# Presentation: 506268

## Health Risk Analyses for Dioxin, Dose-Response Uncertainty, Toxicity Values, and Cumulative Risk

***Molly Finster***
***Environmental Science Division (EVS)***
*July 23, 2008*

## Presentation Overview

- Collaborative IAG
- Introduction to Dioxin
- EPA Dioxin Assessment Chronology
- Dioxin Project
- Current Work
- Acknowledgements

## Collaborative Interagency Agreement

- EPA-NCEA and DOE-Argonne
- Purpose:  Advance risk analyses to support overall 			  health protection
- Interrelated technical areas
- Dioxin and dioxin-like compounds (DLCs)
- Dose-response uncertainty characterization
- Toxicity values
- Cumulative risk assessment

## “Dioxin” is a general term that describes a family of hundreds of chemicals that have a similar chemical structure and induce harm through a similar mechanism

Most toxic compound is 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD
toxicity of other dioxins and chemicals that act like dioxin (e.g. PCBs) are measured in relation to TCDD
toxic equivalency factors (TEFs) 
also, the most well-studied dioxin compound

- “Dioxin” is a general term that describes a family of hundreds of chemicals that have a similar chemical structure and induce harm through a similar mechanism
- Most toxic compound is 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD
- toxicity of other dioxins and chemicals that act like dioxin (e.g. PCBs) are measured in relation to TCDD
*toxic equivalency factors (TEFs) *
- also, the most well-studied dioxin compound

***What is Dioxin?***

## Formed by burning chlorine-based compounds with hydrocarbons: 
waste incineration, forest fires, pulp and paper mills, chemical and pesticide manufacturing

Environmental levels have been declining since the early 1970’s and have been the subject of a number of federal and state regulations and clean-up actions

However, current exposure levels still remain a concern to communities and organizations because of
potential toxicity combined with 
relatively long half-lives in the environment & in human tissues

- waste incineration, forest fires, pulp and paper mills, chemical and pesticide manufacturing
- Environmental levels have been declining since the early 1970’s and have been the subject of a number of federal and state regulations and clean-up actions
- However, current exposure levels still remain a concern to communities and organizations because of
- potential toxicity combined with
- relatively long half-lives in the environment & in human tissues

***Where does Dioxin come from?***

## Why do we care about Dioxin?

- Characterized by EPA as likely human carcinogen
- concern that it might increase the risk of cancer at (higher) background levels of exposure in general US population
- can also cause many non-cancer effects:
*reproductive system and developmental changes *
- at levels 100x times lower than those associated with cancer effects
*alter immune system *
*interfere with hormonal systems*
- Long-standing public fears:
- primary toxic component of Agent Orange (Vietnam vets)
- evacuations at Love Canal, Times Beach (MO), Seveso (Italy)
- found at WTC

## EPA Dioxin Assessment Chronology

-  **1985:****	**Dioxin assessment
** ****May 1991:  ****	**Charge from EPA Administrator to update
** ****1991-1994: ****	**Comprehensive update:** **development of 		topical chapters, peer review
** ****1995:  ****	**EPA Science Advisory Board (SAB) review
** ****1995-2000: ****	**Revision, internal and interagency review
** ****2000-2001: ****	**SAB re-review
** ****2002-2004: ****	**Revision, internal and interagency review
** ****2004-2006: ****	**National Academy of Sciences (NAS) review
** ****2008-2011: ****	**Respond to NAS comments:  complete the 	assessment **  **

## Dioxin Project Scope of Work:  2008 

- Assess key technical issues and develop a scientific foundation for the EPA technical response to the NAS review of the dioxin reassessment
- 3 areas for substantial improvement:
*justification of dose-response models for cancer and noncancer endpoints*
*transparency and clarity in selection of data sets for analysis*
*transparency, thoroughness, and clarity in quantitative uncertainty analysis *
- Identify and evaluate current scientific information
- dioxin literature has continued its significant expansion since the reassessment document was last revised (in 2003)

## Dioxin Project Scope of Work:  2008 

- Involve experts and solicit public input on key studies and technical issues
- Federal Register Notice (targeted for August 2008):  list of candidate studies for public review & addition
- Expert panel meeting (targeted for November 2008):  identify key issues & studies to support the response to comments
- Summarize inputs to guide the technical work plan for completing the dioxin assessment

## Literature Search Strategy & Implementation

- Search the literature and pursue additional information to identify key studies, technical issues, and expertise
- comprehensiveness is crucial
*previous EPA approach not systematic (e.g., limiting criteria applied for existing modeling approaches) *
*extensive earlier literature also in play *
*extensive integration across technical topics *
- Obtain and evaluate potentially relevant studies, and select studies for detailed evaluation
- Review studies, extracting key toxicity data, and synthesize information to frame initial expert input on key studies, issues, and approaches for addressing those issues

## Sheer Volume of Dioxin Literature

## Sheer Volume of Dioxin Literature

| Endpoint | Candidate Papers  |  |  |
| --- | --- | --- | --- |
|  | Identified | Screened & Coded | Retrieved |
| Cancer (CA) | 1081 | 949 | 100 |
| Developmental (DV) | 678 | 479 | 124 |
| Reproductive (RP) | 770 | 454 | 166 |
| Hepatic (HP) | 876 | 340 | 42 |
| Immunological (IM) | 584 | 299 | 77 |
| Neurological (NR) | 420 | 248 | 34 |
| Endocrine (EN) | 643 | 414 | 45 |
| Total | 5052 | 3183 | 588 |

## Extracting Key Toxicity Data

| “Qwik-View” Dose-Response Data from Abstracts for the Reproductive Endpoint |  |  |  |
| --- | --- | --- | --- |
| Author, Year | Species | Exposure/Dose Level | Nature of Effect |
| Mink (1) |  |  |  |
| Hochstein,MS (2001) | Mink, Natural dark
female, mature  | 0.0006 (control), 0.016, 0.053, 0.180, or 1.40 ppb TCDD | High sensitivity of mink to TCDD, and revealed a toenail abnormality |
| Monkey (1) |  |  |  |
| Yasuda,I (2005) | Monkey, rhesus 
female, pregnant | initial dose : 0, 30, or 300 ng/kg subcutaneously; additional injection of 5% of the initial dose every 30 d until 90d after delivery | Lowest-observed adverse-effect level (LOAEL) for TCDD in the rhesus monkey is between 30 and 300 ng/kg |
| Mouse (4) |  |  |  |
| Zhu,BT (2008) | Mouse
female  | 100 μg/kg bw | Increased the hepatic activity for the O-methylation of catechol estrogens and body weight |
| Keller,JM (2007) | Mouse, C3H/HeJ, CBA/J, and
C57BL/10J strains;
female, pregnant  | Exposed on GD13 to 4 different levels of TCDD: control, 0.01, 0.1 and 1.0 μg/kg | Missing M3s only in mice in two strains, C3H/HeJ and CBA/J, and their frequency significantly increased with increasing TCDD exposure; frequency of M1 variant was high in mice in only one strain (C57BL/10J) and was significantly higher in the treated compared with the control group |
| Rat (41) |  |  |  |
| Choi,JS (2008) | Rat
male (40)  | One dose, 50 μg/kg body weight | Induced marked histological changes in the testis, impairs variables related to spermatogenesis, and increases serum oestradiol levels but decreases testosterone levels.  |
| Haavisto,TE (2006) | Rat, Sprague-Dawley 
female, pregnant (dam) | Single oral dose of TCDD: 0, 0.04, 0.2, or 1.0 μg/kg | Body weight of male offspring was reduced after exposure to 1.0 microg/kg TCDD |
| Nishimura,N (2005) | Rat, Holtzman 
female, pregnant | Single oral dose of 1.0 μg TCDD/kg | Exposure to TCDD was responsible for the disruption of thyroid hormone homeostasis |
| Simanainen,U (2004) | Rat , (3 lines): Han/Wistar Long-Evans  
female, pregnant  | 0.03, 0.1, 0.3, or 1 μg/kg | Dose of 1 microg/kg TCDD reduced daily sperm production and growth of the male reproductive organs was not markedly affected |
| Rabbit (1) |  |  |  |
| Moon,DG (2004) | Rabbit
New Zealand white | 1 μg/kg of TCDD | TCDD inhibits spermatogenesis and has a potential harmful effect on erectile function |

## Extracting Key Toxicity Data

| Summary of Selected Toxicity Data, Grouped by Endpoint
 |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Ref.
 | Study Group | Exposure Type, Form, Medium | Duration, Exposure Regimen | Study Dose(s)
(g/kg-d) | Dose for Key Effect
(g/kg-d) | Effect Category | Effect Description | Notes |
| Reproductive |  |  |  |  |  |  |  |  |
| Bell et al. 2007
 | Rat
CRL:WI(Han)
F0 female(5-6 wk old, 30/group)
F1 male(~45/group) | Maternal diet
(supplemented with TCDD) | ~15-16 wk
(dosed for 12 wk, then during mating & pregnancy; dosing terminated at parturition)(F0 killed at wk 10 & 12 of dosing, and at GD16 & GD21; F1 at PND70 or PND120) | control (0), 0.0024, 0.008, 0.046 | 0.0024 | LOAEL | F0 dams: reduction in mean pup body weight on PND1 | Dose-related response; remained throughout lactation |
|  |  |  |  |  |  |  | F0 dams: reduction in pup survival between PND1 to PND4 |  |
|  |  |  |  |  | 0.046 | NOAEL | F0 dams: no adverse effects in the pre-coital time, mating, fertility and fecundity indices |  |
|  |  |  |  |  |  |  | F1 males: no significant difference in uterine/implantation data, % of male offspring, or number of epididymal sperm |  |
|  |  |  |  |  |  | LOAEL | F1 males: at PND70 - 2.1% increase in abnormal sperm & ~15% decrease in testicular spermatids | No significant differences at PND120 |

## Synthesizing and Presenting Information

**Exposure-Response Array for Selected Toxicity Data***** (Grouped by Endpoint**** )*

## Acknowledgements

**Argonne:**
- Maryka Bhattacharyya *(STA)*
- Young-Soo Chang
- Andrew Davidson *(STA)*
- Margaret MacDonell
- Dave Peterson
**NCEA:**
- Belinda Hawkins
- Janet Hess-Wilson
- Glenn Rice
- Jeff Swartout
- Linda Teuschler
- Bette Zwayer

**Summer Interns:**

**Family**

- Caitlin Burke
- Amy Green
- Jonathan Harris
- Vivian Nwachukwu
- Sameera Rahman
- James Shannon
- David Wyker