Physiological changes associated with aging result in lower internal doses of toluene and perchloroethylene in simulations using pharmacokinetic modeling

Physiologically based pharmacokinetic (PBPK) models were developed in order to translate external concentrations into internal dose estimates, but most PBPK models were developed for younger adults. A set of physiological parameters for ages 65, 75, and 85 of both genders were developed and were used with previously established human PBPK models of exposure to toluene and perchloroethylene (PERC) in order to investigate internal dose changes with increasing age. The predicted compartmental concentrations of toluene and PERC for aged adults were lower than predicted concentrations for younger adults, and this suggests that body composition changes with aging do not increase internal doses of inhaled toxicants alone after acute exposure. Hence, susceptibility to either toxicant was not expected to increase solely based on the physiological changes associated with aging. Predictions for a metabolite of PERC, however, were similar in magnitude across ages, which may lead to enhanced susceptibility if metabolic capacity changes with aging.     

Linking fate model in freshwater and PBPK model to assess human internal dosimetry of B(a)P associated with drinking water

In the present study, we demonstrate an integrated modeling approach for predicting internal tissue concentrations of chemicals by coupling a multimedia environmental model and a generic physiologically based pharmacokinetic (PBPK) model. A case study was designed for a region situated on the Seine river watershed, downstream of the Paris megacity, and for benzo(a)pyrene emitted from industrial zones in the region. In this case study, these two models are linked only by water intake from riverine system for the multimedia model into human body for the PBPK model. The limited monitoring data sets of B(a)P concentrations in bottom sediment and in raw river water, obtained at the downstream of Paris, were used to re-construct long-term daily concentrations of B(a)P in river water. The re-construction of long-term series of B(a)P level played a key role for the intermediate model calibration (conducted in multimedia model) and thus for improving model input to PBPK model. In order to take into account the parametric uncertainty in the model inputs, some input parameters relevant for the multimedia model were given by probability density functions (PDFs); some generic PDFs were updated with site-specific measurements by a Bayesian approach. The results of this study showed that the multimedia model fits well with actual annual measurements in sediments over one decade. No accumulation of B(a)P in the organs was observed. In conclusion, this case study demonstrated the feasibility of a full-chain assessment combining multimedia environmental predictions and PBPK modeling, including uncertainty and sensitivity analyses.     

Hepatoprotective and antioxidant effects of Bridelia retusa against carbon tetrachloride-induced hepatotoxicity

The aim of present study was to validate hepatoprotective and antioxidant activities of the bark of Bridelia retusa. The aqueous ethanol extract of B. retusa exhibited highest in vitro hepatoprotective effects as evident from the significantly reduced serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) into the incubation medium of rat hepatocytes with carbon tetrachloride (CCl₄), over the other organic extracts (chloroform, ethylacetate, and methanol). CCl₄ administered through subcutaneous injection produced a marked elevation in the serum levels of GOT, GPT, lactate dehydrogenase, alkaline phosphatase, bilirubin, thiobarbituric acid reactive substances, and decreased in the levels of reduced glutathione, superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and total protein content. The biochemical activities were normalized in the pretreatment of rats induced by CCl₄ with different doses (250 and 500 mg kg^?1) of the aqueous ethanol extract of B. retusa. Histopathological changes induced by CCl₄ were also significantly attenuated by aqueous ethanol extract of B. retusa treatment. The activity of the aqueous ethanol extract of B. retusa at the dose of 500 mg kg^?1 was comparable to the standard drug, silymarin (25 mg kg^?1). The overall data indicated that B. retusa possesses a potent protective effect against CCl₄-induced hepatic damage and oxidative stress.     

Effects of Matricaria chamomilla L. on lipid peroxidation,antioxidant enzyme systems,and key liver enzymes in CCl4-treated rats

In this study, we investigated the effects of Matricaria chamomilla L. extract (MCE) on lipid peroxidation, antioxidant enzyme systems, and several liver enzymes in carbon tetrachloride (CCl₄)-treated rats. Rats were divided into five groups. The first group (control group) was fed on standard feed. The rats in the other groups (CCl₄, MCE50, MCE100, and MCE200) were injected intraperitoneally with 0.8?mL?kg^?1 CCl₄. Moreover, rats in the MCE50, MCE100, and MCE200 groups were gavaged with 50?mg?kg^?1, 100?mg?kg^?1, and 200?mg?kg^?1 MCE, respectively. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, whole blood malondialdehyde (MDA) and glutathione (GSH) levels, and erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activity levels were measured after 14 days of exposure. ALT and AST in the CCl₄ group increased significantly in comparison to the control group (p?4, MCE50, MCE100, and MCE200 groups at different significance levels. In conclusion, the findings suggest that, depending on the dose administered, MCE decreases CCl₄-induced damage and consequent oxidative stress in rats; it affects the antioxidant system positively.     

Transport and dynamics of toxic pollutants in the natural environment and their effect on human health: research gaps and challenge

The source–pathway–receptor (SPR) approach to human exposure and risk assessment contains considerable uncertainty when using the refined modelling approaches to pollutant transport and dispersal, not least in how compounds of concern might be prioritised, proxy or indicator substances identified and the basic environmental and toxicological data collected. The impact of external environmental variables, urban systems and lifestyle is still poorly understood. This determines exposure of individuals and there are a number of methods being developed to provide more reliable spatial assessments. Within the human body, the dynamics of pollutants and effects on target organs from diffuse, transient sources of exposure sets ambitious challenges for traditional risk assessment approaches. Considerable potential exists in the application of, e.g. physiologically based pharmacokinetic (PBPK) models. The reduction in uncertainties associated with the effects of contaminants on humans, transport and dynamics influencing exposure, implications of adult versus child exposure and lifestyle and the development of realistic toxicological and exposure data are all highlighted as urgent research needs. The potential to integrate environmental with toxicological models provides the next phase of research opportunity and should be used to drive empirical and model assessments.     

烧烤场景中基于PBPK模型的人群PAHs暴露评估

为探究烧烤场景中人群多环芳烃(PAHs)的暴露特征与健康风险,使用美国环保署推荐的计算模型和基于生理的药代动力学模型(PBPK)模拟了我国人群的PAHs外暴露剂量和健康风险以及内暴露剂量变化情况。结果表明:1)普通居民和职业人群的日均苯并[a]芘等效摄入剂量为(50±3)ng·d~(-1)和(179±98)ng·d~(-1),其终生致癌风险为7.57×10~(-7)~1.28×10~(-5),均在可接受范围内;2)普通居民暴露后体内组织中PAHs内暴露标志物芘的最大浓度范围依次为肝(6.52~8.67 ng·L~(-1))肾(0.97~1.12 ng·L~(-1))静脉血(0.71~0.94 ng·L~(-1))皮肤(0.64~0.75 ng·L~(-1))脂肪(0.36~0.56 ng·L~(-1)),职业人群暴露后体内组织芘最大浓度为脂肪(2.97ng·L~(-1))皮肤(1.14 ng·L~(-1))≥肾(1.14 ng·L~(-1))肝(0.57 ng·L~(-1))静脉血(0.17 ng·L~(-1));3)膳食是普通人群的主导暴露途经,会导致肝组织浓度最大;呼吸和皮肤接触是职业人群的主导暴露途经,会导致脂肪组织浓度最大;4)暴露标志物芘的组织总富集量关系为职业人群(48 ng·d~(-1))大于普通人群(6~11 ng·d~(-1))。     

Hepatoprotective activity of 1-(4-(Dimethylamino)Benzylidene)-5-(2-Oxoindolin-3-ylidene) Thiocarbohydrazone in rats

The aim of the present study was to evaluate the hepatoprotective activity of 1-(4-(dimethylamino)benzylidene)-5-(2-oxoindolin-3-ylidene) thiocarbohydrazone, a novel isatin derivative against carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Hepatic damage was induced by administration of CCl₄ (1 ml/kg, b.w., p.o.) in combination with liquid paraffin (1:1) as a single dose. The hepatotoxic rats were treated with test compound at doses of 50 or 100 mg/kg for three days and liver damage biomarkers, including activities of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (ALP), and levels of total serum bilirubin (TB) measured in blood samples. Results demonstrated that treatment with test compound at doses of 50 or 100 mg/kg to hepatotoxic rats produced a significant dose-dependent reduction of elevated SGOT, SGPT, ALP activities and TB levels indicating a hepatoprotective effect that was confirmed by histopathological examination of liver tissues. The study results confirmed the hepatoprotective activity of 1-(4-(dimethylamino)benzylidene)-5-(2-oxoindolin-3-ylidene) thiocarbohydrazone in rats.     

生理毒代动力学模型及其在有机污染物水生生态毒理研究中的应用

人类生产和生活使用各种人工合成的化学品,种类和数量急剧增长,对生态系统和人体健康造成了极大威胁。因此,亟需采用高效的方法对数量巨大的化合物进行毒性评价。对生理毒代动力学(PBTK)模型的建立过程及其在污染物生态毒理研究中的应用进行了综述。PBTK模型,又称生理药代动力学(PBPK)模型,是利用生理学和解剖学等原理,将生物体简化为用血流连接的肝、肾和脂肪等各组织器官房室,模拟化合物在生物体内的吸收、分布、代谢和排泄过程。模型参数包括生理参数和生化参数2个部分,可用MATLAB等软件进行模拟。模型已应用于数百余种有机污染物在鱼体等水生生物体的毒代动力学模拟。已有模拟结果能够预测化合物在生物体内的有效剂量,对化合物毒性进行评估,并可用于不同物种、不同剂量和不同暴露途径间的外推,有力推进了污染物生态毒理研究工作的开展。     

Modeling kelp forest distribution and biomass along temperate rocky coastlines

We address the global deficit of data describing kelp forest distribution, relative covers and biomass by testing the ability of species distribution models to predict these attributes at locations where data are currently limited. We integrated biological ground truth data with high-resolution environmental datasets to develop generalized additive models that accurately predict the structure of Laminaria forests within the Bay of Morlaix (48°42′42″N, 3°55′40″W). Forest distribution and proportional covers were predicted using water depth, light availability, wave exposure and sediment dynamics. The biomass of individual kelp species was modeled by supplementing these same variables with measures of seafloor slope and benthic position. Biomass predictions for Laminaria digitata and Laminaria hyperborea contrast the physiological tolerances of these species to light and wave exposure gradients. As a direct management output, we produced high-resolution maps (25 m² grids) that closely match independent field data and provide vital information for marine spatial planning.     

Identification of urinary metabolites in rats administered the fluorine-containing pyrethroids metofluthrin,profluthrin, and transfluthrin

The major metabolites in urine of rats administered the fluorine-containing pyrethroids transfluthrin, profluthrin, and metofluthrin, which are used widely recently as mosquito repellents or mothproof repellents, were identified to establish biological indexes for evaluating the absorption amounts of these pyrethroids in the general population. A single dose of 300?mg?kg^?1 body weight of each pyrethroid was separately administered intraperitoneally to male Sprague-Dawley rats and urine samples were collected until 24 hours after the administration. The metabolites identified by gas chromatography-mass spectrometry were as follows: 2,3,5,6-tetrafluorobenzyl alcohol, 2,3,5,6-tetrafluorobenzoic acid, and 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA) for transfluthrin; 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, 4-methyl-2,3,5,6-tetrafluorobenzoic acid, 4-hydroxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (HOCH₂–FB–Al), and 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid (MCA) for profluthrin; 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, HOCH₂–FB–Al and MCA for metofluthrin. In addition, several compounds estimated to be metabolites were detected as follows: hydroxylated DCCA and its lactone for transfluthrin; 4-hydroxymethyl-2,3,5,6-tetrafluorobenzoic acid (HOCH₂–FB–Ac), hydroxylated MCA and its lactone for profluthrin; 4-methoxymethyl-2,3,5,6-tetrafluorobenzoic acid, HOCH₂–FB–Ac, hydroxylated MCA, and its lactone for metofluthrin. The pyrethroids administered underwent metabolic reactions such as ester hydrolysis and oxidation, and most of the metabolites were excreted as their conjugates into urine. These findings should be useful as basic data for evaluating the health effects of exposure to pyrethroids for the general population.     

Bioavailability of hydrophobic organic contaminants and quality of organic carbon

U.S. laws require that contaminant bioaccumulation potential be evaluated before dredged material can be recycled. Simple fugacity models, e.g. organic contaminant aqueous partition coefficient (K _oc)-derived theoretical bioaccumulation potential, are commonly used to estimate the partitioning of hydrophobic organic contaminants between sediment organic matter and organism lipid. K _oc-derived models, with or without the addition of a soot carbon term, did not accurately or consistently predict total polycyclic aromatic hydrocarbons (PAHs) and polychlorobiphenyls partitioning of eight sediments from ongoing dredging operations onto C₁₈-coated filter paper. These models also failed to predict the partitioning of individual PAHs from these eight sediments. These data underscore the trade-offs between the ease of using simple models and the uncertainty of predicted partitioning values.     

Modeling effects of toxin exposure in fish on long-term population size, with an application to selenium toxicity in bluegill (Lepomis macrochirus)

A primary goal in ecotoxicology is the prediction of population-level effects of contaminant exposure based on individual-level response. Assessment of toxicity at the population level has predominately focused on the population growth rate (PGR), but the PGR may not be a relevant toxicological endpoint for populations at equilibrium. Equilibrium population size may be a more meaningful endpoint than the PGR because a population with smaller equilibrium size is more susceptible to the negative effects of environmental variability. We address the individual-to-population extrapolation problem with modeling utilizing classical mathematical theory. We developed and analyzed a general model applicable to many freshwater fish species, that includes density-dependent juvenile survival and additional juvenile mortality due to toxicity exposure, and we quantified effect on equilibrium population size as a means of assessing toxicity. Individual-level effects are typically greater than population-level effects until the individual effect is large, due to compensatory density-dependent relationships. These effects are sensitive to the recruitment potential of a population, in particular the low-density first-year survival rate S_b. Assuming high S_b could result in underestimating effects of population-level toxicity. The equilibrium size depends directly on S_b, the reproductive potential, the toxin concentration at which mean mortality is 50% (LC₅₀), and the rate at which individual mortality increases with increasing toxin concentration. More experimental data are needed to decrease the uncertainty in estimating these parameters. We then used existing data for selenium toxicity in bluegill sunfish to parameterize a simulation version of the model as an example to assess the effects of environmental stochasticity on toxicity response. Effects of environmental variability resulted in simulated extinctions at much lower toxin concentrations than predicted deterministically.     

Bioaccumulation and toxic effects of copper on growth and oxygen consumption by the postlarvae of Penaeus indicus

The aim of this study was to assess the toxic impact of copper on postlarvae (PL) of the penaeid shrimp Penaeus indicus. Tolerance, growth, oxygen consumption and metal accumulation were investigated in these PL on exposure to copper. Tolerance studies were conducted for 96 h to assess the tolerance limits of P. indicus PL exposed to different concentrations of copper using static renewal bioassay tests. Using the Probit method, the regression equation was calculated as Y=0.4899+2.3562 X, with a correlation coefficient of 0.9707. The 96 h LC₅₀ was 0.8204 ppm. The effect of sublethal (one-fifth of 96 h LC₅₀) copper on PL for short- and long-term exposures revealed a significant (p<0.05) decrease in the rate of oxygen consumption, metabolic rate, mean length, wet and dry weight of the exposed PL over their respective controls which can be attributed to a gradual and time-dependent accumulation of the metal, as noticed in the exposed PL through accumulation studies. Overall, the data suggest that on chronic exposure even sublethal concentrations of copper can reduce the metabolic rate and growth in P. indicus PL. This is perhaps the first attempt to use the wild P. indicus PL as a bioindicator of copper toxicity.     

Temperature and salinity adaptation in the purple shore crab Hemigrapsus nudus: An in vitro metabolic flux study with excised gills

The effects of temperature and salinity acclimation on intermediary metabolism in excised gill homogenates from Hemigrapsus nudus were examined. In general, a decrease in salinity was followed by an increase in the oxidation of the substrates glucose-1-¹⁴C, acetate-1-¹⁴C and glycine-¹⁴C to ¹⁴CO₂. Also, there was an increase in amino acid incorporation into the protein fraction. Both of these metabolic parameters were differentially temperature-sensitive. An enzymic model which may explain the increase in respiration rate observed in several intertidal invertebrates meeting an hypo-osmotic stress is proposed, using data from these experiments and also from the literature.     

Degradation rates of aged petroleum hydrocarbons are likely to be mass transfer dependent in the field

Evidence for on site biodegradation may be difficult to provide at heterogeneous sites without additional experiments in controlled laboratory conditions. In this study, microbial activities measured as CO₂ and CH₄ production were compared in situ, in intact soil cores and in bottle microcosms containing sieved soils. In addition, biodegradation rates were determined by measuring the decrease in petroleum hydrocarbon concentrations at 7°C in aerobic and anaerobic conditions. Elevated concentrations of CO₂ and CH₄ in the soil gas phase indicated that both the aerobic and anaerobic microbial activity potentials were high at the contaminated site. Aerobic and anaerobic microbial degradation rates in laboratory experiments of petroleum hydrocarbons were highest in soils from the most contaminated point and degradation in the aerobic and anaerobic microcosms was linear throughout the incubation, indicating mass-transfer-dependent degradation. Different results for microbial activity measurements were obtained in laboratory studies depending on pretreatment and size of the sample, even when the environmental conditions were mimicked. These differences may be related to differences in the gas exchange rates as well as in changes in the bioavailability of the contaminant in different analyses. When predicting by modeling the behavior of an aged contaminant it is relevant to adapt the models in use to correspond to conditions relevant at the contaminated sites. The variables used in the models should be based on data from the site and on experiments performed using the original aged contaminant without any additions.     

Gas-phase degradation of CCl<Subscript>4</Subscript>, CHCl<Subscript>3</Subscript> and CH<Subscript>2</Subscript>Cl<Subscript>2</Subscript> over metallic Fe

We studied the hydrolysis of gas-phase carbon tetrachloride (CCl₄), chloroform (CHCl₃), and dichloromethane (CH₂Cl₂) over a metallic Fe surface for its application in combination with air stripping and soil vapour extraction. The effects of chlorocarbon concentration, type and preparation of the iron-containing material, humidity, and temperature on process performance are reported. The hydrolysis of chlorinated methane derivatives is catalysed by metallic iron resulting in a noticeable decrease of the reaction temperature. The reaction kinetics were found to be consistent with the Langmuir-Hinshelwood model.     

Exposure assessment,chemical characterization and source identification of PM2.5 for school children and industrial downwind residents in Guangzhou,China

To assess the exposure doses of PM_2.5 and to investigate its chemical components for the subpopulation (i.e., school children and industrial downwind residents), simultaneous sampling of indoor and outdoor PM_2.5 was conducted at an elementary school close to traffic arteries and a residence located in the downwind area of a steel plant in metropolitan Guangzhou in 2010. Chemical components, i.e., organic carbon, elemental carbon and 6 water soluble ions were analyzed in PM_2.5. A survey was also conducted to investigate the time-activity patterns of the school children and the industrial downwind residents. Indoor and outdoor PM_2.5 were 63.2 ± 20.1 and (76.7 ± 35.8) μg/m³ at the school, and 118.8 ± 44.7 and 125.7 ± 57.1 μg/m³ in the community, respectively. Indoor PM_2.5 was found to be highly related to outdoor sources, and stationary sources were the significant contributors to PM_2.5 at both sites. The daily average doses of PM_2.5 for the school children at the school (D _children) and the industrial downwind residents in the community (D _residents) were (7.6 ± 1.9) and (36.1 ± 36.8) μg/kg-day, respectively. The daily average doses of particulate organic mass and SO₄ ^2? were the two most abundant chemical components in PM_2.5. PM_2.5 exposure for the school children was contributed by indoor and outdoor environments by 48.8 and 51.2 %, respectively; for the industrial downwind residents, the contributions were 66.0 and 34.0 %, respectively. Age and body weight were significantly and negatively correlated with D _children, while age, body weight and education level were significantly and negatively correlated with D _residents; gender was not a significant factor at both cases.     

Locating major PM10 source areas in Seoul using multivariate receptor modeling

Identifying the major sources contributing to air pollution is a problem of fundamental importance in developing effective air quality management plans. Multivariate receptor modeling aims to achieve this goal by unfolding the air pollution data into components associated with different sources based on factor analysis models. We analyze the PM₁₀ data obtained from 17 monitoring sites in Seoul to locate the major source regions using multivariate receptor modeling. The model uncertainty caused by the unknown number of sources and identifiability conditions is assessed by posterior probability of each model. The estimated source spatial profiles seem to be consistent with our prior expectation about the PM₁₀ sources in Seoul.     

Moderate seawater acidification does not elicit long-term metabolic depression in the blue mussel Mytilus edulis

Marine organisms are exposed to increasingly acidic oceans, as a result of equilibration of surface ocean water with rising atmospheric CO₂ concentrations. In this study, we examined the physiological response of Mytilus edulis from the Baltic Sea, grown for 2 months at 4 seawater pCO₂ levels (39, 113, 243 and 405 Pa/385, 1,120, 2,400 and 4,000 μatm). Shell and somatic growth, calcification, oxygen consumption and \textNH₄ ⁺ {\text{NH}}_{4}^{ + } excretion rates were measured in order to test the hypothesis whether exposure to elevated seawater pCO₂ is causally related to metabolic depression. During the experimental period, mussel shell mass and shell-free dry mass (SFDM) increased at least by a factor of two and three, respectively. However, shell length and shell mass growth decreased linearly with increasing pCO₂ by 6–20 and 10–34%, while SFDM growth was not significantly affected by hypercapnia. We observed a parabolic change in routine metabolic rates with increasing pCO₂ and the highest rates (+60%) at 243 Pa. \textNH₄ ⁺ {\text{NH}}_{4}^{ + } excretion rose linearly with increasing pCO₂. Decreased O:N ratios at the highest seawater pCO₂ indicate enhanced protein metabolism which may contribute to intracellular pH regulation. We suggest that reduced shell growth under severe acidification is not caused by (global) metabolic depression but is potentially due to synergistic effects of increased cellular energy demand and nitrogen loss.     

RBCA、CLEA及CalTOX模型在苯并[a]芘污染场地健康风险评估中的应用比较

为探讨不同模型对污染场地健康风险评估结果的影响,以苯并[a]芘为例,采用RBCA、CLEA和CalTOX模型对某工业污染场地表层土壤进行健康风险评估,分析了评估结果的差异和原因,同时对模型的主要暴露参数进行了敏感性分析,并推导出基于风险概率分布的土壤修复限值。结果表明,RBCA、CLEA和CalTOX模型计算的苯并[a]芘致癌总风险分别为2.40×10-4、6.32×10-4和7.04×10-6,且经口摄入和皮肤接触2个途径对人体健康造成的危害最大。降解作用是影响CalTOX模型风险评估结果不同于RBCA和CLEA模型的重要因素,3个模型间参数取值及方法学的差异也会导致风险评估结果不同。各模型暴露参数的敏感性排序也有差异。采用基于风险概率分布的方法推导土壤修复限值,RBCA、CLEA和CalTOX模型所得结果分别为0.18、0.08、0.13(不考虑降解作用CalTOX模型)和10.74(考虑降解作用CalTOX模型)mg·kg-1,为各模型直接推导值的1.5～2.6倍。基于风险概率分布的方法可有效降低风险评估过程中参数不确定性的影响,为工业污染场地土壤修复值的制定提供参考。