ATSDR's qualitative conclusions regarding carcinogenicity are presented in the Toxicological Profiles using a weight of evidence approach. This approach relies upon NTP's Annual Report on Carcinogens. Conclusions from IARC, U.S. EPA and OSHA are also presented as appropriate.
Health Canada classifies chemicals into six categories with regard to carcinogenicity based on a modification of the scheme used by the International Agency for Research on Cancer. The following is excerpted from Human Health Risk Assessment for Priority Substances (Health Canada, 1994):
Group I: Carcinogenic to Humans
Data from adequate epidemiological studies indicate that there is a causal relationship between exposure to a substance and an increased incidence of cancer in humans.
Group II: Probably Carcinogenic to Humans
Data from epidemiological studies are inadequate to assess carcinogenicity. However, there is sufficient evidence of carcinogenicity in animal species (i.e., there is an increased incidence of malignant tumours in multiple species or strains, in multiple experiments with different routes of exposure or dose levels, or the incidence, site or type of tumour or age of onset is unusual). Exceptionally, a compound for which the evidence of carcinogenicity is limited but for which there is a strong supporting dataset (on genotoxicity, for example) which indicates that the compound is likely to be carcinogenic would be included in this category.
Group III: Possibly Carcinogenic to Humans
Health Canada has three subgroups in Group III which describe the data in humans and laboratory animals that would result in a classification in this Group. In summary, this includes chemicals for which data from epidemiological studies are inadequate, or which indicate an association between exposure and human cancer but alternative explanations such as chance, bias or confounding cannot be excluded. There is some evidence of increased tumour incidence in animals but the data are limited because the studies involve a single species, strain or experiment; study design (i.e., dose levels, duration of exposure and follow-up, survival, number of animals) or reporting is inadequate; the neoplasms produced often occur spontaneously and have been difficult to classify as malignant by histological criteria alone (e.g., lung and liver tumours in mice). The weight of limited evidence indicates that the compound is genotoxic or results are mixed. Chemicals believed to have an epigenetic mechanism of cancer induction may also be classified in Group III if there are positive cancer studies in long-term animal experiments.
Group IV: Unlikely to be Carcinogenic to Humans
Health Canada has four subgroups in Group IV which describe the data in humans and laboratory animals that would result in a classification in this Group. In summary, this includes chemicals for which there is no evidence of carcinogenicity in adequate epidemiological studies or data are inadequate. There is some evidence of carcinogenicity in well -designed and well-conducted carcinogenicity bioassays in animals, but the results are limited or can be confidently ascribed to species-specific mechanisms of toxicity and/or metabolism which do not appear to be operative in humans.
Group V: Probably Not Carcinogenic to Humans
Health Canada has three subgroups in Group V which describe the data in humans and laboratory animals that would result in a classification in this Group. In summary, this includes chemicals for which there is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies; there is no evidence or inadequate data on carcinogenicity in laboratory animals.
Group VI: Unclassifiable with Respect to Carcinogenicity in Humans
Health Canada has three subgroups in Group VI which describe the data in humans and laboratory animals that would result in a classification in this Group. In summary, this includes chemicals for which data from epidemiological and/or animal studies are inadequate or not available.
An explanation of IARC's methods is available in the Preamble to the IARC Monographs at http://monographs.iarc.fr/ENG/Preamble/index.php. The Preamble to the Monographs sets out the objective and scope of the evaluation programme, the procedures used when making assessments, and the types of evidence considered and criteria used in reaching the final evaluations.
NSF International currently uses the U.S. EPA (2005) weight of evidence narrative approach to cancer classification. The conclusion reached by NSF is included as part of the hazard assessment in a weight of evidence evaluation and cancer characterization section of the oral risk assessment document. If the U.S. EPA or another internationally recognized organization such as the NTP (National Toxicology Program), ATSDR, Health Canada, IARC or other members of the World Health Organization has also classified the chemical, that classification will be included in the risk comparisons and conclusions section of the NSF document, with discussion if the classifications differ. The U.S. EPA and NSF International classifications may occasionally differ if new data have been evaluated by one of the organizations.
An explanation of RIVM's risk assessment methods is available in the following report:
Janssen, PJCM and GJA Speijers. 1997. Guidance on the Derivation of Maximum Permissible Risk Levels for Human Intake of Soil Contaminants. Report no. 711701006, National Institute of Public Health and the Environment. Bilthoven, The Netherlands. January. Available at http://www.rivm.nl/bibliotheek/rapporten/711701006.pdf or at http://www.rivm.nl/en/ (click on Search, type "711701006", then click on document).
An explanation of TCEQ's methods is available in the publication entitled, TCEQ Guidelines to Develop Toxicity Factors” Available at http://www.tceq.texas.gov/publications/rg/rg-442.html . This document is a technical guide that details the process of developing Effects Screening Levels (ESLs), Reference Values (ReVs), and Unit Risk Factors (URFs).
In 1986, the U.S. EPA published general guidelines to be used by Agency scientists in developing and evaluating risk assessments for carcinogens (U.S. EPA, 1986). Almost all of the carcinogen assessments on IRIS were based on the 1986 guidelines. Assessments developed between 1996 and approximately 1999 may have used the 1996 proposed guidelines; and assessments developed between approximately 1999 and early 2005 may have used the 1999 draft guidelines. Both the 1996 and 1999 versions were similar to the 2005 (final) version, and used comparable quantitative approaches. However, the 1996 version included two fewer categories, and both 1996 and 1999 versions differed in some other details from the 2005 guidelines. For more details about the evolution of U.S. EPA’s cancer guidelines, please see http://www.epa.gov/cancerguidelines/.
Below is a brief description of the weight of evidence and cancer classification guidelines from the 1986 guidelines. This is followed by a brief description of the 2005 guidelines.
Description of 1986 Guidelines
The 1986 guidelines specify that information be categorized into one of three types: human data, animal data, and supporting data. The human and animal data are used to make a preliminary judgment as to the likelihood that the agent in question may produce tumors in humans. The supporting data (e.g., genotoxicity, mechanistic data, and pharmacokinetic information) are then used to elevate or downgrade the classification. For a description of the amount and type of data required for a chemical to be assigned to any one of these groups, the reader is referred to the 1986 guidelines (U.S. EPA, 1986). In brief, the categories from the 1986 guidelines, as defined by U.S. EPA, are as follows:
Group A: Carcinogenic to humans
Classification in Group A requires the observation of a statistically significant association between exposure to an agent and malignant or life-threatening benign tumors in humans.
Group B: Probably carcinogenic to humans
EPA divides this group into the categories B1 and B2. Limited human evidence of carcinogenicity in humans is necessary for placement of a chemical in Group B1. Group B2 includes chemicals with sufficient animal evidence, but inadequate human evidence for carcinogenicity.
Group C: Possibly carcinogenic to humans
An agent is classified in Group C when human data are inadequate and animal data demonstrate limited evidence of carcinogenicity (e.g., an increased incidence of benign tumors only; a positive finding of carcinogenicity in one species only; an increased incidence of neoplasms that occur with high spontaneous background incidence)
Group D: Not classifiable as to human carcinogenicity
An agent is classified in Group D when insufficient data are available to make a determination as to carcinogenicity.
Group E: Evidence of noncarcinogenicity for humans
An agent is classified in Group E if there is no increased incidence of neoplasms in at least two well-designed and well-conducted animal studies of adequate power and dose in different species.
Description of 2005 Guidelines
The 2005 guidelines (U.S. EPA, 2005) significantly change the way hazard evidence is weighed in reaching conclusions about an agent's potential for human carcinogenicity. Tumor findings in animals or humans dominated the 1986 classification scheme. Under the 2005 guidelines, decisions are based on all of the evidence, particularly information regarding mode of action at cellular and subcellular levels, as well as toxicokinetics and metabolic processes. Weighing of the evidence includes considering the likelihood of human carcinogenic effects of the agent and the conditions under which such effects may be expressed, as these are revealed in the toxicological and other biologically important features of the agent. This more complete characterization of the expression of carcinogenic potential might include findings that an agent is observed to be carcinogenic by one route, but not another. Alternatively, the agent's carcinogenic activity might be secondary to another toxic effect.
The 2005 guidelines use standard descriptors of conclusions rather than letter designations. The descriptors are incorporated into a brief narrative that explains an agent’s human carcinogenic potential and the conditions that characterize its expression. Significant issues, strengths, and limitations of the data and conclusions are included. The narrative also summarizes the mode of action information that underlies the approach to dose-response assessment. Five categories of descriptors are used, with additional text further defining the conclusion. In brief, the descriptors from the 2005 guidelines are:
“Carcinogenic to Humans”
This descriptor is appropriate when there is convincing epidemiologic evidence demonstrating causality between human exposure and cancer. EPA also considers this descriptor to be appropriate when there is an absence of conclusive epidemiologic evidence to clearly establish a cause and effect relationship between human exposure and cancer, but a number of other criteria are met. The criteria are (1) strong evidence of an association between human exposure and either cancer or key precursor events, (2) extensive evidence of carcinogenicity in animals, (3) the mode(s) of action and key precursor events have been identified in animals, and (4) there is strong evidence that the key precursor events are anticipated to occur in humans and progress to tumors.
“Likely to be Carcinogenic to Humans”
This descriptor is appropriate when the available tumor effects and other key data are adequate to demonstrate carcinogenic potential to humans. Adequate data are within a spectrum. At one end is evidence for a plausible (but not definitively causal) association between human exposure to the agent and cancer, usually with some supporting evidence (not necessarily carcinogenicity data) in animals. At the other end of the spectrum is an agent with no human data, but a positive tumor study in animals and the weight of experimental evidence shows that in experimental animals the agent causes events generally known to be associated with tumor formation.
“Suggestive Evidence of Carcinogenic Potential”
This descriptor is appropriate when the weight of evidence from human or animal data is suggestive of carcinogenicity; a concern for carcinogenic effects in humans is raised, but is judged not sufficient for a stronger conclusion. Examples of such evidence may include: (1) a small and possibly not statistically significant increase in tumors in a single study that is not contradicted by other studies of equal quality in the same system, or (2) a small increase in a tumor with a high background rate in that sex and strain, when there is some evidence that the observed tumors may be due to intrinsic factors. Dose-response assessment is generally not indicated for these agents.
“Data are Inadequate for an Assessment of Human Carcinogenic Potential”
This descriptor is used when available data are judged inadequate to perform an assessment. This includes a case when there is a lack of pertinent or useful data or when existing evidence is conflicting, e.g., some evidence is suggestive of carcinogenic effects, but other studies of equal quality in the same sex and strain are negative.
“Not Likely to be Carcinogenic to Humans”
This descriptor is used when the available data are considered robust for deciding that there is not basis for human hazard concern. This judgment may be based on (1) animal evidence that demonstrates lack of carcinogenic effect in at least two well-designed and well-conducted studies in two appropriate animal species (in the absence of other animal or human data suggesting a potential for cancer effects); (2) extensive experimental evidence showing that the only carcinogenic effects observed in animals are not considered relevant to humans; (3) convincing evidence that carcinogenic effects are not likely by a particular dose route; or (4) convincing evidence that carcinogenic effects are not anticipated below a defined dose range.