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Dr. Tyrone Hayes
January 30, 2009
From Silent Spring to
Silent Night
# 58
Placeholder slideFrom Silent Spring
to Silent Night
Dr. Tyrone Hayes
University of California at Berkeley
January 30th, 2009
N N
N
Cl
N
H
N
H
ATRAZINE
ATRAZINE
IS AN HERBICIDE
USED WITH
MONOCOT CROPS
(CORN, SORGHUM)
AND STONE FRUITS
ATRAZINE
HAS BEEN USED
FOR 48 YEARS
ATRAZINE
80 MILLION POUNDS
USED ANNUALLY
IN THE U.S.
ATRAZINE
IS USED IN
MORE THAN
80 COUNTRIES
ATRAZINE
BUT NOW OUTLAWED
IN ALL OF EUROPE
1
Laboratory
Model
Testes
Ovaries
Testis
Ovaries
O
OH
Testosterone
T
O
OH
TestosteroneHO
OH
Estrogen
Aromatase
EATRAZINE
Atrazine-
Treated
Males
Control
Females
6
0
1
2
3
4
5
Blo
od
te
sto
ste
ron
e (
ng
/mL
)
Control
Males
Hayes et al. 2002
A
AA
B
B
A,B
B
B
Control
Males
Females
Malformed
0.1 1.0ATRAZINE (ppb)
7
6
5
4
3
2
1
0Aro
mata
se (
CY
P19)/
EF
-1-a
E-0
4
Hayes, unpubl. data
0
2
4
6
8
10
12
Su
ccessfu
l P
air
ing
s
Control Atrazine
Hayes, unpubl. data
Control
Males
Atrazine-
Treated
Males
0
33
66
100
Pe
rcen
t F
ert
ile
Hayes, unpubl. data
1
Laboratory
Model
2Comparative
Studies
Leopard
Frog
Testeseggs
3
Field
Studies
1
Laboratory
Model
2Comparative
Studies
ARE THE EFFECTIVE DOSES (> 0.1 PPB)
ECOLOGICALLY RELEVANT?
Runoff Temporary
Pools
PrecipitationPermanent
Water
0.001
0.01
10,000
1,000
100
10
1
0.1
Atr
azin
e (
pp
b)
Intersexes (Hermaphrodites)
DRINKING WATER
2.9 – 29 million
Atrazine use (kg/km2)
Zero or data missing
Less than 0.4
2.5 to 9.29.3 to 28.7More than 28.7
0.4 to 2.4
Atrazine No Atrazine
92% Hermaphrodites 0% Hermaphrodites
1
Laboratory
Model
3
Field
Studies
2Comparative
Studies4Field
Simulations
Atrazine
Metolachlor
Alachlor
Nicosulfuron
Methoxyacetyl
PropiconazoleTebupirimphos
Cyfluthrin
Cyhalothrin
SPRING
Nu
mb
er
at
Meta
mo
rph
osis
X Data
40 50 60 70 80 90
Y D
ata
0
2
4
6
8
10
12
tank001
tank002
tank003
X Data
40 50 60 70 80 90
Y D
ata
0
2
4
6
8
10
Plot 1
tank016
tank017
tank018
X Data
40 50 60 70 80 90
Y D
ata
0
2
4
6
8
10
Plot 1
tank032
tank033
tank033
40 60 80
Control
Atrazine and
S-metolachlor
Mixture of
9 compounds
0
3
6
9
12
0
4
6
8
10
2
0
4
6
8
10
2
Time (days)
Hayes et al., 2006
0.6 ppb Atrazine 15.3 ppb Atrazine
Time to complete tail reabsorption (days)
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80Bo
dy W
eig
ht
(mg
)
Control Atrazine + S-met Mix4000
3000
2000
1000
40 50 60 70 80 90
TR
1000
2000
3000
4000B
W
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000B
W
40 50 60 70 80 90 100
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
40 50 60 70 80 90 100 110
TR
1000
2000
3000
4000
BW
Time to complete tail reabsorption (days)
Bo
dy w
eig
ht
(mg
)
Control Cyfluthrin Nicosulfuron Tebupiromphos
S-metolachlor Metylaxyl Propiconazole -chyalothrin Atrazine
Atr + S-met
(0.1 ppb)
Atraz + S-met
(10 ppb)Bicep II
(0.1 ppb)
Bicep II
(10 ppb)
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
40 50 60 70 80
TR
1000
2000
3000
4000
BW
Alachlor
MIX
CONTROL MIX
Stress hormone
(Corticoids)
Immunosuppression,
Decreased growth,
Retarded development,
Inhibited metamorphosis
pesticides
Pesticide-treated
Males
Control
Males
0
1
2
3
4
Blo
od
Co
rtis
on
e (n
g/m
L)
Stress hormone
(Corticoids)
density
desiccation
temperature
pesticides
pesticides
Stress hormone
(Corticoids)
PESTICIDES
Kesieker,
2002
-- Forson and Storfer, 2006
Atrazine increases rana virus susceptibility
in the tiger salamander, Ambystoma Tigrinum
1
Laboratory
Model
3
Field
Studies
2Comparative
Studies4Field
Simulations
2001 2003
1
Laboratory
Model
3
Field
Studies
2Comparative
Studies4Field
Simulations
1
Laboratory
Model
3
Field
Studies
2Comparative
Studies4Field
Simulations
Santa Margarita Atascadera Salinas
29
31
33
35
37
Sta
ge
Santa Margarita Atascadera Salinas
Len
gth
(m
m)120
60
0
Margarita Atascadera Salinas
Yeast injection (g/ml)
Perc
en
t to
tal
0
20
40
60
80
100
0 0.0125 0.05 0.125 0.2 0.125 0.20 0.0125 0.05 0 0.0125 0.05 0.125 0.2
Santa Margarita Atascadera Salinas
FROM
TO
SILENT
NIGHT
“In ecoepidemiology,
the occurrence of an
association in more
than one species and
species population is
very strong evidence
for causation.” (Fox,
ref. 10, page 368). AMPHIBIANS
FISH
REPTILES
BIRDS
MAMMALS
AMPHIBIANS
FISH
REPTILES
BIRDS
Pipidae
Hylidae
Bufonidae
Ranidae
AMPHIBIANS
FISH
REPTILES
BIRDS
MAMMALS
AMPHIBIANS
FISH
REPTILES
BIRDS
MAMMALS
“There is no direct scientific
information to assess this
hypothesis.”
from EPA, Statement of Anne Lindsay, page 10
Sperm productionSperm production
TestosteroneTestosterone
Atrazine
In rats
(Kniewald et al. 2000)
0
3
6
9
12
18S
perm
nu
mb
er
( x
10
8)
15P < 0.001
60 120
Atrazine (mg/kg)
Control
Males
In humans
Swan et al. 2003
Control
Males
Sub-fertile
Males
0
.03
.06
.09
.12
.18A
tra
zin
e le
ve
l (p
pb
) .15 P < 0.009
Control
Males
Sub-fertile
Males
Field
Workers
(Average)
0
40
80
120
160
240 A
tra
zin
e le
ve
l (p
pb
) 200
Lucas et al. 1993
Atr
azin
e le
ve
l (p
pb
)
Control
Males
Sub-fertile
Males
Field
Workers
(Average)
0
400
800
1200
1600
2400
2000
Applicators
(Maximum)
Lucas et al. 1993
“Atrazine has been a
vital tool for US farmers
for nearly 50 years.”
--Tim Pastoor, Letter to the editor
Terra Haute Tribune Star
Jan 3, 2008
TestosteroneTestosterone
Sperm production
Laryngeal growth
Sperm production
Atrazine
Estrogenaromatase
Vitellogenesis
OogenesisMammary tumors
Prostate cancer
Atrazine (mg/kg)
0 50 100 150 200 250
Se
rum
estr
og
en
(p
g/m
l)
0
20
40
60
80
100
120
140E2+E1
Seru
m T
esto
ste
ron
e (
pg
/ml)
0
5
10
15
20
*
Stoker 2000
P < 0.05Rodents
Control
Females
0
15
30
45
60
75
Ma
mm
ary
tu
mo
r in
cid
en
ce
(%
)
Rodents
10 70 500 1000
Atrazine (ppm)
P < 0.01
Stevens et al. 1994
Sanderson et al. 2001
Control Atrazine
treated
Rela
tiv
e C
YP
19
ex
pre
ssio
n
Or
aro
mata
se
ac
tiv
ity
0
1
2
3
4
6
5
P < 0.05
Human Cells
P < 0.0001In humans
Kettles et al. 1997
“The increase in all cancers combined seen in the overall study group
was concentrated in the company employee group.” (page 1052)
“The increase in prostate cancer in male subjects was concentrated in
company employees.” (page 1052).
“The prostate cancer increase was further concentrated in actively
working company employees.” (page 1053)
“all but one of the cases occurred in men with 10 or more years since
hire”. (page 1052)
“Analyses restricted to company employees also found that the
prostate cancer increase was limited to men under 60 years of age.”
(page 1053).
MacLennan et al. 2002
MacLennan et al. 2002
Control
Males
Exposed
Males
Pro
sta
te c
an
cer
Incid
en
ce
(Ob
serv
ed
/Exp
ecte
d)
0
4
8
“Atrazine has been used safely
for more than 47 years.”
-- Tim Pastoor
Syngenta Crop Protection
Pipidae
Hylidae
Bufonidae
Ranidae
AMPHIBIANS
FISH
REPTILES
BIRDS
MAMMALS
AMPHIBIANS
FISH
REPTILES
BIRDS
MAMMALS
“There is no direct scientific
information to assess this
hypothesis.”
(EPA, page 10)
?
ERER
O
OH
TestosteroneHO
OH
Estrogen
Aromatase
ER
Letrozole
Aromatase
HO
OH
Estrogen
HO
OH
Estradiol
Aromatase
ATRAZINE
ER
Letrozole
Aromatase
O
OH
TestosteroneHO
OH
EstrogenHO
OH
Estrogen
Aromatase
“Novartis Oncology offers treatments
for cancers that range from breast
cancer to leukemia to bone cancer to
carcinoid tumors.” – novartis.com
Clinical Trials of drugs in development…
Image source: FDA and USA.gov
HO
OH
Estradiol
Aromatase
ATRAZINE
ER
Letrozole
Aromatase
O
OH
TestosteroneHO
OH
EstrogenHO
OH
Estrogen
Aromatase
HO
OH
Estradiol
Aromatase
ATRAZINE
ER
Letrozole
Aromatase
O
OH
TestosteroneHO
OH
EstrogenHO
OH
Estrogen
Aromatase
“…use of atrazine according to
the label instructions will not
likely result in harm to human
health or the environment.”
-- Office of Pesticide Programs
US EPA, 2008
Working
Hypothesis
Apical Effects1
Ecological
RelevanceYES
STOPNO
Sex Steroid
Measurements2
Aromatase
Activity ?3
Aromatase
Inhibitor
Study
4
YES
YES
NO Test for
Alternative Effects
NO Test for
Alternative Effects
Working
Hypothesis
Apical Effects1
Sex Steroid
Measurements2
Aromatase
Activity ?3
Aromatase
Inhibitor
Study
4
Ecological
RelevanceYES
YES
YES
STOPNO
NO Test for
Alternative Effects
NO Test for
Alternative Effects
Neural
Damage
Immune
Failure
Prostate
And
Mammary
Cancer
Abortion
Prostate
Disease
Impaired
Mammary
Development
Control Atrazine
Impaired
Growth and Development
Neural
Damage
Immune
Failure
Abortion
Prostate
Disease
Prostate
And
Mammary
Cancer
Impaired
Mammary
Development
Impaired
Growth and Development
Abortion
Prostate
Disease
Impaired
Mammary
Development
“The ultimate decision
is much bigger than science…
…it weighs in public opinion.”
-- Stephen Bradbury
US EPA, Dec 3, 2006
Thank you
Dr. Tyrone Hayes
University of California – Berkeley
tyrone@berkeley.edu
Dr. Tyrone B. Hayes
Dr. Tyrone B. Hayes's work is transforming biology one battle
at a time. From a very early age, he knew that hews
interested in biology, amphibians in particular. Always
fascinated by frogs and toads, this fascination turned into
reality and a career. Dr. Hayes's work paves the way for an
integrative approach to understanding how an organism
reacts to changes in its environment.
Recently his work has gained international recognition for
demonstrating how atrazine, a widely used pesticide which is
now found in many water sources, has been shown to alter
reproductive development (act as an endocrine disruptor) in
frogs even at extremely low levels. Beyond his integrative
work in conservation, he has won numerous teaching
awards, conservation awards, and recognition as a leader in
the scientific community.
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