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Virtual Workshop for Alliance for Cancer Prevention
Endocrine Disrupters and Human Health
Professor Susan Jobling
Institute for the EnvironmentBrunel University [email protected]
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