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PubMed2002

Xenoendocrine disrupters-tiered screening and testing: filling key data gaps.

The US Environmental Protection Agency (EPA) is developing a screening and testing program for endocrine disrupting chemicals (EDCs) to detect alterations of hypothalamic-pituitary-gonadal (HPG) function, estrogen (ER), androgen (AR) and thyroid hormone synthesis and AR and ER receptor-mediated effects in mammals and other animals. High priority chemicals would be evaluated in the Tier 1 Screening (T1S) battery and chemicals positive in T1S would then be tested (Tier 2). T1S includes in vitro ER and AR receptor binding and/or gene expression, an assessment of steroidogenesis and mammalian (rat) and nonmammalian in vivo assays (Table 1). In vivo, the uterotropic assay detects estrogens and antiestrogens, while steroidogenesis, antithyroid activity, (anti)estrogenicity and HPG function are assessed in a 'Pubertal Female Assay'. (Anti-) androgens are detected in the Hershberger Assay (weight of AR-dependent tissues in castrate-immature-male rats). Fish and amphibian assays also are being developed. The fathead minnow assay can identify EDCs displaying several mechanisms of concern, including AR and ER receptor agonists and antagonists and inhibitors of steroid hormone synthesis. An amphibian metamorphosis assay is being developed to detect thyroid-active substances. Several alternative mammalian in vivo assays have been proposed. Of these, a short-term pubertal male rat assay appears most promising. An in utero-lactational screening protocol also is being evaluated. For Tier 2, the numbers of endocrine sensitive endpoints and offspring (F1) examined in multigenerational tests need to be expanded for EDCs. Consideration should be given to tailoring T2, based on the results of T1S. Tier 1 and 2 also should examine relevant mixtures of EDCs. Toxicants that induce malformations in AR-dependent tissues produce cumulative effects even when two chemicals act via different mechanisms of action.

Animals↗
PubMed1998

Experimental assessment of the influence of atmospheric pollutants on respiratory disease.

Asthma is a chronic respiratory disease characterized by inflammation, episodes of usually reversible airways obstruction, and bronchial hyperresponsiveness. The disease has significant health, societal and economic consequences. Experimental assessment methods, including controlled human exposure studies, human and animal dosimetry, as well as animal and in vitro toxicology, can shed light on how air pollutants may cause and/or worsen asthma. A brief summary background on selected classes of air pollutants is provided and selected experimental studies that exemplify novel approaches or suggest new hypotheses are highlighted. Possible directions for future research about the effects of particles, pesticides, ambient air toxicants, and pollutant mixtures on asthma, are also outlined.

Air Pollutants↗
PubMed2002

Primary prevention: phytoprevention and chemoprevention of colorectal cancer.

Considering the various stages of carcinogenesis and the numerous tumor types and available chemoprevention agents, knowledge of the etiology and the type of cancer to be treated, or possibly prevented, and understanding of the mechanisms by which agents exert their chemoprevention benefits may provide for improved strategy in designing therapeutic regimens. Because cancer usually develops over a 10- to 20-year period, it may be necessary for some agents to be provided before or early in the initiation steps of carcinogenesis to have beneficial effects. On the other hand, some agents may be more suitable for CRC prevention if provided at a later stage of carcinogenesis. Gene array, genomics, and proteomics are useful tools in advancing our understanding of the molecular events involved in carcinogenesis and in identifying markers of risk and surrogate end-points for colorectal cancer progression. These techniques may also serve for screening, identifying, and providing treatment targets for high-risk patients populations. Treatment could be developed depending on a patient's individual needs and genomic tumor profile. Clinical markers and surrogate end-points should be considered, together with molecular measurements, to more accurately assess risk. NSAIDs and COXIBs are clinically recognized as chemoprevention agents, and clinical trials evaluating their efficacy are ongoing. Treatment protocols, including dose and timing, remain to be determined, however. DFMO may best be used in combination with other chemoprevention agents. Dietary fiber and calcium supplements, as part of an overall low-fat diet, may decrease CRC risk. Long-term compliance with this regimen may be necessary to effect a beneficial outcome. Folate holds promise but needs further investigation, especially because its beneficial effects may depend on cancer type. Phytochemicals have been identified as strong candidates for use as agents to prevent colorectal cancer in cell culture and in rodent models of carcinogenesis. Their potential as chemoprevention agents must be demonstrated in clinical trials. In vitro and animal studies indicated that combination therapy may be a promising strategy over the monotherapy approach; clinical trials addressing the safety and efficacy of some combinations (DFMO/sulindac, fiber/calcium) are underway. The gastrointestinal tract and other organs are constantly exposed to a mixture of potentially toxic compounds and molecules considered favorable to health. Homeostasis between stress-mediated by toxic compounds and defensive mechanisms, is key for the maintenance of health and the prevention of disease. Whereas aggressive pharmacologic treatment may be necessary for patients at high risk for cancer, dietary supplements may be useful for populations at normal risk. The message for cancer prevention in the general population may well remain: keep a balanced healthy diet, eating a variety from all food groups, as part of a healthy lifestyle that includes moderate exercise.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

The importance of measured end-points in demonstrating the occurrence of interactions: a case study with methylchloroform and m-xylene.

Mixed exposures may result in significant changes in one biomarker of exposure without altering another biomarker, and this may have unknown significance in terms of exposure assessment and overall toxicity of the mixture. Results from a previous investigation showed that human exposure to methylchloroform (MC, 400 ppm) and m-xylene (XYL, 200 ppm) during 4 h did not result in any significant effect on blood concentrations of these solvents, suggesting the absence of interaction between MC and XYL. Those results were adequately described by conducting a physiologically-based toxicokinetic (PBTK) modeling of the MC-XYL interaction in humans; however, the model suggested that urinary excretion of MC metabolites would be reduced as a result of combined exposure, whereas that of XYL metabolites would not be modified. An experimental verification of this model prediction was then undertaken with rats. In this study, Sprague-Dawley rats (n, 5) were exposed during 4 h to MC (400 ppm) or XYL (200 ppm), alone or as a mixture. Results showed that combined exposure did not affect the blood concentration of MC whereas that of XYL was increased throughout the 2-h blood collection period following exposure. The excretion of MC metabolites during a period of 48 h following the onset of exposure, i.e., trichloroethanol (TCE: -71%) and trichloroacetic acid (TCA: -73%), were significantly reduced. Methylhippuric acid (MHA) was not affected by co-exposure to MC as expected from the PBTK model forecasts. These results exemplify the use of a priori PBPK modeling for designing interaction studies and choosing appropriate/sensitive end-points for demonstrating the occurrence of potential interactions.

Animals↗
PubMed1999

DNA-damaging effects of genotoxins in mixture: nonadditive effects of aflatoxin B1 and N-acetylaminofluorene on their mutagenicity in Salmonella typhimurium.

Most animal genotoxicity studies have used exposures to single chemicals; humans, however, are potentially exposed to mixtures of genotoxins. Cancer and developmental toxicity risks associated with genotoxins in mixture are generally estimated by assuming additivity of the components. Two or more genotoxins acting sequentially or simultaneously may present a greater or lesser hazard than that predicted by simple addition of their potencies. Previously, we studied the effect of one genotoxin on the binding of a second genotoxin to DNA in an in vitro system and demonstrated that consecutive binding of the two toxins was not additive. In the present study, the effect of one genotoxin on the mutagenicity of another was evaluated for two well-known genotoxins using the Salmonella assay. Pretreatment of frameshift strains TA98 and TA1538 with AFB1-8,9-epoxide (17.3 ng/plate) enhanced the mutagenicity induced by subsequent exposure to N-acetoxy-acetylaminofluorene (N-AcO-AAF) approximately 2-3 times above theoretical values for additivity. Pretreatment of base-substitution strain TA100 with N-AcO-AAF (0.1 microg/plate) inhibited the mutagenicity following subsequent exposure to AFB1-8,9-epoxide by 3 times below the theoretical additive value. Concentration-response relationships for these enhancing or inhibitory effects were demonstrated using increasing concentrations of the first genotoxin during pretreatment. These results demonstrate effects, other than additive, of sequential exposures to two genotoxins on the induction of mutations in a bacterial system.

2-Acetylaminofluorene↗
PubMed1998

Bullous erythema multiforme following herpes zoster and varicella-zoster virus infection.

Four cases of herpes zoster-induced bullous erythema multiforme (EM) are reported. Three patients presented with widespread skin lesions 10 to 14 days after an episode of thoracic herpes zoster. In these patients a high increase in varicella-zoster virus (VZV) antibody titer was detected, indicating secondary VZV infection. Histologic examinations of skin biopsy from a patient with widespread lesions (case 4) revealed a mixture of EM, toxic epidermal necrolysis and herpetic virus infection. VZV should be included in the list of infectious agents able to trigger EM and Stevens-Johnson syndrome.

Acyclovir↗
PubMedDate not supplied

Herbicides and adjuvants: an evolving view.

The present report examines the in vitro genotoxicity (micronucleus assay) of herbicides and adjuvants and reports on an in vivo human study on potential endocrine effects of pesticides, including herbicides. Adjuvants are used in conjunction with 2,4-dichlorophenoxy acetic acid (2,4-D) and other herbicides. Earlier pesticide applier survey results (n = 709) show that 59% of the applicators used adjuvants, and the majority of this group used paraffinic oils and/or surfactant mixtures. As a beginning effort to explore the role of adjuvants and herbicides in hormonally based reproductive effects, a prospective, controlled study was performed to analyze blood specimens from three different exposure groups (applicators using herbicides only; applicators using both herbicides and insecticides; and applicators using fumigants in addition to herbicides and insecticides; and a control group composed of other agricultural workers including organic farmers). The applicators and controls were age- and smoking-matched. Study subjects (n = 78) were tested before, during, and after completion of pesticide application season for the effects of pesticide products on hormone levels in the bloodstream. Of the applicator exposure groups examined, only the herbicide group showed significant endocrinologic differences from controls. Free testosterone levels were significantly elevated in post-season measurements (p = 0.032), and follicle-stimulating hormone (FSH) was significantly decreased at the height of the season (p = 0.016) and in the post-season (p = 0.010) as compared to controls. These endocrinologic findings are discussed in terms of their possible relationship to potential endocrine effects of herbicides, herbicide contaminants, and adjuvants. In vitro genotoxicity examination compared four different commercially available surfactant mixtures with 12 different commercial herbicide products, including six different chlorophenoxy herbicides. Only one herbicide yielded a significant dose-response curve. All four adjuvants showed positive dose-response effects. These preliminary data suggest that adjuvants are not inert but are toxicologically active components added to herbicide mixtures. Whether adjuvant toxicant effects are additive or are independent of herbicide effects is poorly understood.

Adult↗
PubMed2000

Acute effects of polychlorinated biphenyl-containing and -free transformer fluids on rat testicular steroidogenesis.

Polychlorinated biphenyl (PCB)-based transformer fluids belong to a class of environmentally persistent mixtures with known toxic effects. Here, we studied the acute effects of Askarel (which contains Aroclor 1260) and two substitute transformer fluids (the silicone oil-based DC561 and the mineral oil-based ENOL C) on rat testicular steroidogenesis. Single intraperitoneal (ip; 10 mg/kg body weight) or bilateral intratesticular (itt; 25 microg/testis) injections of Askarel markedly decreased serum androgen levels 24 hr after administration. In acute testicular cultures from these animals, chorionic gonadotropin-stimulated progesterone and androgen productions were severely attenuated. When itt was injected or added in vitro, Askarel inhibited 3ss-hydroxysteroid dehydrogenase (3ssHSD), stimulated 17[alpha]-hydroxylase/lyase (P450c17), and did not affect 17ss-hydroxysteroid dehydrogenase in testicular postmitochondrial fractions. The ip-injected Askarel did not affect 3ssHSD, but inhibited P450c17, suggesting that a more intensive metabolism of peripherally injected Askarel reduces the circulating levels of active ingredients below the threshold needed for inhibition of 3ssHSD and generates a derivative that inhibits P450c17. In contrast to Askarel, itt-injection (25 microg/testis) of DC561 and ENOL C did not affect in vivo and in vitro steroidogenesis. These findings show the acute effects of Askarel, but not silicone and mineral oils, on testicular steroidogenesis.

Animals↗
PubMed2003

Meta-analysis of dioxin cancer dose response for three occupational cohorts.

This article presents a meta analysis of data from three cohorts occupationally exposed to TCDD and related compounds. A statistically significant (p = 0.02) trend was found in total cancer mortality with increasing dioxin exposure. The trend tests show an increase in total cancer at cumulative TEQ (unit of measurement for TCDD-like compounds that is defined as the amount of TCDD that would produce the same toxicity as a mixture of TCDD-like compounds) serum levels that would result from lifetime intake of 7 pg TEQ/kg body weight/day, with no increase at 6 pg/kg/day. A linear dose response provided a good fit to the combined data and predicted an ED(01) (dioxin exposure resulting in a 0.01 increase in lifetime risk of cancer mortality) of 45 pg/kg/day (95% confidence interval, 21-324). The U.S. Environmental Protection Agency estimates that current lifetime human exposures to dioxin average approximately 1 pg/kg/day (99% percentile: 3 pg/kg/day). Although it appears unlikely that current exposures through foods would reach either 7 pg/kg/day or the ED(01), our analysis argues for careful consideration of the upper ranges of long-term average exposures for dioxins.

Cohort Studies↗
PubMed1994

Ozone, NO, and NO2: oxidant air pollutants and more.

This article reviews the acute and chronic toxicity of the three oxidant air pollutants ozone, nitric oxide (NO), and nitrogen dioxide (NO2). The toxicity of binary mixtures of NO2 with other inhaled agents is also discussed. Newer studies are emphasized, especially those published in the last 5 years or still in press. Very recent data from our laboratory that suggest a new cellular mechanism of importance in lung injury in animals exposed to mixtures of ozone and NO2 that may have general relevance with regard to the effects of oxidant air pollutants on the lung are also presented.

Air Pollutants↗
PubMed2000

Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic.

Recent work suggesting that cellular oxidative stress exerts an inhibitory effect on aromatic hydrocarbon receptor (AHR)-dependent gene expression led us to test the hypothesis that pro-oxidant environmental pollutants might alter the induction of detoxification genes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AHR ligand. We found that, in mouse hepatoma Hepa-1 cells, TCDD-inducible cytochrome P450, Cyp1a1, and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase (Nqo1) mRNA accumulation were differentially affected by cadmium (Cd(2+)), chromium (Cr(6+)), and arsenic (As(3+)). Cadmium or arsenic did not change Cyp1a1 mRNA levels but did enhance TCDD-inducible levels of Nqo1 mRNA, an effect that paralleled the ability of these metals to activate a beta-galactosidase gene reporter system regulated by an electrophile response promoter element. Chromium inhibited mRNA accumulation for both Cyp1a1 and Nqo1. Manipulation of cellular thiol status did not modify the response to combined chromium-TCDD exposure, suggesting that the response was not caused by oxidative stress. Chromium did not block DNA-binding competence of the AHR and did not have an effect on mRNA stability, but it inhibited Cyp1a1 gene transcription and the expression of an AHR-dependent luciferase reporter. These data indicate that coexposure to pro-oxidant metals and AHR ligands, which is common in the environment, can disrupt the regulation of phase I and phase II detoxification genes, leading to imbalances in gene expression that may have important consequences for the toxicity of complex mixtures.

Animals↗
PubMed2001

Distribution of cytoskeletal proteins, integrins, leukocyte adhesion molecules and extracellular matrix proteins in plastic-embedded human and rat kidneys.

OBJECTIVE: To study the distribution of cytoskeletal proteins (actin, alpha-actinin, vinculin, beta-tubulin, keratin, vimentin, desmin), adhesion molecules for cell-matrix interations (very later antigens [VLA1-61, beta1, beta2 [CD18], vitronectin receptor [alphavbeta3], CD 11b), leukocyte adhesion molecules (ICAM-1) and extracellular matrix proteins (collagen IV, fibronectin, laminin, vitronectin) in human and rat kidneys by using a superior processing and immunohistochemical staining technique. STUDY DESIGN: Human and rat kidneys were fixed in 2% paraformaldehyde, dehydrated in acetone and processed in a new, low-toxic glycol, methacrylate mixture, especially developed for immunohistochemistry. Both the glomeruli and the interstitial areas were carefully examined and scored semiquantitatively. RESULTS: Immunostained plastic sections showed excellent morphology combined with remarkably well preserved antigenicity. CONCLUSION: The above mentioned provides an excellent tool for the accurate localization of a wide variety of antigens at the light microscopic level.

Animals↗
PubMedDate not supplied

[Biological methods of air purification (review of the literature)].

Biological methods of air purification are reviewed, which can be applied to deep air purification of complex multicomponent mixtures from harmful, toxic and odorous substances at room temperature and atmospheric pressure. Microbiological and technological aspects of the problem are discussed. Operation characteristics of biofilters, bioscrubbers and trickle bed bioreactors are compared. Prospects of air biopurification are considered.

Air Pollutants↗
PubMed1989

Serum-induced proliferation of retinal capillary endothelial cells is inhibited in the presence of retinal extract.

Both crude retinal extract and serum contain growth factors for retinal capillary endothelial cells (EC). This study, however, has shown that the combined presence of both crude retinal extract (bovine) and adult serum, induces profound inhibition of EC growth in vitro. EC grown under these conditions develop as sparse colonies of cells which appear to be inhibited from spreading on the fibronectin-coated surface. The extract/serum mixture is not toxic to the cells since it does not affect the viability and typical cobblestone morphology of established confluent cultures. Combinations of retinal extract with adult sera from various species exert the inhibitory effect but foetal or newborn serum is not affected by the extract. Growth inhibition is also found with crude bovine brain extract but cannot be ascribed to the presence of basic fibroblast growth factor (bFGF) or heparin in the extract, nor to a previously identified heat-labile (56 degrees C, 30 min) inhibitory factor in retinal extract. The inhibition is selective for endothelial cells in that mural cells (pericytes) remain unaffected. The nature and relevance of this inhibitory activity remains to be determined.

Animals↗
PubMed1978

Effect of some herbicides on the toxicity of certain molluscacides against Biomphalaria alexandrina snails.

Studies dealing with the effect of some herbicides on the molluscicidal action of certain molluscicides against B. alexandrina have been carried out. In the first part of the study the toxicity of 3 molluscicides (Copper sulphate, Niclosamide and Frescon) and 3 herbicides (Gramaxone, Preforan and Treflan) was tested individually. Results indicated that the molluscicides were more potent than the herbicides. In the second part, snails were exposed for 24 hr to one of the tested herbicides using LC0 or (Sub. lethal conc) then the toxicity of molluscicides was determined among the same snails. Data indicated that pre-exposure to herbicides caused a synergistic action with copper sulphate, while with Niclosamide and Frescon marked antagonistic effect was observed. In the third part molluscicides and herbicides were mixed in different ratios (1:2, 1:1 and 2:1) and the toxicity of the mixtures was tested. A synergistic effect was observed in the case of copper sulphate plus various herbicides especially with Treflan at 1:2 ratio. With Niclosamide and Frescon slight antagonistic effect was detected.

Animals↗
PubMed1993

[Cobra bite: ophthalmic manifestations].

The venom of the cobra snake contains a mixture of several toxic enzymes and proteins. It has a direct action on the respiratory centers, as well as curariform interference at the neuromuscular junction, resulting in death from respiratory paralysis. It can injure the visual system by damaging the retinal cells, causing bilateral optic neuritis and cortical blindness. Due to a particular configuration of its venom ducts, the African cobra is capable of poisoning both by biting or by spitting its venom. We present an 18-year-old woman with severely impaired visual function which resulted from a cobra bite in childhood.

Adolescent↗
PubMed2006

Composting anaerobic and aerobic sewage sludges using two proportions of sawdust.

Sawdust has been proven to be a good bulking agent for sludge composting; however, studies on the most suitable ratio of sludge:sawdust for sludge composting and on the influence of the sludge nature (aerobic or anaerobic) on the composting reaction rate are scarce. In this study two different sewage sludges (aerobic, AS, and anaerobic, ANS) were composted with wood sawdust (WS) as bulking agent at two different ratios (1:1 and 1:3 sludge:sawdust, v:v). Aerobic sludge piles showed significantly higher microbial activity than those of anaerobic sludge, organic matter mineralization rates being higher in the AS mixtures. The lowest thermophilic temperatures during composting were registered when the anaerobic sludge was mixed with sawdust at 1:1 ratio, suggesting the presence of substances toxic to microorganisms. This mixture also showed the lowest decreases of ammonium during composting. All this matched with the inhibitory effect on the germination of Lepidium sativum seeds of this mixture at the first stages of composting, and with its low values of microbial basal respiration. However, the ANS+WS 1:3 compost developed in a suitable way; the higher proportion of bulking agent in this mixture appeared to have a diluting effect on these toxic compounds. Both the proportions assayed allowed composting to develop adequately in the case of the aerobic sludge mixture, yielding suitable composts for agricultural use. However, the ratio 1:1 seems more suitable because it is more economical than the 1:3 ratio and has a lower dilution effect on the nutritional components of the composts. In the case of the anaerobic sludge with its high electrical conductivity and ammonium content, and likely presence of other toxic and phytotoxic substances, the 1:3 ratio is to be recommended because of the dilution effect.

Aerobiosis↗
PubMed1990

Interaction between components of electroplating industry wastes. Influence of the receiving water on the toxicity of the effluent.

A copper-cadmium-nickel-zinc mixture was assessed in seven different river waters to study metal toxicity to the ciliate protozoan Colpidium campylum, the interactions occurring between metals, and the influence of the receiving water on toxicity. In the range of concentrations tested, which are representative of electroplating industry wastes, the main part of the toxicity can be attributed to copper and to cadmium-copper synergy. A classification of waters, based on a principal component analysis (PCA), was used to examine the main parameters of the water, which can affect the toxicity of metal mixtures. It appears that the mineralization of the water, more than the total organic carbon (TOC), is an important parameter for the expression of toxicity. A strategy for the estimation of ecotoxicological hazard assessment, based on a simplified factorial experiment is proposed. It enables one to study, in a two-step bioassay, the toxicity of an effluent, the influence of river water on its toxicity, and the effects of contact time and dilution. By applying PCA to data from very different waters, it may be possible to estimate the ecotoxicological risk associated with the discharge of an effluent, on the basis of the chemistry of the receiving water.

Journal Article↗