In October 2011, Regulatory Focus contributor Max Sherman, president of Sherman Consulting Services, called attention to what he said was an "important tool for many areas of biomedical research," including toxicity testing for drug products: Zebrafish.
Now regulators with the US Food and Drug Administration (FDA) are calling attention to the same, noting that its National Center for Toxicological Research (NCTR) is heavily invested in using the animal species as a predictable toxicological tool to assess the safety of experimental drug products.
Danio rerio, the zebrafish, is at first glance an unusual candidate for such a heavy regulatory burden as toxicity testing. The tropical freshwater fish is native to Burma and India, and is a staple of aquariums. But since the 1970s, the fish have been identified as a model for testing based on the physical characteristics, which include rapid growth, large numbers of offspring, and eggs that develop outside of the body (thereby allowing easier observation).
These characteristics have now made zebrafish a staple of many laboratories around the world, including the NCTR laboratory in Arkansas.
"Using the embryos of zebrafish as models, we study how various drugs and chemicals affect the organs and systems," explained Jyotshna Kanungo, an FDA research biologist. "We try to get the best possible picture of the hazard that would be involved in taking a drug before it is tested in human patients."
The fish also have a number of other characteristics that make them uniquely situated to predictive toxicology, Kanungo explained. The fish, unlike fruit flies or nematode worms, are vertebrates, and are 80% genetically identical to humans.
"Because the fish share so many common biological pathways with humans, they make excellent test subjects," noted Merle Paule, director of NCTR's Division of Neurotoxicology.
But the fish have another characteristic that makes them better than almost any other species: They're transparent. "It's very exciting, because under a microscope you can watch as their organs and systems develop," Kanungo says. "You can actually see the blood flowing and the heart beating."
The animal's size also confers certain unique advantages. Unlike rats or other species, the fish can easily be maintained in numbers in the thousands. FDA says its NCTR lab can house around 6,000 of the fish, which allows it to test "20 different concentrations of a drug or chemical in just ten minutes, and screen nearly 400 embryos during the same time. The administration of chemicals is also easier, as the fish can simply absorb them through their skin, whereas animals like rats must have the drugs administered manually.
And while the fish isn't the be-all-end-all of toxicity testing, FDA explained that it does function as a sort of "gatekeeper."
"If we introduce a drug/chemical to zebrafish and there's a negative effect, it's a red flag, and it alerts us to take a closer look for toxicity if subsequent studies are warranted," Paule said.
But, as Sherman noted in his article, there are some novel regulatory challenges associated with the use of zebrafish for regulatory purposes.
"Currently, FDA is willing to discuss alternative methods of toxicity and biocompatibility testing," Sherman wrote. "The alternative methods, i.e. zebrafish embryos, should be capable of detecting the same endpoints with the same specificity and sensitivity as currently provided by traditional methods. Any company planning to use zebrafish models should contract the appropriate review division or branch for complete feedback to ensure any changes introduced by the new model can be addressed prior to conducting the test."
The NCTR's own zebrafish research facility, notes Sherman, could very well be the model for such research and validation. FDA noted that the facility is already using zebrafish models to study ketamine, copper nanoparticles, hearing loss and nicotine.
So could the next big thing in regulatory actually be one of the smallest in size? "Stranger things have happened," concluded Sherman.