Toxicology of Industrial Compounds

Recommendations

Info

318 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT contrast, although related to BHT, require higher molecular weights and hydrophobicity in order to retain them in the polymer matrix. This can be achieved, for example, by introducing alkyl chains or (esterified) carboxyalkyl moieties in the para-position to the phenolic hydroxyl group with variations in the aliphatic substitution pattern of the 2- and 6positions. With these modifications the questions arose, whether or not the toxicology of the chemically modified offspring would still be related to that of the phenolic core of the BHT ancestor or completely different, although a common metabolic degradation pathway to structural entities resembling BHT could be anticipated. Clarification of this question was expected to contribute to the understanding of the toxicology of an entire class of phenolic antioxidants. A number of differentially esterified 4hydroxy-3, 5-dialkyl-phenylpropionic acid derivatives were subsequently subjected to subchronic toxicity testing in rats with the result that the effects encountered were largely dependent on the alcohol moiety used for esterification and the size of the alkyl-substituent in the 3- and 5-positions: most frequently, increased liver weights were encountered in compounds with bulky 3,5-substituents such as tert-butyl. In some instances, however, initial hepatomegaly was followed after several weeks or months of treatment by increases in thyroid weights and a proliferation of the thyroid follicular epithelium. The mechanism leading to the latter effect has been investigated in detail using the di-ester of 3-tert-buty1–4-hydroxy-5-methylphenylpropionic acid with ethylene glycol, Compound B, as a model compound (Table 23.1). Blood kinetics and blood metabolites Compound B is a symmetrical di-ester compound (Table 23.1). When administered at a single oral dose of about 10 mg kg −1 body weight to male rats, 14 C-phenyl-labelled Compound B was readily adsorbed, and maximal blood radioactivities were reached after 1 h. Thereafter, blood radioactivity declined rapidly and only minute amounts were detected 48 h after treatment. At any time point investigated Compound A, the free carboxylic acid of Compound B, was the dominating blood metabolite, whereas the parent compound constituted a minor component only (Table 23.2). These findings are indicative of an efficient first pass hydrolysis and suggest that the carboxylic acid metabolite, Compound A, might be responsible for the toxicological profile of this antioxidant in the rat. Liver enzyme induction Compound B was administered in the feed to male rats at dose levels of 50, 150, 500 and 1000 ppm. After treatment for 14 days, absolute liver weights were dose-dependently increased. Biochemically, this
Table 23.1 3.5-Substituted 4-hydroxyphenyl propionic acid esters H.THOMAS ET AL. 319 hepatomegaly was accompanied by an induction of total microsomal cytochrome P450, microsomal epoxide hydrolase and UDPglucuronosyltransferase, cytosolic glutathione S-transferase and peroxisomal β-oxidation. The observed induction of the cytochrome P450 content was reflected in increased activities of ethoxycoumarin O-deethylase as well as lauric acid 11- and 12-hydroxylases (Table 23.3). This suggests an induction of cytochrome P450 isoenzymes of the subfamilies CYP2B and CYP4A. Indeed, increased amounts of CYP2B and CYP4A proteins were found in liver microsomes from treated animals by means of Western-blotting with monoclonal antibodies specific for these iso-enzymes (data not shown). Within 28 days after cessation of a 14-day treatment at
Page 2 and 3:
Toxicology of Industrial Compounds
Page 4 and 5:
This edition published in the Taylo
Page 6 and 7:
8. Pulmonary Toxicity Studies with
Page 8 and 9:
Preface A large number of chemical
Page 10 and 11:
Contributors May Akrawi Department
Page 12 and 13:
Beverly M.Kulig TNO Toxicology, Dep
Page 14 and 15:
Richard A.Versen Schuller MTC, Heal
Page 16 and 17:
1 Biomonitoring and Absorption of I
Page 18 and 19:
4 BIOMONITORING AND ABSORPTION OF I
Page 20 and 21:
Page 22 and 23:
Page 24 and 25:
10 BIOMONITORING AND ABSORPTION OF
Page 26 and 27:
2 Toxicokinetics and Biodisposition
Page 28 and 29:
14 TOXICOKINETICS AND BIODISPOSITIO
Page 30 and 31:
Page 32 and 33:
Page 34 and 35:
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
Page 42 and 43:
Page 44 and 45:
Page 46 and 47:
Page 48 and 49:
Page 50 and 51:
3 Metabolic Activation of Industria
Page 52 and 53:
38 METABOLIC ACTIVATION OF INDUSTRI
Page 54 and 55:
Page 56 and 57:
Page 58 and 59:
4 Sizing up the Problem of Exposure
Page 60 and 61:
46 SIZING UP THE PROBLEM OF EXPOSUR
Page 62 and 63:
Page 64 and 65:
Page 66 and 67:
Page 68 and 69:
Page 70 and 71:
Page 72 and 73:
Page 74 and 75:
5 Metabolism of Reactive Chemicals
Page 76 and 77:
62 METABOLISM OF REACTIVE CHEMICALS
Page 78 and 79:
Page 80 and 81:
Page 82 and 83:
Page 84 and 85:
Page 86 and 87:
6 Methods for the Determination of
Page 88 and 89:
74 METHODS FOR THE DETERMINATION OF
Page 90 and 91:
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
Page 102 and 103:
Page 104 and 105:
PART THREE Pulmonary toxicology of
Page 106 and 107:
92 CARCINOGENIC POTENTIAL OF MAN-MA
Page 108 and 109:
Page 110 and 111:
Page 112 and 113:
Page 114 and 115:
100 CARCINOGENIC POTENTIAL OF MAN-M
Page 116 and 117:
Page 118 and 119:
Page 120 and 121:
Page 122 and 123:
Page 124 and 125:
Page 126 and 127:
Page 128 and 129:
Page 130 and 131:
Page 132 and 133:
118 PULMONARY TOXICITY STUDIES WITH
Page 134 and 135:
Page 136 and 137:
Page 138 and 139:
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
130 PULMONARY HYPERREACTIVITY TO IN
Page 146 and 147:
Page 148 and 149:
Page 150 and 151:
Page 152 and 153:
10 Mechanisms of Pulmonary Sensitiz
Page 154 and 155:
140 MECHANISMS OF PULMONARY SENSITI
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Page 164 and 165:
150 OCCUPATIONAL ASTHMA INDUCED BY
Page 166 and 167:
Page 168 and 169:
Page 170 and 171:
Page 172 and 173:
12 Biomarkers and Risk Assessment K
Page 174 and 175:
160 BIOMARKERS AND RISK ASSESSMENT
Page 176 and 177:
Page 178 and 179:
Page 180 and 181:
Page 182 and 183:
168 EXTRAPOLATION OF TOXICITY DATA
Page 184 and 185:
Page 186 and 187:
Page 188 and 189:
Page 190 and 191:
Page 192 and 193:
Page 194 and 195:
14 Molecular Approaches to Assess C
Page 196 and 197:
182 MOLECULAR APPROACHES TO ASSESS
Page 198 and 199:
Page 200 and 201:
Page 202 and 203:
Page 204 and 205:
Page 206 and 207:
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
198 EVALUATION OF TOXICITY TO THE I
Page 214 and 215:
Page 216 and 217:
Page 218 and 219:
Page 220 and 221:
Page 222 and 223:
208 USE OF LONG-TERM CULTURES OF HE
Page 224 and 225:
Page 226 and 227:
Page 228 and 229:
Page 230 and 231:
Page 232 and 233:
Page 234 and 235:
Page 236 and 237:
PART FIVE Mechanisms of toxicity of
Page 238 and 239:
224 PEROXISOME PROLIFERATION normal
Page 240 and 241:
226 PEROXISOME PROLIFERATION demons
Page 242 and 243:
228 PEROXISOME PROLIFERATION Specie
Page 244 and 245:
230 PEROXISOME PROLIFERATION intend
Page 246 and 247:
232 PEROXISOME PROLIFERATION BENTLE
Page 248 and 249:
234 PEROXISOME PROLIFERATION KRAUPP
Page 250 and 251:
236 PEROXISOME PROLIFERATION POPP,
Page 252 and 253:
18 Neurotoxicity Testing of Industr
Page 254 and 255:
240 NEUROTOXICITY TESTING OF INDUST
Page 256 and 257:
Page 258 and 259:
Page 260 and 261:
Page 262 and 263:
Page 264 and 265:
Page 266 and 267:
Page 268 and 269:
Page 270 and 271:
256 ENDOCRINE TOXICOLOGY OF THE THY
Page 272 and 273:
Page 274 and 275:
Page 276 and 277:
Page 278 and 279:
Page 280 and 281:
Page 282 and 283: 268 ENDOCRINE TOXICOLOGY OF THE THY
Page 294 and 295: 20 Testing and Evaluation for Repro
Page 296 and 297: 282 TESTING AND EVALUATION FOR REPR
Page 314 and 315: PART SIX Toxicity of selected class
Page 316 and 317: 302 SPECIAL POINTS IN THE TOXICITY
Page 324 and 325: 310 TOXICOLOGY OF TEXTILE CHEMICALS
Page 334 and 335: 320 ANTIOXIDANTS AND LIGHT STABILIS
Page 354 and 355: 340 TOXICOLOGY OF SURFACTANTS Inter
Page 356 and 357: 342 TOXICOLOGY OF SURFACTANTS Figur
Page 358 and 359: 344 TOXICOLOGY OF SURFACTANTS probl
Page 360 and 361: 346 TOXICOLOGY OF SURFACTANTS nonio
Page 362 and 363: 348 TOXICOLOGY OF SURFACTANTS and t
Page 364 and 365: 350 TOXICOLOGY OF SURFACTANTS long-
Page 366 and 367: 352 TOXICOLOGY OF SURFACTANTS COULS
Page 368 and 369: 354
Page 370 and 371: 25 Low Dose of a Genotoxic Carcinog
Page 372 and 373: 358 CARCINOGENESIS AT LOW DOSE Tabl
Page 374 and 375: 360 CARCINOGENESIS AT LOW DOSE year
Page 376 and 377: 26 Controversial Mechanistic and Re
Page 378 and 379: 364 CONTROVERSIAL ISSUES IN SAFETY
Page 380 and 381: 366 CONTROVERSIAL ISSUES IN SAFETY
Page 382 and 383:
368 CONTROVERSIAL ISSUES IN SAFETY
Page 384 and 385:
Page 386 and 387:
Page 388 and 389:
374 INDEX 2-bromo-glutathionyl 64 B
Page 390 and 391:
376 INDEX Gas chromatography/mass s
Page 392 and 393:
378 INDEX mRNA analysis 211 Mutagen
Page 394 and 395:
380 INDEX Surfactants 338-55 acute
show all

Toxicology of Industrial Compounds

Create successful ePaper yourself

Delete template?

Save as template?