The carcinogenicity of metals in humans

Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent(VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, may be human carcinogens, but the experimental and epidemiologic data are limited.     

白藜芦醇对小鼠的急性经口毒性和遗传毒性试验研究

目的:了解白藜芦醇的急性经口毒性和遗传毒性,为白藜芦醇的食用、药用安全性评价提供实验依据.方法:按照的规定,对白藜芦醇进行急性经口毒性测定,并通过Ames试验(每皿分别加入5 000、1 000、200、40、8 μg白藜芦醇)、小鼠骨髓嗜多染红细胞微核试验及小鼠精子畸形试验(分别以7.500、3.750、1.875g/kg剂量的白藜芦醇给小鼠灌胃)对其遗传毒性进行评价.结果:白藜芦醇的急性经口最大耐受剂量>15.0 g/kg;3项遗传毒性试验结果均为阴性.结论:在本实验条件下,白藜芦醇对小鼠的急性经口毒性属无毒,未见遗传毒性作用.     

Acute oral toxicity of the herbicide BUREX EKO in pheasants

The aim of this study was to determine the acute LD50, clinical symptoms and pathological changes of acute BUREX EKO intoxication in pheasants according to OECD No 205. Medium lethal dose (LD50) of BUREX EKO in pheasant is 3.84 ml/kg body weight with the upper level of reliability 4.50 ml and lower level of reliability 3.27 ml/kg body weight. As far as the calculation to the effective substance is concerned it is 1077 mg of chloridazone per kg body weight with the interval of reliability from 919 to 1263 mg/kg body weight. Calculated the effective substance of chloridazone (3.84 ml is LD50 of BUREX EKO which contains 1077 mg of chloridazone) BUREX EKO can be classified as the moderately toxic substance to pheasants. There were following clinical symptoms of the BUREX EKO intoxication in pheasants: apathy, drowsiness, incapability to move, ruffled feathers, slight diarrhoea, strenuous respiration, tonico-clonical cramps before death, decease with the head expressively bent rearwards. There was a relatively fast beginning of rigor mortis in dead pheasants. Pathologico-anatomical dissection of the pheasants obtained under conditions of acute intoxication did not reveal any changes on the organs of both experimental and control pheasants which would be immediately connected with the effect of the administered substance. Hyperaemia was recorded by histologico-pathological investigation of the liver and kidneys. No changes on the brain and intestine wall were recorded.     

Estimates of the chromium(VI) reducing capacity in human body compartments as a mechanism for attenuating its potential toxicity and carcinogenicity

Cathepsin L was purified from carp hepatopancreas by a method involving ammonium sulfate precipitation and a series of column chromatographies, in which the enzyme had an affinity toward Concanavalin A and Cibacron Blue F3GA. Its homogeneity was established by Native-PAGE, but two protein bands corresponding to molecular masses of 30,000 (single chain) and 24,000 (heavy chain) migrated on SDS-PAGE. The enzyme exhibited a maximum activity for carbobenzoxy-L-phenylalanyl-L-arginyl-4-methylcoumaryl-7-amide (Z-Phe-Arg-MCA) at pH 5.5-6.0 and 50 degrees C and the remarkable stability at pH 5.0-6.5 and below 40 degrees C. All tested cysteine protease inhibitors and TLCK and chymostatin markedly inhibited its activity, whereas the other serine protease inhibitors and a metalloprotease inhibitor negligibly affected it. In addition, several metal compounds reduced either its activity or stability to differing extents. Although EDTA alone caused an only marginal activation of the enzyme, its maximum activation required both 2 mM cysteine and 1 mM EDTA. The enzyme had an ability to hydrolyze three peptidyl-MCA substrates including Z-Phe-Arg-MCA, but all kinetic constants indicate that Z-Phe-Arg-MCA is the optical substrate to the enzyme.     

Toxicity and carcinogenicity of Cr(VI) in animal models and humans

The toxicity and carcinogenicity of hexavalent chromium (Cr) in animal and human models are reviewed. The focus of this review is not on the well-established fact that hexavalent Cr compounds of low and high water solubility can induce respiratory cancers, but rather this review addresses other types of cancers induced by exposure to hexavalent Cr compounds. Additionally, non-cancer endpoints are also discussed with documentation of human and animal studies showing non-cancer health effects of hexavalent Cr exposure on the respiratory system, GI system, immune system, liver, and kidney. There is an emerging understanding that because hexavalent chromate is isostructural with phosphate and sulfate, it is readily taken up by the G.I. tract and penetrates to many tissues and organs throughout the body. This is supported by animal studies and experiments using human volunteers. From the epidemiological studies, there is suggestive evidence that hexavalent Cr causes increased risk of bone, prostate, lymphomas, Hodgkins, leukemia, stomach, genital, renal, and bladder cancer, reflecting the ability of hexavalent chromate to penetrate all tissues in the body. A high accumulation of Cr(III) in all tissues and organs is a strong indication of the wide toxic potential of exposure to soluble hexavalent Cr in the drinking water and in the ambient environment.     

Molecular genetic events in the development and progression of ovarian cancer in humans

Ovarian tumor development is characterized by specific clinical and pathological features that provide an interesting model of carcinogenesis: first, the pre-invasive and even invasive lesions are difficult to detect; second, a group of cases with a known familial predilection constitute an important heredltary model of carcinogenesis; and third, the category of morphologically borderline ovarian tumors (tumors of low malignant potential) poses several unanswered questions such as: what histologic criteria should be used for their diagnosis; what is their natural history; and what is their molecular relationship to invasive tumors? Recently, molecular studies have contributed to a better understanding of the biology of these tumors, their behavior in vivo, and their response to therapy. This article summarizes the most recent molecular advances.     

The population genetic aspects of the intestinal microbiological phenotype in healthy humans

The principle of the formation of the microbiological phenotype in the intestine of healthy persons was studied by the method of the population-genetic analysis. The microbial composition of the intestinal flora of healthy members of 10 complete families (altogether 50 persons) was studied. The study revealed that practically in all cases the variability of the qualitative and quantitative characteristics of the phenotype under study on the levels of both genera and individual microbial species is formed mainly under the influence of environmental factors. The presence of indigenous bacteria in the intestinal microbiocenosis (including Escherichia coli with normal enzymatic properties) is strongly genetically determined.     

Evaluation of the genotoxic potential of alkylalkanolamines

The production of cell types in the vertebrate retina follows a stereotyped time course. We have focused on a component of the extracellular matrix that may guide this schedule: the laminin beta 2 chain. Here, we have asked directly whether heterotrimeric laminins containing the laminin beta 2 chain can promote the production of presumptive rod photoreceptors ("rods") and have correlated changes in rod production with changes in the production of other cell types. In cultures in which few rods, but many Müller and bipolar cells, are produced, the production of rods can be enhanced sixfold and that of bipolar cells can be reduced by 66%, by exposing cells to a laminin beta 2-rich matrix. Substitution of a laminin beta 2-depleted matrix (created with antisense RNA) returns the density of rods and bipolar cells to control levels. These linked alterations in phenotype expression suggest that laminins may control the choice between rod photoreceptor and rod bipolar cell fates.     

Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus

Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.     

Biochemistry of 1,3-butadiene metabolism and its relevance to 1,3-butadiene-induced carcinogenicity

Recently, the roles of specific P450 isoforms, myeloperoxidase (MPO), GSH-S-transferase and epoxide hydrolase in the metabolism of 1,3-butadiene, and its major oxidative metabolite, butadiene monoxide (BM), were investigated. The results provided evidence for P450s 2A6 and 2E1 being major catalysts of 1,3-butadiene oxidation in human liver microsomes. cDNA-expressed human P450s 2E1, 2A6, and 2C9 catalyzed BM oxidation to meso- and (+/-)-diepoxybutane (DEB), but the rates of BM oxidation in mouse, rat, or human liver microsomes were much lower than the rates of 1,3-butadiene oxidation in these tissues. Human MPO catalyzed 1,3-butadiene oxidation to BM, but MPO incubations with BM did not yield DEB. Rates of BM formation in mouse and human liver microsomes were similar and were nearly 3.4-fold higher than that obtained with rat liver microsomes. However, rat liver epoxide hydrolase activity was nearly 2-fold higher than that of mouse liver microsomes. Rat and mouse liver GSH-S-transferases exhibited similar BM conjugation kinetics, but rats excreted more BM-mercapturic acids compared to mice given low equimolar doses of BM. BM reacted with guanosine and adenosine to yield N7-, N2-, and N1-guanosinyl and N6-adenosinyl adducts, respectively. These results may contribute to a better understanding of the biochemical basis of 1,3-butadiene-induced carcinogenicity.     

Evaluation of the determinants of flow-mediated radial artery vasodilatation in humans

The relative importance of the early peak response during hyperaemia and of the duration of the hyperaemic phase (t1/2: blood flow velocity half time and AUCt1/2: area under the curve of flow velocity at t1/2) in the magnitude of the flow-dependent vasodilatation of the radial artery was determined in humans. Radial artery diameter was measured continuously in 18 healthy volunteers using an echo-tracking system coupled to a Doppler device for the measurement of the radial blood flow. In 9 subjects, arterial parameters were measured at baseline and during 3 hyperaemic tests performed after 2, 5 or 10 minutes of ischaemia. Reproducibility of the measured parameters was studied in 9 other subjects. Radial artery diameter, AUCt1/2 and t1/2 increased proportionally with the duration of ischaemia. In contrast, the peak flow response was already maximal after 5 minutes of ischaemia. The regression analysis showed that the best fit model after stepwise analysis only included t1/2 (r = 0.85, p < 0.001). There was no correlation between the peak flow values and the duration of hyperaemia (r = 0.29, p = 0.14). These results demonstrate that conduit arteries postischaemic flow-dependent vasodilatation in humans is both determined by the peak value and by the duration of the hyperaemic phase and suggest that these two components must be considered when comparing this index of NO release between different groups of subjects.     

Seed banks and molecular maps: unlocking genetic potential from the wild

Nearly a century has been spent collecting and preserving genetic diversity in plants. Germplasm banks-living seed collections that serve as repositories of genetic variation-have been established as a source of genes for improving agricultural crops. Genetic linkage maps have made it possible to study the chromosomal locations of genes for improving yield and other complex traits important to agriculture. The tools of genome research may finally unleash the genetic potential of our wild and cultivated germplasm resources for the benefit of society.     

Visual evoked potential measures of interhemispheric transfer time in humans.

Four experiments testing right-handed adult males examined interhemispheric transfer time (IHTT) estimation with visual evoked potentials (EPs) elicited in response to hemiretinal presentations of checkerboard-flash stimuli. Experiment 1 was a study of the relation between reaction time (RT) and EP measures of IHTT. EP measures provided more valid estimates than RT measures because more subjects showed IHTT in the direction of anatomical prediction. Experiment 2 showed that EPs derived from lateral occipital sites provided more valid and longer IHTT compared with EPs from medial occipital sites. Experiment 3 showed no difference between random versus blocked hemiretinal stimuli. Experiment 4 showed that IHTT derived with a linked-ears reference provided more valid estimates than IHTT derived with a mid-frontal reference and that small changes in stimulus eccentricity did not influence IHTT. The findings of these experiments indicate that noninvasive estimates of visual IHTT can be obtained in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals

In 72 experiments, durable minerals in the form of particles on respirable size and of wide chemical and structural varieties, were implanted in the pleurae of outbred female Osborne- Mendel rats for periods of more than 1 year. The incidence of induced malignant mesenchymal neoplasms correlated well with the dimensional distribution of the particles. The probability of pleural sarcoma correlated best with a number of fibers that measured 0.25 micro or less in diameter and more than 8 micrometer in length, but relatively high correlations were also noted with fibers in other size categories having diameters up to 1.5 micrometer and lengths greater than 4 micrometer. Morphologic observations indicated that short fibers and large-diameter fibers were inactivated by phagocytosis and that negligible phagocytosis of long, thin fibers occurred. The wide variety of compounds used in these experiments suggested that the carcinogenicity of fibers depended on dimension and durability rather than on physicochemical properties.     

Diagnosis of Mycobacterium microti infections among humans by using novel genetic markers

As a result of DNA typing of Mycobacterium microti isolates from animals in the United Kingdom and The Netherlands, we diagnosed four human M. microti infections. These are the first M. microti infections among humans to be reported. Three of the patients were immunocompromised and suffered from generalized forms of tuberculosis. The fourth patient was a 34-year-old immunocompetent male with a persistent cough and undefined X-ray abnormalities. Two of the M. microti infections were recognized by their IS6110 restriction fragment length polymorphism (RFLP) patterns, which showed a high degree of similarity with those of M. microti strains isolated from a pig and a ferret in The Netherlands. The two other human M. microti infections were recognized by using the recently developed DNA fingerprinting method, "spoligotyping," directly on clinical material. All M. microti isolates from the United Kingdom and The Netherlands were found to contain an exceptionally short genomic direct repeat region, resulting in identical two-spacer sequence reactions in spoligotyping. In contrast, the highly similar IS6110 RFLP patterns of the vole strains from the United Kingdom differed considerably from the RFLPs of all M. microti strains isolated in The Netherlands, suggesting that geographic isolation led to divergent strains in the United Kingdom and on the continent.     

Permutational distribution of the log-rank statistic under random censorship with applications to carcinogenicity assays

In the random censorship model, the log-rank test is often used for comparing a control group with different dose groups. If the number of tumors is small, so-called exact methods are often applied for computing critical values from a permutational distribution. Two of these exact methods are discussed and shown to be incorrect. The correct permutational distribution is derived and studied with respect to its behavior under unequal censoring in the light of recent results proving that the permutational version and the unconditional version of the log-rank test are asymptotically equivalent even under unequal censoring. The log-rank test is studied by simulations of a realistic scenario from a bioassay with small numbers of tumors.     

Reflections on the assessment of the toxicity of "dioxins" for humans, using data from experimental and epidemiological studies

"Dioxins" (polyhalogenated dibenzo-p-dioxins and dibenzofurans, PHDDs/PHDFs) have gained considerable scientific interest, and (unjustified or justified) also received tremendous political attention. The data pool available on sources, distribution in the environment, kinetics in animals and humans, and on biological and toxic actions in various species (including humans), is one of the largest among all environmental organic substances; but quality and predictive power of the data on possible effects in humans vary widely, from adequate to not acceptable. This fact is often ignorantly or perhaps even deliberately disregarded, and such divergent data are frequently given the same weight in attempted risk assessments. It must be stressed that the quality of the toxicological data on most "environmental compounds" in general is far below today's standards required for preclinical and clinical data on medicinal substances. The crucial question is whether humans constitute an especially vulnerable species for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the other PHDDs/PHDFs. Since ample data on body burdens and some results of clinical and epidemiological studies on TCDD have become available, answering this question may now be attempted on the basis of a comparison of animal and human data. Quality of the data and the predictive power of the methods used must be considered, dose-response relationships must be critically evaluated, and body burdens achieved in humans and experimental animals must be taken into account. Pitfalls in attempts to extrapolate data from animal studies to humans and limitations of conclusions to be drawn from epidemiological data on humans are discussed in this presentation.