Chemicals carcinogenesis

Cancer is a disease in which the cell proliferation control mechanisms are deregulated. The International Agency for Research on Cancer (lARC) defines a human carcinogen as any agent, the exposure to which increases the incidence of malignant neoplasia in man. At present, about sixty chemical compounds are classified as human carcinogens and a number of others are under heavy suspicion. However, there are many more chemicals which have definitely caused cancer in experimental animals. 

How should the carcinogenic potency of a chemical, i.e., its ability to cause a particular degree of tumour incidence in a test group, be evaluated  

Contact address during sabbatical leave, August 1997 - July 1998 Waldburgstrasse 207A, D-70565 Stuttgart, Germany. 

Abbreviations PAH, polycyclic aromatic hydrocarbon DE, diol epoxide PAHDE, polycyclic aromatic hydrocarbon diol epoxide PAHTC, polycyclic aromatic hydrocarbon triol carbocation TC, triol carbocation BaP, benzo[a]pyrene BeP, benzo[e]pyrene BA, benz[a]anthracene DBA, dibenz[a,h]anthracene BcPh, benzo[c)phenanthrene Ch, chrysene MCh, methylchrysene MBA, 7-methyl benz[a]anthracene DMBA, 7,12-dimethyl benz[a]anthracene EBA, 7-ethyl benz[a]anthracene DB(a,l)P, dibenzo[a,l]pyrene MSCR, mechanism-based structure-carcinogenicity relationship PMO, Perturbational molecular orbital method dA, deoxyadenosine dC, deoxycytosine dG, deoxyguanosine MOS, monoxygenase enzyme system EH, epoxide hydrolase enzyme system N2(G), exocyclic nitrogen of guanine C, electrophilic centre of PAHTC K, intercalation constant CD, circular dichroism LD, linear dichroism. 

Another line of evidence involves the use of standardised experiments on animals [3]. If a chemical produces tumours in multiple tissues and/or multiple species after a relatively short time - of the order of 100 days - and the tumour leads to the death of the animals, then this chemical is considered a strong carcinogen [4,5]. Animal studies define precisely the route, frequency, duration and level of exposure. But how relevant are the test animals to humans This type of assessment is still very costly, time consuming, potentially hazardous to the experimentalists, and has also been criticised for sacrificing a large number of animals for results which are only indirectly related to risks for humans. 

Cancer is a major disease in humans, affecting 25%, and is the cause of death in 20%. Other mammalian species also suffer cancer, including experimental animals such as rats and mice, 

It has been known for a long time that external agents (carcinogens) are capable of causing cancer, namely viruses, radiation, and chemicals, both natural and man-made. This information has been derived from both epidemiology and experiments in animals. 

Probably the earliest such observation was by Sir Percival Pott, an English physician, in 1775. He noted that chimney sweeps, who tended to suffer from scrotal cancer, were also exposed to soot and tar. He correctly connected these two events. More recent research confirmed that coal tar and the aromatic hydrocarbons it contains will cause cancer of the skin in experimental animals. 

Because cancer is usually a progressive disease, and although some types are treatable many are fatal, the study of cancer is of major importance. 

the biochemical changes associated with exposure to carcinogens have been studied in detail, and consequently, the target site and the interactions of carcinogens with it is more clearly understood than in other areas of toxicology. 

Most human cancer is caused by substances in the environment, 

Carcinogenesis develops in three stages initiation, promotion, and progression. Chem-ical substances can act at the initiation stage or at the promotion stage. Moreover, some chemicals have both initiating and promoting activities. 

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley Sons, Inc. 

Source SEER Cancer Statistics Review, 1973-1998, Surveillance, Epidemiology, 

Mutations in genome of somatic cells (spontaneous environmental factors chemicals, radiation, viruses) 

Alterations of genes that regulate apoptosis (increased survival) 

Inactivation of tumor suppressor genes (growth and survival promoting) 

The more we understand about how nongenotoxic carcinogens cause cancer in rodents, the more sophisticated this experimental system can be and the more sophisticated the extrapolation to humans. Recent progress means that today we are able to explain many of these changes at the level of the sequence of DNA itself via the modulation of gene expression. 

---

Difluoronaphthalene [315-52-6] is prepared from 4-fluoro-l-naphthylarnine by the Balz-Schiemann reaction. 1,4-Difluoronaphthalene is used in chemical carcinogenesis studies as a synthon for highly condensed difluoro—polycycHc aromatic hydrocarbons (273). 

P. D. Lawley and co-workers, eds., Topics in Chemical Carcinogenesis University of Tokyo Press, Tokyo, Japan, 1972, 272 pp. 

R. E. Kouri, Genetic Differences in Chemical Carcinogenesis CRC Press Inc., West Palm Beach, Fla., 1980. 

Experimental animal studies have played a key role in the understanding of the mechanisms of chemical carcinogenesis. The duration of development of a cancer in humans may be several decades, and the development probably includes several steps. Furthermore, individual susceptibility is also important for the disease. Therefore, it has been extremely difficult to make the required observations in exposed individuals. 

If enzymes responsible for DNA repair are unable to remove the DNA adduct, or if an error takes place in the repair, then the error in the genetic code remains when the cell divides. Thus, cellular proliferation is also required, in addition to a mutation, for there to be a permanent effect of a chemical compound. Accumulation of genetic errors, i.e., mutations, has been suspected to be an important factor in chemical carcinogenesis. ... 

Third, reactions of activated species of chemical carcinogens with DNA are thought to be of great importance in chemical carcinogenesis. Some chemicals (eg, benzojajpyrene) require activation by monooxygenases... 

Klaunig JE, Siglin JC, Schafer ED, et al. 1991. Correlation between species and tissue sensitivity to chemical carcinogenesis in rodents and the induction of DNA synthesis. Prog Clin Biol Res 369 185-194. 

AMES B N and GOLD L s (1990) Chemical carcinogenesis too many rodent carcinogens. Proc Natln Acad Sci. 87 1112-11. 

Chemical Carcinogenesis Program, Frederick Cancer Research Center, Frederick, MD 21701... 

Our studies on cyclic nitrosamine metabolism are supported by NCI Grants CA-21393, CA23901, and CA12376. This is paper Number 34 in A Study of Chemical Carcinogenesis. ... 

Sander, J. Burkle, G. Schweinsberg, F. "Topics in Chemical Carcinogenesis University Park Press Baltimore, USA, 1973 p 297. 

Varanasi U, JE Stein, M Nishimoto, WL Reichert, TK Collier (1987) Chemical carcinogenesis in feral fish uptake, activation, and detoxication of organic xenobiotics. Environ Health Perspect 71 155-170. 

Trush, M.A. and Kensler, T.W. (1991). An overview of the relationship between oxidative stress and chemical carcinogenesis. Free Rad. Biol. Med. 10, 210-219. 

Pryor, W.A. (1987). Cigarette smoke and the involvement of free radical reactions in chemical carcinogenesis. Br. J. Cancer 55, 19-23. 

Pullman, A., and B. Pullman. 1980. Electrostatic Effect of Macromolecular Structure on the Biochemical Reactivity of the Nucleic Acids. Significance for Chemical Carcinogenesis. Int. I. Quant. Chem., Quant. Biol. Symp. 7, 245. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

---