Risk Assessment (cancer guidelines), the committee concludes that the classification of TCDD as “carcinogenic to humans”—a designation suggesting the greatest degree of certainty about carcinogenicity—versus “likely to be carcinogenic to humans”—the next highest designation—is somewhat subjective and depends largely on the definition and interpretation of the criteria used for classification. The true weight of evidence lies on a continuum, with no obvious point or “bright line” that readily distinguishes between those two categories.

Referring to the specific definitions in EPA’s 2005 cancer guidelines for qualitative classification of chemical carcinogens, the NRC committee was split on whether the evidence met all the criteria necessary for classification of TCDD as “carcinogenic to humans,” although the committee unanimously agreed on a classification of at least “likely to be carcinogenic to humans.” The committee concludes that the weight of epidemiological evidence that TCDD is a human carcinogen is not strong, but the human data available from occupational cohorts are consistent with a modest positive association between relatively high body burdens of TCDD and increased mortality from all cancers. Positive animal studies and mechanistic data provide additional support for classification of TCDD as a human carcinogen. The committee recommends that EPA summarize its rationale for concluding that TCDD satisfies the criteria set out in its cancer guidelines for designation as either “carcinogenic to humans” or “likely to be a human carcinogen.”

If EPA continues to designate TCDD as “carcinogenic to humans” under the new guidelines, it should explain whether this conclusion reflects a finding that there is a strong association between TCDD exposure and human cancer or between TCDD exposure and key precursor events of TCDD’s mode of action (presumably aromatic hydrocarbon receptor [AHR] binding). If its finding reflects the latter association, EPA should explain why that end point (e.g., AHR binding) represents a “key precursor event.”

As noted above, the committee concludes that the distinction between these two categories is based more on semantics than on science and recommends that EPA focus its energies and resources on more carefully delineating the assumptions used in quantitative risk estimates for TCDD, other dioxins, and dioxin-like compounds (DLCs) derived from human and animal studies.

The committee agrees that other dioxins and DLCs are most appropriately classified as “likely to be carcinogenic to humans.” If EPA continues to classify TCDD as “carcinogenic to humans,” more justification will be required to explain why a mixture containing TCDD would not also meet the classification of “carcinogenic to humans.”

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