for chemicals producing neoplastic development. However, it is now known that carcinogens may act by mechanisms that may exhibit a threshold due to the role of target organ toxicity in the carcinogenic process.
In 1983, the National Academy of Sciences (NAS) published a study of how risk assessment should be conducted in the Federal government (2). The NAS established a framework to guide future risk assessment by Federal agencies, which included the use of default assumptions where gaps were present in general knowledge or available data for a particular chemi-cal. As defined by the NAS and is now generally recognized, risk assessment consists of the following four steps:
1. Hazard identification 2. Dose–response assessment 3. Exposure assessment 4. Risk characterization
Hazard identification is the review of relevant biological and medical infor-mation to determine whether or not particular substances may cause adverse health effects. Dose–response assessment defines the relationships between the exposure or dose of an agent and the magnitude of the health response.
This includes a quantitative estimate of the possible impact of a health effect for a range of doses. Exposure assessment produces an estimate of the extent of exposure to the populations of interest. Risk characterization integrates the hazard identification, dose–response assessment, and exposure assess-ment, in order to describe the nature and the magnitude of health risk.
The risk characterization includes presentation of uncertainties and provides a framework to help judge the significance of the risks.
The resulting data are evaluated and chemicals have been classified according to the ‘‘strength of evidence’’ for positive responses, and usually with little regard for studies showing no carcinogenic effects. Major default assumptions used by regulatory agencies are that neoplastic responses in rodents are potentially relevant to human cancer and that target organ site concordance in not necessary for extrapolation to humans. However, it is now recognized that these assumptions are naive and that many tumor types are not relevant for human cancer risk assessment.
One source of hazard identification information is the EPA’s Inte-grated Risk Information System (IRIS), which is available on-line (http:==www.epa.gov=iris). Another source is the IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, published by the International Agency for Research on Cancer (IARC), which is part of the World Health Organization.
2.1. Carcinogen Classifications
An EPA carcinogen group designation that characterizes the strength of evidence for human cancer risk, has been established for each substance reviewed by the intra-agency work group, which consists of scientists from throughout the EPA. The basis for the classification is included in the IRIS database. In the case of the IARC, the classification is based upon the delib-erations by cancer experts from throughout the world at meetings that develop the monographs. The classifications systems for carcinogens vary somewhat among the IARC, other nations and regulatory agencies within the United States.
Traditionally, there has been an alphanumeric system used with Group A (EPA) and Group 1 (IARC) identifying chemicals known to pro-duce cancer in humans based upon epidemiology studies. Other groups such as Groups B and C (EPA) or Group 2 (IARC) identify chemicals that are known to produce cancer in animals but not proven in humans. These are termed probable or possible carcinogens based upon the premise that it is prudent for regulatory purposes to act as if they represent a risk to humans.
However, this does not imply that a causal relationship has been proven between the agent and human cancer. The EPA classification system for the characterization of the overall weight of evidence (animal, human, and other supportive data) of carcinogenicity of a substance includes the following five groups (3):
1. Group A: Human carcinogens. Sufficient evidence from epidemio-logical studies to support a causal association between exposure to the agents and cancer.
2. Group B: Probable human carcinogens. Sufficient evidence of car-cinogenicity based on animal studies. This group is divided into two subgroups. Group B1 is reserved for agents for which there
is limited evidence of carcinogenicity from epidemiological studies. Agents for which there is ‘‘sufficient’’ evidence from ani-mal studies and for which there is ‘‘inadequate evidence’’ or ‘‘no data’’ from epidemiological studies would usually be categorized under Group B2.
3. Group C: Possible human carcinogens. Limited evidence of carci-nogenicity in animals in the absence of human data. This group includes a wide variety of evidence such as (1) a malignant tumor response in a single well-conducted experiment that does not meet conditions for sufficient evidence, (2) tumor responses of marginal statistical significance in studies having inadequate design or reporting, (3) benign, but not malignant tumors with an agent showing no response in a variety of short-term tests for mutagenicity, and (4) responses of marginal statistical signi-ficance in a tissue known to have a high or variable background rate.
4. Group D: Not classifiable as to human carcinogenicity. Inadequate (or negative) human and animal evidence of carcinogenicity, or no data are available.
5. Group E: Evidence of noncarcinogenicity for humans. No evidence for carcinogenicity in at least two adequate animal tests in differ-ent species or in both adequate animal tests in differdiffer-ent species or in both adequate epidemiological and animal studies.
Groups A and B and, in some cases, C are treated similarly for risk assessment purposes. In general, once a chemical has been shown to produce a particular tumor type in rodents by two independent studies, risk assess-ment proceeds regardless of whether humans studies are positive, negative or nonexistent.
2.2. Changes in the Carcinogen Classification Systems
Recently, the EPA has begun to move away from alphanumeric systems for classification and instead to integrate additional information into a weight of evidence approach, which includes the mode of action and exposure conditions required to express a neoplastic response (4). One category
‘‘known=likely’’ may approximately replace the designation of known and probable according to proposed new regulations (5). In the case of agents that have data that raise the suspicion of carcinogenicity, but the data is not adequate to convincingly demonstrate a carcinogenic potential, the designation would be ‘‘cannot be determined.’’
In addition, regulatory agencies have been changing hazard identi-fication methodology by using additional information available for the chemicals. For example, they have been incorporating a ‘‘weight of evidence’’ approach, whereby well-conducted negative studies are used in
the evaluation process (5). Such negative studies may be used to contradict poorly conducted studies that have reported a positive finding.
It is now recognized that certain chemical-induced neoplastic effects in animals within certain target organs may not be predictors of risks for humans, especially at human exposure levels. Such mechanistic evaluations formed the basis for a monograph published by the International Expert Panel on Carci-nogen Risk Assessment (6). In these series of evaluations, evidence whether a chemical produced cancer in animals by a DNA-reactive mechanisms was found to be of primary importance in the assessment of human cancer risk.
The designation of a chemical as producing tumors in animals by a non-DNA-reactive mechanism raises the possibility that these chemicals would not produce cancer in humans. Several chemicals have been evaluated and found to be unlikely to cause cancer in humans. These include the food addi-tives d-limonene (7), butylated hydroxyanisole (8), and saccharin (9).
In those cases where a chemical has been shown to produce neoplasms in animals by a mode of action that could not be operative in humans, risk assessment is not performed based upon such neoplasms. In the case of the EPA’s proposed descriptors (5), such agents would be designated as ‘‘not likely to be carcinogenic in humans.’’ This is the same designation as for chemical that have been shown to be negative in adequate well-conducted rodent testing. The IARC has also begun using cancer mechanism data for risk assessment, and several chemicals including melamine, d-limonene, saccharin, and atrazine were placed in Group 3 (insufficient evidence) based on such considerations (10).