Monograph on the Potential Human Reproductive and ... - OEHHA

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in each group were killed at 96 hr post-dosing. Maternal organs, 6 embryos or fetuses/dam (when possible), and placentas were collected. Samples were analyzed for radioactivity and bisphenol A and/or bisphenol A glucuronide by HPLC/liquid scintillation spectrometry. In all groups, 90–94% of radioactivity was recovered. Elimination of bisphenol A and its metabolites is discussed in Section 2.1.2.4. At 96 hr following dosing, low percentages of the dose were present in carcass (B1– 6%) and tissues such as brain, fat, liver, kidney, ovary, uterus, and skin. The only quantifiable data in placentas and fetuses at 96 hr were obtained in the GD 17 group, and those samples contained 0.01–0.07% of the bisphenol A dose. Standard deviations for maternal and fetal tissues generally exceeded 50% of the mean. Study authors concluded that disposition of radioactivity was similar in pregnant and non-pregnant rats. Toxicokinetic data obtained from plasma profiles are summarized in Table 24. The authors stated that there was high inter-animal variability. The presence of two C max values was noted by the authors, and they stated that it was the result of enterohepatic circulation of radioactivity. Bisphenol A was not quantifiable in most plasma samples. Because bisphenol A glucuronide represented most (B95–99%) of the radioactivity, plasma profiles for that metabolite were nearly identical to profiles for radioactivity. Table 23 Toxicokinetic Endpoints for Bisphenol A in Rats Dosed With 1000 mg/kg bw Bisphenol A on GD 18 a Maternal tissue Endpoint Blood Liver Kidney Fetus C max, mg/L 14.7 171 36.2 9.22 T max, min 20 20 20 20 AUC, mg hr/L 13.1 700 84.0 22.6 Mean retention time, hr 10.6 29.3 12.0 20.0 Variance in retention 203 657 227 419 time, hr squared Half-life, hr From 20–40 min 0.0952 0.178 0.245 0.55 From 40 min–6 hr 2.58 1.75 2.98 1.60 From 6–48 hr 4.65 No data No data 173 a Takahashi and Oishi (2000). BISPHENOL A 187 A second study was conducted by Dormoradzki et al. (2003) to measure bisphenol A and bisphenol A glucuronide concentrations in maternal and fetal tissues. Rats were gavaged with radiolabeled bisphenol A at 10 mg/kg bw on GD 11, 13, or 16. Blood was collected over a 24-hr period. Five rats/group/time period were killed at 0.25, 12, and 96 hr post-dosing. Maternal blood and organs, yolk sacs/placentas, and embryos/fetuses were removed for measurement of bisphenol A and bisphenol A glucuronide. Yolk sacs/placentas and fetuses were pooled at most time periods. Results are summarized in Table 25. At 0.25 hr following dosing, bisphenol A glucuronide concentrations in maternal plasma were similar in groups dosed on GD 11 and 13 but concentrations were 1.7–2 times higher in the group dosed on GD 16. At 12 hr post-dosing in all exposure groups, bisphenol A glucuronide concentrations in maternal plasma were reduced 7to 11-fold from values observed at 0.25 hr. Levels of radioactivity in plasma were not sufficient for analysis at 96 hr post-dosing. Bisphenol A was detected in maternal plasma at 0.25 hr post-dosing in rats that were exposed to a higher radioactive concentration (0.5 mCi compared to 0.2 mCi) on GD 16; bisphenol A concentrations were 26.5-fold lower than bisphenol A glucuronide concentrations. In animals dosed on GD 11, bisphenol A glucuronide was only detected in yolk sac/placenta at 0.25 hr postdosing and the concentration was B17 times lower than the concentration detected in maternal blood for the same time period. With dosing on GD 11, bisphenol A glucuronide was not detected in embryos and bisphenol A was not detected in yolk sac/placenta or embryos. In animals dosed on GD 13, bisphenol A glucuronide was detected in yolk sac/placenta at 0.25 and 12 hr postdosing and concentrations were 9–24-fold lower than those detected in maternal plasma for the same time period. Bisphenol A was also detected in yolk sac/ placenta at 0.25 and 12 hr after dosing on GD 13 and concentrations were similar to those detected in the blood of 2 dams. A lower concentration of bisphenol A was detected in embryos of dams at 0.25 hr following dosing on GD 13, and bisphenol A was the only moiety detected in embryos. Following dosing on GD 16, bisphenol A glucuronide and bisphenol A were detected in yolk sac/placenta at 0.25 and 12 hr post-dosing. Concentrations of bisphenol A glucuronide in yolk sac/ Table 24 Toxicokinetic Data for Radioactivity in Pregnant and Non-Pregnant Rats Gavaged With 10 mg/kg bw 14 C-bisphenol A a Endpoint Non-pregnant GD 6–10 GD 14–18 GD 17–21 C max1, mg eq/L 0.716 0.370 0.482 1.006 T max1, hr 0.25 0.25 0.25 0.25 Cmax2, mg eq/L 0.171 0.336 0.211 0.278 Tmax2, hr 18 12 24 12 Time to non-quantifiable level, hr 72 Not determined 72 96 AUC 14 C, mg-eq � hr/L 6.1 12.4 7.1 10.2 Bisphenol A glucuronide, 5.8 12.3 6.8 9.7 mg-eq � hr/L Percent as bisphenol 95.1 99.2 95.8 95.1 A glucuronide a Dormoradzki et al. (2003). Birth Defects Research (Part B) 83:157–395, 2008
188 CHAPIN ET AL. Table 25 Maternal and Fetal Concentrations of Bisphenol A Following Gavage Dosing of Dams With 10 mg/kg bw Bisphenol A a Bisphenol A concentration, mg/L or mg/kg Maternal plasma Yolk sac/placenta Embryo/fetus Exposure Glucuronide Parent Glucuronide Parent Glucuronide Parent GD 11, 0.2 mCi 0.25 hr 1.06070.258 0.041 0.062 oLOD b oLOD oLOD 12 hr 0.09970.036 oLOD oLOD oLOD oLOD oLOD 96 hr GD 13, 0.2 mCi NA NA oLOD oLOD oLOD oLOD 0.25 hr 0.86870.189 0.078 0.036 0.019 oLOD 0.013 12 hr 0.11770.033 0.008 0.013 0.009 oLOD oLOD 96 hr GD 16, 0.2 mCi Not analyzed due to insufficient radioactivity 0.25 hr 1.76870.783 0.485, 0.129 c 0.22370.104 0.16670.069 0.031, 0.009 c 0.122, 0.020 c 12 hr 0.17470.045 oLOD 0.02570.005 0.03470.002 NA NA 96 hr GD 16, 0.5 mCi Not analyzed due to insufficient radioactivity 0.016 0.008 0.25 hr 1.69970.501 0.06470.025 0.34270.104 0.09570.031 0.01370.008 0.01870.011 Data expressed as mean7SD or single values for individual or pooled data. a Dormoradzki et al. (2003). b Limit of detection (LOD) for bisphenol A reported at 0.005–0.029. c Detected only in two animals at the concentrations listed. placenta were 7- to 8-fold lower than concentrations detected in maternal plasma. From 0.25 to 12 hr, concentrations of bisphenol A decreased 4.9-fold and concentrations of bisphenol A glucuronide decreased 9fold. Mean concentrations of bisphenol A in yolk/sac placenta following exposure on GD 16 were similar to the blood concentration detected in 1 of 2 dams. In yolk sac/placenta and fetuses of dams dosed with a higher level of radioactivity (0.5 mCi) on GD 16, bisphenol A glucuronide and bisphenol A were detected at 0.25 hr following dosing. Compared to concentrations detected in placenta, fetal concentrations of bisphenol A glucuronide were B26-fold lower and bisphenol A concentrations were 5-fold lower. Bisphenol A concentrations were lower than bisphenol A glucuronide concentrations by 3.6-fold in yolk sac/placenta and by 0.7-fold in fetuses. Study authors concluded that there is no selective affinity for bisphenol A or bisphenol A glucuronide by the yolk sac/placenta or embryo/fetus. Kurebayashi et al. (2005) examined distribution of radioactivity in pregnant and lactating rats dosed with 14 C-bisphenol A. Pregnant rats were orally dosed with 0.5 mg/kg bw 14 C-bisphenol A on GD 12, 15, or 18. The rats were killed at 30 min or 24 hr following dosing (n 5 1/time period) and examined by whole-body radioluminography. Study authors noted that the distribution of label was nearly identical in dams at each gestation time point. At 30 min following dosing, the concentration of radioactivity in dam blood was B31– 43 mg bisphenol A eq/L. The highest concentration of radioactivity was detected in maternal liver (B219– 317 mg bisphenol A eq/kg) and kidney (B138–270 mg bisphenol A eq/kg); concentrations in other tissues (lung, ovary, placenta, skin, and uterus) were B10-fold lower. Fetuses, fetal membranes, and yolk sacs did not contain quantifiable levels of radioactivity at 30 min following maternal exposure at any gestation time point. At 24 hr following exposure of dams, radioactivity concentrations in blood (B4–11 mg bisphenol A eq/L) were nearly 3–10-fold lower than values obtained at 30 min following exposure. Levels of radioactivity remained highest in liver. At 24 hr following exposure, radioactivity was only detected in fetuses and fetal tissues from dams dosed on GD 18. Radioactivity levels in fetuses or fetal tissues compared to maternal blood were B30% in fetuses, nearly equal in fetal membranes, and B5-fold higher in yolk sacs. Study authors concluded that there was limited distribution of radiolabel to fetuses. In another study by Kurebayashi et al. (2005), a lactating rat was orally dosed with 0.5 mg/kg bw 14 Cbisphenol A on PND 11 and caged with 5 neonatal rats for 24 hours. One male and one female neonatal rat were killed at the end of the 24-hr period and examined by whole-body radioluminography. The 3 remaining neonates were caged for 24 hr with a dam that was not exposed to bisphenol A. One male and one female neonate were then killed and examined by whole-body radioluminography. In pups killed immediately after being nursed by the lactating dam exposed to 14 Cbisphenol A, most of the radioactivity was detected in intestinal contents (B30–46 mg bisphenol A eq/kg) and lower levels were found in gastric contents and urinary bladder (o10 mg bisphenol A eq/kg). After being nursed for 24 hr by a dam that was not exposed to bisphenol A, radioactivity was only detected in intestinal contents and the level was B20–40% of that measured in pups examined immediately after being nursed by dams receiving 14 C-bisphenol A. An additional 3 lactating dams were dosed with 0.5 mg/kg bw 14 C-bisphenol A on PND 11 for examination of radioactivity in plasma and milk over a 48-hr period. Table 26 summarizes toxicokinetic endpoints for radioactivity in milk and plasma. Study authors concluded that there was significant secretion of 14 Cassociated radioactivity into milk. Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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NTP.will.transmit.the.NTP-CERHR.<st
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National Toxicology Program U.S. De
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nTp brief tainers.with.internal.epo
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Population Adult General. Populatio
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Table 3. Blood and Breast Milk Biom
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Figure 2b. The weight of evidence t
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in.considering.the.biological.plaus
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isphenol.A.as.efficiently.as.adult.
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isphenol.A..For.example,.this.raise
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laboRaToRy aNImal STudIeS In.contra
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of.normal.sex-based.differences.bet
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death.(168),.synaptic.plasticity.(1
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gland.carcinogen.or.that.bisphenol.
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understand.the.possible.long-term.c
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strategies.to.improve.the.sensitivi
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and.cystic.endometrial.hyperplasia.
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cutaneous. injection. 20 . vom. Saa
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are CurrenT exposures To bisphenol
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w/day;.95th.percentiles.0.289.-.0.2
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nTp ConClusions The.NTP.reached.the
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appendix a: inTerpreTaTion of blood
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µg/kg.bw/day.based.on.the.assumpti
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concentrations.from.maternal,.fetal
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Page 67 and 68: Thyroid.Function.in.Juvenile.Female
Page 69 and 70: droxylase.immunoreactivity..76:423.
Page 71 and 72: stanceschimiques.gc.ca/challenge-de
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Page 75 and 76: 226..vom. Saal. FS,. Cooke. PS,. Bu
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Page 79 and 80: appendix i. nTp-Cerhr bisphenol a e
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Page 91 and 92: 168 CHAPIN ET AL. comparison of the
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Page 97 and 98: 174 CHAPIN ET AL. Table 11 Bispheno
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Page 101 and 102: 178 CHAPIN ET AL. Table 15 Estimate
Page 103 and 104: 180 CHAPIN ET AL. Table 17 Maximum
Page 105 and 106: 182 CHAPIN ET AL. 2.0 GENERAL TOXIC
Page 107 and 108: 184 CHAPIN ET AL. fetuses (3.572.7
Page 109: 186 CHAPIN ET AL. Secondary sources
Page 113 and 114: 190 CHAPIN ET AL. Table 27 Bispheno
Page 115 and 116: 192 CHAPIN ET AL. Table 31 Qualitat
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Page 125 and 126: 202 CHAPIN ET AL. suggesting that 4
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Page 135 and 136: 212 CHAPIN ET AL. Table 52 Continue
Page 137 and 138: 214 CHAPIN ET AL. Model and exposur
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Page 141 and 142: 218 Model and exposure Husbandry a
Page 143 and 144: 220 CHAPIN ET AL. Table 54 Differen
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Page 147 and 148: 224 Table 57 In Vitro Genetic Toxic
Page 149 and 150: 226 CHAPIN ET AL. Table 58 In Vivo
Page 151 and 152: 228 CHAPIN ET AL. Table 59 Developm
Page 155 and 156: 232 CHAPIN ET AL. Table 64 Tissue R
Page 159 and 160: 236 CHAPIN ET AL. treatment conditi
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238 CHAPIN ET AL. clinical signs, b
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240 CHAPIN ET AL. Table 71 Benchmar
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242 CHAPIN ET AL. group, 5 from 1 l
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244 CHAPIN ET AL. least significant
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246 CHAPIN ET AL. group was a reduc
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248 CHAPIN ET AL. 100-151 g for fem
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250 CHAPIN ET AL. 3.2.3.2 Developme
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252 CHAPIN ET AL. weights, bispheno
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254 CHAPIN ET AL. 120 mg/kg bw/day
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256 CHAPIN ET AL. comparisons condu
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258 CHAPIN ET AL. the findings of t
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260 CHAPIN ET AL. analyzed.] Anogen
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262 CHAPIN ET AL. purposeful confou
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264 CHAPIN ET AL. increased lordosi
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266 CHAPIN ET AL. that there was a
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268 CHAPIN ET AL. duration of adver
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270 CHAPIN ET AL. doses of potent e
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272 CHAPIN ET AL. Table 74 Effects
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274 CHAPIN ET AL. reproductive orga
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276 CHAPIN ET AL. tyrosine-hydroxly
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278 CHAPIN ET AL. include small sam
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280 CHAPIN ET AL. males/group. [It
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282 CHAPIN ET AL. termination, whic
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284 CHAPIN ET AL. provided a reliab
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286 CHAPIN ET AL. grooming, and out
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288 CHAPIN ET AL. method of oral do
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290 CHAPIN ET AL. reared by their d
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292 CHAPIN ET AL. has been informed
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294 CHAPIN ET AL. buffered paraform
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296 CHAPIN ET AL. unit. Further, th
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298 CHAPIN ET AL. PND 21 and housed
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300 CHAPIN ET AL. Tando et al. (200
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302 CHAPIN ET AL. Purina Certified
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304 CHAPIN ET AL. high-doses of bis
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306 CHAPIN ET AL. born to those dam
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308 CHAPIN ET AL. average weight we
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310 CHAPIN ET AL. study authors con
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312 CHAPIN ET AL. used for extracti
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314 CHAPIN ET AL. jar, and there we
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316 CHAPIN ET AL. of testes and com
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318 CHAPIN ET AL. differentiation o
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320 CHAPIN ET AL. Table 81 Summary
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322 CHAPIN ET AL. Table 82 Continue
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328 CHAPIN ET AL. 600 mg/kg bw/day)
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330 CHAPIN ET AL. (Nagao et al., 19
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332 CHAPIN ET AL. antinuclear antib
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334 CHAPIN ET AL. least 6 animals.
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336 CHAPIN ET AL. Utility (Adequacy
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338 CHAPIN ET AL. stomach weight wa
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340 CHAPIN ET AL. Schirling et al.
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342 CHAPIN ET AL. Endpoint Table 88
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344 CHAPIN ET AL. different diets b
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346 CHAPIN ET AL. with 40 mg vitami
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348 CHAPIN ET AL. the bisphenol A v
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350 CHAPIN ET AL. and determining t
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352 CHAPIN ET AL. expression [to B6
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354 CHAPIN ET AL. indicated] at 0 (
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356 CHAPIN ET AL. concentrations us
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358 CHAPIN ET AL. animals were non-
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360 CHAPIN ET AL. following adjustm
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362 CHAPIN ET AL. Table 94 Treatmen
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364 CHAPIN ET AL. Table 97 Effects
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366 CHAPIN ET AL. Table 99 Treatmen
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368 CHAPIN ET AL. Therefore the NTP
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370 CHAPIN ET AL. weeks before mati
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374 Table 101 Summary of High Utili
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376 Table 102 Summary of Limited Ut
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380 CHAPIN ET AL. from other suppli
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382 CHAPIN ET AL. U.S. populations.
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384 CHAPIN ET AL. 10. Critical desi
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386 CHAPIN ET AL. Engel SM, Levy B,
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388 CHAPIN ET AL. alpha and beta ex
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390 CHAPIN ET AL. Murray TJ, Maffin
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392 CHAPIN ET AL. Ryan BC, Vandenbe
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394 CHAPIN ET AL. Thomas P, Dong J.
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appendix iii. publiC CommenTs and p
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