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The important renal tumors that can be induced by exposure of rats to chemical carcinogens are renal tubule tumors (RTTs) derived from tubule epithelium; renal pelvic carcinoma derived from the urothelial lining of the pelvis; renal mesenchymal tumors (RMTs) derived from the interstitial connective tissue; and nephroblastoma derived from the metanephric primordia. However, almost all of our knowledge concerning mechanisms of renal carcinogenesis in the rodent pertains to the adenomas and carcinomas originating from renal tubule epithelium. Currently, nine mechanistic pathways can be identified in either the rat or mouse following chemical exposure. These include direct DNA reactivity, indirect DNA reactivity through free radical formation, multiphase bioactivation involving glutathione conjugation, mitotic disruption, sustained cell proliferation from direct cytotoxicity, sustained cell proliferation by disruption of a physiologic process (alpha 2u-globulin nephropathy), exaggerated pharmacologic response, species-dominant metabolic pathway, and chemical exacerbation of chronic progressive nephropathy. Spontaneous occurrence of RTTs in the rat will be included since one example is a confounder for interpreting kidney tumor results in chemical carcinogenicity studies in rats. [ABSTRACT FROM AUTHOR]

Differences in cancer incidences between men and women are often explained by either differences in environmental exposures or by influences of sex hormones. However, there are few studies on intrinsic gender differences in susceptibility to chemical carcinogens. We have analyzed the National Toxicology Program (NTP) database for sex differences in rat responses to chemical carcinogens. We found that the odds that male rat bioassays were assigned a higher level of evidence than female rat bioassays was 1.69 (p < .001). Of 278 carcinogenic chemicals in the database, 201 (72%) exhibited statistical gender differences (p ≤ .05) in at least one nonreproductive organ. One hundred thirty of these 201 chemicals induced gender-specific tumors in male rats and 59 in female rats. Sixty-eight chemicals induced tumors in males but no tumors in females. Less than one third (i.e., 19 chemicals) induced tumors in females but not males. Male-specific tumors included pancreatic and skin tumors, and female-specific tumors included lung tumors. For some tumor sites, these differences in gender susceptibility can be associated with literature data on sex hormone receptor expression. In conclusion, gender-specific tumors were common. The male dominance is in line with recent human data, and the male susceptibility to carcinogens should be further studied. [ABSTRACT FROM AUTHOR]

The two-year rodent bioassay is one of several tests that are widely used by governmental regulatory agencies as well as pharmaceutical and chemical companies to determine the carcinogenic potential of chemicals or environmental agents where human exposure is anticipated. That this assay has remained relatively unchanged for the last 25 years is a testament to the power of this approach to identify carcinogens and thus to minimize human exposure. However, there has long been controversy over the specificity and relevance of the rodent bioassay as well as its high cost in terms of time, expense, and numbers of mice. Much discussion has been generated in recent years over how to improve the 2-year rodent bioassay for more accurate and faster detection of potential human carcinogens. Here, we argue that the use of p27 Kip1 ( Cdkn1b ) knockout mouse for carcinogen screening may solve several shortcomings inherent in the conventional bioassay while preserving its best quality, that is, protecting public health by providing reliable in vivo information on the potential of chemicals to cause cancer. [ABSTRACT FROM AUTHOR]

Few studies have examined the carcinogenicity of chemicals toward the urinary bladder in hamsters, and the effect of diet on hamster urine and urothelium has not been reported. Our laboratory recently began investigating the effects of dimethylarsinic acid (DMA) on the hamster bladder, and we noticed subtle urothelial changes even in controls. The possible effect of various diets on hamster urothelium was evaluated by feeding different diets to 4-week-old Syrian Golden hamsters for 5 weeks. The diets examined were Tekland 8656, Purina 5002, Purina 5L79, and NIH-07. Light microscopic examination showed a slight increase in urothelial hyperplasia in hamsters fed Purina 5L79. An increase in the incidence of urinary bladder necrosis, exfoliation, and mild hyperplasia were noted by scanning electron microscopy (SEM) with all dietary preparations except NIH-07. The constituents in the diets producing the urothelial alterations are not known at present, but NIH-07 diet was chosen for experiments to investigate the effects of DMA on the hamster bladder epithelium. Male and female 5-week-old Syrian Golden hamsters were fed 100 ppm DMA for 10 weeks. Examination of urinary parameters showed no treatment-related changes. Light microscopic examination and SEM revealed no changes of the urothelium of DMA-treated male or female hamsters. [ABSTRACT FROM AUTHOR]

A compendium ofcarcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites and to determine whether target sites are the same for chemicals positive in more than 1 species. The source of information is the Carcinogenic Potency Database (CPDB), which includes results of 6073 experiments on 1458 chemicals (positive or negative for carcinogenicity) that have been reported in Technical Reports of the National Cancer Institute/National Toxicology Program or in papers in the general published literature. The published CPDB includes detailed analyses of each test and citations. The CPDB is publicly available in several formats (http://potency.berkeley.edu). Chemical carcinogens are reported for 35 different target organs in rats or mice. Target organs in humans are also summarized for 82 agents that have been evaluated as human carcinogens at a particular target site by the International Agency for Research on Cancer (IARC). Comparisons are provided of target organs for mutagens versus nonmutagens and rats versus mice. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to an article on thresholds in chemical carcinogenesis by William Waddell, published in the May/June 2003 issue of "Toxicologic Pathology."

Summarizes salient features of chemical carcinogenesis and its understanding in terms of fundamental principles of chemistry. Principal pathways to chemical-induced cancer; Equation of Gibbs' free energy; Scale of the linearized distortion.

Presents a response by William J. Waddell to a letter to the editor about his article "Dose-Response Curves in Chemical Carcinogenesis."

Presents a letter to the editor in response to the article "Thresholds in Chemical Carcinogenesis: What are Animal Experiments Telling Us?," by William J. Waddell, published in the 2003 issue of the journal "Toxicologic Pathology."