Dose Chemical Carcinogenesis

Let me tell you something big Give importance to little things  

In the mid-1950s, in response to the burgeoning food additive market and the justifiable concerns that came along with it. New 

Alan S. Kolok, Modem Poisons-. A Brief Introduction to Contemporary Toxicology, DOI 10.5822/ 978-1-61091-609-7J4, 2016 Alan S. Kolok. 

York congressman Jim Delaney initiated a two-year investigation into the use of chemicals in food. The culmination of that investigation was the Delaney Committee Report. The report documented that food additives, in both the number of chemicals and the sheer volume used, were mushrooming. Further, the report noted that of the 704 chemicals used as food additives at the time, only slightly more than half (428) had been appropriately determined safe for consumption, and therefore the risk to the public was unknown and uncertain—which certainly did nothing to allay the concerns of the casual report reader. 

The Delaney Clause generated criticism almost immediately, as it brought a non-quantitative standard to a quantitative issue. At the time of the clause s adoption, only four substances were known to be carcinogenic soot, radiation, tobacco smoke, and p-naphthylamine. Two developments occurred over the next twenty years that brought the problem with the Delaney Clause to the forefront. The first was a dramatic increase in food safety testing. To make a quantitative decision regarding the potential carcinogenicity 

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It is natural to consider one or another of these trans-species dose prescriptions for scaling dose-response relationships in carcinogenesis. But in any chronic effect, such as carcinogenesis, another parameter enters namely, time. Whereas the LDjo describes the acutely toxic properties of a chemical, the relevant dose for carcinogenesis is usually accumulated over a long time. One must consider, therefore, the relationship between daily dose, total lifetime dose, and body weight. The difference in life spans between man and mouse—70 years versus 2 years—amounts to a factor 35. Most analyses, however, consider that it is the daily dose that is more relevant, and that the shorter lifetime of the mouse represents the effects of its higher metabolic rate. The difference between these various interspecies dose conversion schemes is illustrated in Thble 8.1. 

Analysis of dose-incidence relationships for chemical carcinogenesis is further complicated by the fact that the dose of a chemical at its biological site of action depends on a number of metabolic and pharmacokinetic factors which can vary with route of exposure, age,... 

Also access to the target may be a factor. For example, DNA repair seems to be very important in some cases of chemical carcinogenesis and will contribute to the presence of a dose threshold. 

Lutz WK. 1998. Dose-response relationships in chemical carcinogenesis superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes. Mutat. Res. 405 117-24... 

Lutz WK. 2000. A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action. Hum. Exp. Toxicol. 19 566-68... 

Lutz WK. 2001. Susceptibility differences in chemical carcinogenesis linearize the dose-response relationship threshold doses can be defined only for individuals. Mutat. Res. 482 71-76... 

The first benchmark study of dose-response relationships in chemical carcinogenesis was reported by Druckrey (1943) with 4-dimethylaminoazobenzene (4-DAB), also known as butter yellow, in BDIII rats. Within the range of daily dosages from 3 to 30 mg per rat, the time up to the appearance of liver cancer (T) was found to be inversely proportional to the daily dose d). The product of the... 

Lutz, W. K. (1990). Dose-reponse relationship and low dose extrapolation in chemical carcinogenesis. Carcinogenesis 11(8), 1243-1247. 

SCHMAHL, D. (1979) Problems of dose-response studies in chemical carcinogenesis with special reference to N-nitroso compounds. CRC Crit. Rev. Toxicol., 6, 257. 

As to the debate on the use of estimated MTD in chronic toxicity/carcinogenicity studies, recent information may be found in two letters by Abel son (26) and McConnell (27). Abel son suggests that the public has been misinformed through "a media barrage" by the results of chemical carcinogenesis studies in animals, particularly in rodents (26). One of the criticisms from Abelson was the use of "massive doses" (i.e., MTD) which, in his opinion, "vastly exceed those to which humans are likely to be exposed" (26). McConnell... 

Kopp and Portier, 1989) for determining this probability from these types of models. It remains for us to consider how exposure to a chemical carcinogen might alter this time-course. Several mechanisms have been proposed for chemical carcinogenesis which we will consider in the context of this model, emphasizing the Implications of the assumed mechanism on the slope of the dose-response curve at dose zero (i.e. low-dose linear mechanisms vs low-dose non-linear mechanisms). 

The mechanism of chemical carcinogenesis involves a complex multistage process that occurs in certain distinct phases. While genotoxic carcinogens manifest their actions in three phases (1) initiation, (2) promotion, and (3) progression, the mechanisms for nongenotoxic carcinogen can vary and are more complex. The routes of exposure, dose amount, absorption, and distribution of the chemical within the body as well as the nature of the metabolic products, play important roles in the process. 

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