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Rodent Liver Tumours and Human Health Risk Assessment Rhian Cope
Progression to Neoplasia (A)Low-power photomicrograph of an AHF in a control mouse, which is recognizable as dysplastic under higher power (magnification, 63; bar = 100 µm). (B)Higher magnification of AHF in (A) illustrating dysplasia including nuclear enlargement, increased nuclear/cytoplasmic ratio, nuclear hyperchromasia, variation in nuclear size and shape, irregular nuclear borders, and nucleoli that are increased in size and number with irregular borders (magnification, 250; bar = 100 µm).
Progression to Neoplasia (C) LFCA in a liver from a mouse treated with 1 g/L DCA; note irregular border and lack of compression at edge (magnification, 63; bar = 100 µm). (D) Higher magnification of LFCA in (C) illustrating a focus of dysplastic cells within the LFCA (magnification, 400; bar = 100 µm).
Progression to Neoplasia (E) Edge of a large AD from a mouse treated with 3.5 g/L DCA, demonstrating compression of adjacent parenchyma and "pushing" border of lesion (magnification, 63; bar = 100 µm). (F) Higher magnification of AD in (E) illustrating dysplastic cells (magnification, 400; bar = 100 µm).
Foci of Hepatocellular Alteration:“Pre-neoplastic” change Occur spontaneously with age in rats; also occasionally in dogs & non-human primates; Type and number of spontaneous foci vary with strain; Have the characteristics of initiated ± promoted cells; Number increase with exposure to genotoxic carcinogens; Represent an “adaptation” of the hepatocytes to a hostile environment i.e. maladaptive response;
Foci of Hepatocellular Alteration:“Pre-neoplastic” change • Often express placental glutathione S-transferase (GST-P) and are UDP-glucuronosyltransferase negative in rats. Variable expression patterns found in mouse foci; • Elevated replicative DNA synthesis; • Altered expression of various growth factors; • Over responsive to mitogens; • Inherent defects in growth control (i.e. becoming autonomous in terms of growth); • Genomic instability; • Aberrant methylation of p16 TSG; • Mutations of ß-catenin; • Decreased apoptosis; • Clonal origin demonstrable in vitro
Foci of Hepatocellular Alteration:“Pre-neoplastic” change Relevance to humans: • Similar pre-neoplastic foci occur in humans exposed to hepatic carcinogens (both viral and chemical); • Also occur with non-genotoxic hepatocarcinogens i.e. anabolic steroids; • Potentially relevant to humans depending on the mechanism!
Foci of Hepatocellular Alteration:“Pre-neoplastic” change Reversibility: • In the case of chemically stimulated FHA’s, a high proportion will partially or near-completely regress when the stimulus is removed; • Meet the criteria for “initiation + promotion”; • Initiation is irreversible, but initiation is not phenotypically detectable;
FHA Versus Focal Nodular Regenerative Hyperplasiaand Nodular Regenerative Hyperplasia Key differences: • Cells phenotypically normal; • Circumscribed i.e. not invading surrounding normal tissue; • May be divided into pseudolobules by fibrous tissue (focal nodular regenerative hyperplasia); • Not pre-neoplastic. BUT: Can be very difficult to distinguish from AHF!
Foci of Pancreatic Tissue Metaplasia NOT neoplasia; Islands of seemingly “normal” exocrine pancreatic tissue within the liver; Induced by Arochlor1254;
Adenoma Acinar Type(An adenoma is a benign tumor (-oma) of glandular origin)
Adenoma Trabecular Type(An adenoma is a benign tumor (-oma) of glandular origin)
Adenoma – Human Vs Rodent Rodent • Clearly distinguishable from regenerative hyperplasia; • Usually larger than one lobule; • Compress the surrounding tissue; • Loss of normal lobular architecture but portal triads may be present; • Usually multifocal; • Not encapsulated with fibrous tissue;• Humans • Difficult to differentiate from regenerative hyperplasia; • Usually solitary; • Usually encapsulated.
CarcinomaCarcinoma: Carcinoma refers to an invasive malignant tumor consistingof transformed epithelial cells. Alternatively, it refers to a malignanttumor composed of transformed cells of unknown histogenesis, butwhich possess specific molecular or histological characteristics that areassociated with epithelial cells, such as the production of cytokeratins orintercellular bridges.
Carcinoma – Human Vs Rodent• Humans • Mixed cell tumors are relatively common; • Concurrent cirrhosis is common; • Usually associated with chronic hepatitis; • Rarely spontaneous – usually a history of viral exposure and/or aflatoxin exposure and/or alcohol exposure.
Carcinoma – Human Vs Rodent Rodent • Classically metastasize to lung (why?); • Derive from oval cells (pluripotent stem cells) in the periportal area; • Mixed cell tumors (i.e. hepatocyte plus bile duct cell carcinomas) do not occur • Usually do not involve concurrent cirrhosis or chronic hepatitis; • “Spontaneous” in older animals (also in hamsters and beagle dogs); • “Spontaneous” tumors are common, particularly in some strains.
ILSI/HESI MOA Framework Is the weight of evidence sufficient to establish the MOA in animals? • Genotoxic? • Potentially relevant to humans, particularly if tumors at multiple sites; • Nongenotoxic? • Relevance to humans is highly dependent on the mechanism!
ILSI/HESI MOA Framework Are the key events in the animal MOA plausible in humans? • Genotoxic • Do the mutations occur in human cells in vitro and in vivo? • Do the same spectrum of mutations occur? • Is the genotoxic progression similar? • Histopathology • Is the same histopathological life history present in rodents and humans?
ILSI/HESI MOA Framework Are the key events in the animal MOA plausible in humans? • Nongenotoxic? • Relevance is HIGHLY dependent on the mechanism; • Do the hyperplastic effect + antiapoptotic effect occur in humans? • If a receptor-mediated pathway is involved, is this pathway present in humans and of similar pathophysiological relevance? • Is there a clear dose threshold and what is its relationship to human exposure?
ILSI/HESI MOA Framework Taking into account kinetic and dynamic factors, are the key events in the animal MOA plausible in humans? • TK is sufficiently similar to result in relevant concentrations at the site of action? • Promutagens activated to the same extent in humans (i.e. TD issues)? (TD encompasses all mechanisms through which the concentration/amount at the site of action elicits the toxic effect); • If redox damage is critical, does similar metabolism/events occur in humans? • Do the tumors occur in a non-rodent species?
• Observation of tumours under different circumstances lends support to thesignificance of the findings for animal carcinogenicity. Significance isgenerally increased by the observation of more of the following factors: •Uncommon tumour types; •Tumours at multiple sites; •Tumours by more than one route of administration; •Tumours in multiple species, strains, or both sexes; •Progression of lesions from preneoplastic to benign to malignant; •Reduced latency of neoplastic lesions; •Metastases (malignancy, severity of histopath); •Unusual magnitude of tumour response; •Proportion of malignant tumours; •Dose-related increases; •Tumor promulgation following the cessation of exposure.