Tumorigenic Dose

EXAMPLE 22.1. Use of a Trend Text to Assess Tumorigenic Dose Response... 

In order to express the carcinogenic response or potency, a dose descriptor is used, for example the Tumorigenic Dose (TD). The TD is often set at a defined incidence, for example 5%, the TD5, defined as the dose (or concentration) associated with a 5% incidence of mmors. The dose descriptor can serve as the basis for development of an Exposure/Potency Index (EPl), which is the estimated daily human exposure divided by the TD. A calculated EPl of 10 for the TD5 represents a one million-fold difference between the human exposure and that at the lower end of the dose-response curve, on which the estimate of potency is based. 

The T25 value may either be incidentally obtained from the experimental smdy or calculated from other mmor incidences at the selected tumorigenic dose (determined above), using linear extrapolation, i.e., by multiphcahon of the dose with the factor 25/p where p is the acmal mmor incidence (e.g., in case of a net 15% incidence, multiply by 25/15). 

In mice, the tumorigenic dose of benzo[a]pyrene is dependent on the strain. For example. Habs et al. (1980) tested 1.7-4.6 pg benzo[a]pyrene (0.016-0.04 mg/kg/day) in order to determine its dose-response relationship as a carcinogen when topically applied to the backs of NMRI mice throughout their lifetimes. A clear-cut dose-response relationship was seen for benzo[a]pyrene and the induction of tumors. The lowest dose at which skin tumors appeared was 1.7 pg (0.016 mg/kg/day). This strain of NMRI mice also has a high (70%) background incidence rate of systemic tumors, so an evaluation of the effects of benzo[a]pyrene on any organ other than the site of administration was not possible. 

Total tumorigenic dose (in mg/kg body weight) in parentheses, calculated on the basis of an average daily food intake of lOOg/kg body weight. 

Tanaka, K., Smith, P. R, Stromberg, P. C., EydeHoth, R. S., Herold, E. G., Grossman, S. J., Frank, J. D., Hertzog, P. R., Soper, K. A., and Keenan, K. P. (1992). Studies of early hepatocellular proliferation and peroxisomal proliferation in Sprague-Dawley rats treated with tumorigenic doses of clohbrate. Toxicol Appl Pharmacol 116, 71-77. 

In another study, sub-tumorigenic doses of UV light foUowing a single application of 7,12-dimethylbenzan-thracene (DMBA) produced an increased number of malignant tumors in mice (Epstein and Epstein 1962 Adams 1990). 

Safety. Magnesium oxide (fume) has a permissible exposure limit (PEL) (134) (8 hours, TWA), of 10 mg/m total dust and 5 mg/m respirable fraction. Tumorigenic data (intravenous in hamsters) show a TD q of 480 mg/kg after 30 weeks of intermittent dosing (135), and toxicity effects data show a TC q of 400 mg/m for inhalation in humans (136). Magnesium oxide is compatible with most chemicals exceptions are strong acids, bromine pentafluoride, chlorine trifluoride, interhalogens, strong oxidizers, and phosphorous pentachloride. 

Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 

RTECS Registry of Toxic Effects of Chemical Substances number is a unique and unchanging number used to cross-reference the RTECS database, which is a compendium of data extracted from the open scientific literature. Six types of toxicity data are included in each file (1) primary irritation, (2) mutagenic effects, (3) reproductive effects, (4) tumorigenic effects, (5) acute toxicity, and (6) other multiple dose toxicity. 

D-Phenothrin (I) Not likely to be carcinogenic to humans. Rat liver tumors occurred only at excessively toxic doses (limit dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical significance (p < 0.01). Additionally, acceptable mutagenicity studies were negative for mutagenic potential [97] No tumorigenicity was observed [11]. 

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