Carcinogenicity predictors

The use of two species in carcinogenicity studies is based on the traditional wisdom that no single species can be considered an adequate predictor of carcinogenic effects in humans. Absence of carcinogenic activity in two different species is thought to provide a greater level of confidence that a compound is safe for humans than data derived from a single species. 

One may question this reasoning on the basis that data from two poor predictors may not be significantly better than data from a single species. It is also reasonable to expect that the ability of one rodent species to predict a carcinogenic effect in a second rodent species should be at least equal to, if not better than, its ability to predict carcinogenicity in humans. The concordance... 

No. The FDA went too far. Aflatoxins can indeed cause liver toxicity in animals and are also carcinogenic. But they produce these adverse effects only at levels far above the FDA set limit. We should ensure some safety margin to protect humans, but 20 ppb is unnecessarily low and the policy that there is no safe level is not supported by scientific studies. Indeed, it s not even certain that aflatoxins represent a cancer risk to humans because animal testing is not known to be a reliable predictor of human risk. Moreover, the carcinogenic potency of aflatoxins varies greatly even among the several animal species in which they have been tested. Human evidence that aflatoxins cause cancer is unsubstantiated. There is no sound scientific basis for the FDA s position. 

The results from a study employing a human cell line showed that neither 5 nor 50 ppm petroleum-derived JP-5 (PD-JP5) interfered with Snyder-Theilen feline sarcoma virus (ST-FeSV)-directed transformation of human foreskin fibroblastic cells (Blakeslee et al. 1983). Higher concentrations ( 100 ppm) were cytotoxic. It was reported that marine diesel fuel failed to inhibit transformation in this assay, but data were not shown. The study authors consider this in vitro assay to be a useful predictor of carcinogenesis since several known carcinogens have been shown to suppress transformation in cells infected with the ST-FeSV virus by blocking a specific virus gene function (i.e., transformation) noncarcinogens do not inhibit virus-induced cell transformation in this test system. 

Sina, J.F., Bean, C.L., Dysart, G.R., Taylor, V.I. Bradley, M.O. (1983) Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat. Res., 113, 347-391... 

ETAD Information No.7, Significance of the Bacterial Reverse Mutation Test as Predictor for Rodent and Human Carcinogenity, Basle, 1998. 

This package from SimulationsPlus allows prediction of many of the same toxicity endpoints available in TOPKAT but employs different modeling methodology. In addition, QSTRs for estrogen receptor modulation, maximum recommended therapeutic dose, carcinogenic potency, and cardiotoxicity (hERG-encoded K+ channel affinity) are available in ADMET Predictor (,http //www.simulationsplus.com/index.html). 

Chemistry-based toxicity also involves exposure response, individual variability, and altered clearance. However, the proximal toxicant is typically a reactive chemical species. Several current systems are used for this purpose, such as mutagenicity (see Chapter 14) and carcinogenicity software programs, fragment-based chemistry and biology predictors, adduct determinations, and metabolite predictors. 

Poth A, Kunz S, Heppenheimer A (2007) Bhas cell transformation assay as a predictor of carcinogenicity. ALTEX 14 519-521... 

Even if there were no such limitations, epidemiologic analysis is retrospective study it cannot be depended upon for the detection and prevention of potential health hazards to the public. In comparison to epidemiologic studies, animal bioassays are short in duration, relatively inexpensive, easily perfomed under controlled conditions, and are reliable predictors for known human carcinogens. Therefore, from the point of view of identifying and preventing public health hazards, animal bioassay is an invaluable tool. 

A group of about 10 participants discussed the "battery of acceptable tests to be used in the genotoxic evaluation of a new chemical/pesticide. Considerable concern was expressed about reliability and reproducibility of various test systems and reasons for these concerns were addressed. The test methods (assays) chosen should minimize variability. It was generally agreed that good predictors of carcinogenicity are currently available in the battery of mutagenicity assays. 

---