Quantitative Exposure-Response Assessment Approaches to Evaluate Acute Inhalation Toxicity of Phosgene

Phosgene has been a long-term subject of toxicological research due to its widespread use, high toxicity, and status as a model of chemically induced lung injury. To take advantage of the abundant data set for the acute inhalation toxicity of phosgene, methods for exposure-response analysis that use more data than the traditional no-observed-adverse-effect level approach were used to perform an exposure-response assessment for phosgene. Categorical regression is particularly useful for acute exposures due to the ability to combine studies of various exposure durations, and thus provide estimates of effect severity for a range of both exposure concentrations and durations. Results from the categorical regression approach were compared to those from parametric curve fitting models (i.e., benchmark concentration models) that make use of information from an entire dose-response, but only for one exposure duration. While categorical regression analysis provided results that were comparable to benchmark concentration results, categorical regression provides an improvement over that technique by accounting for the effects of both exposure concentration and duration on response. The other major advantage afforded by categorical regression is the ability to combine studies, allowing the quantitative use of a larger data set, which increases confidence in the final result.     

Comparison of the half-lives and regeneration rates of blood clotting factors II,VII, and X in anticoagulant-resistant and susceptible Norway rats (Rattus norvegicus Berk.)

The half-lives and regeneration rates of clotting factors II, VII, and X in the plasma of anticoagulant-resistant and susceptible rats were determined. There is little or no difference in the half-lives of factors II and X in anticoagulant-resistant rats compared to susceptible rats, but the half-life of factor VII is longer in anticoagulant-resistant rats. In anticoagulant-resistant rats critical clotting factors appear to be carboxylated in preference to factor II, whereas the opposite occurs in susceptible rats; this may contribute to an animal’s resistance status.     

Amine promiscuity and toxicology analysis

Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives). If the pharmacodynamic response is driven by free plasma concentration of the drug then extending the plasma drug concentration is a valid approach. Half-life is dependent on the volume of distribution, which in turn can be dependent upon the ionization state of the molecule. Basic compounds tend to have a higher volume of distribution leading to longer half-lives. However, it has been shown that bases may also have higher promiscuity. In this work, we describe an analysis of in vitro pharmacological profiling and toxicology data investigating the role of primary, secondary, and tertiary amines in imparting promiscuity and thus off-target toxicity. Primary amines are found to be less promiscuous in in vitro assays and have improved profiles in in vivo toxicology studies compared to secondary and tertiary amines.     

Comparative toxicology of borates

Inorganic borates, including boric acid, Na, ammonium, K, and Zn borates generally display low acute toxicity orally, dermally, and by inhalation. They are either not irritant or mild skin and eye irritants. Exceptions owing to physiochemical properties do occur. Longer-term toxicological studies have been reported mainly on boric acid or borax where the properties are generally similar on an equivalent boron (B) basis. The critical effects in several species are male reproductive toxicity and developmental toxicity. The doses that cause these effects are far higher than any levels to which the human population could be exposed. Humans would need to consume daily some 3.3 g of boric acid (or 5.0 g borax) to ingest the same dose level as the lowest animal NOAEL. No effects on fertility were seen in a population of workers exposed to borates or to a population exposed to high environmental borate levels. There is remarkable similarity in the toxicological effects of boric acid and borax across different species. Other inorganic borates that simply dissociate to boric acid are expected to display similar toxicity, whereas those that do not dissociate simply to boric acid may display a different toxicological profile.     

Psychotropic drugs and the metabolism of intracerebrally injected tryptamine, 5-hydroxytryptamine, and norepinephrine

Abstract— Rats were injected intracerebrally with labelled tryptamine, 5-hydroxytrypt-amine (5-HT) and norepinephrine (NE). The disappearance of the amines and their metabolites as a function of time was determined. Tryptamine disappeared very rapidly, with a half-life of 5 min in normal animals and of 45 min in rats treated with a monoamine oxidase (MAO) inhibitor. The level of radioactive 5-HT declined in two phases, with half-lives of 45 min and 3 h respectively. The 5-hydroxyindoleacetic acid (5-HIAA) that was formed disappeared with a half-life of approximately 1 h. After inhibition of monoamine oxidase, there was only a single phase of 5-HT disappearance (half-life of 4 h). Reserpine decreased and imipramine increased the amount of 5-HT remaining 4 h after injection. Of the NE injected, 12 per cent was converted to methoxyhydroxyphenylglycol sulphate (MHPGS), which disappeared with a half life of 3 h. Reserpine doubled the amount of methoxyhydroxyphenylglycol sulfate formed, but did not alter its rate of disappearance, its peak concentration occurring about 30 min after injection of NE in both control and reserpine-treated rats.     

Modelling Bioaccumulation and Toxicity of Metal Mixtures

Bioaccumulation of metals in mixtures may demonstrate competitive, anticompetitive, or non-competitive inhibition, as well as various combinations of these and/or enhancement of metal uptake. These can be distinguished by plotting (metal in water)/(metal in tissue) against metal in water and comparison to equivalent plots for single-metal exposure. For the special case of pure competitive inhibition where only one site of uptake is involved, inhibition of metal accumulation in any metal mixture can be predicted from bioaccumulation of the metals when present singly. This is consistent with the commonly used Biotic Ligand Model (BLM) but does not explain bioaccumulation of metals in Hyalella azteca. Options for modelling toxicity of metal mixtures include concentration or response addition based on metal concentrations in either water or tissues. If the site of toxic action is on the surface of the organism, if this is the same as the site of metal interaction for bioaccumulation, if there is only one such type of site, and if metal bioaccumulation interactions are purely competitive (as in the BLM), then metal toxicity should be concentration additive and predictable from metal concentrations in either water or tissues. This is the simplest toxicity interaction to model but represents only one of many possibilities. The BLM should, therefore, be used with caution when attempting to model metal interactions, and other possibilities must also be considered.     

Measuring the bioavailable/toxic concentration of copper in natural water by using anodic stripping voltammetry and Vibrio-qinghaiensis sp.Nov.-Q67 bioassay

Abstract

Bioassays were carried out in the culture media for Vibrio-qinghaiensis sp.Nov.-Q67 and the influences of alkalinity and different concentrations of chloride, ethylene diamine tetraacetic acid (EDTA) and natural derived fulvic acid (FA) on the labile concentration and toxicity of Cu were investigated. The labile concentration of Cu was obtained by differential pulse anodic stripping voltammetry with a double acidification method (DAM-DPASV). Changes in water alkalinity and chloride concentrations did not affect the labile concentration of Cu, but increases of alkalinity and concentrations of chloride reduced the toxicity on Q67. In the presence of EDTA and FA, both labile concentration of Cu and toxicity were reduced. By excluding Cu-carbonate complexes and Cu-chloride from labile concentration, a bioavailable concentration of Cu (or [Cu*]) was obtained and used to predict the acute toxicity of Cu on Q67. For natural waters, the labile concentration of Cu was measured by DAM-DPASV and [Cu*] was calculated by a MINTEQ A2 software based on composition of waters. This procedure was tested for Guanting Reservoir waters by spiking different concentration Cu. The results showed that [Cu*] was a good indicator for Cu toxicity and could be used in field conditions.     

Preparation,Relative Toxicity,Chemotherapeutic Activity,and Pharmacokinetics of Liposomal SJA-95: A New Polyene Macrolide Antibiotic

The research work was designed to compare the relative toxicity, chemotherapeutic activity, and pharmacokinetic parameters of liposomal incorporated SJA-95 with that of free SJA-95, with an objective to reduce toxicity and improve therapeutic activity in vivo. Liposomal-incorporated SJA-95 (Lip SJA-95), prepared using the proliposome method, was found to exhibit a higher LD₅₀ value in mice, and the relative toxicity was about 2.5 times lower than that of the free drug. Lip SJA-95 treatment in experimental mice model of Candidiasis showed increased survival and reduced fungal loads in various organs. The pharmacokinetic profile of the free and liposomal drug was evaluated by administration of free and Lip SJA-95 intravenously to healthy albino rabbits in a crossover fashion. Lip SJA-95 showed an initial fall in plasma levels and longer half-life. The improved microbial clearance following treatment with Lip SJA-95 could be attributed partly to an increased tissue uptake, which was reflected in a marked increase in volume of distribution (V_d) and longer half-life (T_1/2). The present results clearly indicated that Lip SJA-95 treatment led to prolonged survival time, effective microbiological clearance, and reduced toxicity in the mice model of Candidiasis.     

Boron toxicity in barley (Hordeum vulgare L.) seedlings in relation to soil temperature

Boron (B) is an essential micronutrient in crop growth but its sufficiency range is narrow. Boron toxicity is a widespread problem in arid and semi-arid areas with cold weather. We investigated the effect of soil temperature (5, 10 and 15°C) on development of symptoms of B toxicity, plant growth and plant development, and on content and concentration of B in tissue of seedlings of four barley lines grown in soil with high level of available B (12 mg kg^–1). Visual symptoms of toxicity were first observed in the high B soil concentration treatment at 5 °C at 12 days after emergence. Concentration of B in tissue decreased with increasing soil-temperatures. There was no effect of soil temperature on B content or B concentration in plant tissue at the final sample (17 days after emergence). High soil B reduced seedling and leaf emergence rates, although the final seedling emergence and number of leaves were unaffected. Barley lines differed in concentration of B in tissues and visual toxicity symptom development. Adaptation to high B was either through maintaining low tissue B concentration or through tolerance to high tissue B concentration. While the investigated range of temperature does influence B toxicity in barley seedlings, it remains to be determined whether it affects crop yield.     

氯化高汞对大型溞的慢性毒性

在换水静置条件下(25℃),氯化高汞(以Hg++计)对大型溞的48小时LC50值及其可信限为13.5(±2.1)微克/升。试验个体饲以斜生栅藻单个培养,在汞含量为1—21微克/升浓度下,产仔总数经方差分析表明组间差异显著(FF0.05)。各浓度组(X)与产仔总数(Y)的关系为:Y=-51.823X+4320.960(r=-0.904,p0.01)。净增殖率(R0)随浓度升高而逐渐下降。存活和生长用方差分析及D值检验表明对照组与各浓度组之间(差异数分别小于各自的D值20.89和0.1749),没有显著差异。各浓度组对内禀增长能力(rm)和世代平均周期(T)影响不大。根据大型溞的生物学基本参数,其体长的生长模型为: lt=4.57-3.5177e-0.00838t.       

镉和十二烷基硫酸钠对克氏原螯虾的单一和联合毒性

采用静水生物测试法,研究了十二烷基硫酸钠(SDS)和Cd2+对克氏原螯虾的单一和联合毒性效应。结果表明,SDS对克氏原螯虾24、48、72和96h的半致死浓度(LC50)分别为1365.60、1171.72、1128.43和1120.43mg·L-1,安全浓度(SC)为258.79mg·L-1;Cd2+对克氏原螯虾24、48、72和96h的LC50分别为1197.09、142.06、90.85和82.64mg·L-1,SC值为0.6mg·L-1。SDS和Cd2+对克氏原螯虾的毒性分别为低毒和高毒,毒性大小为Cd2+>SDS。联合毒性试验表明,二者毒性比为1∶1,暴露时间为24、48、72和96h时,相加指数(AI)分别为0.335、0.017、0.030和0.032,联合作用结果均为毒性增强的协同作用。     

Half-life of cytoplasmic rRNA and tRNA, of plastid rRNA and of uridine nucleotides in heterotrophically and photoorganotrophically grown cells of Euglena gracilis and its apoplastic mutant W3BUL.

1. For Euglena gracilis half-life data were calculated according to Greenberg's equation (Nature 240, 102-104, 1972) using steady-state specific radioactivities determined for cyt-rRNA, cyt-tRNA and pl-rRNA. 2. For all RNAs equal half-lives were found of 45 and 38 hr, respectively, in heterotrophically and photoorganotrophically grown cells. 3. Using the decay analysis equal half-lives were found for cyt-rRNA, cyt-tRNA and pl-rRNA being 79, 43 and 60 hr, respectively, in heterotrophically and photoorganotrophically grown wild-type cells and the mutant W3BUL. 4. As suggested by the specific radioactivity of intracellular [3H]UMP compared to that of [3H]uracil fed, the remarkable differences between RNA half-lives determined for heterotrophically and photoorganotrophically grown wild-type cells, seem to be caused by a different extent of the de novo synthesis of UMP. 5. Reutilization of RNA breakdown products suggested by increased half-lives of RNAs in the decay analysis compared to those determined by Greenberg's equation seems to occur mainly in heterotrophically grown cells.     

Aluminum stress on sorghum growth and nutrient relationships

Summary Sorghum plants were grown in the greenhouse in modified Steinberg nutrient solution containing ten Al rates (0 to 297 μM) and harvested 28 days after transplanting. Top and root dry weight were not affected by added Al up to 74 μM; but decreased sharply at concentration of 148 μM and greater. Aluminum concentrations in blade 1 (recently matured blade) and plants remained constant from 0 to 297 μM added Al. Root Al concentration increased as added Al increased. No correlation existed between top dry weight and Al concentration in blade 1 or in plant. Root Al concentration was related to top dry weight and root dry weight to estimate the Al critical toxicity level. The Al critical toxicity levle in the root was 54 mmol kg⁻¹ root dry weight basis for either top or root dry weight. In blade 1 Cu concentration negatively correlated with Al while Fe and P were positively correlated. In roots Ca, Mg, Mn and Fe concentrations were negatively correlated with Al while Zn, Cu, P, and K were positively correlated with Al concentration.     

Principles and practice of foliar analysis as a basis for crop-logging in pine plantations

Summary Principles underlying the use of foliar analysis to diagnose nutrient deficiencies in forest crops are outlined, and the application of foliar diagnosis in crop-logging is discussed. The identification of limiting nutrients and the determination of critical foliar concentrations of deficient elements are prerequisites to the successful introduction of crop-logging as a management tool. The method proposed involves determining the shape of the response curve by graphical methods, and developing an equation to describe the selected model by means of regression analysis. The optimum nutrient concentration is calculated as the point of zero change in slope of the curve,i.e. where dy/dx=0, and the critical level is taken as the concentration at which a ten percent reduction in yield occurs.     

Indoor Air Inhalation Risk Assessment for Volatiles Emanating from Light Nonaqueous Phase Liquids

The indoor air inhalation pathway for volatile contaminants in soil and groundwater has received much attention recently. The risk of exposure may be higher when volatile organic compounds (VOCs) reside as constituents of a free product plume below residential or commercial structures than when dissolved in groundwater or adsorbed on soil. A methodology was developed for assessing the potential for vapor phase migration—and associated risk of indoor air inhalation—of volatile constituents from a light nonaqueous phase liquid (LNAPL) plume on top of the water table. The potential risk from inhalation of VOCs in indoor air emanating from a subsurface Jet Fuel 4 (JP-4) plume by hypothetical residential receptors was assessed at a site. Chemicals of concern (COCs) were identified and evaluated using data from the composition of JP-4 mixtures and published chemical, physical, and toxicological data. The method estimates the equilibrium vapor concentrations of JP-4 constituents using Raoult's Law for partial vapor pressure of mixtures based on assumptions about the mixture composition of JP-4. The maximum allowable vapor concentration at the source (immediately above the LNAPL) corresponding to an indoor air target concentration based on acceptable risk levels are calculated using the Johnson and Ettinger model. The model calculates the attenuation factor caused by the migration of the vapor phase VOCs through the soil column above the JP-4 plume and through subsurface foundation slabs. Finally, the maximum allowable soil gas concentrations above the LNAPL for individual constituents were calculated using this methodology and compared to the calculated equilibrium vapor concentrations of each COC to assess the likelihood of potential risk from the indoor air inhalation pathway.     

Radiotracer Studies on Waterborne Copper Uptake,Distribution, and Toxicity in Rainbow Trout and Yellow Perch: A Comparative Analysis

Rainbow trout (Oncorhynchus mykiss) are often used to estimate important biotic ligand model (BLM) parameters, such as metal-binding affinity (log K) and capacity (B_max). However, rainbow trout do not typically occupy metal-contaminated environments, whereas yellow perch (Perca flavescens) are ubiquitous throughout most of North America. This study demonstrates that dynamic processes that regulate Cu uptake at the gill differ between rainbow trout and yellow perch. Rainbow trout were more sensitive to acute aqueous Cu than yellow perch, and toxicity was exacerbated in soft water relative to similar exposures in hard water. Whole body Na loss rate could account for acute Cu toxicity in both species, as opposed to new Cu uptake rate that was not as predictive. Time course experiments using radiolabelled Cu (⁶⁴Cu) revealed that branchial Cu uptake was rather variable within the first 12 h of exposure, and appeared to be a function of Cu concentration, water hardness, and fish species. After 12 h, new branchial Cu concentrations stabilized in both species, suggesting that metal exposures used to estimate BLM parameters should be increased in duration from 3 h to 12+ h. In rainbow trout, 71% of the new Cu bound to the gill was exchangeable (i.e., able to either enter the fish or be released back to the water), as opposed to only 48% in yellow perch. This suggests that at equal exposure concentrations, proportionally more branchial Cu can be taken up by rainbow trout than yellow perch, which can then go on to confer toxicity. These qualitative differences in branchial Cu handling between the two species emphasize the need to develop BLM parameters for each species of interest, rather than the current practice of extrapolating BLM results derived from rainbow trout (or other laboratory-reared species) to other species. Data reported here indicate that a one-size-fits-all approach to predictive modeling, mostly based on rainbow trout studies, may not suffice for making predictions about metal toxicity to yellow perch—that is, a species that inhabits metal-contaminated lakes around northern Canadian industrial operations.     

Measurement of Free Radicals from Smoke Inhalation and Oxygen Exposure by Spin Trapping and Esr Spectroscopy

Research in smoke inhalation has established that free radicals are produced from gases released during combustion and these species impair lung function. Using spin traps and their adducts in an animal model free radicals were measured. Various hyperbaric oxygen regimens were tested in an attempt to attenuate pulmonary damage caused by free radical reactions. Our data demonstrated that persistent oxygen- and carbon-centered free radicals are detectable in intravascular fluids after smoke inhalation. The smoke inhalation model showed however, clearing of spin trap adducts one hour after smoke exposure. Other researchers have found that when 100% oxygen is given at 1 atmosphere absolute (ATA) for 1 h, free radicals were not detectable. However, oxygen given at 2.5 ATA does produce detectable free radicals. With continued exposure at this pressure, the levels of free radicals increase for up to 60min. This study suggests that the level of free radical induced oxygen toxicity may be a function of oxygen pressure and duration of oxygen exposure.     

Investigation of the sublethal effects of some petroleum refinery effluents

In Canada, environmental regulations for protection of the biota from the adverse effects of effluents from petroleum refineries have tended to focus on acute toxicity. There is concern those effluents may have other subtle, but still deleterious, long-term effects on aquatic ecosystems. We have used a battery of toxicity tests to assess the acute toxicity, genotoxicity, and chronic toxicity of effluent samples from two Ontario refineries. The test organisms included representatives of the bacterial, algal, plant, cladoceran, and fish communities. The results of our preliminary study indicate that the effluent samples had little acute toxicity to the test organisms. There were indications of some sublethal toxicity to Ceriodaphnia dubia, Panagrellus redivivus, and Pimephales promelas. One of the effluents inhibited the growth of Selanastrum capricornutum (IC₅₀ of 59.9%) and Lemna gibba (IC₂₅ of 73.3%) and also caused a 15 percent reduction in the germination of Lactuca sativa seeds. The SOS-Chromotest, a commercially available test that measures the activity of a bacterial DNA repair system, detected genotoxic effects in a single effluent that had been concentrated ten fold. There was no apparent relationship between several chemical parameters and the observed sublethal effects. Further research is needed to establish whether or not the observed toxic effects are typical of effluents from Ontario refineries.     

在培养基和食料中添加铅和镉对轮虫种群动态的影响

由于工业活动的影响,墨西哥水体环境中的重金属浓度在上升.浮游动物,尤其是轮虫类,由于对环境变化十分敏感而且是淡水中的常见组成部分,因此被广泛用于生态毒理试验以确定水质标准.在不同的胁迫途径下(如通过培养基或食料),重金属的毒性是不同的.在本研究中,通过在轮虫Brachionus rubens的培养基和食料中添加重金属这两种途径,我们评估了镉和铅的效应.对于这两种重金属,均采用将轮虫置于含0.5×106个/ml绿藻的培养基中或每天喂食经5倍于LC50值的金属处理(1,2和4h)的绿藻.对于在培养基中添加镉,使用了三个毒性水平(0.1,0.2和0.4 mg/L),铅的浓度分别为0.005,0.010 和0.015 mg/L.基于LC50的数据,B.rubens对铅的敏感性要比镉高24倍.镉浓度为0.4 mg/L时,培养基中加入镉造成B.rubens的生长趋缓.而喂食经不同时间处理的绿藻后,轮虫的密度随着食料在重金属中处理时间的延长而减小.培养基中或食料中添加铅时,轮虫种群生长的的趋势与在镉处理下的情况类似.随着培养基中重金属浓度的增加,每天种群增长率(r值)会减小.在培养基和食料处理两种不同途径下,r值会在0.33(对照)到0.02 d-1(经重金属处理)间变化[动物学报 51(1)46-52,2005].     

Varietal differences in mungbean (Vigna radiata) for growth, yield, toxicity symptoms and cadmium accumulation

Increased cadmium (Cd) contamination of soils resulting from industrial activities is critical to crop production. The objective of this study was to find varietal differences for foliar chlorosis and necrosis, growth and Cd accumulation in mungbean (Vigna radiata). Despite substantial varietal differences, increased Cd levels reduced the shoot and root dry weight and the number and area of leaves at different growth stages. Applied Cd stress produced the foliar symptoms such as marginal and intervein chlorosis and scattered necrotic spots on younger leaves while accelerating the senescence of older leaves. Slope of regression equation and correlations of shoot Cd content with foliar Cd toxicity revealed that leaf chlorosis was more damaging than necrosis. At maturity, number of pods per plant and seeds per pod were maximally reduced to 37% and 26%, while 100‐seed weight, seed yield and harvest index showed 61%, 79% and 54% reduction, respectively, as a result of Cd toxicity. Results suggested that although varietal difference exists, the accumulated Cd is mainly toxic to the mesophyll tissue, most probably by interfering with the uptake of essential nutrients, thereby reducing growth and yield at various stages. Therefore, selection programmes based on foliar toxicity criteria may be beneficial for better utilisation of Cd‐polluted soils.