Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals (2017) / Chapter Skim
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Appendix D: Supporting Materials for the Phthalate (Human) Systematic Review
Appendix D: Supporting Materials for the Phthalate (Human) Systematic Review
Pages 271-328
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From page 271... ...
Orthophthalates have been linked to effects on male reproductive-tract development after in utero exposure in human studies. OBJECTIVE AND SPECIFIC AIMS Review Question The overall objective of this systematic review is to answer the question what is the effect of in utero exposure to ortho-phthalates on anogenital distance, hypospadias, or testosterone concentrations in male humans?
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Population: Male humans Exposure: In utero exposure to any of the following ortho-phthalates or the corresponding monoester or oxi dative metabolites: benzylbutyl phthalate (CAS no.
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Furthermore, studies have shown that rats exposed to phthalates have similar sensitivity to decreased fetal testosterone and AGD as they do for decreased INSL-3, and that cryptorchidism is a less sensitive end point compared to reductions in AGD. Because the overall objective of the committee is to use this systematic review with the one being conducted on the animal evidence to evaluate the coherence between effects and dose-response relationships, the committee judged that it would not be useful to include cryptorchidism in the systematic reviews on phthalates.
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. Current guidance on using existing systematic reviews will be used (Robinson et al.
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Reviews that are a good match but with search dates more than a year ago will be updated. If no relevant systematic reviews are found, an independent systematic review will be performed.
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above. Citations will be INCLUDED if they meet the PECO statement criteria: Study includes male humans Study includes in utero exposure Study includes comparison with males exposed in utero at lower concentrations Study measures anogenital distance, anogenital index, anoscrotal distance, anopenile distance, hypospadias, or testosterone concentrations Updated details to instructions and interpretations for full-text screening will be added to the Section D-1f to document the process of the review team during the screening process.
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that outlines an approach to evaluating risk of bias for human epidemiology studies. The risk of bias domains and questions are based on established guidance for observational human studies and randomized controlled trials (Higgins and Green 2011; Viswanathan et al.
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It is also expected that information about confounding, exposure characterization, outcome assessment, and other important issues may be identified during or after data extraction, which can lead to further refinement of the risk of bias criteria. After assessors have independently made risk of bias determinations for a study across all risk of bias questions, the two assessors will compare their results to identify discrepancies and attempt to resolve them.
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Nonhuman animal observational studies can be evaluated using the design features of observational human studies such as cross-sectional study design.
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. If a meta-analysis is conducted a random effects model will be used for the analy s d, e l d ysis.
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2016. Twelve recommendations for integrat ing existing systematic reviews into new reviews: EPC guidance.
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2008. Using existing systematic reviews in com plex systematic reviews.
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He has been developing risk assessment methods and guidance throughout his professional career and is a principal author of the 2012 WHO/IPCS Guidance for Immunotoxicity Risk Assessment for Chemicals. Most recently, he has been working on emerging issues in toxicology and environmental health, including methods to address study quality in terms of risk of bias for human, animal, and mechanistic studies and adaptation of systematic review methods for addressing environmental health questions.
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Sathyanarayana is the center director and clinical director for The Infant Development and Environment Study, which is a multicenter cohort study of phthalate exposures in pregnancy and health outcomes in children. She also chairs EPA's Children's Health Protection Advisory Committee.
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All MeSH terms and key word synonyms will be searched together as one concept using the Boolean operator "OR." Human studies -- The search filter developed by the Cochrane Library to identify human studies (see http://handbook.cochrane.org/ part 2, section 6.4.f) will be modified to comply with PubMed formatting.
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Additional keywords will be identified using the list of synonyms from each Emtree record and added to the keywords from the MeSH records. Toxline The review team will develop the Toxline search strategy by removing any database specific formatting from the PubMed search strategy to create a keyword-only search (Toxline does not employ a controlled vocabulary)
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ester"/exp OR "phthalic acid dimethyl ester"/exp OR "phthalic acid dioctyl ester"/exp OR "benzylbutyl phthalate" OR "benzyl butyl phthalate" OR "butyl benzyl phthalate" OR "butylbenzyl phthalate" OR "butylbenzylphthalate" OR "phthalic acid butyl benzyl ester" OR "butyl-benzyl-phthalate" OR "BBzP" OR "BzBP" OR "BBPHT" OR "85-68-7" OR "Dibutyl Phthalate" OR "Di-n-Butyl Phthalate" OR "Di n Butyl Phthalate" OR "Butyl Phthalate" OR "d n butyl phthalate" OR "dbp" OR "di n butyl phthalate" OR "dibutyl phthalate" OR "dibutylphthalate" OR "phthalic acid di n butyl este" OR "84-74-2" OR "phthalic acid diethyl ester" OR "diethyl phthalate" OR "diethylphthalate" OR "ethyl phthalate" OR "di-ethyl phthalate" OR "DEP" OR "84-66-2" OR "bis (2 ethylhexyl) phthalate" OR "bis (2 ethylhexyl)
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Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity ylphthalate" OR "di-isononylphthalate" OR "Diisooctylphthalate" OR "Dimethylphthalate" OR "DINP" OR "dioctylphthalate" OR "dipentyl benzene-1,2-dicarboxylate" OR "Dmp" OR "dmp30" OR "DNOP" OR "ENJ 2065" OR "fermine" OR "mipax" OR "mugia" OR "octoil" OR "o-phthalate" OR "ophthalates" OR "palatinol" OR "sketofax") AND ("Exposure" OR "Exposed" OR "exposures" OR "exposing")
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Study does not include male humans Study does not report exposure to one or more of the phthalates listed in the PECO statement Study does not have biomonitoring data specific to phthalate exposure Study does not include in utero exposure Study does not assess or report anogenital distance, anogenital index, anoscrotal distance, anopenile distance, hypospadias, or testosterone concentration measured during gestation or at delivery No comparator group (male humans exposed in utero to lower concentrations of phthalates) Not in English Other (explanation required)
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Results Exposure levels (e.g., mean, median, measures of variance as presented in paper, such as SD, SEM, 75th/90th/95th percentile, minimum/maximum) ; range of exposure levels, number of exposed cases Statistical findings (e.g., adjusted β, standardized mean difference, adjusted odds ratio, standardized mortality ratio, relative risk, etc.)
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Acceptable consideration of appropriate adjustment factors includes cases when the factor is not included in the final adjustment model because the author conducted analyses that indicated it did not need to be included, AND there is direct evidence that primary covariates and confounders were assessed using valid and reliable measurements, AND there is direct evidence that other exposures anticipated to bias results were not present or were appropriately measured and adjusted for. In occupational studies or studies of contaminated sites, other chemical exposures known to be associated with those settings were appropriately considered.
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Indirect evidence that appropriate adjustments were made, OR it is deemed that not considering or only considering a partial list of covariates or confounders in the final analyses would not appreciably bias results, AND there is evidence (direct or indirect) that covariates and confounders considered were assessed using valid and reliable measurements, OR it is deemed that the measures used would not appreciably bias results (i.e., the authors justified the validity of the measures from previously published research)
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Probably Low Risk of Bias (+) Indirect evidence that the exposure was consistently assessed using well-established methods that directly measure exposure)
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, such as non-caliper AGD measurements or testosterone measurements using radioimmunoassay, OR it is deemed that the outcome assessment methods used would not appreciably bias results, AND there is indirect evidence that the outcome assessors were adequately blinded to the study group, and it is unlikely that they could have broken the blinding prior to reporting outcomes, OR it is deemed that lack of adequate blinding of outcome assessors would not appreciably bias results, which is more likely to apply to objective outcome measures. Probably High Risk of Bias (-)
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Acceptable consideration of appropriate adjustment factors includes cases when the factor is not included in the final adjustment model because the author conducted analyses that indicated it did not need to be included, AND there is direct evidence that primary covariates and confounders were assessed using valid and reliable measurements, AND there is direct evidence that other exposures anticipated to bias results were not present or were appropriately measured and adjusted for. In occupational studies or studies of contaminated sites, other chemical exposures known to be associated with those settings were appropriately considered.
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Indirect evidence that appropriate adjustments were made, OR it is deemed that not considering or only considering a partial list of covariates or confounders in the final analyses would not appreciably bias results, AND there is evidence (direct or indirect) that covariates and confounders considered were assessed using valid and reliable measurements, OR it is deemed that the measures used would not appreciably bias results (i.e., the authors justified the validity of the measures from previously published research)
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Probably Low Risk of Bias (+) Indirect evidence that the exposure was consistently assessed using well-established methods that directly measure exposure)
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have not been reported, OR and there is indirect evidence that unplanned analyses were included that may appreciably bias results, OR there is insufficient information provided about selective outcome reporting (record "NR" as basis for answer)
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Probably Low Risk of Bias (+) Indirect evidence that cases and controls were similar (e.g., recruited from the same eligible population, recruited with the same method of ascertainment using the same inclusion and exclusion criteria, and were of similar age)
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Indirect evidence that appropriate adjustments were made, OR it is deemed that not considering or only considering a partial list of covariates or confounders in the final analyses would not appreciably bias results, AND there is evidence (direct or indirect) that covariates and confounders considered were assessed using valid and reliable measurements, OR it is deemed that the measures used would not appreciably bias results (i.e., the authors justified the validity of the measures from previously published research)
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, such as non-caliper AGD measurements and testosterone measurements using radioimmunoassays, OR it is deemed that the outcome assessment methods used would not appreciably bias results, AND there is indirect evidence that the outcome assessors were adequately blinded to the study group, and it is unlikely that they could have broken the blinding prior to reporting outcomes, OR it is deemed that lack of adequate blinding of outcome assessors would not appreciably bias results, which is more likely to apply to objective outcome measures.
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have not been reported, OR and there is indirect evidence that unplanned analyses were included that may appreciably bias results, OR there is insufficient information provided about selective outcome reporting (record "NR" as basis for answer)
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Pamela Hartman, who has more than 20 years of professional experience in environmental consulting, specializing in exposure and risk assessment, toxicology, literature search and review, technical editing, and document production. For NIEHS, she has conducted data extraction, study quality reviews, and risk of bias assessments for toxicological and epidemiological studies using DRAGON and HAWC for multiple projects, including perfluorooctanoic acid (PFOA)
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Course Series; Provisional Toxicity Value (PTV) documents; two Nanomaterial Case Study documents; and Dioxin Reassessment.
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SECTION D-2 Results of Literature Searches for Human Studies on the Effects of Phthalates on Male Reproductive-Tract Development Literature searches were performed on August 15, 2016, using the search strategy presented in the Phthalate (Human) Systematic Review Protocol (Section D-1)
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Five human studi of DEHP and AGD (as or AGD (ap were available. Figures D3-1 and D3 il e ies s)
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Ap ppendix D FIGURE D3-2 Data piv of studies that measured DEHP metab vot d bolites and AG (as)
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R N de. -3 r Unexplained inconsistenci U ies: No downngrade.
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) ble re Factors Considered fo Downgrad C or ding Confide ence Risk of bias: No downgrad See Figur D3-3 for th risk of bias assessments for the four stud R N de.
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. In ndirectness: No downgrad The study designs direc addressed the topic of the evaluatio de.
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. In ndirectness: No downgrad The study designs direc addressed the topic of the evaluatio de.
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oss s n . In ndirectness: No downgrad The study designs direc addressed the topic of the evaluatio de.
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. In ndirectness: No downgrad The study designs direc addressed the topic of the evaluatio de.
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Factors Considered fo Downgrad C or ding Confide ence Risk of bias: No downgra R ade. The stud was rated as having a probably low risk of bias (see dy w s Figure D3-3)
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. able Factors Considered fo Upgrading Confidence C or e Large magnit L tude: No upgr rade.
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) CI, Lower CI, Upper P value for Analysis Estimate, mm Bound Bound P value Heterogeneity I2 Primary Analysis -4.07 -6.49 -1.66 0.001 0.876 0.0 w/o Bornehag et al.
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Appendix D Martino-Andrade et al. 2016.10 -1.79 -5.05 1.48 0.283 0.156 43.4 Martino-Andrade et al.
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Thus, the available studies do not support BzBP exposure being associated with decreased AGD. TABLE D5-1 Studies Included in the Meta-Analysis of BzBP and AGD Reference Outcome Mean AGD, mm Exposure Metric Estimate, % Lower CI Upper CI Bornehag et al.
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model pe 10-fold incre er ease in BzBP expo osure. Sensitivit Analyses ty FIGURE D5-2 Sensitivi analyses of human studie of BzBP and AGD perform by leavin one study ou at a ity f es d med ng ut time.
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. TABLE D5-2 Sensitivity Analyses of Human Studies of BzBP and AGD D y H s Beta Estimate, wer CI, Low CI, Up pper P value for e Analysis % changee Bound Bound P valu ue Heterog geneity I2 BzBP primar analysis ry -1.43 -3.47 0.61 0.170 0 0.410 0.00 BzBP w/o Bornehag et al.
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r ease in DBP expos sure. Sensitivit Analyses ty FIGURE D5-5 Sensitivi analysis of human studie of DBP and AGD perform by leaving one study ou at a ity f es d med g ut time.
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. TABLE D5-4 Sensitivity Analyses of Human Studies of DBP and A D y H s AGD Beta Estimate, CI, Loower CI, Upper P value for Analysis % changee Bound d Bouund P value Hete erogeneity I2 DBP primary analysis y -3.13 -5.63 -0.6 64 0 0.014 0.709 0 DBP w/o Bo ornehag et al.
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r ease in DEP expos sure. Sensitivit Analyses ty FIGURE D5-8 Sensitivi analysis of human studie of DEP and AGD perform by leaving one study ou at a ity f es d med g ut time.
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. TABLE D5-6 Sensitivity Analyses of Human Studies of DEP and A D y H s AGD Beta Estim mate, CI, Lower r CI, Upper r P value for e Analysis % change Bound Bound P value geneity Heterog I2 DEP primary analysis y -1.94 -3.88 0.001 0.050 0.204 29.1 DEP w/o Bo ornehag et al.
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model per 10-fold in l e ts ncrease in DIBP ex xposure. FIGURE D5-11 Sensitiv analysis of human studie of DIBP an AGD perfor D vity es nd rmed by leavin one study out at a ng time.
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. TABLE D5-8 Sensitivity Analyses of Human Studies of DIBP and AGD D y H s Beta Estimate, , CI, Low wer CI, Up pper P value fo for % change Bound Boundd P val lue Heterogeneity I2 DIBP primar analysis ry -2.23 -5.15 0.70 0.135 5 0.558 0.00 DIBP w/o Sw et al.
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model per 10-fold in l e ts ncrease in DINP ex xposure. FIGURE D5-14 Sensitiv analysis of human studie of DINP an AGD perfor D vity es nd rmed by leavin one study out at a ng time.
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. TABLE D5-10 Sensitivity Analyses of Human Studie of DINP and AGD D f es d Beta Estim mate, CI, Low wer CI, Up pper P valu for ue Analysis % change Bound Boundd Pvvalue Heterogeneity I2 DINP primar analysis ry -0.96 -4.17 2.25 0.559 0.092 58 DINP w/o Bornehag et al.
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