Dennis Paustenbach PhD DABT September 14 2017 Kansas University Medical Center KUMC 17 th Annual John Doull Lecture Remembering Dr Doull He was a true inspiration for all of us in the field ID: 916177
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Slide1
Using Risk Assessment Methods To Characterize Various Chemical Hazards: Three Case Studies
Dennis Paustenbach, PhD, DABTSeptember 14, 2017Kansas University Medical Center (KUMC)17th Annual John Doull Lecture
Slide2Remembering Dr. Doull
He was a true inspiration for all of us in the fieldHe mentored dozens of, if not a couple hundred, professionals over the years (including me)It is difficult to think of a person who had such an impact who had no enemies. John was one of themHe often asked me to “come to Kansas” and give the kind of lecture that you will hear today
2
Slide3Overview
A little about risk assessmentAsbestos in friction productsWest Virginia spill of 2014Diacetyl…a controversy 3
Slide4What is Health Risk Assessment?
A logical, objective, and quantitative approach to analyzing and interpreting data with the purpose of predicting the potential adverse health effects of exposure to chemical or physical hazards
4
Slide5Kinds Of Risk Assessment
Failure Analysis
Machine parts
Hazard Analysis
Explosion/fire
Actuarial and Natural Disaster
Insurance
Human/Environmental Health Risk
Chemical hazards
5
Slide6There are perhaps 20,000 pages of information in the USA with which you should be familiar
Probably an equal body of knowledge on risk issues developed in the EU and in Australia/New Zealand
For 90% of professionals, it is a 7-15 year journey to master the area …a lot like eating a watermelon (one bite at a time)
A Lot To Learn
6
Slide7Most Regulations In The United States Are Based On Risk Assessment
Water discharge limitsAir emission limitsOccupational health standardsSoil, sediment, and other cleanup limitsFood recallsFish advisories or bansPharmaceutical drug approvals
7
Slide8Human Health Assessments
Occupational
Environmental
Occupational
8
Slide9All Modern-Era Risk Assessments Contain
Four “Chapters”9
Slide10Risk
Characterization
Dose-Response
Assessment
Risk
Management
Hazard
Identification
Exposure
Assessment
Cost/Benefit
Analyses
1
2
3
4
10
Slide11Risk Assessment Integrates…
Acute toxicology dataChronic dataHuman experienceExposure informationFate and transportStatistics and probabilitySocial values (via risk criteria)… into a cohesive analysis with “an answer”
11
Slide12Examples Of “Difficult” Assessments
Abandoned or active industrial sitesIncinerator permittingSupport air/water discharge permitsSite-specific soil and sediment cleanup levelsSome toxic tort cases
12
Slide13Case Study I:
Asbestos In Brake Dust13
Slide14Question….
Was the use of asbestos in brake dust a significant health hazard (1950-80)?14
Slide15Ford Publishes An IH Survey (1968)
Hickish and Knight (1968)Due to interest in UK about asbestos, the authors published a small industrial hygiene study of brake mechanicsExposures were deemed acceptable (0.68 f/cc for cars; 1.75 f/cc for trucks)15
Slide16In 1976, A Hypothesis Generating Paper Was Published By Mt. Sinai
Work conducted in 1975Rohl et al (1976) or Lorimer et al (1976)Just a $10,000 university study
16
Slide17NIOSH Got Interested…1975
A national bulletin was sent to all industrial hygienists and occupational physicians (called NIOSH Intelligence Bulletin)17
Slide18Then Litigation…
More than 250 cases filed by 1980By 2000, more than $1B had been paid to plaintiffs and lawyersOur firm was asked to evaluate the “science” behind the claims in 2001
18
Slide19Published Papers Prior To 1990
About 10 papers had been published on brake dustLynch (1968)Hickish and Knight (1970)Rohl et al. (1976)Rodelsperger et al. (1986)Several NIOSH surveys
BUT, no one attempted to integrate or characterize all the relevant information
19
Slide20The Best Part of Problem Solving In The Environmental Sciences…
You have a chance to assemble dozens of papers on as many as 15 scientific topics….then see if a there is adequate information to “figure out what is going on”A perfect use of the risk assessment method20
Slide21Identifying “Data Gaps” Is Important…
This process focuses you on the research that needs to be conductedOften, someone has done a significant part of the work “in some related science” or in some other part of the world
21
Slide22How We Dissected The Problem
Understand braking processToxicology of wear debris vs. raw asbestosExposure of mechanicsEpidemiology of mechanics22
Slide23Asbestos Brake Pad Contents
Binders
Metal Shavings
Resins
Chrysotile Asbestos
Glues
23
23
Slide24Brake Wear Debris (1000X)
- non-fibrousChrysotile Fibers (1000X)
Conversion Of Chrysotile Asbestos To
Forsterite
Braking
24
Slide25% Chrysotile In Brake Wear Debris
2725
Slide26Looking At Toxicology
26
Slide27Asbestos Fiber Types
Serpentine
Chrysotile
Amphibole
Asbestos
Crocidolite
Amosite
Others
16
27
Slide28Types Of Asbestos
Amosite
Crocidolite
Chrysotile
17
28
Slide29Long residence in lung
Long time for biological processes that could lead to mesothelioma
Short residence in lung
Little time to cause damaging effects
Chrysotile
Amosite
Biopersistence
21
29
Slide30Fiber Length Affects Toxicity
Vehicle mechanics were mostly exposed to chrysotile fibers less than 5 microns.
0
5
10
15
20
Fiber Length in microns
Fibers less than 8 microns are highly unlikely to cause lung disease
Vehicle mechanics were exposed to fibers less than 5 microns
22
30
Slide31Stettler
et al. (2008)
Stettler
, Lloyd E., Douglas D.
Sharpnack
, and Edward F. Krieg. "Chronic inhalation of short asbestos: lung fiber burdens and histopathology for monkeys maintained for 11.5 years after exposure." Inhalation toxicology 20.1 (2008): 63-73.
Primate study
High doses of short chrysotile fibers
No mesothelioma
29
31
Slide32Bernstein et al. (2014)
Bernstein, David M., et al. "Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: Interim results." Toxicology and applied pharmacology 276.1 (2014): 28-46.
Chrysotile-containing brake pads were sanded
Rats inhaled this dust from the brake
No adverse lung effects
30
32
Slide33Hodgson And Darnton (2000)
“At exposure levels seen in occupational cohorts it is concluded that the exposure specific risk of mesothelioma from three principal commercial asbestos types is broadly in the ratio 1:100:500 for chrysotile, amosite and crocidolite, respectively.”
pg. 565
Hodgson, JT, and A Darnton. 2000. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure.
Ann Occup Hyg
44(8):565-601.
19
33
Slide34Relative Potencies Of Fiber Type For Mesothelioma
Chrysotile
Amosite
Crocidolite
0-1
100
500
18
34
Slide35We Then Tackled The Question of Exposure
35
Slide36Exposure Assessment For Asbestos
Need to consider:Asbestos fiber typeAsbestos fiber dimensions (length and diameter)
Concentration of asbestos in the air during repair work
Frequency, duration, and intensity of exposures during tasks performed
33
36
Slide37Paustenbach et al. (2003)
Analyzed published data (~200 samples) regarding exposure of auto brake mechanics to asbestosExposures of auto brake mechanics to asbestos were low
Paustenbach, D.J., et al. 2003. An evaluation of the historical exposures of mechanics to asbestos in brake dust.
Appl
Occup
Environ
Hyg
. 18: 786-804.
37
Slide3817 Studies Show Mechanics Were Not Over-Exposed During Vehicle Repair Activities
2.0 f/cc TWA (1976-1986)
0.2 f/cc TWA (1986-1994)
0.1 f/cc TWA (1994-Present)
36
Slide39Richter et al. (2008)
Examined short-term airborne concentrations experienced by mechanicsNone of the short-term exposures were above the current or historical OSHA excursion levels
Richter, R.O., et al. 2008. An evaluation of short-term exposures of brake mechanics to asbestos during automotive and truck brake cleaning and machining activities.
J Expo Sci Env Epid. Advanced online publication. July 30, 2008.
39
Slide40Jiang et al. (2008)…Clutch Boxes
Jiang, G.C.T., et al. 2008. A study of airborne chrysotile concentrations associated with handling, unpacking, and repacking boxes of automobile clutch discs. Regul Toxicol Pharm. 51: 87-97.
“The results of this study indicate that the handling, unpacking, and repacking of clutches, and the subsequent cleanup and clothes handling by a worker within a short-term period or over the entire workday, result in exposures below the historical and current short-term and 8-h occupational exposure limits for asbestos.”
40
Slide41Madl et al. (2009)…Heavy Equipment
Madl, A.K., et al. 2009. Airborne asbestos concentrations associated with heavy equipment brake removal. Ann Occup Hyg. Advance online publication. June 25, 2009.
“The results indicate that…the airborne concentrations for worker and bystander samples were significantly less than the current occupational exposure limit of 0.1 f/cc…”
41
Slide42Estimating Lifetime Dose
We conducted a time-motion studyCombined with short term and 8 hr dataCalculated lifetime dose in units of fiber/cc-year
42
Slide43Lifetime Exposure Of Mechanics
Finley B., R. Richter, F. Mowat
, S.
Mlynarek
,
D. Paustenbach, J Warmerdam, and P. Sheehan. 2007. Cumulative asbestos exposure for U.S. automobile mechanics involved in brake repair (circa
1950s
–2000). J
Exp
Sci
Environ
Epidemiol
17:644–655
Includes blow-out, grinding, sanding
Cumulative lifetime doses of about 1.0-2.0 f/cc-
yr
of chrysotile
37
43
Slide44What About Automotive Gaskets
?44
Slide45Installation And Removal Of Asbestos Gaskets And Packing (2006)
Removal of gaskets and packing released insignificant concentrations of asbestosMangold, C., K. Clark, A. Madl, and D. Paustenbach. 2006. An Exposure Study of Bystanders and Workers During the Installation and Removal of Asbestos Gaskets and Packings. J
Occup
Environ
Hyg
3(2):87-98.
45
Slide46Literature Review – Replacing Asbestos Gaskets and Packing (2007)
Removal of gaskets and packing released insignificant concentrations of asbestos
Madl, A.K.
, K. Clark, and D.J. Paustenbach. 2007. Exposure to Airborne Asbestos During Removal and Installation of Gaskets and
Packings
: A Review of Published and Unpublished Studies. J
Toxicol
Environ Health, Part B
Crit
Rev 10(4):259-286.
46
Slide47Long-Term Asbestos Concentrations During Gasket and Packing Work
*Includes hand held pneumatic and hand-held power tools; Includes PCME data, where availableCurrent OSHA Permissible Exposure Limit (8 hr TWA)
47
Slide48Epidemiology
48
Slide49Epidemiology Data For Vehicle Mechanics
Numerous data collected by governmental facilities, academic institutions, and private corporationsData collected in U.S. and internationallyIncluded various study designsEvaluated various occupations (in addition to mechanics)
Data consistently showed no increased risk of mesothelioma for career vehicle mechanics
49
Slide50Epidemiology Studies
McDonald and McDonald 1980Petersen and Milham 1980Teta et al. 1983Spirtas et al. 1985Olsen and Jensen 1987Woitowitz and Rodelsperger 1994Coggon et al. 1995Teschke et al. 1997Agudo et al. 2000Milham and Ossiander 2001NIOSH 2002Hansen and Meersohn 2003Hessel et al. 2004Rolland et al. 2005McElvenny et al. 2005
Rake et al. 2009
Rolland et al. 2010
Garabrant et al. 2015
50
Slide51Garabrant et al. (2015)
Meta analysis of auto mechanicsGrouped 16 epidemiology studies of auto mechanics into three tiers based on study qualityAuto mechanics were found to not be at an increased risk for mesothelioma
51
Slide52Increased Risk
No Increased Risk
No Increased Risk Among Mechanics
45
52
Slide53The “weight of the evidence” shows no increased risk of mesothelioma for automotive mechanics
53
Slide54Risk Of Mesothelioma For Various Occupations
Source: Teschke et al. 1997, Table II pg. 165 (most recent 20 years removed)
56
54
Slide55Our Work Generated Additional Interest
55
Slide56Since About 2000…
About 25 relevant papers were published on exposure to brake dust through 20172-3 papers by Weir et al.2-3 papers by Blake et al.More than 10 papers by ChemRisk scientists12 or more papers by various scientists and epidemiologists
56
Slide57What Did Persons Or Corporations Know…
And When?57
Slide58Paustenbach et al. (2004)
“State-of-the-art” evaluation of asbestos in brake linings and pads over last 100 years
Paustenbach, D.J., et al. 2004. Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a “state-of-the-art” review. J
Toxicol
Env
Heal B. 7: 33-110.
58
Slide59Does Epi Data Make Sense When You Consider Potency And Exposure Levels?
59
Slide60Pierce et al. (2008 and 2016)
Pierce, J., MA McKinley, DJ Paustenbach and BL Finley. 2008. An Evaluation of Reported No-Effect Chrysotile Asbestos Exposures for Lung Cancer and Mesothelioma. Crit
Rev
Toxicol
38:191-214.
Studied groups of persons exposed to high levels of chrysotile
“No effect” at 208 f/cc-year for short fiber chrysotile
42
60
Slide61Doses That Do Not Cause Mesothelioma (Chrysotile)
44
0.00093 f/cc-
yr
1.8 f/cc-
yr
208 f/cc-
yr
61
Slide62Our View
Exposure to brake dust posed a de minimus risk to auto and truck mechanics of any asbestos related disease
62
Slide63Case Study II:
The “So Called”Freedom Chemical Spill
63
Slide64The Question…
Did the contamination of drinking water in Charleston, WV cause immediate effects or pose a long-term health risk?64
Slide65Overview
Event Timeline (2014)Overview of Toxicity of crude MCHMCrude contains MCHM plus 5 chemicalsOverview of Toxicity of MetabolitesData Gaps of ImportanceWhat we did
"2014 Elk River chemical spill affected counties" by Justin.A.Wilcox - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons -http://commons.wikimedia.org/wiki/File:2014_Elk_River_chemical_spill_affected_counties.png#mediaviewer/File:2014_Elk_River_chemical_spill_affected_counties.png
65
Slide66Event
January 9, 2014 (Elk River)10,000 gallons released upstream of the water treatment facilityCDC/ATSDR quickly set a short term screening level concentration for drinking water of 1 ppm“Do not use” order began January 9, and ended January 13-18Water was generally not used during this time
66
Slide67Reported Health Complaints
Three reports were released regarding health complaints following the spill:Emergency Department Records from WVBPH and ASTDR (April, 2014)Household Survey CASPER from CDC (April, 2014)Physician and Health Clinic Records from WV DHHR (June, 2014)
67
Slide68Emergency Room Study Details WVBPH And ASTDR (April, 2014)
Records were obtained from 10 hospitals for January 9 through January 23584 records were released. Inclusion was based on whether patients reported that they had exposure to contaminated water
68
Slide69Symptoms Reported At Emergency Rooms (Jan, 2014)*…No Control Data
Note that patients could present with more than one symptom* As reported in WVBPH (ATSDR, 2014, p. 5)
Number of cases
69
Slide70What Did ATSDR Say About These Data?
“People who reported that they swallowed contaminated water or food were more likely to report gastrointestinal symptoms such as nausea, vomiting, and diarrhea.”
70
Slide71ATSDR May Have “Rushed” Their Response
“These data cannot ‘prove’ that MCHM caused the reported symptoms; however, these data are consistent with what is known about MCHM from animal studies.” (p. 6)71
Slide72Health Effects Reported In Household Study(Casper Study)
*As reported in WVBPH (ATSDR, 2014)Number of households
72
Slide73What Did CDC Say About These Data?
“Less than one-quarter of households reported health issues they felt were related to the chemical spill.” (p. 23)“[T]he symptoms reported were similar to what have been reported in the ACE investigation [WVBPH ATSDR 2014].” (p. 23)73
Slide74Composition Of Crude MCHM
MCHM
4-Methylcyclohexanemethanol 68-89%
MMCHM
4-(Methoxymethyl)cyclohexanemethanol 4-22%
MMCHC
Methyl 4-methylcyclohexanecarboxylate 5%
DMCD
Dimethyl 1,4-cyclohexanedicarboxylate 1%
CHDM
1,4-cyclohexanedimethanol 1-2%
Note: Methanol (1%) and Water (10%)
O
CH
3
74
Slide75Predicted Metabolites For MCHM
MCHM
4-Methylcyclohexanemethanol
CHDM
1,4-cyclohexanedimethanol
CHDA
1,4-cyclohexanedicarboxylic acid
DMCD
Dimethyl 1,4-cyclohexanedicarboxylate
H
H
Enzymatic hydrolysis
Oxidation by P450 or alcohol/aldehyde dehydrogenase
Scheme by Steve Green
Oxidation by P450 or alcohol dehydrogenase
75
Slide76MCHM: Overview Of Toxicology
Low acute toxicityLD50 for male/female rats is 933/707 mg/kg bwHighly odorousConsumer odor threshold concentration is 0.55 ppbNot a skin sensitizerGuinea pig footpad testNot mutagenic; not likely carcinogenic Negative Ames test
76
Slide77Characteristics Of MCHM Were A Blessing…
Low toxicityBad smellBad taste
77
Slide78Comparison To Acute Toxicity Of Other Selected Industrial Chemicals
78
Slide79The Methodology For Characterizing The Risk
79
Slide80Odor Test Results
Slide81Odor Threshold Of MCHM
Odor threshold identified for MCHM by WV DHSEM (2014)Expert panelConsumer panelOdor threshold for crude MCHM (Gallagher et al., 2014)
81
Slide82Odor Thresholds For Crude MCHM(WV DHSEM, 2014)
Method of determining odor threshold concentration in water was based on ASTM Method E679Four response levels were identified:Odor Threshold: 50% of testers can just detect the chemicalOdor Recognition: Based on the concentration at which the tester correctly describes the odorOdor Objection (Likeability): Based on the degree of liking of the odor Odor Objection (Complaint): Based on the concentration at which a tester admits that they would object to or complain about an odor
WV DHSEM 2014
82
Slide83Odor Threshold For Crude MCHMExpert Panel (WV DHSEM, 2014)
9 experts were testedPanelists were knowledgeable about the odor of crude MCHM6 women and 3 men were in the panelAll undergraduate and graduate students (all young)
83
Slide84They Found A Classic
Dose-Response Relationship84
Slide85Odor Threshold For Crude MCHM Expert Panel (WV DHSEM, 2014)
WV DHSEM 20140.16 ppb1.6 ppb
2.2 ppb
4.0 ppb
85
Slide86Odor Threshold Varied For Isomers (Gallagher, 2014)
2480 ppb1.2 ppbNo other component of crude MCHM had a detectable odor
Gallagher, 2014
86
Slide87Odor Threshold Of MCHM
Considering the CDC’s recommended screening level (1,000 ppb), the odor threshold for MCHM was sufficiently low that residents would be aware of the contamination.They should not have been exposed at concentrations that would pose a health hazardGallagher 2014
87
Slide88Developmental
Tox Hazard?
Slide89Developmental And Reproductive Effects Had
Not Been Studied…For Numerous Reasons89
Slide90SAR Modeling “Suggested” That Developmental Effects Were “Plausible” At Some Dose
90
Slide91MCHM: Developmental Hazard Based On QSAR
NTP QSAR Analysis for MCHMPredicted possible developmental toxicityOur QSAR Analysis for MCHM Predicted developmental toxicityVega and EPA TEST modelsNo predicted developmental toxicityUsing OECD modelNTP 2014
91
Slide92These Models Do Not Consider Dose…Yet All Chemicals, At Some Dose, Can Be Developmental Toxicants
92
Slide93Developmental Toxicity Is Difficult To Predict By Modeling (And Potency Is NOT Considered)
Many endpoints are possible, encompassing growth, health and performance of offspringRelatively few compounds are in the datasets for developmental toxicity modelingIn the case of MCHM, the results from modeling were inconsistent93
Slide94What We Later Learned About Developmental Toxicity
94
Slide95MCHM: Developmental Toxicity Results From NTP (2015-2016)
NTP completed a range-finding Prenatal Developmental Toxicity Study150, 300, 600, 900 mg/kg bw/day MCHM were testedOvert developmental toxicity was observed at 600 and 900 mg/kg (fairly high doses)The group receiving 900 mg/kg were terminated early due to maternal toxicity
95
Slide96Interpreting The NTP Developmental Screening Study
This range-finding study by the NTP used very high dosesThe highest dose tested was above the LD50Maternal toxicity was observed at the two highest doses usedEffects on the fetuses at these doses were likely secondary to maternal toxicity…irrelevant to predicting human risks96
Slide97What About Carcinogenicity?
97
Slide98No Studies Had Been Conducted. But This Hazard Was Probably
Not Relevant Due To Limited Duration of Exposure98
Slide99Odor, Low Toxicity, And SAR Suggested It Would
Not Be Carcinogenic At Doses To Which Persons Could Be Exposed…And Duration Of Exposure Was Limited99
Slide100Estimating Dose
For Citizens
Slide101Model Estimates Of Exposure
Child 30 day exposure
Adult 30 day exposure
McKone and
Bogen
Approach
0.11 mg/kg/day
0.05 mg/kg/day
101
Slide102Possible Exposure vs. Tox Data
NOEL from 28 day study was 100 mg/kg/dayIf you applied a 1000-fold uncertainty factor to this “safe” dose would yield 0.1 mg/kg/day (screening-level)This is similar to the estimated dose for some persons (the model water concentration was 1 ppm)Results support CDC’s view that 1 ppm in water was unlikely to result in any adverse health effects
102
Slide103What We Did…
Published our review of toxicityConducted exposure assessment of citizensPerformed dermal irritation studyPerformed study on birth outcomes103
Slide104Toxicology Review
104
Slide105Skin Study
105
Slide106Birth Outcome Study
106
Slide107Where ATSDR Landed
They concluded, in early 2017, that there were no chronic hazards likely for the citizens107
Slide108Our Views
An unfortunate incidentYes, thousands were inconveniencedLuckily, warning properties and good communication prevented exposureNo apparent adverse effects for those potentially exposed108
Slide109Case Study III:
Diacetyl
109
Slide110Sometimes (Often) Scientific Thought Is Compromised by Personal Beliefs
Those who have studied history, including the history of science, have concluded that it is very difficult for humans to think in a truly objective mannerIt argues heavily for “double blind” researchIt also argues that the source of funding should be withheld during the peer review process (as reviewers are heavily biased by their beliefs)
110
Slide111Precautionary Principle
“Better safe than sorry”
Loss of public trust in science when we “cry wolf”
Cost of unwarranted regulation and litigation
111
Slide112Diacetyl: A Common Chemical In Many Foods
Provides the taste of butter and is found naturally in many foodsUsed to create a “rich” taste, frequently used in butter, caramel, vanilla, butterscotch, and some fruity flavorsReceived GRAS status as an additive in 1965
112
Slide113The Question….
Is there a valid medical or scientific basis for linking diacetyl and/or butter flavoring to severe lung disease?113
Slide114Brief History Of Diacetyl
114
Slide115Diacetyl And Bronchiolitis Obliterans (BO)
Diacetyl exposure was first implicated as a possible cause of bronchiolitis obliterans in a microwave popcorn production facility in 2000 (Missouri)Disease of the lower airways (deep lung)Rare, irreversible and debilitating
115
Slide116Kreiss et al. (2002) – “Sentinel” Study
First study published of popcorn manufacturing cohortBased on initial NIOSH HHE (not the succeeding 8)Suggested relationship between diacetyl and obstructive diseaseBUTAny “effects” only seen in VERY high exposure groupsAuthors agreed that most cases had exposures to other chemicals off-site (and on-site)No classic diagnostic assay for B.O. was available116
Slide117First Hypotheses: It Must Be Diacetyl
Diacetyl was initially characterized by NIOSH as a marker of industrial exposure to flavorings [no apparent basis except that it was a known irritant]Odd hypotheses, since vapors at the plant contained over 100 VOCs117
Slide118A Focus Of NIOSH
It was a bellwether for suggesting that there might be “other” occupational diseases “out there” that are not being recognized
118
Slide119By 2015, NIOSH Was Convinced
That diacetyl was quite hazardousThat it could cause B.O. in some personsThat it was a deep lung toxicant119
Slide120NIOSH: They Did Study Diacetyl Aggressively
Since 2000, NIOSH has conducted over 20 studies at food and/or flavor facilities (HHE)But, only in 2011 did NIOSH conclude that diacetyl was the cause of bronchiolitis obliteransAll along the way, there were conflicting medical diagnoses and tox data
120
Slide121We Are Reluctant To Be Critical….but I have wondered
I was among the first professionals contacted after Gilster-Mary Lee plant reportBeing so water soluble and odorous, it seemed counter intuitive to have caused this diseaseMy classmate in grad school studied diacetyl in 1977121
Slide122Evaluation Of “Cases”…Not Very Robust
Reported cases of B.O. did not meet the disease criteriaMany were not diagnosed until after visit with plaintiff expert physicianCommon confounders:Off-site/non-occupational exposures to known BO inducersPresence of other chemicals in the workplace
122
Slide123Federal Government’s Animal Toxicology Studies
Since 2000s, the National Toxicology Program (NTP) has completed various animal inhalation studies of diacetylFirst scientific papers published in 2002Most recent and relevant studies (90-day and 2-year) completed in 2011/2012123
Slide124Tox Data
Fairly thorough studies (including a 2 yr study) do not indicate it should be a significant hazard at plausible workplace concentrations
124
Slide125NTP View…On Animal Toxicology
NO scientific papers on the 90-day or 2-year studies have been published to dateNTP/NIOSH has asserted that mice and rats are not good models for evaluating human respiratory toxicitySo why were millions of dollars spent on animal research?125
Slide126Assertions By NIOSH…
Animal inhalation studies are not relevant due to “scrubbing”…this is probably not quite accurateCases of bronchiolitis obliterans have been observed in every flavorings facility (even very low diacetyl exposures cause disease)…failing a biopsy, this claim may or may not be trueDose-response has been clearly demonstrated….I don’t find the data convincingNIOSH believes diacetyl causes obliterans… perhaps; but it seems far from convincing
126
Slide127NTP’s Current View of Results of Animal Toxicology Studies
NTP believes that the results of most studies support that diacetyl can cause BO….Stated that two-year study indicates that diacetyl may be a carcinogen…I don’t interpret the study in the same way127
Slide128NTP’s Conclusions In 2017 Draft Report From 2-year Cancer Study
“there was some evidence of carcinogenic activity…in male Wistar Han rats” in the nose“[t]here was some evidence of carcinogenic activity…in female Wistar Han rats” in the nose“[t]here was no evidence of carcinogenic activity…in male B6C3F1/N mice”“[t]here was equivocal evidence of carcinogenic activity…in female B6C3F1/N mice” in the nose
128
Slide129Other Beliefs By NIOSH
Initially, NIOSH and others suggested that diacetyl exposure caused obstructive diseaseThen, some data (Sensient data) suggested it was restrictiveWe found NIOSH’s conclusions to be questionablePlaintiff experts and NIOSH associate many respiratory ailments (obstructive/restrictive/ mixed/other) to diacetyl exposure
129
Slide130Our Epi Study
We evaluated Sensient cohort (as did NIOSH)Our interpretations of the data were quite differentOur view will probably never be reconciled with that of NIOSH. History will decide… if a definitive epi study is ever conducted130
Slide131Our Follow Up Study (2016)
We have a 7 year follow up on PFT dataNo change in results were observed when properly corrected for obesity, smoking, etc.131
Slide132Let’s Go Over Some Basics
On This Matter132
Slide133Diacetyl Exposure Is Not Uncommon
Detected in outdoor air at low levels concentrationsDetected in indoor air due to the use of certain carpeting adhesivesConcentrations are similar to some productions facilities even several days after installationA component of mainstream and environmental tobacco smokeUsed as an additive, however, the vast majority is formed through pyrolysis
133
Slide134Cases Reports And Epi Studies (2000-2017)
Gilster
-Mary Lee
Sentinel cases
Parmet
and Von Essen 2002
3 GML Sentinel Cases
Alleman
& Darcy 2002
BOOP in Spice Process Technician
Cal-OSHA 2006
CA Case Report Letter
van
Rooy
et al. 2007
3 Cases with
Radiologic Signs of BO
CDC MMWR 2002
Fixed Obstructive
Disease in Microwave
Popcorn Factory Workers
CDC MMWR 2007
Fixed Obstructive
Disease in Flavor
Manufacturing - CA
Akpinar-Elci
et al. 2004
8 GML Sentinel Cases
Modi
et al. 2008
“Flavor-Induced Lung
Disease” in Flavoring
Manuf. Worker
Sahakian
et al. 2008
Asthma in Flavoring Exposed Food Production Workers
Kreiss
et al. 2002
Cross Sectional Study
of GML Microwave Popcorn Manuf. Facility
Akpinar-Elci
et al. 2005
Induced Sputum of Microwave Popcorn workers
Kanwal
et al. 2006
Review of Six Microwave Popcorn Plants (HHEs)
van
Rooy
et al. 2009
Cross-Sectional Study of
Flavoring Manuf. Plant Workers
Lockey
et al. 2009
Cross-Sectional Study of Microwave Popcorn Production Workers
Kim et al. 2010
Cross-Sectional
Flavor Manuf.
Workers in CA
Case Report
Epi
Study
Kreiss et al. 2012
Longitudinal Analysis of Flavor Manuf.
Workers in CA
Cavalcanti
et al. 2012
Bronchiolitis
in Cookie Factory Workers
Akpinar-Elci
et al. 2006
Exhaled Nitric Oxide in Microwave Popcorn Workers
2000
2002
2004
2006
2008
2010
2012
2013
Huff et al. 2013
Bronchiolitis Obliterans in Coffee Workers
Halldin
et al. 2013
Resp. Mortality and BO at GML MW Popcorn Facility
Ronk et al. 2013
Pulmonary Function in Flavorings Workers
Kreiss 2013
Work-Related
Spirometric
Restriction in Flavoring Mfg. Workers
Hendrick
2008
“Popcorn Workers Lung”
in Potato Crisp
Flavoring Manuf. Worker
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Slide135Strangely…
None of the case reports or epidemiology studies have adequately evaluated or controlled for non-occupational exposures to diacetyl … particularly from smoking cigarettesSmokers, comprise a significant fraction of the studied populationsSurprisingly, smokers get huge lifetime diacetyl doses but there is NO increase in the incidence of B.O. in smokers
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Slide136What Has Puzzled Our Research Team…
Even nearly 15 years later, and after 20 papers by NIOSH, it remains unclear to us “why” NIOSH eventually concluded that diacetyl was the likely causative agent for B.O.It was the “predominant ketone” identified in artificial butter flavoring and in mixing room air (but many chemicals have been reported and not all have been speciated in the air)Mixer “operators” were initially found to be at highest risk for developing lung disease…which is logical
136
Slide137An Obvious Characteristic….Continually Neglected By Most Experts
This chemical has a low threshold of smellIt also has a low concentration at which persons are “driven away” (a so-called, self-limiting chemical)Indeed, it is a classic highly water soluble, upper airway, irritant… where over-exposure is highly unlikely
137
Slide138Why Was This Not Detected In 1950-2000?
Diacetyl has been manufactured in the United States since the 1930sLiterally millions of gallons have been placed in tank trucks and drums in dozens of facilities…for 60 years…without any reported effects other than irritationHow could a fatal lung disease be “missed” for decades?138
Slide139How Does One Reach….
“A more likely than not” opinion on a cause/effect relationship?Or, an opinion about a threshold?
139
Slide140The 15 Year Journey….
This is one of the more curious of the chemical journeys of recent yearsOne has the impression that it was the premature hypotheses; similar to silicone breast implants, saccharin, and agent orangeThis chemical is one where toxicologists and occupational physicians and other “experts can agree to disagree”140
Slide141Diacetyl…Where Do Things Stand?
Largely phased out due to health concerns (and litigation!)Some substitutes have similar chemical structure and toxicity, which has led NIOSH and others to warn about these substances as wellWe remain skeptical…for a few reasons
141
Slide142Always Search For A Silver Bullet
When there is a scientific controversy, it is important to conduct one or several studies that deal with any data gapsFor 20 years, health scientists have come to rely less on toxicology studies…and more closely on epidemiology142
Slide143We Thought That A Silver Bullet Might Be Available In The Study Of Smokers
(Who Are Exposed To Diacetyl)143
Slide144We Tackled The Questions About Diacetyl On Several Fronts
We conducted the first field study to assess diacetyl in cigarette smokeIt was published in a highly rated journal144
Slide145Cigarettes….Perhaps The Rosetta Stone
Diacetyl is in mainstream and environmental tobacco smokeUsed as an additive, however, the vast majority is formed through pyrolysisIn published literature dating back to the 1970s, concentrations in smoke inhaled by smokers were as high as 297 ppmB.O. is “less” likely in smokers than non-smokers145
Slide146Diacetyl Exposure And Cigarette Smoking
We measured diacetyl (and 2,3-pentanedione) concentrations in mainstream cigarette smoke using a standard smoking machineTested 6 “tobacco products” 3 smoking regimensISOMassachusetts Department of Public Health (MA)Health Canada Intense (HCI)
146
Slide147Comparison To OELs
The mean diacetyl concentrations in mainstream smoke ranged from 250-361 ppm for all tobacco productsSmoking 1 cigarette in a day (assuming 5 min of smoking) is equivalent to: An 8-hr TWA of > 2.5 ppmA 15-min TWA of > 80 ppmThis greatly exceeds the OELsNIOSHREL (8-hr TWA) – 0.005 ppm (exceeded by 500-fold)ACGIHTLV (8-hr TWA) – 0.010 ppm (exceeded by 250-fold)
147
Slide148Comparison To Current TLV
TLV was set at 0.01 ppm (2012)Based on findings from Kreiss et al. (2002)Used by OSHA to cite companies for overexposure (under General Duty Clause)148
Slide149Workplace Exposures Vs. Smoking
Hundreds of diacetyl samples have been collected in food and flavorings manufacturing facilitiesOnly one peak air sample exceeded the concentration in cigarette smoke [and it not representative of the workplace]The vast majority of longer-term samples are <1 ppm
149
Slide150Important To Identify Proper Dose Metric
For a chronic toxicant, most toxicologists believe that “cumulative lifetime dose” is preferred dose metric (e.g., cancer)For some chemicals, like beryllium, the number of peak exposures above a “significant biologically active” concentration….plus duration…is usually the best dose metricFor diacetyl?150
Slide151Cumulative Diacetyl Exposure (ppm to yrs):
Smoking vs. Occupational Guidelines11 – 191.1 – 1.9
55 – 95
0.225
0.45
151
Slide152How Does One Reconcile The Scientific Observations?
Occupational exposures to diacetyl are far lower than exposures resulting from common smoking habitsYet, epidemiology studies of the diacetyl or flavorings workers have consistently demonstrated worse pulmonary function in non-smokers v. smokers And there is not a single case report of bronchiolitis obliterans resulting from cigarette smoking
152
Slide153Other Considerations
153
Slide154Recent Developments – Diacetyl In Coffee
Diacetyl occurs naturally in roasted coffee beans as a result of chemical reactions during roastingIt is readily measured in the headspace of coffee beans and brewed coffee
154
Slide155Diacetyl Exposures In Coffee Workers
Five cases filed in TX and MO (2012)Alleged exposures to diacetyl in coffee production facilities in Texas and MissouriNIOSH HHE of coffee plantsNot yet publishedFacility owner/flavorings suppliers have been sued
155
Slide156Diacetyl/2,3-P Exposures From Processing Unflavored Coffee (Gaffney et al., 2015)
First published study to characterize workplace exposures during commercial roasting and grinding of unflavored coffee beansExceedance of proposed NIOSH values in most samplesWe estimated that 8-hour TWA exposures were well above NIOSH and ACGIH’s OELs
156
Slide157Our Views
Data indicate that epidemiology studies of food and flavorings workers are severely confounded by non-occupational exposure to diacetyl [e.g., smoking, farming, home popcorn]Our data suggests that NIOSH guidelines and current TLV are unnecessarily lowThe 2 year animal study data deserve more consideration than it has gottenOur coffee and cigarette studies, as well as the toxicology data, indicate that it is unlikely that diacetyl causes bronchiolitis obliterans or other lung diseases following typical occupational exposures
157
Slide158Thank You!
158