bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy of three non‐mammalian test systems in the identification of chemical teratogens
Authors: Sabourin T. D. , Faulk R. T. , Goss L. B.
Published: October 2006

This report concerns an evaluation of three in vitro teratogenesis tests: the Dugesia regeneration assay, the Hydra reaggregation assay and the Xenopus embryo assay. Our approach involves the establishment and/or refinement of test protocols, definition of endpoints, and evaluation of test performance by comparison with available results of in vivo mammalian studies. Chemicals used for preliminary evaluation studies were the known mammalian teratogens, vinblastine sulfate (VIN) and hydroxyurea (HU), a coeffective teratogen, cadmium chloride (Cd), and an National Toxicology Program priority chemical, 9‐aminoacridine hydrochloride (9AA). The Dugesia assay takes advantage of the ability of beheaded flatworms to regenerate and can be completed in 7–14 days. Concentrations of VIN of 3.2 mg 1−1 inhibited auricle formation and further regeneration observed in 3–6 days. Similarly, eyespot and auricle formation was blocked by HU (180 mg 1−1). The duration of regeneration, measured as the time elapsed between decapitation and eyespot formation (control =5 days), was extended by 1–4 days during exposure to 9AA. Sublethal Cd had little effect on regeneration. The Hydra assay is an evaluation of the ability of dissociated cells to regenerate complete organisms when randomly reassociated. A teratogenic test substance is detected by observing the ratio of the minimal effective concentrations of a substance between intact organisms and regenerates. Compounds with a ratio > 2.0 are potential teratogens. The ratios determined for 9AA, VIN, HU and Cd, respectively, were 10.0, 4.0, 2.7 and 1.2. These results indicate that the first three compounds tested positive for teratogenesis. The Xenopus assay has several endpoints, all of which can be compared with embryolethality in order to index teratogenic hazard. A 4‐day test encompasses development from the blastula stage, through hatching, to formation of swimming tadpoles. Reduced growth was noted during exposure to HU concentrations above 50 mg 1−1 (embryolethality of HU was above 200 mg1−1). Significant skeletal abnormalities, recorded as moderate to severe spinal curvature and resultant loss of swimming ability, were observed during exposure to all four test chemicals. However, this phenomenon was apparent at non‐embryolethal concentrations only for HU and VIN. Further abnormalities, such as altered skin pigmentation and osmoregulatory failure were also recorded.
Development of aquarium fish models for environmental carcinogenesis: An intermittentflow exposure system for volatile, hydrophobic chemicals
Authors: Walker William W. , Manning C. Steve , Overstreet Robin M. , Hawkins William E.
Published: October 2006

An intermittent‐flow exposure system was designed to provide stable and manipulative concentrations of volatile and hydrophobic compounds to small aquatic animals for uninterrupted long periods. Test species for 28‐day experiments included two aquarium fishes, the Japanese medaka (Oryzias latipes) and the king cobra guppy (Poecilia reticulata). Test chemicals included trichloroethylene, vinylidene chloride, bis (2‐chloroethyl)ether, ethylene dichloride, and a mixture of carbon tetrachloride, trichloroethylene, chloroform, bromodichloromethane, chlorodibromomethane and bromoform. These compounds are drinking water biorefractories and are potentially carcinogenic. Concentrated aqueous toxicant solutions, delivered from a remote triple carboy dispensing system, were mixed with diluent water within an isolated chamber containing exposure aquaria and test fish. Toxicant concentrations measured throughout each exposure period proved to be stable within acceptable variability ranges as indicated by coefficients of variation generally less than 15%.
Development of aquarium fish models for environmental carcinogenesis: Tumor induction in seven species
Authors: Hawkins William E. , Overstreet Robin M. , Fournie John W. , Walker William W.
Published: October 2006

For small fish species to be utilized as models for carcinogenicity testing they should be capable of developing neoplasms, preferably in multiple tissues, when exposed to known carcinogens. Seven species of small fish were exposed to methylazoxymethanol acetate (MAM‐Ac) and tumor development was monitored. Specimens 6–10 days old were exposed to nominal concentrations of MAM‐Ac up to 100 mg l−1 for 2 h, then transferred to carcinogen‐free water. Hepatic neoplasms developed in the Japanese medaka, guppy, sheepshead minnow, Gulf killifish, inland silverside, rivulus, and fathead minnow. Additionally, neoplasms occurred in other organs and tissues of the medaka (retina, various mesenchymal tissues, exocrine pancreas, kidney, and nervous tissue), guppy (mesenchymal tissue, exocrine pancreas, and kidney), and sheepshead minnow (choroid gland, mesenchymal tissues, and nervous tissue). All tumors were diagnosed in specimens within 1 year post‐exposure. Early signs of liver tumors appeared in medaka and guppy at about 1 month post‐exposure. These studies show that both medaka and guppy would be good models because they appear sensitive to carcinogens, develop tumors in multiple tissues and are easy to breed and maintain. Certain other small fish species also may prove to be good models because of habitat preferences, breeding strategies, or genetic attributes.
Pathology and tumor development through time in guppies dosed with diethylnitrosamine (DEN)
Authors: Parland William K. , Baumann Paul C.
Published: October 2006

Within the last decade unusually high frequencies of neoplasms have been reported in feral fish populations from a variety of locations. At many of these locations organic carcinogens have been noted as a potential cause. We sought to identify toxic effects including neoplasia in fish exposed to an organic carcinogen, and to quantify these effects through time.

We exposed guppies (Poecilia reticulata) to multiple doses of DEN, an organic carcinogen. Fish were then subsampled and examined for liver histopathology at 2‐month intervals over 12 months. Necrotic zones, macrophage centers, bile duct proliferations, enlarged lipid deposits, neoplastic foci, cholangiocarcinomas and hepatoblastomas were quantified by frequency of occurrence and the percentage of liver area involved.

DEN toxicity resulted in necrotic zones that peaked in frequency at the first sample period (2 months). Lipid deposits increased, then plateaued in guppies, indicating a more chronic toxic effect. Similarly, macrophage centers increased through the sampling period. Bile duct proliferation appeared to be of two types: a reversible toxic response which peaked at 4 months and then declined and a less frequent irreversible proliferation which continued to develop into cholangiocarcinoma. Neoplastic foci of mixed hepatocytes and cholangiocytes increased in livers of exposed guppies from the second month, developing into hepatoblastomas, which occurred in almost 100% of exposed guppies by the twelfth month. The irreversible bile duct proliferations and the neoplastic foci had cellular densities different from corresponding control tissue and similar to cellular densities of cholangiocarcinomas and hepatoblastomas, respectively.
Excretion of 3‐hydroxy‐benzo(a)pyrene and mutagenicity in rat urine after exposure to benzo(a)pyrene
Authors: Jongeneelen F. J. , Leijdekkers Ch. M. , Bos R. P. , Theuws J. L. G. , Th. Henderson P.
Published: October 2006

3‐hydroxy‐benzo(a)pyrene (3‐OH‐B(a)P) and mutagenic activity in rat urine were determined after the oral administration of benzo(a)pyrene given in three repeated doses of 10, 20 and 50 μmol kg−1. The procedure for the determination of 3‐OH‐B(a)P consisted of enzymic hydrolysis, separation and HPLC‐analysis. The mutagenic activity of concentrated urine samples was assayed with the Salmonella typhimurium strain TA98 in the presence of S9 mix and β‐glucuronidase. The urinary excretion of 3‐OH‐B(a)P and mutagens showed a correlation and both increased dose‐dependently during the sampling period of 6 days. Data indicated that 3‐OH‐B(a)P can be regarded as a reliable representative of all urinary (pre)‐mutagens derived from benzo(a)pyrene and exposure of rats to benzo(a)pyrene could be detected with greater sensitivity by the HPLC assay of 3‐OH‐B(a)P than with the non‐specific mutagenicity assay.
Method for determining the lung burden of talc in rats and mice after inhalation exposure to talc aerosols
Authors: Hanson R. L. , Benson J. M. , Henderson T. R. , Carpenter R. L. , Pickrell J. A. , Brown S. C.
Published: October 2006

A method has been developed to quantitate talc lung burdens in rats and mice after inhalation exposure to talc aerosols. The method is based on acid‐insoluble magnesium (Mg) determination by flame atomic absorption. Precipitating protein from homogenates of lungs of unexposed rodents with 5% perchloric acid and washing with 5% trichloroacetic acid removed the soluble and naturally occurring Mg. This resulted in residual Mg content averaging 0.43 μg Mg per g lung in rats and less than 0.1 μg Mg per g lung in mice for young rodents less than 12 weeks old. Rodents 12–18 months old had residual mean (±SD) Mg contents of 3.4 ± 2.0 μg Mg per g rat lung (n =17) and 6.5 ± 2.9 μg Mg per g mouse lung (n =12). Thus, the background residual acid‐insoluble Mg content in rodent lungs appears to increase with age. Negligible quantities of Mg were extracted directly from the talc treated by these procedures. Adding 50–2000 μg talc to lungs from unexposed rodents, followed by the sample treatment, gave mean (±SD) Mg recoveries of 89 ± 12% (n =19) for rat lungs and 96 ± 26% (n =15) for mouse lungs. The lung burden of talc in rodents exposed to talc aerosols for 6 h per day, 5 days per week for 4 weeks was determined. Mean lung burdens in rats were 77, 187, and 806 μg talc per g lung (n =10) for exposures at 2.3, 4.3, and 17 mg talc m3, respectively. Mean lung burdens in mice were 114, 325 and 1150 μg talc per g lung (n =10) for exposures at 2.2, 6.3 and 20.6 mg talc m3, respectively. The coefficient of variation for the lung burdens of the different exposure groups ranged from 8 to 21%.
Effects of formaldehyde and acetaldehyde inhalation on rat pulmonary mechanics
Authors: Nascimento Saldiva Paulo Hiláro , do Rio Caldeira Marina Pires , Massad Eduardo , Calheiros Débora Fernandes , Cardoso Luiza Maria Nunes , Miklós Böhm György , Saldiva Carmen Diva
Published: October 2006

Two groups of 12 male Wistar rats received either 243 ppm of acetaldehyde or 5.7 ppm of formaldehyde for 8h a day, 5 days a week during 5 weeks. These levels represent three times the threshold limit values (TLV) for these substances in Brazilian legislation. The animals were evaluated by pulmonary function tests before and after exposure to the pollutants. The data obtained from these rats were compared with those of 12 controls, housed in identical conditions for the same length of time but breathing normal air. The results showed an increase of the functional residual capacity, residual volume, total lung capacity and respiratory frequency in the rats exposed to acetaldehyde atmosphere. The animals exposed to formaldehyde did not present pulmonary function alterations when compared with the controls. The damage caused by acetaldehyde to the peripheral regions of the lung parenchyma, affecting small airways or altering pulmonary elastic properties, is discussed. It is suggested that the Brazilian TLV for acetaldehyde (78 ppm) is not as safe as that for formaldehyde (1.6 ppm).
Fractionation of diesel particle extracts by sephadex LH‐20 and thin‐layer chromatography
Authors: Bechtold W. E. , Dutcher J. S. , Brooks A. L. , Henderson T. R.
Published: October 2006

A method was developed to concentrate fractions high in bacterial mutagenicity from diesel exhaust particle (DEP) extracts. The two‐step fractionation of organic extracts of DEP employed Sephadex LH‐20 followed by thin‐layer chromatography (TLC). In both steps, nitro‐substituted polycyclic aromatic hydrocarbons (nitro‐PAHs) were found to co‐elute with the fractions of highest specific bacterial mutagenic activity. Although recoveries of mass and mutagenicity from the LH‐20 fractionation were high, very low (20–30%) recovery of mutagenicity was found after TLC. Recovery studies using 14C‐labeled 1‐nitropyrene showed that 78% of the compound was recovered unaltered through the combined fractionation. The most bioactive TLC subfraction was chromatographed using gas chromatography with thermionic specific detection. A sizeable peak was found to co‐elute with a nitropyrene standard, but no peak was found co‐eluting with nitrofluoranthene. Triple quadrapole mass spectrometry was used to measure the concentrations of nitropyrene in each of the fractions. Nitropyrene was enriched 160‐fold in the most bioactive TLC subfraction over the starting material, for a final concentration of over 3200 μg g−1. Masses corresponding to several two‐ and three‐ring methylated nitro‐PAHs were found in the same fraction, including nitro‐(methylbiphenyls/methylacenapthenes) and nitro‐(methylanthracenes/methylphenanthrenes).
Welding fumes and chromium compounds in cell transformation assays
Authors: Hansen Karen , Stern Richard M.
Published: October 2006

Fumes generated from mild steel and stainless steel welding were collected on paper filters and tested in the BHK and SHE cell transformation assays. Fumes from the manual metal arc welding of stainless steel (MMA/SS) had a toxic and transforming effect attributable to their Cr(VI) content. The fumes from metal inert gas stainless steel (MIG/SS) welding also had a toxic effect but this was 2–3 times greater than that expected from their soluble Cr(VI) content based on the activity of soluble Cr(VI) from pure chromium compounds. When collected in an impinger, the fumes from MIG/SS were found to contain approximately 10 times the soluble Cr(VI) content of samples collected on filters. This additional Cr(VI), when collected in a water impinger, also exhibited a greater toxicity compared with that found for the additional Cr(VI) collected in an impinger filled with growth medium. This comparison implies the presence of a short‐lived biologically active Cr(VI) species usually lost in conventional sampling techniques. It also implies that there is a detoxification step associated with the formation of Cr(VI) organic complexes. Relatively insoluble Cr(VI) compounds showed a higher toxic and transforming effect in the BHK assay than could be ascribed to the soluble Cr(VI) content of the medium, indicating the importance of phagocytosis as a pathway for the uptake of Cr(VI) and other toxic substances from particulates.
Oxidant gas injury to the lung: A discussion on the functional implications
Authors: Guidotti Tee Lamont
Published: October 2006

Acute toxic inhalation by the oxidant gases, particularly ozone (O3), nitrogen dioxide (NO2) and oxygen (O2) at high tension, has been assumed to be no more than a chemical burn of the epithelial surface. More recently, oxidant toxic inhalation has been appreciated as a complex process involving biochemical, morphological and functional changes which are qualitatively similar although inducible by different agents. Recent advances in pulmonary pathophysiology, inhalation toxicology and particularly endothelial biology now challenge the validity of a theoretical framework which seemed almost complete just 5 years ago. Considerable attention has been paid in recent years to the biochemical events occurring at the moment of and immediately following exposure to the oxidant gases. Progress in elucidating the initial events has been rapid and promises a more complete picture in the near future. Studies of the pathophysiologic mechanisms associated with toxic inhalation by the oxidant gases have been relatively static, however. In this discussion, implications of recent findings in related fields were examined in an effort to identify new hypotheses and directions for investigation.
Partition coefficients of mercury (203Hg) vapor between air and biological fluids
Authors: Hursh J. B.
Published: October 2006

Ostwald partition coefficients for mercury (Hg203) vapor (ng Hg per ml fluid/ng Hg vapor per ml air) were determined for human whole blood, 10.50 (10 °C), 6.62 (22 °C), 4.20 (37 °C); for human plasma, 5.56 (10 °C), 3.63 (22 °C), 2.40 (37 °C); for 0.9% NaCl; 2.65 (22 °C); and for sunflower oil, 80.8 (22 °C). It was shown that the uptake of mercury vapor by whole blood can not be accounted for as the sum of the solubilities of the saline and lipid components, but that when the uptake by hemoglobin is included the agreement is satisfactory. Using the solubility of mercury vapor as determined in this paper, consideration was given to various mechanisms for mobilization of mercury vapor from the lung. The method used for these determinations is recommended for similar studies because of its simplicity and precision.
Evaluation of the systemic toxicity of coal liquefaction‐derived materials following repeated dermal exposure in the rabbit
Authors: McKee Richard H. , Kapp Robert W. , Ward Dennis P.
Published: October 2006

The subchronic toxicity of two materials produced by the EDS direct coal liquefaction process was investigated using adult New Zealand white rabbits as the test species. Recycle solvent (RS: 204–427°C) and fuel oil (FO: 204–538°C) were applied to the intact dorsal surface of rabbits, 5 days per week for 4 weeks. Materials were applied as suspensions (2.5 and 10.0 g 100 ml−1) in white oil. White oil alone was administered to concurrent control groups. Both RS and FO elicited gross signs of toxicity including severe dermal irritation, loss of body weight (16–25%) and mortality (4/20 in the high‐dose group treated with RS). Systemic effects included liver enlargement as evidenced by histologic findings of diffuse hepatocytomegaly, cytoplasmic degeneration and hepatocellular vacuolation as well as elevated serum cholesterol. There was also evidence of testicular, seminal vesicle and thymic atrophy. More pronounced effects were apparent in the high‐dose groups. Testes and epididymides from four of the five FO‐treated male rabbits were unremarkable at the microscopic level. The testes, epididymides and seminal vesicles of the fifth animal were atrophic. Three of ten RS treated rabbits showed testicular atrophy associated with hypo‐spermatogenesis in the testes, aspermia in the epididymides and vesiculitis in the seminal vesicles. Four additional animals showed evidence of seminal vesicle atrophy. The liver enlargement was probably due to compensatory metabolism; however, exposure to similar materials at higher levels has resulted in liver toxicity. Thymic and testicular atrophy may have been a secondary response to dermal irritation, stress or body weight loss.
Effect of phorone‐induced glutathione depletion on the metabolism and hepatotoxicity of carbon tetrachloride and vinylidene chloride in rats
Authors: Siegers C.‐P. , Horn W. , Younes M.
Published: October 2006

Although the depletion of hepatic glutathione in male rats following treatment with phorone (diisopropylidene acetone) did not affect the xenobiotic‐metabolizing microsomal enzyme system, the metabolic elimination of vinylidene chloride (VDC) from the atmosphere of a closed exposure system was inhibited. However, the hepatotoxicity of VDC was enhanced after GSH‐depletion, although no enhancement of VDC‐induced in vivo lipid peroxidation was observed. In contrast, GSH depletion had no influence on the metabolic elimination of carbon tetrachloride, but augmented both the hepatotoxic response to and the in vivo lipid peroxidation induced by CCl4. In the case of VDC GSH‐depletion hepatoxicity was increased because of a change in the metabolic pathway, resulting in production of intermediates of greater toxicity: lack of GSH in CCl4 treated rats renders membrane phospholipids more susceptible to peroxidative damage.
The hepatotoxicity of carbon disulphide in sheep
Authors: Wilkie I. W. , Seawright A. A. , Hrdlicka J.
Published: October 2006

Carbon Disulphide (CS2) caused liver injury when dosed orally (intraruminally) at 0.05 ml per kg body weight to overnight fasted sheep which had been given 200 mg kg−1 DDT intraruminally 1 week previously to enhance the hepatic mixed function oxygenases. The liver lesion was a periacinar hepatocellular vacuolar degeneration, fully developed at 24h and lasting from 4 to 5 days after which the hepatic morphology returned to normal. At 24h after dosing with CS2 there was an increase in total liver water, sodium and potassium ions but without an increase in the concentration of these cations in total liver water, and a 50% reduction in microsomal cytochrome P450 levels. Calcium concentration was either unchanged or only slightly increased. The cytoplasmic vacuoles were mainly distensions of the rough endoplasmic reticulum and contained fine amorphous or fibrillary material, probably originating from damaged smooth endoplasmic reticulum membranes. The transient influx of fluid into these organelles is thought to be due to osmotic action generated by molecules derived from the latter macromolecular membrane fragments. The lesion resembles that seen in the rat due to CS2 after pretreatment with phenobarbitone. In situations in which sheep are drenched with CS2 and CCl4 in combination, it is suggested that the development of hepatic periacinar hydropic change due to the CS2 in animals normally susceptible to CCl4 because of enhanced microsomal cytochrome P450 levels would provide a better chance of survival than if CCl4 alone was administered and extensive periacinar coagulative necrosis occurred.
The mechanisms of action of cyanide on the rabbit aorta
Authors: Robinson Casey P. , Baskin Steven I. , Franz David R.
Published: October 2006

Pretreatment of strips of rabbit aorta with 10−3 M sodium cyanide reduced contractions to 10−8 through 10−4 M norepinephrine (NE) added cumulatively. This antagonism by cyanide was not altered by 4 × 10−6 M ouabain or verapamil, suggesting a lack of involvement of Na+, K+ ATPase or of calcium influx in the antagonism. Cyanide potentiated contractions caused by 3 × 10−3 M potassium, but reduced contractions induced by higher potassium concentrations. Because the antagonism of higher concentrations of potassium and NE were similar, it seems that selective actions on different calcium pools are possibly not involved in the antagonism of agonist‐induced contractions. 10−2 M cyanide contracted rabbit aorta with a mean contraction 16% of that induced by 10−4 M NE. These contractions were potentiated by pretreatment with 4 × 10−6 M ouabain and 4 × 10−6 m verapamil but were unaffected by the serotonin antagonist 2‐bromo lysergic acid diethylamide, 10−4 M (2‐BrLSD), the alpha adrenergic antagonist phentolamine, 4 × 10−5 M, the H1 antihistaminic pyrilamine, 10−5 M, or the antimuscarinic atropine, 10−6 M. The contractions were reduced by 10−4 M 4,4′‐di‐isothiocyano‐2,2′‐stilbene disulfonic acid (DIDS) or chlorpromazine. The reduction may be due to a blockade of anionic channel mechanisms facilitating entry of cyanide into the vascular smooth muscle cell, as both of these agents can block anionic channels in other tissues.
Embryotoxicity of benzalkonium chloride in vaginally treated rats
Authors: Buttar Harpal S.
Published: October 2006

The effects of the spermicide benzalkonium chloride (BKC) were studied on the conceptus of rat. Single doses (0, 25, 50, 100 or 200 mg kg−1) of aqueous solutions of BKC were administered intravaginally (1 ml kg−1) on gestational day 1. The vulval metallic clips, used to prevent leakage of the solution, were removed 24 h post‐treatment. Fetuses were obtained and examined for malformations on day 21 of gestation. Slight to copious amounts of vaginal discharge and vaginitis were noticed in rats treated with the two largest doses of BKC. A dose‐related increase in resorptions and fetal death, reduction in litter size and weight were observed in BKC‐treated dams. The conceptus loss seemed to occur both before and after implantation. BKC did not cause any discernible visceral malformations, although minor sternal defects occured in fetuses exposed to 100 and 200 mg kg−1 of the spermicide. These results suggest that single vaginal application of BKC is embryo‐ and fetocidal in the rat at a dose about 143 times higher than that recommended for controlling conception in women.
Toxicity of aromatic disulphides. I. Generation of superoxide radical and hydrogen peroxide by aromatic disulphides in vitro
Authors: Munday R.
Published: October 2006

The aromatic thiol, thiophenol, is readily autoxidized at neutral pH in a reaction which generates superoxide radical and hydrogen peroxide. The oxidation product, diphenyl disulphide, may be reduced back to thiophenol by glutathione and in the presence of an excess of the latter thiol a reduction/autoxidation cycle for generation of ‘active oxygen’ species is established. The autoxidation reaction is strongly catalyzed by haematin; hemoglobin is also an effective mediator of ‘active oxygen’ generation from the diphenyl disulphide/glutathione couple, being oxidized to methemoglobin in the process.

Certain derivatives of diphenyl disulphide also generate superoxide radical and hydrogen peroxide in the presence of glutathione, although the rate of the reaction is strongly influenced by the nature of the substituent groups. Among the ring‐substituted derivatives of diphenyl disulphide investigated, the rate of ‘active oxygen’ production decreased in the order 4‐amino > 2‐amino > 4‐methyl > unsubstituted > 4‐nitro > 2‐carboxyl; little reaction was detected with the homologous compound, dibenzyl disulphide.
Toxicity of aromatic disulphides. II. Intra‐erythrocytic hydrogen peroxide formation and oxidative damage by aromatic disulphides
Authors: Munday R.
Published: October 2006

Diphenyl disulphide has been shown to generate hydrogen peroxide in erythrocytes in vitro. It also induces oxidative damage (reversible and irreversible haemoglobin oxidation, depletion of non‐protein and protein‐bound thiols) in these cells.

Such changes were also recorded in erythrocytes exposed to 4,4′ ‐diaminodiphenyl disulphide, 2,2′‐diaminodiphenyl disulphide, 4,4′‐dimethyldiphenyl disulphide, 4,4′‐dinitrodiphenyl disulphide, diphenyl disulphide‐2,2′‐dicarboxylic acid and dibenzyl disulphide. The relative potency of these coumpounds in causing erythrocyte damage is correlated with their ability to generate ‘active oxygen’ species in vitro.
Short‐term toxicity studies of vanadium in rats
Authors: Domingo J. L. , Llobet J. M. , Tomas J. M. , Corbella J.
Published: October 2006

Vanadium (in the form of NaVO3) was given in drinking water to groups of 10 male Sprague‐Dawley rats over a period of 3 months at concentrations of 0, 5, 10 and 50 ppm. Vanadium accumulated dose‐dependently in the kidneys and spleen. Appearance, behaviour, food and water consumption, growth and mortality of the treated rats of all groups were not affected during the 3‐month period. Histopathological investigation showed only mild though dose‐dependent lesions in kidneys and spleen. The plasma concentrations of urea and uric acid were increased in the highest exposure groups.
Uptake of cadmium in isolated kidney cells—influence of binding form and in vivo pretreatment
Authors: Jin Taiyi , Nordberg Gunnar F. , Nordberg Monica
Published: October 2006

Uptake of cadmium as 109CdCl2, 109Cd‐cysteine, 109Cd‐albumin and 109Cd‐metallothionein was studied in isolated kidney cells from rat. Cd as 109CdCl2 and 109Cd‐albumin was taken up at similar rates. The uptake of cadmium as 109Cd‐cysteine was greater and that of 109Cd‐metallothionein lower compared with that of the other substances. These observations were made on non‐pretreated cells. In cells taken from rats pretreated with CdCl2 in vivo, the uptake of cadmium as 109CdCl2, 109Cd‐cysteine and 109Cd‐albumin was lower than in cells from non‐pretreated rats. However, the uptake of 109Cd‐metallothionein was considerably enhanced in pretreated cells. In pretreated kidney cells the decreased uptake of Cd (as Cd‐albumin) might be related to protection of the kidney against acute Cd toxicity and increased uptake of metallothionein‐Cd might contribute to the explanation of renal damage in long‐term Cd exposure.
Degeneration and regeneration of respiratory mucosa of rats after exposure to styrene
Authors: Ohashi Yoshihiro , Nakai Yoshiaki , Ikeoka Hiroshi , Koshimo Hiroyuki , Nakata Junko , Esaki Yusuke , Horiguchi Shun'Ichi , Teramoto Keiko
Published: October 2006

The recovery process of pathological changes in the respiratory mucosa following exposure to styrene were experimentally studied to improve the understanding of the respiratory toxicity of styrene. Thirty male SD rats were exposed to 150 ppm or 1000 ppm of styrene for 4 h a day over 3 weeks (5 days a week). They were killed for examination at 1 day or 12 weeks after completion of the exposure sequence. Bilateral mucosal samples from the nasal septum and the trachea of the animals were examined for ciliary activity and subjected to electron microscopy, Complete functional and morphological recovery of the nasal and tracheal mucosa was observed at the 12th week post‐exposure to 150 ppm of styrene. After exposure to 1000 ppm of styrene, almost normal function and morphology of the tracheal mucosa was found at the 12th week post‐exposure, but the nasal mucosa continued to show decreased ciliary activity and an affected morphology.
Platelet population profiles: Significance of species variation and drug‐induced changes
Authors: Eason C. T. , Pattison A. , Howells D. D. , Mitcheson I. , Bonner F. W.
Published: October 2006

Platelet counts are routinely assessed from whole blood samples and recent technical advances enable the total platelet counts to be complemented by additional information which fully profiles the platelet population. In this report the platelet count, mode and mean platelet volumes and platelet profile histograms are presented for eight mammalian species. Species and strain variation in platelet profiles and the degree of volume heterogeneity are presented, and a platelet profile is presented for the marmoset which is previously unreported. The significance of these parameters and their potential importance to the toxicologist are disussed in the light of an observation of a drug‐induced altertaino in a platelet population profile.
Dose requirements, assay procedures and tissue specificity for PCB inductation of P‐450 dependent mono‐oxygenase activity in the rat: Implications for design of studies measuring in vivo induction of human placental monooxygenases
Authors: Wong Thomas K. , Blanton Toni E. , Hunnicutt Colleen K. , Shore David L. , Everson Richard B.
Published: October 2006

Pregnant Sprague‐Dawley and Fisher 344 rats were treated on day 15 of gestation with Aroclor 1254 in a single dose ranging from 0 to 500 mg kg−1 body weight and killed on day 18 of gestation. In the small groups of animals used for this study, no effect was observed on mean maternal liver or placental weight, or the number of fetal resorptions at any of the doses tested. Measurement of aryl hydrocabon hydroxylase (AHH) and 7‐ethoxycoumarin 0‐deethylase (7ECD) activity in tissue homogenates, however, showed that administration of Aroclor 1254 (15 mg kg−1 body weight or greater) induced mono‐oxygenase activity in fetal liver. Both the AHH and 7ECD assay detected effects of PCBs with similar sensitivity, and the findings were comparable when homogenates were assayed instead of microsomes. These data were used to suggest technical approaches to the detection of mono‐oxygenase induction in placental tissue human populations exposed to PCBs.
Comparison of effects of ozone, cadmium chloride and carbon tetrachloride on [14C]antipyrine metabolism in conscious rats
Authors: Dutta Saradindu , Kamat Madhav , Gole Dilip
Published: October 2006

Previously, Graham et al. found evidence that pentobarbital‐induced sleeping time was enhanced in various animals following exposure to 1 ppm of ozone in air. The present study was undertaken to investigate whether similar ozone exposure would cause inhibition of metabolism of another model drug, [14C]antipyrine, in conscious rats. Furthermore, this study also investigated whether, like that of ozone, other lipid‐peroxidizing agents such as cadmium and carbon tetrachloride would affect metabolism of [14C]antipyrine in conscious rats.

The results showed no significant effect of ozone exposure on subsequent metabolism of [14C]antipyrine in conscious rats as revealed by very similar 14CO2 exhalation rate (CER)‐time profiles before and after ozone treatment under various exposure protocols. Even though the exposure to ozone caused no inhibition of antipyrine metabolism in conscious rats, cadmium and carbon tetrachloride, on the other hand, markedly inhibited metabolism of this model drug. In agreement with the reported sex‐difference in toxic effects of cadmium, during the present study the cadmium‐induced inhibitory effect on the CER‐time profiles was observed in male but not in female rats. In contrast, no clear sex‐dependency was noted in the inhibitory effect of carbon tetrachloride on [14C]antipyrine metabolism.
Biotransformation of dimethylarsinic acid in mouse, hamster and man
Authors: Marafante Erminio , Vahter Marie , Norin Harald , Envall Jeanette , Sandström Margareta , Christakopoulos Alexandros , Ryhage Ragnar
Published: October 2006

The metabolism of dimethylarsinic acid (DMA) a common pesticide and the main metabolite of inorganic arsenic in mammals, has been studied in mice, hamsters and man. Mice and hamsters were administered a single dose of 74As‐DMA (40 mg As/kg body weight) orally, while a human subject ingested DMA corresponding to 0.1 mg As/kg body weight. Ion exchange chromatography, paper electrophoresis, thin layer chromatography as well as arsine generation—gas chromatography combined with atomic absorption spectrophotometry or mass spectrometry were used to characterize the arsenic metabolites in urine and feces collected over 48 hours after treatment.

In mice and hamsters 3.5% and 6.4% of the dose, respectively, were excreted in urine in the form of trimethylarsine oxide (TMAO). No TMAO was found in feces. A DMA‐complex was detected in urine and feces. It amounted to about 13% of the dose in mice and 15% in hamsters. About 80–85% of the dose was eliminated in urine and feces in the form of unmetabolized DMA. No demethylation of DMA to inorganic arsenic was observed. In man, about 4% of the dose was excreted in urine as TMAO and about 80% as DMA.
Measurement of polycyclic aromatic hydrocarbons and other pollutants
Authors: Garcia M. Espigares , López J. A. Pérez , Larrubia A. Mariscal , Fernandez‐Crehuet M. , Vargas R. Gálvez
Published: October 2006

A single point study of atmospheric pollution has been carried out in Granada (Spain); suspended particulate matter, sulphur oxides, ammoniac, nitrogen dioxide and polycyclic aromatic hydrocarbons were determined. There were variations in relation to the month and the day of the week. The PAHs have been determined through HPLC, with a mobile phase of acetonitrile–water (75–25). The results of measurements of benzo(a)pyrene were between 1.006 and 0.485 μ m−3 in two different periods of sampling.
The development of contact hypersensitivity in mouse skin is suppressed by tumor promoters
Authors: Czerniecki Brian , Witz Gisela , Reilly Christopher , Gad Shayne C.
Published: October 2006

The ability of tumor promoters to suppress the development of contact hypersensitivity (CHS) was assessed by the mouse ear swelling assay. Application of the complete or second stage tumor promoters phorbol‐12‐myristate‐13‐acetate (PMA, 2 μg), croton oil (1%), benzoyl peroxide (20 mg), mezerein (2 μg), or phorbol‐12‐retinoate‐13‐acetate (PRA, 2 μg) to the abdominal surface of CF‐1 female mice for 1 week (three treatments) prior to the sensitization of the same location with 0.5% 1‐chloro‐2,4‐dinitrobenzene (DNCB) resulted in a 50% suppression (p <0.05) of the CHS response to DNCB. The first stage tumor promoters 4‐O‐Me‐PMA (80 μg), calcium ionophore A23187 (80 μg), hydrogen peroxide (15%) and the non‐promoting analogs phorbol‐12,13‐diacetate (PDA, 20 μg), phorbol (80 μg) or acetone did not suppress the response. The suppression of the development of CHS caused by PMA was dependent on the promoter being applied at the site of induction and was inhibited by application of the phospholipase A2 inhibitor dibromoacetophenone (100 μg), the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 100 μg), or the antiinflammatory steroid fluocinolone acetonide (2 μg). Application of PMA or mezerein 24 h prior to challenge with DNCB, to the ears of mice previously sensitized with DNCB resulted in a significant enhancement of the ear swelling response by 60% and 110%, respectively, compared with controls. The results demonstrate that tumor promoters suppress the development of CHS, and suggest the possibility that second stage promotion may involve suppression of the development of a tumor specific immune response.
The effects of caffeine on the ultrastructure and mitochondrial function of the embryonic chick heart
Authors: Bruyere Harold J. , Noonan John J. , Dong Sophie , Oberley Terry D. , Schmidt Mary J. , Gilbert Enid F. , Shug Austin L.
Published: October 2006

Results from this study indicate that caffeine at an embryotoxic dose equal to the LD40 administered to 3‐day chick embryos produced both ultrastructural and functional abnormalities in embryonic cardiac mitochondria. The principal effects of caffeine on the ultrastructure of embryonic myocardial cells were clearly suggestive of cellular injury and included: (1) a marked disruption of mitochondrial cristae with formation of intramitochondrial myelin‐like figures and (2) intracellular edema. A biochemical analysis of mitochondrial function revealed that caffeine inhibited the capacity of mitochondria to oxidize succinate. However, when pyruvate and malate were employed as substrates for isolated mitochondria, caffeine did not significantly alter mitochondrial function. Interference with embryonic cardiac mitochondrial succinate oxidation and/or fragmentation of mitochondrial membranes are suggested as possible events in the pathogenesis of caffeine‐induced cardiac cell injury which, in turn, may lead to the embryonic death of the chick.
Changes in some histochemically demonstrable enzymes in macrophages exposed to quartz dust in vitro
Authors: Dogra Shashi , Kaw Jawahir Lal
Published: October 2006

Cytochemical studies were carried out on rat alveolar and peritoneal macrophage cultures following exposure to quartz and corundum dusts. Quartz increased the number of ATPase positive cells and brought about an enhancement in the peroxidase and diffusion of the acid phosphatase activity of the exposed cells. In unexposed cell cultures, acid phosphatase activity was higher in alveolar than in peritoneal macrophages and was dependent upon the duration of incubation. Corundum produced no significant effect on the enzyme activity. Quartz treatment did not alter esterase activity whereas corundum exposed cultures showed a decline. A significant increase in mitochondrial succinic dehydrogenase activity was observed in peritoneal macrophages after quartz treatment. The results demonstrate alteration in the marker enzymes of plasma membranes, mitochondria and lysosomes during phagocytosis of quartz dust as the key event of dust cell interaction in vitro.
The effects of amrinone, cyclophosphamide and anti‐platelet serum on platelet production in the gunn rat
Authors: Eason C. T. , Pattison A. , Howells D. D. , Bonner F. W. , Martin J. F.
Published: October 2006

The effect of amrinone on platelet production was differentiated from that of a known bone‐marrow cytotoxic agent (cyclophosphamide) and anti‐platelet serum (APS). The rate of platelet production has been observed over a 4‐day period in the Gunn rat using [75Se]selenomethionine cohort labelling of platelets following administration of either amrinone, 160 mg kg−1 day−1, cyclophosphamide, 30 mg kg−1 day−1 or APS, 0.75 ml. Platelet numbers were reduced by amrinone, cyclophosphamide and APS. The rate of platelet production was increased following APS and suppressed by cyclophosphamide, but the rate of platelet production when expressed as the selenomethionine incorporation in counts per minute (cpm) per 108 platelets appeared to be increased in amrinone‐treated animals. When these values are expressed as radioactivity per unit platelet volume the difference between the control and the amrinone‐treated group was reduced but the difference between the control, APS‐ and cyclophosphamide‐treated groups remained unchanged. It is concluded that in the Gunn rat amrinone affects platelet production by producing fewer, larger platelets.
Acute and neurotoxicity of two structurally related acetylenic compounds: 5,7,11‐dodecatriyn‐1‐ol and 5,7,11,13‐octadecatetrayne‐1,18‐diol
Authors: Gad Shayne C. , Dunn Brendan J. , Gavigan Frances A. , Reilly Christopher , Peckham John C.
Published: October 2006

Two structurally related acetylenic compounds, 5,7,11‐Dodecatriyn‐1‐ol, (Compound A), and 5,7,11,13‐Octadecatetrayne‐1,18‐Diol (Compound B), were evaluated in a tier I toxicology testing program as part of an ongoing research and development program. This battery of acute tests included acute oral, guinea pig maximization, photosensitization, dermal irritation, Ames and multiple genetic endpoint and a 2 week oral fetotoxicity study. Compound A was found to have an oral LD50 of 0.25 ml/kg, be an extreme dermal sensitizer, a mild dermal irritant (PDII of 1.7), and not mutagenic or fetotoxic in the tests employed. Compound B had an oral LD50 greater than 4 g/kg, was a moderate dermal sensitizer and mild dermal irritant (PDII of 1.4), was not mutagenic in the Ames test but weakly increased the incidence of SCEs and gene mutations in Chinese Hamster Ovary cells, and was not fetotoxic. Neither compound was found to be a photosensitizer, but during the course of the photosensitization study Compound A was found to cause neuromuscular signs (including hind limb paralysis) and a bilaterial necrosis of the medulla oblongata in female guinea pigs. A similar lesion was found in female rats receiving a single oral dose of 0.25 ml/kg and in nonpregnant females dosed daily for two weeks at 0.03 ml/kg. Compound B was not found to produce any of these neurologic effects.
Effect of hexacarbons on selected lipids in developing rat brain and peripheral nerves
Authors: Bhatt A. , Khan S. , Pandya K. P. , Sabri M. I.
Published: October 2006

The effects of neurotoxic solvents, i.e. 2,5‐hexanedione (2,5‐HD), 2,5‐hexanediol (2,5‐HDiol) and the non‐neurotoxic solvent, 2,4‐hexanedione (2,4‐HD) (500 mg/kg body wt./day, i.p.), have been studied on the lipid composition of brain and sciatic nerves in weanling rats. Five‐day‐old rats were administered a solvent daily for 21 days. Clinical signs of peripheral neuropathy appeared in 2,5‐HD and 2,5‐HDiol treated groups. Absolute weights of brain, spleen, thymus significantly decreased with 2,5‐HD. Cholesterol content in whole brain homogenates and myelin was significantly reduced with 2,5‐HD and 2,5‐HDiol treatment. There was also a significant reduction in ubiquinone content of brain with 2,5‐HD and 2,5‐HDiol treatment. On exposure to neurotoxic chemicals to weanling rats, significant alteration in lipid profile was observed in the brain, which may be one of the key factors in the development of neuropathy.
An experimental study on the respiratory toxicity of isopropyl alcohol
Authors: Ohashi Yoshihiro , Nakai Yoshiaki , Ikeoka Hiroshi , Koshimo Hiroyuki , Esaki Yusuke , Horiguchi Shuńichi , Teramoto Keiko , Nakaseko Hiroyuki
Published: October 2006

Guinea‐pigs were exposed to 400 ppm or 5500 ppm of isoprophyl alcohol (IPA) for 24 successive hours, and they were killed immediately after the exposure period. The ciliary activities of the nose and trachea were examined. In addition, the epithelium of the nose and trachea was observed by scanning and transmission electron microscopy.

The present study showed that exposure to 400 or 5500 ppm of IPA vapor caused deterioration of the ciliary activity and also some pathological changes. Although our study revealed that exposure to 400 ppm of IPA vapor can affect the mucosa of the nose and trachea, the ciliary activity of the 400‐ppm exposure group was not too poor and morphological changes were rather mild. Recovery from such degeneration might be rapid. Therefore, our study supports the justification of the allowable IPA level recommended by ACGIH.
Removal of urea from alcoholic beverages with an acid urease
Authors: Kobashi Kyoichi , Takebe Sachiko , Sakai Tatsuo
Published: October 2006

Urethan, a cancer causing chemical, was reported to contaminate some alcoholic beverages. Since urethan is formed by heating urea with ethylalcohol, removal of urea is necessary to prevent urethan formation in alcoholic beverages. Acid urease, whose optimal pH lies around 4, lowered urea concentrations in Japanese sake. This finding indicates a protective effect of acid urease on urethan's potential hazards in alcohol.
Heart and lung hypertrophy, changes in blood volume, hematocrit and plasma renin activity in rats chronically exposed to increasing carbon monoxide concentrations
Authors: Penney David G. , Davidson Scott B. , Gargulinski Richard B. , Caldwell‐Ayre Therese M.
Published: October 2006

Changes in blood volume, heart and lung mass and composition and plasma renin activity were examined in two strains of male albino rats inhaling incrementally‐increasing concentrations of CO: 250 ppm for 17 days, 500 ppm for 13–14 days, 750 ppm for 10 days, and 1300 ppm for 10 days. Blood volume increased 86% and erythrocyte mass increased 212% at 1300 ppm, while plasma volume was unchanged or decreased slightly. “Real” hematocrit (hematocrit corrected for plasma trapping) increased from 50% in controls to a peak of 75% at 1300 ppm CO. Wet weight of right ventricle (RV) and combined right and left atria (2A) increased linearly with CO concentration, paralleling changes in blood volume; while real hematocrit increased nonlinearly. Left ventricle + interventricular septum (LV+S) wet weight increased less than RV, but more in Sprague‐Dawley than in Wistar rats. Plots of RV, LV+S and 2A weight vs real hematocrit showed sharp upward inflections at real hematocrit 65%, suggesting a possible role of increased viscosity in CO cardiomegaly at the higher hematocrit. Assymetric septal hypertrophy was not present. Lung weight increased with CO concentration, but was not due to increased lung blood volume or edema. Hydroxyproline measurements on heart and lung failed to show increased collagen content. Plasma renin activity measured by radioimmunoassay was depressed at 500 ppm, but was normal at 750 and 1300 ppm CO. Neither heart, lung,liver nor plasma renin measurements suggest congestive heart failure, supporting previous studies in the rat with chronic carboxyhemoglobinemia, in spite of enormously increased blood volume, hematocrit and heart weight.