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.
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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: | |
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| 10:30 | Break |
| 10:45 | Case Example 2: TCDD and Male Reproductive Effects |
| Moderators: Russ Hauser, Kamin Johnson, Andrew Rooney | |
| Panelists: | |
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| 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: | |
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| 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.
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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:
- 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?
- Are the exposures adequately defined for each research question?
- Should any additional measures be added?
- Should any be modified or removed?
- Are there critical windows of susceptibility that should be considered in defining the exposures for each research question?
- What issues, such as toxicokinetics or analytical artifacts, should be considered in evaluating the internal and external validity of different exposure metrics?
- Are there confounding co-exposures that should be considered?
- Please comment on the appropriateness of the selected comparators.
- 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.
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- Are there additional primary or secondary outcomes that are plausibly caused by altered endocrine function? If so, what are they?
- 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).
- Does the panel agree with the way the committee identified primary and secondary outcomes?
- 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.
- 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.
- Are there effects listed that should not be considered by the committee? If so, please provide an explanation and support for making the change.
- Are there effects not listed that should be considered by the committee? If so, please provide an explanation and support for making the change.
- Are the animal populations relevant for the committee’s statement of task?
- 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.
- 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?
- Are there any particular study designs or characteristics that would make a study more or less valid or reliable?
- 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.
×
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.
×
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.
×
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.
×
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.
×
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.
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