Integration of Epidemiology 

Toxicity Data into Health R

Assessment

Presentation to Presentation to Scientific Advisory Scientific Advisory Panel

July 26-29, 2011

Elizabeth Méndez, Ph.D. 

Health Effects Division

USEPA Office of Pesticide Programs
Draft Framework for Integratin

Epidemiology and Toxicity DaEpidemiology Epidemiology and Toxicity Toxicity Da

• Conce

pts in the Draft 2010 Framework are 

pee

r-reviewed, robust principles & tools 

• Standard practice in epidemiology, toxicology & 

assessment 

• Integrating new approaches based on recomme

from 

• NRC 2007: Toxicit

yg y Testin

g in the 21st Centur

y

• NRC 2009: Science & Decisions: Advancing Risk Ass

• Flexibility to incorporate information from differe• Transparent tool for organizing, reviewing & inte

Transparent tool for organizing, reviewing

& inte

complex information

• February 2010 SAP reviewed Agency’s pro

Draft Framework Draft Framework
M d f A ti Chemical

Dose Response 

Assessment

C d

Population Based

Studies

Mode of Action Characterization

Compounds

Assess

Biological 

Perturbation

Affected

Pathway Dose Response Analysis for 

Perturbations

of Toxicity 

Pathways

Calibrating 

in vitro and human

Dosimetry

Perturbation

Measures of

dose in vitro

Human Exposure

Data 

Metabolite(s)

Hazard Characterization

Exposure Assessment

Risk Characterization
Toxicity Testin

g in the 21 Toxicity Testing in the 21st C

y g st C

• National Research Council: “Toxicity Te

the Twenty

-First Century: A Vision and a Century:

A Vision and

a

Strategy”. 

• The re

p 

ort states that “the committee’s visio

shift away from traditional toxicity testing thon demonstrating adverse health effects in ex

p p

erimental animals toward a dee

per unde

of biologic perturbations in key toxicity pathlead to adverse health outcomes.” 

• H

o e e , e co ee cau o s a u

w

e

v

e

r, th

e committee cauti

o

n

s th

at “virtu

environmental agents will perturb signaling to some degree, a key challenge will be to dwhen such 

perturbations are likel

y to lead to 

effects and when they are not.”
Exposure

Utk D li t T t Ti

Adverse Outcome Pathway

Examp

“Normal”

Uptake‐Delivery to Target Tissues

Perturbation

Cellular response pathway

Biologic

inputs

Normal

Biological

Function

Cell inury,

Inability to

l

Adaptive

Responses

Early cellular

changes

regulate

Molecular

initiating event

Perturbed cellular

response pathway

Adverse outcome

relevant to

risk assessment

Toxicity Pathway

Adverse Outcome Pathway
Mode of Action Framework Mode of Action Framework Framework

Modified Bradford Hill Criteria

• Postulated mode of action 

• Identify sequence of key events on the p

h lth t health ou

tcome

• Experimental support

• Concordance of dose-res

p y onse for ke

y e

• Temporal relationships for key events

• Biological plausibility & coherence• St th i t & ifi it Strength, consis

tency 

& specifi

cit

y

• Other modes of action

• Identify uncertainties

Identify uncertainties

• Conclusion 
Organization of the Draft Framew

Integrating Integrating Epidemiology and Tox

Integrating Epidemiology Epidemiology and Tox

Tox

• Reviewing Epidemiology Studies for U

Pesticide Risk Assessment 

• Types of studies• Scientific factors to consider in reviewing• Benefits & uses of epidemiology in risk 

assessment

• Proposed Weight of the Evidence (WO

Analysis

• Consider mode of action information• Consider experimental toxicity data Consider experimental toxicity data• Consider epidemiology data 
WOE analysis: Non WOE analysis: analysis: Non

-cancer E

cancer E

E

• MOA: Neuroendocrine perturbation o

HPG axis HPG axis

• Ovarian cyclicity disruption• Reproductive senescence• Other reproductive effects

• General toxicity: low birth weight or s

for gestational age for gestational age

• September 2010 SAP concurred with 

Ag y enc

y’s conclusions:

• Epidemiology data useful for hazard 

identification but not robust for dose-resor risk characterization 
WOE Analysis: Cancer E

• Ex

p y erimental toxicit

y data

•

E

pidemiology D

• Mammary gland tumors in rats due 

to HPG axis disruption

• MOA not operative in humans

p gy

• Varying degrees 

• Limitations ran

inconsistency 

th d f • No other tumors identified 

in experimental toxicity data

meth

o

d o

f exp

assessment anof exposed cas

data

• The weight o

• April 2010 SAP reaffirmed 

conclusions of previous 

The weight o

does not supassociation b

ti 

SAPs regarding cancer classification for atrazine as

“not likely to be

a

trazine expo

cancer

as not likely to be

carcinogenic to humans.”
Conclusion

• Non-cancer effects

• Based on experimental toxicity data, L

suppression (BMDL = 2.56 mg/kg/day) 

protective of other effects protective of other effects

• Epidemiology data useful for hazard 

identification but not robust for dose-re

or risk characterization (Presented to tin September 2010)

• C ff t ancer effects

• Available data do not support associat

between atrazine exposure and cancebetween atrazine exposure and cance

Ovarian Cyclicity Disrup

• MOA: HPG axis disruption 

leading to altered reproductive 

• Reproductive se

• Experimental to

Early reproduct

function

• Experimental toxicity data: 

Estrous c

yclicit

y disru

ption in rats

Early reproduct

senescence

• Epidemiology d

Menopause de

• Women ever 

yy p

• Epidemiology data: Menstrual 

cycle disruption

• Women re

portin

g ever usin

g

• Women ever 

 not possib

timing andatrazine emenopausli it d f 

pg g atrazine or lindane during their 

lifetime. 

 not possible to estimate the 

timing of pesticide exposure in

 li

mit

e

d

fre

menopauswomen

 pesticide e

assessme

timing of pesticide exposure in

relation to changes in the menstrual cycle

exposure-assessme

• Different biolog

leading to repro

senescence
Male reproductive Effe

• Decreases in LH lead to decreases in testost

pyg otentiall

y affectin

g andrology

p ( arameters 

(i.

quality)

• Experimental toxicity data

• Rats: Decreased testosterone levels in at high doses 

Rats: Decreased testosterone levels in at high doses

mg/kg/day)

• Pigs: in vitro studies suggest effect on sperm motility 

viability

• Humans:

in vitro n vitro study suggests effect on sperm moti

study suggests effect on sperm moti

viability but no evidence of correlation with impaired rperformance

• E

p gy y idemiology stud

y

• Increase in odds of poor semen quality in association 

exposure. 

 Small sample size with low precision Exposure to more than one pesticide was more frequent a

to more than one pesticide was more frequent a

poor semen parameters
Small for Gestational Age (S

or Low Birth Weight or Low Birth Weight

• Likely due to generalized toxicity and no

associ t d ith t i ia

t

e

d with a

trazine neuroend i ocr n

• Experimental Toxicity Data

• Decreases in fetal/offspring weights at high exp

Decreases in fetal/offspring weights at high exp

doses (

≥ 50 mg/kg/day)

• E

p gy idemiology data

• Increase in prevalence of SGA 

 Possible misclassification of outcome or exposure 

birth registries or maternal self birth registries or maternal self-report of birth weig

report of birth weig

gestational age

• Low birth weight not statistically significant

 Small sample size measure overall Small sample size, measure overall triazine triazine expos

expos

measurements of atrazine exposure during pregnaavailable