Distribution of aldrin and its epoxide (dieldrin) in egg-forming tissues and eggs of laying hens following an oral application.

Laying hens were treated orally with a single dose of aldrin (1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-1,4:5,8-dimethanonaphthalene, AD) 1 mg kg(-1) bw. Concentrations (microg g(-1)) of AD or its epoxide, dieldrin (1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydroendo-,exo-1,4:5,8-dimetha-nonaphthalene, DD), in the main tissues involved in egg formation (blood, liver, ovary, and oviducts) and egg yolk, collected at 1 day after AD dosing, were determined by normal-phase high-performance liquid chromatography. The limits of determination were 0.07 microg g(-1) for AD and 0.08 microg g(-1) for DD, respectively. In extractable fats from the above tissues and egg yolk, AD was found in the egg yolk; however, no AD was found in tissues involved in egg formation. DD was found in all tissues examined here. The DD level was highest in the liver and was lowest in the blood (P<0.01). These results suggest that the epoxidation of AD to DD occurred rapidly in the hen.

The mammalian testis accumulates lower levels of organochlorine chemicals compared with other tissues.

Tissues were obtained from three separate experiments in order to quantify the tissue distribution of organochlorine chemicals that are thought to be potential reproductive toxicants in males: 1) Sprague Dawley rats received 1 microCi of 14C-Aldrin or 14C-Dieldrin (20.6 microCi/micromole) i.p. once a week for three weeks. One week and four weeks after the last injection, tissues were harvested and stored at -80 degrees C. Tissue 14C levels were quantified by scintillation spectrometry. 2) Cis- or trans-nonachlor (0, 0.25, 2.5, 25 mg/kg body weight) were administered daily in corn oil to male rats by gavage for 28 days. Tissues were harvested and frozen at -80 degrees C on the 29th day. Organochlorine residues were extracted and quantified by gas chromatography with electron capture detection. 3) Technical grade toxaphene (0, 0.1, 0.4 or 0.8 mg/kg body weight) was ingested daily by female cynomolgus monkeys of reproductive age for 18 months prior to being mated with control males. Dosing continued during pregnancy and lactation. Their infants received toxaphene via breast milk, and upon weaning, they ingested the same dose as their mothers for 48 to 49 weeks until, at 77 to 80 weeks of age, tissues were harvested and stored at -80 degrees C. Organochlorine residues were extracted and quantified as previously stated. In all three experiments, organochlorine residues in the testis were lower than in most of the other reproductive tract and nonreproductive tract tissues we examined. For example, testicular aldrin and dieldrin levels were <5% the epididymal content; testicular cis- and trans-nonachlor were <25% the epididymal content and, testicular toxaphene levels were <15% of the epididymal content. The reasons for the low degree of accumulation by the testis in comparison with other tissues are unknown. However, the lower testicular content may afford germ cells some protection from the potentially toxic effects of these chemicals.

Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction.

Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment.

Decreasing half-life of dieldrin in egg yolk following a single oral administration of aldrin to laying hens.

Laying hens were treated orally with a single dose of aldrin (AD) 1 mg/kg body weight. Concentrations (microgram/g) of AD or its epoxide (= dieldrin, DD) in the yolk of eggs laid for 21 days after AD treatment were determined by normal-phase high-performance liquid chromatography. The limits of determination were 0.02 microgram/g for AD and 0.03 microgram/g for DD, respectively. After AD treatment, although the low levels of AD (mean 0.02-0.03 microgram/g) were observed only during a three-day period (from 4th to 6th days), DD (mean 0.15 microgram/g) was found already on the 2nd day, indicating that the epoxidation of AD to DD in the hen's body is rapid. The highest level of DD (mean 0.40 microgram/g) was detected on the 6th day, and then DD levels decreased slowly and were detected up to the 21st day. In this decreasing phase, the half-life of DD in the yolk was estimated to be 25.6 days with a 95% confidence interval from 22.7 to 29.4 days.

Cancer dose-response modeling of epidemiological data on worker exposures to aldrin and dieldrin.

The paper applies classical statistical principles to yield new tools for risk assessment and makes new use of epidemiological data for human risk assessment. An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides unusually accurate measures of individual lifetime average daily doses. In the cancer dose-response modeling, each worker is treated as a separate experimental unit with his own unique dose. Maximum likelihood estimates of added cancer risk are calculated for multistage, multistage-Weibull, and proportional hazards models. Distributional characterizations of added cancer risk are based on bootstrap and relative likelihood techniques. The cancer mortality data on these male workers suggest that low-dose exposures to aldrin and dieldrin do not significantly increase human cancer risk and may even decrease the human hazard rate for all types of cancer combined at low doses (e.g., 1 microgram/kg/day). The apparent hormetic effect in the best fitting dose-response models for this data set is statistically significant. The decrease in cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S. Environmental Protection Agency's upper bound on cancer potency based on mouse liver tumors. The EPA's upper bound implies that lifetime average daily doses of 0.0000625 and 0.00625 microgram/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that there is no increase in cancer risk in these workers at these doses or even at doses as large as 2 micrograms/kg/day.

Mortality of workers exposed to dieldrin and aldrin: a retrospective cohort study.

OBJECTIVE: To investigate the occurrence of long term health effects in humans exposed to aldrin and dieldrin, with an update of an earlier retrospective cohort mortality study. METHODS: A group of 570 workers employed between 1 January 1954 and 1 January 1970 either in a production or formulation plant were followed up for mortality until 1 January 1993. There were extensive industrial hygiene data available and biological monitoring data of aldrin and dieldrin for most of the workers. From these data individual estimates were made of the total intake of dieldrin. A total number of 2539.37 person-years at risk was added to the original study. RESULTS: 118 deaths were observed compared with 156 expected. No increase in mortality from liver cancer was found. However, there was an excess in mortality from rectal cancer. This excess was inversely related to the dose gradient. An analysis by job title did not show any excess cancer in any particular job. CONCLUSION: The study does not support a carcinogenic effect of dieldrin and aldrin in humans.

Metabolism of aldrin to dieldrin by rat skin following topical application.

Metabolism of the pesticide aldrin to dieldrin in the rat was studied following topical and ip administration of 0.1-10 mg aldrin/kg body weight. When aldrin was applied topically to the dorsal skin at a dose of 10 mg/kg body weight, absorption was less efficient than after ip administration; lower blood levels of aldrin and dieldrin were seen and peak dieldrin levels were delayed. After ip administration of 1 or 10 mg aldrin/kg body weight, dieldrin was found at similar concentrations in the dorsal and ventral skin 7 hr later, whereas 7 hr after topical administration of 10 mg aldrin/kg, the dieldrin concentration in the skin at the dorsal site of application was four times higher than that at a ventral skin site. Similar differences in dieldrin concentrations between dorsal and ventral skin persisted throughout the 7-hr period following topical application. The results indicate that topically applied aldrin is metabolized to dieldrin in the skin during absorption, but the overall proportion of metabolism that takes place in the skin is small compared with the contribution of the liver. Dieldrin was not detected in the ventral skin remote from the application site 1 hr after topical application of aldrin, whereas a dieldrin concentration of 2.2 nmol/g was detected in the skin of the application site at this time; more than 99% of this dieldrin was probably formed locally by dermal metabolism of percutaneously absorbed aldrin. The efficiency of conversion of applied aldrin to dieldrin decreased with increasing aldrin dose in the range 0.1 to 10 mg/kg.

Comparison of carcinogenicity studies with aldrin and dieldrin.

Laboratory testing of animals is the principal method used to identify chemical carcinogens. However conflicting results are often obtained. This is emphasized in a cross-comparison of 6 aldrin-dieldrin studies; 3 were positive for tumor induction and 3 were negative. Four components of the assays are examined: husbandry, compound administration, observation, and interpretation of results.

Dieldrin and DDT in the tissues of mice fed aldrin and DDT for seven generations.

Seven-Generation Study (P-F6): The concentration and total retention of dieldrin or p,p'-DDT and metabolites were determined in the total carcass of Swiss-Webster mice fed dietary supplements of aldrin 5 or 10 ppm, or DDT 100 ppm, to age 260 days. All groups showed a significant increase in total body retention (and concentration) of dieldrin or total DDT in the total carcass of the F1, F2, and F3 generations. Generally, these increases were related directly to increases in total body lipids, when compared with the P generations. The control (pesticide-free) diet was fed to all F4 generation experimental mice from weaning to age 260. The pesticides absorbed by these animals while in utero and via lactation were found, at the time of sacrifice, to have been excreted completely. When the experimental diets were resumed with the weanlings of the F2 generations, a repetition of the general findings in the P and F1 generations was noted-demonstrating that pesticide retention and total body lipids are closely interrelated, and that a high body lipid content favors a high retention rate of these fat-soluble pesticides. These results support our earlier studies in rats (Deichmann et al., 1972) and investigations with cirrhotic human livers with severe fatty infiltration (Oloffs et al., 1974). Conception became more delayed with each succeeding generation, requiring some degree of "selective" breeding of the F4, F5, and F6 generations.

The comparative cytogenetic effects of aldrin and phosphamidon.

An organochlorinated pesticide (aldrin) and an organophosphorus one (phosphamidon) were administered in human lymphocyte cultures, and the cytogenetic effects were related to the compound concentration. The comparative estimation of the number and type of chromosome aberrations observed in the treatments with various doses of drugs permits the following statements. (a) The aldrin showed a narrow range of clastogenic doses, between 19.125 and 38.25 mug/ml. Since these doses are near the limit for cell survival, the observed chromosome lesions are probably not perpetuated in other abnormal cells. (b) Comparatively, the range of phosphamidon clastogenic doses is very large, scattered between 1.9 and 122 mug/ml. Since, in the phosphamidon treatments, the cellular death begins at a concentration above 244 mug/ml, the chromosome aberrations, induced especially by the low doses, could be maintained in other abnormal cells. In a smaller number of experiments, chromosome examinations were performed after intraperitoneal injections of the drugs into rats and mice, 24 h before harvesting of the bone marrow. The administered doses were low, as compared with those of the experiments in vitro: the minimal doses inducing chromosome aberrations in vivo were, in the aldrin treatments 9.56, and in the phosphamidon treatments, 0.07 mug/g body weight. In the experiments both in vitro and in vivo, the analysis of the frequencies of the abnormal cells and of the chromosome lesion types support the existence of a dose-response correlation. The genetic peril due to low doses of pesticides with a general weak toxic effect is discussed.