Physical differences between human and nonhuman lungs do not allow for a clear line of equivalence to be drawn in these studies, so no direct benefit to human health will be gained.
On Nov. 8, 2019, a telebriefing from the Centers for Disease Control and Prevention (CDC) identified vitamin E acetate as a “potential toxin of concern” in the recent outbreak of lung injuries associated with the use of e-cigarette and vaping products.
During the briefing, Anne Schuchat, MD,
Principal Deputy Director of the CDC, expressed that further animal studies
should be conducted to determine what other lung injuries may be caused by
vitamin E acetate. The Physicians Committee wrote a letter, included below,
to Dr. Schuchat to express disappointment in the call for further animal
studies to be conducted, as the negative effects of vitamin E acetate
inhaled into human lungs are already well documented.
Additionally, the physical differences between human and nonhuman lungs do
not allow for a clear line of equivalence to be drawn in these studies, so
no direct benefit to human health will be gained. The Physicians Committee
encourages the CDC to instead support technologically advanced human-based
research methods, such as 3D models of human lungs, to yield relevant
information faster.
Instead of testing e-cigarette products on animals, we encourage regulatory
agencies to keep dangerous additives or contaminants out of the hands of
consumers. The FDA is moving in this direction, thankfully, announcing on
Jan. 2, 2020 that it will take action against flavored e-cigarette products
that appeal to children, effectively banning all flavors from
cartridge-based e-cigarettes other than tobacco or menthol.
December 2, 2019
Anne Schuchat, MD
Principal Deputy Director
Centers for Disease Control and Prevention (CDC)
1600 Clifton Road, Atlanta, GA 30329
Dear Dr. Schuchat: The Physicians Committee for Responsible Medicine (PCRM)
is a nationwide nonprofit organization comprised of over 175,000 supporters
advocating for efficient, effective and ethical medical practice, nutrition,
and research. In CDC's November 8 telebriefing on lung injury associated
with vaping, we were disappointed by your recommendations for animal studies
of vitamin E acetate and other suspected toxicants. While animal studies are
unlikely to yield information that will better protect public health,
studies using in vitro and ex vivo methods based on human tissue are
especially well-suited to the study of emerging health threats, as they
provide more relevant information and require less time to conduct than
animal studies.
Differences in respiratory physiology among species present difficulties for
extrapolating the results of respiratory toxicology studies in animals to
humans. Whether an animal is an obligate nose breather, the structure of the
nasal turbinates, respiration rate, etc. influence the size and number of
particles reaching the alveoli. For example, rodents are obligate nose
breathers with more convoluted nasal passages than humans, potentially
resulting in test substances being deposited in the nasal passages before
they can cause lung injury.
Fortunately, human tissue-based methods for studying inhalation toxicity are
available. Human airway epithelium can be reconstructed from primary cells
obtained from donor tissue of healthy or diseased origin which are cultured
on porous membranes at the air-liquid interface. Commercially available
reconstructed human airway epithelium models contain multiple cell types,
including ciliated columnar cells, mucus-producing Goblet cells, and basal
cells, and recapitulate key physiological functions. These cultures can
extend to weeks and months allowing the observation of both short term
events, such as changes in ciliary beat frequency, and long term events,
such as Goblet cell hyperplasia. Tissues modeling the small airways and
alveolar regions of the lung tissues generate inflammatory cytokine
responses.
Other methods are based on precision-cut lung slices from donor tissue
obtained in a clinical setting. These cultures contain all lung cell types
present in the tissue at the time of slicing while retaining the native
architecture of the lung including small airways and respiratory parenchyma.
Precision-cut lung slices have been maintained for many weeks and
demonstrate both acute changes, including robust cytokine responses and loss
of viability, and chronic changes, including activated macrophage staining,
collagen deposition, and tissue remodeling. They have also been used to show
no effect level and to identify test substance concentration-specific
reversibility of inflammatory marker expression – a key element in
understanding whether an insult to respiratory tissue may persist or resolve
after test article removal.
We urge CDC to support and conduct studies using human-based tissue to study
the effects of vitamin E acetate and other inhaled toxicants.
Sincerely,
Joseph Manuppello
Senior Research Analyst
Physicians Committee for Responsible Medicine
5100 Wisconsin Ave., NW, Suite 400, Washington, DC 20016
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