[' ', 'P-49', 'EFFECT', 'OF', 'LONG~TERM', 'INHALATION', 'OF', 'N-NITROSODIMETHYLAMINE', 'AND', 'SO,/NO,', 'IN', 'RATS', 'R,', 'G.', 'Klein,', 'I.', 'Janowsky,', 'B.L.', 'Pool,', 'P.', 'Schmezer,', 'R.', 'Hermann,', 'F.', 'Amelung,', 'B.', 'Spiegelhalder', 'and', 'WJ.', 'Zeller', ' ', 'Institute', 'of', 'Toxicology', 'and', 'Chemotherapy,', 'German', 'Cancer', 'Research', 'Center,', '6900', 'Heidelberg,', 'FRG', 'The', 'present', 'report', 'focuses', 'on', 'the', 'toxicological', 'evaluation', 'and', 'his-', 'topathological', 'findings', 'in', 'an', 'ongoing', 'long-term', 'inhalation', 'study', 'with', 'N-nitrosodimethylamine', '(NDMA)', 'with', 'or', 'without', 'SQ)', 'and', 'NO,.', 'Exposure', 'was', 'performed', 'in', 'three', 'NDMA', 'concentrations:', '0.04,', '0.02', 'and', '1.0', 'ppm', '(corresponding', 'to', '120,', '600', 'and', '3000', 'pg/m’).', 'In', 'combination', 'with', 'SO', 'or', 'NO,', '(both', '6', 'ppm)', 'only', 'one', 'concentra-', 'tion', 'of', 'NDMA', '(0.2', 'ppm)', 'was', 'applied,', 'Results', 'indicate', '«', 'significant', 'reduction', 'in', 'survival', 'time', '(7', 'months)', 'when', 'the', 'animals', 'were', 'treated', 'with', 'the', 'highest', 'concentration', 'of', 'NDMA', '(1', 'ppm).', 'Primarily,', 'tumors', 'of', 'the', 'nasal', 'cavity', 'were', 'observed.', 'Incidence', 'of', 'nasal', 'tumors', 'was_', 'highest', 'in', 'the', 'treatment', 'group', 'receiving', '1.0', 'and', '0.2', 'ppm', 'NDMA', '(16/36', 'and', '22/33', 'tumor', 'bearing', 'animals).', 'In', 'the', 'lowest', 'exposure', 'group.of', '0.04', 'ppm', 'only', '5/29', 'nasal', 'cumors', 'were', 'observed', 'so', 'far.', 'The', 'survival', 'time', 'of', 'the', 'latter', 'group', 'was', 'about', 'two', 'months', 'longer', 'than', 'that', 'of', 'the', 'untreated', 'controls,', 'Animals', 'in', 'the', 'combination', 'groups', 'do', 'not', 'show', '«', 'significantly', 'enhanced', 'tumor', 'incidence', 'until', 'now', '(NDMA', '+', 'SO:', '4/9;', 'NDMA', '+', 'NO,:', '7/11;', 'NDMA:', '3/6).', 'No', 'nasal', 'or', 'liver', 'tumors', 'were', 'seen', 'in', 'animals', 'with', 'SO2', 'or', 'NO,', 'alone.', ' ', ' ', ' ', 'SPECIFICITY', 'IN', 'THE', 'METHYLATION', 'OF', 'DNA', 'BY', 'N-NITROSO', 'COMPOUNDS', 'Jamie', 'R.', 'Milligan,', 'Sandra', 'Skotnicki,', 'Shi-Jiang', 'Lu', 'and', 'Michael', 'C,', 'Archer', 'Department', 'of', 'Medical', 'Biophysics,', 'University', 'of', 'Toronto', 'Ontario', 'Cancer', 'Institute,', '500', 'Sherbourne', 'Street,', 'Toronto,', 'Canada', 'M4X', '1K9', 'Although', 'N-nitroso', 'compounds', 'have', 'been', 'known', 'to', 'alkylate', 'DNA', 'for', 'many', 'years,', 'there', 'is', 'little', 'information', 'on', 'the', 'selectivity', 'of', 'this', 'reaction', 'with', 'respect', 'to', 'base', 'sequence,', 'conformation,', 'or', 'particular', '—', 'within', 'the', 'genome,', 'Such', 'information', 'is', 'likely', 'to', 'be', 'crucial', 'for', 'an', 'understanding', 'of', 'the', 'mechanism', 'of', 'carcinogenesis', 'including', 'the', 'tissue', 'and', 'species', 'selectivity', 'associated', 'with', 'ti-uteonn', 'coapounds.', 'We', 'have', 'employed', '4', 'sequencing', 'assay', 'to', 'determine', 'the', 'in', 'vitro', 'reactivity', 'of', 'N-sethyl-N-', 'nitrosourea', '(MNU)', 'with', 'individual', 'nucleotide', 'residues', 'of', 'defined', 'DNA', 'sequences', 'in', 'the', 'noraal', 'B', 'conformation.', 'We', 'have', 'shown', 'that', 'some', 'guanines', 'are', 'more', 'extensively', 'aethylated', 'than', 'others,', 'but', 'the', 'greatest', 'difference', 'in', 'reactivity', 'between', 'guanines', 'ig', 'about', 'S-fold.', 'Furthermore,', 'we', 'found', 'that', 'reaction', 'of', 'MNU', 'at', 'the', '7', 'position', 'of', 'guanine', 'in', 'a(GC)n', 'is', 'attenuated', 'in', 'the', '2', 'fora', 'of', 'DNA', 'relative', 'to', 'the', 'B', 'form.', 'We', 'have', 'also', 'developed', 'a', 'aethod', 'for', 'quantifying', 'alkylated', 'bases', 'in', 'defined', 'gene', 'sequences', 'of', 'tissues', 'following', 'in_vivo', 'carcinogen', 'treataent.', 'Using', 'this', 'method,', 'we', 'have', 'shown', 'that', 'the', 'transcriptionally', 'active', 'albuain', 'gene', 'is', 'damaged', 'by', 'N-nitrosodimethylasine', 'to', 'a', 'much', 'greater', 'extent', 'than', 'the', 'untranscribed', 'IgE', 'gene', 'in', 'rat', 'liver.', 'We', 'have', 'also', 'found', 'that', 'the', 'Ha-ras-1', 'proto-oncogene', 'is', 'extensively', 'sethylated', 'in', 'DNA', 'isolated', 'froa', 'the', 'breast', 'tissue', 'of', 'female', 'rats', 'treated', 'with', 'MNU.', 'The', 'Ha-ras-1', 'gene', 'has', 'been', 'shown', 'to', 'be', 'activated', 'by', 'point', 'mutation', 'to', 'a', 'transforming', 'gene', 'in', 'this', 'model.', 'Our', 'data', 'suggest', 'that', 'local', 'sequence,', 'secondary', 'conformation', 'and', 'transcriptional', 'activity', 'may', 'all', 'influence', 'the', 'reactivity', 'of', 'DNA', 'in', 'the', 'mammalian', 'genoze', 'With', 'chemical', 'carcinogens.']