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The German postgraduate training program in toxicology
Poster Session 3U. General Toxicology I
P 3 U - 3 8 7 1 THE EFFECT OF FOOD RESTRICTION ON BODY I WEIGHTS AND CLINICAL CHEMISTRY IN SPRAGUE DAWLEY RATS J.L. Boiziau *, F. Jabes, C. Deshayes. Laboratoire J. Logeais, 15 rue Denis Papin, 78190 Trappes, France In toxicological studies, changes may be the result of specifics actions of drugs, or the consequence of anorexia [1]. The aim of the study was to determine the effect of food restriction for 4 week on toxicologic parameters. Eighty Sprague-Dawley rats (10/sex/group) were used. Diet restriction was 25, 50 and 75% of control group. Toxicologic parameters were performed (body weights, urinalysis, hematology, biochemistry). For ethical considerations we stopped the females severely restricted (75%) at day 15. At the end of study, all animals were killed, and submitted to a full macroscopic examination. Organ weights were recorded, liver cyt.P450 were evaluated and tissue specimens were examined microscopically. In this poster only the serum chemistry results are discussed. The terminal body weights of the mildly, moderately and severely restricted groups were respectively only about 85, 65 and 35% of controls. Only the liver and thymus weights were decreased in all restricted groups. The principal changes in clinical chemistry were in 75% restricted group. The activities of ALT, ASAT and serum BUN were increased in both sex. The activities of ALKP and serum TP, ALB, TRIG, GLOB were decreased in both sex. Serum TBIL and electrolytes were increased only in males. NH3 was increased in males but decreased in females. Only in the mildly and moderately restricted groups serum GLU was increased. The findings in the mildly and moderately restricted groups may be postulated as an adaptive metabolism. The severe changes in the severely restricted groups could be considered as adverse metabolic alterations. [1] Levin, S., Semler D., and Ruben Z., Toxicol. Pathol., 21, 1-14, 1993.
Keywords: body weight; food restriction; clinical chemistry
P 3 U - 3 8 8 ] COMPARATIVE 52-WEEK STUDY OF 17/3 OESTRADIOL AND ETHINYL OESTRADIOL IN BEAGLE DOGS AND CYNOMOLGUS MONKEYS Mahmoud Attia i, Fran~oise Goldfain 1, Jean-Francois Le Bigot * J, Ibrahim Zayed 2. i CIT, Centre International de Toxicologie, Evreux, France; 20rganon N. V., Oss, The Netherlands 17/5 oestradiol (E2) or ethinyl oestradiol (EE) was administered daily by gavage for 52 weeks to Beagle dogs at the dose levels of 5 mg/kg/day E2 and 0.5 mg/kg/day EE or 2 mg/kg/day which was then decreased to 1.5 and 1 mg/kg/d EE. The dose levels in Cynomolgus monkeys were 5 mg/kg/day E2 and 2 mg/kg/day EE. The effect of hormonal treatment on clinical signs, food consumption, body weight, haematological and blood biochemical parameters were evaluated. Treatment with both oestrogens induced significant mortality in dogs only. Brownish/blackish pigments on the abdomen, small testes and mammary gland swelling were found in both species. Severe alopecia was noted only in dogs. Lower food consumption was observed in dogs and decreased body weight was found in both dogs and monkeys. The effect on body weight was more marked in dogs than in monkeys and more prominent in males than in females. Moderate to severe thrombocytopenia was noted in a cyclical manner in dogs, the effect being more prominent in animals treated with EE than those treated with E2. This thrombocytopenia was one of the major factors contributing to death among the treated dogs. No thrombocytopenia was found in monkeys. In both dogs and monkeys, normocytic nonregenerative anaemia was observed. This was associated with neutrophil leucocytosis in dogs and with prolonged activated partial thromboplastin time in monkeys. Lower inorganic phosphorus
107
was noted in both species. This was associated with higher cholesterol level in dogs and lower alkaline phosphatase activity and higher triglyceride level in the monkeys. These results demonstrated that the dog is more sensitive to oestrogen treatment than the monkey. Considering the known effects in humans, the latter seems to be a more suitable model for toxicological testing of such compounds.
Keywords: beagle dogs; cynomolgus monkeys; 17/5 oestradiol; ethinyl oestradiol
P3U-3891 THE GERMAN POSTGRADUATE TRAINING PROGRAM IN TOXICOLOGY
Sigrun Hesse-Callaway *, Helmut Greim. GSF-Forschungszentrum fiir Umwelt und Gesundheit, Neuherberg/Miinchen, Germany A postgraduate training program in toxicology has been established in Germany, offering theoretical training in toxicology on a modular basis to candidates aiming toward certification as "Expertin-Toxicology, DGPT". The certificat is awarded by the German Society Of Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft far experimemtelle und klinische Pharmakologie und Toxikologie [DGPT]). The precondition is a university degree in medicine, chemistry, biochemistry, biology, or related subject. More than a dozen courses, covering a spectrum of fields in toxicology are held each year at toxicological institutes of universities and research centers throughout Germany specializing in the respective fields. The courses confront candidates with Germany's leading authorities and research facilities in the various fields of toxicology. They provide the best possible education in a spectrum of toxicological subdisciplines. To be eligible to take the oral examination for "Expert-of-Toxicology, DGPT", candidates must have at least five years of full-time professional experience in toxicology, three years of which has been spent in experimental work. They must have gained comprehensive knowledge in at least one topic area, broad knowledge in another two areas and basic knowledge in all 15 stated areas of toxicology. Candidates must submit at least three independent peer-reviewed papers or professional assessments in toxicology or pharmacology. The oral examination is conducted by an elected commission of the DGPT.
Keywords: training in toxicology; certification requirements; Germany AND PATHOLOGICAL EFFECTS OF lP3U-3901 ANATOMICAL PARTIAL VITREOUS BODY REPLACEMENT IN THE CYNOMOLGUS MONKEY Bernard Regnier i, Elizabeth Roberts 2, Bernard Clerc 3 Yves Guichard I. I Pharmakon Europe Domaine des Oncins 69593 L'Arbresle, France; 2 Fermentech Medical Ltd Heriot Watt Research Park, Edinburgh EH14 4AP, Great Britain; 3 Ecole Nationale Veterinaire D'Alfort 7 avenue du Gdndral de Gaulle 94704 Maisons Alfort, France Aqueous humor replacement fluids are in increasing demand. An animal model was developed to assess the local tolerance of sodium hyaluronate, either derived from rooster combs or of bacterial origin, in comparison with isotonic saline. Three groups of one male and one female Macaca fascicularis were put on study, each group receiving one of the fluids in the right eye. The left eye was kept untreated. In order to ensure an exposure of one-week, the test materials were administered in the vitreous body after removal of an equivalent volume of fluid- and not in the aqueous humor because of the rapid turnover of the latter. Ophthalmological examinations (indirect ophthalmoscopy, biomicroscopy and retinography) were performed before treatment and on days 1, 2, 7 and 8. Leucocyte counts were performed on days 1 and 8 for the vitreous body and
P 3 U - 3 8 7 1 THE EFFECT OF FOOD RESTRICTION ON BODY I WEIGHTS AND CLINICAL CHEMISTRY IN SPRAGUE DAWLEY RATS J.L. Boiziau *, F. Jabes, C. Deshayes. Laboratoire J. Logeais, 15 rue Denis Papin, 78190 Trappes, France In toxicological studies, changes may be the result of specifics actions of drugs, or the consequence of anorexia [1]. The aim of the study was to determine the effect of food restriction for 4 week on toxicologic parameters. Eighty Sprague-Dawley rats (10/sex/group) were used. Diet restriction was 25, 50 and 75% of control group. Toxicologic parameters were performed (body weights, urinalysis, hematology, biochemistry). For ethical considerations we stopped the females severely restricted (75%) at day 15. At the end of study, all animals were killed, and submitted to a full macroscopic examination. Organ weights were recorded, liver cyt.P450 were evaluated and tissue specimens were examined microscopically. In this poster only the serum chemistry results are discussed. The terminal body weights of the mildly, moderately and severely restricted groups were respectively only about 85, 65 and 35% of controls. Only the liver and thymus weights were decreased in all restricted groups. The principal changes in clinical chemistry were in 75% restricted group. The activities of ALT, ASAT and serum BUN were increased in both sex. The activities of ALKP and serum TP, ALB, TRIG, GLOB were decreased in both sex. Serum TBIL and electrolytes were increased only in males. NH3 was increased in males but decreased in females. Only in the mildly and moderately restricted groups serum GLU was increased. The findings in the mildly and moderately restricted groups may be postulated as an adaptive metabolism. The severe changes in the severely restricted groups could be considered as adverse metabolic alterations. [1] Levin, S., Semler D., and Ruben Z., Toxicol. Pathol., 21, 1-14, 1993.
Keywords: body weight; food restriction; clinical chemistry
P 3 U - 3 8 8 ] COMPARATIVE 52-WEEK STUDY OF 17/3 OESTRADIOL AND ETHINYL OESTRADIOL IN BEAGLE DOGS AND CYNOMOLGUS MONKEYS Mahmoud Attia i, Fran~oise Goldfain 1, Jean-Francois Le Bigot * J, Ibrahim Zayed 2. i CIT, Centre International de Toxicologie, Evreux, France; 20rganon N. V., Oss, The Netherlands 17/5 oestradiol (E2) or ethinyl oestradiol (EE) was administered daily by gavage for 52 weeks to Beagle dogs at the dose levels of 5 mg/kg/day E2 and 0.5 mg/kg/day EE or 2 mg/kg/day which was then decreased to 1.5 and 1 mg/kg/d EE. The dose levels in Cynomolgus monkeys were 5 mg/kg/day E2 and 2 mg/kg/day EE. The effect of hormonal treatment on clinical signs, food consumption, body weight, haematological and blood biochemical parameters were evaluated. Treatment with both oestrogens induced significant mortality in dogs only. Brownish/blackish pigments on the abdomen, small testes and mammary gland swelling were found in both species. Severe alopecia was noted only in dogs. Lower food consumption was observed in dogs and decreased body weight was found in both dogs and monkeys. The effect on body weight was more marked in dogs than in monkeys and more prominent in males than in females. Moderate to severe thrombocytopenia was noted in a cyclical manner in dogs, the effect being more prominent in animals treated with EE than those treated with E2. This thrombocytopenia was one of the major factors contributing to death among the treated dogs. No thrombocytopenia was found in monkeys. In both dogs and monkeys, normocytic nonregenerative anaemia was observed. This was associated with neutrophil leucocytosis in dogs and with prolonged activated partial thromboplastin time in monkeys. Lower inorganic phosphorus
107
was noted in both species. This was associated with higher cholesterol level in dogs and lower alkaline phosphatase activity and higher triglyceride level in the monkeys. These results demonstrated that the dog is more sensitive to oestrogen treatment than the monkey. Considering the known effects in humans, the latter seems to be a more suitable model for toxicological testing of such compounds.
Keywords: beagle dogs; cynomolgus monkeys; 17/5 oestradiol; ethinyl oestradiol
P3U-3891 THE GERMAN POSTGRADUATE TRAINING PROGRAM IN TOXICOLOGY
Sigrun Hesse-Callaway *, Helmut Greim. GSF-Forschungszentrum fiir Umwelt und Gesundheit, Neuherberg/Miinchen, Germany A postgraduate training program in toxicology has been established in Germany, offering theoretical training in toxicology on a modular basis to candidates aiming toward certification as "Expertin-Toxicology, DGPT". The certificat is awarded by the German Society Of Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft far experimemtelle und klinische Pharmakologie und Toxikologie [DGPT]). The precondition is a university degree in medicine, chemistry, biochemistry, biology, or related subject. More than a dozen courses, covering a spectrum of fields in toxicology are held each year at toxicological institutes of universities and research centers throughout Germany specializing in the respective fields. The courses confront candidates with Germany's leading authorities and research facilities in the various fields of toxicology. They provide the best possible education in a spectrum of toxicological subdisciplines. To be eligible to take the oral examination for "Expert-of-Toxicology, DGPT", candidates must have at least five years of full-time professional experience in toxicology, three years of which has been spent in experimental work. They must have gained comprehensive knowledge in at least one topic area, broad knowledge in another two areas and basic knowledge in all 15 stated areas of toxicology. Candidates must submit at least three independent peer-reviewed papers or professional assessments in toxicology or pharmacology. The oral examination is conducted by an elected commission of the DGPT.
Keywords: training in toxicology; certification requirements; Germany AND PATHOLOGICAL EFFECTS OF lP3U-3901 ANATOMICAL PARTIAL VITREOUS BODY REPLACEMENT IN THE CYNOMOLGUS MONKEY Bernard Regnier i, Elizabeth Roberts 2, Bernard Clerc 3 Yves Guichard I. I Pharmakon Europe Domaine des Oncins 69593 L'Arbresle, France; 2 Fermentech Medical Ltd Heriot Watt Research Park, Edinburgh EH14 4AP, Great Britain; 3 Ecole Nationale Veterinaire D'Alfort 7 avenue du Gdndral de Gaulle 94704 Maisons Alfort, France Aqueous humor replacement fluids are in increasing demand. An animal model was developed to assess the local tolerance of sodium hyaluronate, either derived from rooster combs or of bacterial origin, in comparison with isotonic saline. Three groups of one male and one female Macaca fascicularis were put on study, each group receiving one of the fluids in the right eye. The left eye was kept untreated. In order to ensure an exposure of one-week, the test materials were administered in the vitreous body after removal of an equivalent volume of fluid- and not in the aqueous humor because of the rapid turnover of the latter. Ophthalmological examinations (indirect ophthalmoscopy, biomicroscopy and retinography) were performed before treatment and on days 1, 2, 7 and 8. Leucocyte counts were performed on days 1 and 8 for the vitreous body and