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Chemical carcinogenesis : Too many rodent carcinogens * ( tumor promotion / mutagenesis / mitogenesis / anlmal cancer tests )
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dt, Lois Swirsky G. O. L. |
| Abstract | The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion-about half-of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. carcinogenic effects at low levels. This idea evolved because it was expected that (i) only a small proportion of chemicals would have carcinogenic potential, (ii) testing at a high dose would not produce a carcinogenic effect unique to the high dose, and (iii) chemical carcinogenesis would be explained by the mutagenic potential of chemicals. However, it seems time to take account of new information suggesting that all three assumptions are wrong. Carcinogens Are Common in Rodent Tests In current strategies to prevent human cancer, chronic rodent bioassays are the major source of information used to predict the risk to humans from chemical exposures. This paper addresses the issue of the role of cell division (mitogenesis) in animal cancer tests and the implications of an improved theory ofmechanisms of carcinogenesis for the assessment of cancer hazards to the general population. In animal tests done at the maximum tolerated dose (MTD), about half of the chemicals tested are rodent carcinogens (1-7). We argue that the explanation for a high percentage of chemicals being carcinogens at the MTD is that these high doses stimulate mitogenesis, which increases rates of mutagenesis and carcinogenesis. While chemicals selected for testing are primarily synthetic industrial compounds, the high positivity rate does not imply that synthetic chemicals are more likely to induce tumors in rodents than naturally occurring chemicals. [The chemicals in the human diet are nearly all natural (8).] To the extent that increases in tumor incidence in rodent studies are due to the secondary effects of administering high doses, then any chemical that increases mitogenesis (e.g., by cell killing) is a likely rodent carcinogen. The correct analysis to determine the proportion of rodent carcinogens among chemicals would require a comparison of a random group of synthetic chemicals with a random group of natural chemicals. This analysis has not been done. We have examined the available results from the limited number of natural chemicals tested and have found that about half are rodent carcinogens, just as for the synthetic chemicals (8). The high proportion of carcinogens among chemicals tested at the MTD emphasizes the importance of understanding cancer mechanisms in order to determine the relevance of rodent cancer test results for humans. A list of rodent carcinogens is not enough. The main rule in toxicology is that "the dose makes the poison": at some level, every chemical becomes toxic, but there are safe levels below that. However, the precedent of radiation, which is both a mutagen and a carcinogen, gave credence to the idea that there could be effects ofchemicals even at low doses. A scientific consensus evolved in the 1970s that we should treat carcinogens differently, that we should assume that even low doses might cause cancer, even though we lacked the methods for measuring More than half of the chemicals tested to date in both rats and mice have been found to be carcinogens in chronic rodent bioassays at the high doses administered, the MTD (1-7). Synthetic industrial chemicals account for 350 (82%) of the 427 chemicals tested in both species; about half (212/350) were classified as rodent carcinogens (1-7). Even though the overwhelming weight and number of the chemicals humans eat are natural, only 77 natural chemicals have been tested in both rats and mice; again about half (37/77) are rodent carcinogens (1-6). The high proportion of positives is not due simply to selection of suspicious chemical structures. While some synthetic or natural chemicals were selected for testing precisely because of structure or mutagenicity, most were selected because they were widely used industrially-e.g., they were high-volume chemicals, pesticides, food additives, dyes, or drugs (2). The natural world of chemicals has never been looked at systematically. We explain below why the developing understanding of the mechanisms of carcinogenesis justifies the prediction that a high proportion of all chemicals, natural and synthetic, will prove to be carcinogenic to rodents if tested at the MTD. How to select the MTD is a process that has been changing (9-11). A chemical is classified as to carcinogenicity in our analysis based on the author's positive evaluation in at least one adequate experiment (3-6) using the criteria given in ref. 8. Rodent carcinogens clearly are not all the same: some have been tested many times in several strains and species and others in only one experiment; some (e.g., safrole) are positive in two species and they or their metabolites are genotoxic in animals; some (e.g., D-limonene) are only positive at one site in one species and are not genotoxic. Mechanism of Carcinogenesis It is prudent to assume that if a chemical is a carcinogen in rats and mice at the MTD, it may well be a carcinogen in humans at doses close to the MTD. However, understanding the mechanism of carcinogenesis is critical to the attempt to predict risk to humans at low doses that are often hundreds of thousands of times below the dose at which an effect is observed in rodents. There are two major problems. (i) Within rodents, how can measurable carcinogenic effects at Abbreviation: MTD, maximum tolerated dose. *This is paper no. 1 of a series. tTo whom reprint requests should be addressed. 7772 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. ยง1734 solely to indicate this fact. Proc. Natl. Acad. Sci. USA 87 (1990) 7773 dose rates near the MTD (i.e., at doses that may cause significant cell killing and mitogenesis) be used to estimate the effects in rodents of dose rates so much lower that they will cause little or no cell killing or, at any rate, will cause an amount that is well within the "normal" range of cell death and replacement? (ii) Between species, how can carcinogenic effects in a short-lived species such as the rat or mouse be used to estimate effects in a long-lived species such as the human? Cancer increases with about the fourth or fifth power of age in both short-lived rats and long-lived humans (12-15). In order to achieve a long life-span, humans have evolved many types of defenses that collectively ensure that they are orders of magnitude more resistant to spontaneous cancer at a particular age than rats (12-15). Thus, in both types of extrapolation there may be systematic factors that make the carcinogenic effects vastly less in humans than would be expected from simple extrapolation-so much so, indeed, that no quantitative extrapolation is likely to be possible in the near future from studies at or near the MTD in laboratory animals to the effects of low dose rates in humans (12, 13). The Role of Mitogenesis. The study of the mechanisms of carcinogenesis is a rapidly developing field that can improve regulatory policy. Both DNA damage and mitogenesis are important aspects of carcinogenesis, and increasing either substantially can cause cancer (1, 16-21). Endogenous rates ofDNA damage are enormous. Mutagens are often thought to be only exogenous agents, but endogenous mutagens cause massive DNA damage (oxidative and other adducts) that can be converted to mutations during cell division. We estimate that the DNA hits per cell per day from endogenous oxidants are normally -105 in the rat and -104 in the human (15, 22, 23). These oxidative adducts are effectively but not perfectly repaired; the normal steady-state level of just 8-hydroxydeoxyguanosine (1 of about 20 known oxidative DNA adducts) in ratDNA has been measured as 1/130,000 bases or about 90,000 per cell (22, 24). We have argued that this oxidative DNA damage is a major contributor to aging and the degenerative diseases associated with aging such as cancer. Thus, any agent causing chronic mitogenesis can be indirectly mutagenic (and consequently carcinogenic) because it increases the probability of endogenous promutagenic DNA adducts being converted to mutations (Fig. 1). Furthermore, endogenous rates of DNA damage are so high that it may be difficult for exogenous mutagens to increase the total DNA damage significantly by low doses that do not increase mitogenesis. Mitogenesis is itselfmutagenic in numerous ways (Fig. 1). (i) A dividing cell is much more at risk for mutation than a quiescent cell (27). Cell division allows adducts to convert to mutations. The time interval for DNA repair during cell division is short, and adducts are converted to gaps during |
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