bluuebunny/crossref_metadata_2025 huggingface dataset:
Tobacco Use and Secondhand Smoke Exposure During Pregnancy: An Investigative Survey of Women in 9 Developing Nations
Authors: Bloch Michele , Althabe Fernando , Onyamboko Marie , Kaseba-Sata Christine , Castilla Eduardo E. , Freire Salvio , Garces Ana L. , Parida Sailajanandan , Goudar Shivaprasad S. , Kadir Muhammad Masood , Goco Norman , Thornberry Jutta , Daniels Magdalena , Bartz Janet , Hartwell Tyler , Moss Nancy , Goldenberg Robert
Published: February 2008

Objectives. We examined pregnant women's use of cigarettes and other tobacco products and the exposure of pregnant women and their young children to secondhand smoke (SHS) in 9 nations in Latin America, Asia, and Africa.

Methods. Face-to-face surveys were administered to 7961 pregnant women (more than 700 per site) between October 2004 and September 2005.

Results. At all Latin American sites, pregnant women commonly reported that they had ever tried cigarette smoking (range: 78.3% [Uruguay] to 35.0% [Guatemala]). The highest levels of current smoking were found in Uruguay (18.3%), Argentina (10.3%), and Brazil (6.1%). Experimentation with smokeless tobacco occurred in the Democratic Republic of the Congo and India; one third of all respondents in Orissa, India, were current smokeless tobacco users. SHS exposure was common: between 91.6% (Pakistan) and 17.1% (Democratic Republic of the Congo) of pregnant women reported that smoking was permitted in their home.

Conclusions. Pregnant women's tobacco use and SHS exposure are current or emerging problems in several low- and middle-income nations, jeopardizing ongoing efforts to improve maternal and child health.
Collapsing the Vertical–Horizontal Divide: An Ethnographic Study of Evidence-Based Policymaking in Maternal Health
Authors: Béhague Dominique P. , Storeng Katerini T.
Published: February 2008

Using the international maternal health field as a case study, we draw on ethnographic research to investigate how public health researchers and policy experts are responding to tensions between vertical and horizontal approaches to health improvement. Despite nominal support for an integrative health system approach, we found that competition for funds and international recognition pushes professionals toward vertical initiatives. We also highlight how research practices contribute to the dominance of vertical strategies and limit the success of evidence-based policymaking for strengthening health systems. Rather than support disease-and subfield-specific advocacy, the public health community urgently needs to engage in open dialogue regarding the international, academic, and donor-driven forces that drive professionals toward an exclusive interest in vertical programs.
Impact of sludge thickening on energy recovery from anaerobic digestion
Authors: Puchajda B. , Oleszkiewicz J.
Published: February 2008

This paper presents energy balances for various digestion systems, which include single mesophilic digestion, single thermophilic digestion, two-stage thermophilic-mesophilic digestion system and systems at elevated solids content in sludge. On the basis of a sludge flow containing 30 tons TS/day (equivalent to a 100 ML/d WWTP plant) it was shown that a two-stage thermophilic-mesophilic digestion system generated more available energy than single mesophilic digestion and single thermophilic digestion systems. Sludge thickening offered the greatest amount of available energy; however that energy surplus was offset by the cost of thickening. After the cost of thickening was converted into equivalent energy units it was shown that the price of energy is important in calculation of equivalent energy units related to operation of the thickening plant. Sludge thickening may be beneficial from energy view point compared to conventional mesophilic digestion when price of energy exceeds $0.08CAN kW-hr.
Anammox brings WWTP closer to energy autarky due to increased biogas production and reduced aeration energy for N-removal
Authors: Siegrist H. , Salzgeber D. , Eugster J. , Joss A.
Published: February 2008

Fifty years ago when only BOD was removed at municipal WWTPs primary clarifiers were designed with 2–3 hours hydraulic retention time (HRT). This changed with the introduction of nitrogen removal in activated sludge treatment that needed more BOD for denitrification. The HRT of primary clarification was reduced to less than one hour for dry weather flow with the consequence that secondary sludge had to be separately thickened and biogas production was reduced. Only recently the ammonia rich digester liquid (15–20% of the inlet ammonia load) could be treated with the very economic autotrophic nitritation/anammox process requiring half of the aeration energy and no organic carbon source compared to nitrification and heterotrophic denitrification. With the introduction of this new innovative digester liquid treatment the situation reverts, allowing us to increase HRT of the primary clarifier to improve biogas production and reduce aeration energy for BOD removal and nitrification at similar overall N-removal.
Evaluation of membrane bioreactor performance via residence time distribution: effects of membrane configuration and mixing
Authors: Wang Y. , Ong K. W. , Brannock M. W. D. , Leslie G. L.
Published: February 2008

Unlike conventional wastewater treatment systems that have a single effluent discharge point, membrane bioreactors (MBR) may have multiple extraction points resulting from the location of the membrane element in the reactor. This leads to multiple residence time distributions for an MBR system. One method to characterise the mixing is based on the concept of residence time distribution (RTD). A set of RTDs were generated using the conservative tracer, lithium chloride, for pilot plant MBRs with capacity up to 300 m3/day. Flat sheet and hollow fibre pilot plant MBR systems were operated in parallel on primary effluent collected at the Bedok Water Reclamation Plant in the republic of Singapore. Analysis of the RTD profiles indicated that membrane geometry did not impact on the kinetic conversion associated with nitrification because both MBRs were in well mixed conditions. However, the energy required to achieve perfect mixing with a hollow fibre module MBR, as defined by the velocity gradient, was lower than that with a flat sheet module MBR. The implication is that energy input associated with reactor mixing will depend on the configuration of the membrane. The difference in energy requirements between flat sheets and hollow fibres is such that careful consideration should be given to membrane selection in larger municipal installations.
Nanomaterials as possible contaminants: the fullerene example
Authors: Wiesner M. R. , Hotze E. M. , Brant J. A. , Espinasse B.
Published: February 2008

An assessment of the potential risks posed by nanomaterials will require case-by-case evaluations of the processes controlling exposure and hazards such as toxicity. Factors that control fullerene transport and transformation in aqueous environments and their relationship to toxicity are discussed. Natural organic matter is observed to either increase or decrease nanoparticle stability while trends in reactive oxygen generation run counter to proposed mechanisms of possible fullerene toxicity.
Beating Earnings Benchmarks and the Cost of Debt
Authors: Jiang John (Xuefeng)
Published: February 2008

Prior research documents that firms tend to beat three earnings benchmarks—zero earnings, last year's earnings, and analyst's forecasted earnings—and that there are both equity market and compensation-related benefits associated with beating these benchmarks. This study investigates whether and under what conditions beating these three earnings benchmarks reduces a firm's cost of debt. I use two proxies for a firm's cost of debt: credit ratings and initial bond yield spread. Results suggest that firms beating earnings benchmarks have a higher probability of rating upgrades and a smaller initial bond yield spread. Additional analyses indicate that (1) the benefits of beating earnings benchmarks are more pronounced for firms with high default risk; (2) beating the zero earnings benchmark generally provides the biggest reward in terms of a lower cost of debt; and (3) the reduction in the cost of debt is attenuated but does not disappear for firms beating benchmarks through earnings management. In sum, results suggest that there are benefits associated with beating earnings benchmarks in the debt market. These benefits vary by benchmark, firm default risk, and method utilized to beat the benchmark. Among other implications, this evidence suggests that the relative importance of specific benchmarks differs across the equity and bond markets.
Misreporting Fundraising: How Do Nonprofit Organizations Account for Telemarketing Campaigns?
Authors: Keating Elizabeth K. , Parsons Linda M. , Roberts Andrea Alston
Published: February 2008

The purpose of this study is to examine the frequency, determinants, and implications of misreported fundraising activities. We compare state telemarketing campaign reports with the associated information from nonprofits' annual Form 990 filings to directly test nonprofits' revenue and expense recognition policies. Using a conservative approach that understates the extent to which nonprofit organizations violate the reporting rules, our study indicates that 74 percent of the regulatory filings from nonprofit organizations fail to properly report telemarketing expenses. Smaller nonprofits, less monitored firms, and those with less accounting sophistication are more likely to inappropriately report telemarketing costs as a component of net revenues rather than as expenses. Nonprofits that use external accounting services are more likely to properly classify the cost of their telemarketing campaigns as professional fundraising fees.
The Association between Technological Conditions and the Market Value of Equity
Authors: Matolcsy Zoltan P. , Wyatt Anne
Published: February 2008

The objective of this study is to provide evidence on how technological innovation conditions underlying the firm's investments drive earnings growth and, hence, market value of equity. Technologies develop and flourish or die out through the combined investment decisions of those firms doing the inventing, and those firms that adopt those inventions, and thereby help to spread (or diffuse) the innovations into wider use. Hence, technology is important for the investment decisions of all firms, regardless of whether they patent. We focus on three aggregate measures of technological innovation conditions: the success rate of past technological investments, technology complexity, and the technology development period. We use the interactions between each of these three conditions with earnings to capture the combined effect on market value of a firm's technological innovation environment. Our sample comprises 12,594 U.S. firm years for the period 1990–2000 including firms actively producing new technologies and firms that adopt technologies for their processes and products. Our primary and additional tests suggest that the interactions capture value-relevant information not reflected in commonly used variables including industry, research and development, sales, general, and administration expenses, risk, and growth. We also triangulate our results by providing evidence that aggregate technological innovation conditions predict future earnings and are, hence, instrumental in the earnings-generation process. This paper extends the valuation literature by (1) developing a generalizable framework that explains how technological innovation conditions link to future earnings and therefore map into the market value of equity; (2) developing aggregate measures of technological innovation conditions that are relevant for estimating future earnings and value for all firms; and (3) providing detailed empirical evidence on the relation between these aggregate measures and the market value of equity and earnings for all firms not just those that patent.
Anticariogenic and Antibacterial Properties of a Copper Varnish Using an In Vitro Microbial Caries Model
Authors: Thneibat A. , Fontana M. , Cochran M. A. , Gonzalez-Cabezas C. , Moore B. K. , Matis B. A. , Lund M. R.
Published: February 2008

Clinical Relevance

The topical application of an antibacterial agent may have the potential to decrease the severity of existing root caries lesions or prevent the development of new lesions.
The Effect of Polishing Techniques and Time on the Surface Characteristics and Sealing Ability of Resin Composite Restorations After One-year Storage
Authors: Cenci M. S. , Venturini D. , Pereira-Cenci T. , Piva E. , Demarco F. F.
Published: February 2008

Clinical Relevance

The results of this study suggest that immediate polishing procedures can result in improved short-term surface smoothness results but do not influence smoothness or sealing ability after one-year storage.
Effect of Erosive pH Cycling on Different Restorative Materials and on Enamel Restored with These Materials
Authors: Francisconi L. F. , Honório H. M. , Rios D. , Magalhães A. C. , Machado M. A. A. M. , Buzalaf M. A. R.
Published: February 2008

Clinical Relevance

The different types of restorative materials tested were not able to protect adjacent enamel from erosion. Thus, the ability of a restorative material to prevent tooth erosion should not be considered when choosing a material.
Approaches to the Study of the Sequential Events Governing the Induction and Fixation of Genotoxic Events: An Overview
Authors: Hart Ronald W.
Published: February 2008

Two general approaches to research in the field of toxicology are discussed and. their merits evaluated relative to the elucidation of those parameters which may play an important role on the extrapolation of animal data to human health effects. A number of these parameters are discussed relative to the ability to maintain fidelity of genetic information.
Behavioral Toxicology of Volatile Organic Solvents I. Methods: Acute Effects
Authors: Glowa J. R. , Deweese J. , Natale M. E. , Holland J. J. , Dews P. B.
Published: February 2008

Behavioral toxicity of toluene has been measured in mice. Because of its small size the mouse can be confined in a 251. hermetically sealed chamber for several hours. Toluene was introduced through a port and vaporized by a hotplate. Samples of chamber air for analysis were taken through another port. A smaller mesh cage held the mouse within the larger chamber. Schedule-controlled responding was developed by arranging that a response, breaking a beam of light, was followed by milk under an FI 60-sec schedule. Responding was much more rapid in the presence of stimuli correlated with the FI schedule than when the schedule was not operating. Standard sessions consisted of alternating series of 8 consecutive FI 60-sec and interseries 30-min time-outs.

Following introduction of liquid toluene, the concentration in the chamber reached its asymptote within 60 sec. Toluene disappeared from the atmosphere of the unopened empty chamber at the rate of 0.2%/hr. When the mouse cage was in the chamber the disappearance was 1.5%/hr and when a mouse was also present it was 3.5%/hr. Effects of toluene on the behavior of the mouse reached a plateau within 30 min of continued exposure to a fixed concentration. Concentration-effect curves were constructed from the number of responses in a series of FI's following 30-min exposure to a concentration of toluene as compared to the control number on that day. In some experiments mice were exposed to a single concentration of toluene: in other experiments, more toluene was added after a series of FI so the mice were exposed to incrementally increasing concentrations. The two procedures generated similar concentration-effect curves. Toluene increased the rate of responding in most mice at levels of about 700 ppm. Higher concentrations progressively reduced responding. The ED 50 (the concentration reducing responding by 50%) averaged 1657 ppm in 10 mice.
Enzymatic Changes in Alveolar Macrophages of Rats Exposed to Lead and Nickel by Inhalation
Authors: Murthy Raman C. , Barkley William , Hollingsworth Lois , Bingham Eula
Published: February 2008

In previous inhalation studies, rats exposed to aerosol concentrations of lead oxide (Pb2O3), 150 μg/m3; lead chloride (PbCl2), 100 μg/m3; nickel oxide (NiO), 120 μg/m3; and nickel chloride (NiCl2), 109 μg/m3; significant changes were observed in the lungs and alveolar macrophages. In this study the hydroiytic enzymes, acetylesterase, acid and alkaline phos-phatases, lysozyme, and beta-glucuronidase, in alveolar macrophages and lung washout fluid from rats subjected to the inhalation of the lead and nickel aerosols were examined. Washed alveolar macrophages from animals exposed to lead and nickel aerosols were found to contain reduced quantities of the various hydrolytic enzymes (except for acetylesterase) when compared with those from control rats. On the other hand, a significant increase in enzymatic activity was noted in lung washout fluid from exposed animals. The functional efficiency of macrophages, relative enzyme changes, and the mechanism of action of metals are discussed. It is important to note that the changes observed in these studies were from animals exposed to metallic concentrations near their Threshold Limit Values.
Relation of UV Dose to Antioxidant Modification of Photocarcinogenesis
Authors: Black Homer S. , Lenger Wanda , Thornby John I.
Published: February 2008

Studies were undertaken to examine the influence of various levels of ultraviolet light (UV) on the anticarcinogenic properties of antioxidants. Six groups of female, hairless mice were subjected to daily irradiation until pairs of groups had received a cumulative dose of 21.6, 31.6, and 44 sunburn units respectively. Control groups, at each level of UV, were maintained on a closed formula ration. Experimental groups received the same ration supplemented with a 2% (w/w) antioxidant mixture. Tumor latency, expressed as median time to tumor development, was significantly greater for antioxidant-supplemented animals at all three doses than for similarly UV-dosed controls. The inhibitory response to antioxidants decreased with increasing UV dose. Likewise, antioxidant-supplemented animals, at all three UV doses, exhibited a significantly fewer number of tumors per animal. In the control groups, only the lowest UV dose, when compared to the two higher doses, demonstrated a longer tumor latency period. On the other hand, tumor multiplicity for control animals appeared to be a more sensitive response to UV dose. It is concluded that UV dose influences the degree of photoprotection afforded by antioxidants and is an important experimental parameter to be considered when evaluating potential chemopre-ventive agents.
Potential Role of Intercellular Communication in the Rate-Limiting Step in Carcinogenesis
Authors: Trosko James E. , Chang Chia-cheng
Published: February 2008

In order to ascertain whether there might be a scientific basis for determining practical “thresholds” for “carcinogens,” the concepts of thresholds and carcinogens were examined in the context of some current ideas on cardnogenesis. The observation that cardnogenesis seems to involve the donal expansion of a pre-malignant cell through a series of pheno-typic changes was explained by the initiation/promotion model of cardnogenesis. Unrepaired DNA lesions, acting as substrates for mutations in dividing cells, were speculated to play a role in the initiation phase of cardnogenesis (and indirectly to the promotion phase if the lesions lead to significant cell killing, forcing “compensatory hyperplasia”). Inhibition of intercellular communication, either by cell removal, cell death, growth factors or chemical promoters, was speculated to allow the donal expansion of initiated cells to reach a “critical mass.” During that donal expansion of initiated cells, additional phenotypic changes were speculated to occur during cell replication by mutational and/or epigenetic events. Therefore, it was concluded, on the basis of this model, that conditions which prevented the inhibition of intercellular communication between normal cells and the initiated cell(s) contributed to the rate limiting step of cardnogenesis.

Assuming the initiation and promotion model of cardnogenesis, the classical concepts of “thresholds” and “carcinogens” were viewed as grossly inadequate because they did not symbolically represent the known determinants of the complex carcinogenic process. Unless genetic, developmental stage, tissue, nutritional, stress, life style, as well as concurrent antagonists and/or synergists, factors are known, extrapolation about the potential carcinogenicity of a given chemical from molecular, in vitro or even in vivo experiments or epidemiological data would be extremely risky. It was concluded that, at this stage of our understanding of the mech-anism(s) of carcinogenesis, attempts to determine “thresholds” for “carcinogens” naively assume “carcinogens” are the single determinants for carcinogenesis, and that all chemicals which might influence the appearance of tumors act the same way.
The Importance of Pharmacokinetic Principles in Characterizing Carcinogenic Thresholds for Naturally Occurring and Synthetic Chemicals
Authors: Yesair David W.
Published: February 2008

Many chemicals, both man-made and naturally occuring, can elicit a carcinogenic response either as a mutagenic response in vitro or as a frank tumor in vivo. In both instances emphasis has been placed historically on the dose which elicits the response. When the carcinogenic response is related to the pharmacokinetics of the carcinogen taking into account the dose, the frequency of dosing, andthe relative half lives of the carcinogen, its reactive metabolites and any modified macromolecules, a narrow plateau level of modified macro-molecules is found in specific responsive tissues or species of animals. This plateau threshold concept for carcinogen as defined by the pharmacokinetics, has been evaluated for both chloroform and aflatoxin. The carcinogenic risk associated with plateaus can be evaluated experimentally, and perhaps can be evaluated today with the available data at hand.
Metabolic Activation of Xenobiotics: Ethylene Dibromide and Structural Analogs
Authors: van Bladeren Peter J.
Published: February 2008

A large number of compounds which can enter living organisms are relatively harmless as such, but are transformed by the body into reactive agents. The structure of such a compound is the factor determining its disposition in the organism. Its physicochemical characteristics determine the overall fate in terms of absorption, distribution and excretion, while the chemical structure is the decisive factor in its biotransformation. Whether formation of reactive intermediates occurs depends on what points of attack it has to offer to the different enzyme systems. The extent to which alkylation of cellular macromolecules by reactive intermediates occurs in turn depends on the balance of activating and detoxifying enzymes in the particular cell and on the reactivity of the intermediates towards critical targets in the cell macro-molecules.

Many chemicals undergo several concurrent metabolic pathways. The ratio between these pathways may be a decisive factor determining the extent of adverse effects caused by these chemicals. Small variations in structure may have a drastic effect on the activation and detoxification by competing enzyme systems.

These concepts are elucidated using the examples of ethy-lene dibromide and some structural analogs. Apart from the parent compound itself, two alkylating species may be responsible for the toxic effects of these compounds. Bromo-acetaldehyde is formed by oxidation, catalyzed by cyto-chrome P-450, followed by spontaneous loss of hydrogen bromide; S-2-bromoethylglutathione results from replacement of a bromine atom by glutathione, catalyzed by the glutathione transferases. The latter intermediate possesses a reactivity comparable to sulfur mustard. Results indicate that the reactive glutathione conjugate is responsible for the mutagenic and possibly also the carcinogenic effect of ethy-lene dibromide. However, in vivo, oxidation is quantitatively much more important as a primary process.
Thresholds in Chemical Carcinogenesis
Authors: Van Duuren Benjamin L. , Banerjee Sipra
Published: February 2008

This review deals with the controversial subject of thresholds in chemical carcinogenesis. It is essential to consider this subject in relation to a number of other matters which have a direct bearing on it. These include the use of the maximum tolerated dose (MTD) in animal bioassays. These are at times excessive and not consistent with the definition of the MTD. Many bioassays are carried out at only one or two doses so that reliable dose-response curves and hence a threshold cannot be established. In addition, laboratory animal bioassays even at the lowest doses used are frequently above those encountered in the environment by several orders of magnitude. The various biochemical and biologic events which a xenobiotic is subjected to in vivo are described in more detail in relation to threshold. Also, dose-dependent alterations in metabolic pathways are reviewed for vinyl chloride and 1, 4-dioxane. The value of examining the muta-genidty and cardnogenidty of activated carcinogenic intermediates is examined using a series of chloroalkene epoxides as intermediates. The interdisciplinary approaches that need to be used in risk assessment, which is required by federal regulatory agencies, are pointed out. It is concluded that thresholds do exist for some chemical carcinogens.
Catabolic Functions of Peroxisomes: Modification by Hypoupidemic Drugs
Authors: Lazarow Paul B.
Published: February 2008

The peroxisome is a subcellular organelle that is widely distributed in nature and which carries out both catabolic and anabolic functions (Ann. NY Acad. Sch 386:1-550, 1982). The catabolic functions include respiration (based on the formation and decomposition of H2O2) and the ß-oxidation of fatty acids. A number of drugs share the attributes of beingi) hypo-lipidemic, (2) inducers of the peroxisomal ß-oxidation enzyme system, (Lazarow, Science 197: 580-581, 1977), 3) peroxisome proliferators, and 4) carcinogens in rodents. Reddy et al. (Nature 283: 397-398, 1980) have hypothesized that peroxisome proliferators as a class may be carcinogenic Data is presented showing that bezafibrate, at a suitable hypolipidemic dose in rats, induces peroxisomal ß-oxidation but does not cause the striking organelle proliferation commonly observed with hypolipidemic drugs. Similar results have been obtained with clofibrate treatment of female rats. Christiansen et al. (Eur.). Cell Biol. 26: 77-20, 7987) have shown that feeding rats a diet rich in partially hydrogenated marine oils produces changes in the peroxisomes similar to those caused by bezafibrate. Aspirin, which is weakly hypolipidemic and a weak peroxisome proliferator, is apparently not carcinogenic in humans. The evidence indicates that the hypolipidemic effects and the peroxisome proliferative effects of these drugs are largely (although incompletely) dissociable. It suggests the need for considerable caution in evaluating the relationship, if any, between hypolipidemic and carcinogenic effects.
Artifacts Due to Secondary Pathology: Case Study Examples
Authors: Anderson R. L.
Published: February 2008

The manuscript presents a summary of both biochemical and morphological information that has led to proposed mechanisms by which nitrilotriacetate (NTA) causes urinary tract toxicity that is a necessary precondition for NTA's reported tumorigenidty. These models ascribe urinary tract toxicity to site specific changes in divalent metal distributions between urinary tract tissue and urine that accompany renal clearance of NTA. The proposed models show definable NTA concentration thresholds that must be exceeded before NTA can induce the divalent metal perturbations that are the initiating steps in tissue toxicity, which is a necessary precondition for subsequent carcinogenicity. The proposed mechanisms are consistent with all of the known NTA effects, including urinary tract tumorigenicity noted in chronic exposure studies with high doses of NTA.
Dose Patterns of Cellular Effects Induced by Carcinogens: Evidence for the Presence or Absence of Thresholds
Authors: Williams Jerry R. , D'Arpa Peter
Published: February 2008

The patterns of response of individual cells to carcinogens may be a factor that influences the shape of the dose-response curve for cancer in human populations; thus the existence of a threshold for cellular response may imply a threshold for cancer induction. The patterns of response of cultured mammalian cells to carcinogen treatment is described for four cellular endpoints: cytotoxidty, mutation, sister chromatid exchange, and in vitro transformation. These data, taken in toto, indicate that for some carcinogens a threshold exists for the induction of cellular effects, but for some carcinogens thresholds probably do not exist. Cancer-prone human beings may contain cell populations without thresholds, making them especially sensitive to low doses of environmental carcinogens.
Thresholds in Acute and Long Term Animal Studies
Authors: Uehleke Hartmut
Published: February 2008

The possibilities to define thresholds in general pharmacology and toxicology depend upon the proper knowledge and determination of the most sensitive parameters and relevant targets leading to clinical effects or toxicity. We are generally confronted with the statistical summation of very numerous individual responses and effects at the enzymological, sub-cellular, cellular, organ, or systemic level. In consequence, biological actions of chemicals reveal typical dose-response characteristics described by simple mathematics, and more or less sharp thresholds. Thresholds and targets can change after single and repeated (cumulative) doses by means of altered kinetics and metabolism, by adaptation and modified sensitivity of targets and/or receptors. Most sensitive targets and parameters do not always determine the real thresholds for clinical toxicity. Threshold and specificity of carcinogens can also be modified by similar conditions mentioned. Nutritional factors play an important role in experimental car-dnogenesis, and also for the cancer incidence in man. Frequently, secondary mechanisms such as overloading, induction of cellular growth, mechanical and chemical irritation and damage, and other conditions have simulated real carcinogenic properties of chemical molecules. The important question on the existence and validity of thresholds in carc/nogenes/s must be connected with a solid evaluation of the mode of action of the individual compounds. Otherwise, mathematical calculations of safety limits, definitions of acceptable risks and no-effect levels lack any biological foundation. Finally, the individual perception and social acceptance of risks reveal certain thresholds.
Stages in Cancer Development: Opportunities for Thresholds
Authors: Newberne Paul M.
Published: February 2008

It has now been established that many factors can influence the development of cancer in animal models. Epidemiologic studies support the concept of a similar situation in human populations with particular emphasis on lifestyle. Types of cancer which appear to be excellent candidates for such influences are colon, breast and lung. In the case of each there are antecedent (pre-neoplastic) changes in morphology of focal areas in the organ or tissue and a lag time varying from a few years to decades. It seems logical that thresholds do exist in some such cases and that if a threshold is not exceeded for whatever substance or condition may be primary to the cardnogenesis process, the atypical cellular alterations may regress or at most remain static. Furthermore, factors associated with lifestyle, including diet, can likely determine whether or not the progress toward malignancy is initiated, inhibited, or enhanced in a given organ or tissue. A number of factors or conditions which may relate to inhibiting or enhancing cardnogenesis are considered in this presentation. Mechanisms for such effects may be mediated by raising or lowering thresholds. This area of research requires increased emphasis in our efforts to prevent cancer.
Possibilities for Dietary Fat and antioxidants as Modulators of Mammary Carcinogenesis
Authors: King M. Margaret , McCay Paul B.
Published: February 2008

The problem of defining a threshold for even a single carcinogen is both old and new. If one defines “threshold” as the quantity of carcinogen or other etiologic agent just capable of producing a tumor, then at least a common ground is described. However, this “threshold level” may be modulated upwards or downwards in the organism by various environmental and internal factors. A specific case in point is the known influence of dietary fat, especially polyunsaturated fat as an enhancer of many types of tumors, i.e., it appears to be acting to lower the threshold level of carcinogen that is required to elicit a tumorigenic response. Conversely, many dietary antioxidants such as BHT, BHA, and propyl galIate have been shown to effectively raise the threshold level, or decrease the tumorigenic response to a given level of carcinogen. The possible mechanisms through which the dietary factors modify tumorigenesis will be discussed. These will include specific influences and interactions of dietary factors on 7, 12-dimethylbenz(a) anthracene-induced mammary car-cinogenesis, carcinogen uptake and retention by the target tissue, as well as influences on glandular development which may result in an alteration of the number of possible “targets” available at the time of carcinogen exposure.
Health Effects of Exposure to Diesel Engine Emissions: A Summary of Animal Studies Conducted by the U.S. Environmental Protection Agency's Health Effects Research Laboratories at Cincinnati, Ohio
Authors: Pepelko W. E. , Peirano W. B.
Published: February 2008

In order to evaluate the potentially harmful effects of diesel engine emissions, inhalation exposure studies were carried out using a variety of animal species and strains, and measuring a wide range of toxicological parameters. Exhaust was provided by a 6 cylinder Nissan diesel engine operated 20 hours/day, 7 days/week, during a 2 month preliminary trial and 8 hours/day, 7 days/week during a 2 year, 4 month long-term study. The exhaust was diluted to produce a concentration of 6 mg/m3 particulate matter during the preliminary study and during the first year of the long term study and 12 mg/m3 thereafter. Exposure to diesel emissions did not result in detectable genotoxic effects as measured by increases in sister chromatid exchange (SCE), micronucleus testing and metaphase analysis in Chinese hamster and mouse bone marrow cells or in the morphology of cat sperm. SCE in lung cells from Syrian hamsters, however, was increased at the higher exposure level. The incidence of heritable mutations was not increased in mice. An increase in lung tumor incidence was detected in female Senear mice exposed from conception, but not in males, or in either male or female strain A mice exposed from 6 weeks of age. Voluntary activity was decreased in rats during exposure and learning ability was impaired in adult animals exposed during the early postnatal period. Susceptibility to an infectious challenge was increased in diesel exposed mice. Clearance of particles from the lung was found to be minimal even after 90 days recovery in clean air. Pulmonary function alterations in diesel exposed cats suggested the presence of a lesion restricting the air flow. The integrity of the lung as measured by leakage of 131I labeled protein into the alveoli did not seem to be impaired, but increased collagen synthesis suggested that fibrosis may develop with long-term exposure. The preliminary inhalation study resulted in the induction of xenobiotic metabolizing enzymes in the liver. In later studies, however, enzyme induction was found only in male mice injected with large doses of diesel particulate extract.
Distribution and Elimination of Ingested Mercuric Oxide in Mice
Authors: Berg G. G. , Smith B. S.
Published: February 2008

Neutron-activated mercuric oxide was administered by gavage to female BALB/c mice. Counts of 197Hg and 203Hg in the whole body, urine, and feces were followed for up to 36 days. Elimination of mercury fitted a 3-compartment model. Nonpregnant mice eliminated approximately 87.5% of the dose at a fast rate (t1-2 = 9 hours), 12% at an intermediate rate (t>1/2 = 2 days), and 0.5% at a slow rate (t1/2 = 15 days). Each half-time was approximately 7 times shorter than the corresponding half-time fitted to published data on rats. Mice were also faster than humans in eliminating the ingested mercury. Pregnancy slowed down the intermediate rate of elimination. The total administered dose was recovered from feces and urine in a 9:1 ratio. Organ weights and mercury burdens were measured after serial sacrifice. Peak concentrations were reached within two days, with highest levels in kidneys followed by placentae and livers. In brains, peak concentrations were delayed and low. Subsequent losses of mercury differed widely in rate constants, with fastest overall rates in the brain, intestine, and integument, followed in order by whole body, liver, and kidneys. Ten days after dosing, mercury concentration ratios of placenta to 17-day old fetus were 20:1; 11 days after dosing, and with less than 2% of body burden remaining, while body concentration ratios of mother to neonate were 4:1. The data indicated that mice eliminated mercuric salts faster than had been reported for rats or humans, and that rapid elimination coupled with a placental barrier shielded fetuses from equlibrating with the peak concentrations of mercury found in dams after a single dose.
Behavioral Toxicology of Organic Solvents. II. Comparison of Results on Toluene by Flow-Through and Closed Chamber Procedures
Authors: Glowa J. R. , Dews P. B.
Published: February 2008

Concentration-effect curves for behavioral toxicity of toluene have been determined in 10 mice by a flow-through procedure. The mean of the estimates of concentrations of toluene which reduce responding by 50% is 2329 ppm and by 10% is 1523 ppm. The results are compared with previous determinations that used a closed-chamber procedure. The values then were 1806 ppm and 1299 ppm. The difference in the 2 estimates would have no appreciable effect on decisions on permissible concentrations based on the estimates so the greater simplicity of the closed-chamber method makes it worthy of consideration for routine purposes.
Evaluation of the Teratogenic and Mutagenic Potential of the Oxidative Dyes, 4-Chlororesorcinol, M-Phenylenediamine, and Pyrogallol
Authors: Picciano J. C. , Morris W. E. , Kwan S. , Wolf B. A.
Published: February 2008

Three oxidative dyes were screened for mutagenic and teratogenic potential. A range of mutagenic response was observed using Salmonella typhimurium tester strains, TA 1538 and TA 98 in the presence or absence of metabolic activation. M-phenylenediamine exhibited activity with both strains while 4-chlororesorcinol showed no response in either strain. Pyrogallol exhibited a weak response that showed no linear correlation only in TA 98 in the absence of activation. In teratogenicity studies, the 3 oxidative dyes were administered by gavage to Sprague-Dawley rats on days 6 through 15 of gestation at the following dose levels: 4-chlororesorcinoI at 50,100, and 200 mg/kg; m-phenylenediamine at 45,90, and 180 mg/kg; and pyrogallol at 100,200, and 300 mg/kg. A significant reduction in mean maternal weight gain was noted at the high dose level of each dye. The high dose levels of 4-chlororesorcinol and pyrogallol were embryolethal as indicated by an increase in resorptions. The high dose level of pyrogallol was fetotoxic as evidenced by a decrease in fetal body weights. Evaluation of the number of gross, visceral, or skeletal anomalies/variations revealed no statistically significant differences between dye treated and control groups. Exposure to the positive control agents, Vitamin A and aspirin, resulted in a statistically significant increase in abnormal fetuses with a broad spectrum of gross visceral and skeletal anomalies ranging from a frequency of 18-60%. These studies indicated that the predictability of teratogenicity from bacterial mutagenicity screening is low with the chemical categories under investigation.
2-year Toxicity Study of Doxylamine Succinate in the Fischer 344 Rat
Authors: Jackson Carlton D. , Blackwell Boon-Nam
Published: February 2008

Doxylamine succinate, a commonly used antihistamine, was administered as an admixture in the feed to groups of male and female Fischer 344 rats at dose levels of 0, 500, 1000, and 2000 parts per million (ppm) (based on free amine) for 65 weeks (9 per group) or two years (48 per group). There were no significant treatment-related differences in survival in either sex. Compared to controls, final body weights of rats in the 2000 ppm group were reduced 8.4% and 22.8% in males and females, respectively. Treatment-related, non-neoplastic lesions were found primarily in the liver and parotid salivary gland. Liver lesions consisted of fatty change and degeneration in both sexes; hyperplasia (resulting from degeneration due to leukemia) and atypical cells in males; and hypertrophy, chronic inflammation, and mixed cell foci in females. Both sexes exhibited a treatment-related increase in cytoplasmic alteration in the salivary glands. Liver neoplasms were found only in the highest dose group of male rats. The trend test was significant (p ≤ 0.05) for increased incidence of hepatocellular adenoma and carcinoma with increasing doses of doxylamine, but the increased incidence of either lesion in the high dose group was not significant compared to that in controls. However, when animals with carcinoma or adenoma were combined, the trend test remained significant (p ≤ 0.01), and the incidence of the highest dose group was significantly increased (p ≤ 0.05) over that in controls. No treatment-related increase in neoplasms was found in females, but doxylamine produced a marked dose-related decrease in mammary fibroadenomas. Although not statistically significant, a very rare pineal gland tumor was found in 1 male and 1 female rat in the 2000 ppm group.
Framework for Validation and Implementation of In Vitro Toxicity Tests: Report of the Validation and Technology Transfer Committee of the Johns Hopkins Center for Alternatives to Animal Testing
Authors: Dickens Michael S. , Flint Oliver , Gettings Stephen D. , Hill Richard N. , Lipnick Robert L. , Renskers Kevin J. , Bradlaw June A. , Scala Robert A. , Veronesi Bellina
Published: February 2008

In toxicology the development and application of in vitro alternatives to reduce or replace animal testing, or to lessen the distress and discomfort of laboratory animals, is a rapidly developing trend. However, at present there is no formal administrative process to organize, coordinate, or evaluate these activities. A framework capable of fostering the validation of new methods is essential for the effective transfer of new technology from the research laboratory to practical use. This committee has identified four essential validation resources: chemical bank(s), cell and tissue banks, a data bank, and reference laboratories. We recommend the creation of a Scientific Advisory Board of experts in toxicity testing, representing the academic, industrial and regulatory communities. Test validation acceptance is contingent upon broad buy-in by disparate groups in the scientific community: academia, industry and government. We believe that this can be achieved by early and frequent communication among the parties and agreement upon common goals. The committee hopes that the creation of a validation infrastructure built with the elements described in this report will facilitate scientific acceptance and utilization of alternative methodologies and speed implementation of reduction, refinement and replacement alternatives in toxicity testing.
Drug-Induced Lung Toxicity
Authors: Hollinger Mannfred A.
Published: February 2008

The number of blood-borne chemotherapeutic agents implicated in drug-induced lung toxicity continues to increase, although problems in detection remain. The initiation of drug-induced lung injury can have an immunologic or nonimmunologic basis. If endothelial cells are injured, interstitial pulmonary edema may result. Regardless of the source of injury, the progression of drug-induced lung toxicity is often quite similar, involving (1) parenchymal damage, (2) recruitment of inflammatory cells, and (3) progression of the inflammatory process. If the inflammatory reponse is sufficiently severe and disperse, increased collagen can be deposited in interstitial and intra-alveolar areas. The resulting attenuation of gas exchange can induce dyspnea and possibly death. Recent research suggests mediation of the fibrogenic process via cytokines such as transforming growth factor-β and tumor necrosis factor. Preliminary results demonstrating amelioration of cytokine mediated lung-induced fibrosis in animal models with appropriate antibodies suggest a possible future modality of therapy. Certain amphiphilic drugs are capable of eliciting a more specific form of lung toxicity. This class of drugs can interfere with phospholipid metabolism in pulmonary macrophages. In these cases, phospholipidosis results from phospholipid accumulation. The physiologic sequelae in human phospholipidosis is still uncertain.
Cutaneous Anaphylaxis Induced by 4-Quinolone Antibacterials in Guinea Pigs
Authors: Fort Farrel L. , Hahn Ken
Published: February 2008

Several 4-quinolone antibacterials (norfloxacin HCl, enoxacin, ofloxacin, cinoxacin, ciprofloxacin, and nalidixic acid) were administered intradermally to male and female hairless guinea pigs (Crl:IAF(HA)BR). Immediately prior to the intradermal injection, the guinea pigs were given an intravenous injection of Evans blue dye. The diameter of the blue spots at the sites of intradermal injection 15 to 30 minutes after intradermal injection were used as a measure of cutaneous anaphylactoid activity. The quinolones were given in concentrations ranging from 0.009 to 4.0 mg/mL. Compound 48/80 was used as a positive control, and saline was used as the negative control. All the 4-quinolones tested, except nalidixic acid, were positive for cutaneous anaphylactoid activity. Norfloxacin, enoxacin, and ciprofloxacin were positive at concentrations of 0.13 mg/mL or higher. Ofloxacin and cinoxacin were positive at concentrations of 2.0 mg/mL or higher. Pretreatment with the H1 blocker, chlorpheniramine maleate, resulted in diminished responses. These results demonstrate the potential for adverse cutaneous anaphylactoid reactions, presumably due to release of vasoactive mediators, with 4-quinolone antibacterials, and illustrate a simple method to screen new compounds for this activity.