U.S. EPA - Chemicals Evaluated for Carcinogenic Potential

Science Information Management Branch
Health Effects Division Office of Pesticide Programs
U. S. Environmental Protection Agency
Last update: 3/ 15/ 02

See update (July 2004) in pdf form

BACKGROUND

What is this list?

The List of Chemicals Evaluated for Carcinogenic Potential provides an overview of the compounds evaluated for carcinogenicity by the Health Effects Division of the Office of Pesticide Programs. It also includes evaluations by other groups that HED may use until HED completes its evaluation. This list includes pesticide active ingredients that have been submitted to EPA for registration, reregistration, or special review. The registration of some of these pesticides has been canceled. As new information becomes available, the list may become out-of-date. Therefore, it should not be used as the sole reference regarding the carcinogenic potential for a pesticide. EPA intends to update the list as new evaluations or re-evaluations are completed.

How does EPA review pesticides for potential carcinogenicity?

The Health Effects Division of the Office of Pesticide Programs performs an independent review of studies conducted in mice and rats to evaluate the carcinogenic potential of pesticides. The results of the independent review are peer-reviewed by the Cancer Assessment Review Committee. This committee recommends a cancer classification. The classification will determine how the Agency regulates the pesticide and will include methods for quantification of human risk. In some cases, EPA also requests review by the FIFRA Scientific Advisory Panel. For some chemicals, other groups of EPA scientists have provided the assessment, and OPP uses these assessments.

What factors does EPA consider in its review of cancer risk?

When assessing possible cancer risk posed by a pesticide, EPA considers how strongly carcinogenic the chemical is ( its potency) and the potential for human exposure. The pesticides are evaluated not only to determine if they cause cancer in laboratory animals, but also as to their potential to cause human cancer. For any pesticide classified as a potential carcinogen, the risk would depend on the extent to which a person might be exposed ( how much time and to what quantity of the pesticide) . The factors considered include short-term studies, long-term cancer studies, mutagenicity studies, and structure activity concerns. ( The term Aweight-of- the-evidence@ is used in referring to such a review. This means that the recommendation is not based on the results of one study, but on the results of all studies that are available. )

When does EPA review pesticides for potential carcinogenicity?

EPA reviews studies submitted when a pesticide is proposed for registration. Studies are required in two species ( mice and rats) and two sexes ( males and females) . These studies are required for all pesticides used on food and some non-food pesticides that could lead to long-term exposures in humans. These studies may be reviewed again when a pesticide undergoes reregistration and the cancer classification may be re-evaluated, particularly if new studies have been submitted.

Why are there several different cancer classifications in the list?

EPA s guidelines for evaluating the potential carcinogenicity of chemicals have been updated over the years to reflect increased understanding of ways chemicals may cause cancer. The current guidelines call for greater emphasis on characterization discussions for hazard, dose- response assessment, exposure assessment, and risk characterization, as well as the use of mode of action in the assessment of potential carcinogenesis. EPA does not have the resources to re-evaluate every chemical to determine how it would be described under new guidelines, and there is no reason to re-evaluate chemicals unless there is some new information that could change the basic understanding of that chemical.

How have the guidelines changed?
EPA issued its first set of principles to guide evaluation of human cancer potential in1976. In 1986, EPA issued updated guidance, which included a letter system ( A-E) for designating degree of carcinogenic potential. In the 1986 guidelines, hazard identification and the weight- of-evidence process focused on tumor findings. The human carcinogenic potential of agents was characterized by a six-category alphanumeric classification system ( A, B1, B2, C, and D) .

In 1996, EPA released A Proposed Guidelines for Carcinogen Risk Assessment, @ which used descriptive phrases rather than the alphanumeric classification to classify carcinogenic potential. In the 1996 classification structure, increased emphasis was placed on discussing characterization of hazard, dose-response, and exposure assessments. The hazard and weight of evidence process embraced an analysis of all relevant biological information and emphasized understanding the agent' s mode of action in producing tumors to reduce the uncertainty in describing the likelihood of harm.

By 1999, the science related to carcinogens had advanced significantly. EPA issued draft guidelines that continued the greater emphasis on characterization discussions for hazard, dose- response assessment, exposure assessment, risk characterization and the use of mode of action in the assessment of potential carcinogenesis. In addition, the guidelines included consideration of risk to children, as well as addressing other issues such as nuances related to the amount and adequacy of data on a chemical.

How do the different designations compare?

The short answer is that they cannot be directly compared. Each system s designations refer to the reviews and criteria it contains. A substance that is, for example, a AC@ in the 1986 system may not be directly translatable to any particular category in the later systems. The designation for any substance must be considered in the context of the system under which it was reviewed. A list of the descriptors from the various classification systems and their definitions follows.

Carcinogenicity Classification of Pesticides: Derivation and Definition of Terms in the Various Drafts

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CLASSIFICATION -1999 Draft
The most recent EPA guidance for carcinogenicity classification is presented in the July 1999 Review Draft of the Guidelines for Carcinogen Risk Assessment. The terms used in this document are listed and described as follows:

CARCINOGENIC TO HUMANS .: This descriptor is appropriate when there is convincing epidemiologic evidence demonstrating causality between human exposure and cancer. This descriptor is also appropriate when there is an absence of conclusive epidemiologic evidence to clearly establish a cause and effect relationship between human exposure and cancer, but there is compelling evidence of carcinogenicity in animals and mechanistic information in animals and humans demonstrating similar mode( s) of carcinogenic action. It is used when all of the following conditions are met:
*There is evidence in a human population( s) of association of exposure to the agent with cancer, but not enough to show a causal association, and
*There is extensive evidence of carcinogenicity, and
*The mode( s) of carcinogenic action and associated key events have been identified in animals, and
*The keys events that precede the cancer response in animals have been observed in the human population( s) that also shows evidence of an association of exposure to the agent with cancer.
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 an association between human exposure to the agent and cancer and strong experimental evidence of carcinogenicity in animals; at the other, with no human data, the weight of experimental evidence shows animal carcinogenicity by a mode or modes of action that are relevant or assumed to be relevant to humans.
SUGGESTIVE EVIDENCE OF CARCINOGENICITY, BUT NOT SUFFICIENT TO ASSESS HUMAN CARCINOGENIC POTENTIAL.: This descriptor is appropriate when the evidence from human or animal data is suggestive of carcinogenicity, which raises a concern for carcinogenic effects but is judged not sufficient for a conclusion as to human carcinogenic potential. Examples of such evidence may include: a marginal increase in tumors that may be exposure-related, or evidence is observed only in a single study, or the only evidence is limited to certain high background tumors in one sex of one species. Dose-response assessment is not indicated for these agents. Further studies would be needed to determine human carcinogenic potential.
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 equally pertinent evidence does not confirm a concern.
NOT LIKELY TO BE CARCINOGENIC TO HUMANS .: This descriptor is used when the available data are considered robust for deciding that there is no basis for human hazard concern. The judgment may be based on:
*Extensive human experience that demonstrates lack of carcinogenic effect ( e. g. , phenobarbital) .
*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 human data suggesting a potential for cancer effects) .
*Extensive experimental evidence showing that the only carcinogenic effects observed in animals are not considered relevant to humans ( e. g. , showing only effects in the male rat kidney due to accumulation of " 2u-globulin) .
*Evidence that carcinogenic effects are not likely by a particular route of exposure
*Evidence that carcinogenic effects are not anticipated below a defined dose range.

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CLASSIFICATION -1996
In April 1996, EPA released the Proposed Guidelines for Carcinogen Risk Assessment. This scheme varied from the earlier 1986 scheme in that it used descriptors rather than letters to classify carcinogenic potential. The descriptors are:

KNOWN/ LIKELY .: This category of descriptors is appropriate when the available tumor effects and other key data are adequate to convincingly demonstrate carcinogenic potential for humans.
CANNOT BE DETERMINED .: This category of descriptors is appropriate when available tumor effects or other key data are suggestive or conflicting or limited in quantity and, thus, are not adequate to convincingly demonstrate carcinogenic potential for humans. In general, further agent specific and generic research and testing are needed to be able to describe human carcinogenic potential.
NOT LIKELY .: This is the appropriatedescriptor when experimental evidence is satisfactory for deciding that there is no basis for human hazard concern, as follows ( in the absence of human data suggesting apotential for cancer effects) .

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1986 CLASSIFICATION
The following cancer classification scheme was first introduced in 1986. It was used until 1996.

GROUP A-HUMAN CARCINOGEN .: This group is used only when there is sufficient evidence from epidemiologic studies to support a causal association between exposure to the agents and cancer.
GROUP B-PROBABLE HUMAN CARCINOGEN .: This group includes agents for which the weight of evidence of human carcinogenicity based on epidemiologic studies is " limited" and also includes agents for which the weight of evidence of carcinogenicity based on animal studies is " sufficient. " The group is divided into two subgroups.
Group B1 is reserved for agents for which there is limited evidence of carcinogenicity from epidemiologic studies.
Group B2 is used for Agents for which there is " sufficient: evidence from animal studies and for which there is " inadequate evidence" or " no data" from epidemiologic studies.
GROUP C-POSSIBLE HUMAN CARCINOGEN .: This group is used for agents with limited evidence of carcinogenicity in animals in the absence of human data.
GROUP D-NOT CLASSIFIABLE AS TO HUMAN CARCINOGENICITY .: This group is generally used for agents with inadequate human and animal evidence of carcinogenicity or for which no data are available.
GROUP E-EVIDENCE OF NON-CARCINOGENICITY FOR HUMANS .: This group is used for agents that show no evidence for carcinogenicity in at least two adequate animal tests in different species or in both adequate epidemiologic and animal studies.