IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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CYP2E1 and CYP2F2) inhibited nasal metabolism. Subsequent metabolism of styrene 7,8-oxide by epoxide hydrolase and GST was much higher in rat nasal tissue than in mouse nasal tissue. (d ) Excretion Sumner et al. (1997) compared the metabolism of [7- 14 C]styrene administered by inhalation (250 ppm [1060 mg/m 3 ], 6 h per day for 1–5 days) to B6C3F 1 mice, CD-1 mice and Fischer 344 rats. Rats and CD-1 mice excreted the radioactivity faster than did B6C3F 1 mice following a single exposure, but the rates were similar for the three groups after repeated exposures on 3 or 5 days. Boogaard et al. (2000a) studied the disposition of [ring-U- 14 C]styrene in Sprague-Dawley rats and CD-1 mice exposed by recirculating nose-only exposure (160 ppm [682 mg/m 3 ] for 6 h). Urinary excretion was the primary route of elimination (amounting to 75% of the retained styrene for rats and 63% for mice), and there was little quantitative difference between rats and mice except that mice exhaled 14 CO 2 which amounted to 6.4–8.0% of the retained styrene, while for rats this was only 2%. Whole-body autoradiography showed significantly higher non-specific binding of radioactivity in mouse lung and nasal passages compared with rat lung. 4.1.3 Pharmacokinetic modelling STYRENE 491 Table 11. Metabolism of styrene to styrene 7,8-oxide enantiomers by mouse and rat lung microsomes and isolated Clara cell-enriched fraction Lung microsomes Mouse (n = 4) Rat (n = 5) Clara cell fraction Mouse (n = 4) Rat (n = 3) R-enantiomer S-enantiomer R/S 1.50 ± 0.23 a 0.49 ± 0.09 83.3 ± 27.7 11.2 ± 3.6 0.63 ± 0.06 0.95 ± 0.18 23.0 ± 8.2 11.0 ± 3.2 2.40 ± 0.36 0.52 ± 0.01 3.98 ± 0.75 1.02 ± 0.09 Data from Hynes et al. (1999) Values for R- and S-enantiomers are in nmol/mg protein/min for lung microsomes and in pmol/10 6 cells/min (not corrected for cell type) for Clara cell fractions. The percentages of Clara cells in these fractions were 56% for mouse and 37% for rat. a Mean ± standard error Ramsey and Young (1978) and Ramsey et al. (1980) analysed the pharmacokinetic profile of inhaled styrene in male rats [strain unspecified] and humans. In human volunteers exposed to 80 ppm [341 mg/m 3 ] for 6 h, styrene was cleared from the blood
492 IARC MONOGRAPHS VOLUME 82 according to a two-compartment linear pharmacokinetic model that was similar to that for rats. The model predicted that there would be no accumulation of styrene at this exposure concentration and upon repeated administration. Ramsey and Andersen (1984) developed a physiologically based pharmacokinetic model, which indicated that there was saturation of styrene metabolism at inhaled doses above 200 ppm [852 mg/m 3 ] in mice, rats and humans. At lower levels of exposure, the ratio of styrene concentration in blood to that in inhaled air is controlled by perfusion-limited metabolism. Another physiologically based pharmacokinetic model was based on data collected by Mandrala et al. (1993) to predict concentration–time curves for styrene and styrene 7,8-oxide in blood and tissues (Csanády et al., 1994). At low concentrations, styrene is rapidly removed from blood and the rate of metabolism is limited by the blood flow through the liver. Cohen et al. (2002) developed a pharmacokinetic model viewing the lung as two compartments, the alveolar tract and the capillary bed. This model included both pulmonary and hepatic metabolism and predicted tissue or organ concentrations of styrene and styrene 7,8-oxide (both the S- and R-enantiomers, separately), under specified conditions. It was based on the Csanády et al. (1994) model, which only accounted for styrene metabolism by the liver. The authors indicated that the model has a substantial degree of uncertainty, however, because of inconsistencies between studies in reporting styrene 7,8-oxide levels in blood, which complicated the validation of the model. Filser et al. (2002) compared the modelled concentrations of styrene 7,8-oxide in the lungs of the mouse, rat and human over a range of styrene concentrations assuming 6- or 8-h exposures. The highest concentrations of styrene 7,8-oxide were predicted for the mouse followed by the rat, with humans having by far the lowest concentration. These differences reflected the species differences in the pulmonary metabolism of styrene to styrene 7,8-oxide and subsequent detoxification of the oxide. The most comprehensive modelling for styrene metabolism and styrene 7,8-oxide dosimetry comparing rodents and humans was undertaken by Sarangapani et al. (2002). It expanded upon the Csanády et al. (1994) model by incorporating information on the metabolic production of styrene 7,8-oxide and its decrease in the respiratory tract and was used to predict the concentrations of styrene and styrene 7,8-oxide in blood, liver and respiratory tract. This model predicts a ten-fold lower styrene 7,8-oxide concentration in the terminal bronchioles of rats than in mice exposed to identical concentrations of styrene. The model suggests that styrene 7,8-oxide concentrations in human bronchioles would be 100-fold lower than for the mouse. Tornero-Velez and Rappaport (2001) modified the physiologically based pharmacokinetic model of Csanády et al. (1994) to compare the predicted contribution of styrene 7,8-oxide resulting from metabolism with that from direct exposure in the workplace. They tested their model against air and blood concentrations of styrene and styrene 7,8-oxide in 252 workers in the reinforced plastics industry. Due to efficient detoxification of the oxide formed in the liver, direct exposure via inhalation appeared to be a more important source of styrene 7,8-oxide than the bioactivation of inhaled styrene. The
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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
Page 448 and 449: Styrene is produced mainly by catal
Page 450 and 451: STYRENE 443 Table 3. Use patterns f
Page 452 and 453: STYRENE 445 most samples taken from
Page 454 and 455: STYRENE 447 successive layers of ch
Page 456 and 457: Table 4 (contd) Country and year of
Page 458 and 459: Table 5. Biological monitoring of o
Page 460 and 461: STYRENE 453 Since 1990, the long-te
Page 462 and 463: same products resulted in exposures
Page 464 and 465: STYRENE 457 Ambient air monitoring
Page 466 and 467: 200 μg/kg, although 77% of the foo
Page 468 and 469: 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 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 520 and 521: Table 14 (contd) Test system Result
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,
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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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