bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats
Authors: Ehrich Marion , Shell Linda , Rozum Michael , Jortner B. S.
Published: February 2008

Adult male Long Evans rats were given a single administration of 3 dosage levels of the organophosphorus compounds tri-ortho-tolyl phosphate (TOTP), diisopropyl fluorophosphate (DFP), phenyl saligenin phosphate (PSP), mipafox, malathion, and dichlorvos or the carbamate carbaryl. Acetylcholinesterase and neurotoxic esterase activities were inhibited in a dose-dependent manner, with the highest dosages of all of these compounds inhibiting activities of these enzymes in brain by at least 37% and 64%, respectively, at 4 and 48 hours after administration. Rats given the high doses of TOTP (1000 mg/kg), DFP (3 mg/kg), malathion (2000 mg/kg), and carbaryl (160 mg/kg) weighed significantly less than control rats 14 days after administration. A functional observational battery (FOB) was used to screen for neurotoxic effects 1, 2, and 3 weeks after exposure. All 7 test compounds were capable of causing changes in parameters indicative of behavioral and central nervous system excitability. In addition, dose-related alterations in response to approach were seen in rats given DFP, malathion, dichlorvos, and carbaryl. Mild to moderate myelinated fiber degeneration was seen in the rostral levels of the fasciculus gracilis in rats given TOTP, DFP, PSP and mipafox, but no significant neuropathologic lesions were noted in rats given dichlorvos, malathion, or carbaryl.
Total Quality Approach to Sponsor/Contract Laboratory Interface
Authors: Siconolfi Richard M. , Freeberg Fred E. , Varden Lee V.
Published: February 2008

Good laboratory practice standards (GLPs) were issued with the intended purpose of documenting the quality of laboratory research. These rules have improved laboratory operations and documentation. However, their approach emphasizes inspecting quality as a process rather than for preventing errors in the first place. Total Quality goes beyond GLPs and requires that systems be continually improved to build in quality. This latter approach builds toward elimination of rework that result when GLP inspections uncover unacceptable errors.
An Evaluation of the Reproductive and Developmental Effects of Tara Gum in Rats
Authors: Borzelleca Joseph F. , Egle John L.
Published: February 2008

In a multigeneration reproduction study, tara gum or α-cellulose was administered to male and female Charles River CD rats as a dietary admixture at levels of 5% (50,000 ppm) through 3 successive generations. All matings consisted of 10 males and 20 females per group. All litters were maintained until they were at least 21 days old (end of lactation). Fertility was generally high, and there were no consistent, statistically significant, compound-related adverse effects on any of the parameters evaluated. It is concluded that tara gum, fed at a dietary level of 5% for 3 successive generations, did not adversely affect reproductive performance. In a study designed to assess embryotoxicity and teratogenicity, tara gum was administered as a dietary admixture to mated female rats at levels of 12,500,25,000, and 50,000 ppm from days 6 to 16 postcoitum. No deaths occurred and no compound-related signs or symptoms were observed. Necropsy findings were negative. Examination of fetuses yielded no evidence of embryonic and/or teratogenic potential of tara gum.
Uterine Changes in Female Mice Following Lifetime Inhalation of Wholly Vaporized Unleaded Gasoline: A Possible Relationship to Observed Liver Tumors?
Authors: Macgregor Judith A. , Richter Ward R. , Magaw Renae I.
Published: February 2008

An increased incidence of primary hepatocellular tumors was reported in female B6C3F1 mice following lifetime exposure to high levels (2056 ppm) of wholly vaporized unleaded gasoline. This effect was not observed in male mice, nor in females exposed to either 67 or 292 ppm gasoline. No explanation for the sex and dose-specific effect was discussed in the initial report or has been subsequently published. At necropsy, a decreased incidence of enlarged/cystic uteri was also noted among high dose females; however, no correlating histopathologic changes were reported. Because the liver neoplastic response was limited to the females, and because spontaneous liver tumors are known to be influenced by the hormonal environment, we reexamined the uterine tissues microscopically. We observed a dramatic difference among treatment groups in the severity of cystic endometrial hyperplasia. The incidence of moderate cystic endometrial hyperplasia at the terminal sacrifice was 76% in the control animals whereas none of the animals at the highest exposure level had lesions that were graded moderate or severe. In addition, uterine atrophy was present in 35% of mice examined at the high exposure level and was absent in other groups. The changes noted are consistent with an altered hormonal influence on the uterus. The finding of a decrease in cystic endometrial hyperplasia and an increase in uterine atrophy in the same dose group in which liver tumors were found suggests that these effects may be interrelated.
Teratology Study of a Cross-Linked Polyacrylate Superabsorbent Polymer
Authors: McGrath James J. , Purkiss Laquetta , Christian Mildred , Proctor N. H. , McGrath W. R.
Published: February 2008

The developmental toxicity (embryo-fetal toxicity/teratogenicity) of FAVOR SAB-922 SK, cross-linked polyacrylate superabsorbent (PAS), administered as an inhaled dust in concentrations of 0.3, 1.0, and 10.0 mg/m3 for 6 h/day from day 6 through day 15 of gestation was investigated in time-mated Sprague-Dawley rats. On day 20 of presumed gestation, the rats were asphyxiated with carbon dioxide, necropsied, and examined for pregnancy. Gravid uteri were examined for the number and status of implants, early and late resorptions, live and dead fetuses, and the number of corpora lutea in each ovary. Fetuses were weighed, sexed, and examined for external, soft tissue, and skeletal alterations. There were 315, 297, 299, and 286 liveborn fetuses from 25, 25, 23, and 24 litters in the four respective groups. Fetal processing and evaluations were conducted in compliance with FDA “Good Laboratory Practice Regulations; Final Rule.” The results indicate that breathing PAS in concentrations as high as 10 mg/m3 did not cause statistically significant or biologically important differences in dam body weight, caesarean-sectioning or litter data or the incidences of gross external, soft tissue or skeletal alterations, as compared with the control group values. No alterations believed to be related to PAS occurred in the fetuses of dams exposed to PAS at incidences that exceeded the ranges reported historically. Based on these data, both the developmental and maternal no-observable-effect-levels (NOEL) were greater than the dosage inhaled by rats exposed to the 10 mg/m3 concentration of respirable particulate PAS.
Toxicology of Diethylene Glycol Butyl Ether 1. Exposure and Risk Assessment
Authors: Gingell R. , Krasavage W. J. , Wise R. C. , Knaak J. B. , Bus J. , Gibson W. B. , Stack C. R.
Published: February 2008

Diethylene glycol mono-n-butyl ether (DGBE) is a glycol ether solvent used in many consumer products including hard-surface cleaners and paints; its acetate ester (DGBA) is also used in paints. The highest consumer exposure to DGBE was estimated to be about 0.06 mg/kg/day from use in cleaners, and to DGBA was 0.19 mg/kg/day by inhalation from use in paints. DGBA was shown to be rapidly metabolized to DGBE, and its systemic toxicity was considered to be similar to DGBE. Prior toxicology studies and those required by a 1988 TSCA Final Test Rule, detailed in the following four papers, confirm that DGBE (and by implication DGBA): (1) can be absorbed dermally, (2) is not genotoxic in a battery of assays, (3) is not a systemic nor a reproductive toxicant by the dermal route in rats, and (4) is not neurotoxic by the dermal route in rats. There is an adequate margin of safety between the no observed adverse effect level in the animal studies and the estimated human exposure levels, confirming that there is no risk of systemic toxicity from the use of DGBE or DGBA in consumer products.
Toxicology of Diethylene Glycol Butyl Ether 2. Disposition Studies with 14C-Diethylene Glycol Butyl Ether and 14C-Diethylene Glycol Butyl Ether Acetate After Dermal Application to Rats
Authors: Boatman Rodney J. , Schum Daniel B. , Guest Derek , Stack Carol R.
Published: February 2008

Human dermal exposure to diethylene glycol butyl ether (DGBE) and its acetate derivative (DGBA) may occur through contact with a variety of commercial products. Absorption and elimination of dermally applied doses of 14C-DGBE and 14C-DGBA were determined in Sprague-Dawley rats. The materials were applied under occlusion for 24 hr at dose levels of 0.2 and 2.0 g/kg (undiluted) and as a 10% aqueous solution (0.2 g/kg DGBE). Preliminary washing efficiency studies with soap and water indicated that greater than 89% of each chemical could be removed from rat skin following 5-min exposures. Female rats excreted a larger proportion of the applied dose of DGBE than did male rats. Similar results were obtained with the low dose of DGBE applied neat or as a 10% aqueous solution, suggesting that the low dose represents a saturating dose. The total recovered 14C for all studies with 14C-DGBE ranged from 83% to 89%, with 14C-DGBA, from 80% to 88%. Urinary excretion accounted for the majority of recovered 14C in all studies. The acid, 2-(2-butoxyethoxy)acetate acid was the major urinary metabolite identified. The glucuronide of DGBE was present at levels of from 5.2 to 8.2% of the urinary 14C. The dermal absorption rates were estimated to be 1.58 (DGBA, male), 1.28 (DGBA, female), 0.73 (DGBE, male), and 1.46 (DGBE, female), expressed as mg/cm2/hr.
Toxicology of Diethylene Glycol Butyl Ether 3. Genotoxicity Evaluation in an In Vitro Gene Mutation Assay and an In Vivo Cytogenetic Test
Authors: Gollapudi B. Bhaskar , Linscombe V. A. , Mcclintock M. L. , Sinha A. K. , Stack C. R.
Published: February 2008

DGBE was evaluated in a forward gene mutation assay at the HGPRT locus of CHO cells in culture and in an in vivo mouse bone marrow micronucleus test for cytogenetic damage. DGBE did not elicit a positive response in the CHO/HGPRT assay when tested up to a maximum concentration of 5000 μg/ml with and without an external metabolic activation system (S-9). In the micronucleus test employing three post-treatment bone marrow sampling times (24, 48, and 72 hr), DGBE was ineffective in increasing the incidence of micronucleated polychromatic erythrocytes (MN-PCE) when tested in both sexes up to a maximum tolerated dose of 3300 mg/kg body weight. Thus, these data and those of others indicate a general lack of genotoxic potential for DGBE in short-term tests.
Toxicology of Diethylene Glycol Butyl Ether 4. Dermal Subchronic/Reproduction Study in Rats
Authors: Auletta Carol S. , Schroeder Raymond E. , Krasavage Walter J. , Stack Carol R.
Published: February 2008

The subchronic and reproductive toxicity of diethylene glycol butyl ether (DGBE) by the dermal route was evaluated in Sprague-Dawley rats using a novel combined protocol. DGBE was administered dermally at 10 or 30% v/v in aqueous solutions or undiluted (100%) for 13 weeks under occlusion, 6 hr/day, 5 days/week at a maximum attainable volume of 2 mL/kg. Satellite groups of male and female rats were treated with the top dose of DGBE for 13 weeks, mated, and the females were treated through day 20 of gestation and allowed to deliver and nurse their offspring through day 21 of lactation (weaning). DGBE produced dermal irritation, which was dependent on concentration in incidence, severity, and time of onset and was more severe in females than in males. No corresponding histopathology was evident. The only suggestion of a systemic effect was a slightly increased incidence of urinary occult blood at study termination in the females receiving the 30% or 100% DGBE dose. There was no evidence of histopathologic changes in the testes, and vaginal cytology indicated no adverse effect on estrous cycling. There were no effects on reproductive performance of the DGBE-treated males and females. Litters delivered by treated females contained the same number of live pups as control litters and the growth and survival of pups within the treated litters was comparable to control. No reproductive or systemic toxicity was observed at the highest dose tested—2 g/kg/day.
Toxicology of Diethylene Glycol Butyl Ether 5. Dermal Subchronic Neurotoxicity Study in Rats
Authors: Beyrouty P. , Broxup B. , Losos G. , Robinson K. , Maurissen J. P.J. , Gill M. W. , Stack C. R.
Published: February 2008

Groups of Sprague-Dawley rats were treated dermally with the vehicle, distilled water or with diethylene glycol butyl ether (DGBE) at 10 or 30% v/v aq. solutions or undiluted (0.2, 0.6, or 2.0 g/kg body weight) for 13 weeks under occlusion 6 hr/day, 5 days/week, at the maximum attainable volume of 2 mL/kg. Male and female rats were examined using a functional observational battery (FOB) prestudy, at 1, 6, and 24 hr after the initiation of the first exposure, and prior to treatment on days 7, 14, 35, 63, and 91. Motor activity was determined prestudy and on nontreated days 34, 62, and 90. At the completion of treatment, six control and top dose group animals were perfused for neuropathology. There was no mortality, and the body weights and food consumption were unaffected. Five females in the top dose group had scab formation at the treatment site during the study. There were no other treatment-related clinical findings. The FOB and motor activity tests revealed no findings indicative of a neurotoxic effect, and there were no gross or neuropathological changes that were attributed to treatment. No neurotoxicity or other systemic toxicity was seen at the highest dose tested—2 g/kg/day.
Subchronic Studies of Pyrilamine in Fischer 344 Rats
Authors: Greenman David L. , Morrissey Robert , Gaylor David W. , Allaben William T.
Published: February 2008

This study was designed to determine the subchronic effects of the antihistamine, pyrilamine maleate, and to establish dose levels for a 2-year chronic study. Six male and six female F344 rats received dietary pyrilamine concentrations of 0, 392, 783, 1563, 3122, or 6276 ppm (as the free base) for 14 days. Only weight gain suppression was noted, at 3122 and 6276 ppm, especially in males. When 12 male and 12 female F344 rats were fed pyrilamine for 90 days at 0, 750, 1500, 3000, 6000, or 12,000 ppm, weight gain was suppressed and organ/body weight ratios often were higher than in controls at 3000 ppm and above. Heart/brain and thymus/brain ratios were decreased at 3000 ppm and above in males and at 6000 or 12,000 ppm in females. All rats receiving 6000 or 12,000 ppm pyrilamine exhibited severe diffuse parenchymal cell cytomegaly in the parotid salivary glands with a dose-related decrease in severity and prevalence at lower concentrations. Hepatocellular vacuolization, present only in males, increased in severity with dose, starting at 750 ppm. The severity of liver fatty metamorphosis increased with dose at the three low doses but was less apparent and/or disappeared at 6000 and 12,000 ppm. It was concluded that 3000 ppm pyrilamine would not be life threatening to F344 rats in a chronic study.
A Reexamination of Liver Tumors in Mice Exposed to Wholly Vaporized Unleaded Gasoline
Authors: Magaw Renae I. , Richter Ward R. , Macgregor Judith A.
Published: February 2008

A single lifetime inhalation study of the effects of wholly vaporized unleaded gasoline has been conducted in the mouse. An elevation of hepatocellular tumors was reported only in females and only at the high treatment level (2056 ppm). Several reports of this study have appeared previously in the scientific literature, including a comprehensive summary published in this journal. Different incidence rates were reported for mouse liver tumors in these publications without explanations of how they were calculated of why they differed. To clarify the data, we recently examined the final report of the gasoline study, the individual animal data, and slides prepared from liver tissue collected during the study. The previously reported incidence rates did not take into consideration all animals at risk for tumor development or all animals with hepatocellular tumors. Revised incidence rates are presented for hepatocellular tumors in all mice on study. These rates are approximately 20–25% lower than previously reported.
A Reproductive and Developmental Toxicity Study in CD Rats of LY275585, [Lys(B28),Pro(B29)]-Human Insulin
Authors: Buelke-Sam J. , Byrd R. A. , Hoyt J. A. , Zimmermann J. L.
Published: February 2008

LY275585, [Lys(B28),Pro(B29)]-human insulin, was administered daily by subcutaneous injection at doses of 0, 1, 5, or 20 U/kg. Male rats were treated with LY275585 beginning 2 weeks prior to cohabitation and throughout the mating period. Females assigned to the teratology component of the study were treated for 2 weeks prior to cohabitation with the males and through gestation day (GD) 19. These dams were killed on GD 20 and uterine and fetal examinations were performed. Female rats assigned to the delivery component were treated for 2 weeks prior to cohabitation through postpartum day (PD) 20. Dams were allowed to deliver and maintain their progeny through a 21-day lactation period. After weaning, 1 pup/sex/litter was assigned to the F1 generation, and these animals received no treatment. Survival, growth, behavior, and reproductive performance were evaluated, and reproductive organs were collected for histological evaluation. Treatment of F0 male and female rats with LY275585 resulted in isolated incidences of severe hypoglycemia at 5 and 20 U/kg/day and some modest changes in food consumption and body weight measures at all treatment levels. These changes were anticipated and attributed to the pharmacology of this compound. Mating and fertility of the F0 animals were unaffected by treatment. While slight decreases in fetal body weights and increased fetal runts/litter were observed in the 20-U/kg/day group, PD 1 progeny weights were not affected in the delivery component, and there was no indication of teratogenicity in this study. There were no remarkable treatment-related effects on offspring growth patterns, survival, or reproductive performance, but the F1 animals from the 20-U/kg/day treatment-derived group were more reactive than controls in the startle habituation test. Thus, F0 parental toxicity, related to the hypoglycemic action of LY275585, was found at all doses. A dose of 5 U/kg/day was considered a no-adverse-effect level for developmental toxicity. There were no remarkable effects of LY275585 treatment on F0 or F1 generation reproductive performance at 20 U/kg/day, the highest dose tested in this study.
Evaluation of the Toxicological Risk Associated with the Use of Polyacrylamides in the Recovery of Nutrients from Food Processing Waste (I)
Authors: Schechter LeeAnn , Bernard Bruce K. , Barvenik Frank W. , McNally John G. , Friedman Marvin , Essenfeld Amy , Deskin Randy
Published: February 2008

Trivalent metal ions such as iron and aluminum are currently employed to flocculate liquid-borne solids from food-processing waste streams. These captured nutrient-rich waste solids are disposed of mainly through land applications (e.g., subsoil injection) because of the potential toxicity associated with the metal salts. Low-toxicity, water-soluble polyacrylamide polymers are currently approved for and employed as flocculants in potable water applications. The use of these polymers in food-processing waste streams could enable the captured solids to be recycled as components of animal feed, thus decreasing the burden on landfills and making good use of the proteinaceous matrix. However, polyacrylamides contain very low concentrations of acryl-amide monomer, which is highly toxic and can cause neurotoxicity, cytogenic lesions, and an increase in tumor rates in experimental animals. With use of two industrial food processing wastes, experiments were conducted to determine how acrylamide monomer would partition during a solids/liquid separation and subsequent rendering. Based on the analytical data, 96% of the acrylamide monomer was measured in the water portion after separation. Because of background interferences, acrylamide could not be directly measured in the solids portion. With use of these results and worst-case calculations, <2 ppb of acrylamide could be present in animal feed, thereby making the associated risk de minimis.
Toxicity Studies of Partially Hydrolyzed Guar Gum
Authors: Takahashi Hidehisa , Yang Sung Ik , Fujiki Masaru , Kim Mujo , Yamamoto Takehiko , Greenberg Norman A.
Published: February 2008

The toxicity of partially hydrolyzed guar gum (PHGG, average molecular weight 20,000) was evaluated in a 28-day, repeated oral dosing study (gavage) in rats at doses of 0, 500, and 2,500 mg/kg/day and in Salmonella typhimurium, with and without metabolic activation. PHGG did not elicit any signs of toxicity at the doses tested. PHGG was not mutagenic.
Styrene Impairs Serial Spatial Reversal Learning in Rats
Authors: Bushnell Philip J.
Published: February 2008

To evaluate the effects of styrene exposure on learning, adult male Long-Evans rats learned repeated reversals of a spatial discrimination task. Styrene monomer (50% vol/vol in corn oil) was administered by gavage to groups of eight rats at 500 mg/kg/day, 5 days/week, for 8 weeks in Experiments (Exps) I and II (total dose = 20.0 g/kg) or for 1,3,5, or 8 weeks in Exp III (total dose = 2.5, 7.5, 12.5, or 20.0 g/kg). Control rats received corn oil vehicle for 8 weeks. Reversal training began 8 (Exp I), 10 (Exp II), or 32 (Exp III) weeks after termination of dosing. In Exp I, an instrumental (IN) schedule was used, under which rats received food after each presentation of a “positive” response lever (S+ ) only if they had made at least one response during that presentation of S+. In Exps II and III, an automaintenance (AU) schedule was used, under which rats received food after every presentation of S+, regardless of responding. In all experiments, a second manipulandum (S°) was presented randomly in time with respect to S + and food delivery. A discrimination ratio (DR) was calculated as the proportion of total responses on S+ in each block of 10 trials. A reversal involved switching the reward values of S+ and S°. Serial reversal learning was quantified in terms of trials to criterion. Reversal learning improved similarly in control and treated rats trained under the IN schedule, whereas treated rats trained under the AU schedule failed to improve as much as controls. Reversal learning of some styrene-treated AU rats in Exp III continued to be impaired for > 1 year after treatment. Increased responding on S° featured prominently in the behavioral effect of styrene. An IN schedule requiring suppression of S° responses for food in Exp III revealed a clear deficit in rats exposed to styrene. Not all treated rats were affected by styrene; nevertheless, changes in the affected individuals were as large as those previously observed after trimethyltin-induced lesions of the CNS. The incidence of impairment was not related to the total dose of styrene given, suggesting the action of other, undetermined factors affecting individual sensitivity to styrene.
Use of In Vitro Techniques in Toxicology: When, Why, How?
Authors: Williams Patricia D.
Published: February 2008

In vitro techniques represent tools that the toxicologist can utilize at various stages of drug development to design and select compounds to perform specialized evaluations and to address preclinical or clinical issues that may arise. The use of in vitro technologies contributes to the scientific quality and economy of the safety assessment process as well as to the toxicologists' commitment to the four Rs of reduction, refinement, replacement, and responsibility. In vitro testing programs are facilitated by applying techniques established in other disciplines via trained personnel organized in specific experimental or investigative units. Fulfillment of scientific criteria of predictability, identity, compensatory factors, and mechanisms of injury will determine to what extent in vitro methods are incorporated into the safety assessment process. Key to the contribution of in vitro techniques to toxicology, now and in the future, is a vision and commitment to scientific excellence in the safety assessment process. This commitment requires the continual influx of state-of-the-art technology (both in vitro and in vivo), and active communication among the industrial, regulatory, and academic communities. The commitment to scientific excellence in toxicology will ensure the evolution of more relevant and efficient models of safety assessment. In vitro technologies have the potential to play an increasingly important role in this evolutionary process.
Institutional Policies and Educational Programs: Animals in Research
Authors: Thomas J. A. , Greene M. E.
Published: February 2008

Biomedical research facilities, including academic and industrial settings, need to have established internal and external policies regarding the humane care and use of animals in pharmacologic and toxicologic experimental protocols. Compliance with regulatory and accrediting agencies (e.g., Public Health Service, U.S. Department of Agriculture, American Association for the Accreditation of Laboratory Animal Care) requires institutional support and necessitates recruiting and retaining a quality veterinarian staff. Resources must be available to maintain vivarium physical facilities, including experimental surgery suites, and to provide an acceptable program in occupational health to protect against zoonotic diseases. Through the Institutional Animal Care and Use Committee (IACUC), educational programs, compliance issues, and institutional security measures can be effectively implemented. A close communication liaison must be established between the IACUC, the veterinary staff, institutional public relations, security and the individual investigator. A coordinated policy with both internal and external components is necessary in order to satisfactorily manage the use of animals in toxicologic research.
Acute Toxicity Studies of Xerox Reprographic Toners
Authors: Lin George H. Y. , Mermelstein Robert
Published: February 2008

Typical reprographic toners consist of a thermoplastic polymer or polymers as the major component, a colorant or colorants (carbon black or color pigments), and small quantities of additives such as charge control and/or lubricating/release agents. Another type of toner contains iron oxides and polymers) as the major components. As a complement to the recently published Xerox chronic inhalation studies of toners, we are reporting the acute toxicity studies of some typical Xerox toners. The studies include acute oral toxicity in rats, acute dermal toxicity in rabbits, acute inhalation toxicity in rats, eye irritation in rabbits, skin irritation in rabbits, skin sensitization in guinea pigs, and the repeated-insult patch test in humans. These studies represent our acute toxicity testing using different protocols with various toners carried out during the period 1969–1984. In addition, we recently carried out acute dermal toxicity testing at 5 g/kg with two representative toners, for the purpose of classification of waste toners in the State of California. The test results consistently indicate that all toners were practically nontoxic: oral LD50 from <5 to <35 g/kg; dermal LD50 from <2 to <5 g/kg; and inhalation LC50 (4 h) from <0.17 to <10.2 g/m3. They were nonirritating to the eye and nonirritating/ nonsensitizing to the skin.
Comparison of Oral and Inhalation Exposures to Toluene
Authors: Gospe Sidney M. , Al-Bayati Mohammed A. S.
Published: February 2008

Male Fisher-344 rats were exposed to [14C]toluene by either liquid gavage or vapor inhalation and blood toluene levels were measured by radiospectroscopy. Oral doses of 110, 336, 741, and 911 mg toluene/kg body weight were administered to 82 rats by gavage and blood toluene levels were followed for 6 h. For the inhalation group (120 rats), 3-h exposures to 99, 549, and 1,145 ppm were given and blood toluene levels were measured during this 3-h uptake phase and during a 4-h elimination period. The data for these two exposure methods were fitted to parametric kinetic models, and the resulting curves were then integrated. The blood toluene versus time profiles for oral and inhalation exposures were then compared and the equation: In(oral dosage, mg/kg) = -1.44 + 0.95 In(3-h inhalation exposure concentration, ppm) was derived (where In represents the natural logarithm). This equation describes the relation between toluene inhalation and oral exposure methods used in this study. This investigation demonstrates that oral toluene administration produces high blood toluene concentrations that can simulate the blood levels achieved after inhalation exposure to this solvent.
Routes in Toxicology: An Overview
Authors: Gad Shayne C.
Published: February 2008

How a route of administration is selected, and what concerns govern the development and execution of techniques for administration of various materials by different routes is an essential component of knowledge for the working toxicologist. More than 26 routes see at least some use in toxicology, each with its own specific concerns, advantages, and disadvantages. Most are infrequently used and poorly understood. The purpose of this communication is to summarize these potential routes and to present an overview of some of the factors that may influence results achieved by the use of different routes of administration.
Intravenous Infusion in Dogs and Primates
Authors: Perkin C.J. , Stejskal R.
Published: February 2008

Continuous intravenous infusion allows the intended clinical dosing regime to be better evaluated during preclinical studies. Depending on the test material and vehicle, infusion for up to 6 months in primates and 12 months in beagle dogs is possible, but 28 days is the most frequent duration. Under general anesthesia, medical grade catheters are placed in the vena cava via the femoral vein, passed subcutaneously, and exteriorized between the scapulae. A jacket and tether system are used to connect the catheter to an external pump for dosing and the animals are allowed to move freely within the cages. Dosing usually commences after a 1-week recovery period. Body weight gain, food intake, and general observations indicate that the procedure does not adversely affect the normal laboratory behavior of the animals. Test article infusion periods from a few minutes up to 24 h a day, 7 days a week are used; a low infusion rate ofsaline is used for the balance of the 24-h period. Dosage volumes up to 120 ml/kg/day can be infused for 28 days and larger volumes for shorter periods. Up to three separate catheters can be inserted to allow coadministration of compounds for assessment of potential interactions. Body weight, ophthalmoscopy, blood sampling, electrocardiography, and indirect blood pressure measurement can be performed during infusion. Histopathologic common changes in all species include thrombosis, proliferation of vascular intima, and various local inflammatory changes at the infusion site in the vicinity of the catheter tip. These generally are considered to be due to physical irritation by the catheter. Secondary changes include pulmonary microemboli or thrombosis and histiocytosis in hepatic sinusoids often with erythrophago-cytosis. The main findings associated with infusion of very large volumes are reticulocytosis and increased hematopoiesis. These spontaneous findings must be distinguished from those possibly related to administration of the test material and/or vehicle.
Intranasal Administration
Authors: Gad Shayne C.
Published: February 2008

The intranasal route has gained increased popularity in the pharmaceutical industry in recent years, particularly because of the number of new peptide therapeutic agents. This has led to a corresponding increase in both interest in and performance of toxicity (or as they are called in the pharmaceutical industry, safety assessment) studies by this route. This report reviews the considerations specific to the intranasal route: formulations, devices for administration, special safety concerns, and animal models employed.
The Pacific Rim Good Laboratory Practice Initiatives
Authors: Snyder Frederick
Published: February 2008

The U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) Regulations have been in effect since December 22, 1978, and subsequently have become a way of life for all who need to conduct preclinical safety and health effects studies for regulatory submission. The Organization of Economic Co-operation and Development (OECD) with its world-wide membership of 26 (including Japan), and the European Community (EC) with its 12 members, utilized the GLPs to finalize their own standards. Japan, with its six GLP standards for assessing data integrity and quality, became an integral force in the Pacific Rim and a dominant figure in promulgating OECD GLP standards and directives. Third world countries are identifying with Japanese principles and administrative applications of these standards. This presentation focuses on an overview of Japan's GLP standards.
Counteraction of the Embryolethal Effects, But Not the Maternal Toxicity, of Bropirimine and Tilorone by Coadministration of Indomethacin
Authors: Marks Thomas A. , Black Daniel L. , Terry Roger D.
Published: February 2008

Bropirimine and tilorone are immunomodulators with experimental antiviral and antitumor activities. In earlier studies, treatment with bropirimine resulted in either death of the entire litter, if given once on specific days during or prior to the period of organogenesis, or litter survival comparable with that of controls. For example, bropirimine and tilorone were both found to be embryolethal when administered orally at 400 mg/kg to Upj:TUC(SD)spf rats on day 10 of gestation. Previous studies also have shown that coadministration of progesterone with either of these immunomodulators could prevent the embryolethality but not the pronounced maternal toxicity seen concurrently. Thus, bropirimine and tilorone appear to affect maternal support of the pregnancy rather than having a direct effect on the embryos. Since administration of bropirimine or tilorone appears to mimic the luteolytic effects of prostaglandin F2a, it was hypothesized that coadministration of the prostaglandin synthesis inhibitor indomethacin might prevent such embryolethality. Thus, indomethacin was administered s.c. in combination with bropirimine or tilorone (400 mg/kg orally on day 10 of gestation), at 0.4 or 0.8 mg/rat on days 9-11 (bropirimine experiment) or days 9-12 of gestation; the dams were killed on day 13, at which time the status of each conceptus was ascertained. Although unable to prevent maternal toxicity, which was found 24 h after administration of either immunomodulator, coadministration of indomethacin resulted in a decrease in the embryolethality associated with administration of either immunomodulator on day 10 of gestation. No live embryos were found on day 13 of gestation in five of six pregnant dams given bropirimine only, whereas in the drug-combination groups six of seven (indomethacin at 0.4 mg/day) and six of eight (indomethacin at 0.8 mg/day) pregnant dams had litters containing live embryos. In the tilorone experiment, six of eight litters were completely lost in utero in the group receiving the immunomodulator only. However, only one of four surviving dams had no live embryos in the drug-combination group that received indomethacin at 0.4 mg/day, with all eight surviving dams having live embryos in the group that received 0.8 mg/day of this drug. The results of this study and of earlier combination experiments with progesterone support the following hypothesis: bropirimine or tilorone administration to Upj:TUC-(SD)spf rats on day 10 of gestation inhibits progesterone production by the corpora lutea by a mechanism involving prostaglandin synthesis, resulting in a disruption in maternal support to the pregnant uterus and subsequent embryolethality.
Toxicity of Crataegus (Hawthorn) Extract (WS 1442)
Authors: Schlegelmilch Ronald , Heywood Ralph
Published: February 2008

An extract of Crataegus-WS 1442-standardized by a special process of production and adjusted to 18.75% oligomeric procyanidines, was investigated in single and repeat-dose toxicity studies. No target organ toxicity was defined at high multiples of the human dose (100 times) and the battery of standard mutagenic and clastogenic tests were negative. The results presented are for Crataegus extract WS 1442 only; other preparations of Crataegus have to be investigated case by case.
The Effects of Cadmium and Iron on Catalase Activities in Tubifex
Authors: Chen Tao , Furst Arthur , Chien Paul K.
Published: February 2008

The effects of 1 μ/M Cd(II), alone and in combination with several concentrations of Fe(II), were investigated in Tubifex tubifex (a fresh water worm) by the determination of catalase activities in vivo at 6, 12, 24, and 48 h. At 6 h postexposure the catalase activities in all cadmium-exposed groups dropped below control values. At 12 and 24 h the values rose; at 48 h the catalase activities exceeded control values. The combination of 1 μM Cd(II) plus 100 μM Fe(II) exhibited the least inhibition of catalase activity at 6 h and the most increased activity at 48 h. By comparison, the in vitro results of incubating bovine liver catalase for 6 h with different concentrations of Cd(II) and Fe(II) showed that Cd alone at 10 μLM had no inhibitory effect on catalase activity and that 100 μM Fe(II) decreased the catalase activity to 40% of the control. The effects of Fe(II) on Cd(II) LC50 values were also studied. Adding 100 μM Fe(II) or pretreating for 48 h with a mixture of 1 μM Cd(II) and 100 μM Fe(II) decreased the toxicity of Cd(II) by almost 70%. These studies indicate (a) that a mixture of Cd(II) and Fe(II) will increase catalase activities in vivo after a 2-day exposure and (b) that certain concentrations of Fe(II) can protect the worm against Cd(II) toxicity. One suggested mechanism is that Fe(II) can inhibit Cd uptake and transfer. An enhanced catalase activity appears to protect the worms against the toxic effects of Cd(II).
An Examination of the Drug Review Process Within the United States
Authors: Johns Phillip A.
Published: February 2008

A general overview of the drug review process is presented with emphasis on non-clinical approaches for gaining acceptable exemptions for investigational use of new drugs. Selected non-clinical requirements for approval of marketing or the new drug application are also discussed. Particular attention is given to the trend towards a more rational, scientific approach to the design of studies that are intended to elucidate issues of safety and efficacy. The fundamental purpose of these new approaches is to reduce drug development time and expense and bring newer and better drug therapies to patients. Newer requirements for the conduct and use of kinetics earlier in development are emphasized. The relevance of meetings with the Food and Drug Administration and the effects that meetings are reported to have had on total drug development time are also discussed.
Risk of intraoperative ischemia due to temporary vessel occlusion during standard extracranial–intracranial arterial bypass surgery
Authors: Horn Peter , Scharf Johann , Peña-Tapia Pablo , Vajkoczy Peter
Published: February 2008

Object

Standard extracranial–intracranial (EC–IC) arterial bypass surgery represents a well-recognized procedure in which the aim is to augment distal cerebral circulation. The creation of the bypass requires temporary occlusion of the recipient vessel. Thus, there exists controversy about the risk of standard EC–IC arterial bypass surgery causing ischemic complications due to temporary vessel occlusion. In this prospective study, the incidence of intraoperative ischemia was investigated in symptomatic patients with steno-occlusive cerebrovascular disease and existing hemodynamic insufficiency.

Methods

Twenty consecutive patients (14 women and 6 men; mean age 46 ± 11 years) suffering from recurrent transient ischemic attacks due to occlusive cerebrovascular disease and proven hemodynamic compromise in functional blood flow studies were enrolled in this study. The underlying pathological condition was internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion in 6 cases and ICA or MCA stenosis in 3 cases, whereas 11 patients presented with moyamoya syndrome or moyamoya disease. The surgical procedure consisted of the establishment of a standard superficial temporal artery (STA)–MCA bypass, and was performed while a strict intraoperative management protocol was applied. Patients underwent clinical examination and magnetic resonance (MR) imaging within 48 hours before and after surgery.

Results

The incidence of reversible clinical signs of ischemia was 2 (10%) of 20 patients. Postoperative MR imaging revealed signs of diffusion disturbances in 2 (10%) of 20 cases. The observed diffusion-weighted imaging changes, however, were situated within the dependent vascular territory at risk for ischemia in 1 patient only. No permanent neurological deficit occurred. The temporary vessel occlusion time ranged between 25 and 42 minutes (mean 33 ± 7 minutes). All means are expressed ± the standard deviation.

Conclusions

Temporary vessel occlusion during standard STA–MCA arterial bypass surgery carries a low risk of intraoperative ischemia when a strict perioperative management protocol is applied.
Prolonged recovery of memory functioning after mild traumatic brain injury in adolescent athletes
Authors: Sim Anita , Terryberry-Spohr Lori , Wilson Kathryn R.
Published: February 2008

Object

The current body of sports-related concussion literature is hampered by a lack of research conducted in high school athletes. Accordingly, the authors sought to examine the neuropsychological deficits and recovery patterns after concussive injuries in this population.

Methods

Participants included 419 male and female athletes with a mean age of 15.69 years who underwent baseline testing of their neuropsychological functioning prior to their sports season. Fourteen participants sustained an in-season concussion and were serially reassessed at ~ 2.5, 6, and 10 days postinjury. Fourteen uninjured matched control participants were also reassessed at the end of the school year.

Results

Individuals who sustained in-season concussions demonstrated impairments in reaction time, processing speed, and had delayed memory functioning. Although reaction time and processing speed deficits returned to baseline levels by ~ 6 days postinjury, participants continued to show memory impairments up to 7 days postinjury. Memory impairments were found to resolve by Day 10, however.

Conclusions

The results of the present study suggest that high school athletes demonstrate prolonged memory dysfunction compared with college athletes, and should therefore be treated more conservatively.
Long-term seizure outcome after mesial temporal lobe epilepsy surgery: corticalamygdalohippocampectomy versus selective amygdalohippocampectomy
Authors: Tanriverdi Taner , Olivier Andre , Poulin Nicole , Andermann Frederick , Dubeau François
Published: February 2008

Object

Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion, and little information is available. The aim of this study was to compare seizure outcomes at the 5-year follow-up in patients with medically refractory unilateral mesial TLE (MTLE) due to hippocampal sclerosis (HS) who were treated using a cortical amygdalohippocampectomy (CorAH) or a selective AH (SelAH).

Methods

The authors obtained data from 100 adult patients who underwent surgery for MTLE. Fifty patients underwent a CorAH and 50 underwent an SelAH. Seizure control achieved with each technique was compared using the Engel classification scheme.

Results

Overall, at the 5-year follow-up, favorable (Engel Classes I and II) seizure outcomes were noted in 82 and 90% of patients who had undergone CorAH and SelAH, respectively. Furthermore, 40% of the patients who had undergone a CorAH and 58% of those who had undergone an SelAH were seizure free (Engel Class Ia). There was no statistically significant difference between the 2 surgical approaches in terms of seizure outcome at the 5-year follow-up (p = 0.38).

Conclusions

Both CorAH and SelAH can lead to similar favorable seizure control in patients with MTLE/HS. However, the authors suggest that the transcortical selective approach has the great advantage of minimizing or completely abolishing the impact of dividing several venous and arterial adhesions which are tedious, time consuming, and, at times, associated with some degree of cerebral swelling.
Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence
Authors: Losa Marco , Mortini Pietro , Barzaghi Raffaella , Ribotto Paolo , Terreni Maria Rosa , Marzoli Stefania Bianchi , Pieralli Sandra , Giovanelli Massimo
Published: February 2008

Object

Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that typically cause visual and/or hormonal dysfunction. Surgery is the treatment of choice, but patients remain at risk for tumor recurrence for several years afterwards. The authors evaluate the early results of surgery and the long-term risk of tumor recurrence in patients with NFPAs.

Methods

Between 1990 and 2005, 491 previously untreated patients with NFPA underwent surgery at the Università Vita-Salute. Determinations of recurrence or growth of the residual tumor tissue during the follow-up period were based on neuroradiological criteria.

Results

Residual tumor after surgery was detected in 173 patients (36.4%). Multivariate analysis showed that invasion of the cavernous sinus, maximum tumor diameter, and absence of tumor apoplexy were associated with an unfavorable surgical outcome. At least 2 sets of follow-up neuroimaging studies were obtained in 436 patients (median follow-up 53 months). Tumors recurred in 83 patients (19.0%). When tumor removal appeared complete, younger age at surgery was associated with a risk of tumor recurrence. In patients with incomplete tumor removal, adjunctive postoperative radiotherapy had a marked protective effect against growth of residual tumor.

Conclusions

Complete surgical removal of NFPAs can be safely achieved in > 50% of cases. Visual symptoms and, less frequently, pituitary function may improve after surgery. However, tumor can recur in patients after apparently complete surgical removal. In patients with incomplete tumor removal, radiation therapy is the most effective adjuvant therapy for preventing residual tumor growth.