Virtual Workshop for Alliance for Cancer Prevention

Endocrine Disrupters and Human Health

Professor Susan Jobling

Institute for the EnvironmentBrunel University Londonsusan.jobling@brunel.ac.uk

What is “Endocrine Disruption”?

• It is a change to the normal function of endocrine glands and hormone action, imposed by external (anthropogenic) stressors.

• Endocrine disruption is manifested as threats to sustainable reproduction and health of wildlife and humans.

Examples

– An EDC would be a chemical that blocks the rise in insulin after a meal, or blocks the ability of insulin to work.

– EDC would be a chemical that blocks or reduces the normal production of testosterone

Endocrine disease burden never as high

• Hormonal cancers – breast, prostate, testis

• Genital malformations in boys (testis non-descent, penile malformations)

• Semen quality declining

• Male and female reproduction

• Obesity and type 2 diabetes

The causes?

• …not genetic

• Not explained by better diagnosis

• Environmental factors including chemical exposures

Role for hormones?

Reproduced with permission from Henderson et al. (2000).

More than 800 chemicals known to be endocrine disrupters

Hormonal cancers

• Breast cancer – linked with exposure to– PCDD (4 studies), PCBs and CYP polymorphisms

(4 studies) – Steroidal estrogens and total internal

xenoestrogenic load

• Prostate cancer – linked with exposure to– Pesticides, organophosphates (> 20 studies)– Arsenic (4 studies)– Non-coplanar PCBs (3 positive studies, 1 negative)

• Early life exposure critical• Many chemicals not investigated• No single EDC shows strong associations

Hormonal Action is Life-stage Specific

Developmental Effects are Different from Adult Effects

Development is the most sensitive time for EDC effects:•Lower doses•Time specific effects•Tissue specific effects•Latent and persistent effects•Increased disease risk later in life

1. Low Doses Matter

2. Effects at high dose does not predict effects at low dose

3. Early life exposures produce adverse effects in adulthood

Challenges: Critical windows

Time

Critical windowof causation

Tis

sue

leve

l

MeasurementwindowBirth

Critical windows – irreversible effects

Time

Critical windowof causation in foetal life

Effect later in life

Tis

sue

leve

l

Birth

Early Life Exposure to EDCs

GestationGestation ChildhoodChildhood Reproductive Reproductive LifeLife Middle LifeMiddle Life Later LifeLater LifePubertyPuberty

Exposure to EDCs

The effects of early exposures to EDCs – when organ systems are developing – may be manifested any time in life.

Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action.

Rajapakse, N, E Silva and A Kortenkamp. 2002. Environmental Health Perspectives 110:917–921.

2´,3´,4´,5´-tetrachlorobiphenyl-4-ol 2´,5´-dichlorobiphenyl-4-ol 4´-chlorobiphenyl-4-ol genistein 2,4-dihydroxbenzophenone benzyl-4-hydroxyparabene 2,3,4,5-tetrachlorobiphenyl bisphenol A resorcinol monobenzoate 2,3,4-trichlorobiphenyl phenyl salicylate  

Inaction Sacrifices Human Potential and Costs Money

Trasande & Liu, 2011. Health Affairs 30(5):863-870.

Testing for endocrine disruption captures limited range of effects

Other receptors /pathwaysOther receptors /pathways

Endpoints and assays not yet validated, for which detailed guidance is not yet drafted

Endpoints and assays not yet validated, for which detailed guidance is not yet drafted

OECD Conceptual FrameworkOECD Conceptual FrameworkCurrent testing requirements

Research needs

• Exposure– Exposomics approaches– Technologies for analysis of unknowns

• Mechanisms and test systems– Assay development

• Impacts on human and wildlife health– Combined exposures and epidemiology– Set up new cohorts and sampling strategies– Investigate human and wildlife together

Thank you