Occupational Chemical Carcinogenesis

Abstract

Cancer is not a single disease, but rather is a general term applied to a multitude of diseases and stages of disease, each of clonal origin, that elicit uncontrollable tissue growth. There are more than 100 different types of cancer. In normal tissue the balance between cell reproduction and cell death determines the ultimate size of an organ. This balance is clearly represented after partial hepatectomy where, following removal of as much as two-thirds of the liver, regeneration results in restoration of the liver to its original size. If a normal cell incurs a defect in its growth regulating processes and acquires a growth advantage over other cells in a particular tissue or organ, it may multiply out of control producing a mass of altered cells; this abnormal overgrowth of new tissue is called a tumor or neoplasm. The multistep process of carcinogenesis is thought to involve at least four stages: (1) initiation—the induction of a heritable change in a cell resulting from DNA damage (from endogenous processes or by a DNA reactive environmental agent or its metabolites) that can lead to point mutations, insertions, deletions, or chromosomal aberrations; (2) promotion—the clonal expansion of the initiated cell population; (3) progression—the process whereby benign neoplasms become malignant, as a consequence of increased genomic instability in neoplastic cells that gives rise to additional genetic alterations (i.e., mutations, chromosomal deletions, and/or rearrangements), and (4) metastasis—the spread of cancerous cells to other parts of the body. With increasing knowledge of the number of genes altered in human cancers, it is evident that even a four-stage model is not adequate to describe the carcinogenic process. Two groups of genes control normal tissue growth; protooncogenes promote growth while suppressor genes halt growth. Normal protooncogenes of which there are 300–400 within the human genome regulate cell division and differentiation. If a protooncogene is mutated it may become an activated oncogene that causes the normal regulated cycling pattern of the affected cell to proceed out of control. Most tumors are defined by their cell of origin and their behavior or appearance. Benign neoplasms of epithelial origin are referred to as adenomas or papillomas, and benign neoplasms of mesenchymal origin are referred to as fibromas, osteoma, gliomas, etc. Malignant tumors of epithelial cells are carcinomas, and malignant tumors of mesenchymal tissues are sarcomas. Environmental insults, including ionizing or UV radiation, certain viruses, or various chemical agents can cause genetic damage that converts protooncogenes to oncogenes or inactivates tumor suppressor genes. The simplest definition of a carcinogen is an agent that can cause cancer. However, identifying an agent as a human carcinogen and assessing human risk associated with environmental or occupational exposure is complicated because of the multitude of factors that must be considered: the induction of benign or malignant neoplasms, animal-to-human extrapolations, the influence of mechanistic information on low-dose risk, and the variability in susceptibility among individuals in an exposed population. Tumor induction by occupational chemicals is a multistep process that may involve activation of the compound to a DNA reactive form, binding of the active metabolite (or parent compound, e.g., ethylene oxide) to DNA forming a DNA adduct, faulty repair of the adduct leading to a gene mutation, replication of the altered cell to fix the mutation in the genome, and further genetic alterations (including gene mutations, gene rearrangements and gene or chromosome deletions) that lead to progression to a metastatic cancer. Alternatively, some chemicals or their metabolites may act by “nongenotoxic” mechanisms whereby normal cell cycling patterns are disregulated as a consequence of altered gene expression, perhaps through receptor mediated processes. In this case, changes in cellular function occur without the chemical producing a direct effect on the normal DNA base sequence. Impacting on these considerations is the recognition that humans are exposed to a multitude of chemicals that have mixed mechanisms of action, and humans vary considerably more than inbred or outbred laboratory animals with respect to genetic factors that influence cancer susceptibility. Thus, the predicted effect of a single agent may be affected by the mechanism of tumor induction, genetic differences among individuals, health status, and other exposure circumstances. The first issue in cancer hazard identification is to determine whether exposure to a particular agent can cause a carcinogenic response. The identification of an agent as a carcinogen is based on information from epidemiological studies, experimental animal studies, in vitro evaluations, and assessments of mechanistic data and structure–activity relationships. Data from these sources have shown that carcinogens may act by very different mechanisms (e.g., direct acting or requiring metabolic activation; genotoxic or nongenotoxic) and that carcinogens are not equal in their potential to cause human cancer. In addition, most carcinogens operate by a combination of mechanisms that may vary in different target tissues. Consequently, there has been much debate on the identification of human carcinogens and in particular on the characterization of human risk associated with exposure to such agents. The term “risk” is used in this chapter to indicate the probability of developing cancer from a particular exposure. Because most known human carcinogens are also carcinogenic in animals when adequately tested, the International Agency for Research on Cancer considers that unless there is convincing data in humans to the contrary, “it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans.” Individuals may respond differently to similar exposures to a particular carcinogen. The likelihood of an individual developing cancer in an exposed population depends on extrinsic factors including the intensity, route, frequency, and duration of exposure, as well as on host factors including age, sex, health, nutritional status, and inherited characteristics. Hence, this chapter reviews issues related to the identification of carcinogens and factors that influence human risk. We also provide an update on agents that have been identified as “known” human carcinogens or “probable/reasonably anticipated” human carcinogens by IARC and the National Toxicology Program (NTP), as well as exposure standards developed by the Occupational Safety and Health Administration (OSHA) to reduce worker exposure to these agents. Keywords: Cancer hazard identification; Health laws; Carcinogenic compounds; Cancer epidemiology; Cancer susceptibility; Experimental cancer methods; Case studies; IARC classification; NTP categories; OSHA workplace standards