Summary of Non

Mammalian To

Reevaluatio

Elizabeth 

Senior Scientist, Health 

Office of Pest

mendez.eliz
Status of Reevaluatio

z Approximately 100 studies reviewe

 Mode of action (MOA) Reproductive/developmental effects Immunotoxicity Neurotoxicity Carcinogenesis

z Effects on neuroendocrine function 

sensitive effects 

z Review of additional studies availa

February 2010 ongoing
Mode of Action

z Understanding of MOA expanded:

 2003 MOA: Perturbation of hypothal

pituitary-gonadal (HPG) axis still app

 Activation of the hypothalamic-pituit

(HPA) axis may precede effects on H

• Changes in ACTH, corticosterone, 

progesterone within minutes of e

• Toxicological significance of adren

changes per se
Mode of Action (2)

 General stimulatory effect on 

steroidogenesis not a direct effaromatase 

 Delays in puberty onset in both  Prostatitis related to a decrease 

in atrazine-exposed dams durin

 Mammary gland tumor develop

relevant to humans
Mode of Action

Atrazine

f

c

i

Steroidoge

Adrena

♀and

♂

uProgestero

Corticoste

Gonad

♂

♀

Δ TestostΔ EstrogeΔ Proges

Pituitary

vLH

uACTH

vProlactin

vGnRH pulses

CNS

CRH/AVP

(Catecholamines

Neuropeptides)

(Catecholamines

Neuropeptides)

?

d

e

g

h

u
z Immunotoxicity

 Exposure during development ma

altered immune function in offspr

 Not more sensitive than the atraz

effects on neuroendocrine functio

z Neurotoxicity

 Not more sensitive than the atraz

effects on neuroendocrine functio

 No association between atrazine e

Parkinson’s Disease

Immunotoxicity and Neuro
Conclusions

z Toxic effects due to multilevel intera

variety of systems (i.e., neuroendoc

reproductive, nervous, and immune 

z Activation of the HPA axis followed b

of the HPG axis lead to the most senattributed to atrazine exposure

z Extent of HPA activation (duration o

needed to elicit the decrease in GnRsubsequent LH surge attenuation no
Next Steps: In Preparation for 

z Apply MOA Framework to Analyze Data

 Further characterize HPA/HPG axes inter

• Describe temporal relationship betwe

activation and adverse health outcom

• Better describe dose-response relatio

atrazine exposure, HPA axis activation health outcomes

– Conduct benchmark dose analysis to bet

dose-response curve for the effects on H

z Additional Data Review during the Spring/S

 Data available from February 2010 until  Mammary gland development
Next Steps: In Preparation for 

z Determine duration of exposurez Life stage: Response to chemical expos

through life stages

z Review available non-cancer epidemiologz Weight of evidence analysis integrating e

toxicity and epidemiology data

z Propose new points of departure (PoDs)z Reevaluate FQPA Safety Factor z Reconsider the drinking water sampling 

relation to the toxicological duration of c

 Shorter duration of toxicological conc

more frequent sampling 
MOA Framework

z Postulate MOA: Can the MOA be establishez Describe Key Events: Empirically observab

steps that are necessary elements of the M

z Establish dose-response concordancez Establish temporal concordancez Strength, consistency and specificity of asso

adverse health outcome with key events

z Biological plausibility and coherence: Are k

plausible in humans on a quantitative and q

z Other MOAs: Can other MOAs be ruled outz Statement of confidence, analysis, and imp

Articulates the uncertainties, strengths, weaimplications of the analysis 
MOA Data on Key Eve

z Additional Data Expected in Spring/Summe

 Effect of 4 day atrazine exposure on ACTH, corti

progesterone, and LH

 Effect of atrazine on steroidogenesis in rat granu

al., submitted for publication) 

 Effect of atrazine exposure on GnRH and kisspep Effect of gestational exposure to atrazine on ma An oral (gavage) immunotoxicity and hormone e

the effects of atrazine in male rats

 Male prostate inflammation following low dose m

(manuscript in preparation)
MOA Data on Key Event

z Additional Data Expected in Spring/S

 An oral (gavage) study of the effects of 

estrous cycle and the estrogen-induced hormone (LH) surge in female rats

 Comparison of the effects of atrazine on 

release and the LH Surge in non-adrenacompared to adrenalectomized female W

 Use of a Physiological Based Pharmacok

(PBPK) to characterize atrazine biotransfinactive moieties in relationship to dynamhormone levels and potential adverse ou

 Dose-Response Modeling and Determina

of Departure for Risk Assessment: Valid
Dose-response Concord

z Establish extent of corticosteron

needed to result in adverse hea

z Incorporate these data in POD 

determination
Temporal Concordan

z Duration of changes in GRH, AC

corticosterone, and progesteronfor adverse health outcome

 Changes seen within minutes of e Sustained changes needed to elic

health outcome?

• 1 day, 4 days, 1 week ...

z Atrazine and its metabolites qui

absorbed and distributed in the 
Review of Experimental Data Rayner, J.L., et al. (2005) Adverse effe

exposure to atrazine during a critical pe

mammary gland growth. Tox. Sci. 87

 Rayner, J. et al. (2003) Exposure Para

Necessary for Delayed Puberty and Mam

Development in Long-Evans Rats Expos

Atrazine. Toxicology and Applied Ph

195:23-34 

 Enoch, R.R., et al. (2007) Mammary Gla

Development as a Sensitive End Point a

PrenatalExposure to an Atrazine Metab

Female Long-Evans Rats. Environ. He

115:541–547

Mammary Gland Develo
 Rayner, J. et al. (2007) Atrazine-induce

tract alterations after transplacental an

exposure in male Long–Evans rats Tox

Pharmacol. 218(3):238-248

 Atrazine dose-dependent effects on ma

development in Sprague Dawley and Lo

female rats (in preparation)

 Effects of atrazine-induced mammary g

Sprague-Dawley and Long Evans rats o

induced tumor incidence. (in preparatio

 Coder, P.S. (2010) An Oral Developmen

Atrazine in the Rat, including Cross-Fos

Feeding. Unpublished

Mammary Gland Develo
2011 SAP on Carcinoge

z AHS epidemiology study on atra

human cancer publication

z Integrate experimental carcinog

and epidemiology data (AHS ancancer epidemiology studies)