Computer Simulation Reduces Time to Estimate Chemical Toxicity

Computer simulation has helped a major chemical producer reduce the time needed to assess the toxicity of potential new chemical products from one week to 15 minutes.

The chemical producer develops new product candidates on a regular basis. One of the most important issues in evaluating these candidates is their toxicity. Toxic chemicals stand a higher chance of being prohibited under state and federal laws. Even when they are accepted by regulatory authorities, they are still considerably more expensive to manufacture, test, ship, store, and use because of the need to protect workers from exposure. For these reasons, researchers at the company wanted to know the toxicity of product candidates as accurately and as early as possible in the development process.

In an effort to find the best solution, researchers at the chemical company evaluated the major new computational toxicology products that have come onto the market in recent years. These programs provide far more accurate toxicity measurements than can be achieved with traditional methods of determining toxicity. The chemical company selected TOPKAT (TOxicity Prediction by Computer-Assisted Technology) from Health Designs Inc. (Rochester, NY).

Importance of Toxicity
Performing experiments to determine toxicity of each of new chemical consumes a great deal of time, money, and animal lives. For example, performing an acute oral toxicity test on a single chemical takes about 15 days and costs on the order of $3,000. Mutagenicity testing also takes about 15 days and costs around $2,000. Testing a substance for carcinogenicity takes about 730 days and costs approximately $2 million.

Obviously, it is extremely difficult to generate resources to experimentally testing multiple chemical candidates, especially when it is considered that more than 75% of chemicals in current use have never been tested. In addition, chemical companies are coming under increasing pressure to reduce or eliminate conventional mammalian in vivo toxicological studies.

Read-Across Tables
For that reason, scientists previously developed read-across tables in an effort to estimate the toxicity of product candidates. Similar to the multiplication tables found in elementary schools, these read-across tables consist of structurally related chemicals that are ordered by adding various groups of molecules as you move down or across the table. The new chemical is then located on the chart and the toxicity trends of the chemicals in the same row and column are evaluated to make predictions.

This approach has two main drawbacks. First of all, it takes a long period of time to complete one of these charts, often a week or more if the time required to research the toxicity of all the chemicals in the chart is included. Second, the accuracy of these tables is suspect because of their extreme simplicity. Because of these drawbacks, scientists were unable to evaluate more than a small proportion of their product candidates.

The TOPKAT computer simulation program allows researchers to easily estimate the toxicity of most potential chemicals, making it possible to produce much more accurate manufacturing cost estimates. Sometimes, toxicity estimates even make it possible to shift development resources from a toxic candidate to one that is much safer.

Robust Models
The TOPKAT program utilizes robust, cross-validated Quantitative Structure Toxicity Relationship (QSTR) models for assessing various measures of toxicity. Each QSTR model is associated with a particular toxicity metric. These models have been developed from bioassay results carefully evaluated for accuracy and consistency of protocol. When a chemical is submitted for assessment, the program automatically computes the contributions of its various molecular features and then sums up these contributions to compute the toxicity of the chemical.

TOPKAT Accuracy
The mutagenic potential of a chemical is of great importance, because over 80% of the carcinogens known to man have also been found to be mutagenic. These tests are often used as indicator tests for carcinogenicity because they are much faster and cheaper than classical animal carcinogenicity studies.

Researchers at the chemical manufacturer use the TOPKAT software package to evaluate every product candidate—an average of 50 in a given month. The program not only provides accurate toxicity predictions but also calculates the confidence level of the prediction. These predictions have been shown to correlate very well with animal studies. The software predictions also help to allocate scarce testing resources.

For example, if the program predicts that the median lethal dose of the compound is greater than 5 grams, then limit testing may be all that is required. This is because government regulations for industrial chemicals frequently do not require more specific studies for chemicals whose median lethal dose can be shown to be greater than 2 grams. On the other hand, if the median lethal dose is predicted to be less than 50 milligrams, it's clear that limit testing will be of no value so scientists typically move straight into more specific studies.

All in all, TOPKAT software helps scientists maximize the effectiveness of their research dollars. The software reduces the time required for toxicity predictions to the point that every chemical under consideration for development can easily be examined. This makes it possible to direct developmental resources to less toxic chemicals and to prepare more accurate cost estimates for toxic chemicals for which no safer substitute exists. The net result is the development of safer products at a lower cost.

For more information: Health Designs Inc., 183 East Main Street, Rochester NY 14604. Tel: 716-546-1464. Fax: 716-546-3411.