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Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals (2017)

Chapter: Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity

« Previous: Appendix A: Biosketches of the Committee on Endocrine-Related Low-Dose Toxicity
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Appendix B

Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity

National Academies of Sciences, Engineering, and Medicine
500 Fifth Street NW, Room 100
Washington, DC

February 3, 2016

8:00 Registration
8:30 Welcome and Goals of the Workshop
David Dorman, Committee Chair
8:45 Case Example 1: Phthalates and Male Reproductive Malformations
Moderators: Kamin Johnson, Russ Hauser, Sheela Sathyanarayana
Panelists:
  • Kim Boekelheide, Brown University
  • Jodi Flaws, University of Illinois at Urbana-Champaign (via teleconference)
  • Earl Gray, U.S. Environmental Protection Agency
  • Bernard Jégou, National Institute of Health and Medical Research (France) (via teleconference)*
  • John Meeker, University of Michigan (via teleconference)
10:30 Break
10:45 Case Example 2: TCDD and Male Reproductive Effects
Moderators: Russ Hauser, Kamin Johnson, Andrew Rooney
Panelists:
  • Michael DeVito, National Institute of Environmental Health Sciences*
  • Brenda Eskenazi, University of California, Berkeley (via teleconference)
  • Earl Gray, U.S. Environmental Protection Agency
12:30 Break (Cafeteria on Third Floor)
1:30 Case Example 3: Bisphenol A and Female Reproductive Effects
Moderators: Weihsueh Chiu, Katrina Waters, Karen Robinson
Panelists:
  • Joseph Braun, Brown University
  • Daniel Doerge, U.S. Food and Drug Administration
  • Jodi Flaws, University of Illinois at Urbana-Champaign (via teleconference)
3:15 Break
3:30 Open Microphone
Each speaker has a maximum time limit of 5 minutes. Accompanying written materials are encouraged.
4:00 Adjourn

___________________

* This individual was unable to participate on the day of the workshop.

Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

WORKSHOP HANDOUTS

PECO Statements for Phthalates

(1) Human Study Question: Is in utero exposure to phthalates in humans associated with male reproductive malformations?

TABLE 1 Human PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Males without restriction based on age
Exposure In utero exposure to one or more of the following phthalates: benzylbutyl phthalate (CAS no. 85-68-7), dibutyl phthalate (CAS no. 84-74-2), diethylhexyl phthalate (CAS no. 117-81-7), diisobutyl phthalate (CAS no. 84-69-5), diisononyl phthalate (CAS no. 28553-12-0), diisooctyl phthalate (CAS no. 27554-26-3), and/or dipentyl phthalate (CAS no. 131-18-0). When exposure data to more than one of the selected phthalates are obtained, the exposure data will be considered as a cumulative exposure using appropriate potency factors for individual phthalate congeners.
No restrictions based on route of exposure, based on biomonitoring data (e.g., urine, blood, or other specimens), environmental measures (e.g., air or water concentrations), or indirect measures (e.g., job title).
Comparators Populations exposed at lower levels of the selected phthalates
Outcomes Primary outcomes:
Male reproductive effects, including alterations in fertility or fecundity; effects on sperm production, maturation, transport, morphology, or motility; malformations (hypospadias or cryptorchidism); alterations in size, weight, morphology, histology, or function of male reproductive organs (testis, epididymis, seminal vesicle, prostate, vas deferens, or gubernaculum); and changes in anogenital distance.
Secondary outcomes:
Indicators of male reproductive effects, including altered levels of endocrine or biochemical signaling molecules (fetal testosterone, fetal testis steroidogenic or cholesterologenic proteins, and insulin-like factor 3), receptors, or mRNAs; and changes in cell proliferation.

(2) Animal Study Question: Does in utero exposure to phthalates in nonhuman mammals cause male reproductive malformation?

TABLE 2 Animal PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Male nonhuman mammals without restriction based on species or age
Exposure In utero exposure to one or more of the following phthalates or the corresponding monoester metabolite: benzylbutyl phthalate (CAS no. 85-68-7), dibutyl phthalate (CAS no. 84-74-2), diethylhexyl phthalate (CAS no. 117-81-7), diisobutyl phthalate (CAS no. 84-69-5), diisononyl phthalate (CAS no. 28553-12-0), diisooctyl phthalate (CAS no. 27554-26-3), and/or dipentyl phthalate (CAS no. 131-18-0).
No restrictions based on route of exposure, based on administered dose or concentration, or biomonitoring data (e.g., urine, blood, or other specimen measurements).
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Element Evidence
Comparators Male nonhuman mammal populations exposed to different doses of the selected phthalates or vehicle-only treatment
Outcomes Primary outcomes:
Male reproductive effects, including alterations in fertility or fecundity; effects on sperm production, maturation, transport, morphology, or motility; malformations (hypospadias or cryptorchidism) or alterations in size, weight, morphology, histology, or function of male reproductive organs (testis, epididymis, seminal vesicle, prostate, vas deferens, or gubernaculum); and changes in anogenital distance.
Secondary outcomes:
Indicators of male reproductive effects, including altered levels of endocrine or biochemical signaling molecules (fetal testosterone, fetal testis steroidogenic or cholesterologenic proteins, and insulin-like factor 3), receptors, or mRNAs; and changes in cell proliferation.

PECO Statements for TCDD

(3) Human Study Question: Is developmental exposure to TCDD in humans associated with male reproductive effects?

TABLE 3 Human PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Males without restriction based on age
Exposure Developmental exposure to TCDD (CAS no. 1746-01-6), with no restrictions based on route of exposure, based on biomonitoring data (e.g., urine, blood, or other specimens), environmental measures (e.g., air or water concentrations), or indirect measures (e.g., job title).
To be considered “developmental” the exposure occurred during any of the following: preconception for one or both parents, prenatal to the pregnant female and/or directly to the fetus, or postnatal until sexual maturation.
Comparators Populations exposed at lower levels of TCDD
Outcomes Primary outcomes:
Male reproductive effects, including alterations in fertility or fecundity; effects on sperm production, maturation, transport, morphology, or motility; malformations (hypospadias or cryptorchidism) or alterations in size, weight, morphology, histology, or function of male reproductive organs (testis, epididymis, seminal vesicle, prostate, vas deferens, or gubernaculum); altered age at puberty; and changes in anogenital distance.
Secondary outcomes:
Indicators of male reproductive effects, including altered levels of endocrine or biochemical signaling molecules (testosterone, luteinizing hormone, and insulin-like growth factor-1), receptors, or mRNAs.
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

(4) Animal Study Question: Does developmental exposure to TCDD in nonhuman mammals cause male reproductive effects?

TABLE 4 Animal PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Male nonhuman mammals without restriction based on species or age (including experimental or wildlife models)
Exposure Developmental exposure to TCDD (CAS no. 1746-01-6), with no restrictions based on route of exposure, based on administered dose or concentration, biomonitoring data (e.g., urine, blood, or other specimen measurements), or environmental measurements (e.g., air or water concentrations).
To be considered “developmental” the exposure occurred during any of the following: preconception for one or both parents, prenatal to the pregnant female and/or directly to the fetus, or postnatal until sexual maturation.
Comparators Male nonhuman mammalian populations exposed to vehicle-only treatment in experimental studies or lower levels of TCDD in wildlife studies
Outcomes Primary outcomes:
Male reproductive effects, including alterations in fertility; effects on sperm production, maturation, transport, morphology, or motility; malformations (hypospadias or cryptorchidism) or alterations in size, weight, morphology, histology, or function of male reproductive organs (testis, epididymis, seminal vesicle, prostate, vas deferens, or gubernaculum); altered age at puberty; changes in anogenital distance; nipple or areola retention; and alterations in male-associated reproductive behaviors.
Secondary outcomes:
Indicators of male reproductive effects, including altered levels of endocrine or biochemical signaling molecules (testosterone, luteinizing hormone, insulin-like growth factor-1), receptors, or mRNAs.

PECO Statements for Bisphenol A

(5) Human Study Question: Is exposure to bisphenol A in humans associated with female reproductive effects?

TABLE 5 Human PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Females without restriction based on age
Exposure Exposure to bisphenol A (CAS no. 80-05-7), with no restrictions based on route of exposure, based on exposure media (e.g., food or consumer product concentrations), biomonitoring data (e.g., urine, blood, or other specimen measurements), or indirect measures (e.g., job title).
Comparators Populations exposed at lower levels of bisphenol A
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Element Evidence
Outcomes Primary outcomes:
Female reproductive effects, including alterations in fertility or fecundity (time-to-pregnancy and spontaneous abortion); alterations in ovulation or reproductive cyclicity; alterations in size, weight, morphology, histology, or function of female reproductive organs (ovaries, fallopian tubes, uterus, vagina, and mammary gland); altered age at puberty; adverse effects on lactation; premature reproductive senescence; changes in anogenital distance; changes in timing of breast development; and alterations in pubic hair development.

(6) Animal Study Question: Does exposure to bisphenol A in nonhuman mammals cause female reproductive effects?

TABLE 6 Animal PECO (Population, Exposure, Comparator, and Outcome) Statement

Element Evidence
Population Female nonhuman mammals without restriction based on species or age
Exposure Exposure to bisphenol A (CAS no. 80-05-7), with no restrictions based on route of exposure, based on administered dose or concentration, or biomonitoring data (e.g., urine, blood, or other specimen measurements).
Comparators Female nonhuman mammalian populations exposed to vehicle-only treatment in experimental studies or lower levels of bisphenol A found in background populations.
Outcomes Primary outcomes:
Female reproductive effects, including alterations in fertility or fecundity (time-to-pregnancy, spontaneous abortion, fetal loss, resorptions, and litter size); alterations in ovulation or reproductive cyclicity; alterations in size, weight, morphology, histology, or function of female reproductive organs (ovaries, fallopian tubes, uterus, vagina, and mammary gland); altered age at puberty; adverse effects on lactation; premature reproductive senescence; female-associated reproductive behaviors; and altered mammary gland development.
Secondary outcomes:
Indicators of female reproductive effects, including altered levels of endocrine or biochemical signaling molecules (androstenedione, dehydroepiandrosterone sulfate, estradiol, estrone, insulin-like growth factor-1, luteinizing hormone, sex hormone-binding globulin, and testosterone), receptors, or mRNAs; and changes in cell proliferation.

Questions for Each Panel:

  1. Has the committee framed questions that can be addressed using systematic review methods? What changes would you suggest for the research questions, such as narrowing or widening the scope of each question?
  2. Are the exposures adequately defined for each research question?
    1. Should any additional measures be added?
    2. Should any be modified or removed?
    3. Are there critical windows of susceptibility that should be considered in defining the exposures for each research question?
    4. What issues, such as toxicokinetics or analytical artifacts, should be considered in evaluating the internal and external validity of different exposure metrics?
    5. Are there confounding co-exposures that should be considered?
  3. Please comment on the appropriateness of the selected comparators.
  4. Are the primary or secondary outcomes appropriate?
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
    1. Are there additional primary or secondary outcomes that are plausibly caused by altered endocrine function? If so, what are they?
    2. In general, the primary outcomes are indicators of clinical effects that would be considered adverse whereas the secondary outcomes are considered surrogate measures (e.g., laboratory tests) that may be less predictive of adverse changes (e.g., upstream indicators).
      1. Does the panel agree with the way the committee identified primary and secondary outcomes?
      2. Are there effects listed as primary health outcomes that should be considered secondary outcomes? If so, please provide an explanation and support for making the change.
      3. Are there effects listed as secondary health outcomes that should be considered primary outcomes? If so, please provide an explanation and support for making the change.
      4. Are there effects listed that should not be considered by the committee? If so, please provide an explanation and support for making the change.
      5. Are there effects not listed that should be considered by the committee? If so, please provide an explanation and support for making the change.
  1. Are the animal populations relevant for the committee’s statement of task?
    1. Are there major toxicokinetic or toxicodynamic differences across mammalian species or strains that should be considered in evaluating potential effects of these chemicals? If so, please provide key considerations or differences that should be considered, and to which outcomes such differences are applicable.
    2. Are there nonmammalian models that should be considered equal to or as reliable as mammalian models (e.g., rodents or nonhuman primates) for evaluating potential reproductive effects in humans?
  2. Are there any particular study designs or characteristics that would make a study more or less valid or reliable?
  3. Is the database sufficient to conduct a systematic review to address the PECO question?
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 166
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 167
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 168
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 169
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 170
Suggested Citation:"Appendix B: Workshop on Potential Case Studies for Unraveling Endocrine-Related Low-Dose Toxicity." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 171
Next: Appendix C: Supporting Materials for the Phthalate (Animal) Systematic Review »
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To safeguard public health, the US Environmental Protection Agency (EPA) must keep abreast of new scientific information and emerging technologies so that it can apply them to regulatory decision-making. For decades the agency has dealt with questions about what animal-testing data to use to make predictions about human health hazards, how to perform dose-response extrapolations, how to identify and protect susceptible subpopulations, and how to address uncertainties. As alternatives to traditional toxicity testing have emerged, the agency has been faced with additional questions about how to incorporate data from such tests into its chemical assessments and whether such tests can replace some traditional testing methods.

Endocrine active chemicals (EACs) have raised concerns that traditional toxicity-testing protocols might be inadequate to identify all potential hazards to human health because they have the ability to modulate normal hormone function, and small alterations in hormone concentrations, particularly during sensitive life stages, can have lasting and significant effects. To address concerns about potential human health effects from EACs at low doses, this report develops a strategy to evaluate the evidence for such low-dose effects.

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