ATLA 27.6, November 1999

//ATLA 27.6, November 1999

Precautions and Claims for “Safety” Based on Inadequate Risk Assessment are Hazardous and Expose All Concerned to Risk

Robert D. Combes and Michael Balls

Seeking to protect the human population from the effects of potentially dangerous chemicals and chemical products (for example, medicines and pesticides) is a complex process, which begins with hazard identification and proceeds via exposure estimation to risk assessment and, eventually, to risk management.
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News & Views

ATLA Staff Writer

Chimps to be Released from US Laboratory
LASA Report on The Production and Disposal of Laboratory Rodents Surplus to the Requirements for Scientific Procedures
European Statistics on Laboratory Animal Use
Dutch Laboratory Animal Course
Human Tissue for Biomedical Research
Staff Change
UK Government Bans LD50 Test
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Introduction to Professor W.M.S. Russell’s First Annual FRAME Lecture, Presented at the Royal Society of Medicine, London, on 24 September 1999

Lord Soulsby of Swaffham Prior

A few weeks ago, the 3rd World Congress on Alternatives and Animal Use in the Life Sciences was held in Bologna, Italy. This conference was 40 years on since the publication of The Principles of Humane Experimental Technique by W.M.S. Russell and R.L. Burch. Indeed, the 40-years-on theme was celebrated by a special lecture by Bill Russell in the Aula Magna of the University of Bologna, and in his usual extrovert style he informed and enchanted his audience, as I am sure he will do this evening in the First Annual FRAME Lecture.
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Gastrulating Rat Embryo in a Serum-free Culture Model: Changes of Development Caused by Teratogen 5-Azacytidine

Floriana Bulic-Jakuš, Maja Vlahovic, Gordana Juric-Lekic, Vesna Crnek-Kunstelj and Draško Šerman

Developmental processes in gastrulating rat embryos were investigated by using an original, serum-free, chemically defined model system. 9.5-day-old rat embryos, without extraembryonic membranes, were cultivated at the air–liquid interface in a serum-free medium, with and without a protein supplement, for 2 weeks. A teratogenic, demethylating agent, 5-azacytidine, was added to serum-free and protein-free culture medium and to serum-free medium supplemented with human transferrin. A single dose of 5-azacytidine impaired the survival, growth and differentiation of embryos in protein-free medium and serum-free medium with transferrin. In contrast, repeated exposure to 5-azacytidine was required to impair growth in serum-supplemented medium. It was concluded that the activity of 5-azacytidine was easier to detect in a simple, chemically defined medium than in a serum-supplemented medium. This serum-free in vitro method could be useful in screening for teratogenic or embryotoxic substances during gastrulation, the most critical stage of mammalian development.
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Description of a Dynamic In Vitro Model of the Dog Gastrointestinal Tract and an Evaluation of Various Transit Times for Protein and Calcium

Marianne J.E. Smeets-Peeters, Mans Minekus, Robert Havenaar, Gertjan Schaafsma and Martin W.A. Verstegen

In order to manufacture complete and balanced dog diets, it is important to know the nutrient requirements of dogs and the availability of these nutrients from food. As pet food manufacturers are restricted in their options for (invasive) animal studies, due to ethical constraints, it is important to have alternative methods for researching the effects of various dog diets. To simulate the gastrointestinal tract of the dog, the dynamic gastrointestinal tract model developed by Minekus et al. was further developed and modified in this study. The model consists of four compartments which simulate the stomach and small intestine (duodenum, jejunum and ileum). Each compartment is made of glass, with a flexible inner wall. This wall can be compressed by increasing the pressure of the surrounding water, mimicking the peristaltic movements and mixing seen in vivo. The model is computer-controlled to simulate physiological parameters such as pH, transit time and secretion of digestive juices, as derived from the literature. Gastric meal delivery and the effects of intestinal transit time on protein digestibility and availability for absorption of calcium from dog food were studied to evaluate the model. The gastric meal delivery of dry dog food was identical to a preset curve, which was based on in vivo data from healthy dogs. The emptying time for canned dog food was somewhat slower than the preset values, probably due to the viscosity of the meal. The differences between the preset values and the measured delivery were not significant. The digestibility of protein and the availability of calcium for absorption increased with a longer transit time. A significant difference was found between medium and slow transit times for the nitrogen content in the ileal delivery effluent and the jejunal dialysates (p < 0.05). The same trend was seen for calcium (not significant). The overall conclusion is that the model is a useful tool for mimicking the gastrointestinal tract of dogs. Parameters such as pH, transit time and enzyme activity can be mimicked and can be kept within a physiological range.[/fusion_toggle] [/fusion_builder_column][fusion_builder_column row_column_index="1_2" type="1_1" background_position="left top" background_color="" border_size="" border_color="" border_style="solid" spacing="yes" background_image="" background_repeat="no-repeat" padding="" margin_top="0px" margin_bottom="0px" class="" id="" animation_type="" animation_speed="0.3" animation_direction="left" hide_on_mobile="no" center_content="no" min_height="none"][s2If current_user_cannot(access_s2member_level0)] You need to register (for free) to download this article. Please log in/register here.[/s2If]

Effects of Chromatin Function Inhibitors on Yeast Whole Cells and Spheroplasts

Ekaterini Tiligada, Elias Stavrinidis, Christos Manolis and Andreas Delitheos

Saccharomyces cerevisiae has long been used as an alternative experimental model in the study of cancer and anticancer drug action. Although this simple eukaryote has provided useful information, its value as an experimental model is often controversial due to the presence of the cell wall — a cellular structure which is absent in higher eukaryotes. The aim of this study was to investigate the possible involvement of the cell wall in the ineffectiveness of some anticancer drugs in yeast, by enzymatic removal of the cell wall. The effects of exposing whole-cell cultures and spheroplasts to chromatin function inhibitors for 22 hours were investigated. Vinblastine, etoposide and paclitaxel had no cytotoxic effects on whole-cell cultures either with or without the addition of verapamil. The growth profiles of yeast spheroplasts following drug exposure were similar to those observed in whole cells. These data demonstrate that the resistance of the lower eukaryote to these drugs was not overcome by the enzymatic removal of the cell wall.
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Determination of the Starting Dose for Acute Oral Toxicity (LD50) Testing in the Up and Down Procedure (UDP) From Cytotoxicity Data

Horst Spielmann, Elke Genschow, Manfred Liebsch and Willi Halle

To reduce the number of animals used in acute oral toxicity testing, cytotoxicity data (IC50) can be used to determine the starting dose for in vivo testing by applying the standard regression between IC50 and acute oral LD50 values in the Register of Cytotoxicity (RC). In the RC, the correlation between cytotoxicity, represented by the mean IC50 (IC50x), and the acute oral LD50 of rats and/or mice has been determined for 347 chemicals by applying the linear regression model for log-transformed pairs of IC50 versus oral LD50. The standard regression line of the two toxicity parameters is characterised by an intercept a = 0.625 and regression coefficient b = 0.435, and 252 of 347 chemicals (72.6 %) are located within a dose-range differing by not more than 0.699 (factor FG ≤ log 5) from the standard regression line. In the present study, we have used the RC and its IC50/LD50 regression model to predict the LD50 values from cytotoxicity data for nine chemicals which were tested in an evaluation study of the Up and Down Procedure (UDP). For seven of the nine chemicals, LD50 values (mg/kg) predicted from the RC were in the same doserange as LD50 values determined in vivo, while the dose-range differed by more than one order of magnitude for the two remaining chemicals. Thus, the prediction of LD50 values from cytotoxicity data was promising in this limited data set. It is proposed that a tiered in vitro/in vivo testing approach will reduce animal use in the UDP method. As the first step, the in vitro cytotoxicity of a new chemical is determined. By applying the RC regression and adapting it to the sensitivity of a specific cell line, the LD50 value (mg/kg) can be predicted from the IC50 value. The predicted LD50 dose is then used as the starting dose in the UDP. In the RC model, the precision of the prediction increases with decreasing toxic potential, and the majority of industrial chemicals (around 90%) are not toxic according to EU classification criteria.
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Alternatives to Harmful Animal Use in Tertiary Education

Andrew Knight

On 11 November 1998, Western Australia’s Murdoch University took the groundbreaking step of formally allowing conscientious objection by students to animal experimentation or other areas of their coursework. Murdoch is, to my knowledge, the first Australian university to take this formal step, and its decision will have ramifications for other Australian universities.
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