David B. Clayson

Oxidative DNA damage — The effects of certain genotoxic and operationally non-genotoxic carcinogens

A wide variety of oxidative DNA lesions are commonly present in untreated human and animal DNA. One of these lesions, 8-hydroxydeoxyguanosine, has been shown to lead to base mispairing (mutation) on DNA replication. Other lesions remain to be investigated in this respect. Oxidative DNA lesions on cell replication may, in appropriate circumstances, lead to proto-oncogene activation. Oxidative DNA damage, on fixation, may also lead to cytotoxicity followed by regenerative proliferation. The probable or possible importance of oxidative DNA damage is reviewed for various classes of carcinogens and natural processes, including metal ions, high-energy radiation, miscellaneous chemicals, tumor-promoting agents, polyhydroxyphenols/quinones, lipid metabolism, peroxisome proliferators and thyroid function. It is concluded that although the evidence needs considerable strengthening in many of these examples, the available information indicates the potential importance of oxidative DNA damage in the induction of tumors by these agents. It is also possible that non-cancerous degenerative diseases associated with aging are the result of the accumulation of lesions resulting from unrepaired oxidative DNA damage.

Carcinogenic effects of niridazole

Swiss mice received chronic treatment with the schistosomacide, niridazole, at 3 dose levels. Tumors were found in several organs, including stomach, lung, manary gland, ovary and bladder. Niridazole is, without doubt, carcinogenic to mice.

Occupational bladder cancer

Abstract 4-Aminobiphenyl, 2-naphthylamine, benzidine, 1-naphthylamine and 4-nitrobiphenyl are responsible for occupational bladder cancer in man. Bladder tumors are found in workers who make or use these substances and possibly in those who purify them. The manufacture of auramine and magenta is also associated with the disease. Direct evidence that these chemicals are occupational bladder carcinogens has been obtained from the chemical and rubber industries. Occupational bladder cancer is also a problem in other industries, but in such cases, etiological agents have not been defined. Animal experiments have confirmed that aromatic amines, such as 2-naphthylamine, are carcinogenic and have helped to elucidate their mechanism of action. The problems in protecting workers already exposed to occupational bladder carcinogens and methods which may be used to control the disease are discussed.

Carcinogens and carcinogenesis enhancers

The concept that chemical agents may lead to enhancement of carcinogenesis, rather than to its complete induction, is explored to explain the inexact correlation between carcinogen prescreening tests and the results of whole animal bioassays. It is suggested that carcinogenesis-enhancing agents are non-genotoxic chemicals which are positive in animal carcinogenesis bioassays. The importance of understanding the mechanisms of action of carcinogenesis-enhancing agents is emphasized.

Genotoxicity tests as predictors of carcinogens: An analysis

Differences between the results of numerical validation studies comparing in vitro and in vivo genotoxicity tests with the rodent cancer bioassay are leading to the perception that short-term tests predict carcinogenicity only with uncertainty. Consideration of factors such as the pharmacokinetic distribution of chemicals, the systems available for metabolic activation and detoxification, the ability of the active metabolite to move from the site of production to the target DNA, and the potential for expression of the induced lesions, strongly suggests that the disparate sensitivity of the different test systems is a major reason why numerical validation is not more successful. Furthermore, genotoxicity tests should be expected to detect only a subset of carcinogens, namely genotoxic carcinogens, rather than those carcinogens that appear to act by non-genetic mechanisms. Instead of relying primarily on short-term in vitro genotoxicity tests to predict carcinogenic activity, these tests should be used in a manner that emphasizes the accurate determination of mutagenicity or clastogenicity. It must then be determined whether the mutagenic activity is further expressed as carcinogenicity in the appropriate studies using test animals. The prospects for quantitative extrapolation of in vitro or in vivo genotoxicity test results to carcinogenicity requires a much more precise understanding of the critical molecular events in both processes.

The Importance of Cellular Proliferation Induced by BHA and BHT

Phenolic antioxidants have been used for many years to prevent oxidative spoilage of food (rancidity). They are of major importance in protecting foodstuffs during transportation and storage. Antioxidants thus constitute an essential element in the modem centralized food processing and distribution industries. In Canada, only three phenolic antioxidants are permitted to be added to food: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate (PG). The mean dietary intake of BHA and BHT, as a result of their useas food additives, is relatively low; in Canada the intake overall ages is 7.40 mg/person/day for bothBHA and BHT, leading to a combined totalof 0.26 mg/kg/day (Kirkpatrick andLauer, 1986).

Effects of antioxidants on aflatoxin-induced hepatic tumors in rats

Female Wistar rats pretreated with Aflatoxin B1 (AFB) were administered reduced glutathione, butylated hydroxytoluene, methionine or ascorbic acid on a daily basis, p.o., for 8 months. None of the treatments produced a decrease in incidence or size of hepatic nodules. While there was some evidence that ascorbic acid reduced the incidence of cystic cholangioma, the ascorbic acid and methionine treatment groups also contained significantly fewer animals surviving to the 26-month sacrifice. The lack of effect of glutathione is not consistent with previous work showing a marked glutathione dependent regression of AFB-induced hepatocellular carcinoma.

The inhibition of urease and proteases by sodium saccharin

Sodium saccharin, at concentrations similar to those in the urine of rats fed 1-5% sodium saccharin in their diet, markedly inhibited urease, and 3 proteases in vitro and sodium ion did not appear to play a role in enzyme inhibition. These observations suggest that enzyme inhibition of any of a large number of enzymes may play a role in the tumorigenesis of the urinary bladder by saccharin.

Diet, mutation and cancer

Experimental research designed to determine the effects of variations in diet on the carcinogenic and mutagenic processes is difficult to conduct and even more difficult to interpret in terms of the likely response that such variations will have on the expression of human cancer and mutation. Although some of these difficulties may be due to a failure to persuade adequate numbers of highly trained nutritionists to enter into this type of research, a more germaine reason may be that the high level of complexity of both diet and the disease processes is such as to confound present efforts at interpretation. It is suggested that a stepwise analysis of the effects of dietary factors on each critical stage in carcinogenesis or mutagenesis may ultimately lead to results that are more easily interpreted in terms of human response. To this end it is proposed that studies of DNA-carcinogen or DNA-mutagen adduct formation, or other DNA damage, DNA replication and relevant DNA repair at the target site may be a useful guide to the effect of nutritional changes on mutation and/or cancer initiation. DNA replication at various stages of carcinogenesis, modification of hormonal levels, modification of immune response, or other factors as influenced by diet may provide markers for cancer development. The integration of this data to give an overall perception of the effects of nutrition is briefly discussed.

Trans-Species and Trans-Tissue Extrapolation of Carcinogenicity Assays

From earliest times, mankind has endowed animals with specific human attributes. Language reflects many of these attributes in phrases such as “wise as an owl,” “cunning as a fox,” or “assinine.” Soothsayers have used the detailed morphological examination of outbred animals to predict man’s fate in the future. It is relevant to our present society that none of these attributions were scientific absolutes; they could be manipulated to suit the current political exigencies. Our current mysticism dictates that we regard all agents that induce cancer in animals as having the same effect in man. Although some evidence for this theory exists, and it represents a cautious view, it is again by no means a scientific absolute.