Harmonization of Animal Clinical Pathology Testing in Toxicity and Safety Studies

Weingand, Kurt W.; Brown, G.; Hall, Robert L.; Davies, D. T.; Gossett, Kent A.; Neptun, Doug; Waner, Trevor; Matsuzawa, Toshiaki; Salemink, P. J. M.; Froelke, Wilhelm; Provost, Jean-Pierre; Negro, Gianni Dal; J, Batchelor; Nomura, Mamoru; Groetsch, Horst; Boink, A. B. T. J.; Kimball, Jon; Woodman, David; York, Malcolm; E, Fabianson-Johnson; Lupart, M.; Melloni, Elsa

doi:10.1093/toxsci/29.2.198

Cited by 35 publications

(21 citation statements)

References 17 publications

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“…These recommendations are consistent with previous recommendations regarding clinical pathology testing in carcinogenicity studies, in which clinical pathology testing was not recommended after fifty-two weeks of age (Long and Symanowksi 1998;Weingand et al 1992;Weingand 1996). To assess toxicity at earlier time points, separate smaller chronic toxicity studies are conducted or an alternative combined chronic toxicity/carcinogenicity study design is used.…”

Section: Recommendationssupporting

confidence: 79%

“…It states that samples may be taken for hematology, clinical biochemistry, and urinalysis at the discretion of the study director, although the value of such examination for the assessment of carcinogenic/ oncogenic potential has been questioned (Weingand et al 1996). Further references of OECD guidance documents are made (OECD draft guidance No.…”

Section: Review Of Regulatory Guidelines For Clinical Pathology Testimentioning

confidence: 99%

“…The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing recommended that blood smears should be made only from unscheduled terminations (decedents) and at study termination to aid in the identification and differentiation of hematopoietic neoplasia. Quantitative clinical pathology testing during the second year of a two-year rodent carcinogenicity study was considered generally inappropriate and was not recommended (Weingand et al 1996). Previously, the AACC-DACC/ASVCP Joint Task Force recommended collection of blood samples approximately thirteen, twenty-six, and fifty-two weeks after initiation of chronic toxicity, carcinogenicity, and combined studies.…”

Section: Review Of Literaturementioning

confidence: 99%

“…In addition to the two-year rodent bioassay, alternative carcinogenicity assays such as six-month studies using genetically modified mice have been increasingly used to identify the carcinogenic potential of xenobiotics (Long et al 2010;MacDonald et al 2004;Robinson and MacDonald 2001). Clinical pathology parameters are routinely included in repeat-dose toxicity studies and recognized as sensitive biomarkers of chemically induced changes in various organs Thompson et al 1992;Weingand et al 1996). Guidance documents addressing carcinogenicity studies make only limited reference to the inclusion of clinical pathology testing as part of a two-year rodent bioassay, and none specifically for six-month genetically modified mouse assays.…”

Section: Introductionmentioning

confidence: 99%

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Best Practices for Clinical Pathology Testing in Carcinogenicity Studies

et al. 2011

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The Society of Toxicologic Pathology (STP) and American Society for Veterinary Clinical Pathology (ASCVP) convened a Clinical Pathology in Carcinogenicity Studies Working Group to recommend best practices for inclusion of clinical pathology testing in carcinogenicity studies. Regulatory guidance documents and literature were reviewed, and veterinary pathologists from North America, Japan, and Europe were surveyed regarding current practices, perceived value, and recommendations for clinical pathology testing in carcinogenicity studies. For two-year rodent carcinogenicity studies, the Working Group recommends that clinical pathology testing be limited to collection of blood smears at scheduled and unscheduled sacrifices to be examined only if indicated to aid in the diagnosis of possible hematopoietic neoplasia following histopathologic evaluation. Additional clinical pathology testing is most appropriately used to address specific issues from prior toxicity studies or known test article-related class effects. Inadequate data were available to make a recommendation concerning clinical pathology testing for alternative six-month carcinogenicity assays using genetically modified mice, although the Working Group suggests that it may be appropriate to use the same approach as for two-year carcinogenicity studies since the study goal is the same.

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Section: Recommendationssupporting

confidence: 79%

Section: Review Of Regulatory Guidelines For Clinical Pathology Testimentioning

confidence: 99%

Section: Review Of Literaturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Best Practices for Clinical Pathology Testing in Carcinogenicity Studies

et al. 2011

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“…This paper will focus on the activities of ALT, ALP, and GGT, as these enzymes are generally liver associated and often reported to be altered in association with microsomal enzyme induction. Furthermore, these enzymes are recommended as indicators of hepatocellular (ALT activity) and hepatobiliary (ALP and GGT activities) injury in preclinical studies (Boone et al 2005;Weingand et al 1996). Glutamate dehydrogenase (GLDH) and a-glutathione S-transferase (aGST) have also been shown to be sensitive indicators of hepatocellular injury, however, use of these markers is less common, and data from prospective studies with prototypic inducer compounds are more limited (Giffen et al 2002;O'Brien et al 2002).…”

Section: Commonly Used Biomarkers For Monitoring Hepatic Effectsmentioning

confidence: 99%

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

et al. 2010

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Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.

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Biocompatibility and safety evaluation of a ricinoleic acid‐based poly(ester‐anhydride) copolymer after implantation in rats

Vaisman

Motiei

Nyska

et al. 2009

J Biomedical Materials Res

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The aim of this study was to evaluate the safety and tissue compatibility of an injectable biodegradable poly(ester-anhydride) copolymer of ricinoleic acid (RA) and sebacic acid (SA) in rats. The absorbable biomaterial containing 70% w/w of RA and 30% w/w of SA [P(SA-RA) 3:7] was implanted in rats in two separate studies: (1) at high doses subcutaneously (SC) and intramuscularly (IM) simultaneously into the same animal and (2) intracranially (IC). The safety was established in the high-dose administration experiment. No systemic tissue damage, polymer-related lesions, or abnormalities could be detected in the animals. The histopathological evaluation of the SC and IM P(SA-RA) 3:7 implanted sites suggested a typical foreign body reaction (FBR) to biomaterials, and was characterized by excellent tissue repair and good tissue tolerance. In the second experiment, no neurological deficits or behavior changes suggestive of systemic or localized toxicity were observed in the animals implanted IC with the polymer. Only minimal, well-demarcated inflammatory response was observed on days 14 and 21 and consisted of glia cells. No abnormalities were noted in the brain tissue parenchyma located further from the edges of the implant. These results demonstrated that the P(SA-RA) 3:7 copolymer was tolerated well by the animals and compatible with rat subcutaneous, muscle and brain tissues. The biodegradable polymeric system described here could be used as a scaffold for varied applications in localized and sustained delivery of therapeutic agents.

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Harmonization of Animal Clinical Pathology Testing in Toxicity and Safety Studies

Cited by 35 publications

References 17 publications

Best Practices for Clinical Pathology Testing in Carcinogenicity Studies

Best Practices for Clinical Pathology Testing in Carcinogenicity Studies

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

Biocompatibility and safety evaluation of a ricinoleic acid‐based poly(ester‐anhydride) copolymer after implantation in rats

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