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Title: Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance

Abstract

Background: In July 2017, the National Academies released a report applying systematic review (SR) methods in the evaluation of low dose endocrine effects including an assessment of male reproductive toxicity following in utero phthalate exposure. Objective: We evaluated human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. Methods: PubMed, Embase, and Toxline were searched for observational studies in humans and experimental studies in non-human mammals on August 15 2016. Two trained staff independently screened search results, assessed risk of bias for individual studies, and extracted data sequentially. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. Results: The search yielded 24 relevant studies. Meta-analysis of five human observational prospective cohort studies showed consistent evidence that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in male offspring (-4.07 [CI, -6.49 to -1.66] percent decrease per log10 increase in DEHP metabolites). Meta-analysis and meta-regression of 19 experimental animal studies similarly found consistent evidence of decreased AGD with DEHP treatment, with a dose-response gradient, with heterogeneity explained by species and strain. Conclusions: There is a moderate levelmore » of evidence from human studies and a high level of evidence from animal studies that in utero exposure to DEHP decreases AGD. Based on the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [6];  [7];  [8];  [9];  [10];  [11];  [12]
  1. Department of Molecular and Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
  2. Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&,M University, College Station, TX, USA
  3. Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
  4. Department of Environmental Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  5. Predictive Safety Center, The Dow Chemical Company, Midland, MI, USA
  6. Board on Environmental Studies and Toxicology at the National Academies of Sciences, Engineering, and Medicine, Washington, DC, USA
  7. Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
  8. Office of Health Assessment and Translation, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA
  9. Silent Spring Institute, Newton, MA, USA
  10. Department of Pediatrics, University of Washington, Seattle Children’s Research Institute, Seattle, WA, USA
  11. Department of Comparative Biosciences, College of Veterinary Medicine and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
  12. Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1503524
Report Number(s):
PNNL-SA-130356
Journal ID: ISSN 1093-7404
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Journal of Toxicology and Environmental Health, Part B: Critical Reviews
Additional Journal Information:
Journal Volume: 21; Journal Issue: 4; Journal ID: ISSN 1093-7404
Country of Publication:
United States
Language:
English

Citation Formats

Dorman, David C., Chiu, Weihsueh, Hales, Barbara F., Hauser, Russ, Johnson, Kamin J., Mantus, Ellen, Martel, Susan, Robinson, Karen A., Rooney, Andrew A., Rudel, Ruthann, Sathyanarayana, Sheela, Schantz, Susan L., and Waters, Katrina M. Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance. United States: N. p., 2018. Web. doi:10.1080/10937404.2018.1505354.
Dorman, David C., Chiu, Weihsueh, Hales, Barbara F., Hauser, Russ, Johnson, Kamin J., Mantus, Ellen, Martel, Susan, Robinson, Karen A., Rooney, Andrew A., Rudel, Ruthann, Sathyanarayana, Sheela, Schantz, Susan L., & Waters, Katrina M. Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance. United States. doi:10.1080/10937404.2018.1505354.
Dorman, David C., Chiu, Weihsueh, Hales, Barbara F., Hauser, Russ, Johnson, Kamin J., Mantus, Ellen, Martel, Susan, Robinson, Karen A., Rooney, Andrew A., Rudel, Ruthann, Sathyanarayana, Sheela, Schantz, Susan L., and Waters, Katrina M. Sat . "Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance". United States. doi:10.1080/10937404.2018.1505354.
@article{osti_1503524,
title = {Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance},
author = {Dorman, David C. and Chiu, Weihsueh and Hales, Barbara F. and Hauser, Russ and Johnson, Kamin J. and Mantus, Ellen and Martel, Susan and Robinson, Karen A. and Rooney, Andrew A. and Rudel, Ruthann and Sathyanarayana, Sheela and Schantz, Susan L. and Waters, Katrina M.},
abstractNote = {Background: In July 2017, the National Academies released a report applying systematic review (SR) methods in the evaluation of low dose endocrine effects including an assessment of male reproductive toxicity following in utero phthalate exposure. Objective: We evaluated human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. Methods: PubMed, Embase, and Toxline were searched for observational studies in humans and experimental studies in non-human mammals on August 15 2016. Two trained staff independently screened search results, assessed risk of bias for individual studies, and extracted data sequentially. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. Results: The search yielded 24 relevant studies. Meta-analysis of five human observational prospective cohort studies showed consistent evidence that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in male offspring (-4.07 [CI, -6.49 to -1.66] percent decrease per log10 increase in DEHP metabolites). Meta-analysis and meta-regression of 19 experimental animal studies similarly found consistent evidence of decreased AGD with DEHP treatment, with a dose-response gradient, with heterogeneity explained by species and strain. Conclusions: There is a moderate level of evidence from human studies and a high level of evidence from animal studies that in utero exposure to DEHP decreases AGD. Based on the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans.},
doi = {10.1080/10937404.2018.1505354},
journal = {Journal of Toxicology and Environmental Health, Part B: Critical Reviews},
issn = {1093-7404},
number = 4,
volume = 21,
place = {United States},
year = {2018},
month = {5}
}