R L Joiner

North Carolina State University, Raleigh, NC, United States

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Publications (16)45.73 Total impact

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    ABSTRACT: There is no information on reproductive/developmental effects in mice from dietary estrogen. Therefore, 10 adult CD-1 mice/sex/group were administered dietary 17beta-estradiol (E2) at 0, 0.005, 0.05, 0.5, 2.5, 5, 10, and 50 ppm for 2-week prebreed, mating, gestation, lactation. F1 weanlings (3/sex/litter) were necropsied and 2/sex/litter were retained, with exposure, until vaginal patency (VP) or preputial separation (PPS) and then necropsied. Results included complete infertility at 2.5-50 ppm with normal mating indices. At 0.5 ppm (and above), F0 adult female uterus plus cervix plus vagina weights (UCVW) were increased. At 0.5 ppm: prolonged gestational length; increased F1 stillbirth index; reduced live birth index and litter size; decreased testes and epididymides weights at weaning; unaffected AGD on pnd 0 and 21; delayed PPS; increased undescended testes; unaffected prostate weight; accelerated VP; enlarged vaginas; fluid-filled uteri. At 0.05 ppm: no F0 reproductive effects, increased F1 weanling UCVW; delayed PPS. The NOEL was 0.005 ppm ( approximately 1 microg/kg/day).
    Reproductive Toxicology 03/2008; 25(2):144-60. DOI:10.1016/j.reprotox.2007.11.012 · 3.23 Impact Factor
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    ABSTRACT: This study evaluated the potential for dietary para-nonylphenol (NP; CAS No. 84852-15-3) to affect parental fertility and growth and development of three offspring generations in CD (Sprague-Dawley [SD]) rats, including sperm counts across generations to determine the validity of equivocal reductions observed in the F2 generation by R. E. Chapin et al. (1999, Toxicol. Sci. 52, 80-91). Male rat kidney toxicity was also examined based on inconsistent observations in NP-exposed rats at 2000 ppm but not at 200 or 650 ppm in Purina 5002 (H. C. Cunny et al., 1997, Regul. Toxicol. Pharmacol. 26, 172-178) and at all of these NP concentrations in NIH-07 diet (R. E. Chapin et al., 1999, Toxicol. Sci. 52, 80-91). Concentrations were 0, 20, 200, 650, and 2000 ppm NP in Purina 5002 diet and 0 and 650 ppm NP in NIH-07 diet. 17beta-estradiol (E2) was used as a positive control at 2.5 ppm in Purina 5002 diet. There were no NP effects on any reproductive parameters in any generation, including sperm counts. Kidney toxicity (histopathology) occurred at 650 and 2000 ppm with no clear difference for the two diets. Ovarian weight was decreased at 2000 ppm NP in all generations, with no effect on reproduction. Dietary E2 at 2.5 ppm caused renal, reproductive, and developmental (lactational and peripubertal) toxicity in all generations. This study confirmed that dietary NP is not a selective reproductive toxicant with an no observable adverse effect level (NOAEL) of > 2000 ppm ( approximately > 150 mg/kg/day) and provided an NOAEL for male rat kidney toxicity of 200 ppm NP (approximately 15 mg/kg/day).
    Toxicological Sciences 07/2006; 92(1):295-310. DOI:10.1093/toxsci/kfj203 · 3.85 Impact Factor
  • Trevor Green · Cindy Swain · John P Van Miller · Ronald L Joiner ·
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    ABSTRACT: To better interpret the responses to para-nonylphenol (NP; CASRN84852-15-3) in in vivo toxicity studies, including estrogen-like activity, the bioavailability of 14C-radiolabelled NP has been determined in male and female CD rats following either single oral doses of 10 and 100 mg/kg, single i.v. doses of 10 mg/kg, or repeated daily oral doses of 10 mg/kg for up to 14 d. Up to 80% of an oral dose of NP was rapidly absorbed, the remainder being excreted unchanged in faeces. Excretion was largely complete within 24 h of dosing. Following absorption, NP was metabolised in the liver, with the majority of the metabolites excreted in bile, mainly as glucuronide conjugates. Unchanged NP was found only in bile and urine from female rats given a 100 mg/kg dose, indicating that metabolic saturation occurred. Following repeated dosing, steady state was reached within 7 d. There was no evidence of significant accumulation into tissue compartments nor of a significant change in clearance or the metabolite profiles in urine. These data suggest that the estrogen-like effects observed in toxicity studies with female rats at oral NP doses of approximately 50 mg/kg/d and greater are a result of the increased bioavailability of NP which occurs following metabolic saturation.
    Regulatory Toxicology and Pharmacology 09/2003; 38(1):43-51. DOI:10.1016/S0273-2300(03)00048-5 · 2.03 Impact Factor
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    J Ashby · H Tinwell · PA Lefevre · R Joiner · J Haseman ·
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    ABSTRACT: M. Sakaue et al. (2001,J. Occup. Health vol. 43, pp. 185-190) have described how oral exposure of sexually mature male rats to bisphenol A (BPA) between postnatal days (PND) 91-97 led to a reduction in daily sperm production (DSP) 5 weeks later (18 weeks of age). Activity was observed over the dose range 20 microgram/kg-200 mg/kg BPA, with an absence of activity over the dose range 2 ng/kg-2 microgram/kg BPA. There was no evidence of a dose response relationship over the active dose range (five orders of magnitude range). The observation of endocrine disruption (ED) effects for BPA at such low doses, and in sexually mature animals, was unexpected. It was therefore decided to mount an independent repeat of their study. A total of four independent studies were conducted according to the protocol used by Sakaue et al. Doses of 20 microgram/kg, 2 mg/kg, or 200 mg/kg BPA were administered to adult Sprague-Dawley (SD) rats over PND 91-97, and the studies were terminated when the rats reached the age of 18 weeks. Three different rodent diets were employed (RM3, Purina 5002, and CE2), the last of which had been used by Sakaue et al. BPA failed to give any evidence of ED activities, including the changes in DSP reported by Sakaue et al. 2001. During the course of these studies, the test protocol was adapted to coincide more precisely with that used by Sakaue et al.; this included restricting the number of animals per cage, removing bedding from the cages, and changing to the use of glass water bottles in the cages. The only thing of interest to emerge from our studies was the observation of a significant difference in DSP between the control groups of our first and second study. As the change in diet from RM3 to Purina 5002 was the major difference between those two studies, we conducted a repeat of the second study, but we were unable to confirm the differences seen between the first and second study. The probability that those differences arose either by chance, or as the result of intrinsic study-to-study variability, was strengthened by the absence of significant differences in the sperm parameters in a final (fifth) study where the sperm parameters for control animals maintained on the three different diets were compared under the conditions of the main experiments. No explanation for our failure to replicate the effects reported by Sakaue et al. is evident. A review of DSP values reported in the recent literature is provided and discussed, and it is concluded that use of the term DSP/g testis rather than DSP/testis could increase the sensitivity of DSP assessments.
    Toxicological Sciences 08/2003; 74(1):129-38. DOI:10.1093/toxsci/kfg093 · 3.85 Impact Factor
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    ABSTRACT: Skin contact with nonylphenol ethoxylates (NPE), a group of widely used surfactants, is the primary source of human exposure. Previous studies have shown that the absorption of NPE through human and animal skin in vitro is limited (<1% over 8 hr) [Monteiro-Riviere et al. Toxicol Indust Health 2000; 16:49–57]. The purpose of this study was to examine the percutaneous absorption of NPE and the chemical precursor, nonylphenol (NP), in the isolated perfused porcine skin flap (IPPSF) model for comparison to the in vitro porcine skin flow through (PSFT) diffusion studies. The IPPSF model is considered to accurately predict absorption of chemicals through human skin. The IPPSF was dosed with 100 μl of 1% 14C ring-labeled NP, 14C ring-labeled NPE-4, or 14C ring-labeled NPE-9 in aqueous polyethylene glycol (PEG-400) solution and perfused for 8 hr. All three chemicals were minimally absorbed, with only approximately 0.1% of the applied dose found in the perfusate over the 8-hr collection. This absorbed material represents the systemic exposure expected following skin contact in humans. In addition, less than 1% of the applied dose penetrated into the stratum corneum and underlying dermis, but remained within the skin and did not go through to the perfusate. Thus, the overall potential systemic exposure to these chemicals from skin contact, using a model considered similar to human skin in vivo, is less than 1%. The absorption results of this study were consistent with previous studies in the PSFT model. The penetration of NPEs and NP in the IPPSF was less than the PSFT and is probably more predictive of in vivo human absorption as this model is physiologically closer to human skin. This suggests that the overall potential for skin absorption of these chemicals in humans is even lower than previous estimates.
    Cutaneous and Ocular Toxicology 03/2003; 22(1-2):1-11. DOI:10.1081/CUS-120019325 · 1.12 Impact Factor
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    ABSTRACT: The objective of the study was to determine which period of exposure produces the most marked effects on the reproductive capacity and sexual development of the rat, with particular emphasis on the relative sensitivity of in utero and postnatal exposures. The endocrine active chemical, diethylstilbestrol (DES) was used as an agent known to affect many of the endpoints examined. Hitherto, such comparisons have been made between studies, rather than within a study. Our data will be helpful in the interpretation of future multigenerational assay data. In preliminary studies, DES was shown to be active in the immature rat uterotrophic assay with a lowest detected dose of 0.05 mg DES/kg body weight by sc injection and 10 mg DES/l (1.6 mg DES/kg body weight) by administration in drinking water. A dose of 60 microg DES/l drinking water ( approximately 6.5mg DES/kg body weight/day) was selected for the main study since this represented the midpoint of the drinking water uterotrophic dose response and produced no overt maternal toxicity. The study used 10 groups of concomitantly pregnant animals, including 2 control groups. The first comparison was between the effects of exposure to DES in utero, and exposure from conception to weaning. Another group of animals was exposed to DES in utero and cross-fostered to untreated pregnant females to prevent lactational transfer of DES to pups. Two groups were exposed to DES neonatally, either from birth to postnatal day (PND) 10 (pups thus having only lactational exposure), or from birth until weaning (PND 21; pups thus having both lactational exposure and self-exposure via drinking water). In addition, a dose response study to DES was conducted on animals exposed from weaning to PND 100, when the first phase of the study was terminated. Pups exposed to DES in utero and pups exposed from weaning to PND 100 were bred to assess fertility of the F1 animals and the sexual development of F2 offspring. This last comparison was to determine the extent to which weanling rats could be used in endocrine toxicity studies to assess their potential to show activity in utero. The most sensitive period of exposure for inducing developmental effects in F1 animals was from weaning onwards. The neonatal to weaning period (PND 1-21) was the next most sensitive. Essentially no effects were induced in F1 animals exposed in utero. No effects of any kind were observed in animals only exposed over the early neonatal period of PND 1-10. The mean day of vaginal opening, testes descent, and prepuce separation was only altered in groups where postnatal exposure to DES continued beyond PND 10, or was started at weaning. No changes were observed in anogenital distance or caudal sperm counts. Some changes in organ weights were observed, but the interpretation of these was often confused by concomitant changes in body weight. In general, histopathological examination of tissues yielded no additional information. In breeding studies with animals exposed to DES in utero, or from weaning, reduced litter sizes and marginal advances in the day of vaginal opening were observed in the offspring, together with changes in organ weights. However, no unique sensitivity was noted for exposure in utero. Evaluation of the several exposure periods and the many markers monitored in this study may have individual strengths in individual cases, but when rigorously compared using the reference estrogen DES, many preconceptions regarding their absolute or relative value were not upheld. Further, each of these markers is subject to natural variability, as demonstrated by comparisons made among the 5 separate control groups available in parts of the present study. This variability increases the chance that small changes observed in endocrine toxicity studies employing small group sizes and a single control group, or no concomitant control group, may be artifactual. The most marked effects observed in this study were on the developmental landmarks in the F1 animals induced by exposures after PND 10. Some effects on developmental landmarks and organ weights were observed in F2 animals following exposure either in utero or postweaning. This study therefore does not establish a unique role for exposures in utero or during the early neonatal period.
    Toxicological Sciences 08/2002; 68(1):147-63. · 3.85 Impact Factor
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    ABSTRACT: Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm ( approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD((R)) Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.
    Toxicological Sciences 08/2002; 68(1):121-46. · 3.85 Impact Factor
  • G J Moffat · A Burns · J Van Miller · R Joiner · J Ashby ·
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    ABSTRACT: Both p-nonylphenol (NP) and p-octylphenol (OP) exhibit weak estrogen-like activity in in vitro and in some rodent assays. To help understand the biochemical and molecular basis for these effects, and thus to permit extrapolation of risk to human health, it is important to establish whether these activities are retained by their metabolites. These data are particularly important in light of the knowledge that both NP and OP are rapidly and extensively metabolized to their glucuronide conjugates in rats. The activity of these glucuronide metabolites, however, is unknown. These studies investigated the intrinsic ability of NP, OP, and their principal mammalian metabolites, nonylphenol glucuronide (NPG) and octylphenol glucuronide (OPG), to affect estrogen receptor (ER)- or androgen receptor (AR)-mediated transcription in a yeast transcriptional activation system. Specifically, the estrogen-, anti-estrogen-, androgen-, and anti-androgen-like activities of NP, OP, NPG, and OPG have been assessed using recombinant yeast strains that express either human ER or AR. The two parent compounds, NP (EC(50) 110 nM) and OP (EC(50) 700 nM), exhibited intrinsic estrogen-like activity in this system, and consistent with numerous studies with these chemicals, they were 3-4 orders of magnitude less potent than 17beta-estradiol (EC(50) 500 pM). However, in contrast to the parent molecules, neither NPG nor OPG exhibited any evidence of estrogen-, antiestrogen-, androgen-, or anti-androgen-like activity in these recombinant yeast strains. Therefore, the weak estrogen-like activity noted for NP and OP in vivo at high doses is likely to reflect saturation of parent molecule glucuronidation. At anticipated levels of human exposure to NP and OP such a saturation of detoxification is highly unlikely; therefore, these in vitro data support the conclusion that the potential endocrine hazard posed by NP and OP to humans is likely to be negligible.
    Regulatory Toxicology and Pharmacology 11/2001; 34(2):182-7. DOI:10.1006/rtph.2001.1489 · 2.03 Impact Factor
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    ABSTRACT: Five rodent diets have been evaluated for their possible effect on the sexual development of the rat. Groups of 12 pregnant Alpk rats were fed one of the following combinations of diets during pregnancy and postnatally: RM3/RM1, AIN-76A/AIN-76A, RM3/AIN-76A, Teklad Global 2016 (Global)/Global and Purina 5001/Purina 5001. AIN-76A is phytoestrogen-free while the other diets contained varying amounts of phytoestrogens. The phytoestrogens genistein and daidzein were determined in the diets studied, and the concentrations found agreed with earlier estimates. RM3/RM1 was selected as the control group, as this has been used routinely in this laboratory for the past decade. Determinations were made in offspring of the times of vaginal opening and first estrus among the females, and of prepuce separation and testes descent among the males. At postnatal day (PND) 26 the females from 6 of the 12 litters were terminated and tissue weights measured. Males from 6 of the 12 litters were similarly studied at PND 68. Animals from the remaining litters were transferred to RM1 diet at PND 70. Termination of the study was at PND 128 (males) and PND 140 (females) when body weights and tissue weights were determined. Marked differences in body weight, sexual development, and reproductive tissue weights were observed for rats maintained on AIN-76A or Purina 5001, with only minimal effects among rats maintained on the Global diet. These comparisons were against RM3/RM1 as the reference diet. However, using Purina 5001 as the reference diet reversed the direction of the differences seen when using RM3/RM1 as the reference diet. The differences observed when using RM3/RM1 as reference diet occurred mainly postnatally. In addition, the fact that similar differences were seen for the phytoestrogen-free diet, AIN-76A, and the phytoestrogen-rich diet, Purina 5001, indicate that these effects are more likely to be caused by nutritional differences between the diets that then have centrally mediated effects on rodent sexual development, rather than individual dietary components affecting peripheral estrogen receptors (ER). This proposal is supported by abolition of the uterotrophic activity of AIN-76A and Purina 5001 (relative to RM3/RM1) in the immature rat by coadministration of the gonadotrophin-releasing hormone (GnRH) antagonist ANTARELIX: The present data indicate that choice of diet may influence the timing of sexual development in the rat, and consequently, that when evaluating the potential endocrine toxicity of chemicals, the components of rodent diets used should be known, and as far as is possible, controlled.
    Toxicological Sciences 06/2001; 61(1):115-27. DOI:10.1093/toxsci/61.1.115 · 3.85 Impact Factor
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    J Odum · H Tinwell · J Van Miller · R Joiner · J Ashby ·
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    ABSTRACT: p-Nonylphenol (NP) is weakly estrogenic to rodents and to some species of fish. All evidence to date has indicated that the estrogenic effects of NP are due to the interaction of NP with the estrogen receptor. Recent findings of increased plasma estradiol in fish exposed to NP have, however, led to the proposal of an alternative mechanism for NP-induced estrogenicity in this species, possibly via induction of aromatase enzymes. In the present studies, this hypothesis was investigated in rats using the aromatase inhibitor anastrozole. The results indicated that the uterotrophic action of NP, as with estradiol used as a positive control, is mediated directly by its interaction with uterine ER, rather than an indirect effect via aromatase enzyme induction. Circulating levels of estradiol were unchanged after NP treatment and the aromatase inhibitor anastrozole failed to inhibit NP-induced uterine growth. These results are consistent with previous published data on NP in rodents.
    Toxicology Letters 02/2001; 118(3):165-9. DOI:10.1016/S0378-4274(00)00293-9 · 3.26 Impact Factor
  • H Tinwell · R Joiner · I Pate · A Soames · J Foster · J Ashby ·
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    ABSTRACT: Bisphenol A (BPA) has been evaluated in eight independent immature mouse uterotrophic assays using the subcutaneous route of administration, and in a single study employing oral gavage. The dose range covered was from 0.02 microg to 300 mg/kg BPA and some experiments were supplemented by assessments of uterine hypertrophy and hyperplasia. Pooling of the test data indicates no uterotrophic activity for the chemical. However, in a subset of the subcutaneous injection studies, where control uterine weights were relatively low, significant, but weak, uterotrophic activity was observed over a range of dose levels, but in the complete absence of a dose relationship. In the oral gavage study, no increases in uterine weight were seen, but there were increases in uterine labeling with bromodeoxyuridine at 200-300 mg/kg BPA. The present study illustrated that when a large number of observations are made, a certain level of chance observations may be made, and that surrogates for an increase in uterine weight do not necessarily enhance assay sensitivity, albeit such data may complement uterine weight data. The data indicate that reducing control uterine weights may enhance assay sensitivity, but that animal body weight is an imperfect indicator of control uterine weight. The data also show that it is possible for individual investigators to be unable to confirm their own observations. It is concluded that BPA may be weakly uterotrophic to the mouse under specific conditions of test, and in the complete absence of a dose-response relationship to this activity. However, overall, we have failed to define BPA as reproducibly active in the immature mouse uterotrophic assay, and in that sense, our data are broadly consistent with those reported earlier by Coldham et al. (Environ. Health Perspect. 105, 734-742, 1997) in 1997 using a similar assay.
    Regulatory Toxicology and Pharmacology 09/2000; 32(1):118-26. DOI:10.1006/rtph.2000.1412 · 2.03 Impact Factor
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    ABSTRACT: The purpose of this study was to assess the percutaneous absorption of nonylphenol (NP) and the nonylphenol ethoxylates, NPE-4 and NPE-9, in human, porcine and rat skin. In vitro studies with the NPEs were conducted for 8 h in flowthrough diffusion cells using topical solutions of 0.1, 1.0 and 10% in PEG-400 or 1% in water (NPE-9 only). NP absorption was assessed as a 1% solution in PEG-400. All compounds were 14C ring-labeled and radioactivity in perfusate was monitored over time. Skin deposition was measured at the termination of the experiment. Absorption into perfusate and total penetration (compound absorbed plus compound sequestered in skin) were calculated. Absorption of NPE-4, NPE-9 and NP was similar across all species at less than 1% of the applied dose over 8 h. Penetration was generally below 5% of applied dose, the majority located in the stratum corneum. In all species and for both NPEs, the fraction of dose absorbed was highest for the lowest applied dose. Absorptions expressed as actual mass absorbed over 8 h were similar (approximately 0.3 microg/cm2) across all concentrations. Penetration, but not absorption, was greater from a water vehicle compared to a PEG-400 vehicle, particularly in rat skin. These studies suggest that NP, NPE-4 and NPE-9 were minimally absorbed across skin from all three species. Fractional absorption was concentration-dependent, making the actual absorbed flux constant across all doses.
    Toxicology and Industrial Health 03/2000; 16(2):49-57. DOI:10.1177/074823370001600201 · 1.86 Impact Factor
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    ABSTRACT: Bisphenol A (BPA) is a chemical used primarily as a monomer in the manufacture of numerous chemical products, such as epoxy resins and polycarbonate. The objective of this study was to evaluate potential effects of BPA on sexual development of male rats and was designed to clarify low-dose observations reported as preliminary results by Sharpe et al. (1996). The protocol for the present study followed the same treatment schedule as reported by Sharpe et al. (1995, 1996), but included more treatment groups, a greater number of animals per group, and a more comprehensive number of reproductive endpoints. Groups of 28 female Han-Wistar albino rats were exposed to drinking water that contained 0, 0.01, 0.1, 1.0, or 10 ppm BPA or 0.1 ppm diethylstilbestrol (DES), 7 days per week, for a total of 10 weeks. Treatment of the females began at 10 weeks of age and continued throughout a 2-week premating period, 2 weeks of mating (to untreated males), 21-22 days of gestation, and 22 days of lactation. Offspring weanling males were given untreated drinking water and maintained until 90 days of age when evaluations were made of various reproductive organs. Consistent with Sharpe et al. (1996) the female offspring were not evaluated. No treatment-related effects on growth or reproductive endpoints were observed in adult females exposed to any concentration of BPA. Similarly, no treatment-related effects were observed on the growth, survival, or reproductive parameters (including testes, prostate and preputial gland weights, sperm count, daily sperm production, or testes histopathology) of male offspring from dams exposed to BPA during gestation and lactation. DES administered in the drinking water at 0. 1 ppm resulted in decreased body weight, body weight change, and food consumption in adult females. In addition, an increase in the duration of gestation and a decrease in the number of pups delivered and number of live pups were also observed in animals exposed to DES. In conclusion, these results do not confirm the previous findings of Sharpe et al. (1996) and show that low doses of BPA had no effects on male sexual development in the rat.
    Regulatory Toxicology and Pharmacology 11/1999; 30(2 Pt 1):130-9. DOI:10.1006/rtph.1999.1340 · 2.03 Impact Factor
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    ABSTRACT: An earlier report by Colerangle and Roy indicated that administration of p-nonylphenol (NP) to Noble rats, via subcutaneously implanted mini-pumps at estimated doses of 53.2 and 0.073 mg kg(-1) day(-1) for 11 days, led to proliferation of the mammary gland. Those results indicated a ca. 600-fold enhancement in assay sensitivity to NP over that of the standard 3-day rat uterotrophic assay. The potential importance of these observations led us to repeat the experiments in the Noble rat, as described earlier. Although our earlier results confirmed the reported effects of diethylstilboestrol (DES) on the mammary gland of Noble rats, we found no effects with NP. The present report extends our investigations of the effects of NP and DES on the mammary gland and uterus of other rat strains using both oral dosing and exposure via mini-pumps. The 3-day oral uterotrophic assay responses to NP were similar for immature Alderly Park (Alpk; Wistar-derived) and immature Sprague-Dawley rats. Likewise, oral administration of NP to ovariectomized Alpk rats for 11 days gave responses of a similar magnitude to those seen in the 3-day immature assays and in earlier 3-and 11-day oral assays conducted using Noble rats. Administration of NP via mini-pumps to ovariectomized Alpk rats, at the implant doses employed by Colerangle and Roy, gave a negative uterotrophic response. The highest achieved dose levels of NP in the implant experiment (27 mg kg(-1) day(-1)) were lower than in the above assays and the negative response was therefore consistent with the previously defined minimum detection level for NP in the uterotrophic assay of ca. 40 mg kg(-1) day(-1) day(-1). It is concluded that the uterotrophic activity of NP is independent of the strain of rat, the duration of dosing and the route of exposure. Two mammary gland studies were conducted on NP and DES in the Alpk rat. In the first study (a repeat of the techniques used in earlier studies with the Noble rat), NP was administered via mini-pumps (achieved doses of 0.052 and 37.4 mg kg(-1) day(-3) NP) and produced no effect on mammary gland development, whereas DES gave the expected trophic response. In the second mammary gland study, NP was administered orally to Alpk rats at 100 mg kg(-1) day(-1) for 11 days (a dose that produced a positive uterotrophic response in ovariectomized rats). In this experiment, DES, and to a lesser extent NP, increased mammary gland differentiation and cell proliferation. The present studies have demonstrated that the rat mammary gland responds predictably to oestrogenic stimulation but does not show increased sensitivity to oestrogens when compared to the rat uterus. It is also concluded that the minimum detection level for oestrogenic responses of NP in rodents, following oral, dietary and implant routes of exposure, is ca. 40 mg kg(-1) day(-1).
    Journal of Applied Toxicology 09/1999; 19(5):367-78. DOI:10.1002/(SICI)1099-1263(199909/10)19:5<367::AID-JAT593>3.0.CO;2-C · 2.98 Impact Factor
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    ABSTRACT: Bisphenol A (BPA) is a monomer used in the manufacture of a multitude of chemical products, including epoxy resins and polycarbonate. The objective of this study was to evaluate the effects of BPA on male sexual development. This study, performed in CF-1 mice, was limited to the measurement of sex-organ weights, daily sperm production (DSP), epididymal sperm count, and testis histopathology in the offspring of female mice exposed to low doses of BPA (0, 0.2, 2, 20, or 200 microg/kg/day), by deposition in the mouth on gestation days 11-17. Male sexual development determinations were made in offspring at 90 days-of-age. Since this study was conducted to investigate and clarify low-dose effects reported by S. C. Nagel et al., 1997, Environ. Health Perspect. 105, 70-76, and F. S. vom Saal et al., 1998, Toxicol. Indust. Health 14, 239-260, our study protocol purposely duplicated the referenced studies for all factors indicated as critical by those investigators. An additional group was dosed orally with 0.2 microg/kg/day of diethylstilbestrol (DES), which was selected based on the maternal dose reported to have maximum effect on the prostate of developing offspring, by F. S. vom Saal (1996, personal communication), vom Saal et al. (1997, Proc. Natl. Acad. Sci. U S A 94, 2056-2061). Tocopherol-stripped corn oil was used as the vehicle for BPA and DES, and was administered alone to control animals. No treatment-related effects on clinical observations, body weight, or food consumption were observed in adult females administered any dose of BPA or DES. Similarly, no treatment-related effects on growth or survival of offspring from dams treated with BPA or DES were observed. The total number of pups born per litter was slightly lower in the 200-microg/kg/day BPA group when compared to controls, but this change was not considered treatment-related since the litter size was within the normal range of historical controls. There were no treatment-related effects of BPA or DES on testes histopathology, daily sperm production, or sperm count, or on prostate, preputial gland, seminal vesicle, or epididymis weights at doses previously reported to affect these organs or at doses an order of magnitude higher or lower. In conclusion, under the conditions of this study, the effects of low doses of BPA reported by S. C. Nagel et al., 1997 (see above) and F. S. vom Saal et al., 1998 (see above), or of DES reported by F. S. vom Saal et al., 1997 (see above) were not observed. The absence of adverse findings in the offspring of dams treated orally with DES challenges the "low-dose hypothesis" of a special susceptibility of mammals exposed perinatally to ultra-low doses of even potent estrogenic chemicals. Based on the data in the present study and the considerable body of literature on effects of BPA at similar and much higher doses, BPA should not be considered as a selective reproductive or developmental toxicant.
    Toxicological Sciences 08/1999; 50(1):36-44. DOI:10.1093/toxsci/50.1.36 · 3.85 Impact Factor
  • J Odum · I.T.G. Pyrah · J R Foster · J P Van Miller · R L Joiner · J Ashby ·
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    ABSTRACT: Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause extensive cell proliferation and lobular development in the mammary glands of young adult Noble rats. The chemicals were administered over 11 days via subcutaneously implanted minipumps. The dose level of DES used (0.076 mg/kg/day) was about 70 times higher than its minimum detection level in rodent uterotrophic and reproductive toxicology studies. In contrast, the lowest active dose level of NP (0.073 mg/kg/day) in the Noble rat mammary gland study was about 600 times lower than its minimum detection level in rat uterotrophic and multigeneration studies. The apparent enhanced sensitivity of the Noble rat mammary gland to the estrogenic activity of NP was considered worthy of further study. Ovariectomized Noble rat uterotrophic assays with NP (minimum detection level approximately 40 mg/kg/day, 3 or 11 days, oral gavage) revealed similar assay sensitivity to that observed for earlier immature and ovariectomized Alderley Park (AP) rat uterotrophic assays of this chemical. The response of the ovariectomized Noble rat uterotrophic assay to DES and estradiol was also as expected from earlier immature AP rat assays. It is concluded that the general sensitivity to estrogens of the Noble rat and the AP rat is similar. A repeat of the Noble rat mammary gland study with DES (11 x 0.076 mg/kg/day) and NP (11 x either 0.073 or 53.2 mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a strong positive response to DES and no response to NP. It is concluded that the minimum detection level of NP as a weakly estrogenic material in the rat should be based on the results of rat uterotrophic and multigeneration studies and therefore be set at approximately 40 mg/kg/day. It is also concluded that induced S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to PCNA staining, and that use of subcutaneously implanted minipumps/pellets is inappropriate for risk/hazard assessment studies of chemicals already established as estrogenic in vitro and in vivo, as are NP and DES.
    Regulatory Toxicology and Pharmacology 05/1999; 29(2 Pt 1):184-95. DOI:10.1006/rtph.1999.1286 · 2.03 Impact Factor

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918 Citations
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  • 2003
    • North Carolina State University
      • Center for Chemical Toxicology Research and Pharmacokinetics
      Raleigh, NC, United States
  • 1999-2003
    • General Electric
      Fairfield, California, United States