Tumor incidence

BVdU is degraded by thymidine phosphorylase more rapidly than the natural substrate, thymidine. This rapid enzymic degradation may present a problem in its clinical use. Moreover, herpes vimses develop resistance to BVdU, apparendy because of mutant vimses that have lower thymidine kinase activity. G. D. Seade has dropped further development of BVdU because of increased animal tumor incidence induced by prolonged dosing (1). 

Experiments were conducted in which purified trichloroethylene (1 mg in acetone) was applied to the shaved backs of female ICR/Ha Swiss mice (Van Duuren et al. 1979). In an initiation-promotion study, a single application of trichloroethylene was followed by repeated application of phorbol myristate acetate (PMA) promoter. In a second study, mice were treated with trichloroethylene three times per week without a promoter. No significant tumor incidences were observed in these studies. Doses used in these studies were well below the maximum tolerated dose, which is often not reached in dermal studies. 

Animal studies have shown that tumors can result from both inhalation (Fukuda et al. 1983 Henschler et al. 1980 Maltoni et al. 1986) and oral exposure (Aima et al. 1994 Henschler et al. 1984 NCI 1976 NTP 1990) to trichloroethylene. Unfortunately, some of these studies (NCI 1976) are limited in that they use carcinogenic epoxide stabilizers with the trichloroethylene, which may contribute to the carcinogenicity. The studies also show different responses depending on the sex, species, and strains of animals used and do not point to a particular target organ for increased tumor incidence. Other studies are flawed because of excess... 

Malek B, Kremarova B, Rodova A. 1979. [An epidemiological study of hepatic tumor incidence in subjects working with trichloroethylene. II. Negative result of retrospective investigations in dry cleaners.] Prac Lek 31 124-126. (Czech)... 

Intervention trials confirmed this protective role of lycopene on prostate cancer risk. Three primary intervention studies evaluated the effect of lycopene supplementation on prostate cancer risk or on certain risk markers such as prostate-specific antigen (PSA) plasma concentration or oxidative alterations of leucocyte DNA. - All showed increases of plasma and prostate lycopene levels after diet supplementation with lycopene and inverse correlations between tumor incidence and risk biomarkers. 

Van Den Heuvel R, Gerber GB, Leppens H, et al. 1995. Long-term effects on tumor incidence and survival from 241Am exposure of the BALB/c mouse in utero and during adulthood. Int J Radiat Biol 68(6) 679-686. 

An increased incidence of renal tumors (7 out of 25 combined adenomas and carcinomas) was observed in male Swiss mice fed 0.1% basic lead acetate in the diet for 2 years (Van Esch and Kroes 1969). No renal tumors were found in the control animals. One female in the 1.0% treatment group had a renal tumor. The authors attributed the low tumor incidence in the 1.0% group to early mortality. The cancer effects levels described above are recorded in Table 2-4 and plotted in Figure 2-2. 

For certain chemicals, levels of exposure associated with carcinogenic effects may be indicated in the figures. These levels reflect the actual doses associated with the tumor incidences reported in the studies cited. Because cancer effects could occur at lower exposure levels, the figures also show estimated excess risks, ranging from a risk of one in 10,000 to one in 10,000,000 (10 to 10 ), as developed by EPA. 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

No inhalation slope factor is available for aniline, and the available inhalation studies did not examine the endpoint of carcinogenicity. Based on the chronic oral administration of aniline hydrochloride to CD-F rats (CUT 1982), U.S. EPA in its Integrated Risk Information Systems (IRIS) has estimated an oral slope factor of 5.7x1 OP Vrng/kg/d (U.S. EPA 1994). In that study, spleen tumor incidences in rats administered 0, 200, 600, or 2,000 ppm in the diet were 0/64, 0/90, 1/90, and 31/90, respectively. Aniline also has genotoxic action. 

Both isomers of dimethylhydrazine have been shown to be carcinogenic in rodents following chronic oral exposure and 6-mon inhalation exposure to 1,1-dimethylhydrazine. Increased tumor incidence was observed in mice, although these findings are compromised by the contaminant exposure to dimethylnitrosamine. An increased incidence of lung tumors and hepatocellular carcinomas was also seen in rats but not in similarly exposed hamsters. The U.S. Environmental Protection Agency (U.S. EPA) inhalation slope factors are currently unavailable for dimethylhydrazine. 

None of the mammary tumor incidences exceeded those expected or reported on aged female rats of this strain... 

Morbidity, Viral titer/tissue burden Morbidity, Viral titer/tissue burden Muscle larvae and adult parasite numbers Tumor Incidence (subcutaneous)... 

Urso, P., and Gengozian, N. Depressed humoral immunity and increased tumor incidence in mice following in utero exposure to benzo[a]pyrene, J. Toxicol. Environ. Health., 6, 569, 1980. 

The single most important statistical consideration in the design of bioassays in the past was based on the point of view that what was being observed and evaluated was a simple quantal response (cancer occurred or it didn t), and that a sufficient number of animals needed to be used to have reasonable expectations of detecting such an effect. Though the single fact of whether or not the simple incidence of neoplastic tumors is increased due to an agent of concern is of interest, a much more complex model must now be considered. The time-to-tumor, patterns of tumor incidence, effects on survival rate, and age of first tumor all must now be captured in a bioassay and included in an evaluation of the relevant risk to humans. 

Common viral infections may affect the outcome of carcinogenicity studies by altering survival or tumor incidence. Nevertheless, viral infections did not cause consistent adverse effects on survival or tumor prevalence in control F344 rats from 28 NCI-NTP studies, though body weights were reduced by Sendai and pneumonia viruses of mice (Rao et al., 1989). The probability of such infections can be minimized by using viral-antibody-free animals, which are readily available. 

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