['Book', 'of', 'Abstracts', '—', 'EUROTOX', '94', '5', 'also', 'have', 'normat', 'intracellular', 'glutathiona', 'levels', 'and', 'ratain', 'most', 'morphological', 'features', 'of', 'hepatoeytes', 'in', 'vivo,', 'The', 'purpose', 'of', 'the', 'current', 'study', 'is', 'to', 'evaluate', 'and', 'refine', 'this', 'hepatacyte', 'culture', 'system', 'as', 'a', 'screening', 'system', 'for', 'liver', 'toxins.', 'Initial', 'results', 'indicate', 'that', 'our', 'cultured', 'hepatocytes', 'are', 'sensitiva', 'to', 'a', 'varisty', 'of', 'hepatotoxins,', 'includ-', 'ing', 'acetaminophen', 'and', 'carben', 'tetrachloride.', 'Using', 'acetaminophen', 'as', 'a', 'model,', 'we', 'have', 'demonstrated', 'a', 'clear', 'advantage', 'to', 'using', 'this', 'hepatecyte', 'culture', 'system', 'far', 'screenlng', 'toxins', 'that', 'require', 'hicactivatian:', 'hepatacytes', 'maintained', 'with', 'cur', 'methods', 'are', 'two', 'times', 'more', 'sensitive', 'to', 'acetaminophen', 'than', 'hepatocyte', 'maintained', 'in', 'con-', 'ventional', 'cultura', 'or', 'hepatocyte', 'cell', 'lines', 'that', 'have', 'low', 'levals', 'of', 'P450', 'activity', 'and', 'show', 'no', 'toxicity.', 'In', 'cornparisen', 'studies', 'between', 'labaratories,', 'we', 'have', 'further', 'canfirmed', 'the', 'intetabaratory', 'repraducibifity', 'of', 'tha', 'cultuca', 'systerm', 'and', 'dose', 'response', 'relationships', 'of', 'tha', 'culture', 'system', 'and', 'dose', 'response', 'relationships', 'to', 'CdClp', 'and', 'acetarninophen.', 'Metabolism', 'of', 'NNK', 'in', 'Rats', 'During', 'Low', 'Dose', 'Chronic', 'Administration', 'AL,', 'GIE,', 'Prov', 'S.E', 'Atawodi,', 'C.', 'Kutze,', 'E.', 'Richter.,', 'Walther', 'Syaub-lnstitute', 'of', 'Phacmacology', 'and', 'Toxicology.', 'HER,', 'R', 'Lidwig-Maximilians-University,', 'Munich,', 'Garmany', 'The', 'tobacco-specific', 'nitrosamine,', '4{methylnitrosamino}-14{3-pyridyl}-1-butanane', '(NNK}', 'is', 'a', 'lung', 'carcinogen', 'in', 'ro-', 'dents', 'which', 'may', 'play', 'an', 'important', 'rale', 'in', 'the', 'induction', 'of', 'lung', 'adenocarcinomas', 'in', 'cigarette', 'smokers.', 'In', 'order', 'to', 'simulate', 'the', 'candition', 'in', 'smakars,', 'the', 'metabolism', 'of', 'NNK', 'at', 'low', 'chronic', 'doses', 'was', 'studled', 'using', 'Atzet', 'mini-', 'pumps', 'implanted', 'subcutaneously', 'in', 'the', 'neck', 'of', 'male', 'F344', 'rats', 'welghing', 'about', '200', 'g.', 'The', 'pumps', 'were', 'filled', 'with', '[5-3HFNNK', 'in', 'saline', 'and', 'delivered', '55.4', 'ul/day', 'corresponding', 'to', '180', 'ng', 'NNK', '(0.9', 'pg/kg/day).', 'Total', 'H', 'in', 'uine', 'and', '{accas', 'was', 'determined', 'daily', 'and', 'the', 'metabolites', 'in', 'urine', 'analysed', 'by', 'HPLE.', 'After', '28', 'days', 'the', 'rats', 'ware', 'bled', 'from', 'the', 'abdominal', 'aorta', 'and', 'the', 'concentration', 'of', 'free', 'and', 'bound', '3H', 'in', 'blood', 'detarmined.', 'Excretion', 'of', 'total', '3H', 'reached', 'a', 'plateau', 'within', 'one', 'week', 'approaching', '91', '7%', 'of', 'the', 'cumufative', 'dose', 'with', '79', '9%', 'and', '12', '4%', 'appearing', 'In', 'utine', 'and', 'faaces,', 'respectively.', 'Tha', 'metaholita', 'pattern', 'In', 'urine', 'did', 'not', 'change', 'over', 'time,', 'Products', 'of', 'a-hydroxylatian', 'and', 'N-oxidation', 'accounted', 'for', '62', '&=', '10%', 'and', '34', '&', '4%', 'of', 'total', '°H', 'In', 'urine,', 'respectively.', 'After', '28', 'days', 'hemoglobin', 'binding', 'resulted', 'In', '2', '30-fold', 'higher', 'concantration', 'of', '3H', 'in', 'dialyzed', 'hemoglobin', '(32.5', '=', '11.8', 'pmol/g)', 'as', 'comparad', '10', 'whale', 'hlood', '(1.1', '£', '0.4', 'pmol/mil.', 'by', 'S.E.', 'Atawodi', 'Is', 'an', 'Alexander', 'von', 'Humboldt', 'Research', 'Fellow.', 'Key', 'words:', 'NNK:', 'metabolism;', 'chronic', 'administration:', '/»', 'vive', 'hamoglobin', 'binding', 'Factors', 'Contributing', 'to', 'Mortalities', 'and', 'Tumor', 'Incidence', 'in', 'Sprague-Dawley', 'Rats', 'Used', 'in', 'Carcinogenicity', 'Studies', 'M.', 'Atiia,', 'A.', 'Bécret,', 'R.', 'Glomot,', 'CIT', 'Centre', 'Intermationat', 'de', 'Texicologie,', 'Evrewx.', 'Fiance', 'Data', 'on', 'the', 'factors', 'contributing', '1o', 'mortalities', 'and', 'the', 'incidental', 'tumour', 'analysis', 'in', 'the', 'rats', 'that', 'died', 'or', 'were', 'killed', 'prematurely,', 'are', 'essential', 'for', 'the', 'interpratation', 'of', 'carcinogenicity', 'bicassay.', 'The', 'data', 'on', 'the', 'above-mentioned', 'parameters', 'from', 'Sprague-Dawley', 'COBS-VAF', 'rats', '(Crl:', 'CD', '(SD}', 'BR', 'from', 'Charles', 'River', 'France)', 'used', 'as', 'controls', 'in', '11', 'carcinogenicity', 'studies', 'conducted', 'at', 'C.LT.', 'between', '1988', 'to', '1992', 'were', 'analysed.', 'The', 'major', 'factor', 'contributing', 'to', 'death', 'or', 'premature', 'killing', 'was', 'pituitary', 'tumour', '(43.5%', 'in', 'males', 'and', '68%', 'in', 'famales).', 'The', 'other', 'common', 'factors', 'were', 'killing', 'for', 'humane', 'reasons', 'due', 'to', 'large', 'mass', 'impeding', 'normat', 'lffa', '(8%', 'in', 'males', 'and', '14.5%', 'in', 'females).', 'this', 'in', 'addition', 'to', 'few', 'neoplastic', 'fesions', 'in', 'internal', 'organs', '{from', '0.9%', 'to', '4.5%', 'in', 'animals', 'of', 'both', 'sexas)', 'and', 'very', 'severe', 'chronic', 'tubulointerstitiat', 'nephropathy', 'in', 'males', '{8%).', 'Myeloblastic', 'leukaemia', 'was', 'first', 'diagnosed', 'in', 'femate', 'rats', 'dying', 'after', '11', 'weeks', 'and', 'lymphoblastic', 'lymphoma', 'was', 'first', 'diagnosed', 'in', 'female', 'rats', 'dying', 'after', '18', 'weeks.', 'Few', 'pituitary', 'and', 'mammary', 'neoplasms', 'were', 'diagnosed', 'in', 'female', 'rais', 'dying', 'after', '13', 'weeks.', 'The', 'majority', 'of', 'neoplastic', 'lesions', 'especially', 'those', 'of', 'the', 'endocrine', 'organs,', 'integumentary', 'system,', 'maie', 'and', 'female', 'ganltal', 'organs,', 'liver', 'and', 'kidneys', 'were', 'diagnosad', 'in', 'dying', 'rats', 'from', 'week', '57', 'onwards.', 'Tables', 'containing', 'factors', 'contributing', 'to', 'death', 'or', 'premature', 'kiling', 'and', 'incidental', 'tumour', 'analysis', 'will', 'ba', 'presantad.', 'Koy', 'words:', 'carcinogenicity;', 'factors', 'contributing', 'to', 'mortalities:', 'neoplastic', 'lesions;', 'rat', 'Principles', 'and', 'Patential', 'Benefits', 'of', 'Dose', 'Response', 'Modelling', 'and', 'Benchmark', 'Dose', 'Approach', 'LR,', 'Auton.', 'Zenaca', 'Ceniral', 'Toxicology', 'Laboratory,', 'Macclesfield,', 'UK', 'There', 'is', 'currently', 'much', 'interest', 'in', 'the', 'way', 'that', 'dose', 'response', 'dats', 'from', 'animal', 'toxicity', 'studies', 'are', 'used', 'to', 'set', 'safe', 'levals', 'for', 'human', 'exposure', '1o', 'chemicals.', 'The', 'traditional', 'approach', 'uses', 'tha', 'no', 'observed', 'adverse', 'effect', 'level', '(NOAEL},', 'ie', 'the', 'dose', 'at', 'and', 'below', 'which', 'no', 'adverse', 'effects', 'were', 'ssen,', 'and', 'a', 'suitable', '“safety', 'factor”.', 'An', 'altemnative', 'approach', 'is', 'to', 'fit', 'a', 'mathematical', 'dose-response', 'model', '{o', 'the', 'data', 'from', 'the', 'toxicity', 'study,', 'and', 'use', 'it', 'to', 'calculate', '8', '6klzZg6lLosZ', 'ERTSITFE', 'T', ':', 'P', 'g', 'ey']