Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Net Reproduction Rate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

409 records · Page 23Linked to original sources
PubMed1981

Biological effects of a 765-kV transmission line: exposures and thresholds in honeybee colonies.

Honeybee colonies exposed under a 765-kV, 60-Hz transmission line at 7 kV/m show the following sequence of effects: 1) increased motor activity with transient increase in hive temperature; 2) abnormal propolization; 3) impaired hive weight gain; 4) queen loss and abnormal production of queen cells; 5) decreased sealed brood; and 6) poor winter survival. When colonies were exposed at 5 different E fields (7, 5.5, 4.1, 1.8, and 0.65-0.85 kV/m) at incremental distances from the line, different thresholds for biologic effects were obtained. Hive net weights showed significant dose-related lags at the following exposures: 7 kV/m, one week; 5.5 kV/m, 2 weeks; and 4.1 kV/m, 11 weeks. The two lowest exposure groups had normal weight after 25 weeks. Abnormal propolization of hive entrances did not occur below 4.1 kV/m. Queen loss occurred in 6 of 7 colonies at 7 kV/m and 1 of 7 at 5.5 kV/m, but not below. Foraging rates were significantly lower only at 7 and 5.5 kV/m. Hive weight impairment and abnormal propolization occur at lower E-field intensity than other effects and limit the "biological effects corridor" of the transmission line to approximately 23 m beyond a ground line projection of each outer phase wire. Intrahive E fields of 15-100 kV/m were measured with a displacement current sensor. Step-potential-induced currents up to 0.5 microA were measured in an electrically equivalent bee model placed on the honeycomb in a hive exposed at 7 kV/m. At 1.8 kV/m body currents were a few nanoamperes, or two orders of magnitude lower, and these colonies showed no effects. E-field versus electric shock mechanisms are discussed.

Animals↗
PubMed1992

The effect of peritoneal macrophage-derived factor(s) on ovarian progesterone secretion and LH receptors: the role of calcium.

Macrophages and their secretory products, cytokines, play an integral role in many reproductive processes. In this study we examined the effect of conditioned media from cultured human peritoneal macrophages on progesterone production by granulosa cells and the role of calcium in this process. Macrophages were pretreated with various concentrations of a calcium channel blocker (verapamil) or a calcium ionophore (A23187). Macrophage-conditioned media (MCM) or cell-free media that contained calcium channel modifiers were added at three dose levels to cultured porcine granulosa cells. Progesterone production and LH receptor content were determined. Macrophage-conditioned media alone elevated basal progesterone production, but significantly attenuated granulosa cell LH receptor content. These effects were neither potentiated nor suppressed by pretreating macrophages with verapamil. However, production of the LH receptor lowering factor(s) appeared to be suppressed by calcium ionophore. We conclude that (1) one or more factors produced by macrophages have a net stimulatory effect on basal progesterone production and these factor(s) may not be calcium-dependent and (2) macrophage-derived secretory products reduce granulosa cell LH receptor content. The production of these factor(s) may be calcium-dependent.

Animals↗
PubMed1988

Resumption of puberty after long term luteinizing hormone-releasing hormone agonist treatment of central precocious puberty.

To determine whether puberty resumes normally after long term LHRH agonist (LHRHa) treatment, we studied 16 children with central precocious puberty treated with LHRHa (D-Trp6,Pro9,NEt-LHRH) for 1-4 yr (mean, 3.3 yr). Treatment was discontinued at a mean age of 11.6 +/- 1.3 (+/- SD) yr. Plasma hormone levels, growth velocity, rate of bone maturation, and pubertal stage were assessed at the end of treatment and 3 and 12 months later. Basal plasma sex steroid and basal and LHRH-stimulated gonadotropin levels returned to near-pretreatment levels 3 months after discontinuation of therapy and were fully restored to pretreatment levels at 12 months. Growth velocity, which had been 7.8 cm/yr before treatment, was stable after discontinuation of treatment at approximately 2.6 cm/yr. The predicted height, which had increased during treatment (P less than 0.01), remained stable at approximately 5 cm above the pretreatment predicted height. The rate of bone age advancement (delta bone age/delta chronological age) increased gradually from 0.4 at the end of treatment to the normal value of 0.9 12 months posttreatment. Breast and pubic hair pubertal stages, which were stable throughout treatment and were 4.0 +/- 0.8 (+/- SD) and 3.6 +/- 1.0 at the end of treatment, increased to 4.9 +/- 0.2 and 4.5 +/- 1.0. This approximated the normal rate of 1 stage/yr. Menses occurred in 8 of 12 girls within 1 yr after treatment and in an additional 3 by 20 months after treatment. Six of the girls had menstruated before treatment, and all of these menstruated within 14 months after discontinuing therapy. We conclude that gonadotropin and sex steroid secretion and the clinical progression through puberty appear to resume normally after discontinuation of long term LHRHa treatment of central precocious puberty. Long term follow-up will be required, however, to determine whether the improvement in predicted height of these patients will be achieved, and whether adult reproductive function will be normal.

Body Height↗
PubMed1987

Health and productivity of dairy cows fed polychlorinated biphenyls.

Holstein cows were studied through a complete lactation, a nonlactating period, and 42 days of a subsequent lactation for overt and subtle responses to a commercial mixture of polychlorinated biphenyls. Dosed cows (n = 4) received consecutive 60-day periods of daily dosing with 10, 100, and 1000 mg of Aroclor 1254. Control cows (n = 6) received daily sham doses. The following were recorded: daily milk production, feed intake, and health observations; weekly body weight, temperature, heart and respiratory rates and rectal palpation; semi-monthly clinical chemistry determinations; and monthly milk fat, microbiological culture of quarter foremilk samples, and composite milk somatic cell counts. Mean daily milk production (22.4 +/- 1.1 vs 24.8 +/- 1.0 kg) and net energy of a complete lactation (1.46 +/- 0.05 vs 1.45 +/- 0.03 Mcal/kg dry matter intake) were not different (p = 0.85) for control and PCB-dosed cows. Milk production during the first 42 days of the subsequent lactation was also similar for control and dosed cows. Occurrences of injuries, dysfunctions, and general infections were not related to polychlorinated biphenyl exposure. Intramammary infections were detected for both lactations with 51 and 32 infections detected in microbiological cultures, respectively, for the control and dosed groups. Environmental pathogens were most frequently isolated from cases of clinically apparent mastitis. The majority of quarter infections detected were due to Corynebacterium bovis. Only one animal (dosed, necropsy revealed left oviduct obstructed) failed to conceive with three to six services required before conception for the other control and dosed cows. Exposure to polychlorinated biphenyls resulting in maximal residues in milk fat, near 100 micrograms/g, had no apparent effect on health and productivity.

Animals↗
PubMed1987

Two years of intrauterine contraception with levonorgestrel and with copper: a randomized comparison of the TCu 380Ag and levonorgestrel 20 mcg/day devices.

IUDs releasing 20 mcg/day of levonorgestrel (LNg20) were in randomized trial together with the Copper T, model TCu 380Ag, in seven centers involving 2244 women. Two-year (25 months) gross cumulative pregnancy rates were 0.2 +/- 0.2 and 0.9 +/- 0.3 for the levonorgestrel and copper releasing devices, respectively (P greater than 0.05). There were no ectopic pregnancies in more than 1600 woman-years of use of each device. Removal rates for bleeding and/or pain or for medical reasons other than menstrual problems did not differ significantly between devices. Oligomenorrhea or amenorrhea prompted 10.7 per hundred (gross rate, 8.4 net rate) women using the LNg 20 IUD to request removal in the two-year period, significantly above the 0.2 per hundred rate among women with the Copper IUD (P less than 0.001). At the end of two years an estimated 59.4 per 100 women were continuing use of the LNg 20 IUD, and 67.5 per 100 (P less than 0.001) with the TCu 380Ag. This difference is almost wholly ascribable to a marked reduction in bleeding episodes and days among women using the LNg 20 device with concomitant removal of device. Hemoglobin rose an average of 0.5 g/dl (P less than 0.001) for this group whereas women using the TCu 380Ag experienced a decline of 0.2 g/dl compared with baseline values (P less than 0.001).

Adolescent↗
PubMed1983

Three-year experience with NORPLANT subdermal contraception.

NORPLANTTM (Laboratorios Gutfol, S.A., Mexico City, Mexico) subdermal implants containing levonorgestrel were accepted by 816 women in a two-phase study initiated in 1975 and augmented in 1978. Through 3 years of first-segment use, acceptors experienced five pregnancies, a cumulative net rate of 0.7 per 100, and a gross pregnancy rate of 1.1 per 100. First-segment continuation at 3 years was at the rate of 44.6 per 100, an annual average of 76 per 100. NORPLANT users experienced irregular menstruation, with high interindividual variation, but with normal average numbers of bleeding days and of bleeding episodes. Hemoglobin levels increased moderately during implant use. The incidence of systolic blood pressure readings above 145 mm Hg or diastolic readings above 95 mm Hg was similar to that observed among users of the TCu 200 intrauterine device enrolled under the same selection criteria in the same clinics between the two phases of the NORPLANT study. Comparative data on pregnancy and other rates are also given for these intrauterine device acceptors.

Adolescent↗
PubMed2004

An evolutionary theory of schizophrenia: cortical connectivity, metarepresentation, and the social brain.

Schizophrenia is a worldwide, prevalent disorder with a multifactorial but highly genetic aetiology. A constant prevalence rate in the face of reduced fecundity has caused some to argue that an evolutionary advantage exists in unaffected relatives. Here, I critique this adaptationist approach, and review--and find wanting--Crow's "speciation" hypothesis. In keeping with available biological and psychological evidence, I propose an alternative theory of the origins of this disorder. Schizophrenia is a disorder of the social brain, and it exists as a costly trade-off in the evolution of complex social cognition. Paleoanthropological and comparative primate research suggests that hominids evolved complex cortical interconnectivity (in particular, frontotemporal and frontoparietal circuits) to regulate social cognition and the intellectual demands of group living. I suggest that the ontogenetic mechanism underlying this cerebral adaptation was sequential hypermorphosis and that it rendered the hominid brain vulnerable to genetic and environmental insults. I argue that changes in genes regulating the timing of neurodevelopment occurred prior to the migration of Homo sapiens out of Africa 100,000-150,000 years ago, giving rise to the schizotypal spectrum. While some individuals within this spectrum may have exhibited unusual creativity and iconoclasm, this phenotype was not necessarily adaptive in reproductive terms. However, because the disorder shared a common genetic basis with the evolving circuitry of the social brain, it persisted. Thus schizophrenia emerged as a costly trade-off in the evolution of complex social cognition.

Animals↗
PubMed2004

Some aspects of ecophysiological and biogeochemical responses of tropical forests to atmospheric change.

Atmospheric changes that may affect physiological and biogeochemical processes in old-growth tropical forests include: (i) rising atmospheric CO2 concentration; (ii) an increase in land surface temperature; (iii) changes in precipitation and ecosystem moisture status; and (iv) altered disturbance regimes. Elevated CO2 is likely to directly influence numerous leaf-level physiological processes, but whether these changes are ultimately reflected in altered ecosystem carbon storage is unclear. The net primary productivity (NPP) response of old-growth tropical forests to elevated CO2 is unknown, but unlikely to exceed the maximum experimentally measured 25% increase in NPP with a doubling of atmospheric CO2 from pre-industrial levels. In addition, evolutionary constraints exhibited by tropical plants adapted to low CO2 levels during most of the Late Pleistocene, may result in little response to increased carbon availability. To set a maximum potential response for a Central Amazon forest, using an individual-tree-based carbon cycling model, a modelling experiment was performed constituting a 25% increase in tree growth rate, linked to the known and expected increase in atmospheric CO2. Results demonstrated a maximum carbon sequestration rate of ca. 0.2 Mg C per hectare per year (ha(-1) yr(-1), where 1 ha = 10(4) m2), and a sequestration rate of only 0.05 Mg C ha(-1) yr(-1) for an interval centred on calendar years 1980-2020. This low rate results from slow growing trees and the long residence time of carbon in woody tissues. By contrast, changes in disturbance frequency, precipitation patterns and other environmental factors can cause marked and relatively rapid shifts in ecosystem carbon storage. It is our view that observed changes in tropical forest inventory plots over the past few decades is more probably being driven by changes in disturbance or other environmental factors, than by a response to elevated CO2. Whether these observed changes in tropical forests are the beginning of long-term permanent shifts or a transient response is uncertain and remains an important research priority.

Atmosphere↗
PubMed1992

Estimation of net energy requirements (NEm and NE delta) of lactating beef cows.

Spring-calving Angus cows (n = 24) in moderate body condition were assigned to either a high (H), maintenance-high (MH) to support superior milk, maintenance-low (ML) to support average milk, or low (L) energy diet at 12 d (SD = 4) postpartum. Energy balance for individual cows was determined by body condition change, weight change, and weigh-suckle-weigh milk production estimates. High energy intake increased (P < .05) BW, body condition score (BCS), and megacalories of body energy (BE) by 94 d postpartum. Neither dietary nor BCS accounted for significant (P > .30) variation in days to first ovulation or conception. Fasting heat production was estimated to be 72.5 kcal/BW.75 from the regression of log daily heat production/BW.75 on daily ME intake/BW.75. Rate of daily BW change did not affect concentration of energy in the weight change. Body condition score change was highly correlated (r = .98) to BW change, with each unit of BCS (1 to 5 scale) change associated with 68 kg of BW change. Two methods were used to determine NE for weight change (NE delta) based on empty body weight (EBW) change. Method 1 used the equation: BCS change = -.404 + .0147 (BW change) and Method 2 used only the regression coefficient of this equation to predict daily BCS change. Methods 1 and 2 resulted in similar regression equations: NE delta (Mcal/kg EBW change) = 1.590 + 1.251 (BCS) and NE delta (Mcal/kg EBW change) = 1.317 + 1.251 (BCS). Ranges of estimated protein and lipid in the EBW change, respectively, were 10.0 to 13.7% and 17.1 to 77.2%.

Animals↗
PubMed1993

Prolonged exposure to melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates melatonin receptors in pars tuberalis cells from ovine pituitary.

In photoperiodic mammals, seasonal cycles of growth and reproduction are cued by changes in the duration of the nocturnal profile of secretion of the pineal hormone melatonin. To investigate the likely mode of action of this hormone on target tissues, the effect of prolonged treatment with melatonin on the sensitivity of the adenylate cyclase (AC) system was examined in primary cultures of ovine pars tuberalis (PT) cells. When cells were exposed to melatonin (100 pM or 1 microM) for 16 h, and the hormone was then removed by a series of washes, basal production of cAMP was elevated over that observed in cells not treated with melatonin. Moreover, the rate of accumulation of cAMP after stimulation with forskolin (1 microM) was markedly enhanced in cells previously treated with melatonin compared to that in untreated controls. This sensitization by melatonin of the basal and forskolin-stimulated responses developed gradually and was half-maximal after approximately 8 h of exposure. There was no significant difference between the sensitizing effects of the two melatonin concentrations used. Treatment with melatonin for 24 h reduced the total amount of specific [125I]iodomelatonin binding in PT cell membranes by 30-50%. However, over the same period there was no reduction in the ability of a maximal (1 microM) concentration of melatonin to inhibit forskolin-stimulated cAMP production, indicating the presence of an excess capacity of melatonin receptors in cultured PT cells. Nevertheless, treatment with melatonin for 16 h did result in a 10-fold increase in the IC50 for the inhibition by melatonin of forskolin-stimulated cAMP production. The enhancement of cAMP production after prolonged treatment with melatonin was not masked by the inclusion of isobutylmethylxanthine (1 mM) during the subsequent challenge with forskolin, suggesting that sensitization was not due to a reduction in the activity of cAMP-phosphodiesterase. In control cells, aluminium fluoride caused an inhibition of forskolin-stimulated cAMP production. Prolonged treatment with melatonin abolished the inhibitory effect of aluminium fluoride, suggesting that treatment with melatonin caused a shift in the net balance between the G-protein-mediated stimulatory and inhibitory influences on the AC system. The sensitization of AC was not blocked by the inclusion of cycloheximide (10 micrograms/ml) during prolonged exposure to melatonin, suggesting that de novo protein synthesis is not a requirement for this effect of the hormone. These results constitute the first demonstration of an independent action of melatonin on ovine PT cells that is dependent upon the duration of the endocrine stimulus.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed2001

Body composition and estimated tissue energy balance in Jersey and Holstein cows during early lactation.

The rate and extent of estimated energy mobilization and the relationship between fat depth at the rib and thurl and body condition score (BCS) were investigated in Jersey and Holstein cows in early lactation. Twenty-six cows were paired by breed, parity, and calving date, and were individually fed a total mixed ration ad libitum from parturition through 120 d in milk. Feed intake and milk production were measured daily; body weight (BW), BCS, subcutaneous fat depth, milk composition, and concentration of plasma nonesterified fatty acids were measured every 2 wk. Estimated tissue energy balance (TEB) was calculated using 1989 NRC equations. Net energy intake was greater in early lactation for Holsteins compared with Jerseys, 37.8 and 28.2 Mcal/d, respectively. Milk energy was greater for Holsteins relative to Jerseys, 30.5 versus 21.2 Mcal/d. Fat depth and BCS did not differ between breeds. A positive relationship existed between fat depth and BCS for Jerseys; however, there was no significant relationship for Holsteins. The best-fit regression model for predicting TEB for Holsteins and Jerseys in early lactation included week of lactation, milk composition, and BCS. Jerseys remained in negative TEB for a shorter period of time relative to Holsteins. The TEB nadir was -6.19 and -12.9 Mcal/d, for Jerseys and Holsteins, respectively. Expressed as a proportion of metabolic BW (BW(0.75)), net energy intake did not differ between breeds, yet milk energy and estimated tissue energy loss were greater for Holsteins compared with Jerseys.

Adipose Tissue↗
PubMed2005

Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 ml of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative. The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and that dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months. OBJECTIVES: To determine the effectiveness and acceptability of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH STRATEGY: All studies which might describe randomised controlled trials of progesterone or progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, MEDLINE (1966 to 2005) and EMBASE (1980 to 2005). Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by three review authors and nine trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios (OR) were estimated from the data for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life, satisfaction and acceptability measures were also assessed. MAIN RESULTS: Progesterone or progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about its effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5 to 26 of the menstrual cycle in one trial and was significantly more effective although there was a large reduction in loss from baseline in both groups. Some short term side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment. The LNG IUS has been compared to an endometrial ablation: either transcervical resection of the endometrium (TCRE) (two trials) or balloon ablation (three trials). There was a significantly greater mean reduction in menstrual bleeding in one trial in those undergoing balloon ablation (WMD -45.2 units, 95% CI -56.9 to -33.5), a lower score on the pictorial blood loss chart (PBAC) (WMD 33.2 units, 95% CI 27.2 to 39.2) and higher rates of successful treatment in 3 trials including both balloon and TCRE (OR 0.28, 95% CI 0.14 to 0.58) but the rates of satisfaction with treatment was were similar. There was no conclusive evidence of changes in quality of life between groups but women with the LNG IUS had a greater incidence of progestogenic side effects within one year. The LNG IUS has been compared to hysterectomy in one trial. There was no evidence of a change in quality of life scores but the LNG IUS treatment had lower costs than with hysterectomy, both at one and five-years follow up. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than cyclical norethisterone (for 21 days) as a treatment for heavy menstrual bleeding. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness. The LNG IUS results in a smaller mean reduction in menstrual blood loss (as assessed by the PBAC chart) than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment. Women with an LNG IUS experience more progestogenic side effects compared to women having TCRE for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life. The LNG IUS treatment costs less than hysterectomy but there is no evidence of a difference in quality of life measures between these groups. There are no data available from randomised controlled trials comparing progesterone-releasing intrauterine systems to either placebo or other commonly used medical therapies for heavy menstrual bleeding.

Female↗
PubMed1993

Toxicology and Carcinogenesis Studies of 5,5-Diphenylhydantoin (CAS No. 57-41-0) (Phenytoin) in F344/N Rats and B6C3F1 Mice (Feed Studies).

5,5-Diphenylhydantoin and its sodium salt are primarily used in the treatment of grand mal and psychomotor seizures, often in combination with other anticonvulsants, including phenobarbital. 5,5-Diphenylhydantoin is a suspected human carcinogen and was one of three compounds selected by the NTP to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin were conducted in male and female F344/N rats and B6C3F1 mice. The studies were designed to determine the following: a) the effects of 5,5-diphenylhydantoin in the diet given to rats and mice during the adult (F1) period only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of 5,5-diphenylhydantoin in rats and mice receiving perinatal (F0) exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and c) the effects of combined perinatal and adult exposure to 5,5-diphenylhydantoin. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse Iymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. STUDIES IN F344/N RATS: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 300 to 4,800 ppm 5,5-diphenylhydantoin in the diet. The final mean body weights of males and females exposed to 2,400 or 4,800 ppm were significantly decreased. All groups showed a net weight gain over the study period, although the mean body weight gain of females in the 4,800 ppm group was only one-half that of the controls. Feed consumption also decreased with increasing exposure level. No chemical-related gross lesions were present in the tissues of exposed rats. Microscopically, centrilobular hypertrophy of hepatocytes was observed in the liver of rats in the 4,800 ppm groups. Based on these results, 2,400 ppm was selected as the highest exposure for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels ranged from 80 to 2,400 ppm 5,5-diphenylhydantoin in the diet of the dams. The 2,400 ppm exposure level was found to have reproductive and embryotoxic effects, as none of the sperm-positive females delivered litters. In the 800 ppm group, a greater number of pups died between postnatal day 1 and day 28 than in the control group. No gross external malformations were observed among fetuses or pups surviving to term in any exposure group, and no gross or histopathologic lesions were observed in the animals exposed to 800 ppm for 4 weeks following weaning. Based on these results, 630 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The eight F0:F1 exposure combinations selected for the 2-year study are listed in the table (contained in full report - page 6). In the 2-year study, male and female rats in the 630:2,400 ppm groups evaluated at 9 months had increased relative liver weights. Hematologic evaluations indicated mild but consistent chemical-related increases in erythrocyte and platelet counts in male and female rats. Mild decreases in triglyceride concentrations and alanine aminotransferase enzyme activity were seen generally in the high-exposure groups. In the 2-year study, the survival of exposed rats was similar to that of the controls. However, body weights of exposed rats were lower than those of the controls, and body weights were 11% to 35~ lower in rats receiving adult exposure of 2,400 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. Hepatocellular neoplasms, primarily adenomas, occurred with a positive trend in male rats fed 5,5-diphenylhydantoin only as adults (0:0 ppm, 0/50; 0:800 ppm, 2/50; 0:2,400 ppm, 4/50). There were no increased neoplasm incidences at other sites in exposed males or at any site in exposed females.emales. Perinatal-only or combined perinatal and adult exposure to 5,5-diphenylhydantoin did not enhance the overall incidences of liver neoplasms in male or female rats. However, the finding of 5/49 hepatocellular adenomas in the 630:2,400 male rat group was consistent with the marginally elevated liver neoplasm rate observed in the 0:2,400 group. Decreased incidences of a number of different neoplasms in exposed groups were most likely related to the lower body weights. STUDIES IN B6C3F1 MICE: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 75 to 1,200 ppm 5,5-diphenylhydantoin in the diet. With the exception of one male, all mice exposed to 1,200 ppm died before the end of the study. No other chemical-related deaths occurred. All groups of mice except the 1,200 ppm groups gained weight over the 13-week period; however, an exposure related decrease in body weight gain was seen in males and females. Feed consumption by exposed and control groups was generally similar. Chemical related histomorphologic lesions were present in the liver of exposed mice, particularly 600 ppm males, and consisted of centrilobular hypertrophy of hepatocytes. Females appeared to be less sensitive than males to the effects of 5,5-diphenylhydantoin on growth and on histomorphologic liver lesions. Based on these results, 300 ppm (males) and 600 ppm (females) were selected as the highest exposure levels for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels for males and females ranged from 20 to 600 ppm 5,5-diphenylhydantoin in the diet. In general, reproductive performance and maternal care were poor in all groups, including the controls, thus restricting the sample size and sensitivity of this evaluation. There were no litters in the 600 ppm group, and maternal weight gain was depressed. There were no gross external malformations among pups surviving to term, and no gross or histopathologic lesions were observed in any mice exposed for 4 weeks following weaning. Based on these results, 210 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The F0:F1 exposure combinations selected for the 2-year study are listed in the following table (contained in full report - page 7). For mice evaluated at 9 months, males and females receiving the highest F0:F1 exposure levels had increased relative liver weights. In the 2-year study, the survival of exposed animals was similar to that of the controls; however, body weights were lower for exposed groups, and decreased body weights were most severe in adult females receiving 600 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. The incidences of hepatocellular neoplasms were increased in female mice receiving adult-only exposure (0:0 ppm, 5/48; 0:200 ppm, 14/49; 0:600 ppm, 30/50) or combined perinatal and adult exposure (210:200 ppm, 16/50; 210:600 ppm, 34/50). A marginally increased incidence of liver neoplasms (12/49) occurred in females in the perinatal-only (210:0) exposure group. There were no chemical-related increased incidences of liver neoplasms in males receiving adult-only or perinatal-only exposure. However, males receiving the high-exposure combined perinatal and adult exposure regimen (210:300 ppm) had an increased incidence of liver neoplasms (41/50) compared to the 0:0 (29/50), 0:300 (26/49), and 210:0 (33/50) groups. As a result, there was a significant enhancement (interaction) associated with combined perinatal and adult exposure. Such enhancement of neoplasia did not occur in female mice. Decreased incidences of malignant neoplasms in exposed groups were most likely related to the lower body weights. GENETIC TOXICOLOGY: In general, tests for genotoxic activity of 5,5-diphenylhydantoin were negative. All in vitro testing was performed in the presence and the absence of exogenous metabolic activation (S9). 5,5-Diphenylhydantoin did not induce mutations in Salmonella typhimurium, in L5178Y mouse Iymphoma cells, or in germ cells of male Drosophila melanogaster, nor did it induce chromosomal aberrations in cultured Chinese hamster ovary cells. A small but statistically significant increase was obtained in the cultured Chinese hamster ovary cell test for induction of sister chromatid exchanges in the presence of S9; without S9, no increase in sister chromatid exchanges was observed. In vivo, 5,5-diphenylhydantoin did not induce micronuclei polychromatic erythrocytes or chromosomal aberrations in bone marrow cells of male mice; equivocal results were obtained in an in vivo test for induction of sister chromatid exchanges in mouse bone marrow cells. CONCLUSIONS: Adult-Only Exposure: Under the conditions of these 2-year, adult-only, dietary exposure studies, there was equivocal evidence of carcinogenic activity of 5,5-diphenylhydantoin in male F344/N rats based on marginally increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in female F344/N rats given 240, 800, or 2,400 ppm. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in male B6C3F1 mice given 30,100, or 300 ppm. There was clear evidence of carcinogenic activity of 5,5-diphenylhydantoin in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Perinatal-Only Exposure: Perinatal exposure alone (through dietary administration of 210 ppm 5,5-diphenylhydantoin during the perinatal period) caused a marginal increase in the incidences of hepatocellular neoplasms in female B6C3F1 mice evaluated 2 years after cessation of exposure. In male and female F344/N rats, exposure to 630 ppm during the perinatal period did not influence the incidences of hepatocellular or other neoplasms. Similarly, exposure of male B6C3F1 mice to dietary levels of 210 ppm 5,5-diphenylhydantoin during the perinatal period did not affect neoplasm incidences. No teratologic effects were observed. Combined Perinatal and Adult Exposure: Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings of the increased incidences of hepatocellular neoplasms for adult-only exposures in male F344/N rats and female B6C3F1 mice, although combined exposure did not enhance these neoplastic effects. However, in male B6C3F1 mice, combined perinatal and adult exposure resulted in increased incidences of hepatocellular neoplasms (hepatocellular carcinomas and multiple adenomas) that were not seen when dietary exposure was limited to the adult exposure period only. Synonyms: Diphenylhydantoin; 5,5-diphenyl-2,4-imidazolidinedione Trade names: Difhydan; Dihycon; Di-Hydan; Di-Lan; Dilabid; Dilantin; Ekko; Hydantol; Lehydan; Zentropil

Journal Article↗