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Biomedical subjects

R Gingell

Publications and source records attributed to R Gingell.

At least 19 recordsLinked to original sources
PubMed2000

Reproduction/developmental toxicity screening test in rats with orally-administered 1-hexene.

This study was conducted to provide screening information concerning the potential systemic, reproductive and developmental toxicity of 1-hexene when administered orally, by gavage, to male and female rats using a modified OECD 421 protocol. 1-Hexene was administered at doses of 100, 500, and 1000 mg/kg/day in corn oil; the control group received the vehicle at an equivalent volume. The males were treated for 28 days prior to mating and until euthanasia (44 days of dosing). The females were treated for 14 days prior to mating and during mating, gestation, and lactation until euthanasia (41-55 total days of dosing). Females were allowed to deliver and rear their offspring until lactation day 4. The parental rats were subject to a gross and microscopic examination. Viability and development of the pups were followed through lactation day 4. There was no mortality, and there were no clinical signs of toxicity or differences in body weights, weight gain, feed consumption or organ weights. Copulation and fertility indices, precoital intervals, gestation lengths and pregnancy rates were comparable among the groups, and no signs of prolonged delivery or unusual nesting behaviors were noted. Pup viability, body weights, external observations and necropsy data were comparable among the groups. Pitted kidneys were observed at necropsy for two parental males in the 500 mg/kg/day group and three males in the 1000 mg/kg/day group. Microscopic changes in the kidneys of some male rats from the 100, 500, and 1000 mg/kg/day groups consisted of dose-related accumulations of hyaline droplets in the epithelial cells of the proximal convoluted tubules of the kidneys. In summary, the only treatment-related effect noted in this study was hydrocarbon nephropathy in male rats, which is not considered relevant for human health. The NOAEL for systemic and reproductive toxicity was 1000 mg/kg/day, excluding the finding of male rat hydrocarbon nephropathy.

Administration, Oral↗
PubMed1999

Subchronic inhalation study of 1-hexene in Fischer 344 rats.

The objective of this study was to evaluate the toxicity of 1-hexene following repeated inhalation exposures in male and female Fischer 344 rats. Groups of 40 male and 40 female rats were exposed for 6 hours per day, 5 days per week, over a 13-week period. Treatment groups consisted of air-exposed control (0 ppm) and three test groups of 300, 1000, and 3000 ppm 1-hexene. During the treatment period, the rats were observed daily for clinical signs of toxicity; body weights and neuromuscular coordination [females only] were measured at 7-day intervals. After 7 weeks of exposure and at the end of the treatment period, the rats were subject to macroscopic and microscopic pathology, clinical chemistry, hematology, urinalysis, and sperm counts. No mortalities were observed during the course of the study. No clinical signs of toxicity attributable to 1-hexene exposure were observed. Female rats exposed to 3000 ppm had significantly lower body weights compared to control rats from exposure day 5 persisting throughout the treatment period. Male rats exposed to 3000 ppm had slightly but not statistically significant lower body weights in comparison to controls. Male rats exhibited slightly increased absolute and relative testicular weights, and female rats had slightly decreased absolute [but not relative] liver and kidney weights, at 3000 ppm. There were no gross or microscopic morphological findings attributed to treatment. Exposure to 1-hexene did not affect neuromuscular coordination in females as determined using the Rotarod, nor sperm counts in male rats. Several statistically significant effects in hematology, clinical chemistry, and urinalysis evaluations were observed, but were either of small magnitude or did not correlate with histopathological findings, and thus did not appear to be of biological significance. In summary, the no-adverse-effect-level for this study was determined to be 1000 ppm, based on decreased weight gain in female rats, and on slight organ weight changes in both sexes at 3000 ppm.

Administration, Inhalation↗
PubMed1998

Carotid ultrasound examination in Williams syndrome.

OBJECTIVE: To noninvasively measure arterial wall thickness in a group of patients with Williams syndrome (WS). METHODS: High-resolution, real-time B-mode ultrasonography was used to examine the carotid arteries of 20 patients with WS (ages 7 months to 24.9 years) and 25 control subjects (ages 2.5 years to 25.5 years). RESULTS: The mean combined intimal-medial wall thickness of the patients in the WS group was 0.86 mm +/- 0.08 mm compared with a mean of 0.54 mm +/- 0.05 mm in the control subjects (p < 0.0001). Within the WS group, arterial wall thickness did not vary significantly with gender, patient age, the presence or absence of stenotic cardiac disease, or the presence or absence of hypertension. CONCLUSIONS: The ultrasonographic finding of increased carotid arterial wall thickness across a wide range of patients with WS demonstrates the pervasive nature of the arteriopathy of this disorder. That increased arterial wall thickness was observed in all patients studied suggests that the arteriopathy of WS is related to haploinsufficiency for the elastin gene.

Adolescent↗
PubMed1996

Prechronic toxicity studies on 2-ethylhexanol in F334 rats and B6C3F1 mice.

Data on the subchronic toxicity of 2-ethylhexanol (2EH) were required to establish the dose vehicle and dose levels for oncogenicity studies. In preliminary studies 2EH was given subacutely (11 days) to male and female Fischer 344 rats and B6C3F1 mice as an aqueous emulsion by oral gavage (0, 100, 330, 1000, and 1500 mg/kg/day). Clinical observations were made, body weights, food consumption, clinical chemistries, hematologies, and selected organ weights were measured, and gross and micropathologies were performed. Target organs were the central nervous system, liver, forestomach, spleen, thymus, and kidney in rats and the central nervous system, liver, and forestomach in mice. 2EH was then administered by oral gavage to male and female F344 rats and B6C3F1 mice as an aqueous emulsion (0, 25, 125, 250, and 500 mg/kg/day) for 13 weeks. At 500 mg/kg/day in the rat there was reduced body weight gain (6% male, 7% female), increased relative liver (29% male, 15% female), kidney (16% male, 6% female), stomach (11% male, 16% female), and testes (6%) weights, and moderate gross and microscopic changes in the liver and forestomach. There were no behavioral effects or effects on the spleen or thymus. A no-effect level for target organ effects in the rat was 125 mg of 2EH/kg/day. At 500 mg of 2EH/kg/day in the mouse the only effects were increased relative stomach weights in males (13%) and a low incidence of gross and microscopic findings in the forestomach (male and female) and liver (female). A no-effect level for target organ effects in the mouse was 125 mg of 2EH/kg/day. 2EH was a peroxisome proliferator in the rat but not in the mouse at subchronic dose levels of 500 mg/kg/day. Dose levels in oncogenicity studies were set at 50 mg/kg/day for the absence of treatment-related effects in rats and mice, and 500 and 750 mg/kg/day, respectively, in rats and mice as high doses producing minimal toxicity without altering the life span.

Administration, Oral↗
PubMed1996

Oncogenicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice.

2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisome proliferator in the rat. It is a high-volume chemical intermediate in the preparation of the plasticizers bis-(2-ethylhexyl) adipate (DEHA), bis-(2-ethylhexyl) phthalate (DEHP), and tris-(2-ethylhexyl) phosphate (TEHP), which are weak hepatocellular tumorigens in female mice. In consequence, the oncogenic potential of 2EH was evaluated in male (M) and female (F) rats and mice (50 animals/sex/group). Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35 castor oil) were given five times a week to rats: 0 (water), 0 (vehicle), 50, 150, and 500 mg/kg for 24 months, and to mice: 0 (water), 0 (vehicle), 50, 200, and 750 mg/kg for 18 months. Statistical comparisons of data were made between vehicle controls and treatment groups. There were no differences of biological significance between data from vehicle and water control groups. In rats, there were no dose-related changes at 50 mg/kg. There was reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and 500 mg/kg (M, 33; F, 31%) and an increased incidence of lethargy and unkemptness. There were dose-related increases in relative liver, stomach, brain, kidney, and testis weights at sacrifice. Female rat mortality was markedly increased at 500 mg/kg. There was marked aspiration-induced bronchopneumonia in rats at 500 mg/kg; hematologic, gross, and microscopic changes, including tumors, were otherwise comparable among all rat groups. In mice at 50 and 200 mg/kg there were no dose-related changes and essentially no time-dependent or time-independent adverse trends in liver tumor incidence at the 5% significance level. At 750 mg/kg mouse body weight gain was reduced (M, 26; F, 24%), and mortality increased (M and F, 30%) versus vehicle controls. At 750 mg/kg there was a slight increase in nonneoplastic focal hyperplasia in the forestomach of mice (M 5/50, F 4/50) versus vehicle controls (M 1/50, F 1/50). There were increases in mouse relative liver (F, 21%) and stomach (M, 13%; F, 19%) weights at 750 mg/kg. There was a 12% incidence of hepatic basophilic foci and an 18% incidence of hepatocellular carcinomas in male mice at 750 mg/kg, not statistically significant compared with either control by Fisher's exact test. There was a 12% incidence of hepatic basophilic foci and a 10% incidence of hepatocellular carcinomas in female mice at 750 mg/kg, statistically significant (p < 0.05) compared with vehicle but not with water controls by Fisher's exact test. There were no metastases. Time-dependent and -independent statistical analyses showed an adverse trend in the incidence of hepatocellular carcinomas in male and female mice, correlated with toxicity (expressed as mortality) at 750 mg/kg. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in females (13.1%) lay outside the normal range (0-2%). Under the conditions of these studies 2EH was not oncogenic in rats, but there were weak adverse trends in hepatocellular carcinoma incidence in mice at high dose levels which may have been associated with toxicity. The major effects of chronic dosing were mortality in female rats at 500 mg/kg and in male and female mice at 750 mg/kg, accompanied by reductions in body weight gain in rats at 150 and 500 mg/kg and in mice at 750 mg/kg. Direct comparison of any tumorogenic effects of 2EH given alone to female mice with those due to 2EH formed in vivo from DEHA, DEHP, or TEHP is limited by the high mortality caused by 2ER in female mice at equivalent doses of 2EH. While 2EH may be a contributing factor in the hepatocellular carcinogenesis in female mice associated with the chronic administration of DEHA and DEHP, it is unlikely to be the entire proximate carcinogen.

Animals↗
PubMed1993

The Williams syndrome: evidence for possible autosomal dominant inheritance.

We recently evaluated a mother and son with the Williams syndrome. Documentation of the clinical phenotype in two generations of this family suggests that some cases of the Williams syndrome are autosomal dominantly inherited. Recognition of the heritable nature of the Williams syndrome should prompt careful clinical evaluation of other at-risk relatives in order to provide accurate recurrence risk counseling.

Abnormalities, Multiple↗
PubMed1992

The developmental toxicity of 2-ethylhexanol applied dermally to pregnant Fischer 344 rats.

Undiluted 2-ethylhexanol (2-EH) was administered by occluded dermal application for 6 hr per day on Gestation Days 6 through 15 to pregnant Fischer 344 rats, in range-finding (R) and main (M) studies. The dermal route is considered to be the most relevant for human exposure. Treatment levels were (R) 0.0, 0.5, 1.0, 2.0, and 3.0 ml/kg/day (equivalent to 0, 420, 840, 1680, and 2520 mg/kg/day) and (M) 0.0, 0.3, 1.0, and 3.0 ml/kg/day (equivalent to 0, 252, 840, and 2520 mg/kg/day). Controls (0.0 ml/kg/day, sham controls) received deionized water at 3.0 ml/kg/day. Dermal-positive control groups received undiluted 2-methoxyethanol (2-ME) at (R) 0.5 and 1.5 ml/kg/day and (M) 1.0 ml/kg/day as a reference compound in a similar regimen. An oral reference compound, valproic acid, was administered by gavage in the range-finding study on Gestation Days 6 through 15 at 400 mg/kg/day. The range-finding study employed an untreated (naive) control group. Numbers of plug-positive females per group were (R) 8 and (M) 25. Maternal weight gain was reduced for 2-EH at 1680 (R) and 2520 (R and M studies) mg/kg/day. Exfoliation and encrustation were seen at the application site in both studies at 840, 1680, and 2520 mg/kg. Maternal liver, kidney, thymus, spleen, adrenal, and uterine weights, and gestational and fetal parameters were unaffected by treatment with 2-EH. There were no treatment-related increases in the incidence of individual or pooled external, visceral, and skeletal malformations or variations following the application of 2-EH. The NOAELs for the maternal toxicity of 2-EH were 252 mg/kg/day based on skin irritation and 840 mg/kg/day based on systemic toxicity. The developmental toxicity NOAEL was at least 2520 mg/kg/day, with no teratogenicity. Administration of 2-ME at 840 mg/kg/day resulted in reduced maternal weight gain and food consumption, increased postimplantation loss, reduced numbers of live fetuses per litter, and reduced fetal body weights per litter. The incidence of fetal malformations and variations was increased. Oral administration of VPA produced maternal toxicity, developmental toxicity, and teratogenicity. The Fischer 344 rat is thus susceptible to known rodent teratogens by both the dermal and oral routes. It is concluded that 2-EH is not developmentally toxic by the dermal route in the Fischer 344 rat at and below treatment levels which produce maternal toxicity.

Administration, Cutaneous↗
PubMed1987

Toxicokinetics of 1,2-dibromo-3-chloropropane (DBCP) in the rat.

The objective of this study was to determine the kinetics of absorption, distribution, and elimination of DBCP after intravenous (iv) administration in plasma, and after oral administration in water or corn oil, to conscious, fed, male Fischer 344 rats. Rats were prepared with an external jugular vein cannula and were dosed with 0.1, 1, or 10 mg/kg DBCP into the penile sinus or orally as a solution in water or in corn oil (1 mg/kg only). Blood was sampled at various times up to 12 hr, concentrations of DBCP were determined by gas chromatography, and data were evaluated by classical pharmacokinetic techniques. After oral administration in water, absorption of DBCP was rapid, and the distribution and elimination phase was biexponential. There did not appear to be any saturation of DBCP absorption, distribution, or elimination at the high oral or iv dose. After oral administration of DBCP in a corn oil vehicle, absorption was prolonged, suggesting retention of DBCP in the stomach; this could contribute to the toxic effects of DBCP on the forestomach when chronically administered in corn oil. The areas under the blood concentration/time curve were similar regardless of vehicle, suggesting that systemic toxicity might be independent of the vehicle.

Absorption↗
PubMed1987

Evidence that epichlorohydrin is not a toxic metabolite of 1,2-dibromo-3-chloropropane.

The major urinary metabolite of 14C-epichlorohydrin, after oral administration to rats, was identified previously (Gingell et al. 1985) to be N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine (ACPC) at 36% of the administered dose. In a similar study reported here, 1,2-dibromo-3-chloropropane (DBCP) was metabolized to at least 20 radioactive urinary metabolites. ACPC was only a minor metabolite (4%) of DBCP. Epichlorohydrin was metabolized in vitro by rat liver microsomes to alpha-chlorohydrin, but DBCP was not metabolized to epichlorohydrin or alpha-chlorohydrin under similar conditions. Covalent binding of radioactivity to liver microsomal proteins occurred for both substrates, but was less for 14C-epichlorohydrin than for 14C-DBCP. Addition of 3,3,3-trichloropropylene oxide, an inhibitor of epoxide hydrolase, increased the extent of protein binding of epichlorohydrin, but decreased the amount of 14C-DBCP which was bound. The data indicate the epichlorohydrin is not a significant in vivo nor in vitro metabolite of DBCP in the rat, and is unlikely to be responsible for the toxicity of DBCP.

Animals↗
PubMed1986

Long-term potentiation in the interpositus and vestibular nuclei in the rat.

Previous unpublished experiments from this laboratory had revealed only post-activation depression effects in the cerebellar cortex when its inputs were activated by high frequency trains. In the experiments reported in this paper, we found reliable long-term potentiation (LTP) effects in the deep nuclei (interpositus and vestibular) when stimulation trains were applied to the white matter at the point where inferior peduncle fibers enter the cerebellum. LTP effects were found in both acute and chronic preparations. In the chronic preparations, LTP lasted for at least 8 days in all but one animal.

Animals↗
PubMed1985

Long-term results after excision of fixed subaortic stenosis.

Forty-nine patients underwent surgical excision of fixed subaortic stenosis (discrete fibrous ring and tunnel) between 1968 and 1984 and were followed up for 1 to 16 years (5.8 +/- 4). Twenty-six patients (Group I) had isolated subaortic stenosis and 23 (Group II) had subaortic stenosis and associated cardiac defects. Discrete fibrous ring was present in 46 and tunnel type of obstruction in three patients. For the discrete ring, excision alone was done in 32 patients (four recurrences) and excision with myotomy in 17 (three recurrences). In Group I, there were no operative deaths and one late death from a noncardiac cause. In Group II, one early and two late deaths occurred. The actuarial survival rate for 10 years is 88%. Reoperations were performed in 10 patients, seven for recurrence and three for aortic valve replacement for preexisting aortic regurgitation that had progressed since the primary operation. Cardioplegia was used in 28 patients (one recurrence) and was not used in 21 patients (six recurrences). An operative residual gradient of less than 15 mm Hg was achieved in 25 of 28 patients in whom cardioplegia was used compared to 12 of 21 patients in whom cardioplegia was not used (p = 0.017). These results indicate that complete excision of the ring with the aid of cardioplegia has significantly reduced the recurrence rate of subaortic stenosis (p = 0.033), elimination of the residual gradient at the initial operation has been a significant factor in reducing the recurrence rate (p = 0.017), and addition of myotomy in this series has not altered the outcome.

Adolescent↗
PubMed1984

Congenital diverticulum of the heart of biventricular origin.

An extremely rare diverticulum arising from both ventricles at the caudal end of the intraventricular septum was diagnosed in a 2.9 kg infant. The diverticulum was removed successfully while a coexisting ventricular septal defect was left open for further management. The types and complications of such diverticula are described and the need for early surgical intervention is stressed.

Diverticulum↗
PubMed1982

Microbial mutagenicity of selected hydrazines.

Selected hydrazines and related compounds were examined for their mutagenic activity in S. typhimurium strains TA1535 and TA1537. These in vitro assays were conducted with and without metabolic activation by Aroclor-induced rat-liver enzymes. Relatively high levels of mutagenicity were observed with phenylhydrazine X HCl, methylhydrazine, N'-acetyl-4-(hydroxymethyl)phenylhydrazine, and 4-(hydroxymethyl)benzenediazonium tetrafluoroborate, the stabilized salt of a carcinogenic metabolite of agaritine; only low levels of mutagenicity were observed with other compounds, although most are strong carcinogens. Several of the compounds were highly toxic to the bacteria, and detection of mutagenicity was enhanced by calculating the increase in mutagenic activity on the basis of the surviving fractions of bacteria.

Animals↗
PubMed1981

Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease.

Syrian hamsters present a unique species for induction of pancreatic tumors that in many aspects resemble human pancreatic cancer. The specific response of Syrian hamsters, in contrast to may other rodents, for development of pancreatic ductal (ductular) tumors is not yet known. All pancreatic carcinogens thus far tested show certain common features. They are all nitrosamines that possess or can be metabolized to compounds with 2-oxopropyl- or 2-hydroxypropyl substituents. All but one, N-nitroso-methyl(2-oxopropyl)amine, occur or metabolize to nitrosamines with the ability to cyclize and form structures resembling glucose. Hence it is suggested that this cyclic structure may be responsible for the pancreatic carcinogenicity of these nitrosamines, as has been proposed for the pancreatotropic effect of streptozotocin. It is also of further interest that one pancreatic ductal (ductular) carcinogen, N-nitroso-2-methoxy-2,6-dimethylmorpholine, which possesses a totally cyclic structure, acts, like streptozotocin, as beta-cell cytotoxic and diabetogenic when given in a high single dose. Modification of pancreatic tumor induction has been demonstrated by specific procedures. A high fat diet significantly increases both the incidence and number of induced cancers. Methods for early diagnosis and therapy are being developed and their significance and applicabilities for clinical use will be of major importance. Compared with the other most common types of human cancer, pancreatic cancer has extraordinary characteristics, which make the disease one of the most mysterious of maladies. Consequently, pancreatic cancer represents a serious international problem and requires urgent resolution, especially with regard to its etiology, early diagnosis, prevention, and therapy.

Animals↗
PubMed1981

Metabolism of a DDT metabolite via a chloroepoxide.

The 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethene (DDT) metabolic intermediate 1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU) is partially metabolized in vivo by mice to 2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (alpha OH-DDA) and other metabolites which are excreted in urine. The subsequent DDT metabolic intermediates 1-chloro-2,2-bis(p-chlorophenyl)ethane (DDMS) and 1,1-bis(p-chlorophenyl)ethene (DDNU) are metabolized to alpha OH-DDA to a much lesser extent. These results imply that DDMU may be metabolized via an alpha-chloroepoxide. The authentic DDMU-epoxide, which after oral administration is excreted as alpha OH-DDA, is mutagenic in the Ames assay, and thermally rearranges rapidly to the corresponding alpha-chloroaldehyde, 2,2-bis(p-chlorophenyl)-2-chloroacetaldehyde (alpha Cl-DDCHO). As expected alpha Cl-DDCHO yielded the same urinary metabolites as DDMU-epoxide. This suggested metabolic pathway for DDMU via a chloroepoxide intermediate may account for the tumorigenicity of DDT in mice.

Animals↗
PubMed1981

The binding of 7,12-dimethylbenz[a]anthracene to mammary gland macromolecules in the hamster:effects of Enovid feeding or transplacental exposure to diethylstilboestrol.

The covalent binding of 7,12-[3H]dimethylbenz[a]anthracene ([3H--DMBA) to mammary gland macromolecules was studied in hamsters fed a contraceptive mixture, Enovid, those exposed transplacentally to diethylstilboestrol (DES), and controls. Compared with rats, hamsters are relatively resistant to DMBA mammary carcinogenesis, but susceptibility is increased by either of the above treatments with Enovid or DES. The amount of DMBA bound to DNA and protein ws 4-5 times greater than to RNA, but only DNA binding was persistent. Fifty-three percent of the DNA-bound DMBA was still present after 8 days. The amount of DMBA bound to hamster mammary DNA and its persistence was similar to that found in rats. Neither Enovid nor DES treatment altered the levels of binding to mammary macromolecules, nor their persistence. These results indicate that the species differences in the susceptibility to DMBA-induced mammary carcinogenesis in hamsters and rats, and modification of the former by hormones, is not due to differences in the activation of carcinogens. The role of hormones such as prolactin in the promotion phase of mammary gland carcinogenesis may explain these differences.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Methylation of hamster DNA by the carcinogen N-nitroso-bis (2-oxopropyl)amine.

The alkylation of hamster liver, lung and pancreas DNA by [1-14C]- and [2,3-14C]N-nitrosobis (2-oxopropyl) amine (BOP) has been examined. The specific activity of pancreas DNA after [2,3-14C]BOP administration was only 2% of that when [1-14C]BOP was given. 7-Methylguanine, but not O-6-methylguanine, was found in hydrolysates of liver and pancreas DNA. Nearly equal amount of alkylation were produced in the liver when [1-14C]- and [2,3-14C]BOP were given. At least one-half of the radioactivity in the liver was associated with N-alkylated purines, whereas only 20% was in this form in the pancreas.

Animals↗