Sometimes You Need a Toxicologist
Safety Assessment
Alan Hoberman

Sometimes You Need a Toxicologist

When we introduce a new therapy—whether it’s a re-engineered mosquito, a biologic or a synthetic drug—we have to think about the immediate and long-term implications of the intervention

Physicists, mathematicians and chemists may be exploring the building blocks of our world from the atomic level on up, but physiologists, pharmacologists and toxicologists have to study the higher-level, more complex interactions that occur within and between cellular organism.  We have come to understand that these organisms are so complex that any change from the “normal” balance can lead to a good or bad effect.  As a toxicologist we learn the primary rule of toxicology that the “dose/exposure makes the poison.  Too much or too little of something can have good or bad effects.  Once the balance is disturbed the consequences can be great.

Toxicologists are trained to distinguish the normal from the abnormal or to provide a little more definition; regulatory toxicology is all about identifying a hazard and finding the cause. What is interesting to me is that most toxicologists work in the Safety Assessment Group at a Contract Research Organization, chemical or pharmaceutical company.  In other words while we are trained to look for bad things, we are really tasked to show how something can be used safely. What is the No-Observable-Adverse-Effect Level in animals and how much (dose) can we use safely?  The management of a chemical or drug company tends to believe in the safety and efficacy of their product or drug, and have a difficult time understanding why toxicologists are always killing their good drug or chemical because the margin of safety is too small or does not exist between the efficacious dose and frank toxicity.

This narrow focus on safety or hazard has always annoyed me, but really got to me when I read a recent article about potentially using genetically modified Aedes aegypti mosquitoes to control the spread of vector-borne diseases like Zika. By mating modified male mosquitoes with wild females, you can then pass a lethal gene on to any progeny and kill wild mosquitoes transmitting not just Zika but dengue, and yellow fever. This strategy might be helpful in controlling the spread of deadly viruses, but has anyone thought about the long-term effects of spreading this “common” bacteria in the environment. I have to assume that the overall safety of this new practice has been well thought out, considering the impact of this intervention, but in too many cases we find out too late that fixing one problem introduces a host of other problems.

Here’s a good example. Following the introduction of rabbits to Australia many measures were introduced to control a population that without any predators became a real nuisance.  A typical attempt during the 1950s included the deliberate release of myxoma virus, which kills rabbits in 9-11 days, and is 95% lethal based on research conducted by Australian scientist Frank Fenner. This approach did thin the herds from an estimated 600 million to around 100 million. However, genetic resistance in the remaining rabbits allowed the population to recover to 200–300 million by 1991.

Biologics offers another cautionary tale. With the introduction of large molecules, primarily monoclonal antibodies, it was initially thought that there was no need to test for hazards because of the specificity of the antibodies—they are designed to target different proteins—and the fact that the antibodies were naturally-occurring.  The trained toxicologist quickly recognized that this was a total misunderstanding of the concept of dose, The levels of a human protein that we know are safe are physiological doses that when exposure as a drug occurs, the level of exposure increases to pharmacological levels with unknown direct and side effects. We tend to underestimate the result of exaggerated pharmacology, too much exposure, and the consequences of stopping or lowering a pharmacologic exposure level.

Try Practicing Green Chemistry

So it is clear that when we introduce a new therapy—whether it’s a re-engineered mosquito, a biologic or a synthetic drug—we have to think about the immediate and long-term implications.

Chemicals including the pesticides and herbicides that we are all exposed too need to be evaluated not only for short term effects of exposure but also studied from all aspects of interaction with the environment.  At Yale, a former Environmental Protection Agency official has established a department of Green Chemistry—the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances—and published 12 principles of green chemistry which you can find here.

If we include these 12 principles when we think of substitutes for currently used chemicals, and we understand that any change can be good or bad, we might be able to more easily introduce new chemicals into the environment that have fewer bad side effects, that are less damaging, and overall more beneficial to our society.