Tumorigenicity

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. 

It is not appropriate to generali2e the carcinogenicity of this class of compounds. Nitrofura2one appears to increase the incidence of benign mammary tumors in rats. The tumorigenic activity of fura2ohdone is expressed by an increase in the incidence of spontaneous tumors in both mice and rats. Bioassays of nitrofurantoin in several species of mice and rats failed to reveal any evidence of direct tumorigenic activity. Ovarian tumors have been reported in B C F mice, but these are beheved due to an indirect expression of toxicity (14,15). 

Sulfur dioxide shows some mutagenic effects in microorganisms and fruit flies. Human lymphocyte DNA damage has been observed. It is an equivocal tumorigenic agent by RTECS criteria (183). 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

B. Hunter and co-workers, Coumarin Tumorigenic and Toxic Effects in Prolonged IPietary Administration, Huntingdon Research Centre, personal communication, (1984). 

Tumorigenic mutations occur mainly in three regions involved in DNA binding... 

Figure 9.22 Most tumorigenic mutations of pS3 are found in the regions of the polypeptide chain that are involved in protein-DNA interactions. These regions are loops L2 (green) and L3 (red) and a region called LSH (blue) which comprises part of p strand 9 as well as the C-terminal a helix.

Cho, Y., et al. Crystal structure of a p53 tumor suppres-sor DNA complex understanding tumorigenic mutations. Science 265 346-355, 1994. 

POU regions bind to DNA by two tandemly oriented helix-turn-helix motifs Much remains to be learnt about the function of homeodomains in vivo Understanding tumorigenic mutations The monomeric p53 polypeptide chain is divided in three domains The oligomerization domain forms tetramers The DNA-binding domain of p53 is an antiparallel P barrel... 

N-ras, H-ras, K-ras Signal transduction pathway Inhibition of cell proliferation and colony formation change in morphology, enhanced melanin synthesis decrease of in vivo tumorigenicity... 

Lebeaus, J., Le, C.C., Prosper , M.T., Goubin, G. (1991). Constitutive overexpression of a 89 kD heat shock protein gene in the HBLIOO human mammary cell line converted to a tumorigenic phenotype by the EJ/T24 Harvey ras oncogene. Oncogene 6, 1125-1132. 

Lukacs, K.V., Lowrie, D.B., Stokes, R.W., Colston, M.J. (1993). Tumor cells transfected with a bacterial heat shock gene lose tumorigenicity and induce protection against tumors. J. Exp. Med. 178,343-348. 

Occasionally, some of the animal cells in short-term cultures do not die, but instead survive indefinitely. These types of animal cell cultures, which can divide indefinitely, are called established cell lines. Established animal cell lines have been obtained from both normal and tumorigenic cells. Immortalized animal cell lines have also been successfully obtained from short-term cultures following their transformation with appropriate oncogenes. 

Innes JRM, Ulland BM, Valerio MG, et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice A preliminary note. J Natl Cancer Inst 42 1101-1114. 

GaUi R, Binda E, OrfaneUi U, CipeUetti B, Gritti A, De Vitis S, Eiocco R, Foroni C, Dimeco F Vescovi A (2004) Isolation and characterization of tumorigenic, stem-hke neural precursors from human glioblastoma. Cancer Res 64 7011-7021... 

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. 

A NOAEL (humans) study that produced a tumorigenic response... 

Some laboratory studies with rats and mice have linked trichloroethylene exposure to various types of cancers. Several of these studies, however, should be viewed cautiously, since the tumorigenic activity might be influenced by the presence of direct-acting compounds, namely the epoxides (e.g., epichlorohydrin) added as stabilizers in trichloroethylene. Epoxides are known to be very reactive, and some, such as epichlorohydrin, are potent carcinogens themselves. 

GERWIN B J, SPILLARE E, FORRESTER K, LEHMAN T A, KISPERT J, WELSH J A, PFEIFER A M, LECHNER J F, BAKER s J, VOGELSTEIN B et al. (1992) Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1 , Proc Natl Acad Sci USA, 89, 2759-63. 

As safe nutrient ingredients in many food systems, as well as available from commercial synthesis, the combination of vitamins C and E represents very useful compounds for the nutritional inhibition of formation of tumorigenic N-nitroso compounds. 

Sun, Y. Dwyer-Nield, L. D. Malkinson, A. M. Zhang, Y. L. Thompson,J. A. Responses of tumorigenic and non-tumorigenic mouse lung epithelial cell lines to electrophilic metabolites ofthe tumor promoter butylated hydroxytoluene. Chem.-Biol. Interact. 2003, 145, 41-51. 

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