IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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SOME TRADITIONAL HERBAL MEDICINES 105 tasis in the pancreas, an activated c-N-ras proto-oncogene was detected. All mutations were A → T transversions at either the second or the third base of codon 61. In mice, a mixture of aristolochic acids induced squamous-cell carcinoma in the forestomach and adenocarcinoma in the lung. In the tumours analysed, one forestomach squamous-cell carcinoma and 1/3 lung adenocarcinomas contained activated c-Ha-ras proto-oncogenes both mutated by A → T transversions at the second base of codon 61. (c) In-vitro studies (see Tables 6–8 for details of studies and references) After metabolic activation, aristolochic acid I and aristolochic acid II form adducts in vitro with calf thymus DNA, MCF-7 DNA, plasmids, polydeoxyribonucleotides, oligodeoxyribonucleotides, deoxyribonucleotide-3′-monophosphates (purines), deoxyadenosine and deoxyguanosine. In-vitro systems capable of activating aristolochic acids I and II to reactive species that may form adducts are S9 mix from Aroclor 1254or β-naphthoflavone-pretreated rats, xanthine oxidase, peroxidases (horseradish peroxidase, lactoperoxidase, prostaglandin H synthase), zinc at pH 5.8 and microsomal preparations from various species other than the rat. Aristolochic acid-specific adducts were formed in calf thymus DNA after activation of aristolochic acids I and II with hepatic microsomes from humans, mini-pigs and rats, as well as with microsomes containing recombinant human CYP1A1 and CYP1A2. From studies with specific inducers and selective inhibitors, it can be concluded that most of the microsomal activation of aristolochic acids is due to CYP1A1 and CYP1A2. Activated aristolochic acids I and II react with DNA to form three and two major adducts, respectively. These major adducts co-chromatograph with 7-(deoxyadenosin- N 6 -yl)aristolactam I (dA-AAI), 7-(deoxyguanosin-N 2 -yl)aristolactam I (dG-AAI), 7- (deoxyadenosin-N 6 -yl)aristolactam II (dA-AAII) and 7-(deoxyguanosin-N 2 -yl)aristolactam II (dG-AAII) (see Figure 6), indicating that aristolochic acid reacts preferentially with the exocyclic amino group of purine bases. On the basis of the adduct structures, it can be concluded that reduction of the nitro group is the main metabolic pathway for the activation of aristolochic acid. The major metabolites, the aristolactams, form DNA adducts in vitro after activation by hepatic microsomes or horseradish peroxidase. Adducts with calf thymus DNA are also formed by aristolochic acids I and II in vitro in the presence of rat faecal bacteria. In explants of rat stomach tissue, both acids formed adducts in the DNA of the epithelial layer. DNA adducts have been detected in MCF-7 cells after exposure to aristolochic acid I and in opossum kidney cells after exposure to an aristolochic acid mixture. After reaction of aristolochic acids with DNA, DNA synthesis by T7 DNA polymerase and human DNA polymerase α is mainly blocked at the nucleotide 3′ to the aristolochic acid-induced DNA adducts. This property has allowed the use of polymerase arrest assays that revealed binding of aristolochic acids I and II in vitro to the c-Ha-ras gene and the TP53 gene. Aristolochic acids I and II and the aristolochic acid mixture induced SOS repair and mutations in bacteria. In nitroreductase-deficient strains of Salmonella typhimurium,
Table 6. DNA adduct formation by aristolochic acids (AAs) in vitro Test system Assay Dose Result Reference Adduct formation by AAI in DNA (calf thymus) in vitro with S9 mix a , aerobic Adduct formation by AAI in DNA (calf thymus) in vitro with S9 mix a , anaerobic b Adduct formation by AAII in DNA (calf thymus) in vitro with S9 mix a , aerobic Adduct formation by AAII in DNA (calf thymus) in vitro with S9 mix a , anaerobic b Adduct formation by AAI in DNA (calf thymus) in vitro with xanthine oxidase (0.1 μg/mL), anaerobic b Adduct formation by AAII in DNA (calf thymus) in vitro with xanthine oxidase (0.1 μg/mL), anaerobic b Adduct formation by AAI in polydG in vitro with S9 mix aerobic or anaerobic Adduct formation by AAI in DNA (calf thymus) in vitro with rat faecal bacteria, anaerobic b Adduct formation by AAII in DNA (calf thymus) in vitro with rat faecal bacteria, anaerobic b Adduct formation by AAI in DNA of forestomach and glandular stomach in explanted stomach of rats Adduct formation by AAII in DNA of forestomach and glandular stomach in explanted stomach of rats Adduct formation by AAI with deoxyguanosine and deoxyadenosine in vitro in the presence of xanthine oxidase, anaerobic Standard 32 P-postlabelling 0.4 mM 4 adducts Nuclease P1-enhanced 32 Ppostlabelling UV/vis and fluorescence spectroscopy. Adducts were spectroscopically identified as dG-AAI and dA-AAI. 1 mmol/2 mL 30 μmol/kg bw daily for 5 days (oral) 2 adducts No adducts 2 adducts 4 adducts 2 adducts 2 adducts Same pattern as in vivo (cf Table 4) Same pattern as in vivo (cf Table 4) 4 adducts 2 adducts Same adducts are formed in DNA Schmeiser et al. (1988) Pfau et al. (1990a) Pfau et al. (1990b) 106 IARC MONOGRAPHS VOLUME 82
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WORLD HEALTH ORGANIZATION INTERNATI
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IARC MONOGRAPHS In 1969, the Intern
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iv IARC MONOGRAPHS VOLUME 82 3.2 Th
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vi IARC MONOGRAPHS VOLUME 82 SOME M
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IARC WORKING GROUP ON THE EVALUATIO
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PARTICIPANTS 5 Observer, representi
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PREAMBLE
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10 IARC MONOGRAPHS VOLUME 82 plasms
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12 IARC MONOGRAPHS VOLUME 82 collec
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14 agents present. For processes, i
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16 IARC MONOGRAPHS VOLUME 82 Finall
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18 IARC MONOGRAPHS VOLUME 82 and mi
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20 IARC MONOGRAPHS VOLUME 82 (c) St
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22 IARC MONOGRAPHS VOLUME 82 may le
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24 IARC MONOGRAPHS VOLUME 82 It is
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26 IARC MONOGRAPHS VOLUME 82 Data r
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28 when there is strong evidence th
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30 IARC MONOGRAPHS VOLUME 82 Vol. 7
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GENERAL REMARKS ON THE SUBSTANCES C
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SOME TRADITIONAL HERBAL MEDICINES
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44 which may include, for example,
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46 2. Use of Traditional Herbal Med
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48 IARC MONOGRAPHS VOLUME 82 decade
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50 IARC MONOGRAPHS VOLUME 82 Table
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52 3.2.1 Definition of herbal medic
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metry (Witte et al., 1992). Thin-la
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sex were killed after a seven-week
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4.2.2 Experimental systems SOME TRA
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Table 1. Genetic and related effect
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Riddelliine induced unscheduled DNA
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5.3 Animal carcinogenicity data In
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SOME TRADITIONAL HERBAL MEDICINES 1
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SOME MYCOTOXINS
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172 Aflatoxin G 1 IARC MONOGRAPHS V
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Table 2 (contd) Method no. Aflatoxi
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178 indicates that A. flavus and A.
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Table 4. Occurrence of aflatoxin B1
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182 IARC MONOGRAPHS VOLUME 82 aflat
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Table 6. Co-occurrence of aflatoxin
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186 IARC MONOGRAPHS VOLUME 82 Figur
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188 1.4 International exposure esti
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190 (c) Impact of establishing maxi
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192 IARC MONOGRAPHS VOLUME 82 used
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Table 10 (contd) Reference Area Uni
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198 were collapsed into a conventio
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Table 11 (contd) Reference Area Stu
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202 IARC MONOGRAPHS VOLUME 82 histo
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204 IARC MONOGRAPHS VOLUME 82 resid
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Table 12. Summary of principal case
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208 IARC MONOGRAPHS VOLUME 82 disea
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210 3. Studies of Cancer in Experim
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212 IARC MONOGRAPHS VOLUME 82 diet
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214 3.4 Administration with known c
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216 IARC MONOGRAPHS VOLUME 82 The 8
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218 observed in rat liver slices, a
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222 IARC MONOGRAPHS VOLUME 82 an α
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224 (mainly hepatocellular carcinom
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226 IARC MONOGRAPHS VOLUME 82 but i
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228 lordosis and reduction in conce
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232 IARC MONOGRAPHS VOLUME 82 sampl
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234 In eight subjects (four from Ho
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Table 16 (contd) Test system Result
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240 IARC MONOGRAPHS VOLUME 82 anima
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242 difference between the two stud
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244 IARC MONOGRAPHS VOLUME 82 HBV-t
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246 In a large cohort study in Shan
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248 experimental data in showing th
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250 IARC MONOGRAPHS VOLUME 82 Ander
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252 IARC MONOGRAPHS VOLUME 82 Buetl
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254 IARC MONOGRAPHS VOLUME 82 Denis
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256 IARC MONOGRAPHS VOLUME 82 Galla
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258 IARC MONOGRAPHS VOLUME 82 Heino
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260 IARC MONOGRAPHS VOLUME 82 Jalon
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262 IARC MONOGRAPHS VOLUME 82 Kirk,
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264 IARC MONOGRAPHS VOLUME 82 Lunn,
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266 IARC MONOGRAPHS VOLUME 82 Olubu
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268 IARC MONOGRAPHS VOLUME 82 Roll,
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270 IARC MONOGRAPHS VOLUME 82 Stett
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272 IARC MONOGRAPHS VOLUME 82 Verge
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274 IARC MONOGRAPHS VOLUME 82 Yang,
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Table 1. IARC evaluations Previous
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278 kernels and in less than 0.1% o
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280 2.5.3 Cottonseed A. flavus is a
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294 IARC MONOGRAPHS VOLUME 82 8. Re
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296 IARC MONOGRAPHS VOLUME 82 Guo,
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298 IARC MONOGRAPHS VOLUME 82 Marti
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300 IARC MONOGRAPHS VOLUME 82 Sharm
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302 (d ) Solubility: Soluble in wat
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304 1.4 Occurrence Fumonisins have
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306 Table 1 (contd) IARC MONOGRAPHS
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308 (c) Formation in commodities ot
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312 IARC MONOGRAPHS VOLUME 82 3.1 O
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314 3.2.2 Rat IARC MONOGRAPHS VOLUM
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316 with NDEA and fumonisin B 1, wh
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318 IARC MONOGRAPHS VOLUME 82 In pi
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Figure 2. Allometric relationship b
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322 IARC MONOGRAPHS VOLUME 82 obser
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324 IARC MONOGRAPHS VOLUME 82 Hepat
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326 4.2.3 Related studies IARC MONO
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328 4.3.2 Experimental systems IARC
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330 and litters on postnatal day 21
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Table 4. Genetic and related effect
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334 IARC MONOGRAPHS VOLUME 82 The f
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336 IARC MONOGRAPHS VOLUME 82 (d )
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338 IARC MONOGRAPHS VOLUME 82 treat
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340 4.5.2 Interference with fatty a
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344 5.2 Human carcinogenicity data
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346 IARC MONOGRAPHS VOLUME 82 Alber
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348 IARC MONOGRAPHS VOLUME 82 Chamb
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350 IARC MONOGRAPHS VOLUME 82 Floss
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352 IARC MONOGRAPHS VOLUME 82 Hiroo
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354 IARC MONOGRAPHS VOLUME 82 Lee,
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356 IARC MONOGRAPHS VOLUME 82 Mobio
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358 IARC MONOGRAPHS VOLUME 82 Prelu
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360 IARC MONOGRAPHS VOLUME 82 Savar
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362 IARC MONOGRAPHS VOLUME 82 Steve
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364 IARC MONOGRAPHS VOLUME 82 Flett
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366 IARC MONOGRAPHS VOLUME 82 Yu, C
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368 disulfide, carbon tetrachloride
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Table 1 (contd) Sample matrix Sampl
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Table 3. Naphthalene production (th
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374 1.4 Occurrence 1.4.1 Natural oc
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Table 5. Occupational exposure to n
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378 water assuming a water concentr
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380 (Scheepers & Bos, 1992). The av
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382 (d ) Biodegradation Studies on
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386 3.2 Inhalation exposure 3.2.1 M
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388 3.3.2 Rat Ten BD I and BD III r
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Figure 1. Main metabolic pathways o
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392 IARC MONOGRAPHS VOLUME 82 and t
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394 IARC MONOGRAPHS VOLUME 82 and 1
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396 IARC MONOGRAPHS VOLUME 82 1-240
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398 IARC MONOGRAPHS VOLUME 82 Perfu
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400 Siegel and Wason (1986) reviewe
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402 IARC MONOGRAPHS VOLUME 82 liver
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404 IARC MONOGRAPHS VOLUME 82 to id
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406 IARC MONOGRAPHS VOLUME 82 Alkal
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408 hyperplasia, atrophy, chronic i
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410 had deficient glucose-6-phospha
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Table 10. Genetic and related effec
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Table 10 (contd) Test system Micron
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416 assay with or without metabolic
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418 There is some evidence of devel
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420 IARC MONOGRAPHS VOLUME 82 Bjør
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422 IARC MONOGRAPHS VOLUME 82 Conkl
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424 IARC MONOGRAPHS VOLUME 82 Envir
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426 IARC MONOGRAPHS VOLUME 82 Ho, C
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428 IARC MONOGRAPHS VOLUME 82 Lynch
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430 IARC MONOGRAPHS VOLUME 82 O’B
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432 IARC MONOGRAPHS VOLUME 82 Schee
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434 IARC MONOGRAPHS VOLUME 82 Versc
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STYRENE This substance was consider
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EPA Method 8260B can be used to det
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Styrene is produced mainly by catal
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STYRENE 443 Table 3. Use patterns f
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STYRENE 445 most samples taken from
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STYRENE 447 successive layers of ch
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Table 4 (contd) Country and year of
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Table 5. Biological monitoring of o
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STYRENE 453 Since 1990, the long-te
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same products resulted in exposures
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STYRENE 457 Ambient air monitoring
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200 μg/kg, although 77% of the foo
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Table 8 (contd) Country or region Y
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2.1 Case reports 2. Studies of Canc
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Table 10 (contd) Reference (country
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Table 10 (contd) Reference (country
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STYRENE 469 (95% CI, 1.4-5.2; 10 de
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who had been employed in 1964-70 (t
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elationship for styrene became nega
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atio, 4.4; 95% CI, 1.1-17 in multip
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controls versus 32/32 treated). No
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3.4 Intraperitoneal administration
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Figure 1. Main metabolic pathways f
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STYRENE 483 a maximum and averaged
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(b) Distribution STYRENE 485 An ear
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STYRENE 487 rats with phenobarbital
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STYRENE 489 gavage (100-350 mg/kg b
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CYP2E1 and CYP2F2) inhibited nasal
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model indicated that absorbed styre
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female workers in the glass fibre-r
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STYRENE 497 continuously for seven
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STYRENE 499 exposure concentrations
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STYRENE 501 The frequency of sponta
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STYRENE 503 groups. Only minor gene
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concentrations of styrene in air we
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Table 12. Cytogenetic studies in ly
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Table 13. Genetic and related effec
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(b) Experimental systems (see Table
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Table 14 (contd) Test system Result
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STYRENE 515 styrene 7,8-oxide. Joha
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Styrene 7,8-oxide can bind to DNA w
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STYRENE 519 a small and non-signifi
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STYRENE 521 and immune systems, liv
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STYRENE 523 Artuso, M., Angotzi, G.
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STYRENE 525 Brugnone, F., Perbellin
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STYRENE 527 Coccini, T., Maestri, L
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STYRENE 529 Edling, C., Anundi, H.,
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STYRENE 531 Gobba, F., Galassi, C.,
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STYRENE 533 Horvath, E., Pongracz,
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STYRENE 535 logical Study and the I
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STYRENE 537 Linhart, I., Gut, I.,
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STYRENE 539 Miller, S.L., Branoff,
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STYRENE 541 Newhook, R. & Caldwell,
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STYRENE 543 Pryor, G.T., Rebert, C.
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STYRENE 545 Sielken, R.L. & Valdez-
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STYRENE 547 Tsuda, S., Matsusaka, N
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STYRENE 549 Boffetta, P. (1996b) Ex
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Agent SUMMARY OF FINAL EVALUATIONS
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554 IARC MONOGRAPHS VOLUME 82 DGAL:
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556 IARC MONOGRAPHS VOLUME 82 PMTDI
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558 IARC MONOGRAPHS VOLUME 82 Aldri
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560 IARC MONOGRAPHS VOLUME 82 Benz[
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562 β-Butyrolactone 11, 225 (1976)
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564 IARC MONOGRAPHS VOLUME 82 Chlor
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566 Cyproterone acetate 72, 49 (199
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568 IARC MONOGRAPHS VOLUME 82 Diepo
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570 Ethionamide 13, 83 (1977); Supp
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572 IARC MONOGRAPHS VOLUME 82 Haema
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574 L Lasiocarpine 10, 281 (1976);
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576 IARC MONOGRAPHS VOLUME 82 Methy
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578 IARC MONOGRAPHS VOLUME 82 Nicke
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580 O Ochratoxin A 10, 191 (1976);
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582 IARC MONOGRAPHS VOLUME 82 Polyb
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584 Rhodamine 6G 16, 233 (1978); Su
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586 Sulfafurazole 24, 275 (1980); S
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588 1,1,1-Trichloroethane 20, 515 (
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590 Y Yellow AB 8, 279 (1975); Supp
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Volume 31 Some Food Additives, Feed
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