Review
The computational prediction of toxicity

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Abstract

Recent developments in the prediction of toxicity from chemical structure have been reviewed. Attention has been drawn to some of the problems that can be encountered in the area of predictive toxicology, including the need for a multi-disciplinary approach and the need to address mechanisms of action. Progress has been hampered by the sparseness of good quality toxicological data. Perhaps too much effort has been devoted to exploring new statistical methods rather than to the creation of data sets for hitherto uninvestigated toxicological endpoints and/or classes of chemicals.

Introduction

The individual properties of a chemical are all derived from, and related to, the unique molecular structure of that chemical. These properties include physical properties, chemical properties and toxicological properties. Because these properties are all derived from the molecular structure of the chemical, it follows that relationships also exist between the different properties of the chemical. These principles form the underlying basis for the prediction of toxicity from chemical structure.

There are essentially two basic approaches to the prediction of toxicity from chemical structure. These are the mechanistic approach (the one favoured by the authors) and the statistical approach. In the mechanistic approach, a hypothesis is proposed that links a group of related chemicals with a particular toxicological endpoint. The hypothesis is then used to select physical, chemical or reactivity parameters to establish a structure/activity relationship (SAR). The resulting relationship can then be tested and the hypothesis and parameters refined, until an adequate prediction model is obtained.

The biological activity of a chemical depends on two factors: first, it must be transported from its site of administration to its site of action; second, it must bind to or react with the receptor or target (i.e. biological activity is a function of partition and reactivity) [1]. The chemical may also undergo metabolic transformation during these processes. If a structure/activity model is deficient in modelling either partition or reactivity, only a partial correlation with the biological response is likely to be observed. For a model to be reliable, the dependent property (in this case, toxicity) for all of the chemicals covered by the relationship has to be elicited by a mechanism that is both common to all of the chemicals in the set, as well as relevant to that dependent property. Careful selection of the chemicals to be used in a particular model is implicit in the mechanistic approach. The mechanistic approach to the prediction of toxicity from chemical structure has been reviewed recently [2•].

In the statistical approach, a structure/activity association or correlation is generated between structural fragments or from (often large) numbers of computed parameters from these fragments, and toxicity from collections of toxicological data. These systems use little or no expert judgement in organising or selecting the data to be processed either on the basis of chemical class or by putative mechanism.

In this review some of the recent developments in the computational prediction of toxicity are discussed.

Section snippets

Skin sensitization

The skin sensitization potential of a chemical can be considered to depend upon reactivity (the ability to react with skin protein either directly or after appropriate metabolism) and partition (the ability of the chemical to reach its site of action).

SAR studies of skin sensitization and respiratory sensitization have been reviewed by Karol et al. [3]. In this review, some key criteria for the selection of chemicals for SAR modelling of skin sensitization were set out:

  • 1.

    There are a number of

Eye irritation

Worth and Cronin [17] described the application of embedded cluster modelling to the ECETOC (European Chemical Industry, Ecology and Toxicology Centre) eye irritation data set [18]. The irritant chemicals were found to cluster in a two-dimensional scatter plot of logP (log [octanol/water partition coefficient]) and the first order difference valence connectivity index; the latter appears to be a measure of the degree of branching and/or cyclicity of the structure of the chemical (Fig. 1). The

Mutagenicity/carcinogenicity

Benigni et al. [23•] reviewed the value of QSAR models in predicting carcinogenicity of well-defined classes of chemicals such as aromatic amines. A statistically reliable and informative model of aromatic amine carcinogenic potential was constructed using in vivo data. It was determined that aromatic amines require metabolic activation to yield the ultimate carcinogen or mutagen. The principle pathway was identified as formation of a hydroxylamine that decomposes to a reactive nitrenium ion

Oestrogenic activity

The US Environmental Protection Agency initiative to screen and test over 80 000 chemicals for potential to disrupt the endocrine systems of humans and other vertebrates [29] has stimulated the development of QSAR prediction models to this end [30].

A recent study compares the analysis of relative binding affinity values for the displacement of tritiated 17β-oestradiol from the oestrogen receptor of calf uterine cytosol, for a large number of chemicals [31]. Three QSAR methods were

Decision support

The German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) has developed a rule-based SAR system using the data submitted within the notification procedure for new chemicals of the EU. The system was developed to support regulatory decision making in the assessment of local (skin and eye) irritation/corrosivity hazards of new and existing chemicals. The BgVV database contains proprietary data that cannot be published directly. The database has been evaluated

Conclusions

In reviewing recent developments in the prediction of toxicity from chemical structure, we have attempted to draw attention to some of the problems that can be encountered when working in this area. The prediction of toxicity from chemical structure requires a multi-disciplinary approach covering detailed knowledge of chemistry, toxicology and statistical methods. Given the complexity of most toxicological endpoints, it is not sufficient just to collect data and then attempt to analyse it with

Update

Development of QSAR models for the prediction of oestrogenic activity has continued [43]. Further refinement of the models has resulted in the generation of a ‘flowchart’ approach to filter out chemicals that are unlikely to be active as oestrogen receptor ligands [44•]. The flow chart uses five key structural features (e.g. if a chemical does not contain a ring structure, then it is unlikely to be an oestrogen receptor ligand, etc). The QSAR models are then used to make a quantitative estimate

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •of special interest

  • ••of outstanding interest

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