Showing papers on "Toxicity published in 2012"
TL;DR: It is shown in a pilot study that rhesus macaques injected with phospholipid micelle-encapsulated CdSe/CdS/ZnS quantum dots do not exhibit evidence of toxicity, and chemical analysis revealed that most of the initial dose of cadmium remained in the liver, spleen and kidneys after 90 days.
Abstract: Quantum dots have been used in biomedical research for imaging1,2, diagnostics3,4 and sensing purposes5,6. However, concerns over the cytotoxicity of their heavy metal constituents7,8 and conflicting results from in vitro7,9 and small animal10,11,12,13,14 toxicity studies have limited their translation towards clinical applications. Here, we show in a pilot study that rhesus macaques injected with phospholipid micelle-encapsulated CdSe/CdS/ZnS quantum dots do not exhibit evidence of toxicity. Blood and biochemical markers remained within normal ranges following treatment, and histology of major organs after 90 days showed no abnormalities. Our results show that acute toxicity of these quantum dots in vivo can be minimal. However, chemical analysis revealed that most of the initial dose of cadmium remained in the liver, spleen and kidneys after 90 days. This means that the breakdown and clearance of quantum dots is quite slow, suggesting that longer-term studies will be required to determine the ultimate fate of these heavy metals and the impact of their persistence in primates. Six rhesus macaques injected with a cadmium-based quantum-dot formulation survived without any evidence of toxicity, but cadmium remained in certain organs after 90 days.
412 citations
TL;DR: The results conclusively demonstrate that sub-acute oral exposure to ZnO nanoparticles in mice leads to an accumulation of nanoparticle in the liver causing oxidative stress mediated DNA damage and apoptosis and suggest the need for a complete risk assessment of any new engineered nanoparticle before its arrival into the consumer market.
Abstract: Zinc oxide (ZnO) nanoparticles are finding applications in a wide range of products including cosmetics, food packaging, imaging, etc. This increases the likelihood of human exposure to these nanoparticles through dermal, inhalation and oral routes. Presently, the majority of the studies concerning ZnO nanoparticle toxicity have been conducted using in vitro systems which lack the complex cell-cell, cell-matrix interactions and hormonal effects found in the in vivo scenario. The present in vivo study in mice was aimed at investigating the oral toxicity of ZnO nanoparticles. Our results showed a significant accumulation of nanoparticles in the liver leading to cellular injury after sub-acute oral exposure of ZnO nanoparticles (300 mg/kg) for 14 consecutive days. This was evident by the elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) serum levels and pathological lesions in the liver. ZnO nanoparticles were also found to induce oxidative stress indicated by an increase in lipid peroxidation. The DNA damage in the liver and kidney cells of mice was evaluated by the Fpg-modified Comet assay which revealed a significant (p<0.05) increase in the Fpg-specific DNA lesions in liver indicating oxidative stress as the cause of DNA damage. The TUNEL assay revealed an induction of apoptosis in the liver of mice exposed to ZnO nanoparticles compared to the control. Our results conclusively demonstrate that sub-acute oral exposure to ZnO nanoparticles in mice leads to an accumulation of nanoparticles in the liver causing oxidative stress mediated DNA damage and apoptosis. These results also suggest the need for a complete risk assessment of any new engineered nanoparticle before its arrival into the consumer market.
390 citations
TL;DR: The hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment is supported, as rats were highly resistant to APAP toxicity and mitochondrial protein adducts were significantly lower in rats.
342 citations
TL;DR: Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations and it is concluded that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects.
255 citations
TL;DR: It can be concluded that lead acetate has harmful effect on experimental male albino rats and people are advised to prevent exposure to the lead compound to avoid injurious hazard risk.
Abstract: Objective
To evaluate the effect of different doses of lead acetate (1/20, 1/40 and 1/60 of LD50) on body weight gain, blood picture, plasma protein profile and the function of liver, kidney and thyroid gland.
243 citations
TL;DR: The results show that the higher toxicity of 15-DON is due to its ability to activate the MAPK, which should be taken into account given that cereal-based foods are contaminated with DON and acetylated-DON.
209 citations
TL;DR: Maintenance over time of C(min) between 2 and 7mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
Abstract: Methods: We performed a retrospective study of patients who had trough (Cmin) and peak (Cmax) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when Cmin ≥10 mg/L and/or AUC24 ≥400 mg/L.h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid +rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. Results: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n¼35) versus the linezolid+rifampicin group (n¼10), respectively. Patients in the linezolid group had either significantly higher Cmin [3.71 mg/L (1.43‐6.38) versus 1.37 mg/L (0.67‐2.55), P,0.001] or AUC24 [212.77 mg/L.h (166.67‐278.42) versus 123.33 mg/L.h (97.36‐187.94), P,0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid+rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of Cmin of 6.53 mg/L and/or of AUC24 of 280.74 mg/L.h. Conclusions: MaintenanceovertimeofCminbetween2and7 mg/Land/orofAUC24between160and300 mg/L.h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
192 citations
TL;DR: It is found that treatment of normal mice with a single ≥3 mg/20 g body weight dose of tamoxifen leads to apoptosis of >90% of all gastric parietal cells and metaplasia of zymogenic chief cells within 3 days, and substantial gastric toxicity is a heretofore unappreciated tamoxIFen side effect.
189 citations
TL;DR: Over the course of 14 GLP studies, the gold nanoshells were well tolerated and, when injected iv, no toxicities or bioincompatibilities were identified.
Abstract: Gold nanoshells (155 nm in diameter with a coating of polyethylene glycol 5000) were evaluated for preclinical biocompatibility, toxicity, and biodistribution as part of a program to develop an injectable device for use in the photothermal ablation of tumors. The evaluation started with a complete good laboratory practice (GLP) compliant International Organization for Standardization (ISO)-10993 biocompatibility program, including cytotoxicity, pyrogenicity (US Pharmacopeia [USP] method in the rabbit), genotoxicity (bacterial mutagenicity, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus), in vitro hemolysis, intracutaneous reactivity in the rabbit, sensitization (in the guinea pig maximization assay), and USP/ISO acute systemic toxicity in the mouse. There was no indication of toxicity in any of the studies. Subsequently, nanoshells were evaluated in vivo by intravenous (iv) infusion using a trehalose/water solution in a series of studies in mice, Sprague-Dawley rats, and Beagle dogs to assess toxicity for time durations of up to 404 days. Over the course of 14 GLP studies, the gold nanoshells were well tolerated and, when injected iv, no toxicities or bioincompatibilities were identified.
186 citations
TL;DR: ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose, and the liver, lung, and kidney could be possible target organs for accumulation and toxicity of Zn O nanoparticles was independent of particle size or gender.
Abstract: Background This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats. Methods Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed. Results The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues. Conclusion ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs.
182 citations
TL;DR: It is indicated that Al toxicity is mediated through ROS production and iron accumulation and a remedial route to reduce toxicity due to Al exposure is suggested and genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity.
TL;DR: It was found that, during the photocatalytic process, the TC aromatic ring is not opened and the structure of the identified by-products is quite similar to that of tetracycline and a reaction pathway is proposed.
TL;DR: The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity, and favors the view that HD may be a useful modulator in alleviatingAPAP induced oxidative stress and toxicity.
Journal Article•
TL;DR: The toxicity of cancer chemotherapy is among the most important factors limiting its use and clear delineation and communication of benefits and risks is an essential component of treatment decisions.
Abstract: The toxicity of cancer chemotherapy is among the most important factors limiting its use. Clear delineation and communication of benefits and risks is an essential component of treatment decisions. Gastrointestinal toxicity during chemotherapy is frequent and contributes to dose reductions, delays and cessation of cancer treatment. The development of intervention strategies that could eliminate an expected side effect of chemotherapy is vital. Physiologic changes that can increase the toxicity of chemotherapy are decreased stem cell reserves, decreased ability to repair cell damage, progressive loss of body protein, and accumulation of body fat. Symptoms only arise when physiological functions are altered. The gastrointestinal symptoms arising during cancer chemotherapy can often be cured if newly acquired, and if gastrointestinal physiological deficits are identified. Developing new chemotherapy regimens with similar efficacy but less toxicity should be a priority for future research.
TL;DR: The cytotoxicity of nano-SiO(2) of different sizes was investigated on two renal proximal tubular cell lines and the involvement of oxidative stress in the toxicity was clearly demonstrated.
TL;DR: The results suggest that from a general screening perspective, different cell lines have relatively equal value in assessing general cytotoxicity and that specific organ toxicity cannot be accurately predicted using such a simple approach, and that the prediction can be improved significantly when human C(max) values are incorporated.
TL;DR: It was concluded that irrespective of bioassay systems, earthworms were more susceptible to neonicotinoids than other modern synthetic insecticides.
TL;DR: The data suggest that CLR01 is a promising therapeutic agent for the treatment of Parkinson’s disease and other synucleinopathies.
TL;DR: The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen and provides a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer.
Abstract: Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. These antitumor effects were significantly enhanced upon addition of chloroquine. The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of HMGB1, IFN-γ, IL-6, and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with chloroquine. In tumor cells, chloroquine increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin-V(+)/propidium iodide (PI)(-) cells, cleaved PARP, cleaved caspase-3, and cytochrome c release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer.
TL;DR: It is indicated that AgNPs could be distributed extensively to various tissues in the body, but primarily in the spleen and liver, and there appears to be gender‐related differences in the biokinetic profiles in blood and distribution in lungs and kidneys following an intravenous injection of AgNBP.
Abstract: This study evaluated the acute toxicity and biokinetics of intravenously administered silver nanoparticles (AgNPs) in mice. Mice were exposed to different dosages of AgNPs (7.5, 30 or 120 mg kg(-1) ). Toxic effects were assessed via general behavior, serum biochemical parameters and histopathological observation of the mice. Biokinetics and tissue distribution of AgNPs were evaluated at a dose of 120 mg kg(-1) in both male and female mice. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine silver concentrations in blood and tissue samples collected at predetermined time intervals. After 2 weeks, AgNPs exerted no obvious acute toxicity in the mice. However, inflammatory reactions in lung and liver cells were induced in mice treated at the 120 mg kg(-1) dose level. The highest silver levels were observed in the spleen, followed by liver, lungs and kidneys. The elimination half-lives and clearance of AgNPs were 15.6 h and 1.0 ml h(-1) g(-1) for male mice and 29.9 h and 0.8 ml h(-1) g(-1) for female mice. These results indicated that AgNPs could be distributed extensively to various tissues in the body, but primarily in the spleen and liver. Furthermore, there appears to be gender-related differences in the biokinetic profiles in blood and distribution in lungs and kidneys following an intravenous injection of AgNPs. The data from this study provides information on toxicity and biodistribution of AgNPs following intravenous administration in mice, which represents the worst case scenario of toxicity among all the different administration routes, and may shed light in the future use of products containing AgNPs in humans.
TL;DR: The results showed that the dispersion method, filtration and initial concentration largely affected the toxicity of silver and copper oxide nanoparticles against Daphnia magna, indicating that the dissolved fraction of nanoparticles largely contributes to their acute toxicity.
TL;DR: The objective of this manuscript was to review the literature on release phenomenon as well as in vitro and in vivo toxicity of dental resin composite and Interpretation made from the recent data was outlined.
Abstract: Dental resin composite that are tooth-colored materials have been considered as possible substitutes to mercury-containing silver amalgam filling. Despite the fact that dental resin composites have improved their physico-chemical properties, the concern for its intrinsic toxicity remains high. Some components of restorative composite resins are released in the oral environment initially during polymerization reaction and later due to degradation of the material. In vitro and in vivo studies have clearly identified that these components of restorative composite resins are toxic. But there is a large gap between the results published by research laboratories and clinical reports. The objective of this manuscript was to review the literature on release phenomenon as well as in vitro and in vivo toxicity of dental resin composite. Interpretation made from the recent data was also outlined.
TL;DR: It could be concluded that deltamethrin is highly toxic to catfish even in very low concentration (0.75 μg/l) and fish antioxidants and oxidative stress could be used as biomarkers for aquatic pollution, thus helping in the diagnosis of pollution.
Abstract: The pyrethroid class of insecticides, including deltamethrin, is being used as substitutes for organochlorines and organophosphates in pest-control programs because of their low environmental persistence and toxicity. This study was aimed to investigate the impact of commonly used pesticides (deltamethrin) on the blood and tissue oxidative stress level in catfish (Clarias gariepinus); in addition to the protective effect of α-tocopherol on deltamethrin induced oxidative stress. Catfish were divided into three groups, 1st control group include 20 fish divided into two tanks each one contain 10 fish, 2nd deltamethrin group, where Fish exposed to deltamethrin in a concentration (0.75 μg/l) and 3rd Vitamin E group, Fish exposed to deltamethrin and vitamin E at a dose of 12 μg/l for successive 4 days. Serum, liver, kidney and Gills were collected for biochemical assays. Tissue oxidative stress biomarkers malondialdhyde (MDA) and catalase activity in liver, kidney and gills tissues, serum liver enzymes (ALT and AST), serum albumin, total protein, urea and creatinine were analysed. Our results showed that 48 h. exposure to 0.75 μg/l deltamethrin significantly (p < 0.05) increased lipid peroxidation (MDA) in the liver, kidney and gills while catalase activity was significantly decreased in the same tissues. This accompanied by significant increase in serum ALT, AST activity, urea and creatinine and a marked decrease in serum albumin and total proteins. It could be concluded that deltamethrin is highly toxic to catfish even in very low concentration (0.75 μg/l). Moreover the effect of deltamethrin was pronounced in the liver of catfish in comparison with kidneys and gills. Moreover fish antioxidants and oxidative stress could be used as biomarkers for aquatic pollution, thus helping in the diagnosis of pollution. Adminstration of 12 μg/l α-tocopherol restored the quantified tissue and serum parameters, so supplementation of α-tocopherol consider an effective way to counter the toxicity of deltamethrin in the catfish.
TL;DR: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.
Abstract: Purpose: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. Experimental Design: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. Results: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C max occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF -mutant melanoma tumors and one in an NRAS -mutant melanoma. Conclusion: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types. Clin Cancer Res; 18(17); 4806–19. ©2012 AACR .
TL;DR: A very strong correlation of zebrafish embryo to fish acute toxicity is confirmed and two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels and a compound requiring metabolic activation.
Abstract: The zebrafish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported fish acute toxicity was explored. Our results confirm a very strong correlation of zebrafish embryo to fish acute toxicity. When toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal effects led to a reduced number of outliers. Yet, two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels (permethrin) and a compound requiring metabolic activation (allyl alcohol).
TL;DR: It is suggested that Cu-NPs can induce rBMEC, proliferation at low concentrations and/or induce blood-brain barrier toxicity and potential neurotoxicity at high concentrations.
TL;DR: The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage.
TL;DR: Results suggest that while ingestion was common, gills were the principal sites of AgNP uptake, and which interact with skin surface and were taken up via the gills, AgNPs is a source of toxic Ag ions, while itself contribute partially to its toxicity to fish.
TL;DR: The results suggest that a further reduction in the frequency of misleading positive results in in vitro cytogenetic assays can be achieved with this set of chemicals, by avoiding the use of toxicity measures that underestimate the level of toxicity induced.
Abstract: In a previous publication, Fowler et al. [4] demonstrated that the seemingly high rate of false or misleading positive results obtained in in vitro cytogenesis assays for genotoxicity - when compared with in vivo genotoxicity or rodent carcinogenicity data - was greater when rodent cell lines were used that were also reported to have mutant or non-functional p53. As part of a larger project for improvement of in vitro mammalian cell assays, we have investigated the impact of different toxicity measures, commonly used in in vitro cytogenetic assays, on the occurrence of misleading positive results. From a list of 19 chemicals that produce "false" positive results in in vitro mammalian cell assays [10], six substances that had given positive responses in CHO, CHL and TK6 cells [4], were evaluated for micronucleus induction in vitro, with different measures of toxicity for selection of the top concentration. The data show that estimating toxicity by relative cell count (RCC) or replication index (RI) consistently underestimates the toxicity observed by other measures (Relative Population Doubling, RPD, or Relative Increase in Cell Count, RICC). RCC and RI are more likely to lead to selection of concentrations for micronucleus scoring that are highly cytotoxic and thus could potentially lead to artefacts of toxicity being scored (elevated levels of apoptosis and necrosis), generating misleading positive results. These results suggest that a further reduction in the frequency of misleading positive results in in vitro cytogenetic assays can be achieved with this set of chemicals, by avoiding the use of toxicity measures that underestimate the level of toxicity induced.
Book•
09 Nov 2012
TL;DR: 1. Toxicity Testing for Regulatory Purposes, Testing for Mutagenicity and Genotoxicity, and Microbiotests for Toxicity Evaluation of Biotoxins.
Abstract: 1. Reviews on Toxicity Tests. 2. Toxicity Testing for Regulatory Purposes. 3. New Microbiotests and Specific Test Criteria. 4. Sensitivity Comparisons of Toxicity Tests. 5. Toxicity Testing of Natural Waters. 6. Toxicity Testing of Wastes, Waste Waters and Leachates. 7. Toxicity Testing of Soils and Sediments. 8. Toxicity Testing of Air Pollution. 9. Toxicity Testing of Specific Chemicals. 10. Testing for Mutagenicity and Genotoxicity. 11. Microbiotests for Toxicity Evaluation of Biotoxins. Subject Index: Listing for major subject classes. Subject Index: Alphabetical listing.