Evaluating Pesticides for Carcinogenic Potential

The EPA is committed to using current state-of-the science methods and consider new, scientifically credible approaches that would advance and strengthen our risk assessments. The Office of Pesticide Programs (OPP) is leading multiple efforts to facilitate the use of kinetic information in a weight-of-evidence to help inform dose selection in toxicity testing studies, and aid in better interpretation of dose-response data for risk assessment. Scientists from OPP in conjunction with representative from several countries are currently in the process of drafting guidance on integrating kinetic information into the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) evaluations.

1. How does EPA review pesticides for potential carcinogenicity?
2. What factors does EPA consider in its review of cancer risk?
3. When does EPA review pesticides for potential carcinogenicity?
4. Why are there several different cancer classifications?
5. How have the guidelines changed?
6. How do the different designations compare?

Carcinogenicity classification of pesticides: derivation and definition of terms:

2005 classification
1999 draft classification
1996 classification
1986 classification

1. 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.

2. 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 “weight-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). The Guidance On Use Of Weight Of Evidence When Evaluating The Human Carcinogenic Potential Of Pesticides (pdf) (274.98 KB) for use by the OPP Cancer Assessment Review Committee is to aid in identifying, weighing and documenting the lines of evidence used to reach those conclusions as described in the Agency’s 2005 Guidelines for Carcinogenic Risk Assessment. A detailed discussion on the application of weight-of-evidence is found in the 2005 Guidelines for Carcinogen Risk Assessment (EPA/630/P-03/001B.

3. 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.

4. 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.

5. 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, D, and E).

In 1996, EPA released “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.

In March, 2005, EPA released its final Guidelines for Carcinogen Risk Assessment (EPA/630/P-03/001B). These guidelines represent the culmination of a long development process, replacing EPA’s original cancer risk assessment guidelines (1986) and its interim final guidelines (1999).

6. 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 “C” 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

2005 classification

The following descriptors from the 2005 Guidelines for Carcinogen Risk Assessment can be used as an introduction to the weight of evidence narrative in the cancer risk assessment. The examples presented in the discussion of the descriptors are illustrative. The examples are neither a checklist nor a limitation for the descriptor. The complete weight of evidence narrative, rather than the descriptor alone, provides the conclusions and the basis for them.

Carcinogenic to humans. This descriptor indicates strong evidence of human carcinogenicity. It covers different combinations of evidence.

This descriptor is appropriate when there is convincing epidemiologic evidence of a causal association between human exposure and cancer.

Exceptionally, this descriptor may be equally appropriate with a lesser weight of epidemiologic evidence that is strengthened by other lines of evidence. It can be used when all of the following conditions are met:
- there is strong evidence of an association between human exposure and either cancer or the key precursor events of the agent's mode of action but not enough for a causal association, and
- there is extensive evidence of carcinogenicity in animals, and
- the mode(s) of carcinogenic action and associated key precursor events have been identified in animals, and
- there is strong evidence that the key precursor events that precede the cancer response in animals are anticipated to occur in humans and progress to tumors, based on available biological information.

In this case, the narrative includes a summary of both the experimental and epidemiologic information on mode of action and also an indication of the relative weight that each source of information carries, e.g., based on human information, based on limited human and extensive animal experiments.

Likely to be carcinogenic to humans. This descriptor is appropriate when the weight of the evidence is adequate to demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the descriptor “Carcinogenic to Humans.” Adequate evidence consistent with this descriptor covers a broad spectrum. As stated previously, the use of the term “likely”as a weight of evidence descriptor does not correspond to a quantifiable probability. The examples below are meant to represent the broad range of data combinations that are covered by this descriptor; they are illustrative and provide neither a checklist nor a limitation for the data that might support use of this descriptor. Moreover, additional information, e.g., on mode of action, might change the choice of descriptor for the illustrated examples. Supporting data for this descriptor may include:

an agent demonstrating a plausible (but not definitively causal) association between human exposure and cancer, in most cases with some supporting biological, experimental evidence, though not necessarily carcinogenicity data from animal experiments;
an agent that has tested positive in animal experiments in more than one species, sex, strain, site, or exposure route, with or without evidence of carcinogenicity in humans;
a positive tumor study that raises additional biological concerns beyond that of a statistically significant result, for example, a high degree of malignancy, or an early age at onset;
a rare animal tumor response in a single experiment that is assumed to be relevant to humans; or
a positive tumor study that is strengthened by other lines of evidence, for example, either plausible (but not definitively causal) association between human exposure and cancer or evidence that the agent or an important metabolite causes events generally known to be associated with tumor formation (such as DNA reactivity or effects on cell growth control) likely to be related to the tumor response in this case.

Suggestive evidence of carcinogenic potential. This descriptor of the database is appropriate when the weight of evidence is suggestive of carcinogenicity; a concern for potential carcinogenic effects in humans is raised, but the data are judged not sufficient for a stronger conclusion. This descriptor covers a spectrum of evidence associated with varying levels of concern for carcinogenicity, ranging from a positive cancer result in the only study on an agent to a single positive cancer result in an extensive database that includes negative studies in other species. Depending on the extent of the database, additional studies may or may not provide further insights. Some examples include:

a small, and possibly not statistically significant, increase in tumor incidence observed in a single animal or human study that does not reach the weight of evidence for the descriptor "Likely to Be Carcinogenic to Humans." The study generally would not be contradicted by other studies of equal quality in the same population group or experimental system (see discussions of conflicting evidence and differing results, below);
a small increase in a tumor with a high background rate in that sex and strain, when there is some but insufficient evidence that the observed tumors may be due to intrinsic factors that cause background tumors and not due to the agent being assessed. (When there is a high background rate of a specific tumor in animals of a particular sex and strain, then there may be biological factors operating independently of the agent being assessed that could be responsible for the development of the observed tumors.) In this case, the reasons for determining that the tumors are not due to the agent are explained;
evidence of a positive response in a study whose power, design, or conduct limits the ability to draw a confident conclusion (but does not make the study fatally flawed), but where the carcinogenic potential is strengthened by other lines of evidence (such as structure-activity relationships); or
a statistically significant increase at one dose only, but no significant response at the other doses and no overall trend.

Inadequate information to assess carcinogenic potential. This descriptor of the database is appropriate when available data are judged inadequate for applying one of the other descriptors. Additional studies generally would be expected to provide further insights. Some examples include:

little or no pertinent information;
conflicting evidence--that is--some studies provide evidence of carcinogenicity but other studies of equal quality in the same sex and strain are negative. Differing results, that is, positive results in some studies and negative results in one or more different experimental systems, do not constitute conflicting evidence, as the term is used here. Depending on the overall weight of evidence, differing results can be considered either suggestive evidence or likely evidence; or
negative results that are not sufficiently robust for the descriptor, “Not Likely to Be Carcinogenic to Humans.”

Not likely to be carcinogenic to humans. This descriptor is appropriate when the available data are considered robust for deciding that there is no basis for human hazard concern. In some instances, there can be positive results in experimental animals when there is strong, consistent evidence that each mode of action in experimental animals does not operate in humans. In other cases, there can be convincing evidence in both humans and animals that the agent is not carcinogenic. The judgment may be based on data such as:

animal evidence that demonstrates lack of carcinogenic effect in both sexes in well-designed and well-conducted studies in at least two appropriate animal species (in the absence of other animal or human data suggesting a potential for cancer effects),
convincing and extensive experimental evidence showing that the only carcinogenic effects observed in animals are not relevant to humans,
convincing evidence that carcinogenic effects are not likely by a particular exposure route (see Section 2.3), or
convincing evidence that carcinogenic effects are not likely below a defined dose range.

A descriptor of “not likely” applies only to the circumstances supported by the data. For example, an agent may be “Not Likely to Be Carcinogenic” by one route but not necessarily by another. In those cases that have positive animal experiment(s) but the results are judged to be not relevant to humans, the narrative discusses why the results are not relevant.

Multiple descriptors. More than one descriptor can be used when an agent's effects differ by dose or exposure route. For example, an agent may be “Carcinogenic to Humans” by one exposure route but “Not Likely to Be Carcinogenic” by a route by which it is not absorbed. Also, an agent could be “Likely to Be Carcinogenic” above a specified dose but “Not Likely to Be Carcinogenic” below that dose because a key event in tumor formation does not occur below that dose.

1999 draft classification

The terms used to describe carcinogenic potential in the July 1999 “Review Draft of the Guidelines for Carcinogen Risk Assessment” are listed and defined 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 alpha-2-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.

1996 classification

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 appropriate descriptor 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 a potential for cancer effects).

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.