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Appendix C: Supporting Materials for the Phthalate (Animal) Systematic Review
Pages 172-270

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From page 172... ... Ortho-phthalates have been linked to effects on male reproductive-tract development after in utero exposure in animal 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 fetal testosterone in nonhuman male mammals? Read the entire page →
From page 173... ...  Fetal testosterone concentration (e.g., measured from testes, serum, or plasma taken in utero) METHODS Problem Formulation and Protocol Development The review question and specific aims were developed and refined through a series of problem formulation steps. Read the entire page →
From page 174... ... 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 human 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. Read the entire page →
From page 175... ... . Current guidance on using existing systematic reviews will be used (Robinson et al. Read the entire page →
From page 176... ... 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. Read the entire page →
From page 177... ... Study does not assess or report anogenital distance, anogenital index, anoscrotal distance, ano penile distance, hypospadias, or fetal testosterone concentrations 8. No comparator group (animals exposed to different doses of phthalates or vehicle-only treatment) Read the entire page →
From page 178... ... The review team will attempt to contact authors of included studies to obtain missing data considered important for evaluating key study findings (e.g., level of data required to conduct a meta-analysis) Read the entire page →
From page 179... ... Any remaining discrepancies will be considered and resolved with the review team. The final riskof bias rating for each question will be recorded along with a statement of the basis for that rating. Read the entire page →
From page 180... ... . The review team will also perform sensitivity analyses on the exclusion of individual studies in succession. Read the entire page →
From page 181... ... X X X X X X * Experimental animal studies are controlled exposure studies. Read the entire page →
From page 182... ... . Confidence rating are indepe gs endently assessed by mem mbers of the r review team, and discrepa ancies will be resolved by con nsensus and consultation with technical advisors as n c w l needed. Read the entire page →
From page 183... ... 2008. Using existing systematic reviews in com plex systematic reviews. Read the entire page →
From page 184... ... She creates and implements systematic review search strategies across multiple databases and provides comprehensive reference, research, and information services to multiple departments within the School of Medicine. She received an MLIS from the University of Pittsburgh and an MPA from the University of Baltimore. Read the entire page →
From page 185... ... 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. He led the team that developed the OHAT approach to systematic review. Read the entire page →
From page 186... ... All MeSH terms and key word synonyms will be searched together as one concept using the Boolean operator "OR."  Animal studies -- The review team will adapt the search filter published in Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M Enhancing search efficiency by means of a search filter for finding all studies on animal experimentation in PubMed. Read the entire page →
From page 187... ... 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) Read the entire page →
From page 188... ... Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity "Genitalia, Male"[Mesh] OR "Testosterone"[Mesh:NoExp] Read the entire page →
From page 189... ... 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) Read the entire page →
From page 190... ... Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity set:ti,ab OR marmosets:ti,ab OR cebuella:ti,ab OR hapale:ti,ab OR octodon:ti,ab OR chinchilla:ti,ab OR chinchillas:ti,ab OR gerbillinae:ti,ab OR gerbil:ti,ab OR gerbils:ti,ab OR jird:ti,ab OR jirds:ti,ab OR merione:ti,ab OR meriones:ti,ab OR rabbits:ti,ab OR rabbit:ti,ab OR hares:ti,ab OR hare:ti,ab OR cats:ti,ab OR cat:ti,ab OR felis:ti,ab OR dogs:ti,ab OR dog:ti,ab OR canine:ti,ab OR canines:ti,ab OR canis:ti,ab OR sheep:ti,ab OR sheeps:ti,ab OR mouflon:ti,ab OR mouflons:ti,ab OR ovis:ti,ab OR goats:ti,ab OR goat:ti,ab OR capra:ti,ab OR capras:ti,ab OR rupicapra:ti,ab OR chamois:ti,ab OR haplorhini:ti,ab OR monkey:ti,ab OR monkeys:ti,ab OR anthropoidea:ti,ab OR anthropoids:ti,ab OR saguinus:ti,ab OR tamarin:ti,ab OR tamarins:ti,ab OR leontopithecus:ti,ab OR hominidae:ti,ab OR ape:ti,ab OR apes:ti,ab OR pan:ti,ab OR paniscus:ti,ab OR "pan paniscus":ti,ab OR bonobo:ti,ab OR bonobos:ti,ab OR "pan troglodytes":ti,ab OR gibbon:ti,ab OR gibbons:ti,ab OR siamang:ti,ab OR siamangs:ti,ab OR nomascus:ti,ab OR symphalangus:ti,ab OR chimpanzee:ti,ab OR chimpanzees:ti,ab OR prosimians:ti,ab OR "bush baby":ti,ab OR prosimian:ti,ab OR bush babies:ti,ab OR galagos:ti,ab OR galago:ti,ab OR pongidae:ti,ab OR gorilla:ti,ab OR gorillas:ti,ab OR pongo:ti,ab OR "pongo pygmaeus":ti,ab OR orangutans:ti,ab OR lemur:ti,ab OR lemurs:ti,ab OR lemuridae:ti,ab OR horse:ti,ab OR horses:ti,ab OR pongo:ti,ab OR equus:ti,ab OR cow:ti,ab OR calf:ti,ab OR bull:ti,ab OR chicken:ti,ab OR chickens:ti,ab OR squirrel:ti,ab OR squirrels:ti,ab OR chipmunk:ti,ab OR chipmunks:ti,ab OR suslik:ti,ab OR susliks:ti,ab OR vole:ti,ab OR voles:ti,ab OR lemming:ti,ab OR lemmings:ti,ab OR muskrat:ti,ab OR muskrats:ti,ab OR lemmus:ti,ab OR otter:ti,ab OR otters:ti,ab OR marten:ti,ab OR martens:ti,ab OR martes:ti,ab OR weasel:ti,ab OR badger:ti,ab OR badgers:ti,ab OR ermine:ti,ab OR mink:ti,ab OR minks:ti,ab OR sable:ti,ab OR sables:ti,ab OR gulo:ti,ab OR gulos:ti,ab OR wolverine:ti,ab OR wolverines:ti,ab OR minks:ti,ab OR mustela:ti,ab OR llama:ti,ab OR llamas:ti,ab OR alpaca:ti,ab OR alpacas:ti,ab OR camelid:ti,ab OR camelids:ti,ab OR guanaco:ti,ab OR guanacos:ti,ab OR chiroptera:ti,ab OR chiropteras:ti,ab OR bat:ti,ab OR bats:ti,ab OR fox:ti,ab OR foxes:ti,ab OR donkey:ti,ab OR donkeys:ti,ab OR mule:ti,ab OR mules:ti,ab OR zebra:ti,ab OR zebras:ti,ab OR shrew:ti,ab OR shrews:ti,ab OR bison:ti,ab OR bisons:ti,ab OR buffalo:ti,ab OR buffaloes:ti,ab OR deer:ti,ab OR deers:ti,ab OR bear:ti,ab OR bears:ti,ab OR panda:ti,ab OR pandas:ti,ab OR "wild hog":ti,ab OR "wild boar":ti,ab OR fitchew:ti,ab OR fitch:ti,ab OR beaver:ti,ab OR beavers:ti,ab OR jerboa:ti,ab OR jerboas:ti,ab OR capybara:ti,ab OR capybaras:ti,ab) 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-benzylphthalate" 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 "ophthalates" OR "palatinol" OR "sketofax") Read the entire page →
From page 191... ... Appendix C canis OR sheep OR sheeps OR mouflon OR mouflons OR ovis OR goats OR goat OR capra OR capras OR rupicapra OR chamois OR haplorhini OR monkey OR monkeys OR anthropoidea OR anthropoids OR saguinus OR tamarin OR tamarins OR leontopithecus OR hominidae OR ape OR apes OR pan OR paniscus OR "pan paniscus" OR bonobo OR bonobos OR "pan troglodytes" OR gibbon OR gibbons OR siamang OR siamangs OR nomascus OR symphalangus OR chimpanzee OR chimpanzees OR prosimians OR "bush baby" OR prosimian OR bush babies OR galagos OR galago OR pongidae OR gorilla OR gorillas OR pongo OR "pongo pygmaeus" OR orangutans OR lemur OR lemurs OR lemuridae OR horse OR horses OR pongo OR equus OR cow OR calf OR bull OR chicken OR chickens OR squirrel OR squirrels OR chipmunk OR chipmunks OR suslik OR susliks OR vole OR voles OR lemming OR lemmings OR muskrat OR muskrats OR lemmus OR otter OR otters OR marten OR martens OR martes OR weasel OR badger OR badgers OR ermine OR mink OR minks OR sable OR sables OR gulo OR gulos OR wolverine OR wolverines OR minks OR mustela OR llama OR llamas OR alpaca OR alpacas OR camelid OR camelids OR guanaco OR guanacos OR chiroptera OR chiropteras OR bat OR bats OR fox OR foxes OR donkey OR donkeys OR mule OR mules OR zebra OR zebras OR shrew OR shrews OR bison OR bisons OR buffalo OR buffaloes OR deer OR deers OR bear OR bears OR panda OR pandas OR "wild hog" OR "wild boar" OR fitchew OR fitch OR beaver OR beavers OR jerboa OR jerboas OR capybara OR capybaras) Read the entire page →
From page 192... ... Study does not include nonhuman mammals Study does not report phthalate exposure to one or more of the phthalates listed in the PECO statement Study does not report oral exposure to phthalates Study does not quantify exposure to phthalates Study does not include in utero exposure Study does not assess or report anogenital distance, anogenital distance, anoscrotal distance, anopenile distance, hypospadias, or fetal testosterone concentration No comparator group (different doses or vehicle-only treatment) Not in English Other (explanation required) Read the entire page →
From page 193... ... Method to control for litter effects in developmental studies (* information bias) Read the entire page →
From page 194... ... , benchmark dose (BMD) analysis, statistical significance of other dose levels, or other estimates of effect presented in paper. Read the entire page →
From page 195... ...  Indirect evidence that at the time of assigning study groups the research personnel did not know what group animals were allocated to and it is unlikely that they could have broken the blinding of allocation until after assignment was complete and irrevocable,  OR it is deemed that lack of adequate allocation concealment would not appreciably bias results. Probably High Risk of Bias (-) Read the entire page →
From page 196... ...  Indirect evidence that the same vehicle was used in control and experimental animals,  OR it is deemed that the vehicle used would not appreciably bias results,  AND identical non-treatment-related experimental conditions are assumed if authors did not report differences in housing or husbandry. Probably High Risk of Bias (-) Read the entire page →
From page 197... ...  Indirect evidence that loss of animals was adequately addressed and reasons were documented when animals were removed from a study,  OR it is deemed that the proportion lost would not appreciably bias results. This would include reports of no statistical differences in characteristics of animals removed from the study from those remaining in the study. Read the entire page →
From page 198... ... after initial exposure in all study groups,  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.  Note: Fetal testosterone measured in testes, media in which testes had been incubated, or fetal blood-derived media. Read the entire page →
From page 199... ... Probably Low Risk of Bias (+)  Indirect evidence that litter effects were appropriately considered in the study design or analysis, using one of the following approaches:  The dam used as the statistical unit of analysis,  OR the fetus/pup used as the statistical unit of analysis AND litter effects were appropriately considered in the analysis BUT the statistic method used to address litter effects was not stated. Read the entire page →
From page 200... ... Additions to the Review Team The following committee members were added to the review team to supplement expertise:  Weihsueh Chiu is a professor in the Department of Veterinary Integrative Biosciences in the College of Veterinary Medicine and Biomedical Sciences at Texas A&M University. Before join ing the university, he worked at the US Environmental Protection Agency (EPA) Read the entire page →
From page 201... ... SECTION C-2 Results of Literature Searches for Animal 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 (Animal) Systematic Review Protocol (Section C-1) Read the entire page →
From page 202... ... SECTION C-3 Funding Sources of the Animal Studies on Phthalates and Male Reproductive-Tract Development Sources of funding were used to evaluate publication bias in terms of whether a particular sector funded more studies than another. Reference Government Industry Other Unknown Adamsson et al. Read the entire page →
From page 203... ... van den Driesche et al. 2012 X (UK Medical Research Council, EU) Read the entire page →
From page 204... ... g tly cal DEH and AGD HP D Nine eteen animal studies of DE EHP and AG were avai GD ilable; 3 used the mouse m d model and 16 used 6 the rat mo odel. Factors Considered fo Downgrad C or ding Confide ence  Risk of bias: Downgraded. Read the entire page →
From page 205... ... C : . DEHP and Fetal Testos d sterone Twe elve animal st tudies of DEH and fetal testosterone w HP were availabl 11 used th rat model and 1 le; he used the mouse model. Read the entire page →
From page 206... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-3 Data pivo of animal st C ot tudies of DEHP and AGD so rted by dose. I HAWC: http P In ps://hawcproject.org/ summary/d data-pivot/asse essment/351/z1-phthalate-effe ect-agd-all/. Read the entire page →
From page 207... ... Appendix C Ap FIGURE C4-4 Data piv of animal studies of DEH and AGD sorted by stud In HAWC: https://hawcproject. Read the entire page →
From page 208... ... Re e esults are gennerally consisstent across sstudies in the high e do range. ose FIGURE C4-5 Risk of bias heatmap of studies of DEHP and fetal testosterone i rodents. Read the entire page →
From page 209... ... Appendix C Ap FIGURE C4-6 Data pivo of animal st C ot tudies of DEHP and fetal test P tosterone sorte by dose. In HAWC: https://hawc ed / project.org g/summary/data a-pivot/assessm ment/351/dehp-effect-agd/. Read the entire page →
From page 210... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-7 Data pivot of anima studies of DEHP and f p al fetal testosteroone sorted by study. In HA AWC: wcproject.org/su https://haw ummary/data-p pivot/assessme ent/351/dehp-ef ffect-testostero one-dose-respo onse/. Read the entire page →
From page 211... ... o ably high risk of bias ratin be k ng ca ause they lack reporting on the outco ked g ome assessmment. Other cooncerns were related to wh hether th researchers were blinde to the stud groups dur he s ed dy ring outcome assessment a not contr and rolling fo litter effect See Figure C4-8. Read the entire page →
From page 212... ... The follow ualizations presenting data on hypospadias in terms of the percentage of litters wing links have additional visu n e f affected (htttps://hawcproj ject.org/summa ary/data-pivot/a assessment/351/dehp-effect-hy ypospadias-litte ers-affected/) o litter or incidence (https://hawcpro ( oject.org/summ mary/data-pivot t/assessment/35 51/dehp-effect -hypospadias-liitter-incidence/) Read the entire page →
From page 213... ... The follow wing links have additional visuualizations presenting data on hypospadias in terms of the percentage of litters n e f affected (https://hawcp project.org/sum mmary/data-pivot/assessment/3 351/dehp-effec ct-hypospadias -- litters-affected d-doseresp/) or litter incidence (https://hawc l e cproject.org/sum mmary/data-piv vot/assessment/ /351/dehp-effecct-hypospadias s-litterincidence-d dose-resp/) Read the entire page →
From page 214... ... (2005) , whi could be explained by study design fea he ich y n tu ures. Read the entire page →
From page 215... ... Appendix C Ap FIGURE C4-12 Data pi ivot of animal studies of Bz l zBP and AGD in rats sorted by dose. In H d HAWC: https://hawc / project.org g/summary/data ment/351/bzbp-effect-agd/. Read the entire page →
From page 216... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-13 Data pi ivot of animal studies of BzBP and AGD in rats sorted by study. In H HAWC: https:/ //hawc project.org g/summary/data ment/351/bzbp-effect-agd-do a-pivot/assessm ose-response/. Read the entire page →
From page 217... ... FIGURE C4-14 Risk of bias heatmap of studies of BzBP and fe testosteron in rats. In H f p f etal ne HAWC: https:/ //hawc project.org g/summary/visu ual/328/. Read the entire page →
From page 218... ... FIGURE C4-16 Data pivot of animal studies of Bz l zBP and fetal testosterone in rats sorted b study. In HA n by AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/bzbp-ef ffect-testostero one-dose-respo onse/. Read the entire page →
From page 219... ... One study did no control for litter effects, but it reporte no hyposp he m e ot ed padias. See Figure C4 -- 17. Read the entire page →
From page 220... ... Consi istent effects observed acr ross multiple stud ie Inconsisten es. ncies could be explained by study desig features. Read the entire page →
From page 221... ... Appendix C Ap FIGURE C4-20 Data pivot of animal studies of DB and AGD in rats sorted by dose. In HAWC: https://hawc l BP / project.org g/summary/data a-pivot/assessm ment/351/dbp-e effect-agd/. Read the entire page →
From page 222... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-21 Data pivot of animal studies of DB and AGD in rats sorted by study. In H l BP HAWC: https:/ //hawc project.org g/summary/data a-pivot/assessm ment/351/dbp-e effect-agd-dose e-response/. Read the entire page →
From page 223... ... DBP and Fetal Testost F terone Twelve studies of DBP and effects on fetal testosteron in rats wer available. T s d ne re Factors Considered fo Downgrad C or ding Confide ence  Risk of bias: No downgrad See Figure C4-22. Read the entire page →
From page 224... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-23 Data pivot of anima studies of DBP and fetal testosterone in rats sorted b dose. In HA p al D n by AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/dbp-eff fect-testosteron ne/. Read the entire page →
From page 225... ... Appendix C Ap FIGURE C4-24 Data pivot of animal studies of DBP and fetal t p l testosterone in rats sorted b study. In HA n by AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/dbp-eff fect-testosteron ne-dose-respon nse/. Read the entire page →
From page 226... ...  Unexplained inconsistencies: No dow U wngrade. Incid dence of hyppospadias app peared to be con e si istent across studies within similar dose ranges. Read the entire page →
From page 227... ... The follow wing links have additional visu ualizations presenting data on hypospadias in terms of the percentage of litters n e f affected (h https://hawcproj ject.org/summaary/data-pivot/a assessment/3511/dbp-effect-hy ypospadias-litte ers-affected/) o litter or incidence (https://hawcpro ( oject.org/summ mary/data-pivot t/assessment/35 51/dbp-effect-h hypospadias-litt ter-incidence/) Read the entire page →
From page 228... ... The follow wing links have additional visu ualizations presenting data on hypospadias in terms of the percentage of litters n e f affected (https://hawcpro ( oject.org/summmary/data-pivot t/assessment/35 51/dbp-effect-h hypospadias-litt ters-affected-do ose-res po/) or litter incidence (https://haw e wcproject.org/suummary/data-pi ivot/assessmennt/351/dbp-effecct-hypospadiass-litterincidence-d dose-respo/) Read the entire page →
From page 229... ... In H p f etal ne HAWC: https:/ //hawc project.org g/summary/visu ual/332/. FIGURE C4-29 Data pivot of animal studies of DIBP and fetal testosterone i rats sorted b dose. Read the entire page →
From page 230... ... FIGURE C4-30 Data pivot of animal studies of DI l IBP and fetal testosterone in rats sorted b study. In HA n by AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/dibp-ef ffect-testostero one-dose-response/. Read the entire page →
From page 231... ... One w ot b ogy f would expect a treatment-related decrease in t AGD at these dose levels given the incr A g rease in fetal testosterone; however, on one of the four ; nly e st tudies showed a clear trea d atment-related decrease in AGD (Bob d n berg et al. Read the entire page →
From page 232... ... FIGURE C4-33 Data pi ivot of animal studies of DIN and AGD in rats sorted by study. In H NP HAWC: https:/ //hawc project.org g/summary/data a-pivot/assessm ment/351/dinp -- effect-agd-dos se-response/. Read the entire page →
From page 233... ... Only studies in rats were available so cross-species con C : s e s si istency could not be evalua ated. FIGURE C4-34 Risk of bias heatmap of studies of DINP and fe testosteron in rats. Read the entire page →
From page 234... ... DPP and Fetal Testost F terone Four studies of DPP and effect on fetal tes r D ts stosterone in r were avai rats ilable. Factors Considered fo Downgrad C or ding Confide ence  Risk of bias: No downgrad See Figure C4-37. Read the entire page →
From page 235... ... FIGURE C4-36 Data pivot of animal studies of DI l INP and fetal testosterone in rats sorted b study. In HA n by AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/dinp-ef ffect-testostero one-dose-response/. Read the entire page →
From page 236... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C4-38 Data pivot of anima studies of DPP and fetal testosterone in rats sorted b dose. In HA p al D n by AWC: wcproject.org/su https://haw ummary/data-p pivot/assessme ent/351/dpp-eff fect-testosteron ne/. Read the entire page →
From page 237... ... Appendix C Ap FIGURE C4-39 Data pivot of animal studies of DPP and fetal t p l D testosterone in rats sorted by study. In HA n AWC: https://haw wcproject.org/su ummary/data-p pivot/assessme ent/351/dpp-eff fect-testosteron ne-dose-respon nse/. Read the entire page →
From page 238... ... SEC CTION C-5 Supp porting Infor rmation for the Meta-ana t alyses of Stud of DEHP dies P ME ETA-ANALY YSES OF RA STUDIES ON DEHP AND AGD AT S FIGURE C5-1 Results of meta-analys of studies on DEHP and A o ses o AGD in differ rent strains of r using the random rat a effects model. Read the entire page →
From page 239... ... TABLE C5-2 Overall Analyses and Sensitivity Analyses of Rat Studies of DEHP and AGD Without Strain Subgrouping CI, Lower CI, Upper P value for Analysis Estimate Beta Bound Bound P value tau I2 Heterogeneity AICc Primary Analyses Overall intrcpt -3.96 -5.07 -2.85 0.000 3.48 45.74 0.000 680.05 Trend in log10(dose) log10(dose) Read the entire page →
From page 240... ... TABLE C5-3 Benchmark Dose Estimates for DEHP and AGD in Rats Analysis BMR BMD CI, Lower Bound CI, Upper Bound All strains Linear in dose100 -5.1 332 276 415 All strains Linear-Quadratic in dose100 -5.1 271 178 418 LE Linear in dose100 -5.1 268 168 659 SD Linear-Quadratic in dose100 -5.1 294 166 NA W Linear-Quadratic in dose100 -5.1 154 99 282 Benchmark dose estimates were calculated for an effect size of 5%. The benchmark dose was calculated using the linear or linear-quadratic model, with the model selection based on the lowest AIC (including correction for small sample size) Read the entire page →
From page 241... ... Indicates the lowest AIC Cc. FIGURE C5-2 Benchma dose estima from rat st C ark ates tudies of DEHP and AGD. Read the entire page →
From page 242... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city MET TA-ANALYS OF MOU STUDIE ON DEH AND AGD SES USE ES HP D FIGURE C5-3 Results of meta-analyse of studies on DEHP and A C o es n AGD in mice us sing the random effects mode m el. Read the entire page →
From page 243... ... Appendix C Ap FIGURE C5-4 Benchma dose estima from mous studies of D C ark ates se DEHP and AGD D TABLE C5-5 Benchmar Dose Estima for DEHP and AGD in M C rk ates Mice Analysis BMR BMD CI, Lowe Bound er C Upper Bound CI, d Linear in do ose100 -5.1 253 146 N NA Linear-Quad dratic in dose100 0 -5.1 110 86 1 148 243 Read the entire page →
From page 244... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city A-ANALYSE OF RAT DATA ON F META ES FETAL TEST TOSTERON NE FIGURE C5-5 Results of meta-analys of studies on DEHP and fetal testostero in differen strains of rat using o ses o one nt t the random effects model m l. Read the entire page →
From page 245... ... TABLE C5-7 Overall Analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal Testosterone Without Subgrouping CI, Lower CI, Upper P value for Analysis Estimate Beta Bound Bound P value tau I2 Heterogeneity AICc Primary Analyses Overall intrcpt -110.14 -136.73 -83.54 0.000 76.76 98.49 0.000 386.87 Trend in log10(dose) log10(dose) Read the entire page →
From page 246... ... . ct TABLE C5-8 Benchmar Dose Estima for DEHP and Fetal Test C rk ates tosterone (Effe Size of 5%) Read the entire page →
From page 247... ... . TABLE C5-9 Benchmar Dose Estima for DEHP and Fetal Test C rk ates tosterone (Effe Size of 40% in Rats ect %) Read the entire page →
From page 248... ... . For fetal testosterone, there was also a statistically significant overall effect and linear trends in log10(dose) Read the entire page →
From page 249... ... 0^2) I(dose100 -0.01 -0.24 0.22 2 0.927 Sensitivity Analyses A Overall minu Ashby et al. Read the entire page →
From page 250... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city FIGURE C6-2 Benchma dose estima from rat st C ark ates tudies of BzBP and AGD. P TABLE C6-2 Benchmar Dose Estima for BzBP and AGD in Ra C rk ates a ats Analysis BMMR BMD B CI, Lower B Bound CI, Upper Bound d Linear in dose100 d -5.1 248 2 205 315 Linear-Qua adratic in dose e100 -5.1 252 2 164 377 250 Read the entire page →
From page 251... ... CI, Lower CI, Upper Pvvalue for Analysis Estim mate Beta Bound Bound P value tau I2 Heeterogeneity AIC Cc Overall intrcp pt -78.4 47 -125.70 -31.24 0.001 77.72 98.17 0.0 000 122.09 Trend in log1 10(dose) log10 0(dose) Read the entire page →
From page 252... ... Th linear-quad he dratic model had the lowest AICc, and benchmark d h d dose estimate from this m es model were 12 mg/kg-day [95 CI: 8, 22] for a 5% cha m 5% ange (BMR = -5.1) Read the entire page →
From page 253... ... Appendix C Ap FIGURE C6-5 Meta-analyses of studie of DBP and AGD in rats. Read the entire page →
From page 254... ... 0.18 0.01 0.35 0.039 Sensitivity Analyses Overall minus Struve et al. 2009 intrcpt -6.87 -8.94 -4.80 0.000 7.86 89.45 0.000 484.30 Overall minus Barlow et al. Read the entire page →
From page 255... ... Appendix C Ap FIGURE C6-6 Benchma dose estima from rat st C ark ates tudies of DBP and AGD. TABLE C6-6 Benchmar Dose Estima for DBP an AGD in Rat C rk ates nd ats Analysis BMMR BMD B CI, Lower B Bound CI, Upper Bound d Linear in dose100 d -5.1 212 2 183 251 Linear-Qua adratic in dose e100 -5.1 153 1 115 216 255 Read the entire page →
From page 256... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low-Dose Toxicity w c FIGURE C6-7 Meta-ana C alyses of studie of DBP and fetal testostero in rats. Read the entire page →
From page 257... ... TABLE C6-8 Benchmark Dose Estimates for DBP and Fetal Testosterone in Rats Analysis BMR BMD CI, Lower Bound CI, Upper Bound Linear in dose100 -5.1 17 14 22 Linear in dose100 -51.1 174 143 222 Linear-Quadratic in dose100 -5.1 12 8 22 Linear-Quadratic in dose100 -51.1 125 85 205 257 Read the entire page →
From page 258... ... Th linear-quad he dratic model had the lowest AICc, and benchmark d h d dose estimate from this m es model were 5.6 [95% CI: 4.8 6.4] for a 5% change (B 8, 5 BMR = -5.1) Read the entire page →
From page 259... ... Appendix C Ap FIGURE C6-9 Meta-analyses of studie of DPP and fetal testostero ne in rats. Read the entire page →
From page 260... ... 8.93 6.44 11.42 0.000 Sensitivity Analyses Overall minus Howdeshell intrcpt -99.93 -130.63 -69.23 0.000 78.63 98.31 0.000 307.12 et al. 2008 Overall minus Beverly intrcpt -92.57 -121.32 -63.81 0.000 77.71 98.07 0.000 341.24 et al. Read the entire page →
From page 261... ... .1 58 50 68 DI IISOBUTYL PHTHALA ATE (DIBP) For fetal testosteerone, there was also a st w tatistically sig gnificant ove erall effect an linear tren in nd nds log10(dose and dose, with an overal effect that is large in ma e) Read the entire page →
From page 262... ... Therefor the heterog re, geneity does not affect the con e clusion th DIBP expo hat osure affects fetal testoster f rone in the rat t. FIGURE C6-11 Meta-an C nalyses of stud of DIBP an fetal testoste dies nd erone in rats. Read the entire page →
From page 263... ... . The la of ack statistical significance of these effe was robu to leaving out individu studies and restricting to the ects ust ual highest do group from each study The linear model had the lowest AICc and due to the lack of st ose m y. Read the entire page →
From page 264... ... By contrast, for fetal testostero there wa a statistical significant overall effec and linear t c f one, as lly t ct trends in log10(dose) and dose with an overall effect th is large in magnitude ( e, hat n (>50% change) Read the entire page →
From page 265... ... TABLE C6-14 Benchmark Dose Estimates for DINP and AGD in Rats Analysis BMR BMD CI, Lower Bound CI, Upper Bound Linear in dose100 -5.1 NA 684 NA Linear-Quadratic in dose100 -5.1 NA 706 NA TABLE C6-15 Overall Analyses of Rat Studies of DINP and Fetal Testosterone* CI, Lower CI, Upper P value for Analysis Estimate Beta Bound Bound P value tau I2 Heterogeneity AICc Overall intrcpt -63.95 -86.35 -41.55 0.000 31.16 83.28 0.000 118.16 Trend in log10(dose) Read the entire page →
From page 266... ... Application of Syste ematic Review Methods in an Overall St w Strategy for Ev valuating Low w-Dose Toxic city TABLE C6-16 Benchma Dose Estim C ark mates for DINP and Fetal Tes P stosterone in Ra ats Analysis BMR B BMD CI, Lower BBound CI, Upper Bound d Linear in dose100 d -5.1 - 68 59 80 Linear in dose100 d -51.1 - 676 588 795 Linear-Qua adratic in dose e100 -5.1 - 76 49 145 Linear-Qua adratic in dose e100 -51.1 - 701 552 847 FIGURE C6-14 Benchm C mark dose estim mates from rat studies of DIN and AGD. Read the entire page →
From page 267... ... Appendix C Ap FIGURE C6-15 Meta-analyses of stud of DINP an fetal testoste rone in rats. C n dies nd e 267 Read the entire page →
From page 268... ... Stero O A rd. oidogenesis in f fetal male rats is reduced by DDEHP and DINP, but end D docrine effects of DEHP are not modulated by DEHA in fetal, prepub d n bertal and adul male lt rats. Read the entire page →
From page 269... ... 2009. Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single ad ministration in pregnant rats. Read the entire page →
From page 270... ... 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration. Read the entire page →

From page 172...

... Ortho-phthalates have been linked to effects on male reproductive-tract development after in utero exposure in animal 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 fetal testosterone in nonhuman male mammals?

Appendix C: Supporting Materials for the Phthalate (Animal) Systematic Review Pages 172-270

Appendix C: Supporting Materials for the Phthalate (Animal) Systematic Review
Pages 172-270