Carcinogenic process

Drinking water and various submixtures National Institute of of the full seven-chemical mixture as a Environmental Health promoter in the carcinogenic process Sciences (arsenic, benzene, chloroform, chromium, lead, trichloroethylene, and phenol) (rats)... 

For example, 7,12-dimethylbenz[a]anthracene is a particularly potent carcinogen for the mammary gland of young female Sprague-Dawley rats after oral or intravenous administration (25,26), dietary benzo[a]pyrene leads to leukemia, lung adenoma and stomach tumors in mice (27), and either of these hydrocarbons can induce hepatomas in male mice when injected on the first day of life (28). Nevertheless, the mouse skin system has proved to be particularly valuable because of the rapidity of tumor induction, the ease of detection of tumors and because the multi-stage nature of the carcinogenic process was experimentally established in this system. 

The developments which led to the present day concepts of the metabolic activation of hydrocarbons did not arise from the classical approach of identifying metabolites of greater biological potency than the parent compound, but from an approach dependent upon the assumption (or presumption) that the interaction of carcinogens with DNA is a key event in the initiation of the carcinogenic process. Brookes and Lawley (49) found in 1964 that when radioactive hydrocarbons are applied to the skin of mice, they become covalently bound to the DNA of the skin. Moreover, the extents of binding to DNA for various hydrocarbons followed fairly closely their relative carcinogenic activities. 

Reactivity of protonated epoxide. There is believed to be a zone of intermediate epoxide reactivity that is optimum for initiating the carcinogenic process [57-59], The molecule must be able to undergo the necessary reactions, yet not be so active it will interact prematurely with other cellular species. 

Initiation Mutation induced by a chemical reactive substance causing cell changes being a step in a carcinogenic process. [NIH]... 

What emerges here is a picture in which the carcinogenic process is influenced by a fairly long list of factors, and is either aided or inhibited by these factors. When we administer a chemical to lab animals and count tumors at the end of their lives, we are observing only two points, and not particularly interesting points, connected by a long sequence of molecular and cellular events. 

We might now examine some of the information that has contributed to this picture of the carcinogenic process. 

Now most people are not exposed to PAHs in this way, and no one is exposed to the phorbol esters, which are strictly laboratory chemicals. But this is not the point. The Berenblum-Shubik promotion studies, and hundreds more that have been explored in the past five decades, have contributed substantially to our understanding of the carcinogenic process. Some chemicals appear to possess both initiating and promoting properties - they are complete carcinogens - while others seem to be primarily involved in the promotion stage of the process. 

These few examples reveal the practical applications of some of the emerging scientific views regarding the actions of chemicals that induce cancers in animals. The development of information to test the LNT hypothesis (the standard default) is an important area of research that can not only improve the basis for risk assessment, but can also more generally advance knowledge of carcinogenic processes. 

The first step of the dose-response assessment is the evaluation of the data within the range of observation. If there are sufficient quantitative data and adequate understanding of the carcinogenic process, a biologically based model may be developed to relate dose and response data. Otherwise, as a default procedure, a standard model can be used to curve-fit the data. For each mmor response, a POD from the observed data is estimated to mark the beginning of extrapolation to lower doses. The POD is an estimated dose (expressed in human-equivalent terms) near the lower end of the observed range, without significant extrapolation to lower doses. 

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. 

For the nature of the carcinogenic process, EFSA considered it appropriate that an additional factor of 10 would account for human variability in DNA-repair and cell cycle control. 

Chronic exposure to hepatotoxic doses of DMN has also been found to suppress humoral and cellular immunity in mice. DMN is geno-toxic in a wide variety of assays inducing DNA synthesis, chromosomal aberrations, sister chromatid exchange, and bacterial mutations. " The formation of DNA adducts by metabolites of DMN may play a critical role in the carcinogenic process."... 

TCE carcinogenesis may require exposure to high doses sufficient to cause cellular necrosis. Repeated cycles of necrosis and regeneration would occur with the emergence of hyperplasia and then neoplasia. Low exposures commonly encountered in human studies are not sufficient to initiate the carcinogenic process. 

Already in 1982, it was suggested that the intermediate chromium(V) state is involved in the carcinogenic process.9 Reactive Cr(V) and Cr(IV) intermediates may be harmful in many ways acting as tyrosine phosphatase inhibitors, or by forming organic radicals upon reaction with cellular reductants, which in turn can react with O2 and lead to reactive oxygen species.10 Reaction of chromium(VI) with... 

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