Introduction Species differences exist in Fc domain-containing molecule transfer/biodistribution to the embryo-fetus during pregnancy. Placentation was reviewed and placental neonatal Fc receptor (FcRn) quantitation in the chorioallantoic placenta (CAP) and/or inverted yolk sac placenta (InvYSP) was investigated across species throughout gestation to further understand and inform developmental toxicity testing of Fc domain-containing molecules.Methods Quantitative mass spectrometry was used to quantify FcRn protein in CAP and/or InvYSP throughout gestation in mouse, rat, guinea pig, rabbit, and nonhuman primate (NHP). In human placental tissues, immunohistochemistry was used to localize FcRn distribution during each trimester.Results FcRn protein was detected and concentration increased throughout gestation in mouse, rat, guinea pig, and rabbit; with InvYSP concentration markedly higher compared with CAP at all gestational ages. In contrast, NHP FcRn protein concentration in the CAP remained constant throughout gestation. In humans, during 1st trimester, FcRn occurred in decidua, maternal endothelium, and maternal and fetal macrophages. During 2nd trimester, fetal FcRn increased in syncytiotrophoblasts and fetal chorionic vessels. FcRn expression decreased in maternal endothelium near term.Conclusions FcRn protein was detected throughout gestation (including organogenesis) in placental tissue of all animal species. Regardless of FcRn location, these data support that Fc domain-containing molecules can access the embryo-fetus throughout gestation in all species, with the extent of transfer likely depending on FcRn concentration and size of the placenta. This information on placental FcRn ontogeny will help improve study design and translation of nonclinical developmental toxicity data to human safety assessment of Fc domain-containing molecules.

BACKGROUND:Gestation periods of rodents and humans differ dramatically. Due to their brief time in utero, rodent offspring develop faster than humans, but at birth they are considerably less developmentally mature than human neonates. Because fetuses are harvested near-term in embryo-fetal development studies, some fetuses which lag others in developmental schedules may be characterized as malformed. However, if allowed to continue, many deficits in developmental timing would be eliminated quickly during the early lactational period. Consequently, it is important to appreciate the perinatal development of test species to inform interpretation of test results. METHODS:This paper reviews the comparative timing as well as pre and postnatal development of exemplar organs for the purpose of providing context in interpreting rodent data and extrapolating them to human hazard assessment. The selected organs and developmental processes include ossification of the skeleton; septation of the cardiac atria and ventricles; surfactant synthesis in the lung; establishment of the intestinal lining and maturation of gastrointestinal absorption; myelination of the brain and establishment of the blood-brain barrier. RESULTS:Comparative perinatal biology should be used in interpreting rodent test data to avoid mis-classifying substances. Due to the compressed development schedule of rodents compared with humans, delays in rodent development may be misinterpreted as malformations. Delays in lung maturation may explain some cases of early deaths in normally appearing rat pups. Invoking perinatal biology does not obviate study findings, but it can provide context that informs interpretation.

Developmental and reproductive toxicity testing (DART) safety tests are expensive and time-consuming. The future of DART testing is trending toward in vitro and in silico systems (and potentially artificial intelligence). Forward-looking academic programs have embraced the new test systems, but regulatory decisions remain based on decades-old, whole-animal testing. Many regulatory scientists have neither whole-animal DART testing experience nor academic training in embryology/developmental biology, comparative anatomy, and epidemiology. Consequently, some new medicines and chemicals have been misidentified as developmental toxicants by those eager to protect the public but lacking requisite in-depth DART/epidemiology training/experience to make informed interpretations. Additionally, some unqualified individuals have been appointed to health leadership roles. Sadly, their mandates are often accepted forthwith, foregoing independent evaluation by experts, resulting in misclassification of substances as "teratogens by fiat"-Regulatogens. Potential long-term remedies to address this crisis are discussed, but implementation and effective results will take years. Immediate remedies require qualified scientists/experts to step forward and challenge the validity and interpretation of poor science/improper interpretation underlying decisions that lack rigor, and proffer appropriately interpreted data with conclusions that are explainable to all stakeholders, including the public.

Birth Defects ResearchVolume 116, Issue 3 e2326 CORRESPONDENCE Comments on "Maternal–fetal safety evaluation of an aqueous extract of Casearia sylvestris [AECS] leaves in rats" (Nagaoka et al., 2023 [DOI: 10.1002/bdr2.2257]) L. David Wise, Corresponding Author L. David Wise [email protected] orcid.org/0000-0002-2280-0725 Independent Teratologist, Philadelphia, Pennsylvania, USA Correspondence L. David Wise, Independent Teratologist, Philadelphia, PA, USA. Email: [email protected]Search for more papers by this authorJohn M. DeSesso, John M. DeSesso orcid.org/0000-0002-3134-4207 Exponent, Inc., Alexandria, Virginia, USASearch for more papers by this author L. David Wise, Corresponding Author L. David Wise [email protected] orcid.org/0000-0002-2280-0725 Independent Teratologist, Philadelphia, Pennsylvania, USA Correspondence L. David Wise, Independent Teratologist, Philadelphia, PA, USA. Email: [email protected]Search for more papers by this authorJohn M. DeSesso, John M. DeSesso orcid.org/0000-0002-3134-4207 Exponent, Inc., Alexandria, Virginia, USASearch for more papers by this author First published: 23 March 2024 https://doi.org/10.1002/bdr2.2326Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Open Research DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analyzed in this study. REFERENCES Charles River. (n.d.). Historical control data [HCD]. Reproductive toxicology data, rats (e.g., Netherlands, Pennsylvania, Edinburgh, Ohio). https://www.criver.com/products-services/safety-assessment/toxicology-services/developmental-and-reproductive-toxicology-dart/historical-control-data?region=3601 Google Scholar Clark, R. L., Antonello, J., Grossman, S., Wise, L. D., Anderson, C., Bagdon, W. J., Prahalada, S., MacDonald, J. S., & Robertson, R. T. (1990). External genitalia abnormalities in male rats exposed in utero to finasteride, a 5α-reductase inhibitor. Teratology, 42, 91–100. https://doi.org/10.1002/tera.1420420111 10.1002/tera.1420420111 CASPubMedWeb of Science®Google Scholar DeSesso, J. M., & Scialli, A. R. (2018). Bone development in laboratory mammals used in developmental toxicity studies. Birth Defects Research, 110, 1157–1187. https://doi.org/10.1002/bdr2.1350 10.1002/bdr2.1350 CASPubMedWeb of Science®Google Scholar Gallavan, R. H., Holson, J. F., Stump, D. G., Knapp, J. F., & Reynolds, V. L. (1999). Interpreting the toxicologic significance of alterations in anogenital distance: Potential for confounding effects of progeny body weights. Reproductive Toxicology, 13(5), 383–390. https://doi.org/10.1016/s0890-6238(99)00036-2 10.1016/S0890-6238(99)00036-2 CASPubMedWeb of Science®Google Scholar Organisation for Economic Cooperation and Development. (2018). Test no. 414: Prenatal developmental toxicity study. In OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/9789264070820-en Google Scholar Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. The FASEB Journal, 22, 659–661. https://doi.org/10.1096/fj.07-9574LSF 10.1096/fj.07-9574LSF CASPubMedWeb of Science®Google Scholar Wise, L. D., Buschmann, J., Feuston, M. H., Fisher, J. E., Hew, K. W., Hoberman, A. M., Lerman, S. A., Ooshima, Y., & Stump, D. G. (2009). Embryo-fetal developmental toxicity study design for pharmaceuticals. Birth Defects Research. Part B: Developmental and Reproductive Toxicology, 86(6), 418–428. https://doi.org/10.1002/bdrb.20214 10.1002/bdrb.20214 CASPubMedWeb of Science®Google Scholar Wise, L. D., Vetter, C. M., Anderson, C. A., Antonello, J. M., & Clark, R. L. (1991). Reversible effects of triamcinolone and lack of effects with aspirin or L-656,224 on external genitalia of male Sprague–Dawley rats exposed in utero. Teratology, 44(5), 507–520. https://doi.org/10.1002/tera.1420440505 10.1002/tera.1420440505 CASPubMedWeb of Science®Google Scholar Volume116, Issue3March 2024e2326 ReferencesRelatedInformation

Women comprise approximately 40% of the global workforce, and many women continue to work during pregnancy. Although occupational exposure limit values (OELVs) are intended to protect all workers, many OELVs may have been established without consideration of the unique changes in pregnant workers, and many chemicals lack OELVs altogether. A short educational course was developed to address the informational needs of health professionals who have responsibility to ensure a safe workplace for pregnant employees. The course was designed to raise awareness of the key elements in risk management and their application to the pregnant worker, such as physiological changes of pregnancy that influence susceptibility to exposures; guidance for nonclinical data interpretation; exposure assessment and control strategies; and risk management in practice in a diverse regulatory environment. This paper summarizes the course content and is intended to support informed risk management decision making to protect the health of pregnant workers and their offspring.

Food-grade titanium dioxide E171 was administered in feed to Sprague Dawley rats in an extended one-generation reproductive toxicity (EOGRT) study (OECD Test 443). The dosed diet (0, 100, 300, or 1000 mg/kg body weight/day) started 10 weeks before mating and continued throughout the study. After weaning, pups were allocated to Cohorts 1 A/1B (to assess reproductive toxicity), 2 A/2B (to assess developmental neurotoxicity), and 3 (to assess developmental immunotoxicity); in addition, Cohort 1B was mated to produce an F2 generation and satellite F0 animals were evaluated for colonic aberrant crypt foci (ACF). In F0 animals, there were no systemic toxicity or reproductive effects, no treatment-related histopathological changes, and no ACF in the colon. Serum estradiol or testosterone concentrations were not changed in F0 or F1 animals. No pre-/postnatal developmental changes related to treatment were noted in F1 animals, and the reproductive performance of F1 Cohort 1B animals was unaffected. F2 pups showed no abnormalities in pre- or postnatal development (postnatal days 4-8). No treatment-related developmental neurotoxicity was observed in Cohorts 2 A/2B. Although no treatment-related immunotoxicity was observed in Cohort 3, the positive control did not induce the expected response; this segment of the study will be repeated. Analyses of blood and urine showed negligible systemic absorption of E171 from the gastrointestinal tract upon dietary ingestion. The no observed adverse effect level (NOAEL) for parental systemic toxicity, reproductive toxicity, offspring toxicity, and developmental neurotoxicity was considered 1000 mg/kg body weight/day. For developmental immunotoxicity, a NOAEL was not determined owing to insufficient T-cell-dependent antibody response in the positive control. Our study provides robust data on the reproductive toxicity and preneoplastic potential of E171.

The authors report no conflict of interest. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND:Based on new testing, we re-assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure.METHODS:Literature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool.RESULTS:Eleven pertinent animal investigations were identified; five with quality scores of 1 were evaluated in-depth. The NTP 13-week drinking water study of NaCN in rats reported significantly decreased water intakes and reduced cauda epididymal weights; altered sperm parameters occurred in high-dose rats. When compared to contemporaneous historical control data (HCD), the mean cauda epididymal weights of cyanide-treated rats in the NTP study were within HCD, whereas control weights exceeded HCD. A new 13-week drinking water study used the same design with additional features (individually caged rats, "paired water" controls, thyroid hormone determinations, post-treatment recovery) and found a smaller decrease in water consumption (11% versus 18% at 300 ppm) and no treatment-related changes in male reproductive measures. Although thyroid/parathyroid weights were increased at 300 ppm, histopathology and thyroid hormone levels were unaffected. The remaining high-quality cyanide studies reported no adverse findings in male reproductive organs. Unconfounded sperm measures were not adversely affected in any quality 1 studies.CONCLUSIONS:Changes in the male reproductive system reported after cyanide exposure in the NTP study were not reproducible, unlikely to be treatment-related, and should not be used as the sole basis for human health assessments.

GENERAL COMMENTARY article Front. Toxicol., 04 December 2023Sec. Developmental and Reproductive Toxicology Volume 5 - 2023 | https://doi.org/10.3389/ftox.2023.1293873

Outsourcing of preclinical developmental and reproductive toxicology testing (DART) is accelerating, but the availability of experienced, well-qualified individuals responsible for DART is diminishing. Current DART training at all levels is anemic. We identify four requisite training areas including hands-on technical skills, scientific knowledge, management, and oral/written communications. We suggest that comprehensive training could be accomplished through DART-targeted certificate programs or post-baccalaureate curricula designed and funded by the combined efforts of industry consortia, contract research organizations, government, and academia. Graduates of such training would be better able to serve as DART technicians, study directors, study monitors or regulatory scientists.

BackgroundA new derived (i.e., calculated) endpoint of developmental toxicology has appeared in a very few studies since 1990. This endpoint is adjusted mean live fetal weight per litter or adjusted fetal weight. Given our lack of familiarity with the endpoint, we evaluated the basis, prevalence, methods, and usefulness in embryo-fetal developmental toxicity (EFDT) studies in rats.MethodsLiterature searches were performed with key terms using PubMed and Google Scholar. Major textbooks were consulted but lack of any mention of the endpoint. Unpublished EFDT data, which are readily available online, were utilized to test adjustment methods.ResultsPertinent information on factors that influence fetal weight goes back a century. Four papers utilizing rats were found in which fetal weights were adjusted using either statistical or formula-based methods to adjust fetal weights. Only one study showed a clear benefit to the endpoint when there was a marked decrease in live litter size; this pointed to situations in which the new endpoint might be useful. The lone formula-based adjustment method was found to be lacking adequate testing and justifications. A new experimental alternative formula-based adjustment is shown to produce results very similar to statistical methods.ConclusionsFrom this assessment, we recommend that adjusted fetal weight should not be a routine endpoint at this time. However, there are likely cases where this derived endpoint could aid interpretation. We encourage other investigators to examine previous EFDT study data to establish guidance on the use of adjusted mean live fetal weights.

The gastrointestinal (GI) system absorbs nutrients and xenobiotics, excretes waste, and performs immunologic and endocrine functions. The subdivisions of the mature gut and the complexity of their corrugated, absorptive luminal surfaces differ greatly among mammals. Regardless, the embryonic gut tube in all mammalian species arises when cephalocaudal folding incorporates the roof of the yolk sac into the embryo. The gut tube quickly lengthens and bulges into the umbilical cord. Upon reentry into the abdominal cavity, the gut tube begins to differentiate-a process that continues until well into the lactation period. Differentiation of the small intestine involves (1) increasing the absorptive surface area of the lumen; (2) establishing mechanisms to control the pH of luminal contents; (3) forming a hierarchical vascular system for distribution of absorbed nutrients; (4) developing a complex enteric nervous system to control motility; (5) providing a system for replenishment of cells; and (6) contributing to the immunity of the organism. Because the length of gestation varies among species typically used in safety tests and is much shorter than human gestation, the state of GI maturation at the time of parturition differs significantly. Differences in GI maturation can contribute to species differences in the rate and extent of absorption; these differences must be considered when designing and interpreting pharmacological/toxicological studies and extrapolating safety test results to humans.

INTRODUCTION:Quaternary ammonium compounds (QUATs) are commonly found in cleaning products, disinfectants, hand sanitizers, and personal care products. They have been used for >50 years and are considered safe when used according to directions. Recent papers report reduced fertility and neural tube defects in rodents after low-level exposures. To determine if QUATs interfere with mammalian reproduction and development, we conducted a methodical assessment of all available data.METHODS:A systematic literature search identified 789 potential articles. Review of titles and abstracts found eight relevant studies, including two dissertation chapters; to these, 10 unpublished, guideline-compliant developmental and reproductive toxicity (DART) studies of QUATs (alkyldimethylbenzylammonium chloride [ADBAC] and dialkyldimethylammonium chloride [DDAC]) were added. ToxRTool was utilized to evaluate all 18 studies for data quality.RESULTS:Six studies were scored as "reliable without restriction"; four studies were considered "reliable with restriction" (mainly due to small rabbit group sizes). No test article-related, adverse DART endpoints were reported in these studies. ToxRTool scored the remaining eight studies as "not reliable." The unreliable studies failed to fully describe methods and/or endpoints, did not quantify (and in some cases, did not verify) exposures, utilized non-standard test methods, reported endpoints incorrectly, and assessed endpoints at inappropriate times. Some (not all) unreliable studies reported adverse effects after 7.5 mg QUATs/kg/day (mice), but these results were inconsistent. The reliable studies tested exposures ≥100 mg/kg/day (rats) with no effects.CONCLUSIONS:The available weight of evidence indicates no adverse DART effects after QUATs exposures at anticipated concentrations and normal use.