bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical assessment of the genotoxicity of the in vitro interaction between chlordecone and carbon tetrachloride in rat hepatocytes
Authors: Ikegwuonu Fidelis I. , Mehendale Harihara M.
Published: October 2006

The genotoxic potential of the administration of carbon tetrachloride alone or carbon tetrachloride to chlordecone‐pretreated rats was investigated using an in vivo–in vitro animal model and a battery of biochemical assays to measure DNA repair in rat hepatocytes. Whereas carbon tetrachloride alone was not genotoxic, chlordecone or chlordecone in combination with carbon tetrachloride was genotoxic. The need for further investigation into the mechanism underlying the interaction between chlordecone and carbon tetrachloride is indicated strongly by the results of the present study.
Dithiocarbamate analog N‐(4‐methoxybenzyl)‐N‐dithiocarboxy‐D‐glucamine reduces the retention of ingested cadmium in rats
Authors: Kargačin B. , Kostial K. , Arežina R. , Singh P. K. , Jones M. M. , Cikrt M.
Published: October 2006

This study was performed to evaluate the effect of oral and intraperitoneal treatment with N‐(4‐methoxybenzyl) D‐glucamine dithiocarbamate monohydrate (MeOBDCG) after a single oral administration of 115mCd to 6‐week‐old rats. Oral treatment reduced the retention of 115mCd in the whole body, gut, liver and kidney by 5, 3, 4 and 3 times respectively, and intraperitoneal treatment reduced the retention by 7,2.5, 16 and 4.5 times, respectively. This finding is new, since it was believed that oral dithiocarbamate treatment would increase the toxicity and absorption of ingested cadmium.
Complexing of toxic hydrolysable tannins of yellow‐wood (Terminalia oblongata) and harendong (Clidemia hirta) with reactive substances: An approach to preventing toxicity
Authors: Murdiati Tri Budhi , McSweeney Christopher S. , Lowry J. B.
Published: October 2006

Ruminants consuming either tannic acid or hydrolysable tannins from the Australian yellow‐wood tree (Terminalia oblongata) and the Indonesian shrub Clidemia hirta are intoxicated by simple phenolics liberated in the gut. The affinity of these tannins and of the simple phenolic gallic acid for the two proteins casein and pepsin, polyvinylpyrolidone (PVP), activated charcoal and Ca(OH)2 was examined in vitro. The studies were undertaken to predict the effect of these phenolics on digestion and to identify substances that would act as antidotes by precipitating phenolics. Tannins but not gallic acid were precipitated as stable complexes with both pepsin and casein at pH 3–5. Optimal complexing of tannin with protein occurred at a weight ratio of 1:1. Ionic strength and temperature did not affect the amount of tannin precipitated from solution with protein. The precipitation of tannins with PVP and Ca(OH)2 was unaffected by pH within the range 2–8 while maximum binding with activated charcoal occurred between pH 3 and 7. In contrast to protein, the other substances complexed with gallic acid; only gallic acid‐PVP complexess were affected by pH. Calcium hydroxide bound more tannin and gallic acid on a weight basis than PVP and charcoal. Both Ca(OH)2 and activated charcoal should complex with phenolics in the forestomach, abomasum and intestines.

The reaction of hydrolysable tannins and proteins at the pH found in the abomasum suggests that hydrolysable tannins would interfere with enzyme function and protein digestion post‐ruminally rather than in the forestomach.
Toxicity of 1,4‐bis(aminocyclohexyl)methane
Authors: Kennedy G. L.
Published: October 2006

1,4‐Bis(aminocyclohexyl)methane (PACM; CAS No. 1761‐71‐3) is a white solid considered for use in polymeric systems. PACM is moderately toxic systemically, with the acute oral lethal dose in rats between 670 and 1000 mg kg−1. PACM is a weak dermal sensitizer in the guinea pig. Instillation of as little as 10 mg of PACM to the rabbit eye produces severe injury. This damage could be permanent and was not reduced by rinsing the eye with water. Dogs given oral doses of 50 mg PACM kg−1 5 days per week for up to 18 months showed kidney and liver damage, along with local irritation of the gastrointestinal tract. The chemical is highly irritating and contact with it should be avoided.
Immunotoxicity of tri‐n‐butyltin oxide (TBTO) and tri‐n‐butyltin chloride (TBTC) in the rat
Authors: Bressa G. , Hinton R. H. , Price S. C. , Isbir M. , Ahmed R. S. , Grasso P.
Published: October 2006

In a 1‐month feeding trial, pure and commercial tri‐n‐butyltin oxide (TBTO) and tri‐n‐butyltin chloride (TBTC) were fed to rats at concentrations of 5 ppm and 25 ppm. At all times, the mean body weight gain and the food consumption was significantly less in rats treated with 25 ppm pure TBTO or pure TBTC as compared to control rats or rats receiving commerical TBTO. Histological examination of the thymus of rats treated for 7 days with TBTO showed atrophy with severe lymphocytic depletion in the cortex. After 28 days of exposure, most of the lesions reversed and the thymus became markedly smaller than in control rats, both in absolute terms and in relation to body weight. Seven days of exposure to TBTO increased liver weight but this change was reversed during a further 3‐week exposure. Tin concentrations were the highest in livers and kidneys. Concentrations in the thymus were less than one‐fifth of hepatic values. Changes in the rats treated with the commercial TBTO were very similar. Rats treated with TBTC showed lower tin levels and less immunotoxicity as compared to those treated with TBTO.
Joint toxic action of binary mixtures of osteolathyrogens at malformation‐inducing concentrations forXenopusEmbryos
Authors: Dawson Douglas A. , Wilke Teresa S.
Published: October 2006

The joint action of binary mixtures of the osteolathyrogens semicarbazide (SC), β‐aminopropionitrile (βAPN) and penicillamine (PNC) were determined at malformation‐inducing concentrations forXenopusembryos. Tests were static with renewal every 24 h for the 96‐h test period. Simultaneous tests on each individual component of the binary mixtures alone gave baseline malformation data (EC50) for joint action analyses. Toxic unit analysis and isobole diagrams were used to determine the type of joint action for 3:1, 1:1 and 1:3 mixtures of each combination. The joint action was concentration additive (strictly additive) for SC with βAPN and response additive (less‐than‐additive) for SC with PNC and βAPN with PNC. The joint actions were not changed when only osteolathyrogenic lesions, rather than all types of malformations, were considered. The different specific location and character of PNC lesions, as opposed to those for SC and βAPN, may signify a different type of osteolathyrogenic effect for PNC. The mixture testing approach has potential value in determining compounds that act similarly.
Difference in liver and serum malathion carboxylesterase and glucose‐6‐phosphatase in detecting carbon tetrachloride‐induced liver damage in rats
Authors: Brondeau M. T. , Coulais C. , de Ceaurriz J.
Published: October 2006

Microsome, cytosol and serum malathion carboxylesterase (MaCEst) activity was assessed in rats after single i.p. administration of carbon tetrachloride (CCl4) in doses ranging from 0.05 to 1 ml kg−1. MaCEst activities were compared with those of glucose‐6‐phosphatase (G6‐Pase) as an indicator of endoplasmic reticulum damage and serum glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SHD) as indicators of liver cytolysis. The data showed a dose‐dependent increase in GLDH and SDH serum activities (175% and 68%) from 0.05 ml kg−1; an increase in serum G6‐Pase (31%) and a decrease in microsomal G6‐Pase (38%) was apparent only after 0.5 or 1.0 ml kg−1 doses. MaCEst activity was unaffected. The results demonstrate that, under these experimental conditions, serum and subcellular measurements of MaCEst activity failed to reveal the liver toxicity of CCl4.
Biliary excretion of hexachloro‐1,3‐butadiene and its relevance to tissue uptake and renal excretion in male rats
Authors: Payan J. P. , Fabry J. P. , Beydon D. , de Ceaurriz J.
Published: October 2006

Renal, biliary, pulmonary and faecal excretion experiments were carried out with labelled hexachloro‐1,3‐butadiene ([14C]HCBD) in male Sprague‐Dawley rats, given orally (p.o.) and intravenously (i.v.) in doses of 1 and 100 mg kg−1 as a solution in polyethylene glycol. The radioactivity excreted over 72 h was determined in rats fitted with exteriorized biliary cannulae and in rats whose bile ducts remained fully functional, respectively. In addition, bile duct–duodenum cannula‐linked rats, of which the donor was given 100 mg kg−1 [14C]HCBD orally and the recipient had also a bile fistula, were examined within 30 h for radioactivity in the excreta, the kidney, the liver and the plasma. In non‐cannulated rats, fractional urinary excretion decreased when the dosage increased and amounted to 23% and 8.6% after i.v. injection or 18.5% and 8.9% after p.o. administration of 1 and 100 mg kg−1, respectively. Pulmonary excretion of radioactivity was<9% and was not affected by the increase in dosage. In bile duct‐cannulated rats, fractional urinary excretions were similar irrespective of the dose and the route of administration and amounted to ca. 7.5% of the dose. Decrease in fractional biliary excretion occurred with increase in dosage (88.7% vs 72%) after i.v. injection and (66.8% vs 58%) after gavage. In cannulated rats, faecal excretion was<0.5% after i.v. injection and accounted for 3% and 16% of the dose after p.o. administration of 1 and 100 mg kg−1, respectively. In rats linked in a cascade fashion, the donors excreted 3%, 45% and 19.5% of the dose in the urine, the bile and the faeces versus 2%, 16.8% and 8.4% for the recipients, respectively. Renal, hepatic and plasma radioactivity concentrations represented 0.26, 0.11 and 0.013% g−1 of the dose in the donors versus 0.15, 0.07 and 0.009% g−1 of the dose in the recipients. Biliary decline may result from a saturation of the hepatobiliary mechanism after i.v. injection and/or a saturation of gastrointestinal HCBD absorption after p.o. administration. The results indicate that at least 80% of the biliary metabolites of HCBD undergo biliary recycling and constitutes about 40% of renal excretion and tissue uptake of [14C]HCBD at the high dose level. They also support the assumption that decline in fractional urinary excretion with increase in HCBD dosage was unlikely to be due to renal saturation but was probably the result of hepatobiliary saturation and/or defective enterohepatic circulation of HCBD metabolites.
Bioassay of organophosphate nerve agents in soil using neuronal tissue cultures
Authors: Sawyer Thomas W. , Weiss M. Tracy , D'Agostino Paul A. , Provost Lionel R. , Hancock James R.
Published: October 2006

A soil sample originating from an area of suspected chemical warfare activity was subjected to chemical analysis and bioassay. Sarin and several related compounds were confirmed in the soil by capillary column gas chromatography–mass spectrometry (GC–MS); however, the binding of these compounds to the soil hindered quantitation. The chemical results were then compared to those obtained by bioassay in primary cultures of chick embryo forebrain neurons. By comparing the sample's anticholinesterase activity against those of purified standards in chick embryo neuron cultures, a reasonable agreement was found between the chemical and bioassay semi‐quantitative estimates of sarin content in the soil extract. Furthermore, the in vitro system appears to offer a sensitive technique for the estimation of sarin remaining bound to the soil following solvent extraction as well as for an assessment of the potential toxicity of the contaminated soil in vivo.
Hexachlorobenzene (HCB) suppresses circulating progesterone concentrations during the luteal phase in the cynomolgus monkey
Authors: Foster Warren G. , McMahon Avril , Villeneuve David C. , Jarrell John F.
Published: October 2006

Hexachlorobenzene (HCB) is a known reproductive toxin. However, the full spectrum of its reproductive toxicity is unknown. Consequently, the effect of HCB on serum oestradiol (E2) and progesterone (P4) concentrations during the follicular (days 1–9), periovulatory (days 10–14) and luteal (days 15 to beginning of next menses) phases was investigated in the spontaneously cycling cynomolgus monkey. Adult female cynomolgus monkeys (n = 16) were randomly assigned to one of four treatment groups and orally dosed with gelatin capsules containing HCB (0.0, 0.1, 1.0 and 10.0 mg kg−1 body wt. day−1) mixed with glucose. A 10‐week acclimitization phase was followed by 13 weeks of dosing. HCB induced a dose‐dependent suppression of serum P4 concentrations during the luteal phase. However, circulating levels of P4 were unaffected during the follicular and periovulatory phases of the menstrual cycle. Serum E2 concentrations, body weight, menstrual cycle length and duration of menses were not affected by HCB treatment. The range of menstrual cycle length and duration range of menses, however, were broader in the highest dose group. We conclude that HCB interfers with mechanisms regulating ovarian steroidogenesis and suppresses P4 levels during the luteal phase in the cynomolgus monkey.
Oral administration of d‐penicillamine causes neonatal mortality without morphological defects in cd‐1 mice
Authors: Rousseaux C. G. , Macnabb L. G.
Published: October 2006

D‐Penicillamine (DPA) causes axial skeletal defects in rats and fetal lethality when given as 0.83% and 1.6% of the diet, but its mechanism of action on the axial skeleton is unknown. We have been using submerged fetal CD‐1 mouse limb‐bud organ cultures to evaluate the mechanisms of teratogenesis in the developing murine limb. Before attempting to evaluate the in vitro effects of DPA, a dose response morphological teratology study was undertaken using CD‐1 mice to determine the effects of DPA on the mouse and determine the potential of using the mouse limb‐bud assay to investigate the terata produced by DPA. Groups (n = 8) of nulliparous pregnant mice (vaginal plug = day 0 of gestation) were dosed, via oral gavage, with 0, 250, 500, 1000 and 2000 mg kg−1 DPA for the first 12 days of gestation. Body weights and food consumption were measured daily. On day 18, fetuses were removed by Caesarian section. Two‐thirds of the fetal skeletons were stained with alcian blue and alizarin red and then cleared and examined for defects. Soft‐tissue defects were examined in the remaining one‐third using a modification of the Wilson freehand technique. Maternal body weight gains were not different before day 12 of the experiment, but differed in the interval of day 13–18 (P = 0.004). No group differences were noted in male/female ratios, site of implantation, implantation numbers and number of fetuses. Decreased survivability was seen in the 2000 mg kg−1 group. No treatment‐related defects were seen. As the main purpose of this experiment was to determine a dose at which limb defects occurred, the results indicate that the CD‐1 mouse does not appear to be a good model for DPA‐induced skeletal defects.
Effect of chloroquine on oestrus cycle and ovulation in cyclic rats
Authors: Okanlawon Abayomi O. , Ashiru Oladapo A.
Published: October 2006

We conducted experiments to determine the effects of chloroquine (CQ) on the oestrus cycle and ovulation in 4‐day cyclic rats. There were two treatment groups. Group I animals had chloroquine phosphate (40 mg kg−1 body wt.) administered intraperitoneally (i.p.) starting from dioestrus day 1, once a day, 5 days a week for 4 weeks. Oestrus smear was monitored by daily saline vaginal lavage. Control rats received an equal volume of physiological saline. All animals were sacrificed at the end of the 4th week of treatment.

Group II animals also received chloroquine phosphate (40 mg kg−1 body wt.) administered in a single dose at either 0900 h or 1800 h pro‐oestrus, and on the morning of oestrus the rats were killed. Trunk blood was collected in each group at the time of sacrifice, centrifuged and the serum stored for subsequent radioimmunoassay of luteinizing hormone (LH), follicle stimulating hormone (FSH) and oestrogen. The fallopian tube was dissected out and a search made for the ova.

Results showed that administration of chloroquine altered the oestrus cycle (i.e. the rats showed a persistent dioestrus smear), lowered serum oestrogen and luteinizing hormone levels while serum FSH was unaltered, prevented the expected ovulation when injected at 0900 h pro‐oestrus and did not affect ovulation in rats injected at 1800 h pro‐oestrus. This study supports the notion that chloroquine has an adverse effect on hypothalamo‐pituitary ovarian systems.
Teratogenic assessment of four solvents using the frog embryo teratogenesis assay—xenopus (FETAX)
Authors: Dresser Todd H. , Rivera Edna R. , Hoffmann Florence J. , Finch Robert A.
Published: October 2006

The Frog Embryo Teratogenesis Assay—Xenopus (FETAX) was used to assess the teratogenic potential of four solvents. Embryos of the South African clawed frog, Xenopus laevis, were exposed for 96 h to ethanol, dimethyl sulfoxide (DMSO), formamide or glycerol formal. Exposure groups were maintained using a static renewal system in which the exposure media were changed at 24‐h intervals. Survival was monitored at 24‐h intervals. Length, as an indicator of growth effects, and developmental malformations were determined at the end of the assay (96 h). Using this information, the 96‐h LC50, the 96‐h EC50 (Malformation), and the no observable effect levels (NOELs) for mortality, malformation and length were determined for each solvent. The teratogenic index [TI = 96‐h LC50/96‐h EC50 (Malformation)] also was calculated for each of the solvents. DMSO apeared to be the least toxic or teratogenic solvent examined, with a pooled LC50 of 1.92%, a pooled EC50 (Malformation) of 1.57% and TI values of 1.20 and 1.24 in replicate trials. Formamide appeared to be the most toxic solvent, with a pooled LC50 of 1.04%. Data trends suggested that ethanol was the most teratogenic solvent tested, with a pooled EC50 (Malformation) of 1.04% and TI values of 1.42 and 1.50. The results obtained in the present work for ethanol and DMSO were compared to previously published FETAX results for these two solvents. The present results are in close agreement with these results from other laboratories, thus providing further evidence supporting the interlaboratory reproducibility of FETAX results.
Effect of period of exposure on the developmental toxicity of butyl benzyl phthalate in rats
Authors: Ema Makoto , Itami Takafumi , Kawasaki Hironoshin
Published: October 2006

The objective of the present study was to determine if periods of exposure would modify the developmental toxicity of butyl benzyl phthalate (BBP). Pregnant Wistar rats were given BBP at a dose of 2.0% in the diet on days 0–20, days 0–7, days 7–16 or days 16–20 of pregnancy. Food consumption and body weight gain were decreased in the pregnant rats given BBP. All dams given BBP on days 0–20 exhibited complete resorption of all the implanted embryos. Post‐implantation loss in the pregnant rats given BBP on days 0–7 or 7–16 was higher than that in the control and pair‐fed pregnant rats. No increase in post‐implantation loss was found in the pregnant rats given BBP on days 16–20. Pre‐implantation loss in the BBP‐treated groups was comparable to the control and pair‐fed groups. Striking teratogenicity was detected in fetuses of the dams given BBP on days 7–16. Cleft palate and fusion of the sternebrae were predominantly observed. About 95% of the fetuses in this group had cleft palate. The incidence of malformations in this group was significantly and markedly higher than that in the control and pair‐fed groups.
Inhalation exposure of rats to metal aerosol. I. Effects on pulmonary surfactant and ascorbic acid
Authors: Kováčiková Zuzana , Chorvatovičová Darina
Published: October 2006

Female albino Wistar rats were exposed to <5 μm particles separated from nickel refinery waste. The generated aerosol of 50 mg m−3 mainly consisted of metal oxides, the most toxic being NiO and Cr2O3. The exposure of 5 h per day, 5 days per week, lasted for 4 weeks or 4 months. At the end of the exposure period the amounts of pulmonary surfactant and ascorbic acid were estimated in both exposed and control rats. The amount of pulmonary surfactant was elevated after both exposure times, while ascorbic acid increased significantly (P < 0.02) only after 4 weeks of exposure.
Design and evaluation of an exhaled breath sampler for biological monitoring of organic solvents
Authors: Periago J. Francisco , Luna Aurelio , Morente Antonio , Zambudio Alfonso
Published: October 2006

We designed a breath sampler based on a tube which collects the final portion of exhaled air. The passage of successive fractions through a layer of activated charcoal is controlled by a three‐way valve. This system was validated in a controlled atmosphere of n‐hexane and toluene at four concentrations between 12 and 110 mg m−3 and 12 and 115 mg m−3, respectively. Uptake volumes of 0.1, 0.2 and 0.3 I were tested at relative humidities of 46% and 98%. There were no significant differences in the recoveries obtained under any of the conditions tested. We confirmed the reproducibility between successive samples in volunteers and exposed workers, and found no significant differences between the different sampling conditions studied. Our system enriches the sample in an adsorbent cartridge by collecting successive fractions of end‐exhaled breath from one or more exhalations until the amount required by the analytical method has been accumulated. It is portable, economical and highly operative in the field.
Subacute oral toxicity of 2‐butyne‐1,4‐diol in rats
Authors: Jedrychowski Ryszard A. , Czajkowska Teresa , Gorny Roman , Stetkiewicz Jan , Stetkiewicz Irena
Published: October 2006

2‐Butyne‐1,4‐diol was given to male and female Wistar Imp:DAK rats by oral gavage for 28 consecutive days in daily doses of 1, 10 or 50 mg kg−1 day−1. After 28 days all animals were necropsied. Blood samples were obtained and selected organs were weighed and prepared for histological examination. Treatment‐related effects in the high‐dose group consisted of: fatal cases in both sexes; depressed body weight gain in males; increase of absolute and/or relative weights of liver and kidneys in both sexes; decreased red blood cell count, haematocrit value and haemoglobin concentration in female rats and elevated reticulocyte count and leukocyte count in both sexes; increased total serum protein content in females, elevated glucose concentration in males and higher activity of sorbitol dehydrogenase in both sexes; and hisiopathological evidence of hepatotoxicky and nephrotnxicity in decedents, and hepatic and splenic changes in survivors. Minor hepatic, splenic and erythrocytic changes were also found in some females given the middle dose. The dose of 1 mg kg−1 day−1 was considered to be the no‐observed‐effect level (NOEL), and 10 mg kg−1 day−1 the lowest‐observed‐eflfect level (LOEL).
Mechanism of citrinin‐induced dysfunction of mitochondria. I. Effects on respiration, enzyme activities and membrane potential of renal cortical mitochondria
Authors: Chagas Generoso M. , Campello Annibal P. , Klüppel Ma. Lúcia W.
Published: October 2006

Citrinin depresses the phosphorylation efficiency of rat renal cortical mitochondria, as inferred from the decrease of the respiratory control coefficient (RC) and ADP/O ratios. The transmembrane potential (Δψ) developed by energized mitochondria and the depolarization upon ADP addition are also decreased. Citrinin (1.0 mM) inhibits almost all enzymes linked to the respiratory chain and increases the activity of succinate cytochrome c reductase and succinate oxidase (coupled). Malate and glutamate dehydrogenases are also inhibited. The inhibitory action of citrinin on phosphoryiation efficiency could be related to the following findings: the effect on complex I; the action on the ATP synthetase complex; the partial inhibition of the transmembrane potential.
Experimental design‐based quantitative structure—toxicity relationship of some local anaesthetics using the PLS method
Authors: Norinder Ulf
Published: October 2006

A quantitative structure‐toxicology (LD50) relationship for some N‐alkylsuccinimides is presented. The relationship is based on a small and carefully selected training set using experimental design methodology. The good predictability, an overall r2 value of 0.75, with such an approach is demonstrated. Factors such as large N‐alkyl groups, substitution in the aromatic ring and a long side chain between the two nitrogens are favourable for low toxicity.
Embryolethality and teratogenicity of butyl benzyl phthalate in rats
Authors: Ema Makoto , Itami Takafumi , Kawasaki Hironoshin
Published: October 2006

Pregnant Wistar rats were given butyl benzyl phthalate (BBP) at a dose of 2.0% in the diet on days 0–20, days 0–11 or days 11–20 of pregnancy. Food consumption and body weight gain were decreased in pregnant rats given BBP. Pre‐implantation loss in the BBP‐treated groups was comparable to that in the control and pair‐fed groups. All dams given BBP on days 0–20 or days 0–11 exhibited complete resorption of all the implanted embryos. No increase in post‐implantation loss was found in pregnant rats given BBP on days 11–20. Marked teratogenicity was detected in fetuses of the dams given BBP on days 11–20. Cleft palate and fusion of the sternebrae were predominantly observed. Seventy‐two of the 134 fetuses had a cleft palate. The incidence of malformations in this group was significantly and markedly higher than that in the control and pair‐fed groups. In conclusion, the administration of BBP during the first and second half of pregnancy produced embryolethality and teratogenicity, respectively.
Indirect and lactation‐associated changes in renal alkaline phosphatase of newborn rats prenatally exposed to cadmium chloride
Authors: Saillenfait A. M. , Payan J. P. , Ban M. , de Ceaurriz J.
Published: October 2006

Pregnant Sprague‐Dawley rats were intraperitoneally injected with physiological saline solution (vehicle) or cadmium chloride (CdCl2) at 2.5 mg kg−1 body wt. on days 8, 10, 12 and 14 of gestation. Offspring were examined for renal alkaline phosphatase activity (ALP) on postnatal days (PND) 3 and 12, and for kidney metallothionein (MTh) and for liver, kidney and entire gastrointestinal tract 109Cd content at birth and on PND 3 and 12. No effects were observed on neonatal survival or on body, liver and kidney weights of pups up to PND 12. Newborns born and fed by mothers exposed to CdCl2 during pregnancy exhibited a significant decrease in ALP activity on PND 3. Conversely, no significant changes were observed in newborns lactatcd by surrogate non‐treated mothers. Renal MTh increased with age but was not influenced by maternal treatment. Traces of 109Cd were present in the liver at birth (5–7 ng). Thereafter, 109Cd was mainly found in the gastrointestinal tract of newborns lactated by their biological mothers (610–690 ng on PND 12), with a marginal uptake in the liver (10–12 ng on PND 12). 109Cd was not detectable in the kidneys at any age (< 4 ng).

These results show that prenatal exposure to Cd cannot be the sole aetiological agent in the induction of the subtle and transitory changes in renal biochemistry observed in offspring born and fed by female rats intraperitoneally injected with 2.5 mg CdCl2 kg−1 body wt. on days 8, 10, 12 and 14 of gestation. The resofts also contradict the role of a direct effect on the kidney.
The local lymph node assay: Results of a final inter‐laboratory validation under field conditions
Authors: Scholes E. W. , Basketter D. A. , Sarll A. E. , Kimber I. , Evans C. D. , Miller K. , Robbins M. C. , Harrison P. T. C. , Waite S. J.
Published: October 2006

The local lymph node assay (LLNA) assesses the sensitizing activity of chemicals by measurement of primary lymphocyte proliferation in lymph nodes draining the site of application. In this final inter‐laboratory stady the consistency of LLNA results between laboratories and with guinea pig maximization test (GPMT) data was examined under ‘field’ conditions. Nine chemicals were evaluated independently by each laboratory according to guidelines for test concentration and vehicle selection developed during previous validation studks to ensure assay optimization. Equivalent predictions of sensitization potential were obtained by all laboratories for eight chemicals. Five of seven chemicals identified as sensitizers in the GPMT were correctly identified in the LLNA—four by all laboratories and 1 (4‐chloroaniline) by one laboratory only—although in this latter case, two other laboratories obtained clear dose responses, suggestive of sensitization. The LLNA identified correctly those chemicals predicted to be extreme or strong sensitizers in the GPMT. The remaining two chemicals were non‐sensitizers in the guinea pig and failed to elicit positive proliferative responses in the LLNA. These data demonstrate that sensitivity and reliability of the LLNA is retained when chemicals are evaluated independently, and that it provides a reliable pre‐screen for the identification of chemicals with significant sensitization potential.
The effect of a commercial 2,4‐d formulation on chemical‐ and viral‐induced tumor production in mice
Authors: Blakley B. R. , Gagnon J. M. , Rousseaux C. G.
Published: October 2006

Male CD‐1 mice were exposed to a commercial formulation of 2,4‐dichlorophenoxyacetic acid (2,4‐D), the amine derivative, in the drinking water at concentrations ranging from 0 to 0.163% of the formulated product, equivalent to approximately 0–50 mg kg−1 day−1 2,4‐D content. The effect of 2,4‐D on urethan‐induced pulmonary adenoma formation was evaluated following a 105‐day exposure. Urethan‐induced sleeping times observed following an i.p. injection of urethan (1.5 mg g−1) after 3 weeks of 2,4‐D exposure were not altered by 2,4‐D, indicating that 2,4‐D did not influence urethan elimination. Pulmonary adenoma production, which was evaluated 84 days after urethan injection, was enhanced by 2,4‐D exposure but had no effect on tumor size. The effect of 2,4‐D on the incidence of spontaneous murine lymphocytic leukemia was evaluated during the 365‐day treatment period. Mortality associated with the leukemia virus was not altered by 2,4‐D treatment. Exposure to this commercial 2,4‐D product at moderately high levels of exposure may modify the development or expression of certain tumors in CD‐1 mice. The mechanism of the co‐carcinogenic or tumor‐promoting activity associated with 2,4‐D exposure remains to be determined.
Development and validation of a highperformance liquid chromatographic method for the determination of benzophenone‐3 in rats
Authors: Abdel‐Nabi Ismail M. , Kadry Abdelrazak M. , Davis Richard A. , Abdel‐Rahman Mohamed S.
Published: October 2006

A precise, accurate, selective and sensitive liquid chromatographic method for the determination of benzophenone‐3 in rat biological fluids and different tissues has been developed. The minimum detection limit for benzophenone‐3 was 2.0 ng ml−1 and the retention time was 6.01 min. Standard curves for benzophenone‐3 were linear in a wide range of concentrations in methanol and different body fluids, ranging from 6.25 ng ml−1 to 100 μg ml−1. To detect benzophenone‐3 in rat whole blood after oral administration, HCl hydrolysis was required. Benzophenone‐3 was found to produce a peak blood concentration 1 h after administration. Free benzophenone‐3 in urine represented a very small percentage during the first 12 h after administration, while a higher concentration of the glucuronide conjugate was detected in the same time period.
Acute and subacute toxicity of 7.5% hypertonic saline/6% dextran‐70 (hsd) in dogs 1. serum immunoglobulin and complement responses
Authors: Summary James J. , Dubick Michael A. , Zaucha Gary M. , Kilani Ahmed F. , Korte Don W. , Wade Charles E.
Published: October 2006

Clinical use of modern dextran solutions has been limited by concerns of anaphylactoid reactions. To assess the short‐term antigenic response to 7.5% hypertonic saline in 6% Dextran‐70 (HSD), sera were obtained from dogs involved in the acute and subacute toxicology testing of HSD and its individual components, and analyzed for IgG, IgM and C3 complement. In separate studies, beagles were infused i.v. with a single dose of HSD or its components at 20 ml kg−1 (the maximum tolerated dose; MTD), or the MTD daily for 14 days, and serum was obtained prior to and at various times after infusion up to 14 days. In both studies, despite serum dextran concentrations exceeding 2000 mg dl−1, no induction of IgG, IgM or C3 complement concentrations were observed. In addition, serum IgG immunoelectrophoretic patterns were of normal curvature, position and intensity; the immunoprecipitin bands were not displaced, bowed, inhibited or thicker than the normal preinfusion immunoelectrophoretograms.

The data suggest that single or multiple HSD i.v. injections, as much as five times the proposed therapeutic level for the treatment of hypovolemia, evoked no increase in antibody titers in dogs. Therefore, therapeutic use of HSD in the treatment of hemorrhagic shock should not be associated with widespread concomitant allergic complications.
Mutagenicity studies on two triphenylmethane dyes, bromophenol blue and tetrabromophenol blue
Authors: Lin George H. Y. , Brusick David J.
Published: October 2006

Bromophenol blue and tetrabromophenol blue are two triphenylmethane dyes. Triphenylmethane derivatives and their structurally related compounds, such as fluoresceins and xathenes, are widely used as industrial dyes for foods, drugs, cosmetics, textiles, printing inks or laboratory indicators. Since a number of these types of dyes have been reported to be genotoxic, safety concerns on these two dyes of interest have been raised. Consequently, a battery of genetic toxicology assays, including the Ames Salmonella/microsome assay, L5178Y TK+/− mouse lymphoma assay, mouse micronucleus test and mitotic recombination assay with yeast Saccharomyces cerevisiae strain D5, has been performed on each of the two dyes. The results of the evaluations indicate that both bromophenol blue and tetrabromophenol blue were not active and can be considered non‐genotoxic for the three genetic endpoints assessed (gene mutation, chromosome aberrations and primary DNA damage). Genetic activities in some structurally related compounds of these dyes have been reported but may be attributed to the presence of mutagenic impurities rather than the compound itself.
The influence of fenarimol on dna synthesis and mitotic activity in rat liver
Authors: Palut Danuta , Ludwicki Jan , SzlȩLzak‐Kopeć Joanna
Published: October 2006

Fenarimol administered in one single oral dose of 125 or 62.5 mg kg−1 body wt. day−1, respectively, stimulated rat liver enlargement at a dose‐independent rate. Three single doses of fenarimol produced dose‐dependent liver growth, whereas five single doses caused no further increase in liver weight. This increase was accompanied by an increase in hepatic DNA synthesis and mitotic activity, with a peak on the first day after the beginning of the experiments. The increase in binuclear hepatocytes and signs of necrosis suggested that the hepatomitogenic effect reflected a compensatory hyperplasia. After both three and five single doses the hepatomitogenic effect was supressed, as a result of tolerance development.
Effects of nickel hydroxycarbonate on alveolar macrophage functions
Authors: Arsalane K. , Aerts C. , Wallaert B. , Voisin C. , Hildebrand H. F.
Published: October 2006

The metabolic effects of different concentrations of nickel hydroxycarbonate (NiHC) on guinea pig alveolar macrophages (GPAMs) were investigated. Exposure to high concentrations of NiHC (6.25 and 12.5 μg 10−6 cells) led to cell vacuolization. Morphological changes were associated with a dramatic reduction in the steady‐state level of cellular adenosine triphosphate (ATP), i.e. ATP levels were reduced by 35% (P < 0.001) and 53% (P < 0.01), respectively. Low concentrations of NiHC (0.0625 and 0.125 μg 10−6 cells) did not induce morphological changes but increased cellular ATP content by 19% (P < 0.01) and 12% (P < 0.05), respectively. Effects of NiHC (0.125 and 6.25 μg 10−6 cells) on cell oxidative metabolism were studied. The chemiluminescence was significantly increased (P < 0.001) by the lower but not the higher concentration. A slight inhibition of total superoxide dismutase (P < 0.05) and a decrease of catalase activity were demonstrated (P < 0.05) for the high dose, while the low dose decreased the levels of reduced and total glutathione. In conclusion, the effects of NiHC on alveolar macrophages are characterized by an overproduction of free radicals for low concentrations and the depletion of cellular reserve energy, particularly ATP, for high concentrations.
Preliminary report on the use of zinc in vivo to protect against nitrogen mustard toxicity in female Balb/cJ mice
Authors: Shackelford Mary E. , Tobey Robert A.
Published: October 2006

Previous studies with cultured normal human fibroblasts indicated that treatment of cells with zinc before exposure to an alkylating agent enhanced cell survival by seven‐ to ninefold. To establish whether a similar zinc‐induced protective response could be elicited in vivo, we conducted a preliminary experiment in which Balb/cJ female mice were treated with zinc (2 mg kg−1 body weight) or saline by intraperitoneal (i.p.) injection at 48, 36, 24 and 12 h before i.p. administration of the alkylating agent nitrogen mustard (4 mg kg−1 body weight). Of the animals that received saline before nitrogen mustard, 57% died as compared with only 20% in the group treated with zinc before administration of the alkylating agent. As was observed in the studies of cells in culture, the results described in this report may suggest the existence in Balb/cJ female mice of a zinc‐mediated protective response against nitrogen mustard toxicity.
Evaluation of the dermal carcinogenicity of lubricant base oils by the mouse skin painting bioassay and other proposed methods
Authors: Chasey K. L. , McKee R. H.
Published: October 2006

Lubricant base oils are petroleum products that are predominantly derived from the vacuum distillation of crude oil. Various types of refinement can be employed during the manufacturing process, and evidence suggests that certain of the associated process streams produce skin cancer. Polycyclic aromatic compounds (PACs), some of which are considered as the causative agents, are removed, concentrated or chemically converted during the refinement process. In order to understand the effects of various types of refinement processes on carcinogenic potential, 94 oils were evaluated in the mouse epidermal cancer bioassay. This Exxon database is unique, because of the wide range of crude oils and processing histories represented. Seven processing history classifications are described, and conclusions concerning the impacts of each refinement process on dermal carcinogenicity are discussed.

This research also included an evaluation of selected biological and chemical test methods for predicting carcinogenic potential. These included a modified version of the Ames test for mutagenicity, as well as analytical characterizations of the polycyclic aromatic structures in the oils. For classification purposes, a sample was considered to be carcinogenic if it resulted in the production of two or more tumor‐bearing animals (in test groups of either 40 or 50 animals). The modified Ames test was considered to be positive if the mutagenicity index was ≥ 2.0, and PAC analyses were similarly designated as positive or negative according to proposed guidelines. All of the alternative test methods showed similar agreement with dermal carcinogenicity bioassay data; concordance values were ≥ 80%. However, each test was incorrect in ca. 10%–20% of the cases evaluated. Thus, while these methods may have great value as screening tests, the results should not be used in preference to dermal carcinogenicity data for hazard identification or labeling purposes.
Early cytotoxic effects induced by bis‐chloroethyl sulphide (sulphur mustard): [Ca2+]i rise and time‐dependent inhibition of B77 fibroblast serum response
Authors: Hua A. , Daniel R. , Jasseron M. P. , Thiriot C.
Published: October 2006

Early cytotoxic events were studied on B77 fibroblasts. Cells were treated with sulphur mustard (SM) in short‐term experiments in which cell viability was unchanged, as evaluated by the neutral red cytotoxicity test. This treatment was correlated to two early signs of cytotoxicity. The intracellular Ca2+ concentration [Ca2+ ]i level in SM‐treated Fura‐2‐loaded fibroblasts showed a significant dose‐dependent increase. This observed rise was sustained, in contrast to the Ca2+ signal induced by serum, and was already visible 5–10 min after the addition of SM to cell suspensions in vitro. Modification of the extracellular Ca2+ concentration in the medium had no effect on the cytosolic calcium rise caused by SM, suggesting release from intracellular Ca2+ pools. Furthermore, a time‐dependent inhibition of the [Ca2+ ]i transient increase induced by growthfactors (as evaluated by the fetal calf serum (FCS) response) was observed within the first hour of exposure. These latter results suggest that early alterations of calcium distribution induced by SM could be one of the earliest markers of SM intoxication.
S‐adenosyl‐L‐methionine prevents and reverses erythrocyte membrane alterations in cirrhosis
Authors: Muriel Pablo
Published: October 2006

Transmethylation is an important means of altering the biological activity of a wide variety of compounds. In human and experimental CCI4‐liver cirrhosis the intrahepatic content of S‐adenosyl‐L‐methionine (SAM), an active methyl donor, and the SAM‐transmethylase activity are markedly reduced. Previously, it has been reported that SAM administration preserves hepatocyte plasma membrane Na+/K+‐ATPase and Ca2+‐ATPase activities in cirrhotic rats. Therefore, the aim of this work was to study the effect of SAM administration on the membrane lipid composition and the ATPase activity on erythrocytes derived from CCI4‐cirrhotic rats. Male Wistar rats were used in these experiments. In group 1, cirrhosis was induced by i.p. administration of CCI4. Animals of group 2 received, in addition to CCI4, three daily doses of SAM (20 mg kg−1, i.m.). Group 3 consisted of cirrhotic animals that, after 8 weeks of CCI4 treatment, received SAM (20 mg kg−1, i.m., three times daily) for 4 weeks without discontinuation of CCI4. Group 4 included animals treated with SAM alone. Seventy‐two hours after the end of treatment the rats were anaesthetized, blood was collected by heart puncture and the erythrocyte plasma membranes were isolated. The Na+/K+ ‐and (Ca2+ + Mg2+)‐ATPase activities and the cholesterol (CH) and phospholipid (PL) contents were determined in the plasma membranes. The Na+/K+ ‐ and Ca2+ ‐ATPase activities were both significantly decreased (twofold) in the CCI4‐treated group as compared to controls. Administration of SAM completely prevented this fall in both ATPases. In group 4, the Na+/K+ ‐ATPase activity was partially restored but the Ca2+‐ATPase activity was completely restored. CCI4 increased the CH/PL ratio; however, this alteration was not observed in the group treated with CCI4+ SAM simultaneously and was completely reversed in group 4. Since the increase in the membrane CH/PL ratio decreases the membrane fluidity and thus changes the enzyme activity, two mechanisms by which SAM preserves the ATPase activity in cirrhotic rats could be by preventing the increase in the CH/PL ratio and by methylation of phospholipids.
Beneficial effect of acetylcysteine on cisplatin nephrotoxicity in rats
Authors: Appenroth Dorothea , Winnefeld Klaus , Schröter Heinz , Rost Michael
Published: October 2006

The influence of acetylcysteine (ac‐cys) on cisplatin (CP) nephrotoxicity was investigated in female Wistar rats. Administration of 0.6 mg CP 100 g−1 body wt. was followed by oliguria and proteinuria, as well as a significant increase of blood urea nitrogen concentration. The i.p. administration of 0.6 mg CP 100 g−1 body wt. concomitantly with 100 mg ac‐cys 100 g−1 body wt. s.c. completely abolished the nephrotoxic effects of CP. However, following this, the Pt concentration in kidney was decreased significantly by ac‐cys treatment. This was caused by the enhanced urinary excretion of Pt. The same effect on CP nephrotoxicity appeared when CP and ac‐cys were dissolved together in solution prior to injection. It could be shown that in this solution a ligand exchange reaction of CP by ac‐cys started immediately, resulting in increased renal excretion and decreased Pt concentration in kidney.

From our results we concluded that the protective effect of ac‐cys on CP nephrotoxicity is based on the formation of a complex unsuitable for tubular reabsorption.
The toxicology of chromium with respect to its chemical speciation: A review
Authors: Katz Sidney A. , Salem Harry
Published: October 2006

The properties of trivalent and hexavalent chromium are reviewed with respect to acute and chronic oral toxicity, dermal toxicity, systemic toxicity, toxicokinetics, cytotoxicity, genotoxicity and carcinogenicity. The hexavalent chromium compounds appear to be 10–100 times more toxic than the trivalent chromium compounds when both are administered by the oral route. Dermal irritancy and allergy are more frequently caused by contact with soluble hexavalent chromium compounds. The cytotoxicity of soluble and insoluble hexavalent chromium compounds to fibroblasts is 100‐1000 times greater than that demonstrated by trivalent chromium compounds. In short‐term tests, the hexavalent chromium compounds demonstrated genotoxic effects four times more frequently than did the trivalent chromium compounds. Carcinogenicity appears to be associated with the inhalation of the less soluble/insoluble hexavalent chromium compounds. The toxicology of chromium does not reside with the elemental form. It varies greatly among a wide variety of very different chromium compounds. Oxidation state and solubility are particularly important factors in considering the toxicity of chromium with respect to its chemical speciation.
Mutagenic potential of nitroguanidine and nitrosoguanidine in the Drosophila melanogaster sex‐linked recessive lethal assay
Authors: Gupta Raj K. , Korte Don W. , Reddy Gunda
Published: October 2006

Nitroguanidine (NG) and its degradation product nitrosoguanidine (NSG) were evaluated for their mutagenic potential by using Drosophila melanogaster sex‐linked recessive lethal (SLRL) assay. Following 72 h of feeding exposure, NG and NSG at concentrations of 4–8 μg ml−1 and 15–20 mg ml−1, respectively, were not mutagenic in the test system. The frequencies of mutations for NG and the negative control were 0.188% and 0.096%, respectively. The frequencies of mutations for NSG and the negative control experiments were 0.049% and 0.05%, respectively. The positive control mutation frequencies were 15% and 17.8% for the two assays. The differences between the mutation frequencies of NG and NSG and their negative controls were not significant.