After more than 40 years of evaluating the hazards of chemicals by testing animals to extrapolate human health effects, the US National Toxicology Program is shifting gears. Under the direction of Associate Director Brian Berridge, the program is embracing innovative technologies such as artificial intelligence and in vitro human cell systems in hopes of making chemical hazard assessments more relevant to people.
The NTP is also flipping its process for chemical hazard assessment upside down. Rather than starting with individual chemicals or classes of chemicals and looking for their health hazards, the program is looking into whether particular diseases that have a big impact on public health have chemical origins.
Berridge joined the NTP in January 2018, after more than a decade working for the pharmaceutical company GlaxoSmithKline. There, he was the first to lead a group examining the role of animals in drug development. The group was started “with an intent to try to eliminate animals in drug development” to be socially responsible, Berridge says.
▸ Current position: Associate director, US National Toxicology Program
▸ Previous positions: Director, worldwide animal research strategy, GlaxoSmithKline; toxicological pathologist and cardiovascular safety expert, GlaxoSmithKline and Eli Lilly and Company
▸ Education: DVM, Oklahoma State University; PhD, veterinary medicine, Texas A&M University
▸ Biggest goal this year: Embrace and build confidence in innovative technologies for evaluating the health hazards of chemicals
“That was a great aspiration, and I hope to see the day when we get there, but that is not a near-term reality,” Berridge says. “We really needed to optimize the way we used animals, then progressively decrease our dependence on them.” That is the direction he took the group at GSK, and he intends to do the same at the NTP. “I want us to do more piloting of novel technology,” he says.
The NTP was established in 1978 to improve the ability of the federal government to make public health decisions using the most up-to-date science. Under the umbrella of the US Department of Health and Human Services, the program coordinates toxicology information across multiple federal agencies, including the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention.
Berridge is pushing the envelope at the NTP so that federal agencies get chemical hazard information that is relevant to humans faster. “We have to understand what technologies are out there, bring them in, test them, and help them to evolve to get to places where we need them to be,” Berridge tells C&EN.
One area that excites Berridge is in vitro systems that use human-derived stem cells to construct complex 3-D structures that mimic tissues and organs. Such tools are helping scientists better understand the mechanisms that underlie the toxicity of chemicals to humans, he says.
Berridge is also keeping a close eye on techniques to investigate genetic diversity in both animals and human cellular systems. The throughput of genome-sequencing technologies is increasing while the cost of the technologies is decreasing. “I think we will do more to understand genetic variability in populations” to learn more about genetic factors that play a role in susceptibility to certain chemical effects, Berridge says.
Mathematical modeling techniques that predict how chemicals are absorbed, distributed, metabolized, and excreted are also improving, Berridge notes. These models help decrease some of the uncertainty involved in extrapolating exposures from laboratory animals to humans.
“All of those tools are ultimately going to be part of how we approach creating or bringing more human precision or translation to the assessments that we do,” Berridge says.
To that end, the NTP is undergoing a strategic realignment to focus on areas where it has “the most opportunity for impact on public health,” Berridge notes. In the past, the NTP has focused on evaluating the health hazards of single chemicals or classes of chemicals. The program is now reversing that assessment process by starting with diseases of interest rather than chemical agents of interest.
“There is a lot of cardiovascular disease in the world,” Berridge says. “Should we be looking to understand what possibly is contributing to the incidence of cardiovascular disease?” That is a very different approach than looking at whether a particular agent causes cardiovascular disease or other hazard, he explains.
For now, the program has identified three so-called health-effects innovation areas—carcinogenicity, cardiovascular disease, and neurological and developmental toxicity. The goal is to fill in the gaps in current toxicological assessment capabilities in each of the three sectors.
For carcinogenicity, “you could argue we don’t have a gap,” Berridge says. “We do the 2-year rodent study all of the time.” NTP scientists are hoping to find alternative, preferably nonanimal, tests that have faster throughput for identifying chemicals that increase the risk of cancer. The NTP plans to investigate in vitro and in silico systems, as well as shorter-duration in vivo tests for carcinogenicity. “We need to reinvent how we do carcinogenicity assessments,” Berridge says. “It will be about building a strategy, not an individual assay, but actually a strategy.”
The gaps in the other two areas are larger. “We have a pretty well-defined paradigm in pharma for how you do cardiovascular assessments,” Berridge says. “Cardiovascular assessment is much less established in environmental toxicology.” Berridge studied cardiovascular, drug-induced safety challenges while working in the pharmaceutical industry. Before that, he studied cardiovascular pathology related to cardiovascular devices in humans at the Texas Heart Institute.
In the area of neurological and developmental toxicity, the NTP is exploring another tool sometimes used in the pharmaceutical industry: computer vision-aided assessments. The idea is to capture animal behavior around the clock, particularly during the night, when rodents are most active, by attaching cameras to the animals. The goal is to have software mine behavior information to “give us new insights into how behavior reflects health in those animals,” Berridge says.
Along the same lines, the NTP is looking into techniques that couple high-content imaging with in vitro systems that use human-derived cells. These technologies allow imaging of multiple structural components inside cells to illuminate changes in cell structure and function over time. “The proliferation of structural labels for cells and the ability of imaging systems to detect them are going to give us a lot more information about what is happening at the cell and tissue level,” Berridge says.
With these novel technologies, however, comes another challenge—an incredible amount of data “that the average human will not be able to wrap their head around,” Berridge notes. “We will need computational approaches to be able to handle the volume of data, integrate it, and extract meaningful information,” he says.
Artificial intelligence and machine learning “will allow us to mine novel things from that data that we haven’t been able to in the past,” Berridge predicts. “That said, I think we are on the front end of that,” he notes, suggesting that such methods will play a much bigger role in toxicology in the years to come.
Beyond the three health-effects innovation areas, the NTP is facilitating collaboration to better understand diseases that have a relatively high incidence of early mortality. One of those diseases is chronic kidney disease of unknown origin (CKDu), which has hit agricultural workers particularly hard in areas with high heat and humidity in Central America, Southeast Asia, and Africa.
People in less-developed parts of the world are dying from chronic kidney disease at young ages, Berridge says. These people do not have the normal risk factors for kidney disease, such as diabetes and high blood pressure, he adds. “Is this associated with pesticide use or some contamination by heavy metals in the water because of where these folks live?” The NTP has experience assessing the hazards of pesticides and heavy metals in animals. “We can go back and look at our animal studies and see if we see lesions that are consistent with what is being described in these workers,” Berridge suggests.
The NTP is in a unique position to coordinate partnerships to study diseases like CKDu, which may be on the rise because of increasing temperatures and humidity in some parts of the world. “There is some suspicion that the disease is also present in the US, but that has not been studied as well,” Berridge says. The NTP hopes to use its infrastructure to facilitate collaboration across the communities interested in CKDu, he says.
Being a government entity, the NTP is also in a position to examine innovative technologies and build confidence in them, Berridge believes. “I am not driven by typical academic expectations for pursuing research dollars. I am not constrained by typical corporate profit motives,” he says. “We have the ability and the flexibility to pursue innovations like nobody else does.” Toxicology safety assessment has always been a very conservative science. In order to test chemicals differently, “somebody has to build confidence in that different way,” Berridge says. “I think that is the role for the NTP to play.”