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Endocrine Disrupting Chemicals
Major Areas of Controversy
James C. Lamb, Ph.D., DABT, ATS
Alexandria, VA
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Outline
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Endocrinology 101
Endocrine Disruption History
Definition of an EDC
Examples of Controversies
 Non-monotonic Dose Response Curves
 Policy reports by various organizations (eg., WHO)
 EU regulatory policy
 Conclusions
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Hormones
 Chemical messengers that
affect
 Growth
 Reproduction
 Behavior
 Migration
 Many other functions
Estradiol-17β
Source: www.3dchem.com/imagesofmolecules/Estradiol.jpg.
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Sources and Targets of Hormones
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Brain
Thyroid
Gonads
Pancreas
Adrenal glands
 Every part of the body is a target of one or more
hormones
 EDCs work in various ways
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Hormones and Endocrine Disruption
 Hormones are chemical messengers
 Move from organ A to B with a biological purpose and control
 Endocrine disruptor is "an exogenous substance
which causes adverse effects in an organism, or its
progeny, subsequent to changes in the endocrine
system.“ Weybridge Conference (1996)
 Many possible chemical modes of action are
implicated in the definition
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Evolution of the EDC Issue
 Diethylstilbestrol
 Exposures in the 1950s, effects in the 1970s
 Human effects
 Mouse model
 Environmental effects of various substances
 “Wingspread” and other conferences and books on the
hypothesis (1992 term “Endocrine Disruptor” invented)
Are we at risk of harm from
environmental exposures to EDCs?
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Endocrine Disrupting Chemicals
How did this come about?
 Children whose mothers took DES in 50’s-70’s
 NIEHS – program on “environmental estrogens” in the
1970s to present
 1992 the term Endocrine Disruptor is invented
 FQPA 1996 led to current EPA testing of pesticides and
drinking water contaminants for endocrine activity
Now national and international policy and scientific
issues on EDCs…
 Complicated scientific and regulatory issues
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Defining an
Endocrine Disrupting Chemical (EDC)
Exposure
Contributes to
Adverse Effect
Endocrine-Mediated
Mode-of-action
EDC
Altered Function of
Endocrine System
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Dose Response Curves
 Three common
dose response
curves
 Linear
 Non-monotonic
 Sigmoidal
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Cytotoxicity
80 substances cited by Vandenberg et al., 2012
 Often seen and seldom meaningful NMDR
 A response occurs, but the target cell, organ or
organism is overcome by toxicity at a higher level
 Less relevant to EDCs than other MOAs (lose 45% of
the 80 chemicals evaluated)
Danish Centre on Endocrine Disrupters, 2013
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Tale of Two Reports
2002 report
Early 2013 report
World Health Organization (WHO)
and
International Programme on
Chemical Safety (IPCS)
World Health Organization (WHO)
and
United Nations Environment
Programme (UNEP)
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Intervening 10 years
Thousands of publications
Improved surveillance of exposure and effects
Advances in lab and field testing
Increased application of advance methodologies to
looks at initiating events
 New endpoints and pathways
 Wider engagement of the scientific community
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Critical Review
 Reviewed described process and methods
 Compared to 2002 report
 Evaluated all chapters to identify common strengths
and weaknesses
 Identified key issues and concerns
 Select examples of unsupported claims
 Not a comprehensive assessment or re-evaluation
 Manuscript accepted in Reg Tox Pharm
 Open Access (Lamb et al., 2014; reference at end)
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Overall Concerns Identified in
WHO-UNEP 2012 Report
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Not an objective, state-of-the-science review
Not an update of WHO-IPSC 2002 report
Causation is often inferred – not established
Controversial topics are poorly addressed
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Inference – Not Causation
 Focused on one or two elements of
definition of endocrine disruptor
 No systematic process for assessing
causation
 Did not adopt framework from 2002
report
 “best professional judgment”
 Separate discussion of exposure
 Biological plausibility and MOA of causal
relationship cannot be addressed
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Spot the Differences…
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Spot the Differences…
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Example:
Diseases “induced” by EDCs
Summary for Decision-Makers
WHO-UNEP 2012
State-of-the-Science Review
Endometriosis
Developmental exposure “now
hypothesized” to contribute to risk
Autoimmune thyroid disease
“it is possible that EDCs play an
important role in the development of
these [autoimmune] diseases”
Heart disease/hypertension
No data provided on specific EDCs
Alzheimer disease and
Parkinson disease
Diseases not even mentioned in main
report
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Recent NTP Study on BPA
 Conducted by FDA/NCTR
 Two papers published in Toxicological Sciences
 Part of a $32 million NTP/NIEHS investigation into BPA
called CLARITY that has been discussed since 2008
 Withering criticism as soon as the paper was released
 Similar process with an EPA study on BPA
 Two contrasting versions in the press
http://www.motherjones.com/environment/2014/03/scientists-slam-fda-study-bpa
http://www.forbes.com/sites/trevorbutterworth/2014/04/09/bpa-the-scientists-the-scare-the-100-million-dollar-surge/
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Conclusions
 Natural and synthetic chemicals can have hormonal
activity
 All elements of the definition of an EDC (endocrine
MOA, altered function, adversity) must be considered
 Exposure is also critical
 Public reaction is highly susceptible to those
misinterpreting the data
 Substantial differences around the world in how
regulators respond
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Critical Comments on the WHO-UNEP State of the
Science of Endocrine Disrupting Chemicals – 2012
PREPARED BY:
James C. Lamb IVa, Paolo Boffettab, Warren G. Fosterc,
Julie E. Goodmand, Karyn L. Hentza, Lorenz R. Rhombergd,
Jane Staveleya, Gerard Swaene, Glen Van Der Kraakf, Amy L. Williamsa
a Exponent; b
Icahn School of Medicine at Mount Sinai; c McMaster University;
d Gradient; e Exponent/Maastricht University; f University of Guelph
This independent review has been commissioned by joint funding from:
American Chemistry Council (ACC)
CropLife America (CLA), CropLife Canada (CLC) and Croplife International (CLI)
European Chemistry Industry Council (Cefic)
European Crop Protection Association (ECPA)
In press, available online in Regulatory Pharmacology and Toxicology