In his letter, Predicting chemicals causing cancer in animals as human carcinogens (Occup Environ Med 2010;67:720), Huff surprisingly finds opportunity to promote long-term carcinogenesis bioassays using animals in response to an editorial by Suarthana et al. (Occup Environ Med 2009;66:713e14), Predicting occupational diseases. In their editorial, Suarthana et al. generalize from the development of diagnostic models to predict sensitisation to occupational allergens. Suarthana et al. mention no animal studies and conclude that “[t]here is now an opportunity to develop prediction models for diverse occupational diseases, especially given the existing large epidemiological studies (emphasis added).”

In particular, Huff asserts that “findings from independently conducted bioassays on the same chemicals are consistent, albeit sometimes with additional or different target sites[.]” In fact, a comparison of 121 bioassays from the U.S. National Toxicology Program (NTP) database with those in the published scientific literature found that the studies produced consistent results only 57 percent of the time [1].

Huff also claims that “less than10% of all chemicals if evaluated in bioassays would be predicted to be carcinogenic.” In our analysis of more than 500 NTP bioassays, we show that 259 of the substances evaluated produced evidence of carcinogenicity in at least one group of animals. However, only 89 of these were subsequently classified as known or probable human carcinogens by NTP itself [2]. Even fewer, 40 and 16 respectively, were so classified by the U.S. Environmental Protection Agency and the International Agency for Research on Cancer. This high false positive rate is thought to be largely an indirect effect of increased cell proliferation in response to cell injury and death caused by the near toxic doses of test substances used in the bioassay [3]. Huff also observes that there are more similarities than differences between rodents and humans. However, species-specific modes of action operating in rats or mice but not in humans, including those mediated by α2μ-globulin, peroxisomes, and thyroid-stimulating hormone, also contribute to the high rate of false positives [4].

We must also stress the suffering that animals endure in the bioassay. Not only must they live in the barren, stressful conditions of the laboratory – often including daily forced feeding or forced inhalation – but many will also suffer from exposure to near toxic doses of test substances. This exposure is normally expected to produce lethargy, anemia, diarrhea, weight loss, and other symptoms of sickness and distress.

According to NTP’s own estimates, each bioassay requires killing 860 animals, $2-4 million and five years to plan, conduct, and evaluate. As a result, NTP has conducted an average of only 12 bioassays per year over the past several decades. Considering that humans are potentially exposed to as many as 80,000 environmental chemicals, more than 32 thousand years, 68 million animals, and $160 billion would be required to test them all at this rate.

The time has clearly come for antiquated animal tests like the bioassay to be abandoned in favor of modern, human-relevant methods such as the epidemiological studies recommended in Suarthana et al’s editorial, high-throughput in vitro methods, and computational toxicology.

Joseph Manuppello

[1] Gottmann E, Kramer S, Pfahringer B, et al. Data quality in predictive toxicology: reproducibility of rodent carcinogenicity experiments. Environ Health Perspect 2001;109:509-14.

[2] PETA. Wasted money, wasted lives: A layperson’s guide to the problems with rodent cancer studies and the National Toxicology Program. Norfolk, VA: People for the Ethical Treatment of Animals. 2006. http://www.mediapeta.com/peta/pdf/Wasted-money PDF.pdf (accessed 17 Sept 2010).

[3] Gaylor DW. Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens? Regul Toxicol Pharmacol 2005;41:128-33.

[4] Cohen SM. Human carcinogenic risk evaluation: an alternative
approach to the two-year rodent bioassay. Toxicol Sci 2004;80:225-9.

Conflict of Interest: The author is employed by People for the Ethical Treatment of Animals.