PETA Workshop Furthers Work on Developing Alternate Testing Strategies for Studying the Effects of Nanomaterials in the Lung

A workshop organized by People for the Ethical Treatment of Animals (PETA) Science Consortium Ltd. has led to several publications developing alternate testing strategies (non-animal methods) for studying nanomaterial effects in the lung.

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10,000 publications, over a decade of research, and still no elucidation of a “nano-specific” health effect

Last month’s Society for Risk Analysis Nano Risk (II) Workshop focused on how to move the field forward in terms of using alternative testing strategies for risk analysis (alternatives to animal testing). My colleagues at Vireo Advisors prepared a case study analysis with nanoscale titanium dioxide. A well studied substance used in many applications, we reviewed 96 papers that involved alternative testing or comparisons to animal testing and developed them into a database. When we tried to compare the studies, we couldn’t, because each was performed a little differently, or the details were not well enough described. So, while there is a pretty large database of studies, many of the data are not all that consistent and do not allow for quantitative risk analysis. This is most disappointing given that 1) people have been calling for standardization in nano-toxicology testing for years, 2) we limited analysis to studies from the last 5-7 years, figuring they would be of higher quality, 3) some of these studies represent significant government investment (and of course government investment comes from tax dollars, including yours and mine!).

So, when I saw the headlines about the paper, “Nanosafety research – are we on the right track?” [Krug 2014Agewandte Chem Ind Ed 53:2-18], I jumped right in to see what perspective this renowned expert would offer. His review of about 1000 of the more than 10,000 publications on environmental health and safety of engineered nanomaterials published since 2000 concludes that, “Most of these studies, however, do not offer any kind of clear statement on the safety of nanomaterials.” Are you shocked by this revelation? This has been my perspective, but I find the amount of evidence overwhelming. It certainly resonates with our recent TiO2 experiment.

Others of Krug’s conclusions also resonate. In our analysis of TiO2, we found only one study that included doses judged to be “environmentally relevant” or at realistic exposure levels. Krug reported many studies were conducted under “overload” conditions, rendering the results meaningless for interpreting toxicity. It’s a commonly accepted fact that the dose makes the poison, so by running experiments at too high doses, substances can appear more toxic than they may actually be. It would be like trying to run a diabetes diet study on Halloween, when subjects are full of candy.

The most significant of Krug’s findings for me is that of all of this work, little contributed to the knowledge of a specific “nano-effect”. That is, from all of this effort and investment, including building the infrastructure for several large nanocenters, we still cannot say definitely whether there are any unique effects from exposure to nanomaterials.

Does this obviate the need for the field of nanotoxicology? No, but it calls on researchers to pay due attention to the real world implications of their work. Many of the studies were reportedly not performed by toxicologists, which is a problem. They didn’t use negative or positive controls, they failed to measure or report physical or chemical properties in a way that allows doses to be confidently characterized, and the assay methods used were not standardized. Our TiO2 analysis corroborates these findings as well. When non-specialists review such studies, they may not have the perspective to interpret the quality of the study. What would help is if researchers and reviewers would pay more attention to the relevance of these studies for understanding the impacts nanomaterials in real world applications, and report what they do and do not tell us about health risks. A novel assay not tested outside of one’s lab is not going to provide conclusive evidence. At a minimum, poorly controlled studies have no place in the peer reviewed literature.

While a major issue for funders and publishers (should these studies be accepted/published?), it’s an even bigger issue for risk assessors and end users. I’ve been calling the results of toxicology studies on nanomaterials equivocal for a decade, and will continue to in the near term. I will also continue to keep the bullet point in my slide deck that “no nano-specific effect has been identified”. Because of poor characterization, the job of determining acceptable dose levels is even more challenging, reinforcing my approach to focus on mitigating potential exposure through the use of nano-life cycle risk assessment to minimize risks from nanomaterials. I predicted in 2005 that it would be 20 years before we answered some of the critical toxicology questions for nanomaterials, and 10 years in, we appear to be on exactly such a course. The bottom line, the state of the science for toxicology of nanomaterials is still in adolescence in terms of environmental relevance.

International Workshop and Collaboration on Nanomaterial Safety: An international collaboration on in vitro testing strategies

Vireo Advisors, the University of Alberta’s Ingenuity Lab and others are collaborating with the Society for Risk Analysis to evaluate the potential to use alternative test strategies (ATS) to improve our ability to assess nanomaterial toxicity and environmental impact. READ THE STORY ON NANOWERK!

NANO RISK ANALYSIS (II) A Workshop to Explore How a Multiple Models Approach can Advance Risk Analysis of Nanoscale Materials September 15-16, 2014, Washington, DC  REGISTRATION NOW OPEN: FOR POSTERS DEADLINE EXTENDED to August 1!

This workshop brings together experts from diverse disciplines to explore ways in which Alternative Testing Strategies (ATS) may be combined to create a Weight of Evidence (WOE) or “multiple models” approach to inform context –specific decisions about risk from exposure to novel nanoscale materials. The goal is to advance a common understanding of the state of the science, early lessons, current opportunities, and next steps for developing ATS for use in decision making for nanoscale materials.

 The specific decision focus for this first “state of the science and practice” evaluation is the initial set of screening level decisions that a risk manager would need to make about seeking further (specific) data or declaring obvious safety for a novel nanoscale material.  The output of the workshop will be a set of recommendations reported to the OECD Working Party on Manufactured Nanomaterials (WPMN) and via peer reviewed publications and web-based portals about ways in which these approaches may be practically applied in the near term to improve environmental decision making by governmental and industrial organizations. The output of the workshop holds potential for transformation through risk screening approaches that promote safer and more sustainable material and technology development.

Read more: Nanomaterial safety: An international collaboration on in vitro testing strategies
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3D Printing Accelerates Toxicity Testing with Nanomaterials

As a fan of nanotechnology innovation, it doesn’t take a lot of digging to find inspiration in new developments with potential for radical shifts in how we as a society meet our needs and wants. 3D printing, or additive manufacturing, has captured my imagination, as a tool for safer technologies, more efficient manufacturing, resource conservation, and innovation. Combine these two technologies, and see how close the future really is.

Today’s focus is on bioprinting. Using magnetic nanoparticles, people are commercializing ways to build 3D cell systems for testing toxicity of substances to organs. Talk about high throughput screening! These systems can conduct thousands of tests to screen new drugs, chemicals, additives in systems that mimic human organs. Wait, they mimic human organs? With 3D printing, now researchers are able to “print” tissues in 3D – like your hip, or your liver. Can you imagine, on your next trip to Fatima, a new shop just outside the shrine custom printing anatomical models of ears and lungs made from 3D printing instead of mold injection? More seriously, by the time some of us need hip replacements, 3D printing will custom fit our new hips, with biocompatible materials. And, by then, our toxicology testing paradigm may be based on these alternative testing strategies using bioprinting to mimic systems biology.

That is the goal, anyway. If you’ve read my book, you know I assign less weight to in vitro, or cell based assays, as predictive toxicology tools, because they are models with limited ability to capture the complexity our bodies have. I’m all for screening methods that focus and prioritize further testing, as long as they are reliable as indicators of behavior. Standard cell culture assays study interactions at the cellular level, not the organ level, a critical piece to understanding the potential effects. These 20th century tests (back in the days of the first test tube baby, they were state of the art) were developed to screen drugs, and have been applied with some success to screening chemicals for toxicity. Part of the issue is the geometry. The cells form a layer in a petri dish (or more often now a microarray vial), which is very different than a 3D organ system. Now, we have the ability to create 3D models of our tissues, and this steps us firmly into the 21st century of toxicity testing innovation. Bioprinting is a real example of the power of converging (bio, nano and info) technology to advance us more quickly to developing safer and more sustainable products.

Stay tuned for more about these fascinating developments, including upcoming workshops to learn more about how advanced these techniques are for conducting risk assessments of nanomaterials. In the meantime, liver anyone?