Search for Existing Systematic Reviews

The review team will consider using existing systematic reviews to address or help to address its research question. English-language systematic reviews conducted within the last 3 years will be sought. The review team will incorporate prior reviews, update prior reviews, and/or use the reviews as part of its searching, depending on determination of their relevancy and quality (Whitlock et al. 2008). Current guidance on using existing systematic reviews will be used (Robinson et al. 2014, 2015, 2016).

Use of Existing Reviews

Eligible systematic reviews of high quality will be reviewed, considering date of search and match with the PECO statement as well as availability of data from the primary studies, how risk of bias was conducted, and other factors. Current reviews considered a good match will be used to address the research question. 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.

Literature Search for Independent Systematic Review

The review team will collaborate with an information specialist (JB) who has training, expertise, and familiarity with developing and performing systematic review literature searches. A variety of methods will be used to identify relevant data (see below). Literature searches will not be limited by publication date.

Screening Process

References retrieved from the literature search will be screened for relevance and eligibility against the evidence selection criteria using DistillerSR (Evidence Partners; https://www.evidencepartners.com). Screeners from the review team will be trained with an initial pilot phase on 25 studies undertaken to improve clarity of the evidence selection criteria and to improve accuracy and consistency among screeners. Screening forms are presented in Section D-1c.

Data Analysis and Evidence Synthesis

The review team will qualitatively synthesize the body of evidence for each outcome and, where appropriate, a meta-analysis will be performed. If a meta-analysis is performed, summaries of main characteristics for each included study will be compiled and reviewed by two team members to determine comparability between studies, to identify data transformations necessary to ensure comparability, and to determine whether heterogeneity is a concern. The main characteristics considered across all eligible studies include the following:

• Study design (e.g., cross-sectional, cohort)
• Details on how participants were classified into exposure groups (e.g., quartiles of exposure)
• Details on source of exposure data (e.g., questionnaire, area monitoring, biomonitoring)
• Measurement of biomonitoring data specific to phthalate exposure for each exposure group
• Health outcome(s) reported
• Conditioning variables in the analysis (e.g., variables considered confounders)
• Type of data (e.g., continuous or dichotomous), statistics presented in paper, access to raw data
• Variation in degree of risk of bias at individual study level

The review team expects to require input from subject-matter experts to help assess the heterogeneity of the studies. Subgroup analyses to examine the extent to which risk of bias contributes to heterogeneity will be performed. Situations where it may not be appropriate to include a study are when data on exposure or outcome are too different to be combined or other circumstances that may indicate that averaging study results would not produce meaningful results. When considering outcome measures for conducting meta-analyses, continuous outcome measures, such as beta coefficients (and their associated confidence intervals) from regression analysis, are preferred. A secondary alternative, when there are more than two groups, is to conduct a regression analysis of the odds or risk ratios across exposure groups and to use the derived beta coefficient. A tertiary alternative when there are only two groups (e.g., higher and lower exposure) is to use the odds or risk ratio itself.

TABLE D1-1

OHAT Risk of Bias Tool.

TABLE D1-2

Answers to the Risk of Bias Questions.

If a meta-analysis is conducted, a random effects model will be used for the analysis. Heterogeneity will be assessed using the I-squared statistic. Interpretation of I-squared will be based on the Cochrane Handbook: 0% to 40% (might not be important); 30% to 60% (may represent moderate heterogeneity); 50% to 90% (may represent substantial heterogeneity); 75% to 100% (considerable heterogeneity). Additionally, as described in the Cochrane Handbook, for the last three categories, the importance of the I-squared will be interpreted considering not only the magnitude of effects but also the strength of the evidence (90% two-tailed confidence interval).

The review team will also perform sensitivity analyses on the following aspects:

• Sensitivity to exclusion of individual studies in succession,
• Sensitivity to alternative exposure metrics (if available), and
• Sensitivity to alternative outcome metrics (if available).

It is unlikely that there will be enough studies or information to meaningfully assess publication bias or to perform subgroup analyses, so no such analyses are planned.

In the event that these proposed methods for data analysis are altered to tailor to the evidence base from included studies, the protocol will be amended accordingly, and the reasons for change will be justified in the documentation.

Confidence Rating: Assessment of the Body of Evidence

The quality of evidence for each male reproductive outcome will be evaluated using the GRADE system for rating the confidence in the body of evidence (Guyatt et al. 2011; Rooney et al. 2014). More detailed guidance on reaching confidence ratings in the body of evidence as “high,” “moderate,” “low,” or “very low” is provided in NTP (2015, see Step 5). In brief, available studies on a particular outcome are initially grouped by key study-design features, and each grouping of studies is given an initial confidence rating by those features.

The initial rating is downgraded for factors that decrease confidence in the results, including

• high risk of bias
• unexplained inconsistency
• indirectness or lack of applicability
• imprecision
• publication bias

The initial rating is upgraded for factors that increase confidence in the results, including

• large magnitude of effect
• dose-response relationship
• consistency across study designs/populations/animal models or species
• consideration of residual confounding
• other factors that increase our confidence in the association or effect (e.g., particularly rare outcomes)

The reasons for downgrading (or upgrading) confidence may not be due to a single domain of the body of evidence. If a decision to downgrade is borderline for two domains, the body of evidence is downgraded once in a single domain to account for both partial concerns based on considering the key drivers of the strengths or weaknesses. Similarly, the body of evidence is not downgraded twice for what is essentially the same limitation (or upgraded twice for the same asset) that could be considered applicable to more than one domain of the body of evidence. Consideration of consistency across study designs, human populations, or animal species is not included in the GRADE guidance (Guyatt et al. 2011); however, it is considered in the modified version of GRADE used by OHAT (Rooney et al. 2014).

Confidence ratings are independently assessed by members of the review team, and discrepancies will be resolved by consensus and consultation with technical advisors as needed. Confidence ratings will be summarized in evidence profile tables.

PubMed

A search string employing medical subject heading (MeSH) terms and keyword synonyms will be developed. The PubMed search strategy will be considered the primary search strategy and will provide the basis of the other electronic search strategies. To assist in compiling these terms, the review team will conduct a text analysis of eight articles known to the authors. These articles were selected because they represent both American and non-American publications and will help identify spelling variants. The search strategies will address each of the following concepts:

• Phthalates—The review team will use the MeSH database (http://www.ncbi.nlm.nih.gov/mesh) to find all MeSH heading and Supplementary Concept headings that relate to the following phthalates: the CAS numbers to these 11 phthalates: benzylbutyl phthalate (CAS no. 85-68-7), dibutyl phthalate (CAS no. 84-74-2), diethyl phthalate (CAS 84-66-2), 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), dimethyl phthalate (CAS no. 131-11-3), di-n-octyl phthalate (CAS no. 117-84-0), diisodecyl phthalate (CAS no. 26761-40-0), and/or dipentyl phthalate (CAS no. 131-18-0). The review team will mine the “Entry Terms” list for each of the controlled vocabulary terms identified and include all unique keyword synonyms listed for each. CAS registry numbers for each phthalate substance will also be included in the list of search terms. All MeSH terms, Supplementary Concept terms, keyword synonyms, and CAS registry numbers will be searched together as one concept using the Boolean operator “OR.”
• Exposure—The review team will use the MeSH database (http://www.ncbi.nlm.nih.gov/mesh) to find all MeSH heading and Supplementary Concept headings that relate to the exposure concept. The review team will mine the “Entry Terms” list for each of the controlled vocabulary terms identified and include all unique keyword synonyms listed for each. All MeSH terms and keyword 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.
• Outcomes—The review team will use the MeSH database (http://www.ncbi.nlm.nih.gov/mesh) to find all MeSH heading and Supplementary Concept headings that relate to male genital abnormalities.

Each of the above concepts will be searched together using the Boolean operator “AND.” There will not be limitations on date of publication, language, or publication type. All citation records will be exported to EndNote. Additional citations identified through the search processes identified below will also be exported to the project EndNote library. Duplicates will be removed from the citation library using the “Find Duplicates” tool in EndNote as well as a manual review of citations by the project librarian to identify any duplicates not found during the automated process. The number of citations found in each database will be recorded, as well as the number of duplicates and final tally of unique citations. The final library of citations will be uploaded to the Health Assessment Workspace Collaboration Web-based tool (www.hawcproject.org) for systematic reviews where they will be reviewed by the team.

Embase

The controlled vocabulary database Emtree is used by Embase. For each MeSH term identified through the process above, Emtree will be searched for the appropriate corresponding term. 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).

PubMed

(“butylbenzyl phthalate” [Supplementary Concept] OR “Dibutyl Phthalate”[Mesh] OR “diethyl phthalate” [Supplementary Concept] OR “Diethylhexyl Phthalate”[Mesh] OR “diisobutyl phthalate” [Supplementary Concept] OR “diisononyl phthalate” [Supplementary Concept] OR “diisooctyl phthalate” [Supplementary Concept] OR “dimethyl phthalate” [Supplementary Concept] OR “di-n-octyl phthalate” [Supplementary Concept] OR “benzylbutyl phthalate”[tw] OR “benzyl butyl phthalate”[tw] OR “butyl benzyl phthalate”[tw] OR “butylbenzyl phthalate”[tw] OR “butylbenzylphthalate”[tw] OR “phthalic acid butyl benzyl ester”[tw] OR “butyl-benzyl-phthalate”[tw] OR “BBzP”[tw] OR “BzBP”[tw] OR “BBPHT”[tw] OR “85-68-7”[tw] OR “Dibutyl Phthalate”[tw] OR “Di-n-Butyl Phthalate”[tw] OR “Di n Butyl Phthalate”[tw] OR “Butyl Phthalate”[tw] OR “d n butyl phthalate”[tw] OR “dbp”[tw] OR “di n butyl phthalate”[tw] OR “dibutyl phthalate”[tw] OR “dibutylphthalate”[tw] OR “phthalic acid di n butyl este”[tw] OR “84-74-2”[tw] OR “phthalic acid diethyl ester”[tw] OR “diethyl phthalate”[tw] OR “diethylphthalate”[tw] OR “ethyl phthalate”[tw] OR “di-ethyl phthalate”[tw] OR “DEP”[tw] OR “84-66-2”[tw] OR “bis (2 ethylhexyl) phthalate”[tw] OR “bis (2 ethylhexyl) phthalate”[tw] OR “bis (2 ethylhexyl) phthalate”[tw] OR “bis (2 ethylhexylphthalate)”[tw] OR “Bis(2-ethylhexyl)phthalate”[tw] OR “DEHP”[tw] OR “di (2 ethylhexyl) phthalate”[tw] OR “di 2 ethylhexyl phthalate”[tw] OR “di 2 ethylhexylphthalate”[tw] OR “Di-2-Ethylhexylphthalate”[tw] OR “diethylhexyl phthalate”[tw] OR “Dioctyl Phthalate”[tw] OR “octoil”[tw] OR “phthalic acid di 2 ethylhexyl ester”[tw] OR “phthalic acid diethylhexyl ester”[tw] OR “117-81-7”[tw] OR “di-iso-butyl phthalate”[tw] OR “DiBP”[tw] OR “84-69-5”[tw] OR “di-isononylphthalate”[tw] OR “ENJ 2065”[tw] OR “ENJ-2065”[tw] OR “di-isononyl phthalate”[tw] OR “di-iso-nonyl phthalate”[tw] OR “DINP”[tw] OR “28553-12-0”[tw] OR “Diisooctylphthalate”[tw] OR “27554-26-3”[tw] OR “diamyl phthalate”[tw] OR “dipentyl phthalate”[tw] OR “phthalic acid dipentyl ester”[tw] OR “dipentyl benzene-1,2-dicarboxylate”[tw] OR “di-n-pentyl phthalate”[tw] OR “131-18-0”[tw] OR “Dimethyl phthalate”[tw] OR “Dimethylphthalate”[tw] OR “Avolin”[tw] OR “Citrola”[tw] OR “Dmp”[tw] OR “dmp30”[tw] OR “fermine”[tw] OR “methyl phthalate”[tw] OR “mipax”[tw] OR “mugia”[tw] OR “palatinol m”[tw] OR “sketofax”[tw] OR “131-11-3”[tw] OR “Di-n-octyl phthalate”[tw] OR “di n octyl phthalate”[tw] OR “di n octylphthalate”[tw] OR “dioctyl phthalate”[tw] OR “dioctylphthalate”[tw] OR “di(n-octyl)phthalate”[tw] OR “phthalic acid di n octyl ester”[tw] OR “DNOP”[tw] OR “117-84-0”[tw]) AND (“Maternal Exposure”[Mesh] OR “Environmental Exposure”[Mesh:NoExp] OR “Prenatal Exposure Delayed Effects”[Mesh] OR “Exposure”[tw] OR “Exposed”[tw] OR “exposures”[tw] OR “exposing”[tw] AND (“Genital Diseases, Male”[Mesh] OR “Genitalia, Male”[Mesh] OR “Testosterone”[Mesh:NoExp] OR “Androgens”[Mesh] OR “Anogenital”[tw] OR “AGD”[tw] OR “AGI”[tw] OR “ASD”[tw] OR “APD”[tw] OR “Urogenital”[tw] OR “Penile”[tw] OR “penis”[tw] OR “Anoscrotal”[tw] OR “Anopenile”[tw] OR “anorectal”[tw] OR “Testosterone”[tw] OR “androgen”[tw] OR “androgens”[tw] OR “Hypospadias”[tw] OR “hypospadia”[tw] OR “Testis”[tw] OR “testes”[tw] OR ((“Anorectal”[tw] OR “genital”[tw] OR “genitals”[tw] OR “testes”[tw] OR “rectum”[tw]) AND (“malformation”[tw] OR “malformations”[tw] OR “development”[tw] OR “abnormalities”[tw] OR “abnormality”[tw] OR “dysplasia”[tw])) OR (“Male”[tw] and (“genital”[tw] OR “genitals”[tw] OR “genitalia”[tw])) OR (“Anus”[tw] AND (“genital”[tw] OR “genitals”[tw] OR “genitalia”[tw]))) NOT (((“Animals”[Mesh] NOT (“Animals”[Mesh] AND (“Humans”[Mesh]))))

Embase

“phthalic acid benzyl butyl ester”/exp OR “phthalic acid dibutyl ester”/exp OR “phthalic acid diethyl ester”/exp OR “phthalic acid bis(2 ethylhexyl) 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) phthalate” OR “bis (2 ethylhexyl) phthalate” OR “bis (2 ethylhexylphthalate)” OR “Bis(2-ethylhexyl)phthalate” OR “DEHP” OR “di (2 ethylhexyl) phthalate” OR “di 2 ethylhexyl phthalate” OR “di 2 ethylhexylphthalate” OR “Di-2-Ethylhexylphthalate” OR “diethylhexyl phthalate” OR “Dioctyl Phthalate” OR “octoil” OR “phthalic acid di 2 ethylhexyl ester” OR “phthalic acid diethylhexyl ester” OR “117-81-7” OR “di-iso-butyl phthalate” OR “DiBP” OR “84-69-5” OR “di-isononylphthalate” OR “ENJ 2065” OR “ENJ-2065” OR “di-isononyl phthalate” OR “di-isononyl phthalate” OR “DINP” OR “28553-12-0” OR “Diisooctylphthalate” OR “27554-26-3” OR “diamyl phthalate” OR “dipentyl phthalate” OR “phthalic acid dipentyl ester” OR “dipentyl benzene-1,2dicarboxylate” OR “di-n-pentyl phthalate” OR “131-18-0” OR “Dimethyl phthalate” OR “Dimethylphthalate” OR “Avolin” OR “Citrola” OR “Dmp” OR “dmp30” OR “fermine” OR “methyl phthalate” OR “mipax” OR “mugia” OR “palatinol m” OR “sketofax” OR “131-11-3” OR “Di-n-octyl phthalate” OR “di n octyl phthalate” OR “di n octylphthalate” OR “dioctyl phthalate” OR “dioctylphthalate” OR “di(n-octyl)phthalate” OR “phthalic acid di n octyl ester” OR “DNOP” OR “117-84-0” AND (‘male genital system disease'/exp OR ‘male genital system'/exp OR ‘testosterone'/exp OR ‘androgen'/de OR “Anogenital”:ti,ab OR “AGD”:ti,ab OR “AGI”:ti,ab OR “ASD”:ti,ab OR “APD”:ti,ab OR “Urogenital”:ti,ab OR “Penile”:ti,ab OR “penis”:ti,ab OR “Anoscrotal”:ti,ab OR “Anopenile”:ti,ab OR “anorectal”:ti,ab OR “Testosterone”:ti,ab OR “androgen”:ti,ab OR “androgens”:ti,ab OR “Hypospadias”:ti,ab OR “hypospadia”:ti,ab OR “Testis”:ti,ab OR “testes”:ti,ab OR ((“Anorectal”:ti,ab OR “genital”:ti,ab OR “genitals”:ti,ab OR “testes”:ti,ab OR “rectum”:ti,ab) AND (“malformation”:ti,ab OR “malformations”:ti,ab OR “development”:ti,ab OR “abnormalities”:ti,ab OR “abnormality”:ti,ab OR “dysplasia”:ti,ab)) OR (“Male”:ti,ab and (“genital”:ti,ab OR “genitals”:ti,ab OR “genitalia”:ti,ab)) OR (“Anus”:ti,ab AND (“genital”:ti,ab OR “genitals”:ti,ab OR “genitalia”:ti,ab))) AND (‘prenatal exposure'/exp OR ‘environmental exposure'/exp OR ‘exposure' OR ‘exposed' OR ‘exposures' OR ‘exposing' NOT (‘animal'/exp NOT (‘animal'/exp AND ‘human'/exp))

Toxline

((“117-81-7” OR “117-84-0” OR “131-11-3” OR “131-18-0” OR “27554-26-3” OR “28553-12-0” OR “84-66-2” OR “84-69-5” OR “84-74-2” OR “85-68-7” OR “Avolin” OR “BBPHT” OR “BBzP” OR “bis 2 ethylhexylphthalate” OR “Bis 2-ethylhexyl phthalate” OR “butylbenzylphthalate” OR “butyl-benzyl-phthalate” OR “BzBP” OR “Dbp” OR “DEP” OR “di n octylphthalate” OR “DiBP” OR “diethylphthalate” 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 “o-phthalates” OR “palatinol” OR “sketofax”) AND (“Exposure” OR “Exposed” OR “exposures” OR “exposing”) AND (“Anogenital” OR “AGD” OR “AGI” OR “ASD” OR “APD” OR “Urogenital” OR “Penile” OR “penis” OR “Anoscrotal” OR “Anopenile” OR “anorectal” OR “Testosterone” OR “androgen” OR “androgens” OR “Hypospadias” OR “hypospadia” OR “Testis” OR “testes” OR ((“Anorectal” OR “genital” OR “genitals” OR “testes” OR “rectum”) AND (“malformation” OR “malformations” OR “development” OR “abnormalities” OR “abnormality” OR “dysplasia”)) OR (“Male” and (“genital” OR “genitals” OR “genitalia”)) OR (“Anus” AND (“genital” OR “genitals” OR “genitalia”))) NOT (animals OR animal OR mice OR mouse OR rats OR rat OR rodent OR rodents OR fish)

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. Figure D3-3 shows the risk of bias assessment for each study.
• Unexplained inconsistencies: No downgrade. Although there is some inconsistency in results across studies, the differences can be explained (at least partially) by different study populations, different ranges of exposure within study population, and differences in timing of collection of urine samples (first trimester vs later samples). Despite these differences, there is general consistency of associations with respect to direction and magnitude of effects (smaller AGD with higher DEHP metabolite exposure).
• Indirectness: No downgrade. The studies directly addressed the effect of prenatal exposure to DEHP on AGD in males, defined the window of exposure, and assessed the outcome within an appropriate amount of time.
• Imprecision: No downgrade. Most of the studies included 95% confidence intervals to assess precision of associations.
• Publication bias: No downgrade (see Table D3-1).

Sources of funding were used to evaluate publication bias in terms of whether a particular sector funded more studies than another.

FIGURE D3-3

Risk of bias heatmap of studies of DEHP and AGD in humans. In HAWC: https://hawcproject.org/summary/visual/341/.

TABLE D3-1

Sources of Funding for the Human Studies on Phthalates.

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. No evidence of a large magnitude of effect size.
• Dose-response: No upgrade. No evidence of dose-response curve based on one study that performed quartile analyses (see Figure D3-4).
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. See Figure D3-3 for the risk of bias assessments for the four studies.
• Unexplained inconsistencies: No downgrade. Although there is some inconsistency in results across studies, the differences can be explained (at least partially) by different study populations, different ranges of exposure within the study population, and differences in timing of collection of urine samples (first trimester vs later samples).
• Indirectness: No downgrade. The study designs directly addressed the topic of the evaluation.
• Imprecision: No downgrade. All but one study (Swan 2008) included 95% confidence intervals to assess precision of associations.
• Publication bias: No downgrade (see Table D3-1).

FIGURE D3-4

Data pivot of the Jensen et al. (2016) study of sumDEHP metabolites and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/sum-dehp-effects-agd-ap-agd-and-agi-quartiles/.

FIGURE D3-5

Data pivot of studies that measured MBzP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mbzp-effects-agd-ap-or-agd/.

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. No evidence of a large magnitude of effect size.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. See Figure D3-3 for the risk of bias assessments for the four studies.
• Unexplained inconsistencies: No downgrade. Although there is some inconsistency in results across studies, the differences can be explained (at least partially) by different study populations, different ranges of exposure within the study population, and differences in timing of collection of urine samples (first trimester vs later samples). Despite these differences, there is general consistency of associations with respect to direction and magnitude of effects (smaller AGD with higher MBP metabolite exposure).
• Indirectness: No downgrade. The study designs directly addressed the topic of the evaluation.
• Imprecision: No downgrade. All but one study (Swan 2008) included 95% confidence intervals to assess precision of associations.
• Publication bias: No downgrade (see Table D3-1).

FIGURE D3-6

Data pivot of studies that measured MBP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mbp-effects-agd-or-agd-ap/update/.

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. No evidence of a large magnitude of effect size.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. See Figure D3-3 for the risk of bias assessments for the four studies.
• Unexplained inconsistencies: No downgrade. Results are largely null except for Swan (2008).
• Indirectness: No downgrade. The study designs directly addressed the topic of the evaluation.
• Imprecision: No downgrade. All but one study (Swan 2008) included 95% confidence intervals to assess precision of associations.
• Publication bias: No downgrade (see Table D3-1).

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. No evidence of a large magnitude of effect size.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

FIGURE D3-7

Data pivot of studies that measured MEP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mep-effects-agd-or-agd-ap/.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. See Figure D3-3 for the risk of bias assessments for the three studies.
• Unexplained inconsistencies: No downgrade. Results are largely null, except for Swan (2008), and they are consistent across two other larger studies (Swan et al. 2015; Jensen et al. 2016).
• Indirectness: No downgrade. The study designs directly addressed the topic of the evaluation.
• Imprecision: No downgrade. All but one study (Swan 2008) included 95% confidence intervals to assess precision of associations.
• Publication bias: No downgrade (see Table D3-1).

FIGURE D3-8

Data pivot of studies that measured MIBP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mibp-effects-agd-or-agd-ap/.

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. The effect estimates were generally null.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. The study was rated as having a definitely low risk of bias (see Figure D3-3).
• Unexplained inconsistencies: No downgrade.
• Indirectness: No downgrade.
• Imprecision: No downgrade.
• Publication bias: No downgrade (see Table D3-1).

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. The effect estimates were generally null.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Study measured and adjusted for important known confounders.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. See Figure D3-3 for the risk of bias assessments for the three studies.
• Unexplained inconsistencies: No downgrade. Although there is some inconsistency in results across studies, the differences can be explained (at least partially) by different study populations, different ranges of exposure within study population, and differences in timing of collection of urine samples (first trimester vs later samples).
• Indirectness: No downgrade. The study designs directly addressed the topic of the evaluation.
• Imprecision: No downgrade.
• Publication bias: No downgrade (see Table D3-1).

FIGURE D3-10

Data pivot of studies that measured MCOP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mcop-effects-agd-or-agd-ap/.

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. No evidence of a large magnitude of effect size.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders. Little evidence that unmeasured confounding would affect the results across studies. Direction of potential residual confounding bias is unknown.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. The study was rated as having a probably low risk of bias (see Figure D3-3).
• Unexplained inconsistencies: No downgrade.
• Indirectness: No downgrade.
• Imprecision: No downgrade.
• Publication bias: No downgrade (see Table D3-1).

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Study measured and adjusted for important known confounders.

Factors Considered for Downgrading Confidence

• Risk of bias: No downgrade. The studies were rated as having probably or definitely low risk of bias (see Figure D3-3).
• Unexplained inconsistencies: No downgrade.
• Indirectness: No downgrade.
• Imprecision: No downgrade.
• Publication bias: No downgrade (see Table D3-1).

Factors Considered for Upgrading Confidence

• Large magnitude: No upgrade. The effect estimates were generally null.
• Dose-response: No upgrade. Unable to assess because no quartile data were available.
• Residual confounding: No upgrade. Studies measured and adjusted for important known confounders.

FIGURE D3-12

Data pivot of studies that measured MCPP and AGD (as) or AGD (ap). In HAWC: https://hawcproject.org/summary/data-pivot/assessment/350/mcpp-effects-agd-or-agd-ap/.

Primary Analysis

In the primary analysis, four studies (see Table D5-1), with beta coefficients standardized to a percent change per log₁₀ change in BzBP exposure, were analyzed using a random effects model. A summary estimate of -1.43 [95% CI: -3.47, 0.61] (p = 0.17) was found (see Figure D5-1). There was no significant heterogeneity, with an estimated I² value of 0% (Q statistic was not statistically significant). In the sensitivity analyses (see Figures D5-2 and D5-3 and Table D5-2), effect sizes ranged from -0.15 to -2.21, none of which were statistically significant. In sum, although a small effect was observed, the precision of the estimate was not sufficient to rule out chance. 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.

FIGURE D5-1

Meta-analysis of human studies of BzBP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in BzBP exposure.

Sensitivity Analyses

FIGURE D5-2

Sensitivity analyses of human studies of BzBP and AGD performed by leaving one study out at a time.

FIGURE D5-3

Sensitivity analyses of human studies of BzBP and AGD performed by restricting analysis to the same outcome measure (AGD [ap]).

TABLE D5-2

Sensitivity Analyses of Human Studies of BzBP and AGD.

Primary Analysis

In the primary analysis, four studies (see Table D5-3), with beta coefficients standardized to a percent change per log₁₀ change in DBP exposure, were analyzed using a random effects model. A summery estimate of -3.13 [95% CI: -5.63, -0.64] (p = 0.014) was found (see Figure D5-4). There was no significant heterogeneity, with an estimated I² value of 0% (Q statistic was not statistically significant). In the sensitivity analyses (see Figures D5-5 and D5-6 and Table D5-4), effect sizes ranged from -1.85 to -4.02, and remained statistically significant in three of the five analyses. Specifically, dropping either the Swan (2008) or Swan et al. (2015) studies resulted in summary estimates that were no longer statistically significant. There was no observed heterogeneity in any sensitivity analysis results (I² = 0).

Overall, there is consistent evidence of a small decrease in AGD being associated with increasing DBP exposure, of magnitude around 3% for each log₁₀ increase in DBP exposure. However, some uncertainty remains because the statistical significance of this result depends on the Swan (2008) or Swan et al. (2015) studies. On the other hand, there was no observed heterogeneity, so it is likely that this sensitivity is related to the decreased statistical power when dropping studies.

TABLE D5-3

Studies Included in the Meta-Analysis of DBP and AGD.

FIGURE D5-4

Meta-analysis of human studies of DBP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DBP exposure.

Sensitivity Analyses

FIGURE D5-5

Sensitivity analysis of human studies of DBP and AGD performed by leaving one study out at a time.

FIGURE D5-6

Sensitivity analysis of human studies of DBP and AGD performed by restricting analysis to the same outcome measure (AGD [ap]).

TABLE D5-4

Sensitivity Analyses of Human Studies of DBP and AGD.

Primary Analysis

In the primary analysis, four studies (see Table D5-5), with beta coefficients standardized to a percent change per log₁₀ change in DEP exposure, were analyzed using a random effects model. A summary estimate of-1.94 [95% CI: -3.88, 0.001] (p = 0.0501) was found (see Figure D5-7). There was some heterogeneity, with an estimated I² value of 29%, though the Q statistic was not statistically significant. In the five sensitivity analyses (see Figures D5-8 D5-9 and Table D5-6), effect sizes ranged from -1.11 to -2.54; only one of the five analyses was statistically significant. Additionally, heterogeneity with I²>50% was observed in three of the five sensitivity analyses (though none were statistically significant). Thus, while the primary analysis suggests DEP exposure being associated with decreased AGD, the effect size is small (e.g., as compared to DEHP or DBP), the statistical significance of the result was not robust, and some heterogeneity was observed.

TABLE D5-5

Studies Included in the Meta-Analysis of DEP and AGD.

FIGURE D5-7

Meta-analysis of human studies of DEP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DEP exposure.

Sensitivity Analyses

FIGURE D5-8

Sensitivity analysis of human studies of DEP and AGD performed by leaving one study out at a time.

FIGURE D5-9

Sensitivity analysis of human studies of DEP and AGD performed by restricting analysis to the same outcome measure (AGD [ap]).

TABLE D5-6

Sensitivity Analyses of Human Studies of DEP and AGD.