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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. 

June 7, 2018   animal testing

 

EPA

Recently, as reported in Science  and other outlets, the Physicians Committee and People for the Ethical Treatment of Animals (PETA) found that in 2017, the first year of implementing the amended Toxic Substances Control Act (TSCA), the Environmental Protection Agency (EPA) required or requested roughly 10 times the number of animal tests for new chemicals as it had in previous years. In this post, we provide context on the circumstances leading to this alarming increase, explain how we uncovered it, and update you, our members and supporters, on what we are doing to reduce this inexcusably high number.

In June 2016, President Barack Obama signed into law the Lautenberg Chemical Safety Act, the first substantive amendment to TSCA in its 40-year history. The Physicians Committee and other organizations worked to ensure  that the law, which strengthened EPA’s ability to regulate industrial chemicals, would not result in a massive increase in animal testing.

In implementing the new law, EPA is required to determine whether new chemicals entering commerce pose unreasonable risks to human health or the environment. While EPA has long used human-relevant methods in its review of new chemicals—for example, predicting a chemical’s potential for toxicity based on its structural similarities to other, already characterized chemicals—it still requires chemical manufacturers to conduct animal toxicity tests in some situations. 

Because animal tests are not predictive of human health, a bipartisan group of senators and NGOs lobbied to ensure that language was included in the law that will, over time, reduce and ultimately replace the use of animals in chemical testing. As a result, the amended TSCA not only explicitly includes this historic goal but also provides the means to achieve it.

When requiring the development of new information, EPA is required to explain the basis for any decision requiring the use of vertebrate animals and to employ a tiered testing process, by which the results of screening-level tests—which use few or no animals—and assessments of available information inform its decisions on whether to require additional tests. Also, EPA and companies are required to consider and use scientifically appropriate nonanimal methods.

Finally, EPA is required to develop a strategic plan to promote the development and implementation of alternative methods and to report to Congress on its progress every five years. We have submitted extensive comments on this strategic plan a promising draft of which EPA released in March.

However, rather than wait for EPA’s first report, the Physicians Committee and PETA checked to see how much new animal testing EPA was requiring under its new chemicals review. We reviewed each consent agreement that EPA and chemical manufacturers entered into since EPA began implementing the amended TSCA in 2016. We were shocked to learn that in 2017, within these consent agreements, the agency required or requested 352 animal tests in which approximately 77,051 animals would be used.

It is important to note that it is very unlikely that all of these tests will be conducted. Most of EPA’s testing requirements are triggered by chemical manufacturers exceeding limits on time or production volume. If a manufacturer stops manufacturing before the time limit, or continues to manufacture the chemical below a certain volume limit, the tests need not be conducted. In addition to these testing requirements, EPA sometimes requests that manufacturers conduct tests in order to remove restrictions it has imposed on commerce. These “pended” testing requests can be reevaluated prior to the tests being conducted in case new information has become available which could prevent the test.

In 2017, a variety of animal tests were requested, including tests for skin sensitization and eye and skin irritation/corrosion—extremely painful tests on mice and rabbits for which acceptable alternatives exist. These tests would be conducted on numerous species of animals, including fish, guinea pigs, mice, rabbits, and rats. In contrast, in 2015, prior to TSCA reform, the agency required or requested only 27 animal tests for new chemicals, while in 2016, the number was 45. These tests would have used approximately 9,121 and 7,027 animals, respectively.

We immediately requested and received a meeting with top EPA officials to discuss the reasons for this alarming increase and steps EPA is taking to reduce its animal testing requests. At our meeting, EPA assured us that recently, it has begun relying more on “pended” testing requests than on triggered testing requirements, and this appears to be consistent with our preliminary review of 2018 consent agreements. However, we have so far found no adequate justifications for the decisions to require testing on vertebrate animals, which is required under the amended TSCA.

We also asked that EPA contact each company with which it entered a consent agreement to conduct animal tests for skin sensitization and inform it of EPA’s new policy to accept nonanimal tests, released in March of 2018. This action would prevent the deaths of hundreds of animals, and we are optimistic that EPA will take this step.

We continue to press EPA on these and related points and will update you on our progress in future blogs.

May 24, 2018   other

 

All of Us

Ever wonder how a person’s individual lifestyle, environment, and biological make-up can affect their health? The National Institutes of Health (NIH) is on a mission to find out.

Last week the NIH opened nationwide enrollment for their ambitious All of Us Research Program. The All of Us Research Program aims to engage one million participants across the United States to reshape the way people conduct research. This large-scale, longitudinal study will give researchers better insights into the biological, environmental, and behavioral influences that affect diseases. All of Us differs from other research studies in that it does not focus on a single disease or population. This research program will cover a variety of health conditions and will function as a national research resource for thousands of studies.

All of Us is a key component of the federal Precision Medicine Initiative (PMI). Precision medicine is an innovative method that takes into account individual differences in genetics, lifestyles, and environments to develop personalized care. The PMI intends to replace the “one-size-fits-all” approach to healthcare by bringing together researchers, health care providers, and patients to work together.

“The All of Us Research Program is an opportunity for individuals from all walks of life to be represented in research and pioneer the next era of medicine. The time is now to transform how we conduct research—with participants as partners—to shed new light on how to stay healthy and manage disease in more personalized ways. This is what we can accomplish through All of Us.”

—Francis S. Collins, M.D., Ph.D., director, National Institutes of Health

Many research studies lack depth and diversity, which restricts the generalizability of the results. All of Us aims to engage participants from “all walks of life”—it welcomes healthy and sick individuals of all backgrounds and regions of the country. By partnering with one million or more diverse volunteers across the United States, the All of Us Research Program will enable research to more accurately prevent and treat a range of health conditions, both rare and common. A research study this large will have the statistical power to detect associations between environmental and/or biological exposures and a wide variety of health outcomes. Anyone over the age of 18 who is living in the United States is eligible to sign up. Children will likely be able to join in the next few years.

Participants will be asked to give consent, agree to share their health records, and complete health surveys. Participants may also be asked for physical measurements and blood and urine samples. The samples will be collected at participating health care centers located throughout the country. Over the next ten years or so volunteers may be invited to share more data through health surveys, fitness trackers, or other research studies. Throughout the program, All of Us will share data and information with individuals. Participants can receive certain study results to help them know more about themselves. They may even get the chance to have their genome sequenced!

The All of Us Research Program is a human-relevant research study that is designed to improve human health. This program has the capability to alter research and healthcare in profound ways. Using human-focused methods, like this epidemiological study, paired with technological advances in research, is a step towards advancing human health through innovative research, while saving animal lives. All of Us offers numerous scientific opportunities. It has the potential to measure one’s risk for diseases based on genetic and environmental exposures, to identify why individuals respond differently to drugs, to develop new disease classifications and relationships, and to lead to advances in precision medicine. This type of scientific study could shape the way people conduct research far in the future—and that’s good for all of us.

 

Yesterday Physicians Committee toxicologist and vice president for research policy Kristie Sullivan, M.P.H., testified at two legislative hearings in Sacramento. Before the Assembly Committee on Environmental Safety and Toxic Materials, Sullivan described our support for AB 2474, which would require the California Department of Toxic Substances Control to review and, if appropriate, adopt two potential alternatives to a current live fish test it currently requires manufacturers to conduct on hazardous waste.

She also joined Social Compassion in Legislation and Lush Cosmetics to testify in support of SB 1249, the California Cruelty-Free Cosmetics Act, which would ban the marketing and sale of cosmetics that have been tested on animals in California.

Both bills successfully passed out of those committees. We’ll keep working on them as they move toward floor votes, so stay tuned for more details on how you can support these bills.


Physicians Committee Letterhead

AB 2474 Testimony

My name is Kristie Sullivan and I am a toxicologist, a California resident, and the vice president for research policy at the Physicians Committee. I have worked with experts to modernize testing protocols and regulations at the international, national, and state level for 15 years.

We support HB 2474 because it offers the DTSC the opportunity to assess advances in test method development and toxicology practice to take a more intelligent approach to toxicity testing.

Analyses have shown that daphnia are similar to fish, if a bit more sensitive, to toxic materials. The daphnia test is similar to the fish adult and embryo tests; groups of Daphnia pulex or magna are exposed to the test material and several dilutions and the number of “immobilized” daphnia are counted after 24 and 48 hours. The material is determined to be toxic if a certain percentage of daphnia fail to survive.

Daphnia are an important food source for fish and other aquatic organisms, making the daphnia toxicity test an indicator of potential effects of a waste on aquatic systems beyond the specific species of fish used in the current test.

In addition to consideration of the two test alternatives, we suggest implementing a tiered approach that takes the chemical characteristics of the waste into account in order to determine what, if any, testing should take place. This is now common practice in other regulatory jurisdictions.

In my opinion, the two tests are scientifically appropriate, and are likely to be adaptable for California’s need to ensure protection of aquatic life against a range of volatile, liquid, and solid wastes, while saving animals and state resources.

 


Physicians Committee Letterhead

SB 1249 Testimony

My name is Kristie Sullivan and I am a toxicologist, a California resident, and the vice president for research policy at the Physicians Committee.

In 1944 a test called the Draize rabbit eye test was created. This test involves placing chemicals in restrained rabbits’ eyes for 24 hours, then the animals are observed for signs of eye damage. If the test substance is a pressurized aerosol, the rabbits’ eyes are held open and the product is sprayed directly into the eye from about 4 inches away. Depending on the severity, rabbits experience pain, redness, swelling, discharge, and blindness. Rabbits were originally chosen because they do not produce tears, therefore unlike humans they cannot wash any of the product out of their eyes.

Fortunately, nonanimal methods based on human corneal, skin, immune, and other human cells and tissues are widely available to use in place of this and other tests. In fact, nonanimal methods for skin allergy perform better and are more accurate than the original animal test. Despite this progress, animal testing—including the Draize test—continues.

It is estimated that around 400,000 animals are killed worldwide each year to test cosmetics or cosmetic ingredients. In my experience, manufacturers conduct animal testing for a number of reasons, including institutional resistance, liability protection, regulatory expediency, labeling, or legal requirements. Policy initiatives—like this bill—are needed to ensure that cosmetics and personal care products sold in California are not tested on animals for any reason.

More than 35 countries have already enacted restrictions or bans on the testing of cosmetics or the marketing of animal-tested cosmetics. Citizens understand that animals shouldn’t suffer for the newest wrinkle cream or shampoo scent, and this bill creates that beautiful future.

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