Health Risks from Dioxin and Related Compounds Evaluation of the EPA Reassessment (2006) / Chapter Skim
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5 Cancer
5 Cancer
Pages 108-143
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From page 108... ...
6-7 to 6-8) : evidence from the occupational cohort studies that dioxin exposure increases mortality from cancer aggregated over all sites and from lung cancer "and, perhaps, other sites"; evidence from bioassays of cancer in both sexes of multiple species at multiple sites; and evidence regarding dioxin's mode of action, including mechanistic evidence that dioxin acts as a tumor promoter via receptor-mediated pathway(s)
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From page 109... ...
updated this study again on a subcohort of 3,538 workers (with 256 cancer deaths) and used data from 170 members of this cohort for which estimated external exposures and known serum dioxin levels were available to establish a quantitative dose-response assessment.
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From page 110... ...
. There are three major issues to consider regarding EPA's review of the epidemiological studies investigating the relationship between dioxin exposure and cancer.
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From page 111... ...
Overall, the committee concurs with the value of conducting analyses of total cancers, given the potential for dioxin to affect multiple types of cancer and the limited precision of risk estimates for individual cancer types. Nonetheless, the potential for effects limited to specific types of
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From page 112... ...
The key comparisons were not between industrial workers and the general population, which is quite susceptible to confounding by lifestyle factors, but among subsets of workers with different levels of estimated dioxin exposure. It is not likely that smoking histories would differ markedly among men located at different jobs within the industrial plant or in relation to duration of employment.
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From page 113... ...
No evidence is available for estrogen-mediated DNA damage resulting from dioxin exposure, but oxidative DNA damage has been documented after 30 weeks administration of dioxin (Tritscher et al.
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From page 114... ...
114 1978 al. et 1982a 2005 1982a 1982b Reference Kociba NTP NTP NTP NTP uterus liver cavity, Increases cavity, oral Tumor oral lung, thyroid of cavity Sites Oral Lung, Thyroid Liver Liver, Liver Liver, Skin Sex Male Female Male Female Female Male Female Female 10, 5 104 10, 3, weeks 0.01, for 0.005 for Bioassays 10, mg/kg, 104 mg/kg/wk (females)
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From page 115... ...
115 1987 1987 al.
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From page 116... ...
116 HEALTH RISKS FROM DIOXIN AND RELATED COMPOUNDS TABLE 5-2 TCDD, Other Dioxins, and DLC Cancer Bioassays Congener Bioassay Dioxins 2,3,7,8-TCDD Rat (M,F) /mouse (M,F)
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From page 117... ...
. The committee agrees with EPA that TCDD, other dioxins, and DLCs appear to enhance tumor development in female rat liver via tumor promotion.
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From page 118... ...
In any case, the committee agrees with EPA's general conclusion that there is sufficient evidence from epidemiological studies, animal bioassays, and mode of action studies to support the qualitative conclusion that TCDD, other dioxins, and DLCs are likely to cause cancer in humans with adequate conditions of dose and duration of exposure. Committee's Perspective on Whether the Scientific Evidence Supports Classification of Dioxin As a Known Human Carcinogen After extensive discussion of EPA's revised definition of "carcinogenic to humans" and "likely to be carcinogenic to humans" provided in EPA's
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From page 119... ...
119 ng/kg)
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From page 120... ...
. The committee was in general agreement that the epidemiological evidence, although not "strong," was generally consistent with a positive association between occupational dioxin exposure and mortality from all cancers, but the magnitude of the effect was modest, and the limited evidence for any specific tumor type being significantly associated was of some concern.
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From page 121... ...
The committee recognizes that the 2003 Reassessment used a different definition of "carcinogenic to humans" based on EPA's 2003 draft carcinogen risk assessment guidelines. The committee found that the argument provided by EPA in the 2003 Reassessment to support its position that the epidemiological data met the criterion of "strong evidence of an association" between dioxin exposure and cancer risk was unconvincing.
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From page 122... ...
. On the basis of a review of the literature, including the detailed review prepared by EPA and presented in Part II of EPA's Dioxin Risk Assessment and new literature available since the last EPA review, the committee concludes that, although it is not possible to scientifically prove the absence of linearity at low doses, the scientific evidence, based largely on mode of action, is adequate to favor the use of a nonlinear model that would include a threshold response over the use of the default linear assumption.
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From page 123... ...
However, these effects are secondary to a series of downstream events that are secondary to Ah receptor activation, a phenomenon that would be likely to cause the dose-response relationship to be sublinear at low doses. It is recognized that a roughly linear increase in response with increasing dose will occur at doses above a minimal response level (e.g., 1% or 5% excess risk)
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From page 124... ...
to suggest that DLCs and dioxins other than TCDD exhibit TCDDlike responses in proportion to their receptor binding affinity (generally reflected in their toxic equivalency factors [TEFs]
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From page 125... ...
. Similarly, the induction of liver tumors from peroxisome proliferators was also deemed to occur via a threshold-type response but was further deemed largely irrelevant to humans because of species differences in peroxisome proliferator activated receptor (PPAR)
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From page 126... ...
(100%) xxx At this time, safety assessment is the default approach for tumors that arise through a nonlinear mode of action; however, EPA continues to explore methods for quantifying dose-response relationships over a range of environmental exposure levels for tumors that arise through a nonlin ear mode of action.
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From page 127... ...
2005) show a consistent sigmoidicity to the tumor dose response.
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From page 128... ...
, the ED01 body burdens for these 13 dose-response relationships ranged from 14 to 1,190 ng/kg. The corresponding LED01 values ranged from 10 to 224 ng/kg.
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From page 129... ...
Because dioxin is presumed to promote tumor growth at a wide range of sites, EPA should explain why it chose not to evaluate the dose-response relationship for "all tumors combined" in the animal studies if it considers this approach to be appropriate for use in human epidemiological studies. The committee notes that extrapolation of results across species is highly uncertain, even when dose is scaled to account for body burden.
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From page 130... ...
EPA identifies 1 × 10-3 pg TEQ/kg of body weight per day (pg/kg-day) -1 "as an estimator of upper bound cancer risk for both background intakes and intakes above background" (Part III, pp.
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From page 131... ...
. The ED01 values are reported as lifetime average body burdens for dioxin (LABB, ng/kg)
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From page 132... ...
This risk estimate satisfies the requirement that risk (infinity) = 1 -- that is, as dose increases, the risk approaches 100%.
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From page 133... ...
The ED01 values are expressed in terms of lifetime average body burden (LABB) , ng of dioxin/kg of body weight.
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From page 134... ...
134 HEALTH RISKS FROM DIOXIN AND RELATED COMPOUNDS (b -- see column 3 of Table 5-5 in this report) is normally distributed with a mean equal to the parameter's central estimate (b -- see column 3 of Table 5-5)
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From page 135... ...
(2001) study is 1.38 ng/kg of body burden if the power function is used, more than an order of magnitude less than the ED01 of 18.6 ng/kg calculated using the piecewise linear function.
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From page 136... ...
The transparency of the uncertainty of CSF calculations, and thus risk estimates, would be substantially improved if the document presented CSF ranges and risk estimates calculated from both ED01 and ED05 values to illustrate the importance of this assumption. Consideration of Alternative Dose-Response Functional Forms Because there are so many functional forms from which to choose for the purpose of modeling dose response, EPA should establish criteria for selecting acceptable solutions.
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From page 137... ...
8-67) and that it "leads to unreasonably high risks at low exposure levels, based on calculations of the attributable risk that this model would predict from background dioxin levels in the general population" (Reassessment, Part III, p.
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From page 138... ...
Uncertainty Associated with Estimation of Historical Exposures The assumed half-life for dioxin in humans plays a major role in the backextrapolation of dioxin lipid concentrations to the estimation of peak body burdens in occupational cohorts. The Reassessment states, "Using published first-order back-calculation procedures, the relatively small difference (<10100-fold)
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From page 139... ...
-1. On the basis of this range, EPA concludes that "A slope factor estimate of approximately 1 × 10-3 per pg of dioxin per kg of body weight per day represents EPA's most current upper bound slope factor for estimating human cancer risk based on human data" (Part III, p.
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From page 140... ...
. In any case, a more thorough consideration of plausible alternative values for key assumptions is needed to portray accurately to risk managers the magnitude of uncertainty that underlies the quantitative risk estimates derived from epidemiological studies.
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From page 141... ...
represents a "key precursor event." · The committee considers the distinction between these two categories to be based more on semantics than on science and recommends that EPA spend its energies and resources more carefully delineating the assumptions used in quantitative risk estimates for TCDD, other dioxins, and DLCs derived from human and animal studies. Quantitative Risk Estimation of Cancer Potency · The committee concludes that there is an adequate scientific basis to support the hypothesis that the shape of the relationship between dioxin dose and cancer risk is sublinear at low doses, perhaps reflecting responses indistinguishable from background risk at doses below which dose-response data are available, including evidence that (1)
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From page 142... ...
The committee recommends that EPA consider the full range of data, including the new NTP animal bioassay study on TCDD for quantitative dose-response assessment. Characterization of Uncertainty Surrounding Cancer Risk Estimates · EPA should characterize more completely the uncertainty associated with risk estimates inferred from the epidemiological data by (1)
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From page 143... ...
· On the whole, it was the committee's impression that EPA's narrative in discussing epidemiological studies in Part III of the Reassessment tended to focus on positive findings without fully considering the strengths and limitations of both positive and negative findings. Part III of the Reassessment would be strengthened if EPA clearly identified specific inclusion criteria for those studies for which quantitative risk estimates were determined.
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