Atrazine Re-Evaluation: 

Scientific Considerations in Pot

Sensitivity of Infants & Childr

Presentation to Scientific Advisory Panel

July 26-29, 2011

Eli b th Eliza

b

eth Mé dn

dez, Ph D. . 

Health Effects Division

USEPA Office of Pesticide Programs USEPA Office of Pesticide Programs
FQPA 10X Safety Fac

Analysis

The FFDCA, as amended by the FQPA (1996), reqA t i i l tt ti t th t ti l i Agency 

to give special attention 

to the po

tenti

al ris

and children. Specifically, FQPA instructs EPA, in “reasonable certainty of no harm” finding, that in “th

th h ld ff t thres

h

old effec

ts, an additi l t f ld i f 

dditional ten

f

old margin o

f 

the pesticide chemical residue and other sources oshall be applied for infants and children to take into 

potenti l a pre- an

d post-natal ii d 

l toxicity an

d comp

data with respect to exposure and toxicity to inchildren.” Section 408 (b)(2)(C) further states tha

Administrator may use a different margin of safety 

pesticide chemical residue only if, on the basis of r

data, such margin will be safe for infants and childr

additional margin of safety is referred to as the “FQFactor.” 
FQPA 10X Safety Fac

Analysis

• H d C id ti Hazar

d

Considerations

• Important Issue: available data to assess 

lifestages

• Consider all the relevant information

• Mode of action Mode of action• Animal database of toxicology studies• Dose-response relationships• Human relevance of animal findings• Epidemiology findings
FQPA 10X Safety Fac

Analysis

• Hazard Considerations (cont’d)

• Consider all relevant information

• Neuroendocrine MOA relevant for reproduct

developmental effects

• Epidemiology findings discussed during Sep

Epidemiology findings discussed during Sep

SAP meeting

 Qualitative information on human relevance of an Not sufficiently robust to establish causal associa
FQPA 10X Safety Fac

Analysis

• Hazard Considerations (cont’d)

• Ex

p y erimental toxicit

y studies

• Core guideline toxicity studies (multigenerati

reproduction and developmental toxicity stud

• St di ifi St

udies on specific lif t es

tages ( t ti ges

t

ation, per

peripubertal, and reproductive age)

• None of the available studies provide endpo

None of the available studies provide endpo

(i.e., more sensitive) than studies on LH atte
FQPA 10X Safety Factor 

Analysis

AUTHOR (YR) EXPOSURE NOAEL/LOAEL /k /d ( ) 

mg/k

g/day

Gestational Exposure

(2008) GD14-parturition 10/50 D

R t l (2005) GD 13 19 NA/100 DeRayner et al. (2005) GD 13-19 NA/100 De

gla

Rayner et al. (2005) GD 17-19 NA/100 De

gla

R t l (2007) Rayner et al. (2007) GD 15-19 NA/100 

Fraites et al.

(2011) GD 14-21 20/100

Decr

and p

Davis et al.

(2011) GD 14-21 20/100

Decr

and p

0-4

†Decreased maternal body weight was also observed at the 100 mg/kg/day dose level 
FQPA 10X Safety Factor

Analysis

AUTHOR (YR) EXPOSURE NOAEL/LOAEL mg/kg/day 

Perinatal Exposure

PND1

4 12 5/25 Prosta

Stoker 1999

-

4 12.5/25 Prosta

PND 6-9 NA/25 Non-s

prosta
FQPA 10X Safety Factor

Analysis

NOAEL/LOAEL AUTHOR (YR) EXPOSURE mg/kg/day EFF

Peripubertal Exposure

Stoker et al ., 2001 PND 23 to 53 6.25/12.5 Delayed P

Trentacoste et al ., 2001 PND 22 to 47 50 lowest dose/100 Delayed PStoker et al ., 2001 PND 23 to 53 25/50 Decreased Trentacoste et al ., 2001 PND 22 to 47 50 lowest dose/100 Decreased Stoker et al ., 2001 PND 23 to 53 ND/200 Decreased 

testicular T 

Trentacoste et al ., 2001 PND 22 to 47 ND/50 Decreased 

47

Friedmann, 2002 PND 22 to 47 ND/50 Decreased 

serum T on 

Pogrimic et al ., 2009 PND 23 to 50 50/200 Decreased 

PND 50

Laws (2000) PND 22 41 25/50 Delayed VLaws (2000) PND 22-41 25/50 Delayed V

‡ Lowest dose tested
FQPA 10X Safety Factor 

Analysis

• Multi

-Lifestage Lifestage study

• Exposure encompassing prenatal, postnata

p p eri

pubertal, and adult lifesta

ges

• Evaluated female offspring only

• No effects on LH at 

≤ 50 mg/kg/day (highes

tested)

• Inconsistent with preponderance of peer reviewe

(e.g., Foradori et al. 2009, Cooper et al. 2007, 20

Morseth et al. 1996).

• Slight delay in VO (1.4 – 2.3 days) at 50 mg

exposure started in utero but not if it starte

p y ostnatall

y
FQPA 10X Safety Factor

Analysis

Multi-Lifestage Study
FQPA 10X Safety Factor

Analysis

• Summary

• Data available spanning Data available spanning lifesta

lifesta

from conception to adulthood

• No evidence o

f a unique quant

susceptibility in the developing 

organism
FQPA 10X Safety Factor

Analysis

• Summary (Cont’d)

• Reproductive/developmental effects 

consistent with perturbations of the H

• D i LH ti l k 

Decreases in LH serve as sentinel ke

in atrazine’s neuroendocrine MOA thato adverse outcomes in rats 

(y

dela

ys in 

onset, ovarian cyclicity disruption, inhsuckling-induced prolactin release/pro

• No effects at doses lower than those eliciting 

No effects at doses lower than those eliciting 

surge attenuation in adult female rats (BMDL1 

2.56 mg/kg/day). 

FQPA 10X Safety Fac

Analysis

AUTHOR (YR) EXPOSURE NOAEL/LOAEL mg/kg/day 

Cooper (2007) 4days adult cycling ♀ NA/25 ↓ GnRH release

Cooper (2000) 1 day adult cycling ♀ NA/300 mg/kg ↓ LH surge, estrous cyclicity disruptio

3 day adult cycling ♀ NA/50 ↓ LH surge

Cooper 2000 & 2010 4- day yg adult cycling ♀ 1.56/3.12 ↓ LH surge

Morseth (1996) 26 week 1.8/3.65 ↓ LH surge, estrous cyclicity disruptioCooper (1996) 21 days NA/75 estrous cyclicity disruptionStoker et al., 2000 PND 23 to 53 NA/12.5 Delayed PPSTrentacoste et al., 2001 PND 22 to 47 50 lowest dose/100 Delayed PPS

Stoker et al., 2001 PND 23 to 53 25/50 Decreased VP and SV

Trentacoste et al., 2001 PND 22 to 47 50 lowest dose/100 Decreased VP and SV

Stoker et al., 2001 PND 23 to 53 150/200 Decreased intra-testicular T on PND 

Trentacoste et al., 2001 PND 22 to 47 ND/50 Decreased T on PND 47

Friedmann, 2002 PND 22 to 47 ND/50 Decreased test. and serum T on PNPogrimic et al., 2009 PND 23 to 50 50/200 Decreased T/DHT on 

PND 50

Laws et al., 2009 (2010) 15 minutes - ♂ rats 5./50 mg/kg ↑ACTH. CORT, progesteroneFraites et al., 2009 15 minutes – cycling ♀ N.A./75 mg/kg atrazine 60.2 mg/kg DIA ↑ACTH. CORT, progesteronePruett et al., 2009 1 hour – adult ♀ mice N A /200 mg/kg atrazine N.A./200 mg/kg atrazine N A /200 mg/kg atrazine N.A./200 mg/kg atrazinePruett et al., 2003 6 hours– adult ♀ mice N.A./100 mg/kg atrazine N.A./100 mg/kg atrazine

Fraites et al., 2009 4 days – cycling ♀ N.A./12.5 mg/kg/day atrazine or 10 mg/kg/day DIA ↑ACTH. CORT, progesteroneMcMullin (2004) 5 days – OVXD ♀ NA/30 ↓ LH surgeForadori (2009) 4 days – adult ♀ NA/50 ↓ LH surge 50/100 ↓ GnRH immunoreactive cellsZorrilla (2010) Ex vivo 1/10 μM ↓ GnRH release

PND 22-41 25/50 Delayed VO

Laws (2000)

PND 22 41 25/50 Delayed VOPND 42-149 50/100 Disrupted cyclicity

Shibayama (2009)

2 or 4 weeks – start treating 5 wk old ♀ 30/300 Disrupted cyclicity, ↓ ovarian and ute

2 weeks pre-mating to GD 7 300/NA No effect in fertility

Rosenberg (2008) GD14-parturition 10/50 Delayed PPS

Rayner 2007 GD 15-19 NA/100 Delayed PPS, prostatitisStoker 1999

PND1-4 6.25/12.5 Prostatitis

PND 6-9 NA/25 Non-stat sig prostatitis
FQPA 10X Safety Factor

Analysis

Life Stage Life Stage LH Hormone LH Hormone Apical 

(NOAEL/LOAEL)

Apical 

NOAE

Pre-Natal (Fetus)

• 10/70 mg/kg/

ossification 

• 10/50 mg/kg/

10/50 mg/kg/

• 20/100 mg/k

pup weight, vVO

Perinatal (Lactational)

• 12.5/25 mg/k

prost titi a

s

Peripubertal

• 6.25/12.5 mg

prostatitis, de

• 25/50 mg/kg

va

g p

inal o

pen

• 50/100 mg/k

vaginal opentestosterone

Adult 2.56/4.92 mg/kg/day *(4 day 

exposure)

• 50/100 mg/k

cyclicity

*BMDL/BMD @ 1 standard deviation