endocrine disruption does this pose special difficulties when assessing risk? sue barlow independent...
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ENDOCRINE DISRUPTION ENDOCRINE DISRUPTION DOES THIS POSE SPECIAL DOES THIS POSE SPECIAL DIFFICULTIES WHEN ASSESSING DIFFICULTIES WHEN ASSESSING RISK?RISK?
Sue BarlowSue BarlowIndependent Consultant in ToxicologyIndependent Consultant in Toxicology
ScopeScope
Distinguish between endocrine disrupter Distinguish between endocrine disrupter and potential endocrine disrupterand potential endocrine disrupter
Discuss the special difficulties with ED Discuss the special difficulties with ED evidenceevidence
Discuss the WHO/IPCS model for Discuss the WHO/IPCS model for evaluating evidence on EDs and evaluating evidence on EDs and illustrate with an exampleillustrate with an example
[Summary evidence on pesticides with [Summary evidence on pesticides with ED activity]ED activity]
DEFINITIONSDEFINITIONS
Endocrine disruptorEndocrine disruptor A substance or mixture that alters function(s) of A substance or mixture that alters function(s) of the endocrine system causing adverse effects the endocrine system causing adverse effects in an intact organism, or its progeny, or in an intact organism, or its progeny, or (sub)populations(sub)populations
Potential endocrine disruptorPotential endocrine disruptor A substance or mixture that possesses A substance or mixture that possesses properties that might be expected to lead to properties that might be expected to lead to endocrine disruption in an intact organism, or endocrine disruption in an intact organism, or its progeny, or (sub)populationsits progeny, or (sub)populations
WHAT ARE THE SPECIAL WHAT ARE THE SPECIAL DIFFICULTIES?DIFFICULTIES?
Is endocrine disruption a new phenomenon?Is endocrine disruption a new phenomenon?
Are there more endocrine-active chemicals Are there more endocrine-active chemicals than we thought?than we thought?
Do standard toxicity tests address Do standard toxicity tests address endocrine-related endpoints?endocrine-related endpoints?
WHAT ARE THE SPECIAL WHAT ARE THE SPECIAL DIFFICULTIES?DIFFICULTIES?
Can they have unusual dose-response Can they have unusual dose-response curves?curves?
Dose-response curvesDose-response curves
Non-monotonic dose-Non-monotonic dose-response curveresponse curve
Effect of hexachlorobenzene (an androgen agonist) on androgen response in prostate cancer cellsThe 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 WHAT ARE THE SPECIAL DIFFICULTIES?DIFFICULTIES?
Can they be active at low doses?Can they be active at low doses?
Should all effects be seen as adverse?Should all effects be seen as adverse?
How can the evidence How can the evidence
be assessed?be assessed?
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETYINTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
The IPCS GLOBAL ASSESSMENTof the State of the Science
OF ENDOCRINE DISRUPTORS(GAED)
2002
www.ehponline.org/who/
CAUSAL CRITERIA CAUSAL CRITERIA FOR ASSESSING FOR ASSESSING ENDOCRINE DISRUPTORSENDOCRINE DISRUPTORS
GAED used causal criteria for GAED used causal criteria for assessing EDs adapted from assessing EDs adapted from
the Bradford-Hill criteria (1965), the Bradford-Hill criteria (1965),
widely used for assessing human widely used for assessing human epidemiological evidenceepidemiological evidence
PURPOSE OF THE PURPOSE OF THE CAUSAL CRITERIACAUSAL CRITERIA Provide a Provide a frameworkframework to assemble and review the to assemble and review the
body of knowledge on an adverse health event with body of knowledge on an adverse health event with a potential endocrine-related basisa potential endocrine-related basis
Use Use multiple lines of evidencemultiple lines of evidence to bring considerable to bring considerable amounts of information to bearamounts of information to bear
Focus on the Focus on the underlying biological alterationsunderlying biological alterations in the in the direct line between an exposure and an adverse direct line between an exposure and an adverse outcomeoutcome
Assess the Assess the overall coherence and strength of the overall coherence and strength of the evidenceevidence that a particular situation is, or is likely to that a particular situation is, or is likely to be, due to an alteration in an endocrine systembe, due to an alteration in an endocrine system
Identify Identify research gapsresearch gaps
CAUSAL CRITERIA CAUSAL CRITERIA FRAMEWORK FRAMEWORK
Statement of HypothesisOutcome of concernStressor of Concern
Assessment FactorsTemporalityStrength of associationConsistency Biological PlausibilityRecovery
Overall Strength of Evidence
For the outcomeFor the hypothesisFor an EDC
mechanism
CAUSAL CRITERIA CAUSAL CRITERIA ASSESSMENT FACTORSASSESSMENT FACTORS
TemporalityTemporality Does the presumed cause of the Does the presumed cause of the outcome of concern precede its outcome of concern precede its appearance ? appearance ?
Strength of AssociationStrength of Association What is the incidence rate ?What is the incidence rate ?What is the risk attributable to What is the risk attributable to exposure ? exposure ? Shape of dose-response curve ? Shape of dose-response curve ?
Consistency of ObservationsConsistency of Observations Are there similar or dissimilar Are there similar or dissimilar findings in the literature ? findings in the literature ? Is it seen in multiple geographic Is it seen in multiple geographic areas and/or species ?areas and/or species ?Does it occur at similar doses ?Does it occur at similar doses ?
Biological PlausibilityBiological Plausibility Is there a possible/known endocrine Is there a possible/known endocrine mechanism of action ?mechanism of action ?
Evidence of RecoveryEvidence of Recovery Is the adverse outcome reversible Is the adverse outcome reversible when exposure diminishes?when exposure diminishes?
CASE STUDY CASE STUDY Human Sperm Quality Human Sperm Quality
HypothesisHypothesis
Global reductions in human semen Global reductions in human semen
quality over time are related to exposure quality over time are related to exposure
to oestrogenic and/or anti-androgenic to oestrogenic and/or anti-androgenic
chemicals during critical phases of testis chemicals during critical phases of testis
developmentdevelopment
The initial evidence The initial evidence
Sperm Counts
Trends in human sperm Trends in human sperm quality quality
TemporalityTemporality
No data No data
Strength of associationStrength of association
No data for causal No data for causal associationassociation
Moderate for effect Moderate for effect
Consistency of with other Consistency of with other observationsobservations
No data for causal No data for causal associationassociation
Weak for effectWeak for effect
Several studies show significant decline in spermSeveral studies show significant decline in spermquality over time but no data on preceding chemicalquality over time but no data on preceding chemicalexposures, especially during early developmentexposures, especially during early development
No data relating possible cause (chemicals) to No data relating possible cause (chemicals) to ↓ sperm ↓ sperm Carlsen et al. meta-analysis 1938-1990 shows 50%Carlsen et al. meta-analysis 1938-1990 shows 50%decline over 50 yearsdecline over 50 years1.5% per year in USA; 3.5% per year in Europe1.5% per year in USA; 3.5% per year in Europe
No data on consistency of effect and exposureNo data on consistency of effect and exposureLongitudinal studies in single centres:Longitudinal studies in single centres: 10 show decline10 show decline 6 improvement6 improvement 8 no change 8 no change Two ‘time to pregnancy’ studies not consistent with Two ‘time to pregnancy’ studies not consistent with
declinedecline
Trends in human sperm Trends in human sperm qualityquality
Biological Biological plausibilityplausibility
StrongStrong
RecoveryRecoveryNo dataNo data
Endogenous oestrogens control testis Endogenous oestrogens control testis development (but prenatal exposure to development (but prenatal exposure to DES, OCs no effect on human fertility)DES, OCs no effect on human fertility)
Support from related trends in human Support from related trends in human testis cancer and male reproductive testis cancer and male reproductive tract abnormalities tract abnormalities
Support from animal studies Support from animal studies (e.g. prenatal exposure to oestradiol, (e.g. prenatal exposure to oestradiol,
nonylphenol, methoxychlor, nonylphenol, methoxychlor, vinclozolin, phthalates, dioxins)vinclozolin, phthalates, dioxins)
No relevant dataNo relevant data
Overall strength of Overall strength of evidence on sperm evidence on sperm qualityquality
Human health Human health outcomeoutcome
Putative Putative stressors of stressors of
concernconcern
Strength of Strength of evidence for evidence for hypothesishypothesis
Strength of Strength of evidence evidence for EDC for EDC
mechanismmechanism
Decline in Decline in human sperm human sperm
qualityquality
Oestrogens & Oestrogens & anti-anti-
androgensandrogensNo dataNo data WeakWeak
CONCLUSIONSCONCLUSIONS
Interpreting data on endocrine disruption requires Interpreting data on endocrine disruption requires good knowledge of endocrinology, mechanisms of good knowledge of endocrinology, mechanisms of action and toxicologyaction and toxicology
In vitro evidence can indicate possible hazard but is In vitro evidence can indicate possible hazard but is insufficient by itself to demonstrate risk to humansinsufficient by itself to demonstrate risk to humans
In vivo evidence from animal studies shows several In vivo evidence from animal studies shows several pesticides are EDspesticides are EDs
Conventional risk assessment approaches can be Conventional risk assessment approaches can be applied to in vivo data and may allow setting of applied to in vivo data and may allow setting of acceptable exposure limitsacceptable exposure limits
Lack of studies on human health outcomes with Lack of studies on human health outcomes with adequate pesticide exposure history precludes adequate pesticide exposure history precludes conclusions on causality conclusions on causality
Annex on pesticides Annex on pesticides with endocrine activity with endocrine activity
PESTICIDES WITH PESTICIDES WITH ENDOCRINE ACTIVITYENDOCRINE ACTIVITY
ENDOCRINE ENDOCRINE ACTIVITYACTIVITY
EFFECTS EFFECTS EXAMPLES EXAMPLES
Oestrogenic Oestrogenic
in vitroin vitro &/or &/or in vivo in vivo
(ERα,β agonists)(ERα,β agonists)
Bind to oestrogen Bind to oestrogen receptorsreceptors
Proliferation in breast Proliferation in breast cancer cell linescancer cell lines
↑ ↑ UUterine weight in terine weight in uterotrophic assay uterotrophic assay
Chlordane Chlordane
o,po,p’-DDT ’-DDT
DieldrinDieldrin
EndosulfanEndosulfan
FenarimolFenarimol
FenvalerateFenvalerate
ToxapheneToxaphene
Methoxychlor metabMethoxychlor metab
PESTICIDES WITH PESTICIDES WITH ENDOCRINE ACTIVITYENDOCRINE ACTIVITY
ENDOCRINE ENDOCRINE ACTIVITYACTIVITY
EFFECTS EFFECTS EXAMPLES EXAMPLES
Inhibition of aromataseInhibition of aromatase
(Converts testosterone (Converts testosterone to oestradiol)to oestradiol)
Inhibit male mating Inhibit male mating behaviourbehaviour
Fenarimol Fenarimol
ImazalilImazalil
ProchlorazProchloraz
ConazolesConazoles
Induction of aromataseInduction of aromatase FeminisationFeminisation
Delays puberty in Delays puberty in malesmales
AtrazineAtrazine
Inhibition of 5α-Inhibition of 5α-reductasereductase
(Converts testosterone (Converts testosterone to dihydrotestosterone)to dihydrotestosterone)
↓↓ Prostate growth Prostate growth AtrazineAtrazine
PESTICIDES WITH PESTICIDES WITH ENDOCRINE ACTIVITYENDOCRINE ACTIVITY
ENDOCRINE ENDOCRINE ACTIVITYACTIVITY
EFFECTS EFFECTS EXAMPLES EXAMPLES
Suppression of Suppression of luteinising luteinising hormone and hormone and prolactin surges prolactin surges
(Hypothalamus)(Hypothalamus)
Delay pubertyDelay puberty
Disturb oestrous cyclesDisturb oestrous cycles
Reduce implantationReduce implantation
Earlier onset of Earlier onset of mammary tumours mammary tumours
Atrazine Atrazine
Androgenic Androgenic
(AR agonists)(AR agonists)
Masculinisation of Masculinisation of femalesfemales
No known pesticide No known pesticide examplesexamples
PESTICIDES WITH PESTICIDES WITH ENDOCRINE ACTIVITYENDOCRINE ACTIVITYENDOCRINE ENDOCRINE
ACTIVITYACTIVITYEFFECTS EFFECTS EXAMPLES EXAMPLES
Anti-androgenicAnti-androgenic
(AR antagonists)(AR antagonists)
In male offspring: In male offspring:
↓ ↓ AAnogenital distancenogenital distance
Nipple retentionNipple retention
HypospadiasHypospadias
↓ ↓ TTestis and other sex estis and other sex organ weightsorgan weights
↓↓ Sperm count, fertilitySperm count, fertility
Delay pubertyDelay puberty
Hershberger assay in Hershberger assay in immature males:immature males:
↓ ↓ 2ry sex organ growth2ry sex organ growth
p,p’p,p’-DDE -DDE
Fenarimol Fenarimol
Fenitrothion Fenitrothion
FenvalerateFenvalerate
Linuron Linuron
Methoxychlor metabMethoxychlor metab
ProchlorazProchloraz
Procymidone Procymidone
Vinclozolin Vinclozolin
REGULATORY ACTIONSREGULATORY ACTIONS
Atrazine: banned in EU in 2003 because of Atrazine: banned in EU in 2003 because of unavoidable water contaminationunavoidable water contamination
TBT: Most antifoulant uses phased out by TBT: Most antifoulant uses phased out by 2003, remaining uses by 20082003, remaining uses by 2008
Alkyl phenols and their ethoxylates: EU Alkyl phenols and their ethoxylates: EU Directive prevents use as co-formulants in Directive prevents use as co-formulants in new products from 2005; voluntary UK new products from 2005; voluntary UK agreement to replace AP(E)s in existing agreement to replace AP(E)s in existing pesticide formulationspesticide formulations
Vinclozolin, Procymidone, Fenarimol: Vinclozolin, Procymidone, Fenarimol: EU discussing phasing out all usesEU discussing phasing out all uses