Publications by authors named "Eveline de Rijk"

12 Publications

  • Page 1 of 1

Scientific and Regulatory Policy Committee Best Practices: Documentation of Sexual Maturity by Microscopic Evaluation in Nonclinical Safety Studies.

Toxicol Pathol 2021 Mar 4:192623321990631. Epub 2021 Mar 4.

510456Idorsia Pharmaceuticals Limited, Allschwil, Switzerland.

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623321990631DOI Listing
March 2021

Toxicity of copper oxide and basic copper carbonate nanoparticles after short-term oral exposure in rats.

Nanotoxicology 2019 02 19;13(1):50-72. Epub 2018 Nov 19.

a National Institute for Public Health and the Environment (RIVM) , Bilthoven , Netherlands.

Copper oxide (CuO) nanoparticles (NPs) and copper carbonate nanoparticles (CuCO(OH) NPs have applications as antimicrobial agents and wood preservatives: an application that may lead to oral ingestion via hand to mouth transfer. Rats were exposed by oral gavage to CuO NPs and CuCO(OH) NPs for five consecutive days with doses from 1 to 512 mg/kg and 4 to 128 mg/kg per day, respectively, and toxicity was evaluated at days 6 and 26. Both CuO NPs and CuCO(OH) NPs induced changes in hematology parameters, as well as clinical chemistry markers (e.g. increased alanine aminotransferase, ALT) indicative of liver damage For CuO NPs histopathological alterations were observed in bone marrow, stomach and liver mainly consisting of an inflammatory response, ulceration, and degeneration. CuCO(OH) NPs induced morphological alterations in the stomach, liver, intestines, spleen, thymus, kidneys, and bone marrow. In spleen and thymus lymphoid, depletion was noted that warrants further immunotoxicological evaluation. The NPs showed partial dissolution in artificial simulated stomach fluids, while in intestinal conditions, the primary particles simultaneously shrank and agglomerated into large structures. This means that both copper ions and the particulate nanoforms should be considered as potential causal agents for the observed toxicity. For risk assessment, the lowest bench mark dose (BMD) was similar for both NPs for the serum liver enzyme AST (an indication of liver toxicity), being 26.2 mg/kg for CuO NPs and 30.8 mg/kg for CuCO(OH) NPs. This was surprising since the histopathology evidence demonstrates more severe organ damage for CuCO(OH) NPs than for CuO NPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17435390.2018.1530390DOI Listing
February 2019

Review of Sexual Maturity in the Minipig.

Toxicol Pathol 2016 06 21;44(4):607-11. Epub 2016 Apr 21.

WIL Research, A Charles River Company, Hambakenwetering 7, 5231 DD) 's-Hertogenbosch, the Netherlands.

It is important to know whether the animals used in toxicology studies are sexually mature. As minipigs are being used increasingly in toxicity studies, we reviewed published data on the age of sexual maturity in the minipig. Maturity in females was assessed on the basis either of normal cycles of progesterone secretion or of the histological presence of corpora lutea and, in males, was assessed on the histological appearance of the seminiferous tubules and epididymides. In female Göttingen minipigs, the first progesterone peak was at 3.7 to 4.2 or 6.1 to 6.5 months of age. These animals were in the presence of a boar. In female Göttingen minipigs in toxicology studies, which were not in the presence of a boar, at least 1 corpus luteum in the ovaries was present in only 50% of the females by 6.5 months of age, while all were mature by 7.7 months of age. Histological maturity in the male Yucatan minipig is reported to be attained at about 4.4 months old, but in male Göttingen minipigs at about 2 months old, although the definition of maturity may have been different in the 2 studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623316642881DOI Listing
June 2016

Sexual Maturation in the Female Göttingen Minipig.

Toxicol Pathol 2016 Apr 16;44(3):482-5. Epub 2016 Feb 16.

WIL Research Europe B.V., Department of Toxicology, Hertogenbosch, Netherlands.

In the literature, experimental data on sexual maturation of female Göttingen minipigs are lacking. This may impede a reliable evaluation of reproductive functioning, particularly in the young (immature) sow used in toxicity studies. To find suitable method(s) to detect ovulation during in-life, a pilot study was performed with 3 adult sows (approximately 10-11 months), followed by a study with 14 immature females (approximately 3-4 months). From the tested parameters, progesterone analysis was the most reliable predictor. First progesterone peaks were observed in 13 sows at 3.7-4.2 or 5.5-6.5 months with a cycle length of 17-22 days. One sow did not show progesterone release until necropsy at 7 months of age. Histopathology of the reproductive organs confirmed sexual maturity for all sows, except the one without progesterone peak. In conclusion, the age range of sexual maturity of female Göttingen minipigs (3.7-6.5 months) is much wider than previously thought, and in-life progesterone analysis is a useful tool to determine sexual maturity of individual animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623315621413DOI Listing
April 2016

Postnatal development of the testis in the rat: morphologic study and correlation of morphology to neuroendocrine parameters.

Toxicol Pathol 2015 Apr 11;43(3):326-42. Epub 2014 Sep 11.

WIL Research, Hillsborough, North Carolina, USA.

Histopathologic examination of the testis from juvenile rats is often necessary to characterize the safety of new drugs for pediatric use and is a required end point in male pubertal development and thyroid function assays. To aid in evaluation and interpretation of the immature testis, the characteristic histologic features of the developing rat testis throughout postnatal development are described and correlated with published neuroendocrine parameter changes. During the neonatal period (postnatal day [PND] 3-7), seminiferous tubules contained gonocytes and mitotically active immature Sertoli cells. Profound proliferation of spermatogonia and continued Sertoli cell proliferation occurred in the early infantile period (PND 8-14). The spermatogonia reached maximum density forming double-layered rosettes with Sertoli cells in the late infantile period (PND 15-20). Leptotene/zygotene spermatocytes appeared centrally as tubular lumina developed, and individual tubules segregated into stages. The juvenile period (PND 21-32) featured a dramatic increase in number and size of pachytene spermatocytes with the formation of round spermatids and loss of "infantile" rosette architecture. In the peri-pubertal period (PND 32-55), stage VII tubules containing step 19 spermatids were visible by PND 46. The presented baseline morphologic and endocrinologic information will help pathologists distinguish delayed development from xenobiotic effects, determine pathogenesis when confronted with nonspecific findings, and identify sensitive time points for targeted study design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623314547279DOI Listing
April 2015

Estrous cycle-dependent morphology in the reproductive organs of the female Göttingen minipig.

Toxicol Pathol 2014 Dec 26;42(8):1197-211. Epub 2014 Mar 26.

Department of Toxicology, WIL Research Europe B.V, 's-Hertogenbosch, Netherlands.

The present study describes the normal histology of female reproductive organs during the estrous cycle in the Göttingen minipig. For this purpose, sexually mature females were sacrificed at different phases of the cycle (follicular/proliferation, ovulation, and early-, mid-, and late-luteal/secretory phase). Ovaries, uterus, cervix, vagina, and mammary gland tissues were processed for microscopic evaluation. Sexual maturity was assured by selecting females in which at least 1 progesterone peak was measured. Stage-distinguishing features in ovaries were the Graafian follicles (disrupted vs. nondisrupted) and corpora lutea of recent and preceding cycles (size, cell morphology, and structural composition). In the uterus, stage-specific markers were epithelial morphology, secretory activity (using periodic acid-Schiff/hematoxylin staining), and epithelial mitosis and/or apoptosis. The other reproductive organs were not suitable to discriminate between the different phases of the cycle due to a high morphologic variability (mammary gland, and vagina) or absence of clear morphologic differences between the phases (cervix). The increased use of young minipigs (frequently immature/peripubertal) in preclinical testing requires more knowledge on the histologic cyclic changes. With the present morphologic description of the morphologic characteristics of the reproductive tract in recently ovulating minipigs, a guidance for staging the estrous cycle and determination of sexual immaturity is provided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623314526136DOI Listing
December 2014

Proliferative and nonproliferative lesions of the rat and mouse male reproductive system.

Toxicol Pathol 2012 Aug;40(6 Suppl):40S-121S

Huntingdon Life Sciences, East Millstone, New Jersey 08875, USA.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the male reproductive system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the Internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the male reproductive system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623312454337DOI Listing
August 2012

Selected Background Findings and Interpretation of Common Lesions in the Female Reproductive System in Macaques.

Toxicol Pathol 2008 Dec;36(7):142s-163s

Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

The authors describe a selection of normal findings and common naturally occurring lesions in the reproductive system of female macaques, including changes in the ovaries, uterus, cervix, vagina, and mammary glands. Normal features of immature ovaries, uteri, and mammary glands are described. Common non-neoplastic lesions in the ovaries include cortical mineralization, polyovular follicles, cysts, ovarian surface epithelial hyperplasia, and ectopic ovarian tissue. Ovarian neoplasms include granulosa cell tumors, teratomas, and ovarian surface epithelial tumors. Common non-neoplastic uterine findings include loss of features of normal cyclicity, abnormal bleeding, adenomyosis, endometriosis, epithelial plaques, and pregnancy-associated vascular remodeling. Hyperplastic and neoplastic lesions of the uterus include endometrial polyps, leiomyomas, and rarely endometrial hyperplasia and endometrial adenocarcinoma. Vaginitis is common. Cervical lesions include endocervical squamous metaplasia, polyps, and papillomavirus-associated lesions. Lesions in the mammary gland are most often proliferative and range from ductal hyperplasia to invasive carcinoma. Challenges to interpretation include the normal or pathologic absence of menstrual cyclicity and the potential misinterpretation of sporadic lesions, such as epithelial plaques or papillomavirus-associated lesions. Interpretation of normal and pathologic findings is best accomplished with knowledge of the life stage, reproductive history, and hormonal status of the animal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0192623308327117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070965PMC
December 2008

Spermatogenesis in the cynomolgus monkey (Macaca fascicularis): a practical guide for routine morphological staging.

Toxicol Pathol 2007 Apr;35(3):395-404

Department of Toxicology and Drug Disposition, Organon, 5340 BH, Oss, The Netherlands.

The cynomolgus monkey (Macaca fascicularis) is widely used in regulatory toxicity studies. Especially in studies on male contraception, the male reproductive tract can be an important target system. The aim of the present paper is to describe a practical approach for morphological staging of spermatogenesis in routinely prepared paraffin sections. Results obtained using this approach could help to determine possible drug-related effects on spermatogenesis. As a guide to the investigators, photomicrographs of Bouin-fixed, paraffin-embedded and H&E or PAS stained sections from testis tissue are presented to illustrate the twelve successive morphological stages (cell associations) of normal spermatogenesis. Sexually immature or peripubertal monkeys sometimes are included in toxicity studies. Since the morphological features of the testes of such monkeys can be mistaken for treatment-related abnormalities, the morphologic characteristics of these testes are described and discussed briefly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01926230701230346DOI Listing
April 2007

A fast histochemical staining method to identify hyaline droplets in the rat kidney.

Toxicol Pathol 2003 Jul-Aug;31(4):462-4

Organon, Department of Toxicology and Drug Disposition, 5340 BH Oss, The Netherlands.

Hyaline droplet formation in the proximal tubular cells of the kidney commonly occurs under different pathological conditions in experimental animals. In rats, intracytoplasmic hyaline droplet formation is predominantly associated with accumulation of the male rat-specific alpha(2u)-globulin, whereas under other (pathological) conditions (eg, histiocytic sarcoma and chronic progressive nephropathy [CPN]) other proteins are involved. Staining methods to visualize hyaline droplets either need plastic embedded material or time-consuming (immuno)histochemical methods. A fast Chromotrope-Aniline-Blue-staining on formalin-fixed paraffin-embedded kidneys taking only 30 minutes is described. Using this method, hyaline droplets consisting of different types of proteins are easily recognized by their bright-red color.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01926230390213775DOI Listing
March 2004

Multifocal ductal cell hyperplasia in the submandibular salivary glands of Wistar rats chronically treated with a novel steroidal compound.

Toxicol Pathol 2003 Jan-Feb;31(1):1-9

Organon, Department of Toxicology and Drug Disposition, 5340 BH Oss, The Netherlands.

A high incidence of multifocal ductal hyperplasia was observed in the submandibular salivary gland of rats treated for 26 weeks with a high dose of a novel synthetic steroid with combined estrogenic and progestagenic properties. Hyperplastic foci consisted of microcystic duct-like structures lined by a single or multilayered epithelium, sometimes showing a tendency towards a cribiform growth pattern. The hyperplastic ducts wereembedded in a collagen-rich stroma and surrounded by numerous myoepithelial cells. Immunohistochemical methods used for the detection of estrogen- and progesterone receptors revealed that progesterone receptors were abundantly present in the nucleus of epithelial cells within the lesions, exclusively. Estrogen receptors could not be detected in both the normal tissue and hyperplasic foci. The morphological, ultrastructural, and immunohistochemical characteristics strongly suggest that these hyperplastic lesions originated from the intercalated ducts. The rodent-specific granular duct cell was not involved in the pathogenesis as was clearly demonstrated by the lack of immunoreactive epidermal growth factor within the lesions. Lesions were not observed in studies with progestagens and estrogens alone or with other combined estrogen/progestagen compounds, suggesting that the specific ratio of estrogenic and progestagenic activity of the present steroid had played an important role in the development of ductal hyperplasia in this study. Lesions of the intercalated ducts, as described in this study, have not been reported before in the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01926230390173798DOI Listing
July 2003

Pregnancy dating in the rat: placental morphology and maternal blood parameters.

Toxicol Pathol 2002 Mar-Apr;30(2):271-82

Organon, Department of Toxicology and Drug Disposition, Oss, The Netherlands.

The rat is commonly used as a model in studies on embryology and reproduction toxicology. Surprisingly, the current literature does not provide a comprehensive reference data set on placental development in rat. Therefore, we have evaluated morphological changes of the placenta and maternal blood parameters during pregnancy of the Sprague-Dawley rat. The morphologic data presented in this study may be useful as reference material. This study revealed that placental development in the rat is a well-defined process, characterized by key synchronized morphological events at specific points in time, convenient for laboratory practice and provides the toxicologist with a sensitive tool to distinguish between normal and abnormal placental development and to detect fetal and placental mismatches. During rat pregnancy, significant changes were observed in maternal blood parameters strongly reminiscent of those observed in pregnant women. These changes included: (a) decreased blood cell volume as a result of hemodilution, (b) increased white blood cell counts reflecting the response of the mother to the fetal allograft, (c) increased blood clotting values, (d) decreased plasma glucose and increased lipid content maximizing fetal glucose availability and maternal energy conservation, and (e) decreased electrolyte values reflecting plasma volume expansion. It was concluded that the combined data set on placental morphology and maternal blood parameters in pregnant rats provides powerful tools for recognition of abnormal pregnancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/019262302753559614DOI Listing
April 2002