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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?


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.


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




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




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