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Sang- Hee Jeong , DVM, PhD (e-mail: jeongsh@hoseo) Department of Applied BioToxicology

Human Health Risk Assessment of Bisphenol -A (WHO/FAO 안전성 평가 동향 ). Sang- Hee Jeong , DVM, PhD (e-mail: jeongsh@hoseo.edu) Department of Applied BioToxicology GLP Research Center Hoseo University  165, Sechul , Baebang , Asan city, 336-795, Korea. Overview.

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Sang- Hee Jeong , DVM, PhD (e-mail: jeongsh@hoseo) Department of Applied BioToxicology

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  1. Human Health Risk Assessment of Bisphenol-A (WHO/FAO 안전성 평가 동향) Sang-HeeJeong, DVM, PhD (e-mail: jeongsh@hoseo.edu) Department of Applied BioToxicology GLP Research Center Hoseo University  165, Sechul, Baebang, Asan city, 336-795, Korea

  2. Overview 1) Risk assessment procedure 2) Viewpointsof stakeholders 3) Point of departure for risk assessment 4) Human health impact 5) Health based guidance level 6) Recommendations 7) Gap of knowledge 8) Risk management options based on the recommendations of risk assessment (Alternative materials)

  3. FAO/WHO Expert Meeting for Risk Assessment of Bisphenol A (BPA) 2010. 11.1-11.5, Canada Ottawa 31 Experts (Toxicologists, Analytical chemistry) 목적 - BPA의 저용량 위해성 평가 - 생식독성, 신경계 영향, 행동발달에 대한 영향 - 대체물질 검토

  4. 1) Risk Assessment Process 위해성 확인 - 물리화학적 특성, 독성 (NOAEL), 체내동태 Hazard Identification 위해성특성규명 - 용량반응관계 - 종간차이, 개체차이 - 일일섭취내용량(TDI) Hazard characterization 노출평가 - 식품중노출원 - 일일섭취추정량(EDI) Exposure Assessment 위해도 특성화 - 고도민감군확인 - TDI/EDI - 관리방안권고 Risk Characterization

  5. 위해평가를 위한 자료 독성 평가 • Physicochemical properties • Usage status • Biological evaluation - Absorption/Distribution/metabolism/ Excretion - Biotransformation • Toxicity - Acute, short & long term toxicity test - Tumorigenicity - Genotoxicity - Reproductive toxicity - Developmental toxicity - Neurobehavoiral effects - Hormonal effects - Other toxicity • Special impacts - Human epidemiology - Biomonitoring - Metabolic disorders 노출평가 • Chemical properties • Toxicokinetics • Depletion • Analytical methods • Monitoring data • Food consumption • Estimated daily intake

  6. 평가를 위한 자료 채택

  7. 동물에서의 영향 확인 재현성이 있는가? Yes No 관련 기전이 알려져 있거나 설명가능한가? No Yes (Via other pathway) Yes (Via known Pathway-ER) 사람에서의 영향을 입증하는 자료가 있는가? No Yes 사람에서의 노출수준이 위해수준인가? Yes No 인체위해 우려수준임 인체위해 우려수준 아님 인체위해성 우려 여부 결정

  8. Viewpointsof Stakeholders 2010. 11.1., Canada Ottawa Stakeholders (25 organizations and companies) - Food & Consumer Products of Canada - European Federation of Bottled Water - Abbott Laboratories - The Dow Chemical company and etc. Main concerns raised - BPA 의 저용량 영향, 민감군, 민감시기 평가 필요 - 대체물질에 대하여 유통기간 변화에 대한 평가 필요 - 대체물질 대한 충분한 수준의 안전성 평가 필요 (glass, polypropylene, polyethersulfone, polyethylene terphthlate, PVC, polyamide, tritan copolymer and etc)

  9. Bisphenol A (BPA)- Pointof Departure • Synthetic monomer used in production of polycarbonate plastics and epoxy resins - 우유병, 식품용기, 내부코팅물질 • Displays estrogenic activity through activation of ERs • Pleiotropiceffects - estradiol과 비교시 30% 만이 공통 gene 발현 • Estrogenicpotency - in vitro (1,000배 낮음) - invivo (1,000-10,000 배낮음)

  10. Metabolism and Toxicokinetics Extensively absorbed from GIT - 용해도 (0.5-1.3 mmol/L), logko/w (2.2-3.4) Phase II metabolism in the gut and liver - glucuronide conjugates는 ER에결합능 없음 Interspecies difference (종간차이) - 설치류: bioavailability(2.8%), billiary excretion, enterohepatic recirculation, fecal excretion (반감기: 20-80 hrs) - 영장류 또는 사람: bioavailability(0.9-1.9%), excrete conjugated forms of BPA in urine in 6 hrs (반감기: < 2 h) Limited lactational transfer - 수유중인 신생자는 모체보다 300-500배 낮음 Placental transfer only for aglycone BPA - 태아의 BPA 수준은모체의 실질장기중 수준과 유사

  11. Biological Activities of BPA (Non-monotonic dose response curve) Blindsided by hormonally-active compounds → Low dose effects

  12. BPA exposure to human body • Analytical methods - Validated according to IUPAC guidelines - MS- or MS/MS-based isotope dilution methods • Sources and occurrence of BPA - PC plastics, epoxy resins (water bottles, food containers) - PVC, thermal paper • Migration of BPA from PC (the worst-case realistic uses) - 플라스틱병에끓는물을 붓고 → 분유를 넣고 → 식힌다 - 플라스틱 용기에 음식을 넣고 95 ℃ 에서 30분간 데움

  13. Biomonitoring of BPA in human body and presumed daily exposure a Calculation based on a urine volume 44 ml/kg bw b Calculation based on a urine volume 159 ml/kg bw

  14. BPA exposure to human body

  15. BPA exposure to human body Worst case: daily consumption of 100% packaged food Best case: daily consumption of 25% packaged food

  16. Epidemiology • 일부 인체역학연구에서 위해가능성을 보이는 결과가 발표되었으나 연구설계 및 해석에 있어 아직은 제한적임 (추가적인 연구가 필요함) - Cross-sectional design, 단순 BPA 분석 • Urinary BPA correlates with sperm quality - fewer sperm, fewer live sperm, problems in swimming • BPA alters age of pubertal onset • Prenatal BPA exposure, especially during early pregnancy → later development of externalizing behaviors (aggression, hyperactivity in female children) • BPA exposure → CVD, diabetes

  17. Biological Activities of BPA - 설치류 시험에서 발암성에 대한 근거 미흡 - BPA diglycidyl ether: 인체 비발암물질 (Group 3 by IARC) Epigenetic mechanism for cancer progression Exposure to BPA in utero results in alteration of CpGmethylation - Hoxa 10 gene: increase of binding Erα both in neurons and during cancer progression - PDE4D4 gene: increased susceptibility to prostate cancer with aging

  18. Cellular brain sex differences (일관된 연구결과는 부족) • BPA on the number of neurons in the anteroventralperiventricularpreoptic area that express tyrosine hydroxylase (TH) → eliminate the sexual dimorphism seen in control males and females (BPA exposed female offspring → a decrease of TH to control male levels) • Developmental exposure to BPA permanently alters activity levels of TH → eliminate the sexual dimorphism observed in unexposed animals)

  19. Current TDI = 50㎍/kg bw/day But, are there low dose effects? Not yet clear to be evaluated Toxicity Carcinogenicity Acute, repeated toxicity Reproductive & developmental Geno- toxicity • NOAEL 50 mg/kg bw/day • Low acute toxicity • non mutagen • Perinatal exposure render prostate & mammary gland more susceptible to development of neoplasia • Effects on liver, kidney, BW • not induce cell transformation • LOAEL 50 mg/kg bw/day • NOAEL 5 mg/kg bw/day • non genotoxic Neurobehavioral, neuroendocrine Cardiovascular effects Metabolic disorders • Changes in anxiety • Not yet evaluated • Adiposity • Diabetes • Metabolic syndrome • But, not sufficient for conclusion • Convergence of anatomical brain sex differences

  20. Risk characterization and conclusion • POD (NOAEL, BMDL) of low dose effects can not be established due to lack of data • Formanyconventional end points, POD are much higher than estimated human exposure ( no health concern) • Some emerging new end-points show association with BPA at lower level - sex-specific neurodevelopment, anxiety, preneoplastic changes in mammary glands and prostate, impaired sperm parameters • The POD for low dose effects are close to the estimated human exposure - Low dose effects POD: <1mg/kg bw/day, HBGL: <10 ㎍/kg bw/day - The highest estimated exposure occurs in infants 0-6 months of age who are fed liquid formula out of PC bottles: 2.4 μg/kg bw/day at the mean and 4.5 μg/kg bw/day at the 95th percentile

  21. StakeholderMeeting • 14 stakeholders made presentation or provided submissions - Need a validated , harmonized analytical methodology - Conduct studies on the leaching of BPA from polycarbonate feeding utensils under conditions of sterilization - Many low dose exposure studies are not suitable for use in risk assessment - Current epidemiological studies are cross-sectional in design and not suitable for risk assessment - Clarify concentration of BPA in food in its ready to consume form - Establish a uniform safe level of BPA in infant formula - All alternative coatings need to be thoroughly evaluated for performance for the full shelf life of the product and for safety - Media needs to base communication on fact

  22. Alternative materials • Glass, polypropylene, polyethersulfone, polyethylene terephthalate, high-density polyethylene, PVC, polyamide, silicone, tritan copolymer polyester, polyacrylates, vinyl resins, oleoresins • New or existing alternative materials would need to be assessed for safety human exposure

  23. Current regulations or reviews • 한국 - 젖병의 용출 기준규격: 3 mg/kg (BPA) - 식품 용기포장: 0.6 ppm(BPA) - 유아용젖병 제조시BPA 사용금지 • EU - BPA 함유 젖병 제조, 수입, 판매 금지 - TDI : 0.05 mg/kg bw/day • 캐나다 - Provisional TDI: 0.025 mg/kg bw/day - Infantformula: No BPA (ALARA) • 미국 - RfD : 0.05 mg/kg bw/day - 유아용젖병 제조시BPA 사용금지 (주별로설정)

  24. Data Gaps • BPA level in breast milk • BPA migration from paper packaging to food • BPA concentration in unpackaged food • Contribution of dermal exposure to overall exposure • Biomonitoring data on fetal and early-life BPA exposure • Biomarker for long-term exposure • Validated protocols for anxiety testing • Age –dependent changes on anxiety and related behaviors • Dose-response analysis for anatomical brain sex differences • Human pharmacokinetic studies • BPA impact on human semen quality • Large prospective studies on the association of BPA with pubertal development, CVD, diabetes

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