Characterizing interspecies uncertainty using data from studies of anti-neoplastic agents in animals and humans.

For most chemicals, the Reference Dose (RfD) is based on data from animal testing. The uncertainty introduced by the use of animal models has been termed interspecies uncertainty. The magnitude of the differences between the toxicity of a chemical in humans and test animals and its uncertainty can be investigated by evaluating the inter-chemical variation in the ratios of the doses associated with similar toxicological endpoints in test animals and humans. This study performs such an evaluation on a data set of 64 anti-neoplastic drugs. The data set provides matched responses in humans and four species of test animals: mice, rats, monkeys, and dogs. While the data have a number of limitations, the data show that when the drugs are evaluated on a body weight basis: 1) toxicity generally increases with a species' body weight; however, humans are not always more sensitive than test animals; 2) the animal to human dose ratios were less than 10 for most, but not all, drugs; 3) the current practice of using data from multiple species when setting RfDs lowers the probability of having a large value for the ratio. These findings provide insight into inter-chemical variation in animal to human extrapolations and suggest the need for additional collection and analysis of matched toxicity data in humans and test animals.

Relative cancer potencies of selected dioxin-like compounds on a body-burden basis: comparison to current toxic equivalency factors (TEFs).

Recent National Toxicology Program (NTP) cancer bioassay data for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and a mixture of these three compounds offer opportunities to assess the accuracy of current World Health Organization (WHO) 1998 toxic equivalency factors (TEFs) for these compounds under a variety of assumptions. An evaluation of the current TEF values for these compounds using body burden in nanograms per kilogram as the dose metric is presented. Average lifetime body burdens were estimated for all compounds at all dose groups based on measured tissue concentrations at 4 time points during the 2-yr NTP studies. Poly-3 adjusted tumor incidences for hepatocellular adenomas, cholangiocarcinomas, and the two tumors combined were modeled using a quantal multistage model and the Hill model with lifetime average body burden as the dose metric. Benchmark doses for a 10% response (BMD10) for each compound and the mixture were estimated. With TCDD as the reference standard, relative potency (REP) estimates were derived from ratios of the BMD10 estimates for PCB 126, 4-PeCDF, and for the toxic equivalent (TEQ) mixture. On a body-burden basis, PCB 126 and 4-PeCDF were 2- to 3-fold and 10- to 12-fold less potent than predicted based on the WHO TEFs, respectively, while the TEQ mixture was approximately 3- to 5-fold less potent than predicted by the TEFs. The current WHO TEF values, which were derived from data on noncancer endpoints evaluated on an administered dose basis, overpredict the carcinogenic potency of these compounds on a body-burden basis compared to TCDD.