Tumor incidence models

The tumor count data from the animal carcinogenicity experiment is then used to estimate the relationship between the ED and t imor incidence using standard tumor incidence models. The most commonly used model is the linearized multistage model (Anderson, et al., 1983), which is a modified version of the multistage model of Armitage and Doll (1954). There are numerous other models that have been employed, some of which are based upon statistical arguments and some of which attempt to mimic biological theory (see eg Krewski and Brown, 1980). ... 

The tumor incidence model is then used to estimate a safe ED defined as that equivalent dose which yields a negligible increase in risk for the tumor over the background risk. For the purposes of risk estimation, it is assumed that this safe ED represents the safe ED in humans. It remains only to convert this safe ED in humans into a safe human exposure level. As before, a model relationship is assumed between the ED and exposure dose in humans (usually the same conceptual model as was used in the animal species) and parameter estimates are obtained. In addition to obtaining parameter estimates from the fields previously mentioned, a considerable number of parameters are estimated as simple allometric formulae of parameters which are easily obtained in animals, such as body weight. The complexity of these models, the number of parameters and the number of experiments used to estimate the parameters contribute to the overall uncertainty in the safe dose estimates. 

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. 

Host resistance Bacterial models—Listeria monocytogenes (mortality or spleen clearance) Streptococcus species (mortality) Viral models—influenza (mortality) Parasitic models—Plasmodium yoelii (parasitemia) or Trichinella spiralis (muscle larvae counts and worm expulsion) Syngeneic tumor models—PYB6 sarcoma (tumor incidence) B16F10 melanoma (lung burden). 

The methods we advocate for routine use for the analysis of tumor incidence tend, therefore, not to be based on the use of formal parametric statistical models. For example, when studying the relationship of treatment to incidence of a pathological condition and wishing to adjust for other factors (in particular, age at death) that might otherwise bias the comparison, methods involving stratification are... 

The linear component of the LMS model, qi (i.e., one of the parameters of the polynomial), is approximately equivalent to the slope at low doses of the dose-response relationship between the tumor incidence and the dose. This linearity at low dose is a property of the formulation developed for the multistage model and is considered by proponents to be one of its important properties. This linear component of the polynomial, qi, is used to carry out low-dose extrapolation. The linear response at low doses is considered to be conservative with regard to risk, as the dose-response relationship at low doses may well be sublinear. Although supralinearity at low doses cannot be excluded, it is usually considered to be unlikely. 

In the absence of sufficient data to develop a robust, biologically based model for quantitative risk assessment, a single curve-fitting model for each type of data set is preferred. It is noted that many different curve-fitting models have been developed, and those that fit the observed data reasonably well may lead to several-fold differences in estimated risk at the lower end of the observed range. Therefore, the US-EPA uses a standard curve-fitting procedure for tumor incidence data. 

A nonlinear approach should be selected when there are sufficient data to ascertain the mode of action and to conclude that it is not linear at low doses, and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses. The POD is in this case generally a BMDL when incidence data are modeled. A sufficient basis to support this nonlinear procedure is likely to include data on responses that are key events in the carcinogenic process. This means that the POD may be based on these precursor response data, for example hormone levels or mitogenic effects, rather than tumor incidence data. A nonlinear approach can be used to develop an RfD or an RfC. This approach expands such reference values, previously reserved for threshold effects, to include carcinogenic effects determined to have a nonlinear mode of action. A nonlinear approach should generally not be used in cases where the mode of action has not been ascertained. 

Anticarcinogenic Activity of CLA. Anticarcinogenic activity of synthetically prepared CLA was first tested in the two-stage mouse epidermal carcinogenesis model. In this study, 7 days, 3 days, and 5 min prior to 7,12-dimethylbenz[a]anthracene (DMBA) application, CLA was applied directly on the shaved backs of individual mice at doses of20,20, and 10 mg, respectively (7). Control mice were treated similarly with linoleic acid or acetone. All mice were given TPA to effect tumor promotion. It was found that CLA treated mice developed only about half as many papillomas and exhibited a lower tumor incidence than control mice. 

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. 

The effect of dietary cholesterol (7) on mammary tumor development was examined in female Sprague-Dawley rats exposed to the carcinogen MNU [47]. Tumor incidence in the compound 7 group (67%) was significantly lower than in the control group (96%) which suggested that dietary 7 inhibits mammary tumor development in this model. Taraxasterol (239), on oral administration, showed remarkable inhibitory effects on mouse spontaneous mammary tumors using C3H/OuJ mouse [42]. 

Dimethylhydrazine (DMFI)-induced rat colon carcinogenesis model was used for evaluation of the synergistic inhibitory effect between curcumin and catechin in light of ACF formation and tumor incidence. The results of this... 

Thus, the excretory pattern of fecal secondary bile acids observed in these studies correlated with colon tumor incidences in animal models. These studies also suggest that high dietary intake of certain types of fat may be necessary for the full expression of risk for colon cancer. 

Vitamin A and its derivatives, the so-called retinoids (1 ), exert anti-tumor activity at a variety of organ sites in various animal model systems (2-8). Recent studies suggest that high serum levels of vitamin A (retinol) are related to a reduced tumor incidence in human populations (9-10), and that a high dietary intake of foods rich in vitamin A reduces tumor yield (11-14). Thus, there is considerable interest, and effort made in elucidating the mechanism by which vitamin A and retinoids exert anti-tumor activity. 

In the initial study by Ip et al. (1991), the authors fed rats a standard diet or that diet supplemented with 0.5, 1.0 or 1.5% CLA, 2 weeks prior to and following administration of the carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA). At the end of the experiment, the total number of mammary adenocarcinomas in the groups fed 0.5, 1.0 and 1.5% CLA was reduced by 32, 56 and 60% compared to the control, respectively. Tumor incidence, tumor multiplicity (number of tumors per rat) and total tumor weight were reduced to a similar degree. This tumor inhibition by CLA is in contrast to linoleic acid, which promotes tumor development in this model. 

Evidence of tumorigenic effects of the drug in rodent models should be evaluated in light of the tumor incidence and latency, the pharmacokinetics of the drug in the rodent models as compared to humans, and data from any ancillary or mechanistic studies that are informative with respect to the relevance of the observed effects to humans. 

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