing surface indene groups was synthesized by the sol-gel method, followed by metallation with ZrCl(4)2THF. The resulting phases were characterized by Rutherford backscattering spectrometry (RBS), 13C and 29Si magic angle spin nuclear magnetic resonance, X-ray photoelectron spectroscopy, and diffuse reflectance infrared Fourier transform spectroscopy. According to RBS measurements, metal content was 0.2- to 0.3-wt% Zr/SiO2 for the grafted systems and 4.5-wt% Zr/SiO2 for the phase prepared by the sol-gel method. The solid phases were evaluated for the adsorption/preconcentration of lindane and heptachlor epoxide from aqueous solution. For comparative reasons, the commercial LC-18 phase was also evaluated. Analyte concentration was monitored by gas chromatography electron capture detection. For the grafted phases, the coordination sphere around the metal center seems not to influence the adsorption/desorption properties of these phases vis-a-vis the studied analytes. In the case of the phases prepared by the sol-gel method, recovery results were comparable to those observed for LC-18. Experiments using ZrO2 and ZrO2/SiO2 phases led to lower recovery results.