bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategic Use of Immunosuppressants and Anti-TNF in Inflammatory Bowel Disease
Authors: Louis Edouard
Published: September 2013

Controlled trials and meta-analyses have shown that immunosuppressants are effective in steroid-dependent Crohn's disease (CD) and, although less well demonstrated, ulcerative colitis (UC). It has also been demonstrated that anti-TNF are effective in steroid-dependent and steroid-refractory CD and UC. Anti-TNF can also decrease hospitalization rate and the need for surgery. This seems also to be the case for immunosuppressants. The early use of anti-TNF seems more effective than later use, and early mucosal healing is associated with decreased rate of surgery. On the contrary, early use of purine analogues does not seem to improve outcome in CD. Anti-TNF therapies have been shown superior to immunosuppressants and combination therapy superior to anti-TNF monotherapy in inducing steroid-free remission and mucosal healing. The main strategic questions which remain at this stage include: When to start immunosuppressants or anti-TNF? Is there still a place for immunosuppressant monotherapy? How to optimize anti-TNF? Is it possible to stop anti-TNF? The main justification of immunosuppressant monotherapy is the low cost of this treatment and the possibility of achieving a very stable and long-standing remission in a subset of patients. According to this and provided there is no rapid need for more effective therapy, this treatment could be tried in any inflammatory bowel disease patient not correctly maintained after a course of steroids and 5-aminosalicylic acid. However, the failure to respond to this treatment should be recognized early and a step up to anti-TNF considered. An anti-TNF treatment should be considered early in patients at risk of rapid evolution towards tissue damage and complications. The benefit/risk of the immunosuppressant + anti-TNF combination therapy should be assessed on a case-by-case basis. Anti-TNF treatment should always be fully optimized by adapting dosage and potentially adding an immunosuppressant before considering treatment failure. Treatment de-escalation should only be considered when a long-standing stable remission has been achieved both clinically and biologically. The cost sparing and theoretical decrease in complication risk should be put in perspective with the risk of relapse and disease progression.
Challenging Question: Is Treating Inflammatory Bowel Disease an Art or Strictly an Evidence-Based Matter?
Authors: Khanna Reena , Mosli Mahmoud H. , Feagan Brian G.
Published: September 2013

Although evidence-based medicine (EBM) is the gold standard for clinical practice, misconceptions among health care providers regarding EBM are common. The medical management of inflammatory bowel diseases (IBD) has advanced substantially over the last 20 years as a direct result of the wealth of new evidence generated by randomized controlled trials. Integrating EBM and traditional clinical skills results in optimal care tailored to the individual patient. This article addresses the role of EBM in the management of IBD and dispels some of the common misconceptions about the use of EBM in practice.
Perforating Crohn's Disease: Conservative and Surgical Treatment
Authors: Sampietro Gianluca M. , Casiraghi Silvia , Foschi Diego
Published: September 2013

Surgery is a part of the clinical history of patients with Crohn's disease (CD) since nearly all the patients receive at least one surgical procedure. The main indication for surgery is obstruction, but 50-60% of patients present a concomitant perforating disease at surgery, and 10% of patients have a primary indication for abscess or fistula. Generally, fistulas are classified on an anatomical basis, indicating the site of origin followed by the target (i.e. ileocolic, ileovesical, etc.). Enteroenteric fistulas are frequently asymptomatic and are not always considered an indication for surgery. However, in case of bypass with severe malnutrition or bacterial overgrowth (i.e. duodenal involvement), surgery is the only option. Enterovesical, enteroureteral and enterobiliary fistulas, due to their potential for septic complications, are a definite indication for surgery. Enterogenital fistulas have an indication mainly for their impact on the quality of life. Enterocutaneous fistulas are, in most cases, a late surgical complication, and the indication and timing for treatment are due to their output volume. Abscesses may be present alone or in association with enteric fistulas. The initial approach is conservative, and a percutaneous drainage should be a good treatment or a bridge to elective surgery. Since a modern surgical approach to CD has to be minimally invasive and highly conservative whenever possible, the presence of perforating disease should be well characterized in order to plan a laparoscopic approach and to reduce the amount of resected bowel, in case combining resection and strictureplasty. Perforating CD necessitates a multidisciplinary approach involving, behind the gastroenterologist and the surgeon, the radiologist, the urologist, the gynecologist and the nutritionist in order to obtain the best tailored treatment.
Management of Postoperative Recurrence of Crohn's Disease
Authors: van Lent Anja U. , D'Haens Geert R.
Published: September 2013

The course of Crohn's disease (CD) is unpredictable and potentially destructive. The percentage of patients requiring surgery at some stage in their disease accumulates to over 70%. After resection of the affected intestine, reappearance of CD occurs in the majority of patients. Prophylactic medical therapy to reduce the rate of postoperative recurrence has been proven to be effective, yet the incidence of recurrence remains high. Patient profiling (risk stratification) is important in this postoperative setting. High-risk patients (associated with e.g. smoking, the need of repetitive surgery and penetrating disease) require strong immunosuppressive treatment, which should be commenced immediately after surgery, when recurrent disease activity begins. Additionally, early screening endoscopy should be performed to monitor treatment effect. The efficacy of thiopurines is shown to be higher than mesalazine or imidazole antibiotics alone for preventing and ameliorating endoscopic recurrence of CD postoperatively; however, anti-tumor necrosis factors (anti-TNFs) are increasingly considered the most potent agents. In patients with a risk factor for early postoperative recurrence, the first line of treatment is 6-mercaptopurine, in combination with imidazole antibiotics if tolerated, followed by anti-TNFs. When lesions are found at colonoscopy, therapy should be upscaled. We propose a treatment algorithm to direct therapeutic management of CD postoperatively.
Managing IBD Outside the Gut: Ocular Manifestations
Authors: Calvo P. , Pablo L.
Published: September 2013

Extraintestinal manifestations are common in inflammatory bowel disease (IBD), being reported in over 25% of patients. Ocular complications of IBD occur in around 10% of cases, but may precede systemic symptoms and are usually nonspecific. Complications of therapy, such as cataracts or glaucoma from steroid use or keratoconjunctivitis sicca related to 5-aminosalicylic acid medications, may also involve the eyes. The pathogenesis remains unclear, but factors such as the extent of intestinal disease, disease activity, and the presence of associated arthritis have been associated with ocular involvement. Conjunctivitis, episcleritis, scleritis and uveitis are by far the most common ophthalmic complications of IBD. However, posterior uveitis, intraretinal hemorrhages, vasculitis, choroiditis, optic neuropathy, and vaso-occlusive phenomena may also occur. The most frequent severe ocular manifestation is anterior uveitis (more common in women). It usually presents as a mild anterior nongranulomatous uveitis (60% of the cases). The inflammation in the eye and the inflammation in the gut are rarely correlated. Patients with uveitis, scleritis, and other anterior segment inflammation usually respond to steroids (topical, periocular or systemic). If the inflammation is resistant to steroids, or if appreciable steroid adverse effects are encountered, systemic immunosuppressive treatment should be considered; this is more likely in HLA-B27-positive patients with uveitis. Evaluation of the eye should be a routine component in the care of patients with IBD.
Use of Immunosuppressants and Biologicals in Patients with Previous Cancer
Authors: Beaugerie Laurent
Published: September 2013

Thiopurines promote Epstein-Barr virus-related lymphomas, nonmelanoma skin cancers and acute myeloid leukemias. Anti-tumor necrosis factor (anti-TNF) agents may inhibit or activate carcinogenesis according to the cellular pathways that are activated. A mild increase in the risk of melanoma has been reported in patients exposed to anti-TNF agents. Transplanted patients with previous history of cancer are at high risk of cancer recurrence when receiving posttransplant immunosuppressive therapy, particularly within the first 2 years of treatment. Few data exist for patients with chronic inflammatory disease. In the CESAME cohort that included essentially patients receiving thiopurines, there was no excess incidence of recurrent or new cancer associated with exposure to immunosuppressive therapy in the patients with previous cancer at cohort entry. In clinical practice, the decision to start or resume immunosuppressive therapy in inflammatory bowel disease (IBD) patients with recent cancer should be discussed case by case with cancer specialists. However, taken into account the experience of transplant specialists, it could be suggested not to consider a waiting period for women with adequately treated uterine high-grade cervical dysplasia. For invasive cancers, a waiting period of 2 years should be considered if possible. During this period, treatment of IBD should be restricted to 5-aminosalicylic acid, steroids, nutritional therapy, or surgery, except in case of aggressive IBD that cannot be controlled by these methods. A longer waiting period of 5 years could be recommended for the most aggressive forms of cancers, such as melanomas, aggressive breast cancers, sarcomas, urinary tract cancers, and myelomas.
Cross-Sectional Imaging Modalities in Crohn's Disease
Authors: Allocca Mariangela , Fiorino Gionata , Danese Silvio
Published: September 2013

The standard tools assessing the activity of Crohn's disease (CD) measure the severity of symptoms (the Crohn's Disease Activity Index) or the degree of endoscopic lesions (the Crohn's Disease Endoscopic Index of Severity, the Simplified Endoscopy Score), not the global bowel damage. It is necessary to find new instruments able to assess the structural and functional damage to the intestine and the progression over time. We reviewed recent publications on the accuracy of abdominal ultrasound (US), computed tomography enterography (CTE), and magnetic resonance imaging enterography (MRE) for the assessment of CD. US, CTE and MRE have been shown to have a high and comparable diagnostic accuracy for both the diagnosis and complications of CD, but US and MRE have the major advantage of not imparting ionizing radiation. In summary, findings from these imaging modalities with endoscopic lesions and surgical history incorporating into the Lémann score will allow measuring the global bowel damage at specific time and the progression of disease over time and assessing the impact of different strategies.
Autologous Meatal Skin Graft Implantation and Intratympanic Injection of Pseudomonas aeruginosa: A New Experimental Mouse Model of Acquired Middle Ear Cholesteatoma
Authors: Si Yu , Chen Yu Bin , Chen Qia Xin , Liu Yi , Jiang Huai Li , Zhang Zhi Gang , Huang Xi
Published: September 2013

Aim: To create an experimental model for the biomedical research of middle ear cholesteatoma. Methods: Cholesteatoma was induced in the right ears of mice. An autologous meatal skin graft was implanted into the middle ear via the tympanic membrane followed by an intratympanic injection of Pseudomonas aeruginosa. Six weeks after surgery, the formation of acquired cholesteatoma was evaluated by macroscopic examination, CT scan, and histological analysis. The expressions of TNF-α, IL-1β, and IL-6 were measured with real-time PCR. Auditory-evoked brain stem response was used for assessing the changes in hearing levels. Results: None of the mice died during the modeling time. By the sixth postoperative week, cholesteatoma had successfully formed in 23 out of 25 mice, which equals a success rate of 92%. A CT scan revealed that the cholesteatoma was eroding the cochlea. Furthermore, histological analysis demonstrated a cystic structure covered by stratified squamous epithelium and keratin desquamation in the lamellae inside the cystic cavity in the bullae. All mice with experimentally induced cholesteatoma showed hearing impairment and an upregulated expression of TNF-α, IL-1β, and IL-6. Conclusion: The present study successfully developed a mouse model of acquired middle ear cholesteatoma, which provides an extremely valuable tool for auditory and biomedical research. The modeling approach is technically easy and has a high success rate.
Pyloric Gland Adenoma: A Case Report
Authors: Çakar Ekrem , Bayrak Savaş , Paşaoğlu Esra , Çolak Şükrü , Bektaş Hasan , Güneyi Ayhan
Published: September 2013

Endoscopic procedures are the gold standard in identifying, monitoring and treating gastrointestinal system lesions. The evaluation of benign, precancerous and malignant characteristics of these lesions requires good endoscopic inspection and precise pathological examination. Pyloric gland adenoma is a rare precancerous lesion defined in recent years and herein is reviewed in the present case along with the literature.
Liver Unidentified Bright Object in a Septic Patient
Authors: Peternac Daniel , Patak Michael Andreas , Gubler Christoph
Published: September 2013

The typical sonographic appearance of liver hemangiomas is a well-demarcated hyperechoic mass with homogeneous echodensity. Focal liver lesions may change their ultrasound characteristics over time. We present a case of dynamic pattern of liver hemangiomas during a state of systemic inflammation.
Causal Evidence that Rotational Moisture Advection is Critical to the Superparameterized Madden–Julian Oscillation
Authors: Pritchard Michael S. , Bretherton Christopher S.
Published: September 2013

The authors investigate the hypothesis that horizontal moisture advection is critical to the eastward propagation of the Madden–Julian oscillation (MJO). Consistent diagnostic evidence has been found in recent MJO-permitting global models viewed from the moisture-mode dynamical paradigm. To test this idea in a causal sense, tropical moisture advection by vorticity anomalies is artificially modulated in a superparameterized global model known to produce a realistic MJO signal. Boosting horizontal moisture advection by tropical vorticity anomalies accelerates and amplifies the simulated MJO in tandem with reduced environmental gross moist stability. Limiting rotational horizontal moisture advection shuts the MJO down. These sensitivities are robust in that they are nearly monotonic with respect to the control parameter and emerge despite basic-state sensitivities favoring the opposite response. Speedup confirms what several diagnostic lines of evidence already suggest—that anomalous moisture advection is fundamental to MJO propagation. The rotational component is shown to be especially critical. Amplification further suggests it may play a role in adiabatically maintaining the MJO.
GNSS Radio Occultation Constellation Observing System Experiments
Authors: Bauer Peter , Radnóti Gábor , Healy Sean , Cardinali Carla
Published: September 2013

Observing system experiments within the operational ECMWF data assimilation framework have been performed for summer 2008 when the largest recorded number of Global Navigation Satellite System (GNSS) radio occultation observations from both operational and experimental satellites were available. Constellations with 0%, 5%, 33%, 67%, and 100% data volume were assimilated to quantify the sensitivity of analysis and forecast quality to radio occultation data volume. These observations mostly constrain upper-tropospheric and stratospheric temperatures and correct an apparent model bias that changes sign across the upper-troposphere–lower-stratosphere boundary. This correction effect does not saturate with increasing data volume, even if more data are assimilated than available in today’s analyses. Another important function of radio occultation data, namely, the anchoring of variational radiance bias corrections, is demonstrated in this study. This effect also does not saturate with increasing data volume. In the stratosphere, the anchoring by radio occultation data is stronger than provided by radiosonde and aircraft observations.
Evaluation of Various Approximations in Atmosphere and Ocean Modeling Based on an Exact Treatment of Gravity Wave Dispersion
Authors: Dukowicz John K.
Published: September 2013

Various approximations of the governing equations of compressible fluid dynamics are commonly used in both atmospheric and ocean modeling. Their main purpose is to eliminate the acoustic waves that are potentially responsible for inefficiency in the numerical solution, leaving behind gravity waves. The author carries out a detailed study of gravity wave dispersion for seven such approximations, individually and in combination, to exactly evaluate some of the often subtle errors. The atmospheric and oceanic cases are qualitatively and quantitatively different because, although they solve the same equations, their boundary conditions are entirely different and they operate in distinctly different parameter regimes. The atmospheric case is much more sensitive to approximation. The recent “unified” approximation of Arakawa and Konor is one of the most accurate. Remarkably, a simpler approximation, the combined Boussinesq–dynamically rigid approximation turns out to be exactly equivalent to the unified approximation with respect to gravity waves. The oceanic case is insensitive to the effects of any of the approximations, except for the hydrostatic approximation. The hydrostatic approximation is inaccurate at large wavenumbers in both the atmospheric and oceanic cases because it eliminates the entire buoyancy oscillation flow regime and is therefore to be restricted to low aspect ratio flows. For oceanic applications, certain approximations, such as the unified, dynamically rigid, and dynamically stiff approximations, are particularly interesting because they are accurate and approximately conserve mass, which is important for the treatment of sea level rise.
Socially Responsible Investment in France
Authors: Crifo Patricia , Mottis Nicolas
Published: September 2013

Socially responsible investment (SRI) in France is based on a “best in class” approach as opposed to the “exclusion” approaches used in other countries such as the United States or United Kingdom, where the rejection of sin stocks has been dominant historically. The objective of this research note is to examine whether the French SRI market, by focusing more on financial rather than on ethical considerations, compared with other countries such as the United States, the United Kingdom, or even Sweden, may lead to a form of “mainstreaming” of SRI processes. The authors explore several convergent mechanisms. First, the authors analyze the importance of the mainstreaming issue in the history of SRI as well as in the contemporaneous debate in the academic literature on the links between financial and extrafinancial (SRI) performance. Second, the authors review the role played by ethical finance laws adopted in France in the early 2000s in the development of the SRI market. Finally, the authors discuss the results of a survey of French SRI analysts working both for large institutional investors and asset managers in France in 2009.
Transferring Control to Others
Authors: Morgan Leslie A. , Brazda Michael A.
Published: September 2013

This study examines qualitative data describing transfers of control over life tasks (e.g., managing money, overseeing care) to close others in terms of the control by and outcome for the older person. The extant caregiving literature includes limited focus on how such task transfers occur, who controls them, and the reactions of older adults. The literature on control, however, provides extensive data that declining control has negative outcomes. Employing data from interviews with 77 adults in assisted living settings, narratives were identified where task transfers were discussed. These 26 instances were reviewed by the authors and categorized as chosen or not chosen by the older adult and their reactions categorized as positive, negative or neutral; if the initial narrative segment was ambiguous, further reading of the informant’s interview or that of a family member were added to better understand these cases. Findings show that chosen transfers of tasks to children or others were linked with a positive reaction in all instances identified, while a majority of cases where tasks were taken over by others, the reactions were negative. While literature suggests that declining control is linked to negative outcomes, our findings suggest that the process involved when tasks are transfer to others (delegated or taken by them) may be an important, under-investigated element with potential implications for future research and practice.
Response of the Pulmonary Surfactant System To Phosgene
Authors: Frosolono M.F. , Currie William D.
Published: September 2013

Rats were exposed to 240 ppm·min phosgene (1.0 ppm for 4 hrs) in a Rochester-type chamber. At intervals thereafter over a 4 day period, lungs were removed for determination of wet weight; total, microsomal and surfactant protein concentrations; surfactant phospholipid concentrations; and 1-acyl-2-lyso-phosphatidylcholine: palmitoyl-CoA acyl transferase activity. Immediately upon termination of the phosgene exposure, microsomal protein and acyl transferase activity were reduced below, and lung wet weight was elevated above, control levels. From Day 1 through Day 3 after the exposure, all measured parameters, except for the phosphatidylinositol constituent of the surfactant fraction, were increased above the control values. In general, maximum levels were observed on Day 2; however, the acyl transferase activity and surfactant concentration continued to increase on Day 3. The results suggest (a) components of the pulmonary surfactant system may be involved in maintenance of pulmonary fluid balance and (b) the presence of excess water in the lungs as a result of phosgene exposure may represent a signal for increased synthesis of anti-edematogenic materials in order to promote removal of the inappropriate fluid.
Therapeutic Strategy in Phosgene Poisoning
Authors: Diller Werner F.
Published: September 2013

For the treatment of phosgene poisoning, glucocorticoids and positive pressure ventilation can be recommended as well as supporting measures such as physical rest, antitussives, buffers, sedatives, antibiotics, antispasmodics and possibly diurectics. Roentgenological evaluation of the lungs is advisable. A therapeutic strategy is presented which is based on the phosgene exposure intensity.
New Risk Assessment Initiatives in Epa
Authors: Anderson Elizabeth L. , Ehrlich Alan M.
Published: September 2013

This paper describes EPA's recent efforts to ensure consistency and technical competence of the agency's risk assessments. These include five risk assessment guidelines proposed in November 1984 and January 1985 and establishment of a Risk Assessment Forum. The technical provisions of the five guidelines have been outlined.
Novel Methods for the Estimation of Acceptable Daily Intake
Authors: Dourson Michael L. , Hertzberg Richard C. , Hartung Rolf , Blackburn Karen
Published: September 2013

This paper describes two general methods for estimating ADIs that circumvent some of the limitations inherent in current approaches. The first method is based on a graphic presentation of toxicity data and is also shown to be useful for estimating acceptable intakes for durations of toxicant exposure other than the entire lifetime. The second method uses dose-response or dose-effect data to calculate lower CLs on the dose rate associated with specified response or effect levels. These approaches should lead to firmer, better established ADIs through increased use of the entire spectrum of toxicity data.
Structure-Activity Considerations in Risk Assessment: a Simulation Study
Authors: Lavenhar Steven R. , Maczka Carol A.
Published: September 2013

The use of quantitative structure-activity relationships (QSAR) is considered with respect to estimating the carcinogenic risk of untested chemicals. SAR derived from a retrospective classification of a series of aromatic amines were used to study the estimation of carcinogenic risk by analogy. Using pattern recognition methods, a series of molecular descriptors were developed for a data set of aromatic amines that supported a linear discriminant function capable of separating compounds testing positively for carcinogenicity from those testing negatively. Linear discriminant analysis correctly categorized the compounds as positive or negative in 94.9% of the cases. For each aromatic amine within the subset of positive compounds, the most appropriate analogue was identified using physicochemical, topological, geometric and electronic molecular descriptors as variables. An upper-limit unit risk estimate was calculated for each compound that was a positive carcinogen within the data set using the linearized multistage model. The actual risk and the risk estimated by analogy to a congener were compared for each compound within the positive subset. The results support estimating both qualitative and quantitative carcinogenic risk by analogy for this particular data set.
Development of an Acceptable Factor To Estimate Chronic End Points From Acute Toxicity Data
Authors: Venman Bradly C. , Flaga Christine
Published: September 2013

Acceptable daily intake (ADI) values are routinely developed for threshold toxicants from NOAELs determined from human or animal chronic or subchronic data. These NOAELs are then divided by appropriate uncertainty factors ranging from 10 to 1000 depending on the quality of the data. However, for the vast majority of chemicals used industrially, adequate toxicity data needed to use this process are not available. Thus, a procedure to estimate a chronic toxicity endpoint from acute toxicity data, such as an oral rat LD50, becomes necessary. An acute-to-chronic application factor of 0.0001 was developed, which when multiplied by an oral LD50 for an individual chemical, yields a surrogate chronic NOAEL. This figure can then be used to estimate an acceptable daily exposure for humans. The process used to estimate this application factor is detailed.
Issues On Health Risk Assessment At Hazardous Waste Sites and Resource Recovery Facilities in Region Ii
Authors: Cam Vinh
Published: September 2013

This paper examines the issues involved in health risk assessments at hazardous waste sites and resource recovery facilities in Region II and emphasizes the programmatic aspects of the problem and the integration of risk assessment into the permitting process for these facilities. Suggestions for the R&D agenda and policy needs to support a risk assessment strategy in this area are also discussed.
The Behavioral Effects of Prenatal and Early Postnatal Lead Exposure in the Primate Ma Ca Ca Fascicularis
Authors: Hopper David L. , Kernan William J. , Lloyd W. Eugene
Published: September 2013

Female Macaca fascicularis monkeys were given daily oral doses of 3.0 and 4.25 mglkg lead, as lead nitrate, prior to breeding, and exposure was maintained throughout gestation and terminated at parturition. No overt signs of lead toxicity were observed in the maternal monkeys. The offspring were tested at 6 to 18 months of age on a three-choice non-spatial form discrimination paradigm, and at 19 to 26 months of age on a response inhibition task. When compared to controls, the lead-exposed infants showed a deficit in form discrimination performance which continued during the entire period of testing. A deficit in response inhibition performance was also observed in exposed infants when compared to controls. How ever, the deficit was temporary, as the performance of all groups was similar at the termination of testing. The observation of a per sistent deficit in form discrimination up to 18 months following the termination of exposure suggests that lead-induced behavioral changes may be permanent. These findings are cause for concern since behavioral deficits in the offspring were observed at maternal gestational whole blood lead levels within a concentration range (30 to 70 μg/dl) associated with occupational exposure.
A Composite Model for Multiple Assays of Skin Irritation
Authors: Cruzan George , Dalbey Walden E. , D'Aleo Christopher J. , Singer Edward J.
Published: September 2013

A model for skin irritation was developed for simultaneous evalua tion of the influence on irritation of abrasion, occlusion, and dura tion of treatment and for fulfillment of requirements for labeling considerations under DOT, CPSC-FHSA, OSHA, and EEC. This model greatly reduces the number of animals required to address submissions under multiple agencies compared to performing each test separately. In this model, which we have called a Composite Skin Irritation test, a test material is placed on three pairs of intact and abraded sites on each rabbit; one pair of sites is occluded for 4 hours, one for 24 hours, and the other left unoccluded for 24 hours.

Results are presented from 88 composite tests with 80 petroleum- related materials. For the materials tested, abrasion of the skin had no effect on the irritation response. Occlusion of the test site gener ally did not result in dramatic increases in response, except for petroleum refinery streams with a boiling range below 500° F. Exposure for 4 hours rather than 24 hours generally resulted in less irritation; however, for individual compounds, -the irritation from the 4-hour exposure could not be predicted from the response to the 24-hour exposure. Of the 80 materials tested, 12 would be labeled as skin irritants under CPSC guidelines, three under OSHA, and 20 under EEC. Of the 20 that would be labeled under EEC criteria, only seven would be labeled under CPSC criteria. At least for petroleum-related materials, results from skin irritation studies performed under one set of conditions cannot be used to predict the degree of irritation that would be produced under a dif ferent set of exposure conditions.
Peroxisome Induction Studies On Seven Phthalate Esters
Authors: Barber Eugene D. , Astill Bernard D. , Moran Elizabeth J. , Schneider Bernard F. , Gray Tim J.B. , Lake Brian G. , Evans John G.
Published: September 2013

Seven phthalate esters, representing a variety of chain lengths and degrees of branching in the alcohol moiety, were tested for their ability to produce peroxisome proliferation in the Fischer 344 rat. Di(2-ethylhexyl)adipate (DEHA) was tested using the same protocol and di(2-ethylhexyl)phthalate (DEHP) was run with each study as an internal control. Each ester was administered in the feed for a period of 21 days at levels of 2.5%, 1.2% and either 0.6% or 0.3%. DEHP and DEHA were also fed at levels of 0.1% and 0.01%. The animals were sacrificed and samples of liver were prepared for both light and electron microscopy. Serum samples were assayed for both triglyceride and cholesterol. The remaining portion of the liver was homogenized and assayed for cyanide-insensitive palmitoyl-CoA oxidation, lauric acid 11-hydroxylase and lauric acid 12-hydroxylase. The results show that there is approximately a ten-fold difference between the weakest and strongest esters in terms of their potency to induce changes in relative liver weight and in several of the biochemical parameters. In general, the longer chain esters were more potent than the shorter chain ones, and branched chain esters seemed more potent than straight. Several statistical analyses of the dataset have been performed and all render similar conehcsions. The results of one of these evaluations are presented elsewhere in this volume (Lin, 1987).
The Use of Multivariate Analysis To Compare Peroxisome Induction Data On Phthalate Esters in Rats
Authors: Lin Lawrence I-Kuei
Published: September 2013

This paper contains statistical evaluations of the effect of 9 different plasticizers on rat hepatic peroxisome proliferation. There were 9 21-day feeding studies with one plasticizer in each study. The plasticizers are: di(2-ethylhexyl)phthalate (DEHP), butyl benzyl phthalate (BBP), 711 phthalate (711P), di(n-butyl)phthalate (DBP), di(undecyl)phthalate (DUP), di(isodecyl)phthalate (DIDP), di(isononyl)phthalate (DINP), 610 phthalate (610P), and di(ethylhexyl)adipate (DEHA). For each plasticizer, several dosage (as % of diet) groups, plus a negative control group (0%) and a reference control group (1.2% DEHP) were included. There were 5 males and 5 females, approximately 5 weeks old, per group per plasticizer, for a total of 470 animals.

For each animal, body weight and food intake ivere measured prior to treatment and twice a week during the treatment period. Animals were necropsied at the end of the 21-day treatment period. Selected organs and blood samples of each animal were collected for measuring hepatic enzymes, proteins, fat stains, organ weights and serum fats. The endpoints included electron microscopy examination of liver peroxisome proliferation and liver histological abnormalities. The statistical evaluation utilized a multivariate approach that condensed a cornplex phenornenon into certain meaningful and simple endpoints for quantitative comparisons. The dose of each plasticizer that would protect 99% and 99.9% of rats against peroxisome proliferation (xx% statistically predicted dose, or xx% SPD) was estimated.

Marked differences were seen in the ability of the 9 test conipoziilds to cause hepatic peroxisome proliferation in rats. The graphic ranking of overall potency is, in order from most potent to least potent: DEHP, DIDP, DINP, DBP, DEHA, DUP, BBP, 711P and 610P. The ranking in terms of 99.9% SPD is: DEHP, DINP, DIDP, DBP, 610P, DUP, DBP, 711P and DEHA. It was also found that the histological findings of reduced basophilia or increased eosinophilia were highly correlated with peroxisome proliferation (r = 0.94). The other histological findings were incidental observations for specific plasticizers.
Health Among Municipal Sewage and Water Treatment Workers
Authors: Scarlett-Kranz Janet M. , Babish John G. , Strickl Daniel , Lisk Donald J.
Published: September 2013

Municipal sewage treatment plant workers are potentially exposed to a multitude of industrial chemicals and pathogenic microorga nisms. A questionnaire survey of working habits, lifestyle and symptoms of illness was conducted among 189 municipal sewage treatment plant workers processing between three and ten million gallons of wastewater daily in 16 plants in New York State between March and July of 1984. Water treatment plant workers in the same cities comprised the comparison group. Sewage workers reported a significantly higher frequency of headache, dizziness, sore throat, skin irritation and diarrhea within the month imme diately preceding receipt of the questionnaire, after controlling for various possible confounders. Eye and skin irritation were signifi cantly associated with exposure to mutagens. The health signifi cance of these findings and possible sources of error in assessing risk are discussed.
Immunogenetically Controlled Autoimmune Reactions Induced by Mercury, Gold and D-Penicillamine in Laboratory Animals: a Review from the Vantage Point of Premarketing Safety Studies
Authors: Balazs Tibor
Published: September 2013

Mercury and gold salts as well as d-penicillamine can cause glome rulonephritis by an autoimmune mechanism in man. The suscepti bility to this effect of these chemicals is controlled by the genes of the major histocompatibility complex (MHC). The presence of cer tain alleles confers sensitivity. The role of MHC-linked genes has been demonstrated also in the rat and mouse in the development of autoimmunity induced by these chemicals. While Brown Norway rats and AS W mice were sensitive, several other strains were resist ant. Also an interaction of MHC with background genes has been shown in determination of the response to HgCl2. In conventional toxicity studies, use of a single inbred strain of laboratory animals obviously handicaps the detection of a reaction of this nature.
Chronic Carcinogenesis Studies of Acrolein and Related Compounds
Authors: Lijinsky William , Reuber Melvin D.
Published: September 2013

Acrolein and two of its more stable derivatives, the oxime and the diethylacetal, and the related allyl alcohol were given in drinking water to groups of 20 male and 20 female F344 rats at doses close to the maximum that could be tolerated by the animals, for most of their lifetime. Acetaldoxime served as a control for the hydroxy lamine derivative of acrolein. Most of the tumors were common in untreated rats of this strain. Only adenomas of the adrenal cortex in females were more numerous than in untreated controls. Acro lein itself was too toxic to hamsters to conduct a carcinogenesis study. Acrolein oxime, acrolein diethylacetal and allyl alcohol were all quite toxic to hamsters, but 2 mg per week by gavage was toler ated by groups of 20 male Syrian hamsters. There was a small number of tumors of the pancreatic ducts and of the forestomach in the treated hamsters, but the incidence was not statistically sig nificant.
Summary Review of the Health Effects Associated With Phenol
Authors: Bruce Robert M. , Santodonato Joseph , Neal Michael W.
Published: September 2013

Phenol, a monohydroxy derivative of benzene, occurs naturally in animal waste and by decomposition of organic wastes. It is also produced by man, originally by fractional distillation of coal tar, but more recently by cumene hydroperoxidation and toluene oxi dation. As a result of large production volume and natural sources, occupational and environmental exposure to phenol is likely. Phenol poisoning can occur by skin absorption, vapor inhalation, or ingestion, and, regardless of route of exposure, can result in det rimental health effects. Acute toxicity has been observed in man and experimental animals, resulting in muscle weakness, convul sions, and coma. In addition, studies have shown that although teratogenic effects have not been associated with exposure to phenol by either inhalation or oral route, high doses of phenol are fetotoxic. This paper addresses these studies and others in an attempt to determine if human health is at risk to those levels of phenol present in the environment and workplace. However, because data are limited, further research is necessary to analyze the mutagenic and carcinogenic potential of this chemical.
A Human Cell Beryllium Acute Toxicity Assay
Authors: Clarke S.M. , Barrick C.W.
Published: September 2013

A rapid, inexpensive beryllium acute toxicity assay using human erythrocyte ATP levels has been developed. The assay uses a photometric measurement of the luciferin-luciferase reaction in erythrocytes incubated in HEPES buffer with the tested toxicant. Incubation in HEPES significantly increases the sensitivity of erythrocytes to beryllium when compared to incubation in either plasma or physiological saline. After a one-hour incubation period in HEPES buffer and beryllium there is a loss of 50% of the erythrocyte A TPat 3 μg/ml of beryllium, and an 80% loss of ATP at 5 μg/ml of beryllium. The source of human erythrocytes does not appear to influence the test. Erythrocytes from 10 individuals, one with chronic beryllium disease and another with an acute sensitivity to beryllium, all gave similar biphasic dose-response curves to beryllium.
Epidemiology of Chronic Occupational Exposure To Formaldehyde: Report of the Ad Hoc Panel On Health Aspects of Formaldehyde
Authors:   Universities Associated for Research and Education in Pathology, Inc
Published: September 2013

An independent, international panel of scientists reviewed and evaluated the relevant literature on occupational and environmental exposure to formaldehyde and subsequent epidemiology of cancer in exposed populations. Studies of topical sites (respiratory tract and skin) were considered separately from non-topical sites (other major organ systems) and individual assessments were made of evidence of site-specific cancer risk within the broader categories. In addition to the studies per se, the Panel also took into account critiques and reviews of the published reports. The Panel concluded that: 1) for no malignancy in man is there convincing evidence of a relationship with formaldehyde exposure and 2) furthermore, that if a relationship does exist, the excess risk, in absolute terms, must be small. An apparent lack of consistency among the studies in site-specific cancer risk and uncertainty resulting from unresolved confounding by known risk factors were identified by the Panel as significant obstacles to more definitive conclusions.
Applicability of Cancer Risk Assessment Techniques To Other Toxic Effects
Authors: Gaylor David W.
Published: September 2013

The purpose of this paper is to investigate the applicability of cancer risk assessment techniques to other endpoints. The discussion is limited to the problem of high to low dose extrapolation. Although developed to describe cancer data, the multistage model has a general sigmoidal shape which makes it amenable to describe the dose-response of many non-cancer endpoints. At low doses the multistage model is essentially a general polynomial model. Low-dose linear extrapolation provides an upper limit on convex (curving upward) dose-response curves. Low-dose linearity is expected if exposure to a toxic substance augments a disease process which is already operating in unexposed animals. Incorporation of pharma. cokinetic information may prove useful in simplifying dose-response relationships and may result in lower estimates of risk. A descriptive model can be used to estimate a lower confidence limit on a dose expected to produce a disease incidence, for example, of 1% of the animals (LED01). Then, the LED01/100 provides an estimate of the dose for which the risk is estimated to be less than 10-4. It appears that some of the techniques used for cancer risk assessment can be used or modified for quantal non-cancer endpoints.
Personal and Indoor/Outdoor Nitrogen Dioxide Exposure Assessments of 23 Homes in Taiwan
Authors: Chan Chang-Chuan , Yanagisawa Yukio , Spengler John D.
Published: September 2013

Indoor and outdoor nitrogen dioxide (NO2) concentrations of 23 homes from two areas in Taiwan, the city of Taipei and a rural village in central Taiwan, were measured concurrently from December 1987 to January 1988. NO2 measurements were carried out by Palmes tube for one week and filter badges for two days. In Taipei, the mean NO2 concentrations outdoors, in the kitchens, in the livingrooms, and in the bedrooms were 40.1 ppb, 34.4 ppb, 32.1 ppb, and 29.7 ppb for one week, and were 25.7 ppb, 25.6 ppb, 22.6 ppb, and 20.5 ppb for two days. In the village of central Taiwan, the corresponding concentrations were 23.5 ppb, 24.5 ppb, 20.4 ppb, and 17.5 ppb for one week, and 20.3 ppb, 24.7 ppb, 18.8 ppb, and 15.4 ppb for two days. The NO2 concentrations of all microenvironments in Taipei were significantly higher than those in the village of central Taiwan. The outdoor NO2 concentrations were significantly higher than the indoor NO2 concentrations in Taipei. The NO2 measurements in the kitchens were higher than all other measurements indoors and outdoors in the village of central Taiwan. The houses which used natural gas as cooking fuel had slightly higher indoor NO2 concentrations than the houses which used LPG as cooking fuel in Taipei city. Cement houses had slightly higher indoor NO2 concentrations than brick houses. The mean of housewives' exposures was 30.8 ppb in Taipei and 19.9 ppb in the village of central Taiwan. The explanation power of the housewife's exposure to NO2 was 72% by the time weighted-average model and 70% by the simple linear regression model.
Assessment of the Delayed Neurotoxicity of Tributyl Phosphate, Tributoxyethyl Phosphate, and Dibutylphenyl Phosphate
Authors: Carrington Clark D. , Lapadula Daniel M. , Othman Mohamed , Farr Craig , Nair Rashmi S. , Johannsen Frederick , Abou-Donia Mohamed B.
Published: September 2013

There industrial organophosphorus compounds were tested for their ability to cause organophosphorus compound-induced delayed neurotoxicity (OPIDN) in the adult hen. The compounds tested were tributyl phosphate (TBP), tributoxyethyl phosphate (TBEP), and dibutylphenyl phosphate (DBPP). The acute oral LD50 of TBP and DBPP were estimated to be 1,863 and 1,500 mg/kg, respectively, and the dose equal to the LD50 was used as a test dose. The acute oral LD50 of TBEP was greater than 5,000 mg/kg and 5,000 mg/kg was used as a test dose. An oral dose of 750 mg tri-o-cresyl phosphate (TOCP) was used as a positive control. For the acute delayed neurotoxicity test, hens were given two test doses of the test materials 21 days apart and killed 21 days after the second dose. None of the hens given TBP, TBEP, or DBPP exhibited nerve damage or clinical signs which distinguished them from untreated control animals. A single dose of TOCP resulted in paralysis and a histopathological profile typical of a distal neuropathy. For the assay of the inhibition of esterases, hens were killed 24 hours after a single dose equal to the greater of either the LD50 or 5000 mg/kg. TOCP administration resulted in over 90% inhibition of brain neurotoxic esterase (NTE), but none of the other three compounds inhibited NTE to an extent (<70%) which would be expected to result in OPIDN. Administration of TOCP, TBEP, or DBPP resulted in approximately a 70% decrease in plasma butyrylchol-inesterase (BuChE) activity. TBP caused a 2–3 fold increase in BuChE activity. TBEP administration resulted in about 45% inhibition of acetycholinesterase (AChE) in brain. These results indicate that TBP, TBEP, and DBPP are all unlikely to cause OPIDN with any single sublethal dose.
A Promising Indicator of Neurobehavioral Toxicity Using the Nematode Caenorhabditis Elegans and Computer Tracking
Authors: Williams Phillip L. , Dusenbery David B.
Published: September 2013

A promising screening test for neurotoxicity has been developed using a computer tracking system and a species of nematode, Caenorhabditis elegans. The animals are viewed in dark-field illumination by a video camera interfaced directly to a microcomputer. Several hundred nematodes are tracked simultaneously and rates of locomotion and frequency of change of direction are reported in real time. This system can rapidly obtain reliable data on a variety of behavioral parameters relating to locomotion and response to sensory stimulation. Initial testing has examined the effects of six chemicals on locomotion. Four metals (copper, beryllium, mercury, and lead) and two organophosphate pesticides (malathion and vapona) have been studied. Copper and beryllium were chosen as chemicals that have not been shown to be neurotoxins and the other four chemicals were chosen as substances known to be neurotoxins. Our findings indicate that the rate of movement of exposed nematodes compared to the rate of movement of vehicle controls may prove to be useful as an indicator of neurotoxicity.