산단사업과 생체지표

1. 산단사업과 생체지표 백 도명

2. 산업단지의 특성 • 중화학공업단지 • 교통: 사람과 물자의 이동 • 연계: 연관공정에 따른 물질이동 및 연결 • 용수: 공정 및 폐수 • 배출: 임해(바다) 및 임산(산)으로 차단 • 지원: 직접 고용, 간접 고용

3. 산업단지에서 화학물질 • 배출원 • 매체이동 • 침적 및 저장 • 분해 및 변환 • 노출 : • 농도(공간밀도), • 속도(시간밀도), • 생체 내 이동 및 분포, 배출 • 초기 건강영향 • 질병

4. internal dose early biological effects biologically significant dose alterations in structure/ function chemical-specific biomarkers of exposure non-specific, but risk-relevant biomarkers of risk biomarkers of individual susceptibility Biomarkers in the assessment of risks from toxic environmental chemicals exposure (environmental concentration) dose-response relationship adverse effects chemical or metabolite in blood or urine e.g. lead in blood e.g. mutations, gene expression, urine α-macroglobulin product of interaction with biologically relevant cellular component e.g. DNA adducts e.g. precancerous cells

5. 생체 내 화학물질측정의 목적 • 측정되는 개인이나 집단의 노출과 건강영향에 대한 평가 • 노출 혹은 건강영향 가능성의 평가 • Are humans exposed to a specific chemical? • Which environmental chemicals are humans exposed to? • 노출 혹은 건강영향 여부의 평가 • What is the level of such exposure? • Does the exposure observed entail a significant health risk? • Is exposure changing over time, and in which direction? • 노출 혹은 건강영향 정도의 평가 • What is the magnitude of such risk? • What attributes modify this risk, at the group or at the individual level? • Is a certain population exposed more than another?

6. 평가목적에 따른 측정의 조건 • 측정되는 개인이나 집단의 대표성 (representativeness) • 측정대상 자체 개인들에 대한 평가 • 측정대상이 대표하는 집단에 대한 평가 • 측정의 의미를 살릴 수 있음 (validity) • 개인 노출/건강영향 지표로서의 의미 • 집단 노출/건강영향 지표로서의 의미

7. 노출 지표의 기본조건 • 노출 가능성(contact)을 파악하기 위하여서는 가능한 노출원의 존재가 알려져야 함 • Exogenous vs endogenous • 혈중 PCB의 의미(?) • 노출 여부(exposure)를 파악하기 위하여서는 노출원, 노출경로가 알려져야 함 • One of the multiple routes • 요중 카드뮴의 의미(?) • 노출 정도(dose)를 파악하기 위하여서는 노출원, 노출경로, 경로별 노출여부 혹은 노출농도가 알려져야 함 • Still cut (snap shot) 과 movie (integrated) • 혈중 VOC의 의미(?)

8. 건강영향 지표의 기본조건 • 건강영향 가능성(harmful)을 파악하기 위하여서는 적어도 biopersistence가 알려져야 함 • 건강영향 여부(toxic)를 파악하기 위하여서는 적어도 health hazard가 알려져야 함 • 건강영향 정도(risk)를 파악하기 위하여서는 dose-response와 toxicokinetics가 알려져야 함

9. Requirements of Biomarkers as Valid Risk Index 분석의 조건 • chemical specificity • measurable in accessible & relevant tissue 해석의 조건 • exhibit exposure-marker relationship • meaningful relationship between levels in surrogate and target tissue • reflect exposure over appropriate time- period • relevance to risk

10. 분석의 조건 • 정확한 측정이 되었다는 조건 • 측정과정 상에 다른 오염물질 오염이 없음 • 측정이 대표성을 가지고 노출평가 및 건강평가에 적절하게 이루어 짐 • 정확한 분석이 이루어진다는 조건 • 분석결과가 재현성이 있음 • 분석결과가 평균적으로 정확한 수준을 반영할 수 있음 • 민감한 분석이 이루어진다는 조건 • 분석시료의 양이 충분함 • 충분한 양의 시료를 바탕으로 분석결과가 적절한 dose-response를 추정할 수 있도록 not-detectable 이상의 결과를 제시할 수 있음

11. 해석의 조건 • Noisy Background • source of variation이 알려져야 함 • Exposure-Marker Relationship • 노출과 marker 간에 (선형적) 상관성이 있어야 함 • Surrogate-Target tissue Relationship • Marker와 표적장기 dose 간에 (선형적) 상관성이 있어야 함 • Time-response Relationship • 시간에 따른 변화와 risk relevance가 알려져야 함

12. S-phenylmercapturic acid [Farmer et al., Chem. Biol. Interact. 153-154 (2005) 97-102] • Sources of Variation, Background Levels

13. Exposure – Marker Relationship Urinary 1-hydroxypyrene as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons (PAH) [Brand & Watson, Ann Occup Hyg.47 (2003) 349-78]

14. linear scale Extrapolation from occupational (high) to environmental (low) levels may underestimaterisk Albumin adducts versus exposure [Qu et al., Res. Rep. Health Eff. Inst. 115 (2003), 1-87] log-scale

15. exposure biom. of exposure effect effect biomarker of effect biomarker of exposure exposure exposure biom. of effect effect effect biom. of exposure biom. of exposure biom. of effect Surrogate versus Target Tissue Relationship • Lifetime • Dose-response • sources of variation, background levels • use in biomarker-based risk assessment

16. Urinary metabolites vs same-day exposure Hemoglobin adducts vs average exposure 1,3-Butadiene • Exposure assessment: • Over a 60-day interval, each worker's personal exposure was • measured 8-10 times • Workplace area concentrations also measured • Study designed to permit different expression times to be considered • for different biomarkers NO CORRELATION BETWEEN BIOMARKERS OF EXPOSURE AND SISTER-CHROMATID EXCHANGES

17. adverse health effects exposure biologically significant dose early biological effects alterations in structure/ function internal dose EXPOSURE WINDOW hours - days months + days - weeks Time-response Relationship

18. modulation of biomarker and disease by chemoprevention case-control studies; prospective studies; chemoprevention/ intervention trials validated biomarker of risk Biomarker validation Validation of analytical methodology (specificity, sensitivity, accuracy, reproducibility) HUMAN STUDIES ANIMAL STUDIES - dose-response - surrogate vs target tissue - dose-response - inter-individual variation - background levels Relatively few biomarkers have been fully validated validated biomarker of exposure Groopman, 1999

19. SCENARIO 1: Biomarkers of exposure for at least one of the following environmental pollutants/matrices/population groups will be measured in all Member States participating in the EU Pilot Project: Methylmercury in scalp hair women in childbearing age Lead in whole blood women and children Cadmium in urine women in childbearing age Cotinine in urine women and children

20. SCENARIO 2: In addition to scenario 1, metabolites of phtalates, PAHs and further biomarkers listed below could be measured preferably by at least 5 Member States, according to national interests and focuses. PHTHALATES in urine [DEHP, DINP and DBP metabolites] PAHs in urine [Pyrene and Phenathrene] BFRs in blood [Decabromophenylether (DBDE), Tetrabromo bisphenol A (TBBPA),] Hexabromocyclododecane PFCs in blood [PFOA, PFOS, PFOSA] OP-Pesticides in urine [Dimethylphosphate (DMP), Diethylphosphate (DEP), Di{m}ethylthiophospahte (D{m}ETP), p-Nitrophenol, etc] Pyrethroids in urine [4-Fluoro-3-phenoxybenzoic acid, cis/trans-3- (2,2)Dichlorovinyl-2,2-dimethylcyclopropane]

21. SCENARIO 3: In addition to scenario 1 and 2, some Member States indicated the inclusion of new biomarker and research activities as prerequisites, a third scenario may include development and research eg. by use of ‘Omics’. This scenario has not been further developed by the IG.

22. 윤리적 조건 • 대상에게 측정의 정확한 의미를 전달할 수 있음 • 의미의 의미 • Not sensitivity specificity • Latency • 대안의 여부 • 그에 따른 동의를 받을 수 있음 • 자신의 행동을 자신이 결정

23. Fully valid informed consent has four components (criteria) 1.     Competence- the person(s) giving consent must be deemed mentally competent to do so. In the case of research on children, the researcher has responsibility for determining whether or not the parent/legal representative’s is in a fit state of mind to give consent.° 2.      Information-sufficient information must be given for the person to make an informed choice. It is through communication and the information sheet that the level of information provided is determined. The information sheet, prepared by the researcher, is assessed by the research ethics committee (REC) although there are few guidelines as to a minimum standard of content. 3.      Understanding-the person giving consent must be considered capable of making a reasoned choice. The researcher obtaining consent must judge the level of understanding of the patient(s). 4.     Voluntary participation-the person giving the consent must do so voluntarily and must recognize that withdrawal from the study is possible at anytime without this affecting care.

24. Informed consent: authenticity of consent • Consent of both parents and children? • What is the age of being knowledgeable/competent for self determination? • Who should ask for consent? • How informed is a consent? (Who should give the information and how, written, video, oral, updates regularly - How to inform children from different ages ?) • How to treat “given consent” in long term follow up studies? • Withdrawal from the study: individual versus societal right • Withdrawal possible at any time? • Destruction of samples and/or data after withdrawal of participants from the study? • Right to know & right not to know • Communication of results when link with health risk is not clear • Communication of individual results or aggregated data? • ....