Oncogene effects

Eadier reports of a link between testicular cancer and DMF exposure have not been corroborated ia a study of 4000 Du Pont employees (34). Very recendy, inhalation studies ia mice and rats have shown no oncogenic effect from DMF (35). The International Agency for Research on Cancer (lARC) has concluded that evidence associating DMF with cancer ia animals is "iaadequate," but has classified DMF as "possibly carciaogenic to humans" (Group 2B) (36). 

No oncogenic effects were observed in rats or mice [73]. 

Resmethrin (I) Likely to be carcinogenic to humans based on increased incidences of benign and malignant liver tumors in female rats and male mice. A low-dose extrapolation approach was applied to the experimental animal data in order to estimate human cancer risk [100]. No oncogenic effects were seen [101]. 

Infante PF, Tsongas TA. 1982. Mutagenic and oncogenic effects of chloromethanes, chloroethanes, and halogenated analogues of vinyl chloride. Environmental Science Research 25 301-327. 

Concurrent control information is the most important factor in the statistical analysis needed to confirm the presence of an oncogenic effect. 

In a carcinogenicity study, rats and mice were given the liquid orally at two different dose levels, 5 days a week for 78 weeks." Both female and male test animals exhibited early mortality compared with untreated controls, and a variety of neoplasms were found in both treated animals and controls. Although rats of both sexes demonstrated a positive dose-related trend, no relationship was established between the dosage groups and the species, sex, type of neoplasm, or sites of occurrence. The lARC concluded that an evaluation of the carcinogenicity of 1,1,1-trichloroethane could not be made. In a subsequent study, rats exposed at 15 00 ppm 6 hours/day, 5 days/week for 2 years showed no oncogenic effects. ... 

No oncogenic effects decreased body weight, reduced hemoglobin and hematocrit (Reed 1982)... 

The effect of oncogenic mutations at position 61 can also be explained using the Ras-GAP complex. GIn61 has a central function in GTP hydrolysis in that it contacts and coordinates the hydrolytic water molecule and the O-atom of y-phosphate of GTP and thus stabilizes the transition state. Amino acids with other side chains apparently cannot fulfil this function, as shown by the oncogenic effect of Ghi61 mutants in which Ghi61 is replaced by other amino acids (other than Glu). 

Mutations in the ras family of proto-oncogenes (comprising H-ray, N-roj and K-ras) are very common. The ras inhibitor, trans-farnesylthiosalicylic acid (FTS, sahrasib), exhibits profound anti-oncogenic effects in many cancer cell lines. 

Although tumor induction has mostly been documented in patients treated for cancer, long-term cyclophosphamide treatment for non-neoplastic conditions can also increase the incidence of certain neoplasms. Whether this oncogenic effect is a consequence of drug-induced chromosomal aberrations rather than immunosuppression is unclear. An increased incidence of bladder cancers, skin cancers, and myeloproliferative disorders was found in a 20-year follow-up study of 119 patients with rheumatoid arthritis, and a high dose of cyclophosphamide (mean total dose of 80 g) was the main susceptibihty factor (47). 

Couderc, B., Prats, H., Bayard, F., and Amalric, F., Potential oncogenic effects of basic fibroblast growth factor requires cooperation between CUG- and AUG-initiated forms, Cell Regul., 2, 709, 1991. 

Haun CC, Kinkead ER, Vemot EH, et al. 1984. Chronic inhalation toxicity of unsymmetrical dimethylhydrazine Oncogenic effects. AFAMRL-TR-85-020. 

For example, simazine is involved in a groundwater issue. Simazine has an LDbU of approximately 5,000 mg/kg [13]. This is less acutely toxic than table salt, which has an LD q of approximately 4,000 mg/kg [14]. Simazine can be fed in the diets of rodents for their lifetime at 3,000 ppm without any remarkable effect [15] or administered daily at 215 mg/kg/day in an National Cancer Institute (NCI) bioassay without oncogenic effect [16]. 

The development of an ADI is essentially the same in the NAS procedures, the EPA Food Tolerance procedures, and the NACA proposal for groundwater. An ADI is determined by dividing the NOEL in the most sensitive species by a suitable Safety Factor (SF). Safety Factors for subchronic or repeat administration are usually 1,000 for chronic or lifetime studies, 100 is used. Species conversions can be based upon mg/kg, ppm in the food, or body surface area conversion [29]. Currently, non-oncogenic effects are considered on an mg/kg basis without attempts to correct for species differences. Risk assessment procedures for oncogenic risk employed by the EPA are based upon surface area extrapolations in an attempt to relate to man [30]. 

An oncogene formed by either of the first two mechanisms encodes an oncoprotein that differs from the normal protein encoded by the corresponding proto-oncogene. In contrast, the other two mechanisms generate oncogenes whose protein products are identical with the normal proteins their oncogenic effect is due to production at higher-than-normal levels or in cells where they normally are not produced. 

Overproduction of anti-apoptotic proteins (e.g., Bcl-2) can lead to inappropriate cell survival and is associated with chronic lymphoblastic leukemia (CLL) and other cancers. Loss of proteins that promote apoptosis (e.g., p53 transcription factor and PTEN phosphatase) have a similar oncogenic effect. 

For some types of epigenetic carcinogens, such as hormones (Table 1), noncovalent binding to specific cellular receptors Is undoubtedly essential to their oncogenic effects. Effects on cell membranes may underlie the action of carcinogens that operate as tumor promoters. For the organochlorlne pesticides that act as tumor promoters (see below), such effects on cell membranes may be critical. 

Preclinical studies of zanamivir revealed no evidence of mutagenic, teratogenic, or oncogenic effects (pregnancy category C). 

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