bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of the Involvement of Opiate Receptors in Producing the Central and Peripheral Effects Caused by Two New Antidiarrheal Drugs, Loperamide and SC-27166
Authors: Mackerer C. R. , Clay G. A. , East P. F.
Published: November 2007

A review of the morphinomimetic activities of the antidiarrheal drugs loperamide and nufenoxole (SC-27166) is presented. These agents bind, in an agonist manner, to opiate receptor sites of brain and myenteric plexus and probably produce their therapeutic actions and side effects through this receptor. Although both agents produce potent opiatelike effects in the myenteric plexus of the small intestine in vivo, CNS side effects are not seen until very high doses are administered. The narcotic-type abuse potential appears to be low for loperamide and may be even lower for nufenoxole. The marked separation of central and peripheral activities probably results from a differential pattern of absorption and distribution that results in a low concentration of drug at receptor sites in the brain and a high concentration at sites in the myenteric plexus.
An Analysis of the Hydra Assay's Applicability and Reliability as a Developmental Toxicity Prescreen
Authors: Johnson E.M. , Newman L.M. , Gabel B.E.G. , Boerner T.F. , Dansky L.A.
Published: November 2007

A large and diverse group of chemicals was evaluated in the Hydra assay, and the outcomes were compared with those of standard developmental toxicity evaluations using data from pregnant mammals. Hydra correctly identified each of the substances previously found by in vivo tests to be uniquely hazardous to in utero development. Its overall accuracy was over 90%, and all of its errors were false positives. The fact that these positives were indeed false could have been established subsequently by routine testing in mammals. In no instance did the assay indicate that a chemical was not uniquely hazardous to the conceptus when higher level tests indicated that it was, i.e., 0 false negatives. The possible areas for continued refinement of the assay and expansion of its scope of use as well as perceived problems and limitations are discussed in detail.
Proceedings of the Workshop on One-vs Two-Generation Reproductive Effects Studies
Authors: Francis Elaine Z. , Kimmel Gary L.
Published: November 2007

The Workshop on One-vs Two-Generation Reproductive Effects Studies was held on October 21-22, 1987. It was organized by the USEPA's Office of Pesticides and Toxic Substances and Office of Research and Development and was supported by the Agency's Risk Assessment Forum. The purpose of the workshop was to address the central question: Is a single-generation reproductive effects study sufficient to assess the reproductive toxicity potential of chemicals that do not bioaccumulate? In response to this question, the panel of nine participants concluded that, by itself, a one-generation reproductive effects study is insufficient to identify all potential reproductive toxicants and that a two-generation study is needed for an adequate assessment. The panel did not support placing much importance on bioaccumulation as related to reproductive toxicity testing mainly because it is not the only critical factor that may account for effects in a second generation but not in the first. In studying broader issues, the panel accomplished several goals that hopefully may serve to direct future development in reproductive toxicity testing: (1) the purpose of a reproductive effects study was defined, (2) a minimal set of end points necessary for adequate evaluation of reproductive toxicity was determined, (3) some alternative reproductive effects test methods were recommended, (4) greater flexibility in choosing a test protocol on a case by case basis was encouraged, and (5) areas that need further research were identified.
Isobolographic, Algebraic, and Search Methods in the Analysis of Multiagent Synergy
Authors: Berenbaum Morris C.
Published: November 2007

A combination of doses d1, d2, dn of n agents shows zero interaction when d1/D1 + d2/D2. + dn/Dn = 1, where D1,D2, Dn are the doses of the individual agents isoeffective with the combination. In synergy, the sum in this equation is less than 1, and in antagonism, it exceeds 1. This equation may be used to calculate the expected (zero interactive) effect of any combination, irrespective of the shapes of the dose-response curves of the agents and of whether they are linear or nonlinear, similar or dissimilar. For a given set of agents, finding the combination that has the maximum therapeutic (or toxic) effect may be logistically a huge problem because of the large number of variables (e.g., dose, dose interval, number of doses) that are generally involved. This problem may be tackled by (1) response surface methods, in which an equation (usually a low-order polynomial) is fitted to the observed effects of a number of different combinations, and the maximum on this response surface is found mathematically, or by (2) direct search methods, in which the response surface is explored one combination at a time without preconceived ideas about its form. For problems with many variables, direct search methods are more economic.
The Use of Kernel Estimators in Describing Human T Lymphocyte Proliferation Induced by Phorbol Esters and Ca2+ Ionophore
Authors: Staniswalis Joan G. , McCrady Carl W.
Published: November 2007

A nonparametric method for analyzing the mitogenic count data generated from in vitro T cell stimulation by phorbol dibutyrate (PDBu) and ionomycin (I) is described. Antigen receptor initiated T cell activation is transduced by the combined second messenger actions of phospholipid metabolites diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates protein kinase C, and IP3 serves to elevate cytosolic Ca2+ levels. Pharmacological agents, such as phorbol esters and the Ca2+ ionophore ionomycin, mimic DAG and IP3, respectively. Consequently, they can be used to initiate T lymphocyte activation and subsequent proliferation. Given mitogenic count data measured by 3H-thymidine incorporation, a kernel estimate of the proliferative response surface is used to develop a confidence region for the optimal combination level of PDBu and ionomycin for maximum T cell proliferation. The experimental data analysis was validated with a small computer simulation study. The resulting confidence regions have high coverage probabilites robust with respect to the shape of the underlying proliferative response surface. This bias robustness is important in this application because the shape of the response surface may vary among individuals. Thus, this procedure will allow for optimization of an individual's T cell proliferative response.
Modeling Multiple Agent Interactions in Behavioral Pharmacology
Authors: Wessinger William D. , Evans Eric B.
Published: November 2007

Drugs of abuse frequently are self-administered in combinations, thus the study of the behavioral pharmacology of drug interactions has important public health implications. The effect-addition and the dose-addition models are predictive models frequently used to interpret such investigations. The aims of the present study were to empirically validate these predictive models using simple drug combinations. The effects of combinations of pentobarbital (PB) with itself or PB with secobarbital (SB) were studied using an inverted screen test in mice and a milk consumption test in rats. When evaluated using the effect-addition model the interactions between PB and itself were generally greater than effect-additive, suggesting that greater effects were obtained when giving the drug by two separate injections. In contrast, when evaluated using the dose-addition model, the interactions between PB and PB were dose-additive as would be expected for a drug interacting with itself. Similar results were obtained for the interaction of PB and SB using the mouse inverted screen test. These results suggest that the dose-addition model is a better model for evaluating drug interactions. The interactions observed for PB and SB using the rat milk drinking test generally were greater than effect-additive when analyzed using the effect-addition model. In contrast, using the dose-addition model, the interactions between PB and SB were generally infra-additive, suggesting that these two drugs have different mechanisms in decreasing milk consumption.
Qualitative Evaluation of Sister Chromatid Exchanges Elicited by Combinations of Genotoxic Compounds Using Response Surface Methodology
Authors: Solana Richard P. , Carter Walter H. , Wilson John D. , Chinchilli Vernon M. , Carchman Richard A.
Published: November 2007

Response surface methodology (RSM), a collection of statistical and mathematical techniques, can empirically model multiple agent interactions. The use of RSM allows modeling of the interaction at all levels of each agent, rather than focusing on a single level of effect, thereby describing the changing interaction present. Further, this technique allows qualitative analysis of the resultant model of the combination exposure for existing interactions. RSM was used in the statistical analysis of sister chromatid exchanges (SCE) elicited by combination exposures of genotoxic agents, ethylnitrosourea (ENU) with cis-diaminedichloroplatinum (II) (DDP), and DDP with x-rays. ENU and DDP each exhibited curvilinear concentration-related increases in SCEs. X-ray exhibited a linear increase in SCEs. For the DDP-x-ray combination, RSM analysis indicates a less-than-additive interaction, suggested by the nonparallel concentration-response curves of one agent at varying concentrations of the other. For the DDP-ENU combination, an increasingly less-than-additive interaction was detected. This descriptive ability is shown to be useful in suggesting hypotheses about mechanisms of action. Employing a polynomial model assumes effect-addition as an underlying assumption of additivity. Models with other underlying assumptions of additivity also can be used.
Training for Animal Welfare
Authors: Larson Jean
Published: November 2007

The Laboratory Animal Welfare Act of 1985 mandates training for a wide spectrum of individuals. A profile of each group of individuals requiring training is presented. These groups include students, animal caretakers, research and animal technicians, investigators, and principal investigators. An educational profile is provided for each group. Their educational needs are described, with examples of available training materials. This information provides the necessary analysis of the groups that must be trained in order to develop an effective training program.
The Animal Welfare Act's Impact on the Scientist
Authors: Glosser James W. , York Phyllis B.
Published: November 2007

The bond between animals and humans has existed for a long time. Humans are entrusted with the stewardship for animal care and well-being as a part of their use. Legislation has addressed humane care of animals in the United States since 1873. The United States Department of Agriculture (USDA) is responsible for administering many of these laws, including the Animal Welfare Act. Recent amendments to the Animal Welfare Act require regulations to be established for the exercise of dogs and the psychological well-being of primates. It also requires the establishment of an Institutional Animal Committee, training for scientists, consideration of alternatives by the principal investigator, and the establishment of an information service at the National Agricultural Library.
Services of the Animal Welfare Information Center at the National Agricultural Library
Authors: Larson Jean
Published: November 2007

The National Agricultural Library (NAL) was created by the first Commissioner of Agriculture after the establishment of the United States Department of Agriculture (USDA) by the Organic Act of 1862. The NAL now includes a diverse collection of 1.9 million items that are in English and many foreign languages, covering multiple subjects and different formats, including electronic. The Animal Welfare Information Center (AWIC) was established in response to the Animal Welfare Act of 1985 to provide information on employee training, to prevent duplication of animal research, and for improved methods of animal research. The services and access to these services are described. Many items on animal welfare have been collected with primary emphasis on training. Access to this information is through the bibliographic database AGRICOLA. Other available products and services, including references, referrals, database searches, bibliographies on special topics, fact sheets, and a traveling tabletop exhibit, are described, and means of obtaining materials are provided.
Perspectives on In Vivo Testing of Biomaterials, Prostheses, and Artificial Organs
Authors: Anderson James M.
Published: November 2007

The goal of in vivo testing of a medical device is to determine the safety or biocompatibility of the device in a biological environment. Biocompatibility is the ability of a medical device to perform with an appropriate host response in a specific application. Biocompatibility assessment is considered to be a measure of the magnitude and duration of adverse alterations in homeostatic mechanisms that determine the host response. Perspectives are provided on the role of injury, tissue responses to medical devices, and blood responses to medical devices. The concept of the normal foreign body reaction is presented. The potential importance of the macrophage, an important component of the foreign body reaction, in controlling the biocompatibility in the in vivo environment is discussed.
Perspectives on In Vitro Toxicity for Medical Devices
Authors: Northup Sharon J.
Published: November 2007

In vitro toxicity testing has found widespread application in its use for screening materials for medical devices. Cytotoxicity tests, which have been in use for nearly 20 years, have been validated for intralaboratory repeatability, interlaboratory reproducibility, and correlation with acute animal toxicity assays. The three primary cytotoxicity assays, i.e., direct contact, agar diffusion, and elution tests, allow a selection between assay and material characteristics. Mutagenicity assays have had limited application to materials testing because of the insoluble nature of the materials and the low level of extractable chemicals, which are generally below the sensitivity limit of these assays. In vitro blood compatibility tests for hemolysis and complement activation are used primarily for blood contacting materials in applications where there is a large surface area of material for ex vivo applications.
The Qualitative and Quantitative Risks of Incinerating Hazardous Wastes
Authors: Harris Robert , Washburn Stephen
Published: November 2007

Incineration is becoming an increasingly popular method of treatment and disposal for both hazardous and municipal solid waste. Concerns about potential health risks associated with the operation of incineration facilities, however, have led to public opposition to their siting in several communities. The process of risk assessment is a useful tool for providing a quantitative basis for decision makers evaluating such siting concerns.
Symposium VI: New Statistical Approaches to the Qualitative Interpretation of Toxicology Data
Authors: Byrd D.M.
Published: November 2007

This symposium describes some new statistical methods of use in the analysis of toxicology data for purposes of hazard evaluation, particularly as related to the qualitative phase of carcinogen risk assessment. C.J. Portier discusses life table analysis of cancer bioassays. Current assumptions about the lethality of treatment and tumor can lead to incorrect interpretation of results. D.W. North provides an introduction to the concepts of Bayesian statistics and shows how the application of judgmental probabilities can assist in reaching broad conclusions. L.B. Lave and G.S. Omenn apply a Bayesian method to estimate the likelihood of bioassay outcomes given short-term test data. The best screening test is not necessarily the most accurate or the least expensive. W.P. Darby and J.K. Gohagan use a bayesian method to integrate data from different bioassays of the same substance. In a case study of saccharin, they show that the totality of results can lead to conclusions that differ from those achieved with a single bioassay.
Screening Toxic Chemicals: How Accurate Must Tests Be?
Authors: Lave L.B. , Omenn G.S.
Published: November 2007

A decision analysis framework is used to explore the value of screening tests for carcinogenicity. Whether a test lowers the social cost of screening depends on the test's sensitivity, specificity, and cost and the social cost of misclassification (exonerating carcinogenic chemicals or condemning noncarcinogenic chemicals). The model shows that the best screening test need not be either the most accurate or the least expensive.
Analysis of Bioassay Data Drawn from Several Sources
Authors: Darby W.P. , Gohagan J.K.
Published: November 2007

This article presents a review of some important considerations for scientists and regulatory decision makers who are charged with the task of drawing a conclusion from an existing and growing body of bioassay data to evaluate the toxicity of a compound. Two general approaches are outlined, based on classic statistical methods and on Bayesian statistical methods. Their advantages and disadvantages are discussed in relation to the overall decision-making process. The article concludes by presenting an application of the Bayesian approach to the body of bioassay data available at the time of the regulatory decision concerning the link between saccharin and bladder cancer.
Neoplasms in Rats Ingesting Acrylonitrile for Two Years
Authors: Gallagher G.T. , Maull E.A. , Kovacs K. , Szabo S.
Published: November 2007

Male Sprague-Dawley rats ingested 0, 20 ppm, or 500 ppm of acrylonitrile in drinking water for 2 years. Rats receiving 500 ppm of acrylonitrile exhibited early mortality and retarded weight gain. Tumors of Zymbal's gland were associated in dose-response fashion with acrylonitrile exposure. Age-associated incidence of pituitary adenomas containing immunoreactive prolactin was decreased in acrylonitrile-treated rats. A decrease in pituitary tumor incidence also was observed in rats treated with low doses of acrylonitrile, suggesting that reduction in this tumor frequency was not because of early death. No increases were found in tumors of other organ systems, but a trend toward development of forestomach papillomas was noted in rats receiving the highest concentration of acrylonitrile.
Preliminary Toxicity Data on New Ethylenediamine Derivatives Designed for Iron Chelation
Authors: Rosenkrantz H. , Metterville J.J.
Published: November 2007

During development of iron chelators for the treatment of iron overload in Cooley's anemia, the opportunity arose to obtain some acute and subacute toxicity data on hydroxybenzyl-ethylenediamine (HBED) derivatives, hydroxyphenyl-ethylenediamine (HPED) congeners, and ethylenediamine-phenylacetic acid (EDHPA) compounds. Such data permitted correlations among structure, toxicity, and efficacy parameters useful for further syntheses. Young, adult male mice were used to perform acute intraperitoneal (IP) or oral (PO) LD50 studies, and hypertransfused groups were treated IP or PO with vehicle, Desferal, or test chelators once daily for 7 days. Changes in behavior, weights of spleen, liver, and feces, and urine volume and gross pathology were monitored. In the HBED series, esterification of acetic acid groups with or without acetylation of phenolic hydroxyl groups increased LD50 values, and the major behavioral change was decreased exploratory activity. Dimethylenephosphonate derivatives of HBED were more toxic. Single treatment with compounds in the EDHPA and HPED series yielded IP LD50 values between 175 and 325 mg/kg. After subacute treatment, active compounds were found in each series, and efficacy was related to toxicity. Chelation effectiveness was usually greater by the IP route than orally. The major toxic signs were reduction in organ weights and excreta output.
The Distribution and Toxicological Effects of Inhaled Methyl Bromide in the Rat
Authors: Jaskot R.H. , Grose E.C. , Most B.M. , Ménache M.G. , Williams T.B. , Roycroft J.H.
Published: November 2007

Sixty-day-old male CD rats were exposed by nose only to 14C-methyl bromide (55 ppm) for 3 min. The data indicated that the liver, lung, and kidney were the major organs of 14C distribution immediately after exposure. Up to 32 hr after exposure, the major routes of excretion were pulmonary (14CO2) and renal, with approximately 43% and 21% of the total inhaled radiolabel being eliminated, respectively. In separate experiments, 60-day-old CD male rats were exposed by whole body inhalation for 6 hr/day for 5 and 10 days to 30 ppm methyl bromide or filtered air. Glutathione (GSH) S-transferase and glucose-6-phosphate dehydrogenase (G-6-PDH) activities were increased in the lung. A decrease in GSH-reductase and GSH-S-transferase activities were found in the liver. Serum chemistries indicated a decrease in Cholinesterase, BUN, uric acid, and cholesterol, and leucine aminopeptidase exhibited an increase in activity. These data indicate that methyl bromide is quickly distributed to all tissues after inhalation and rapidly metabolized. A small percentage is cleared slowly and incorporated into metabolic pools, as evidenced by 25% of the initial dose of 14C-methyl bromide found in the rat 32 hr postexposure and the alterations found in hepatic enzyme activities.
Toxicological Evaluation of Neosugar: Genotoxicity, Carcinogenicity, and Chronic Toxicity
Authors: Clevenger M.A. , Turnbull D. , Inoue H. , Enomoto M. , Allen J.A. , Henderson L.M. , Jones E.
Published: November 2007

Neosugar, a fructooligosaccharide mixture, was tested for genotoxicity in three assays: (1) microbial reverse mutation assays in Salmonella typhimurium (Ames assay) and Escherichia coli WP2 uvr A, (2) the L5178Y mouse lymphoma TK± mammalian cell mutation assay, and (3) an assay for the induction of unscheduled DNA synthesis (UDS) in human epithelioid cells (HeLa S3). Each assay was conducted at a wide range of dose levels, both with and without metabolic activation. Test results gave no indication that neosugar possessed any genotoxic potential. The carcinogenicity and chronic toxicity of neosugar were examined in Fischer 344 rats. Rats were fed diets containing 0, 8000, 20,000, or 50,000 ppm neosugar for 104 weeks. No dose-related effects on survival, growth, hematology, blood chemistry, organ weights, or nonneoplastic lesions were observed. The incidence of rare and spontaneous tumors was comparable between control and neosugar treatment groups, with the exception of pituitary adenomas in male rats. In light of the background incidence of this tumor and an equivocal dose-response trend, it is unlikely that neosugar treatment is related to the incidence of pituitary adenomas in male rats. The results of this study indicate that neosugar is nonmutagenic and that rats are not adversely affected by chronic neosugar exposure.
Inhalation Toxicity of Chlorotrifluoroethylene (CTFE)
Authors: Gad S.C. , Rusch G.M. , Reigle K.S. , Darr R.W. , Hoffman G.M. , Peckham J.C. , Schardein J.L.
Published: November 2007

In a pilot 2-week inhalation toxicity study, male and female CD rats were exposed to mean levels of 0, 33, 61, 119, and 241 ppm of chlorotrifluoroethylene (CTFE) 6 hr/day, 5 days/week for 2 weeks. In a concurrent phase of the same pilot study, groups of five pregnant rats were exposed to the same levels of CTFE from day 6 through day 19 of gestation. Effects were limited to depression in rates of body weight gains, elevated kidney/body weight ratios, and toxic nephrosis in groups exposed to 241 ppm, and depressed body weight gains in males and pregnant females exposed to 119 ppm. No embryotoxicity, fetotoxicity, or developmental effects were observed in the pregnant pilot-study animals. In a subchronic study, male and female F-344 rats were exposed 6 hr/day, 5 days/week for 13 weeks at mean levels of 0, 29, 62, and 121 ppm. No animals died as a result of being exposed to CTFE. Indications of effects on the kidneys included increased organ weights, alterations in clinical chemistry parameters and clinical observations, and alterations in microscopic structure. Males also showed alterations in body weights and absolute and relative liver weights, which were reversible after cessation of exposure. Dose-response was evident in both sexes, although males were more sensitive, with 29 ppm being a limited effect level in the males. A group of animals maintained for 2 weeks after the completion of exposure showed marked remission from the observed effects.
Short-Term Toxicity (One-and Ten-Day Gavage) of Barium Chloride in Male and Female Rats
Authors: Borzelleca J.F. , Condie L.W. , Egle J.L.
Published: November 2007

To assess adverse effects that might be caused by an event resulting in high levels of barium in drinking water, rats were gavaged with barium chloride (BaCl2 at dosage levels of 30, 100, and 300 mg/kg in a 1-day study and at 100, 145, 209, and 300 mg/kg for 10 days, and the effects were determined. LD50 values for male and female rats were found to be 419 (352–499) and 408 (342–487) mg/kg BaCl2, respectively. In the 1-day exposure study, decreases in body weight and liver/brain weight ratios and increase in kidney weight as a percentage of body weight appeared to be related to barium ingestion at 300 mg/kg. After 10 days of exposure to barium, survival of females was substantially lower at 300 mg/kg. A reduction in ovaries/brain ratio at 300 mg/kg appeared to be barium-induced. There was a decrease in BUN at 300 mg/kg in males and at all dose levels in females. No other effects were attributed to barium. Histopathological findings were negative in both the 1-and 10-day studies. It is concluded that short-term oral exposure to BaCl2 at doses up to 209 mg/kg produces no significant adverse health effects.
Tumor-Promoting, Initiating, and Hepatotoxic Effects of 3,4,3',4'-Tetrabromobiphenyl (34-TBB) in Rats
Authors: Dixon D. , Sleight S.D. , Aust S.D. , Rezabek M.S.
Published: November 2007

Female, 180–200 g Sprague-Dawley rats were used to determine if 3,4,3',4'-tetrabromobi-phenyl (34-TBB) is a promoter or initiator in a two-stage hepatocarcinogenesis assay. To test for promotion, rats were partially hepatectomized (PH) 24 hr before initiation (day 1) with 10 mg of diethylnitrosamine (DEN)/kg body weight given intraperitoneally (IP). Thirty days later, promotion was with 34-TBB (0.1,1 or 5 mg/kg) or phenobarbital (PB) (500 mg/kg) in diets for 180 days. To test for initiation, rats were PH and were initiated on day 1 with 34-TBB (1, 5, or 10 mg/kg) orally or DEN (10 mg/kg) IP. On day 31, promotion was with 500 mg of PB/kg of diet for 180 days. Noninitiated and non-PH rats were used to assess the histological and ultrastructural tissue changes associated with administration of 34-TBB in the diet for 180 days. Tumor promotion-initiation were assessed by counting and measuring hepatic enzyme-altered foci (EAF) with gamma-glutamyl transpeptidase (GGT) activity. Congener 34-TBB acts as a promoter in experimental hepatocarcinogenesis in rats, as evidenced by increased numbers of GGT-positive EAF. Also, 34-TBB may have initiation potential, as suggested by increased numbers of EAF in rats initiated with 34-TBB and promoted by PB. Dietary administration of 34-TBB for 180 days is not severely toxic in rats, as evidenced by mild histological and ultrastructural changes and minimal alterations in organ and body weights. Congener 34-TBB does not accumulate in liver and adipose tissue of rats.
Evaluation of In Vivo Mutagenicity of Low-Dose Methylene Chloride in Mice
Authors: Raje R. , Basso M. , Tolen T. , Greening M.
Published: November 2007

Methylene chloride, a widely used industrial solvent, has been shown to be mutagenic by in vitro tests. The aim of this study was to determine in vivo mutagenicity. Groups of 20 Swiss-Webster (S/W) male mice were injected subcutaneously three times/week with 5 ml/kg of 5% vol/vol or 10% vol/vol solution of methylene chloride in corn oil for 4 weeks, followed by 1 week of no treatment. Other groups of 20 S/W male mice were exposed to airflow of 10 L/min carrying 100, 150, or 200 ppm of methylene chloride daily for 2 hr/day, 5 days/week for 6 weeks. Each study contained appropriate negative controls. Mating was started 1 week later for the injection group and 2 days later for the inhalation group. Each male mouse was mated with a S/W virgin adult female. The mating was allowed to continue for 2 weeks. Presence of a vaginal plug was taken as a sign of successful mating and was designated as day 0 of gestation. On day 17, the females were killed, and the fetuses were removed and processed. Male mice were killed, and the testes were removed, preserved in 10% formalin, and processed. No significant difference in any of the mutagenicity parameters was found between control and treated groups. No microscopic lesions were found in testes of the treated males.
Principles of Screening in Toxicology with Special Emphasis on Applications to Neurotoxicology
Authors: Gad Shayne C.
Published: November 2007

It is not generally recognized that the major activity or function of classic descriptive toxicology is the use of screening tests for detecting the presence or absence of an effect, Generally, such screens have been directed at the detection of a single end point of effect, such as lethality, mutagenicity, or neurobehavioral effects. Such screens have a common set of operating characteristics that are not widely appreciated and that make traditional approaches to statistical analysis insensitive and inefficient in comparison to other available methods. Also, all too often control and historical data are not incorporated to strengthen either the design or analysis processes. Just as often overlooked is the intended objective or function of a screen, which acts as the biologic equivalent of a form of exploratory data analysis (EDA). As such, screens act to identify areas-compounds (i.e., explore or discover responses) that then either require further research (to confirm the existence of an effect and evaluate the relevance of any hazard to humans) or pass a compound on as representing low probability of a hazard. This fundamental discovery function forces screens to be designed to be very sensitive and, in so doing, requires that positive findings be understood to be flags that say “Look here” (and not that a material is, for example, a neurotoxicant). Discrimination, in other words, though important, is secondary. In this article, the characteristics and uses of screens in toxicology are presented and reviewed, along with overviews of the types and philosophy of screening operations. The relevance of these factors to the special case of neurotoxicology is pointed out, with specific examples and implications.
Behaviors in the Home Cage Reveal Toxicity: Recent Findings and Proposals for the Future
Authors: Evans Hugh L.
Published: November 2007

Nervous system impairment is prominent among signs of chemical toxicity in humans and animals, yet evaluation of behavioral and neurologic responses is seldom included in premarket screening. The sensitivity and validity of automatically recorded rodent locomotor activity, whether inside or outside of the home cage, justifies its inclusion in first-tier testing. Home cage behaviors are studied in the toxicologic laboratory using quantitative techniques from behavioral neuroscience. A practical, noninvasive, automated system was developed and validated at New York University, in accord with Federal guidelines for testing neurotoxicity. Effects of neurotoxicants on motor activity, eating, drinking, and the daily cycle of rest-activity indicate sensitivity to a variety of chemicals as well as new avenues to the understanding of mechanisms of toxicity. The rat's pattern of nocturnal activity is particularly sensitive to neurotoxicants and thus deserves additional attention. The coefficient of variability of various end points did not correlate with sensitivity to toxicants. This underscores the need for behavioral data to supplement theoretical considerations in test selection. The system's advantages are economy, high data capacity, humaneness, accessible and well-known end points, widely available equipment, automation, and the potential for direct comparisons of several different animal species.
Development of Tier I Neurobehavioral Testing Capabilities for Incorporation into Pivotal Rodent Safety Assessment Studies
Authors: Haggerty G. C.
Published: November 2007

A functional observational battery and an automated test of motor activity have been developed in this laboratory in response to present and future needs for routine assessment of behavioral function in acute and repeated dose rodent safety assessment studies. Data have been collected for untreated 42–49-day-old animals of both sexes in order to gain information on normal ranges of responses in animals of this age as well as to determine the relative variability of the various test measures. Data will continue to be added to this database, both for animals of this age range and for other age ranges. A validation strategy has been outlined that emphasizes the characterization of behavioral profiles of both pharmacologic agents and chemically related neurotoxins, as well as the importance of determining how well these results translate to those observed in humans exposed to the same test agents. The logistical and economic factors associated with neurobehavioral testing and the importance of intralaboratory standardization are discussed in detail. Both controllable and difficult to control environmental and experimental variables that can affect the outcome of a behavioral study are identified. The problems associated with neurobehavioral data interpretation and the importance of a multisystem approach to interpreting functional changes in the context of toxicology studies are discussed.
A Neurofunctional Test Battery for Evaluating the Effects of Long-term Exposure to Chemicals
Authors: Kulig Beverly M.
Published: November 2007

In order to determine the neurotoxic potential of long-term chemical exposures, a battery of tests was developed to evaluate changes in spontaneous activity, grip strength, coordinated movement, two-choice visual discrimination performance, and peripheral nerve conduction velocity in the rat. To evaluate the reliability and sensitivity of these tests, experiments examining the effects of acrylamide on measures of motor and peripheral nerve function were conducted. In addition, the use of discretetrial discrimination procedures to assess changes in learned performance was also examined in experiments with styrene and n-hexane. Results with acrylamide indicated that tests of peripheral and motor function were capable of detecting and describing the progressive development of peripheral nervous system effects. Further, studies with styrene and n-hexane demonstrated the sensitivity of discrete-trial techniques to both the acute and chronic effects of solvent exposure. Taken together, these studies demonstrate the applicability of neurofunctional measurements to chronic exposure studies for determining the range, time course, and severity of chemically induced nervous system effects. The differences in profiles of neurotoxic effects produced by different chemicals emphasize the need for a battery of tests to fully describe the range of functional effects produced by chemical exposures.
Neurologic Approach to Neurotoxicologic Evaluation in Laboratory Animals (Abstract)
Authors: Mattsson J. L. , Albee R. R. , Eisenbrandt D. L.
Published: November 2007

The neurotoxicologic potential of a compound is best evaluated with information from a wide variety of tests. Our philosophy is that tests should be applicable across species and emphasize complementarity to neuropathology. Electrophysiologic tests comparable to those in human clinical neurology fulfill these requirements. Animals are not anesthetized but are physically restrained during the tests. Routine tests include flash evoked potentials, auditory brainstem responses to clicks and tone pips, somatosensory evoked potentials, and caudal nerve action potentials. Tests can be added (e.g., H-reflex, EMG, EEG, etc.) or deleted as circumstances warrant. A careful clinical examination of all animals (functional observational battery) and, for rats, a test of grip strength are used as well. Neuropathology typically includes perfusion fixation and special stains of histologic sections from the central and peripheral nervous systems. Approximately half of the animals are retained as a recovery group for subsequent tests if warranted by the results of the neurotoxicologic evaluation. The neurologic approach, in conjunction with standard toxicologic studies, provides data with the necessary breadth and depth for a comprehensive evaluation of neurotoxicity.
Screening for Neurotoxicity Using a Neurologically Based Examination and Neuropathology
Authors: O'Donoghue John L.
Published: November 2007

Testing chemicals for toxicity by screening methods is an integral part of providing high-quality products and processes. Screening tests must be sensitive, reproducible, readily performed by a trained staff, generally acceptable across laboratories, costeffective, timely, and predictive of significant hazards. The screening process begins with routine acute and subacute tests commonly in use in toxicology laboratories worldwide. When these tests indicate a neurotoxicologic effect or when structure-activity analysis suggests a concern, more specific tests, including a neurologically based functional observational battery (FOB) and neuropathology, are indicated. The FOB provides a highly structured framework for collection of clinical signs. When teamed together, the FOB and neuropathology examinations are complementary tests that provide a clinicopathologic description of a neurotoxicant that can be used for risk assessment.
Motor Activity and Screening for Neurotoxicity
Authors: Mac Phail R. C. , Peele D. B. , Crofton K. M.
Published: November 2007

Automated measures of motor activity have been used extensively to determine the functional impact of a wide range of chemical exposures, nervous system alterations, and environmental manipulations. The many factors that recommend motor activity for the routine preliminary assessment (screening) of the neurotoxic potential of chemicals include its noninvasive nature, ease of testing, availability of automated test equipment, and objectivity of the data. In this article, measures of motor activity were evaluated for their reliability, sensitivity, efficiency, and specificity. Motor activity measures were shown to be highly reliable both between subjects comprising a control group and across experimental control group replications. The sensitivity of motor activity measures generally is comparable to more sophisticated measures of neurobehavioral integrity, whereas their efficiency is characteristically superior. Although some questions may remain concerning the specificity of motor activity measures, data were presented to show that chemical-induced general malaise or sickness is not always associated with changes in motor activity. Motor activity measures possess many features that make them ideal for inclusion in a screening battery for neurotoxicity.
Neuropathologic Screening in Rodent and Other Species
Authors: Krinke G. J.
Published: November 2007

In screening for neurotoxicity, the purpose of neuropathologic evaluation is to detect and characterize morphologic changes and to demonstrate their absence at low levels or in cases showing only functional effects. Attempts to identify the cellular targets of neurotoxicity are made in pattern-finding studies by thorough examination of selected individuals shortly after exposure to high levels of the suspected toxicants. When the target areas and suitable investigative techniques have been established, a screening for dose-effect relationship and no-effect level can be carried out. Methods of examination routinely used in toxicologic pathology are insufficient to detect subtle neural lesions; special techniques, including perfusion fixation, embedding in plastic, isolation of nerve fibers, and quantitation, are required. The areas of the nervous system to be examined are selected according to functional signs and mechanisms of action. Despite the presence of metabolic and anatomic interspecies differences, the occurrence of neurotoxicity in any animal model may be relevant to humans.
Screening for Neurotoxic Disease in Humans
Authors: Arezzo Joseph C. , Schaumburg Herbert H.
Published: November 2007

Detection of neurotoxic disease is a formidable task requiring clinical, epidemiologic and detective skills,(1) Rarely does neurotoxic insult occur in isolation, and rarely are precise details of the putative exposure known. False positive and false negative diagnoses of neurotoxicity are common because of the similarity of the major signs and symptoms with those associated with metabolic, traumatic, or age-related diseases. No single test or sign is pathognomonic for neurotoxic disease; routine clinical laboratory results and imaging procedures are generally of little value. Exposure to a specific toxin can result in a vastly different clinical profile depending on the magnitude and route of exposure. For example, acute high level exposure to acrylamide causes a toxic encephalopathy with convulsions and hallucinations; prolonged low level exposure causes distal sensory loss. Since metabolites are often the toxic moiety, it is rarely possible to predict neurotoxicity by examining the chemical formula of agents. Thus, the neurotoxic properties of n-hexane and methyl- n-butylketone are attributable to a common gamma-diketone metabolite (2,5-HD), whereas chemically related compounds (i.e., heptane, pentane) have failed to produce experimental neuropathy. Nontoxins also can enhance toxic situations. Symptoms may intensify for months after exposure is stopped (coasting), and, conversely, dysfunction may not appear until years of low level exposure. Preexisting subclinical nervous system dysfunction (i.e., carpal tunnel syndrome) may first become manifest after toxic exposure (unmasking phenomena). The onset of symptoms, particularly negative symptoms, can be insidious and may continue undetected by patient and physician. It is suggested that neurotoxic damage in early life can enhance late life central nervous system dysfunction, such as Parkinson's disease.
Statistical Analysis of Screening Studies in Toxicology with Special Emphasis on Neurotoxicology
Authors: Gad Shayne C.
Published: November 2007

Screens have a common set of operating characteristics that are not widely appreciated and that make traditional approaches to statistical analysis both insensitive and inefficient in comparison to other available methods. Traditional methods also do not incorporate additional data as it is generated. Such incorporation would serve to strengthen both the design and analysis processes and is essential in the case of screens. Traditional methods of analysis (contingency tables, rank sum, and ANOVA methods) are overviewed briefly, and their weaknesses are discussed. The concept of power and the factors influencing it are discussed. Alternative approaches to analysis of univariate (control charts and central tendency plots) and multivariate (analog contrast plots and multidimensional cluster plots) data from screens are presented, and their performance is evaluated. The resulting general principles of design and analysis of screens for neurotoxicology are presented. The alternative approaches are shown to be superior to traditional approaches in performance toward meeting the objectives of screens.
Generation of Dose-Response Data Using Activity Measures
Authors: Mullenix Phyllis J. , Kernan William J. , Tassinari Melissa S. , Schunior Ann
Published: November 2007

The measurement of activity is being employed as a routine test to screen for neurotoxicity. Yet the detection capability of many activity monitoring techniques is limited to the extent that the potential for false negative results is present. This study dissects a drug-induced change in behavior to illustrate the relative importance of various measures in the delineation of dose-response information. This type of analysis is crucial for understanding what measures are needed to generate meaningful activity data. The behavioral response to four doses of amphetamine is determined using three independent measures of change, the number of behavioral initiations, total time, and time structure. Subjectivity in the identification of behavior was minimized by using a computer pattern recognition system to classify all acts. It was found that the biggest contributor to dose-response delineation was the measure of time distribution and sequence, a measure ignored by most automated activity devices available today. Both the behavioral act and the measures used must be specifically identified to avoid artificial summations that could underestimate or overestimate the overall effect on behavior.
Quantitation in Neuropathology
Authors: Broxup B. , Losos G. , Yipchuck G.
Published: November 2007

Qualitative neuropathologic evaluations are appropriate for initial screening of compounds for neurotoxicity. In the future, advances in tissue preparation and computer technology will make quantitative evaluation of some nervous tissue structures more routine. These evaluations will be used as part of tier II studies to determine dose-responses or no-effect levels. Quantitative methods can enable small but significant differences to be detected, and the data can be subjected to statistical analysis.
Current Regulation and the Authorities' Viewpoint on Neurotoxicity Testing in Denmark
Authors: Larsen Jens-Jørgen
Published: November 2007

Prevention and limitation of exposure to neurotoxic substances and products are achieved in Denmark on the basis of the Act on Chemical Substances and Products, the Working Environmental Act, the Environment Protection Act, and other legislation. It is the Danish authorities' viewpoint that a neurotoxic effect in humans is a serious health hazard, that should be prevented or limited to the greatest possible extent. The Danish regulation does not include guidelines for specific neurotoxicity testing apart from the OECD test of OP-substances for delayed neurotoxicity. International efforts to introduce a test program for evaluation of potential neurotoxic substances are considered of great importance and are fully supported. Within the European Economic Community EEC, Denmark has proposed a decision to be taken about labeling of selected solvents considered to be neurotoxic. The labeling consists of a warning indicating “Serious health hazards following long-term exposure.” Such enterprises and the acknowledgment of about 2,500 Danes to recover disability pension because of solvent-induced chronic brain damage confirm the seriousness of the Danish authorities' view on neurotoxic substances.
Promoting Effect of Metal Compounds on Liver, Stomach, Kidney, Pancreas, and Skin Carcinogenesis
Authors: Kurokawa Y. , Takahashi M. , Maekawa A. , Hayashi Y.
Published: November 2007

Systemic studies have been completed in Japan to detect those chemicals in the environment that act as promoters. Well-established two-stage models for liver, stomach, kidney, pancreas, and skin carcinogenesis were employed to detect the promoting effect of Zn Cl2, Cr Cl2, Cd Cl2, Ni Cl2, and Hg Cl2. As a result, Ni Cl2 was found to act as a promoter in renal carcinogenesis.