Guidelines for Combining Neoplasms for Evaluation of Rodent Carcinogenesis Studies

McConnell, Ernest E.; Solleveld, Hendricus A.; Swenberg, James A.; Boorman, Gary A.

doi:10.1093/jnci/76.2.283

Cited by 38 publications

(1 citation statement)

References 35 publications

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“…If all the intestinal tumors are analyzed together (small intestine leiomyosarcomas, small intestine adenocarcinoma, and colon sarcoma), proflavine (CASRN 92-62-6) would test positive in the already performed rat-RCB [58]. However, experts on long-term rodent bioassays have not recommended such a specific combination of tumors to interpret the data [59]. Hence, there is a lack of certainty on whether that hypothetical (but certainly statistical) increase in the incidence of intestinal tumors was caused by proflavine.…”

Section: On Specific Drugsmentioning

confidence: 99%

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators

Suárez-Torres

Orozco

Ciangherotti

2021

Fundamemntal Clinical Pharma

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The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays.Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs.Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.

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Section: On Specific Drugsmentioning

confidence: 99%

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators

Suárez-Torres

Orozco

Ciangherotti

2021

Fundamemntal Clinical Pharma

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Chronic Toxicity and Carcinogenic Evaluation of Diisononyl Phthalate in Rats☆☆☆

Lington

Bird

Plutnick

et al. 1997

Fundamental and Applied Toxicology

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Groups of 110 Fischer 344 rats/sex were fed diisononyl phthalate (DINP) at dietary levels of 0, 0.03, 0.3, and 0.6 wt% for periods up to 2 years. Interim sacrifices of 10 predesignated rats/sex/dose were at 6, 12, and 18 months with surviving animals sacrificed at 24 months. At study termination, survival was in excess of 60% for every group. At the mid or high dose, the following biological effects were noted: slight decreases in food consumption and body weight; slight increase in mortality; a dose-related increase in relative organ weights of liver and kidney; and some slight effects on urinalysis, hematologic, and clinical chemistry parameters. No peroxisome induction was observed in livers of treated rats compared with controls. No clear treatment-related nonneoplastic or neoplastic lesions were found. However, mononuclear cell leukemia (MNCL) and changes known to be associated with an increased incidence of MNCL were seen in the mid-dose and high-dose groups. A literature review suggests that MNCL is a common finding in aging F344 rats and that this increased incidence in rats treated with DINP is not relevant to man. A clear no-observed-effect level was demonstrated for all biological end points at a dietary level of 0. 03 wt% or approximately 17 mg/kg/day of DINP.

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Occurrence and relevance of chemically induced benign neoplasms in long-term carcinogenicity studies

1989

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Recent carcinogenicity studies conducted and evaluated by the National Toxicology Program/National Institute of Environmental Health Sciences were examined to determine the frequency of chemically increased incidences of neoplasia. Many of the chemicals originally selected for study were chosen because of an a priori suggestion that they might be carcinogens. Of the 143 chemical studies evaluated, usually involving male and female rats and mice, 42 (29%) did not induce any neoplasms, 20 (14%) gave marginal or equivocal neoplastic responses, and 81 (57%) showed positive neoplastic responses in one or more of the 524 species-gender experiments. Of these 81 positive studies, 60 (74%) were considered positive based on malignant neoplasia, 16 (20%) were positive due primarily to benign neoplasia, but had supporting evidence of malignant neoplasia in the same organ/tissue, and 5 (6%) were positive based only on benign neoplasia. These five chemicals are a) allyl isothiocyanate (transitional cell papillomas of the urinary bladder in male rats), b) 2-amino-4-nitrophenol (tubular cell adenomas of the kidney in male rats), c) asbestos intermediate range chrysotile (adenomatous polyps of the large intestine in male rats), d) decabromodiphenyl oxide (neoplastic nodules of the liver in male and female rats), and e) nitrofurazone (fibroadenomas of the mammary gland in female rats and benign mixed tumors and granulosa cell tumors of the ovary in female mice). For all but one of these lesions (mammary gland), the occurrence in historic controls is low. Thus, only 5 of the 143 chemicals studied (3.5%) induced benign neoplasia alone, and those observed benign neoplasms are known to progress to malignancy. Accordingly, we consider chemically induced benign neoplasia to be an important indicator of a chemical's carcinogenic potential in rodents, and believe it should continue to be made an integral part of the overall weight-of-the-evidence evaluation process for identifying potential human health hazards.

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Guidelines for Combining Neoplasms for Evaluation of Rodent Carcinogenesis Studies

Cited by 38 publications

References 35 publications

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators

Chronic Toxicity and Carcinogenic Evaluation of Diisononyl Phthalate in Rats☆☆☆

Occurrence and relevance of chemically induced benign neoplasms in long-term carcinogenicity studies

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