Acute Systemic Toxicity: U.S. Regulatory Testing News

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In the Spotlight

Acute Systemic Toxicity: U.S. Regulatory Testing News

by Sherry Ward, AltTox Contributing Editor
Posted: November 27, 2017

Updated Acute Systemic Toxicity Section on AltTox

Dr. John ‘Jack’ R. Fowle has published a new section on AltTox, “Acute Systemic Toxicity: Regulatory Testing Overview.” Highlights include two recent U.S. Environmental Protection Agency (EPA) policy initiatives: 1) EPA’s intent (along with five other U.S. agencies) to move away from “the commonly used animal toxicity tests, referred to as ‘the six-pack,’ for acute toxicity testing of pesticide products,” and 2) EPA’s March 2016 draft policy “to waive all acute dermal lethality studies for pesticide products.” Dr. Fowle explains that “these actions are expected to result in a significant reduction in animal use, signaling a pivot from animal to non-animal based testing approaches and represent a major change in how acute toxicity testing will be conducted.”

Following a thorough explanation of the traditional animal based testing approaches, “to provide context,” Dr. Fowle continues on to explain currently accepted in vivo approaches that reduce animal use in acute systemic toxicity testing, as well as opportunities for the use of bridging and waiving of test requirements and the use of Adverse Outcome Pathways (AOPs) in an Integrated Approach to Testing and Assessment (IATA) as promising alternative approaches in acute systemic toxicity.

These approaches, along with new initiatives such as the one described below, are expected to allow EPA and other U.S. agencies to eliminate the use of animals for acute oral systemic toxicity testing over the next three years.

ICCVAM Project on Predictive Models for Acute Oral Systemic Toxicity

One of of the Interagency Coordinating Committee on the Validation of Alternative Method’s (ICCVAM’s) high priority efforts is to develop alternative test methods for EPA six-pack tests; acute oral systemic toxicity is one of these tests.

As part of this effort, ICCVAM is initiating a project to develop in silico models for predicting acute oral systemic toxicity. Computational scientists and others are invited to develop in silico models that predict any or all of five specified endpoints using the provided datasets of rat oral acute toxicity to build and test their models. “Models developed for the project that meet criteria defined by the project organizing committee will be used to generate consensus predictions for the acute oral toxicity endpoints of interest to regulatory agencies.”

Additional information for model developers is provided online, and interested parties are asked to contact the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The deadline for submitting prediction results from the developed models to NICEATM is February 9, 2018. Project results will be presented at the Predictive Models for Acute Oral Systemic Toxicity Workshop in Bethesda, Maryland on April 11-12, 2018.

Progress on ICCVAM’s U.S. Strategic Roadmap

Last year, Dr. Warren Casey provided some background on recent ICCVAM/ NICEATM efforts to develop an implementation strategy for incorporating animal alternative test methods in U.S. regulatory practices in his article “Implementing The Vision For Toxicity Testing In The 21st Century: An Opportunity For Action.”

Since that time, there has been a flurry of activity to finalize ICCVAM’s U.S. Strategic Roadmap. Three public meetings in 2017 have updated and requested comments from the public. Information from these meetings can be found in various articles and webcasts, including the following:

Presentations at the September 18-19 meeting of the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM)
Video recordings of the September 18-19 and several other 2017 meetings are available on the National Institutes of Health Videocast website

The draft roadmap lays out three strategies to achieve the goal of replacing animal tests:
• Encourage adoption and use of new methods
• Establish confidence in new methods
• Connect developers of new methods with those who will ultimately use them

Although the final version of the Strategic Roadmap is planned for release in November 2017, a September 11 draft, “The U.S. Strategic Roadmap: New Approaches to Evaluate the Safety of Chemicals and Medical Products,” is the only version publicly available at this time. At least part of the urgency in finalizing this roadmap is the upcoming two-year deadline for EPA to finalize their strategic plan to reduce vertebrate animal use for regulatory testing under the Toxic Substances Control Act (TSCA). ICCVAM’s Strategic Roadmap is an important element in supporting that goal.

U.S. EPA – Alternative Test Methods to Reduce Vertebrate Animal Testing under the Toxic Substances Control Act

The Lautenberg Chemical Safety for the 21st Century Act (LCSA) that was signed into law on June 22, 2016 requires EPA to create a strategic plan to “promote the development and implementation of alternative test methods and strategies to reduce, refine, or replace vertebrate animal testing” within two years of enactment.

Dr. Louis Scarano’s presentation at the September 2017 SACATM meeting said “The intent of Section 4(h) is clear – to develop and use methods and strategies that will not require the use of vertebrate animal testing to evaluate chemical substances or mixtures in the United States under TSCA.” He went on to outline some draft goals and objectives for the EPA’s strategic plan.

EPA held a public meeting on November 2, 2017 “to obtain input from interested parties and the public on the Agency’s development of the Strategic Plan.” Further inputs on the draft strategic plan can be submitted at (docket EPA-HQ-OPPT-2017-0559) through January 3, 2018. The EPA’s first public draft of this plan is expected to be released in April 2018. A videocast of the November 2 meeting is also available.