Extrapolation of the Carcinogenic Potency of Fibers from Rats to Humans

In 1999 Berry published a model for mesothelioma incidence following fiber exposure. He concluded, that the influence of the solubility of fibers on the mesothelioma rate is 17 times higher in humans than in rats. This conclusion may be helpful for evaluating the carcinogenic risk from man-made vitreous fibers, but it had little influence on some recent discussions. It has been demonstrated using this model, that in an injection experiment with rats, fibers with elimination constants of 0.1/year and 1/year—which would approximately correspond to crocidolite and perhaps ceramic fibers—differ in their mesothelioma risk only by a ratio of 3.2:1. In contrast, for humans exposed continuously from age 20 to age 60 a risk ratio of 4,750:1 is obtained. This result may be helpful for the assessment of the human cancer risk e.g., from exposure to refractory ceramic fibers. However, uncertainty is large, since the life-span of rats is too low to measure the elimination rate of bio-persistent fibers sufficiently.     

Estimation of Epidermal Carcinogenic Potency

Estimation of Epidermal Carcinogenic Potency. MCKEE, R. H.,NICOUCH, M. J., SCALA, R. A., AND LEWIS, S. C. (1990). Fundam.Appl. Toxicol. 15, 320–328. This report compared two statisticalmethods of estimating tumor latency, the Weibull distributionmodel and the Kaplan-Meier method. Parallelism of dose-responsecurves of different materials and quantitative reproducibilityof dermal carcinogenesis data were also examined. The Weibullmethod has the advantage of producing parameter estimates, evenwhen tumor yield is low. The Kaplan-Meier method, on the otherhand, is free of distribution assumptions. Overall, since thecomparisons of potency are made on the basis of parameters fromthe same assumed distribution on the same strain of animal,the Weibull estimates are favored. A comparison of dose-responsedata for benzo[a]pyrene and catalytically cracked clarifiedoil indicated that the slopes of the two dose-response curveswere significantly different. Thus the relative carcinogenicpotencies of different materials vary with dose, and potencycomparisons must necessarily be dose-specific. The quantitativereproducibility of dermal carcinogenesis bioassays was alsoassessed. The dose-response curves from the three studies ofone material had significantly different slopes. Thus the resultssuggested that there were sources of biological variabilitywhich could contribute to experimental error     

T25: A Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Species/Site Specificity and Mutagenicity

Abstract: A simplified carcinogenic potency index, the T25, is proposed as a practical method for the inclusion of potency considerations in carcinogen classification systems. The T25 is the chronic daily dose in mg per kg bodyweight which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life span of that species. Calculated T25 values of a set of 113 US National Cancer Institute/National Toxicology Program (NC/NTP) carcinogens showed excellent correlation (correlation coefficient 0.96, P<0.0001) with the carcinogenic potency index TD50 of Peto et al. (1984). The mean of T25 values for 51 transspecies, multiple common site NCI/NTP carcinogens were 10-fold lower than those for 62 NCI/NTP single species, single site carcinogens. For these 113 carcinogens, the mean T25 values were approximately 3-fold lower for agents that were also mutagenic in Salmonella compared to the non-mutagenic agents.     

Association between Carcinogenic Potency and Tumor Pathology in Rodent Carcinogenesis Bioassays

Association between Carcinogenic Potency and Tumor Pathologyin Rodent Carcinogenesis Bioassays. GOLD, L. S., WARD, J. M.,BERNSTEIN, L., AND STERN, B. (1986). Fundam Appl. Toxicol. 6,677–690. Carcinogenic potency (TD50) estimated from theresults of 88 NCI/NTP carcinogenesis bioassays was examinedby common target sites in rats and mice. Other indicators ofa chemical's hazard were investigated, including whether tumorswere induced at more than one site in a single sex-species groupof test animals, whether tumors may have caused the death ofthe animal or were found at sacrifice, and whether metastasesof induced tumors occurred. These hazard indicators are sometimesinterrelated; however, the potency (TD50) values of chemicalswhich are hazardous by each of these measures spanned a widerange. Carcinogens which caused some type of fatal tumor weremore likely than other carcinogens to cause tumors in multipleorgan sites and multiple sex-species groups. Since these otherhazard indicators were not related to carcinogenic potency,they should be included along with potency estimates such asthe TD50 in summarizing the potential dangers of human exposuresto a carcinogen and in comparisons of hazard among carcinogens.     

Influence of Certain Calcium-channel Blockers on Some Aspects of Lorazepam-dependence in Mice

The effect of acute and chronic treatments of the calcium-channel blockers, isradipine, diltiazem and flunarizine in protecting against lorazepam dependence has been demonstrated in mice. Dependence was induced by twice-daily administration of lorazepam (1 mg kg^?1) for 10 days, doubling the dose during the next 10 days. Withdrawal symptoms and changes in the noradrenaline, dopamine and 5-hydroxytryptamine content of different regions of the brain were observed after either 24-h withdrawal or flumazenil administration. Isradipine inhibited lorazepam withdrawal symptoms, the effect being accompanied in the 24-h withdrawal group by significant decreases in the noradrenaline and dopamine content of the thalamus and hypothalamus and in the noradrenaline content of the mid-brain. In the flumazenil-treated group isradipine produced significant decreases in mid-brain noradrenaline and dopamine levels and in the dopamine content of the thalamus and hypothalamus. Diltiazem did not, on the other hand, afford significant protection against lorazepam withdrawal symptoms and did not induce any significant change in the neurotransmitters studied. Flunarizine significantly inhibited lorazepam withdrawal symptoms, an effect accompanied by significant reduction in noradrenaline and dopamine levels in the thalamus and hypothalamus. Dopamine was also significantly reduced in the cerebral cortex. Similar effects were produced in the flumazenil-treated group, and the noradrenaline content was reduced in the medulla, pons and cerebellum. It was concluded that isradipine and flunarizine might be of value in ameliorating lorazepam withdrawal symptoms.     

An Empirical Comparison of Methods Used to Estimate Carcinogenic Potency in Long-Term Animal Bioassays: Lifetable vs Summary Incidence Data

An Empirical Comparison of Methods Used to Estimate CarcinogenicPotency in Long-Term Animal Bioassays: Lifetable vs SummaryIncidence Data. GOLD, L. S., BERNSTEIN, L., KALDOR, J., BACKMAN,G., AND HOEL, D. (1986). Fundam. Appl. Toxicol. 6, 263–269.Two methods forestimating carcinogenic potency from animal carcinogenesisbioassays (TD50-defined in the paper) are compared, one basedon lifetable data and one based on summary incidence data. Thelifetable analysis adjusts for the differential effects of toxicityamong dose groups and for differences in the time pattern oftumor incidence, while summary incidence analysis does not.However, summary data are all that are usually available inthe published results of animal cancer tests. Using NCI bioassayresults which provide full lifetable data, we compare lifetableand summary estimates of potency and their statistical significanceas well as the estimated shape of the dose—response curve.There is substantial agreement between these methods of analysisin terms of potency estimation, although lifetable estimatesare usually more potent. But there are some notable differencesin the estimated shape of the dose—response curve, suggestingthat both target site selection and method of analysis playan important role in risk estimation.     

Chronic Toxicity and Carcinogenic Evaluation of Diisononyl Phthalate in Rats

Groups of 110 Fischer 344 rats/sex were fed diisononyl phthalate(DINP) at dietary levels of 0, 0.03, 0.3, and 0.6 wt% for periodsup to 2 years. Interim sacrifices of 10 predesignated rats/sexsol;dosewere at 6, 12, and 18 months with surviving animals sacrificedat 24 months. At study termination, survival was in excess of60% for every group. At the mid or high dose, the followingbiological effects were noted: slight decreases in food consumptionand body weight; slight increase in mortality; a dose-relatedincrease in relative organ weights of liver and kidney; andsome slight effects on urinalysis, hematologic, and clinicalchemistry parameters. No peroxisome induction was observed inlivers of treated rats compared with controls. No clear treatment-relatednonneoplastic or neoplastic lesions were found. However, mononuclearcell leukemia (MNCL) and changes known to be associated withan increased incidence of MNCL were seen in the mid-dose andhigh-dose groups. A literature review suggests that MNCL isa common finding in aging F344 rats and that this increasedincidence in rats treated with DINP is not relevant to man.A clear no-observed-effect level was demonstrated for all biologicalend points at a dietary level of 0.03 wt% or approximately 17mgsol;kgsol;day of DINP.     

Diesel Exhaust Is Not a Pulmonary Carcinogen in CD-1 Mice Exposed under Conditions Carcinogenic to F344 Rats

Differences among laboratory animal species in the pulmonarycarcinogenicity of chronic inhalation exposure to diesel exhausthave raised several important interpretive issues. Under similarheavy exposure conditions, it is clear that diesel exhaust isa pulmonary carcinogen in rats, but not in Syrian hamsters.Previous reports give conflicting views of the response of mice,which is presently considered equivocal. This report describescarcinogenicity results from a bioassay of CD-1 mice conductedin parallel with a previously reported bioassay of F344 rats(Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208–221).Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24months at soot concen trations of 0.35, 3.5, or 7.1 mg/m³ causedaccumulations of soot in mouse lungs similar to those in lungsof rats and, like the results from rats, did not significantlyaffect survival or body weight. In contrast to the dose-relatedneoplastic response of rats, however, the exposures of micedid not increase the incidence of lung neoplasms. This findingis consistent with other data showing that mice, as well asSyrian hamsters, differ from rats in their lung neoplastic andnonneoplastic responses to heavy, chronic inhalation exposureto diesel exhaust soot and several other particles. Althoughrodents serve as useful indicators of potential human carcinogenichazards, it is not yet clear which, if any, rodent species havelung neoplastic responses that are useful for quantitative predictionsof human lung cancer risk from chronic inhalation of poorlysoluble, respirable particles.     

A Comparison of Oral and Rectal Absorption of L-Dopa Esters in Rats and Mice

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (<0.01 µg/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 µg/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.     

Effect of Aminoethylpyrroles on Carrageenan-induced Inflammation and on Lipid Peroxidation in Rats: Some Structural Aspects

Abstract— Nine 3-(2-aminoethyl)pyrrole derivatives were investigated as anti-inflammatory agents in the carrageenan-induced rat paw oedema model and as antioxidants in the non-enzymatic lipid peroxidation assay. It was found that the derivatives which were substituted with a p-toluenesulphonyl group exhibited considerable anti-inflammatory activity and some also showed antioxidant properties. However, the presence of a p-toluenesulphonyl group did not invariably lead to activity. A structural feature which was essential for both activities was the aminoethyl side chain. Although a relationship between the antiinflammatory and the antioxidant activities was not apparent, the combination of these properties could be useful.     

Carcinogenic Evaluation of Estazolam via Diet in CD Strain Sprague-Dawley Rats and B6C3F1 Mice for 2 Years

Carcinogenic Evaluation of Estazolam via Diet in CD Strain Sprague-DawleyRats and B6C3F1 Mice for 2 Years. KIMURA, E. T., FORT, F. L,,BURATTO, B., TEKELI, S., KESTERSON, J. W., HEYMAN, I. A., ANDCUSICK, P. K. (1984). Fundam. Appl. Toxicol. 4, 827–842.A comparative toxicity and carcinogenicity study was carriedout for 2 years with estazolam, a benzodiazepine, via diet inSprague-Dawley rats (0.5, 2, and 10 mg/kg/day) and in B6C3F1mice (0.8, 3, and 10 mg/kg/day). In rats, no biologically significantchanges were seen with respect to mortality, clinical signs,food consumption, or occurrence of palpable masses. Body weightgain in females (10 mg/kg/day) was depressed 12.6% and reflecteda maximum-tolerated dosage (females). Spontaneous and incidentalnonneoplastic lesions were consistent with aging in this speciesand unrelated to drug treatment. No biologically significantdifferences in tumor incidences occurred. Mice were more responsiveto estazolam as suggested by (1) increased mortality (males)at 10 mg/kg/day, (2) increased food consumption and body weightgains (females), (3) withdrawal signs characterized by hyperactivity/aggressivenessand convulsions, and (4) appearance of dose-related nodularhyperplasia of the liver due to the relatively high dosagesused coupled with the propensity of benzodiazepines to enhanceliver enzyme induction. Several spontaneous benign and malignanttumors observed in all groups were not considered to be drugrelated. Based on the findings in these studies, estazolam wasnot considered to be carcinogenic when administered via dietto either rats at 0.5, 2, and 10 mg/kg/day or to mice at 0.8,3, and 10 mg/kg/day for 2 consecutive years.     

Comparison of the T Cell-Independent Antibody Response of Mice and Rats Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmentalcontaminant that produces adverse effects on the immune systemof experimental animals. In this study, the effect that TCDDhas on the antibody plaque-forming cell (PFC) response to theT cell-independent (TI) antigen trinitrophenyl-lipopolysaccharide(TNP-LPS) was compared in adult female B6C3F1 mice and F344rats. Mice or rats were given a single intraperitoneal injectionof TCDD at doses ranging from 1 to 30 µg/kg, 7 days priorto immunization with TNP-LPS by intravenous injection. Threedays later body, spleen, thymus, and liver weights were measuredand the PFC response to TNP-LPS was determined. Thymus weightswere decreased at 10 and 30 µg TCDD/kg, whereas spleenweights were decreased and liver weights increased in mice dosedat 3,10, and 30 µg/kg. Mice dosed at 10 and 30 µgTCDD/kg had suppressed PFC responses and serum hemagglutinationliters. In rats, thymus weights were decreased and liver weightsincreased at 3, 10, and 30 µg TCDD/kg; however, the PFCresponse and serum hemagglutination titers to TNP-LPS were suppressedonly at 30 µg/kg TCDD. TCDD did not affect splenic lymphocytesubsets evaluated by flow cytometry. These results indicatethat TCDD suppresses the TI antibody response to TNP-LPS inboth B6C3F1 mice and F344 rats, with mice more sensitive tosuppression by TCDD than rats.     

Comparison of Fetotoxic Effects of a Dermally Applied Complex Organic Mixture in Rats and Mice

A high-boiling (288–454?C), coal-derived complex organicmixture (COM) has been shown to be teratogenic in rats followinginhalation and oral routes of exposure. To determine whethersimilar changes also occur after dermal exposure to this COM,pregnant rats and mice were exposed during periods of organogenesis(Days 11 to 15 of gestation). Shaved backs were painted with0, 500, or 1500 mg/kg of the COM (control, low, or high dose,respectively); the exposed area was not occluded. Maternal weightgain during the gestation period decreased with increasing dosein rats but not in mice. Examination of rat fetuses on Day 20of gestation showed that resorptions had occurred in more than90% of low-and high-dose litters (vs 6% in the control group).In mice, fetal examinations on Day 18 of gestation showed thatresorptions occurred in 71% of litters from both exposure groups(vs 14% in the controls). Fetal measurements indicated thatboth the weight and the length of rat fetuses decreased withincreasing dose, but mouse fetuses were unaffected. Cleft palates,absent in the control groups, were observed in 50 to 55% ofthe high-dose group and 5 to 8% of the low-dose fetuses of bothspecies. Small fetal lungs occurred in nearly 100% of the exposedrat fetuses and in 25% of the high-dose mice; the incidenceof small lungs was 1% in control animals. Other variations observedin exposed groups included edema and reduced ossification inthe rat and renal pelvic cavitation in the mouse. In conclusion,dermal exposure of dams to COM resulted in life-threateningmorphological alterations in fetuses of both species similarto those seen following exposure by Other routes.     

Gender Aspects of Liver Slice Incubations with N,N, N-Triethylene-thiophosphamide (Thio-TEPA) in Rats and Mice

This study was conducted to investigate if biotransformation of N, N, N-triethylene-thiophosphoramide (thio-TEPA) by liver slice incubations reflects the established gender pattern for rat and mouse. Liver slices from rat and mice of both genders were incubated with start concentrations of thio-TEPA of 5.2, 26, 52 and 104 μM for up to 240 min. Male rat liver slices eliminated thio-TEPA faster and formed more TEPA than female liver slices at any concentration. No gender difference was found for the elimination of thio-TEPA in mice, however, the female liver slices formed less TEPA than the male ones. Apparently female rat liver slices formed less TEPA than female mice liver slices. It is concluded that the liver slice incubation system in a robust manner reflects gender differences in rat drug biotransformation with special reference to thio-TEPA. It is also confirmed that these aspects of gender are less pronounced in the examined mouse species than in rats.     

A Direct Comparison of Anti-microRNA Oligonucleotide Potency

Purpose  

Cataloguing endogenous miRNA targets by inhibiting miRNA function is fundamental to understanding the biological importance of each miRNA in gene regulatory pathways. Methods to down-regulate miRNA activity may help treat diseases where over-expression of miRNAs relates to the underlying pathophysiology. This study objectively evaluates the in vitro potency of different anti-miRNA oligonucleotides (AMOs) using various design and modification strategies described in the literature as well as some novel modification strategies.     

避孕药释放激素激动剂对大鼠卵巢的致癌作用

目的通过实验大鼠的实验研究对避孕药释放激素的致癌作用进行研究。方法选用TR2近交系大鼠分组选用女性外用避孕药膜,针对不同剂量分成实验三组和对照组进行实验研究。结果应用Anthwin软件分析抑制素融合基因表达产物的理化曲线,由Parker法预测的曲线可以看出重组蛋白质N端40-80,100-140,220-258为抗原性较强的区域。不同剂量的抑制素pcINH质粒DNA经脂质体介导免疫大鼠,差异有统计学意义。结论合理剂量的避孕药与致癌性无相关性。