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!