IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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STYRENE 487 rats with phenobarbital (oral dose of 80 mg/kg bw daily for three days) enhanced the hepatic microsomal metabolism of styrene approximately six-fold. Elovaara et al. (1991) compared the influence of acetone, phenobarbital and 3-methylcholanthrene on the urinary metabolites of male Han/Wistar rats exposed to styrene by inhalation (2100 mg/m 3 for 24 h) and found increases of 30–50% in the excretion of phenylglyoxylic acid and mandelic acid in the rats treated with acetone (1% in drinking-water for one week) but not in the other groups. Co-administration by intraperitoneal injection of toluene (217 mg/kg bw) suppressed the metabolism of styrene (228 mg/kg bw) in Wistar rats (Ikeda et al., 1972). Co-administration of ethanol (2 mM) decreased the uptake and metabolism of styrene (given as a 28.8-μM solution) in a perfused rat liver system in fed animals and increased these parameters in fasted animals. This was associated with increased levels of NADPH due to oxidation of ethanol (Sripaung et al., 1995). Salmona et al. (1976) compared formation of styrene 7,8-oxide and its further transformation to styrene glycol by epoxide hydrolase in microsomal preparations from different tissues from CD rats and found mono-oxygenase and epoxide hydrolase activity in liver, lung and kidney, but not in heart, spleen and brain, with the highest activities in male rat liver. When apparent hepatic V max values for the metabolism of styrene to styrene 7,8oxide by styrene mono-oxygenase were compared among species, the order was Dunkin Hartley guinea-pig > New Zealand rabbit > Swiss mouse > Sprague-Dawley rat (Belvedere et al., 1977). However, the order for the metabolism of styrene 7,8-oxide to styrene glycol by epoxide hydrolase was rat > rabbit > guinea-pig >mouse, so that the V max ratios for epoxide hydrolase vs styrene mono-oxygenase were 3.9, 2.4, 1.6 and 1.4 for the rat, rabbit, guinea-pig and mouse, respectively. Watabe et al. (1981) reported that liver microsomal preparations from male Wistar rats preferentially formed S-styrene 7,8-oxide over R-styrene 7,8-oxide (R- to S-ratio, 0.77). Foureman et al. (1989) examined the stereoselectivity of styrene 7,8-oxide formation in the livers of male Sprague- Dawley rats and found an R- to S- ratio of 0.65. This ratio increased to 0.92 in phenobarbital-treated rats. This R- to S-ratio contrasts with results indicating preferential formation of R-styrene 7,8-oxide in the liver of CD-1 mice (ratio R/S, 1.2–1.8) (Carlson, 1997a; Hynes et al., 1999) and in pulmonary microsomes from rabbits (ratio of 1.6) (Harris et al., 1986). Mendrala et al. (1993) compared the kinetics of styrene and styrene 7,8-oxide metabolism in rat, mouse and human livers in vitro. K m values for styrene epoxidation by mono-oxygenase were similar for the three species. The V max values, however, varied from 13 nmol/min/mg protein for B6C3F 1 mice, 11 nmol/min/mg protein for Fischer 344 rats, 9.3 nmol/min/mg protein for Sprague-Dawley rats to 2.1 nmol/min/mg protein for humans (average of five donors). V max values for epoxide hydrolase were similar for all three species (14–15 nmol/min/mg protein). Nakajima et al. (1994a) compared the rates of styrene metabolism using microsomal preparations from different sources. At a low substrate concentration (0.085 mM), the rates of hepatic metabolism decreased from mouse (2.43 nmol/mg protein/min) to rat
488 IARC MONOGRAPHS VOLUME 82 (1.07 nmol/mg protein/min) to human (0.73 nmol/mg protein/min), whereas at a high styrene concentration (1.85 mM), the rates were in the order of rat (4.21 nmol/mg protein/min) to mouse (2.72 nmol/mg protein/min) to human (1.91 nmol/mg protein/ min). Activity in pulmonary microsomes from 38 individuals was much lower (0.006– 0.0125 nmol/mg protein/min) than in liver. Carlson et al. (2000) also observed low activity for styrene metabolism in microsomal preparations from six human lungs. Styrene 7,8-oxide formation was detectable in only one human sample (0.088 nmol/mg protein/ min). [The Working Group noted that enzyme activity measurements based upon analysis of whole organ homogenates do not reflect the substantial differences that exist between cell types, as has been demonstrated by immunohistochemical methods for CYP2E1 and CYP2F2 in lung (Buckpitt et al., 1995; Green et al., 1997).] A few studies have described the formation of the ring-hydroxylated product 4-vinylphenol after exposure of rodents to styrene. Bakke and Scheline (1970) reported finding 4-vinylphenol in amounts up to 0.1% of the dose in enzymatically hydrolysed urine of male rats [strain unspecified] dosed orally with styrene (100 mg/kg bw). Similarly, Pantarotto et al. (1978) identified small amounts of 4-vinylphenol, 4-hydroxymandelic acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid in the urine of male Sprague- Dawley rats administered styrene intraperitoneally. More recently, when rats and mice were exposed by inhalation to [ring-U- 14 C]styrene, Boogaard et al. (2000a) reported finding 14 CO 2, suggesting that ring hydroxylation may occur followed by ring opening. The fraction of the dose eliminated as 14 CO 2 varied from 6.4–8.0% of the retained dose of styrene in mice to 2% of the retained dose in rats. Watabe et al. (1984) demonstrated the formation of 4-vinylphenol using 14 C-labelled styrene and a rat hepatic microsomal preparation fortified with NADPH after addition of a large amount of unlabelled 4-vinylphenol as a trapping agent. They suggested that 4-vinylphenol was formed via the 3,4-oxide but very rapidly metabolized to 4-hydroxystyrene-7,8-glycol. Carlson et al. (2001) were unable to confirm 4-vinylphenol formation when styrene was incubated with hepatic and pulmonary microsomal preparations from CD-1 mice and Sprague-Dawley rats. However, considerable 4-vinylphenol-metabolizing activity, as determined by the loss of 4-vinylphenol, was observed in both mouse and rat liver and lung microsomal preparations. This activity was three times higher in mouse liver microsomes than in rat liver microsomes and eight times higher in mouse lung microsomes than in rat lung microsomes, and it was completely absent in the absence of NADPH. Studies with cytochrome P450 inhibitors indicated the involvement of CYP2E1 and CYP2F2. Several studies have focused on the pharmacokinetics of styrene and some species comparisons. Ramsey and Young (1978) exposed Sprague-Dawley rats to styrene by inhalation at concentrations of 80, 200, 600 and 1200 ppm [341, 852, 2560 and 5110 mg/m 3 ] for up to 24 h. The increase in styrene concentration in blood with increased exposure concentration was non-linear, indicating saturation of metabolism after about 6 h of exposure. Filser et al. (1993) compared male Sprague-Dawley rats and B6C3F 1 mice exposed to styrene by inhalation in a closed chamber (550–5000 ppm [2340–21 300 mg/m 3 ]), by intraperitoneal injection (20–340 mg/kg bw) or by oral
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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
Page 444 and 445: STYRENE This substance was consider
Page 446 and 447: 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 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 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
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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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