Tissue binding of 2-acetylaminofluorene in BAlB/c and C57Bl/6 mice during chronic oral administration.

Blood and tissue binding levels of [9-14C]2-acetylaminofluorene ([9-14C]2-AAF) administered in the diets of female BALB/c and C57Bl/6 mice, were determined. Blood and liver levels reached a plateau after 2--4 weeks, while levels in bladder tissue continued to increase. Binding levels two weeks administration were determined in liver, bladder, kidney, lung, spleen, heart and skeletal muscle. In every instance the binding was linear over a dose range of 0.5--500 ppm 2-AAF. Removal of the 2-AAF in the diet after 48 weeks resulted in a rapid loss of radioactivity from blood and liver, with little or no loss from bladder tissue. The linear dose-response relationship of tissue binding correlated well with the previously reported linear dose response curve for liver tumors but did not correlated with the reported non-linear dose response curve for bladder tumors. A reversed correlation was found in the ability of the tissue to remove bound fluorene residues and the observed rate of tumor occurrence following discontinued administration of the carcinogen.

A multi-generation toxicity evaluation of p,p'-DDT and dieldrin with Japanese quail. I. Effects on growth and reproduction.

A toxicity Evaluation of DDT and dieldrin was conducted using Japanese Quail. The effects of feeding DDT (5 and 50 ppm of diet) and dieldrin (0.1 and 1.0 ppm of diet) in this four generation study (parental, F1, F2 and F3) were examined in terms of growth, viability, and/or reproduction of offspring. Ten groups (including controls and replicates of groups) contained 21 birds/group for the parental generation, and 21-35 chicks for each respective generation study. At 50 ppm DDT, a marginal decrease in egg hatch-ability of F2 generation was evidenced; the decrease appeared related to a slight decrease in fertility rather than egg production or hatchability of fertile eggs. Data accumulated from all other experimental groups were within the expected range and were comparable to control data.

Organophosphate pesticide inhibition of cholinesterase in laboratory animals and man and effects of oxime reactivators.

The responses of rabbit whole blood cholinesterase following intravenous infusion or percutaneous application of dialkylphosphate inhibitors and injection of oxime enzyme reactivators. The experiments were conducted to determine the structure-activity relationships of the inhibitors and the reactivators, establish the mechanisms of enzyme inhibition, and investigate other factors affecting the toxicity of organophosphate esters including percutaneous absorption and conversion of dithioates to the more reactive respective ozones. Intravenous infusion of dialkylphosphate esters produced dose and time dependent inhibition, followed by a spontaneous, but incomplete recovery. The lack of complete recovery was not totally due to the "aging" phenomona as measurable enzyme reactivation could be induced subsequent to the spontaneous recovery. The need for revision of the enzyme inhibition model is discussed.

A multi-generation toxicity evaluation of P,P'-DDT and dieldrin with Japanese quail. II. Tissue residues analyses.

Selected tissues and egg yolks of Japanese Quail fed diets containing DDT or dieldrin in a four-generation (parental, F1, F2 and F3) study were analyzed for residues of parent compound and/or specific metabolites. Diets containing DDT (5 and 50 ppm) or dieldrin (0.1 and 1.0 ppm) were fed to each generation for 10 wks followed by a 12-wk recovery period in order to determine generation-accumulative effects, maximum residue levels and decline of residues during recovery. Tissue-residue storage and intergeneration transmission for DDT and dieldrin were generally similar and were related to dietary levels. Tissue residues in newly hatched birds were elevated initially for each generation subsequent to the parents, but any cumulative effects between generations were transitory, as residues after 5-to-10 wks were similar in each generation. Tissue residues in all groups showed a decline during the 12-wk recovery period. Decline during recovery was greater for females than males, probably attributable to egg production. Egg yolk residues for birds fed 5.0-ppm DDT declined to near control levels during the recovery period; at 50 ppm, residues declined but remained elevated above controls. For the quail fed dieldrin, residue levels were above those in controls; as with DDT the subsequent decline was more marked in the females.

Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol or 17beta--estradiol.

To study the long term effects of estrogen administration in mice, virgin female C3H/HeJ mice are being fed diets containing 0, 10, 100 or 500 ppb of diethylstilbestrol (DES) or 0, 100, 1000, or 5000 pph of 17beta-estradiol (E2) from 6 to 110 weeks of age. C3HeB/FeJ mice are being fed diets containing 08 10, 100, or 500 ppb DES FROM 6 TO 136 WEEKS OF AGE. Pathologic studies were conducted on 396 such mice sacrificed at 52 weeks and on over 500 others sacrificed at various intervals. After 52 weeks on 500 ppb DES or 5000 ppb E2, the cervix of both populations often showed stromal mucoid changes and adenosis characterized by focal replacement of squamous by columnar epithelium lining the cervical canal assoicated with glandular downgrowths into the subjacent stroma. The uterine horns showed hyperplastic glands, which often penetrated the muscularis, and focal endometrial and perivascular hyalin deposits. The ovaries showed atrophy with absence of corpora lutea. Ceroid deposits were increased in the ovaries and adrenals. Sternal bony trabeculae were increased. The incidence of uterine cervical adenosis and of mammary hyperplastic alveolar nodules and tumors (mainly type B, Dunn's classification), was higher in C3H/HeJ than in C3HeB/FeJ mice. Mice on lower doses of DES or E2 had less frequent and severe similar changes. Tumors observed to date only in estrogen-treated mice included 4 endometrial adenocarcinomas and an adenoacanthoma of a uterine horn, 14 cervical adenocarcinomas often appearing to arise from areas of adenosis, a vaginal squamous cell carcinoma, a cervical granular cell myoblastoma, 1 sternal and 3 cranial osteosarcomas, and a mesothelioma. The majority of the malignancies occurred in C3H/HeJ mice. These findings indicate that the mammary tumor virus factor facilitates DES-induced mammary tumorigenesis in C3H mice and may contribute to other DES-induced malignant and premalignant lesions.

Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17 beta-estradiol.

To study the long term effects of estrogenic diets, 2160 virgin female C3H/Hel mice, having a high titer to the mammary tumor virus factor (MMTV), were fed diets containing 0, 10, 100, 500, or 1000 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 weeks of age; 1368 virgin female C3HeB/FeJ mice, having a low titer to the MMTV, were fed diets containing 0, 10, 1000, or 500 ppb DES from 6 to 136 weeks. In estrogen-treated mice, the incidence of cervical adenosis and of mammary hyperplastic alveolar nodules was increased and the time to development of mammary adenocarcinomas was shortened. These changes tended to increase with dose and time and appeared earlier in the C3H/HeJ mice. Other tumors observed included 32 cervical and 20 endometrial adenocarcinomas, 16 cervical granular cell myoblastomas, 12 peritoneal mesotheliomas involving the uterus, 2 cervical and 4 vaginal squamous cell carcinomas, 2 ovarian teratomas, 6 osteosarcomas, 25 pheochromocytomas and 3 thyroid carcinomas. Of these tumors, 1 cervical and 2 endometrial adenocarcinomas, and 4 pheochromocytomas occurred in C3HeB/FeJ control mice at 104-130 weeks; none occurred in C3H/HeJ controls. This study indicates that the MMTV facilitates the development of mammary lesions in C3H mice, that estrogens predispose C3H mice to endometrial and cervical adenocarcinomas, and that cervical adenosis may be a precursor of cervical adenocarcinoma in C3H mice and serve as an early indicator of the potential uterine carcinogenicity of a test compound. It supports the view that the C3H mouse may serve as an animal model for uterine adenocarcinomas and adenosis in women exposed to estrogens.

One-year toxicity of orally administered acrolein to the beagle dog.

Forty-eight dogs were separated into four groups of six males and six females. Acrolein (0.1% aqueous) was administered in gelatin capsules to three of these groups at dosing levels of 0.1, 0.5 and 1.5 mg kg-1 day-1 based on results of a range-finding study. After 4 weeks, the high dose was increased to 2 mg kg-1 day-1. The fourth group received deionized water in the same number of gelatin capsules as the high-dose group. Dosing was 7 days per week for 53 weeks. Blood and biochemical measurements were made pretest and at 3-month intervals thereafter. At termination, all dogs were subjected to full necropsy and histological examination. The major test effect noted was frequent vomiting after dosing. This was observed to be dose-dependent and the frequency decreased with time, indicating an adaptive effect. One mid-dose female died during the test and was diagnosed as having died of severe bronchial pneumonia, probably a result of vomitus aspiration. Serum albumin, calcium and total protein values were depressed in high-dose animals throughout the study. Some variability in red blood cell parameters and coagulation times were noted but the significance of these effects was not obvious.

Subchronic oral administration of acemannan in the rat and dog.

Acemannan is the USAN-accepted name for long-chain polydispersed beta-(1,4)-acetylated polymannose with interspersed O-acetyl groups, with a mannose monomer/acetyl ratio of approximately 1:1. This complex polysaccharide is extracted from Aloe vera (barbadensis Miller); the technical material contains approximately 78% acemannan. Technical grade acemannan was administered po to rats for 14 d at 5% of the diet and for 6 mo at up to 2,000 mg/kg/d, and to beagle dogs for 90 d at up to 1,500 mg/kg/d without significant effect on any parameter measured in either species.