Risikovurderinger som grunnlag for normer i EU Steinar Øvrebø, Toksikologisk seksjon Statens arbeidsmiljøinstitutt Oslo 01.04.03 Grenseverdier - administrativ norm 1 01.04.03 Grenseverdier - administrativ norm 2 2003 Tirsdag 1 april 2003 Lifetime risk values for selected situations Situation Lifetime risk per 100 000 Extra high risk Smoking (all causes of death) 21900 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) 35 01.04.03 Grenseverdier - administrativ norm 3 01.04.03 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 1989 01.04.03 Grenseverdier - administrativ norm 5 01.04.03 Grenseverdier - administrativ norm 6 1
Noen definisjoner innledningsvis Administrative normer, OEL og TLV OEL yrkeseksponeringsgrenser? Historien om OEL stammer fra 1886 (MAK) Norge har en historie fra 1978 og 1950 01.04.03 Grenseverdier - administrativ norm 7 01.04.03 Grenseverdier - administrativ norm 8 Første OELs (MAK) - Karl Bernhard Lehman in 1886 Bureau of Mines Technical Paper -1921 Sovietunionen hadde liste med 900 stoffer i 1930 ACGIH, modell for mange OEL lister første i 1946 01.04.03 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 01.04.03 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. 01.04.03 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 54-11-5 0,5 0,5 0,5 0,5 0,47-0,5 0,5 - Formic acid 64-18-6 9 9 9 9,6 9,5 5 9 9,4 5 STEL 1 9,4 Acetic acid 64-19-7 25 25 25 25 25 13 25 25 10 STEL 5 25 Methanol 67-56-1 260 130 266 266 270 250 260 262 50 STEL 5 260 Acetonitrile 75-05-8 70 50 68 68 68 50 70 70 50 STEL 10 Picric acid 88-89-1 0,1 0,1 0,1 0,1 0,1-0,1-0,1 - Naphthalene 91-20-3 50 50 53 - - - 50 52 40 STEL 20 Nitrobenzene 98-95-3 5 5 5 5,1-5 5 5 3 Resorcinol 108-46-3 45 45 46 46-45 45 45 45 Diethylamine 109-89-7 30 30 30 30 15 30 15 30 30 Pyridine 110-86-1 15 15 16 16 16 7 15 16 5 STEL 5 Carbon dioxide 124-38-9 9000 9000 9150 9150 9100 9000 9000 9000 tja9000 Oxalic acid 144-62-7 1 1 1 1-1 1 Cyanamide 420-04-2 2 2 2 2-2 2 Calcium dihydroxide 1305-62-0 5 5 5 5 - - 5 Disphosphorus pentoxide 1314-56-3 1 1 1 2 1 1 1 Disphosphorus pentasulphid1314-80-3 1 1 1 1 1-1 Cresols (all isomers) 1319-77-3 22 22 22 22 22 4,5 22 Platinum (metallic) 7440-06-4 1 0,002 1 5 0,002 0,002 0,002 Lithium hydride 7580-67-8 0,025 0,025 0,025 0,025 IIb - 0,025 Bromine 7726-95-6 0,7 0,7 0,7 0,66 0,66 0,7 0,7 Phosphorus pentachloride 10026-156 1 1 0,9 0,87 1-1 Nitrogen monoxide 10102-43-9 30 30 31 31-30 30 Pyrethrum 8003-34-7 5 5 5 5 5-5 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) 2 2 2 2 IIb - 2 01.04.03 Grenseverdier - administrativ norm 12 2
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? 01.04.03 Grenseverdier - administrativ norm 13 01.04.03 Grenseverdier - administrativ norm 14 http://sis.nlm.nih.gov/toxtutor/tox1/index.html 01.04.03 Grenseverdier - administrativ norm 15 01.04.03 Grenseverdier - administrativ norm 16 01.04.03 Grenseverdier - administrativ norm 17 01.04.03 Grenseverdier - administrativ norm 18 3
Hvor farlige er kreftfremkallende stoffer? Eller hva er risikoen ved eksponering for et kreftfremkallende stoff? 01.04.03 Grenseverdier - administrativ norm 19 01.04.03 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. 01.04.03 Grenseverdier - administrativ norm 21 01.04.03 Grenseverdier - administrativ norm 22 Multistage model 01.04.03 Grenseverdier - administrativ norm 23 01.04.03 Grenseverdier - administrativ norm 24 4
01.04.03 Grenseverdier - administrativ norm 25 01.04.03 Grenseverdier - administrativ norm 26 01.04.03 Grenseverdier - administrativ norm 27 01.04.03 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.. http://sis.nlm.nih.gov/toxtutor/tox1/index.html 01.04.03 Grenseverdier - administrativ norm 29 01.04.03 Grenseverdier - administrativ norm 30 5
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 01.04.03 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 01.04.03 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 01.04.03 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 01.04.03 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 01.04.03 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 01.04.03 Grenseverdier - administrativ norm 36 6
120 % of control (viability) 100 80 60 40 20 Mouse Human Rat Hamster 0 0 10 20 30 40 50 Concentration of paracetamol (mm) from Davis et al. Adv Exp Med Biol 197 (1986) 993-1003 01.04.03 Grenseverdier - administrativ norm 37 01.04.03 Grenseverdier - administrativ norm 38 Developmental toxicity profile of Thalidomide (3) Threshold doses (mg/kg*day oral) O H N O N O O Thalidomide (50-35-1) Developmental toxicity profile of Thalidomide (4) Threshold doses (mg/kg*day oral) Growth. Deadt/ab Malform. Funct. Mouse 50 62 62 Rat 50 50 ca67 Rabbit 50 *25 Hamster ca0.75 Cat 500 Dog 200 30 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 *45 01.04.03 Grenseverdier - administrativ norm 39 Human 0.5 c 0.5 c 1 c 0.5 c 01.04.03 Grenseverdier - administrativ norm 40 Styret for arbeidstilsynet Treparts sammensetning Myndigheter representert? Representanter fra arbeidstaker organisasjoner Representanter from arbeidsgiver organisasjoner 01.04.03 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 01.04.03 Grenseverdier - administrativ norm 42 7
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 01.04.03 Grenseverdier - administrativ norm 43 New procedures - new routines (3) 1-2 3-4 5-6 Warning Collection and preparation of Data Propo sal of Document norm productionand annot ation 9-10 13-14 17-18 21-22 7-8 11-12 15-16 19-20 Hearing Evaluation of hearing Tripartite consultations 23-24 Time months Board decisions After w. 01.04.03 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 01.04.03 TEAN 01.04.03 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