u-shaped dose response curves - mclaughlin centre
TRANSCRIPT
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1Health Risk Assessment of Essential Metals
U-Shaped Dose Response Curves
Current risk assessment & management modelsCurrent Issues and Activities
Implications for U-Shaped Curves on risk characterization
Michael DoursonToxicology Excellence for Risk Assessment (TERA)
Cincinnati, Ohio, USA
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2Health Risk Assessment of Essential Metals
HAZARDIDENTIFICATION
RfDs & RSDsDOSE RESPONSE
EXPOSURE ASSESSMENT
RISK CHARACTERIZ-
ATION
BEST AVAILABLE TECHNOLOGY
ENGINEERING OPTIONS
PUBLIC RESPONSE
POLITICAL CONSIDERATIONS
NAS 1983
COST
Risk Assessment/Management Model
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3Health Risk Assessment of Essential Metals
Risk Assessment & Management Model in a Nutshell
Hazard Identification: IS THIS STUFF TOXIC?Dose-Response Assessment: HOW TOXIC IS THIS STUFF?Exposure Assessment: WHO IS EXPOSED TO THIS STUFF, HOW MUCH, HOW OFTEN, AND FOR HOW LONG EACH TIME?Risk Characterization: SO WHAT?Risk Management: SO WHAT ARE YOU GOING TO DO ABOUT IT?
(Don Barnes, 1993)
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4Health Risk Assessment of Essential Metals
Derivation of Tolerable Daily Intake (TDI), Reference Dose (RfD) & Risk
Specific Doses (RSDs)Provides a scientific basis for evaluating whether existing environmental exposures are impacting public health. Promotes risk communication by informing the public of potential adverse effects of chemical exposure.Enhances product stewardship efforts by providing more complete health and safety guidance to chemical manufacturers.
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5Health Risk Assessment of Essential Metals
General Method for Setting
TDI, RfD or RSDs
TDI, RfD or RSD = Point of Departure/UF or Risk/Slope
where:
Point of Departure = No Observed Adverse Effect Level (NOAEL) or Benchmark Dose (BMD) divided by a composite Uncertainty Factor (UF).
Risk = your choice of generally 1 person in 10,000 to 1 person in 1,000,000 divided by slope of dose response curve at BMD.
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6Health Risk Assessment of Essential Metals
Several Judgments Are Needed
such as...
the choice of the most appropriate point of departure of the critical effect, often from experimental animal data, and
the choice of the appropriate uncertainty factor or risk level based on a review of the entire data base.
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7Health Risk Assessment of Essential Metals
Critical Effect
RfD or RSD POD
Concentration
HORMONE CHANGE
INHIBITION OF IODINE UPTAKE HYPOTHYROIDISM(1ST ADVERSE EFFECT)
NEONATAL CNSEFFECTS
FELLOAEL
% R
espo
nse
Thyroid Tumors
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8Health Risk Assessment of Essential Metals
Current Issues and Activities:Critical Effect & Point of Departure
Trend: better characterizing dose response of critical effect in low-dose region. For example,
Benchmark dose (BMD), categorical regression and Markov-Chain Monte Carlo for toxicokinetic models (Andersen and Clewell, multiple publications).Cooperative agreements to address dose-response approaches for mutagenic chemicals (Moore and Haber, 2006).Evaluation of severity, adversity, adaptation, compensation, hormesis and essentiality in critical effect.
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9Health Risk Assessment of Essential Metals
Current Issues and Activities:Use of Precursor Data
Trend: increasing use of precursor data to judge mode of action.For example,
Meek (2008) Mode of action frameworks for evaluating experimental animal evidence in relationship to humansU.S. National Institute for Occupational Safety and Health research for evaluating biomarkers; includes Bayesian network for using biomarker data (publications under development). U.S. Environmental Protection Agency (EPA) research on the pathology-physiological progression to develop criteria to categorize endpoints (society presentations made).
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10Health Risk Assessment of Essential Metals
Current Issues and Activities:Uncertainty Factors
Trend: using chemical data to move from default values of 10-fold. For example, International Programme on Chemical Safety (IPCS, 2005) methods for using chemical-specific adjustment factors (CSAFs) (multiple published papers).SOT Award-winning papers on implications of genetic polymorphisms for development of uncertainty factors and CSAFs, children’s risk, and methods for addressing human variability (Haber et al., 2002).The default is to use data; use 10-fold reluctantly.
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Increasing Dose
Background
BeneficialEffect
AdverseEffect
Point ofDeparture
(e.g., BMDNOAEL)
TDI,RfD
Does an essential level exist above the range of the TDI, RfD or RSD?
RSD
?
cancer
non-cancer
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12Health Risk Assessment of Essential Metals
Implications for Essentiality on RfD or RSDs & Risk Characterization
A Risk Assessment Definition for Essential Elements…
Statistical or biological significant increases in adverse effects at both lower and higher doses from an optimal or background point in the dose response curve.
A Risk Assessment Definition for Hormesis…
Statistical or biological significant decreases in adverse effects below background in the low dose region.
With either definition, low, but yet still measurable doses, exhibit a positive, beneficial effect.
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13Health Risk Assessment of Essential Metals
BackgroundRange
Increasing Dose
BeneficialEffect
General Form of the Essentially/Hormesis Curves
AdverseEffect
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14Health Risk Assessment of Essential Metals
Mechanisms for Hormesis (partial listing)
Essential nutrients – such as chromium & copper Overcompensation & induction of protective responses –increased heat shock proteins from mild heat stress or gutathione from oxidative stressBenefits and risks to different organs---low dose ethanol benefits in heart, but high dose problems in CNS & liverShifts in response spectrum – cyclophosphamideincreased resistance to flu; decreased resistance to tumors.Stimulatory and inhibitory receptors within same organ (apomorphine)Masking---antimicrobial stimulation of growth masking overall toxicity measured by changes in body weight
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Increasing Dose
NOAEL, BMD ofadverse effect
TDI,RfD
CSAF
RDA
RSD
NOAEL, BMD ofessential effect
SF
cancer
non-cancer
BackgroundRange
AdverseEffect
BeneficialEffect
The current approach to the essentiality problem; separate groups
that may or may not talk to one another develop “safe” levels.
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16Health Risk Assessment of Essential Metals
A Way Forward?
Case by Case (current approach for essential nutrients)
A Mode of Action (MOA) approach: Are MOAs the same and effect severities similar?
No and No, develop “RDA” and RSD or RfD, allow overlap if biology indicates (Scott Baker--copper), or plot composite effect/benefit curve by addressing severity via categorical regression No and Yes, plot composite data using new models, determine nadirYes and No, plot composite effect/benefit curve by addressing severity via categorical regression Yes and Yes, plot using new models, determine nadir
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Increasing DoseIncreasing Dose
BackgroundRange
TDI,RfD
Is mechanism the same? Effect severity similar? No and No: Develop RDA, and RSD, TDI or RfD;combine curves (as below) or model via categorical regression(see next presentation by Daniel Krewski)
AdverseEffect
RSDBeneficial
Effect
Point ofDeparture
cancer
non-cancer
RDA
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•Total mortality: J-shape response for ethanol intake
•Cancer: no apparent increase until higher drinking levels
•Cardiovascular: U-shaped response
•Coronary Heart Disease: L-shaped threshold effect
Is mechanism the same? Effect severity similar? No and Yes: Plot composite data using new models, determine nadir
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19Health Risk Assessment of Essential Metals
Is mechanism the same? Effect severity similar? Yes and No: Plot composite effect/benefit curve by addressing severity via categorical regression .
Could not think of such an example.
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•Survivors of Hiroshima and Nagasaki
•Radiation hormesis
•8 cGy is optimum for suppression of leukemia
•Dr. Luckey’s claim that “low dose radiation is stimulating and essential for life!”
Is mechanism the same? Effect severity similar? Yes and Yes: Plot using new models and determine nadir
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21Health Risk Assessment of Essential Metals
Research on Essentiality
Essentiality is “testable” at low doses relevant to actual human exposures.Essentiality provides evidence that two thresholds likely exist for toxic effects in an individual; this evidence may aid in the estimation of these thresholds in populations.Knowledge of the shape of the low dose curves of the critical effect for both essentiality and toxicity would allow for estimating the nadir in the dose response assessment.
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22Health Risk Assessment of Essential Metals
Conclusions
The existing risk assessment & management model is general and can incorporate essential elements, but it lacks precision. A mode of action framework may provide approaches for characterizing risk and benefit of essential elements, but must address the differing severity of effects.Current dose response data gaps hinder the evaluation of the the risk and benefit of several essential elements; new modeling methods, such as categorical regression need to be further explored.
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23
Extra slides
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Is This Hormesis?
•Hepatic DNA was obtained from 8 – 15 female rats given methylene chloride orally.
•Only one data point was observed to show an “apparent” protective effect.
•Bars indicate 95% CI
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25Health Risk Assessment of Essential Metals
Areas of Uncertainty to Consider in Noncancer Dose Response Assessment
Res
pons
e
Dose
0.1
UFH
UFS
UFL
UFD
UFA
Chronic Human Chronic AnimalSub-chronicAnimal
Reproductive
PBPKmodel
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Within Within Human Human ExtrapolationExtrapolation
(Dourson et al., 2002)
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Within Within Human Human ExtrapolationExtrapolation
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28Health Risk Assessment of Essential Metals
5b.
Within Within Human Human ExtrapolationExtrapolation
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29Health Risk Assessment of Essential Metals
Casarett and Doull, 6th Edition, page 19
Within Within HumanHumanExtrapolation Extrapolation
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30Health Risk Assessment of Essential Metals
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31Health Risk Assessment of Essential Metals
Mortality in CR B6C3F1 Mice As a Function of the Dose of Benzyl Acetate
•DR curve with minima at the middle dose at 18 mos. And a minima at the low does at 24 mos.
•Survival at 0 dose keeps deteriorating with age.
•Mortality is inhibited at the medium doses of compound.
Dose (ppm)
0
5
10
15
20
25
0 1000 2000 3000
24 Months18 MonthsM
orta
lity
(%)