Biomedical subjects

R G York

Publications and source records attributed to R G York.

At least 19 recordsLinked to original sources

PubMed2000

Lack of effects of nose-only inhalation exposure on testicular toxicity in male rats.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.

Animals↗

PubMed1997

Terminology of developmental abnormalities in common laboratory mammals (version 1).

This paper presents the first version of an internationally-developed glossary of terms for structural developmental abnormalities in common laboratory animals. The glossary is put forward by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology, and represents considerable progress toward harmonization of terminology in this area. The purpose of this effort is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Nonpreferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed and defined separately, instead of repeating their definitions for each observation. Syndrome names are generally excluded from the glossary, but are listed separately in an appendix. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Comments, questions, suggestions, and additions from practitioners in the field of developmental toxicology are welcomed on the organization of the glossary as well as on the specific terms and definitions. Updates of the glossary are planned based on the comments received.

Animals↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (1). Fertility study in rats by oral administration].

Fertility and developmental toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats. Male rats were given NS-21 orally from 60 days before mating to the day of necropsy, and female rats were given NS-21 orally from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 2, 30 and 500 mg/kg. On day 20 of pregnancy, the females were sacrificed and their fetuses examined. At the 500 mg/kg dosage level, one male and one female died. Salivation and dilated pupils occurred at the 30 and 500 mg/kg dosage levels, and rales occurred at 500 mg/kg. Body weights and food consumption were decreased, and water consumption was increased in both males and females at the 500 mg/kg dosage level. Decreases in the numbers of corpora lutea and implantations per litter and a lower number of live fetuses per litter were found at the 500 mg/kg dosage level. However, the incidence and number of postimplantation loss per litter were comparable among the treatment and control groups. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 2 mg/kg for general toxicity in parental animals, and 30 mg/kg for reproductive function of the parent animals and for embryo-fetal development.

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (2). Teratogenicity study in rats by oral administration].

A study of teratogenicity and developmental toxicity of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats. Female rats were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the remaining pregnant rats (twenty-three per dose level) were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, rales, partially closed eyes and reduced activity were observed in pregnant rats. Decreases in body weight gain, food consumption and water consumption were observed in the dams at the 300 mg/kg dosage level. Fetal body weights were decreased at the 300 mg/kg dosage level. The drug never altered the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, sex ratio, placental weight, and external, visceral and skeletal development of fetuses. NS-21 did not affect the delivery of dams, the number of live newborns, birth index, body weight or survival index. Nor did NS-21 have any adverse effect on the postnatal development of the offspring, including physical and functional development, emotionality, motor activity, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity in mother animals. 300 mg/kg for reproductive function in mother animal and 25 mg/kg for developmental toxicity.

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (3). Teratogenicity study in rabbits by oral administration].

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (4). Perinatal and postnatal study in rats by oral administration].

A study of the effect of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats during the perinatal and lactational periods. Female rats(thirty-three per dose level) were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, reduced activity, salivation and rales were observed in dams, and five dams died. Decreases in body weight gain, food consumption and water consumption were also observed in the dams at the 300 mg/kg. The number of remaining implantation sites was increased at 300 mg/kg, indicating fetal mortality. The number of live newborns, birth index and survival index at the birth were decreased at the 300 mg/kg dosage level. Reduced activity, paleness in color and/or discoloration were observed for many pups at the 300 mg/kg on lactation day 0. Body weights of male and female offspring at the birth were also decreased at the 300 mg/kg dosage group. Survival index at the 4 days was decreased at the 300 mg/kg dosage level. Body weight gains of male and female offspring were decreased at the 300 mg/kg during the lactational period and after weaning. NS-21 did not affect the postnatal development of the offspring, including physical and functional development, motor activity, emotionality, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity and reproductive function in mother rats and 25 mg/kg for developmental toxicity of their offspring.

Administration, Oral↗

PubMed1996

Maternal reproductive effects of oral salicylic acid in Sprague-Dawley rats.

Clinical and experimental evidence indicates that exposure to relative ly large doses of acetylsalicylic acid (ASA) prolongs parturition. However, little is known about the dose-response relationship for salicylate-related effects on labor and gestation. As well, the relative potency of salicylic acid (SA) as compared with ASA for these reproductive effects has not been well investigated. This study was designed to define a dose-response relationship for salicylic acid (SA) effects on labor and gestation times in Sprague-Dawley rats. Pregnant females received oral doses of 20,80, or 200 mg/kg/day sodium salicylate, or 260 mg/kg/day acetylsalicylic acid (ASA), as a positive control, on days 15 through 21 of gestation (sperm positive = day 0). Onset of labor was followed in each animal beginning on day 21 of gestation. The data failed to demonstrate a substantial potency difference between ASA and SA but some differences in toxicity were observed. Relative to controls, gestation times were unaffected by SA. SA treatment resulted in a dose-related trend towards increased duration of labor which was statistically significant at 200 mg/kg/day of SA. ASA treatment of pregnant females resulted in both prolonged labor and gestation times. Both the highest administered dose of SA and ASA treatment contributed to increased maternal peripartum death. Overall, the study confirms a dose-response relationship for SA-induced maternal reproductive effects and supports a no observable effect level (NOEL) for this compound of 80 mg/kg/day for adverse effects on parturition.

Administration, Oral↗

PubMed1995

Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous reproductive toxicity and teratology studies (Segment I, II and III) of this compound in rats and teratology study in rabbits. The test compound was dissolved in physiological saline, which was also given as the vehicle control. Rats were administered at a dosage of 0.06, 0.16 and 0.62 mg/kg/day in the male Segment I study. Dose levels in the other studies in rats including the female Segment I were 0.16, 0.31 and 0.62 mg/kg/day. In the Segment I study, no treatment-related abnormalities were observed in reproductive parameters or fetuses. In the Segment II study, slightly retarded fetal ossification was noted at 0.31 mg/kg/day or more, but the incidence of malformation did not increase. In the Segment III study, death of the dams and abnormal tooth growth of offspring were observed at 0.16 mg/kg/day or more. Further Segment III study showed that the no toxic effect level was 0.003 mg/kg/day. In the rabbit teratology study, dose levels were 0.01, 0.025 or 0.05 mg/kg/day. No toxic effects on pregnant females or their litters were observed at up to 0.05 mg/kg/day.

Abnormalities, Drug-Induced↗

PubMed1994

Ten and ninety-day toxicity studies of 1,2-dichloroethane in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received 1,2-dichloroethane in corn oil by gavage for 10 or 90 consecutive days. The doses for the 10-day study were 10, 30, 100, and 300 mg/kg; the 90-day study doses were 37.5, 75, and 150 mg/kg. There were ten animals per sex per dose group. In the 10-day study, all female animals died in the high dose group and only 2 of 10 males survived. Final body weights and weight gain along with hematology and clinical chemistry findings were not different from controls. The only relative organ weight which was significantly different was the liver in males exposed to 100 mg/kg. The main histopathological lesion exhibited was multifocal to diffuse inflammation of the mucosal and submucosal layers of the forestomach in the 100 mg/kg dose group. This change was minimal in both males and females. In the 90-day study there were no treatment-related effects pertaining to clinical observations. Body weight gain and total food consumption were significantly decreased in high dose males. There were slight but significant differences in hemoglobin, hematocrit, red blood cell count, platelets, albumin, and alkaline phosphatase values in the 75 and/or 150 mg/kg groups in one or both sexes. In males, relative brain, kidney, and liver weights were significantly increased at 75 and 150 mg/kg. There were also differences in spleen, adrenal, and testes weights (absolute and/or relative). In females, absolute and/or relative kidney and liver weights were significantly increased at 150 mg/kg (liver) and at 75 and 150 mg/kg (kidney). There were no apparent treatment-related effects pertaining to mortality, ophthalmology, gross pathology, or histopathology.

Analysis of Variance↗

PubMed1993

Quaternary silsesquioxane: a developmental toxicity study in rats.

The developmental toxicity of an antimicrobial organosilicon quaternary ammonium chloride (Quaternary Silsesquioxane) was evaluated in rats. Groups of 25 pregnant CD rats were administered 100, 300, or 1000 mg/kg/day of test material by gavage as a single daily dose on Days 6 through 15 of gestation at a volume of 10 ml/kg. The control group received only corn oil as the vehicle. Cesarean examinations were performed on all females on Gestation Day 20 followed by evaluation of the fetuses for teratogenicity. Maternal effects included a slight but statistically significant increase in relative liver weights at the 1000 mg/kg/day dose level. Using these hepatic changes as an adverse effect, the maternal no observable adverse effect level for this study was identified at 300 mg/kg/day. The number of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, the fetal body weights, the crown-rump length, and the gravid uterine and corrected body weights were not affected by the administration of Quat-Silsesquioxane. The occurrence of external and internal soft tissue malformations and variations and the incidences of skeletal malformations and variations in the treated groups were not significantly different from those in the control group. These results demonstrated that oral administration of Quat-Silsesquioxane as high as 1000 mg/kg/day did not produce teratogenicity or other indications of developmental toxicity in the rat conceptus.

Animals↗

PubMed1993

Ten and ninety-day toxicity studies of 2,4-dimethylphenol in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received 2,4-dimethylphenol daily by gavage for 10 or 90 consecutive days. The 10-day acute study doses were 0, 60, 120, 600 and 1200 mg/kg; the 90-day subchronic study doses were 0, 60, 180 and 540 mg/kg. Corn oil was used as the vehicle. In the 10-day study, all the high dose animals died. At 600 mg/kg there was a significant increase in relative liver weight in females and several significant alterations in hematologic and clinical chemistry values in both sexes. Histopathological examination revealed changes associated with the forestomach in all dose groups. The 90-day study had numerous compound-related deaths at the 540 mg/kg level. In addition, the final body weight in high dose males and females was significantly less while absolute lung weights and relative liver weights in females, and relative brain, kidney and testes weights in males were also altered. Significant clinical chemistry findings in high dose animals (540 mg/kg) included reduced creatinine and increased cholesterol in both sexes, with increased triglycerides and decreased AST in males only. Histopathologic evaluation revealed hyperkeratosis and epithelial hyperplasia of the forestomach in males and females in the middle and high-dose groups.

Animals↗

PubMed1993

Ten and ninety-day toxicity studies of 2-chlorophenol in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received 2-chlorophenol in corn oil daily by gavage for 10 or 90 consecutive days. The 10-day study doses were 13, 64, 129 and 257 mg/kg while the 90-day subchronic study doses were 17, 50 and 150 mg/kg. In the 10-day study, hematologic and clinical chemistry, food and water consumption, absolute and relative organ weights, and histopathological findings revealed no compound or sex-related effects. In the 90-day study there were no significant gross or histopathological findings that were treatment-related in either sex. There were statistically significant differences between control and treated groups associated with hematology, clinical chemistry and organ weights; however, none of the differences were considered to be biologically meaningful.

Animals↗

PubMed1992

Developmental toxicity evaluation of inhaled citral in Sprague-Dawley rats.

Citral is a commonly used fragrance and flavour ingredient that has demonstrated a potential for teratogenicity in chick embryo screening studies. To investigate potential mammalian developmental toxicity, pregnant Sprague-Dawley rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentrations of 0, 10 or 34 ppm as vapour, or 68 ppm as an aerosol/vapour mixture. Dams were killed on gestation day 20 and the foetuses were removed and evaluated for gross, visceral and skeletal malformations. Exposure to 68 ppm was maternally toxic, with reduced body-weight gains, ocular opacity, breathing difficulty, nasal discharge and salivation noted in the dams. No maternal toxicity was seen at the lower vapour exposure levels. The number of corpora lutea, implantations, resorptions, foetal viability, litter size, and sex ratio were not adversely affected by citral at any exposure level tested, and no exposure-related malformations were observed. At a maternally toxic exposure level, a slight reduction in mean foetal body weight and a slight increase in the incidence of hypoplastic bones were noted. Results of this study indicate that citral does not produce developmental toxicity in the rat when administered by inhalation at concentrations up to a maternally toxic exposure level.

Abnormalities, Drug-Induced↗

PubMed1990

Ninety-day oral toxicity study of dibromochloromethane in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received dibromochloromethane daily by gavage to evaluate its subchronic toxicity. Dose levels were 0, 50, 100, and 200 mg.(kg-day)-1, with 10 animals/sex/group for 90 consecutive days. Corn oil was used as the vehicle. No changes were found in mortality, clinical signs, ophthalmoscopic examinations, or hematology that were considered to be related to treatment. Mean final body weight and body weight gain (weeks 0-13) were significantly decreased in male and female high dose animals relative to the vehicle control. Food consumption was decreased in males in a dose-related fashion, reaching statistical significance at the highest treatment level. Indications of hepatotoxicity in the clinical chemistry included elevated alanine amino-transferase (mid and high dose males) and alkaline phosphatase (high dose males and females). Increased serum creatinine (mid- and high dose males and high dose females) and decreased potassium (high dose males) were considered to be suggestive of nephrotoxicity. Absolute and relative weights of several organs in male and female animals were depressed and were related to the decreased body weights. The decreases in brain and thymic weights, and increases in liver and kidney weight (female only) were considered to be treatment related. Histopathological changes included findings of lipidosis of the liver and slight to moderate degenerative changes within the proximal tubular cells of the kidney. Based on the results of this study, the (LOAEL) lowest observed adverse effect level for DCBM when administered to Sprague-Dawley rats in corn oil gavage was 50 mg.(kg-day)-1.

Administration, Oral↗

PubMed1988

Teratogenic effects of trichloroacetonitrile in the Long-Evans rat.

Trichloroacetonitrile (TCAN) is among a number of contaminants found in drinking water produced by reactions of chlorine with background organic material. Long-Evans rats were intubated with TCAN (0, 1, 7.5, 15, 35, 55 mg/kg) in a tricaprylin vehicle on gestation days 6-18. The highest dose tested (55 mg/kg) was lethal in 21% of the dams and produced 100% resorptions in two-thirds of the survivors. Only one maternal death was seen at the next-lower dose; however, fetal weight and viability were decreased in a dose-related manner. The percentage of embryolethality was 13.9% at the lowest dose and 78.4% at the high dose, with resorption of entire litters seen at 7.5 mg/kg and above. At all doses, cardiovascular (interventricular septal defect, levocardia, common carotid, and right-sided aortic arch and ductus arteriosus) and urogenital (hypoplastic, missing, misplaced and fused kidneys, and hypoplastic uterine horns) malformations were seen in the offspring. Frequency of these malformations was dose related, ranging from 8% to 35% at the 1.0- and 35-mg/kg doses, respectively. The incidence of total soft tissue malformations was statistically significant at 15 and 35 mg/kg. There were no significant treatment-related changes in the incidence of skeletal malformations. The no-effect dose was established by statistical analysis to be 1.0 mg/kg/day.

Abnormalities, Drug-Induced↗

PubMed1987

Alteration of effective exposure of dam and embryo to caffeine and its metabolites by treatment of mice with beta-naphthoflavone.

The effect of treatment of pregnant C57BL/6J (B6) and AKR/J (AKR) mice with the cytochrome P-450 inducing agent beta-naphthoflavone (beta NF) on caffeine metabolism and on exposure of dam and embryo to caffeine and to its metabolites theophylline (TP), theobromine (TB), paraxanthine (PX), and trimethyluric acid (TMUA) was investigated. Treated dams were given either 20 or 80 mg beta NF/kg ip on Days 9 and 10 of gestation. Caffeine, 175 mg/kg, was given ip on Days 11 and 12 of gestation. Concentrations of caffeine and its metabolites were monitored in maternal plasma and in embryo homogenates at 0.083, 0.25, 0.5, 1, 2, 4, and 6 hr after the second caffeine injection. Effective exposure was expressed as the area under the concentration-time curve from 0 to 6 hr. Caffeine loss in B6 mice was best described by an expression incorporating capacity-limited kinetics. Pretreatment induced formation of TB and PX, while it induced elimination of all three of the monodemethylated metabolites, in B6 mice. Consequently, pretreatment caused marked reductions in exposure of B6 dams and embryos to both caffeine and TP. Exposure to TB and PX was less consistently affected, although it was reduced by pretreatment with 80 mg beta NF/kg. In contrast, exposure of AKR dams and embryos to caffeine and its metabolites was only slightly affected by beta NF pretreatment. The prevalence of paw malformations in the offspring of treated mice correlated well with effective exposure to both caffeine and TP, but not at all with the administered caffeine dose.

Animals↗

PubMed1987

Evaluation of the teratogenic effects of Tri-ortho-cresyl phosphate in the Long-Evans hooded rat.

The developmental toxicity of tri-ortho-cresyl phosphate (TOCP) was evaluated in Long-Evans rats. Pregnant rats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughout organogenesis from gestation Days 6 through 18 (Day of sperm = Day 0). The highest dose tested (350 mg/kg) was lethal in 28% of the dams; no maternal deaths or toxicity were observed in the 87.5 or 175 mg/kg dose groups. There were no significant differences noted among the experimental and control groups for preimplantation loss or resorption. Fetal weights for both sexes in the TOCP groups were significantly greater than in the control group; however, no difference among the TOCP groups was observed. Malformation rates were too low to warrant statistical analysis. Numerous soft tissue and skeletal variations were observed in both control and TOCP-treated groups; there were no significant differences in the frequency of variations among the dose groups. The results of this study indicate that TOCP is not teratogenic in the Long-Evans rat.

Abnormalities, Drug-Induced↗

PubMed1986

Sequence of the amino terminal half of rat testis-specific histone variant H1t.

H1t is a testis-specific H1 histone variant that appears during the meiotic phase of spermatogenesis in mammals. The sequence of the first 108 residues of rat H1t have been determined and compared to boar H1t and also to a consensus sequence characteristic of standard somatic H1 variants. The two versions of H1t share a common pattern of divergence from the standard somatic consensus. For example, they both share many substitutions within the H1 globular region (residues 40-110), a portion of the molecule that is virtually invariant among the common somatic variants. Within the entire region sequenced, there are 28 shared locations where both forms of H1t differ from the somatic consensus. However, identical substitutions occur at only 15 of these sites, and each protein also differs from the consensus at five (boar) or ten (rat) additional locations that are not shared. These results establish that H1t from diverse sources shows a characteristic pattern of divergence from the sequence of standard somatic H1 proteins. However, it is also clear that there is great tolerance for species-specific variation within this H1 class.

Amino Acid Sequence↗