Carcinogen activation, human

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

NTP determined that there was clear evidence of carcinogenicity in male rats based on the increased incidence of renal neoplasms and no evidence of carcinogenic activity in female rats (NTP 1989). The EPA classified hexachloroethane as a possible human carcinogen (Group C). The slope factor calculated by EPA is 1.4xl0 2 (mg/kg/day) 1 for both the oral and inhalation routes of exposure (IRIS 1995). IARC has determined that hexachloroethane is not classifiable as to human carcinogenicity (Group 3). 

Unfortunately, not all combinations of chemical additives in water-based fluids are completely compatible, and side reactions leading to various byproducts have been noted. The best known of these side reactions is the reaction between the corrosion inhibitor nitrite and the emulsifiers di- and triethanolamine (7) to form N-nitrosodiethanolamine (NDE1A), a nitrosamine reported to have carcinogenic activity (8, 9, 10). In fact, most nitrosamines are carcinogenic, and no animal species which has been tested is resistant to nitrosa mine-induced cancer. Although there is no direct evidence that firmly links human cancer to nitrosamines, it is unlikely that humans should be uniquely resistant. 

The use of two species in carcinogenicity studies is based on the traditional wisdom that no single species can be considered an adequate predictor of carcinogenic effects in humans. Absence of carcinogenic activity in two different species is thought to provide a greater level of confidence that a compound is safe for humans than data derived from a single species. 

Aflatoxin Bi (AFB) is a mold metabolite which has been observed to be acutely toxic and carcinogenic to a wide variety of animals (5,6) and has been implicated in human primary hepatic carcinoma (7, 8). Diets deficient in protein have been reported to increase the susceptibility of mammals to acute AFB toxicity and the induction of cancer (2, 9, 10, 11, 12, 13). Increased dietary proteins have increased the carcinogenic activity of AFB fed to rats (1 4) and trout (15.). Supportive of this latter finding has been the reported direct relationship between dietary protein content and AFB-DNA adduct formation in vivo in rats (16, 17). 

ACA has been classified by the International Agency for Research on Cancer as probably carcinogenic to humans. It has a carcinogenic potency in rats similar to that of other carcinogens in food. Furthermore, ACA has neurotoxic activity and may induce heritable damage. 

Particular attention has been focused on the toxic effects of aromatic hydrocarbons because these chemicals have proven highly carcinogenic to humans and marine life. Of greatest concern are the PAHs, which are toxic to the benthos at the ppb level. The most common compounds are shown in Figure 28.20 their structures are based on fused aromatic rings. These high-molecular-weight compoimds are very nonpolar and, hence, have low solubilities. Once in seawater, they tend to adsorb onto particles and become incorporated in the sediments. The toxicity of PAHs is enhanced by photochemical reaction with UV radiation. Photo-activated toxicity is especially problematic in shallow-water sediments, such as found in estuaries. 

The identification of the carcinogenic potential of substances often requires the consideration of a large set of data. An important part of the assessment of the available data concerns the evaluation of the mode of action underlying the carcinogenic activity, as this information also allows an evaluation of possible human relevance, existence of thresholds, and comparability with stmcturaUy... 

Williams, G.M. 1997. Chemicals with carcinogenic activity in the rodent liver mechanistic evaluation of human risk. Cancer Lett. 117 175-188. 

PBNA has been tested for carcinogenicity in a number of species without conclusive results. There was no evidence of carcinogenic activity in male or female rats or in male mice fed 2500 or 5000 ppm in the diet for 2 years. The lack of carcinogenicity in rats may be related to an inability to metabolize PBNA to the known animal and human urinary bladder carcinogen P-naphthylamine. There was equivocal evidence for carcinogenicity in female mice, as indicated by the occurrence of two rare kidney tumors. Chemical-related non-neoplastic lesions, including nephropathy, karyomegaly, and hyperplasia, occurred in the kidneys of both species. 

It is not possible on the basis of present knowledge of the relationship of chemical structure to the carcinogenic activity of a chemical to predict how many of the millions of compounds in nature, or the tens of thousands of compounds in commerce, are carcinogenic. Although relatively few chemicals have been observed to cause cancer in human populations, those that have (Thble 5.1), and the himdreds of other substances for which there is some evidence of carcinogenicity in laboratory animals (Thble 5.2), include compounds of widely diverse structures. 

Darroudi, F. Natarajan, A.T. (1993) Metabolic activation of chemicals to mutagenic carcinogens by human hepatoma microsomal extracts in Chinese hamster ovary cells (in vitro). Mutagenesis, 8, 11-15... 

Survey of compounds which have been tested for carcinogenic activity. U.S. Department of Health and Human Services (formerly U.S. Department of Health, Education, and Welfare, indicated in earlier volumes). Eighteen volumes between 1951 and 1984. 

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