{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:22:50Z","timestamp":1766514170286,"version":"build-2065373602"},"reference-count":52,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hydroxyurea (HU) is a valuable therapy for individuals with sickle cell anemia. With increased use of HU in children and throughout their lives, it is important to understand the potential effects of HU therapy on their development and fertility. Thus, studies were conducted to identify appropriate doses to examine long\u2010term effects of prenatal and early postnatal HU exposure and to understand kinetics of HU at various life stages. Pregnant Sprague Dawley dams were administered HU (0\u2013150 mg\/kg\/day) via oral gavage from gestation days 17 to 21 and during lactation. Pups were dosed with the same dose as their respective dam starting on postnatal day (PND) 10 and up to PND 34. There was minimal maternal toxicity, and no significant effects on littering at any dose of HU. Starting on ~PND 16, offspring displayed skin discoloration and alopecia at doses \u226575 mg\/kg\/day and lower body weight compared to controls at doses \u2265100 mg\/kg\/day. Gestational transfer of HU was observed, but there was minimal evidence of lactational transfer. Our toxicokinetic studies suggest that the internal dose in offspring may be altered due to age, but not due to sex. The plasma area under the curve, a measure of systemic exposure, at doses tolerated by offspring was threefold to sevenfold lower than the internal therapeutic dose in humans. Therefore, strategies to establish clinically relevant exposures in animal studies are needed. Overall, these data are useful for the design of appropriate nonclinical studies in the future to evaluate the consequences of long\u2010term HU treatment starting in childhood.<\/jats:p>","DOI":"10.1002\/jat.4087","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T01:41:24Z","timestamp":1606354884000},"page":"1007-1020","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tolerability and age\u2010dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8286-4408","authenticated-orcid":false,"given":"Madelyn C.","family":"Huang","sequence":"first","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie J.","family":"Turner","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Vallant","sequence":"additional","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica G.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Social and Scientific Services  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine J.","family":"Price","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5632-0159","authenticated-orcid":false,"given":"Timothy R.","family":"Fennell","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0234-3798","authenticated-orcid":false,"given":"Melanie A.","family":"Silinski","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9512-090X","authenticated-orcid":false,"given":"Suramya","family":"Waidyanatha","sequence":"additional","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristen R.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherry R.","family":"Black","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reshan A.","family":"Fernando","sequence":"additional","affiliation":[{"name":"RTI International  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-300X","authenticated-orcid":false,"given":"Barry S.","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Division of the National Toxicology Program National Institute of Environmental Health Sciences  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"issue":"2","key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/S0022-3565(25)27189-0","article-title":"The distribution, excretion and metabolism of hydroxyurea\u2010C14","volume":"150","author":"Adamson R. 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