Alan M Goldberg

Alan M Goldberg
Johns Hopkins University | JHU · Department of Environmental Health Sciences

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116
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Publications

Publications (116)
Article
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This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explaine...
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Today, engineered three-dimensional tissue models from human cells of the skin, cornea, mucosa, and respiratory tract are widely used in pharmaceutical, chemical, consumer, and cosmetic industries as alternatives to animal testing. The currently available scientifically valid 3D tissue-engineered models, however, are protected by patents and/or are...
Article
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Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, i...
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Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A gener...
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Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. An important building block of this strategy that has emerged during the last years ar...
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Due to public pressure, in vivo methods of toxicity testing is being attempted to be replaced by in vitro methods, such as cell and organ culture, computer modelling and modified LDS0 tests using lesser number of animals. Specifically in the case of Draize eye imtancy test using rabbits, a number of refinements have-been incorporated by different w...
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Full-text available
Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, i...
Article
The role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (...
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Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivi...
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Development of improved communication and education strategies is important to make alternatives to the use of animals, and the broad range of applications of the 3Rs concept better known and understood by different audiences. For this purpose, the Center for Alternatives to Animal Testing in Europe (CAAT-Europe) together with the Transatlantic Thi...
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Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternative methods to current animal testing protocols and guidelines. An immediate goal is to develop test methods that are capable of screening large numbers of chemicals. This document provides recommendations for developing alternative...
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To the Editor: Cutler et al. bring welcome attention to the importance of new and reemerging zoonotic diseases in the industrialized world (1). However, they make no mention of industrialized systems of food animal production, major sources of antimicrobial drug–resistant bacterial pathogens (2) that are among the most globally prevalent and emergi...
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A replacement alternative to the rabbit eye irritation test has been sought for many years. First published in 1944 by FDA toxicologist J. H. Draize, the test, now known as the Draize Eye Test, has been used extensively to assess eye safety. It has also been a focal point for concern regarding its animal use. In 1992, Molecular Devices developed th...
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The notion of test method validation, when applied to in vitro models, has been subjected to standards, practices, and regulatory mandates that may represent significant barriers to the development of new methods based on target toxicological pathways, mode of action, and mechanistic endpoints. Currently, there is an expectation that toxicity test...
Article
On FRAME's 40th anniversary, I had the opportunity to examine FRAME and CAAT's missions as closely linked to those of their universities. The roles of education, research and service are key, both to the universities and to our two centres. By examining the current programmes, and identifying the needs of the future, the research activities, policy...
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Recent advances in the area of neuroscience have led to an increased understanding of nociception in mammals, including a recently discovered single gene mutation in humans that leads to complete pain insensitivity. Work on knock-out mice is already underway. This presents the biomedical sciences with the questions of if and how pain insensitive an...
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In this report we present the findings from a nanotoxicology workshop held 6-7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health i...
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This is the report of the first workshop on Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity (DNT) Testing into International Hazard and Risk Assessment Strategies, held in Ispra, Italy, on 19-21 April 2005. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and jointly organiz...
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Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are col...
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The workshop objectives were to explore progress in implementing new, revised and alternative toxicological test methods across regulatory evaluation frameworks and decision-making programs in the United States, to identify barriers and to develop recommendations to further promote adoption of approaches that reduce, refine, or replace the use of a...
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Reducing animal suffering often has the unexpected benefit of yielding more rigorous safety tests
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To address the growing need for scientifically valid and humane alternatives to developmental neurotoxicity testing (DNT), we propose that basic research scientists in developmental neurobiology be brought together with mechanistic toxicologists and policy analysts to develop the science and policy for DNT alternatives that are based on evolutionar...
Article
As Russell and Burch suggested more than 40 years ago, the most humane science is the best science. The path ahead is clear: pain and distress must be eliminated in animal experiments or reduced to an absolute minimum, and, as scientists, we must use the most humane approaches in our research. To accomplish the best science, we must train those who...
Article
There are a number of national and international efforts designed to screen chemicals for toxicity. Although the emphasis in terms of the specific chemicals is different, e.g. endocrine disruptors, children's health, High Production Volume (HPV), the European Registration, Evaluation and Authorisation of Chemicals (REACH) programme, the purpose is...
Article
My paper will focus on those events happening within the United States during the last year. The issue of including or excluding rats, birds and mice from inclusion under the Animal Welfare Act has been a difficult battle for both those that wish to exclude them and those that wish to include these animals under this legislation. As of the writing...
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This article examines the status and application of alternatives defined as replacements, refinements, and reduction for screening high production volume (HPV) chemicals. It specifically focuses on the Screening Information Data Set (SIDS), a series of toxicological tests recommended by the Organization for Economic Cooperation and Development to s...
Article
The TestSmart program was developed in response to the High Production Volume Chemical Challenge, a voluntary initiative under which chemical producers provide basic toxicity data on chemicals produced in greater than one million pounds annually. Specifically, under the Challenge, chemical producers will generate data as needed to complete the Scre...
Chapter
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This chapter reveals that the field of toxicology has evolved from describing the consequences of exposure to chemicals, to studying xenobiotics in animals, to mechanistically based studies of both animals and cell or tissue cultures. During the 1990s, in vitro studies of cell and tissue cultures, such as the Ames mutagenicity assay, have become im...
Article
The publication in 1959 of Russell and Burch's ThePrinciplesofHumaneExperimentalTechnique initiated a new era in the history of the debate between science and animal protection, the era of alternatives. Although Russell and Burch never used the word (speaking instead of the : replacement, reduction, and refinement), and although the animal protecti...
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Scientific principles demand that before newly developed alternative methods for safety testing are fully embraced by the industrial or regulatory community, they reliably and reproducibly predict the designated toxic end point. The process used to determine reliability and reproducibility is termed validation, and it generally culminates with a hi...
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Conceptually, irritant contact dermatitis (irritation) and allergic contact dermatitis (ACD) in man should provide the ideal platforms to launch in vitro toxicology into the pantheon of in vitro testing assays. In theory, irritant dermatitis has been considered by most a simple area of cutaneous biology, whereas ACD is a complex area of biology. Ho...
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The authors are at the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), Johns Hopkins School of Public Health, 111 Market Place, Suite 840, Baltimore, MD 21202-6709, USA. E-mail: caat{at}caat.spharbor.jhu.edu In 1959, British scientists William M. S. Russell and Rex L. Burch wrote that scientific excellence and humane use of laborato...
Article
The Three Rs, reduction, refinement and replacement, were introduced in 1959 by Russell & Burch in their important publication The Principles of Humane Experimental Technique. These Three Rs are now collectively referred to as alternatives. Using the letter R, we have developed an expanded list of Rs not only to stimulate our own thinking, but to e...
Article
A modular concept to validate nonwhole animal test methods is proposed. The concept follows the definition, first suggested by Dr. John Frazier in OECD Environment Monograph 36, that validation is the use of a test for a specific purpose. The principles of the concept were all presented in a document describing a framework for validation by Goldber...
Chapter
As a science, toxicology defines the interaction between chemical and/or physical agents and the consequences of the alterations to living tissues, cells, and intact organisms. Another purpose for the study of these biological consequences is to delineate and understand the risk to humans and animals from exposure, either intentionally or accidenta...
Article
The development and application of in vitro alternatives designed to reduce or replace the use of animals, or to lessen the distress and discomfort of laboratory animals, is a rapidly developing trend in toxicology. However, at present there is no formal administrative process to organize, coordinate, or evaluate validation activities. A framework...
Article
The development and application of in vitro alternatives designed to reduce or replace the use of animals, or to lessen the distress and discomfort of laboratory animals, is a rapidly developing trend in toxicology. However, at present there is no formal administrative process to organize, coordinate, or evaluate validation activities. A framework...
Article
This paper reviews advances in the validation of alternative methods for eye irritation testing since the 1987 publication, A Critical Evaluation of Alternatives to Acute Ocular Irritation Testing (1). We have highlighted details of methods that appear promising and identified the minimum needs and endpoints necessary to develop a battery or batter...
Article
Biomedical endeavours can be divided into three major categories: research, education, and testing. Within the context of each of these categories, activities involving whole animals have made major contributions and will continue to do so in the future. However, with technological developments in the areas of biotechnology and computers, new metho...
Chapter
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two enzymes that are important because of the role they play in neurotransmission and metabolism of exogenous and endogenous substrates. While both enzymes hydrolyze acetylcholine (ACh), they do so at significantly different rates, AChE being approximately 10X faster (Main, 1976). Bot...
Article
Morphologic alterations of the hippocampal mossy fiber pathway after postnatal lead exposure have been observed in rats. It is hypothesized that lead might perturb zinc pools found in this pathway. To test this hypothesis, rat pups were exposed to lead indirectly by administering 0.2% lead acetate to dams via the drinking water during lactation for...
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Quantitative and qualitative studies suggest that zinc is concentrated in the mossy fiber boutons of the hippocampus and is believed to exist as a chelatable cytosolic pool. These studies were aimed at testing the hypothesis that a zinc-binding protein(s) or an amino acid pool in the cytosol is responsible for the sequestration of zinc. For compari...
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Previous autoradiographical studies utilizing 65Zn demonstrated an apparent concentration of 65Zn in the mossy fiber boutons of the hippocampus. To examine the speciation of the 65Zn pool found in this neuronal pathway, we investigated the in vivo incorporation of systemic 65Zn into rat hippocampus compared with other brain regions. We were especia...
Article
Copper and zinc play important roles in the metabolic functions of the central nervous system. The effect of the chelating agent diethyl-dithiocarbamate (DDC) on the nervous system may be related to its effect on the kinetics and distribution of these essential metals. This study was designed to investigate the effects of DDC on copper and zinc con...
Article
These experiments were designed to test the extent to which the concentration of extracellular choline affects the synthesis and subsequent release of acetylcholine (ACh) by rat cortex in vitro. We found that the rate of potassium-depolarized ACh release from rat cortical minces was significantly accelerated when choline chloride was added to the i...
Article
The chloride dependence of acetylcholine (ACh) synthesis and release and of choline uptake was studied in synaptosomal preparations from rat brain. The substitution of propionate for chloride, in the presence of 35 mM-potassium, lowered the ACh content of the synaptosomes. However, in the presence of 5 mM-potassium, the ACh level in synaptosomes wa...
Article
This presentation focused on describing the unique aspects of nervous tissue which make it susceptible to toxicological insult. It reviewed the published literature of compounds that have been studied in tissue culture of nerve tissue and compared the data in vivo toxicity studies with that obtained from the tissue culture system. Further, neuronal...
Article
Primary cell cultures of mouse embryo spinal cords were used to study the biological effects of exposure to organophosphate esters and neurotoxic amino acids. The effects of exposure were correlated with markers of cholinergic function. The purpose of this study was to examine the mechanisms whereby xenobiotics produce neurotoxicologic damage.
Article
Misonidazole is a 2-nitroimidazole compound developed as a hypoxic cell sensitizer for cancer radiotherapy. Because neurotoxicity has occurred in clinical trials, the authors examined the neuropathology of intoxicated rats. In the peripheral nervous system, changes consisted of distal axonal degeneration in intramuscular nerve branches, and edema i...
Article
Diisopropylphosphorofluoridate (DFP) increased the specific activity of choline acetyltransferase (ChAT) in mouse spinal cord cell cultures but paraoxon did not, though both toxicants inhibited cholinesterase activity to a comparable extent. This effect of DFP was observed after prolonged exposure but not after short-term application to the culture...
Article
This chapter discusses the effects of inorganic lead on cholinergic transmission. Low levels of inorganic lead chronically administered during critical periods of development result in behavioral alteration and neurochemical changes. Among the changes seen consistently are alterations in central and peripheral cholinergic function. Administration o...
Article
1. The effects of disuse on the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) have been investigated in the sciatic nerve and leg muscles of the rat. 2. Disuse was produced by blockade of nerve conduction by repeated subperineurial injection of tetrodotoxin (TTX), and the effects were compared to those of denervation....
Article
The pathways for synthesis of deanol into ACh exist. Unclear, at the present time, is the magnitude and significance of these potential routes. There are a multitude of questions that should be studied in great detail. For example a number of studies have documented the conversion of deanol to choline; the location of these biotransformations and c...
Article
A model system has been developed for studying the release of endogenous acetylcholine from the vascular perfused phrenic nerve-hemidiaphragm of the rat. A method is described for cannulating the diaphragmatic vein. This cannulated preparation is placed in a specially designed Plexiglass chamber. The small volume of perfusion necessary to maintain...
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Mice chronically exposed to lead during initial periods of development demonstrate increased levels of spontaneous motor activity. Their behavioral responses to a number of drugs indicate a decrease in central cholinergic activity. Studies utilizing peripheral nervous tissue have shown a decreased evoked and an elevated spontaneous release of ACh b...
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