Issues in the design and interpretation of chronic toxicity and carcinogenicity studies in rodents: approaches to dose selection.

For more than three decades chronic studies in rodents have been the benchmark for assessing the potential long-term toxicity, and particularly the carcinogenicity, of chemicals. With doses typically administered for about 2 years (18 months to lifetime), the rodent bioassay has been an integral component of testing protocols for food additives, pesticides, pharmaceuticals, industrial chemicals, and all manner of byproducts and environmental contaminants. Over time, the data from these studies have been used to address an increasing diversity of questions related to the assessment of human health risks, adding complexity to study design and interpretation.

The effects of different levels of dietary restriction on non-neoplastic diseases in male Sprague-Dawley rats.

Background And Aims: The primary purpose of the present study was to investigate the effects of 10, 25, and 40% dietary restriction (DR) on non-neoplastic diseases in rodents at 58 and 110 weeks of age, and to determine whether low-level DR (10 and 25%) can increase the survival rate and decrease variability in chronic bioassay studies.

Methods: Male Sprague-Dawley (SD) rats (NCTR colony) were divided into four nutritional groups, consisting of an ad libitum (AL) group with unlimited access to the NIH-31 diet, and three dietary restricted (DR) groups given the NIH-31 diet reduced in amount by 10, 25, and 40%.

Results: At 110 weeks of age, the incidence of cardiomyopathy was 95, 75, 45, and 15% for AL and 10, 25, and 40% DR rats, respectively; the incidence of nephropathy was 55, 20, 15, and 0% for AL and 10, 25, and 40% DR rats, respectively.

Risk-assessment implications of mechanistic model's prediction of low-dose nonlinearity of liver tumor risk for mice fed fumonisin b(1).

A two-stage, clonal-expansion model of liver tumor risk in mice was developed by Kodell et al. (Food Addit Contam 18:237-253, 2001) based on the hypothesis that fumonisin B(1), a naturally occurring mycotoxin in corn, is not genotoxic, but rather causes cancer through the disruption of sphingolipid metabolism. This disruption is assumed to cause an increase in apoptosis, in response to which cells proliferate to compensate for reduced tissue mass.

Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction.

Studies of C57BL/6 mice are often restricted to one sex, with limited characterization of pathology as a function of age. As part of the National Institute on Aging/National Center for Toxicological Research Collaboration on Biomarkers, over 3000 males and 1500 females of this strain were raised, maintained, and used to evaluate longevity under specific pathogen-free conditions. A diet commonly used in testing the impact of agents was fed ad libitum or was restricted to 60% of normal consumption, starting when the mice were 14-16 weeks of age.