Last week, I was privileged to attend the Future Tox II conference in Chapel Hill, NC. This conference, sponsored by the Society of Toxicology, was focused on recent advances in in vitro and in silico toxicology, as directed towards improvements in predictive toxicology. The two day conference drew over 200 scientists from 13 different countries in North and South America, Europe and Asia. Twenty-two talks by invited experts were supplemented by 50 posters showing results from ongoing research projects, to provide a snapshot of the current state of the science.
In order to understand the scope of Future Tox II, a brief consideration of the history of toxicology is necessary. Toxicology is the science of poisons, and is concerned with all aspects of toxic substances – where they occur, why they are toxic, what symptoms they produce. Predictive toxicology seeks to determine how much of a particular substance one must be exposed to, and for how long, to cause a particular toxic effect. In the 20th century, predictive toxicology became extremely important, as governments moved to establish agencies to monitor and regulate toxic substances in foods, drugs, cosmetics and the environment as a whole, in order to improve the public health and safety. Examples of these agencies in the U.S. are the Food and Drug Administration, the Environmental Protection Agency, and the Consumer Product Safety Commission. Analogous agencies exist in all other industrialized countries worldwide.
The toxic effects of substances were largely determined by testing them on animals (in vivo methods), then attempting to extend the findings in animals to human beings. While this system was imperfect, it was substantially better than simply monitoring deleterious effects on the population and trying to retroactively identify the toxic substances that caused them. However, animal testing has many drawbacks. It is time-consuming and expensive, and results obtained in animals don’t always extrapolate well to humans. Additionally, some people consider animal testing unethical. For these and other reasons, toxicologists are actively seeking non-animal methods for toxicity testing.
Non-animal methods fall into two broad classes – in vitro and in in silico methods. In vitro methods use cells or other components derived from animals, instead of live animals or organs from animals, as test subjects. In silico methods use computer analysis of existing data to arrive at conclusions. An advantage of in vitro methods is that biological material derived from humans instead of other species can be used for experiments. Similarly, in silico methods can use data derived from humans instead of animals. A disadvantage of both methodologies is that they are conducted at lower level of biological organization than whole animal studies, so there is still an extrapolation problem. However, some in silico models do attempt to model higher biological levels such as tissues and organs, or specific environments for ecotoxological studies.
Toxicologists are currently employing in vitro and in in silico methods to define adverse outcome pathways (AOPs) for diverse toxic effects. An AOP attempts to link a temporal series of events to an observed toxic effect of a particular substance, beginning with a unique molecular initiating event. Once the AOP for a particular substance has been worked out, toxicologists have a mechanistic explanation for the toxic effect of that substance. The ultimate goal is to be able to use that mechanistic explanation to predict how much of a substance an organism must be exposed to, to produce the toxic effect. This, in turn, allows the toxicologist to predict allowable levels of the substance in foods, products or in the environment. Furthermore, once the AOP for a particular toxic effect has been defined, it is reasonable to assume that any chemical that can be linked to it will cause the same effect, so in theory, groups of related chemicals can be defined without the need for laboratory testing. This is extremely important, because the number of potentially toxic chemicals that are entering the environment is so large that it is impossible to test each one individually.
The task these scientists have set for themselves is daunting. A thorough understanding of AOPs, which are ultimately the building blocks of living systems, will translate into improved human health and safety, as well as a more complete understanding of life itself. Future Tox III, which will occur in about two years, is already in the planning stage. It is through continuous, organized and sustained efforts like this that science will continue to ensure that humanity’s future is a bright one.