IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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Table 14 (contd) Test system Result a Without exogenous metabolic system With exogenous metabolic system Dose b (LED or HID) Reference Sister chromatid exchange, human lymphocytes in vitro + NT 12 Chakrabarti et al. (1997) Sister chromatid exchange, human lymphocytes in vitro + NT 12 Zhang et al. (1993) Micronucleus test, human lymphocytes in vitro + NT 12 Laffon et al. (2001) DNA alkali-labile sites (alkaline single-cell gel electrophoresis assay), + 100 ip × 1 Vaghef & Hellman C57BL/6 mouse liver, kidney, bone marrow and lymphocytes in vivo (1998) DNA alkali-labile sites (alkaline single-cell gel electrophoresis assay), ddY mouse organs in vivo + 400 ip × 1 Tsuda et al. (2000) DNA alkali-labile sites (alkaline single-cell gel electrophoresis assay), CD-1 mouse organs in vivo + 400 ip × 1 Sasaki et al. (1997) DNA adducts (N7-guanine), salmon testis DNA in vitro + NT 11 Koskinen et al. (2000) DNA adducts (N7-guanine) in human embryonic lung fibroblasts in vitro + NT 1.2 Vodicka et al. (1996) DNA adducts (N7-guanine) in human whole blood, in vitro + NT NR Pauwels & Veulemans (1998) DNA adducts (O 6 -guanine) in human lymphocytes in vitro (+) NT 24 Bastlová et al. (1995) DNA adducts (O 6 -guanine), rat liver in vivo + 4260 mg/m 3 (inh.), 6 h/d, 5 d/w, 104 w Otteneder et al. (1999) a +, positive; (+), weak positive; –, negative; NT, not tested; NR, not reported b LED, lowest effective dose; HID, highest ineffective dose; in-vitro tests, μg/mL; in-vivo tests, mg/kg bw/day; d, day; ip, intraperitoneal; inh., inhalation c Positive results reported in insecticide-resistant (IR) strains at 600 μg/mL (5mM) d GSTM1-null more sensitive STYRENE 513
514 increase in the induction of micronuclei in human lymphocytes treated in vitro. These results are consistent with those previously reviewed. Three recent studies have reported that DNA strand breaks and alkali-labile sites are induced in multiple tissues (lung, liver, kidney, bone marrow and lymphocytes) of mice exposed to styrene 7,8-oxide by a single intraperitoneal injection at doses of 100–400 mg/kg bw. Results from previously evaluated studies of induction of cytogenetic damage in rodents exposed to styrene 7,8-oxide in vivo were predominately negative. Two of three studies reported some evidence of exposure-related sister chromatid exchange induction and two of four studies reported that styrene 7,8-oxide induced chromosomal aberrations. Neither of the two micronucleus studies previously evaluated reported increases in the frequency of micronuclei following exposures to styrene 7,8-oxide via intraperitoneal injection (IARC, 1994b). 4.5 Mechanistic considerations IARC MONOGRAPHS VOLUME 82 Following chronic exposure to styrene, a carcinogenic response has been observed only in mouse lung, but not in tissues of rats. Studies in humans and experimental animals and with tissues from both rodents and humans in vitro using a variety of experimental approaches have attempted to determine the mode of action for the styrene toxicity and carcinogenicity observed in experimental animals. In general, the objectives of many of these studies have been (1) to explore the basis for the observed interspecies differences in tumour response between rats and mice, (2) to determine the critical steps in styrene carcinogenicity and (3) to identify the most likely chemical species responsible for the initiation of tumour development. At least two plausible modes of action, which are not mutually exclusive, for styrene carcinogenicity are suggested by the existing data. One involves a DNA-reactive mode of action initiated by the metabolic conversion of styrene to styrene 7,8-oxide, a genotoxic metabolite of styrene, and the subsequent induction of DNA damage in target tissues; the other involves cytotoxic effects in lungs of mice exposed to styrene. For either mode of action, interspecies differences in the metabolism and toxicokinetics of styrene and styrene 7,8-oxide that exist between rats and mice are likely to play a key role. 4.5.1 Interspecies differences in toxicokinetics and metabolism A number of studies in human volunteers and in workers occupationally exposed to styrene by inhalation (summarized by Bond, 1989) have shown that styrene toxicokinetics and metabolic pathways are qualitatively similar in humans and experimental animals, although there are quantitative differences. In humans, between 60 and 70% of inhaled styrene is absorbed and more than 85% of the absorbed styrene is eliminated in the urine as mandelic and phenylglyoxylic acids. These metabolites are formed following hydrolysis of styrene 7,8-oxide, which indicates that humans metabolize styrene to
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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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54 3.2.8 Individual supply Herbal m
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58 3.3.2 Germany (see Kraft, 1999;
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60 beyond placebo, and this informa
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62 3.3.5 Canada The Canadian Food a
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64 of adverse reactions to OTC drug
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66 IARC MONOGRAPHS VOLUME 82 3.3.12
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68 IARC MONOGRAPHS VOLUME 82 Jellin
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70 IARC MONOGRAPHS VOLUME 82 Simila
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72 IARC MONOGRAPHS VOLUME 82 Figure
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74 diameter of 4-6 cm or more, lobe
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76 1.2 Use 1.2.1 Aristolochia conto
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78 1.3.3 Aristolochia fangchi Compo
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80 1.6.2 Structural and molecular f
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82 chromatographic separation with
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84 may contain aristolochic acids.
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86 IARC MONOGRAPHS VOLUME 82 A bila
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88 received distilled water. The an
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90 IARC MONOGRAPHS VOLUME 82 Figure
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92 varied from undetectable (< 0.02
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94 lochic acids enhanced immune res
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96 4.4 Genetic and related effects
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Table 3 (contd) Details of study DN
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Table 4. DNA adduct formation with
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Table 4 (contd) Details of study Co
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Table 5 (contd) Species Treatment I
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Table 6. DNA adduct formation by ar
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Table 6 (contd) Test system Assay D
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Table 6 (contd) Test system Assay D
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Table 7. Polymerase action on arist
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Table 8 (contd) Test system Drosoph
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116 of the forestomach and lung of
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118 lochic acid II (three metabolit
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120 IARC MONOGRAPHS VOLUME 82 Che,
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122 IARC MONOGRAPHS VOLUME 82 Healt
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124 IARC MONOGRAPHS VOLUME 82 Nishi
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126 IARC MONOGRAPHS VOLUME 82 Schme
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128 IARC MONOGRAPHS VOLUME 82 Yang,
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130 Figure 1. Morinda officinalis H
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132 1.3.2 Morinda officinalis A num
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134 by Soxhlet extraction with ethy
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136 2.1 Case-control studies 2.1.1
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138 3. Studies of Cancer in Experim
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140 1,3-Dihydroxy-2-hydroxymethylan
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142 4.3 Reproductive and developmen
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Table 1 (contd) Test system Result
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146 5.1 Exposure data 5. Summary of
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148 IARC MONOGRAPHS VOLUME 82 Brigg
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150 IARC MONOGRAPHS VOLUME 82 Nusko
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D. SENECIO SPECIES AND RIDDELLIINE
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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
Page 470 and 471: 2.1 Case reports 2. Studies of Canc
Page 472 and 473: Table 10 (contd) Reference (country
Page 474 and 475: Table 10 (contd) Reference (country
Page 476 and 477: STYRENE 469 (95% CI, 1.4-5.2; 10 de
Page 478 and 479: who had been employed in 1964-70 (t
Page 480 and 481: elationship for styrene became nega
Page 482 and 483: atio, 4.4; 95% CI, 1.1-17 in multip
Page 484 and 485: controls versus 32/32 treated). No
Page 486 and 487: 3.4 Intraperitoneal administration
Page 488 and 489: Figure 1. Main metabolic pathways f
Page 490 and 491: STYRENE 483 a maximum and averaged
Page 492 and 493: (b) Distribution STYRENE 485 An ear
Page 494 and 495: STYRENE 487 rats with phenobarbital
Page 496 and 497: STYRENE 489 gavage (100-350 mg/kg b
Page 498 and 499: CYP2E1 and CYP2F2) inhibited nasal
Page 500 and 501: model indicated that absorbed styre
Page 502 and 503: female workers in the glass fibre-r
Page 504 and 505: STYRENE 497 continuously for seven
Page 506 and 507: STYRENE 499 exposure concentrations
Page 508 and 509: STYRENE 501 The frequency of sponta
Page 510 and 511: STYRENE 503 groups. Only minor gene
Page 512 and 513: concentrations of styrene in air we
Page 514 and 515: Table 12. Cytogenetic studies in ly
Page 516 and 517: Table 13. Genetic and related effec
Page 518 and 519: (b) Experimental systems (see Table
Page 522 and 523: STYRENE 515 styrene 7,8-oxide. Joha
Page 524 and 525: Styrene 7,8-oxide can bind to DNA w
Page 526 and 527: STYRENE 519 a small and non-signifi
Page 528 and 529: STYRENE 521 and immune systems, liv
Page 530 and 531: STYRENE 523 Artuso, M., Angotzi, G.
Page 532 and 533: STYRENE 525 Brugnone, F., Perbellin
Page 534 and 535: STYRENE 527 Coccini, T., Maestri, L
Page 536 and 537: STYRENE 529 Edling, C., Anundi, H.,
Page 538 and 539: STYRENE 531 Gobba, F., Galassi, C.,
Page 540 and 541: STYRENE 533 Horvath, E., Pongracz,
Page 542 and 543: STYRENE 535 logical Study and the I
Page 544 and 545: STYRENE 537 Linhart, I., Gut, I.,
Page 546 and 547: STYRENE 539 Miller, S.L., Branoff,
Page 548 and 549: STYRENE 541 Newhook, R. & Caldwell,
Page 550 and 551: STYRENE 543 Pryor, G.T., Rebert, C.
Page 552 and 553: STYRENE 545 Sielken, R.L. & Valdez-
Page 554 and 555: STYRENE 547 Tsuda, S., Matsusaka, N
Page 556 and 557: STYRENE 549 Boffetta, P. (1996b) Ex
Page 558: Agent SUMMARY OF FINAL EVALUATIONS
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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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