Virtual Workshop for Alliance for Cancer Prevention Endocrine Disrupters and Human Health Professor Susan Jobling Institute for the Environment Brunel University London

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 window of causation Tissue level Measurement window Birth

Critical windows – irreversible effects Time Critical window of causation in foetal life Effect later in life Tissue level Birth

Early Life Exposure to EDCs GestationGestationChildhoodChildhood Reproductive Life Middle Life Later Life PubertyPuberty 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 Environmental Health Perspectives 110:917–921. 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, Health Affairs 30(5):

Testing for endocrine disruption captures limited range of effects Other receptors /pathways Endpoints and assays not yet validated, for which detailed guidance is not yet drafted OECD Conceptual Framework Current 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