US Environmental Protection Agency uses Certara’s Simcyp Simulator to support toxicological triage

Published: 11-Nov-2016

Simcyp Simulator allows population variability to be factored into risk-based prioritisation

Certara, the leading provider of decision support technology and consulting services for optimising drug development and improving health outcomes, has announced that the US Environmental Protection Agency (EPA) is using its Simcyp Population-based Simulator to support the agency’s high-throughput toxicity testing programme.

The Simcyp Simulator is being used to determine which commercial chemicals are more likely to pose a risk to human health and should receive additional testing.

“We are proud to partner with the US EPA to enhance its toxicity screening programme and help improve human health,” said Certara Chief Executive Officer, Edmundo Muniz, MD, PhD. “The Simcyp Simulator allows individual variability to be factored into the EPA’s research; it simulates the behaviour of virtual populations and not just an “average” person, making the results more accurate for everyone.”

“As funding and time constraints limit the number of chemicals that we can test each year, we use the Simcyp Simulator to facilitate risk-based prioritization and help to ensure that we evaluate the most potent chemicals first,” said John Wambaugh, physical scientist at the National Center for Computational Toxicology in the Office of Research and Development of the EPA.

There are thousands of chemicals in commercial use and hundreds more are introduced every year. The EPA is tasked with assessing the potential toxicity of these chemicals as effectively and efficiently as possible.

As current chemical testing is expensive and time consuming, only a small fraction of those chemicals have been fully evaluated to determine whether they could pose a risk to human health. While a chemical such as a pesticide, which is intended to be toxic, is very rigorously tested under the law, a dye which has a relatively familiar chemical structure might not be tested at all.

The EPA begins by measuring how long a pool of human liver cells or hepatocytes takes to clear the chemical. It then enters that data into the Simcyp Simulator, which simulates variations in human height, weight, and blood flow to organs.

The Simcyp Simulator allows the EPA to predict differences in chemical clearance levels and determine whether a chemical would accumulate or be removed from the body. The EPA can then determine what the range of plasma concentrations would be for that chemical in the US population at a specific exposure rate.

By combining the hepatocyte clearance data with the Simcyp population variability data, the EPA can determine which chemicals are the most potent – would produce the highest blood level with the lowest dose – and make them higher priority for additional deeper studies. It is possible for plasma concentrations to vary by 100 fold between two chemicals at the same concentration.

The EPA has publicly released hepatocyte and clearance data on 543 chemicals and has just completed measurements for about another 200.

The EPA has also begun using the Simcyp Simulator’s ability to model paediatric populations. Barbara Wetmore, PhD, human exposure modelling scientist at the EPA, obtained Cytochrome P450 (CYP) enzyme-specific data for about a dozen chemicals and used the Simcyp Simulator to demonstrate the difference in plasma concentrations that they would produce in an adult and a child. Research is just beginning in this area because there is little data currently available on the metabolizing enzymes for most chemicals.

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