Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning

Journal Article · Mon Mar 15 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.11.021· OSTI ID:21344888

Auerbach, Scott S ^[1]; Shah, Ruchir R; Mav, Deepak ^[2]; Smith, Cynthia S; Walker, Nigel J; Vallant, Molly K; Boorman, Gary A ^[1]

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1. National Toxicology Program, National Institute of Environmental Health Sciences, NIH, RTP, NC 27709 (United States)
2. SRA International, RTP, NC 27709 (United States)

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency.

• OSTI ID: 21344888
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 243; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AFLATOXINS
AMINES
AMINO ACIDS
ANIMALS
ANTIGENS
AROMATICS
ASCORBIC ACID
AZAARENES
AZOLES
BODY
CARBOXYLIC ACIDS
CARCINOGENS
DIGESTIVE SYSTEM
DISEASES
DOSES
GENES
GLANDS
HAZARDOUS MATERIALS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
INDOLES
LIVER
MAMMALS
MATERIALS
MYCOTOXINS
NEOPLASMS
NITROSAMINES
NITROSO COMPOUNDS
ORGANIC ACIDS
ORGANIC BROMINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRROLES
RATS
RODENTS
TESTING
TOXIC MATERIALS
TOXINS
TRYPTOPHAN
VALIDATION
VERTEBRATES
VITAMINS