New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations
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Transcript of New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations
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New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations
James Bus, PhD, DABT, ATS
The Dow Chemical Company“Beyond Science and Decisions: From Problem Formulation to Dose Response”
Workshop I, March 16-18, 2010
Austin, Texas
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The Paradigm Shift: Low-dose linear response default assumption for cancer and non-cancer endpoints
• Did Silver Book seriously considered critical alternative, i.e., all responses exhibit practical thresholds (non-linear behaviors)?
• Evidence of thresholds (non-linear behavior) for all responses:• Radiation and chemical hormesis• DNA-reactive substances – genotoxicity assays• Whole animal cancer and non-cancer bioassays
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Assumption of Linearity: The “natural chemicals” conundrum
• Tens’s of thousands of natural chemicals in everyday environment• Many present in significant doses in “healthy foods” • Exhibit full range of toxicologic properties associated with anthropogenic
chemicals, including genotoxic activity• Silver Book default assumption of linear low-dose toxicity responses further
magnifies natural chemical conundrum, i.e., otherwise “healthy” foods are judged to be even “unhealthier”
• Future risk assessment paradigm must be able to differentiate healthy food from true chemical risks
>>> What can new tools of toxicology and exposure science reveal?
Author/Date
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Susceptibility: Dose response implications
Dose
Response
Wild-type
Genetic susceptibility
PON1 KO?
Author/Date
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Nonlinear Dose Response for Micronuclei (MN) in Reticulocytesas Measured by Flow Cytometry
0 0.01 0.1 0.5 1 5 10 25 500
5
10
15
20
MMS
MNU
Dose group (mkd, 4d)
Ret
icu
locy
te-M
N (
‰ a
ve)
*
**
*
**
Author/Date
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Number of Genes Significantly Changed
25 mkd 50 mkd
1.5 fold 8 112
2 fold 3 79
3 fold 2 38
4 fold 2 31
5 fold 0 20
Genes Significantly Changed in Liver vs. Control as Measured by Microarray
0
25
50
75
100
125
0.5 5 50
MMS (mkd, 4d)
Ge
ne
s S
ign
ific
an
tly
Ch
an
ge
d v
s. C
on
tro
l (#
)
↝ Agilent complete rat genome(41,121)
↝ GeneSpring prefilter (21,205)
↝ ANOVA p<0.001 (126) Tukey’s post-hoc p<0.05↝
(20 and 121)
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Mega-Fish Study: Non-linear Response to Genotoxic Carcinogen Dibenzo[a,l] pyrene
Bailey et.al., Chem.Res.Toxicol. 22: 1264-1276 (2009)
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Value of new tools of toxicology: Modes of Action
• Rapid identification of “alternative” modes of action• Liver tumors: PPARα vs CYP P450 enzyme induction
• Improved animal models, e.g., humanized mice• Identify and test potential animal-model-specific responses
• Test hypothesized “common” and/or “cumulative” modes of action• AhR-mediated toxicity
• Assess question of “how to add” risks of complex mixtures
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Exposure-dosimetry relationships: Implications for future risk assessment • Advancements in analytical and modeling technologies rapidly
improving both animal dosimetry and human exposure evaluations (biomonitoring)
• Refinements to “Margin of Exposure” approaches• “Biomonitoring Equivalents” approach (Hays et.al.,
Reg.Toxicol.Pharmacol 47: 96-109, 2007)• Internal dosimetry for short half-life compounds
» Steady-state concentrations under conditions of toxicity test» Peak and/or steady-state AUCs in human exposures
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Linking Animal Toxicity Tests to Human Exposure
From: Hays et.al., Reg.Toxicol.Pharmacol 47: 96-109, 2007
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Linking Animal Test Doses to Human Exposure
Saghir et.al., TAAP Saghir et.al., TAAP 211: 245, 2006211: 245, 2006
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Summary
• New tools of toxicology offer unprecedented opportunities to better characterize the shape of the dose response under dose-exposure conditions relevant to real world exposure
• Emerging data provides biological basis for existence of toxicological thresholds (non-linearities), even for genotoxic substances
• Human exposure advances and information can be integrated into dose-response considerations of toxicity tests
• Opportunities to improve Margin of Exposure risk approaches• Objective: Differentiate “healthy” from “harmful”