This study aims to explore the analgesic and anti-inflammatory effects of borneol, a traditional Chinese medicine, on photodynamic treatment of acne. Here, we found that borneol significantly decreased the auricular swelling rate and pain threshold of rats. We also showed that borneol noticeably reduced macrophage and lymphocyte infiltration. The number of Th cells was significantly higher in the control PDT group than in the PDT plus borneol treatment group (P < 0.05). The expression of IL-6, TNF-α, and IL-8 mRNA and proteins were noticeably lower in the treatment group in comparison to those of the PDT control group, while PDT plus borneol activated the p38-COX-2-PGE2 signaling pathway, increasing expression in the treatment group. Borneol has significant analgesic and anti-inflammatory effects on PDT of acne, and enhances the healing of acne by activating p38-COX-2-PGE2 signaling pathway.

Background Exposure to arsenic has been reported to affect the nervous system in a number of ways. Various epidemiological studies suggest cognitive impairment in subjects following exposure to environmental arsenic. The goal of the present study was to determine if supplementation of exogenous α-lipoic acid (ALA) could ameliorate sodium arsenite (NaAsO2) induced adverse effects on learning and memory and synaptic connectivity in rat hippocampus. Methods Accordingly, NaAsO2 alone (1.5/2.0 mg/kg bw) or NaAsO2 along with ALA (70 mg/kg bw) was administered by intraperitoneal (i.p.) route from postnatal day (PND) 4 – 17 to Wistar rat pups (experimental groups) and the Control groups received either distilled water or no treatment at all. After carrying out Elevated Plus Maze (EPM) and Morris Water Maze (MWM) test, the fresh brain tissues were collected on PND 18 and processed for Golgi Cox staining. Results Observations of MWM test revealed impaired learning and memory in iAs alone treated animals as against those co-exposed to iAs and ALA. In Golgi stained hippocampal sections of iAs alone treated animals, decreased dendritic arborization and reduced number of spines in pyramidal neurons (CA1) and granule cells (DG) was observed whereas neuronal morphology was preserved in the controls and ALA supplemented groups Conclusions These observations are suggestive of beneficial effects of ALA on iAs induced effects on learning and memory as well as on hippocampal neuronal morphology.

The aquatic pollution due to sawmill wood wastes constitutes a major threat to hydro-chemical and fauna characteristics of the aquatic ecosystems. When this kind of organics wastes enter aquatic environment it can be taken up by aquatic organisms through respiration and/or through their diet. This could concurrently result in oxidative stress and later having adverse effect on physiological and biochemical function. The importance of fish in the society cannot be over emphasized, hence there is the need to know the influence of sawmill wood wastes on the water quality and fish. Therefore, this work aims to study the impact of five species of wood wastes on a type of fish named common carp (Cyprinus carpio) known as the most widely cultured fish species in the world and on its aquatic environment. The monitoring of water parameters showed deterioration in water quality. The activities of superoxide dismutase (SOD), Catalase (CAT), glutathione peroxidase (GPx) and lipid peroxidation (MDA) were investigated to evaluate the degree of oxidative stress. According to t-student, there was a significant difference compared to control (P < 0.05) in the level of SOD, CAT, GPx and MDA activities in fish exposed to 5 g·l-1 of each sawdust except for GPx, a non-significant difference (p > 0.05) was noted in the case of Beech and Dibetou. When the dispersed amount was about 0.375 g·l-1 we noted a significant difference in the level of SOD and GPx, except for GPx a non-significant difference was detected in the case of Cedar. The level of CAT was significantly difference just in the case of Cedar and Dibetou and that of MDA was significantly difference just in the case of Beech and Mahogany. We conclude therefore that sawmill wood waste not only impact the water quality adversely but also alters the levels of different enzymes activities in Cyprinus Carpio fish by the inhibition of SOD, CAT and GPx activities and by the production of MDA, which reflects response to oxidative stress. This study provides a rational use of these enzymes as suitable biomarkers with different degrees of specificity and as important tool for environmental monitoring.

Prednisolone is a synthetic glucocorticoid used clinically for treating allergies, inflammation, and autoimmune diseases. Long-term prednisolone use has been shown to have negative effects on physiology and mood. We aimed to study the pharmacology and toxicology of glucocorticoid-like drugs by investigating behavioral and hypothalamic–pituitary–interrenal (HPI) axis effects in a zebrafish model. Zebrafish embryos 24 h post fertilization were exposed to 25 μM prednisolone. Their behavior was investigated 5 days post fertilization (dpf), and their HPI axis-related activity and related neurotransmitter levels were investigated 3, 4, 5, and 6 dpf. The behavior results showed that exposure to prednisolone resulted in decreased autonomic activity and low sensitivity to light. qRT-PCR and ELISA results showed decreased activity of the HPI axis and increased secretion of dopamine and serotonin after exposure to prednisolone. This study provides us with new insights into understanding the effects of glucocorticoids on the HPI axis.

Pendimethalin (PM) is a selective herbicide, widely present in aquatic environment. It causes detrimental effects in fishes, but little is known regarding its reproductive toxicity. The present study was carried out in Clarias batrachus exposed to sub lethal concentrations of PM for 30, 45 and 60 days. Male fish showed a significant increase in plasma 17-βestradiol (E2) however plasma E2 in females was not affected. Plasma testosterone levels were significantly decreased in both sexes. In male plasma vitellogenin (VTG) and gonadal aromatase activity was increased irrespective of herbicide concentration and exposure duration. In females concentration and time dependent reduction in plasma VTG but no significant change in the gonadal aromatase activity were observed. Results indicated that PM act as endocrine disruptor but act differentially in male and female fishes and plasma E2, T and VTG levels and aromatase activity can be considered as reliable biomarkers for PM toxicity in fishes.

Adverse effects of non-occupational exposure to cadmium (Cd) are increasingly acknowledged. Since our previous study has showed that orally acquired Cd affects skin, the contribution of genetic background to dermatotoxicity of oral cadmium was examined in two rat strains, Albino Oxford (AO) and Dark Agouti (DA), which differed in response to chemicals. While similar accumulation of Cd in the skin of both strains was noted, the skin response to the metal differed. DA rat individuals mounted antioxidant enzyme defense in the skin already at lower Cd dose, in contrast to AO rats which reacted to higher metal dose solely (and less pronounced), implying higher susceptibility of DA strain to Cd dermatotoxicity. Epidermal cells from both strains developed stress response, but higher intensity of antioxidant response in AO rats implied this strain`s better ability to defend against Cd insult. Cd induced epidermal cells` proinflammatory cytokine response only in DA rats. Increased IL-10 seems responsible for the lack of response in AO rats. Differences in the pattern of skin/epidermal cell responsiveness to cadmium give a new insight into repercussion of genetic variability to dermatotoxicity of orally acquired cadmium, bearing relevance for variations in the link between dietary cadmium and inflammation-based skin pathologies.

In our previous study we demonstrated that the fruit ripening retardant Daminozide or Alar causes change in life history traits, distortion of adult wing structure, DNA damage in brain cells and mutagenic effects in fruit fly Drosophila melanogaster. As a continuation of the previous study the present work is designed to explore the metabolic modification of Daminozide following ingestion, the effects of Daminozide on the expression of genes which are pivotal for wing development and molecular interactions of Daminozide with those proteins involved in wing patterning. We demonstrated through reporter gene construct assay using X-gal staining method and transgenic Drosophila melanogaster stocks that the vestigial, wingless and decapentaplegic genes in wing imaginal disc from 3rd instar larvae exhibited reduced expression when exposed to Daminozide in compare to control larvae. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) of those genes confirmed that exposure to Daminozide reduces the transcription level of those genes. In silico approach with molecular docking study revealed Daminozide may bind and interfere with the optimal functioning of expressed wing signaling proteins.

Scientific research can provide us with factual, repeatable, measurable, and determinable results. As such, scientific research can provide information that can be used in the decision-making process in the care of patients and in public policy. Although it has been suggested that ethylmercury (C2H5Hg+)-containing compounds do not cross the blood-brain barrier (BBB), this review examines the literature that addresses the question as to whether ethylmercury-containing compounds cross the BBB. The review will begin with cellular studies that provide evidence for the passive and active transport of mercury species across the BBB. Then, animal and clinical studies will be presented that specifically examine whether mercury accumulates in the brain after exposure to ethylmercury-containing compounds or Thimerosal (an ethylmercury-containing compound used as a preservative in vaccines and other drugs that metabolizes or degrades to ethylmercury-containing compounds and thiosalicylate). The results indicate that ethylmercury-containing compounds are actively transported across membranes by the L (leucine-preferring)-amino acid transport system (LAT) transport system, the same as methylmercury-containing compounds. Further, 22 studies from 1971 to 2019 show that exposure to ethylmercury-containing compounds (intravenously, intraperitoneally, topically, subcutaneously, intramuscularly, or intranasally administered) results in accumulation of mercury in the brain. In total, these studies indicate that ethylmercury-containing compounds and Thimerosal readily cross the BBB, convert, for the most part, to highly toxic inorganic mercury-containing compounds, which significantly and persistently bind to tissues in the brain, even in the absence of concurrent detectable blood mercury levels.

Triclosan is widely used in consumer products as an antimicrobial agent. Epidemiological studies have reported the association of triclosan with adverse birth outcomes. The toxic effects of triclosan on the developing stages of zebrafish are reported, however, its role as behavioral modifier is limited. In the present study, adult zebrafish were exposed to triclosan (0.3 and 0.6 mg/L) for 48 hrs and the exploratory behavior was analyzed using ZebraTrack. Triclosan exposed group showed significantly reduced locomotion concomitant with increased freezing duration. They also showed erratic movements suggesting that triclosan induced anxiety-like behavior in adult zebrafish. Next, we tested the hypothesis that the anxiety-like behavior is linked to altered acetylcholinesterase activity. We found that the triclosan exposure decreased acetylcholinesterase activity in the brain and skeletal muscle but acetylcholinesterase (ache) gene was significantly down-regulated only in the skeletal muscle of the adult zebrafish exposed to triclosan. In addition, we also observed a down-regulation of myelin basic protein (mbp) gene in the skeletal muscle of adult zebrafish treated with triclosan. Thus, our data indicates that even short exposure of triclosan is potent enough to induce behavioral anomalies in adult zebrafish that appear to involve acetylcholinesterase and other structural proteins especially in the skeletal muscle.

We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

Osteoarthritis (OA) is the gradual loss of articular cartilage and decrease in subchondral space. One of the risk factors Exposure to cadmium (Cd) through tobacco smoke has been identified as a major OA risk factor. There are no reports addressing the role of Cd in OA progression at the molecular level. Our findings revealed that Cd can promote the activation of metalloproteinases (MMP1, MMP3, MMP9 y MMP13), affecting the expression of COL2A1 and ACAN, and decreasing the presence of glycosaminoglycans and proteoglycans through an inflammatory response related to IL-1β y a IL-6, as well as oxidative by producing ROS like O2-• and H2O2. In conclusion, our findings suggest a cytotoxic role of Cd in the articular cartilage, which could affect OA development.

The present study has investigated developmental neurotoxicity of Metam sodium (MS), from gestational day 6 and throughout the gestation period until delivery. Therefore, mated female mice were orally exposed on a daily basis to 0 (control), 50, 100 or 150 mg of MS/kg of body weight and their standard fertility and reproductive parameters were assessed. The offspring were examined for their sensorimotor development, depression and cognitive performance. Our results showed that MS exposure during pregnancy led to one case of mortality, two cases of abortion and disturbed fertility and reproductive parameters in pregnant dams. In offspring, MS induced an overall delay in innate reflexes and sensorimotor performances. Furthermore, all prenatally treated animals showed an increased level of depression-like behavior as well as a pronounced cognitive impairment in adulthood. These results demonstrated that prenatally exposure to MS causes a long-lasting developmental neurotoxicity and alters a wide range of behavioral functions in mice.

Purpose This study was designed to evaluate the protective effects of allicin against diclofenac sodium induced hepatonephro toxicity in rats. Methods Sixty male Wister albino rats were assigned into six groups. The control group received calcium carbonate and corn starch. 2nd group received diclofenac sodium (2 mg/kg bw orally) for 30 days. 3rd group received allicin (45 mg/kg bw orally) for 30 days. 4th group administrated diclofenac sodium as in the 2nd group and allicin (15 mg/kg bw orally) for 30 days. 5th group received diclofenac sodium as in the 2nd group and allicin (30 mg/kg bw orally) for 30 days. 6th group received diclofenac sodium as 2nd and allicin (45 mg/kg bw orally) for 30 days. Results Diclofenac sodium significantly elevated activities of serum aspartate aminotransferase and alanine aminotransferase and serum levels of creatinine and urea. In addition, it induced hyperglycemia, lipid peroxidation, pathological alteration and caspase 3 protein expression in hepatic and renal tissues. However, it decreased reduced glutathione concentration and proliferating cell nuclear antigen protein expression in hepatic tissues. In contrast, allicin modulated the diclofenac sodium induced alteration in liver and kidney functions and structures dose dependently. Conclusion This study indicated that allicin had potential preventive effects against diclofenac sodium induced hepatonephro toxicity in rats.

Introduction Pesticides are widely used around the world, and rural workers have greater risk of poisoning. The use of biomarkers for insecticides can contribute to the diagnosis and prevention of poisoning. Objective To identify, in the scientific literature, the biomarkers of occupational exposure to insecticides of different insecticide classes. Methods The PubMed, Lilacs and Embase databases were analyzed using a systematic search strategy and in accordance with the criteria established by the PRISMA methodology. Articles with information related to the use of biomarkers to identify active ingredients, or insecticide metabolites, or effects on the human biological matrices were analyzed. Results A total of 840 studies was found, and 30 met the selection criteria. The search identified 118 results for insecticide biomarkers, of which 45% were of exposure, 42% of effect, and 14% of susceptibility. Additionally, 78 were possible biomarkers, and only 67 confirmed to be different biomarkers for insecticides. Acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 3,5,6-trichloro-2-pyridinol (TCP-y), specific for Chlorpyrifos, were among the most common biomarkers identified; however, most metabolites found were non-specific. Conclusion Various insecticide biomarkers were mentioned; nonetheless, only a few are specific and used to identify the wide range of insecticides to which farm workers are exposed.

Glycogen and lipid disruptions represent a spectrum of metabolic disorders that are crucial risk factors for cardiovascular disease in estrogen-progestin oral contraceptive (COC) users. L-glutamine (GLN) has been shown to exert a modulatory effect in metabolic disorders-related syndromes. We therefore hypothesized that GLN supplementation would protect against myocardial and renal glycogen-lipid mishandling in COC-treated animals by modulation of Glucose-6-phosphate dehydrogenase (G6PD) and xanthine oxidase (XO) activities. Adult female Wistar rats were randomly allotted into control, GLN, COC and COC + GLN groups (six rats per group). The groups received vehicle (distilled water, p.o.), GLN (1 g/kg), COC containing 1.0 µg ethinylestradiol plus 5.0 µg levonorgestrel and COC plus GLN respectively, daily for 8 weeks. Data showed that treatment with COC led to metabolically-induced obesity with correspondent increased visceral and epicardial fat mass. It also led to increased plasma, myocardial and renal triglyceride, free fatty acid, malondialdehyde (MDA), XO activity, uric acid content and decreased glutathione content and G6PD activity. In addition, COC increased myocardial but not renal glycogen content, and increased myocardial and renal glycogen synthase activity, increased plasma and renal lactate production and plasma aspartate transaminase/alanine aminotransferase (AST/ALT) ratio. However, these alterations were attenuated when supplemented with GLN except plasma AST/ALT ratio. Collectively, the present results indicate that estrogen-progestin oral contraceptive causes metabolically-induced obesity that is accompanied by differential myocardial and renal metabolic disturbances. The findings also suggest that irrespective of varying metabolic phenotypes, GLN exerts protection against cardio-renal dysmetabolism by modulation of XO and G6PD activities.

Exposure to metal oxide nanomaterials potentially occurs at the workplace. We investigated the toxicity of two Fe-oxides: Fe2O3 nanoparticles and nanorods; and three MFe2O4 spinels: NiZnFe4O8, ZnFe2O4, and NiFe2O4 nanoparticles. Mice were dosed 14, 43 or 128 µg by intratracheal instillation. Recovery periods were 1, 3, or 28 days. Inflammation – neutrophil influx into bronchoalveolar lavage (BAL) fluid – occurred for Fe2O3 rods (1 day), ZnFe2O4 (1, 3 days), NiFe2O4 (1, 3, 28 days), Fe2O3 (28 days) and NiZnFe4O8 (28 days). Conversion of mass-dose into specific surface-area-dose showed that inflammation correlated with deposited surface area and consequently, all these nanomaterials belong to the so-called low-solubility, low-toxicity class. Increased levels of DNA strand breaks were observed for both Fe2O3 particles and rods, in BAL cells three days post-exposure. To our knowledge, this is, besides magnetite (Fe3O4), the first study of the pulmonary toxicity of MFe2O4 spinel nanomaterials.

The European City Fish project aimed to develop a generic methodology for ecological risk assessment for urban rivers. Since traditional methods only consider a small fraction of substances present in the water cycle, biological effect monitoring is required for a more reliable assessment of the pollution status. A major challenge for environmental risk assessment (ERA) is the application of adverse outcome pathways (AOP), i.e. the linking of pollutant exposure via early molecular and biochemical changes to physiological effects and, ultimately, effects on populations and ecosystems. We investigated the linkage between responses at these different levels. Many AOP aspects were investigated, from external and internal exposure to different classes of micropollutants, via molecular key events (MKE) the impacts on organs and organisms (fish physiology), to changes in the population dynamics of fish. Risk assessment procedures were evaluated by comparing environmental quality standards, bioassay responses, biomarkers in caged and feral fish, and the impact on fish populations. Although no complete AOP was observed, indirect relationships linking pollutant exposure via MKE to impaired locomotion were demonstrated at the most polluted site near a landfill for chemical waste. The pathway indicated that several upstream key events requiring energy for stress responses and toxic defence are likely to converge at a single common MKE: increased metabolic demands. Both fish biomarkers and the bioanalytical SIMONI strategy are valuable indicators for micropollutant risks to fish communities.

Magnetic silver nanoparticles (MNPAg) are interesting nanotechnology materials with borderless environmental science, that can be used to disinfect water contaminated with pathogenic bacteria. The use of MNPAg leads to increased risk of nanomaterial contamination in the environment, especially natural water sources, with harmful effects on the ecosystem. This study investigating survival and enzyme activity of magnetic O-carboxymethylchitosan loaded silver nanoparticle on Artemia salina. The results showed that mortality increased with increasing concentrations of MNPAg. O-Carboxymethylchitosan loaded silver nanoparticles were found to be more toxic, with a LC50 of 902.1 mg/L for γ-Fe2O3/Ag without reducing agent. Accumulation of silver on Artemia salina depends on the type of nanoparticle. Accumulation of nanoparticle containing polymers (carboxymethylchitosan/γ-Fe2O3/Ag without reducing agent, carboxymethylchitosan/γ-Fe2O3/Ag reduced with sucrose and carboxymethylchitosan/γ-Fe2O3/Ag reduced with NaBH4) were found to be higher than γ-Fe2O3/Ag reduced with NaBH4, γ-Fe2O3/Ag reduced with sucrose and γ-Fe2O3/Ag without reducing agent under the same experimental conditions. The antioxidant enzyme (CAT, SOD and GST) activities increased slightly following exposure, indicating that the toxic effects are related to oxidative stress. The combined results so far indicate that MNPA does not have the potential to affect aquatic organisms when released into the ecosystem.

Dithiocarbamates (DTCs) like mancozeb (MZ) and disulfiram (DS) are used throughout agriculture and medicine and have been implicated in neurotoxicity. Little research has been studied on the reported myopathies caused by these compounds. Their pathogenesis and mechanism of muscle toxicity has not been fully studied. The aim of this study is to investigate if DTCs alter striated muscle tissues in vivo. Long-Evans rats were treated with either MZ or DS followed by analysis of muscle biomarkers and metal levels. DS resulted in increases in serum lactate dehydrogenase (LDH), cardiac troponin, and myoglobin levels. Creatine kinase-MB serum levels decreased. Mancozeb only showed an increase in serum LDH. Both MZ and DS-treatment resulted in altered metal levels in the myocardium but not skeletal muscle. Ultrastructural alterations included damaged mitochondria and myofibril splitting. The presence of multivesicular bodies, and alterations of the intercalated disc were also seen.

Chronic exposure of mixed-metal intoxication has been associated with prolonged oxidative stress and severe hepatorenal damage. This present study demonstrates the hepatoprotective and renoprotective activity of Croton zambesicus (C-ZAMB) leaves, naturally occurring phenolic compounds against chronic mixed-metal (EOMABRSL) induced toxicity. 0.5 ml of EOMABRSL via oral route induced chronic hepatoxicity and nephrotoxicity on exposure for 98 days (non-withdrawal) and 70 days (withdrawal) by abnormal alteration in the levels of endogenous antioxidants. Moreover, EOMABRSL induced hepatorenal damage by increasing the markers of liver toxicity (ALT, AST, ALP, GGT and bilirubin) and kidney failure (creatinine, urea, uric acid, and renal electrolytes-Na+ and K+). Both non-withdrawal and withdrawal approaches of EOMABRSL-exposed animals exhibited hepatorenal dysfunctions by increasing the activity of eco-51-nucleotidase (51ENT) followed by the decreased in the activity of lactate dehydrogenase (LDH)-index of cellular ATP. These results were further supported by the histopathological examination of nephritic cells, hepatocytes and splenocytes, manifested by hepatocellular necrosis, swelling or degeneration of tubular kidney epithelial cells as well as coalescing splenic periarteriolar lymphoid sheaths (PALSs) and lymphoid haemosiderin. The chronic EOMABRSL intoxication was ameliorated by administration of phenolic antioxidants from C-ZAMB leaves. Therefore, our study supports the view that phenolic C-ZAMB leaves may mediate hepatorenal wellness on chronic exposure to mixed-metal intoxication

The increased presence of emergent compounds, such as pharmaceuticals drugs, in the aquatic compartment has been acknowledged as an evolving environmental issue whose consequences are not yet fully characterized. Specific classes of pharmaceutical drugs, such as fluoroquinolone antibiotics, can exert toxic effects to non-target species with ecological significance, since these compounds are environmentally stable and persistent, and may interact with some of the key physiologic processes of organisms. Despite such characteristics, knowledge about the effects of these drugs is still scarce, especially to non-target organisms. The present study aimed to evaluate the effects of chronic and acute exposures of the cladoceran Daphnia magna to the ciprofloxacin. Putative toxic effects were assessed, following acute and chronic exposures to ecologically relevant concentrations of ciprofloxacin, through enzymatic (cholinesterase – ChEs, catalase – CAT, glutathione S-transferases – GSTs) and non-enzymatic (thiobarbituric acid reactive substances – TBARS, glycogen – Gly) biomarkers. In addition, we also determined behavioural (swimming distance – SD) and morphological (body length of the first brood – BL1B) endpoints in animals exposed to this drug. Ciprofloxacin acute exposure resulted in increased CAT and ChEs activities, and inhibited GSTs activity. After chronic exposure, ChEs activity was significantly inhibited, while GSTs activity was significantly enhanced. TBARS levels were only increased at higher concentrations of ciprofloxacin. CAT activity and Gly content did not evidence a clear and significant pattern of variation. SD was slightly inhibited during dark cycles. BL1B presented a significant decrease for animals subjected to an intermediate concentration. Results showed that even ecologically relevant concentrations of ciprofloxacin may cause oxidative stress in individuals of D. magna. The present study showed important data that corroborate the occurrence of significant biochemical alterations in key features of an aquatic organism when exposed to relevant levels of a widely used antibiotic, establishing essential links between environmental exposure to this specific drug and putative toxic challenges that may result in irreversible changes and damages, especially at the individual level. However, changes in the size of neonates suggest that population alterations are likely to occur under real scenarios of chronic contamination by this drug.

CCA (Chromium Copper Arsenate) treated wood, widely used in outdoor residential structures and playgrounds, poses considerable dangers of leaching of its components to the environment. In this study, mouse kidney samples were used to evaluate the effects of CCA, chromium trioxide (CrO3) and arsenic pentoxide (As2O5) on cell pathophysiology by flow cytometry. Samples were collected after 14, 24, 48 and 96 hours of animal exposure. While Cr had no statistically significant cytostatic effects, As2O5 induced a S-phase delay in animals exposed for 24 h, and over time a G0/G1 phase blockage. The effects of CCA in S-phase were similar, but more severe than those of As2O5. Since environmental and public health hazards due to the long durability of CCA-treated wood products, these data confirm that CCA has profoundly toxic effects on cell cycle, distinct from the compounds themselves. These cytostatic effects support cell cycle dynamics as a valuable endpoint to assess the toxicity of remaining CCA-treated infrastructures, and the expected increased waste stream over the coming decades.

In vitro to in vivo extrapolation (IVIVE) for next-generation risk assessment (NGRA) of chemicals requires computational modeling and faces unique challenges. Using mitochondria-related toxicity data of troglitazone (TGZ), a prototype drug known for liver toxicity, from HepaRG, HepG2, HC-04, and primary human hepatocytes, we explored inherent uncertainties in IVIVE, including cell models, cellular response endpoints, and dose metrics. A human population physiologically-based pharmacokinetic (PBPK) model for TGZ was developed to predict in vivo doses from in vitro point-of-departure (POD) concentrations. Compared to the 200-800 mg/d dose range of TGZ where liver injury was observed clinically, the predicted POD doses for the mean and top one percentile of the PBPK population were 28-372 and 15-178 mg/d respectively based on Cmax dosimetry, and 185-2552 and 83-1010 mg/d respectively based on AUC. In conclusion, although with many uncertainties, integrating in vitro assays and PBPK modeling is promising in informing liver toxicity-inducing TGZ doses.

Cadmium is highly toxic and can cause oxidative damage, metabolic disorders, and reduced lifespan and fertility in animals. In this study, we investigated the effects of cadmium in Drosophila melanogaster, performing transcriptome analysis by using tag-based digital gene expression (DGE) profiling. Among 1970 candidate genes, 1443 were up-regulated and 527 were down-regulated following cadmium exposure. Using Gene Ontology analysis, we found that cadmium stress affects three processes: transferase activity, stress response, and the cell cycle. Furthermore, we identified five differentially expressed genes (confirmed by real-time PCR) involved in all three processes: Ald, Cdc2, skpA, tefu, and Pvr. Pathway analysis revealed that these genes were involved in the cell cycle pathway and fat digestion and absorption pathway. This study reveals the gene expression response to cadmium stress in Drosophila, it provides insights into the mechanisms of this response, and it could contribute to our understanding of cadmium toxicity in humans.

In this review, a wide array of bioaccumulation markers and biomarkers, used to demonstrate exposure to and effects of environmental contaminants, has been discussed in relation to their feasibility in environmental risk assessment (ERA). Fish bioaccumulation markers may be applied in order to elucidate the aquatic behavior of environmental contaminants, as bioconcentrators to identify certain substances with low water levels and to assess exposure of aquatic organisms. Since it is virtually impossible to predict the fate of xenobiotic substances with simple partitioning models, the complexity of bioaccumulation should be considered, including toxicokinetics, metabolism, biota-sediment accumulation factors (BSAFs), organ-specific bioaccumulation and bound residues. Since it remains hard to accurately predict bioaccumulation in fish, even with highly sophisticated models, analyses of tissue levels are required. The most promising fish bioaccumulation markers are body burdens of persistent organic pollutants, like PCBs and DDTs. Since PCDD and PCDF levels in fish tissues are very low as compared with the sediment levels, their value as bioaccumulation markers remains questionable. Easily biodegradable compounds, such as PAHs and chlorinated phenols, do not tend to accumulate in fish tissues in quantities that reflect the exposure. Semipermeable membrane devices (SPMDs) have been successfully used to mimic bioaccumulation of hydrophobic organic substances in aquatic organisms. In order to assess exposure to or effects of environmental pollutants on aquatic ecosystems, the following suite of fish biomarkers may be examined: biotransformation enzymes (phase I and II), oxidative stress parameters, biotransformation products, stress proteins, metallothioneins (MTs), MXR proteins, hematological parameters, immunological parameters, reproductive and endocrine parameters, genotoxic parameters, neuromuscular parameters, physiological, histological and morphological parameters. All fish biomarkers are evaluated for their potential use in ERA programs, based upon six criteria that have been proposed in the present paper. This evaluation demonstrates that phase I enzymes (e.g. hepatic EROD and CYP1A), biotransformation products (e.g. biliary PAH metabolites), reproductive parameters (e.g. plasma VTG) and genotoxic parameters (e.g. hepatic DNA adducts) are currently the most valuable fish biomarkers for ERA. The use of biomonitoring methods in the control strategies for chemical pollution has several advantages over chemical monitoring. Many of the biological measurements form the only way of integrating effects on a large number of individual and interactive processes in aquatic organisms. Moreover, biological and biochemical effects may link the bioavailability of the compounds of interest with their concentration at target organs and intrinsic toxicity. The limitations of biomonitoring, such as confounding factors that are not related to pollution, should be carefully considered when interpreting biomarker data. Based upon this overview there is little doubt that measurements of bioaccumulation and biomarker responses in fish from contaminated sites offer great promises for providing information that can contribute to environmental monitoring programs designed for various aspects of ERA.

Flavonoids are reported to be powerful antioxidants in cell free systems. They naturally occur as glycosides rather than as aglycon. In this study the ability of the flavonoid quercetin and its glycosides, quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucoside and quercetin-3-O-(6″-O-acetyl)-glucoside, to protect in vitro rat C6 glioma cells from oxidative damage induced by cumene hydroperoxide was investigated. Cumene hydroperoxide induced cell death and lipid peroxidation. The cytotoxicity of cumene hydroperoxide could be prevented by the radical scavenger dimethyl thiourea and the ferric iron chelator deferoxamine, indicating that its cytotoxic activity is related to the generation of reactive oxygen radicals in the ferrous iron dependent Fenton reaction. Quercetin, in a concentration range of 10-100 μM, but neither rutin nor the other two glycosides, were able to protect C6 cells from cytotoxicity and lipid peroxidation. Furthermore, cytoprotective concentrations of quercetin proved to be cytotoxic itself. These results call in question potential beneficial effects of dietary intake or therapeutic use of naturally occurring flavonoids.

Safety of Keum-Yeon-Cho (NosmoQ), a tobacco substitute composition, was evaluated in terms of acute- and 4 weeks repeated-inhalation toxicity, mutagenicity, and immunotoxicity using Balb/c mice. The air inside the inhalation chamber was collected and analyzed by GC-MS. In acute inhalation toxicity test, male and female mice were exposed to 40 Keum-Yeon-Cho cigarettes. The 50% lethal concentration (LC(50)) of NosmoQ was considered to be much higher than 40 cigarettes in both sexes. In 4-week repeated inhalation toxicity test, male and female mice were exposed for 6 h/day, 5 days/week for 4 weeks to 10 and 20 cigarettes per day, while control mice were exposed to filtered air. Our data indicated that no observed adverse effect level (NOAEL) of Keum-Yeon-Cho should be over 20 cigarettes per day. Results of Salmonella typhimurium reversion assay with/without histidine moiety, in vivo chromosomal aberration and in vivo micronucleus assays using mouse bone marrow cells revealed that Keum-Yeon-Cho has no mutagenicity. Evaluation of peripheral cellular immunity of mice treated with Keum-Yeon-Cho using in vitro lymphocyte proliferation assay showed no significant difference in mean stimulation index (SI) between mice exposed to Keum-Yeon-Cho and control mice. Mean CO concentrations and total particulate matter contents of 10 and 20 cigarettes were 21.1±1.23 and 40.7±1.21 ppm (mean±S.D., n=5), and 25.7±3.09 and 59.0±4.0 mg dry weight (mean±S.D., n=5), respectively. Although at negligible concentration (less than ppb level) several polycyclic aromatic hydrocarbons (PAHs) were also detected, these results indicate that NosmoQ has no toxic effect on mice.

As tri-n-butyltin (TBT), one of the environmental pollutants, is accumulated in wild animals, concern regarding the toxicity of TBT in both wildlife and human is increasing. TBT has been reported to increase intracellular Ca(2+) concentration in several types of cells. In order to examine how Ca(2+) is involved in TBT-induced cell death, the effect of TBT on rat thymocytes has been compared with that of A23187, a calcium ionophore, under various concentrations of external Ca(2+) using a flow cytometer and fluorescent probes. Although both TBT and A23187 were toxic to cells under normal Ca(2+) condition, under external Ca(2+)-free condition the cytotoxic action of TBT was potentiated without changing the threshold concentration while that of A23187 was completely abolished. A23187 attenuated the TBT-induced descent in cell viability under normal Ca(2+) concentration despite intracellular Ca(2+) concentration was increased. As external Ca(2+) concentration increased, the TBT-induced increase in number of dead cells gradually decreased whereas the number of cells in an early stage of apoptosis increased. Results suggest that Ca(2+) has contradictory actions on the process of TBT-induced cell death in rat thymocytes.

Cigarette smoking is a major risk factor for bladder cancer. Some chemicals from cigarette smoke e.g. aromatic amines, are metabolized in the liver and excreted in urine as either glucuronide or acetyl conjugates. These metabolites undergo pH mediated activation to reactive nitreneum ions that may lead to DNA adducts, initiating bladder tumorigenesis in some smokers. We hypothesize that changing the pH of smokers urine will impact the mutagenic outcome of these metabolites. Overnight samples were collected from smokers (n=11) and nonsmokers (n=11) and stored at -70°C. Each urine sample was adjusted to neutral (7.0), basic (8.2) and acidic (5.5) pH. Mutagenic activity was assessed with the Ames test utilizing the Salmonella Typhimurium strain YG1024 microsuspension assay. Urine from smokers was significantly mutagenic compared with nonsmokers (P<0.001). In both the groups, there was no difference between urine adjusted at different pH (P>0.05). We conclude that changing the pH of smokers urine might not affect their subsequent risk for bladder cancer.

Diabetes is associated with an abnormal incidence of hypothyroidism, which exacerbates hyperglycaemia, so further damaging already compromised erythrocytic defence mechanisms. Methaemoglobin formation is a useful measure of the health of these mechanisms, as it determines the resistance of diabetic erythrocytes to sustained oxidative stress. The effect of l-tri-iodothyronine (T(3)) was, therefore, studied on nitrite and monoacetyldapsone hydroxylamine (MADDS-NHOH) mediated methaemoglobin formation in diabetic and non-diabetic human erythrocytes. Diabetic erythrocytes showed less sensitivity compared with non-diabetics to methaemoglobin formation mediated by both compounds. A 30 min pre-incubation with T(3) at 3 and 30 nM did not affect nitrite-mediated methaemoglobin formation compared with control observations in both cell types. In diabetic erythrocytes incubated with T(3) at 30 nM, there were significant increases in MADDS-NHOH-mediated methaemoglobin formation compared with control in both diabetic and non-diabetic cells. Studies comparing blood isolated from diabetic patients stabilised on thyroxine (T(4); 50 μG/day), T(4)-free diabetics and non-diabetics, showed that T(4) supplementation significantly increased MADDS-NHOH-mediated methaemoglobin formation compared with T(4)-free diabetic cells so that for two time points, T(4)-treated diabetic erythrocytic methaemoglobin formation was indistinguishable from that of non-diabetics. These studies indicate that T(4) supplementation improves some erythrocytic oxidant defence mechanisms in a time dependent manner.

In the present study significantly increased lipid peroxidation value (LPP) after a single intraperitioneal injection of lead acetate (LA) (100 mg/kg b.w.) indicated enormous generation of Reactive Oxygen Species (ROS). Lead-induced ROS has a direct inhibitory effect on the growth and differentiation of the spermatogonial cells showing a significant decline in sperm count. Chromosomal analysis of the primary spermatocytes at week 4 post-treatment in lead-treated mice revealed significantly higher no of aberrant cells including chromosomal deficiency, autosomal and XY-asynapsis plates compared to untreated control mice, Sperm morphology studies at week 1-4 and at week 8 post-treatment, indicated higher percentage of deformed sperm population compared to vehicle injected groups of mice. Supplementation of vitamin C (Vit C) at a dose of 10 mg/kg body weight to lead-treated mice groups, however, significantly reduced the LPP with a concomitant increase in sperm count, marked decrease in the no of aberrant cells and significant decline in the percentage of morphologically abnormal sperm population. Protective role of Vit C in combating lead-induced oxidative stress in mice testicular cells, has been discussed.

The effects of sulfur dioxide (SO(2)) on levels of thiobarbituric acid reactive substances (TBARS), levels of reduced glutathione(GSH) and the activities of Cu,Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were investigated in brains and livers of Kunming albino mice of both sexes. SO(2) at different concentrations (22, 56 and 112 mg/m(3)) was administered to animals of SO(2) groups in different exposure chambers for 6 h/day for 7 days, while control groups were exposed to filtered air in the same condition. Our results show that SO(2) caused lipid peroxidation and changes of antioxidative status in brains and livers of mice. Exposure to SO(2) at all concentrations tested caused significantly the increase of TRARS levels in brains and livers of mice. For the brains, activities of these antioxidant enzymes and levels of GSH were significantly unaltered by SO(2) at low concentrations, except significant increase of GSH levels in the brains of male mice; however, SO(2) at higher concentrations caused significantly decreases of GSH levels and activities of these antioxidant enzymes. For livers, SO(2) at all concentrations tested decreased significantly activities of SOD relative to control animals; SO(2) tended to decrease activities of GPx and CAT, but only the decreases of GPx and CAT activities caused by SO(2) exposures of higher concentrations (56 and 112 mg/m(3)) were statistically significant. SO(2) also tended to decrease levels of GSH, but only at 112 mg/m(3) caused significantly decrease of GSH levels in livers of both sexual mice. Unexpectedly, the decreases of activities of these antioxidative enzymes caused by SO(2) at different concentrations in brains and livers of mice did not follow a linear dose-response curves. In many respects, the decreased percentages of the activities of each antioxidative enzyme (SOD or GPx or CAT) caused by SO(2) at 22, 56 and 112 mg/m(3) in brains and livers of mice were similar. These results lead to conclusion that SO(2) exposure can caused oxidative damage to brains and livers of mice, and SO(2) is a toxin to brain and liver of mammals, not only to respiratory system. Further work is required to understand toxicological role of SO(2) on multiply or even all organs in human and animal.

Monofluorinated polycyclic aromatic hydrocarbons (F-PAHs) are useful reference compounds for a broad spectrum of PAH studies. The pyrene metabolite 1-hydroxypyrene is often used as a biomarker of PAH exposure. Two species, isopod (Porcellio scaber) and flatfish (Platichthys flesus), that produce 1-hydroxypyrene as the major intermediary metabolite and have distinct phase-II conjugates, were selected to investigate the cytochrome P450 catalyzed metabolism of 1-fluoropyrene. The fluorine atom blocks one of the four most favored carbon atoms, yielding different metabolite patterns and the results obtained in the selected species were compared with metabolite profiles obtained for unsubstituted pyrene. Charge densities in 1-fluoropyrene measured with (13)C-NMR were used to predict possible positions of hydroxylation, which were confirmed by (19)F-NMR. Additionally, the retention behaviour of conjugated 1-fluoropyrene metabolite isomers in reversed-phase liquid chromatography on a polymeric alkyl-bonded phase was interpreted based on the slot model. Whereas three phase-I metabolites were found in isopod hepatopancreas, only two were observed in flatfish bile. Phase-II metabolism appeared unaffected by the fluorine substituent. It was concluded that the phase-I enzyme cytochrome P450 is non-regioselective in the isopod: the activation is mostly influenced by the electron density distribution. In contrast, the enzymatic oxidation in the flounder is more selective. These differences will affect to what extent pyrene metabolite measurements can be used to assess the impact of PAHs to different species.

The wide range of potential health beneficial effects of isoflavones, including a chemoprentive action, have prompted us to study the potential benefits of genistein and daidzein in an experimental model of environmental pollution impact on lung tissue. A diesel engine placed was used to generate reproducible emissions including both gaseous and particulate matters that are commonly found in urban atmospheres. Isoflavones were added to culture medium of rat lung slices 2 h prior to their exposure to pollutants for 3 h. Intracellular ATP and GSH levels, TNFα production, nucleosome assay and TUNEL labeling were monitored. Isoflavones showed almost total in vitro protection against inflammatory and pro-apoptotic responses in lung slices. Isoflavones 0.3 and 1 μmol/l protected against exhaust induced GSH depletion. Isoflavones 0.3 μmol/l appeared to exert the most beneficial effects. In conclusion, this study points out the potential interest of soy isoflavones consumption in polluted areas. Further studies should be undertaken to verify that similar effects could be obtained after in vivo administration of isoflavones.

Within the group of botanical products there is a large range of variation with regard to their properties. Some products are identical to foods while others come close to or are medicines. Botanical products are regulated differently within the different member states of the European Union (EU) and globally. They are regulated either as food or as medicinal products, and in the latter case often with simplified registration procedures. These differences are caused by differences in traditional use, in cultural and historical background, in scientific substantiation and in enforcement of current legislation. One may expect that in the future differences will remain, unless EU legislation is enacted with sufficient room for different approaches. The strengths and weaknesses of the different regulatory procedures have been reviewed and evaluated as well as the current methods for quality, efficacy and safety evaluation. Criteria to categorize botanical products have been defined, such that botanical products can be regulated under the current food and medicinal regulations. Furthermore, a decision tree has been developed as a tool to distinguish herbal medicinal products from botanical health products and vice versa, and to provide a stepwise framework for the assessment of safety and efficacy.

We have studied the effects of dipyridamole treatment on the fatty acid composition of the main lipid classes of chick serum bearing in mind the relationship between platelet aggregation and eicosanoids production from arachidonic acid. In the free fatty acids, percentages of MUFA and n-6 PUFA fell. The effects of dipyridamole appeared to be less pronounced in triglyceride fraction, but more so in serum phospholipids and cholesterol esters. The percentage of arachidonic acid was significantly reduced by dipyridamole, as well as that of different n-3 PUFA present in phospholipid fraction. The percentage of linoleic acid in serum cholesterol esters was significantly lowered by dipyridamole, whereas that of arachidonic acid did not change significantly. Our results suggest that decreased arachidonic acid in the serum phospholipids and linoleic acid in all lipid classes may be of importance in order to dipyridamole participation in several pathologies characterized by an imbalance in the production of vasodilator and vasoconstrictor prostanoids.

The freshwater Amphipod Gammarus pulex is a sensitive indicator organism for environmental contamination. In this study, effects of heavy metal lead acetate were investigated by using electron microscopy techniques. Control group was not expose to lead acetate but experimental group was for 96 h. The ultrastructural changes of hepatopancreatic ceca cells were studied in these two groups by electron microscopy techniques analysing cellular structure, structure of organelles and vacuolization. The number of cells based on the toxic effects of lead acetate was increased compared with the control group. The number and length of cell microvilli was decreased. Additionally degenerated mitocondria, dilation of golgi vesicules and cytoplasmic vacuolization were observed. The results of present study suggest that the exposure to the lead acetate may cause some ultrastructural changes on hepatopancreatic ceca of digestive system in Gammarus pulex. The significance of this change in terms of environmental toxicology needs to be further studied.

An integrated approach of clinical toxicology and epidemiology is an essential ingredient in environmental health risk management through molecular epidemiology and environmental genomics. The last decade has also seen the emergence of several biochemical markers useful in chemical risk assessment and in epidemiological studies. An appraisal of the concepts involved, the approaches required, and the potential scope of this approach is attempted here.

Inhalational exposure to organic solvents is known to exert neurotoxic effects. Using the new multielectrode dish system (Panasonic) the effects of chronic exposure to trichloroethylene (TCE) on neuronal plasticity were assessed in different regions of the adult rat brain. Two groups of Long-Evans rats were exposed to 0 ppm or 500 ppm TCE, respectively, 6 h/day, 5 days/week for 6 months. Long-term potentiation (LTP) as well as paired-pulse potentiation/inhibition were assessed in slices from the visual cortex and the hippocampus. In addition, several behavioral tests were performed. Trichloroethanol concentrations were measured in blood and trichloroacetic acid concentrations were determined in urine. While TCE exposure impaired LTP as well as paired-pulse potentiation in hippocampal slices, no effects were seen in cortical slices. Our data demonstrate brain region specific functional changes following TCE exposure with the hippocampus being more vulnerable than the visual cortex. The behavioral measurements revealed no TCE related effects.

Oystercatchers (Haematopus ostralegus) foraging on the canal 'Zeehavenkanaal' in the Netherlands have been shown to accumulate appreciable amounts of contaminants, especially hexachlorobenzene. The present study was performed to assess the embryotoxic effects of the present contaminants. To this end, a two step approach was followed. In step one, the toxic effects of hexachlorobenzene were studied in the chicken embryo bioassay, using concentrations realistic for the field situation. In step two, yolks of oystercatcher eggs were extracted and the embryotoxic potency of this extract was studied in the same bioassay, using doses of 1, 10 and 100% of the contaminant load in one average egg. The extract contained hexachlorobenzene and PCBs. However, presence of other compounds could not be excluded, since these were not analysed. Hexachlorobenzene induced a nonsignificant decrease in lymphocyte density in the bursa of Fabricius. The egg extract caused a 3.5 fold induction of EROD activity at the highest dose applied, and decreased lymphocyte density in the bursa of Fabricius.

Excess moisture and microbial growth have been associated with adverse health effects, especially in the airways, of the inhabitants of moisture-damaged buildings. The spores of Penicillium spp. are commonly present in the indoor air, both in moisture-damaged and in reference buildings, though their numbers seem to be significantly higher in the damaged buildings. To assess the potential of Penicillium spinulosum to evoke harmful respiratory effects, mice were exposed via intratracheal instillation to a single dose of the spores of P. spinulosum, isolated from the indoor air of a moisture-damaged building (1×10(5), 1×10(6), 5×10(6), 1×10(7) or 5×10(7) spores). Inflammation and toxicity in lungs were evaluated 24 h later. The time-course of the effects was investigated with the dose of 5×10(6) spores for 28 days. The fungal spores caused mild transient inflammation. The spore exposure transiently increased proinflammatory cytokine (TNFα and IL-6) levels in bronchoalveolar lavage fluid (BALF) in a dose- and time-dependent manner. The highest concentrations of both cytokines were measured at 6 h after a single dosage. The spore exposure did not cause expression of inducible nitric oxide synthase in lavaged cells. Neutrophils were acutely recruited into airways, but the response leveled off in 3 days. Neither cytotoxicity nor major changes in vascular permeability (i.e. increases in albumin, total protein, lactate dehydrogenase or hemoglobin levels in BALF) were observed in the lungs. Considering the profile and magnitude of the changes and the dose of the spores, we conclude that P. spinulosum has a low potential to cause acute respiratory inflammation, nor does it cause direct cytotoxicity.

Exposure of fish over 96 h to 40 and 80% of LC(50) (24 h) of aqueous latex extracts of Euphorbia royleana and Jatropha gossypifolia of family Euphorbiaceae significantly altered the level of total protein, total free amino acids, nucleic acids, pyruvate, lactate, glycogen and as well as protease activity also in muscle, liver and gonadal tissue of the fish Channa punctatus. The alterations in all the biochemical parameters were significantly dose-dependent. Withdrawal study also shows that there is a partial recovery in the levels of glycogen, pyruvate, lactate and nucleic acids, but nearly complete recovery in total protein, total free amino acids level and protease activity in all the three tissues of the fish after the 7th day of the withdrawal of treatment, which supports the view that the plant product is safer in use as pesticides for control of common weed fishes in culture ponds.

A large and growing body of literature is available on the neurotoxicity of methylmercury and PCBs as expressed in the behavior of both humans and laboratory animals. Methylmercury and PCBs will be compared with PCBs with attention directed at overlaps and distinctions in their profiles of neurotoxicity. It is possible with methylmercury and, to a lesser extent, with PCBs to characterize the sensory, motor, and cognitive consequences of exposure. Methylmercury is emerging as a life-span developmental neurotoxicant: adverse effects of exposure have been identified in development and during aging in human populations as well as in laboratory animals. Less is known about the PCBs on this count. While the mechanisms of neurotoxicity are not understood for either class of compounds, emerging clues are pointing to the possibility of overlap in some mechanisms of neurotoxicity.

Exposure to lead (Pb) or polychlorinated biphenyls (PCBs) during early development has been associated with deficits in cognitive function in children (Pediatrics 87 (1991) 219; N. Engl. J. Med. 335 (1996) 783). These effects persist in the child long after exposure has ceased and body burdens have diminished. Despite intensive research, no consensus on the mechanisms of neurotoxicity of these chemicals has resulted. As the primary neurotoxic action of these agents is to impair cognitive ability, a number of laboratories have examined and reported on the detrimental the effects of Pb or PCBs on hippocampal synaptic transmission and long-term potentiation (LTP) in animals exposed during the perinatal period. Use-dependent synaptic plasticity, of which hippocampal LTP is the primary model system, is a fundamental property of neuronal function. In forebrain structures such as amygdala and hippocampus, LTP and related processes are purported to represent a physiological substrate for memory. During brain ontogeny, this type of plasticity guides the establishment and maintenance of synaptic connections in cortical structures based on sensory input. We postulate that the actions of PCBs and Pb in the developing nervous system perturb activity-dependent plasticity and promote organizational changes in brain. Aberrant connectivity derived from perturbations in activity-dependent plasticity during development may manifest as impaired LTP and cognitive ability in the adult organism.

Methylmercury (MeHg) epidemics and studies in fish-eating populations have provided invaluable insights into the neurotoxic sequelae of MeHg exposure. MeHg is a ubiquitous environmental contaminant, and its accumulation in the food chain will continue to pose health risks given anthropogenic and natural contamination. This review briefly addresses recent epidemiological data associated with exposure to MeHg in fish-eating populations, identifies mechanisms of MeHg transport into the central nervous system (CNS), and discusses various theories on cellular processes afflicted by MeHg, which most certainly include astrocytic failure to maintain the composition of the extracellular fluid.

Our research group is carrying out studies on neurobehavioral changes associated with eating fish from the Upper St. Lawrence River (Québec, Canada) and the Lower Tapajós River (Brazilian Amazon). Here, these studies are reviewed with respect to exposure, effects and intervention. Although mercury (Hg) levels in piscivorous fish are similar in both regions, in the Amazon, fish constitutes the dietary mainstay, while in Quebec, fish consumption is primarily occasional. Mercury exposure of Amazonian fish-eaters was considerably higher than Québec (median blood total Hg: 28 and 1 μg/l, respectively), but fish from the St. Lawrence contain multiple contaminants. For the Tapajós River, increasing hair Hg was associated with reduced motor and visual functions. Comparison of neurobehavioral performance of Québec fish-eaters and non fish-eaters showed a consistent pattern of information processing slowing among the former; these deficits were not related to blood methyl Hg levels. Early changes associated with exposure can be used to trigger intervention. Since fish provide important essential nutrients, mitigation must balance the beneficial and harmful effects. In Canada, advisories from environmental and health agencies consider both these aspects. In the Amazon, we are currently involved in a participatory research whose goal is to reduce Hg absorption, while maintaining fish consumption.

Consumption of PCB-contaminated sport fish from Lake Ontario has been reported to be associated with diminished female fecundity. To identify Polychlorinated biphenyl (PCB) congeners and other pesticides that might be associated with reduced fecundity, we followed 102 women aged 20-34 years attempting pregnancy who completed daily diaries for 12 at risk menstrual cycles. Fecundity referred to time-to-pregnancy (TTP) or the number of at risk menstrual cycles required for pregnancy. Blood specimens were obtained for 88 (86%) women and were analyzed using gas chromatography and electron capture for 66 PCB congeners and seven pesticides. Laboratory values were recovery, background and fat corrected prior to natural log transformation. Using stepwise discriminant analysis, congeners IUPAC #205 and #206 and hexaclorobenzene were significantly and positively associated with increasing TTP when women were categorized as becoming pregnant in the first or first three at risk menstrual cycles, respectively. Congeners #205 and #206 are reported to have (anti) estrogenic structural activity.

Quantification of exposure to environmental contaminants such as endocrine active chemicals (EACs) during critical periods of development, particularly in utero, remains largely unexplored. Therefore, we tested the hypothesis that EACs can be detected and quantified in second trimester human amniotic fluid. Amniotic fluid was obtained from women (n=175) undergoing routine amniocentesis between 14 and 21 weeks gestation. Samples were assayed by gas chromatography/mass spectrometry (GC/MS) for common organochlorine contaminants and dietary phytoestrogens. The DDT metabolite p,p'-DDE was found in approximately 25% of amniotic fluid samples (mean±S.D., 0.15±0.06 ng/ml) whereas the dietary phytoestrogens, genistein and or daidzein were found in 96.2% of samples tested (0.94±0.91 and 1.08±0.91 ng/ml, respectively). Our results demonstrate that: (1) human amniotic fluid is a suitable biological medium to evaluate developmental exposure to EACs, and (2) fetuses are exposed to biologically active levels of EACs in mid pregnancy.

Analyses of xenobiotics in human tissues are used to screen individuals whose habits or environments put them at high risk of overexposure, for the surveillance of exposure patterns over time and between places, and as part of research to identify the sources and pathways of exposure in a population. Both study goals and technical considerations should guide the choice of which xenobiotics to sample and in which tissues. Understanding the absorption and distribution of the specific compound to be measured is essential to the choice of when to sample and how to interpret results. Laboratory quality is of major concern. A particular issue in the statistical treatment of results are those near to the laboratory's detection limit. Theoretical concepts are discussed in the context of studies of xenobiotic exposure among eaters of Great Lakes and St. Lawrence River sport fish.

We summarize and discuss issues that emerged from a workshop entitled 'Human and Animal Neurotoxicology-From Exposure to Great Lakes Pollutants' that was held as part of the May 2000 Annual Meeting of the International Association of Great Lakes Research in Cornwall, Ontario, Canada. The most apparent and distressing finding was the lack of communication that currently exists between scientists of different sub-disciplines-including in vitro and in vivo toxicologists, epidemiologists and risk assessors. Although all participants agreed that integrated, multi-disciplinary research is the only avenue that offers a realistic chance of identifying, characterizing and eventually preventing the adverse consequences of developmental exposure to neurological and reproductive toxicants, there was little consensus on how to achieve this goal. We leave to the readers of this Special Issue of Environmental Toxicology and Pharmacology the daunting task of implementing the greater degree of communication needed to begin to solve problems due to developmental exposure to environmental contaminants.

Gel filtration chromatography was performed on cytosol preparation of hen spinal cord to find molecular target(s) for organophosphorus-induced delayed neurotoxicity (OPIDN). Three binding peaks of [(3)H]diisopropyl phosphorofluoridate (DFP), an organophosphate that induces OPIDN, were separated from the cytosol preparation. The activities of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) that has been proposed as a screening method for OPIDN eluted in the fractions within these two DFP binding peaks. However, the other peak had none of the activities of AChE and NTE. Therefore, this DFP binding proteins in cytosol may be peculiar to the pathogenesis of OPIDN.