Effect, carcinogenic physiological

Methanol is not classified as carcinogenic, but can be acutely toxic if ingested 100—250 mL may be fatal or result in blindness. The principal physiological effect is acidosis resulting from oxidation of methanol to formic acid. Methanol is a general irritant to the skin and mucous membranes. Prolonged skin contact with methanol vapor or Hquid can cause dermatitis. Methanol vapor can cause eye and respiratory tract irritation, nausea, headaches, and dizziness. 

Although the positive effects of ERT have been well established, it has been shown that the cell proliferative actions of estrogen can increase the incidence of breast cancer in some patients. In addition, duration of exposure to physiological levels of unopposed estrogens is an established risk factor for breast, uterine, and ovarian cancer. In an effort to attain pharmaceutical agents that oppose the carcinogenic... 

Aside from the explosive hazard of A-nitrosamides, it also has been observed that many A-nitroso compounds have a serious physiological effect on mucous membranes and on the skin. Apparently, this corrosive action is not observed in the case of A,A -dinitroso-A,A -dimethyloxalamide [37a, b]. Even so, considering that some A-nitroso compounds are reputed to be carcinogenic, due care should be exercised in the handling of all nitroso compounds. 

The cyclooxygenase (COX) enzyme is known to exist as two distinct isoforms. COX-1 is a constitutively expressed housekeeping enzyme found in nearly all tissues and mediates physiological responses. COX-2 is an inducible form expressed primarily by cells involved in the inflammatory response. Several tissues low in CYP expression are rich in COX, which is believed to have significance in the carcinogenic effects of aromatic amines in these organs. 

The benchmark dose method is particularly useful when the mode of action of a chemical that causes stochastic effects is thought to be nonlinear. In these circumstances, the response is assumed to decrease more rapidly than linearly with decreasing dose. Alternatively, the mode of action may theoretically have a threshold for example, the carcinogenicity of a substance may be a secondary effect of its toxicity or of an induced physiological change that is itself a threshold phenomenon. 

The diet should meet all nutritional requirements of the species tested and should be free from impurities that might influence the outcome of the test. Dietary contaminants and levels of various nutrients have been shown to alter physiologic processes of animals. Rodents should be fed and watered ad libitum with food replaced at least weekly. When a nonrodent such as the dog is used, it should be fed daily. At present, three types of diets are used conventional (standard), synthetic, and various open-formula diets. Of these, the first two are more widely used in carcinogenicity bioassays. Whichever diet is chosen, suppliers must ascertain by periodic monitoring the nutrient quality and the contaminant level in the basal diet. The researchers should know the effect of the dietary regimen on metabolism and animal longevity. 

The mid and low doses for a carcinogenicity study are to provide information for assessing the relevance of the study findings to humans. The low dose should be equal to, or a multiple of, the maximum dose proposed for human testing. The rationale for the selection of the low and mid dose needs to be provided on the basis of pharmacokinetic linearity and saturation of metabolic pathways, human exposure and therapeutic dose, pharmacodynamic response in the test species, alteration in the normal physiology of the test species, mechanistic information and the potential for threshold effects, and the unpredictability of toxicity progression observed in other toxicology studies. 

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