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

More documents

Recommendations

Info

[0.23 mg/L]. Bisphenol A dimethylacrylate was also tested, and most results were similar to those observed with bisphenol A. The study authors concluded that ovarian steroidogenesis might be a target of bisphenol A toxicity. Strengths/Weaknesses: Potential estrogenic effects were observed at 10 -5 M bisphenol A. Decreases in responses observed at the 10 -4 M concentration are likely due to nonspecific cytotoxicity. Bisphenol A-mediated responses in progesterone endpoints appeared to reach a near maximum at the lowest dose level examined. There was no mention of whether phenol red-free media were used or whether fetal bovine serum was charcoalstripped. The serum likely contained steroids, which would have been potential confounding factors. Also, it appears that cell viability was not examined after the incubation period. With exception of the highest dose level, there was no dose response (inconsistent trends); the statistical flags are potentially due to random chance. Since this was an in vitro study, the potential effects of metabolism could not be assessed. Utility (Adequacy) for CERHR Evaluation Process: Due the weaknesses and limitation in the experimental design, this study is considered inadequate. Mohri and Yoshida (2005), supported by the Japanese Ministry of Education, Science, Sports, and Culture, examined the effects of bisphenol A and 17b-estradiol exposure on calcium oscillations in immature mouse oocytes. Immature oocytes with intact germinal vesicles were obtained from 8–12-week-old CD-1/ICR mice and incubated in bisphenol A [purity not indicated] in a DMSO vehicle at concentrations of 0 or 10 nM [2.3 lg/L] to 100 mM [23 mg/L] for 60 min. Calcium oscillations were measured using a Fura-2 dye and image analyzer. Data were analyzed by Student t-test. At 100 mM [23 mg/ L] bisphenol A, the duration of calcium oscillations was significantly shortened and the oscillations became irregular. The same findings were observed following exposure to 17b-estradiol at concentrations that were 10,000-fold lower than that of bisphenol A, producing the same effect. The study authors stated that estrogens may affect the oocyte by regulating calcium oscillations and that bisphenol A could affect oocyte maturation. Strengths/Weaknesses: This study appears to have been well conducted; however, because this study used an in vitro system, metabolism could not be assessed. It is unclear if calcium oscillations play a role in oocyte maturation in other species, including humans. Utility (Adequacy) for CERHR Evaluation Process: This study is not considered useful for the evaluation process. 4.2.2 Male.. Studies on the androgenicity of bisphenol A, including Hershberger assays, are discussed in Section 2.2.3. 4.2.2.1 Rat: Yamasaki et al. (2002a), support not indicated, conducted a 28-day exposure study that provided some information on the reproductive organs of male and female rats. [Complete details of this study are included in Section 2. Results for males are discussed in this section, and results for females are discussed in Section 4.2.1.1.] CD rats were fed a commercial diet (MF Oriental Yeast Co.) and housed in stainless steel wire mesh cages. Ten 7-week-old rats/sex/ group were gavaged with bisphenol A [98% purity] at 0 Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 341 (olive oil vehicle), 40, 200, or 1000 mg/kg bw/day for 28 days. Due to the death of 1 animal exhibiting clinical signs in the 1000 mg/kg bw/day group, the high-dose was reduced to 600 mg/kg bw/day on Day 8 of the study. In an additional study, rats were exposed to ethinyl estradiol at 0, 10, 50, or 200 mg/kg bw/day for 28 days. There were no treatment-related abnormalities in sperm or alterations in blood levels of thyroid hormones, FSH, LH, 17b-estradiol, prolactin, or testosterone. Changes in relative reproductive organ weights [assumed to be relative to body weight] included a 28% decrease in relative ventral prostate weight and 21% increase in relative testis weight in the high-dose group. No gross or histopathological alterations were reported for reproductive organs. The study authors concluded that change in estrous cyclicity was the only useful endpoint for evaluating the endocrine-mediated effects of bisphenol A. In comparison, male rats exposed to the mid and/or high doses of ethinyl estradiol experienced decreased prostate, seminal vesicle, and pituitary weights; increased testis weight; and histopathological alterations in prostate, seminal vesicle, mammary gland, and testis. Strengths/Weaknesses: This study was well-conducted, used an appropriate route of administration, a positive control group, adequate sample sizes, a range of doses, and evaluations of both sexes. A weaknesses include an insufficient duration of exposure to examine the full spermatogenic cycle. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate and of high utility for the evaluation process. Takahashi and Oishi (2001), support not indicated, examined the effects of bisphenol A exposure on testis of rats. F344 rats were fed standard, soy-containing diet (CE-2; Clea Japan) and housed in stainless steel suspended cages. Four-week-old male rats (n 5 8/group) were administered bisphenol A (99.0% purity) through diet at concentrations of 0, 0.25, 0.5, or 1.0% for 44 days. The study authors estimated bisphenol A intake at 235, 466, and 950 mg/kg bw/day. The stability of bisphenol A in the diet was verified. Food intake was measured, and animals were weighed and observed daily for clinical signs. Rats were killed when mean body weight of controls reached B200 g. Testosterone levels were measured in serum using an ELISA method. Preputial gland, testes, epididymides, prostate, seminal vesicles, kidneys, and liver were weighed. The testis was fixed in buffered 6% formaldehyde and examined histologically. Statistical analyses included Bartlett test, ANOVA, Dunnett or Scheffé parametric test, Kruskall–Wallis test, Dunnett non-parametric test, Wilcoxon rank sum test, w 2 test, Mantel–Haenzel test, and Fisher exact test. Statistically significant findings are summarized in Table 88. Body weight gain and terminal body weights were reduced in males of the mid- and high-dose groups. Food intake was said to be slightly decreased according to dose. Absolute organ weight effects included decreased weight of preputial glands at all doses; liver in the mid- and high-dose group; and seminal vesicles with coagulation glands, dorsal and lateral prostate, and hypophysis at the high-dose. [The Expert Panel assumes that by coagulation gland, the authors mean the anterior prostate or coagulating gland.] Significant organ weight effects relative to body weights are
342 CHAPIN ET AL. Endpoint Table 88 Effects Observed in Male Rats Exposed to Bisphenol A Through Diet a Dose, % in diet [mg/kg bw/day] 0.25 0.5 1.0 BMD10 BMDL10 BMD1SD BMDL1SD Terminal body weight Relative weight 2 k 13% k 18% 0.55 [522] 0.42 [399] 0.41 [389] 0.30 [285] Dorsal and lateral prostate 2 2 k 32% 0.29 [276] 0.22 [209] 0.52 [494] 0.36 [342] Preputial gland b k 22% k 26% k 25% 0.13 [124] 0.09 [86] 0.18 [171] 0.12 [114] Liver 2 k 10% k 14% 0.69 [656] 0.56 [532] 0.30 [285] 0.23 [218] Kidney No. rats with: m 8% m 8% m 12% 0.99 [940] 0.69 [656] 0.50 [475] 0.34 [323] Seminiferous tubule degeneration c 2 m to 6/8 m to 5/8 Disorganization of Stage I–VI spermatids (1 severity) c m to 4 of 8 2 2 Disorganization of Stage I–VI 2 2 m to 6 of 8 0.36 [342] 0.22 [209] spermatids (21 severity) c % Seminiferous tubules in stages I–VI k 59% k 70% k 53% IX–XI m 3.4-fold m 5.2-fold m 4-fold XII–XIV m 3.2-fold m 3.6-fold m 3-fold a Takahashi and Oishi (2001). b Benchmark doses were estimated using a polynomial model. c Control value 5 0of8. m,k Statistically significant increase, decrease compared to controls; 2no statistically significant effect compared to controls. summarized in Table 88. Changes in relative organ weights included decreased preputial gland weight and increased kidney weights at all doses, decreased liver weight at the mid- and high-dose, and decreased dorsal and lateral prostate weight at the high-dose. Testicular lesions observed with bisphenol A treatment included seminiferous tubule degeneration at the mid and highdose, disorganized spermatids at all dose levels, and differences in percentages of seminiferous tubules in spermatogenic stages at all dose levels. Although it does not appear that statistical significance was attained, dose-related increases in arrested spermatogenesis and disappearance of elongated spermatids were also reported. There were no significant effects on serum testosterone concentrations. The study authors concluded that bisphenol A was toxic to the testis and accessory sex organs of F344 rats at a minimum toxic dose of 235 mg/kg bw/day. Findings suggest a hormonal effect on hormonedependent reproductive tissues at all doses examined. The lowest dose level, 0.25% in diet, exhibited histopathological changes in the testes, most strikingly described as a large alteration in the relative frequency of the different stages of the seminiferous epithelium. Due to techniques used for fixation and embedding of the testes, the histopathological analyses may be of limited value. Strengths/Weaknesses: This study reports a relatively well conducted study with a relevant route of administration. General toxicity was demonstrated. Formalin produces excessive shrinkage of testes when followed by paraffin embedding and is inappropriate especially when staging will be conducted. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate and of high utility for the evaluation process. Sakaue et al. (2001), supported by the Japanese Science and Technology Agency, examined the effect of bisphenol A exposure on spermatogenesis in the adult rat. Animals were fed CE-2 chow (CLEA Japan) and housed in stainless steel wire caging. Thirteen-week old male Sprague–Dawley rats (5/group) were gavaged for 6 days with the ethanol/corn oil vehicle or bisphenol A (99.6% purity) at doses 0.020, 0.200, 2, 20, or 200 mg/kg bw/day. The high-dose was based on a preliminary experiment that demonstrated reduced daily sperm production in a Holtzman rat gavaged with 200 mg/kg bw/day bisphenol A for 6 days. In this study, rats were killed 2 days following dosing (at 14 weeks of age) or at 18 weeks of age. Testes were weighed. Sperm endpoints were measured from one testis. Histopathological examinations were conducted on the other testis after fixation in Bouin fluid, paraffin embedding, and staining with hematoxylin and eosin. Statistical analyses included Student ttest, ANOVA, and Fisher protected least significant difference test. There were no changes in daily sperm production/g testis at 14 compared to 18 weeks of age. [No data were shown for 14-week-old rats, and results of bisphenol A treatment were not discussed.] Bisphenol A did not significantly affect body or testis weight at 18 weeks of age. In the 18-week-old rats, daily sperm production and daily sperm production/g tissue were significantly reduced [by B25%] in all bisphenol A treatment groups. The study authors noted the lack of a dose–response relationship and that daily sperm production in treated groups at 18 weeks of age was comparable to that of 14week-old controls. Histopathological evaluations of testis revealed no evidence of atrophy or disrupted spermatogenesis in the seminiferous tubules. [Data were not shown by study authors.] Birth Defects Research (Part B) 83:157–395, 2008
Page 1:
National Toxicology Program U.S. De
Page 4 and 5:
[This page inTenTionally lefT blank
Page 6 and 7:
Page 8 and 9:
NTP.will.transmit.the.NTP-CERHR.<st
Page 10:
National Toxicology Program U.S. De
Page 13 and 14:
Page 15 and 16:
nTp brief tainers.with.internal.epo
Page 17 and 18:
Population Adult General. Populatio
Page 19 and 20:
Table 3. Blood and Breast Milk Biom
Page 21 and 22:
Figure 2b. The weight of evidence t
Page 23 and 24:
in.considering.the.biological.plaus
Page 25 and 26:
isphenol.A.as.efficiently.as.adult.
Page 27 and 28:
isphenol.A..For.example,.this.raise
Page 29 and 30:
laboRaToRy aNImal STudIeS In.contra
Page 31 and 32:
of.normal.sex-based.differences.bet
Page 33 and 34:
death.(168),.synaptic.plasticity.(1
Page 35 and 36:
gland.carcinogen.or.that.bisphenol.
Page 37 and 38:
understand.the.possible.long-term.c
Page 39 and 40:
strategies.to.improve.the.sensitivi
Page 41 and 42:
• • Howdeshell.et.al. (55).repo
Page 43 and 44:
and.cystic.endometrial.hyperplasia.
Page 45 and 46:
cutaneous. injection. 20 . vom. Saa
Page 47 and 48:
are CurrenT exposures To bisphenol
Page 49 and 50:
w/day;.95th.percentiles.0.289.-.0.2
Page 51 and 52:
nTp ConClusions The.NTP.reached.the
Page 53 and 54:
appendix a: inTerpreTaTion of blood
Page 55 and 56:
µg/kg.bw/day.based.on.the.assumpti
Page 57 and 58:
concentrations.from.maternal,.fetal
Page 59 and 60:
12.. Padmanabhan. V,. Siefert. K,.
Page 61 and 62:
In..Research.Triangle.Park,.NC:.RTI
Page 63 and 64:
65.. Alonso-Magdalena. P,. Laribi.
Page 65 and 66:
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
Page 77 and 78:
solid.phase.extraction-high.perform
Page 79 and 80:
appendix i. nTp-Cerhr bisphenol a e
Page 81 and 82:
158 CHAPIN ET AL. the CERHR Core Co
Page 83 and 84:
160 CHAPIN ET AL. referred to as 4,
Page 85 and 86:
162 CHAPIN ET AL. concentrations in
Page 87 and 88:
164 CHAPIN ET AL. Food (no. sampled
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
Page 95 and 96:
172 CHAPIN ET AL. the blood of male
Page 97 and 98:
174 CHAPIN ET AL. Table 11 Bispheno
Page 99 and 100:
176 CHAPIN ET AL. Table 13 Summarie
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
Page 117 and 118:
194 CHAPIN ET AL. Table 33 Toxicoki
Page 119 and 120:
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
Page 127 and 128:
204 CHAPIN ET AL. low following ora
Page 129 and 130:
206 CHAPIN ET AL. scaling and speci
Page 131 and 132:
208 CHAPIN ET AL. 60-100% in each d
Page 133 and 134:
210 CHAPIN ET AL. related. No histo
Page 135 and 136:
212 CHAPIN ET AL. Table 52 Continue
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:
Page 155 and 156:
232 CHAPIN ET AL. Table 64 Tissue R
Page 157 and 158:
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
Page 167 and 168:
244 CHAPIN ET AL. least significant
Page 169 and 170:
246 CHAPIN ET AL. group was a reduc
Page 171 and 172:
248 CHAPIN ET AL. 100-151 g for fem
Page 173 and 174:
250 CHAPIN ET AL. 3.2.3.2 Developme
Page 175 and 176:
252 CHAPIN ET AL. weights, bispheno
Page 177 and 178:
254 CHAPIN ET AL. 120 mg/kg bw/day
Page 179 and 180:
256 CHAPIN ET AL. comparisons condu
Page 181 and 182:
258 CHAPIN ET AL. the findings of t
Page 183 and 184:
260 CHAPIN ET AL. analyzed.] Anogen
Page 185 and 186:
262 CHAPIN ET AL. purposeful confou
Page 187 and 188:
264 CHAPIN ET AL. increased lordosi
Page 189 and 190:
266 CHAPIN ET AL. that there was a
Page 191 and 192:
268 CHAPIN ET AL. duration of adver
Page 193 and 194:
270 CHAPIN ET AL. doses of potent e
Page 195 and 196:
272 CHAPIN ET AL. Table 74 Effects
Page 197 and 198:
274 CHAPIN ET AL. reproductive orga
Page 199 and 200:
276 CHAPIN ET AL. tyrosine-hydroxly
Page 201 and 202:
278 CHAPIN ET AL. include small sam
Page 203 and 204:
280 CHAPIN ET AL. males/group. [It
Page 205 and 206:
282 CHAPIN ET AL. termination, whic
Page 207 and 208:
284 CHAPIN ET AL. provided a reliab
Page 209 and 210:
286 CHAPIN ET AL. grooming, and out
Page 211 and 212:
288 CHAPIN ET AL. method of oral do
Page 213 and 214: 290 CHAPIN ET AL. reared by their d
Page 215 and 216: 292 CHAPIN ET AL. has been informed
Page 217 and 218: 294 CHAPIN ET AL. buffered paraform
Page 219 and 220: 296 CHAPIN ET AL. unit. Further, th
Page 221 and 222: 298 CHAPIN ET AL. PND 21 and housed
Page 223 and 224: 300 CHAPIN ET AL. Tando et al. (200
Page 225 and 226: 302 CHAPIN ET AL. Purina Certified
Page 227 and 228: 304 CHAPIN ET AL. high-doses of bis
Page 229 and 230: 306 CHAPIN ET AL. born to those dam
Page 231 and 232: 308 CHAPIN ET AL. average weight we
Page 233 and 234: 310 CHAPIN ET AL. study authors con
Page 235 and 236: 312 CHAPIN ET AL. used for extracti
Page 237 and 238: 314 CHAPIN ET AL. jar, and there we
Page 239 and 240: 316 CHAPIN ET AL. of testes and com
Page 241 and 242: 318 CHAPIN ET AL. differentiation o
Page 243 and 244: 320 CHAPIN ET AL. Table 81 Summary
Page 245 and 246: 322 CHAPIN ET AL. Table 82 Continue
Page 251 and 252: 328 CHAPIN ET AL. 600 mg/kg bw/day)
Page 253 and 254: 330 CHAPIN ET AL. (Nagao et al., 19
Page 255 and 256: 332 CHAPIN ET AL. antinuclear antib
Page 257 and 258: 334 CHAPIN ET AL. least 6 animals.
Page 259 and 260: 336 CHAPIN ET AL. Utility (Adequacy
Page 261 and 262: 338 CHAPIN ET AL. stomach weight wa
Page 263: 340 CHAPIN ET AL. Schirling et al.
Page 267 and 268: 344 CHAPIN ET AL. different diets b
Page 269 and 270: 346 CHAPIN ET AL. with 40 mg vitami
Page 271 and 272: 348 CHAPIN ET AL. the bisphenol A v
Page 273 and 274: 350 CHAPIN ET AL. and determining t
Page 275 and 276: 352 CHAPIN ET AL. expression [to B6
Page 277 and 278: 354 CHAPIN ET AL. indicated] at 0 (
Page 279 and 280: 356 CHAPIN ET AL. concentrations us
Page 281 and 282: 358 CHAPIN ET AL. animals were non-
Page 283 and 284: 360 CHAPIN ET AL. following adjustm
Page 285 and 286: 362 CHAPIN ET AL. Table 94 Treatmen
Page 287 and 288: 364 CHAPIN ET AL. Table 97 Effects
Page 289 and 290: 366 CHAPIN ET AL. Table 99 Treatmen
Page 291 and 292: 368 CHAPIN ET AL. Therefore the NTP
Page 293 and 294: 370 CHAPIN ET AL. weeks before mati
Page 297 and 298: 374 Table 101 Summary of High Utili
Page 299 and 300: 376 Table 102 Summary of Limited Ut
Page 303 and 304: 380 CHAPIN ET AL. from other suppli
Page 305 and 306: 382 CHAPIN ET AL. U.S. populations.
Page 307 and 308: 384 CHAPIN ET AL. 10. Critical desi
Page 309 and 310: 386 CHAPIN ET AL. Engel SM, Levy B,
Page 311 and 312: 388 CHAPIN ET AL. alpha and beta ex
Page 313 and 314: 390 CHAPIN ET AL. Murray TJ, Maffin
Page 315 and 316:
392 CHAPIN ET AL. Ryan BC, Vandenbe
Page 317 and 318:
394 CHAPIN ET AL. Thomas P, Dong J.
Page 319 and 320:
Page 321:
appendix iii. publiC CommenTs and p
show all

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

Create successful ePaper yourself

Delete template?

Save as template?