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Highest Dose Level (highest + dose_level)

Distribution by Scientific Domains

Medical Sciences	40%

Selected Abstracts

Epoxiconazole causes changes in testicular histology and sperm production in the Japanese quail (Coturnix coturnix japonica)

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2008
Konstanze Grote
Abstract The fungicide epoxiconazole (Epox), a triazole, belongs to the group of azole compounds that are extensively used as fungicides in various fruit crops. The frequent use of agricultural lands for wintering by migrating birds can be the source of their increased dietary intake of agricultural pesticides. We investigated whether exposure to Epox causes effects on avian fertility and reproduction, using the Japanese quail (Coturnix coturnix japonica) as a model species for the assessment of reproductive effects of pesticides in wild birds. Epox was administered to adult Japanese quail for three weeks at dietary levels of 10, 50, and 500 ppm, and possible effects on reproduction were investigated. Epox administration resulted in a significantly decreased number of spermatids in the 50- and 500-ppm dose groups. Histopathology showed a reduced number of testicular canaliculi with visible germ cells and a reduction in spermatid number. However, testis weight was not affected up to the highest dose level. No impact was observed on hormone levels, fertility, and reproductive outcome, as laying rate and percentage of fertile eggs were not altered. Likewise, treatment had no influence on the egg or chick parameters evaluated. A time- and dose-related transfer of Epox into the eggs was determined in all treatment groups. We conclude that dietary treatment of Japanese quail with 50 and 500 ppm of the triazole fungicide Epox resulted in a clear impact on the testis. The evaluation of the additional endpoints spermatid count and testicular histology have proven useful and are recommended for future studies on avian reproduction. [source]

Statistical issues on the determination of the no-observed-adverse-effect levels in toxicology

ENVIRONMETRICS, Issue 4 2001
Takashi Yanagawa
Abstract The determination of a safe exposure level for toxic agents, often defined as the highest dose level with no toxic effect and termed the no-observed-adverse-effect level (NOAEL) is reviewed. The conventional methods based on statistical tests are criticized, particularly when the sample size is small, and an alternative method, which is based on the Akaike information criterion (AIC), is discussed. The method is extended to the estimation of the NOAEL for continuous data. Computer programs for Windows 95/NT for determining the NOAEL by the AIC approach are developed and its application to practical data is illustrated with examples. Copyright © 2001 John Wiley & Sons, Ltd. [source]

Subchronic toxicity of chloral hydrate on rats: a drinking water study

JOURNAL OF APPLIED TOXICOLOGY, Issue 4 2002
R. Poon
Abstract The subchronic toxicity of chloral hydrate, a disinfection byproduct, was studied in rats following 13 weeks of drinking water exposure. Male (262 ± 10 g) and female (190 ± 8 g) Sprague-Dawley rats, ten animals per group, were administered chloral hydrate via drinking water at 0.2, 2, 20 and 200 ppm. Control animals received distilled water only. Gross and microscopic examinations, serum chemistry, hematology, biochemical analysis, neurogenic amine analysis and serum trichloroacetic acid (TCA) analysis were performed at the end of the treatment period. Bronchoalveolar fluids were collected at necropsy and urine specimens were collected at weeks 2, 6 and 12 for biochemical analysis. No treatment-related changes in food and water intakes or body weight gains were observed. There were no significant changes in the weights of major organs. Except for a mild degree of vacuolation within the myelin sheath of the optic nerves in the highest dose males, there were no notable histological changes in the tissues examined. Statistically significant treatment-related effects were biochemical in nature, with the most pronounced being increased liver catalase activity in male rats starting at 2 ppm. Liver aldehyde dehydrogenase (ALDH) was significantly depressed, whereas liver aniline hydroxylase activity was significantly elevated in both males and females receiving the highest dose. A dose-related increase in serum TCA was detected in both males and females starting at 2 ppm. An in vitro study of liver ALDH confirmed that chloral hydrate was a potent inhibitor, with an IC50 of 8 µM, whereas TCA was weakly inhibitory and trichloroethanol was without effect. Analysis of brain biogenic amines was conducted on a limited number (n = 5) of male rats in the control and high dose groups, and no significant treatment-related changes were detected. Taking into account the effect on the myelin sheath of male rats and the effects on liver ALDH and aniline hydroxylase of both males and females at the highest dose level, the no-observed-effect level (NOEL) was determined to be 20 ppm or 1.89 mg kg,1 day,1 in males and 2.53 mg kg,1 day,1 in females. This NOEL is ca. 1000-fold higher than the highest concentration of chloral hydrate reported in the municipal water supply. Copyright © 2002 Crown in the right of Canada. Published by John Wiley & Sons, Ltd. [source]

Pharmacokinetics and safety of oral almotriptan in healthy male volunteers

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2004
J. McEwen
Abstract Almotriptan (LAS 31416) is a new, oral, specific 5-hydroxytryptamine1B/1D receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5,200 mg. The elimination half-life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%,39%) during 12 h post-dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Radiation and breast carcinogenesis,

PEDIATRIC BLOOD & CANCER, Issue 5 2001
John D. Boice Jr.
Abstract With the possible exception of radiation-induced leukemia, more is known about radiation-induced breast cancer than any other malignancy [1, 2]. Fourteen cohort studies have provided quantitative information on the level of risk following a wide range of doses in different populations around the world. Comprehensive studies have been conducted in Canada, Germany, Japan, Sweden and other Nordic countries, the United Kingdom, and the USA (Table I). Key features are the linearity in the dose response (i.e., a straight line adequately fits the observed data), and the effect modification of age at exposure (i.e., risk is inversely related to exposure age and exposures past the menopausal ages appear to carry a very low risk); and the minimal effect of fractionating dose on subsequent risk [3]. A recent combined analysis of almost 78,000 women and 1,500 breast cancer cases from eight cohorts confirmed the downturn in risk at the highest dose levels (related in part to the killing of cells rather than transformation) and that fractionation of dose has little influence on risk, at least on an absolute scale [4]. It is not known whether persons predisposed to cancer are at enhanced risk of radiation-induced breast cancer from low-dose exposures, although this seems unlikely [5]. New data on the effects of high doses following childhood exposures will be forthcoming from long-term studies of the survivors of childhood cancer (6,8). Med. Pediatr. Oncol. 36:508,513, 2001. © 2001 Wiley-Liss, Inc. [source]