The Significance of Mouse Liver Tumor Formation for Carcinogenic Risk Assessment: Results and Conclusions from a Survey of Ten Years of Testing by the Agrochemical Industry

Carmichael, Neil G.; Enzmann, Harald; Pate, Ian; Waechter, F.

doi:10.2307/3433897

Cited by 12 publications

(17 citation statements)

References 33 publications

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“…In a retrospective examination of data from 138 carcinogenicity studies in mice, increased liver weight at twelve months was typically associated with development of liver tumor by eighteen to twenty-four months (Carmichael et al 1997). An increased liver weight of 110% at one year was not associated with liver tumorigenesis, whereas liver tumorigenicity was seen if the one-year liver weight was 150% of control values (Carmichael et al 1997). A similar correlation between liver weight at fifty-two weeks and ultimate hepatocarcinogenicity in mice was reported by scientists at the NTP (Haseman et al 1997).…”

Section: Liver Enlargement and Hepatocarcinogenicitymentioning

confidence: 99%

Hepatic Enzyme Induction

et al. 2010

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Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics.

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Section: Liver Enlargement and Hepatocarcinogenicitymentioning

confidence: 99%

Hepatic Enzyme Induction

et al. 2010

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“…In contrast, PB is a well-known potent inducer of hepatic xenobiotic metabolizing oxidative enzymes, which results in a pronounced hepatocellular hypertrophy and ultimately in liver tumor formation in rodents (Carthew, Edwards, and Nolan 1998). The strong induction of enzymes is believed to play a part in the mechanism of rodent liver tumorigenesis by PB and similar enzyme-inducing agents (Carmichael et al 1997).…”

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confidence: 99%

Gene Expression Dose-Response of Liver with a Genotoxic and Nongenotoxic Carcinogen

et al. 2006

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Tumorigenic mechanisms due to chemical exposure are broadly classified as either genotoxic or nongenotoxic. Genotoxic mechanisms are generally well defined; however nongenotoxic modes of tumorgenesis are less straightforward. This study was undertaken to help elucidate dose-response changes in gene expression (transcriptome) in the liver of rats in response to administration of known genotoxic or nongenotoxic liver carcinogens. Male Big Blue Fischer 344 rats were treated for 28-days with 0, 0.1, 0.3, 1.0, or 3.0 mg/kg/day of the genotoxin 2-acetylaminofluorene (AAF) or 0, 10, 30, 60, or 100 mg/kg/day of the nongenotoxin phenobarbital (PB). Transcriptome analysis was performed using the relatively focused Clontech Rat Toxicology II microarray (465 genes) and hybridized with 32P-labeled cDNA target. The analysis indicated that after 28 days of treatment, AAF altered the expression of 14 genes (9 up- and 5 down-regulated) and PB altered the expression of 18 genes (10 up- and 8 down-regulated). Of the limited genes whose expression was altered by AAF and PB, four were altered in common, two up-regulated, and two down-regulated. Several of the genes that show modulation of transcriptional activity following AAF and PB treatment display an atypical dose-response relationship such that the expression at the higher doses tended to be similar to that of control. This high-dose effect could potentially be caused by adaptation, toxicity, or tissue remodeling. These results suggest that the transcriptional response of the cells to higher doses of a toxic agent is likely to be different from that of a low-dose exposure.

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“…Increases in LWs have been examined for relationships with liver tumor risk in 2-year carcinogenicity studies in rodents. 14,36 In a survey of 138 agrochemicals examined in mice, a relative increase in LW of ≥150% of control values after 1 year of treatment was positively correlated with the induction of liver tumors at 2 years. 36 The average relative LW of top dose animals in negative studies of 110% of control 36 was similar to our threshold of 117%.…”

Section: Resultsmentioning

confidence: 99%

“…14,36 In a survey of 138 agrochemicals examined in mice, a relative increase in LW of ≥150% of control values after 1 year of treatment was positively correlated with the induction of liver tumors at 2 years. 36 The average relative LW of top dose animals in negative studies of 110% of control 36 was similar to our threshold of 117%. In a survey of mouse and rat NTP studies examining correlations between LW and/or histological parameters and carcinogenesis, Allen et al 14 found that hepatocellular hypertrophy was the best single predictor of liver cancer in mice.…”

Section: Resultsmentioning

confidence: 99%

Thresholds Derived From Common Measures in Rat Studies Are Predictive of Liver Tumorigenic Chemicals

et al. 2020

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We hypothesized that typical tissue and clinical chemistry (ClinChem) end points measured in rat toxicity studies exhibit chemical-independent biological thresholds beyond which cancer occurs. Using the rat in vivo TG-GATES study, 75 chemicals were examined across chemical-dose-time comparisons that could be linked to liver tumor outcomes. Thresholds for liver weight to body weight (LW/BW) and 21 serum ClinChem end points were defined as the maximum and minimum values for those exposures that did not lead to liver tumors in rats. Upper thresholds were identified for LW/BW (117%), aspartate aminotransferase (195%), alanine aminotransferase (141%), alkaline phosphatase (152%), and total bilirubin (115%), and lower thresholds were identified for phospholipids (82%), relative albumin (93%), total cholesterol (82%), and total protein (94%). Thresholds derived from the TG-GATES data set were consistent across other acute and subchronic rat studies. A training set of ClinChem and LW/BW thresholds derived from a 38 chemical training set from TG-GATES was predictive of liver tumor outcomes for a test set of 37 independent TG-GATES chemicals (91%). The thresholds were most predictive when applied to 7d treatments (98%). These findings provide support that biological thresholds for common end points in rodent studies can be used to predict chemical tumorigenic potential.

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The Significance of Mouse Liver Tumor Formation for Carcinogenic Risk Assessment: Results and Conclusions from a Survey of Ten Years of Testing by the Agrochemical Industry

Abstract: A survey was performed on the results of 138 carcinogenkicty studies conducted in various mouse strins by the agrochemical industry over the period [1983][1984][1985][1986][1987][1988][1989][1990][1991][1992][1993]

Cited by 12 publications

References 33 publications

Hepatic Enzyme Induction

Hepatic Enzyme Induction

Gene Expression Dose-Response of Liver with a Genotoxic and Nongenotoxic Carcinogen

Thresholds Derived From Common Measures in Rat Studies Are Predictive of Liver Tumorigenic Chemicals

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