1. Backgrounds and Thresholds in Non-Cancer Dose-Response: Implications for Low-Dose Risk Lorenz Rhomberg, PhD ATS Gradient
Beyond “Science and Decisions”:
From Issue Identification to Dose-Response Assessment
Austin, TX 16 March 2010

2. THREE LINES OF ARGUMENT:
White et al EHP 117(2):283
Science and Decisions – Chapter 5
THREE LINES OF ARGUMENT:
Additivity to Background Processes that Produce Background Disease;
Heterogeneity in Sensitivity Among Humans;
Observed Linearity of Noncancer Effects in Epi Studies (of Criteria Pollutants)

3. Exposure Misclassification in Epidemiology
Biases Toward Flat Dose-Response
and Obscures True Thresholds
Brauer et al. 2002
Risk Anal 22(6):1183

4. Heterogeneity Leads to a Lognormal Distribution, Not Low-Dose Linearity
Lutz WK Carcinogenesis 11(8):1243

5. Additivity to Background

6. BIOLOGICAL ARGUMENTS MODELING ARGUMENTS (for thresholds)
(for additivity-to-background and low-dose linearity)

7. Individual Fate vs. Collective Function
Higher Level Need
Collective Function
repair R E D U N D A N C Y

8. Defenses Reduce Impact (mostly molecular)
Detoxification and clearance
Alternative targets
Tolerate Impact (mostly cellular & organ/system)
Excess Capacity
Redundancy
Counteract Impact (mostly cellular & organ/system)
Homeostasis
Compensation
Repair Damage (DNA)
THIS SLIDE WAS NOT USED IN PRESENTATION

9. Pathophysiological Progression
Figure 1. Pathogenesis of fibrosis from the tissue perspective.

10. Population Distribution of Internal State
REL
FREQ
Value of Key Internal Variable

11. Some % Beyond Threshold – Leading to a Background Rate of Disease
REL
FREQ
Value of Key Internal Variable

12. Even a Small Shift in Distribution of Internal State Leads to Greater % Beyond Threshold
REL
FREQ
Value of Key Internal Variable

13. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
… and how do they match up with our observations and understanding of non-cancer toxicity?
REL
FREQ
Value of Key Internal Variable

14. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
(1) Background Disease is the same as adverse effects observed at high dose
REL
FREQ
Value of Key Internal Variable

15. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
(2) BG Disease exists in the target population
it is their background that is being added to
REL
FREQ
Value of Key Internal Variable

16. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
(3) Extreme value of internal variable is sufficient to cause/enable BG disease
REL
FREQ
Value of Key Internal Variable

17. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
(4) Continuous distribution of underlying key internal factor
not a distinct sub-population with other causes
broad continuity between “normal” and “abnormal” ranges
REL
FREQ
Value of Key Internal Variable

18. What Biological Assumptions Does Such Additivity-to-BG Implicitly Make?
(5) Small doses do indeed shift the distribution
ie, the effect on the internal variable is assumed to be linear/no-threshold!
REL
FREQ
Value of Key Internal Variable

19. The OTHER tail!
… with a shift in distribution, fewer individuals are in the extreme of the tail one is moving away from!
REL
FREQ
Value of Key Internal Variable

20. What human disease states are equivalent to animal endpoints?
EP = BG
BG in Humans
Threshold within Existing Variation
Continuity of Mainstream and Affected
Small Doses Shift Distribution
Are usual IRIS endpoints observed as (uncommon) occurrences in natural populations?
What human disease states are equivalent to animal endpoints?

21. What human disease states are equivalent to animal endpoints?
EP = BG
BG in Humans
Threshold within Existing Variation
Continuity of Mainstream and Affected
Small Doses Shift Distribution
What human disease states are equivalent to animal endpoints?
How common?
Is the MoA for background human disease the same as high-dose animal adverse effects?

22. Is it unhealthy merely to be on the edges of normal variation?
EP = BG
BG in Humans
Threshold within Existing Variation
Continuity of Mainstream and Affected
Small Doses Shift Distribution
MoA? How does just crossing the threshold precipitate disease? What is biologically necessary? Sufficient?
Is it unhealthy merely to be on the edges of normal variation?

23. EP = BG
BG in Humans
Threshold within Existing Variation
Continuity of Mainstream and Affected
Small Doses Shift Distribution
Is there a gradual gradation between normal and abnormal states? How does this gibe with our notions of “healthy” “normal” and “disease” as distinct states?
In view of pathophysiological progression of toxicity, what evidence for widespread intermediate states?

24. Role of homeostasis, control processes, and defenses?
EP = BG
BG in Humans
Threshold within Existing Variation
Continuity of Mainstream and Affected
Small Doses Shift Distribution
Why does the dose shift the distribution in a linear/no-threshold way? Are we just assuming linearity at a lower level of biological organization?
Role of homeostasis, control processes, and defenses?

25. Two Views of the Living System
Delicate balance
Toxicity is falling off the edge of normal, and normal goes to the edge
Robust, self-controlling in the face of environmental fluctuations
Toxicity is a cascade of failures of control processes pushed too far

26. Questions
How do “biological” and “modeling” views and their conceptions of underlying process match up?
How general is an additivity to background issue expected to be? What would need to be shown?
How should our vast experience with apparently threshold toxicity enter the discussion?