Toxicology of Industrial Compounds

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272 ENDOCRINE TOXICOLOGY OF THE THYROID Table 19.4 Species and energy dependence of enhanced thyroxine accumulation in vitro Key: ↑T 4, increase; ↓T 4, decrease; ↔T 4, no change; Temperature? ATP?, temperature/ATP dependent; NA, not applicable. hepatocellular T 4 accumulation. The correlation between in vivo—in vitro species-specific toxicological effects is also evident (Figure 19.10 and Table 19.4). One of the features of temelastineinduced thyroid toxicology in vivo was the apparent species-specificity to the rat (Atterwill et al., 1989; Poole et al., 1989). Temelastine-mediated thyroid follicular hypertrophy and hyperplasia was not observed in dog, mouse or monkey following temelastine treatment (Figure 19.10). In vitro, no enhanced thyroxine accumulation in response to temelastine or phenobarbital was observed in guinea pig or dog hepatocytes (Aylward et al., 1994). In support of these findings, it has been demonstrated that the guinea pig is insensitive to thyroid pathological changes after phenobarbital or βnaphthoflavone administration in vivo (Johnson et al., 1993; Wyatt et al., 1993). In support of, and as an extension of these findings, we now present important new findings to demonstrate conclusively that some of the rapid ‘effectors’ of thyroid toxicity via the liver, such as temelastine, do so independently of a primary action on UDP-GT, whereas other cytochrome P450 inducers such as phenobarbital may have a combined effect. This work was carried out using hepatocytes prepared from UDP-GT system deficient Gunn rats. Studies on Gunn rat hepatocytes in vitro Hepatocytes were prepared from the normal or Gunn rat (deficient in UDP- GT isozymes conjugating thyroxine) and exposed to either temelastine or phenobarbital (2 or 20 µM) for 3 h as before (Aylward et al., 1994). The results show (Figure 19.11) that whereas temelastine was able to enhance thyroxine accumulation in both types of hepatocytes, phenobarbital only produced alterations in hormone accumulation in normal cells, supporting
C.K.ATTERWILL AND S.P.AYLWARD 273 Figure 19.10 Effect of temelastine on 125I-T4 clearance (from Atterwill et al., (1989)).
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Toxicology of Industrial Compounds
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This edition published in the Taylo
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8. Pulmonary Toxicity Studies with
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Preface A large number of chemical
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Contributors May Akrawi Department
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Beverly M.Kulig TNO Toxicology, Dep
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Richard A.Versen Schuller MTC, Heal
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1 Biomonitoring and Absorption of I
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4 BIOMONITORING AND ABSORPTION OF I
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10 BIOMONITORING AND ABSORPTION OF
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2 Toxicokinetics and Biodisposition
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14 TOXICOKINETICS AND BIODISPOSITIO
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3 Metabolic Activation of Industria
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38 METABOLIC ACTIVATION OF INDUSTRI
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4 Sizing up the Problem of Exposure
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46 SIZING UP THE PROBLEM OF EXPOSUR
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5 Metabolism of Reactive Chemicals
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62 METABOLISM OF REACTIVE CHEMICALS
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6 Methods for the Determination of
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74 METHODS FOR THE DETERMINATION OF
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PART THREE Pulmonary toxicology of
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92 CARCINOGENIC POTENTIAL OF MAN-MA
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100 CARCINOGENIC POTENTIAL OF MAN-M
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118 PULMONARY TOXICITY STUDIES WITH
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130 PULMONARY HYPERREACTIVITY TO IN
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10 Mechanisms of Pulmonary Sensitiz
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140 MECHANISMS OF PULMONARY SENSITI
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150 OCCUPATIONAL ASTHMA INDUCED BY
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12 Biomarkers and Risk Assessment K
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160 BIOMARKERS AND RISK ASSESSMENT
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168 EXTRAPOLATION OF TOXICITY DATA
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14 Molecular Approaches to Assess C
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182 MOLECULAR APPROACHES TO ASSESS
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198 EVALUATION OF TOXICITY TO THE I
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208 USE OF LONG-TERM CULTURES OF HE
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Page 236 and 237: PART FIVE Mechanisms of toxicity of
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Page 252 and 253: 18 Neurotoxicity Testing of Industr
Page 254 and 255: 240 NEUROTOXICITY TESTING OF INDUST
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Page 296 and 297: 282 TESTING AND EVALUATION FOR REPR
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322 ANTIOXIDANTS AND LIGHT STABILIS
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340 TOXICOLOGY OF SURFACTANTS Inter
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342 TOXICOLOGY OF SURFACTANTS Figur
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344 TOXICOLOGY OF SURFACTANTS probl
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346 TOXICOLOGY OF SURFACTANTS nonio
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348 TOXICOLOGY OF SURFACTANTS and t
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350 TOXICOLOGY OF SURFACTANTS long-
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352 TOXICOLOGY OF SURFACTANTS COULS
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354
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25 Low Dose of a Genotoxic Carcinog
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358 CARCINOGENESIS AT LOW DOSE Tabl
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360 CARCINOGENESIS AT LOW DOSE year
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26 Controversial Mechanistic and Re
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364 CONTROVERSIAL ISSUES IN SAFETY
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374 INDEX 2-bromo-glutathionyl 64 B
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376 INDEX Gas chromatography/mass s
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378 INDEX mRNA analysis 211 Mutagen
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380 INDEX Surfactants 338-55 acute
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