u-shaped dose response curves - mclaughlin centre

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


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


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)


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.


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.


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.


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


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.


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).


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.

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


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.


BackgroundRange

Increasing Dose

BeneficialEffect

General Form of the Essentially/Hormesis Curves

AdverseEffect


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

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.


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

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

•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


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.

•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


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.


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.

23

Extra slides

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


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

Within Within Human Human ExtrapolationExtrapolation

(Dourson et al., 2002)


5b.



Casarett and Doull, 6th Edition, page 19

Within Within HumanHumanExtrapolation Extrapolation


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

(%)

u-shaped dose response curves - mclaughlin centre

Documents