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

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0.0002 0.011 0.0082 0.0069 0.0050 0.0002 0.014 0.0083 0.015 0.0089 5.0 Park et al. (2004) 5.0 0.020 No dose Sakaue et al. response (2001) k Relative epididymis weight k Relative ventral prostate weight ICR mice, i.p. every 3 days k Sperm concentration 0.5 over 2 weeks m Sperm abnormalities 0.5 Sprague–Dawley rat, k Daily sperm production (absolute and per g o0.020 gavaged with 0.020, 0.200, testis) 2, 20, or 200 x 6 days Sprague–Dawley rat, k Daily sperm production (absolute and per g 0.002 gavaged with 0.000002, testis) 0.00002, 0.0002, 0.002, 0.020, 0.200, or 2 x 6 days 0.020 Data presentation does not permit modeling. Sakaue et al. (2001) Single dose Takahashi and study Oishi (2003) Birth Defects Research (Part B) 83:157–395, 2008 B200 (single Single dose Takahashi and dose) study Oishi (2003) B400 (single Single dose Takahashi and dose) study Oishi (2003) BISPHENOL A Single dose Takahashi and study Oishi (2003) 20 7 5 9 6 Takahashi and Oishi (2003) 20 3 2 16 9 235 124 86 171 114 NTP (1984); Morrissey et al., (1989) Wistar or Holtzman SD rat No effect on reproductive organ (diet) histopathology, daily sperm production, epididymal sperm reserves, or serum testosterone Wistar rat (s.c.) k Terminal body weight, absolute and relative reproductive organ weight; altered testicular histopathology CD-1 (ICR) mouse (diet) m Absolute testis weight, kabsolute epididymis weight; no effect on testis histopathology, epididymal sperm reserves, daily sperm production, or serum testosterone C57BL/6CrSlc mouse No effect on reproductive organ weights; no B400 (single (diet) effect on testis histopathology, epididymal dose) sperm reserves, daily sperm production, or serum testosterone Wistar rat, 2 or 20 i.p. 4 k ventral prostate weight 2 days/week x 1 month k Serum testosterone 2 k Preputial gland relative weight o235 Reproductive assessment by continuous breeding CD-1 mouse, B2.4, 4.2, or No adverse effects on fertility r8.1 8.1 over 18-week continuous breeding period, s.c. implant a Dose levels expressed as a mean of the estimated male-female target dose levels. b Benchmark doses are shown for the generation with the lowest values. m,k Statistically significant increase, decrease compared to controls; 2 no statistically significant effects compared to controls. 377
378 CHAPIN ET AL. Table 103 Summary of Blood LH and Testosterone Changes in Experimental Animal Studies Endpoints/protocol LH effects a Testosterone effects a Reference High Utility Experimental animal studies with oral exposure Adult male and female rats 2 at 40–1000 mg/kg bw/day 2 at 40–1000 mg/kg bw/day Yamasaki et al. (2002a) gavaged for 28 days 4-week-old male rats fed Not examined 2 at 235–950 mg/kg bw/day Takahashi and Oishi (2001, bisphenol A in diet for 44 or or 200 mg/kg bw/day 2003) 60 days Multiple generation gavage k in F0 adult females at 0.0002, 2 Ema et al. (2001) dosing study in rats 0.002, and 0.020 mg/kg bw/ day but not at high dose (0.2 mg/kg bw/day); not considered treatmentrelated. Experimental animal studies with parenteral exposure Female lambs i.m. injected at 4– 2 on blood levels during Not examined Evans et al. (2004) 11 weeks of age; ovariectomy treatment; k pulsatile at 9 weeks of age secretion after treatment with 3.5 mg/kg bw biweekly Limited utility Experimental animal studies with oral exposure Male rats gavaged from PND k at 0.0024 mg/kg bw/day but k at 0.0024 mg/kg bw/day but Akingbemi et al. (2004) 21–35 2 at higher doses (0.010– 2 at higher doses (0.010– 200 mg/kg bw/day) 200 mg/kg bw/day) Male rats gavaged from PND m at 0.0024 mg/kg bw/day 2 at 0.0024 mg/kg bw/day Akingbemi et al. (2004) 21–90 4-week-old mice fed bisphenol Not examined 2 at 400 mg/kg bw/day Takahashi and Oishi (2003) A through diet for 2 months Experimental animal studies with parenteral exposure 4-week-old male rats s.c. dosed Not examined 2 at 200 mg/kg bw Takahashi and Oishi (2003) on 4 days/week for 1 month 4-week-old male rats i.p. Not examined k at 20 mg/kg bw Takahashi and Oishi (2003) injected for 1 month a Unless otherwise stated, animals were examined immediately after the treatment period. m,k Statistically significant increase/decrease compared to controls; 2 no statistically significant effects compared to controls. Utility (Adequacy) for CERHR Evaluation Process: This study suggests that fish are sensitive to bisphenol Ainduced abnormalities in reproductive endpoints. Because this study was conducted in fish, it is not useful in the evaluation. Ortiz-Zarragoitia and Cajaraville (2006), supported by the European Commission, examined the effects of bisphenol A exposure on the reproductive and digestive systems of adult blue mussels. For a period of 3 weeks, mussels were exposed to bisphenol A in acetone vehicle at 0 or 50 ppb [lg/L] [no information on purity or culture ware was provided]. Additional compounds were also tested but will not be discussed. Ten mussels/ sex/group were examined at the end of the exposure period. The digestive gland was examined for volume of peroxisomes and peroxisomal proliferation. Gonads were histologically evaluated and assessed for alkali-labile phosphate level, a vitellogenin-like protein that is a possible biomarker of endocrine disruption. Statistical analyses included ANOVA followed by Duncan post-hoc test, Kruskall–Wallis, and Mann–Whitney U test. Bisphenol A had no effect on gonadal development, gonadal alkali-labile phosphate levels, or digestive gland peroxisomal proliferation or peroxisomal volume. However, observations of follicular brown cell aggregates and gonadal hemocyte infiltration in 35% of male and female mussels indicated severe gamete resorption. Strengths/Weaknesses: This study evaluated bisphenol A-induced alterations in several reproductive endpoints in adult mussels. Severe gamete resorption was observed. Weaknesses include the failure to confirm bisphenol A concentrations in the test water and the use of only 1 concentration. Utility (Adequacy) for CERHR Evaluation Process: Because this study was conducted in the mussel, it is not useful in the evaluation. 4.3 Utility of Reproductive Toxicity Data 4.3.1 Human. One high utility study of 42 men occupationally exposed to bisphenol A diglycidyl ether and 42 unexposed men evaluated the relationship Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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[This page inTenTionally lefT blank
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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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• • Howdeshell.et.al. (55).repo
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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
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Thyroid.Function.in.Juvenile.Female
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droxylase.immunoreactivity..76:423.
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stanceschimiques.gc.ca/challenge-de
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Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
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226..vom. Saal. FS,. Cooke. PS,. Bu
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solid.phase.extraction-high.perform
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appendix i. nTp-Cerhr bisphenol a e
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158 CHAPIN ET AL. the CERHR Core Co
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160 CHAPIN ET AL. referred to as 4,
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162 CHAPIN ET AL. concentrations in
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164 CHAPIN ET AL. Food (no. sampled
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166 CHAPIN ET AL. Table 6 Continued
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168 CHAPIN ET AL. comparison of the
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170 CHAPIN ET AL. Table 8 Urinary C
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172 CHAPIN ET AL. the blood of male
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174 CHAPIN ET AL. Table 11 Bispheno
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176 CHAPIN ET AL. Table 13 Summarie
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178 CHAPIN ET AL. Table 15 Estimate
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180 CHAPIN ET AL. Table 17 Maximum
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182 CHAPIN ET AL. 2.0 GENERAL TOXIC
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184 CHAPIN ET AL. fetuses (3.572.7
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186 CHAPIN ET AL. Secondary sources
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188 CHAPIN ET AL. Table 25 Maternal
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190 CHAPIN ET AL. Table 27 Bispheno
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192 CHAPIN ET AL. Table 31 Qualitat
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194 CHAPIN ET AL. Table 33 Toxicoki
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198 CHAPIN ET AL. appeared to occur
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200 CHAPIN ET AL. Table 43 Biliary
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202 CHAPIN ET AL. suggesting that 4
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204 CHAPIN ET AL. low following ora
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206 CHAPIN ET AL. scaling and speci
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208 CHAPIN ET AL. 60-100% in each d
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210 CHAPIN ET AL. related. No histo
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212 CHAPIN ET AL. Table 52 Continue
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214 CHAPIN ET AL. Model and exposur
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216 CHAPIN ET AL. Model and exposur
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218 Model and exposure Husbandry a
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220 CHAPIN ET AL. Table 54 Differen
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222 CHAPIN ET AL. Table 56 Anti-And
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224 Table 57 In Vitro Genetic Toxic
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226 CHAPIN ET AL. Table 58 In Vivo
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228 CHAPIN ET AL. Table 59 Developm
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232 CHAPIN ET AL. Table 64 Tissue R
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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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324 CHAPIN ET AL. Table 84 Summary
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Page 253 and 254: 330 CHAPIN ET AL. (Nagao et al., 19
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Page 259 and 260: 336 CHAPIN ET AL. Utility (Adequacy
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Page 297 and 298: 374 Table 101 Summary of High Utili
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Page 307 and 308: 384 CHAPIN ET AL. 10. Critical desi
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Page 321: appendix iii. publiC CommenTs and p
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