Cancer bioassay

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

In recent decades, the development of chemical, biochemical, and biological techniques has allowed the creation of analytical tools which can be used to facilitate the identification of the mechanisms involved in neoplastic transformation. Animal models remain, however, the most widely used approach of investigation. Cancer bioassays are usually conducted in rodents (rats and mice) and the experimental protocol takes 18-24 months and it is followed by extensive histopathological and statistical analysis. The procedure is time and... 

Phenol has been tested in animals for carcinogenicity by the oral and dermal routes, but results are equivocal. In a chronic NCI cancer bioassay (NCI 1980), a significant incidence of tumors (pheochro-mocytomas of the adrenal gland, leukemia, or lymphomas) occurred only in male rats exposed to the lowest dose level (2,500 ppm, 277 mg/kg/day) of phenol but not in male or female mice or male rats exposed to a higher dose level (5,000 ppm, 624 mg/kg/day). Since tumors occurred only in males in one of the two species tested, and since a positive dose-response relationship was not established, this study does not provide sufficient evidence to conclude that phenol is carcinogenic when administered by the oral route. Dermal application of phenol has been shown to result in tumors in mice phenol is a tumor promoter when it is applied after the application of the tumor initiator DMBA (Boutwell and Bosch 1959 Salaman and Glendenning 1957 Wynder and Hoffmann 1961). However, this effect occurs at dose levels of phenol that produce severe skin... 

Now, finally, the significance of all this. Because, as a practical matter, it is difficult to conduct bioassays with more than 100-150 animals per dose level (usually split evenly between males and females), it can be seen from the above table that in the best of circumstances, with a zero or very low incidence outcome in control animals, it would be necessary for a tested compound to induce something like an 8-15% tumor incidence before we could fairly label it a carcinogen. This is a fairly large risk, yet our typical cancer bioassay has what might be called a limit of detection at about this level. Like chemical assays, bioassays are limited in their ability to detect effects - in this case, the carcinogenicity of a chemical substance. 

The various government scientists who, in the 1960s and 1970s, were devising standardized cancer bioassay protocols, recognized the... 

Yes, but with caution. Reference has been made several times to the fundamental biological similarities of mammalian species, and to the expected similarities in response to chemical toxicity in animals and human beings. These expectations have been borne out in a large proportion of those cases in which there has been an opportunity to obtain toxicity data in both humans and animals, so that it would be imprudent to ignore the results of cancer bioassays. At the same time these results need to be carefully scrutinized, because they can easily mislead. 

Let us skip by the question of the adequacy of the animal tests used to identify these agents. The general quality of the animal test is obviously of great importance in the overall evaluation and these questions cannot be ignored in the case of cancer bioassays any more than they can in any other type of toxicity test. But the more interesting questions arise when we move beyond the question of study quality. 

Each monograph reviews all pertinent epidemiological studies and cancer bioassays in experimental animals. Mechanistic and other relevant data are also reviewed. With regard to epidemiological studies, cancer bioassays, and mechanistic and other relevant data, only reports that have been published or accepted for publication in the openly available scientific literature are reviewed. Data from government agency reports that are publicly available are also considered. 

This model assumes that any dosage effect has the same mechanism as that which causes the background incidence. Low-dose linearity follows directly from this additive assumption, provided that any fraction of the background effect is additive no matter how small. A best fit curve is fitted to the data obtained from a long-term rodent cancer bioassay using computer programs. The estimates of the parameters in the polynomial are called Maximum Likelihood Estimates (MLE), based upon the statistical procedure used for fitting the curve, and can be considered as best fit estimates. Provided the fit of the model is satisfactory, the estimates of these parameters are used to extrapolate to low-dose exposures. 

Because of the lack of appropriate cancer bioassays and epidemiological studies, the EPA has determined that HMX is not classifiable as to its human carcinogenicity. ... 

Lifetime cancer bioassays using orally exposed animals were not located. In a shorter-term study, exposure to p-cresol in the feed for 20 weeks produced an increased incidence of forestomach hyperplasia in hamsters, suggesting that this cresol isomer may have the potential to act as a promoter of forestomach carcinogenesis in this species (Hirose et al. 1986). However, promotion potential was not tested directly. p-Cresol did not produce forestomach hyperplasia in rats (Altmann et al. 1986), but rats are generally less sensitive than hamsters to inducers of forestomach lesions. 

Cancer. Studies found no relationship between endogenous p-cresol levels in the urine and the occurrence of large bowel cancer (Bone et al. 1976) or bladder cancer (Renwick et al. 1988) in humans. There are no data available regarding the carcinogenicity of exogenous cresols in humans. No cancer bioassays have been conducted in animals, but the results of a promotion study in mice suggested that cresols can be cancer promoters. Cresols have some ability to interact with mammalian DNA in vitro, but it is impossible to assess the potential hazard to humans without more information. 

Limited carcinogenicity data for chlorine dioxide and chlorite do not indicate a particular cancer concern, but adequate animal cancer bioassays have not been performed. Genotoxicity testing has produced mixed results. Chlorine dioxide and chlorite do not appear to be reproductive toxicants. 

Absorption, Distribution, Metaboiism, and Excretion. There is relatively little quantitative information on the systemic absorption of inhaled carbon tetrachloride in animals and humans, with estimates ranging from 30% to 60% (Lehmann and Schmidt-Kehl 1936 McCollister et al. 1951). In order to confirm the dose absorbed during inhalation exposures to carbon tetrachloride, it would be useful to determine the systemic uptake of carbon tetrachloride in additional animal experiments, with special attention to concentration- and time-dependency of absorption. It may be useful to conduct short-term studies of the relative absorption, disposition, and toxicity of inhaled versus ingested carbon tetrachloride. Such studies can yield information pertinent to route-to-route extrapolation and may be more economical than conducting a 2-year inhalation cancer bioassay of carbon tetrachloride. 

In the absence of definitive human data, risk assessment may have to depend on the results of cancer bioassays in laboratory animals, short-term tests, or other experimental methods. Hence the following issues must be addressed under such circumstances the ability of the test system to predict risks for man (quantitatively as well as qualitatively) the reproducibility of test results the influence of species differences in pharmacokinetics, metabolism, homeostasis, repair rates, life span, organ sensitivity, and baseline cancer rates extrapolation across dose and dose rates, and routes of exposure the significance of benign tumors fitting models to the data in order to characterize dose-incidence relationships and the significance of negative results. 

In laboratory animal studies, a cancer bioassay was conducted with groups of 100 (50 male, 50 female) Fischer 344 rats in which the rats were exposed ad libitum to an estimated 0, 20, or 40 mg/kg/day dose of... 

Just within the past decade have definitive animal studies for arsenic-induced carcinogenesis emerged with positive results (Kitchin, 2001 Hughes, 2002 Rossman, 2003 Wanibuchi et al., 2004 Cohen et al., 2006 Waalkes, Liu and Diwan, 2007). Up until this point, standard lifetime cancer bioassays with inorganic... 

Haseman JK. 1983. Patterns of tumor incidence in two-year cancer bioassay feeding studies in Fischer 344 rats. Fundam Appl Toxicol 3 1-9. 

Ashby J. Expectations for transgenic rodent cancer bioassay models. Toxicol Pathol 2001 29 177-82. 

---