Risikovurderinger som grunnlag for normer i EU

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1 Risikovurderinger som grunnlag for normer i EU Steinar Øvrebø, Toksikologisk seksjon Statens arbeidsmiljøinstitutt Oslo Grenseverdier - administrativ norm Grenseverdier - administrativ norm Tirsdag 1 april 2003 Lifetime risk values for selected situations Situation Lifetime risk per Extra high risk Smoking (all causes of death) Smoking (cancer only) 8800 High risk Motor vehicle, USA, 1975 (deaths) 1600 Elevated risk Frequent airline passenger (deaths) 730 Cirrhosis of liver, moderate drinker (deaths) 290 Motor accidents, pedestrians, USA, 1975 (d.) 290 Skiing, 40 h per year (deaths) 220 Moderate risk Light drinker, one beer per day (cancer) 150 Drowning deaths, all recreational causes 140 Air pollution, USA benzo(a)pyrene (cancer) 110 Natural background radiation, sea level (cancer) 110 Frequent airline passenger, cosmic rays (cancer) 110 Low risk Home accidents, USA, 1975 (deaths) 88 Cycling (deaths) 75 Diagnostic X-rays, USA (cancer) 75 Very low risk Person living in brick building, additional natural radiation (cancer) Grenseverdier - administrativ norm Grenseverdier - administrativ norm 4 Extremely low `rare-event` risk One transcontinental air flight per year, natural radiation (cancer) 4 From IARC Scientific Publications No. 90 Non-occupational Exposure to Mineral Fibres Grenseverdier - administrativ norm Grenseverdier - administrativ norm 6 1

2 Noen definisjoner innledningsvis Administrative normer, OEL og TLV OEL yrkeseksponeringsgrenser? Historien om OEL stammer fra 1886 (MAK) Norge har en historie fra 1978 og Grenseverdier - administrativ norm Grenseverdier - administrativ norm 8 Første OELs (MAK) - Karl Bernhard Lehman in 1886 Bureau of Mines Technical Paper Sovietunionen hadde liste med 900 stoffer i 1930 ACGIH, modell for mange OEL lister første i Grenseverdier - administrativ norm 9 Norsk OEL historie Arbeidstilsynet benyttet OELs fra ACGIH fra omkring 1950 to 1973 I 1973/74 publiserte Yrkehygienisk Institutt en norsk liste basert på ACGIH verdiene I 1978 Arbeidstilsynet publiserte sin første egne liste Grenseverdier - administrativ norm 10 Administrative normer versus grenseverdier Normene er satt ut fra tekniske, økonomiske og medisinske vurderinger. Selv om normene overholdes, er man derfor ikke sikret at helsemessige skader og ubehag ikke kan oppstå. Juridiske følger av administrative normer Normene er anbefalinger og i seg selv ikke juridisk bindende. Normene blir først juridisk bindende når de forekommer i konkrete pålegg fra Arbeidstilsynet eller i forskrifter utgitt av Arbeidstilsynet Grenseverdier - administrativ norm 11 ACGIH examples of low variability in Europe Substances for which indicative limit values exist due to Commission Directive 91/322/EEC10 mg/m3 Substance CAS* EU Norge Spania Storbritannia Tyskland Sverige Danmark Australia Ungarn USSR Japan Nicotine ,5 0,5 0,5 0,5 0,47-0,5 0,5 - Formic acid ,6 9, ,4 5 STEL 1 9,4 Acetic acid STEL 5 25 Methanol STEL Acetonitrile STEL 10 Picric acid ,1 0,1 0,1 0,1 0,1-0,1-0,1 - Naphthalene STEL 20 Nitrobenzene , Resorcinol Diethylamine Pyridine STEL 5 Carbon dioxide tja9000 Oxalic acid Cyanamide Calcium dihydroxide Disphosphorus pentoxide Disphosphorus pentasulphid Cresols (all isomers) ,5 22 Platinum (metallic) , ,002 0,002 0,002 Lithium hydride ,025 0,025 0,025 0,025 IIb - 0,025 Bromine ,7 0,7 0,7 0,66 0,66 0,7 0,7 Phosphorus pentachloride ,9 0, Nitrogen monoxide Pyrethrum Barium (soluble compounds as Ba) 0,5 0,5 0,5 0,5 0,5 0,5 0,5 Silver (soluble compound as Ag) 0,01 0,01 0,01 0,01 0,01 0,01 0,01 Tin (inorganic compounds as Sn) IIb Grenseverdier - administrativ norm 12 2

3 Worldwide occupational exposure limits (OEL) for formaldehyde in 1994 NIOSH 0.1 C (15 min) World Health Organization (WHO) 0.24 TWA ACGIH (1991) 0.3 C Denmark 0.3 C Germany 0.4 STEL USSR (former) 0.4 TWA Germany 0.5 TWA U.S. Occupational Safety and Health Administration 0.75 TWA (OSHA, 1992)Hungary, Yugoslavia 0.8 TWA Finland, Norway, Sweden 1.0 C ACGIH (1990), AIHA, Australia, Austria, Germany, 1.0 TWA Italy, the Netherlands, Switzerland/OSHA Brazil, Chile 1.6 TWA Bulgaria 0.8 STEL Australia, Belgium, India, Japan, the Netherlands, 2.0 C Venezuela ACGIH (1990), AIHA, Argentina, France, 2.0 STEL the Netherlands, OSHA, United Kingdom Hungary 1.6 STEL Czech Republic, Poland 1.6 TWA Argentina, Mexico, United Kingdom 2.0 TWA People's Republic of China 2.5 TWA Australia 3.0 STEL Rumania 3.2 C Czech Republic 4.1 C Indonesia 5.0 C Egypt, Republic of China 5.0 TWA Note. All limits were obtained from one of the following publications: WHO (1977), Cook (1986), AIHA (1990), ACGIH (1989, 1992). C, ceiling value (maximum instantaneous concentration). STEL, short-term exposure limit (15 min; up to 4 times per day). TWA, time-weighted average (8 h/d). Framgangsmåter for å sette OELs og administrative normer Basert på data fra epidemiologiske undersøkelser, forsøk med mennesker eller dyreforsøk Setter så en grense basert på disse dataene der ingen skader på kort eller lang sikt oppstår - er det mulig? Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm 18 3

4 Hvor farlige er kreftfremkallende stoffer? Eller hva er risikoen ved eksponering for et kreftfremkallende stoff? Grenseverdier - administrativ norm Grenseverdier - administrativ norm 20 Response Rate Observable Response Range Response Rate Unobservable Response Range Extrapolation to low doses variations between 3 models Dose (mg/kg DDT) Dose (mg/kg DDT) The fit of most dose response models to data in the range tested in animal studies is generally similar. However, because of the differences in the assumptions upon which the equations are based, the risk estimates at low doses can vary dramatically between the different models Grenseverdier - administrativ norm Grenseverdier - administrativ norm 22 Multistage model Grenseverdier - administrativ norm Grenseverdier - administrativ norm 24 4

5 Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm Grenseverdier - administrativ norm 28 Begrensninger i beskyttelse ACGIH...a small percentage of workers may experience discomfort... EU...may not provide adequate protection for every individual... Grenser med og uten terskel EU Health based OELs...clear threshold dose below which exposure to the substance in question is not expected to lead to adverse effects... Pragmatic OELs...for some adverse effects (in particular genotoxicity, carcinogenicity and respiratory sensitisation) it may not be possible on present knowledge to define a threshold Grenseverdier - administrativ norm Grenseverdier - administrativ norm 30 5

6 General principles graduation of effects No effects observed Compensatory effects or early effects of dubious significance without adverse health consequences Early health impairment (clear adverse effects) Overt disease, possible death Grenseverdier - administrativ norm 31 Responses to irritants graduation No effects observed; no awareness of exposure Very slight effects; awareness of exposure Slight irritant effects or nuisance (e.g. smell); easily tolerable Significant irritation/nuicance, overt health effects; barely tolerable Serious health effects (e.g. Pulmonary oedema); intolerable Grenseverdier - administrativ norm 32 (1) General procedure for setting OELs Assemble all available data on hazard of the substance Determine whether the database adequate for the setting of an OEL Identify the adverse effects that may arise from exposure to the substance Establish which adverse effect(s) is (are) considered to be crucial in deriving the level of the OEL Identify the relevant studies (in humans or animals) which characterise these key effects. Carefully review the quality of these studies Establish whether the substance acts via a nonthreshold mechanism or whether a conventional (threshold) toxicological model can be used Grenseverdier - administrativ norm 33 (2) General procedure for setting OELs Assess the dose/response data for each key effect. Establish no observed adverse effect levels (NO(A)Els) wherver possible, otherwise establish lowest observed adverse effect levels (LO(A)Els) Decide whether a short term exposure limit (STEL) is required in addition to an 8 hr time weigthed (TWA) limit Establish a numerical value for an 8 hour TWA OEL Establish a numerical value for STEL (if required) Document the entire process such the rationale for the OEL is clear Grenseverdier - administrativ norm 34 Information relevant to the establishment of OELs Information on non-threshold effects Information on long term effects and the effects of repeated exposure by an apropriate route Information on short term (acute) effects (effects of a single exposure) Information of target organ(s) and the nature of the effects Information on the methodology of measurement of airborne levels Grenseverdier - administrativ norm 35 Human and animal data and laboratory studies Individual case reports, studies in human volunteers, cross-sectional studies and cohort and case-control studies Repeated exposure data, single exposure data, routes of exposure and toxicokinetic data Other information Grenseverdier - administrativ norm 36 6

7 120 % of control (viability) Mouse Human Rat Hamster Concentration of paracetamol (mm) from Davis et al. Adv Exp Med Biol 197 (1986) Grenseverdier - administrativ norm Grenseverdier - administrativ norm 38 Developmental toxicity profile of Thalidomide (3) Threshold doses (mg/kg*day oral) O H N O N O O Thalidomide ( ) Developmental toxicity profile of Thalidomide (4) Threshold doses (mg/kg*day oral) Growth. Deadt/ab Malform. Funct. Mouse Rat ca67 Rabbit 50 *25 Hamster ca0.75 Cat 500 Dog Guinea pig a Pig 15 Cyno monkey 10 *10 Rhesus monkey 12 *12 Stump-tailed monkey *5 Bonnet monkey *5 Japanese Monkey *20 Baboon 5 *5 Marmoset 45 * Grenseverdier - administrativ norm 39 Human 0.5 c 0.5 c 1 c 0.5 c Grenseverdier - administrativ norm 40 Styret for arbeidstilsynet Treparts sammensetning Myndigheter representert? Representanter fra arbeidstaker organisasjoner Representanter from arbeidsgiver organisasjoner Grenseverdier - administrativ norm 41 Nye rutiner (1) Documents 1. Identity of the substance 2. OELs Norway and other countries 3. Chemical and Physical Data 4. Toxicological Data and Health effects 5. Use and Exposure 6. Evaluation 7. Recommendation (Conclusion) 8. References Grenseverdier - administrativ norm 42 7

8 Nye rutiner (2) Criteria for priority of substances Norway high OEL relative other countries Missing OEL for important substance New OEL published by EU New Criteria document from NEG Risk evaluation EU New import Documentation about substance Proposal from Institutes, Organisations etc Trades in focus Grenseverdier - administrativ norm 43 New procedures - new routines (3) Warning Collection and preparation of Data Propo sal of Document norm productionand annot ation Hearing Evaluation of hearing Tripartite consultations Time months Board decisions After w Grenseverdier - administrativ norm 44 New procedures - new routines (4) EXPERT GROUP Summary of important studies Dose response associations Critical effect(s) Recommendations Establish their own rules, key document TEAN Grenseverdier - administrativ norm 45 New procedures - new routines (5)??? Still a tripartite system Not fully health based Relative transparent system Weight of health, economy and technical considerations? Grenseverdier - administrativ norm 46 8