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U.S. EPA’s Dioxin Reassessment: The Current State Of Scientific Understanding

U.S. EPA’s Dioxin Reassessment: The Current State Of Scientific Understanding. William H. Farland, Ph.D. Acting Deputy Assistant Administrator for Science Office of Research and Development U.S. Environmental Protection Agency 6/28/04. The Concept of Toxicity Equivalence (TEQ).

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U.S. EPA’s Dioxin Reassessment: The Current State Of Scientific Understanding

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  1. U.S. EPA’s Dioxin Reassessment:The Current State Of Scientific Understanding William H. Farland, Ph.D. Acting Deputy Assistant Administrator for Science Office of Research and Development U.S. Environmental Protection Agency 6/28/04

  2. The Concept of Toxicity Equivalence (TEQ)... Total TEQ = Ccongener X TEFcongener Toxicity Equivalence of CDDs/CDFs/PCBs =

  3. Four of 17 Toxic CDD/CDF Congeners and One of the 11 Toxic PCBs Account for Most of the Toxicity in Human Tissue Concentrations These five compounds make up about 80% of the total TEQ in human tissue • 2,3,7,8-TCDD • 1,2,3,7,8-PCDD • 1,2,3,6,7,8-HxCDD • 2,3,4,7,8-PCDF • PCB 126

  4. Sources and Pathways to Human Exposures Sources*: • Combustion • Metal Smelting, Refining, Processing • Chemical manufacturing • Biological and Photochemical Processes • Reservoir sources • Others? Pathways: • Ingestion of soil, meats, dairy products, fish • Inhalation of vapors and particulates • Dermal contact with soils *For more details, see EPA Inventory

  5. Key Findings of the ReassessmentExposure Document • Environmental levels have declined since the ‘70s • Current US regulatory efforts have addressed most of the known large industrial sources (~80% reduction between ’87 and ’95; further reductions anticipated) • Open burning of household wastes is the biggest unaddressed contemporary source identified so far. • There remain many uncharacterized sources that could be significant (ag. burning, ceramics, forest fires, secondary steel, reservoir sources) • Exposure to general population has declined but currently averages ~1pg/kg/day

  6. Adult Average Daily Intake of CDDs/CDFs/dioxin-like PCBs 2000 Draft Estimate: ~ 65 pg TEQDFP-WHO98/day Soil ingestion Vegetable fat Soil dermal contact Other meats Poultry Freshwaterfish and shellfish 6% Pork 5% 19% Marine fish and shellfish Beef 7% 14% 1% Inhalation 4% 16% Eggs 21% Milk Dairy

  7. Key Findings of the Reassessment Exposure Document (continued) • General Population Exposure is from animal fats in the commercial food supply -- Local sources make little contribution to most peoples’ exposure -- Environmental levels in meat & dairy production areas major contributor • Air deposition onto plants consumed by domestic meat and dairy animals is the principal route for contamination of commercial food supply • Reservoir sources are a significant component of current exposure and may dominate future exposure -- accounts for most coplanar PCB exposure -- unknown contribution for D/Fs • Special populations may be more exposed but prevalence is not well substantiated

  8. Dioxin Exposure Variability Dioxin intakes for general population may reach levels at least 3 times the mean Support:  99th percentile total animal fat consumption is 3 times the mean 99th percentile blood level is 3 times the mean Potentially highly exposed populations may exceed this range: Nursing infants Subsistence fishers/farmers in contaminated areas Occupational groups (historical)

  9. Dioxin Exposure Trends • Environmental levels: • Peaked in late 60s/early 70s; declined since based on sediment data • Decline also supported by Emissions Inventory which shows significant decrease from 1987 to 1995 (~80%) • Human tissue data suggest current levels are about half of 1980 levels (55 to 25 pg TEQDFP/g lipid) • Steady state PK modeling of current intake levels project tissue levels of about 11 pg TEQDFP/g lipid.

  10. Molecular Changes Altered Metabolism Altered Proliferation/ Differentiation Altered Homeostasis Biochemical Alterations Cellular Effects Tissue/Organ Effects Overt Toxicity (Wasting/Death) Effects of Dioxins Multiple effects in multiple tissues of both sexes of multiple species throughout the vertebrate kingdom

  11. Key Findings of the Reassessment Health Document • Toxic equivalents (TEQ) provide the best means for evaluating mixtures -- Use WHO98 TEFs -- Include coplanar PCBs • Body burden is the best dose metric for estimating risk • Environmental mixtures of dioxin-like compounds are likely to be carcinogenic to humans and 2,3,7,8-TCDD is carcinogenic to humans. • Dioxins produce a variety of noncancer effects in animals & humans -- Developmental Toxicity -- Immunotoxicity -- Endocrine Effects -- Chloracne -- Others

  12. Dioxin-like Compounds and Human Carcinogenicity Complex Environmental Likely to be Mixtures carcinogenic 2,3,7,8-TCDD  Carcinogenic to humans Other dioxin-like Likely to be compounds carcinogenic Based on: • Unequivocal animal carcinogen • Limited human information (epidemiological/other) • Mechanistic plausibility Cancer potency increasingly focusing on human studies Note: In February 1997, the International Agency for Research on Cancer (IARC) classified TCDD as a Category 1, “Known” human carcinogen. In 1999, the U.S. DHHS 9th Report on Carcinogens (ROC) proposed the same, and finalized this listing in 2001 (9th ROC, as revised).

  13. Summary of All Site Cancer ED01s and Slope Factor Calculations from Published Studies ED01/LED01 (95% lower bound) ng/kg Slope factor1, All cancer risk/pg/kg/day STUDY Hamburg cohort, Becher et al. 1998 NIOSH cohort, Steenland et al. 20012 BASF cohort, Ott and Zober, 1996 Sprague-Dawley rats, Kociba et al. 1978; Goodman and Sutter, 1992 (pathology) 6.0 – 32.2 0.9 – 5.1 x 10-3 18.6 (11.5) 1.5 x10-3 (2.5x10-3) 50.9 (25.0) 0.57 x10-3 (1.2 x 10-3) 31.9 (22) 3 0.97 x10-3(1.4 x 10-3) BMD dose 38 (27.5) 0.80 x10-3(1.1 x 10-3) BMD dose Upper bound estimates in parentheses See Footnotes – next slide

  14. Cancer Dose Response - Foot Notes 1. Assumes 25% of body weight is lipid; 80% of dioxin dose is absorbed from the normal diet in humans; the TCDD half-life is 7.1 years in humans. Background all cancer mortality rate calculated through lifetable analysis to 75 years. Summary results are for male all cancer risk, because the male lifetime (to 75 years) all cancer risk is greater than for females, leading to correspondingly higher cancer slope factors. As detailed in Chapter 8, RelRisk(ED01) = 0.99 + 0.01/Risk(0 dose). Based on the manner in which the dose-response data were calculated using Cox Regression rate ratio analyses, risks are given as cancer slope factors for 1 pg/kg/day above background, assumed 5 ppt TCDD in lipid. 2. Steenland et al. (2001) power model results are not included as this formula predicts unreasonably high attributable risks at background dioxin levels in the community due to the steep slope of the power curve formula at very low levels. 3. Modeled using U.S. EPA benchmark dose software, version 1.2, with either dose or adipose concentration as the metric. 50% absorption assumed from food pellets in animals. BMD = 0.00176849 ug/kg/day. BMDL = 0.00122517 ug/kg/day. Therefore, rat LED01 = 1.2251 x 25 x 0.5/ln2 = 22 ng/kg; human equivalent LED01 = 22 x ln2 x 1000/2593/0.8 = 7.38 pg/kg/day; slope factor = 0.01/7.38 = 1.4 E-3 risk/pg/kg/day

  15. Non-cancer Dose/Response Modeling • Use body burden (Ng/Kg BW) as dose metric • Accounts for differences in half-life • Shape of dose/response curve • Most toxic responses are non-linear • Most biochemical response and 40% of complex responses are linear • Derive ED01/ED10 within/close to experimental data

  16. Body Burdens (Ng/Kg) Associated With Effects MOE* I 4 I 0.1 - 8 I 10 I 0.3 - 2 I 4 I 0.6 - 16 I I 0.1 - 7 I 0.4 - 17 I I 2 • Adverse Effects • Developmental neurotoxicity: 22 • Developmental/reproductive toxicity: 0.7 - 42 • Developmental immunotoxicity: 50 • Adult immunotoxicity: 1.6 - 12 • Endometriosis: 22 • Cancer 3.3 - 80 • Biochemical Effects • CYP1A1 Induction: 0.6 - 33 • CYP1A2 Induction: 2.1 - 83 • Functional Effects • Oxidative stress: 10 *MOE = effect level /current average U.S. background body burdens of 5 Ng/Kg

  17. US/International Comparisons * Body burden from original publication; ATSDR used intake of 0.12 ng/kg/day ** Based on TMI = 70 pg/kg

  18. Similarities/Differences with EPA Similarities • Focus on lowest adverse effects • Use body burden as dose metric (except ATSDR) • Suggest additional decrease in intake necessary • Assume cancer will be insignificant at guidance level • Choose safety/uncertainty factor (3.2-90) to account for NOAEL/LOAEL, PD, human variability • Choose safety assessment vs. MOE/QRA Differences

  19. Key Findings of the Reassessment Risk Characterization • Cancer slope factor is based primarily on recently published analyses of human studies and is revised upward by a factor of ~6 over the 1985 EPA value based on 1978 study in rats. • Cancer risks to the general population may exceed 10-3 (1 in 1,000) from background (dietary) exposure but are likely to be less and may even be zero for some individuals • Adverse non-cancer effects have been observed in animal and humans within 10 times background exposure. It is likely that part of the general population is at, or near, exposure levels where adverse effects can be anticipated

  20. Summary • Dioxin science has evolved rapidly; more data lead to better understanding, but more questions. • Expanded human data on cancer reinforces our previous concern for the potential for human health impacts. • Identification of non-cancer effects in animals and human are sufficient to generate a similar level of concern to cancer • Environmental levels and human exposure are declining but are still at a level of concern • Current source characterization is complex with uncontrolled burning and reservoir sources potentially playing a significant role.

  21. SAB Report The SAB Report (May 31, 2001): • Commends the Agency on providing a careful and thorough review of the dioxin literature • Suggests improvements in the following areas: • More focus on non-cancer effects • Increased emphasis on Mode of Action • More clarification of uncertainty • Discusses lack of SAB panel consensus on several key dioxin science issues • Cancer Characterization – Carcinogen vs. Likely Carcinogen? • Margin of Exposure (MOE) and/or Reference Dose (RfD)? • Upper Bound Estimate of Cancer Risk? • Recommends that the Agency expeditiously move forward with finalization of EPA’s Dioxin Reassessment (On the Internet at www.epa.gov/science1/fiscal01.htm)

  22. Major Issues Identified in SAB/Public Comments Addressed • Sparse data to derive national means • for sources/pathways • Lack of information on dioxin-like PCBs • in exposure document • State of validation of exposure models • Trends in environmental/body burden levels • TEFs/TEQs • Impact of human data on hazard and • risk characterization • Significance of enzyme induction and other • biochemical effects • Relative roles of data, scientific inference, and science policy

  23. GAO Report In May 2001, U.S. Senators John Breaux and Thad Cochran requested that the Congress’s General Accounting Office (GAO) conduct a study on the draft dioxin reassessment that focuses on: • EPA’s discussion and characterization of dietary exposure risks; • Comparisons between the World Health Organization’s and EPA’s approaches to dioxin exposure and estimates of dietary levels; and • Responsiveness to external peer review and other comments in the draft reassessment.

  24. GAO Report (cont.) Major findings in the report: • Positive comments regarding development process, quality, and inclusiveness of the Agency’s draft reassessment • EPA's work “largely reflects the recommendations and suggestions provided to the agency by the two most recent independent peer review panels.” • GAO commented that the data on dioxin levels in food supporting EPA’s October 2000 draft reassessment were a significant improvement over the 1994 draft although citing some aspects and limitations of EPA’s dietary exposure discussion. GAO raised the issue of the currency of the dietary survey data referenced in the Agency’s reassessment.

  25. GAO Report (cont.) Major findings in the report (cont.): • Commented that the TEF approach is the internationally accepted scientific method for risk assessments of dioxins • Commented that EPA and the scientific community conclude that dioxins can cause a variety of cancer and noncancer health effects; that they act in the same way in animals and humans; and that some effects could occur at or near the levels to which the general population is now being exposed • GAO noted that EPA and WHO used different approaches to estimating human safety/risk.

  26. Status and Next Steps • Science Advisory Board (SAB) review; May 1995 • Report received from the SAB; Fall 1995 • Major SAB comments -- revision and re-review of Chapter 8: Dose-Response Modeling and Risk Characterization; add TEF Chapter • Internal and Inter-Agency Review of TEF Chapter and revised Integrated Summary and Risk Characterization • SAB re-review of revised D/R and TEF Chapter and Integrated Summary and Risk Characterization -- November 1 and 2, 2000 • SAB/Executive Committee review of Nov. meeting draft report and letter to Administrator -- May 31, 2001 • Internal and Inter-Agency Review of D/R and TEF Chapter and revised Integrated Summary and Risk Characterization -- Oct. 2003 • National Academy of Sciences Review of Selected Issues – 2004-2005

  27. NAS REVIEW The National Academies’ Research Council will review EPA’s 2004 draft to assess whether EPA’s risk estimates are scientifically robust and whether there is a clear delineation of all substantial uncertainties and variability. Focus on: • cancer characterization • modeling assumptions, including use of TEFs; • dose ranges and associated likelihood estimates for identified human health outcomes; • selection of studies as the basis of the assessment; • quantitative approaches to uncertainty analysis.

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