[ Beeping ]
[ Music ]
>> Thank you so much for joining us for the ninth We Were There.
It, Not everything is better with butter flavoring:
popcorn lung disease, and the dangers of diacetyl.
This is a fascinating story of phenomenal epi work
with a little bit of luck.
About the location and a lot
of fantastic lab work to back up the story.
Without further ado, it's my pleasure
to introduce Dr. Anne Schuchat, the Deputy Director for CDC.
Thank you.
[ Applause ]
>> Thanks so much, Phoebe, and welcome everybody
to today's installment of We Were There.
There's probably no symptom more concerning
than the difficulty breathing.
My, probably one of the most memorable experiences I had
as a intern.
Newly in the hospital on my first night
on call in internal medicine.
Was going into the intensive care unit to follow a patient
who was fighting for life.
Very, very difficult to ventilate.
Today he would be waiting for a lung transplant.
But in that evening, my job was just to try
to keep him alive through the night.
As I was looking at the background
for today's installment.
I realized that even
that individual could have potentially gotten
that devastating disease through his job.
I think we take for granted that our jobs don't make us sick.
But as we learn the mystery that was uncovered in the,
in the sleuthing that was done on this front.
We realize that even today there are potential work-related
serious conditions.
I don't want to go through the story
because it's a very good one.
But in this cold weather where everybody's huddling
with their Netflix stream and eating their popcorn.
This is a kind of a cautionary tale.
So without further ado, I'd like to introduce our fabulous lineup
of all-women speakers today.
And welcome to We Were There.
>> Thank you, Dr. Schuchat.
And without further ado,
I'd like to introduce Dr. Kathleen Kreiss,
our first speaker and Disease Detective.
>> Thank you, Phoebe.
Our story is how we discovered that diacetyl,
which is the principle component
of butter flavoring is not safe to breathe.
Despite the Food and Drug Administration's assurance
that it's safe to eat.
The backstory is instructive.
In 1999, a 51-year-old worker
at a Missouri microwave popcorn plant developed disabling
skin disease.
And his fissured, bleeding hands
and feet precluded him from working.
He lost a Worker's Compensation claim
for occupational skin disease.
At which point he acknowledged that he couldn't breathe either.
His wife knew of four of her husband's former coworkers
who had respiratory difficulties.
And she suspected that the cause
of their disease was occupational.
She gave names and contact information to her lawyer's son.
The lawyer had no experience with work-related claims.
And he passed the information to a Worker's Compensation lawyer
in Kansas City two hours away.
By interviewing the five former workers with lung problems,
he found three more workers with lung complaints.
And passed medical records for the eight former workers.
To an occupational medicine physician.
The eight former workers reported cough
and progressive shortness of breath with any exertion.
They had developed symptoms at ages 27 to 51.
Which was much earlier than customary for smokers at risk
for emphysema or chronic obstructive pulmonary disease.
In any case, five of the eight had never smoked
or had smoked very little.
The respiratory problems dated from 1992 to 2000
with no common accidental exposure at work.
Their symptoms started five months to nine years
into their employment at the microwave popcorn plant.
None of them thought that they had a work-related cause
of disease.
Because they had no pattern of symptoms
that was worse at work.
Or better on vacation.
Or better after leaving work
because of the respiratory disability.
The occupational physician, Dr. Allen Parmet noted that four
of the eight former workers were listed for lung transplant.
Which was unusual coming from a small, rural community
in southwest Missouri.
Who shared a common last employment
at a microwave popcorn plant.
Although they had a variety of diagnoses, asthma,
emphysema, bronchitis.
Their difficulty getting air out of their lungs and no response
to asthma medications was suggestive
of bronchiolitis obliterans.
Medical textbooks describe bronchiolitis obliterans or BO
as a rare lung disease.
Workers with BO have a single, overwhelming exposure
to a lung toxin such as nitrogen oxides in silos.
If they survive this respiratory emergency,
they seem to recover completely.
Then several weeks later,
they develop difficulty blowing air out of their lungs.
That is obstruction to airflow.
No medications helped their breathing difficulties.
Unlike asthma and chronic obstructive lung disease.
And for that reason, lung transplant appears
to be the only option when their obstruction
on breathing tests is bad enough.
Chest x-rays and diffusing capacity
which reflects the lungs' ability
to transfer gases are not helpful in diagnosis.
None of the eight popcorn plants, cases reported
such a textbook history.
But Dr. Parmet knew that the cases didn't have asthma
or smoking-related lung disease.
He reported a cluster of suspect bronchiolitis obliterans
to a sanitarian at the Missouri Department
of Health and Social Services.
And that sanitarian called CDC in May of 2000.
CDC referred the report to Hector Ortega,
EIS Officer in the Division of Respiratory Disease Studies
in Morgantown, West Virginia.
At the National Institute for Occupational Safety and Health.
We told the sanitarian to obtain the medical records
to confirm the diagnoses.
Dr. Ortega and I called back to the sanitarian
at the Missouri Health Department every month to check
on the medical records' findings which never surfaced.
We eventually contacted the new state epidemiologist,
Dr. Eduardo Samos.
And within three days, he had reviewed the records
and requested our assistance.
In investigating under the state's authority.
Spirometry, a type of breathing test can document normal
and abnormal patterns but can't differentiate among diagnoses.
A person with healthy lungs can take a deep breath and blast it
out quickly, as indicated
in the normal scarlet slide, line in the slide.
Persons with emphysema, asthma,
or bronchiolitis obliterans have difficulty blowing out rapidly
as shown in the two curves to your left.
They have obstruction to airflow
which results in a scooped pattern.
They often trap air in the lungs which results
in greater lung volumes in these plots of airflow against volume.
The other breathing test pattern's called restriction.
And this pattern reflects fibrosis.
That is lung scarring.
When a person with scarred,
inflamed lungs takes a deep breath, they can't get air
into their small lungs because they're stretching their scars.
But they can get air out quickly.
So although textbooks at the time said
that bronchiolitis obliterans had an obstructive
breathing pattern.
We now know that BO can have obstructive, restrictive,
or normal breathing tests.
This is the microwave popcorn plant
at which the eight former workers worked.
Kernel popcorn is delivered to this plant,
and workers package it in polyethylene bags.
And in microwave popcorn bags.
Inside the plant, there was a large room with many lines
in which a machine operator, shown by the circle.
Filled microwave bags
with popcorn kernels and flavored oil.
Which came from the holding tanks
on the mezzanine above them.
The bags were sealed and placed in boxes for shipping
in the production area.
This large packaging area also had a small quality
control room.
Where three QC workers popped the bags to test
for unpopped kernels and salt content.
Here you can see the popcorn being put
into the bag by a machine.
Overseen by machine operators on each production line.
And this is the mixing room which opened
to the packaging area.
For shelf stability in grocery stores,
microwave popcorn needs a solid fat
with flavorings at room temperature.
Artificial butter flavorings have many chemicals
in proprietary recipes.
The predominant chemical is diacetyl.
Which is a four-carbon dicarbonyl.
It's the same com-- compound that's found in real butter.
But it's much more concentrated.
One mixer per shift dumped microfine salt
and heated liquid butter flavoring
into a heated tank of soybean oil.
Which was then pumped up to the mezzanine holding tanks.
Which you saw above the packaging lines.
The holding tanks fed the heated mixture of oil, flavorings,
and salt that was squirted
into the microwave bags of kernel popcorn.
The Missouri State EIS Officer, Joe Malone,
and NIOSH EIS Officer, Rich Canjois.
Reported the first hint of risk in the factory.
Of the eight cases among former workers, four were mixers
of butter flavoring and heated oil.
When we went to the factory,
we found there was only one mixer working on each shift.
Obviously they had very high risk.
Since we estimated that there had only been
about 13 former mixers since 1992.
When the first Sentinel case became symptomatic.
The other four workers worked in microwave packaging.
And there were no cases seen among workers
who packaged unflavored popcorn or worked
in offices or the warehouse.
In contrast to the formal worker findings,
none of the current mixers had abnormalities
in our cross-sectional evaluation of 117 workers.
Among the 135 employees.
This likely reflects a healthy worker effect.
In which ill workers leave employment.
Nevertheless.
The employees had a burden of respiratory illness compared
to the National Health and Nutrition examination survey
of the U.S. population.
The prevalences of respiratory symptoms
and respiratory diagnoses were two
to three times that expected.
About a quarter of the workers had abnormal breathing tests,
that is barometry.
The prevalence of the patterns barometry that we thought
at the time was characteristic of bronchiolitis obliterans.
Was three times that expected.
And the abnormality did not respond to asthma medications.
Three workers had severe abnormalities
in breathing tests.
Putting them into the range
of the former workers listed for lung transplants.
Other screening tests such as x-rays and a measure
of gas exchange were normal.
We concluded that there was a lot of unrecognized,
work-related lung disease among current workers.
We have measured the average diacetyl exposures
for each job category.
And we then estimated cumulative exposure for each worker
on the bases of the average exposure.
And length of time in each job he or she held.
Here you can see that workers in the highest quartile
of cumulative exposure had higher proportions
of abnormal spirometry than other quartiles.
There was an exposure-response relationship.
Between flavoring exposure as reflected by diacetyl.
And risk of abnormality.
So collectively, we had satisfied several
of the criteria listed by Sir Austin Bradford Hill
for a causal relationship between flavoring exposure
and occupational lung disease.
Exposure preceded the disease in the former sentinel cases.
The magnitude of risk among current workers was high.
With never-smokers having a 10.8-fold risk
of abnormal breathing tests, compared to the U.S. population.
And exposure-response relationship existed.
And alternative explanations were unlikely
for a rare disease.
In the meantime, our team was investigating other microwave
popcorn plants.
And four of five other plants had cases consistent
with bronchiolitis obliterans.
Especially in mixers.
This fulfilled the criterion of replication
of our findings in other populations.
With this documentation that flavoring exposure risk existed,
our NIOSH engineers
and industrial hygienists helped the plant
to control flavoring exposures.
The company isolated the mixing room with airlock doors.
And the mezzanine holding tanks from the packaging area.
Flavoring and holding tanks were exhausted, temperatures
of heated tanks were lowered.
And ventilation for dilution was increased.
Flavoring transfers were closed.
Instead of workers having
to manually add flavors to the mixing tank.
And mixers began wearing supplied air respirators.
Exposures to diacetyl decreased.
As a result of these interventions over three years,
average diacetyl concentrations fell on this logarithmic scale
for these three job categories.
Mixers, machine operators on the packaging lines,
and quality control workers
who popped 100 microwave popcorn bags per shift.
Mixer exposures dropped from about 38 parts per million
to less than one part per million.
In packaging and quality control,
exposures at our last survey in 2003,
were all below detectible limits.
Below about .005 parts per million.
Mixers still needed supplied air respiratory protection.
In that mixing room concentrations exceeded those
associated with prior cases in packaging and quality control.
Although no current mixer had abnormal breathing tests
in the initial cross-sectional survey.
Five months later, a 23-year-old mixer had had a dramatic fall
of 1300 milliliters in the volume of air that he could blow
into a spirometer in the first second of the FEV1.
In the second follow-up survey, five months after that,
he had lost an additional 700 milliliters.
For a total loss of two liters in ten months.
And he decided to leave employment at the popcorn plant.
His breathing tests then stabilized somewhat
over the remaining surveys.
But he was left with severe lung disease.
This worker demonstrated that frequent medical screening
with breathing tests
in flavoring-exposed workplaces could identify those
with rapid declines in their breathing test measurements.
Hopefully before workers became disabled.
These rapid decliners could be relocated to lower,
or no-exposure positions.
And also indicated where more protective measures were needed.
As flavoring exposures were reduced
in this microwave popcorn plant, our medical screening
with breathing tests showed that annualized declines
in the breathing test results,
the forced expired air volume in one second.
Declined among the 27 workers who participated
in all eight cross-sectional surveys.
In 2001, the first year of follow-up,
average FEV1 fell by 142 milliliters.
In 2002, FEV1 fell
in these same individuals by 46 milliliters.
In 2003, the third year of follow-up,
the FEV1 fall was 22 milliliters.
And this last average decline per year is what we would expect
in an unexposed population.
By reducing flavoring exposures,
the company interrupted the average airway damage reflected
in breathing tests decline in this plant.
Of course medical screening identifies individuals
who require secondary prevention by decreasing exposure.
Or medical removal.
Ultimately, medical screening
and exposure control requires standard setting
with a permissible exposure limit promulgated
by the regulatory agency, the Occupational Safety
and Health Administration in the Department of Labor.
With dissemination of the microwave popcorn story,
the chest physicians of California reported diagnoses
of bronchiolitis obliterans.
In two workers from flavoring manufacturing plants
in California in 2004 and 2006.
Unlike the microwave popcorn industry exposures.
Flavoring workers may be exposed
to about 2000 flavoring chemicals in batch operations.
That differ from hour to hour, and from day to day.
This variability in chemical exposures makes exposure
characterization nearly impossible.
However, diacetyl is used to make many flavorings
such as nut and fruit flavors.
Since flavors are generally regarded as safe to ingest
by the Food and Drug Administration.
The flavoring industry had not considered chemical
breathing hazards.
As shown in this picture
of a worker weighing a poured ingredient in open containers.
And no respiratory protection.
In response to the case reports, the California Department
of Health and Cal/OSHA.
Partnered in a unique, preventive program for workers
in the flavoring industry from 2006 to 2009.
Sixteen companies reported identifiable medical screening
data to the Health Department in exchange
for preventive consultation by the Cal/OSHA regulatory agency.
And avoidance of compliance fines.
Thomas Kim, the California EIS Officer,
analyzed the aggregate breathing tests
from the first cross-sectional screening reported
by the companies.
He showed that the four companies using the most
diacetyl per year each had four cases
with abnormal breathing tests.
Consistent with bronchiolitis obliterans.
Because they were unresponsive to asthma medication.
In the California flavoring industry,
more cases developed during longitudinal screening.
And the same four companies
with four-person clusters of lung disease.
Had workers with excessive declines
in their breathing tests with follow-up medical screening.
In both the sentinel plant and the flavoring plants
in California, some cases had onset
of chest symptoms ten years before these investigations.
In 1985, NIOSH had investigated a cluster
of bronchiolitis obliterans in a flavoring plant.
Making flavorings, flavors for the baking industry.
In 1993 to 1996, Jim Lockey from the University
of Cincinnati had studied a cluster
of bronchiolitis obliterans in the flavoring plant
with which he had a confidentiality agreement.
What were the barriers to recognition of the diacetyl risk
in the 15 years before our popcorn plant investigation?
Well, physicians usually diagnosed patients with cough,
wheezing, shortness of breath with common illnesses
such as asthma, bronchitis,
and chronic obstructive lung disease.
The latter especially in people who have ever smoked.
Even most chest physicians have never seen a patient
with bronchiolitis obliterans.
And if so, it was a textbook presentation
of an overwhelming noxious exposure followed by recovery.
And then development
of untreatable difficulty getting air out on exhaling.
Individual cases could only be attributed to preceding exposure
if he or she had been healthy before surviving dramatic
pulmonary edema.
Following an accident.
No one had reported indolent onset,
onset of bronchiolitis obliterans
from ongoing exposure.
With cases occurring one by one over several years.
Even for a rare disease, attribution of individual cases
to an exposure is not possible
without epidemiologic risk factors.
And as you know, epi investigation requires a cluster
of disease in a defined population such as a workforce.
The clusters in two flavoring workforces before the microwave
popcorn plant investigation were not
epidemiologically investigated.
But the hundreds or thousands of chemicals
in flavoring plants precluded identifying an unknown
chemical cause.
The eight sentinel cases
in the microwave popcorn plant investigation occurred
in a rural factory outside of Jasper, Missouri.
There were two chest physicians locally who saw all the cases.
Referred several of them to national referral centers.
Which sometimes missed the diagnosis.
And knew of their common employment.
One of them contacted OSHA which reported
that there were no respiratory hazards in the plant.
OSHA enforces regulations.
But no regulations exist for unknown hazards.
A public health agency would have been a better contact,
as known by Dr. Parmet
who contacted the Missouri Department
of Health and Social Services.
The sanitarian was not likely
to know what suspected bronchiolitis obliterans was.
And did the right thing calling CDC.
Luckily, the Atlanta respondent called NIOSH
and specifically the Division of Respiratory Disease Studies.
There we knew that eight cases
in a small food production factory with four severe enough
to be listed for a lung transplant was
something unknown.
We wanted to investigate
but needed a Health Department invitation.
Since our only right of entry at NIOSH is a request
by three current workers.
A labor union, or management.
We had the tools, questionnaires, breathing tests,
chest x-rays and exposure assessment expertise.
To conduct on-site characterization
of the plant population.
We recognized that a population
with 26% abnormal breathing tests
and excess chest symptoms was anomalous.
And had ongoing risk.
Thus, we could establish epidemiological risk factors
such as diacetyl exposure.
And rule out smoking as the cause.
Compared to flavoring manufacture,
we were only dealing with components of butter flavoring.
And exposure of volatiles
for specific job categories were the same
over an eight-hour shift.
Although the predominant volatile was diacetyl.
We could only say initially that it was a marker
of the causative agent.
To fulfill the last of Sir Austin Bradford Hill's criteria
for causal inference from epidemiological associations,
we needed to demonstrate biologic plausibility
from toxicologic studies.
And that is why we turned to Ann Hubbs
who will share an exciting story of her continuing investigations
of a brand-new area in toxicology.
And with that, I'd like to introduce Ann.
Who is a Research Veterinary Medical Officer at NIOSH
in Morgantown, West Virginia.
>> Thank you.
[ Applause ]
So in the Health Effects Laboratory Division,
we look at causes of disease very often.
And this was not just my work.
I'm just up here speaking.
So there were many people involved in this work.
Into the biological plausibility from popcorn workers' lung
and its molecular mechanisms.
So butter flavoring vapors were originally associated
with disease in workers.
But we thought the actual cause, not a marker, would be diacetyl.
Let me explain why.
This is a GC mass spec of the vapors.
So we're talking the, the gas phase.
Of artificial butter flavoring.
Here we're looking at the abundance
of a series of molecules.
And as they come off, with time, from the GC mass spec.
And these are the names of some of the many compounds that make
up those complex vapors.
But we were interested and concerned with diacetyl
because one it was an agent of unknown toxicity,
and we knew the safety or toxicity of some of the others.
And the other thing was its chemical structure told us it
could be a significant risk.
So it was immediately a suspect and here's why.
This is the structure of diacetyl.
It's a four-carbon compound.
On each side is a methyl group, something that's not going
to be particularly reactive.
But in the middle
of the molecule are two carbonyl carbons.
Double bonds here between carbon and oxygen.
And they're adjacent carbon molecules.
And what that allows the electrons to do is to move
around between those two carbon groups.
So I don't like to show diacetyl this way.
Let's show it the way the body sees it.
With its dancing electrons.
So the electrons move around.
And in moving around, they can react with other structures.
And biological molecules interact with diacetyl.
So it would likely be a reactive compound.
It could be causing problem.
But would it target the airways?
Because these workers largely had airway disease.
So we looked at what happened in the airways of rats
that were exposed to butter flavoring vapors or diacetyl.
And we saw a common pattern emerge.
When they were exposed to butter flavoring vapors, or diacetyl,
we saw the death of the cells that lined the airways.
And so if the exposure was sufficient,
there was significant damage.
And we also knew like any other structure.
When you damage the lining of an airway, it will scar.
Biologists call this fibrosis.
We often talk about pulmonary fibrosis
when it's out in the deep lung.
But the airways can also scar.
And that gives us fixed airways disease.
What this looks like to someone like me who is a pathologist.
Is that instead of this wonderful carpet of epithelium
that lines the airway.
We instead see in the diacetyl-exposed airways
that this carpet has been disrupted.
And so rather than having intact cells, we see cell loss.
And we see the products of cell necrosis and the response
to that out here in the lining.
And we would expect a scar to develop.
And a scarred airway is fixed.
Colleagues at the National Institute
for Environmental Health Sciences
in Duke did repeated exposures to diacetyl.
And they found that indeed that was the case.
So with repeated exposures to diacetyl.
And this is the image from the airway of a rat.
We see this fibrous connective tissue here.
That is part of a scar.
And in fact this polypoid structure's actually healed back
to the airway, obstructing it.
But it wasn't just diacetyl.
It was a related compound that caused similar damage.
With sufficient exposure.
This is another butter flavoring vapor.
This is. And here this should 2,3-pentanedione be an airway.
But in fact this trichrome stain is showing early
fibrosis here.
In what should be the airway passage.
And this is very much an obliterative lesion.
Hence, bronchiolitis obliterans.
So we have these dancing electrons.
And we asked why is the airway epithelium damaged
by diacetyl in 2,3-pentanedione?
In its simplest form, it is just that both
of these compounds share this reactive alpha dicarbonyl group.
And in diacetyl, there is one carbon here.
And in 2,3-pentanedione there are two.
So these are extremely similar structures.
But what is going on?
They're reactive.
They're both alpha dicarbonyl compounds.
But really importantly, they react with amino acids,
the building block of protein.
So go where the data takes you.
And the data tells us the hypothesis might have something
to do with that.
And that protein damage underlies airway epithelial
toxicity of diacetyl.
So why would we care about protein?
Well, either one of them can damage protein function.
It's not just they're damaging those proteins.
But the proteins don't act right.
So colleagues at the National Institute
for Environmental Health Sciences
in Duke University looked at the activity
of some representative proteins.
Enzyme activity.
And exposure time in minutes to diacetyl or 2,3-pentanedione.
So looking at how much activity was left with time.
And in fact, both of them caused loss of protein function.
But okay, protein?
Really? Why is protein damage important?
That's because protein is what determines everything,
for the most part.
That happens in the cell.
So this is a cell.
And we all know genes are important, right?
That's why we got the genes we got from our parents.
And that is because of DNA.
But actually, I'm going to tell you
that DNA is mostly important after you're born.
Because it produces protein.
So DNA transcribes to RNA.
and that's translated into protein.
And that's why cells do what cells do, for the most part.
But there's another side to proteins.
It's not all about your genes and us thinking
that DNA is important.
Protein quality has to be controlled
at the other side, too.
We have to have control of the quality of proteins.
And that's where research has been exploding
in the past few decades.
So when a protein is damaged or if it's a normal protein.
And it's supposed to end its life.
What is supposed to happen is that protein is recognized
by a molecule called ubiquitin.
Sometimes more than one molecule and mostly
at a specific site called K48 ubiquitin.
And K48 ubiquitin, sometimes multiple molecules like that.
Here as little orange balls, the color of butter.
They then go to a structure called the protyism.
And there they get recycled.
And what ends up happening is you get the amino acids back.
What a wonderful system.
But if we have too many damaged proteins there.
Something else can kick in.
And that is a process that's mediated
by K63-linked ubiquitin.
Usually multiple molecules this time linked as K63 ubiquitin
which actually refers to the lysine group.
And then there's another very important protein.
Which is sequestosome 1.
Sequestosome 1 makes a scaffold
that sequesters those damaged proteins.
So that they don't have their toxic effects in the cell.
So it sequesters them in air
and then you've got to get rid of them.
So you send them to the lysosome.
And this is a process called autophagy.
And it's also really, really important.
It controls getting rid of those toxic proteins you can't get rid
of by recycling.
And it also has a number of other biological processes.
But instead of recycling, it's throwing it out in the trash.
So our approach was to look at ubiquitin in autophagy
after diacetyl exposure.
Because diacetyl damages proteins.
And here's how.
And this is why it's important.
Damaged proteins are toxic to cells.
Ubiquitin is the central mediator
of protein quality control.
And the Nobel Prize was awarded for its discovery in 2004.
This is very important.
And ubiquitin depletion is toxic.
Because you dysregulate all the proteins.
The cell doesn't work right.
Some proteins live too long.
Damaged proteins accumulate.
Amino acids are depleted.
And ubiquitin identifies proteins
that are no longer needed or damaged.
And that's the big summary.
It's important in controlling lifespan in normal proteins
and damaged, toxic ones.
Proteins are recycled into their constituent amino acids
in the proteasome.
And in the presence of overwhelming protein damage,
ubiquitin can send damaged proteins
for destruction in the lysosome.
As a process known as autophagy
for which the 2016 Nobel Prize was awarded.
So when we look at an airway.
And in this case, we have stained the airway epithelium
so that it is green.
And you can see the, the cell junctions here in bright green.
And we've also stained for ubiquitin.
And you really don't see anything.
It's kind of a pink haze because we stain for ubiquitin in red.
In this control airway from a rat.
Actually, this is a mouse.
But in the diacetyl-exposed airway from a mouse.
Instead, what you see is still the airway epithelium.
It's a little damaged and shriveled up here.
But what you see in red is that ubiquitin has gathered together
in discrete areas of the cell.
So we wondered if protein quality control had actually
been disrupted.
And so we wanted to look at the scaffolding protein.
The sequestosome 1,
that sequesters those damaged proteins.
Maybe it was doing something.
And this is again the airway of a diacetyl-exposed mouse.
Here we've stained in green sequestosome 1.
And we're looking at it under green fluorescent light.
If we look at this same airway section,
this is the lining epithelium in red.
This is ubiquitin.
Now if they're both in the same spot, we're going to see red
and green at the same time.
And that's going to give us yellow.
There's the yellow!
The little ubiquitin is lining up right along the scaffold in,
in autophagy-related process.
So we wanted to see hey, what happened to the lysosomes?
That's where your,
the ubiquitin's supposed to go in autophagy.
And so here's the airway with the lysosomes in green.
Again, we've stained ubiquitin in red.
And now we're going to look at the lysosome should be yellow.
If the ubiquitin is in the lysosome, bingo!
There it is.
We have autophagy.
Actually, when we, that being me, micro dissected the airways
out from the diacetyl-exposed mice.
And we looked at a western blot
in band intensity, by molecular weight.
The free ubiquitin is just little molecules
out there before they're complexed with protein.
And the process had actually depleted the free ubiquitin
in the airway-enriched fraction.
So there was loss of free ubiquitin, the central mediator
of protein quality control.
In the diacetyl-exposed airways.
So what do we think is happening to the pathways.
For proteins damaged by diacetyl?
What we believe happens is the protein, when it's been damaged
and is now misfolded and damaged and toxic.
Is recognized by ubiquitin.
We probably have some K48 ubiquitin links.
We're not quite certain of that yet.
But what we know is something goes wrong in terms
of this proteasomal process.
It appears to have been overwhelmed
or maybe the function has somehow been altered.
But it can't keep up with the damaged protein.
Instead, the alternate pathway
for handling overwhelming damage begins to play a role.
And we see a response to overwhelming protein damage.
With the accumulation of ubiquitin
in the scaffolding protein, sequestosome 1.
And we see its movement to the lysosome.
And autophagy taking over.
So proteins are going out in the trash.
And are being damaged.
So the mechanisms
of flavorings-related lung disease appear to be
that butter flavoring vapors damage airway lining.
Diacetyl and 2-3-pentanedione are major toxic components
of butter-flavoring vapors.
And if we look at diacetyl itself
and the mechanisms of its damage.
We know that it damages proteins.
And that diacetyl inhalation overwhelms the protein quality
control in the airway lining.
And the data are consistent with protein damage.
As the fundamental mechanism for flavorings-related lung disease.
And we have additional mechanistic studies
that are ongoing today.
And with that, I would like to introduce our next speaker,
Kristin Cummings.
Who will talk about where this research is going
in the field today.
[ Applause ]
>> Well, thank you.
It's a pleasure to be here today.
I do have a confession to make.
This series is called We Were There.
But I wasn't actually there for these early investigation
that Doctors Kreiss and Hubbs so eloquently described.
I joined CDC as an Epidemic Intelligence Service Officer
in 2005.
Assigned to NIOSH in Morgantown, West Virginia.
My EIS classmates were busy investigating things
that CDC was famous for.
Like outbreaks of measles and fungal carotiditis in the U.S.
and HIV and malaria globally.
I on the other hand had been assigned
to a group looking at butter.
One confused classmate asked, "Are you working
on the obesity epidemic?"
[Laughter] The idea that butter vapors could pose a health
hazard was just not on people's radar.
And yet the work that Doctors Kreiss and Hubbs
and their many colleagues had done.
Made clear this was an important public health problem.
The cluster of lung disease cases
at the microwave popcorn plant in Missouri served
as a sentinel health event.
Warning that a larger community was at risk.
Initially that community comprised the former
and current workers at the same plant.
Afterall, they had been working
in the same environment as the case patients.
And were also exposed to butter flavorings.
And indeed the investigative team showed that other workers
at that plant had been adversely affected
by their workplace exposure.
Some with lung function deficits as severe as those seen
in the sentinel cases.
As Dr. Kreiss described.
But this wasn't the only microwave popcorn plant
in the country.
If workers at one plant were developing lung disease related
to butter flavorings.
The community at risk must also include workers
at other microwave popcorn plants.
That use butter flavorings.
NIOSH investigators conducted extensive evaluations
at five other microwave popcorn plants.
Finding workers with lung disease in all but one.
This finding indicated the risk did indeed go beyond the
sentinel plant.
Exposures to diacetyl associated with disease were as low
as 0.02 parts per million.
Or 20 parts per billion.
Which is much lower than exposures measured
in the sentinel plant.
The need for respiratory protection
and engineering controls to reduce exposures was evident.
Of course microwave popcorn was not the only food product made
with butter flavorings.
The community at risk potentially included other food
production workers.
Making such things as candy, cookies,
and snack foods like potato chips.
As well as the workers manufacturing the
flavorings themselves.
Investigators asked if NIOSH had ever seen cases of lung disease
in industries other than microwave popcorn.
And reviewed the archives containing records
of prior investigations.
Well it turns out, there really is nothing new under the sun.
NIOSH had seen lung disease
in flavoring-exposed workers before.
In 1985, 15 years before Dr. Kreiss
and her colleagues were alerted to the cluster
of lung disease cases
at the Missouri microwave popcorn plant.
NIOSH had conducted a health hazard evaluation
at a flavoring manufacturing facility.
The evaluation was requested by the facility's management
after two employees developed severe lung disease
over a short time period.
I think it's worthwhile to spend a moment reviewing these cases
which are now more than 30 years old.
The first case occurred in a 28-year-old man
who was a nonsmoker and was without respiratory complaints
when he began working in the mixing room in 1983.
He noticed the onset of shortness of breath
with exertion after five months on the job.
He was found to have severe airways obstruction
that was described as mildly responsive to bronchodilators.
He left employment after one year.
He had no improvement in symptoms
or lung function despite treatment with bronchodilators.
And steroids and cessation of the workplace exposure.
Case two is remarkably and tragically similar.
In 1984, after the worker in case one became too ill
to continue working in the mixing room.
A 30-year-old healthy man who was also a nonsmoker.
Replaced him in that job.
He developed shortness of breath four months later.
And was found to have severe airways obstruction.
Which was described as minimally responsive to bronchodilators.
He left employment after just five months.
And like the worker in case one, had no improvement
in symptoms or lung function.
NIOSH investigators recognized these cases
as bronchiolitis obliterans.
And they concluded that they were likely caused
by an exposure in the mixing room of the facility.
Yet unlike at the sentinel microwave popcorn plant,
they were unable to pinpoint the cause.
It's tempting to attribute this difference
to the superior technology, for air sampling available
to the 21st century team.
Compared to their 20th century counterparts.
Or perhaps some unique combination of tenacity
and brilliance among the more contemporary investigators.
[Laughter] It just wouldn't stop
until they had identified the culprit.
Unfortunately, the best explanation is one
that probably plays a greater role in science
than we would like to admit.
And that's chance.
The team investigating the cases of lung disease
at the sentinel microwave popcorn plant was absolutely
outstanding in terms of their training, experience,
insights and approach.
And they were also extremely lucky.
Let me explain what I mean.
On the next few slides is a list of ingredients used
at the flavoring manufacturing plant which I've taken
from the health hazard evaluation report.
Did anyone spot diacetyl?
So it's listed there a couple of times.
In different forms, along with more than 200 other ingredients.
In a batch operation like this one, exposures will vary day
to day and hour to hour.
As workers fulfill customer orders.
That might range from essence of strawberry to steak flavor.
In contrast, here is an exhaustive list
of the ingredients used to make microwave popcorn.
The process was the same from day to day, hour to hour.
Whereas the investigators at the flavoring plant
in 1985 were searching for the proverbial needle in a haystack.
The investigators at the microwave popcorn plant
in 2000 were dealing with just a handful of ingredients
and a far more predictable exposure profile.
Meaning that they were in a much better position to zero
in on the cause of the lung disease among workers.
Identifying the cause meant that the recommendation
for worker protection.
Could be targeted to address diacetyl's
specific characteristics.
For instance, in 1985,
the investigators recommended controls
and at reducing exposures to dust.
Because they noticed that the mixing room was very dusty.
Yet such controls would not necessarily be effective
against diacetyl.
Which was a volatile organic compound rather than a dust.
Fifteen years later, investigators
at the microwave popcorn plant could recommend controls
specific to diacetyl.
Which were likely to be more effective.
Well, by 2007, the issue of lung disease related
to diacetyl was picking up traction.
As often happens when an occupational illness
is identified.
Members of the general public began
to ask if they were at risk.
Would popping microwave popcorn at home before watching a movie
or the Super Bowl cause irreversible lung damage.
NIOSH and other experts emphasized
that all known cases had occurred in workers.
Who had been exposed repeatedly and on a daily basis
to relatively high levels of diacetyl.
The exposures at home were simply not comparable.
And then a physician contacted the Food and Drug Administration
to report a possible consumer case.
The case reported to the FDA was
that of a 53-year-old man who worked in sales.
An exhaustive, exhaustive clinical evaluation turned
up no explanation for his disease.
It would have likely been tossed
in the idiopathic basket had his physician not asked a seemingly
odd question.
"Do you by any chance like microwave popcorn?"
His response was something along the lines of,
"How did you know that?
I'm Mr. Popcorn."
And he went on to describe a decade-long habit
of consuming multiple bags per day.
And a fondness for inhaling the vapors after opening each bag.
The press jumped on the story with major outlets
like the New York Times, Reuters,
and the big television networks running stories.
Their headlines varied from fairly staid
to somewhat sensational.
But the upshot was the same.
A frightening disease that had been limited
to workers was now a threat to the general public.
The next day, industry leaders collectively responsible for 80%
of all microwave popcorn sales in the U.S. announced.
That they were removing diacetyl from their recipes
for butter-flavored microwave popcorn.
Although there were comments that these plans had been
in progress for months.
The timing of the announcement suggested that the need
to address perceptions
of consumer risk played at least some role.
In motivating implementation.
As it turns out, there has not been a widespread outbreak
of lung disease in consumers.
And it's likely that the risk
to the general public is extremely low.
Mr. Popcorn was not the tip of an iceberg.
But whether undertaken for workers,
the general public, or both.
This voluntary move by the industry was welcome.
After all, it was consistent with the hierarchy
of controls a tenet
of occupational health that emphasizes.
The effectiveness of steps such as elimination and substitution
of a hazard over less effective measures.
Like administrative controls,
and personal protective equipment.
Which put the burden of exposure reduction on the worker.
Getting rid of diacetyl and replacing it
with something else seemed like the right thing to do.
At this point, our work shifted from a focus on diacetyl
to broader questions about the inhalational risk
of food-flavoring chemicals more generally.
We would learn that substitution does not always resolve an
occupational hazard.
And that the presence of one particular inhalational hazard
in a workplace does not preclude the existence of others.
In a sense, the community at risk was the same.
But the exposures were changing.
In 2008, I was the medical officer
for a health hazard evaluation
at a bakery mixed manufacturing facility.
Workers combined ingredients to produce dry bakery mixes
such as buttermilk pancake mix.
Ingredients included liquid butter flavors which are added
to large mixing tanks as pictured here.
The management informed us that they had asked their suppliers
to remove all diacetyl from their flavorings.
When we asked what diacetyl had been replaced by.
They replied that they didn't know.
As we would learn, flavoring manufacturers used related alpha
diketones with additional carbon groups in place of diacetyl.
And we heard a little bit about this from Dr. Hubbs.
As you can see here, diacetyl is also known as 2,3-butanedione.
The substitutes have the same chemical structure,
but a longer tail.
So 2, 3-pentanedione had one extra carbon group.
2, 3-hexanedione two extra carbon groups.
And 2, 3-heptanedione three extra carbon groups.
Well my colleagues in the laboratory found
that the predominant ingredient
in the new flavoring was 2, 3-pentanedione.
Exposures to 2, 3-pentanedione
at this bakery mixed facility were as high
as 91 parts per billion.
At the time, we didn't know whether 2,
3-pentanedione was toxic.
And if so, what a safe level would be.
But we were concerned about the structural similarities
between diacetyl and 2, 3-pentanedione.
And the measured exposures which were comparable
to the diacetyl exposures.
That had been associated with disease
in the microwave popcorn industry.
These findings stimulated the subsequent experimental work
that Dr. Hubbs described.
Confirming that 2,
3-pentanedione is also a respiratory toxin.
Well in 2011, I led a health hazard evaluation
at a large flavoring manufacturing facility
that was phasing out use of diacetyl.
Again, we found that the predominant substitute was 2,
3-pentanedione.
Yet it was notable that we detected 2, 3-pentanedione
in a minority of air samples.
At least during our visit, most workers were not being exposed
to diacetyl or its substitute.
But that didn't mean that they didn't have flavoring
chemical exposures.
These photos, show the research
and development area on the left.
And the samples preparation area on the right.
The many bottles representing different flavoring chemicals
are evident in each photo.
And this is really the 1985 list
of ingredients in pictorial form.
This was clearly a very complex environment.
Where workers were potentially exposed to hundreds
of flavoring chemicals.
Most of which have poorly-characterized
inhalational toxicity.
So we offered questionnaire and lung function testing
to the current workers.
Who numbered about 400.
And we found that participants
with higher flavoring chemical exposure
from longer plant tenure.
Or more time spent in production areas.
Had significantly more respiratory symptoms
and lower lung function.
Than their coworkers.
And we urged a proactive approach.
That acknowledged that in flavoring manufacturer, diacetyl
and its substitutes were unlikely
to be the only inhalational hazard.
In the absence of certainty, overall exposure reduction
and medical surveillance are prudent.
More recently, we published a summary
of NIOSH health hazard evaluations of microwave popcorn
and flavoring manufacturing facilities.
From 2012 to -- sorry, 2000 to 2012.
Just over 1400 workers from nine facilities
in eight states participated in NIOSH medical evaluations.
Including questionnaire and spirometry testing.
We examined respiratory abnormalities using several
different mutually exclusive case definitions.
So the most stringent was pathologist-reported.
And just four workers or 0.3%
of all participants met a biopsy-based definition
of bronchiolitis obliterans.
The next two definitions were probable and possible.
And they were defined by abnormal lung function.
Together they accounted for about 20% of the participants.
Which is about twice as high.
A prevalence of abnormal lung function
as we would expect to find.
Finally, symptoms only referred to participants
with normal lung function.
But who reported cough or shortness of breath.
And over 400 over about 29% met this definition.
Which is also roughly twice expected.
So we concluded that the burden of respiratory abnormalities
in these workers indicates flavoring-related
health effects.
That go far beyond the few biopsy-proven cases of disease.
Well in 2013, our attention turned to the risk
of flavoring-related lung disease in the coffee industry.
We reported two cases of bronchiolitis obliterans
which is also called obliterans bronchiolitis.
Among workers at a coffee facility in Texas.
Five clinical cases would ultimately be diagnosed.
And this facility roasted coffee beans.
Producing both unflavored and flavored coffee.
A subsequent health hazard evaluation at the facility found
that diacetyl and 2,
3-pentanedione levels were elevated in the flavoring room.
Where flavors such as vanilla
and hazelnut were added to roasted coffee.
Exposures were also elevated in the separate grinding
and packaging room where unflavored coffee was produced.
The source was not the flavoring room itself.
It had separate ventilation and was under negative pressure.
Compared to the rest of the plant.
So as it turns out, roasting
and grinding unflavored coffee beans releases these volatile
organic compounds.
Meaning that the health risk was not necessarily limited
to areas.
Where flavorings were used.
That being said, all of the clinical cases
at this facility occurred in workers who had spent
at least some of their employment
in the flavoring room.
So it was not possible to attribute any of the cases
to unflavored coffee alone.
The risk to workers of roasting
and grinding unflavored coffee is an area
of ongoing investigation for NIOSH.
Well one of NIOSH's responsibilities is
to develop recommended exposure limits for specific substances
which OSHA takes into consideration.
When setting legally binding permissible exposure limits.
In 2016, NIOSH released its criteria
for recommended standard for diacetyl and 2, 3-pentanedione.
Setting its recommended exposure limits at five parts per billion
and 9.3 parts per billion respectively.
The document included recommendations
for engineering controls.
Respiratory protection.
Hazard communication
and periodic medical surveillance of exposed workers.
To date, federal OSHA has not issued a permissible
exposure limit.
Although Cal/OSHA in California issued a diacetyl standard
in 2010.
I mentioned hazard communication.
One of the primary means of communicating hazards
to workers is the safety data sheet.
Yet these may not always include information
about diacetyl and its substitutes.
You recall that when we asked the management
of the bakery mix facility.
What had been substituted for diacetyl
in their diacetyl-free flavorings.
They didn't know.
That was in part because it hadn't been declared
on the safety data sheet.
Where constituents may be omitted if found
in small amounts or considered proprietary.
Recently we looked at 26 flavorings used
at two coffee facilities to compare what was included
in the safety data sheet.
Versus what was actually in the flavoring.
We found that none of these safety data sheets
listed diacetyl.
Although it was in 81% of the samples.
Similarly, non-listed 2, 3-pentanedione although it was
in 58% of the samples.
While we can't be certain why this discrepancy existed.
We did note that all
of the safety data sheets contained trade
secret designations.
So under these circumstances, we concluded
that a precautionary approach is warranted
when working with flavorings.
Including exposure monitoring
and exposure reduction strategies.
Well as you might imagine, the issue of flavorings
and lung disease took on a litigious tone.
With workers and consumers suing employers,
manufacturers, and even grocers.
And in one difficult episode,
a manufacturer suing NIOSH and NIOSH employees.
Information that became available during
tort proceedings.
Shed light on why the epidemic
in the microwave popcorn industry occurred when it did.
In the 1990s, in the context
of an ever-increasing national waistline.
The market for low-fat snacks was also growing.
To create low-fat popcorn, it's necessary
to lower the oil content.
Which negatively affects the taste.
To make up for the missing oil,
manufacturers increased the diacetyl content
of the butter flavorings.
And added more butter flavoring to their recipes.
Exposing workers to far greater concentrations
of diacetyl than ever before.
So to the extent that flavoring lung disease came to light
because of the low-fat food craze.
My EIS classmate had been right.
I was working on the obesity epidemic.
[Laughter] And getting a first-hand introduction
to the law of unintended consequences.
I played a small part in this incredible story.
I've tried throughout the presentation
to include the names of authors.
In order to acknowledge the many people whose scientific
contributions were so critical.
Yet the scientists alone could not do this work
without an incredible support team.
From the medical industrial hygiene
and laboratory technicians.
Who collected the data.
To the travel preparers who made sure we got there and back
on so many field studies.
Beyond those in the respiratory health division.
I want to recognize the invaluable contributions
of our colleagues in other NIOSH divisions and offices.
In-state and local health departments across the country.
And in-state and federal OSHA sites.
I also want to acknowledge the astute clinicians who recognized
that their patients had something more
than routine asthma or chronic obstructive lung disease.
And took the time to reach out to public health authorities.
And of course this work could not have been,
succeeded without the participation of workers,
the support of labor unions where they existed.
And the cooperation of management and industry
who are ultimately in the position
to implement the recommendations we made.
To protect their workers.
Thank you very much.
[ Applause ]
>> Thank you.
>> I think we can now take questions.
>> Thank, thanks for just a beautiful set
of investigations and stories.
And the incredible presentations.
The comment that it's okay to eat these things but not
to in-- inhale them, I guess.
Raises the question of they being and whether they're--
you have information about particular chemicals
that are used in flavoring.
For e-cigarettes or for vaping.
That cause concerns for you or whether there's a science
of that or those exposures yet?
>> You want to take that?
>> NIOSH participated in the original workshop that was done
by the FDA when they were determining whether
or not they wanted to regulate the e-cigarettes.
And we did present data on diacetyl
and 2, 3-pentanedione there.
And that is the extent to which we have been involved.
Because that is more an FDA issue
and an indoor air pollution issue.
Which we've been less involved in.
However, there have been studies that were done for instance
by Joseph Allen, I think, was one of the first people.
To publish on the composition.
Dr. Parcelionos in Greece has also published on the issue.
And there is significant diacetyl concentration
or at least was in those original e-cigarette vape,
its liquids.
And it is a concern.
I don't know how much regulation has occurred.
But one of the huge concerns is the vaping
of e-cigarette liquids that do contain diacetyl intentionally
bypasses the nose.
And would deliver those alpha dicarbonyl compounds
to the deep lung.
So it is a concern for the most part.
In terms of the intentional inhaling of them.
That's more of an FDA issue.
So we have not particularly gone there.
>> But I think the other comment I would make is
that inhalation toxicology is very expensive
and is not routine.
And so the designation by the Food and Drug Administration.
That flavorings that are currently
in commerce are generally regarded as safe.
It is a label the FDA uses.
And yet that label is really,
really is derived from the industry.
And industry experts.
It does not reflect toxicologic testing.
>> The, the trade group Flavoring
and Extract Manufacturers' Association has actually made a
public statement regarding that.
Their, their designation by FEMA.
And that's the flavoring FEMA.
Not the other one.
Is intended to mean that the substance is safe to eat.
There is a lot of controversy because I think the wording
as it was defined is as intended to be used.
And you know if you ask some people.
It's intended that the worker makes it.
In terms of the worker issue.
But when it comes to the flavors
that people are vaping in e-cigarettes.
That is an intended use.
And FEMA does not approve that process.
>> And just in follow-up.
I thought you know you're sort of looking
through the biologic possibility was so beautiful.
And I think you made the case for being able to predict
that certain chemicals are likely to be problematic.
I wonder whether the industry has sort of absorbed that.
In their you know research for better flavoring.
>> I, I don't know where they're at in regards to that.
That is part of where we are at.
Is, is can we predict which ones are going to be a hazard.
And also do we go beyond the compounds
that are directly reactive?
To those that may be metabolized within the airway epithelium
to target that same ubiquitin proteasome pathway.
And so that is ongoing research.
>> Dr. [inaudible]?
>> Thank you again, also for a great series of talks.
I was wondering if you're in a position to comment
on what the manufacturers knew, when they knew it.
And what do they communicate to the producers
of butter-flavored products?
And what responsibility they have
to do some product stewardship, perhaps?
And if they weren't doing that well in the past,
are they doing it better now?
>> I'll start on that.
The Flavoring and Extract Manufacturers' Association has a
lot of proprietary data from chemical manufacturers.
And in the early 1990s, one of the manufacturers
of diacetyl actually conducted toxicologic studies.
In rodents, and noted that the rodents had respiratory disease.
And that was reported to the Flavoring
and Extract Manufacturers' Association.
In an unpublished monograph.
We became aware that such a monograph existed.
But that it was considered confidential in the courts.
And we eventually contacted the medical director
of that chemical manufacturer.
Who sent us the entire monograph.
And we had been provided only the first three pages
by the Flavoring and Extract Manufacturers' Association.
Withholding the animal studies that, that basically documented.
That there was a respiratory hazard.
So you know I think that work had been done in Germany.
And I don't know what the,
the legal responsibilities would have been.
But it was an international chemical company.
You know with respect
to the buttermilk bakery mix investigation
that Kristin described and was involved in.
The baking mix company was precluded
in their contractual obligation to the flavoring suppliers
from reverse engineering.
To find out what was in the flavoring.
And so the only way that they found out was
because of NIOSH testing and telling them what was
in their flavoring that they had bought.
So the whole trade secret regulations are very difficult
from a public health point of view.
The other point I would make is
that since industry often has much better information
than the academic community or government agencies.
And since even the 1985 outbreak
in the flavoring company supplying flavored materials
to the baking industry.
Those cases did come to litigation.
We didn't know that of course at the time.
But one of the thoughts that I had was maybe there ought
to be surveillance of litigated cases.
Which would allow public health agencies to know
about what might be arising.
>> Good luck.
[Laughter]
>> Yeah, I just wanted to make a comment.
Maybe you have some thoughts.
It was Dr. Cummings was very interesting to see
that the individual consumer case had such prompt response.
When you think about sort of the industry research
and very careful work.
And I think you, you have this double-edged sword
that industrial exposure's likely to be higher.
And likely to be a cleaner case for exposure outcome.
But has its own set of complexity in terms
of the effectors to change versus consumer concern.
And reputation and credibility
and you know what really makes us try to lower risk.
You know or companies want to lower risk rapidly.
It made me wonder how closely NIOSH works with other parts
of CDC or with others.
Who are engaged in the same exposures?
But not for the workplace exposures.
Whether we have opportunities for more collective impact
with that kind of collaboration?
>> I would, I would agree with you that it does seem like the,
the level of evidence needed for action is different
for workers versus the public.
And I do wonder if you know case,
paper in the New England Journal in 2002.
That showed there was an association with diacetyl
that couldn't say it was diacetyl.
But you saw that beautiful [inaudible] response graph.
Had that been in consumers,
we might have seen a different response.
It may not have taken five years as it did to,
to have the industry announce.
That they were removing diacetyl.
In terms of collaboration with other groups at CDC.
I mean certainly NIOSH is, is open to that.
And is always looking for opportunities to collaborate.
>> Attributed that to, that the-- [inaudible]
[ Inaudible ]
>> There, there hasn't been continuing surveillance.
I mean, we did surveillance in the sentinel plant
for almost three years.
But we have, we have little information
about what's happened after we left.
One of the issues that was very clear in California was when,
when Cal/OSHA and the Health Department in California.
You know asked for voluntary cooperation.
The flavoring industry companies to surveil their workforce.
Only about one of the commercial suppliers of,
of spirometry had adequate quality spirometry.
And you know it, it's not difficult to do spirometry.
But quality control is, is really necessary.
And it was clear from looking
at the physicians' signings relative to reports.
That they had no idea even what was a completely
unphysiologic response.
So I think industry across the country has probably not had the
benefit of good surveillance.
Because it isn't available from the private sector.
And -- .
>> That's another challenge is that many
of these workforces have high turnover.
So particularly in the coffee industry
that we've been studying more recently.
You know the average tenure, when we ask,
"How long have you worked at this plant?"
Is, is often less than a year or two.
So in order to follow the population over time.
You'd have to try to track down people
who might be pretty transient.
So that's another challenge.
>> Sorry, and just a follow up.
Like did the plant implement like any engineering controls
or have their workers use respirators?
Can you comment briefly on that side of the [inaudible]?
>> Well certainly in the sentinel plant.
We worked with them to implement the controls.
You know as industry has,
as service jobs have replaced industrial jobs in this country.
The availability of industrial engineering has gone
down markedly.
And we really, and we saw evidence of that even
in the sentinel plant.
When we told them that they had to exhaust their tanks
that held heated flavoring.
On the mezzanine, they exhausted them into the general plant air.
Which at the time was common to the packaging area.
And when we came and said well, you've exhausted them.
But you've exhausted them to create a worse situation.
You know it was only then,
that those got exhausted to the outdoor air.
So you know I think it's, it's challenging.
And in the absence of regulation and enforcement.
I suspect we have a whole bunch of plants across the country
that are still producing these cases.
>> So I'm wondering if you've considered or thought
about whether there's other lung disease might be present amongst
the people who don't respond?
Over long term?
Is it possible there could be some cancer risk
over many years of exposure?
Short of getting a, a obliterans-type of condition?
>> The National Toxicology Program has recently completed
lifetime carcinogenicity studies mice and in rats.
And they did have limited evidence.
Or it may have been equivocal evidence that,
of carcinogenicity from diacetyl.
And I don't remember the actual numbers.
They were respiratory tract adenocarcinomas, as I recall.
Of the nose, which in the rodent absorbs a lot of these things.
And there may, it may have been of the lung as well.
Nose often puts, having the same cell type of origin
as the human lung does.
And because it does symmetry, maybe the targeting rodents.
But the workplace data, we don't yet have human data.
And but it doesn't appear to be a powerful carcinogen.
Due to the nature of how it kills cells.
I would expect it to be a powerful promoter.
But that work has not been done.
That's just a hypothesis.
>> Yeah, I would, I would consider that similar
to asbestos, the smoking exposure action might
be critical.
>> Yeah, that kind
of interaction is what one would predict.
Because the cells are not going to have their normal defenses.
And once they're induced, they're going to proliferate
and fix any genetic damage done by a co-carcinogen.
But, but those studies have not been done.
That is a hypothesis.
>> Can you clarify
with a biologic possibility why you think it,
the disease continues to get worse
after they're out of the plants?
>> There's actually not much evidence
that there's progression after exposure ceases.
At least after about two years.
Many of the clinical cases had horrible coughs
for about two years until after they left the plant.
And then their cough resolved somewhat.
But their shortness of breath, you know persisted.
But in general I think that, that the reason many
of these cases have not come to lung transplant is
that they have a very different natural history.
Than people who have emphysema, for example.
Who put, are put on lung transplant lists.
And equivalent pulmonary function deficits,
the flavoring-related cases.
You know seem to not progress which is not the case
with smoking-related lung disease.
>> From a point of view
of individuals entering the, the practice.
Of public health today.
It's a, a lot of good lessons in what you were presenting.
The, the, the things that you observed.
The tools that we had.
The insights we had at hand, going back to the 1985 study.
Which, which was a you noted, many, many ingredients.
Only a couple limited cases.
And I think some of the rules of thumb
that you were basically presenting to people were.
Think about the way that industry's changing.
Consider the way that use of materials is changing.
Perhaps looking at the coffee industry today
with so many small packaging
and formulating companies coming into play.
I think these are some questions that,
that everyone could keep in mind as they.
Either practice within, within formal public health
or get trained at universities to go into business.
Or even through schools to educate students better.
So that when they go into the workforce,
they're recognizing some of these situations.
That have, have gone way beyond control.
Before they're, before they're recognized
and protection is provided.
So thanks for the re-recapping the history.
And I think especially, emerging manufacturing and the changing,
the changing workforce across the world.
Also climate change and how
that changes the conditions of exposure.
And so thank you again.
>> Thank you.
Are there any other questions
from Envision or from the audience?
Thank you very much for your attention.
[ Applause ]