Carl-Gustaf Bornehag Professor in Public Health Sciences Karlstad University, Sweden The Great Lake District Lake Monona, Madison, Wisconsin, USA THEO COLBORN 1927-2014 In order to understand endocrine disrupting chemicals it might be good to learn what we know about our natural endocrine system Firstly, our natural hormones are of the greatest importance for a healthy development during the entire life span from the moment of conception until death Secondly, hormones mediate effects via specific interactions with proteins known as receptors Response I Target cell I Response II Secreting cell Blood vessel Not a target cell No receptor Wrong receptor Target cell II Thirdly, hormones acts at very low concentrations Fourthly, hormones often exhibit non-linear and non-monotonic dose responses 1493-1541 Fifthly, hormones are life stage dependent Example of estrogen exposure Organizational (irreversible) “programming” Activational (reversible) Endocrine Disrupting Chemicals (EDCs) -Natural estrogen hormone Binding Adverse health effect EDCs are not poisons! Cleaning & Personal care products Building materials Toys Sources for EDCs are everywhere… Dietary, cook wares and packages Reasons for emerging public health concern for EDC-exposure Low doses/non-monotonic Early life is important The wide range of health effects The low dose controversy exemplified by bisphenol A The low dose controversy exemplified by bisphenol A Myer et al., 2008 Response The dose-response paradigm Phillippus Aureolus Theophrastus Bombastus von Hohenheim Paracelsus 1493-1541 Dose Response Non-monotonic dose responses Toxicity Programming Dose Regulatory science Response MTD 1493-1541 LOAEL NOAEL Safe dose Safety factors Dose Exposure Early life is important David Barker (1938-2013) The fetal period is important for chronic diseases later on in life, e.g., hypertonia, diabetes, cardiovascular diseases... Birth weight Low birth weight & Centile crossing Body weight Macrosomia IUGR*** Median IUGR Birth Wean Adult Stress Infections Malnutrition Pharmaceuticals Environmental chemicals Environmental influences during development A 70 year old man with cardiovascular disease A 60 year old man with Parkinson's disease A 50 year old women with breast cancer A 40 year old man with diabetes A 30 year man who is infertile A 20 year old man with overweight A 10 year old boy with asthma A 6 year old boy with autism A newborn with malformed genitals Livsmedelsverkets inventering visar att upp till 66 vattentäkter i landet kan vara kontaminerade med PFAS från brandskum Endocrine Disrupting Chemicals (EDCs) -Natural estrogen hormone Binding Adverse health effect Cleaning & Personal care products Building materials Toys Sources for EDCs are everywhere… Dietary, cook wares and packages Natural hormones Estrogen Testosterone Thyroids. etc. EDCs “Xenoestrogens” Anti-androgens Group Phthalates (urine) Parent compound Metabolite n>LOD DEP MEP 2,356 67.97 (60.30 - 76.60) 511.49 DBP MBP 2,356 63.99 (57.72 - 70.94) 236.03 BBzP MBzP 2,356 16.11 (14.17 - 18.32) 101.59 MEHP MEHHP MEOHP MECCP 7OH-MMeOP 7OXO-MMeOP 7CX-MMeOP 2,356 2,356 2,356 2,356 2,356 2,356 2,356 3.28 (2.98 - 3.61) 6.82 (6.14 - 7.58) 3.06 (2.81 - 3.34) 10.84 (10.00 - 11.75) 17.30 67.57 46.33 65.30 60.18 20.92 78.31 BPA 2,356 1.54 (1.48 - 1.91) 6.37 Triclosan 2,356 0.75 (0.61 - 1.18) 315.41 PFNA PFDA PFUnDA PFDoDA PFHxS PFHpA PFOA PFOS 2,372 2,373 2,373 2,244 2,373 2,297 2,373 2,373 0.54 (0.53 - 0.54) 0.26 (0.25 - 0.26) 0.21 (0.20 - 0.21) 0.03 (0.02 - 0.03) 1.31 (1.29 - 1.33) 0.02 (0.02 - 0.02) 1.61 (1.58 - 1.63) 5.24 (5.17 - 5.32) DEHP DiNP Phenols (urine) Perfluorinated compounds (serum) Phenols PFCs GM (95% CI) (ng/mL) 14.49 (13.23 - 15.87) 9.73 (8.86 - 10.68) 14.25 (13.03 - 15.58) 95% (ng/mL) Natural hormones Estrogen Testosterone Thyroids. etc. EDCs “Xenoestrogens” Anti-androgens Phthalates A shorter AGD Incomplete masculinization Bornehag et al., 2015 Replacement of phthalates in PVC DiNP (2000) DEHP DINCH (2010) Non-phthalate Natural hormones Estrogen Testosterone Thyroids. etc. EDCs “Xenoestrogens” Anti-androgens Phthalates A shorter AGD Incomplete masculinization Bornehag et al., 2015 Prenatal phthalate exposure and sexual development (AGD) DiNP (2000) DEHP DINCH (2011) Non-phthalate Percentile (ng/mL) Monoester Metabolite MEHHP 25th 50th 75th 6.0 11.4 20.1 Swan et al., 2005 Likelihood of shorter AGD 4.6x 13x 1st trimester DiNP exposure increase the risk for shorter AGD in 196 SELMA boys (21m) OR (95% CI) 10 1 0,1 1st ref 2nd 3rd MEP MEP 4th 1st ref 2nd 3rd MBP MBP 4th 1st ref 2nd 3rd MBzP MBzP 4th 1st ref 2nd 3rd 4th 1st ref 2nd 3rd 4th DEHPsum DiNPsum DEHPsum DiNPsum Phthalate metabolites in quartiles Bornehag et al., 2015 The four most used phthalates in Sweden 2012 (above 1000 ton/year) DPHP DEHP DIDP DINP Kemi 2014 EDCs are not poisons! Risk assessment of EDCs should include • • • • • • • Low doses & non-monotonic dose responses Critical exposure periods during development Delayed (trans-generational) effects Programming rather than toxicity The mixture problem (“cocktail”) Knowledge based on principles of endocrinology Use all available information, not only GLP!!! – GLP! – Academic scientific studies incl. cell and animal models as well as epidemiological investigations Vandenberg et al., 2013, Reproductive Toxicology Regulatory decision and research on EDCs have to be based on principles of endocrinology!
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