Occupational Chemical Carcinogenesis Ronald L Melnick PhD

1.0 Introduction

1.1 General Concepts of Multistage Carcinogenesis

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): (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 (2).

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 (3). 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. Similarly a mutation in a suppressor gene may damage the growth-halting program of the cell and thereby allow unabated cell division. p53 is the most commonly found mutated tumor suppressor gene in human cancers. The proliferating mass of altered cells may undergo additional changes during the progression stage that allow these cells to metastasize, that is, escape from their site of origin and invade surrounding tissues or remote organs of the body. The abnormal cells of a benign tumor become malignant (i.e., cancerous) when they acquire additional genetic changes that enable them to invade and destroy adjacent normal tissue or to metastasize to distant sites. Thus, the cancer cell is one that has lost the ability to respond to signals to differentiate into specialized cells, stop dividing, or even die. Carcinogenesis is the multistep process that leads to the production of cancers or malignant neoplasms that elicit uncontrollable growth and dissemination.

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. Genes involved in regulating cell division, differentiation, adaptive responses, signal transduction, and programmed cell death could be adversely affected by exposure to certain chemicals. Thus, environmental pollutants can pose a persistent cancer risk, especially to workers who may be exposed to higher levels of these agents than the general population. 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 (4). 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. Hueper and Conway (5) defined carcinogens as "chemical, physical and parasitic agents of natural and man-made origin which are capable under proper conditions of exposure, of producing cancers in animals, including man, in one or several organs and tissues, regardless of the route of exposure and the dose and physical state of the agent used." Similarly, an Interdisciplinary Panel on Carcinogenicity (6) stated that "the carcinogenicity of a substance in animals is established when administration in adequately designed and conducted experiments results in an increase in the incidence of one or more types of malignant (or, where appropriate, a combination of benign and malignant) neoplasms in treated animals as compared to untreated animals maintained under identical conditions except for exposure to the test compound." In addition to causing an increase in incidence of tumors in treated animals versus controls, a chemical may be considered carcinogenic if it causes tumors earlier in treated animals than in controls or if it causes an increase in the number of tumors per organ (i.e., tumor multiplicity).

Concerning the issue of whether benign neoplasms are indicators of human risk, the National Cancer Advisory Board (7) stated that "benign neoplasms may endanger the life of the host by a variety of mechanisms including hemorrhage, encroachment on a vital organ, or unregulated hormone production" and that "benign neoplasms may represent a stage in the evolution of a malignant neoplasm and in other cases may be 'end points' which do not undergo transition to malignant neoplasms." A similar view was given by an Interdisciplinary Panel on Carcinogenicity (6) and by the Office of Science and Technology Policy (8) which reported that "truly benign tumors in rodents are rare and that most tumors diagnosed as benign really represent a stage in the progression to malignancy." Furthermore, it is not yet known whether benign neoplasms in rodents correspond to benign or malignant neoplasms in other species, including humans. Accordingly, chemically induced benign neoplasms in rodents should be considered important indicators of a chemical's carcinogenic activity, and they should continue to be made an integral part of the overall weight-of-the-evidence evaluation process for identifying potential human carcinogens (9).

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 (2). 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 (10) 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.

1.2 U.S. Occupational Safety and Health Laws Related to Risks from Exposures to Hazardous Substances

During the past 30 years, several laws have been promulgated to protect workers from the harmful effects of hazardous agents in the workplace (11). The Occupational Safety and Health Act of 1970, administered by OSHA, includes the following: (1) requires employers to provide safe working conditions for their employees, (2) prescribes mandatory occupational safety and health standards including exposure limits for toxic chemicals, (3) requires assessment of chemical hazards and notification to workers of their exposure to such hazards, and (4) establishes the National Institute for Occupational Safety and Health (NIOSH) "to develop and establish recommended safety and health standards." The Act authorized OSHA to promulgate occupational safety and health standards for toxic materials that ensure "to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life."

Based on the belief that any exposure to a carcinogen is not safe, OSHA interpreted the Congressional mandate to mean that carcinogens should be regulated to the lowest level feasible. However, in the 1980 benzene decision (448 US 607, 1980), the U.S. Supreme Court ruled that before OSHA "can promulgate any health or safety standard, the Secretary (of Labor) is required to make a threshold finding that a place of employment is unsafe—in the sense that significant risks are present and can be lessened by a change in practices." The Supreme Court did not define "significant risks" but wrote "if the odds are one in a billion that a person will die from cancer by taking a drink of chlorinated water, the risk clearly could not be considered significant. On the other hand, if the odds are 1 in a 1000 that regular inhalation of gasoline vapors that are 2% benzene will be fatal, a reasonable person might well consider the risk significant and take appropriate steps to decrease or eliminate it." Noting that significant risk can exist in the face of scientific uncertainty, the Court maintained that OSHA is "free to use conservative assumptions interpreting data with respect to carcinogenicity risking error on the side of overprotection rather than underprotection." Thus, OSHA performs quantitative risk assessments using human and/or animal data to determine if an occupational exposure poses a significant risk to workers; risks greater than 1 extra cancer death per 1000 are considered significant (12). The OSHA risk assessments and proposals for revised standards are published in the Federal Register and are open for evaluation and comment by scientists and interested parties (e.g., industry, labor groups, consumers). Informal hearings follow this process.

In contrast to OSHA, the U.S.EPA regulates excess cancer risks in the general population in the range of one per million. Though a significant risk may be clearly indicated in an occupational setting, the promulgation of a new or revised occupational standard requires demonstration that achieving such an exposure standard is both economically and technologically feasible. Hence, improving control technology will reduce worker exposures to carcinogenic agents (13).

The Toxic Substances Control Act (TSCA) created by the U.S. Congress in 1976 is administered by the U.S.EPA for the purpose of (1) regulating the production, processing, importation, and use of chemical substances that present unreasonable risk to human health or the environment; (2) requiring notification of production of new chemicals or significant new use of existing chemicals; (3) requiring toxicity testing for chemicals listed in the TSCA Inventory (generally high production volume/high exposure chemicals or chemicals that U.S.EPA believes may present an unreasonable risk to human health or the environment); and (4) requiring record keeping and reporting of any hazardous effects of any chemical to human health or the environment (11). The main source of recommendations for toxicity studies is the Interagency Testing Committee, an advisory committee that sets testing priorities for TSCA-regulatable substances.

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