Toxicology of Industrial Compounds

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20 Testing and Evaluation for Reproductive Toxicity ANTHONY K.PALMER Huntingdon Research Centre, Huntingdon Introduction Most of the presentations at this meeting refer to high level, scientific investigations of one or two, highly important, high production volume chemicals, for which an adverse effect has been demonstrated. They are studies of characterisation, because they elaborate on known effects using a wealth of available information. But, how were the adverse effects of these few substances first discovered, what were the initial clues? Sadly, for many, the observation of adverse effects in humans was the trigger to intensive investigations, which is akin to ‘shutting the stable door after the horse has bolted’. This presentation is concerned with detecting effects of substances for which little or no information is available and, preferably, before they cause harm to humans. This requires a different kind of science, for which the main asset is the ability to predict, with reasonable accuracy, possible activity from minimal information. It requires wide experience and a balance between imagination and pragmatism. These attributes are especially important for toxicity to reproduction, which triggers instinctive reactions in even the coolest and most objective scientist. Identifying the cause of adverse effects on human reproduction has long been surrounded by controversy and uncertainty. In respect of the evaluation of substances for reproductive toxicity this state of affairs seems likely to persist for years to come. The main obstacle to any attempt to rationalise the situation is that any discussion on evaluation almost inevitably gravitates to the black hole of regulatory guidelines. All guidelines are flawed because science fact is compromised by bureaucracy and science fiction. For many reasons, but especially the unwillingness of any establishment to change the status quo, guidelines provide the worst starting point for developing a strategy for evaluation. Most guidelines are concerned only with methods for gathering specified information. On its own this information (on hazard) is insufficient and needs to be supplemented with other information, from other sources, to
Table 20.1 Production volume triggers for industrial chemicals Table 20.2 EC Annex VII and VIII toxicity tests for industrial chemicals A.K.PALMER 281 Notes: Tests for ecotoxicity are not included. Progression, by rote, from base set to level 2 would involve duplication of effort in several areas. The state of confusion regarding testing for toxicity to reproduction is portrayed by the failure to decide on requirements at base set level and the curious mixture of old and new terminology regarding tests. predict whether humans might be affected. Most guidelines are a watershed in a broader spectrum of testing and assessment. They represent a point at which it may be decided that the only way to gather more information is to take the final step of exposing humans. Exposure of humans provides the
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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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330 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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Toxicology of Industrial Compounds

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