RIFMs RESPIRATORY PROGRAM

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RIFMs RESPIRATORY PROGRAM CHEMICAL
RESPIRATORY ALLERGYFairleigh Dickinson
UniversityMasters Program in Cosmetic
SciencePerfumeryHackensack, NJ 24 October
2006

• Daniel Isola
• Program Manager, Respiratory Program
• The Research Institute for Fragrance Materials,
  Inc. (RIFM)
• The International Scientific Authority for the
  Safe Use of Fragrance Materials
• Woodcliff Lake, NJ USA
• disola_at_rifm.org

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RIFM SCIENTIFIC PROGRAM
PUBLICATIONS
DATABASE
RESEARCH TESTING

• FFIDS
• Group Summaries
• Fragrance Material Reviews
• ScientificPublications

• 4,557 Materials
• 2,600 Fragrance Materials
• gt 48,000 Lit. References
• gt 95,00 Studies
• Human Health
• Environmental

Respiratory Program
Fragrance Allergy
Human Health Methodology
Environmental Methodology
Group Health/Environmental Testing
Use Level Testing
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THE RIFM RESPIRATORY PROGRAM

• Concerns regarding inhaled fragrances on chemical
  intolerance (CI), asthma, respiratory allergy,
  indoor air quality, fragrance free zones, sensory
  responses
• Strategy
• Quantitate human exposures
• Assess safety in use
• Address critical issues
• Investigate models
• Collaborate
• Communicate

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RESPIRATORY PROGRAM WORKING GROUP

• Greg Adamson Quest International
• Rahman Ansari Quest International
• Joel Burdick Bath Body Works
• Kathleen Cater Dial Corporation
• Eileen Hedrick Belmay
• Thomas Re LOréal
• Kevin Renskers Takasago
• Kenneth Schrankel IFF
• Glenn Sipes University of Arizona REXPAN
• William Troy Firmenich
• Frederick Joachim SC Johnson

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FRAGRANCE MATERIAL SELECTION CRITERIA

• High volume of use
• Up to 5,000 metric tons/yr
• Range of volatilities
• 0.001-1.2 mm Hg _at_ 200C
• Different chemical classes
• Aldehydes, cyclic terpenes, esters, ketones,
  phenols
• Associated with toxicity, directly or indirectly
• Skin/lung irritant, skin sensitizer

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SELECTED FRAGRANCE MATERIALS

• Benzyl acetate (BA)
• Eugenol
• a-Hexylcinnamaldehyde (HCA)
• HHCB
• Hydroxycitronellal (HO-C)
• ?-Ionone (ß-I)
• d-Limonene (d-L)
• Linalool
• Methyl dihydrojasmonate (MDJ)
• 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclo
  penta-?-2-benzopyran

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AEROSOL STUDY

• Formulation 0.06 each of the 9 fragrance
  materials, 0.20 BHA 0.50 emulsifier, 29.00
  propellant, 69.76 water
• Simulated exp. space 8 ft x 8 ft x 8 ft, 0.6 air
  changes/hr
• Sampling locations Adult/child breathing zone
  (5/1.5ft height, 3 ft from spray origin)
• 5 second spray Air sampled at various time
  intervals from start of spray to 125 minutes. Av.
  max particle conc. were 412 (TS) and 548 (CS)
  particles/cm3. Spray rate 1g/sec.
• More than 90 of airborne particles were
  respirable (lt2.5 µm), 60-70 were sub-micron
  (lt1.0 µm)

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DATA SUMMARY (simulated aerosol exposure)
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HEATED OIL AIR FRESHENER STUDY

• 21 g test solution, 8.9 each, 9 test fragrances
  total fragrance percentage 80.1, 19.9 vehicle
  (dipropylene glycol monomethyl ether),
  Temperature 600 C
• Simulated exp. space 8.2 ft x 4.9 ft x 4.9 ft, 1
  air change per hour
• Approx. 2-3 g released after 701 hrs
• Some fragrance remained in the wick
• Av individual fragrance concentration in air
  depended upon its volatility
• Total fragrance concentration after 1 hr was 1768
  µg/m3 after 701 hrs it was 137. Data fit model
  of a decaying source

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PREDICTED ROOM CONCENTRATIONS (µg/m3)
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FINE FRAGRANCE EXPOSURE

• Same 9 surrogate materials at 2.2 in vehicle
  (80 ethanol/20 water)
• Simulated exposure space 14.5m3
• Two pump actuations at 3 head and neck sites on
  manikin from 3.5 inches 0.1g released with each
  actuation
• Sampling at adult and child heights and at 0, 1.5
  and 5.0 ft from source
• Three families of conc. curves observed
• Particulate fragrance material exposure at a
  maximum during the first minute post-application
  Particles lt1.0 µm
• Major exposure from vapor phase

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FRAGRANCE MATERIAL CONCENTRATIONS 0 FT.
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FRAGRANCE MATERIAL CONCENTRATIONS 1.5 FT.
Airborne Concentration at 5' Height and 1.5'
Distance
0
50
100
150
200
250
300
350
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PEAK FINE FRAGRANCE CONCENTRATIONS
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FRAGRANCE EXPOSUREPeak Concentrations (ug/m3)
Chamber 1759 at 1 hrRoom 557 at 1 hr 956 at
3 hr
Adult 2165 at 1 min Child 1753 at 6 min
Adult 1030 at 10 min, 0 ft 1042 at
5 min, 1.5 ft 881 at 10 min, 5
ft Child 711 at 5 min, 0 ft 2065
at 5 min, 1.5 ft 681 at 10 min, 5 ft
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DATA SIGNIFICANCE

• Demonstrated exposure varies with product form
  and material volatility
• Found exposures differ between child and adult
  breathing zones
• Data reproducible physiological significance to
  be assessed
• Particle mass size data
• Pressurized aerosol 978 µg/m3, lt2.5 µm
  Fine
  fragrance 74 µg/m3, 0.5 to lt5.0 µm
• ACGIH Guidelines for unclassified particles
  10
  mg/m3 inhalable, 3 mg/m3 respirable
• Model exposure assessments unique to product form
• Data for design of clinical studies to assess
  potential health effects

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SIMULATED EXPOSURE STUDIESSummary

• Pressurized Aerosol Air Freshener
• Manuscript accepted for publication in
  Environmental Science and Technology
• Heated Oil Plug-In Air Freshener
• Study complete
• Manuscript submitted to Environmental Science and
  Technology. Undergoing rewrite
• Fine Fragrance
• Manuscript in preparation for submission to
  Environmental Science and Technology

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CLINICAL STUDY (in progress)

• Based on simulated exposure study data
• Protocol approved by an advisory panel
• Asthma/allergy or irritation
• Mild/moderate asthmatics
• Pilot study followed, if necessary, by a
  definitive study
• Physiological, sensory, biochemical endpoints
• FEV1, nasal lavage, exhaled NO, biomarkers,
  induced sputum, immune and inflammatory cells

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CLINICAL STUDY ADVISORY PANEL

• William S. Cain, PhD.University of
  CaliforniaSan Diego School of Medicine
• Professor, Department of Surgery (Otolaryngology)
• Pamela Dalton, PhD.
  University of
  Pennsylvania
  
  Monell Chemical Senses Center
• Experimental Psychology
• Mark J. Utell, MD.
  
  University of Rochester Medical Center
• Professor of Medicine and Environmental Medicine
• Director, Pulmonary/Critical Care and
  Occupational Medicine

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INDIVIDUAL SUBJECT/FM

• Normal Subjects, 15 min Exposure

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PREDICTIVE VALUE

• Indoor air quality
• Assess similar materials based on
  physical-chemical characteristics
• Understand indoor air chemistry and breathing
  zone (near head) chemistry
• i.e. what you breathe in may not be what you
  think it is

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b-IONONE OH/O3 PRODUCTS (Preliminary, unpublished
data, Forester Wells, NIOSH)
Fragrance additive (violets)
O3
OH
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LINALOOL

• C10H18O
• Common terpenoid alcohol (floral - Lillies of the
  Valley)
• Pvp 21 pa (25 oC) odor threshold 1 ppm
• Contained in 21 of 31 products (Cooper et al.,
  1992)
• Soaps, colognes, perfumes
• 51 to 75 of fragrance
• Major oxidation product MVT (0.85 molar yield)
• 5-methyl-5-vinyl-tetrahydrofuran-2-ol
• formaldehyde, acetaldehyde, acetone
• hydroxyl-dialdehydes, hydroxyl-carboxylic acids,
  4-oxopentanal

linalool
d-limonene
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PARTICLE SIZE DISTRIBUTION BY COUNT - AEROSOL
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PARTICLE SIZE DISTRIBUTION BY MASS - AEROSOL
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Numbers and Surface Area of Particles of Unit
Density of Different Sizes at a Mass
Concentration of 10 µg/m3 Particle Diameter
Particle Number Particle Surface Area µm
1/cm3 µm2/cm3 0.02
2,400,000 3016 0.1 19,100
600 0.5 153 120 1.0
19 60 2.5 1.2
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WHATS IN YOUR BREATHING ZONE?

• Your head

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GENETIC POLYMORPHISM STUDY (K. Binkley, MD. U of
Toronto)

• Shared genetically determined predisposition
• Prevalence of panic disorder-associated receptor
  allele in chemically intolerant (CI) subjects
• DNA analysis of CI subjects
• Polymerase chain reaction technique
• Presence of panic disorder-associated receptor
  alleles (cholecystokinin-B CCK-B)
• Other polymorphisms
• Elucidate genetic basis for physiologic syndromes
  with a psychological component

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CHEMICAL RESPIRATORY ALLERGY

• Allergy a hypersensitive reaction initiated by
  immunologic mechanisms
• Respiratory Allergy a hypersensitive reaction
  in the respiratory tract after exposure to an
  allergen which initiated an immunologic reaction
• Occupational asthma variable airflow limitation
  and/or hyper-responsiveness and/or inflammation
  attributable to the workplace.
• Asthma (NB Hypersensitivity often characterized
  as asthma)
• Allergic or nonallergic
• Th1/Th2, Ig mediated
• Respiratory tract includes nasal and associated
  structures, airways, and lung cells

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CHEMICAL RESPIRATORY ALLERGY

• A chronic lung disease characterized by
• Airway inflammation where many cells and cellular
  elements play a role
• Airway obstruction or narrowing usually
  reversible, either spontaneously or with
  treatment
• Airway hyper-responsiveness to a variety of
  stimuli
• Effects different areas of the lung
• Consistent with immune mechanisms

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CHEMICAL RESPIRATORY ALLERGY

• Latency and Memory
• Type I (immediate) or Type IV (delayed)
• Clinical picture symptomless changes
• Specificity and Sensitivity
• Response to one allergen and not another effects
  only a portion of the exposed population
• Different from respiratory irritation (reaction
  to injury, transient, no immune response)
• Reactive Airways Dysfunction Syndrome (RADS)
  features of asthma and chemical sensitivity
• Extrinsic Allergic Alveolitis (EAA)
• Chronic Obstructive Pulmonary Disease (COPD)

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CA Herrick and K Bottomly. 2003 May3(5)405-12
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WHAT MAKES A CHEMICAL AN ALLERGEN?

• Inherent nature of the chemical
• Penetrates a barrier
• Bind/complex with larger molecule
• Chemical interacts with the immune system
• Immune system responds to the chemical

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Nose Lung Interaction (BUSSE, W.W., 2003. WAO,
Vancouver)
Allergen
Nose
Rhinitis
Allergic Reaction
Lung
Asthma
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NONALLERGIC ASTHMA
Th lymphocytes
Cytokine (IL-5)
Eosinophil activation (IL-4, IL-5 release)
Inflammation (similar to allergic asthma)
Bronchial hyperresponsiveness
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ALLERGIC ASTHMA
Allergen
Th lymphocytes
Cytokines (e.g. IL-4, IL-13)
B-cells
Plasma cells
Antibodies (IgE)
Receptor binding
Mast cells
Eosinophils
Mediators (e.g. histamine)
Inflammation
Airway hyperresponsivenessAirflow obstruction
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MODEL DEVELOPMENT

• What is necessary information
• Routes of exposure dermal, inhalation
• Negative controls
• Sensitivity specificity
• Mechanisms of actions necessary for appropriate
  risk/hazard assessment
• IgE mediated
• Th1, Th2 mediated
• Other

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MODEL VALIDATION

• Identify potential respiratory allergens
• Cellular vs physiological changes
• Th1, Th2 bias
• Dermal or inhalation routes of exposure
• Asthma/respiratory allergy/respiratory irritation
• LLNA cytokine profiling
• Pulmonary lymph nodes
• Inhalation challenge, Con. A re-stimualtion

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Epicutaneous Inhalation Antibodies IgG1,
IgE IgG1, IgE, IgG2a Bronchoal
veolar lavage (BAL) ? eosinophils ?eosinophils
Lung histology perivascular perivascular
peribronchiolar peribronchiolar ?
eosinophils ? eosinophils Mucus secretion
(PAS staining) Lung
cytokines IL-4, IL-5, IL-13 IL-4, IL-5, IL-13
IFN-?
Th2
Th2 Th1
Overall response
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ISSUES

• Both the skin and airway represent potential
  sites for sensitization to environmental
  antigens.
• Sensitization at either site can result in
  subsequent airway inflammatory responses with
  characteristics of asthma upon re-exposure to
  inhaled antigen.
• The skin could be an important site for
  sensitization aeroallergens, contributing to
  future airway disease.

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CYTOKINE PROFILES

• Promising approach
• Mitogen vs. non-mitogen stimulated lymph node
  cultures different results? (Mitogens stimulate
  lymphocyte transformation)
• Dose dependent? Time dependent?
• Mix of Th1 and Th2 cytokines using classic
  contact and respiratory allergens
• Does not always correlate with total IgE

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WHAT INDUSTRY NEEDS

• Models that correctly identify chemicals that
  cause respiratory allergy and consistent with
  clinical experience
• Tiered approach for assessment to reduce in vivo
  testing
• Prefer in vitro approaches using cell based
  systems
• QSAR
• Robust In vivo models that do not drive more
  testing
• Need potency risk assessment
• The Science Must Be Right

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WORKSHOP

• Chemical Respiratory Allergy Workshop (July 06,
  London. RIFM sponsored)
• International panel of experts
• Define chemical respiratory allergens/allergy
• Can contact allergens cause respiratory
  sensitization
• Animal models
• Manuscript in preparation

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ACKNOWEDGEMENTS

• Dr. Josje Arts, TNO, Netherlands
• Dr. David Basketter, Unilever, UK
• Dr. David Bernstein, University of Cincinnati
• Dr. Richard Corsi, University of Texas at Austin
• Dr. Paul Cullinan, Brompton Hospital, UK
• Dr. Rebecca Dearman, Syngenta/CTL, UK
• Dr. Christina Herrick, Yale University Medical
  Center
• Dr. Meryl Karol, University of Pittsburgh
• Dr. Frieke Kuper, TNO, Netherlands
• Dr. Kathy Sarlo, PG, USA
• Dr. Mark Utell, University of Rochester Medical
  Center
• Drs. C.D. Forester J.R. Wells, NIOSH,
  Morgantown, WV

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OTHER ISSUES

• Typical asthma, exercise asthma, or
• Respiratory sensitization vs respiratory
  irritation
• Upper airways effects on lower airways
• Olfaction effects, trigeminal nerve
• Neural pathways
• Dermal component

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IN THE FUTURE

• Animal and in vitro models for respiratory
  sensitization and irritation
• RD50 studies, respiratory sensitization studies
• Meet the needs of the Group Summaries
• Inhalation studies with dermal systemic
  endpoints
• Additional simulated exposure clinical studies
• Chemical interactions in the air exhaled air
  analysis
• Structural Activity Relationships (SAR)
• Workshops and seminars

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THANK YOU!

• Daniel Isola
• Program Manager, Respiratory Safety
• Research Institute for Fragrance Materials, Inc.
  (RIFM)
• 50 Tice Boulevard, 3rd floor
• Woodcliff Lake, NJ 07677
• phone [phone], ext. 113
• fax [phone]
• E-mail disola_at_rifm.org