2003.11.25 JEMS/BMS
2 N H C C C NH 2 Furylfuramide (AF-2)
Dibenzo[a, l ]pyrene ( DBP) PAH
Mutant Frequencies of lacz and cii gene Induced by DBP and AF2 600 500 400 cii lacz cii lacz 300 200 100 0 Liver 6 mg/kg 120 mg/kg AF-2 DBP Control Forestomach Colon Spleen
AF2 Bacteria specific mutagen TA1535,1538 aflatoxin B1, B[a]P, DMBA AF2
sensitivity)
sensitivity)???
Food Additives Tested in NTP Rodent Bioassay and Their Results of the Ames Test Carcinogenicity 3 Mutagenicity 5 27 28 47 from How Many Food Additives Are Rodent Carcinogens? F.M. Johnson, Env. Mol. Mutagen. 39, 69-80 (2002)
Effect of Administration Route on Rodent Carcinogenicity Noncarcinogens Carcinogens 16 4 7 10 16 17 1
TRENDS in Pharmacological Sciences Vol. 22 No.6 June 2001 Key challemges for toxicologists in the 21st century Lewis L. Smith Syngenta CTL, Alderley Park, Macclesfield, Cheshire, UK
Much of the safety evaluation of drugs and chemicals involves administration of a large dose of the compound to a small number of animals to characterize the effect, followed by the extrapolation of this to a large number of people exposed to a small dose of the compound.
Safety factor Safety factor 10 for interindividual variation (SNPs) Safety factor 10 for human might be more sensitive Safety factor 10 for safety reason in some cases At least 100 and sometimes 1000 is applied 1000
DDT 2,2-bis(p-chlorophenyl) -1,1,1-trichloroethane DDT had saved ~50 million lives and averted more than 1 billion illness It was found, at high doses, to increase liver tumors in mice Public concerns over the environmental effects were enhanced by the publication of Silent Spring in 1962. Sweden 1970, USA 1972, Japan 1972 WH 1979 1996 South Africa 4117 ( 95) 27000 99)
Natural mutagen
Ames -1 1ppm DDT PCB EDB
Ames -2 800
Ames -3
Aristolochic acid CH N 2 C N C NH R R R 1 AAI ;R=H 2 3 CH AAII;R=CH 3 N 2 Structure of aristolochic acid I (AAI ;R=CH 3 ) and aristolochic acid II (AAII;R=H). R R N R NH (Aristolochia fangchi) N N N N HN C NH 4 (da-n 6 -AA) 5 N N N H HN C (dg-n 2 -AA) Chinese herb nephropathy
1500 Aristrochic acid (lacz) Aristolochic acid (lacz) (cii) Aristolochic acid (cii) 1000 500 (x 10-6 ) 0 CH N 2 R Aristolochic acid
Environmental Pollution, Pesticides, and the Prevention of Cancer: Misconceptions BRUCE N. AMES AND LIS SWIRSKY GLD FASEB J. Vol 11, 1041-1052 (1997) #1 #2 #3 #4
#5 #6 #7 #8 #9
Ames
Hazard Identification Risk assessment
(1) 2.25pg/kgbw/ 1.19 7.01pgTEQ/kgbw/ )
24 179-184 (2002) #1 #2 #3non-genotoxic carcinogen #4
#5 #6 #7 #8 #9
in vito in vivo bacteria yeast mammalian human ( DNA ( transgene endogene vs
NR Forward mutation
Positive rate
Top 10 micronucleus-inducing chemicals in 100 IARC carcinogens (Groups 1, 2A and 2B) Rank Chemicals Dose (mg/kg) Max MN Groups Antineoplastic 1 Diepoxybutane 108 5.34 2B 2 Cisplatin 3 5.20 2A * 3 Melphalan 20 4.24 1 * 4 Dacarbazine 225 4.04 2B * 5 N-methyl-N-nitrosourea 38 3.82 2A 6 Daunomycin 10 3.65 2B * 7 4-Aminobiphenyl 100 3.20 1 8 Chlorambucil 16 2.98 1 * 9 2-Methylaziridine 40 2.88 2B 10 1,3-Propane sultone 72 1.92 2B Data from Evaluation of the rodent micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) The summary report of the 6th collaborative study by CSGMT/JEMS MMS. Mutation Res. 389, 3-122. (1997)
DNA Genomics, Proteomics, Metabonomics
Hazard Identification Risk Evaluation SNPs Mutagenomics, Mutaproteomics, Mutametabolomics, IT population Germ Cell Mutagenesis,