Virtual Workshop for Alliance for Cancer Prevention

1. Endocrine Disrupters and Human Health Professor Susan Jobling Institute for the Environment Brunel University London susan.jobling@brunel.ac.uk Virtual Workshop for Alliance for Cancer Prevention

2. 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.

3. 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

4. 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

15. The causes? • …not genetic • Not explained by better diagnosis • Environmental factors including chemical exposures

16. Role for hormones? Reproduced with permission from Henderson et al. (2000).

17. More than 800 chemicals known to be endocrine disrupters

18. 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

19. Hormonal Action is Life-stage SpecificDevelopmental Effects are Different from Adult Effects • Low Doses Matter • Effects at high dose does not predict effects at low dose • Early life exposures produce adverse effects in adulthood • 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

20. Challenges: Critical windows Measurement window Tissue level Birth Critical window of causation Time

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

22. Early Life Exposure to EDCs Gestation Childhood Puberty Reproductive Life Middle Life Later Life Exposure to EDCs The effects of early exposures to EDCs – when organ systems are developing – may be manifested any time in life.

23. 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

24. Inaction Sacrifices Human Potential and Costs Money Trasande & Liu, 2011. Health Affairs 30(5):863-870.

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

26. 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

27. Thank you