bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of daily interrupted nursing on body weight and survival of fischer 344 rat pups
Authors: Zelenak Janice P. , Snellings William M.
Published: October 2006

The effects on Fischer 344 rat pup body weight and survival were investigated when the dam was separated from her litter and deprived of food and water, approximately 7 h per day, from day 5 to day 21 of the postnatal period. This separation procedure simulates an inhalation reproduction study in whch only the dams are exposed to the test material during lactation. The dams and pups were observed daily for clinical signs, and the number of pups in each litter and their body weights were determined on days 4, 9, 14 and 21 after parturition. When pups and dams were so separated, there was no effect on pup survival, but the pup body weights were moderately lower for this group by the end of the postnatal observation period.
Carbon disulphide intrauterine sensitization
Authors: Tabacova Sonia , Nikiforov Bojidar , Balabaeva Liudmila
Published: October 2006

This study was designed to evaluate the effect of carbon disulphide (CS2) exposure during pregnancy in two subsequent generations. Albino rats (F1), which had been prenatally exposed by maternal inhalation to teratogenic (200 and 100 mgm−3) and subteratogenic (10 and 0.03 mg m−3) concentrations of CS2, were reared until maturity and mated to produce an F2 generation. During pregnancy the F1 females were again subjected to CS2 exposure at the same concentrations as the F0 females throughout gestation. Pre‐and postnatal development of F1 and F2 generations, as well as the corresponding maternal effects, were studied. Embryonic lethality, weight, congenital malformations, indices of lipid and energy metabolism, DNA and some liver drug metabolizing enzymes in maternal and fetal tissues were studied at term. Postnatal viability, physical and behavioral development, and hexobarbital sleeping time of the progeny were evaluated. Comparisons of CS2 effect on F1 and F2 generations were performed. A marked increase in CS2‐induced teratogenicity was found in the F2 generation, together with retarded development of MFO system and increased postnatal behavioral effects. The results point to intrauterine sensitization of progeny to CS2‐This effect is discussed in the light of possible interference of the agent with the hormonal programming of intrauterine development.
Effect of vehicle on the pharmacokinetics and uptake of four halogenated hydrocarbons from the gastrointestinal tract of the rat
Authors: Withey Jim R. , Collins Brian T. , Collins Peter G.
Published: October 2006

A variety of low molecular weight aliphatic chlorinated hydrocarbons have a history of use in the processing of foods, and their presence in potable water supplies has also been demonstrated. In this study, the relative uptake of four different aliphatic chlorinated hydrocarbons (methylene chloride, dichloroethane, chloroform and trichloroethylene) was studied after administration, by intragastric intubation, at the same dose level as corn‐oil or aqueous solutions. Serial blood samples were collected over a 5‐h period and uptake was assessed as the calculated area under blood concentration‐time curves. A significant decrease in the rate and extent of uptake was observed for the compounds when administered as an oil solution as compared with an aqueous solution. Lower peak concentrations and an increase in the time taken to reach peak concentration, after dosing with corn oil solutons, was also observed.
Odor as an ald to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution
Authors: Amoore John E. , Hautala Earl
Published: October 2006

The body of information in this paper is directed to specialists in industrial health and safety, and air and water pollution, who need quantitative data on the odor thresholds of potentially hazardous chemical vapors and gases. The literature, largely unorganized, has been reviewed for 214 compounds and condensed into tables based on consistent units. Data on the volatility, solubility, ionization and water‐air distribution ratio at 25°C are included. From the currently recommended threshold limit value (TLV), a safe dilution factor and an odor safety factor are calculated for each compound. The equivalent data are presented for both air and water dilutions of the chemicals. Available data are summarized on the variability of odor sensitivities in the population, and the increased odor concentrations that are required to elicit responses from persons whose attention is distracted, or who are sleeping. This information is reduced to calibration charts that may be used to estimate the relative detectability, warning potential and rousing capacity of the odorous vapors. Each compound has been assigned a letter classification, from A to E, to indicate the margin of safety, if any, that may be afforded by the odor of the compound as a warning that its threshold limit value is being exceeded.
Blood‐flow distribution in the mouse
Authors: Stott William T. , Dryzga Mark D. , Ramsey John C.
Published: October 2006

Blood‐flow distribution was determined in pentobarbital‐anesthetized male B6C3F1 mice, using intracardially administered 141Ce‐radiolabelled microspheres (10μm). The proportion of cardiac output and blood flow per g tissue was determined in 18 organs and tissues, including the nasal cavity, lobes of the liver, individual kidneys and sections of the intestinal tract. To provide comparative data, blood‐flow distribution was also determined in pentobarbital‐anaesthetized male Fischer 344 rats. In general, there was close agreement between the distribution of blood flow between these two rodent species. The bladder and large intestine of mice appear to receive more, while the testes receive less, of the cardiac output than in rats. Rat liver and kidney, however, appear to receive approximately twice the amount of blood on a weight basis as in the mouse.
The neurotoxicity of trimethyltin chloride in hamsters, gerbils and marmosets
Authors: Brown A. W. , Verschoyle R. D. , Street B. W. , Aidridge W. N. , Grindley H.
Published: October 2006

Trimethyltin chloride (TMT) was given to Syrian hamsters, gerbils and marmosets, and the changes in the brain were studied 1 day to 7 weeks later by light and electron microscopy. Within the marmoset brain, TMT was found to be uniformly distributed, similar to that in the rat. In all three species, signs of poisoning included whole‐body tremors and prostration, while death might occur in 3–4 days; in marmosets ataxia, agitation, aggression and occasional fits were also observed. Bilateral symmetrical neuronal necrosis and chromatolysis were seen in the majority, which involved the hippocampus, pyriform cortex, amygdaloid nucleus, neocortex, various brain stem nuclei and in marmosets the retina. The probably lethal dose of TMT in all three species is approximately 3 mg kg−1, while the LD50 for the rat is 12.6 mg kg−1. The lower figure is probably related to lack of binding to haemoglobin in contrast to the binding in the rat. TMT does not bind to human haemoglobin and thus the predicted lethal dose for humans may be about 3 mg kg−1 (15.1 μmolkg−1), while the dose required to produce neuronal damage could well be less.
Correction factors for determining body exposure from forearm percutaneous absorption data
Authors: Guy Richard H. , Maibach Howard I.
Published: October 2006

Evaluation of toxic exposure via the skin is invariably based upon forearm percutaneous absorption data and an appropriate area multiplication factor. Published experimental data clearly show, however, substantial site variation in skin penetration such that the use of forearm data may produce an inaccurate prediction of total body exposure. Using literature results for cutaneous absorption as a function of anatomic position and accepted estimations of human body surface areas, correction factors for use with forearm penetration data have been evaluated. Calculations have been performed for an adult, a small child and a neonate. Examples of limited exposure to specific regions of the body have also been assessed relative to predictions based upon percutaneous absorption across forearm skin. It appears that the use of forearm skin penetration data alone underestimates body exposure by at least a factor of two.
Dimethoxyethylphthalate metabolism: Teratogenicity of the diester and its metabolites in the pregnant rat
Authors: Campbell J. , Holt Daphne , Webb M.
Published: October 2006

The rat foetus, in contrast with the maternal liver and placenta, has little or no ability to hydrolyse di‐(2‐methoxyethyl)‐phthalate (DMEP) to mono‐2‐methoxyethylphthalate (MMEP). At short times after the administration of DMEP to the dam on the 14th day of gestation, however, both the di‐ and mono‐ester are present in the foetus. Clearance of total phthalate from the foetus and placenta, is rapid and the foetal burden is reduced by 96% between 45 min and 4h. Although MMEP, when injected into the dam at the same molar dose level, crosses the placenta, its concentration in the foetus is lower than that after the injection of DMEP. MMEP (2.49 mmol kg−1), is no teratogenic when administered as an aqueous solution of the sodium salt on day 8, 10, 12 or 14 of gestation, in contrast with the same molar dose of the liquid DMEP. The alcohol, 2‐methoxyethanol (ME), when administered as a single injection at this dose level (2.49 mmol kg−1), however, is highly teratogenic and its effects cannot be differentiated clearly from those of DMEP. These results, which indicate the possibility that ME, derived by metabolism of DMEP, may be the teratogenic agent, suggest that both the rate of hydrolysis to the monoester and the chemical properties of the liberated alcohol, could be important determinant factors in the teratogenic activities of different phthalate diesters.
Differentation of rat embryo cells in culture: Response following acute maternal exposure to teratogens and non‐teratogens
Authors: Flint O. P. , Orton T. C. , Ferguson R. A.
Published: October 2006

An in vivo–in vitro test system with high sensitivity to teratogens has been developed and validated. A single acute intra‐peritoneal injection of teratogens (18) and non‐teratogens (13) was administered to pregnant rats on the 12th day after fertilisation, and uteri were removed after 16 h by laparotomy. 34–36 Embryos somites were selected, and mid‐brain (CNS) and fore‐limb buds (LB) were dissected free and dispersed as single‐cell suspensions in Ham's F12 culture medium. The cells were cultured as micromass cell islands for 5 days, and discrete foci of neuronal cells differentiated in CNS cultures and chondrocytes in LB cultures. After 5 days, differentiation as determined by number of stainable foci of differentiated cells and 3H‐GABA incorporation in CNS or 35SO4 incorporation in LB and growth (as determined by total protein) were measured. Both differentiation and growth of CNS and LB cultures were markedly reduced following exposure of the dam to teratogens, whereas no significant effect was observed with non‐teratogens. One teratogen (amaranth) and one non‐teratogen (nitrilotriacetic acid) were classified as false negative and positive, respectively; the sensitivity of the test (proportion of teratogens correct) was therefore 92% and the specificity (proportion of non‐teratogens correct) was 94%. Inhibition of growth and differentiation in the rat embryo cell cultures following maternal exposure forms the basis of a short‐term in vitro test for teratogens.
A probit analysis program for the personal computer
Authors: Schoofs Gary M. , Willhite Calvin C.
Published: October 2006

Application software for economical and convenient calculation of median effective doses, confidence limits, potency ratios and slopes of quantal dose‐response curves using a microcomputer is presented. The PASCAL language program is stored on diskette and it is compatible with many commercially available microcomputer systems. The program will simultaneously calculate the parameters for up to 20 different treatments and a total of 100 doses. Comparisons between the results of calculations of the LD50 of thiopental in mice using the PASCAL program, a modem‐accessed commercially available probit analysis program and three, widely accepted manual calculation methods are made. The results of calculations of parallelism and the potency ratio between thiopental and phenobarbital‐induced death in mice are shown.
The acute toxicity of coal liquefaction‐derived materials
Authors: McKee R. H. , Biles R. W. , Kapp R. W. , Hinz J. P.
Published: October 2006

The acute toxicity of a series of potential streams from the EDS coal liquefaction process have been assessed in animal bioassays. In general, the materials present minimal acute toxic hazards. However, there was some evidence of ocular and dermal irritation. These results indicate that eye and dermal contact should be minimized, particularly when the process streams contain high concentrations of phenolic materials.
Quantitation of specific myeloid cells in rat bone marrow measured by in vitro35S‐sulphate incorporation
Authors: Wright A. F. , Rose M. S.
Published: October 2006

A biochemical measurement which can be used for quantitation of specific early myeloid cells in rat bone marrow has been developed. This measurement consists of a rapid, simple assay for the in vitro quantitation of 35S‐sulphate incorporation into rat bone marrow cells. Incubation of bone marrow cells with 35S‐sulphate led to a time‐dependent increase in radioactivity obtained in perchloric acid insoluble fractions of bone marrow cell suspensions. This incorporation was inhibited by cyanide and puromycin. Autoradiography has demonstrated the radiolabel to be specifically associated with immature cells of the myeloid series. The cells most active in this respect were eosinophils. When rats were treated with endotoxin, the rate of 35S‐sulphate incorporation was increased. Cell number measurements, using conventional histopathology and a Coulter Counter, demonstrated that endotoxin caused an initial release of mature granulocytes from the bone marrow. The regeneration of this mature population in the marrow was rapid, and was characterized by an increase in the number of immature cells and a concomitant increase in the rate of 35S‐sulphate incorporation measured in preparations of bone marrow cells in vitro. Furthermore, this response to endotoxin has demonstrated that Coulter Counting techniques can be used to distinguish specific populations of cells (e.g. mature granulocytes) within the bone marrow.
Lung oedema – microscopic detection
Authors: Hammond T. G. , Mobbs M.
Published: October 2006

During routine inhalation toxicity studies, microscopic examination of tissues from iungs which have shown small, but statistically significant increases, in organ weight has failed to show evidence of any pathological change. Historically, increases, thought to be due to mild oedema, have been difficult to identify microscopically. A method suitable for dealing with large numbers of rodents has been developed, which can detect microscopically changes associated with small increases in lung weight. The lungs were inflated with formalin vapour and fixed in 10% buffered formalin. Histological processing methods were varied to obtain the best demonstration of oedema. Fixation methods were compared using α‐naphthylthiourea‐induced oedematous lungs. The left lobe was inflated with formalin vapour and the rest of the lung was distended with 10% buffered formalin. The best demonstration of oedema followed formalin vapour fixation. Evidence of oedema, indicated by lung weight increases of approximately 10%, was seen microscopically in formalin‐vapour‐fixed lungs, but was not seen in the lobes distended with 10% buffered formalin. Application of this technique to other species including cats and dogs has also proved successful.
Excretion and peripheral metabolism of 1, 2‐3H‐testosterone and androgens in rats following intoxication with organophosphorous insecticides 1 — acute exposure
Authors: Gradowska‐Olszewska Iwona , Brzezinski Jacek , Rusiecki Wladyslaw
Published: October 2006

The effects of methylbromphenvinfos (MBFV) and fenitrothion on androgen levels, excretion and peripheral metabolism were studied in male rats. The insecticides were administered orally in high, single doses. Plasma testosterone levels and urinary excretion of 11‐deoxy‐17‐ketosteroids had increased 24 and 48 h after MBVF administration. During the same time period, fenitrothion reduced plasma and urine androgens, but after 72 h significant increases in steroid levels and excretion were apparent. Investigation of the peripheral metabolism of 3H‐testosterone indicated that fenitrothion markedly diminished the urinary excretion of 3H‐androstenedione during the first 48 h and then increased its level after 72 h. Simultaneously, 3H‐testosterone elimination was increased during the first 24–48 h and then decreased after 72 h. These data suggest that MBFV and fenithrothion in high doses can produce significant alteration in physiological hormonal balance of the male reproductive system.
Lack of synergistic effect between arsenic, mercury and ethyl methane sulfonate on the frequency of chromosomal aberrations in mice
Authors: Poma K. , Kirsch‐Volders M. , Susanne C. , Degraeve N.
Published: October 2006

The influence of arsenic and mercury on the frequency of chromosome aberrations induced by ethylmethane sulfonate was studied in mice. No synergistic effects could be demonstrated in somatic and germ cells of mice given a combined treatment of arsenic trioxide solution (As2O3, 12 mg per kg body weight) or of mercuric chloride solution (HgCl2, 6 mg per kg body weight) with ethylmethane sulfonate (EMS, 200 mg per kg body weight).
Morphological and immunocytochemical study of rat pancreatic beta cell changes induced by cyclizine
Authors: Hanai Nobuo
Published: October 2006

Wistar rats were treated daily with cyclizine (50–75 mg kg−1) and autopsied every week until the eighth week of the treatment. Although no evident change could be detected by either serum analysis or by light microscopy from the first week to the fourth week, electron microscopy revealed that beta cells showed depletion of secretory granules and cystic dilation of the rough endoplasmic reticulum from the first week. A significantly higher level of plasma glucose and a lower level of plasma insulin than those of untreated rats were recognized from the fifth week. A diabetic pattern was also observed in the glucose tolerance test which was conducted at the seventh week. From the sixth week, large cytoplasmic vacuoles were observed light microscopically in islet cells. Electron microscopic examination revealed that the vacuoles originated from the rough endoplasmic reticulum in beta cells, while no prominent change was found on the Golgi apparatus. In addition to the above findings, immunocytochemical study with anti‐insulin serum demonstrated that the staining intensity of the beta cell cytoplasm became weaker (as judged by light microscopy) from the fifth week, but large cytoplasmic vacuoles were stained positively under both the light microscope (PAP method) and the electron microscope (enzyme‐labelled antibody method). These findings suggested that the depletion of secretory granules and accumulation of insulin or its precursor in the rough endoplasmic reticulum occurred in beta cells. The diabetogenic effect of cyclizine on rats is discussed with reference to the immunocytochemical findings.
Effects of vincristine, maytansine, and cis‐platinum on behavioral and electrophysiological indices of neurotoxicity in the rat
Authors: Rebert Charles S. , Pryor Gordon T. , Frick M. Suzanne
Published: October 2006

The effects of the antineoplastic drugs vincristine, maytansine and cis‐platinum were studied to determine the appropriateness of a behavioral and electrophysiological test battery for characterizing the neurotoxicity of such therapeutic compounds. Single‐ and repeated‐dose studies in rats were performed initially, to establish doses for the subchronic neurobehavioral study. Measurements obtained in the subchronic study included body weight, rectal temperature, forelimb and hindlimb grip strengths; performance of a multisensory conditional avoidance response task and other behavioral tests; and a series of evoked responses (ventral caudal nerve action potential, brainstem auditory response and responses from other modalities). The drugs were injected intraperitoneally 5 days per week for 7 weeks. The rats were tested weekly during baseline, treatment and recovery phases. Each drug caused a different pattern of effects, but they all altered body weight, rectal temperature, peripheral nerve conduction velocity, the somatosensory evoked potential and undifferentiated motor activity. cis‐Platinum was the most toxic, and maytansine was the least toxic. The results indicated that some elements of the test battery were useful for evaluating the neurotoxicity of anticancer drugs. However, other tests – notably, a test of negative geotaxis and the cortical auditory evoked response – were unreliable.
Levels of lactate dehydrogenase and creatine kinase in plasma of fluoride‐treated rabbits
Authors: Nedeljković M. , Matović V. , Soldatović D.
Published: October 2006

The effect of different concentrations of fluoride (as sodium fluoride) on the enzymes lactate dehydrogenase (LDH, EC 1.1.1.27) and creatine kinase (CK, EC 2.7.3.2) in rabbit plasma was investigated in vivo and in vitro. Rabbits were dosed orally, for 30 days, with fluoride at 2, 10 or 20 mg per kg body weight as sodium fluoride. LDH and CK levels were determined at 10‐day intervals during the treatment. Fluoride, depending on the applied dose, inhibited, had no effect or stimulated the investigated enzymes in vivo. On the other hand, fluoride had no effect on the activity of LDH and CK in vitro.
The nephrotoxicity for mice of deisopropylngaione, a minor furanoid component of toxic myoporaceous essential oils
Authors: Lee J. S. , Seawright A. A. , Hrdlicka J.
Published: October 2006

Deisopropylngaione (DIN) is one of a family of hepatotoxic furanosesquiterpenoid essential oils which is found in small amounts (5%) in the leaves of some specimens of the Australian plant Myoporum deserti. DIN differs from other furanoid myoporaceous essential oils in that it also causes lesions in the lungs and kidneys. At the near LD50 dose rate of 150 mg kg−1 given by intraperitoneal injection, DIN is able to cause lethal renal proximal tubular necrosis without causing significant injury to the liver and lungs in adult male mice. Following dosing, there is an increase in kidney weight due mainly to increase in water content which reaches a maximum within 16–24 h. This is accompanied by degeneration and necrosis of the proximal tubular epithelium, with proteinuria and glucosuria lasting up to 9 days in non‐lethally affected mice. Marked body weight loss due to the intoxication causes a marked increase in the kidney weight:body weight ratio lasting between 9 and 18 days. Residual lesions are still present in the kidneys at 32 days, but recovery is eventually complete. DIN is structurally similar to the sweet potato toxic furan 4‐ipomeanol and, like the latter, is probably injurious to the kidneys through toxic metabolism by the cytochrome‐P450‐containing monooxygenases of the proximal tubular epithelium. Although slight renal injury is occasionally observed in livestock poisoned by myoporaceous plants, it is unlikely that DIN is the cause. So far, DIN, like 4‐ipomeanol, appears to be unequivocally nephrotoxic only for the male mouse.
Pre‐clinical toxicology of nitazoxanide – a new antiparasitic compound
Authors: Murphy James R. , Friedmann Jean‐Charles
Published: October 2006

The acute and subchronic toxicological effects of nitazoxanide were investigated at levels near and in excess of the therapeutic dose in rats, mice, dogs and cats. Single oral gavage doses of 0.625–10 g per kg body weight were administered to rats and mice. Single oral doses of 1–10 g per kg body weight were administered in capsules to dogs and cats. Acute oral LD50 values were greater than 10 g kg−1 in rats, dogs and cats, and 1.4 g kg−1 in mice. Systemic toxicity was evaluated in a repeated dose study in rats at doses of 50, 150 and 450 mg per kg per day for 14 weeks. The highest dose group exhibited intense salivation, increased liver and spleen weight, and decreased thymus weights. Variances between control and treated organ weights were not confirmed by histopathological evaluation. Nitazoxanide was negative when tested in the Ames Salmonella assay using five tester strains with and without metabolic activation at levels from 1 to 100 mg per plate. The drug was also shown to be non‐irritating in a test for eye irritation potential.
Nuclear enlargement – an early change produced in mouse epidermis by carcinogenic chemicals applied topically in the presence of a promoter
Authors: Ingram Andrew John , Grasso Paul
Published: October 2006

A series of 27 compounds, including 11 polycyclic hydrocarbons, 8 proximate carcinogens and 8 other compounds, were tested for their ability to induce epidermal nuclear enlargement in mouse skin. The materials were applied topically in methyl ethyl ketone containing 0.1% croton oil, repetitively for 3 days. Nuclear enlargement present on the fourth day was determined with the aid of a Quantiment image‐analysing computer. The results obtained indicated a close correlation between the topical carcinogenicity of the test compounds and their ability to induce epidermal nuclear enlargement in the presence of croton oil.
Chromosomal aberrations and fetotoxic effects of atmospheric arsenic exposure in mice
Authors: Nagymajtényi L. , Selypes A. , Berencsi G.
Published: October 2006

Fetal chromosomal damage and toxicity were investigated in mice exposed to the atmospheric concentrations of 28.5 mg m−3, 2.9 mg m−3 and 0.26 mg m−3 of arsenic for 4 h per day on the 9th, 10th, 11th and 12th days of gestation. On the 18th day, the fetuses were removed, and the following parameters were examined: the number of dead fetuses, retardation in growth, osteogenesis and chromosomal aberrations in liver cells. It was found that exposure to As2O3 at 28.5 mg m−3 caused fetotoxic effects and chromosomal damage, while the two lower exposures produced no significant changes with the exception of a slight decrease (9.9 and 3.1%, respectively) in fetal weight.
Hepatotoxicity in albino rats exposed ton‐octane andn‐nonane
Authors: Khan Sumsullah , Pandya K. P.
Published: October 2006

Effects ofn‐octane andn‐nonane (1 ml per kg body weight daily) on hepatic and serum enzymes, which reflect abnormal liver function and concentration of lipid and nucleic acid (serum and liver), were studied after 2 and 7 days intraperitoneal administration to albino rats. Decreased activities of serum acetylcholine esterase and carboxyl esterase were observed, together with an increase in FDP aldolase activity. Significant decrease in the concentration of albumin, total protein, and total and esterified cholesterol in serum have been noted aftern‐octane andn‐nonane administration for 7 days. Also, free cholesterol content of liver was elevated significantly after solvents exposure.
Preclinical toxicity of the new antineoplastic agent, ametantrone acetate, in mice and dogs
Authors: Watkins J. R. , Kim S. N. , Jayasekara U. , Anderson J. A. , Fitzgerald J. E. , de la Iglesia F. A.
Published: October 2006

Ametantrone acetate (anthracenedione diacetate, NSC 287513) is an experimental antineoplastic agent with activity against a comprehensive panel of solid transplantable tumors in mice. The studies reported here were aimed at establishing the toxicologic profile of this drug. Studies in mice and dogs were carried out to establish tolerable levels. In mice, LD10, LD50 and LD90 values were respectively, 26, 35 and 47 mg kg−1 28 days following single intravenous injection and 22, 67 and 206 mg kg−1 14 days after single intraperitoneal injection. Hemorrhage and necrosis of the small intestine occurred in intercurrent deaths. A 5‐day, consecutive intraperitoneal dosing study yielded 28 day, LD10, LD50 and LD90 values of 18, 21 and 26 mg kg−1, respectively, in mice. Bone marrow hypoplasia, lymphoid depletion and focal cardiac changes were observed in animals which died during the 28‐day postdose observation period. In dogs, single intravenous injections repeated twice at intervals of 3–8 weeks resulted in leukopenia and thrombocytopenia at a dose of 2.71 mg kg−1 and decreased myeloid : erythroid ratios at a dose of 0.68 mg kg−1. Five consecutive daily intravenous injections in dogs of 0.7 mg kg−1 induced significant clinical and laboratory signs of toxicity but 0.35 mg kg−1 day−1 was tolerated. In dogs, bone marrow, lymphoid tissue and gastrointestinal tract in both sexes and gonads in the males were target organs for toxicity. Clinical signs and clinical laboratory abnormalities abated in surviving mice and dogs. The spectrum of tissue changes induced by ametantrone was qualitatively similar to that elicited with other intercalating agents.
In vivo percutaneous absorption studies of volatile solvents in hairless mice. I. Description of a skin‐depot
Authors: Susten A. S. , Dames B. L. , Niemeier R. W.
Published: October 2006

A stainless‐steel skin‐depot is discussed that may be used during short‐term studies to measure directly percutaneous absorption of radiolabeled, volatile chemicals through the skin of unanesthetized, unrestrained hairless mice. The skin‐depot is glued to the backs of the mice using cynaocrylate glue. The top portion of the depot contains activated charcoal (or other sorbent) to capture for analysis the portion of the test chemical which normally evaporates from the treatment site. This allows the use of metabolism cages for the capture of expired breath, as well as urine and feces. Thus, dermal absorption of the test chemical can be summed directly from the radioactivity found in excreta (urine and feces), the animal carcass (including the skin treatment site) and expired breath.
The effect of prednisolone on the foetotoxicity of cadmium in pregnant mice
Authors: Selypes A. , Lorencz R. , Berencsi G. , Dési I.
Published: October 2006

The effects of prednisolone was investigated on the foetoxicity of cadmium. CFLP female mice were given a single i.p. dose of 2.5 mg cadmium (Cd) per kg body weight on day 5 or 9 of gestation. This treatment significantly decreased both the number of live foetuses and foetal weights on day 18 of gestation. Prednisolone (0.1 mg kg−1) given daily from the day of cadmium treatment death, prevented the effects of cadmium on foetal weights in both groups, and on the number of live foetuses when cadmium was given on day 9 of gestation. When Cd was given on day 13 of gestation similar treatment with prednisolone did not influence either litter size or the weights of 1‐day old pups.
Renal effects of aluminium in uraemic rats and in rats with intact kidney function
Authors: Bräunlich H. , Fleck Ch. , Kersten L. , Stein G. , Laske V. , Müller A. , Keil E.
Published: October 2006

The effect on renal function following administration of aluminium i.p., five times weekly (0.05 or 0.5 mg kg−1 body weight) to partially nephrectomized (5/6 NX) or intact female rats was examined. The observed loss of concentrating ability, characterized by increased urine volume and an increased sodium excretion, as well as increased renal excretion of p‐aminohippurate (demonstrable after low‐dose treatment with nephrotoxins) can be interpreted as an initiation of kidney function injury. No distinct differences in reponse were observed between partially nephrectomized and intact animals.
A correlation of induced mixed‐function oxidase specific activity to C—H bond strengths in partially chlorinated monocyclic hydrocarbons
Authors: Brownlee L. J. , Hollebone B. R.
Published: October 2006

The nature of structure–function relationships between the mixed‐function oxidase (MFO) system and certain chemically related xenobiotics has been studied. The total hepatic induction index has been modified and used to investigate whether the induction of hepatic MFO is primarily a response to molecular shape (entropic) or to the strength of specific carbon–hydrogen bond strength (enthalpic). Using both Sprague‐Dawley male rats and ring doves (Streptopelia risoria) and testing with benzene, 1,2,4‐trichlorobenezene, cyclohexane and γ‐1,2,3,4,5,6,‐hexachlorocyclohexane as both inducers and substrates, a response of the MFO system to substrate C—H bond strength has been found.
The mechanism of biooxidation of mercury
Authors: Wigfield Donald C. , Tse Season
Published: October 2006

The mechanism of oxidation of mercury by peroxidase is reported. The reaction is first order both in mercury and in peroxidase Compound I, and involves a one‐step two‐electron oxidation. The enzyme acts as a recycling chemical oxidant.
Comparative sensitivity of survival‐adjusted chi‐square and normal statistics for the mutagenesis fluctuation assay
Authors: Goodall C. M. , Stephens O. B. , Moore C. M.
Published: October 2006

Three statistics for analysis of microtitre plate mutagenesis fluctuation tests were studied by simulation, and in enzyme‐activated assays of dimethylnitrosamine and diethylnitramine. A survival‐adjusted χ2 statistic (‘Gsq’) was compared with Katz's normally distributed statistic (‘Phi’), and with the survival‐independent statistic (‘Zsq’) of Gilbert. When toxicity was either very low or high, the Phi statistic either could not be evaluated over the whole range of possible background mutant frequencies, or sometimes it indicated unusually high levels of statistical significance, even when the other tests were negative. The survival‐adjusted Gsq closely followed the Zsq statistic throughout the experimentally useful range of toxicities and mutant background values, with some improvement in sensitivity. Within the range 80 ± 10% survival approximately, Katz's statistic ‘Phi’ was the most sensitive. The choice of statistical test could affect the estimate of the minimal effective mutagenic concentration by a factor of 10–100. For screening unknowns, both types of test (Phi and Gsq (or Zsq)) may help in detecting suspect pro‐mutagens and in designing a confirmatory assay. Bacterial population statistics are needed to assess the value of statistically positive results.
Toxic response of hamster embryo cells on exposure to mixtures of Ni2+ and benzo(a)pyrene
Authors: Uziel M. , Owen B. , Butler A.
Published: October 2006

Exposure of hamster embryo cells (HEC) to mixtures of benzo(a) pyrene and soluble Ni2+ neutral salts elicits additive responses in the enhanced nucleoside excretion assay. Ni2+ shows no significant excretion response until concentrations near 10 μM are reached. Addition of 0.4 micromolar benzo(a)pyrene and 30 μM, or 325 μM Ni2+ to HEC cultures results in total excretion equal to the sum of excretions induced by the individual chemicals. These observations suggest that excretion of pyrimidines may be a useful measure of biological dosimetry.
Urinary α1‐microglobulin as an indicator protein of renal tubular dysfunction caused by environmental cadmium exposure
Authors: Tohyama Chiharu , Kobayashi Etsuko , Saiko Hiroshi , Sugihara Naoko , Nakano Atsuhiro , Mitane Yuko
Published: October 2006

An epidemiologic investigation was carried out to clarify the significance of the urinary excretion of α1‐microglobulin (α1‐MG) in people aged 50 years and over living in a Cd‐polluted area in Japan. Approximately 80% of the population participated in the health examination. The urinary and serum levels and the relative clearance of α1‐MG to creatinine clearance were compared with various parameters (age, urinary β2‐microglobulin (β2‐MG), total protein, Cd, Cu and Zn, serum β2‐MG, creatinine and blood urea nitrogen and relative clearances of α1‐MG, β2‐MG, inorganic phosphate and uric acid). It was found that the urinary excretion of α1‐MG is closely associated with the urinary Cd and Cu and with the indices of renal dysfunction listed above. These results suggest that the urinary α1‐MG level masrkedly reflects a degree of proximal tubular dysfunction and that it may be useful as one of the screening measures for proximal tubular dysfuction caused by environmental Cd exposure.
Comparative inhalation hazards of aluminum and brass powders using bronchopulmonary lavage as an indicator of lung damage
Authors: Thomson S. M. , Burnett D. C. , Bergmann J. D. , Hixson C. J.
Published: October 2006

Bronchopulmonary lavage has been used as a rapid screening test for acute lung injury from many pneumotoxic chemicals. We demonstrated the efficacy of lavage fluid analysis for detection of acute pulmonary damage from inhaled metal dusts. Groups of male, Fischer 344 rats were exposed 4 h to one of five dosage levels of either brass (200, 100, 50, 10, 1 mg m−3) or aluminum (1000, 200, 100, 50, 10 mg m−3). At 24 h, 14 days and 3 months post‐exposure (PE), rats were evaluated for physiological and histological alterations to correlate with enzymatic and cytological profiles of lavage fluid. At 24 h PE, there were dose‐related increases in lactate dehydrogenase and protein in lavage fluid of the brass exposed rats, acute inflammatory response in terminal airways, increases in macrophages and neutrophils, and increased pulmonary resistance. All reactions were resolved by 14 days PE. In contrast, alumium powder produced no alteration in pulmonary function, but elicited persistent changes in enzymatic and cytological lavage fluid parameters with multifocal microgranlomas in lungs and hilar lymph nodes. Bronchopulmonary lavage analysis was useful as an indicator of inhalation hazards of brass and aluminum powders.
Acute toxicity of brass particles to Daphnia magna
Authors: Johnson Dennis W. , Haley Mark V. , Hart Gayle S. , Muse William T. , Landis Wayne G.
Published: October 2006

The aquatic toxicity of brass particles was examined. Acute, 48 hour bioassays were performed using the water flea, Daphnia magna. Tests were conducted with uniform suspensions of uncoated brass particles, brass particles coated with a Teflon solution, silica particles, and titanium dioxide particles. The Teflon coating solution and the supernatant of the brass suspension (after settling of the brass) also were tested. All tests were conducted according to guidelines set forth by the US Environmental Protection Agency and the Organization for Economic Cooperation and Development. Mean EC50 determinations of 20.0 μg l−1 and 23.6 μg l−1 were calculated for uncoated brass particles and coated brass particles, respectively. The silica, titanium dioxide, and Teflon each had an EC50> 1 g−1. Chemical fate studies demonstrated that the brass dissociated to its ionic components of copper and zinc quickly at pH 2.0. At pH 5.0 and 6.5, the dissociation occurred too slowly to account for the observed toxicity. The data suggested that the toxicity is due to filtration by the daphnids and subsequent ingestion. EC50 determinations for the brass particles are nearly identical with published EC50 values for copper salts.
Evaluation of the relationship between chemical and biological monitoring of low‐level lead poisoning
Authors: Wigfield Donald C. , Wright Sandra C. , Chakrabarti Chuni L. , Karwowska Regina
Published: October 2006

Blood lead levels, together with δ‐aminolevulinic acid dehydratase activity determinations have been measured on rats dosed with up to 1000 ppm lead acetate in their drinking water for periods up to 5 weeks. Despite evidence of a compensation mechanism developing in the enzyme determinations, enzyme activity ratios, if properly chosen, still correlate reasonably well (r=0.87) with blood lead levels. Activity ratios using data on the shoulders of pH‐activity profiles (e.g. activity ratios of 6.4 and 7.2), however, give much less satisfactory correlations. These data provide a more stringent test of the chemical monitor–biological monitor correlation than has previously been possible.
Induction of aryl hydrocarbon hydroxylase in rat tissue following intratracheal instillation of diesel particulate extract and Benzo[a]pyrene
Authors: Chen K. C.
Published: October 2006

The potential for aryl hydrocarbon hydroxylate (AHH) induction by inhaled diesel particles was assessed by intratracheal administration. Benzo[a]pyrene, (B[a]P) a reference compound, or an extract of particles, dissolved in gelatin‐saline solution was administered to Fischer 344 rats at several dose levels. Twenty‐four hours after administration of B[a]P or diesel particulate extract, the AHH activity increased in a dose‐response manner in the lung, but not in liver. The maximum increase in the AHH activity in the lung was observed 12 h after intratracheal instillation of B[a]P (5 mg/kg), and the levels remained elevated for seven days. The AHH activity in the liver reached the maximum 24 h after the administration, and returned rapidly to control values. In contrast, intratracheal instillation of diesel particulate extract resulted in a significant increase of AHH activity in the lungs only after doses greater than 6 mg kg−1. The activity, however, declined rapidly and returned to control values within 75 h. The liver AHH activity in this instance, remained unchanged throughout the experimental period. These data indicate that in the lung, hydrocarbons extracted from diesel particles are weak enzyme inducers and exposure to these compounds by intratracheal administration did not result in AHH induction in the liver. The results suggest that doses higher than those normally expected from occupational exposures will be required to induce AHH activity in organs examined.
Significance of the dog as ‘second animal species’ in toxicity testing for establishing the lowest ‘no‐toxic‐effect level’
Authors: Appelman L. M. , Feron V. J.
Published: October 2006

The toxicity data of 66 compounds adequately tested in the rat (as ‘prime animal species’) and in the dog (as ‘second animal species’) were studied to find out for how many of these compounds the study in dogs led to a lower ‘no‐toxic‐effect level’ (NTEL) than that found in the rat. From a quantitative point of view such information would contribute to a better insight into the desirability of toxicity studies in dogs, because acceptable daily intakes and permissible exposure levels in man are generally based on the lowest NTEL.

For 44% of the compounds the NTEL in the dog was lower than that in the rat. When rat NTEL was divided by the arbitrary factor of 10, the adjusted NTEL was lower than the dog NTEL for 86% of the compounds tested in sub‐chronic studies, and for 80% of the compounds tested in chronic studies. Whether it is justifiable to substitute such an adjusted NTEL for a study in dogs should be judged from compound to compound. It mainly depends on the size of the margin between the NTEL in the rat (as ‘prime animal species’) and the (expected) actual exposure level in humans, and also on the acceptability of loosing additional qualitative toxicological information. When this margin is large enough (e.g. 1000 or more), a study in dogs might be superfluous, despite the loss of qualitative data. Such an approach could lead to a reduction of the number of animals in toxicity testing and also to a reduction of the costs.
The distribution of arsenic and cobalt in patients with laryngeal carcinoma
Authors: Collecchi Paola , Esposito Mauro , Brera Silvio , Mora Enzo , Mazzucotelli Ambrogio , Oddone Massimo
Published: October 2006

The objective of this study was to evaluate tissue and plasma concentrations of arsenic and cobalt in an attempt to discove the role of these elements in the malignant process. Using neutron activation analysis, arsenic and cobalt levels were determined in plasma and in non‐malignant and malignant human tissue in 15 patients with laryngeal carcinoma. Arsenic and cobalt levels were about 60% higher in tumor than in adjacent non‐malignant tissue (P<0.001): arsenic 72.4±18.0 ng/g versus 43.1±9.4 in non‐malignant tissues, and cobalt 68.7±7.3 ng/g versus 39.6±7.0 in non‐malignant tissues. Mean plasma arsenic and cobalt levels were also significantly higher in patients with laryngeal carcinoma than in healthy control subjects.
The effect of topically applied n‐butylester of 2,4‐dichlorophenoxyacetic acid on the immune response in mice
Authors: Blakley Barry R. , Schiefer Bruno H.
Published: October 2006

Six‐week‐old female CD‐1 mice were administered the n‐butylester of 2,4‐dichlorophenoxyacetic acid (2,4‐D). The 2,4‐D ester was applied dermally at dosages ranging from 0 to 500 mg/kg (2,4‐D content) in the acute studies and 0 to 300 mg/kg in the 3 week subacute studies. Following acute exposure, antibody production against sheep red blood cells was supressed at higher exposure levels. Evidence of clinical toxicity, myotonia and depression, and histopathological alterations in the central nervous system including perivascular edema and ganglial cell necrosis, was also seen in the mice. No alterations were observed in the T‐ and B‐lymphocyte proliferative responses induced by concanavalin A, a T‐lymphocyte mitogen, or Escherichia coli lipopolyaccharide, a B‐lymphocyte mitogen. Subacute 2,4‐D ester exposure which produced minimal clinical or pathological alterations, had no effect on antibody production, but did enhance the B‐ and T‐lymphocyte proliferative responses. The immunosuppressive effects of acute 2,4‐D ester exposure which were observed in this study, were unlikely a direct immunological alteration, but rather a secondary manifestation of the clinical syndrome. Since the subacute exposure levels may be more comparable to occupational or environmental exposure, it is unlikely that 2,4‐D esters will have any major immunotoxicological significance in agricultural communities.
The long‐term study in rodents for identifying carcinogens: Some controversies and suggestions for improvements
Authors: Feron Victor J. , Kroes Robert
Published: October 2006

Despite increasing standardization and international harmonization of the long‐term carcinogenicity study in rodents there are still areas of controversy such as high‐dose selection, duration of the test period, combining or not combining the chronic toxicity and the carcinogenicity study, the use of historical control data, conditions for redundancy of the study, and significance of studies of restricted design. It is discussed that the ‘Maximum Tolerated Dose’, or doses above and below the ‘metabolic break‐point’ should be included. In general a test period of 24 months is adequate, but the protocol should be flexible enough to allow extension beyond 24 months. Major advantages of the combined chronic toxicity/carcinogenicity study are that the toxicity and carcinogenicity data are obtained with the same sample of the test compound using the same batch of animals kept on the same diet under the same environmental conditions. It is discussed that the use of historical control data will not lead to a final conclusion on carcinogenic or noncarcinogenic potential of a compound. A long‐term carcinogenicity study is considered redundant (a) when adequate (semi‐chronic) toxicity studies including reproduction and mutagenicity tests and pre‐screens for carcinogenicity, do not indicate mutagenic or carcinogenic activity, and (b) when there is a wide margin (e.g. 1000) between the ‘no‐observed‐adverse effect level’ and the (presumed) exposure level in humans. Studies of restricted design and conduct may clearly demonstrate carcinogenicity but also may easily lead to inconclusive results.