Occupational Respiratory Concerns in
the New Millennium
Howard M. Sandler, M.D.
Sandler Occupational Medicine Associates, Inc.
January 07, 2008
Sandler Occupational Medicine Associates © 2008
Body Organ Systems Affected by
Occupational Exposures
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Skin
Respiratory
Central Nervous System, PNS
Liver
Kidney
Endocrine
Reproductive
Cardiovascular
Gastrointestinal
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HUMAN
RESPIRATORY
SYSTEM
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Range of Occupational Lung Disorders
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Asthma (RAD)
RADS
Lung Cancer
Hypersensitivity Pneumonitis
Chemical Pneumonitis
Bronchiolitis Obliterans (BO) / BOS
COPD
Interstitial Lung Disease
Chronic Cough
World Trade Center Lung
Infectious Diseases Spread in the Workplace
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Toxicology Aspects in Respiratory
Disease
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Vapor
Particle
Absorbed Substance
Size Matters
Dose – Response
Distribution
Metabolism
Latency
Specificity of Effect
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Deposition in Respiratory Tract
Location
Particle Size (mm)
> 15 mm
10-15 mm
5-10 mm
<5 mm
Outer Portion Nasal Passage
Nasal Turbirates, Pharynx
Considered INHALED – Major
Airways Trachea, Major Stem
Bronchi
Considered RESPIRABLE –
Terminal Bronchioles, Alveoli
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Are There Thresholds for all
Adverse Health Effects?
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Acute effects – odor related symptoms
Chronic effects – subtle neurocognitive effects
Mutagenicity
Carcinogenicity
Immunotoxicity
Genotoxicity
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LOW DOSE EXPERIMENTS
HEALTH
EFFECT
THRESHOLD
EXPOSURE LEVEL
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Selected Odor Recognition Thresholds
(PPM)
Lowest Reported
OT
TLV
Formaldehyde
Hydrogen Sulfide Gas
Methyl Ethyl Gas
Toluene (Petroleum)
0.27 ppm
.00015 ppm 10 ppm
.25 ppm
200 ppm
.021 ppm
50 ppm
Trichloroethylene
.05 ppm
50 ppm
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PEL
.75 ppm
Sound Science for General Causal
Inference
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Structure Analogy
In Vitro Studies (Ames Test)
Animal Studies (Species to Species, Dosing)
Pharmacokinetics
Epidemiological Approaches
Conducting An Experiment
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Reactive Airway Disease (RAD)
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2-15% of general population
1.2 - 15.4% - Attributable to workplace
2 - 4% of all workers
Reversible disease of the pulmonary airways
Chronic asthma
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Reactive Airway Disease (RAD)
• Increasing frequency
• Increasing severity
• Age-related incidence
• Correlation with neurobehavioral disorders
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RAD Prevalence
PREVELANCE
%
10
20
30
40
50
(years)
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60
Age
Reactive Airway Disease (RAD)
• Allergic Asthma
• RADS
• Non-Specific Triggers
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RAD Associated Conditions
• Rhinitis
• Sinusitis
• Nasal Polyposis
• Atopic Dermatitis
• GERD (also causes IPF)
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OBESITY COST FACTORS
Total Annual Direct Medical Costs - $75-$100B
Total Annual Costs to Business - ???
Weight reduction reduces risk factors and costs
for care for these obesity-related conditions:
Condition
Annual U.S. Medical
Cost
% of Cost Attributable to
Obsesity
Hypertension
$ 1.6 billion
17%
Type 2 Diabetes
$ 2.4 billion
61%
Coronary Heart Disease
$ 2.3 billion
17%
Gallbladder Disease
$ 705 million
30%
Osteoarhritis
$ 57 million
24%
Others Not Specified
Sleep Apnea
GERD/Asthma
Cancer
Stroke
Source: Watson Wyatt Worldwide
(Endometrial, Breast and Colon)
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Occupations that Can Carry Risk of
Occupational Asthma
Industry/Occupation
Agent(s)
Potential Exposure
Animal breeding/handling
Animal Antigens
2,000,000
Baking
Flour, insects, mite debris
230,000
Hairdresser
Sodium/potassium
persulfate
13,500
Coffee processor
Green coffee beans
12,900
Detergent enzyme worker
Proteases
5,700
Farm workers
Animal antigens, vegetable
dusts
4,500,000
Food additive worker
Tartrazine
14,000
Grain handler
Grain, insect debris dust
97,000
Laboratory worker
Animal antigens
11,000
Chromium salts
2,000
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Occupations that Can Carry Risk of
Occupational Asthma (Cont’d)
Industry/Occupation
Agent(s)
Potential Exposure
Lumber & woodworking
Wood dusts
1,646,000
Milling
Flour, insects, mite debris
16,000
Paper products
manufacturer
Natural glues
130,000
Pharmaceutical worker
Penicillin, ampicillin
8,000
Plastics industry
Disocynates (TDI, HDI,
MDI)
11,500
Anhydrides (PA, TCPA)
4,020
Diethylene tri& tetramine
5,100
Platinum refiner
Platinum salts
300
Printer
Vegetable gums
6,000
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Bronchiolitis Obliterans
• Fibrotic Process affecting small airways
• Interstitium usually spared
• Clinical picture of fixed airway disease –
Severe COPD (restrictive, mixed)
• Proliferative (BOOP), Constrictive
(Concentrically Scarred/Stenotic Airways)
• Dx – History, PE, PFTs, CXR, HRCT, Bx
• Sx – Gradual/progressive/acute cough, SOB,
fever, night sweats, weight loss
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Bronchiolitis Obliterans (Cont’d)
• CXR – usually normal (possible
hyperinflation)
• PFTs – Decreased FEV1, increased lung
volumes, normal diffusion capacity/some
decreased FVC/minimal changes
• HRCT – air trapping, thickened airway walls,
haziness
• Biopsy – Open v Transbronchial, narrowing or
complete destruction of airways (chronic
inflammation and fibrosis)
• CT/HRCT findings in BO similar to those in
asthma
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Clinical Syndromes Associated with
Histologic Bronchiolitis, with or without
Obliterans
Inhalation Injury
• Toxic fume inhalation
• Irritant gases
• Mineral dusts
• Organic dusts
• Volatile flavoring agents
Postinfectious
• Diffuse lesions
• Localized lesions
• Drug-induced reactions
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Clinical Syndromes Associated with
Histologic Bronchiolitis, with or without
Obliterans (Cont’d)
Idiopathic
• No associated diseases
• Cryptogenic bronchiolitis
• Respiratory bronchiolitis-associated interstitial
lung disease
• Cryptogenic organizing pneumonia
• Associated with other diseases
• Associated with organ transplantation
• Associated with connective tissue disease
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Food Flavorings
• Approximately 1,037 possible respiratory
hazard flavorings
• Aldehydes, ketones, acids, thiols, sulfides
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Flavoring Substances with OSHA PELs
And/Or NIOSH RELs
Substance:
• Acetaldehyde
• Acetic Acid
• Isoamyl Acetate
• Isoamyl Alcohol
• 2-Butanone
• Butyl Acetate
• Isobutyl Acetate
• Butyl Alcohol
• Isobutyl Alcohol
• Butylated Hydroxytolene
• Butyl Lactate
• Ethyl Acetate
• Ethyl Acrylate
• Ethyl Alcohol
• Ethyl Formate
• Formic Acid
• Furfural
• Furfuyl Alcohol
• Glycerol
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Flavoring Substances with OSHA PELs
And/Or NIOSH RELs (Cont’d)
Substance:
• 2-Heptanone
• 4-Heptanone
• Methyl Mercaptan
• 4-Methyl-2-Pentanone
• Propionic Acid
• Propyl Acetate
• Isopropyl Acetate
• Propyl Alcohol
• Isopropyl Alcohol
• Pyridine
• Valeraldehyde
• Phenol
• Styrene
• Trimethylamine
• Acetone
• 4-Methyl-3-Penten-2-one
• 1- Butanethiol
• 2,6-Dimethyl-4-Heptanone
• Resorcinol
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Flavoring Substances with OSHA PELs
And/Or NIOSH RELs (Cont’d)
Substance:
• Isophorone
• Benzenethiol
• Diphenyl Ether
• Hydrogen Sulfide
• Cyclohexanone
• 2-Methylcyclohexanone
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Diacetyl (2,3- Butanediol)
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C4H6O2
Yellowish liquid
Odor – strong; rancid, chlorine-like
Odor threshold - 8.6 ppb
Vapor pressure – 56.8 mm Hg at 25 deg C
Naturally occurring substance found in food
tobacco smoke contaminant
No PEL, REL, TLV, etc
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Microwave Pop-Corn Processing –
Missouri Plant
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8 workers with BO (ages 29 – 53)
Equal gender distribution
Latency – 0.5 – 5 years
One smoker (protective factor?)
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Conclusions
• There are numerous substances and conditions (e.g.,
heating) involved in the manufacture of MW pop-corn;
specifically various particulates (oil/grease and salt)
and numerous volatile organic compounds (over 100
VOCs) have been identified by the lead governmental
agency, NIOSH in this research effort (Kullman, 2005)
• It is unclear whether diacetyl is the actual etiologic
agent in whole or, part or is simply an indicator of
exposure (OSHA, 2003; Harber, 2006; Hubbs, 2002)
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Conclusions (Cont’d)
• Kreiss, 2007 – Review, Causation?
• Egilman, 2007 – Industry Conspiracy, NO Threshold
• Schlesinger, 1998 – Critical Review for BO Risk Factors –
Flavorings/Diacetyl not Identified
• Dr. Cecile Rose – National Jewish Medical and Research Center,
Denver
– “Prior” Consultant to Flavorings Industry (FEMA)
– July 18, 2007 Letter to FDA
– Consumer with BO and Hx of Making Several Bags of
Extra Butter Flavored MW Popcorn for Several Years
– Found Similar Diacetyl Airborne Levels to Those
Reported in QA Unit of Popcorn Manufacturing Plant
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International Labor Office
(ILO) 1980
Pneumoconiosis
Classification
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Silicosis & Asbestosis Deaths in the
U.S. by Year
Silicosis
Asbestosis
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Age-Adjusted All Pneumoconiosis Mortality Rates by County
US Residents age 15 and over, 1983 - 1992
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Age-Adjusted Silicosis Mortality Rates by County
US Residents age 15 and over, 1983 - 1992
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Exposure, Morbidity and Mortality
• Silicosis Risk
– 1 – 95% of Workers at OSHA PEL Over
– 40 – 45 Years Working Lifetime
– 1 – 7% at ½ NIOSH REL – 0.025 mg/m3
– 20% Increased Risk at 0.04 mg/m3 for 45
Years
– Current Prevalence Unknown
– 300 Deaths Per Year
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SOMA Exposure and EPI Study
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6,000 Cohort, Stone/Gravel/Mining
Long-term – Morbidity (Various Endpoints
Exposure Modeling Precision
Confounding Control
Objectives
– Dose-response Refinement
– Health Effects Non-Silicosis
– Disease Progression
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Overall Silica Sampling Results
Respirable Silica (mg/m3)
Year
No. of
samples
Reported
OEs
Mean
Range
> REL (0.05)
> PEL (~0.1)
2000
335
21 (6%)
0.024
0 – 1.286
36 (11%)
17 (5%)
2001
382
17 (4%)
0.021
0 – 2.038
28 (7%)
13 (3%)
2002
473
11 (2%)
0.013
0 – 0.664
30 (6%)
10 (2%)
2003
1181
51 (4%)
0.017
0 – 1.112
101 (9%)
36 (3%)
2004
1053
52 (4%)
0.024
0 – 5.408
80 (8%)
44 (4%)
2005
1191
34 (3%)
0.018
0 – 1.770
52 (6%)
25 (3%)
2006
1079
55 (5%)
0.019
0 – 1.002
97 (9%)
37 (3%)
Overall
5694
256 (4%)
0.020
0 – 5.408
451 (8%)
194 (3%)
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Percentage Over PEL / TLV
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Silicosis by Division
Silicosis Confirmation by Division 2006
9
8
7
6
Carolina
5
Northwest
4
Southwest
3
2
1
0
1
Division
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Aggregate FEV1 Data
Average FEV1 from Aggegate Data
5
4.5
4
Value
3.5
3
2.5
2
1.5
1
0.5
0
2001
2003
Year
FEV 1
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2005
Biomarkers
• Biological Molecules Used as a Marker of
the Substance or Process of Interest
– Chromosomal aberrations
– Actual substance in blood, urine, etc.
– Metabolite
– Mutations
– Imaging studies (MRI, PET, SPECT)
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“Cytogenetics”
• What is cytogenetics?
• What are cytogenetic “markers” and are they
useful in occupational and environmental
health evaluation?
• Cytogenetics and exposure specificity
• Cytogenetics and the carcinogenisis “cascade”
• Cytogenetics and risk of disease
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Diesel Sampling Information
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[Source:
Royal Academy of Engineering, Nanoscience and nanotechnologies, July 2004]
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Ultrafine vs. Nanoparticles
• Both are particles <100 nm
• Ultrafine – occur either
naturally or unintentionally
– Welding fumes
– Diesel exhaust
– Volcanoes
– WTC dust
• Nanoparticle – engineered
on purpose
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Quantum Effects
• The reduced size of nanoparticles results
in property changes, in comparison to the
bulk material:
– Electrical
– Mechanical
– Chemical
– Optical
TiO2 microspheres from sunscreen
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Nano-Consumer Products
• According to the Andrew Maynard Wilson
Center for Scholars, as of November 2006,
>350 consumer products and/or product lines
contain some nanotechnology
• www.nanotechproject.org/consumerproducts
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Nanoparticles and Health Effects
• Questionable Inflammation in Animals
• No Known Human Health Effects
• Hard to Study in Humans, Multiple
Exposure Parameters
• Extrapolation Form WTC Data?
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Thank You For Your Interest
“We invite you to visit our newly designed
website at www.somaonline.com!”
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