The risk assessment methodology has now been used extensively in a wide variety of circumstances, and due to the quality of the database the results have ranged from reasonable estimates of cancer probability for known
human carcinogens to controversial risk speculations that are seemingly improbable. Consequently, it is important to understand that quality and validity of the data regarding a particular chemical greatly affects the relia-bility of the risk estimate. Even where the data are technically sound but the extrapolation of risk to humans is unclear, the relevance to human risks may be questionable. It is likely that many chemicals pose no cancer risk to humans at any realistic exposure level although risks can be calculated.
Risk assessment does not determine real probabilities of an individual or a population developing cancer from a particular agent. Calculated risks are intended to provide upper-bound estimates, and one must understand that the real risks may be much lower or zero (3). In other words, one cannot deduce the true probability of cancer causation by doing a risk assessment calculation since there are usually several health protective assumptions that inflate the risk. An excellent argument has been made that a MOE-type approach (Fig. 1) be used for assessment of all toxic effects including cancer, since the toxicological information generally available does not warrant numerical estimates of risk at low levels of human exposure (20).
Risk assessment does provide a framework for decreasing the prob-ability of harm from chemical exposures. Consequently, it is useful for reg-ulatory purposes. The coincidence of real probability and risk assessment calculations will be greater for those agents that have been shown to cause cancer in epidemiology studies, which can be used for dose-response assess-ment and in which the exposure levels are close to or within the range of observation. However, for those agents that are positive in animal studies but are negative or untested in epidemiology studies, extrapolation is always problematic.
The mode of action by which an agent causes cancer in animals is of primary importance for extrapolation to humans. The induction of neopla-sia through a mechanism that is likely to operate both in humans and rodents, such as DNA adduct formation leading to mutation, tends to increase the validity of risk assessment. In contrast, many chemical-related cancer mechanisms are now known to be either unique to the rodent or are suspected to only occur in the rodent at very high exposure levels. In such cases, risk assessment would unrealistically calculate risks to humans.
One of the most important developments in risk assessment is the iden-tification of species-specific modes of actions for some carcinogenic effects in rodents. As a consequence, the EPA has determined that tumors formed in the male rat related to a2m-globulin nephropathy are not relevant to humans (21). Also, the IARC has determined that chemicals producing tumors by this mode of action do not pose a risk to humans (22). In addition, IARC has found that other agents producing bladder tumors involving calcium phosphate-containing precipitate formation, such as saccharin and certain chemicals producing thyroid follicular-cell neoplasms, do not pose a risk to humans.
The future of risk assessment lies in the development of better epide-miology data and the diversification of rodent to human extrapolation methods based upon sound scientific data regarding mode of action. Conse-quently, more and more emphasis is being placed on the generation of data regarding cancer mechanisms for use in quantitative risk assessment. As additional data becomes available, the use of chemical-specific information that replaces the traditional default assumptions will provide a enhanced scientific certainty in the risk assessment process.
REFERENCES
1. Armitage P, Doll R. The age distribution of cancer and multistage theory of carcinogenesis. Br J Cancer 1954; 8:1–12.
2. National Research Council. Risk Assessment in the Federal Government:
Managing the Process. Washington, DC: National Academy Press, 1983.
3. US Environmental Protection Agency. Guidelines for carcinogen risk assess-ment. Fed Reg 1986; 41:33992–34005.
4. Wiltse J, Dellarco VL. US Environmental Protection Agency guidelines for carcinogen risk assessment: past and future. Mutat Res 1996; 365:3–15.
5. US Environmental Protection Agency. Proposed guidelines for carcinogen risk assessment. Fed Reg 1996; 61:17960–18011.
6. International Expert Panel on Carcinogen Risk Assessment. The use of mechanistic data in the risk assessments of ten chemicals: an introduction to the chemical-specific reviews. Pharmacol Ther 1996; 71:1–5.
7. Whysner J, Williams GM. d-Limonene mechanistic data and risk assessment:
absolute species-specific cytotoxicity, enhanced cell proliferation and tumor promotion. Pharmacol Ther 1996; 71:137–151.
8. Whysner J, Williams GM. Butylated hydroxyanisole mechanistic data and risk assessment: conditional specific-specific cytotoxicity, enhanced cell proliferation and tumor promotion. Pharmacol Ther 1996; 71:137–151.
9. Whysner J, Williams GM. Saccharin mechanistic data and risk assessment:
urine composition, enhanced cell proliferation and tumor promotion. Pharma-col Ther 1996; 71:225–252.
10. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Monograph 73, 2000.
11. Gaylor DW, Axelrad JA, Brown RP, Cavagnaro JA, Cyr WH, Hulebak KL, Lorentzen RJ, Miller MA, Mulligan LT, Schwetz BA. Health risk assessment practices in the US Food and Drug Administration. Regul Toxicol Pharmacol 1997; 26:307–321.
12. Whysner J, Williams GM. International cancer risk assessment: the impact of biologic mechanisms. Regul Toxicol Pharmacol 1992; 15:41–50.
13. Travis CC, White RK. Interspecific scaling of toxicity data. Risk Anal 1988;
8:119–125.
14. US Environmental Protection Agency. Guidelines for exposure assessment. Fed Reg 1992; 57:22888–22938.
15. Environmental Protection Agency. Risk Assessment Guidance for Superfund.
Vol. 1. Human Health Evaluation Manual. Part A. EPA=540=1-89=002, 1989.
16. US Environmental Protection Agency. A Descriptive Guide to Risk Assessment Methodologies for Toxic Air Pollutants. EPA-453=R-93–038, Office of Air Quality, 1993.
17. Food Safety Council. Quantitative risk assessment. Fd Cosmet Toxicol 1980;
18:711–734.
18. Rodricks JV, Brett SM, Wrenn GC. Significant risk decisions in Federal regu-latory agencies. Regul Toxicol Pharmacol 1987; 7:307–320.
19. Travis CC, Crouch EAC, Wilson R, Klema ED. Cancer risk management: a review of 132 regulatory decisions. Environ Sci Technol 1987; 21:415–420.
20. Gaylor DW, Kodell RL, Chen JJ, Krewski D. A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty=safety factors. Regul Toxicol Pharmacol 1999; 29:151–157.
21. Baetcke KP, Hard GC, Rodgers IS, McGaughy RE, Tahan LM . Alpha2u -Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. Washington, DC: Risk Assessment Forum, US Environmental Protection Agency, 1991.
22. Capen C, Dybing E, Rice J, Wilbourn J, eds. Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis, IARC Scientific Publications No. 147. Lyon, France: IARC, 1998.
7
Cancer Risk Assessment I: How Regulatory Agencies Determine What
Is a Carcinogen
Jerry M. Rice
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., U.S.A.
1. INTRODUCTION
The first stage in cancer risk assessment is the process known as carcinogenic hazard identification. This is the qualitative determination that a substance, complex mixture, agent, or exposure is capable of causing cancer in humans, that is, it is a carcinogen.
An agent is a carcinogen if exposure to it causes an increased incidence of malignant neoplasms at one or more anatomic sites in humans, experi-mental animals, or both. In experiexperi-mental animal studies, carcinogenicity may also be indicated by increased multiplicity or accelerated appearance of neoplasms. Known human carcinogens include certain infectious agents;
all forms of ionizing radiation; and a wide variety of chemical agents and mixtures, some of which occur naturally and some of which are produced by human activities. Carcinogens rarely increase the frequency of tumors at all organ sites, in either humans or experimental animals. Most carcino-gens cause tumors at a single site or at a limited number of sites, which in the
Chief (Emeritus), IARC Monographs Programme, International Agency for Research on Cancer, Lyon, France.
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case of chemicals is largely determined by pathways of metabolism and by the routes of exposure, which affect the dose of active carcinogen delivered to various tissues. Inorganic arsenic, for example, causes human skin cancer when taken in medicinals by ingestion; lung cancer when inhaled under occupational circumstances such as smelting of metal-containing ores; and both of the above plus cancers of the urinary tract and certain other internal organs when present at high concentrations in drinking water (1).
Essentially, all neoplasms occur at some ‘‘natural’’ or ‘‘background’’
frequency. Some human neoplasms are so regularly associated with expo-sure to a specific agent that diagnosis of a case automatically raises the suspicion that the patient was exposed to a known carcinogen (e.g., mesothelioma suggests previous exposure to asbestos; clear-cell carcinoma of the female reproductive tract suggests prenatal exposure to diethylstilbes-trol), but these are exceptions. For most kinds of tumors, at nearly all anatomic sites, it is rarely possible, on the basis of either morphological or molecular characteristics of an individual neoplasm that has been caused by a specific agent, to distinguish it reliably from other cancers of the same kind that may occur naturally or as a result of concurrent exposure to some other carcinogen. This applies to both humans and experimental animals.
Accordingly, conclusions regarding causality are almost always based on statistical analyses of tumor frequencies in exposed vs. nonexposed popula-tions. Genetical, molecular, or morphological markers of exposure to a spe-cific carcinogen may sometimes indicate that a spespe-cific case of cancer has resulted from exposure to a specific agent (e.g., base-pair-specific mutation of the tumor suppressor gene TP53 can implicate exposure to aflatoxin B1in human hepatocellular carcinoma). At present, for chemicals and chemical mixtures this situation is the exception rather than the rule.
For suspect agents that are already present in the environment, data that are relevant for carcinogenic hazard identification may be available in the international scientific literature. These may include epidemiological studies of health effects, including cancer experience, in exposed human populations. When such studies exist, they are of primary interest for assess-ing possible carcinogenic hazard. In the case of widely studied agents or exposures (e.g., ionizing radiation, human papillomaviruses, tobacco use) the database for carcinogenic hazard identification may be extremely robust, and is often strengthened by the existence of studies from several different laboratories or study groups. This allows assessment of the consistency of findings among different studies. Consistently positive findings from several independent studies are strong evidence that a carcinogenic hazard truly exists. However, even for many agents whose existence in the environment has been recognized for decades, epidemiological studies that are adequate to establish whether a given substance is or probably is not a human carci-nogen do not exist. Those studies that do exist often are limited by the fact that most environmental exposures are not ‘‘pure’’ exposures to a single
substance (e.g., 1-nitropyrene), but rather to multiple suspect substances or to complex mixtures of substances (e.g., to many different nitro-polynuclear aromatic hydrocarbons and other substances that occur together in diesel engine exhaust). In such cases additional data are needed to decide whether a specific substance is in fact a carcinogen.
Carcinogenicity, like most other forms of toxicity, increases in severity with increasing duration and intensity of exposure. However, the relative potencies of various carcinogens are highly variable. Low levels of exposure, especially to weak carcinogens, may not be detectable, either by epidemio-logical methods in human populations or by increased tumor frequency in bioassays in experimental animals. For this reason, negative epidemiological and experimental findings must be treated with caution when there are strong reasons to suspect that an agent may be carcinogenic, as when a substance is markedly similar in chemical structure to known carcinogens, or if it possesses biological properties that are often associated with carcino-genicity, such as mutagenicity in mammalian or nonmammalian cells and organisms. The most convincing data for establishing carcinogenicity are those that show a statistically significant increasing trend in tumor incidence with increasing intensity and duration of exposure, as well as statistically significantly increased incidences of tumors in populations that have been exposed to doses above the minimum level of detection.
A broadly based data set on which carcinogenic hazard identification can be based includes:
Epidemiological studies
Carcinogenicity bioassays in laboratory animals (where appropri-ate)
Studies of genetical and related effects in laboratory animals and in human cells, or even in exposed humans
Studies of mode(s) of carcinogenic action of the agent.
Commonly, however, decisions on whether to treat a substance as a carcino-gen must be taken on the basis of incomplete data sets, which lack data from one or more of these categories. For example, for truly novel substances, such as new agricultural chemicals (e.g., herbicides or insecticides) or new drugs, there is no epidemiology. The basis for carcinogenic hazard identifi-cation then consists of carcinogenicity studies in experimental animals, gen-erally rats and conventional and=or genetically engineered mice, together with studies on the metabolism of the agent, its genetical and related effects in experimental animals in vivo and in microorganisms, animal cells, and often human cells in vitro. There may also be studies on the mode of action of the agent as a carcinogen in animals. Such studies will usually have been conducted, or contracted for, by a single commercial entity for purposes of compliance with regulatory requirements. Results of such studies that are submitted to regulatory agencies are often unpublished and are usually
regarded by the sponsor as proprietary information, i.e., trade secrets, that may never be published in a scientific journal. The database for evaluation of new chemicals as possible carcinogens may therefore be much more limited, and previous scientific peer review much less vigorous, than for environmental agents that have been studied more widely.
Agencies that have responsibilities for carcinogenic hazard identifica-tion exist in several internaidentifica-tional organizaidentifica-tions, including the Commission of the European Union and the World Health Organization (WHO). Such agencies also exist in many individual countries, at the national level and sometimes also within the governments of constituent geopolitical units, such as individual states of the United states of America (e.g., California).
Generally, all such agencies work from the same basic kinds of data, but they differ fundamentally in whether they evaluate:
Agents and exposures that already exist in the human environment or
Novel substances proposed for introduction into that environment.
Within the WHO, an internationally recognized carcinogen identification program is conducted by the International Agency for Research on Cancer (IARC). The IARC Monographs on the Evaluation of Carcinogenic Risks to Humans is an international, interdisciplinary approach to carcinogenic hazard identification. Monographs evaluations are assessments of the strength of the published scientific evidence for the existence of an environ-mental carcinogenic hazard to humans, but they are qualitative rather than quantitative in nature and do not address issues of relative carcinogenic potency. Also, the Monographs are confined to published scientific data, and therefore do not evaluate novel agents about which only proprietary data exist. The Monographs are published as a basis for cancer prevention initiatives, which are not limited to regulation. The IARC is not a regulatory agency, and the Monographs explicitly avoid any recommendation regarding regulation or legislation. The Monographs are widely consulted by regula-tory agencies worldwide, however, and the series can serve as a model for how regulatory agencies determine what is a carcinogen, and how different kinds of data are used to make carcinogenic hazard identifications. The criteria applied, and some examples of overall evaluations based on those criteria, are summarized in the following pages.
2. IARC MONOGRAPHS IDENTIFICATIONS