In Silico Models for Hepatotoxicity.

In this chapter, we review the state of the art of predicting human hepatotoxicity using in silico techniques. There has been significant progress in this area over the past 20 years but there are still some challenges ahead. Principally, these challenges are our partial understanding of a very complex biochemical system and our ability to emulate that in a predictive capacity.

Adverse Outcome Pathway (AOP) Informed Modeling of Aquatic Toxicology: QSARs, Read-Across, and Interspecies Verification of Modes of Action.

Alternative approaches have been promoted to reduce the number of vertebrate and invertebrate animals required for the assessment of the potential of compounds to cause harm to the aquatic environment. A key philosophy in the development of alternatives is a greater understanding of the relevant adverse outcome pathway (AOP). One alternative method is the fish embryo toxicity (FET) assay.

Investigation of the Verhaar scheme for predicting acute aquatic toxicity: improving predictions obtained from Toxtree ver. 2.6.

Assessment of the potential of compounds to cause harm to the aquatic environment is an integral part of the REACH legislation. To reduce the number of vertebrate and invertebrate animals required for this analysis alternative approaches have been promoted. Category formation and read-across have been applied widely to predict toxicity.

Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models.

The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models.

A review of the use of in silico methods to predict the chemistry of molecular initiating events related to drug toxicity.

Introduction: Drug toxicity pathways can be extremely complex and difficult to fully understand. However, understanding specific parts of the pathway may be simpler. Every toxicity pathway starts with a molecular initiating event (MIE).

The use of a chemistry-based profiler for covalent DNA binding in the development of chemical categories for read-across for genotoxicity.

An important molecular initiating event for genotoxicity is the ability of a compound to bind covalently with DNA. However, not all compounds that can undergo covalent binding mechanisms will result in genotoxicity. One approach to solving this problem, when in silico prediction techniques are being used, is to develop tools that allow chemicals to be grouped into categories based on their ability to bind covalently to DNA.

Using In Silico Tools in a Weight of Evidence Approach to Aid Toxicological Assessment.

Integrated testing strategies are an important and useful approach to reduce animal usage in toxicity testing. Increased usage of integrated testing strategies is foreseen in current chemical legislation, e.g.

Definition of the applicability domains of knowledge-based predictive toxicology expert systems by using a structural fragment-based approach.

The applicability domain of a (quantitative) structure-activity relationship ([Q]SAR) must be defined, if a model is to be used successfully for toxicity prediction, particularly for regulatory purposes. Previous efforts to set guidelines on the definition of applicability domains have often been biased toward quantitative, rather than qualitative, models. As a result, novel techniques are still required to define the applicability domains of structural alert models and knowledge-based systems.