Feasibility of metabolic parameter estimation in pharmacokinetic models of carbon tetrachloride exposure in rats1

Carbon tetrachloride (CCl₄) is a toxic chemical that was once used in degreasers and detergents, and some remnants of the chemical may be present in the water supply. Physiologically-based pharmacokinetic (PBPK) modeling can assist in understanding resulting internal doses of CCl₄ after exposure, but the pharmacokinetic parameters describing the metabolism of CCl₄ are not well characterized. The goal of this study was to provide insights into how to more accurately estimate these values in rats using PBPK modeling and data from previous studies. Three different PBPK models were constructed to describe CCl₄ exposure in rats via inhalation, oral ingestion, and venous injection. Each of these models was compared to data, and sensitivity analysis was performed for each model to determine whether the available data could be used to accurately determine the metabolic parameters of interest. These parameter sensitivities were so low that optimization to the available data yielded physiologically unrealistic results. Model sensitivities were analyzed for different doses and routes of exposure in order to find experimental conditions that would allow for greater identifiability of the metabolic parameters. Data were simulated from these models at optimal conditions with varying levels of noise from a normal distribution. Optimizations were then performed to confirm that the original values could be obtained. The experiments developed are left as suggestions for investigators who wish to further pursue estimating these metabolic parameters.     

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.     

Modeling pesticide fate in a small tidal estuary

The exposure analysis modeling system (EXAMS), a pesticide fate model developed by the U.S. Environmental Protection Agency, was modified to model the fate of the herbicides atrazine and metolachlor in a small tidally dominated estuary (Bath Creek) in North Carolina, USA where freshwater inflow accounts for only 3% of the total flow. The modifications simulated the changes that occur during the tidal cycle in the estuary, scenarios that are not possible with the original EXAMS model. Two models were created within EXAMS, a steady-state model and a time-variant tidally driven model. The steady-state model accounted for tidal flushing by simply altering freshwater input to yield an estuary residence time equal to that measured in Bath Creek. The tidal EXAMS model explicitly incorporated tidal flushing by modifying the EXAMS code to allow for temporal changes in estuary physical attributes (e.g., volume). The models were validated with empirical measurements of atrazine and metolachlor concentrations in the estuary shortly after herbicide application in nearby fields and immediately following a rain event. Both models provided excellent agreement with measured concentrations. The steady-state EXAMS model accurately predicted atrazine concentrations in the middle of the estuary over the first 3 days and under-predicted metolachlor by a factor of 2–3. The time-variant, tidally driven EXAMS model accurately predicted the rise and plateau of both herbicides over the 6-day measurement period. We have demonstrated the ability of these modified EXAMS models to be useful in predicting pesticide fate and exposure in small tidal estuaries. This is a significant improvement and expansion of the application of EXAMS, and given the wide use of EXAMS for surface water quality modeling by both researchers and regulators and the ability of EXAMS to interface with terrestrial models (e.g., pesticide root zone model) and bioaccumulation models, we now have an easily-accessible and widely accepted means of modeling chemical fate in estuaries.     

一些致突变剂与致癌剂分子流行病学的研究进展

分子流行病学是一种新兴的并迅速发展的研究领域。它结合了内剂量、生物有效剂量、生物效应和个体易感性效应等流行病方法学的实验检测方法，如接触性生物标记：尿中的代谢物、DNA加合物；蛋白质加合物和彗星实验参数检测的DNA损伤；效应性生物标记：染色体畸变、姊妹染色单体交换、策核、次黄嘌呤－鸟嘌呤磷酸核糖转移酶基因（HPRT）的突变，编码p53或p21蛋白的肿瘤基因的活化；易感性生物标记：CYP1A1、GSTM1、GSTT1、NAT2等基因的多态性。但无论什么实验都需要人类监测的可靠根据。直到现在仍不能解释基因型、接触性生物标记与效应性生物标记之间的关系。     

Consequences of immune system aging in nature: a study of immunosenescence costs in free-living Tree Swallows

Immunosenescence, the aging of the immune system, is well documented in humans and laboratory models and is known to increase infection risk, morbidity, and mortality among the old. Immunosenescence patterns have recently been unveiled in various free-living populations, but their consequences in the wild have not been explored. We investigated the consequences of immunosenescence in free-living Tree Swallows Tachycineta bicolor through a field experiment simulating a bacterial infection (challenge with lipopolysaccharide, LPS) in females of different ages during the nestling rearing period. We assessed behavioral and physiological responses of females, as well as growth and quality of their offspring, to determine the costs associated with the simulated infection. Results of the experiment differed between the two years of study. In the first year, old females challenged with LPS lost more body mass and reduced their nest visitation rates more, and their offspring tended to grow slower compared to similarly challenged younger females. In contrast, in the second year, old females did not appear to suffer larger costs than younger ones. Interestingly, immunosenescence was only detected during the first year of the study, suggesting that it is the dysregulated immune function characteristic of immunosenescent individuals rather than age per se that can lead to higher costs of immune defense in old individuals. These results provide the first evidence of costs of immunosenescence in free-living animals and support the hypothesis that old, immunosenescent individuals pay higher costs than younger ones when faced with a challenge to their immune system. Our results also suggest that these costs are mediated by an exaggerated sickness behavior, as seen in laboratory models, and can be modulated by ecological factors such as weather conditions and food availability.     

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.     

防污漆中活性物质海洋环境风险评估关键技术探讨

防污漆中的活性物质对海洋生态环境和人类健康造成的潜在风险受到日益广泛的关注,一些发达国家已建立了针对活性物质海洋环境风险评估的技术体系,但我国相关研究目前尚属空白。综述了防污漆活性物质海洋环境风险评估的研究背景、相关法规、技术标准和发展现状,针对环境风险评估的2个重要组成部分(危害性评估和暴露评估)中的关键技术进行了探讨。在危害性评估中,重点分析和比较了受试生物物种的选择原则、生态毒理数据的要求以及预测无效应浓度的推导方法和应用范围;在暴露评估中,系统阐述了活性物质在水环境中释放速率的计算及修正方法、环境浓度的预测模型、现有的暴露场景及其局限性等。本文以期为我国开展防污漆活性物质海洋环境风险评估提供研究基础和科学依据,并提出了今后的研究重点和方向。     

Life history of Gonatus onyx (Cephalopoda: Teuthoidea): ontogenetic changes in habitat, behavior and physiology

In the present study 670 individuals of Gonatus onyx (Cephalopoda: Teuthoidea) were observed in Monterey Bay, California from a remotely operated vehicle. The vertical distribution of this species was bimodal, with peaks at 400 and 800 m depth during the day and 300 and 500 m during the night. The bimodal distribution reflects a life stage shift between younger, schooling juveniles living in shallower water and older, solitary adults which live deeper. Ontogenetic changes in behavior associated with this life stage shift are reflected in the physiology of the organisms as well. Both aerobic and anaerobic metabolism, as estimated using mitochondrial and glycolytic enzymes, decline with increasing body mass, suggesting reduced locomotory capacity in deeper-living adults. Oxygen consumption rates were also determined in relation to oxygen partial pressure. Oxygen consumption regulation was similar between juvenile and adult squids. The critical oxygen partial pressures (29 to 30 mmHg) correspond precisely to the oxygen concentrations found at the depth of maximal abundance for day and night populations of juveniles and adults, respectively. Behavioral and physiological changes with ontogeny of G. onyx are believed to result from reduced visual predator/prey interactions in the light-limited deep sea. Received: 7 February 1999 / Accepted: 26 January 2000     

Regression models to estimate total concentrations of polybrominated diphenyl ethers: data from NHANES 2003–2004

The objective of this study was to develop regression models to estimate the total concentration of polybrominated diphenyl ethers in serum based on the known concentrations of a limited number of congeners. Because of the possible adverse health effects associated with the exposure to polybrominated diphenyl ethers, it is of interest to know their total concentrations. Data from the National Health and Nutrition Examination Survey for 2003–2004 (N = 1859) were used to develop regression models to estimate both wet weight and lipid-adjusted total concentrations. Only the knowledge of three congeners, namely, 2,2′,4,4′-tetrabromodiphenyl ether, 2,2′,4,4′,5-pentadibromodiphenyl ether, and 2,2′,4,4′,5,5′-hexabromodiphenyl ether was required to use these models. Other than the concentrations of these three congeners, age, gender, and smoking status were the only information needed to use these models. Optionally, models were developed that could also use the race/ethnicity of the participants. All models explained more than 98% of the known variability in the observed total concentration levels. Over 98% of the model generated, predicted values were found to be within 5% of the observed values.     

蔬菜常用农药在地下水中残留风险评估

为明确蔬菜常用农药在地下水中的环境风险,运用China-Pearl和SCI-GROW模型开展地下水环境暴露评估,并根据我国成人和儿童暴露参数推导25种农药预测无效应浓度(PNEC)。研究发现,25种农药PECgw为0~18.340μg·L-1,成年人PNECgw为0.003~19.654 mg·L-1,儿童PNECgw为0.001~23.253 mg·L-1。成年人和儿童的RQgw值均小于1,表明25种农药按照登记用量使用,我国成人和各年龄阶段儿童直接饮用施用农药区域地下水的环境风险可接受。     

Hematological study of petrol station workers exposed to unleaded petrol

This study was undertaken to assess the level of exposure of petrol station workers to toxic components of unleaded petrol and to investigate whether this exposure, under normal working conditions, is associated with any significant changes in hematological parameters. In this cross-sectional study, 400 subjects (200 exposed and 200 reference subjects) were included. Atmospheric concentrations of benzene (B), toluene (T), and xylene (X) (BTX) were measured and all subjects underwent complete blood counts and white blood cell differential tests. The geometric means of airborne concentrations of BTX were lower than their recommended exposure limits. The results of blood tests showed that the means of red blood cell distribution width and hematocrit parameters, while within the normal range, were significantly different in the two groups. In conclusions, the average exposure level of petrol station workers to BTX did not exceed the current threshold limit values for these chemicals. Additionally, overt hematotoxicity is unlikely to be the outcome of exposure to unleaded petrol under the conditions described in our study. Possible long-term consequences of subtle, clinically insignificant changes in the hematological parameters of exposed employees observed in this study deserve further investigation.     

Influence of simulated tidal cycles on aromatic hydrocarbon uptake and elimination by the shore crab Hemigrapsus nudus

Specimens of the intertidal crab Hemigrapsus nudus (Dana, 1851) were collected near Sitka, Alaska, in 1983, and were used in laboratory experiments to determine the influence of periodic exposure to air on the toxicity, uptake, and elimination of two aromatic hydrocarbons, toluene and naphthalene. Three tidal cycles were simulated; i.e., crabs spent 0, 33, or 66% of the time in air and the remainder of the time in toxicant or seawater solutions. Naphthalene was 10 to 20 times more toxic than toluene: naphthalene caused locomotory impairment or killed the crabs more rapidly and at concentrations lower than those of toluene. In tissues, naphthalene was accumulated faster and to higher concentrations than was toluene. Exposure to air 66% of the time reduced mortality as well as the rate at which toluene and naphthalene were accumulated and lost. Crabs exposed to air had significantly higher respiration rates than those submerged in seawater; thus, reduced rates of accumulation and loss of hydrocarbons were not caused by general metabolic quiescence. Exposure to air reduced the time the crabs were in contact with water-borne hydrocarbons and, therefore, reduced toxicity of the hydrocarbons. Once crabs had accumulated the toxicants, however, elimination was hindered by exposure to air, even for the somewhat volatile compound toluene.     

Metal-contaminated potato crops and potential human health risk in Bolivian mining highlands

This study assessed metals in irrigation water, soil and potato crops impacted by mining discharges, as well as potential human health risk in the high desert near the historic mining center of Potosí, Bolivia. Metal concentrations were compared with international concentration limit guidelines. In addition, an ingested average daily dose and minimum risk level were used to determine the hazard quotient from potato consumption for adults and children. Irrigation water maximum concentrations of Cd, Pb and Zn in mining-impacted sites were elevated 20- to 1100-fold above international concentration limit guidelines. Agricultural soils contained total metal concentrations of As, Cd, Pb and Zn that exceeded concentration limits in agricultural soil guidelines by 22-, 9-, 3- and 12-fold, respectively. Potato tubers in mining-impacted sites had maximum concentrations of As, Cd, Pb and Zn that exceeded concentration limits in commercially sold vegetables by 9-, 10-, 16- and fourfold, respectively. Using conservative assumptions, hazard quotients (HQ) for potatoes alone were elevated for As, Cd and Pb among children (range 1.1–71.8), in nearly all of the mining-impacted areas; and for As and Cd among adults (range 1.2–34.2) in nearly all of the mining-impacted areas. Only one mining-impacted area had a Pb adult HQ for potatoes above 1 for adults. Toxic trace elements in a major regional dietary staple may be a greater concern than previously appreciated. Considering the multitude of other metal exposure routes in this region, it is likely that total HQ values for these metals may be substantially higher than our estimates.     

Contest behavior and other reproductive efforts in aging breeders: a test of residual reproductive value and state-dependent models

Two models have been proposed to explain age-related changes in reproductive performance. State-dependent models predict that reproductive effort depends on the magnitude of surplus energy reserves, which often varies with age. Contrary to this prediction, there was no significant effect of starvation on the outcome of contests for carcasses by female Nicrophorus orbicollis despite weight loss by starved females relative to controls. The residual reproductive value (RRV) model predicts that individuals adjust their current reproductive effort based on potential for future reproduction. Younger adults are predicted to restrain reproductive effort because they are less willing to risk their potentially longer reproductive careers. This model was tested empirically for several components of reproduction. Age was found to be strongly correlated with dominance when two similarly sized females discovered a carcass on the same day. Age also had a small positive effect on egg mass and was positively correlated with ovipositing at least one egg. Age did not affect nesting performance (the degree of carcass burial or the value of a prepared carcass for another female). Age also had no effect on fecundity when a female bred alone but was an important factor when two females were in direct competition. Changing RRV related to aging appears to be a robust determinant of contest outcomes in burying beetles, but effects on other components of reproductive effort in the present and previous studies are more variable, perhaps because of effects of changing state.     

水体甲苯、乙苯和二甲苯对斑马鱼的毒性效应

以斑马鱼(Brachydanio rerio)为实验生物,采用半静态实验方法,研究了甲苯、乙苯和二甲苯的水生生态毒性效应.研究表明,水体中甲苯、乙苯和二甲苯对斑马鱼96h半致死浓度LC50分别为77.5、31.0和34.8mg·L-1,根据化学物质对鱼类毒性分级标准,3种物质均属中等毒性,其毒性大小顺序为:乙苯>二甲苯>甲苯.在最高暴露浓度下,斑马鱼均出现了剧烈、无序游动,并伴有抽搐等现象,其中暴露在甲苯中的斑马鱼行为改变更为严重.分析认为,3种物质对斑马鱼毒性大小与疏/亲水性有关,疏水性越强,对水生生物的毒性作用越大.     

挥发性有机物混合暴露对小鼠脑组织的氧化损伤及学习记忆能力的影响

为探讨挥发性有机物混合急性暴露对小鼠脑组织氧化损伤及学习记忆能力的影响,选用雄性昆明种小鼠50只,随机分为对照组和4个染毒组。1到4号染毒组中甲醛、苯、甲苯和二甲苯浓度依次为:(1.0+1.1+2.0+2.0)、(3.0+3.3+6.0+6.0)、(5.0+5.5+10.0+10.0)、(10.0+11.0+20.0+20.0)mg·m~(-3)。各染毒组混合气体组分的浓度分别是我国室内空气质量标准(GB/T18883—2002)的10、30、50和100倍。结果显示,在Morris水迷宫实验第4天,2、3和4号染毒组小鼠的逃避潜伏期分别为(68.9±10.3)、(72.2±4.0)和(71.5±5.1)s,比对照组(48.5±10.1)s显著延长(P<0.05或P<0.01),但小鼠的脑体比和抓力在染毒期间没有明显变化。同时,随着染毒剂量的增加,小鼠脑组织中GSH含量显著降低,ROS和MDA含量显著升高。研究表明,挥发性有机物混合暴露可导致小鼠学习记忆能力降低,而脑组织氧化损伤可能是引起神经毒性,导致学习记忆能力降低的原因之一。     

Bioaccumulation of cadmium,lead and zinc in liver and kidney of red fox (Vulpes vulpes) from NW Spain: influence of gender and age

Cd, Pb, and Zn were quantified in liver and kidney of red foxes (Vulpes vulpes) which were hunted during the 2003–2011 hunting seasons in Galicia (NW Spain). The effects of age and gender were evaluated to determine whether these variables should be included in future biomonitoring studies. The concentrations of hepatic and renal Cd (average 0.6 and 1.3 µg/g) and Pb (0.8 and 0.06 µg/g, respectively) were similar to background levels, with no known toxicological relevance. Similarly, the average levels of Zn in liver and kidney (77 and 17 µg/g) were in the range of physiological levels for canids. Although no significant gender-dependent variations were observed, the effect of aging was evident: the levels of hepatic Pb and both hepatic and renal Cd were higher in adults than in juveniles. Age should be included as a parameter during future biomonitoring programs focusing on trace metal bioaccumulation in red foxes.     

Predicting arsenic concentrations in groundwater of San Luis Valley,Colorado: implications for individual-level lifetime exposure assessment

Consumption of inorganic arsenic in drinking water at high levels has been associated with chronic diseases. Risk is less clear at lower levels of arsenic, in part due to difficulties in estimating exposure. Herein we characterize spatial and temporal variability of arsenic concentrations and develop models for predicting aquifer arsenic concentrations in the San Luis Valley, Colorado, an area of moderately elevated arsenic in groundwater. This study included historical water samples with total arsenic concentrations from 595 unique well locations. A longitudinal analysis established temporal stability in arsenic levels in individual wells. The mean arsenic levels for a random sample of 535 wells were incorporated into five kriging models to predict groundwater arsenic concentrations at any point in time. A separate validation dataset (n = 60 wells) was used to identify the model with strongest predictability. Findings indicate that arsenic concentrations are temporally stable (r = 0.88; 95 % CI 0.83–0.92 for samples collected from the same well 15–25 years apart) and the spatial model created using ordinary kriging best predicted arsenic concentrations (ρ = 0.72 between predicted and observed validation data). These findings illustrate the value of geostatistical modeling of arsenic and suggest the San Luis Valley is a good region for conducting epidemiologic studies of groundwater metals because of the ability to accurately predict variation in groundwater arsenic concentrations.     

Threshold to maturity in a long-lived reptile: interactions of age, size, and growth

Thresholds to sexual maturity—either age or size—are critical life history parameters. Usually investigated in short-lived organisms, these thresholds and interactions among age, size, and growth are poorly known for long-lived species. A 34-year study of captive green turtles (Chelonia mydas) that followed individuals from hatching to beyond maturity provided an opportunity to evaluate these parameters in a long-lived species with late maturity. Age and size at maturity are best predicted by linear growth rate and mass growth rate, respectively. At maturity, resource allocation shifts from growth to reproductive output, regardless of nutrient availability or size at maturity. Although captive turtles reach maturity at younger ages than wild turtles, the extensive variation in captive turtles under similar conditions provides important insights into the variation that would exist in wild populations experiencing stochastic conditions. Variation in age/size at maturity should be incorporated into population models for conservation and management planning.     

An assessment of copper,zinc and cadmium contamination and their ecotoxicological effects in O. mediterranea Costa, 1853 (Amphipoda,Talitridae)

This study was conducted to compare metals bioaccumulation in the Talitrid O. mediterranea collected from the banks of Bizerte lagoon. Individuals were exposed to a series of contaminated soil with different concentrations of cadmium, copper, and zinc. Biological and physiological responses were highlighted. Body metals concentrations were measured in the talitrid using flame atomic emission spectrometry. Results showed that after the second week, the mortality increased especially with cadmium exposure, and a mass gain was obtained between weeks for copper and zinc. Furthermore, the concentration factor indicated that O. mediterranea could be considered as a macroconcentrator of copper and zinc. Histopathological analysis showed that the different metals concentrations induced significant changes in the morphology and in the ultrastructural organisation of hepatopancreatic cells. Significant alterations obtained after metals exposure were the increase in the number of the majority cell organelles. Also, heavy metals were present in the form of numerous granules with different size in the cell surface. Furthermore, metals exposure affected the brush border causing the disruption of microvilli filament. Through these results, O. mediterranea could be a good indicator providing measurable responses. It could be an attractive candidate for the biochemical study of heavy metals toxicity in coastal ecosystems.