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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3 Phthalates and Male Reproductive-Tract Development
3 Phthalates and Male Reproductive-Tract Development
Pages 41-114
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From page 41... ...
. Male reproductive outcomes found in animal studies from in utero exposure to phthalates has been referred to as "phthalate syndrome" and include decreased anogenital distance (AGD)
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From page 42... ...
MnBP Diethylhexyl phthalate DEHP Mono-2-ethylhex phthalate (437 xyl 76-20-9)
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One systematic review focused on animal studies and the other on human studies. This chapter first presents the methods that were used to conduct the two reviews.
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From page 44... ...
Systematic Review Population: Male humans Exposure: In utero exposure to any of the following ortho-phthalates or the corresponding monoester or oxidative metabolites: benzylbutyl phthalate (CAS no.
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From page 45... ...
that might affect the magnitude and even the direction of the apparent effect. Internal validity or risk of bias was assessed for individual studies using a tool developed for the OHAT method that outlines an approach to evaluating risk of bias for experimental animal and human studies (NTP 2015)
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From page 46... ...
Uses of meta-analyses and meta-regression of experimental animal studies is provided in Box 3-3, and the methods used for performing meta-analyses, meta-regression, and benchmark dose estimation are summarized in Box 3-4. The main characteristics considered across all eligible human studies include the following: Study design (e.g., cross-sectional, cohort)
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From page 47... ...
t review ar rticle and not a systematic review. No relevant prot c tocols for onngoing systemmatic reviews were s found in PROSPERO or CAMARA P o ADES.
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There is a long history of performing meta-analysis for human epidemiology and clinical trial data, but its benefits for experimental animal studies are not widely recognized.
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: Here yi is the observed effect size for group i; μ is the average true effect size; μ + ui is true effect size for group i, which is normally distributed ui ~ N(0,τ2)
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; study d d ify o n does not includ in utero exp de posure (n = 6) ; study ; does not as ssess or report anogenital distance, anogeni index, anos ital scrotal distance anopenile di e, istance, hyposp padias, or fetal testosterone conccentrations (n = 73)
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From page 51... ...
A review of the reference lists of the 13 human studies identified an additional six publications that were potentially relevant. Those publications underwent the same screening process as the publications found through database searches, and three publications met the inclusion criteria (see Figure 3-6)
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; study does not assess or report anogenital distance, anogenital index, anoscrotal distance, anopenile distance, hypospadias, or testosterone concentrations measured during gestation or at delivery (n = 4) ; or other reason (n = 10)
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From page 53... ...
Animal Health Effect Results on DEHP Effects on AGD Summary of the Evidence. There were 19 experimental animal studies that evaluated DEHP and AGD.
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PND 1 900 mating Wistar rat: Study 2 0, 3, 10, 30, 100 Oral (gavage) GD 7-PND 16 GD 1 = day after AGD (mm)
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PND 22 positive NOTE: BW, body weight; GD, gestation day; ND, not defined; PND, postnatal day.
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In rats, t effects co the ould be consid dered large an ro nd bust, with overall summ mary estimate having z-s cores3 of ≥7. Moreover, these effect sizes es .0.
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and evidence of an effect result in a conclusion that there is a high level of evidence that fetal exposure to DEHP is associated with a reduction in AGD in male rats. Alterations in Fetal Testosterone Concentrations Summary of the Evidence.
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GD 7-21 GD 1 = day after mating Testes and plasma GD 21 Wistar rat 0, 10, 30, 100, 300 Oral (gavage) GD 7-21 GD 1 = day after mating Testes production GD 21 (5 h incubation)
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From page 59... ...
The initial rating for the confi g idence in the animal studie was es high beca ause they involved control lled exposure exposures occurred pri to outcom outcomes were es, ior me, measured on individua animals, an a concurren control com al nd nt mparison grou was used (see Figure 3-2 for up OHAT method for rati confidenc Confiden in the bod of evidenc was not do m ing ce)
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From page 60... ...
. TABLE 3-5 Profile of the Confidence in the Body of Evidence on DEHP and Fetal Testosterone Concentrations in Animals Factors Decreasing Confidence Factors Increasing Confidence " -- " If No Concern; "↓" If Serious " -- " If Not Present; "↑" If Concern to Downgrade Confidence Sufficient to Upgrade Confidence Unexplained Inconsistency Residual Confounding Consistency Across Large Magnitude Publication Bias Species/Models Dose Response Rare Outcome Risk of Bias Indirectness Imprecision INITIAL FINAL Phthalate CONFIDENCE CONFIDENCE RATING (# of studies)
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From page 61... ...
. TABLE 3-6 Summary of Animal Studies of DEHP and Hypospadias Window of In GD Definition Reference Species/Strain Doses, mg/kg-day Route of Exposure Utero Exposure in Study Andrade et al.
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, a moderate confidence rating in the body of evide r b ence and evid dence of an e effect result in a conclusion that n there is a moderate lev of eviden that fetal exposure to DEHP is ass vel nce sociated with an increased inci d dence of hypospadias in male rats. The data sugg that Spra h i T gest ague-Dawley rats might be more sensit e tive to DEHP tha Wistar rats an s.
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From page 63... ...
. Benchmark dose estimates were calculated for an effect size of 5% (BMD5; see Appendix C, Tables C5-3 and C5-5)
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and dose for Sprague-Dawley and Wistar rats separately, with reduced heterogenei ty. Sprague-Dawley rats appeared somewhat less sensitive than Wister rats, with smaller overall effect sizes, smaller trend in log10(dose)
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From page 65... ...
Phthalates and Male Reproductive-T s Tract Develop pment FIGURE 3-10 Results of the meta-regr 3 ressions of stud on DEHP and AGD in r dies rats. The overa effect of trea all atment in each stra is shown at the bottom of each subgroup analysis abov as the chang per 100 mg/ ain t f p ve ge /kg-day.
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he he e 00 7 of the 11 rat studies were ultimat 1 tely included The studies by Borch et al.
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From page 67... ...
and dose for Sprague-Dawley and Wistar rats separately, with reduced heterogenei ty. Sprague-Dawley rats appeared to be slightly more sensitive than Wister rats, with slightly larger overall effect size and trend in log10(dose)
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Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE 3-12 Results of the meta-reg 3 o gressions of stu udies on DEHP and fetal test P tosterone in different strains of rat. The overal effect of trea ll atment for each strain is shown at the bott tom of each su ubgroup analys as the chan per sis nge 100 mg/kg g-day.
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The risk of bias ratings for the individual studies are presented in Figure 3-13. The primary factors of concern for human studies are confounding, exposure characterization, and outcome assessment (including blinding of outcome assessors)
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From page 70... ...
Multiple regression Maternal age, smoking Japan, 1999-2002 MEHP, MEHHP, MEOHP; mean AGD (ap) analysis for each phthalate status, urinary daidzein of 29 ± 9 weeks gestational weeks At delivery metabolite or the sum of and equol concentrations, several phthalate metabolites gestational week, and AGD index used in birth order analyses Swan 2008 Prospective cohort, 106 sumDEHP metabolites; MEHP; AGD (ap)
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Usin the ng OHAT method (see Fi igure 3-3) , a moderate con m nfidence ratin in the body of evidence (described a ng y e above)
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, and the dearth of studies, the committee determined that the data were inadequate to draw any conclusions. The committee also recognized that human studies on fetal testosterone production in relation to phthalate exposure are logistically very difficult to conduct, and it is not possible to directly determine fetal testis testosterone production.
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From page 73... ...
Time of exposure measurement: The first trimester is preferred over the second trimester, which is preferred over the third trimester, because the male programming window is in the first tri mester. Exposure metric: Sum of DEHP metabolites is preferred over MEHP, which is preferred over any of the other DEHP metabolites, because the sum better reflects the parent compound expo sure.
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From page 74... ...
ardize effect sizes across studies, each reported be coefficien was divide by h eta nt ed the mean value of the reported outc come measure prior to con e nducting the mmeta-analysis The result i that s. is each beta coefficient is standardized to a percen change in A s nt AGD per log1 change in u 10 urinary DEHP me P oncentrations.
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From page 75... ...
There was no evidence of heterogeneit in the prim o f ty mary analysis, and this resul was lt robust to removing ind dividual studie The result was also rob to 50 add es. t bust ditional sensit tivity analyse that es used alterrnative effect size estimate In about 80% of these sensitivity a es.
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EVIDENCE INTEGRATION FOR AGD Evidence synthesis for AGD was conducted in a three-part process. First, the confidence ratings for the human and animal studies were translated into conclusions about level of evidence of health effects using the procedure outlined by OHAT (performed earlier in this chapter)
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From page 77... ...
Fetal exposure of m marmosets to MBP at 500 mg/kg-day d o 0 during gestation weeks 7-15 did not affect plasma testosterone levels at birth or h d s hypospadias o other chang in or ges reproductive-tract deve elopment (McKinnell et al.
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From page 78... ...
. Decreased Production of Fetal Testis Testosterone The committee's systematic review found a high level of evidence that in utero exposure to DEHP in rats is associated with a reduction in fetal testosterone levels.
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From page 79... ...
, an initial hazard conclusion was reached that DEHP is presumed to be a reproductive hazard to humans. Consideration of Mechanistic Data Decreased Testosterone Following DEHP Exposure As mentioned earlier, mechanistic data available on the rat support the hypothesis that decreased production of fetal testis testosterone occurs in animals following fetal exposure to DEHP.
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Using the OHAT haza identification scheme (see Figure 3 e ard 3-4) , an initia hazard con al nclusion is reached that DEHP is suspected to be a repro P d oductive haza to humans ard s.
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Thus, these estimates are by and large concordant; however, the dose ranges in which these estimates have been observed differ substantially between humans and rats. A direct comparison of DEHP exposure in animal and human studies included in the systematic reviews was not possible because exposure is measured differently in the studies.
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From page 82... ...
Amniotic fluid should reflect a more integrated exposure with less variability, but there are few human studies that measure phthalate metabolites in amniotic fluid and even fewer that measured them in rats. Even though pharmacokinetic differences between humans and rats or marmosets have been demonstrated, and may explain why humans might be more 82
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From page 83... ...
The sections below will briefly discuss how the available data compare with DEHP and will provide initial hazard identification conclusions for AGD, fetal testosterone, and hypospadias. Animal Health Effect Results for Other Phthalates AGD As with DEHP, phthalate exposure in all the animal studies of other phthalates encompassed the entirety of the male programming window, and AGD measurements taken at the earliest postnatal age were used in the analysis.
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Maternal Urinary Levels of MEHP in Studies Included in the Systematic Review of Human Studies Bornehag et al.
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29.78 ng/mL (maximum) Amniotic Fluid Levels of MEHP in Studies Included in the Systematic Review of Human Studies Huang et al.
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From page 86... ...
( GD 0-21 PND 0 50 250 Spr rague-Dawley rat (F2) ( GD 0-21 PND 0 50 250 NOTES: The earliest life stage evaluat is shown when multiple observation ti T e ted w imes were asse essed.
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2009 9 Wistar rat GD 6 to PND 1 G PND 1 94 291 N
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Using the OHAT method (see Figure 3-3) , a very low confidence rating in the body of evidence and questionable evidence of an effect result in a conclusion that there is an inadequate level of evidence to assess whether fetal exposure to DINP is associated with a decrease in AGD in male rats.
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From page 89... ...
summary/v TABLE 3- Profile of the Confidence in the Body of Evidence on BzBP, DBP, a DINP and AGD in Anim -15 t e o and mals Factor Decreasing Con rs nfidence Factors Increas ing Confidence " -- " If No Concern; "↓" If Serious N f " -- If Not Present; "↑" If Sufficient to -- " o Concern to Downgrade Confidence Upgrade Co onfidence Large Magnitude Publication Bias Species/Models Dose Response Rare Outcome Inconsistency Confounding Unexplained Risk of Bias Consistency Indirectness Imprecision INITIAL Residual Across ii FINAL L CONFIDEN NCE Phthalate CONFIDENCE RATING RATING es) (# of studie BzBP High (6 rata)
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Using the OHAT method (see Figure 3-3) , a high confidence rating in the body of evidence and evidence of an effect result in a conclusion that there is a high level of evidence that fetal exposure to BzBP is associated with a decrease in fetal testosterone in male rats.
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From page 91... ...
van den Dries sche et al. 2012 Wistar rat GD 19.5 -20.5 GD 21.5 D None 500 [87]
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From page 92... ...
. Leve of Evidenc in the Health Effect.
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Boberg et al. 2011 Wistar rat GD 7-21 GD 21 300 600 [49]
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Leve of Evidenc in the Health Effect. Using the OH el ce U HAT method (see Figure 3-3)
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, a high c confidence rati in the bod of evidenc and eviden of an effe result in a conclusion t ing dy ce nce ect that there is a high level of evvidence that fetal exposure to DPP is as f e ssociated with a decrease in fetal testost h n terone in male rats. e A suummary of th confidence ratings on all the phthala and effects on fetal t he e a ates testosterone in ani n mals is prresented in an evidence pro n ofile in Table 3-21.
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(2009 van den Dr l.
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From page 97... ...
Using the OHAT method (see Figure 3-3) , a high confidence rating in the body of evidence and evidence of an effect result in a conclusion that there is a high level of evidence that fetal exposure to DBP is associated with an increase in hypospadias in rats.
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From page 98... ...
org/summa ary/visual/338/ /. TABLE 3- Profile of the Confidence in the Body of Evidence on BzBP and DB and Hyposp -24 t e o BP padias in Anim mals Factor Decreasing Confidence rs Factors Increa asing Confidence " -- " If No Concern; "↓" If Serious N f " -- If Not Present "↑" If Sufficient to -- " t; t Concern to Downgrade Connfidence Upgrade CConfidence Unexplained Inconsistency Residual Confounding Consistency Across Magnitude Publication Bias Species/Models Dose Response Large M it d Rare Outcome Risk of Bias Indirectness Imprecision INITIAL ii FINA AL CONFIDENC CE Phthalate CONFIDEENCE RATING RATIN NG s)
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From page 99... ...
Human Health Effect Results on Other Phthalates As with DEHP, the relevant human studies used state-of-the-art analytical chemistry methods to measure urinary phthalate metabolites and included collection of and adjustment for important potential confounding variables, such as measures of urinary dilution, infant body size, and maternal demographic factors. The key risk of bias evaluation factors for the human studies were whether the study designs or analyses accounted for important confounding and modifying variables, exposure characterization, and outcome assessment.
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are included for comparison. TABLE 3-27 Profile of the Confidence in the Body of Evidence on Phthalates and AGD in Humans Factors Increasing Factors Decreasing Confidence Confidence " -- " If No Concern; "↓" If " -- " If Not Present; Serious Concern to Downgrade "↑" If Sufficient to Confidence Upgrade Confidence Large magnitude Publication Bias Dose response inconsistency Confounding Unexplained Risk of Bias Indirectness INITIAL Imprecision Residual FINAL CONFIDENCE Phthalate Metabolite(s)
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From page 101... ...
In HAWC: https:/ me t H //hawcproject.o org/summary/v visual/366/. TABLE 3- Summary of Meta-Analy of Human Studies of BzB DBP, DEP DIBP, DINP and AGD -28 o yses BP, P, P Phthalate Summar Estimate ry (no.
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From page 102... ...
Using the OHAT method (see Figure 3-3) , a moderate confidence rating in the body of evidence and evidence of an effect result in a conclusion that there is a moderate level of evidence that fetal exposure to DBP and DEP are associated with a reduction in AGD in male infants.
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From page 103... ...
. TABLE 3-29 Initial Hazard Evaluations for Other Phthalates and AGD in Humans Animal Studies Human Studies Level of Confidence Level of Evidence Level of Confidence Level of Evidence Initial Hazard Phthalate in Evidence in the Health Effect in Evidence in the Health Effect Evaluations BzBP High High Moderate Inadequate Presumed human hazard DBP High High Moderate Moderate Presumed human hazard DEP Inadequate Inadequate Moderate Moderate Suspected human hazard DIBP Inadequate Inadequate Moderate Inadequate Not classifiable DIDP Inadequate Inadequate Inadequate Inadequate Not classifiable DINP Very Low Inadequate Moderate Inadequate Not classifiable TABLE 3-30 Initial Hazard Evaluations for Other Phthalates and Fetal Testosterone in Humans Animal Studies Human Studies Level of Confidence Level of Evidence Level of Confidence Level of Evidence Initial Hazard Phthalate in Evidence in the Health Effect in Evidence in the Health Effect Evaluations BzBP High High Inadequate Inadequate Presumed human hazard DBP High High Inadequate Inadequate Presumed human hazard DEP Inadequate Inadequate Inadequate Inadequate Not classifiable DIBP High High Inadequate Inadequate Presumed human hazard DINP High High Inadequate Inadequate Presumed human hazard DPP High High Inadequate Inadequate Presumed human hazard TABLE 3-31 Initial Hazard Evaluations for Other Phthalates and Hypospadias in Humans Animal Studies Human Studies Level of Confidence Level of Evidence Level of Confidence Level of Evidence Initial Hazard Phthalate in Evidence in the Health Effect in Evidence in the Health Effect Evaluations BzBP Moderate Moderate Inadequate Inadequate Suspected human hazard DBP High High Inadequate Inadequate Presumed human hazard FINDINGS AND RECOMMENDATIONS Systematic Reviews Consistency and Transparency: The committee found that the systematic review process was valuable because it provided a framework for identifying, selecting, and evaluating evidence in a consistent and explicit manner; maximized transparency in how the assessments were per formed; and facilitated the clear presentation of the basis for scientific judgments.
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From page 104... ...
, whereas most animal studies measured fetal testosterone in the testes of rodents. Targeted animal studies that evaluate the relationship between phthalate exposure and changes in testosterone concentrations in bio logical matrices more relevant to measures taken in human studies could help address this data gap.
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Low-Dose Effects The committee concluded that the human studies provide a moderate level of evidence that fetal exposure to DEHP is associated with decreases in AGD in humans. Uncertainty in the internal doses of humans relative to experimental animals limited the ability to draw conclusions about the prediction of low-dose effects based on experimental animal studies.
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From page 106... ...
2004. Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl)
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From page 107... ...
2015. Prenatal phthalate exposures and anogenital distance in Swedish boys.
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From page 108... ...
2014. Prenatal di-n-butyl phthalate exposure alters reproductive func tions at adulthood in male rats.
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From page 109... ...
2011b. Dose-response as sessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate.
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From page 110... ...
2007. Mapping gene expression changes in the fetal rat testis following acute dibutyl phthalate exposure defines a complex temporal cascade of re sponding cell types.
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2015. In utero exposure to diisononyl phthalate caused testicular dysgenesis of rat fetal testis.
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2001. Androgen-mediated development in male rat offspring exposed to flutamide in utero: Permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues.
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2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure.
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From page 114... ...
2007. Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure.
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