Abstract  Acute inflammation induces changes in liver proteins with an increase in synthesis of positive acute-phase proteins such as alpha1-acid glycoprotein (alpha1-AGP) and a decrease in synthesis of negative acute-phase proteins such as albumin. This is associated with muscle wasting, mediated by increased proteolysis and impaired protein synthesis. As protein metabolism can be altered in other situations (malnutrition, growth) by the form of the dietary nitrogen, we studied the effects of the molecular form of nitrogen on liver and skeletal muscle adaptation, looking at gene expression for two acute-phase proteins (albumin and alpha1-AGP) and a number of muscle proteins (alpha1-actin, ubiquitin and C9 proteasome subunit). Two groups of 24 Wistar rats (250 g) were injected S/C with 0.125 ml turpentine/rat and were fed one of two liquid diets. These diets had caloric, nitrogen, carbohydrate and lipid content but differed in the molecular form of the nitrogen source (whole protein [WP] versus peptide hydrolysate [PH]). Liver and muscle adaptation were studied at 18, 42 or 66 h after turpentine injection. Weight, deoxyribonucleic acid and protein content of the liver were significantly higher with the WP diet than with the PH diet at 42 h and 66 h. There was more alpha1-AGP messenger ribonucleic acid (mRNA) at 18 h and less albumin mRNA at 42 h. Thus, the PH diet causes a more rapid increase in alpha1-AGP mRNA content and a smaller decrease in albumin mRNA content after turpentine injection than the WP diet. However, the changes in plasma acute-phase proteins (albumin and alpha1-AGP) were similar with the two diets. In skeletal muscle, there was no change in mRNA levels for the C9 proteasome subunit at any time point with both diets compared to the controls. However, there were greater ubiquitin mRNA levels at 18|h and less alpha-actin mRNA levels at 18 h, 42 h and 66 h following turpentine injection in the two dietary groups than in the controls. These results suggest that the molecular form of nitrogen ingested regulates hepatic gene transcription or mRNA stability of acute-phase proteins, during the early period of inflammation, but did not affect the expression of muscle proteins, which was altered by turpentine injection. Post-transcriptional control of acute-phase protein genes may contribute to the maintenance of similar plasma levels.

Abstract  BACKGROUND: Interleukin (IL) 6 has an important role in the regulation of acute-phase proteins (APPs) during an acute-phase response. We studied IL-6 and other cytokines to determine if they regulate serum APP levels in the same way under the condition of the aberrant, long-lasting 'acute-phase response' that occurs in patients with chronic inflammation and cancer.

METHODS: Serum levels of nine positive APPs [CRP, SAA, C1-INH, Bf, C5, C8, C9, alpha 1-acidic glycoprotein (AGP) and haptoglobin] and two negative APPs [transferrin and alpha 2-HS glycoprotein (AHSG)] were measured using immunochemical methods in 59 multiple myeloma patients and in 72 healthy control subjects. Serum IL-6 and tumour necrosis factor (TNF) alpha levels were determined by bioassays.

RESULTS: IL-6 was negatively correlated with five out of nine (C1-INH, C8, C9, AGP and haptoglobin) positive APPs but positively correlated with C-reactive protein (CRP). When patients with high and low IL-6 serum concentration were compared, CRP levels were higher, AGP and haptoglobin levels were lower in the high- than in the low-L-6 group, whereas no significant difference between the two groups was found in levels of the other positive and negative APPs. TNF-alpha levels were negatively correlated with transferrin and AHSG levels. No difference in the levels of positive APPs was observed between patients with low and high TNF-alpha serum concentration. By contrast, levels of both transferrin and AHSG were significantly lower in the high- than in the low-TNF-alpha group.

CONCLUSIONS: These findings indicate that, except for regulation of the negative APPs by TNF-alpha, the mechanism of APP regulation is different under the conditions of the short-term and the chronic, long-lasting 'acute-phase reaction'.

Abstract  C biosynthesis at extrahepatic sites remote from plasma C may be important in the protection of tissues against inflammation and infection but may also contribute to tissue injury. This latter possibility is particularly relevant in the central nervous system (CNS), where several cell types are susceptible to damage by C. We have previously shown that human astrocyte-derived tumor cell lines synthesize and secrete all of the components of the activation pathways of C. In this study, we demonstrate that these cells also produce the components (C6, C7, C8, and C9) and regulators (S-protein and clusterin) of the lytic terminal C pathway. The terminal components produced are hemolytically active, and secretion is markedly up-regulated by the inflammatory cytokine IFN-gamma. Primary human fetal astrocytes also expressed C6, C7, S-protein, and clusterin. The human monocyte/macrophage cell line, used here as a model for microglia, also produced all terminal components and regulators when appropriately stimulated. These studies raise the prospect of the intrathecal synthesis of a complete, functional C system and its regulators in the inflamed CNS. Intrathecal C synthesis may be important in the resolution of infection and inflammation but, given the C susceptibility of some CNS cell types, may also exacerbate damage in demyelination and neurodegeneration.

Abstract  Coagulase-negative staphylococci are well recognized in medical device-associated infections. Complement activation is known to occur at the biomaterial surface, resulting in unspecific inflammation around the biomaterial. The human serum protein vitronectin (Vn), a potent inhibitor of complement activation by formation of an inactive terminal complement complex, adsorbs to biomaterial surfaces in contact with blood. In this report, we discuss the possibility that surface-immobilized Vn inhibits complement activation and the effect of Vn-binding staphylococci on complement activation on surfaces precoated with Vn. The extent of complement activation was measured with a rabbit anti-human C3c antibody and a mouse anti-human C9 antibody, raised against the neoepitope of C9. Our data show that Vn immobilized on a biomaterial surface retains its ability to inhibit complement activation. The additive complement activation-inhibitory effect of Vn on a heparinized surface is very small. In the presence of Vn-binding strain, Staphylococcus hemolyticus SM131, complement activation on a surface precoated with Vn occurred as it did in the absence of Vn precoating. For S. epidermidis 3380, which does not express binding of Vn, complement activation on a Vn-precoated surface was significantly decreased. The results could be repeated on heparinized surfaces. These data suggest that Vn adsorbed to a biomaterial surface may serve to protect against surface-associated complement activation. Furthermore, Vn-binding staphylococcal cells may enhance surface-associated complement activation by blocking the inhibitory effect of preadsorbed Vn.

Abstract  Lupus erythematosus (LE) was first described as a clinical dermatological entity in 1851. The possibility of serious systemic manifestations became recognized by 1872 as the result of the work of M. Kaposi. Since then, it took a long time before LE was recognized to be an immunological disease. Recognition of antinuclear antibodies and their deposition at the basal membrane region in skin resulted in two concepts of LE pathogenesis. In one, antibody complexing and complement activation with generation of the membrane attack complex (C5-C9) is thought to be the origin of the chronic inflammatory reaction. In the other, antibody deposition enables antibody dependent cellular cytotoxicity, leading to hydropic degeneration of the basal epidermal layer and subsequent chronic inflammation. Norris postulated in 1993, that the epidermis acts as a pro-inflammatory organ, in which an UVB-induced increase in cytokine production is followed by increased expression of adhesion molecules on keratinocytes as well as dermal endothelial cells. Translocation of certain antigens (i.e. Ro & La) to which circulating auto-antibodies exist in LE, enables recognition by adhesion molecule directed skin-invading T cells with subsequent cytotoxic effector activity. A persistent chronic inflammatory reaction then ensues. A similar development in knowledge may be seen in the history of immunodermatology. Originally, lupus erythematosus could not be recognized as an immune disease, since concepts of immunology were virtually non-existent when LE was first described. Immunology, In the first half of this century, was mainly antibody-oriented and thus came the concept of (S)LE as an antibody-mediated disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract  Sixteen pyrrolizidine alkaloids (PAs) were examined for their genotoxic potency in the wing spot test of Drosophila melanogaster following oral application. This in vivo assay tests for the induction of somatic mutation and mitotic recombination in cells of the developing wing primordia. All PAs tested except the C9-monoester supinine were clearly genotoxic. Depending on their chemical structure, however, genotoxicity of the PAs varied widely in a range encompassing about three orders of magnitude. In general, macrocyclic diester-type PAs were the most and 7-hydroxy C9-monoester types the least genotoxic representatives studied, while open diesters were intermediate in this respect. Stereoisomeric PAs mostly showed similar, but sometimes also clearly unequal genotoxicity. An increasing number of hydroxy groups in the PA molecule seemed to reduce its genotoxic potency. With respect to the structure/activity relationships, there appears to be a good correlation between hepatotoxicity of PAs in experimental rodents and genotoxicity in the wing spot test of Drosophila. This suggests that PAs are bioactivated along similar pathways in the mammalian liver and in the somatic cells of Drosophila. The genotoxic potential of PAs in the Drosophila wing spot test and their carcinogenic potential in mammals also seem correlated, although the information in the literature on carcinogenicity of the non-macrocyclic PAs with moderate to low genotoxic potency is concededly limited. Comparisons with other genotoxicity tests suggest that the wing spot test is particularly suitable for genotoxins like PAs, on the one hand because of the versatile metabolic bioactivation system of Drosophila and on the other hand also because of its excellent sensitivity to the crosslinking agents among the genotoxins.

Abstract  A sensitive sandwich ELISA was applied to the measurement of the terminal component of complement C9 in CSF and plasma from 40 tension headache patients (reference group), 33 affected by clinically definite MS and 10 by aseptic meningitis. The levels of C9 in plasma were increased in aseptic meningitis. The determinations of CSF/plasma C9 ratio and C9 index, equal to (CSF C9/plasma C9): (CSF albumin/plasma albumin), thus accounting for changes of plasma C9 levels as well as damaged blood brain barrier, documented the existence of local consumption of C9 in aseptic meningitis. In contrast, only borderline alterations were evident in MS. The results indicate that local consumption of total C9 in CSF is an additional variable reflecting an acute inflammation within the CNS, but not demonstrable in MS, a chronic inflammatory CNS disorder.

Abstract  One of the requirements of the 1990 Clean Air Act Amendments (CAA) is that 1-h ozone nonattainment areas that are classified severe or higher category are required to operate a network of photochemical assessment monitors (PAMS) to provide hourly measurements of volatile organic compounds (VOCs) comprising of Carbon number < 12 (C2-C12), along with carbonyl measurements at 3-h intervals during the summer ozone season. Often collocated with PAMS are 24-h-integrated canister and cartridge-based measurements of selected air toxic compounds, thereby providing an oortunity for inter-comparison and validation of both sets of data. In this study, we report such a comparison and estimates of trend for benzene, m-, p- and o-xylene, toluene, ethylbenzene, 1, 2,4-trimethylbenzene, formaldehyde and acetaldehyde at Bronx, NY. The analysis shows that hourly PAMS and 24-h-integrated air toxics are in good agreement with each other exhibiting similar trends and that the PAMS with the higher temporal resolution offers information on excursions of the toxic compounds that would be quite useful in assessment of acute health effects. These findings were also found to be applicable to other locations such as South De Kalb, GA; Gary, IN and Lynn, MA. (c) 2007 Elsevier Ltd. All rights reserved.

Abstract  The present study examines the influence of Ca2+ as (CaSO4), dissolved organic carbon (DOC) and pH on chronic water-borne lead (Pb) toxicity to the larval fathead minnow (Pimephales promelas) under flow-through conditions. The 30 day LC50 for low hardness basic test water (19 mg CaCO3 L− 1) was 39 (range: 27–51) μg dissolved Pb L− 1 and was greatly increased by increasing concentrations of CaSO4 and DOC to as much as 1903 (range: 1812–1992) μg dissolved Pb L− 1. Both reduced and increased pH (6.7 and 8.1, respectively) compared to control pH of 7.4 appeared to increase Pb toxicity substantially. Whole body Pb accumulation did not reflect water chemistry and thus exhibited no correlation with Pb induced mortality. One possible explanation for this lack of correlation is that mortality occurred predominantly during the first 4–6 days of exposure, whereas Pb accumulation was determined in surviving fish at the end of 30 days of exposure. Chronic Pb exposure resulted in a general iono-regulatory disturbance affecting K+, Na+ and Ca2+ homeostasis. However, recovery of Na+ and K+ levels and reversal of effects on Ca2+ homeostasis during continued exposure strongly suggest fathead minnow can acclimate to Pb. The gills accumulate the highest Pb concentrations during chronic exposure but the skeleton contains the largest mass of Pb by contributing up to not, vert, similar 80% of whole body Pb. In conclusion, water chemistry characteristics like Ca2+ and DOC should be considered for chronic water quality criteria.

Abstract  Biosorptions the effective method for the removalf heavy metalons from wastewaters. Results are presented showing the sorptionf Pb(II) from solutions by biomassf commonly available, filamentous green algae Spirogyra sp. Batch experiments were conducted toetermine the biosorption propertiesf the biomass andt wasbserved that the maximum adsorption capacityf Pb(II)on was around 140mgmetal/gf biomass at pH 5.0n 100min with 200mg/Lfnitial concentration. Temperature changen the range 20-40egrees C affected the adsorption capacity and the naturef the reaction was found to be endothermicn nature. Uptake kinetics follows the pseudo-second-order model and equilibriums wellescribed by Langmuirsotherm. Isotherms have been used toetermine thermodynamic parametersf the process, viz., free energy change, enthalpy change and entropy change. Various propertiesf the algae, as adsorbent, exploredn the characterization part were chemical compositionf the adsorbent, thermal analysis by TGA, surface area calculation by BET method, surface morphology with scanning electron microscopemages and surface functionality by FTIR. FTIR analysisf algal biomass revealed the presencef amino, carboxyl, hydroxyl and carbonyl groups, which are responsible for biosorptionf metalons. The resultsndicated that the biomassf Spirogyra sp.s an efficient biosorbent for the removalf Pb(II) from aqueous solutions.

Abstract  The aimf the present studys to evaluate the seasonal fluctuationf heavy metalsn thesopod Porcellio laevis at four uncontaminated subtropical locations. This study was carriedut at fourifferent field sitesn Assiut, Egypt. The concentrationsf cadmium, lead, copper, and zincn animal, soil, and litter (mug/gry weight) were monthly recordeduring the period from June 2002 till May 2003. There was littleifferencen metal accumulation trends between the sites. In general, thesopod showed significantncreased Pb and Zn concentrationuring summer and spring months, whereas this was not the case for Cd and Cu. The bioaccumulation (BAF) and bioconcentration factors (BCF)f the metals revealed marked seasonal changes throughout the year. Generally, BAFf metals were higheruring summer and spring, and BCF were higheruring summer and autumn. Comparing the metal accumulation with climatic fluctuations (measured)t was speculated that temperature was the main factor causing seasonal fluctuationsf thenternal metal concentrationn thesopod.

Abstract  Theiversityf nematode-trapping fungi (NTF)n two lead (Pb) minesn Yunnan Province, China wasnvestigatedn 2004. In total, 20 species belonging to five genera weredentified from 500 samples collected at the Lanping and the Huize mines. Pb concentrations ranged from 216 approximately 7,150 mg/kg for the former and 132 approximately 13,380 mg/kg for the latter, respectively. The fungi wereividednto five groups basednifferent trapping mechanisms. The trapping-net producer group contained the largest numberf species, with nine. Two predators, Dactylellina ellipsosporum and Arthrobotrysligospora, were found at frequenciesf 32.85% and 15.41%, respectively. Theiversityndexesf NTF were positively correlated with Pb pollution levelsn both the Lanping Mine (r=0.66) and the Huize Mine (r=0.72), suggesting that theistributionf NTF was not negatively affected by Pb contamination. For most strainsf a given species, there was no significantifference (P>0.01)n the Pb tolerance between the strainssolated from habitats with lowr high Pb concentrations. However, Pb toxicity exerted adverse effectsn trap formation and predacious capabilityf fungi. Weiscuss the possible metal tolerance mechanisms and their relationships to the survival strategyf NTFn Pb-polluted environments.

Abstract  The effectf two earthworm species, Lumbricus rubellus and Eisenia fetida,n the fractionation/bioavailabilityf Pb and Zn before and after soil leaching with EDTA was studied. Four leaching steps with total 12.5 mmol kg(-1) EDTA removed 39.8% and 6.1%f Pb and Zn, respectively. EDTA removed Pb from all soil fractions fairly uniformly (assessed using sequential extractions). Zn was mostly presentn the chemicallynert residual soil fraction, which explainsts poor removal. Analysisf earthworm casts and the remainderf the soilndicated that L. rubellus and E. fetida actively regulated soil pH, butid not significantly change Pb and Zn fractionationn non-remediated and remediated soil. However, the bioavailabilityf Pb (assessed using Ruby's physiologically based extraction test)n E. fetida casts was significantly higher thann the bulkf the soil. In remediated soil the Pb bioavailabilityn the simulated stomach phasencreased by 5.1 times.

Abstract  Influence of Halimione portulacoides, commonly found in temperate salt marshes, on sediment metal contents, speciation and potential mobility in case of sediment re-suspension was evaluated. Both colonized and non-colonized sediments were studied for total Cd, Cu, Pb and Zn contents and metal fraction exchangeable to water collected in situ. Sediment elutriates, prepared with water collected from each site, were used to simulate a sediment re-suspension phenomenon. As the characteristics and degree of contamination of sediments may influence system behaviour, salt marshes of two Portuguese estuaries, Cavado (NW coast) and Sado (SW coast), were studied. Cu, Pb and Zn contents higher than ERL (quality guideline, effect range-low) were observed, indicating potential risks for living organisms. Strong Cu-complexing organic ligands, also determined in both water and elutriates, were higher in rhizosediment elutriates, at concentrations similar, or even higher, to those of Cu. Such ligands condition metals speciation in the water column and probably also metal bioavailability. From rhizosediment significant amounts of Cu and Zn were transferred to the aqueous phase, concentrations 2-8 times higher than concentrations present in water. In contrast, elutriates of non-colonized sediment removed metals from water, Cu and Zn levels in elutriates being 2-6 times lower than initial ones. Cd and Pb levels in water and elutriates were not measurable in most cases. Results clearly indicate that metals potential solubility in the rhizosphere of plants was markedly higher than that in the surrounding sediment. The obtained results indicated that H. portulacoides presence (and probably other salt marsh plants) may cause a marked increase in metals concentrations in dissolved phase (pore water or even water column if rhizosediment is re-suspended). As salt marsh plants may be abundant in temperate and subtropical estuaries and costal lagoons, this phenomenon should not be disregard in future studies towards the sustainable management of such environments.

Abstract  Three hundred and one women who in their most recent pregnancy had given birth to an infant with an important congenital defect were individually matched with 301 women whose children were normal. Both cases and referents were drawn from a comprehensive survey of pregnancies in Montreal, 1982-4, and limited to women employed 30 or more hours a week until at least the 13th week of gestation. Occupational exposure to chemicals was investigated and the results classified without knowledge of case-referent status. In matched pair analysis the overall frequency of chemical exposure was higher in cases than referents (63:47), due to excesses in the cardiac and miscellaneous defect groups (ratios of 10:5 and 15:7 respectively). In analyses by nine chemical categories only exposure to aromatic solvents showed a clear excess (18:8; p approximately equal to 0.04), most evident in the urinary tract group (9:0). A comparison of cases and referents exposed to aromatic solvents showed that most of the excess was associated with toluene; the defects were varied but predominantly renal-urinary or gastrointestinal.

Abstract  Interest is increasing in the role of variations in the human genome (polymorphisms) in modifying the effect of exposures to environmental health hazards (often referred to as gene-environment interaction), which render some individuals or groups in the population more or less likely to develop disease after exposure. This review is intended for an audience of environmental health practitioners and students and is designed to raise awareness about this rapidly growing field of research by presenting established and novel examples of gene-environment interaction that illustrate the major theme of effect modification. Current data gaps are identified and discussed to illustrate limitations of past research and the need for the application of more robust methods in future research projects. Two primary benefits of incorporating genetics into the existing environmental health research framework are illustrated: a) the ability to detect different levels of risk within the population, and b) greater understanding of etiologic mechanisms. Both offer opportunities for developing new methods of disease prevention. Finally, we describe a basic framework for researchers interested in pursuing health effects research that incorporates genetic polymorphisms.

Abstract  Some farmland in Shenyang had been irrigated with industrial wastewater since 1962. Although wastewater irrigation was ceased in 1992, soil had been heavily polluted by heavy metals, especially by Cd. For better understanding processes of soil-heavy metal interactions, in particular, the mobility and retention mechanism of heavy metal in soil, a study on the transport and fate of heavy metals in soil zones from Shenyang suburb was carried out by column leaching tests in laboratory. Breakthrough curves of Pb, Cd, Cr(VI) and As(V) fitted by Thomas model and Yoon-Nelson model. The results of fitted breakthrough curves showed that transport rates of the four heavy metals in the soil zones followed the order: Cr(VI)>As(V)>Cd>Pb, which indicated that Cr(VI) was much more mobile, and Pb was comparatively unmovable. Cr in effluents and As were almost entirely Cr(VI) and As(V), respectively, and no Cr(III) and As(III) was ever detected during the leaching tests. The contents of Pb, Cd, Cr and As in leached soils decreased in the order of Pb>Cd>Cr>As, which suggested that adsorption ability of soil to Pb was greatest and to As was least. The methods of selective sequential extraction and solvent extraction were used to determine the fractions of Pb, Cd, Cr, As and the valent states of Cr, As [Cr(VI) or Cr(III), As(V) or As(III)] in original soils and in leached soils. After leaching tests, the relative and absolute concentrations of exchangeable, carbonate, Fe-Mn oxide and organic fraction of each element were all increased, which enhanced the potential mobility and risk of Pb, Cd, Cr and As to soil /groundwater system. The relative concentrations of Cr(III) and As(III) in different depth of the soil zones after leaching tests were increased by about 6.0% and 5.6%, respectively. Cr(III) and As(III) tended to be adsorbed by soils, which reduced the mobility of them into groundwater.

Abstract  The tumorigenicity of chloral hydrate (CH), trichloroacetic acid (TCA), trichloroethanol (TCE), malondialdehyde (MDA), crotonaldehyde, acrolein, and 4-hydroxy-2-nonenal (HNE) was tested in the B6C3F(1) neonatal mouse. Mice were administered i.p. injections of CH (1000, 2000, 2500, and 5000 nmol per animal), TCA (1000 and 2000 nmol), TCE (1000 and 2000 nmol), MDA (1500 and 3000 nmol), crotonaldehyde (1500 and 3000 nmol), acrolein (75 and 150 nmol), and HNE (750 and 1500 nmol) at 8 and 15 days of age. At 12 months, only male mice treated with the positive control chemicals, 4-aminobiphenyl (500 and 1000 nmol) and benzo[a]pyrene (150 and 300 nmol), had incidences of tumors in the liver significantly higher than the solvent control. Additional male mice were dosed as described above and their livers were excised at 24, 48 h, and 7 days after the final dose. Liver DNA was isolated and analyzed by 32P-postlabeling/high-performance liquid chromatography (HPLC) and HPLC/electrochemical detection for MDA-derived adduct (M(1)G) and 8-oxo-2'-deoxyguanosine (8-OHdG) formation, respectively. At 24 and 48 h after the final dose, CH- and TCA-treated mice exhibited significantly higher M(1)G levels than the controls. 8-OHdG formation was also induced by CH, TCA, and MDA. These results suggest that under these experimental conditions the B6C3F(1) neonatal mouse is not sensitive to carcinogens that induce an increase in endogenous DNA adduct formation through lipid peroxidation or oxidative stress.

Abstract  Bioavailability of metals in soil is a major factor influencing estimates of risk associated with exposure of ecological receptors. Metal concentrations in soil are often compared to ecological screening benchmarks, which are based on total concentrations in soil. Often, the total concentration is not correlated with toxicity. No standardised method exists for determining the bioavailability of metals in soil to ecological receptors. Several surrogate measures of bioavailability were compared to the results of a battery of toxicity tests using copper (Cu), lead (Pb), and zinc (Zn)-contaminated soils collected from a former industrial area. A calcium chloride (CaCl(2)) extraction, cyclodextrin (HPCD) extraction, simulated earthworm gut (SEG) test, and earthworm bioaccumulation test were performed using the soils. Extractable metals using the CaCl(2) solution were not correlated with any biological responses of earthworms (Eisenia andrei), collembola (Folsomia candida), northern wheatgrass (Elymus lanceolatus), or alfalfa (Medicago sativa L.). Concentrations of metals in the HPCD extracts were highly variable and were not adequate for revealing adverse effects. E. andrei tissue concentrations were variable but were predictive of adverse effects to invertebrates. The results of the SEG test correlated with most of the biological endpoints. Bioavailable Cu was correlated with adverse effects to invertebrates and plants using the SEG test. Overall, coefficients of determination associated with the relationships between the biological responses and each measure of bioavailability indicated that those for the SEG test were greater than those for the other surrogate measures of bioavailability. Further validation is required before this test is routinely used to estimate metal bioavailability and toxicity.

Abstract  Exposure of experimental animals to toxaphene induces hepatic cytochrome P-450 (CYP). Although chronic administration of toxaphene to mice was found to cause an increased incidence of liver tumors, a mechanism for its carcinogenicity has yet to be elucidated. We investigated two potential mechanisms of toxaphene-induced carcinogenicity: peroxisomal proliferation and DNA binding. Peroxisomal proliferation was evaluated by measuring the level of immunodetectable CYP 4A1, an isozyme of CYP that is specifically induced by peroxisomal proliferators, in hepatic microsomes from CD1 mice that were treated by oral gavage for seven consecutive days with corn oil vehicle or 10, 25, 50 or 100 mg kg(-1) toxaphene. In comparison to control mice, toxaphene-treated mice had increased liver weight, increased liver/body weight ratios and increased levels of total hepatic CYP and cytochrome b5. No increase in the level of immunodetectable levels of CYP 4A1 was found in hepatic microsomes from toxaphene-treated mice when compared to controls. In contrast, increases in immunodetectable CYP 4A1 were detected in hepatic microsomes from mice treated with the peroxisomal proliferator clofibrate. These findings suggest that toxaphene-induced induction of CYP may not involve CYP 4A1 and that peroxisomal proliferation may not be involved in toxicity. Significant increases in immunodetectable levels of CYP 2B were, however, detected in toxaphene-treated mice, and are consistent with earlier reports demonstrating that toxaphene, like many other pesticides, induces the phenobarbital-inducible subfamily of CYP. Analysis of DNA adduct levels in the livers of toxaphene-treated mice by DNA 32P-post-labeling showed no evidence of DNA adduct formation. TAX - MUS,CD-1

Abstract  Endosulfan is a widely used broad-spectrum organochlorine pesticide, which acts as a contact and stomach poison. Nontarget species, such as cattle, fish, birds, and even humans, are also affected. Studies on the genotoxicity and mutagenicity of endosulfan have been inconsistent and nothing is known about the genotoxicity of its metabolites. In the present study, endosulfan (as a commercial isomeric mixture and as the alpha- and beta-isomers), and metabolites of endosulfan (the sulfate, lactone, ether, hydroxyether, and diol derivatives) were assayed for their ability to induce DNA damage in Chinese hamster ovary (CHO) cells and human lymphocytes using the Comet assay and were assayed for their mutagenicity using the Salmonella reversion assay (Ames test with TA98, TA97a, TA102, TA104, and TA100, with and without S9 activation). The compounds produced statistically significant (P < 0.01), concentration-dependent (0.25-10 microM) increases in DNA damage in both CHO cells and human lymphocytes. Endosulfan lactone caused the most DNA damage in CHO cells, while the isomeric mixture of endosulfan produced the greatest response in lymphocytes. The test compounds also were mutagenic in Salmonella strains at concentrations of 1-20 mug/plate (P < 0.05), with TA98 being the most sensitive strain and the diol and hydroxyether metabolites producing the highest responses. The results indicate that exposure to sublethal doses of endosulfan and its metabolites induces DNA damage and mutation. The contribution of the metabolites to the genotoxicity of the parent compound in Salmonella and mammalian cells, however, is unclear, and the pathways leading to bacterial mutation and mammalian cell DNA damage appear to differ.

Abstract  The California Department of Pesticide Regulation (CDPR) and the United States Environmental Protection Agency (USEPA) released revised draft risk assessments for the pesticidal active ingredient, endosulfan, just 2months apart, in November 2007 and January 2008. The exposure estimates, critical to risk assessment, were calculated by each agency using dissimilar approaches in certain aspects. The scenarios for which exposures and risks were estimated also varied somewhat between the two agencies, although there were substantial overlaps that allowed specific comparisons of exposure and risk estimates. Reasons underlying major differences in estimates of exposure for field workers working in treated crops (reentry exposure) are discussed in this paper. Differences in dislodgeable foliar residue levels calculated by CDPR and USEPA, reflecting endosulfan residues encountered by field workers entering treated orchards and fields, contributed the most to discrepancies in reentry exposure estimates between the two agencies. Additionally, because of differences in legal mandates CDPR estimated exposures for members of the public exposed to endosulfan in ambient air and when swimming, whereas USEPA did not. Exposures calculated for bystanders adjacent to a pesticide application suggest a potential health concern, but estimated swimmer exposures did not.

Abstract  Endosulfan (6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,3,4-benzo(e)dioxathiepin-3-oxide) is a broad-spectrum chlorinated cyclodiene insecticide. This study was performed to elucidate the stereoselective metabolism of endosulfan in human liver microsomes and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of endosulfan. Human liver microsomal incubation of endosulfan in the presence of NADPH resulted in the formation of the toxic metabolite, endosulfan sulfate. The intrinsic clearances (CL(int)) of endosulfan sulfate from beta-endosulfan were 3.5-fold higher than those from alpha-endosulfan, suggesting that beta-endosulfan would be cleared more rapidly than alpha-endosulfan. Correlation analysis between the known P450 enzyme activities and the rate of the formation of endosulfan sulfate in the 14 human liver microsomes showed that alpha-endosulfan metabolism is significantly correlated with CYP2B6-mediated bupropion hydroxylation and CYP3A-mediated midazolam hydroxylation, and that beta-endosulfan metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in human liver microsomes and the incubation study of cDNA-expressed enzymes also demonstrated that the stereoselective sulfonation of alpha-endosulfan is mediated by CYP2B6, CYP3A4, and CYP3A5, and that that of beta-endosulfan is transformed by CYP3A4 and CYP3A5. The total CL(int) values of endosulfan sulfate formation catalyzed by CYP3A4 and CYP3A5 were consistently higher for beta-endosulfan than for the alpha-form (CL(int) of 0.67 versus 10.46 microl/min/pmol P450, respectively). CYP2B6 enantioselectively metabolizes alpha-endosulfan, but not beta-endosulfan. These findings suggest that the CYP2B6 and CYP3A enzymes are major enzymes contributing to the stereoselective disposition of endosulfan.

Abstract  Endosulfan is persistent in the environment and toxic to wildlife. Legal mandates necessitate that a risk assessments be performed for endosulfan by the California Department of Pesticide Regulation (CDPR) and the United States Environmental Protection Agency (USEPA). This hazard identification (hazard ID) compared critical no-observed effect levels (NOEL) for acute, subchronic and chronic exposure intervals between the agencies. NOELs were discussed in light of their application to numerous exposure scenarios (occupational, general population and dietary). Only the acute oral NOELs differed between CDPR (0.7 mg/kg/day) and USEPA (1.5 mg/kg/day). Pregnant rabbits were considered by CDPR to be more responsive to low gavage doses of endosulfan than non-pregnant female or male rats in the acute study selected by USEPA. NOELs for other exposure routes and durations were similar between agencies. CDPR and USEPA concurred that a Food Quality Protection Act (FQPA, 1996) Safety Factor is not needed after evaluating all studies including a Developmental Neurotoxicity study. The SF was reduced to 1x. NOELs generated from this hazard ID will be used to calculate the Margins of Exposure for all scenarios and subsequently the risk characterization for endosulfan.

Abstract  The possibility of evaluating occupational exposure to mesitylene based on the determination of unchanged solvent in capillary blood or 3,5-dimethylbenzoic acid in urine was investigated. The volunteers were exposed to mesitylene in a toxicological chamber (range 10-150 mg/m3). Concentrations of solvent or its metabolite in biological material were determined by gas chromatography. The toxicokinetic data concerning retention in the lung, absorption and elimination of mesitylene and its metabolite in biological fluids were obtained. The highest correlation coefficient value was obtained for the relationship between the absorbed dose of mesitylene and the excretion rate of 3,5-dimethylbenzoic acid in urine (r = 0.95). The biological indices of exposure for mesitylene have been proposed, taking the maximum allowable concentration (MAC) value in Poland (100 mg/m3) as the basis.