Addressing combined effects of Addressing combined effects

Addressing combined effects of
pesticides in the EU regulatory
framework
Prof Andreas Kortenkamp
Brunel University London
Info
o session
sess o o
on cu
cumulative
u at e risk
s assess
assessment
e t for
o
pesticides, EFSA Parma 11 Feb 2014
Legal requirements
“… at present risk assessment on the combined effects of
chemicals in a mixture is not commonly carried out
out, nor
required by most EU regulations.”
SCHER, SCENIHR, SCCS (EU Scientific Committees on Health and Environmental Risks, Emerging
and Newly Identified Health Risks, and Consumer Safety) (2011) Toxicity and Assessment of
Chemical Mixtures. European Commission, DG Health & Consumers, Brussels
2
The long road to implementation
1996
US Food Quality Protection Act calls for CRA of pesticides with a common MoA
2002
US EPA Guidance on CRA of Pesticide Chemicals that have a Common MoA
g
p
p
, triazines,, chloroacaetanilides,, carbamates
2002–07 US EPA CRAs for organophosphates,
2005
EU Pesticide MRL regulation calls for the development and use of methodologies for CRA of pesticide residues (introduced upon initiative of the EP)
2005–08
2005
08 EFSA working groups on CRA established, Scientific Colloquium on CRA,
Evaluation of existing methodologies, Recommendation of a tiered approach.
2009
Test result of a suggested methodology for the case of triazole fungicides.
Conclusions: appropriate but not yet applicable on a routine basis…
2009
Requirement for mixture risk assessments established under the new
EU PPP regulation:
Active substances and plant protection products shall not have any harmful
effects
ff t on h
human health,
h lth taking
t ki into
i t accountt known
k
cumulative
l ti and
d synergistic
i ti
effects where the scientific methods accepted by the Authority to assess such
effects are available,... (Article 4)
Ongoing EFSA continues methodological work
Dec 13
Scientific opinion on relevance of dissimilar mode of action and its appropriate
application for cumulative risk assessment of pesticide residues in food
3
“Synergisms” – killing mosquito
larvae
Deltamethrin
Deltamethrin +
piperonylbutoxide
Piperonylbutoxide inhibits cyp isoforms, but is not
toxic to larvae on its own
Fakoorziba et al. (2008)
Food Environ Toxicol 24, 19
4
Prediction of mixture effects
• Prediction of mixture effects when effects of
components are known – applicable only if all
p
produce
p
effect of interest
components
• Assumption: chemicals act without interfering
with each other
• Effects can be p
predicted by
y using
g dose
(concentration) addition or
independent action
5
Independent action
• Stochastic principles
• Additivityy expectation: effect multiplication
• Si
Simultaneous
lt
exposure: stochastic
t h ti
principles only fulfilled when components
show different modes of action in inducing
the same effect
6
Dose (concentration) addition
• Agents
A
t behave
b h
lik
like “dilutions”
“dil ti
” off each
h other
th
• Contribute to joint effect in proportion to their
dose
• Additivity expectation: addition of equieffective doses
• Applied to combinations of similarly acting
chemicals
7
Rat developmental toxicity
Birth
GD 7
Dosing
PND 16
Dam
Male
offspring
AGD
PND 1
Retained nipples
PND 13
Organ weights
Malformations
Malformations
PND 47
PND 16
8
Three AR antagonists
Hass et al. 2007 EHP 115 Suppl 1, 122
Dose addition
9
16 algal toxicants
Faust et al. (2003) Aquat Toxicol 63, 43
Aclonifen
8-Azaguanine
g
Azaserine
CCCP
Chloramphenicol
DTMAC
Fenfuram
Kresoxim-methyl
Metalaxyl
y
Metazachlor
Metsulfuron-methyl
Nalidixic acid
Norflurazon
Paraquat
Terbutylazim
Triadimenol
Conc addition
Conc addition
Independent
action
Independent
action
10
Prediction of combination effects
Dose addition provides good approximations of observed effects
Retained nipples
Vtg induction (fish)
Micronuclei
Androgen receptor antagonism
11
Synergism: penile malformations
Christiansen et al.
al 2009 EHP 117,
117 1839
Finasteride
Vinclozolin
DEHP
Prochloraz
12
What is the correct concept?
• DA or IA?
• Often
Often, DA and IA predictions are identical –
irrespective of modes of action!
• Are
e hypotheses
ypot eses about modes
odes o
of act
action
o a
reliable basis for making choices?
13
Mixtures of anticancer drugs
Different sites of action
120
corrected % ce
ell killing
g
100
IA
80
60
CA
40
20
0
-20
1e-6 1e-5 1e-4 1e-3 1e-2 1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6
Drug Concentration (µM)
14
Mixtures of aneugens
Different sites and mechanisms of action
Ermler et al. 2013, Arch Toxicol (in press)
15
What is the correct concept?
• WHO / IPCS (2009): Use dose addition as a
d f lt unless
default,
l
th
there iis evidence
id
tto th
the contrary
t
• Dose addition is sufficiently conservative, but
sometimes independent action predicts stronger
mixture effects
• Driver: slopes of dose-response curves
16
What should be grouped?
Grouping criteria?
•
US EPA: Common mechanisms – similar chemical structures
•
US National Acad of Sciences (2008): Similar structures too narrow common adverse outcomes
•
Mechanisms: an unreliable g
grouping
p g criterion – information often not
available
•
Data on common adverse outcomes also often not available
•
Data requirements for pesticide authorisation not geared towards making
grouping decisions based on modes of action
17
When is a mixture safe?
Dose addition
Intake2
Intake1
+
T l bl D
Tolerable
Daily
il IIntake
t k 1
<1
T l bl D
Tolerable
Daily
il IIntake
t k 2
Mixture effect is equal
q
to effect at TDI if every
y component
p
is p
present at
TDI / n
Independent action
E 1,2,..n
[(1-e1)(
)(1-e2))...(1-e
( n)]
1 2 n = 1 - [(
No mixture effect if all components are present at zero effect levels
100 agents with 1% effect:
joint effect = 63%
100 agents with 0.1% effect:
joint effect = 9.5%
18
When is a mixture safe?
• Dose addition: dependent on number of components and
sum of toxic units
• Independent action: Are ADI always zero effect levels? –
What about chemicals without ADI?
• A matter for risk assessment
•
“…for Human Health effects, if the intended level of protection is achieved for
each individual
eac
d dua substance,
substa ce, the
t e level
e e of
o concern
co ce for
o mixtures
tu es o
of d
dissimilarly
ss
a y
acting substances should be assumed as negligible.”
•
SCHER, SCENIHR,
SCHER
SCENIHR SCCS (EU Scientific Committees on Health and Environmental Risks
Risks,
Emerging and Newly Identified Health Risks, and Consumer Safety) (2011) Toxicity and
Assessment of Chemical Mixtures. European Commission, DG Health & Consumers, Brussels
19
What is dissimilarity?
Clear definitions not available
•
Reference cases for strictly dissimilarly acting mixtures are rare in mammalian toxicology
•
Only one example where independent action was shown to be applicable
•
The number of chemicals exceeds the number of available dissimilar modes of action
20
Mixture risk assessment methods
Can we apply experimental mixture prediction concepts in risk
assessment practice?
Requirements of experimental assessment concepts (DA, IA):
•
•
•
The same endpoint was measured for single components and mixture
D
Dose-response
d t for
data
f single
i l components
t and
d mixture
i t
Allow predictions for a large range of effects
Simplifications
• Hazard Index (HI)
• Point of Departure Index (PODI)
• Relative Potency Factors (RPF)
21
Hazard index
•
•
•
EL - exposure level,
l
l e.g. iintake
t k iin mg/kg/d
/k /d
AL - acceptable level, e.g. ADI or TDI
EL and AL must be expressed in the same unit
Simplifications:
• AL not necessarily in relation to same endpoint
• Different uncertainty factors may have been used to define AL
• AL represent effect
ff
doses associated with the same (small
(
or
zero) effect
22
Example: Antiandrogens
Kortenkamp and Faust 2010, Int J Androl 33, 463
23
Bottlenecks
Information about exposures and reference
doses must be available
• Data
ata gaps a
are
e tthe
e rule
u e – a vast
ast number
u be o
of cchemicals
e ca s a
are
e
not toxicologically assessed
• Approx 800 chemicals with ADI (TDI) vs 10,000, 20,000,
???? with food relevance
• 134,000 chemicals pre-registered under REACH
24
Acknowledgements
• Financial support
from European
Union:
• ACE project
• EDEN project
j t
• CONTAMED
• UK FSA
Contamed
25
The end
Thank
a
you!
you
26

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