{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:58:30Z","timestamp":1785909510572,"version":"3.56.0"},"reference-count":20,"publisher":"Walter de Gruyter GmbH","issue":"3","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We reviewed published manuscripts from toxicology and epidemiology reporting harmful health effects and doses of persistent organic pollutants (POPs), published between 2000 and 2021. We found 42 <jats:italic>in vitro<\/jats:italic>, 32 <jats:italic>in vivo<\/jats:italic>, and 74 epidemiological studies and abstracted the dose associated with harm in a common Molar unit. We hypothesized that the dose associated with harm would vary between animal and human studies. To test this hypothesis, for each of several POPs, we assessed the significance of variation in the dose associated with a harmful effect [categorized as non-thyroid endocrine (NTE), developmental neurotoxicity (DNT), and Thyroid] with study type (<jats:italic>in vitro, in\u00a0vivo<\/jats:italic>, and Epidemiology) using a linear model after adjustment for basis (lipid weight, wet weight). We created a Calculated Safety Factor (CSF) defined as the toxicology dose divided by epidemiology dose needed to exhibit significant harm.<\/jats:p>\n               <jats:p>Significant differences were found between study types ranging from &lt;1 to 5.0 orders of magnitude in the dose associated with harm. Our CSFs in lipid weight varied from 12.4 (95% confidence interval (CI) 3.3, 47) for NTE effects in Epidemiology relative to <jats:italic>in vivo<\/jats:italic> studies to 6,244 (95% CI 2510, 15530) for DNT effects in Epidemiology relative to <jats:italic>in vitro<\/jats:italic> in wet weight representing 12.4 to 6.2 thousand-fold more sensitivity in people relative to animals, and mechanistic models, respectively. In lipid weight, all CSF 95% CI lower bounds across effect categories were less than 6.5. CIs for CSFs ranged from less than one to four orders of magnitude for <jats:italic>in vivo<\/jats:italic>, and two to five orders of magnitude for <jats:italic>in vitro<\/jats:italic> vs. Epidemiology. A global CSF for all Epidemiology vs. all Toxicology was 104.6 (95% CI 72 to 152), significant at p&lt;0.001.<\/jats:p>","DOI":"10.1515\/reveh-2021-0105","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T13:11:05Z","timestamp":1651669865000},"page":"401-408","source":"Crossref","is-referenced-by-count":8,"title":["Determination of safe levels of persistent organic pollutants in toxicology and epidemiology"],"prefix":"10.1515","volume":"38","author":[{"given":"Tom","family":"Muir","sequence":"first","affiliation":[{"name":"Environment Canada , 70 Townsend Ave , Burlington , ON , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel E","family":"Michalek","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences , UT Health San Antonio , San Antonio TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond F","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine , UT Health San Antonio , San Antonio TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"2023111406422740240_j_reveh-2021-0105_ref_001","doi-asserted-by":"crossref","unstructured":"Krimsky, S. The unsteady state and inertia of chemical regulation under the U.S.Toxic Substances Control Act. PLoS Biol 2017;15:e2002404. https:\/\/doi.org\/10.1371\/journal.pbio.2002404.","DOI":"10.1371\/journal.pbio.2002404"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_002","doi-asserted-by":"crossref","unstructured":"Gross, L, Birnbaum, L. Regulating toxic chemicals for public and environmental health. PLoS Biol 2017;15:e2004814.https:\/\/doi.org\/10.1371\/journal.pbio.2004814.","DOI":"10.1371\/journal.pbio.2004814"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_003","doi-asserted-by":"crossref","unstructured":"Gwinn, MR, Axelrad, DA, Bahadori, T, Bussard, D, Cascio, WE, Deener, K, et al.. Chemical risk assessment: traditional vs public health perspectives. AJPH (Am J Public Health) 2017;107:1032\u20139. https:\/\/doi.org\/10.2105\/ajph.2017.303771.","DOI":"10.2105\/AJPH.2017.303771"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_004","doi-asserted-by":"crossref","unstructured":"Vogel, SA, Roberts, JA. Why the toxic substances control act needs an overhaul, and how to strengthen oversight of chemicals in the interim. Health Aff 2011;30:898\u2013905. PMID: 21555473. https:\/\/doi.org\/10.1377\/hlthaff.2011.0211.","DOI":"10.1377\/hlthaff.2011.0211"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_005","unstructured":"National Academy Press. Effect of polybrominated diphenyl ethers on neurodevelopment. In: Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals; 2017. Chapter 4: Chapter 4 link: https:\/\/www.nap.edu\/read\/24758\/chapter\/6#135."},{"key":"2023111406422740240_j_reveh-2021-0105_ref_006","doi-asserted-by":"crossref","unstructured":"Pose-Juan, E, Fernandez-Cruz, T, Simal-Gandara, J. State of the art on public risk assessment of combined human exposure to multiple chemical contaminants. Trends Food Sci Technol 2016;55:11\u201328. https:\/\/doi.org\/10.1016\/j.tifs.2016.06.011.","DOI":"10.1016\/j.tifs.2016.06.011"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_007","doi-asserted-by":"crossref","unstructured":"Hayes, S, Becker, R, Leung, A, Aylward, L, Pyatt, D. Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective. Regul Toxicol Pharmacol 2007;47:96\u2013109.https:\/\/doi.org\/10.1016\/j.yrtph.2006.08.004.","DOI":"10.1016\/j.yrtph.2006.08.004"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_008","unstructured":"Health Canada Pest Management Regulatory Agency. Use of Uncertainty and Safety Factors in the Human Health Risk Assessment of Pesticides. Ottawa, Ontario, Canada: Regulatory Proposal PRO2007-01; 2007."},{"key":"2023111406422740240_j_reveh-2021-0105_ref_009","doi-asserted-by":"crossref","unstructured":"Canton, R, Sanderson, T, Letcher, R, Bergman, A, van den Berg, M. Inhibition and induction of aromatase (cyp19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells. Toxicol Sci 2005;88:447\u201355 https:\/\/doi.org\/10.1093\/toxsci\/kfi325.","DOI":"10.1093\/toxsci\/kfi325"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_010","doi-asserted-by":"crossref","unstructured":"Cant\u00f3n, R, Sanderson, T, Nijmeijer, S, Bergman, A, Letcher, R, van den Berg, M. In vitro effects of brominated flame retardants and metabolites on CYP17 catalytic activity: a novel mechanism of action? Toxicol Appl Pharmacol 2006;216:274\u201381.https:\/\/doi.org\/10.1016\/j.taap.2006.05.007.","DOI":"10.1016\/j.taap.2006.05.007"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_011","doi-asserted-by":"crossref","unstructured":"Cant\u00f3n, R, Scholten, D, Marsh, G, de Jong, P, van den Berg, M. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs). Toxicol Appl Pharmacol 2008;227:68\u201375. https:\/\/doi.org\/10.1016\/j.taap.2007.09.025.","DOI":"10.1016\/j.taap.2007.09.025"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_012","doi-asserted-by":"crossref","unstructured":"Hamers, T, Kamstra, J, Sonneveld, E, Murk, A, Kester, M, Andersson, P, et al.. In vitro profiling of the endocrine-disrupting internal dose of brominated flame retardants. Toxicol Sci 2006;92:157\u201373.https:\/\/doi.org\/10.1093\/toxsci\/kfj187.","DOI":"10.1093\/toxsci\/kfj187"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_013","doi-asserted-by":"crossref","unstructured":"Antunes Fernandes, E, Hendriks, H, Van Kleef, R, van den Berg, M, Westerink, R. Potentiation of the human GABAA receptor as a novel mode of action of lower-chlorinated non-dioxin-like PCBs. Environ Sci Technol 2010;44:2864\u20139. https:\/\/doi.org\/10.1021\/es902321a.","DOI":"10.1021\/es902321a"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_014","doi-asserted-by":"crossref","unstructured":"Marchesini, G, Meimaridou, A, Haasnoot, W, Meulenberg, E, Albertus, F, Mizuguchi, M, et al.. A Biosensor discovery of thyroxine transport disrupting chemicals. 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Toxicol Sci 2016;153:215\u201324. https:\/\/doi.org\/10.1093\/toxsci\/kfw129.","DOI":"10.1093\/toxsci\/kfw129"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_017","doi-asserted-by":"crossref","unstructured":"Ritter, L, Arbuckle, T. Can exposure characterization explain concurrence or discordance between toxicology and epidemiology? Toxicol Sci 2007;97:241\u201352.https:\/\/doi.org\/10.1093\/toxsci\/kfm005.","DOI":"10.1093\/toxsci\/kfm005"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_018","unstructured":"Rhomberg, L, Lewandowski, T. Methods for identifying a default cross-species scaling factor. Prepared for Risk Assessment Forum. Washington, DC: U.S. Environmental Protection Agency 2004. Gradient Corporation Contract 3W-0477-NASX 2004."},{"key":"2023111406422740240_j_reveh-2021-0105_ref_019","doi-asserted-by":"crossref","unstructured":"Staskal, D, Hakk, H, Bauer, D, Diliberto, J, Birnbaum, L. Toxicokinetics of polybrominated diphenyl ether congeners 47, 99, 100, and 153 in mice. Toxicol Sci 2006;94:28\u201337. https:\/\/doi.org\/10.1093\/toxsci\/kfl091.","DOI":"10.1093\/toxsci\/kfl091"},{"key":"2023111406422740240_j_reveh-2021-0105_ref_020","doi-asserted-by":"crossref","unstructured":"Szabo, DT, Diliberto, J, Huwe, J, Birnbaum, L. Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice. 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