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1.
Crit Rev Toxicol ; 37(9): 729-837, 2007.
Article in English | MEDLINE | ID: mdl-17957539

ABSTRACT

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. An earlier ILSI RSI working group developed a set of principles for the selection of doses for chronic rodent studies (ILSI, 1997). The present report builds on that work, examining some of the issues that arise and offering new perspectives and approaches for putting the principles into practice. Dose selection is considered both from the prospective viewpoint of the choosing of dose levels for a study and from the retrospective interpretation of study results in light of the doses used. A main theme of this report is that the purposes and objectives of chronic rodent studies vary and should be clearly defined in advance. Dose placement, then, should be optimized to achieve study objectives. For practical reasons, most chronic studies today must be designed to address multiple objectives, often requiring trade-offs and innovative approaches in study design. A systematic approach to dose selection should begin with recognition that the design of chronic studies occurs in the context of a careful assessment of the accumulated scientific information on the test substance, the relevant risk management questions, priorities and mandates, and the practical limitations and constraints on available resources. A stepwise process is described. The aim is to increase insofar as possible the utility of an expensive and time-consuming experiment. The kinds of data that are most commonly needed for dose selection and for understanding the dose-related results of chronic rodent studies, particularly carcinogenicity studies, are discussed as "design/interpretation factors." They comprise both the inherent characteristics of the test substance and indicators of biological damage, perturbation or stress among the experimental animals. They may be primary toxicity endpoints, predictors or indicators of appropriate dose selection, or indicators of conditions to be avoided in dose selection. The application and interpretation of design/interpretation factors is conditioned by the study objectives-what is considered desirable will depend on the strategy for choice of doses that is being followed. The challenge is to select doses that accommodate all of the issues raised by the relevant design/interpretation factors. Three case studies are presented here that illustrate the interplay between study objectives and the design and selection of doses for chronic rodent studies. These examples also highlight issues associated with multiple plausible modes of action, multiple pathways for biotransformation of the chemical, extraneous high-dose effects, the use of modeling in dose selection, and the implications of human exposure levels. Finally, looking to the future, the report explores seven potential paradigm shifts for risk assessment that will significantly impact the design and interpretation of toxicity and carcinogenicity studies.


Subject(s)
Carcinogenicity Tests/methods , Dose-Response Relationship, Drug , Animals , Carcinogens/toxicity , Humans , Research Design , Rodentia
2.
Aging Clin Exp Res ; 16(1): 68-78, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15132295

ABSTRACT

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. The severity of chronic heart and kidney diseases was significantly reduced in all DR rat groups, with significant DR-dependent linear trends for these diseases. Moreover, DR prevented the progression of skin irritation to foot ulcers, and reduced the age-related degeneration in the adrenal, lacrimal, and thymus glands, and the liver. CONCLUSIONS: These results clearly indicate that even low DR levels were effective in preventing or slowing the progression of these non-neoplastic diseases.


Subject(s)
Cardiomyopathies/prevention & control , Diet , Food Deprivation , Kidney Diseases/prevention & control , Aging/physiology , Animal Nutritional Physiological Phenomena , Animals , Cardiomyopathies/epidemiology , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Chronic Disease , Disease Progression , Humans , Kidney Diseases/epidemiology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Longevity , Male , Rats , Rats, Sprague-Dawley
3.
Nonlinearity Biol Toxicol Med ; 2(1): 35-43, 2004 Jan.
Article in English | MEDLINE | ID: mdl-19330107

ABSTRACT

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. The resulting differential increase in the number of pre-neoplastic cells at risk of mutation during cell division is assumed to lead to an increase in the incidence of tumors. Two-year liver tumor incidences predicted by the model using data on organ weight, cell proliferation, and sphingolipid metabolism provided a reasonable match to the actual 2-year observed incidences in a study conducted at the National Center for Toxicological Research. The predictions indicated no risk at low doses (even a possible hormetic effect) and high risk at high doses in females, as well as a complete absence of a dose response (or perhaps, a hormetic effect) in males. This paper provides a commentary on the risk-assessment implications of the modeling results, pointing out that the model's low-dose predictions provide scientific support and justification for the U.S. Food and Drug Administration's low-ppm guidance levels in corn products. These guidance levels are significantly higher than would be obtained using linear extrapolation, the method most often used for genotoxic carcinogens and other carcinogens for which low-dose linearity cannot be ruled out.

4.
J Gerontol A Biol Sci Med Sci ; 57(11): B379-89, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12403793

ABSTRACT

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. Cardiac, renal, and central nervous system pathologies were significantly inhibited by dietary restriction (DR), as were bone degeneration, inflammation, hyperplasia, amyloid induction, and atrophy of secretory organs. Hematological disorders and tumors were among the most common problem in this strain, and they were ameliorated by DR. In males, for other neoplasms, adrenal adenomas, liver tumors, and hemangiomas combined with hemangiosarcomas were decreased by DR, variably in onset and progression. In females, DR decreased pituitary tumors, mammary tumors, and alveolar carcinomas, again variably in onset and progression.


Subject(s)
Aging/physiology , Diet , Disease Susceptibility , Edible Grain , Food Deprivation/physiology , Longevity/physiology , Animal Feed , Animals , Body Weight , Female , Male , Mice , Mice, Inbred C57BL , Survival Rate
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