Critique of Carcinogenicity/Oncogenicity Studies in Mice and Rats Performed at Huntingdon Life Sciences

Murry J. Cohen, M.D.; Stephen R. Kaufman, M.D.; and Jerry Vlasak, M.D.
September 2001

Two research teams from Huntingdon Life Sciences have been investigating the carcinogenicity/oncogenicity of various chemicals in nonhuman animals in order to predict the potential effects of these chemicals in humans. One research team measured the carcinogenicity of sucralose in rats[1] and mice,[2] and a second research team measured the oncogenicity of tributyl phosphate in rats.[3] These studies are invalidated by the standard criticisms of toxicity emperiments on nonhuman animals.

It is never possible to extrapolate animal findings to humans with confidence. To do so, it is necessary to know, in addition to the animal data, results of human studies. However, with knowledge of human data, the animal data are unnecessary (and possibly misleading). What may be carcinogenic in animals may not be so in humans, and vice-versa. In a National Cancer Institute study, onlt 7 of 19 known human carcinogens caused cancer in rodents given high doses over their lifetimes, using the Standard National Cancer Institute Protocol.[4]

A well-known toxicology test reads, "All known chemical carcinogens in man, with the possible exception of arsenic, are carcinogenic in some species but not in all laboratory animals,"[5] John Leavitt of the Linus Pauling Institute has written of severe drawbacks using animals to understand human cancer.[6] Science editor Philip Abelson has asked, "Are humans to be regarded as behaving biochemically like huge, obese, inbred, cancer-prone rodents?"[7] An editorial in Clinical Oncology states "Occasionally, individuals have had the temerity to ask why so much effort is devoted to the study of animal tumors rather than the readily available, but emotionally disturbing, human problems. It is in fact hard to find a single common solid human neoplas where management and expectation of cure have been markedly influenced by the results of laboratory research. Most human cancers behave differently from the artificially produced animal model and…many clinicians must wonder why so little attention appears to be paid to the human condition."[8] An Office of Tedchnology Assessment report on the causes of cancer attached more weight to epidemiologic data than to animal experiments because its authors argued that animal tests "cannot provide reliable risk assessments."[9] It is not surprising, that, in general, animal tests of carcinogenesis have proved inconsistent.[10]

While the shorter life spans of mice may be very convenient for researchers, this is hardly a benefit when results from a species requiring 45 days to grow from birth to adulthood are applied to humans, who require more than 6500 days to reach adulthood. This is especially troubling when considering prenatal exposure to drugs. Mice have a gestational period of only 20 days, while in humans it typically runs about 270 days, a disparity that can contribute to the dramatic differences in developmental toxicity of drugs between species tested and humans.

In general, tumors prevalent in rodents, such as pituitary, liver, and thyroid tumors, are uncommon in humans, whereas tumors common in humans, such as those of the prostate, colon, and rectum, are rare in rodents.[11] The usage of mice for carcinogenicity testing is problematic because the species has a high spontaneous incidence of tumors. Additionally, mouse mammary, lymphomatous, hepatic, and pulmonary tumors are questionable as legitimate sources of data from which to understand human cancer.[12], [13] Liver and lung tumors, in particular, are difficult because "their malignancy is often difficult to establish."[14] One research group concluded that induction of liver cancer in mice by the pesticide dieldrin-aldrin did not predict human risk.[15] Also mice produce tumors in response to substances (i.e., organochlorine pesticides)[16] that do not cause cancer in rats.

When the carcinogenicity of 214 chemicals were compared in rats and mice, the correlation between the two species was only 70 percent.[17] Likewise, only 130 of 226 chemicals (58%) shown to be carcinogenic in either rats or mice were so in both species.[18] Liver tumor can be induced in a mouse without parallel tumor induction in a rat or hamster.[19] Benzidine causes bladder tumors in humans, liver tumors in hamsters, and acoustic tumors in rats.[20] Griseofulvin causes tumors in mice, but not in humans.[21] (sic) In long-term carcinogenicity tests, rodents develop cancers from compounds given in extremely high doses that pose no appreciable risk to humans under typical exposure conditions because these doses cause artificial tissue irritation and cell profliferation.[22]

The latter was the case in toxicity studies testing the carcinogenicity of saccharin in rats. Rats were given the equivalent of 1,100 cans of saccharin-containing soda, which caused bladder cancer in some of the animals.[22] Extrapolating the data to humans was complicated by the observation that saccharin-induced bladder cancers occurred only in male rats because they possess a protein in greater quantity than female rats (and lacking in humans) that interacted with saccharin to form irritating crystals that caused cancer in the male rats' bladders. The fact that some rats developed cancers did not clarify whether or not saccharin caused cancer in humans. On the contrary, it led to an unnecessary saccharin scare, for it turned out that saccharin does not cause cancer in humans. Likewise, animals (sic) tests may screen out useful drugs, such as the injectable contraceptive Depo-provera, which was banned in the United States around 1973 because it caused cancer in dogs and baboons. However, in 1993, the FDA lifted the ban on the drug because 20 years of human experience in those countries which did not prohibit its use showed it was not a human carcinogen.[23]

In addition, there are hidden and manifold variables that confound and undermine toxicity data from animals in laboratories. For example, bedding may contain carcinogens. This covert contaminant altered the data in an American study of liver and mammay tumors in mice. A chemical tested on identical strains of mice in the United States and Australia produced a much higher incidence of tumors in the American study because the bedding used contained a carcinogen - shavings from cedar trees.[24] However, absence of bedding frustrates natural desires among mice, and the resulting stress may increase cancer rates. In addition, viral contamination of laboratory mice with LDH-virus - widely distributed in nature - is a common biological contaminant of mice in laboratories and may increase the incidence and growth rates of certain tumors.[25]

It should not be surprising that rat and mouse toxicities differ from human toxicity, given the myriad anatomical, physiological, and pathological differences between rodents and humans. Rodents weigh only a few ounces or pounds. Rats and mice synthesize vitamin C in their bodies; humans do not. Rats have much higher activity of the 5-desaturase enzyme system - a part of the body's machinery for processing fats in the diet - than humans. Rats absorb iron differently than humans. Rat urine contains alpha-2U-globulin, which causes bladder irritation and cancer when exposed to other chemicals; human urine does not. Rats are physiologically unable to vomit toxins. Rats have no gall bladders and digest fats differently from humans. Rats obtain vitamin D by licking their fur.[26], [27], [28]