Transcript Endocrine Disruption - Pesticides Safety Directorate

ENDOCRINE DISRUPTION
DOES THIS POSE SPECIAL
DIFFICULTIES WHEN ASSESSING
RISK?
Sue Barlow
Independent Consultant in Toxicology
Scope

Distinguish between endocrine disrupter and
potential endocrine disrupter

Discuss the special difficulties with ED
evidence


Discuss the WHO/IPCS model for evaluating
evidence on EDs and illustrate with an
example
[Summary evidence on pesticides with ED
activity]
DEFINITIONS

Endocrine disruptor
A substance or mixture that alters function(s) of
the endocrine system causing adverse effects
in an intact organism, or its progeny, or
(sub)populations

Potential endocrine disruptor
A substance or mixture that possesses
properties that might be expected to lead to
endocrine disruption in an intact organism, or
its progeny, or (sub)populations
WHAT ARE THE SPECIAL
DIFFICULTIES?

Is endocrine disruption a new phenomenon?

Are there more endocrine-active chemicals
than we thought?

Do standard toxicity tests address
endocrine-related endpoints?
WHAT ARE THE SPECIAL
DIFFICULTIES?

Can they have unusual dose-response
curves?
Dose-response curves
Non-monotonic doseresponse curve
Effect of hexachlorobenzene
(an androgen agonist) on
androgen response in
prostate cancer cells
The red line is the level of
response obtained by DHT
without any HCB present.
At levels of HCB exposure
around 1 nM (parts per billion)
there was up to a doubling of
the androgenic response in
the presence of DHT.
But at very high levels, the
androgenic response was
repressed.
WHAT ARE THE SPECIAL
DIFFICULTIES?

Can they be active at low doses?

Should all effects be seen as adverse?
How can the evidence
be assessed?
The IPCS GLOBAL ASSESSMENT
of the State of the Science
OF ENDOCRINE DISRUPTORS
(GAED)
2002
www.ehponline.org/who/
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
CAUSAL CRITERIA
FOR ASSESSING
ENDOCRINE DISRUPTORS

GAED used causal criteria for
assessing EDs adapted from
the Bradford-Hill criteria (1965),
widely used for assessing human
epidemiological evidence
PURPOSE OF THE
CAUSAL CRITERIA

Provide a framework to assemble and review the
body of knowledge on an adverse health event with
a potential endocrine-related basis

Use multiple lines of evidence to bring
considerable amounts of information to bear

Focus on the underlying biological alterations in the
direct line between an exposure and an adverse
outcome

Assess the overall coherence and strength of the
evidence that a particular situation is, or is likely to
be, due to an alteration in an endocrine system

Identify research gaps
CAUSAL CRITERIA
FRAMEWORK
Statement of Hypothesis
Outcome of concern
Stressor of Concern
Assessment Factors
Temporality
Strength of association
Consistency
Biological Plausibility
Recovery
Overall Strength of Evidence
For the outcome
For the hypothesis
For an EDC mechanism
CAUSAL CRITERIA
ASSESSMENT FACTORS
Temporality
Does the presumed cause of the
outcome of concern precede its
appearance ?
Strength of Association
What is the incidence rate ?
What is the risk attributable to
exposure ?
Shape of dose-response curve ?
Consistency of Observations
Are there similar or dissimilar
findings in the literature ?
Is it seen in multiple geographic
areas and/or species ?
Does it occur at similar doses ?
Biological Plausibility
Is there a possible/known endocrine
mechanism of action ?
Evidence of Recovery
Is the adverse outcome reversible
when exposure diminishes?
CASE STUDY
Human Sperm Quality

Hypothesis
Global reductions in human semen
quality over time are related to exposure
to oestrogenic and/or anti-androgenic
chemicals during critical phases of testis
development
The initial evidence
Sperm Counts
Trends in human sperm quality
Temporality
No data
Strength of association
No data for causal
association
Moderate for effect
Consistency of with other
observations
No data for causal
association
Weak for effect
Several studies show significant decline in sperm
quality over time but no data on preceding chemical
exposures, especially during early development
No data relating possible cause (chemicals) to ↓ sperm
Carlsen et al. meta-analysis 1938-1990 shows 50%
decline over 50 years
1.5% per year in USA; 3.5% per year in Europe
No data on consistency of effect and exposure
Longitudinal studies in single centres:
10 show decline
6 improvement
8 no change
Two ‘time to pregnancy’ studies not consistent with
decline
Trends in human sperm quality
Biological
plausibility
Strong
Recovery
No data
Endogenous oestrogens control testis
development (but prenatal exposure to
DES, OCs no effect on human fertility)
Support from related trends in human
testis cancer and male reproductive
tract abnormalities
Support from animal studies
(e.g. prenatal exposure to oestradiol,
nonylphenol, methoxychlor,
vinclozolin, phthalates, dioxins)
No relevant data
Overall strength of evidence
on sperm quality
Human health
outcome
Putative
stressors of
concern
Decline in
human sperm
quality
Oestrogens &
antiandrogens
Strength of Strength of
evidence for evidence
hypothesis
for EDC
mechanism
No data
Weak
CONCLUSIONS





Interpreting data on endocrine disruption requires
good knowledge of endocrinology, mechanisms of
action and toxicology
In vitro evidence can indicate possible hazard but is
insufficient by itself to demonstrate risk to humans
In vivo evidence from animal studies shows several
pesticides are EDs
Conventional risk assessment approaches can be
applied to in vivo data and may allow setting of
acceptable exposure limits
Lack of studies on human health outcomes with
adequate pesticide exposure history precludes
Annex on pesticides with
endocrine activity
PESTICIDES WITH
ENDOCRINE ACTIVITY
ENDOCRINE
ACTIVITY
Oestrogenic
in vitro &/or in vivo
(ERα,β agonists)
EFFECTS
Bind to oestrogen
receptors
Proliferation in breast
cancer cell lines
↑ Uterine weight in
uterotrophic assay
EXAMPLES
Chlordane
o,p’-DDT
Dieldrin
Endosulfan
Fenarimol
Fenvalerate
Toxaphene
Methoxychlor metab
PESTICIDES WITH
ENDOCRINE ACTIVITY
ENDOCRINE
ACTIVITY
EFFECTS
EXAMPLES
Inhibition of aromatase
(Converts testosterone
to oestradiol)
Inhibit male mating
behaviour
Fenarimol
Imazalil
Prochloraz
Conazoles
Induction of aromatase
Feminisation
Delays puberty in
males
Atrazine
Inhibition of 5αreductase
(Converts testosterone
to dihydrotestosterone)
↓ Prostate growth
Atrazine
PESTICIDES WITH
ENDOCRINE ACTIVITY
ENDOCRINE
ACTIVITY
EFFECTS
EXAMPLES
Suppression of
luteinising
hormone and
prolactin surges
(Hypothalamus)
Delay puberty
Disturb oestrous cycles
Reduce implantation
Earlier onset of
mammary tumours
Atrazine
Androgenic
(AR agonists)
Masculinisation of
females
No known pesticide
examples
PESTICIDES WITH
ENDOCRINE ACTIVITY
ENDOCRINE
ACTIVITY
Anti-androgenic
(AR antagonists)
EFFECTS
EXAMPLES
In male offspring:
↓ Anogenital distance
Nipple retention
Hypospadias
↓ Testis and other sex
organ weights
↓ Sperm count, fertility
Delay puberty
Hershberger assay in
immature males:
↓ 2ry sex organ growth
p,p’-DDE
Fenarimol
Fenitrothion
Fenvalerate
Linuron
Methoxychlor metab
Prochloraz
Procymidone
Vinclozolin
REGULATORY ACTIONS




Atrazine: banned in EU in 2003 because of
unavoidable water contamination
TBT: Most antifoulant uses phased out by 2003,
remaining uses by 2008
Alkyl phenols and their ethoxylates: EU Directive
prevents use as co-formulants in new products from
2005; voluntary UK agreement to replace AP(E)s in
existing pesticide formulations
Vinclozolin, Procymidone, Fenarimol:
EU discussing phasing out all uses