Neonatal Mouse Tumorigenicity Bioassay

Fu, Peter P.; Tungeln, Linda S. Von; Yi, Ping; Xia, Qingsu; Casciano, Daniel A.; Flammang, Thomas J.; Kadlubar, Fred F.

doi:10.1177/009286159803200311

Cited by 14 publications

(23 citation statements)

References 65 publications

(83 reference statements)

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“…One study indicated that aflatoxin B1, which forms DNA adducts in both neonatal and adult tissues, induced tumors only in the neonate (Fu et al, 1998). This was presumed to be a result of the replication capacity and relative rate and efficiency of repair in the neonate versus the adult, thereby allowing for a higher probability of conversion of an adduct to a mutation.…”

Section: Mutagenic Efficiencymentioning

confidence: 99%

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Jarabek

Pottenger

Andrews

et al. 2009

Critical Reviews in Toxicology

115

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The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

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Section: Mutagenic Efficiencymentioning

confidence: 99%

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Jarabek

Pottenger

Andrews

et al. 2009

Critical Reviews in Toxicology

115

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“…In the neonatal mouse bioassay, newborn mice are generally treated with carcinogens one to four times during the preweanling period (1-22 days of age) and killed at 8-12 months of age [6,7]. When tested with the proximate and ultimate carcinogenic metabolites of chemicals, such as the metabolites of benzo[a]pyrene, benzo[a]pyrene trans-7,8-dihydrodiol, and benzo[a]pyrene trans-7,8-diol-9,10-epoxide, the animals developed tumors much earlier and therefore were sacrificed at as early as 22-26 weeks of age [37].…”

Section: A Historical Background and General Considerationsmentioning

confidence: 99%

“…Genotoxic chemical carcinogens are defined as chemicals that exert tumorigenicity through mechanisms involving the formation of covalently bound carcinogen-DNA adducts that lead to mutation. In this review, nongenotoxic chemical carcinogens are defined as chemicals that exert tumorigenicity through secondary mechanisms that may include the formation of DNA adducts from endogenous lipid peroxidation or oxidative stress, induction of hypomethylation or hypermethylation, modulation of sex hormones, and induction of peroxisome proliferation [6,7].…”

Section: B Bioassay Of Genotoxic Chemical Carcinogensmentioning

confidence: 99%

“…The majority of chemicals tested for tumorigenicity in the neonatal mouse have been genotoxic chemicals [6,7,34,38]. Various classes of genotoxic chemical carcinogens have been studied, including polycyclic aromatic hydrocarbons (PAHs) [9,10,[36][37][38], halogenated PAHs [33,39], nitrated PAHs [40][41][42], food pyrolysis products (heterocyclic amines) [30,31], complex environmental mixtures [43,44], nitrosamines [34], mycotoxins [34], vinyl compounds [34], azo dyes [34], aromatic amines [34], and allylarenes, including estragole and safroles [34].…”

Section: B Bioassay Of Genotoxic Chemical Carcinogensmentioning

confidence: 99%

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Metabolic Activation Capacity of Neonatal Mice in Relation to the Neonatal Mouse Tumorigenicity Bioassay

Tungeln

Hammons

et al. 2000

Drug Metabolism Reviews

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The neonatal mouse tumorigenicity bioassay is a well-developed animal model that has recently been recommended as an alternative tumorigenicity bioassay by the International Conference on Harmonization (ICH) for Technical Requirements for the Registration of Pharmaceuticals for Human Use. There are sufficient data to conclude that this animal model is highly sensitive to genotoxic chemical carcinogens that exert their tumorigenicity through mechanisms involving the formation of covalently bound exogenous DNA adducts that lead to mutation. On the other hand, it is not sensitive to chemical carcinogens that exert tumorigenicity through a secondary mechanism. The metabolizing enzymes present in the neonatal mouse, particularly the cytochromes P450, are critical factors in determining the tumorigenic potency of a chemical tested in this bioassay. However, compared to the metabolizing enzymes of the adult mouse and rat, the study of the metabolizing enzymes in neonatal mouse tissues has been relatively limited.

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“…Thus far, over 150 chemicals have been evaluated in the neonatal mouse assay. In the US, the FDA has recently selected a variety of pharmaceuticals, which were either positive or negative in 2-year carcinogenicity bioassays and included genotoxic and non-genotoxic agents, for evaluation in the neonatal mouse assay (6,7).…”

Section: Introductionmentioning

confidence: 99%

Neonatal Mouse Model: Review of Methods and Results

et al. 2001

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The neonatal mouse model, in various forms, has been used experimentally since 1959 and a large number of chemicals have been tested. The neonatal model is known to be very sensitive for the detection of carcinogens that operate via a genotoxic mode of action. In contrast, it is known not to respond to chemicals that act via epigenetic mechanisms, commonly observed in the two-year carcinogenicity studies. As such, the model has a high sensitivity and speci city in its response. Dose selection for the neonatal model is based on the maximum tolerated or feasible dose. Traditionally, compounds have been tested via the IP route of administration in this model. In some cases, this has limited the amount of material that can be administered because of the low dosing volumes (10 to 20 l L) that can be administered IP. For the ILSI project, the neonatal model was adapted for oral administration, which has the advantages of being the same route for which most pharmaceuticals are administered. In addition, a 10-fold increase in the volume of administration (100 to 200 l L) and the ability to dose drugs in suspension, permits much higher doses to be used as compared to the IP route of administration. The spontaneous tumors in the neonatal model occurred mainly in the liver of male mice and lung of male and female mice with a few tumors observed in the Harderian gland. The positive control, DEN produced a robust, uniform, and reproducible tumor response with the target organs essentially limited to liver and lung. A total of 13 compounds out of the 21 ILSI ACT compounds were evaluated in the neonatal model involving 18 studies with duplicate studies for some compounds. The genotoxic carcinogens including those used as positive controls were clearly positive (cyclophosphamide, diethylnitrosamine, 6-nitrochrysene). The non-genotoxic rodent carcinogens were clearly negative (chlorpromazine, sul soxazole, sulfamethoxazole, clo brate, DEHP, haloperidol, metaproteranol, and phenobarbital). The non-genotoxic human carcinogen (cyclosporin) was clearly negative. The two other human carcinogens phenacetin and DES were negative and interestingly estradiol was negative in one of the two oral studies, but was clearly positive in the other. Considering the mode of action for three of the human carcinogens (DES, cyclosporin and phenacetin), which were negative in this model, the mode of action in humans is likely to be epigenetic. Overall, for the 3 clearly genotoxic chemicals, all were positive. For the 9 clearly non-genotoxic chemicals, all 9 were negative. The two human carcinogens for which genotoxicity may or may not play a role (DES and phenacetin) were negative and estradiol was positive in 1 of the two oral studies. Overall, the extensive database for compounds tested in the neonatal mouse model would support its use as an alternative model for the assessment of the carcinogenic potential of a chemical. The model responds to chemicals that act via a genotoxic mode of action that represent a greater concern for human cancer...

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Neonatal Mouse Tumorigenicity Bioassay

Cited by 14 publications

References 65 publications

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Metabolic Activation Capacity of Neonatal Mice in Relation to the Neonatal Mouse Tumorigenicity Bioassay

Neonatal Mouse Model: Review of Methods and Results

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