Carcinogenic dose level

There was no evidence for a subthreshold dose for these carcinogens, since no deviation from linearity was recognizable even at the lowest carcinogenic dose level despite latency periods approaching the average life expectancy of the test species (2.5 years). 

Table 7. Effect of a carcinogenic dose level of lactofen on hepatic parameters in male CD-I mice (adapted from Butler et al. (80))...

At one time benzene was widely used as a solvent This use virtually disappeared when statistical studies revealed an increased incidence of leukemia among workers exposed to atmospheric levels of benzene as low as 1 ppm Toluene has replaced benzene as an inexpensive organic solvent because it has similar solvent properties but has not been determined to be carcinogenic m the cell systems and at the dose levels that benzene is... 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

In the pharmaceutical industry, most carcinogenicity studies have employed at least three dose levels in addition to the controls, but four levels have occasionally been used (PMA, 1988). The use of three or four dose levels satisfies regulatory requirements (Speid et al., 1990) as well as scientific and practical considerations. If a carcinogenic response is observed, information on the nature of the dose-... 

Group comparison tests for proportions notoriously lack power. Trend tests, because of their use of prior information (dose levels) are much more powerful. Also, it is generally believed that the nature of true carcinogenicity (or toxicity for that matter), manifests itself as dose-response. Because of the above facts, evaluation of trend takes precedence over group comparisons. In order to achieve optimal test statistics, many people use ordinal dose levels (0,1,2..., etc.) instead of the true arithmetic dose levels to test for trend. However, such a decision should be made a priori. The following example demonstrates the weakness of homogeneity tests. 

Examples where use of the Log-Rank Test might be appropriate include comparing survival times in carcinogenity bioassay animals which are given a new treatment with those in the control group or comparing times to liver failure for several dose levels of a new NSAID where the animals are treated for 10 weeks or until cured, whichever comes first. 

A mutated cell may reproduce and begin the formation of a carcinogenic mass (tumor), and mutations may occur after acute or chronic exposure. The specific relationship between acute or chronic exposure rate and cancer risk is hotly debated, although current U.S. regulations conservatively adopted the linear no threshold (LNT) model. This model states that risk is linearly proportional to the total dose even at the smallest possible dose levels (risk is associated with all levels of dose no matter how small). An alternate model theorizes that no measurable adverse health effects appear below doses of about 10 to 25 rem (0.1 to 0.25 Sv). Data supporting both models are limited and, to be conservative, levels of exposure should be kept as low as reasonably achievable (ALARA). Victim and emergency responder doses and dose rate may not be easily controlled in the event of a terrorist attack. However, methods to achieve ALARA exposures are described in Chapters 4 and 5. 

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. 

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