Crumpton T., Atkins DS., Zawia NH.*, Barone S (Department of Biomedical Sciences, University of Rhode Island, Kingston, RI 02881-0809, USA): Lead exposure in pheochromocytoma (PC12) cells alters neural differentiation and Sp1 DNA-binding. Neurotoxicol, 22(1), 2001, 49-62. [70 Ref]

Previous studies have revealed that lead modulates the DNA-binding profile of the transcription factor Sp1 both in vivo and in vitro). Sp1 is a zinc finger protein, that is selectively up-regulated in certain developing cell types and plays a regulatory role during development and differentiation. In NGF-stimulated PC12 cells, Sp1 DNA-binding activity was induced within 48 h of exposure of NGF naive cells. Exposure of undifferentiated PC12 cells to lead alone (0.1 uM) also produced a similar increase in Sp1 DNA-binding. Since lead altered the DNA-binding profile of Spl in newly differentiating cells, neurite outgrowth was assessed as a morphological marker of differentiation to determine whether or not the effects of lead on differentiation were restricted to the initiation phase (unprimed) or the eleboration phase of this process (NGR-primed). NGF-primed and unprimed PC12 cells were prepared for bioassay following exposure to various concentrations of NGF and/or lead. Neurite outgrowth was measured at 48 and 72 h during early stages of NGF-induced differentiation and at 14 h in NGF primed/replated cells. In the absence of NGF, exposure to lead alone (0.5, 0.05, 0.1 uM) promoted measurable neurite outgrowth in unprimed PC12 cells at 48 and 72h. A similar phenomenon was also observed in primed/replated PC12 cells at 14 h. However, this effect was two to five times greater than unprimed control cells. In the presence of NGF, a similar trend was apparent at lower concentrations, although the magnitude and temporal nature was different from lead alone. In most cases, the administration of higher lead concentrations (1 and 10 uM), in both, the absence or presence of NGF, was less effective than the lower concentrations in potentiating neurite outgrowth. These results suggest that lead alone at low doses may initiate premature stimulation of morphological differentiation that may be related to lead-induced alterations in Spl binding to DNA.

Hwang KY., Schwartz BS., Lee BK., Strickland PT., Todd AC., Bressler JP (Division of Toxicological Sciences, Department of Environmental Health Sciences, School of Hygiene and Public Health, Room 7032,615 North Wolfe Street, Baltimore,MD21205,USA): Associations of lead exposure and dose measures with erythrocyte protein kinase C activity in 212 current Korean lead workers. Toxicol Sci, 62(2), 2001, 280-288. [53 Ref]

Lead can replace calcium in enzyme assays that measure protein kinase C activity and lead activates protein kinase C in human erythrocytes after exposure to lead in vitro. To examine the relevance of these observations to lead exposure in humans, we studied the associations of lead found in blood or tibia with activation of protein kinase C in erythrocytes isolated from workers in the industry. We examined erythrocytes among 212 lead worker, with a mean (±SD) age of 39.1 (10.0) years and exposure duration of 8.1 (6.5) years and measured protein kinase C activation by an in vitro back-phosphorylation assay. After adjustment for potential confounding factors (age and sex), tibia lead and exposure duration were significantly associated with erythrocyte protein kinase C activation (both p values < 0.05). No associations were observed between protein kinase C activation and blood-lead or zinc-protoporphyrin levels. These findings suggest that human exposure to lead results in activation of erythrocyte protein kinase C, which may be directly relevant to the neurotoxicity of lead.

Vujanovic V., Smoragiewticz W., Krzysztyniak K (Institute de Recherche en Biologie Vegetale et Department de Sciences Biologiques, Universite de Montreal, 4101, Rue Sherbroke East, Montreal, Quebec, Canada H1X2B2): Airborne fungal ecological niche determination as one of the possibilities for indirect mycotoxin risk assessment in indoor air. Environ Toxicol, 16(1), 2001, 1-8. [44 Ref]

Based on the microbiological analysis of air samples from occupied spaces, some possibilities for indirect risk assessment of mycotoxin-related health problems are proposed. Airborne fungi could be classified on the basis of the relationship between the two environmental factors and their combinations i.e. temperature and water requirements (water activity a w). One type involves three different groups of molds, selected on the basis of the quantitative and qualitative information about the ability of fungi to sporulate under different environmental conditions: group(i), represented by Aspergillus nidulans, A. Niger, and A ochraceus, and characterized by sporulation which was more dependent on temperature than on water activity; (ii), represented by A. flavus and A. versicolor in which sporulation was approximately equal and depended on both the temperature changes and a w alterations; and (iii), represented by Cladosporium sp., Penicillium cyclopium, and p. Citrinum, in which sporulation depended more on alteration of the a w conditions than on temperature changes. Another type is characterized by four sporulation rates with two levels of mycotoxin risk accumulation in the spores (conidia) of each mold species: large (la) and moderate (lb) sporulation rates with a risk of mycotoxin accumulation (aw >= 86: t >= 12 C); rare sporulation (lla) and absence of sporulation (llb), without risk of mycotoxin accumulation (a w <= 86; t <= 12 C). In conclusion, providing a useful guide for two dimensions, temperature and water activity for each of the three phases of fungal growth, i.e. germination, growth, and sporulation, could be important for determination of the fundamental niche of each fungus and its ability to form or accumulate mycotoxin. Special emphasis should be given to the indirect mycotoxin risk assessment in heating, ventilation, and air conditioning systems.

Babich H., Zuckerbraum HL (Departments of Biology, Stern College for Women, Yeshiva University, 245 Lexington Avenue, New York, New York 10016, USA): In vitro cytotoxicity of glyco-S-nitroso-thiols: a novel class of nitric oxide donors. Toxicol In Vitro, 15(3), 2001, 181-190. [38 Ref]

The cytotoxicities of the nitric oxide (NO) donors, S-nitroso-N-acetylpencillamine (SNAP) and three glyco-SNAPs, glucose-1- SNAP, glucose-2-SNAP, and fructose-1-SNAP, towards the human gingival epithelioid S-G cell line and three human carcinoma cell lines derived from tissues of the oral cavity were compared using the neutral red (NR) assay. In general, the glucose-SNAPs were more cytotoxic than SNAP, which, in turn, was more cytotoxic than fructose-1-SNAP. Further studies focused on the response of S-G cells to glucose-2-SNAP. The cytotoxicity of glucose-2-SNAP was attributed to NO, as glucose-2-SNAP (tl/2=20 h at 28 C) aged for 4 days was nontoxic, toxicity was eliminated in the presence of hydroxocobalamin, a specific NO scavenger, and toxicity was not noted with glucose-2-AP (the parent compound used to construct glucose-2-SNAP). Exposure of cells to glucose-2-SNAP resulted in a lessening of the intracellular level of glutathione and cells pretreated with the glutathione-depleter, 1,3-bis(chloroethyl)-1-nitrosourea , were more sensitive to a subsequent challenge with gluscose-2-SNAP. Cytotoxicity of gucose-2-SNAP was lessened upon coexposure with the antioxidants, myricetin. N-acetyl-L-cysteine, and L-ascorbic acid. S-G cells exposed to glucose-2-SNAP exhibited bi- and multinucleation. Death of S-G cells exposed to glucose-2-SNAP apparently occurred by apoptosis, as demonstrated with fluorescence microscopy by the appearance of brightly stained, hypercondensed chromatin in spherical cells and of membrane blebbing and by the DNA ladder of oligonucleosome-length fragments noted with gel electrophoresis. In comparison with other classes of NO donors the sequence of toxicity towards S-G cells was S-nitrosoglutathione> glucose SNAPs>SNAP, sodium nitropruside>spermine NONOate>DPTA NONOate>DETA NONOate> fructose-1-SNAP>>SIN-1.

Tickner JA., Schettler T., Guidotti T., MacCally M., Rossi M (Lowell Center for Sustainable Production, Department of work Environment, University of Massachusetts Lowell, One University Ave, Lowell, MA 01854, USA): Health risks posed by use of Di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: A critical review. AM J Ind Med, 39(1), 2001, 100-111. [105 Ref]

Polyvinyl chloride plastics (PVC), made flexible through the addition of di-2-ethylhexyl phthalate (DEHP), are used in the production of a wide array of medical devices. From the late 1960s, leaching of DEHP from PVC medical devices and ultimate tissue deposition have seen documented. A critical review of DEHP exposure , metabolism , and toxicity data from human and animals studies was undertaken. A brief analysis of alternatives to DEHP-plasticized PVC for use in medical device manufacture was completed. DEHP leaches in varying concentrations into solutions stored in PVC medical devices. Certain populations, including dialysis patients and hemophiliacs may have long-term exposures to clinically important doses of DEHP, while others, such as neonates and the developing fetus, may have exposures at critical points in development. In vivo and in vitro research links DEHP or its metabolites to a range of adverse effects in the liver, reproductive tract, kidneys, lungs, and heart. Developing animals are particularly susceptible to effects on the reproductive system. Some adverse effects in animal studies occur at levels of exposure experienced by patients in certain clinical settings. DEHP appears to pose a relatively low risk of hepatic cancer in humans. However, given lingering uncertainties about the relevance of the mechanism of action of carcinogenic effects in rodents for humans and interindividual variability, the possibility of DEHP-related carcinogenic responses in humans cannot be ruled out. The observed toxicity of DEHP and availability of alternative to many DEHP containing PVC medical devices presents a compelling argument for moving assertively, but carefully, to the substitution of other materials for PVC in medical devices. The substitution of other materials for PVC would have an added worker and community health benefit of reducing population exposures to DEHP, reducing the creation of dioxin from PVC production and disposal, and reducing risks from vinyl chloride monomer exposure.

Hansen DK., LaBorde JB., Wall KS., Hinson WG., Pipkin JL., Shaddock J., Lyn-Cook L., Young JF (National Center for Toxicological Research, Division of Genetic Reproductive Toxicology, 3900 NCTR Road, Jefferson-AR72079-9502, USA): Dose-response of retinoic acid induced stress protein synthesis and teratogenesis in mice. Rep Toxicol, 15(1), 2001, 31-41. [56 Ref]

Stress proteins are synthesized in response to a variety of stressors, including several teratogenic agents. However, their role, if any, in the teratogenic process is unknown. We have previously demonstrated that all -trans-retinoic acid administered to pregnant CD-1 mice on gestational day 11 or 13 produced limb defects and cleft palate near term in a dose-responsive manner. This chemical also induced the synthesis of several nuclear stress proteins in embryonic tissues within several hours of dosing. The stress proteins were only observed in tissues that eventually became malformed and not in tissues that appeared normal at term. In the current work, we examined the stress response in embryonic target tissues after several different doses of retinoic acid. The nuclear stress proteins were synthesized in dose-related manner and at a lower retinoic acid dose than doses producing malformations in the corresponding tissue at birth. 

Ji BT., Silverman DT., Stewart PA., Blair A., Swanson GM., Baris D., Greenberg RS., Hayes RB., Brown LM., Lillemoe KD., Schoenberg JB., Pottern LM., Schwartz AG., Hoover RN (Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Executive Plaza South, Room 8120 Bethesda MD 20892, USA): Occupational exposures to pesticides and pancreatic cancer. Am J Ind Med, 39(1), 2001, 92-99. [46 Ref]

An increased risk of exposure to pesticides for pancreatic cancer has been suggested in a number of epidemiologic studies. Cases (N=484), aged 30-79 years were diagnosed in 1986-1989. Controls (N=2095) were a random sample of the general population. Information on usual occupation and potential confounding factors was obtained. A job-exposure matrix (JEM) approach was used to estimate the level of occupational exposure to pesticides. A significant trend in risk with increasing exposure level of pesticides was observed, with ORs of 1.3 and 1.4 for low and moderate/high exposure levels, respectively. Excess risks were found for occupational exposure to fungicides (OR=1.5) and herbicides (OR=1.6) in the moderate/high level after adjustment for potential confounding factors. An increased risk for insecticide exposure was disappeared after adjustment for fungicide and herbicide exposures. Results of our occupation-based analysis were consistent with those from the JEM-based analysis. Our results suggest that pesticides may increase risk of pancreatic cancer, and indicate the need for investigations that can evaluate risk by specific chemical exposures. 

Carpentier P., Foquin A., Kamenka JM., Rondouin G., Natoli ML., Groot DMG., Lallement G (Centre de Recherches du Service de Sante des Armees, Unite de Neurotoxicologie, BP87,38702 La Tronche Cedex, France): Effects of thienyl-phencyclidine (TCP) on seizure activity and brain damage produced by soman in Guinea-pigs: ECoG correlates of neurotoxicity. Neurotoxicol, 22(1), 2001, 13-28. [55 Ref]

The capacity of thienyl-cyclohexylpiperidine (TCP), a non-comparative blocker of the N-methyl-D-aspartate (NMDA) receptor, to counteract the convalsant, lethal, and neuropathological effects of 2xLD50 of soman (an irreversible inhibitor of cholinesterase) was investigated in guinea pigs treated by pyridostigmine and atropine sulphate. The effects of a weak dose of TCP (1mg/kg) used in the present study globally reproduced those previously obtained with a higher dose (2.5 mg/kg; [Neurotoxicology 15 (1994) 837): TCP was again most protective when given curatively within the fist hour of soman-induced seizures. In this condition, (a) paroxymal activity ceased in 10-20 min, (b) all the animals survived. (c) the majority of them recovered remarkably well and did not show any brain damage 24h after the intoxication, and (d) the minimal duration of seizure activity normally required for producing soman-induced brain damage in other pharmacological environments was increased from 10 to 40 min to 80 min. Strikingly, when TCP was given 120 min after seizure onset, it failed to show any anticonvulsant activity but still provided neuroprotection in the hippocampus. The present study also gives additional evidence that in soman poisoning. (a) the development of brain damage depends on the occurrence of ECoG seizures. (b) the topographical distribution of lesions depends on seizure duration, and (c) an increase of the relative power in the lowest (delta) frequency band might be a reliable marker of neuronal degradation. All these findings confirm that (a) glutamatergic NMDA receptors are involved in the mechanisms of soman-induced seizures and brain damage, (b) non-competitive antagonists of NMDA receptors might be promising candidates for post-treatment of soman poisoning, and (c) ECoG parameters from ECoG tracings and power spectrum might serve as useful external predictors for soman-induced neuropathological changes. 

Zhang P., Omaye ST (Environmental Sciences and Health Graduate Program and the Department of Nutrition, Mail Stop 142, University of Nevada, Reno, NV 89557, USA): Antioxidant and prooxidant roles for B-carotene, a-tocopherol and ascorbic acid in human lung cells. Toxicol In Vitro, 15(1), 2001, 13-24. [60 Ref]

Experiments were conducted to determine the antioxidant and prooxidant effects of B-carotene, a-tocopherol and ascorbic acid on human lung cells at different oxygen (O2) tensions. Free radical initiator, 2.2'-azobis (2-amidinopropane) dihydrochloride (AAPH), was used to induce the cellular damage associated with lipid peroxidation, protein oxidation and DNA breaks. Under hypoxic conditions (0 torr O2 tension) all compounds produced a concentration-dependent antioxidant effect,. Mixtures of the three compounds exhibited greater protective affects than any individual compound. At 143 torr O2 tension, all compounds exhibited concentrations dependent protective effects against AAPH-induced cellular lipid, protein and DNA damage. At 722 torr O2 tension, cells exhibited a consistent increase in lipid peroxidation (isoprostane formation), protein oxidation (carbonyl formation ) and DNA damage (p53 protein accumulation). B-Carotene (1.5 um) produced a prooxidant effect by promoting 12% isoprostane formation. Protein oxidation and DNA damage at 722 torr O2 tension was not increased by B-cerotene. However, the antioxidant effect of B-carotene was attenuated. The antioxidant effects of a-tocopherol, ascorbic acid, and mixtures of the threeantioxidant compounds also were reduced by the high O2 conditions. These results partially substantiate the hypothesis that the antioxidant and prooxidant effects of B-carotene are dependent on O2 tension and concentration of B-carotene. Such findings may partially explain why selected populations, such as smokers, respond adversely when supplemented with B-carotene. 

Wilhelm M., Battista HJ., Obendorf D (Institute of Analytical Chemistry and Radiochemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria): HPLC with simultaneous UV and reductive electrochemical detection at the hanging mercury drop electrode: a highly sensitive and selective tool for the determination of benzo-diazepines in forensic samples. J Anal Toxicol, 25(4), 2001, 250-257. [20 Ref]

A versatile, sensitive, and selective high-performance liquid chromatography (HPLC) procedure for the determination of common benzodiazepines and some of their most frequently occurring metabolites in forensic samples was developed and optimized with respect to effective and rapid sample preparation and high selectivity of the analytical assay. The optimized method includes liquid-liquid extraction of the drugs with chloroform followed by isocratic reversed-phase chromatography on a LiChrospher-100 RP-8ec column (150x4.6-mm i.d.) with a mobile phase consisting of 0.03 mol/L acetate buffer (pH4.6)/acetonitrile (55:45, v/v). The use of dual-mode detection made up of UV-detection (250 nm) in series with reductive electrochemical detection (-1.4 V vs Ag/AgC1) at the hanging mercury drop electrode permits the detection and quantitation of benzodiazepines even in degraded samples with higher selectivities than usually reached with conventional HPLC techniques. Depending on the actual benzodiazepine species, detection limits are in the range of 2.0 to 14.1 ng/ml. Mean recovery values of the drugs from blood range from 82 to 92 percent; within-day and day-to-day repeatabilities typically lie between 3 and 9 percent. Several case work examples demonstrate the high selectivity and remarkably low matrix sensitivity of the described assay. 

Adams SM., Giesy JP., Tremblay LA., Eason CT (CENTOX (Centre for Environmental Toxicology), Landcare Research, PO Box 69, Lincoln, New Zealand): The use of biomarkers in ecological risk assessment recommendations from the Christchurch conference on biomarkers in ecotoxicology. Biomarkers, 6(1), 2001, 1-6. [19 Ref]

A conference to assess and evaluate biomarkers in environmental protection was organized by the Centre for Environmental Toxicology (CENTOX) in Christchurch, New Zealand, 14-16 July, 1999. The aims of the meeting were to assess the current status of the application of biomarkers, to identify emerging concepts for their practical use in environmental bioassessment, and to raise recommendations for ensuring their continued inclusion into ecological risk assessment (ERA). Biomarkers are extremely topical in ecotoxicological research as they provide functional measures of receptor species, exposure to environmental stressors that can be better related to the adverse effects of human activities. This effects-based information can be used in support of environmental management and regulation. 

Tricklebank KA (School of Environmental and Marine Sciences, Tamaki Campus, University of Auckland, Private Bag 92019, Auckland 1, New Zealand): Histological alterations in fish from Sydney reefs: possible biomarkers for environmental effects? Biomarkers, 6(1), 2001, 26-32. [18 Ref]

This study examines the utility of histopathology in the damselfish, Parma microlepis, as a biomarker for the effects of organochlorine pesticides and hexachlorobenzene (HCB). Linkage between organochlorine residue concentrations and contaminant- associated histological effects in fish were examined using field collections and a manipulative field experiment. The distribution of 11 frequently identified organochlorines were measured in wild fish at different spatial scales, spanning 270 km of costline centered around the Sydney region. Histopathology was used to investigate possible effects on liver, gills and gonad tissues in these fish. Pearson correlations and correlative multivariate statistical techniques were used to explore possible associations between concentrations of organochlorines in fish collected from the field and histological alterations in tissues. Only 6% of correlations between organochlorine residues and histological alterations in fish from field collections, were significant. A weak correlation was found between the occurrence of lamellar fusion in gills and the concentration of aldrin and dieldrin in a manipulative field experiment. A hypothetical model is suggested to explain these results.



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