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B isphenol A 의 노출과 위해성 조사

B isphenol A 의 노출과 위해성 조사. 숙명여자대학교 약학대학 독성학교실 양미희. 강의요점. 일반인에서 BPA 노출과 건강 BPA 취급 작업자의 BPA 노출과 건강. 최근 bisphenol A 의 독성 증거. 표현형의 변화 : phenotypical changes (epigenetic changes): Dolinoy et al. 2007. Second hit theory. 어린 시절 bishpenol A 에 노출은 성숙 후 전립선암유발물질로 인한 암화를 촉진.

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B isphenol A 의 노출과 위해성 조사

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  1. Bisphenol A의 노출과 위해성 조사 숙명여자대학교 약학대학 독성학교실 양미희

  2. 강의요점 일반인에서 BPA노출과 건강 BPA 취급 작업자의 BPA 노출과 건강

  3. 최근 bisphenol A의독성 증거 표현형의 변화: phenotypical changes (epigenetic changes): Dolinoy et al. 2007

  4. Second hit theory • 어린 시절 bishpenol A에 노출은 성숙 후 전립선암유발물질로 인한 암화를 촉진 (Prins et al., 2006;2007)

  5. ⁢ Bisphenol A의 용도 - 폴리카보네이트, 에폭시 수지 생산 시 모노머 - 폴리카보네이트 : 생수통, 유아용젖병, 식품보관용기 등 - 에폭시 수지 : 음료 및 식품 캔 내부의 코팅제, 음식용기 등의 코팅제로 사용 - 국내 사용량 : 8만 5천 8백 72톤/년 (2002년 기준)

  6. ⁢ Toxicity Estrogenic effects Developmental/reproductive/endocrine toxicity ⁢ Guideline Values US EPA RfD (1993) : 0.05 mg/kg b.w./day EU temporary TDI (2002) : 0.01 mg/kg b.w. ⁢ 국내 식품 용기 ·포장 용출규격 : 2.5mg/L (식품공전, 2005)

  7. ⁢ 국내외 Bisphenol A의 노출량 자료(일반인) GM : geometric mean

  8. ⁢ 외국 Bisphenol A의 노출량 자료(임산부)

  9. Epoxy resin Polycarbonate resin Hologenated BPA Polyester resin Bisphenol A 水添BPA Phenoxy resin Stabilizer Formaldehyde resin Polysulfone resin Uses of bisphenol A

  10. ♀ ♀ ♂ ♀ Control Worker Worker ｝ Occupational Exposure Environmental ｝ Exposure urine urine urine Exposure Biological Monitoring Assessment Health Children ♀ ♀ ♂ ♂ Effects ? ?

  11. H HO C OH H H HO C OH CH3 CH3 HO C OH CH3 CH3 HO OH C CH2 CH3 1) bis(p-hydroxyphenyl)methane (Bisphenol F) 2) 1,1-bis(4-hydroxyphenyl)ethane 3) 2,2-bis(4-hydroxyphenyl)propane (Bisphenol A) 4) 2,2-bis(4-hydroxyphenyl)butane (Bisphenol B) Structural formulas of bisphenol A and its derivatives

  12. Bisphenol A sulfate 5-hydroxybisphenol A Urine Bisphenol A Feces Bisphenol semiquinone Bisphenol A mono-glucuronide DNA binding Urine Bisphenol A di-glucuronide 4,5 Bisphenol-O-quinone Metabolic map (general)

  13. Japanese Studies (Kawamoto et al.) • Development of urinary bisphenol A analysis • Surveys 1) University students 2) Workers in a secondary processing factory 3) Workers in a manufacturing workplace

  14. Measurement of urinary bisphenol A concentration

  15. Bisphenol A Bis(hydroxyphenyl)propane Contamination Analysis Free Total (Glucuronide) = (Total) - (Free) General conception of bisphenol A measurement

  16. Transfer 400 µl of supernatant to a new tube Resolve with 60% of acetonitrile 200 µl HPLC HPLC Urine 500 µl 2.0M Sodium Acetate (pH 5.0) 30 µl Add ß-glucuronidase and H2O 70 µl H2O 70 µl Add Add Incubation at 37 °C for 3 hrs 2N HCl 100 µl Add Extraction by 5 ml of Ethylacetate with IS Shaking and centrifugation Evaporation with N2 gas Total bisphenol A Free bisphenol A Pretreatment of urine

  17. HPLC condition HPLC: Hitachi L-7000 series UV detector L-7400 Column oven L-7300 Auto sampler L-7200 Pump L-7100Column: Tosoh TSK gel ODS-80TM (reverse phase)Excitation: 275 nm, Emission: 300 nmMobile phase: D.W.: ActCN: THF=125:40:35Flow rate: 1.0 ml/minSample volume: 40 µl

  18. Chromatograms of standard mixture and urine samples a) Standard mixture (1,1-bis(4-hydroxyphenyl)ethane 100 µg/l, bisphenol A 100 µg/l, bisphenol B 200 µg/l) b) Control urine spiked standard mixture (final conc.: 1,1-bis(4-hydroxyphenyl)ethane 100 µg/l, bisphenol A 100 µg/l, bisphenol B 200 µg/l) c) Worker's urine with gluculonidase treatment (total) d) Worker's urine without gluculonidase treatment (free) 1: 1,1-bis(4-hydroxyphenyl)ethane 2: Bisphenol A IS: Internal standard (Bisphenol B)

  19. Emission wavelength scan by the excitation at 275 nm and excitation wavelength scan by the emission at 300 nm of the peaks the standard solution (a) and of the same retention time of the urine sample (b ) (a) Standard solution (b) Urine sample Em; 300 nm Ex; 275 nm Ex; 275 nm Em; 300 nm

  20. 7 1.2 x 10 7 1 x 10 6 8 x 10 6 6 x 10 6 4 x 10 6 2 x 10 0 20 40 60 80 100 y = 99959x + 262900, r = 0.999 Peak area 0 Bisphenol A concentration spiked into urine (µg/l) Relationship between bisphenol A concentration and area peak

  21. 1) Urinary bispehnol A concentration of Students

  22. Study subjects Students Survey in 1992 M 46 (21-34 y.o. mean; 24.1) F 4 (21-34 y.o. mean; 23.5) Survey in 1999 M 49 (19-24 y.o. mean; 21.6) F 7 (19-22 y.o. mean; 20.7)

  23. 1999 1992 p<0.001 p<0.001 70 60 50 40 Bisphenol A concentration (µg/g creatinine) 30 n.s. 20 10 0 Total Free Glucuronide Comparison of bisphenol A concentrations in the urine samples collected in 1992 and 1999

  24. 70 60 50 40 Total bisphenol A concentration (µg/g creatinine) 30 20 10 0 b c d b c d 1999 1992 Total bisphenol A concentration by drinking habit a: >5 days/week b: 2-4 days/week c: 0-1 day/week d: non-drinker

  25. 70 60 50 40 Bisphenol A concentration (µg/g creatinine) 30 20 10 0 Nonsmoker Smoker Nonsmoker Smoker 1999 1992 Urinary bisphenol A concentration by smoking

  26. A B C D A B C D A: usually not taken B: 0-1 cup/day C: 1-2 cups/day D: >3 cups/day 70 60 50 40 Total bisphenol A concentration (µg/g creatinine) 30 20 10 0 1999 1992 Total bisphenol A concnetration by coffee and tea consumption

  27. 45 30 1,1-bis(4-hydroxyphenyl)ethaneconcentration (µg/g creatinine) 15 0 1992 1999 1992 1999 1992 1999 Total Free Glucuronide Comparison of 1,1-bis(4-hydroxyphenyl)ethane concentrations in the urine samples collected in 1992 and 1999

  28. A B C D A B C D A B C D 40 1,1-bis(4-hydroxyphenyl)ethane conc. (µg/g cre) 20 0 Total Free Glucuronide 1,1-bis(4-hydroxyphenyl)ethane concentration by tea and coffee consumption A: usually not taken B: 0-1 cup/day C: 1-2 cups/day D: >3 cups/day

  29. 1880 1900 1920 1940 1960 1980 2000 1.10 1.09 1.08 1.07 Sex ratio （men/female） 1.06 1.05 1.04 1.03 1.02 Year Sex ratio for live birth in Japan

  30. Secondary processing factory • Polymerization of diglycidylether of bisphenol A • Exposed workers: male; 19, female; 6 43.6 ± 13.8 y.o. • Control workers: male; 35, female; 17 45.1 ± 13.3 y.o.

  31. (n+2)CH 2– CHCH2Cl O CH 2– CH - CH2 O CH3 O C OCH2CHCH2 O CH3 1) Taffy process CH3 Bisphenol A C OH + (n+1) HO CH3 Epichlorohydrin (n+2)NaOH CH3 OH O C OCH2CHCH2 CH3 n Bisphenol A epoxide resin + (n+2)NaCl + (n+2)H2O The production of bisphenol A epoxide resin

  32. O O 2) Advance process CH3 Bisphenol A diglycidylether 2) mCH2CHCH2 O C OCH2CHCH2 O CH3 CH3 Bisphenol A C OH + n+ HO CH3 CH3 O CH2CHCH2 OCH2CHCH2 C OH CH3 n+m-1 CH3 m > n Bisphenol A epoxide resin O C OCH2CHCH2 O CH3 The production of bisphenol A epoxide resin

  33. P< 0.001 80 70 60 50 40 bisphenol A conc. (µg/g・cre) 30 20 10 0 -10 Control BPADGE Urinary bisphenol A concentration of BPA diglycidylether (BPADGE) handling workers and control workers

  34. Sex distribution of children of workers who who handle bisphenol A diglycidyl ether

  35. Manufacturing workplaces Exposed workers (male; 31, female; 0) 35.5 ± 12.7 y.o. Control workers (male; 10, female; 0) 40.8 ± 9.3 y.o.

  36. 16000 14000 12000 10000 8000 6000 4000 2000 0 -2000 P< 0.001 P=0.0191 P< 0.001 bisphenol A conc. (µg/g・cre) after before control Urinary bisphenol A concentration of the workers serving in bisphenol A production process and their control workers

  37. P< 0.001 80 70 60 50 40 bisphenol A conc. (µg/g・cre) 30 20 10 0 -10 Control BPADGE Urinary bisphenol A concentration of BPA diglycidylether (BPADGE) handling workers and control workers

  38. 16000 14000 12000 10000 8000 6000 4000 2000 0 -2000 P< 0.001 P=0.0191 P< 0.001 bisphenol A conc. (µg/g・cre) after before control Urinary bisphenol A concentration of the workers serving in bisphenol A production process and their control workers

  39. Sex distribution of children of workers who are engaged in bisphenol Amanufacturing process

  40. Oral administration 10 mg/Kg BW 100 mg/Kg BW 800 mg/Kg BW* CO2 Feces (M) 81±4%, (F) 72±6% (M) 82±6%, (F) 69±4% (free BPA: 86-93%) (M)56%(F:34%, G: 30, H:35)* (H: hydroxy bisphenol A) Urine (M)16±4% (F:11%, G:60, S:3), (F) 24±7% (F:6%, G:84, S:3) (M)14±2% (F:10%, G:57, S:2), (F) 28±2% (F:12%, G:70, S:4) (M) 28% (F:<1%, G:>98, S:0)* (F: free, G: glucuronide, S: sulfate)

  41. Oral administration 100 ug/Kg BW [ring-14C(U)]Bisphenol A Feces (M) 1 - 3 %, (F) 1 - 5% Urine (M) 84.8%, (F) 81.9% (Kurebayashi et al. 1999)

  42. Primary processing Secondary processing Manufacturing Consumers Diglycidyl ether Polymerization Products Bisphenol A Polycarbonate resin Products modeling Exposure 3 μg (1992) < 1μg (1999) 500 μg 15 μg

  43. Manufacturing industry [exposure] combined single Consumer Primary processing industry Secondary processing industry [number of subjects] small large The relation between the number of subjects and exposure

  44. Change of inside wall coating of food cans Reduction of polycarbonate food containers Effects on fetus Comparison Pregnancy ・Sex ratio ・Genital organs Pregnancy ・Congenital disorders ・Others Effects on secondary sex characterics Born at 1978 Delivery 18 12 Born at 1986 12 18 Delivery Year 1990 1995 2000 2005 2010 2015 Exposure to Bisphenol A Future study about health effects of Bisphenol A

  45. 향후 과제 • 비스페놀 A의 TLV(직업환경 참고치, 산업허용한도, threshold limit value), BEI(생물학적 모니터링, biological exposure indices) : ??? • 노출최소화전략이 필요: 지속적 biomonitoring 실시 • 근로자의 복지;기업의 책임, win-win

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