Toxicology of Industrial Compounds

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290 TESTING AND EVALUATION FOR REPRODUCTIVE TOXICITY Table 20.7 OECD 422: EGME, tabular summary Notes: [] Treatment at 500 and 1000 mg kg −1 withdrawn prior to mating due to loss of condition and mortality. Animals in withdrawal phase. NE not examined pp=post partum Bold type indicates treatment effect. At 100 mg kg −1 profound effects on spermatogenesis were evident. Some pregnancies were obtained, but no live young were born indicating effects on females and the conceptus. For the high dosage groups, effects on testes and epididymides remained evident several weeks after withdrawal of treatment. The duration of pregnancy was increased with a consequent increase in mean pup weight. Values for numbers of implantations, live young and litter weight were reduced indicating slow recovery. This does not appear to have been mentioned in the extensive literature on EGME. reproductive toxicity. A more sensible strategy would be to identify a relevant species before testing. It is pointless to conduct a test in an unsuitable species and doubly pointless to conduct tests in two irrelevant species. The requirement for detailed examination of foetuses for abnormalities is based on an exaggerated perception of risk prompted by fear. For many reasons the risk of inducing abnormalities is extremely low. Those same reasons make detection by direct observation of malformations unreliable.
Table 20.8 Post-natal detection of prenatal effects A.K.PALMER 291 Notes: Prenatal effects include any soft tissue or skeletal changes (variants, anomalies or malformations) or altered foetal weight. Post-natal effects include reduced litter size at birth, reduced mean foetal weight or increased post natal mortality. In the few studies in which post-natal effects were not detected, prenatal changes were of a ‘minor’ nature (e.g. reduced ossification) and sometimes not conclusive. The lower number of litters reared in the Japanese Experiment 2 design would contribute to the slightly higher rate of ‘failures’. Where more serious prenatal effects such as the observation of malformations or prenatal death were observed a post-natal effect was always observed. The dimensions of the tests we conduct are too small and dosage regimes are contradictory to the basic principle that malformations are induced by application of a precise dosage at a precise time. Whilst direct observation of malformations is unreliable the saving grace is that induced malformations always occur within a wider spectrum of embryotoxicity. This wider spectrum provides a more reliable, if indirect, means of detecting substances that might cause malformations. Also, these effects are important in their own right. Major effects such as altered offspring weight and prenatal death can be observed postnatally. For example both EC Segment I and Japanese Experiment 2 studies include examinations for foetal abnormalities as well as postnatal observations. A survey of such studies shows that, when malformations were observed, a post-natal effect was always observed (Table 20.8). Surveys such as this should have been conducted or sponsored by agencies and industry before formulating guidelines. Why have they not done so? The obsession with abnormalities is based on the fear of another thalidomide. The great contradiction is that a considerable number of rat embryotoxicity studies with thalidomide failed to provided convincing demonstration of teratogenicity. Conversely, reproduction studies in rats provided unequivocal, post-natal evidence of effect in the form of a marked reduction in the number of females with young and a marked reduction in
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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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PART FIVE Mechanisms of toxicity of
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224 PEROXISOME PROLIFERATION normal
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226 PEROXISOME PROLIFERATION demons
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228 PEROXISOME PROLIFERATION Specie
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230 PEROXISOME PROLIFERATION intend
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232 PEROXISOME PROLIFERATION BENTLE
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234 PEROXISOME PROLIFERATION KRAUPP
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236 PEROXISOME PROLIFERATION POPP,
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18 Neurotoxicity Testing of Industr
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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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Toxicology of Industrial Compounds

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