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` National Toxicology Program's Report
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` of the
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`Organized by the
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` National Institute of Environmental Health Sciences, NIH
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` National Toxicology Program
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`Sponsored by the
`U.S. Environmental Protection Agency
`and the
`National Institute of Environmental Health Sciences, NIH
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`National Toxicology Program
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`ClearCorrect Exhibit 1072, Page 1 of 487
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`National Toxicology Program's Report
`of the
`Endocrine Disruptors Low-Dose Peer Review
`
`August 2001*
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`*This report represents the views and expert opinions of the Low-Dose Peer Review Panel
`that met October 10-12, 2000, in Research Triangle Park, NC. Public comments received
`in response to this report are included as Appendix C.
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` National Toxicology Program, U.S. Department of Health and Human Services
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` National Institute of Environmental Health Sciences, National Institutes of Health
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` Research Triangle Park, NC
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`This report is available on the National Toxicology Program (NTP) web site:
`http://ntp-server.niehs.nih.gov/htdocs/liason/LowDoseWebPage.html
`Hard copies of this report can be obtained by contacting:
`NTP Office of Liaison and Scientific Review
`NIEHS, NIH
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` P.O. Box 12233, MD A3-01
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` Research Triangle Park, NC 27709
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` 919-541-0530 (phone)
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` 919-541-0295 (fax)
`liaison@starbase.niehs.nih.gov (e-mail)
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`ClearCorrect Exhibit 1072, Page 2 of 487
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`TABLE OF CONTENTS
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`EXECUTIVE SUMMARY .............................................................................i
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`Peer Review Organizing Committee ......................................................................... viii
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`Subpanels: Chairs, Rapporteurs, Panelists ................................................................ ix
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`Selected Studies from Principal Investigators........................................................... x
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`Selected Studies: Requested Parameters ................................................................... xvi
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`Issues Relative to the Evaluation of Endocrine Low-Dose Studies .......................... xxix
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`Subpanel Questions and Issues.................................................................................. xxxi
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`Peer Review Agenda ................................................................................................. xxxiii
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`CHAPTER 1
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`Report of the Bisphenol A Subpanel .............................................................1-1
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`CHAPTER 2
`Report of the Other Environmental Estrogens
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`and Estradiol Subpanel...................................................................................2-1
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`CHAPTER 3
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`Report of the Androgens and Antiandrogens Subpanel ..............................3-1
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`CHAPTER 4
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`Report of the Biological Factors and Study Design Subpanel ....................4-1
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`CHAPTER 5
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`Report of the Statistics Subpanel ...................................................................5-1
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`CHAPTER 6
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`Report of the Dose-Response Modeling Subpanel .......................................6-1
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`Appendix A
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`Detailed Evaluations of Individual Studies ...................................................A-1
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`Appendix B
`Investigators' Responses to "Issues Relative to the
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`Evaluation of Endocrine Low-Dose Studies" ...............................................B-1
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`Appendix C
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`Public Comments.............................................................................................C-1
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`Executive Summary
`
`Purpose and Background
`
`At the request of the U.S. Environmental Protection Agency (EPA), the National Toxicology
`Program (NTP)/National Institute of Environmental Health Sciences (NIEHS) organized and
`conducted an independent and open peer review aimed at evaluating the scientific evidence on
`reported low-dose effects and dose-response relationships for endocrine disrupting chemicals in
`mammalian species that pertain to assessments of effects on human health. The peer review took
`place in Research Triangle Park, North Carolina, on October 10-12, 2000. The members of the peer
`review organizing committee are listed in Table 1.
`
`The purpose of this meeting was to establish a sound scientific foundation upon which the U.S. EPA
`could determine what aspects, if any, of its standard guidelines for reproductive and developmental
`toxicity testing need to be modified to detect and characterize low-dose effects of endocrine
`disruptors. Results from this review may also influence how other national and international agencies
`select doses, endpoints, animal models, and testing regimens for reproductive and developmental
`studies of endocrine active agents. In particular, the NTP is interested in evaluating the scientific
`underpinnings of dose-response relationships for reproductive toxicants. For this peer review, "low-
`dose effects" referred to biological changes that occur in the range of human exposures or at doses
`that are lower than those typically used in the EPA's standard testing paradigm for evaluating
`reproductive and developmental toxicity. The U.S. EPA’s current recommended methods are
`described in the document “Health Effects Test Guidelines OPPTS 870.3800 Reproduction and
`Fertility Effects” (EPA 712-C-98-208, August 1998). The focus of this review was on “biological
`change” rather than on “adverse effect” because, in many cases, the long-term health consequences of
`altered endocrine function during development have not been fully characterized.
`
`The peer review panel (the Panel) included individuals from academia, government, and industry
`with expertise in receptor/molecular biology, experimental and clinical endocrinology, reproductive
`and developmental toxicology, statistics, and mathematical modeling. The Panel was divided into
`five subpanels: Bisphenol A, Other Environmental Estrogens and Estradiol, Androgens and
`Antiandrogens, Biological Factors and Study Design, and Statistics and Dose-Response Modeling.
`Table 2 identifies the members of each subpanel.
`
`This peer review used a unique and novel approach to resolve a controversial but very important
`environmental health issue. Fifteen principal investigators of primary research groups active in this
`field were asked to provide their individual animal data on selected parameters for independent
`statistical re-analysis by the Statistics Subpanel prior to the meeting. The Organizing Committee
`requested the raw data on specific parameters in 59 different studies. The selected studies are listed
`by principal investigator in Table 3 and the requested parameters from each study are given in Table
`4. Data were willingly submitted from 49 of the 59 selected studies. In general, the primary reasons
`that certain requested data sets were not provided was that the data were not available in an electronic
`format as specified by the Statistics Subpanel or the raw data were in the possession of collaborators
`and could not be provided in the requested time frame. Studies for which requested data sets were not
`submitted by principal investigators for independent review by the Statistics Subpanel were used as
`background information by the Panel. In addition to submitting their raw data, principal investigators
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`were asked to provide for each study responses to a list of 23 questions (Table 5) on issues relevant to
`the evaluation of endocrine low-dose studies; these questions addressed animal source and
`specification, animal husbandry, chemical characterization, administration of test agent, treatment of
`controls, evaluation of endpoints, and methods of data analysis. Investigators from these research
`groups were also available at the meeting to give formal presentations of their findings and to have
`informal discussions with individual subpanels. Because of the extreme rigor of this evaluation
`process and the extensive analyses of raw data performed by the Statistics Subpanel, unpublished
`studies were also included in this peer review.
`
`The selected studies included treatments with bisphenol A, diethylstilbestrol, ethinyl estradiol,
`nonylphenol, octylphenol, genistein, methoxychlor, 17β–estradiol, and vinclozolin, or effects of diet
`or intrauterine position. Exposure periods included in utero, neonatal, pubertal, adult, in utero
`through neonatal, in utero through puberty, and in utero through adult. Requested parameters
`included organ weights (prostate, testis, epididymis, seminal vesicle, preputial gland, uterus, and
`ovary), perinatal measures (e.g., anogenital distance), pubertal measures (e.g., age at vaginal opening,
`first estrus, preputial separation, and testis descent), and other relevant factors (e.g., daily sperm
`production, sperm count, serum hormone levels, lymphocyte proliferation in response to anti-CD3,
`histopathology, estrous cyclicity, receptor binding, estrogen receptor levels, gene expression, and
`volume of sexually dimorphic nuclei of the preoptic area of the hypothalamus). To conduct this
`evaluation within a reasonable time frame, the focus of this review was on reproductive and
`developmental effects. The extensive literature on dioxin and dioxin-like compounds was excluded
`because EPA was finalizing its extensive and rigorous reevaluation of dioxin risk. Phthalate esters
`were also excluded because separate evaluations on these compounds were being conducted by the
`NTP Center for the Evaluation of Risks to Human Reproduction. A future workshop may focus on
`low-dose effects of dioxin-like compounds.
`
`The Statistics Subpanel analyzed the raw data from 39 of the 49 submitted studies over a 6-week
`period and provided results from these analyses to the other subpanels prior to the peer review
`meeting. These analyses provide greater insight on the experimental data than is typically apparent in
`most peer-reviewed research articles, consequently, the statisticians’ report was critical for each of
`the subpanel reviews. The Dose-Response Modeling group provided theoretical dose-response
`models based on mechanisms of receptor-mediated processes, as well as empirical dose-response
`models of endocrine-related effects prior to the meeting. Several important statistical issues were
`identified by the subpanel and are addressed in their report; these include study sensitivity (power),
`adjustment for litter effects, pooling of control groups, exclusion of statistical outliers, accounting for
`body weight differences on organ weight effects, appropriateness of the selected statistical
`methodology, and data heterogeneity across dose groups. All of these matters, plus experimental
`design and conduct issues, were taken into consideration by each of the subpanels in their evaluations
`of the individual studies during the peer review. The statisticians and modelers participated in the
`other subpanel reviews to ensure that their analyses and models were appropriately used by the
`subpanels.
`
`The Panel evaluated data from the major, selected studies that support the presence or absence of
`low-dose effects in laboratory animals and that would be relevant for human health assessments.
`Low-dose effects analyzed by the Panel should be considered as effects occurring at NOELs (no-
`observed-effect levels) since this review did not distinguish adverse versus non-adverse effects.
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`However, the Panel did compare, when appropriate, its analyses to existing NOAELs (no-observed-
`adverse-effect levels) or LOAELs (lowest-observed-adverse-effect levels) reported by EPA or others.
`The Panel was also asked to consider biological and mechanistic data that might influence the
`plausibility of low-dose effects and to identify study design issues or other biological factors that
`might account for differences in study outcomes. Conclusions from the Panel on the existence of low-
`dose effects and the shape of the dose-response curve for endocrine active substances in the low-dose
`region were based on the totality of available knowledge. The specific questions and issues
`formulated by the Organizing Committee for the subpanels to address in this peer review are given in
`Table 6.
`
`This unique scientific peer review provided an extraordinarily rigorous, open, transparent, and
`objective evaluation of the scientific evidence showing the presence or absence of low-dose effects of
`endocrine disrupting agents and an opportunity for participation by all stakeholders. The subpanels’
`independently prepared reports follow the Executive Summary. Highlights of the subpanels’ findings
`are given below.
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`Peer Review Subpanel Findings
`
`Bisphenol A
`
`Based on EPA’s estimate that the lowest-observed-adverse-effect level (LOAEL) for oral exposure to
`bisphenol A in rats is 50 mg/kg/day, the Subpanel used 5 mg/kg/day as a cutoff dose for low-dose
`effects, regardless of the route or duration of exposure or the age/life stage at which exposure
`occurred.
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`� Several studies provide credible evidence for low-dose effects of bisphenol A; these include
`increased prostate weight in male mice at six months of age and advanced puberty in female mice
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`after in utero exposure to 2 or 20 µg/kg/day, and low-dose effects on uterine growth and serum
`prolactin levels that occurred in F344 rats but not in Sprague-Dawley rats exposed to 0.5
`mg/kg/day. The latter findings demonstrate a clear difference in sensitivity to the estrogenic effects
`of bisphenol A in these two strains of rats.
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`� Several large studies in rats and mice, including multigenerational studies in Sprague-Dawley rats,
`found no evidence for a low-dose effect of bisphenol A despite the considerable strength and
`statistical power those studies represent.
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`� For those studies that included DES exposure groups, those that showed an effect with bisphenol A
`showed a similar low-dose effect with DES (e.g., prostate and uterus enlargement in mice), while
`those that showed no effect with bisphenol A also found no effect with DES.
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`� Discrepancies in experimental outcome among studies showing positive and negative effects of
`bisphenol A may have been due to different diets with differing background levels of
`phytoestrogens, differences in strains of animals that were used, differences in dosing regimen, and
`differences in housing of animals (singly versus group). Although some studies attempted to
`replicate previous findings, body weights and prostate weights of controls differed between these
`studies. Studies also differed in the extent of analysis of dosing solutions.
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`� The Subpanel concluded that “there is credible evidence that low doses of BPA [bisphenol A] can
`cause effects on specific endpoints. However, due to the inability of other credible studies in several
`different laboratories to observe low dose effects of BPA, and the consistency of these negative
`studies, the Subpanel is not persuaded that a low dose effect of BPA has been conclusively
`established as a general or reproducible finding.”
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`� Data are insufficient to establish the shape of the dose-response curve for bisphenol A in the low
`dose region, and the mechanism and biological relevance of reported low dose effects are unclear.
`
`� The Subpanel identified areas for additional research that would clarify uncertainties about low-
`dose effects of bisphenol A, these include:
`1) additional low-dose studies, including the development and use of sensitive and easily
`measured molecular endpoints, following in utero or early neonatal exposure to conclusively
`establish low-dose effects of bisphenol A as a general, reproducible phenomenon;
`2) pharmacokinetic data in multiple species and strains of animals to characterize fetal uptake,
`metabolism, and elimination of bisphenol A and its metabolites;
`3) mechanistic data on estrogen receptor occupancy during critical periods of development, effects
`of specific receptor antagonists, and responses in estrogen-receptor knock-out mice;
`4) additional studies on intrauterine position effects;
`5) characterization of genetic and epigenetic factors that affect responses to bisphenol A and
`hormones in general, e.g., factors that lead to strain and species differences in sensitivity;
`6) mechanistic studies on the effects of bisphenol A on regulation of transcriptional activity, from
`gestation through adulthood.
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`Other Environmental Estrogens and Estradiol
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`The subpanel developed an operational definition for “low-dose effects” that was based on the dose-
`response data for the selected endpoints for each agent under evaluation. Low-dose effects were
`considered to be occurring when a nonmonotonic dose-response resulted in significant effects below
`the presumed NOEL expected by the traditional testing paradigm.
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`� Low-dose effects were clearly demonstrated for estradiol and several other estrogenic compounds.
`The shape of the dose-response curves for effects of estrogenic compounds varies with the endpoint
`and the dosing regimen. Theoretical models based on mechanisms of receptor-mediated processes,
`as well as empirical models of endocrine-related effects, produced dose-response shapes that were
`either low-dose linear, or threshold-appearing, or non-monotonic (e.g., U-shaped or inverted U-
`shaped). Low-dose effects of the estrogenic agents evaluated by the Subpanel include the
`following:
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`� Estradiol (ovarian steroid with greatest estrogenic activity) - Low-dose effects include changes in
`serum prolactin, LH, and FSH in ovariectomized rats at a dose of approximately 3 µg/kg/day.
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`� Diethylstilbestrol (DES, a non-steroidal synthetic estrogen that had been used to prevent
`spontaneous abortions and to enhance cattle weight gain) - DES is a transplacental carcinogen in
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`humans. There is clear evidence of a low-dose effect on prostate size by DES (at 0.02 µg/kg) in
`mice.
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`� Genistein (isoflavone derived from soy) - Low dose effects were observed in F1 offspring following
`dietary exposure to 25 ppm, these include a decrease in the volume of sexually dimorphic nuclei of
`the preoptic area (SDN-POA) of the hypothalamus in male rats (approaching female-like volumes),
`changes in mammary gland tissue in male rats, and an increase in proliferation of splenic T-
`lymphocytes stimulated with anti-CD3.
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`� Methoxychlor (insecticide) - Classic estrogenic activity occurs in F1 rats following in utero and
`perinatal exposure to 5 mg/kg/day or higher doses. Low-dose immune system effects occur in F1
`offspring following dietary exposure to 10 ppm methoxychlor (approximately equal to 1
`mg/kg/day).
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`� Nonylphenol (industrial compound identified in drinking water supplies) – Low-dose effects in F1
`rats following dietary exposure to 25 ppm include a decrease in SDN-POA in males, an increase in
`relative thymus weight, an increase in proliferation of splenic T-lymphocytes stimulated with anti-
`CD3, and a prolonged estrus in females.
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`� Octylphenol (an intermediate for the production of surfactants) - There was no evidence of low-
`dose effects in a five-dose multigeneration study in rats.
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`� Areas of future research include:
`1) multiple dose studies and modeling of dose-response relationships,
`2) need for replication of low-dose findings in other studies or in other laboratories,
`3) determination of the toxicological significance of volume changes in SDN-POA in male rats
`and the relationship between estrogenic activity and stimulation of lymphocyte proliferation.
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`Androgens and Antiandrogens
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`The Subpanel’s review focused on low-dose effects of vinclozolin, a fungicide that is an androgen
`receptor antagonist. NOAELs for vinclozolin were established from studies in rats; these levels are 6
`mg/kg/day for acute dietary exposure and 1.2 mg/kg/day from chronic dietary exposure. No studies
`have been conducted on vinclozolin at doses below its NOAEL.
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`� Exposure of pregnant rats to vinclozolin at six doses ranging from 3.125 to 100 mg/kg/day results
`in reduced anogenital distance (female-like), increased incidence of areolas, and permanently
`reduced ventral prostate weight in male offspring. For these effects, the dose-response curves
`appeared linear to the lowest dose tested. Reproductive tract malformations and reduced ejaculated
`sperm numbers were observed only at the two highest doses. Thus, dose-response relationships are
`not equivalent among endpoints affected by exposure to vinclozolin.
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`� Antiandrogens have been shown to act as androgen receptor antagonists, inhibitors of 5α–reductase
`activity, and/or inhibitors of steroidogenesis. In addition to vinclozolin, other agents (or their
`metabolites) that have been identified as antiandrogens include p,p’-DDT (insecticide), flutamide
`and Casodex (pharmaceuticals developed to treat prostate cancer), finasteride (pharmaceuticals
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`developed to treat benign prostate hyperplasia), methoxychlor (pesticide), procymidone (fungicide),
`linuron (herbicide), ketoconazole (fungicide), and certain phthalate esters (plasticizers). For
`finasteride, which acts as a 5α–reductase inhibitor, the dose-response for reduction in anogenital
`distance (linear) was different than that for increased hypospadias (threshold-appearing).
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`� There are no data available on low-dose effects of environmental chemicals that act as androgen
`mimics.
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`� Future research needs include the following:
`1) further testing of the hypothesis that the dose-response for antiandrogens is linear to the
`NOAEL/LOAEL,
`2) development of mechanism-based assays for the detection of androgen mimics,
`3) development and utilization of molecular and biochemical markers as sensitive indicators of
`low-dose effects of androgenic and antiandrogenic agents,
`4) characterization of dose-response relationships for androgenic and antiandrogenic agents in
`different species and in multiple strains,
`5) development of dosimetry/mechanistic models for exposures occurring during in utero and
`early neonatal development.
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`Biological Factors and Study Design
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`� Several factors may account for discrepant findings on low-dose effects of particular endocrine
`active agents, these include:
`1) intrauterine position, although not essential for the detection of low-dose effects, may be
`important in evaluating variability in response;
`2) strain and substrain differences in response, which could occur due to genetic differences or
`selective breeding to maintain high rates of fecundity and growth;
`3) diet with varying background levels of phytoestrogens and differences in caloric intake might
`influence reproductive parameters;
`4) differences in caging (e.g., stainless steel, polycarbonate), bedding material, or housing (group
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`versus individual) could influence study outcomes;
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`5) seasonal variation, which has been reported to affect sex ratios in rodents.
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`� Comments on the multigeneration test. The traditional multigeneration reproduction study protocol
`includes exposure of animals through most critical windows of sexual differentiation in the F1
`generation and an assessment of the F2 generation through postnatal day 21. This protocol provides
`substantial information on reproductive effects, but limited information on developmental effects.
`Frequently, litter size is reduced on postnatal day 4 (usually to 4 males and 4 females) and litter size
`is further reduced at weaning (postnatal day 21) so that only one animal/sex/litter is held until
`adulthood. The reduction in number of treated animals evaluated may provide inadequate power to
`detect low incidence responses (e.g., reproductive tract malformations). Further, a number of
`sensitive or subtle endocrine-related endpoints are not routinely evaluated, and evaluations of F2
`pups on or around postnatal day 21 may not reveal effects on reproductive tract organs that are not
`yet fully developed. This concern is underscored by the fact that certain endocrine active chemicals
`were negative in standard multigeneration and prenatal studies.
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`� Additional design factors for future studies:
`1) Because of clear species and strain differences in sensitivity, animal model selection should be
`based on responsiveness to endocrine active agents of concern (i.e. responsive to positive
`controls), not on convenience and familiarity.
`2) Pharmacokinetic data need to be routinely generated, using appropriately sensitive methods, to
`characterize the dosimetry of the test chemical or its metabolites in target tissues.
`3) Caution is needed in implementing experimental designs to reduce animal variability (e.g.,
`controlled feeding, individual housing), because factors such as body weight and stress can
`influence reproductive endpoints.
`4) The biological/toxicological relevance of specific endpoints affected by endocrine active agents
`would benefit from measuring functional parameters or collecting mechanistic data on related
`biomarkers of effect.
`5) The long-term health consequences of early changes induced by endocrine active agents, e.g.,
`prostate enlargement or accelerated uterine development, need to be determined.
`6) Windows of susceptibility to endocrine disrupting chemicals need to be identified from
`mechanistic data, and empirical tests need to include exposures at those times.
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`Overall Conclusions
`
`� Low-dose effects, as defined for this review, were demonstrated in laboratory animals exposed to
`certain endocrine active agents. The effects are dependent on the compound studied and the
`endpoint measured. In some cases where low-dose effects have been reported, the findings have not
`been replicated. The toxicological significance of many of these effects has not been determined.
`
`� The shape of the dose-response curves for these effects varies with the endpoint and dosing
`regimen, and may be low-dose linear, threshold-appearing, or non-monotonic.
`
`� The traditional multigeneration reproduction study protocol has not revealed major reproductive or
`developmental effects in laboratory animals exposed to endocrine active agents at doses
`approaching their NOAELs set by the standard testing paradigm. However, few multigenerational
`studies have been conducted over expanded dose ranges, and endpoints such as cancer of reproductive
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`organs or neurobehavioral effects are generally not evaluated in multigenerational studies.
`
`� The Panel recommended additional research to replicate previously reported key low-dose findings,
`to characterize target tissue dosimetry during critical periods of development, to identify sensitive
`molecular markers that would be useful in understanding mechanistic events associated with low-
`dose effects, and to determine the long-term health consequences of low-dose effects of endocrine
`active agents.
`
`� The findings of the Panel indicate that the current testing paradigm used for assessments of
`reproductive and developmental toxicity should be revisited to see if changes are needed regarding
`dose selection, animal model selection, age when animals are evaluated, and the endpoints being
`measured following exposure to endocrine active agents.
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`Table 1. Peer Review Organizing Committee
`
`William Allaben
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`National Center for Toxicological Research
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`Food and Drug Administration
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`Christopher De Rosa
`Agency for Toxic Substances and Disease Registry
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`Penny Fenner-Crisp
`US Environmental Protection Agency, currently at International Life Sciences Institute
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`Lynn Goldman
`Johns Hopkins University
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`Sandra Inkster
`US Consumer Products Safety Commission
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`Jim Kariya
`US Environmental Protection Agency
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`Robert Kavlock
`US Environmental Protection Agency
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`George Lucier
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`National Institute of Environmental Health Sciences (retired)
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`National Institutes of Health
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`Ronald Melnick (Chair)
`National Institute of Environmental Health Sciences
`National Institutes of Health
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`Eisuke Murono
`Centers for Disease Control and Prevention
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`Mary Wolfe
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`National Institute of Environmental Health Sciences
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`National Institutes of Health
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`Roxanne Hall (meeting coordinator)
`National Institute of Environmental Health Sciences
`National Institutes of Health
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`Table 2. Subpanels: Chairs, Rapporteurs, Panelists
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`Bisphenol A
`George Stancel (Chair), University of Texas at Houston
`Gail Prins (Rapporteur), University of Illinois at Chicago
`Ralph Cooper, US Environmental Protection Agency
`Warren Foster, Health Canada
`Jun Kanno, National Institute of Health Sciences – Japan
`John Faust, California Environmental Protection Agency
`
`Other Environmental Estrogens and Estradiol
`Michael Gallo (Chair), UMDNJ-Robert Wood Johnson Medical School
`Kenneth Reuhl, (Rapporteur), Rutgers University
`Mari Golub, California Environmental Protection Agency
`Claude Hughes, UCLA School of Medicine
`Richard Lyttle, Wyeth-Ayerst Research
`Lynne McGrath, Schering-Plough Research Institute
`Patricia Whitten, Emory University
`
`Androgens and Antiandrogens
`Shuk-Mei Ho (Chair), University of Massachusetts Medical School
`Terry Brown (Rapporteur), Johns Hopkins University School of Public Health
`George Daston, The Procter & Gamble Company
`Mitch Eddy, National Institute of Environmental Health Sciences
`Lorenz Rhomberg, Gradient Corporation
`Elizabeth Wilson, University of North Carolina at Chapel Hill
`
`Biological Factors and Study Design
`John Moore (Chair), Sciences International, Inc.
`Julian Leakey (Rapporteur), National Center for Toxicological Research
`Sue Barlow, Consultant
`Paul Foster, Chemical Industry Institute of Toxicology
`Robert Luebke, US Environmental Protection Agency
`Robert Maronpot, National Institute of Environmental Health Sciences
`Cory Teuscher, University of Illinois at Urbana-Champaign
`
`Statistics and Dose-Response Modeling
`Joseph Haseman (Co-chair, Statistics), National Institute of Environmental Health Sciences
`John Bailer, Miami Universtiy of Ohio
`Ralph Kodell, National Center for Toxicological Research
`Richard Morris, Analytical Sciences, Inc.
`Kenneth Portier, University of Florida
`Michael Kohn (Co-chair, Modeling), National Institute of Environmental Health Sciences
`Hugh Barton, US Environmental Protection Agency
`Jim Cogliano, US Environmental Protection Agency
`Rory Connolly, Chemical Industry Institute of Toxicology
`Robert Delongchamp, National Center for Toxicological Research
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`ClearCorrect Exhibit 1072, Page 12 of 487
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`Table 3. Selected Studies from Principal Investigators
`
`John Ashby, Zeneca Central Toxicological Laboratory, United Kingdom
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`1. Ashby, J., H. Tinwell, et al. (1999). “Lack of effects for low dose levels of bisphenol A and
`diethylstilbestrol on the prostate glad of CF1 mice exposed in utero.” Regulatory Toxicology and
`Pharmacology 30: 156-166.
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`2. Ashby, J., H. Tinwell, et al. (2000). “Current issues in Mutation Research. DNA adducts,
`estrogenicity and rodent diets.” Mutation Research (in press).
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`3. Ashby, J., H. Tinwell, et al. (2000). “Uterotrophic activity of a "phytoestrogen-free" rat diet.”
`Environmental Health Perspectives 108(1): A12-A13.
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`4. Ashby, J., H. Tinwell. (2000). “Activity of bisphenol A in pregnant SD and Alpk rats: preliminary
`data.” (Unpublished Abstract).
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`5. Odum, J., P. A. Lefevre, et al. (1997). “The rodent uterotrophic assay: critical protocol features,
`studies with nonylphenols and comparison with a yeast estrogenicity assay.” Regulatory
`Toxicology and Pharmacology 25: 176-188.
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`6. Odum, J. and J. Ashby (1999). “Neonatal exposure of male rats to nonylphenol has no effect on
`the reproductive tract.” Toxicological Science (in press).
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`7. Odum, J., I. T. G. Pyrah, et al. (1999). “Comparative activities of p-nonylphenol and
`diethylstilbestrol in noble rat mammary gland and uterotrophic assays.” Regulatory Toxicology
`and Pharmacology 29: 184-195.
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`8. Odum, J., I. T. G. Pyrah, et al. (1999). “Effects of p-nonylphenol and diethylstilbestrol on the
`alderley park rat: comparison of mammary gland and uterus sensitivity following oral gavage or
`implanted mini-pumps.” Journal of Applied Toxicology 19: 367-378.
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`9. Tinwell, H., R. Joiner, et al. (2000). “Uterotrophic activity of bisphenol A in the immature
`mouse.” Regulatory Toxic