OELs and Sensation: Irritation or Odor as basis for an OEL; do's and don't's Dr. Kirsten Sucker MEDICHEM 2016, Basel, 01.09.2016
Irritant-Research: Quality assured limit values for prevention More than 50% of OELs based on avoidance of sensory irritation Ammonia Alcohol Aldehyde Ketone Amine Acids Annoyance Concentration Irritation 2
Target organs: eyes and upper respiratory tract Water solubility high medium low Eyes Nose Larynx Throat Trachea Bronchial tubes Bronchioles Alveoli 3
Konzentration Distinction: odor complaints / sensory irritation OEL Adversity increases with increasing dose odor / annoyance sensory irritation threshold 4
Konzentration Distinction: sensory irritation/ tissue irritation OEL Adversity increases with increasing dose odor/annoyance sensory irritation threshold tissue irritation threshold 5
Konzentration General exposure- / effect-continuum OEL Adversity increases with increasing dose odor/annoyance sensory irritation threshold tissue irritation threshold Applies in principle for humans and animals! 6
Current data situation? Konzentration OEL Adversity increases with increasing dose odor/annoyance sensory irritation threshold tissue irritation threshold Human data (NOEC human ) Animal data (NOAEC animal ) 7
Konzentration Information content of the data? OEL Adversity increases with increasing dose odor/annoyance sensory irritation threshold tissue irritation threshold Acute / low exposure Adaptive / reversible effects Chronic / high exposure Adverse effects 8
Konzentration Forced solution - Extrapolation animal human! OEL Adversity increases with increasing dose odor/annoyance sensory irritation threshold tissue irritation threshold Extrapolation factor (Interspecies) 9
Health-based exposure limits Joint Working Group Limit values derivation for substances with local effects MAK Commission of the German research Foundation (DFG) & Subcommittee III of the Committee for Hazardous Substances (AGS) of the Federal Ministry of Labor and Social Affairs 2010 2014 Research advisory panel Irritative Effects Accident insurance institutions, MAK, AGS since 2003 10
Derivation of an interspecies factor (upper respiratory tract) Comparative analysis of substances with different data quality Good and complete» Human NOAEC & animal NOAEC chronic» Ethyl acrylate» Formaldehyde» Methyl metacrylate Good, but partly incomplete» Human NOAEC & Tier NOAEC sub-chronic» Acetaldehyde» Ammonia» Hydrogen sulfide» n-butyl acetate» 2-Ethylhexanol Incomplete» n-butylamine» Chlorine» Methyl acetate» Vinyl acetate 11
Concentration/log ppm Generation of quality-assured human data: ethyl acrylate MAK 1986: Observations in humans Additionally to irritation effects, prolonged exposure to 50-75 ppm leads to drowsiness, headache and nausea. 50 ppm derived as LOEL for irritation effects in humans 5 ppm set as MAK-value based on animal data 4 2 0-2 -4-6 95%-Percentile Irritation threshold MAK-value Odor threshold 5%-Percentile ethyl acrylate 12
Gold standard : Controlled human exposure studies ethyl acrylate - exposure steps 1-10 ppm 5 ppm 0,5-5 ppm 2,5 ppm 0 ppm 13
MAK 2015: limit value = 2 ppm based on human data Results Experience: intensive odor ( disgusting ) und subj. strong eye irritation Significantly increased eye-blink frequencies (about 30 %) at peak concentrations of 10 ppm (1-10 ppm) Physiology: increased eye-blink frequency (obj. eye irritation); increased Substance P in nasal lavage (neurogenic inflammation) Behavior: increased reaction time and error rate in performance tests (distraction effect) ethyl acrylate - exposure steps 14
Procedure suggested for setting an OEL from data regarding sensory irritation Assessment based on all available toxicological & epidemiological data Yes Substance with local effect in the upper respiratory tract? No OEL setting outside the scope of the manuscript Human data available? No Animal data available? No Case by case decision Yes Yes Limit setting possible Proposed default factor ief = 3 15
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since 2014 for about ca. 60% of the hazardous substances (MAK and AGS) limit values were derived according to the new concept 17
Remaining open issues? Intra-species Factor human-human e.g. non-allergic vs. allergic persons, tidal volume / physical activity, gender- and age differences 18
Remaining open issues? Intra-species Factor human-human e.g. non-allergic vs. allergic persons, tidal volume / physical activity, gender- and age differences Time-Factor e.g. Short vs. long term exposure, acute vs. chronic effects 19
Odor & limit value setting OSHA (1989) regulated three chemicals based on adverse odor effects» Isopropylether» Phenylether» Vinyltoluol based on worker complaints and the assumption that these substances can cause distraction effects creating safety hazards 20
Distinction: odor complaints / sensory irritation OEL Adversity increases with increasing dose odor / annoyance sensory irritation threshold 21
Occasions for indoor investigations Not known 7% Rest 5 % Health complaints 37% Suspicion of exposure 12% Prevention 17% Odors 22% Arbeitsgemeinschaft ökologischer Forschungsinstitute (AGÖF) e.v. (www.agoef.de) 22
Guide values for indoor air Area of precaution RW I Precaution RW II Effect-related Risk area No adverse health impacts even at life-long exposure Exposure that is undesirable for health reasons could pose a health hazard No action required Target value during clean-up efforts Need for action for the sake of precaution requires immediate action 23
Naphthalene: comparison of OEL & RW I / RW II Parameter or factor OEL-Derivation (2010) RW-Setting (2013) Point of departure: nasal epithelia inflammation Inter-species variability (rat human) Intra-species variability ( average human sensitive human) Time extrapolation (short animal study long-term exposure human) Exposure time/week 1,6 mg/m³ (rat acute (2010)) NOAEC 1 (human not more sensitive than rat) 5 mg/m³ (rat sub-chronic (2012)) NOAEC 3 (employee) 10 (general population) 1 (no increased effect with time) 1 (Concentration more relevant than dose) 1 2 (sub-chronic chronic) 5,6 (6 h/d, 5 d/w vs. 24 h/d, 7 d/w) Particularly sensitive population --- not considered 2 (Children: insufficient data) Most sensitive species in animal study --- not considered 2 (F344-rat less sensitive than SD-rat) Total factor 3 448 Limit value OEL: 0,53 mg/m³ (2010) RWI: 0,01 mg/m³; RWII: 0,03 mg/m³ (2013) 24
Exposure-Response Model of Odor Annoyance socioeconomic factors other environmental stressors Context related influence factors Behavioural changes Odour impact Odor Perception perception unacceptable Annoyance annoyance % affected persons Physical with and impairments emotional complaints of well-being Person related influence factor Complaints sociodemographic characteristics environmental worry coping health 25
Do s and don'ts in OEL setting for odors and irritants» Generate quality assured data with controlled human exposure studies (gold standard)» Use scientific based extrapolation factors (e.g. ief 3 for animal data from chronic inhalation studies)» Separate odor complaints and sensory irritation effects» Take odor effects as additional information (e.g. adaptation as adverse effect, if odor is a warning signal before irritation occurs)» Consider psycho-social confounding factors (age, gender, sensitivity, stress, etc.) 26
Competence Network Irritant- Research 27