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

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BISPHENOL A Table 34 Distribution of Radioactivity to Tissues at 24 Hr Following Dosing With Radiolabeled Bisphenol A a PND 4 PND 7 PND 21 AUC AUC mg � AUC ratio Half- AUC mg � ratio of AUC mg � AUC ratio Tissue Half-life hr hr/kg of doses life hr hr/kg doses Half-life hr hr/kg of doses Females, 1 mg/kg bw Brain 11.7 0.4 6.7 0.2 3.6 0.1 Liver 18 7.5 7.9 7.1 3.6 2.9 Kidney 18.1 9.4 7.3 9.5 5.0 3.0 Ovary 11.7 7.3 6.0 3.5 3.7 0.9 Uterus 7.4 8.3 6.2 3.0 3.4 1.0 Carcass 11.2 22.2 10.0 16.6 4.0 8.3 Plasma 19.5 9.4 6.4 7.8 3.6 3.5 Females, 10 mg/kg bw Brain 7.2 3.3 8.3 8.0 2.5 12.5 4.9 1.7 17.0 Liver 11.1 44.8 6.0 10.0 59.6 8.4 4.5 39.1 13.5 Kidney 15.2 43.9 4.7 8.6 66.6 7.0 5.3 36.5 12.2 Ovary 6.5 136.2 18.7 5.0 69.7 19.9 3.6 21.1 23.4 Uterus 15.2 127.0 15.3 4.8 108.5 36.2 3.4 30.6 30.6 Carcass 6.6 112.8 5.1 7.0 130.7 7.9 4.8 100.9 12.2 Plasma 9.2 61.0 6.5 8.1 67.0 8.6 3.7 59.0 16.9 Males, 1 mg/kg bw Brain 14.1 0.3 6.0 0.3 3.4 0.1 Liver 19.7 6.1 6.6 7.3 3.7 3.2 Kidney 19.3 8.5 7.0 8.6 4.6 3.4 Testis 10.3 3.4 5.7 2.0 3.4 0.8 Carcass 11.1 22.2 9.0 17.3 4.1 9.0 Plasma 24.0 9.2 6.6 7.7 3.4 4.2 Males, 10 mg/kg bw Brain 3.1 4.7 15.7 8.0 2.9 9.7 4.7 1.7 17.0 Liver 11.6 48.4 7.9 11.8 62.0 8.5 5.1 40.9 12.8 Kidney 5.4 68.9 8.1 9.8 59.6 6.9 6.9 30.4 8.9 Testes 5.8 36.8 10.8 7.6 22.1 11.1 5.2 8.1 10.1 Carcass 8.3 111.7 5.0 8.6 135.5 7.8 4.8 95.2 10.6 Plasma 6.9 113.0 12.3 9.9 69.0 9.0 4.0 62.0 14.8 a Domoradzki et al. (2004). Table 35 Toxicokinetic Endpoints for Bisphenol A in Blood Following Dosing of Rats by Gavage or Injection a Exposure route and doses (mg/kg bw) Endpoint 10 oral 100 oral 10 i.p. 100 i.p. 10 s.c. 100 s.c. Males Tmax, hr N/A 0.083 0.5 0.25 0.75 0.5 Cmax, mg/L, hr c b 0.2270.09 0.6970.08 9.771.27 0.3970.16 5.1970.98 Time to non-quantifiable concentration, hr 0.083 0.75 8 12 18 24 AUC, mg � hr/L Females 0.1 1.1 16.4 2.6 24.5 Tmax, hr 0.25 0.25 0.25 0.25 4 0.75 Cmax, mg/L, hrb 0.0470.03 2.2971.82 0.8770.15 13.1374.13 0.3470.06 3.9770.6 Time to non-quantifiable concentration, hr 1 24 72 48 72 AUC, mg � hr/L 0.42 4.4 1.4 26.2 3.1 31.5 Missing values were not determined. a Pottenger et al. (2000). b Mean7SD. c Non-quantifiable (0.01 mg/g at 10 mg/kg bw and 0.1 mg/g at 100 mg/kg bw). route, as noted by approximate proportionate increases summarized in Table 36. Concentrations of radioactivity in Cmax and AUC values from the low to the high-dose. were dependent on exposure route and to a lesser extent, Toxicokinetics data for radioactivity in plasma are dose and sex. AUC values for radioactivity were lowest Birth Defects Research (Part B) 83:157–395, 2008 195
196 CHAPIN ET AL. Table 36 Toxicokinetics for Radioactivity Following Dosing of Rats with Bisphenol A Through Different Exposure Routes a Exposure route and doses (mg/kg bw) Endpoint 10 oral 100 oral 10 i.p. 100 i.p. 10 s.c. 100 s.c. Males T max, hr 0.25 0.25 0.5 0.25 1 0.75 Cmax, mg eq/L, hr 0.7370.22 3.9271.93 1.2670.09 29.3711.7 0.6170.24 6.3370.43 Time to non-quantifiable 72 72 96 96 96 144 concentration, hr AUC, mg-eq � hr/L 8.1 66.5 16.9 170 15.5 218 Females Tmax, hr 0.083 0.25 0.25 0.5 0.75 0.75 Cmax, mg eq/L, hr 1.8270.66 28.3378.64 2.2770.19 67.8177.33 0.5270.06 5.6670.95 Time to non-quantifiable 72 72 72 120 120 168 concentration, hr AUC, mg-eq � hr/L 9.54 94.9 15.3 247 21.6 297 a Pottenger et al. (2000). Table 37 Toxicokinetic Values for Bisphenol A in Adult Rats Exposed to Bisphenol A Through the Intravenous or Oral Route a Bisphenol A dosing 0.1 mg/kg 10 mg/kg Endpoint bw, i.v. bw, gavage Distribution half-life, min 6.171.3 Terminal elimination 0.970.3 21.377.4 half-life, hr AUC, mg � hr/L 16.173.2 85.6733.7 Systemic clearance, 107.9728.7 mL/min/kg Steady-state volume of 5.672.4 distribution, L/kg Cmax, mg/L 14.7710.9 Tmax, hr 0.270.2 Apparent volume of 427372007.3 distribution, L/kg Oral clearance, mL/min/kg 2352.17944.7 Absolute oral bioavailability, % 5.372.1 Data presented as mean7SD. a Yoo et al. (2001). following oral exposure. Time to non-quantifiable concentration was longest following s.c. dosing. For most groups, C max and AUC values were proportionate across doses within the same exposure route. A second part of the study examined metabolites and is summarized in Section 2.1.2.3. Upmeier et al. (2000) examined toxicokinetics in rats exposed to bisphenol A through the oral or i.v. route. Ovariectomized DA/Han rats (130–150 g bw) were exposed to bisphenol A by i.v. injection with 10 mg/kg bw or oral gavage with 10 or 100 mg/kg bw. Blood was collected from treated rats at multiple time points until 2 hr following i.v. dosing and 3 hr following oral dosing. Three to five rats were sampled during each time period. To reduce stress, only some of the rats were sampled at each time point. In control animals, blood was collected 2 hr following dosing with vehicle. Bisphenol A concentrations in plasma were measured by GC/MS. Dosing with 10 mg/kg bw i.v. resulted in a maximum plasma concentration of 15,000 mg/L bisphenol A. Concentrations decreased to 700 mg/L within 1 hr, 100 mg/L within 2 hr, and non-detectable concentrations by 24 hr followingexposure. The apparent final elimination halflife was estimated at 38.5 hr. In rats gavaged with 10 mg/ kg bw, an initial maximum blood concentration of 30 mg/ L was obtained at 1.5 hr. A decrease in bisphenol A blood concentration at 2.5 hr was followed by a second peak of 40 mg/L at 6 hr, leading study authors to conclude that enterohepatic cycling was occurring. The same patterns of bisphenol A concentrations in blood were observed following gavage dosing with 100 mg/kg bw. Peak concentrations were observed at 30 min (150 mg/L) and 3 hr (134 mg/L) following exposure. According to the study authors, the differences in peak concentrations observed between the two doses suggested lower bioavailability at the high-dose than at the low dose. Oral bioavailability of bisphenol A was estimated at 16.4% at the low dose and 5.6% at the high-dose. Yoo et al. (2001) examined toxicokinetics of a low i.v. dose and a higher gavage dose of bisphenol A in male rats. Five adult male Sprague–Dawley rats/group were administered bisphenol A by i.v. injection at a dose of 0.1 mg/kg bw or by gavage at a dose of 10 mg/kg bw. Multiple blood samples were collected until 3 hr following i.v. dosing and 24 hr following gavage dosing. HPLC was used to measure bisphenol A concentrations in serum. Route-specific differences in mean systemic clearance were analyzed by Student t-test. Results are summarized in Table 37. The study authors noted biexponential decay of serum bisphenol A concentrations following i.v. dosing, significantly longer elimination half-life with oral than i.v. exposure, and low oral bioavailability of bisphenol A. Kurebayashi et al. (2003) conducted a series of studies to examine toxicokinetics and metabolism of bisphenol A in adult F344N rats exposed through the oral or i.v. route. In these studies, radioactivity levels were measured by scintillation counting. Bisphenol A or its metabolites were quantified by HPLC, electrospray ionization/MS, or nuclear magnetic resonance. As discussed in greater detail in Section 2.1.2.4, fecal excretion was the main 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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12.. Padmanabhan. V,. Siefert. K,.
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In..Research.Triangle.Park,.NC:.RTI
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65.. Alonso-Magdalena. P,. Laribi.
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91.. Calabrese.EJ,.Baldwin.LA.(2003
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
Page 73 and 74: Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
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
Page 81 and 82: 158 CHAPIN ET AL. the CERHR Core Co
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Page 89 and 90: 166 CHAPIN ET AL. Table 6 Continued
Page 91 and 92: 168 CHAPIN ET AL. comparison of the
Page 93 and 94: 170 CHAPIN ET AL. Table 8 Urinary C
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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 and 110: 186 CHAPIN ET AL. Secondary sources
Page 111 and 112: 188 CHAPIN ET AL. Table 25 Maternal
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 121 and 122: 198 CHAPIN ET AL. appeared to occur
Page 123 and 124: 200 CHAPIN ET AL. Table 43 Biliary
Page 125 and 126: 202 CHAPIN ET AL. suggesting that 4
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Page 129 and 130: 206 CHAPIN ET AL. scaling and speci
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Page 137 and 138: 214 CHAPIN ET AL. Model and exposur
Page 139 and 140: 216 CHAPIN ET AL. Model and exposur
Page 141 and 142: 218 Model and exposure Husbandry a
Page 143 and 144: 220 CHAPIN ET AL. Table 54 Differen
Page 145 and 146: 222 CHAPIN ET AL. Table 56 Anti-And
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 153 and 154: 230 CHAPIN ET AL. Table 62 Toxicoki
Page 155 and 156: 232 CHAPIN ET AL. Table 64 Tissue R
Page 157 and 158: 234 CHAPIN ET AL. Table 68 Toxicoki
Page 159 and 160: 236 CHAPIN ET AL. treatment conditi
Page 161 and 162: 238 CHAPIN ET AL. clinical signs, b
Page 163 and 164: 240 CHAPIN ET AL. Table 71 Benchmar
Page 165 and 166: 242 CHAPIN ET AL. group, 5 from 1 l
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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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