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Chemical Carcinogenesis: Too Many Rodent Carcinogens* (Tumor Promotion/Mutagenesis/Mitogenesis/Anlmal Cancer Tests) BRUCE N

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Chemical Carcinogenesis: Too Many Rodent Carcinogens* (Tumor Promotion/Mutagenesis/Mitogenesis/Anlmal Cancer Tests) BRUCE N Proc. Nati. Acad. Sci. USA Vol. 87, pp. 7772-7776, October 1990 Medical Sciences Chemical carcinogenesis: Too many rodent carcinogens* (tumor promotion/mutagenesis/mitogenesis/anlmal cancer tests) BRUCE N. AMEStt AND Lois SWIRSKY GOLDt§ tDivision of Biochemistry and Molecular Biology, Barker Hall, University of California, Berkeley, CA 94720; and §Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, Berkeley, CA 94720 Contributed by Bruce N. Ames, July 19, 1990 ABSTRACT The administration of chemicals at the max- carcinogenic effects at low levels. This idea evolved because imum tolerated dose (MTD) in standard animal cancer tests is it was expected that (i) only a small proportion of chemicals postulated to increase cell division (mitogenesis), which in turn would have carcinogenic potential, (ii) testing at a high dose increases rates of mutagenesis and thus carcinogenesis. The would not produce a carcinogenic effect unique to the high animal data are consistent with this mechanism, because a high dose, and (iii) chemical carcinogenesis would be explained by proportion-about half-of all chemicals tested (whether nat- the mutagenic potential ofchemicals. However, it seems time ural or synthetic) are indeed rodent carcinogens. We conclude to take account of new information suggesting that all three that at the low doses of most human exposures, where cell assumptions are wrong. killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. Carcinogens Are Common in Rodent Tests More than halfof the chemicals tested to date in both rats and In current strategies to prevent human cancer, chronic rodent mice have been found to be carcinogens in chronic rodent bioassays are the major source of information used to predict bioassays at the high doses administered, the MTD (1-7). the risk to humans from chemical exposures. This paper Synthetic industrial chemicals account for 350 (82%) of the addresses the issue of the role of cell division (mitogenesis) 427 chemicals tested in both species; about half (212/350) in animal cancer tests and the implications of an improved were classified as rodent carcinogens (1-7). Even though the theory ofmechanisms ofcarcinogenesis for the assessment of overwhelming weight and number of the chemicals humans cancer hazards to the general population. In animal tests eat are natural, only 77 natural chemicals have been tested in done at the maximum tolerated dose (MTD), about halfofthe both rats and mice; again about half (37/77) are rodent chemicals tested are rodent carcinogens (1-7). We argue that carcinogens (1-6). The high proportion ofpositives is not due the explanation for a high percentage of chemicals being simply to selection of suspicious chemical structures. While carcinogens at the MTD is that these high doses stimulate some synthetic or natural chemicals were selected for testing mitogenesis, which increases rates of mutagenesis and car- precisely because of structure or mutagenicity, most were cinogenesis. While chemicals selected for testing are primar- selected because they were widely used industrially-e.g., ily synthetic industrial compounds, the high positivity rate they were high-volume chemicals, pesticides, food additives, does not imply that synthetic chemicals are more likely to dyes, or drugs (2). The natural world of chemicals has never induce tumors in rodents than naturally occurring chemicals. been looked at systematically. We explain below why the [The chemicals in the human diet are nearly all natural (8).] developing understanding of the mechanisms of carcinogen- To the extent that increases in tumor incidence in rodent esis justifies the prediction that a high proportion of all studies are due to the secondary effects of administering high chemicals, natural and synthetic, will prove to be carcino- doses, then any chemical that increases mitogenesis (e.g., by genic to rodents iftested at the MTD. How to select the MTD cell killing) is a likely rodent carcinogen. The correct analysis is a process that has been changing (9-11). to determine the proportion of rodent carcinogens among A chemical is classified as to carcinogenicity in our anal- chemicals would require a comparison of a random group of ysis based on the author's positive evaluation in at least one synthetic chemicals with a random group of natural chemi- adequate experiment (3-6) using the criteria given in ref. 8. cals. This analysis has not been done. We have examined the Rodent carcinogens clearly are not all the same: some have available results from the limited number ofnatural chemicals been tested many times in several strains and species and tested and have found that about half are rodent carcinogens, others in only one experiment; some (e.g., safrole) are just as for the synthetic chemicals (8). positive in two species and they or their metabolites are The high proportion of carcinogens among chemicals genotoxic in animals; some (e.g., D-limonene) are only pos- tested at the MTD emphasizes the importance ofunderstand- itive at one site in one species and are not genotoxic. ing cancer mechanisms in order to determine the relevance of rodent cancer test results for humans. A list of rodent Mechanism of Carcinogenesis carcinogens is not enough. The main rule in toxicology is that "the dose makes the poison": at some level, every chemical It is prudent to assume that if a chemical is a carcinogen in becomes toxic, but there are safe levels below that. How- rats and mice at the MTD, it may well be a carcinogen in ever, the precedent ofradiation, which is both a mutagen and humans at doses close to the MTD. However, understanding a carcinogen, gave credence to the idea that there could be the mechanism of carcinogenesis is critical to the attempt to effects ofchemicals even at low doses. A scientific consensus predict risk to humans at low doses that are often hundreds evolved in the 1970s that we should treat carcinogens differ- of thousands of times below the dose at which an effect is ently, that we should assume that even low doses might cause observed in rodents. There are two major problems. (i) cancer, even though we lacked the methods for measuring Within rodents, how can measurable carcinogenic effects at The publication costs of this article were defrayed in part by page charge Abbreviation: MTD, maximum tolerated dose. payment. This article must therefore be hereby marked "advertisement" *This is paper no. 1 of a series. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 7772 Downloaded by guest on September 23, 2021 Medical Sciences: Ames and Gold Proc. Natl. Acad. Sci. USA 87 (1990) 7773 dose rates near the MTD (i.e., at doses that may cause replication. Endogenous or exogenous damage is therefore significant cell killing and mitogenesis) be used to estimate generally increased if cells are proliferating. the effects in rodents of dose rates so much lower that they (ii) During cell division, single-stranded DNA is without will cause little or no cell killing or, at any rate, will cause an base-pairing or histones and is thus more sensitive to damage amount that is well within the "normal" range of cell death than double-stranded DNA. and replacement? (ii) Between species, how can carcinogenic (iii) Cell division triggers mitotic recombination, gene effects in a short-lived species such as the rat or mouse be conversion, and nondisjunction, which together seem orders used to estimate effects in a long-lived species such as the of magnitude more effective than an independent second human? Cancer increases with about the fourth or fifth power mutation (28-32) in converting a heterozygous recessive gene of age in both short-lived rats and long-lived humans (12-15). (e.g., a tumor-suppressor gene) to homo- or hemizygosity. In order to achieve a long life-span, humans have evolved Heterozygotes at the human HLA-A gene are spontaneously many types of defenses that collectively ensure that they are converted to homozygotes during cell division (33). The orders of magnitude more resistant to spontaneous cancer at above mechanisms could account for gross chromosomal a particular age than rats (12-15). Thus, in both types of alterations that occur frequently in human tumors (34-40). extrapolation there may be systematic factors that make the (iv) Cell division allows gene duplication, which can in- carcinogenic effects vastly less in humans than would be crease expression of oncogenes that are otherwise weakly expected from simple extrapolation-so much so, indeed, expressed (41). that no quantitative extrapolation is likely to be possible in (v) Cell division can increase the expression ofthe myc and the near future from studies at or near the MTD in laboratory fos oncogenes (42). animals to the effects of low dose rates in humans (12, 13). (vi) Cell division allows 5-methyl-cytosine in DNA to be The Role of Mitogenesis. The study of the mechanisms of lost, which can result in dedifferentiation (43, 44), thus often carcinogenesis is a rapidly developing field that can improve causing further mitogenesis. regulatory policy. Both DNA damage and mitogenesis are In support of high "spontaneous" mutation rates in divid- important aspects of carcinogenesis, and increasing either ing cells is the observation that background hypoxanthine substantially can cause cancer (1, 16-21). phosphoribosyltransferase mutations that arise in vivo in Endogenous rates ofDNA damage are enormous. Muta- human T lymphocytes arise preferentially in dividing T cells gens are often thought to be only exogenous agents, but (45-48). The well-known mitotic instability oftumors (tumor endogenous mutagens cause massive DNA damage (oxida- progression) might be explained by the fact that cells in some tive and other adducts) that can be converted to mutations tumors are proliferating constantly.
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