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Good Science

July 2018


July 18, 2018   asthma

 

The first in a series of three posts examining asthma research and testing methods, this post provides some general information about asthma research and testing methods and how they can be improved.

Asthma: Chances are either you or someone you know is affected by it. But how do researchers study asthma and how can we do a better job?

Asthma is one of the leading chronic health conditions in the United States. More than 26 million people are known to have asthma nationwide, and the prevalence is rising. Each year, asthma in the United States costs approximately $56 billion in medical costs, lost school and work days, and early deaths. Asthma is attributed to approximately 500,000 hospitalizations and over 3,500 deaths annually, yet there is no cure.

Asthma is a chronic lung disease that inflames and narrows the bronchial tubes—or airways—that carry air into and out of the lungs. A combination of poorly understood genetic and environmental factors contribute to any one person’s asthma diagnosis. But in most people, asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. People who suffer from asthma have inflamed airways that can strongly react to inhaled or ingested substances such as environmental allergens, chemicals, sulfites in foods and drinks, medications, air pollution, and other irritants. When the bronchial tubes react, the muscles around them tighten and the cells inside the airways produce excess mucus, which further restricts airflow. Asthma symptoms can range from mild to severe and may cause hospitalizations and even death.

Over the past several decades, research has identified two types of prescribed asthma therapeutics, which are classified as either controllers or relievers. Controllers are long-term control medicines that help reduce airway inflammation and prevent asthma symptoms. Relievers, or “rescue” medicines, relieve asthma symptoms on the onset of a flare-up. Despite decades of research, neither of these types of medications addresses the underlying cause or causes of disease, and significant asthma-related morbidity and excess healthcare use and costs persist. 

Animals have been extensively used in asthma research to examine mechanisms of disease, the activity of gene and cellular pathways, and to develop and test drug therapies. Numerous animal species are used for experiments, including mice, guinea pigs, dogs, cats, sheep, and horses, among others. Unsurprisingly, animals are poor candidates for studying asthma because the anatomy, immune system, and inflammatory responses exhibited by animal lungs differ greatly from those in humans. Animals used to study this condition do not exhibit symptoms similar to human asthma—asthma is a human disease—, so typically the disease has to be artificially introduced in the airways. Animals also have different airway architecture and different breathing behaviors that affect where the inhaled irritant “lands” in the lung and therefore how the organism reacts. Furthermore, the distribution of lung inflammation is different, and many animals become tolerant after repeated allergen exposure. Therefore, key features of human asthma cannot be recreated in animal models.

Researchers can learn much more about the complexity and diversity of asthma from human-relevant research rather than animal experiments. Instead of genetically modifying mice or subjecting animals to inhalation chambers or extreme, unnatural sensitizing processes, researchers can focus on promising, human-relevant research methods. For example, since asthma is such a widespread condition, epidemiological studies using human volunteers with asthma can provide key information on likely triggers and responses to drugs.

In recent years, researchers have developed a small airway-on-a-chip that enables analysis of human lung inflammation and drug responses in vitro. This model is a small silicone chip lined with human cells that can simulate human lung inflammatory disorders like asthma. It can be used to detect synergistic effects of asthma triggers and to identify biomarkers of disease exacerbation as well as responses to anti-inflammatory compounds.

Genetics are thought to be a significant risk factor in the development of the disease. Many genetic studies are currently taking place in the field of asthma research, such as sampling cell cultures from people with asthma and analyzing them to see which genes are different and how that impacts their potential response to treatment. A person’s environment can impact their genes, which makes genetic asthma research complicated, but gaining a better understanding of the genetic contributors to human asthma will lead to improvements in diagnosis, treatment, and, hopefully, prevention.

Human-based approaches offer a more relevant and personalized way to examine this human disease. After decades of asthma exploration there is sufficient research but insufficient progress. Asthma is a complex disease with a lot of diversity, making sophisticated human-relevant approaches necessary to deepen our knowledge of this universal human health condition. 

Stay tuned for an in-depth discussion of some promising human-cell-based models for research and testing!

References

  1. National Center for Health Statistics: Asthma. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/nchs/fastats/asthma.htm. Published March 31, 2017. Accessed July 5, 2018.
  2. Asthma. National Institutes of Health National Heart, Lung, and Blood Institute Web site. https://www.nhlbi.nih.gov/health-topics/asthma. Accessed July 5, 2018.
  3. Benam KH, Villenave R, Lucchesi C, et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nature Methods. 2016;13:151-157.
  4. Corry DB, Irvin CG. Promise and pitfalls in animal-based asthma research. Immunologic Research. 2006;35:279-294.

July 12, 2018   government and food policy

 

TSCA

On June 22, 2018, the U.S. Environmental Protection Agency (EPA) published its Strategic Plan to Promote the Development and Implementation of Alternative Test Methods Within the TSCA Program. The Frank R. Lautenberg Chemical Safety Act for the 21st Century (LCSA), which amended the Toxic Substances Control Act (TSCA), required EPA to publish this strategic plan to reduce and replace vertebrate animal testing within two years after the date of its enactment.

In our comments on the draft plan, the Physicians Committee welcomed EPA’s commitment to promoting human-relevant, nonanimal test methods, and we are pleased to report that this commitment is not only retained in the final version, but also strengthened in several important ways. 

The Physicians Committee is especially pleased that in the coming months, EPA plans to launch a new website dedicated to “new approach methodologies,” or NAMs, within the TSCA program. NAMs include nonanimal methods and strategies that provide information that is equivalent to or better than that provided by antiquated animal methods. Examples of NAMs include in vitro toxicology tests that use human cell culture and in silico modeling that predict a chemical’s potential for toxicity based on its structure.

Recently, we reported a dramatic increase in testing requirements for new chemicals under TSCA. While EPA did not address our concerns directly in its strategic plan, in its response to comments, it indicated that an official response is being handled separately. In a number of cases, EPA requested specific animal tests for which alternatives are available. At a minimum, this indicates a need for training in alternatives for EPA staff who are reviewing new chemical notices. In its strategic plan EPA acknowledges the need for training and education for EPA scientists and managers, the regulated community, interested stakeholders, and the public as an integral part of the implementation of its strategy.

Passed in June 2016, the LCSA is the first U.S. legislation that requires companies to use alternative methods to reduce the use of animals in chemical testing. Congress took over a decade to update TSCA, and the Physicians Committee worked tirelessly throughout the process to ensure that legislative language requires EPA to reduce and replace the use of animals. We will continue to work with EPA to ensure that it implements this requirement to the fullest extent.