CRM CRM 181
TG424 TG42419971995TG407 PBPK PBPK DNA DNA
PBPK C C art vein Ramsey & Andersen (1984) ( Qalv Cinh Qt Cvein ) ( Qt Qalv PN ) = + + { ( )} Qi Ci = i Pi ( C ) art Ci dai dt = Qi Qt Pi ( C ) art Cl max ( Cl ) ( Cl ) = Q P + dal dt l V Pl Km Pl l GST P450 Q alv = Cinh = Qt = PN= Pi= Qi = V max KmMickaelis-Menten l=
PBPK AUC AUC Approaches for the Application of PBPK Models and Supporting Data in Risk Assessment (EPA/600/R-05/43A, June 2005, External Review Draft) http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=135427
6000 5000 4000 3000 100% 80 60 DCM: B6C3F1 P450 GST AUC(DCM) (Andersen et al., 1987) GST AUC(DCM) DCM 2000 40 GST 1000 20 P450 GST mg DCM/liter tissue mg DCM/liter tissue 0 0 2000 4000 ppm 250 a mg/kg/day b AUC(DCM) (mg/liter) x hr a NTP, 1986 b National Coffee Association, 1983
PBPK GST 1,4- DNA- AUC
TG424 TG42419971995TG407 PBPK PBPK DNA DNA
PBPK GST 1,4- * * * DNA-* AUC *
(Aplastic anemia), (acute myelogenous leukemia,aml) (lymphoid malignancies) Absolute lymphocyte count): : 5-19 ppm ---> () Ha-ras gene
Protein adducts DNA adducts P4502E1 Benzene O Benzene oxide Oxepin Fe/OH GSH O GSH-Transferase Epoxide hydrolase OH O [ O ] O O trans,trans -Muconaldehyde* OH (MUC) (highly reactive, hematotoxic, topoisomerase trans,trans-muconic acid (MA) (excreted in Urine: exposure marker in human) inhibition) OH S-CH 2 -CH(NHCOCH 3 )COOH S-Phenylmercapturic acid Glucuronide Sulfate P4502E1 HO Phenol OH HO Glucuronide Sulfate Hydroquinone* Protein adducts P450 DNA adducts OH Glucuronide OH OH 1,2,4-Benzene triol* P450 Catechol* NQO1 OH OH OH (polymorphism) 1,2-Benzene dihydrodiol* Peroxidases/autooxidation (Myeloperoxidase: MPO) *:mutagenic NQO1? Protein adducts O O O O o-benzoquinone O O Protein adducts NQO1 4,4'-Diphenoquinone p-benzoquinone (highly reactive, oxidative stress, topoisomerase inhibition, inhibits pre-il-1 to IL-1) OH OH 4,4'-Biphenol NQO1: NAD(P)H:quinone oxidoreductase
(U.S.EPA, 2002) CYP2E1 GSH transferases >> NAD(P)H:quinone oxidoreductase CYP2E1xNQO1 CYP2E1 NQO1 (95% CI) 8 1.0 6 2.4 (0.6 9.7) 21 2.9 (1.0 8.2) 13 7.6 (1.8 31.2)
> >
EU / WHO-IPCS The Sapphire Group U.S. EPA WHO Canada TERA European Risk Assessment Report, ACRYLONITRILE (Final Report, 2004) Environmental Health Criteria 28, Acrylonitrile (1983) Toxicological Review of Acrylonitrile (Final Draft, 2004) TOXICOLOGICAL PROFILE FOR ACRYLONITRILE, 1990 Concise International Chemical Assessment Document 39, ACRYLONITRILE (2002) Priority Substances List Assessment Report Acrylonitrile (2000) Acrylonitrile: Inhalation Cancer Risk Assessment (1997) 257 484 64 365 195 347 93 324 32 262 55 243 41 113
U.S. EPA NICNAS WHO / Ambient Water Quality Criteria for the Protection of Human Health: Acrylonitrile (1998) Acrylonitrile Priority Existing Chemical Assessment Report No. 10 ( 2000) Air quality Guidelines for Europe, Second Edition, Chapter 5.1 Acrylonitrile (2000) Chronic Toxicity Summary, ACRYLONITRILE(2001) 26 71 64 62 9 19 6 14
IARC BUA ECB ATSDR NICNAS EPA CANADA CRM
CRM (a) (b) (c) CRM CRM
NOAEL 2004 The Sapphire 2004 Group, Inc. The California Saophire 2001 2004 OEHHA Group, Inc. 2 x 10-3 mg/m 3 (UF=500) RfD=0.2 mg/kg/ (UF=180) RfC=0.7 mg/m 3 (UF=10) Cancer Value = 0.1 mg/m 3 RfC5 x 10-3 mg/m 3 (UF=30) Cancer Value = 0.009 mg/kg/ NOEL 1 mg/m 3 (Muto et al., 1992) NOAEL 32 mg/kg// NOAEL 21.7 mg/m 3 NOAEL( 7.4 mg/m 3 BMD 05 (Maltoni et al., 3.3 mg/m 1977,1987; Toxicology 3 BMD Research Laboratory, 05 1980; Johannsen and 0.15 mg/m Levinskas, 2002a; 3 2002b; Quast, 2002) in vivo 5/7 PBPKNOAELBMD (Gagnaire et al., 1998) LED 1SD = NOAEL NOAEL(21.7 mg/m 3 ) (10 m 3 /day20 m 3 /)250/ (Sakurai et CEOBMD5% al., 1978) 365/ (LED 05 )(0.014 mg/l) NOAEL(7.4 mg/m 3 ) Point of Departure (POD) POD CEOKedderis PBPK(21.3 mg/m 3 ) et al. (1996)PBPK UF=220 BMD5%BMD Toxicology Research 05 ) (3.3 mg/m Laboratory, 1980) 3 ) Cancer Value CEOMD5% (0.15 mg/m 3 )UF=305 x 10-3 mg/m 3 (LED 05 )(0.014 mg/l) Point of Departure (POD) POD PBPK(1.7 mg/kg/) UF=200 WHO 2002 TC 05 = 6.0 mg/m 3 95%LCL = 4.5mg/m 3 1.1 x 10-2 / (mg/m 3 ) TD 05 = 2.3 mg/kg/ (95%LCL = 1.4 mg/kg/) 2.2 x 10-2 / (mg/kg/) Toxicology Research Laboratory, 1980) (Johannsen and Levinskas, 2002b) 6 TC 05 TC 05 =35 mg/m 3 ()52 mg/m 3 24 [(6hr/)/(24hr/)] x [(5 /)/(7 /)] TC 05 TC 05 TD 05 =2.0 mg/kg/() 1.8 mg/kg/() TD 05 () x (26/24) x (26/24) 2
(U.S. EPA, 1998) EU (2004) The Sapphaire Group, Inc. (2004) NOAEL RfD= 1 g/kg/ RfD=200 g/kg/ 1 mg/kg/ 0.25 mg/kg/ 32 mg/kg/ (Tandon et al. 1988) (Johannsen and Levinskas, 2002 (Gagnaire et al., 1998) UF=1,000 PBPKNOAEL UF=180TERA PBPK PBPK Gagnaire et al.(1998) (ASAP) ASAP) BMDNOAEL
(ASAP) 5/ mg/kg/ (7/) mg/kg/ ASAP (V) MeanS.D. 0 0 167 32 (n=10) 12.5 8.9 157 31 (n=12) 25 17.9 158 31 (n=12) 50 35.7 126 42 (n=12) BMD BMD (mg/kg/) BMDL (mg/kg/) p Linear 29.6 18.8 0.588 Polynomial 33.1 17.6 0.503 Power 34.1 19.7 0.510 Hill 32.3 18.7 BMDBMDL:BMD95% 10 10101012 RfD = 20g/kg/ g/kg/
(U.S. EPA, 1998) EU (2004) The Sapphaire Group, Inc. (2004) CRM NOAEL RfD=1 g/kg/ RfD=200 g/kg/ RfD =20 g/kg/ 1 mg/kg/ 0.25 mg/kg/ 32 mg/kg/ 20 mg/kg/ (Tandon et al. 1988) (Johannsen and Levinskas, 2002 (Gagnaire et al., 1998) (Gagnaire et al., 1998) UF=1,000 PBPKNOAEL UF=180 TERA BMDNOAEL UF=1,000
CRM / EU European Risk Assessment Report (2004) 257 484 WHO-IPCS Environmental Health Criteria 28 (1983) 64 365 The Sapphire Group Toxicological Review (Final Draft, 2004) 195 347 U.S. EPA Toxicological Profile (1990) 93 324 WHO Canada Concise International Chemical Assessment Document 39 (2002) Priority Substances List Assessment Report (2000) 32 262 55 243 CRM 72 123 NICNAS Priority Existing Chemical Assessment Report No. 10 ( 2000) 64 62
PBPK
P450 2E1 MOF GSTH (+) GSH (-) ) (-) 0.25, 0.2, 0.02) 75, 5, 5)
/ Ca
PBPK