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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New tools of toxicology and exposure science opportunities for informing low dose evaluations

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


The paradigm shift low dose linear response default assumption for cancer and non cancer endpoints
The Paradigm Shift Opportunities for Informing Low-Dose Evaluations : 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


Assumption of linearity the natural chemicals conundrum
Assumption of Linearity: Opportunities for Informing Low-Dose Evaluations 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?


Value of new tools of toxicology dose response
Value of new tools of toxicology: Opportunities for Informing Low-Dose Evaluations Dose-response

Naciff et.al., Tox.Sci. 2005


Genetic susceptibility Opportunities for Informing Low-Dose Evaluations

Susceptibility: Dose response implications

PON1 KO?

Wild-type

Response

Dose


* Opportunities for Informing Low-Dose Evaluations

*

20

MNU

MMS

15

*

Reticulocyte-MN (‰ ave)

10

*

*

5

*

0

0

0.01

0.1

0.5

1

5

10

25

50

Dose group (mkd, 4d)

Nonlinear Dose Response for Micronuclei (MN) in Reticulocytesas Measured by Flow Cytometry


Genes significantly changed in liver vs control as measured by microarray

125 Opportunities for Informing Low-Dose Evaluations

100

75

Genes Significantly

Changed vs. Control (#)

50

25

0

0.5

5

50

MMS (mkd, 4d)

Genes Significantly Changed in Liver vs. Control as Measured by Microarray

↝ 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)


Mega fish study non linear response to genotoxic carcinogen dibenzo a l pyrene
Mega-Fish Study: Non-linear Response to Genotoxic Carcinogen Dibenzo[a,l] pyrene

Bailey et.al., Chem.Res.Toxicol. 22: 1264-1276 (2009)


Value of new tools of toxicology modes of action
Value of new tools of toxicology: Dibenzo[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


Exposure dosimetry relationships implications for future risk assessment
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


Linking animal toxicity tests to human exposure
Linking Animal Toxicity Tests to Human Exposure risk assessment

From: Hays et.al., Reg.Toxicol.Pharmacol 47: 96-109, 2007


Linking animal test doses to human exposure
Linking Animal Test Doses to Human Exposure risk assessment

Saghir et.al., TAAP 211: 245, 2006


Summary
Summary risk assessment

  • 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”


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