ENDOCRINE DISRUPTION DOES THIS POSE SPECIAL DIFFICULTIES WHEN ASSESSING RISK?

1. ENDOCRINE DISRUPTION DOES THIS POSE SPECIAL DIFFICULTIES WHEN ASSESSING RISK? Sue Barlow Independent Consultant in Toxicology

2. Scope • Distinguish between endocrine disrupter and potential endocrine disrupter • Discuss the special difficulties with ED evidence • Discuss the WHO/IPCS model for evaluating evidence on EDs and illustrate with an example • [Summary evidence on pesticides with ED activity]

3. DEFINITIONS • Endocrine disruptor A substance or mixture that alters function(s) of the endocrine system causing adverse effects in an intact organism, or its progeny, or (sub)populations • Potential endocrine disruptor A substance or mixture that possesses properties that might be expected to lead to endocrine disruption in an intact organism, or its progeny, or (sub)populations

4. WHAT ARE THE SPECIAL DIFFICULTIES? • Is endocrine disruption a new phenomenon? • Are there more endocrine-active chemicals than we thought? • Do standard toxicity tests address endocrine-related endpoints?

5. WHAT ARE THE SPECIAL DIFFICULTIES? • Can they have unusual dose-response curves?

6. Dose-response curves

7. Non-monotonic dose-response curve Effect of hexachlorobenzene (an androgen agonist) on androgen response in prostate cancer cells The 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.

8. WHAT ARE THE SPECIAL DIFFICULTIES? • Can they be active at low doses? • Should all effects be seen as adverse?

9. How can the evidence be assessed?

10. The IPCS GLOBAL ASSESSMENTof the State of the Science OF ENDOCRINE DISRUPTORS(GAED)2002www.ehponline.org/who/

11. CAUSAL CRITERIA FOR ASSESSING ENDOCRINE DISRUPTORS • GAED used causal criteria for assessing EDs adapted from the Bradford-Hill criteria (1965), widely used for assessing human epidemiological evidence

12. PURPOSE OF THE CAUSAL CRITERIA • Provide a framework to assemble and review the body of knowledge on an adverse health event with a potential endocrine-related basis • Use multiple lines of evidence to bring considerable amounts of information to bear • Focus on the underlying biological alterationsin the direct line between an exposure and an adverse outcome • Assess the overall coherence and strength of the evidence that a particular situation is, or is likely to be, due to an alteration in an endocrine system • Identify research gaps

13. CAUSAL CRITERIA FRAMEWORK Statement of Hypothesis Outcome of concern Stressor of Concern Assessment Factors Temporality Strength of association Consistency Biological Plausibility Recovery Overall Strength of Evidence For the outcome For the hypothesis For an EDC mechanism

14. CAUSAL CRITERIA ASSESSMENT FACTORS

15. CASE STUDY Human Sperm Quality • Hypothesis Global reductions in human semen quality over time are related to exposure to oestrogenic and/or anti-androgenic chemicals during critical phases of testis development

16. Sperm Counts The initial evidence

17. Temporality No data Strength of association No data for causal association Moderate for effect Consistency of with other observations No data for causal association Weak for effect Several studies show significant decline in sperm quality over time but no data on preceding chemical exposures, especially during early development No data relating possible cause (chemicals) to ↓ sperm Carlsen et al. meta-analysis 1938-1990 shows 50% decline over 50 years 1.5% per year in USA; 3.5% per year in Europe No data on consistency of effect and exposure Longitudinal studies in single centres: 10 show decline 6 improvement 8 no change Two ‘time to pregnancy’ studies not consistent with decline Trends in human sperm quality

18. Biological plausibility Strong Recovery No data Endogenous oestrogens control testis development (but prenatal exposure to DES, OCs no effect on human fertility) Support from related trends in human testis cancer and male reproductive tract abnormalities Support from animal studies (e.g. prenatal exposure to oestradiol, nonylphenol, methoxychlor, vinclozolin, phthalates, dioxins) No relevant data Trends in human sperm quality

19. Overall strength of evidence on sperm quality

20. CONCLUSIONS • Interpreting data on endocrine disruption requires good knowledge of endocrinology, mechanisms of action and toxicology • In vitro evidence can indicate possible hazard but is insufficient by itself to demonstrate risk to humans • In vivo evidence from animal studies shows several pesticides are EDs • Conventional risk assessment approaches can be applied to in vivo data and may allow setting of acceptable exposure limits • Lack of studies on human health outcomes with adequate pesticide exposure history precludes conclusions on causality

21. Annex on pesticides with endocrine activity

22. PESTICIDES WITH ENDOCRINE ACTIVITY

23. PESTICIDES WITH ENDOCRINE ACTIVITY

24. PESTICIDES WITH ENDOCRINE ACTIVITY

25. PESTICIDES WITH ENDOCRINE ACTIVITY

26. REGULATORY ACTIONS • Atrazine: banned in EU in 2003 because of unavoidable water contamination • TBT: Most antifoulant uses phased out by 2003, remaining uses by 2008 • Alkyl phenols and their ethoxylates: EU Directive prevents use as co-formulants in new products from 2005; voluntary UK agreement to replace AP(E)s in existing pesticide formulations • Vinclozolin, Procymidone, Fenarimol: EU discussing phasing out all uses