VIEW:425 DATA:2020-03-20

Consensus evaluations of the strength of the evidence of cancer in humans, the evidence of cancer in experimental animals, and the mechanistic evidence are made using transparent criteria and defined descriptive terms. The Working Group then develops a consensus overall evaluation of the strength of the evidence of carcinogenicity for each agent under review.

An evaluation of the strength of the evidence is limited to the agents under review. When multiple agents being evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single and unified evaluation of the strength of the evidence.

The framework for these evaluations, described below, may not encompass all factors relevant to a particular evaluation of carcinogenicity. After considering all relevant scientific findings, the Working Group may exceptionally assign the agent to a different category than a strict application of the framework would indicate, while providing a clear rationale for the overall evaluation.

When there are substantial differences of scientific interpretation among the Working Group members, the overall evaluation will be based on the consensus of the Working Group. A summary of the alternative interpretations may be provided, together with their scientific rationale and an indication of the relative degree of support for each alternative.

The categories of the classification refer to the strength of the evidence that an exposure is carcinogenic and not to the risk of cancer from particular exposures. The terms probably carcinogenic and possibly carcinogenic have no quantitative significance and are used as descriptors of different strengths of evidence of carcinogenicity in humans; probably carcinogenic signifies a greater strength of evidence than possibly carcinogenic.

(a) Carcinogenicity in humans

Based on the principles outlined in Part B, Section 2, the evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

Sufficient evidence of carcinogenicity: A causal association between exposure to the agent and human cancer has been established. That is, a positive association has been observed in the body of evidence on exposure to the agent and cancer in studies in which chance, bias, and confounding were ruled out with reasonable confidence.

Limited evidence of carcinogenicity: A causal interpretation of the positive association observed in the body of evidence on exposure to the agent and cancer is credible, but chance, bias, or confounding could not be ruled out with reasonable confidence.

Inadequate evidence regarding carcinogenicity: The available studies are of insufficient quality, consistency, or statistical precision to permit a conclusion to be drawn about the presence or the absence of a causal association between exposure and cancer, or no data on cancer in humans are available. Common findings that lead to a determination of inadequate evidence of carcinogenicity include: (a) there are no data available in humans; (b) there are data available in humans, but they are of poor quality or informativeness; and (c) there are studies of sufficient quality available in humans, but their results are inconsistent or otherwise inconclusive.

Evidence suggesting lack of carcinogenicity: There are several high-quality studies covering the full range of levels of exposure that humans are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and the studied cancers at any observed level of exposure. The results from these studies alone or combined should have narrow confidence intervals with an upper limit below or close to the null value (e.g. a relative risk of unity). Bias and confounding were ruled out with reasonable confidence, and the studies were considered informative. A conclusion of evidence suggesting lack of carcinogenicity is limited to the cancer sites, populations and life stages, conditions and levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.

When there is sufficient evidence, a separate sentence identifies the target organ(s) or tissue(s) for which a causal interpretation has been established. When there is limited evidence, a separate sentence identifies the target organ(s) or tissue(s) for which a positive association between exposure to the agent and the cancer(s) was observed in humans. When there is evidence suggesting lack of carcinogenicity, a separate sentence identifies the target organ(s) or tissue(s) where evidence of lack of carcinogenicity was observed in humans. Identification of a specific target organ or tissue as having sufficient evidence or limited evidence or evidence suggesting lack of carcinogenicity does not preclude the possibility that the agent may cause cancer at other sites.

(b) Carcinogenicity in experimental animals

The evidence relevant to carcinogenicity from studies in experimental animals is classified into one of the following categories:

Sufficient evidence of carcinogenicity: A causal relationship has been established between exposure to the agent and cancer in experimental animals based on an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories and/or under different protocols. An increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices (GLP), can also provide

sufficient evidence.

Exceptionally, a single study in one species and sex may be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour, or age at onset, or when there are marked findings of tumours at multiple sites.

Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, for example,

(a) the evidence of carcinogenicity is restricted to a single experiment and does not meet the criteria for sufficient evidence; (b) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; (c) the agent increases tumour multiplicity or decreases tumour latency but does not increase tumour incidence; (d) the evidence of carcinogenicity is restricted to initiation-promotion studies; (e) the evidence of carcinogenicity is restricted to observational studies in nonlaboratory animals (e.g. companion animals); or (f) there are unresolved questions about the adequacy of the design, conduct, or interpretation of the available studies.

Inadequate evidence regarding carcinogenicity: The studies cannot be interpreted as showing either the presence or the absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data are available on cancer in experimental animals.

Evidence suggesting lack of carcinogenicity: Well-conducted studies (e g. conducted under GLP) involving both sexes of at least two species are available showing that, within the limits of the tests used, the agent was not carcinogenic. The conclusion of evidence suggesting lack of carcinogenicity is limited to the species, tumour sites, age at exposure, and conditions and levels of exposure covered by the available studies.

(c) Mechanistic evidence

Based on the principles outlined in Part B, Section 4, the mechanistic evidence is classified into one of the following categories:

Strong mechanistic evidence: Results in several different experimental systems are consistent, and the overall mechanistic database is coherent. Further support can be provided by studies that demonstrate experimentally that the suppression of key mechanistic processes leads to the suppression of tumour development. Typically, a substantial number of studies on a range of relevant end-points are available in one or more mammalian species. Quantitative structure-activity considerations, in vitro tests in non-human mammalian cells, and experiments in non-mammalian species may provide corroborating evidence but typically do not in themselves provide strong evidence. However, consistent findings across a number of different test systems in different species may provide strong evidence.

Of note, “strong” relates not to potency but to strength of evidence. The classification applies to three distinct topics:

(a)    Strong evidence that the agent belongs, based on mechanistic considerations, to a class of agents for which one or more members have been classified as carcinogenic or probably carcinogenic to humans. The considerations can go beyond quantitative structure-activity relationships to incorporate similarities in biological activity relevant to common key characteristics across dissimilar chemicals (e.g. based on molecular docking, -omics data).

(b)    Strong evidence that the agent exhibits key characteristics of carcinogens. In this case, three descriptors are possible:

(1)    The strong evidence is in exposed humans. Findings relevant to a specific tumour type may be informative in this determination.

(2)    The strong evidence is in human primary cells or tissues. Specifically, the strong findings are from biological specimens obtained from humans (e.g. ex vivo exposure), from human primary cells, and/or, in some cases, from other humanized systems (e.g. a human receptor or enzyme).

(3)    The strong evidence is in experimental systems. This may include one or a few studies in human primary cells and tissues.

(c)    Strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Certain results in experimental animals (see Part B, Section 6b) would be discounted, according to relevant criteria and considerations in authoritative publications (e.g. Capen et al., 1999; IARC, 2003). Typically, this classification would not apply when there is strong mechanistic evidence that the agent exhibits key characteristics of carcinogens.

Limited mechanistic evidence: The evidence is suggestive, but, for example, (a) the studies cover a narrow range of experiments, relevant end-points, and/or species; (b) there are unexplained inconsistencies in the studies of similar design; and/or (c) there is unexplained incoherence across studies of different end-points or in different experimental systems.

Inadequate mechanistic evidence: Common findings that lead to a determination of inadequate mechanistic evidence include: (a) few or no data are available; (b) there are unresolved questions about the adequacy of the design, conduct, or interpretation of the studies; (c) the available results are negative.

(d) Overall evaluation

Finally, the bodies of evidence included within each stream of evidence are considered as a whole, in order to reach an overall evaluation of the carcinogenicity of the agent to humans. The three streams of evidence are integrated and the agent is classified into one of the following categories (see Table 4), indicating that the Working Group has established that:

The agent is carcinogenic to humans (Group 1)

This category applies whenever there is sufficient evidence of carcinogenicity in humans.

In addition, this category may apply when there is both strong evidence in exposed humans that the agent exhibits key characteristics of carcinogens and sufficient evidence of carcinogenicity in experimental animals.

The agent is probably carcinogenic to humans (Group 2A)

This category generally applies when the Working Group has made at least two of the following evaluations, including at least one that involves either exposed humans or human cells or tissues:

•    Limited evidence of carcinogenicity in humans,

•    Sufficient evidence of carcinogenicity in experimental animals,

•    Strong evidence that the agent exhibits key characteristics of carcinogens.

If there is inadequate evidence regarding carcinogenicity in humans, there should be strong evidence in human cells or tissues that the agent exhibits key characteristics of carcinogens. If there is limited evidence of carcinogenicity in humans, then the second individual evaluation may be from experimental systems (i.e. sufficient evidence of carcinogenicity in experimental animals or strong evidence in experimental systems that the agent exhibits key characteristics of carcinogens).

Additional considerations apply when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans for one or more tumour sites. Specifically, the remaining tumour sites should still support an evaluation of sufficient evidence in experimental animals in order for this evaluation to be used to support an overall classification in Group 2A.

Separately, this category generally applies if there is strong evidence that the agent belongs, based on mechanistic considerations, to a class of agents for which one or more members have been classified in Group 1 or Group 2A.

The agent is possibly carcinogenic to humans (Group 2B)

This category generally applies when only one of the following evaluations has been made by the Working Group:

•    Limited evidence of carcinogenicity in humans,

•    Sufficient evidence of carcinogenicity in experimental animals,

•    Strong evidence that the agent exhibits key characteristics of

carcinogens.

Because this category can be based on evidence from studies in experimental animals alone, there is no requirement that the strong mechanistic evidence be in exposed humans or in human cells or tissues. This category may be based on

strong evidence in experimental systems that the agent exhibits key characteristics of carcinogens.

As with Group 2A, additional considerations apply when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans for one or more tumour sites. Specifically, the remaining tumour sites should still support an evaluation of sufficient evidence in experimental animals in order for this evaluation to be used to support an overall classification in Group 2B.

The agent is not classifiable as to its carcinogenicity to humans (Group 3)

Agents that do not fall into any other group are generally placed in this category.

This includes the case when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans for one or more tumour sites in experimental animals, the remaining tumour sites do not support an evaluation of sufficient evidence in experimental animals, and other categories are not supported by data from studies in humans and mechanistic studies.

An evaluation in Group 3 is not a determination of non-carcinogenicity or overall safety. It often means that the agent is of unknown carcinogenic potential and that there are significant gaps in research.

If the evidence suggests that the agent exhibits no carcinogenic activity, either through evidence suggesting lack of carcinogenicity in both humans and experimental animals, or through evidence suggesting lack of carcinogenicity in experimental animals complemented by strong negative mechanistic evidence in assays relevant to human cancer, then the Working Group may add a sentence to the evaluation to characterize the agent as well-studied and without evidence of carcinogenic activity.

(e) Rationale

The reasoning that the Working Group used to reach its evaluation is summarized so that the basis for the evaluation offered is transparent. This section

1    integrates the major findings from studies of cancer in humans, cancer in

2    experimental animals, and mechanistic evidence. It includes concise statements of

3    the principal line(s) of argument that emerged in the deliberations of the Working

4    Group, the conclusions of the Working Group on the strength of the evidence for

5    each stream of evidence, an indication of the body of evidence that was pivotal to

6    these conclusions, and an explanation of the reasoning of the Working Group in

7    making its evaluation.

 

Preamble-2019.pdf

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