Index

Accelerators of nitrosation, 4 y-Aminobutyrate, 173 Activated N-nitrosamines, 73 E-Aminocaproic acid, 172 Agricultural chemicals, 3, 6 Aminopyrine, 6 Aldehydes, 4 Ampicillin, 97 Aliphatic nitrosamines, 203 Ampicillin resistance, 47 Alkanolamines, 4 Analgesic, 5 Alkanesulfonates, 131 Arginine, 6 Alkonium ion, 85, 86 Arylating agent, 86 Alkylated nucleic acids, 201 Aryl groups, 249 Alkylation of DNA, 61, 189 ArK-locus, 236 Alkylating agent, 2, 60, 113, 114,201 Ascorbic acid, 4 Alkylating agent, formation of a reactive, 39 Asymmetrical oxygenated nitrosamines, 210 Alk"yldiazonium ions, 61, 84 06-Alkylguanine, 61, 113,202 06-Alkylguanine, repair activity, 63 Bacon, ni trosamines in, 112 7-Alkylguanine, 71,202 Bacterial mutagenesis tests, 5 Alkyliodides and bromides, 61 Bacterial reduction, 5 Alkylnitrites, 3 Bacteriophage induction assay, 92 Alkylsulfonates, 61,131 Bacteriophage lambda, 91 Alkylureas, 6 Beer, nitrosamines in, 3 Allantoin,6 Benzidine, 163 a-Acetoxy nitrosamines, 169 Benzopyrene, 65 a-I-Antitrypsin, 159 Beta carbon, in nitrosomethylethylamine, 206 Alpha carbon, susceptibility to activation, 219 Betel nuts, 223 Alpha-hydroxylation, 167, 172, 184 5-Bromo-2' -deoxyutidine, 135 Alpha-hydroxynitrosamines, 73, 167 1, 4-Butanediol, 168, 170, 173, 175, 179 Alpha oxidation, 180,214,219,224 inhibition of, 38 Alpha tocopherol, 4 Canavanine resistance, 236 Amine Carbamate insecticides, 100 secondary, 1, 5, 6 Carbonyl compounds, 4 tertiary, 3, 5 Carcinogenic damage, 234

265 266 Index

Carcinogenic potency, 123 Dinitroso-2, 6-dimethylpiperazine, 19, 135, 137, Carcinogenic mechanisms, 183 138,217,218 Carcinogenesis, two stage, 199 Dinitrosohomopiperazine, 19, 133,217,258 Carcinogenesis, and structural symmetry, 55 Dinitroso-2-methylpiperazine, 19, 137, 138,217 Carcinogenic risk, 5,6,8 Dinitrosopiperazine, 19,38,49,137,138,217, Carbonyl,6 218,258 Carbonium ion, 168 Diphenhydramine, 6 primary, 86 Dipyrone,6 secondary, 86 Disulfiram, 6 Carboxynitrosopiperidines, 137 DNA Cellular macromolecules, 2, 207 alkylation of, 47, 250, 257 Cheese, 5 binding to protein, 162 Chinese hamster cells, (V79), 120,236 damaging agent, 97 Chinese hamster ovary cell~, 130, 236 repair, 233 Chloral,4 Dose-response curve, 34 Chlordiazepoxide, 6 Dried milk, 4 Chlorpheniramine,6 Drosophila melaIZO"aJter, 236 Chlorpromazine, 6 Drosophila X-linked recessive lethal system, Chromatid breaks, 233 130,236 Chromosomal abberations, 233, 236 Drugs, 3,6 Chromosomal breaks, 236 Cigarette smoke, 212 Clofibrate, 252 Environmental mixtures and effluents, 234 Cosmetic preparations, 4 Epoxide formation, 39,223 Croton oil, 199 Esophageal tumors, 251 Cured meat and fish, 5 Esophagus, methylation in, 203 Cyclic nitrosamines, 16, 38 Ethers, 208 Cyclophosphamide, 136 Ethoxylating agent, 203 Cytochrome-linked mixed function oxidases, 45 Ethylating agents, 114 Cytosolic fraction, 155, 157, 162 Ethylation of DNA, 40 Ethyldiazonium ions, 84 O"-Ethylguanine, 82, 112, 114 Ethylmethanesulfonate, 133 Excision repair deficient mutants, 236 Dealkylation, oxidative, 45 Excision repair system, 47, 48 Deuterium substitution, 206, 211 Dialkylnitrosamines, 102, 168 Dialkylsulfates, 61 Fenuron,6 Diazohydroxide, 168 Filamentation,91 Diazonium ions, 85, 86, 169 Flue gases, 3 Diethanolamine,4 Fluorine, substitution in nitrosamines, 207 Diethylamine, 2 Food preservatives, 129 Dimethylamine, 2, 4, 5, 172 Formaldehyde, 4, 152 Dimethyldodecylamine,6 Dimethyldodecylamine-N-oxide,6 Dimethylnitrosamine, binding to protein, 162 ,l3-Galactosidase, 92, 97 Dimethylnitrosamine de methylase 1,62,65,67, "allocus,.263 149, 152, 155, 157, 160, 161, 162, 163 Gene mutations, 233, 235 Dimethylnitrosamine demethylase II, 152 Genetic toxicants, 235 Dimethylsulfoxide, 150, 159, 163 Genotoxic/ genotoxicity, 203 Dinitroso-2, 5-dimethylpiperazine, 19, 38, 217 Genotoxicology of nitrosamine, 235 Index 267

Genotoxic properties, 233, 235 Lipophobicity, 53 Glutathione, 4 Lipopolysaccharide barrier, 47 Guanine 06-methyltransferase, 113 Liposolubility, 250 Guvacine, 223 Liquid preincubation assay, 13 Liquid suspension assay, 13 Liver necrosis, 1 Haloethanes, 131 Liver parenchymal cells, 251 Hamster liver, S9, 34, 38,96, 163, 254 Lucanthone, 6 Hemangioendothelial sarcomas, 251 Lymphoma of the thymus, 218 Hepatocellular carcinomas, 172 Hepatocytes, 120 Hepatotoxins, 251 Heterocyclic nitrosamines, 131, 167 Mammalian cell systems, 236 1, 6-Hexanediol, 173 Mammalian enzymes, 234 HGPRT, Jee Hypoxanthine-guanine Mammalian stomach, 2 phospho ribosyl transferase Meat-curing mixtures, 129 Human leukocyte culture system, 130, 137 Metabolic activation, 234 Hydrochlorothiazide, 6 Metabolism of N-nitrosamines, 235 Hydrophilic, 211 Metal ions, 4 4-Hydroxybutanal, 175, 179 Methapyrilene, 6, 252 y-Hydroxybutyrate, 168, 170, 172, 173, 175, 179 Methomyl, 249 2-Hydroxyethyl species, 256 3-Methyladenine glycosylase, 113 a-Hydroxylation, 167, 172, 184 Methylating agem, 206, 256, 258 6- H ydroxy-n-hexanal, 180 3-Methylcholanthrene,65 a-Hydroxynitrosamine, 73, 167 Methyldiazonium ion, 84 a-Hydroxnitrosopyrrolidine, see Methylmethanesulfonate,64 Nitroso-2-hydroxypyrrolidine Methylphenidate, 221 ,B-Hydroxynitrosopyrrolidine, Jee 7-Methylguanine, 70,71,78,79 Nitroso-3-hydroxypyrrolidine 06-Methylguanine, 70, 71, 78, 79, 80 2-Hydroxytetrahydrofuran, 168, 169, 171, 172, Methylguanidine,6 173,175,179,184 Methyl groups, oxidizable, 206 Hypoxanthine-guanine phosphoribosyl Methyl substitution, 38 transferase (HGPRT) locus, 130 Microsomal fraction, 155, 157, 162 Microsomes metabolism by, 161 Inhibition of nitrosation, 4 supernatant, 173, 178, 184 Initiators, 199 Milk,129 Insecticides, nitroso-derivatives of, 6, 106 Mitosis, 225 Molecular configuration and conformation, 212 Monomethylnitrosamine,61 Monuron,6 Kinetic assay of induction, 97 Morpholine, 4, 6,214 Kupffer cells, 172 analogs, 109 derivatives, 103 Mouse liver, S9, 150 Lambda repressor, 91, 92,113 Mouse skin, 189 Lambda lysogen,92 Mouse skin assay, 249 Leukemia of the thymus, 218 Multiplex CHO system, 131 Leukocytes, human, 236 Mutagenesis Lex A mutation, 94 and aliphatic nitrosamines, 54,73 Lipophilic, 211 and chemical ring size, 49 268 Index

Mutagenesis, (collta) N-Nitroso-, (collt'd) and chemical ring substitution, 51 benzylurea, 41, 201, 250 DNA repair in, 48 bis-(2-chloroethyl)amine, 54, 208, 209 and halogen substitution, 52 bis-(2-chloropropyl)amine, 54, 209 nitrosamines as model compounds in, 56 bis-(2,2-diethoxyethyl)amine,209 NMU-induced,81 bis-(2-ethoxyethyl)amine,208 and structural symmetry, 55 bis-(2-cyanoethyl)amine, 85, 208 Mutagenic intermediates, 120 bis-(2-cyanomethyl)amine, 208, 209 Mutagenicity, chemical structure and, 34, 38,48 bis-(2-hydroxypropyl)amine, 4, 24,40, 54, Mutagenic potency, 74, 122 163,207,209,210,254 and chemical structute, 13 bis-(2-methoxyethyl)amine, 54, 208 Mutants, canavanine-resistant, 46 bis-(2-oxopropyl)amine, 24, 40, 210, 254 Mutations, reversion and forward, 236 bis-(2-trifluoroethyl)amine, 209 4-t-butylpiperidine, 19, 39, 83, 86, 219, 221 n_butylurea,201 Nad locus, 236 buxten, 104 Neurospora conidia, 46 carbaryl, 6, 104, 199 Nitrilotriacetic acid, 6 carbofuran, 104 Nitrite, 4, 5 3-chloropiperidine, 52, 224 Nitrite, fish and meat cured with, 5 4-chloropiperidine, 52,137,224 Nitrogen oxides, 3 cimetidine, 28, 249, 257 Nitrosamides, 28,60 4-cyclohexylpiperidine, 19,39,105,109,222 Nirrosamines cyclohexylurea, 20 I activated, 184 diallylamine, 24, 40, 54,121,209,211,239, acyclic, 24,40, 239 254 in air, 4 dibenzylamine, 39, 207 aromatic, 24 3, 4-dibromopiperidine, 52, 105,224 asymmetric, oxygenated, 210 3, 4-dibromopyrrolidine, 52, 221 cyclic, 48, 49, 102, 168, 172, 180, 240, 245 di-sec-butylamine,86 cyclic alkylated, 52 di-n-butylamine, 24, 40, 102, 163, 205, 258 dialkyl,48, 168 3, 4-dichloropiperidine, 52, 105, 137,224 mutagenic activity of, 184 3, 4-dichloropyrrolidine, 221 nonmutagenic,253 diethanolamine, 4, 24, 40, 41, 54, 86, 203,207, a-substituted, 86 208,209,210,252,253,256 /3-substituted carcinogenic, 85 diethylamine, 2, 24, 40, 63, 81, 85, 94,101, N-Nitrosamines, 63, 64,120,131,172,239 108, 121, 133, 163,201,203,204,205,207, Nitrosating agents, 2 251,258 N-Nitroso- 2, 3-dihydroxypropylallylamine, 28, 41 acetoxydibenzylamine, 24, 39, 203 dihydroxypropylethanolamine, 28, 41, 211 acetoxydimethylamine, 203 dihydroxypropyl-2-oxopropylamine, 28, 211 4-acetyl-3, 5-dimethylpiperazine, 19, 38,219 di-isobutylamine, 24,40, 258 aldicarb, 104 di-isopropanolamine, see allylethanolamine, 28, 211 bis (2 -hydroxypropy I) amine allylhydroxypropylamine, 28, 211 di-isopropylamine, 4, 86, 203 allylurea, 107,201,257 dimethylamine, 1,4,24,40,45,46,61,63,74, n-amylurea,201 85,94,101,108,121,132,133,149,152, anabasine, 220 155,161,189,201,204,205,251,256 azetidine, 16,38,49, 103,212 2, 6-dimethylmorpholine, 19, 215, 218, 248, baygon,106 258 4-benzoyl-3, 5-dimethylpiperazine, 19, 38, 2, 6-dimethylmorpholine-cis and trans, 103, 219,254 109,215 Index 269

N-Nitroso-, (com'ti) N-Nitroso-, (col1t'd) 2, 4-dimethyl-l, 3-oxazolidine, 16 iminodipropionitrile, see 4, 4-dimethyl-l, 3-oxazolidine, 16 bis-(2-cyanoethyl)amine 3, 5-dimethylpiperazine, 19,218,219 isobutylurea, 41, 250 2, 6-dimethylpiperidine, 52, 86, 137,221 isonipecotic acid, 53, 223 3, 5-dimethypiperidine, 19,39,51 2-isopropyl-4, 4-dimethyl-l, 3-oxazolidine, 16 3. 5-dimethylpiperidine-cis and trans, 19 isopropylurea,201 2, 5-dimethylpyrrolidine, 133,219 landrin, 104 di-n-octylamine, 24, 40, 54, 205 methomyl, 104 diphenylamine, 3, 24, 39, 203, 255 methylacetonitrile, 209 di-n-propylamine, 24, 40,86,201,208,209, methylallylamine, 209 258 methylaniline, 24, 39,83,86,202,206,255 dodecamethyleneimine, 19, 38, 214 methylbenzylamine, 24, 39, 206 3,4-epoxypiperidine, 19, 38,223 methyl-II-butylamine, 28, 40, 124,201,204 ethanoloxopropylamine, 28, 210 methyl-tert-butylamine, 202 ethanolhydroxypropylamine, 28, 41, 86, 210, methyl-4-carboxybenzylamine, 24, 39 253,256,259 methyl-2-carboxyethylamine, 205 ethyldimethylurea, 34, 42 methyl-3-carboxypropylamine, 28, 41, 205, ethylethoxyamine, 203 256 2-ethyl-5-methyl-l, 3-oxazolidine, 16 methyl-4-chlorobenzylamine, 24 ethylnitroguanidine, 28, 41, 68, 75, 77, 85, methyl-4-cyanobenzylamine, 24 199,249,257 methylcyclohexylamine, 24, 39, 202, 207 2-ethyl-4-methyl-l, 3-tetrahydrooxazine, 19 methl-l1-decylamine, 28, 205 2-ethyl-l, 3-tetrahydrooxazine, 19 methyldiethylurea, 34,42,201 ethylurea, 41, 42,78,82, 199,250,257 methyldihydroxypropylamine, 28, 41,210 ethylurethane, 41, 199,249 methyl-l1-dodecylamine, 28, 205 fluroethylurea, 42, 201, 250, 257 methylethylamine, 28, 40, 54, 55, 85, 108, guvacine, 53 204,205,206,239,248,252,255,258 guvacoline, 19,39,53, 105, 137,223 methyl-4-fluoroaniline, 24, 39, 207, 255 heptamethyleneimine, 19,38,49,213 methyl-4-fluorobenzylamine, 24 hexamethyleneimine, 19,49,168,171,173, methyl-n-heptylamine, 28, 204 180, 185,213 methyl-lz-hexylamine, 28, 204 n-hexylurea, 41, 107,201,250 methyl-2-hydroxypropylamine, 28, 41, 210 a-hydroxydimethylamine,61 methyl-isopropylamine,54 hydroxyethylurea, 42, 201, 250, 256 methylmethoxyamine, 28, 110, 203 2-hydroxyhexamethyleneimine, 180 methyl-4-methoxybenzylamine, 24 3-hydroxyhexamethyleneimine, 169, 181 methyl-4-methylbenzylamine,24 4-hydroxyhexamethyleneimine, 169, 181, 183, 2-methylmorpholine, 19,216,258 185 methylneopentylamine, 28, 40, 54, 55, 85, 3-hydroxypiperidine, 137, 180,224 206,240,252,255 4-hydroxypiperidine, 105, 180,224 methyl-4-nitroaniline, 24, 39, 207 hydroxyproline, 3, 220 methyl-4-nitrobenzylamine, 24 hydroxypropyloxopropylamine, 28 methylnitroguarlidine, 2, 28, 64, 68, 75, 97, 2-hydroxypropylurea, 201, 250 111,199,249,257 3-hydroxypropylurea, 34, 201, 250 methyl-ll-nonylamine, 28, 205 2-hydroxypyrrolidine, 175, 180 methyl-ll-octadecylamine, 28 3-hydroxypyrrolidine, 168, 172, 180, 220 methyl-n-octylamine, 28, 204 iminodiacetaldehyde, 209 2-methyl-l, 3-oxazolidine, 16,216,258 iminodiacetic acid, 3, 208, 209 5-methyl-l, 3-oxazolidine, 4,16,216,258 iminodiacetonitrile, see 5-methyloxazolidone, 249 bis-(2-cyanomethyl)amine methyl-2-oxopropylamine, 28, 41,210,254 270 Index

N-Nitroso-, (Wilt a) N-Nitroso-, (crmta) methyl-n-pentylamine, 28,40,204 tetrahydro-l, 3-oxazine, 4,19,38,215,258 methylphenidate, 16, 39, 223 1,2,3, 6-tetrahydropyridine, 19, 38, 39,49, methylphenylcarbamate, 104 105, 222, 240 methyl-2-phenylethylamine, 24, 39, 55, 124, 1,2,3, 4-tetrahydropyridine, 19,38, 105,222 206,259 2,2, 6, 6-tetramethylpiperidine, 52, 221 N-methylpiperazine, 3, 133,218 thiazolidine, 16,38 2-methylpiperidine, 51, 105,221 thiomorpholine, 19, 38, 215 3-methylpiperidine, 51, 137,221 tridecylurea, 41, 201, 250 4-methylpiperidine, 51, 105,221 triethylurea, 34, 42 3-methyl-4-piperidone, 19,39,225 trihydroxydipropylamine, 28, 211 methyl-n-propylamine, 28,40, 85, 163, 204, 2,2, 5-trimethyl-l, 3-oxazolidine, 16 210 2,4, 4-trimethyl-l, 3-oxazolidine, 16 methyl-n-tetradecylamine, 28, 40, 205 3,4, 5-trimethylpiperazine, 19,218,254 3-methyl-ll. '-tetrahydropyridine, 19, 38 trimethylurea, 34, 42 methyl-n-tridecylamine, 28,40 undecylurea, 201, 250 methyl-trifluoroethylamine, 206, 209 N-Nitrosoalkylamides,2 methyl-n-undecylamine, 28, 205 N-Nitrosoalkylcarbamates, 100 methylurea, 41, 63, 64, 79, 111, 199,257 N-Nitrosoalkylguanidines, 100 methylurethane, 2, 199, 249 Nitrosoalkylureas, 34, 100-102 morpholine,4, 19, 38,49, 103, 133,214,21 5, N-Nitroso compounds, 61, 62, 63 258 ethylating, 75, 78 nipecotic acid, 53,137,223 formation in the stomach, 5 nornicotine, 16,220 human exposure to, 6 octamethyleneimine, 19, 38,49,103,213 methylating, 75, 78 1, 3-oxazolidine, 4,16,38,103,215,216,258 propylating, 75, 78 oxazolidone,249 N-Nitroso dialkylamines, 83 oxopropylallylamine, 28, 211 N-Nitrosodimethylamine, poisoning by, 1,60 phenmetrazine, Jee N-Nitroso-N-ethyl compounds, 60, 63, 80 2-phenyl-3-methylmorpholine N-Nitroso-N-methyl compounds, 60, 6.3, 78, 80 phenylbenzylami'1e, 24, 39, 203, 207, 255 Nitrosotrialkylureas, 34 phenylethylurea, 41,201,250,257 Nitrous acid, 1, ), 4 2-phenyl-3-methylmorpholine, 19, 133,216 Nucleophiles, 3 4-phenylpiperidine, 19,39,53,104,109,219, 221,222 phenylurea, 34, 201 Open-chain nitrosamines- pipecolic acid, 53, 223 symmetrical/unsymmetrical, 207 piperazine, 38, 45,103,121,130,137,138, Organotropy, of nitrosamines, 172 217, 218, 240 a-oxidation, 180,214,219,224 piperidine, 19,38,39,49,53,86, 104, 108, a-oxidation, inhibition of, 38 123,130,137,168,172,180,213,220,221, /l-oxidation, 172,205, 216 258 Oxidative dealkylation, 45 4-piperidone, 19,39,105,137,224 Oxygen, alkylation, 61 proline, 3, 5, 53, 220 Oxygenated nitrosopiperidines, 225 propylnitroguanidine, 68, 75, 77, 85 Oxytetracycline, 4, 6 n-propylurea, 42, 201, 257 Ouabain, 121, 123,236 pyrrolidine, 5,16,38,48,49,53, 101, 103, 133,162, 168,170,177,184,212,214,219, 220,258 pyrroline, 16, 38, 49, 221, 240, 254, 258 Pancreatic duct, 210, 215 sarcosine, 205, 209 Permeability mutation, envA, 93 Index 271 Peroxyacyl nitrites and nitrates, 3 Sister chromatid exchange, 130,135,137,236 Pesticides, 41 Smog, 3 Phage induction, 252 Sodium nitrite, 2 Phage induction assay, 234 Somatic mutation theory, 233 Phenacetin, 163 Soybean trypsin inhibitor, 159 Phenmetrazine, 5, 216 Specificity, species and organ, 45 Phenols, 4 Steric factors, 38 Phenyldiazonium ions, 207 Steric hindrance, 39, 245 Piperazine, 6 Stomach, 5 Piperidine, 6 Structure, chemical Piperidine substitution, 104 and biological activity, 46 Piperine, 6 and mutagenic activity, 13 Plate incorporation assay, 1.) Substituted aliphatic nitrosamines, 207 Platinum (/I) chloramines, 13 I 4-Substituted nitrosopiperidines, 39 Point mutation, 2)0 Succinic semialdehyde, 172 Polycyclic aromatic hydrocarbons, 120, 1.'> 1, 199 Sulfhydryl groups, 72 Prokaryotic systems, 259 Synthetic cutting oils, 4 Promuragens/ carcinogens, 46 Prophage induction assay, 92 Proteins, nitrosaInine metabolizing, 82 Proximate carcinogen, 250 Tannins, 4 2-Pyrrolidone, 172 Thiocyanate, 3 6-Thioguanine, 121, 123, 130,236 Thiram,6 Quinacrine, 01 [IH]Thymidine, 135 Quinolines, 131 Tobacco smoke, 129,213,220 a-Tocopherol, 4 Tolazamide,6 Tolbutamide, 6 Rat liver S9, 34, 38,96, 150, 163,255 Trace impurity, 34 recA protein, 91 Transitional cell carcinomas of the urinary Reticulo-endothelial tumors, 172 bladder, 204 Rubber factories, 2 I 4 Transnitrosation, 5, 218 Rubber industry, ~) Transplacental effect, 5 Transport across membranes, 250 Tribenzylamine, 3 S-8 fraction, 178 Triethanolamine, 4 SaccharomyceJ cereviJiae, 236 Trypsin, 159 Saccharomyces gene conversion test, 130 Tumor promotors, 61 Saliva, 5 Tyr locus, 236 Salmonella, 182 Salmollella histidine reversion assay, 46, 130, 131,235 Salmonella mammalian-microsome Unsaturation, effect on carcinogenesis, 222 mutagenicity assay, 13, 34, 234 Urea, 172