Issue 01 here - Irish Society of Toxicology

Vol.01,Issue01
ISTNewsletter
2012
WelcomefromtheSocietyPresident
As President of the Irish Society of Toxicology, I would like to present to you the latest edi on of
the Society’s newsle er. As a member , you are part of a family of professionals from a diverse
range of backgrounds including academia, government and industry, and who are involved in
toxicology (including medical aspects of toxicology) and ecotoxicology throughout the island of
Ireland. All share a common goal of crea ng a safer and healthier environment by advancing the
science of toxicology and ecotoxicology.
Insidethisissue
These past years have seen a redevelopment of the Society with a view to encouraging greater
par cipa on from the members and, together with our annual conference, Spring mee ng and
travel scholarship programme, we have undertaken a complete overhaul of the Society website
(h p://www.toxicologyireland.com). We now ac vely encourage dynamic membership and are
very keen to facilitate the inclusion of relevant ar cles for the IST newsle er as well as online
access, the no fica on of toxicology‐related events and relevant news items by members. We are
constantly developing the func onality of the website and hope to be able to facilitate the inclu‐
sion of professional profiles on the website, should members express an interest in doing so.
Appropriate content can be submi ed by fully paid‐up members on the ‘Contacts’ sec on of the
website.
Irish Society of Toxicology Travel
Scholarships 2011 ....................... 6
Human Biomonitoring ................ 2
University College Dublin Renal
Disease Research Group ............. 3
Toxic Chemicals in Consumer Prod‐
ucts ............................................. 4
Regulatory approaches to Endocrine
Disruptors ................................... 8
Computa onal Approaches Applied
to the Field of Toxicology ……….10
Bisphenol A …………………………...14
IST Conference & AGM 2012 ….16
Specialpointsofinterest
Like any professional society, it is impera ve that we reach as many of our poten al members as
we can. So if you think your colleagues, either in your immediate place of work or in your wider
professional network, would benefit from IST membership, then please bring the Society to their
a en on.
Many thanks for your con nued support of the Irish Society of Toxicology.
Sincerely,
Dr. John Moriarty, IST President
 Renal Toxicity Group
 Travel Scholarships
 Toxicology of consumer prod‐
ucts
 In silico approaches to toxicolo‐
gy
 Human biomonitoring seminar
 IST Annual Conference
1
HumanBiomonitoring
Human Biomonitoring (HBM) is the determi‐
na on of human exposure to environmental
agents using biomarkers that focus on expo‐
sures, diseases and/ or disorders and gene c
suscep bility, and their poten al rela on‐
ships. This is accomplished through direct
analysis of invasive (e.g. blood) or non‐
invasive (e.g., hair, urine) human body sam‐
ples. This permits an es ma on of the popu‐
la on exposure to current or poten al envi‐
ronmental hazards.
To facilitate an expansion of HBM within
Europe, and to ensure that the methodolo‐
gies used would permit interna onal com‐
parisons, a structure was established in 2009
that would (a) harmonise na onal ac vi es
on HBM and (b) coordinate associated pro‐
grammes across the EU. This Consor um to
Perform HBM on a European Scale, or
‘COPHES’, subsequently set up a pilot feasi‐
bility study called ‘DEMOCOPHES’ to deter‐
mine if a pan‐European harmonised ap‐
proach to HBM was possible.
The IST is ac vely involved in Hu‐
man Biomonitor‐
ing in Ireland established to oversee the implementa on
of this pilot study in Ireland. This inves gat‐
ed biomarkers for mercury, cadmium,
phthalates and environmental tobacco
smoke in human hair and urine from a cohort
of 120 mother and child pairs. This cohort
was equally divided in terms of urban and
rural representa on. In addi on to the actu‐
al biological sampling, informa on was also
gathered on poten al sources of exposure,
lifestyle and the socio‐economic status of the
par cipants. A similar approach has been
taken in the other EU member states. The
ul mate goal of COPHES is to support envi‐
ronmental, health and chemical policy needs
in the EU. A report on the DEMOCOPHES
pilot project is due by the end of 2012.
Further informa on can be viewed at h p://
www.eu‐hbm.info/cophes.
Updates on
ac vi es in Ireland can be viewed at h p://
www.hse.ie/eng/services/News/
democophes.
A DEMOCOPHES Management Group was
HumanBiomonitoring
IrishSocietyofToxicologySpring2012Seminar/Webinar
The Spring mee ng saw a welcome return to the IST calendar this year. It was hosted by the
Conway Ins tute in UCD which facilitated broadcast by Webinar, another first for the society.
Four speakers presented on the theme of HBM:
ISTroleinDEMOCOPHES

One of the most notable aspects of
the COPHES structure in the EU
members states is the par cipa on
of toxicological experts at every level

including the DEMOCOPHES pilot
project.
Given this reality, and thanks to the

foresight of IST members on the Irish
DEMOCOPHES Management Group,
the IST were approached in 2011 for
a suitable nominee.

The IST was delighted when Prof.
Michael Ryan, Professor Emeritus of
Pharmacology in UCD, accepted the
nomina on.
Dr. Ludwine Casteleyn from the Center for Human Gene cs at the University of Leuven in
Belgium and a COPHES coordinator presented on ‘A step by step approach to European
harmonized HBM in health and Environment’. Dr. Casteleyn discussed the challenges faced
in data interpreta on, laboratory standardisa on and policy development.
Dr. Maurice Mulcahy, Regional Chief Environmental Health Officer with HSE‐West & Na on‐
al Contact for the Irish DEMOCOPHES Management Group, gave a presenta on en tled
‘Making smoking history: the Irish smoking ban and beyond.’ Dr. Mulcahy gave details on
the impact of the Smoking Ban on public health.
Dr. Iona Pra , Chair of the EFSA Panel on Food Contact Materials, Enzymes and Flavourings
gave a presenta on en tled ‘Persistent Organic Pollutants (POPs) in breast milk: an indica‐
tor of body burden of the Irish popula on’. Dr. Pra discussed the results of various HBM
studies in Ireland which involved the analysis of breast milk to monitor exposure to POPs.
Dr. Mary O'Mahony, Specialist in Public Health Medicine, HSE‐South & Member of EUROCAT
(European Surveillance of Congenital Anomalies) presented on ‘Biomarkers & Biomonitor‐
ing: a public health overview & the EURObioCAT proposal.’ Dr. O'Mahony discussed HBM
from the medical prac oner’s standpoint and how this provides a very useful tool for de‐
tec ng exposure and iden fying risk groups in society as well as assessing the impact of
interven ons.
The Webinar op on proved popular among delegates as it provided a cost effec ve op on for
a ending without compromising on interac vity. The commi ee of the IST has agreed to explore
this op on, where possible, for future mee ngs. The presenta ons will soon be available on the
IST website at www.toxicologyireland.com/home.php.
2
ResearchInterest
The Renal Disease Research Group is
based in the UCD Conway Ins tute
of Biomolecular and Biomedical
Research at University College Dub‐
lin, Ireland. The group is led by Dr.
Tara McMorrow and Prof. Michael P.
Ryan, and has significant exper se in
the areas of kidney disease, toxicolo‐
gy, pharmacology and epithelial
biology.
Dr.
Tara
McMorrow is a
Conway Fellow
Hair‐like structures known as cilia (red), located on the surface of kidney epithelial cells, may be damaged or lost upon carcinogen exposure. and
a
Lecturer
Senior
in
Pharmacology at the UCD School of
INFOCUS:TheRenalDiseaseResearchGroup
Biomolecular and Biomedical Scienc‐
es. Dr. McMorrow is a commi ee
member of the Irish Society of Toxi‐
At the RDRG, the primary goal of our research is to expand the understanding of kidney func on
and physiology under normal condi ons and determine how these func ons are affected in vari‐
ous diseases. Of par cular interest are the mechanisms that underlie the development and pro‐
gression of end‐stage renal disease, diabe c nephropathy, renal cancers and drug‐induced ne‐
phrotoxicity. The aim is to develop novel diagnos c and prognos c strategies for preven on and
treatment of these diseases, and to iden fy novel therapeu c targets for future drug develop‐
ment. Toxcicology and toxicity screening are also major focus areas and the group is currently
involved in developing new toxicity screening pla orms for regulatory tes ng of chemical and
drug safety. The RDRG has extensive experience in the following techniques and technologies: in
vitro cell culture models, proteomic screening and profiling, In vivo animal models, transcriptom‐
ic and metabolomic profiling, human clinical sample collec on, cell imaging techniques and high
content analysis.
Recent research from the RDRG has demonstrated that known renal carcinogens disrupt cilia
structure and func on in tubular epithelial cells. The primary cilium is a highly specialised senso‐
ry and signal transduc on hub which plays a central role in diverse cellular processes such as
differen a on, polarity and cell cycle progression. Primary cilia are absent in several cancer cell
types such as breast and pancrea c cancers. In a study, recently published in the American Jour‐
nal of Physiology ,we have demonstrated that exposure to certain carcinogens significantly re‐
duced the percentage of ciliated renal cells (Radford et al. Am J Physiol (2012) 302(8):F905‐16).
Transcriptomic analysis iden fied several important signalling pathways involved in media ng
these effects. The work was carried out in conjunc on with collaborators in Austria, Switzerland
and The Netherlands as part of the EU FP6 project, CarcinoGENOMICS. The RDRG plans to ex‐
pand this research by characterising mechanisms of primary cilium loss during carcinogenesis and
explore the applica on of this research as a novel screening method for poten al chemical car‐
cinogenicity.
The group is currently funded by grants from the European Union (6th and 7th Framework), the
CEFIC Long‐Range Ini a ve, the Health Research Board of Ireland of Ireland, Cys nosis Founda‐
on Ireland, the American Cys nosis Associa on. Visit www.ucd.ie/renal for more informa on.
cology.
Dr. McMorrow has pub‐
lished over 30 peer‐reviewed ar cles
and has co‐authored several book
chapters in cancer biology, toxicolo‐
gy and renal disease.
Prof. Michael P
Ryan is Professor
Emeritus
of
Pharmacology at
UCD and a Con‐
way Fellow. He
has served as Dean of Doctoral
Studies and Postdoctoral Training at
University College Dublin and was
Head of the Department of Pharma‐
cology in UCD for over 25 years and
a Senior Lecturer in Pharmacology in
the UCD School of Biomolecular and
Biomedical Sciences. Prof. Ryan has
published over 80 peer‐reviewed
ar cles and has co‐authored book
chapters in cancer biology, toxicolo‐
gy and renal disease
3
TheHumanHealthImplicationsofToxic
ChemicalsinConsumerProducts
Hiddenhazardsinhouseholdproducts
Many synthe c and natural chemicals are pre‐
sent in a very wide range of consumer products
ranging from, for example, foods, perfumes,
cosme cs, household cleaning agents, furni‐
ture, carpets, food containers, toys, fuels and
hardware equipment. Many of these substanc‐
es enter the food chain accidentally, as in the
2008 Irish pork crisis, or deliberately as hap‐
pened in China with the contamina on of baby
food with melamine. Some of these chemicals
have significant toxic proper es and may cause
various adverse effects on human health de‐
pending on the dose/amount and the dura on
of exposure. Media coverage of toxic chemical
incidents is o en sensa onal and the headlines
can be downright inaccurate. At the same
me, certain elements in the media o en pro‐
mote dietary supplements simply because they
appeal to the consumer while presuming no
adverse or uncertain health effects. Many in
the organic movement assert that their prod‐
ucts contain ‘no chemicals’! A well‐known Irish
chef and hotelier recently boasted that his
focus was ‘green, chemical‐free, GM‐free food’.
Again, a producer of ‘natural’ cosme cs
claimed on RTE‐1 television recently that his
Professor Jim Heffron is emeritus
professor of Biochemistry University
College Cork.
He held academic
posi ons at Mayo Clinic and Gradu‐
ate School of Medicine, USA, the
Witwatersrand University Medical
School, South Africa and was Royal
Society‐Royal Irish Academy Re‐
search Fellow at University College
cosme cs contained ‘no chemicals’. It is li le
surprise then that the consumer is confused
about the safety of food and household prod‐
ucts in general. The new EU chemical safety
assessment system, ‘REACH’, aims to prevent
harmful chemicals being used in industry gen‐
erally and to protect the consumer from harm‐
ful exposure. Regre ably, consumers appear
unaware of the reality of REACH and its protec‐
ve poten al.
Tolerable intake levels for dioxin are roughly 10 million mes lower than those for cyanide! London. His research on the human
gene c disorder Malignant Hyper‐
Clearly then, it may be helpful to the consumer to outline what scien sts mean when referring to
toxicity and toxic. Where be er to start than with the famous statement of Paracelsus of Renaissance
mes viz, “All chemicals are poisons; there is none that is not a poison. The right dose differen ates a
poison from a remedy”. Paracelsus, a Swiss‐German physician and alchemist, coined this aphorism
almost five hundred years ago and it remains the accepted opera ng principle of those in the field of
toxicology worldwide to this day. Thus, even water is toxic and there are many examples of adverse
ac ons of water in both humans and animals. It is essen al to note other qualifiers of toxicity, for
example, the period over which a person is exposed to a chemical – is it short‐term or acute or is the
dura on of exposure long‐term over many months or years (chronic). Equally important determinants
of toxicity are the species in which toxicity is assessed and the route by which a chemical enters the
body. Two chemicals which illustrate these qualifiers are dioxin and cyanide. Dioxin, a term referring
to a mixture of chlorinated dibenzodioxins produced during uncontrolled burning of plas c waste and
certain solvents, is a chronic poison whose toxicity in humans is 3,000 mes less than in the test ro‐
dent, the guinea pig.
thermia led to discovery of the MH
gene and to advances in biochemical
toxicology of anaesthe cs and pollu‐
tants.
Jim has long established
research links with the pharmaceu ‐
cal industry and was adviser and
contributor to the WHO’s Air Quality
Guidelines for Europe (2000). He is
an elected Member of the Royal Irish
Academy, Fellow of the Royal Socie‐
ty of Chemistry, member of the
American
Chemical
Society
and
Yet we read in the popular media that it is the most toxic chemical known. While it is true that dioxin
is extremely toxic, a natural chemical – the so‐called botulinum toxin from Clostridium botulinum – is
several orders of magnitude more toxic than dioxin and by far the most toxic chemical known. Dioxin
is classified as a definite human carcinogen by the World Health Organisa on (WHO) but, being a non‐
genotoxic carcinogen, a Tolerable Weekly Intake of 14 pg per kg body weight has been established.
Thus, the dose to which the body can be exposed every week over a life me, without incurring any
adverse health effects, is extremely low. In the case of cyanide, we know it is an acute ac ng chemical
which blocks respira on and has a similar level of toxicity in animals and humans. The UK Commi ee
on Toxicity has recommended a Tolerable Daily Intake of 20 μg per kg body weight per day – roughly
10 million mes the limit for dioxin!
Chartered Scien st (UK). He gradu‐
ated from University College Dublin
with a First Class BSc in Biochemistry
under the late Professor E.J. Conway
FRS and then completed research for
the PhD degree there. He has pub‐
lished in Nature, PNAS of USA,
Bri sh Medical Journal, etc., and is a
member of the editorial board of
Drug Analysis and Tes ng (Wiley).
He was awarded the DSc by NUI and
Royal Irish Academy Silver Medal for
dis nguished biochemical research.
4
Therehavebeenseveralrecenthighpro ile
casesoftoxicchemicalsinconsumerproducts
butthosethatstandoutintermsofimplicaThere have been several recent high profile cases of toxic chemicals in consumer products but
those that stand out in terms of implica ons for human health are:
1. Dioxins: a er an earlier instance in Belgium in 1999, dioxins were detected (primarily) in pork
meat and meat/eggs in Ireland and Germany in 2008 and 2010, respec vely. In both instances
the dioxins entered the food chain from animal feedstuff. Dioxins were also detected in guar
gum imported from India by a firm in Switzerland; the gum is a soluble dietary fibre extracted
from seeds of the guar plant and is a common addi ve in foods such as yoghurt.
2. Melamine was iden fied in baby food on sale in China. Melamine and its metabolite cyanuric
acid are poten al kidney toxicants. Melamine is a triazine with six nitrogen atoms overall in the
molecule. It gives a false‐posi ve protein test and was used deliberately to adulterate the baby
food. Some babies died and over 300,000 suffered various adverse effects such as anorexia,
vomi ng, polyuria and crystal forma on in the kidney tubules. Previously in 2007, melamine had
been found in cat and dog food imported from China to the United States.
3. Diethylene glycol was found in toothpaste in China. This is used as a thickening agent in
toothpaste and is also present as a contaminant in glycerol and polyethylene glycol. It is a poten‐
al kidney toxicant.
4. Bisphenol‐A (BPA) is used in the manufacture of polycarbonate plas c and epoxy resins. It is
present in impact‐resistant safety equipment and baby bo les, as protec ve coa ngs inside
metal food containers and as composites and sealants in den stry. BPA has been banned in baby
bo les by the EU since June 2011 on the basis of it being a reproduc ve hazard to children. Safer
alterna ves to BPA are being developed.
“we urgently need an emerging risks policy com‐
bined with that of toxicovigilance” 5. Acrylamide has gained considerable press since it was detected at significant levels in some
toasted, baked and grilled carbohydrate‐rich foods by Swedish researchers in 2002. The neuro‐
toxicity of acrylamide has been known for some me but more recent studies have shown that
the compound is genotoxic and a probable human carcinogen. It is a further example of a hazard
that has probably always been present wherever carbohydrate‐rich foods have been prepared by
the above processes but has remained undetected and unsuspected un l the Swedish analyses
of 2002.
6. Formaldehyde is found in a wide array of products and its main uses are in resins which act as
adhesives in par cle board, plywood and many wood products. It is employed by anatomists,
pathologists, mor cians and zoologists as a fixa ve and preserva ve for ssues and microscopic
studies. It is a well‐known respiratory and eye irritant and has been recently classified as a car‐
cinogen under the US Na onal Toxicology Program. Unacceptable levels of formaldehyde have
been found in some hair smoothing solu ons and workers have reported headaches, nosebleeds,
burning eyes and asthma a acks a er using these solu ons and other hair straighteners.
7. Trans fats are fa y acids present in hydrogenated vegetable oils and are employed in the
manufacture of margarines and bu er subs tutes. They are more rigid structures resembling
that of a saturated fa y acid. Evidence indicates such fats increase the risk of cardiovascular
disease by raising LDL cholesterol levels, increasing the total cholesterol to HDL cholesterol ra o
and promo ng systemic inflamma on via the TNF system.
5
TheTravelScholarship
Scheme
Each year, the Irish Society of Toxi‐
cology holds an open compe
on
for its student members for travel
scholarships to enable them to work
in laboratories abroad or a end
workshops and conferences abroad.
The value of each award does not
normally exceed €1,000 and they are
open to students with relevant
backgrounds from third level colleg‐
es in the Republic of Ireland and
Northern Ireland. The
me period
within which an award can be imple‐
mented is a full calendar year from
TheIrishSocietyofToxicologyTravelScholarshipAwardWinnersin2011
April to April.
The overall aim of the scheme is to
increase awareness of Toxicology as
a mul disciplinary subject.
While
the majority of successful candidates
to date have been postgraduate
students, a number of undergradu‐
ate students have also been success‐
ful and the Society par cularly en‐
courages undergraduate students to
apply.
Further informa on on the Travel
Scholarship scheme, including guid‐
ance notes and the applica on form,
can be obtained on the Society’s
website,
www.toxicologyireland.com.
6
My name is Pratap C. Naha; I have been awarded
a Travel Scholarship from the Irish Society of
Toxicology in 2011. I am a 4th Year PhD student
at the FOCAS Research Ins tute in the Dublin
Ins tute of Technology in Kevin Street. My PhD
work focused on the eco and in vitro mammalian
toxicological assessment of polymeric nano‐
materials under the supervision of Prof. Hugh
Byrne.
As a recipient of a 2011 IST Travel Scholarship
award, I was able to a end and give a pla orm
presenta on at the pres gious 21st SETAC
(Society of Environmental Toxicology and Chem‐
istry) European conference in Milan, Italy in May
2011.
The tle of my presenta on was
‘Interac on of nanosized Poly (amido) amine
dendrimers with fresh water ecological organ‐
isms and fish cells’.
My research area was essen ally the developing
field of nanotoxicology. Briefly, this involved
inves ga on into the poten al interac on of
PAMAM dendrimers and a series of PNIPAM and
NIPAM/BAM nanopar cles at the cellular and sub
‐cellular levels. This assessment involved a full
physico‐chemical characteriza on of each nano‐
material and evalua on of their mammalian
toxicity (in vitro) and ecotoxicity. Their mecha‐
nism of toxicity was explored in terms of intracel‐
lular Reac ve Oxygen Species genera on, the
forma on of DNA adducts, DNA damage, apopto‐
sis and finally cell death, and these results were
used to inform the interpreta on of the Structure
Ac vity Rela onship of the nanomaterials gov‐
erning the toxicological response. I hope to
con nue my research and gain a more in‐depth
understanding of the molecular toxicity mecha‐
nis c pathways important in the development of
biocompa ble materials for biomedical applica‐
ons and drug delivery systems.
I was delighted with
the
opportunity
afforded me by this
award to a end
such an important
mee ng.
At this
conference I not
only presented my
research work, but
Pratap C. Naha I also got to net‐
IST Travel Scholarship work with so many
awardee, 2011 scien sts working
in different areas
and exchange ideas with them. And I also visited
the beau ful city of Milan!
My name is Hilary Cassidy and in 2002 I completed a Bachelor of Science Degree in Toxicology in
Athlone Ins tute of Technology. During this course I completed three months’ work experience
in the Therapeu c Drug Monitoring (TDM)/Toxicology laboratory at Beaumont Hospital which
developed my interest in this area. I am currently a PhD student at the Conway Ins tute of Bio‐
molecular and Biomedical Research in University College Dublin, working in the Renal Disease
Research Group (www.ucd.ie/renal) and specialising in the field of renal toxicology.
In my research I focus on chronic kidney disease (CKD), renal transplanta on and immunosup‐
pressant therapies. In par cular, I am interested in the development of drug‐induced kidney
disease in transplant recipients which is a direct result of the strict immunosuppressant regime
that these pa ents must adhere to for the preven on of organ re‐
jec on. Immunosuppressant drugs, such as cyclosporine A, have
vastly decreased gra rejec on rates since their implementa on,
but the use of these drugs is complicated by the wide range of organ
toxici es they incite, the most significant, and possibly ironic, toxici‐
ty being nephrotoxicity. The detec on and monitoring of these
adverse drug effects associated with immunosuppressant regimes
are par cularly challenging as rela vely few tests exist for measur‐
ing immunosuppressive drug or drug metabolite levels and no single
test exists for detec ng the wide range of known adverse drug
effects. The hope is that new high‐throughput ‘omic’ techniques
Hilary Cassidy could help iden fy combina ons of biomarkers that might be used
IST Travel Scholarship awardee, 2011 to inexpensively and non‐invasively iden fy transplanta on prob‐
lems far earlier and far more robustly than is currently possible.
Metabolomics is ideally suited for monitoring drugs and drug metab‐
olites as well as for tracking the drug‐induced changes to organ func on and organ metabolism.
Improved diagnos c tests could increase transplant survival rates by offering a more sensi ve
detec on of changes in kidney func on, thereby allowing doctors to make changes in a pa ents’
immunosuppressive regime.
“I would highly recommend this award to any student studying within the broad area of toxi‐
cology who wishes to expand their knowledge” As a recipient of the IST travel scholarship award in 2011, I was able to a end and present a re‐
search poster at the 10th HUPO World Congress which took place in Geneva, Switzerland in Sep‐
tember 2011. The Human Proteome Organisa on (HUPO) is an interna onal scien fic organiza‐
on represen ng and promo ng proteomics through interna onal coopera on and collabora‐
ons by fostering the development of new technologies, techniques and training. This mee ng
was of par cular relevance to my research as it included specific sessions on pharma‐toxicology
and biomarker discovery and valida on, both areas of significant relevance to my work. I re‐
ceived posi ve feedback on the research that I presented and also useful sugges ons for future
experiments. At the conference I made contacts with several laboratories conduc ng similar
research and with whom I am now in regular contact.
I would like to express my gra tude to the IST for awarding me the travel scholarship. This fund‐
ing granted me the opportunity to present my results to other researchers working in the same
field, as well as offering me the opportunity to network with researchers from other universi es
and industry, opening doors for me to establish useful contacts throughout other European and
interna onal labs and giving rise to the possibility of work collabora ons. Some of the research
presented at the conference has also recently been published. I would highly recommend this
award to any student studying within the broad area of toxicology who wishes to expand their
knowledge.
Johnston O., Cassidy H., O'Connell S., O'Riordan A., Gallagher W., Maguire P.B., Wynne K., Cagney
G., Ryan M.P., Conlon P.J. and McMorrow T., Iden fica on of β2‐microglobulin as a urinary bi‐
omarker for chronic allogra nephropathy using proteomic methods. Proteomics Clinical Applica‐
ons, 5(7‐8):422‐31, 2011.
7
GettingtogripswithEndocrineDisrupting
Chemicals
ReportsfromEurope
The first day of the conference was devot‐
ed to the scien fic aspects of endocrine
disrup on. The keynote lecture on endo‐
crine disrup on was given by Linda Birn‐
baum of the US Na onal Ins tute of Envi‐
ronmental Health Sciences (NIEHS). Other
presenta ons concerned:

Dr. Iona Pra , member of the IST

and Chair of the EFSA Panel on Food
Contact Materials, Enzymes, Flavour‐
ings and Processing Aids, gives us

two related reports/updates from
Europe. The first report is from a

conference organised by the Europe‐
an Commission that addressed the
scien fic and policy challenges pre‐
sented
by
endocrine

disruptors
while the second concerns the regu‐
latory status of the endocrine dis‐
ruptor, Bisphenol A.
The effects of endocrine disruptors
on human health (Tracey Woodruff,
University of California)
The effects of endocrine disruptors
on wildlife health (Susan Jobling,
Brunel University)
Whether or not endocrine disruptors
are ‘special’ (Jerry Heindel, NIEHS)
Sources of exposure to endocrine
disruptors (Ake Bergman, Stockholm
University)
The OECD Conceptual Framework for
tes ng and iden fica on of endo‐
crine disruptors (Laurence Musset,
OECD)
Proposals for the development of criteria
for classifica on of endocrine disruptors –
an overview (Andreas Kortenkamp, Brunel
University as contained in his report for
the European Commission on state of the
art on endocrine disruptors)
European Conference on
endocrinedisruptors
The first day also included two panel dis‐
cussions, in which the audience had the
opportunity to debate issues with the
speakers plus other invited panelists.
The 2nd day of the conference was devot‐
ed to presenta ons from various stake‐
holders on what policy objec ves should
be followed and what ac ons should be
taken in rela on to exposure of the popu‐
la on to endocrine disruptors. These
stakeholders included the Endocrine Soci‐
ety, the European Consumers' Organisa‐
on (BEUC), ChemTrust UK, the European
Chemical Industry (CEFIC) and the Europe‐
an Trade Union Confedera on. Presenta‐
ons were also given by the Danish Presi‐
dency and the US EPA. In general, all
these presenta ons (with the excep on of
that from CEFIC) stressed that there was
now sufficient evidence of adverse health
effects of endocrine disruptors in humans,
and that ac on had to be taken to control
exposure. This was reflected in the panel
discussion that followed, in which the
audience had the opportunity to debate
issues with the presenters.
In June of 2012, the European Com‐
mission – specifically the Directorate
Discussions during the mee ng centred around the usual points of controversy which
incidentally, had also been debated at the EFSA colloquium earlier in June. These include:
 What cons tutes a low dose
 What is the significance of non‐monotonic dose‐responses (assuming they exist)
 Are endocrine‐disrup ng effects truly adverse, par cularly at low doses, or purely
adap ve?
 The use of peer‐reviewed published data as opposed to guideline GLP studies
General Environment – organised a
conference to address the scien fic
and policy challenges that currently
exist when addressing the issue of
endocrine disrup ng chemicals in
our environment. The event a ract‐
ed in the region of three hundred
delegates represen ng not only the
It was notable that the majority of par cipants at the conference appeared to be
suppor ve of the hypothesis that endocrine disruptors were responsible for adverse
effects on human health and in the environment.
European Commission, but EFSA, the
EU Member States, academic scien‐
sts, industry, trade unions, consum‐
er bodies/NGOs. Opening presenta‐
ons were given by the commission‐
ers for the Environment, Research,
Innova on & Science and Health &
Consumer Policy.
8
Thekeyconclusionsincludedthefollowing:
1.
Although there are s ll considerable uncertain es regarding the impact of
endocrine‐disrup ng substances on human health and the environment,
sufficient knowledge has been amassed on the adverse effects of these
substances to take regulatory ac on;
2.
The test methodology (OECD conceptual framework) is now sufficiently robust (at
the higher levels of the framework, supported by screening tests at the lower
levels) to enable iden fica on of endocrine disruptors, although there are s ll
gaps;
3.
Criteria to ‘classify’ endocrine disruptors need to be developed as a ma er of
urgency, in order to enable regulatory ac on;
4.
There are divided opinions as to whether potency should form part of such
criteria;
5.
More research is needed into assessment of exposure of popula ons to
endocrine disruptors, in par cular to mixtures of such substances, and the
poten al effects of mixtures;
6.
More understanding of the underlying (epigene c) mechanisms, recognising that
these extend beyond effects on oestrogen, androgen and thyroid hormone
receptors;
7.
Informa on on human health effects and effects on wildlife/the environment
must be more closely integrated in order to improve the overall knowledge base,
in par cular mechanis c data.
Following the conference the Commission (DG Environment in consulta on with other
DGs) will review its 1999 strategy on endocrine disruptors and will, by the end of
2013, propose criteria for their iden fica on/classifica on including specific criteria
for the iden fica on of pes cides and biocides with endocrine‐disrup ng proper es.
This is par cularly necessary because the updated legisla on in these areas specifically
indicates that such substances should not be authorised as pes cides/biocides.
‘….there is now sufficient evidence of adverse health effects of endocrine disruptors in humans and ac on has to be taken to control exposure’ DiaryDates
Congress Centre
Interlaken
Switzerland
September 1 to 4, 2013
h p://www.eurotox2013.com/
welcome.html Coex,
Seoul
Korea
June 30–July 4, 2013
h p://www.ict2013seoul.org/ September 1 to 4, 2013
h p://www.eurotox2013.com/
welcome.html Henry Gonzalez Conven on Cen‐
ter
San Antonio
Texas
March 10–14, 2013
h p://www.toxicology.org/AI/
MEET/AM2013/ 9
Computational Approaches Applied to the
FieldofToxicology
TrendsinToxicology
Dr. Brendan Murray, gives us an
introduc on into the world of in
silico techniques and the use of
computa onal tools applied to the
field of toxicology.
Brendan works as a regulatory toxi‐
The basis for toxicological tes ng and safety
screening is ul mately the poten al benefit to
humans and animals that will accrue (i.e. lack
of toxicity & increased efficacy). This entails
defining the hazard of exposure to drugs and
chemicals, par cularly new en es, under‐
standing the risk when it exists, and pre‐
ven ng or minimising that risk. This concept
holds whether one is doing drug discovery,
environmental, or regulatory toxicology. New
technologies provide computa onal tools that
when used alongside tradi onal in vitro and in vivo models are redefining how toxicologists
in chemical and pharmaceu cal industries
work to ensure successful product outcomes.
Real and substan al cost benefits are realised
during this process as limited resources may
be op mally directed following the screening
of large collec ons of virtual compounds in
the pursuit of new chemical en es.
chemical from its structure (fig. 1). Connec v‐
ity mapping achieves similar aims but uses
gene transcrip on signatures. While these
approaches serve to iden fy hazard, actual
risk depends on many different factors. Next
genera on QSARs will need to incorporate
the mechanis c understanding of experts into
their computa onal models in order to arrive
at be er toxicological predic ons. One of the
main problems with in vivo animal toxicity
studies is the extrapola on of derived end‐
points to humans, or effects seen at high
experimental doses to low environmental
doses to which humans are usually exposed.
Typically the extrapola ons have been per‐
formed on the basis of administered doses
without knowledge of internal dosimetry.
The advent of physiologically based pharma‐
cokine c (PBPK) modelling makes it possible
to calculate and predict internal dose metrics.
Within the last two decades tremendous
advances have been made with respect to
combinatorial chemistry, analy cal tools that
feed the “–Omics” revolu on, data storage
and mining, computer hardware and so ware
analysis tools. Massive data genera on ne‐
cessitates the use of advanced mathema cs
and sta s cs as we strive to iden fy rela on‐
ships between the data and the observed
toxicological endpoint. Data interpreta on
represents one area of mathema cs in toxi‐
cology. Of more profound interest (and diffi‐
culty) is modelling with the ul mate aim of
predic ng the consequences of chemical
interac ons with biological systems especially
when it results in a mul ‐target, mul ‐
mechanis c and complex endpoint such as
organ carcinogenicity. This la er type of
mathema cal modelling includes quan ta ve
structure ac vity rela onships (QSAR), which
a empts to predict the toxicity profile of a
There are innumerable compounds wai ng
to be synthesised and/or tested for regulatory
compliance but it is infeasible to achieve this
through the use of tradi onal toxicity tes ng
from a whole‐animal system‐based model.
Instead, alterna ve methods u lising in vitro and in par cular in silico models or computa‐
onal approaches are increasingly being rec‐
ognised as the way forward for chemical risk
assessment and iden fica on of the toxic
poten al of candidate molecules in lead selec‐
on and drug discovery.
cologist for the Pes cides Registra‐
on & Control Division of the De‐
partment of Agriculture, Food and
the Marine.
A self‐confessed techie, he adminis‐
ters and develops the IST website
at: www.toxicologyireland.com.
ISTWebsite
The primary mode of predic ve safety
evalua on is changing from experimenta on
to an informa on and knowledge‐based pro‐
cess. In silico or computa onal approaches
when applied to the field of toxicology involve
the applica on of mathema cal and comput‐
er models to predict effects and understand
the events that result in an adverse response.
Please visit h p://
www.toxicologyireland.com for the
latest news regarding the IST. Con‐
tribu ons to site content welcome.
Many changes will proceed over the
next few months with a more
streamlined design and featured
Figure 1. In silico methods help to screen out chemicals with unwanted molecular proper es that may result
in toxicity if allowed to proceed Amiodarone is an example of a ca onic amphiphilic drug (CAD). The poten‐
al of such a compound to induce phospholipidosis is fairly well predicted by a few calculated physico‐
chemical proper es – the basic pKa value (or pKb), the amphiphilicity expressed as a vector sum (dashed line)
and the lipophilicity as log P.
news ar cle sec on being planned.
10
The primary advantage of computer based
tools is the ability to analyse, arrange, and
search vast amounts of biological data
(including but not limited to sequence, struc‐
ture, and microarray data) quickly and in a
structured manner, par cularly when such
data includes pa erns, noise, ambiguity,
missing values, imprecision and uncertainty.
In silico toxicity predic on techniques may be
coarsely classified into methods that model
biochemical events that are relevant for tox‐
icity (Molecular Modelling), techniques that
mimic human reasoning about toxicological
phenomena (Expert Systems) and methods
that derive predic ons from a training set of
experimentally determined data (Data Driven
Systems).
Global structure‐ac vity rela onships
(SARs) / models that have been developed
using a noncongeneric set of chemicals en‐
compassing a number of different biological
mechanisms, poten ally offer significantly
shorter mes for the discovery of new molec‐
ular en es and at a lower expense by priori‐
sing candidates for more expensive assays
when required. Commercially available toxici‐
ty predic on systems like DEREK (Deduc ve
Es ma on of Risk from Exis ng Knowledge)
and MCASE (Mul ple Computer Automated
Structure Evalua on) were developed from
data taken from public sources. They are
validated with a large training set of diverse
structures and can therefore be used before
any wet laboratory results. These expert
systems offer the capability of screening thou‐
sands of virtual compounds. This has shi ed
drug companies’ efforts toward applying
these new dry biology technologies in early
lead op misa on and help avoid fu le entries
into the clinical trial phase by early‐stage
elimina on.
The fact that chemicals with similar struc‐
tures tend to exhibit equivalent ac vi es is
the basis of computa onal toxicology. Nu‐
merous reports illustrate the use of computa‐
onal approaches. Examples include the
discovery of HIV‐1 Integrase inhibitors, novel,
selec ve inhibitors of P. falciparum dihydro‐
folate reductase, the development of
donepezil hydrochloride for the treatment of
Alzeimer’s disease, and inves ga ons into the
varia on in the observed inhibitory ac vity
among sialic acid analogues for use in treat‐
ment against influenza and the occurrence of
side effects through interac on with human
neuraminidases. Other examples abound,
including structural bioinforma cs, molecular
dynamics, molecular docking, an microbial
pep de predic on, signal pep de predic on,
iden fying GPCRs and their types, predic ng
CYP‐related metabolic proper es for screen‐
ing etc.
In silico methods may compliment in vitro methods as shown here in this
novel genomic predic on technique
for
screening
hepatotoxic
com‐
pounds. Schema c diagram of the
computa onal model construc on
and valida on processes. The hepa‐
tocellular toxicity predic on was
developed
through
five
dis nct
steps. The first was the iden fica‐
on of hepatocellular toxicity bi‐
omarker genes by correla on analy‐
sis with serum ALT. The second was
‘….in silico models or computa onal approaches are increasingly being recognised as the way for‐
ward for chemical risk assessment’ the homologous gene match be‐
tween human and rat while the third
was the selec on of the COXEN
biomarkers among human homolo‐
gous
hepatocellular
toxicity
bi‐
omarkers obtained from the second
The majority of these computa onal ap‐
proaches are involved in the drug discovery
and development process but increasingly are
being used to support wider chemical product
authorisa on by regulatory authori es. Ex‐
amples include the use of toxicogenomics
with short term animal models to inves gate
nongenotoxic carcinogenesis, the use of QSAR
predicted TD50 values to determine the risk
specific dose (RSD) for genotoxic impuri es,
predic ve models of acute oral toxicity in rats,
the use of allergen sequence fragments with
machine learning techniques, and the SDAP
bioinforma cs tools that use analysis of local
sequence and structure to iden fy poten al
protein allergens. Computa onal toxicology
is different to those approaches used for
iden fying drug candidates or aiding in lead
op misa on. It serves to iden fy toxicity
pathways, rapidly determine the toxicity
poten al of large numbers of chemicals cov‐
ering different life stages, genders and spe‐
cies. Key to the success of this field is the
construc on and cura on of large‐scale data
repositories necessary to hold the data from
new technologies as well as the mathema cal
and sta s cal tools to aid in the interpreta‐
on of this informa on .
Computa onal toxicology relies on the
availability of a wide diversity of so ware
tools (table 2) that run on a variety of
pla orms such as Windows, MAC OS and
Linux. The so ware tools can be open source
or proprietary. The European Commission’s
Joint Research Centre (JRC) has been develop‐
ing a range of user‐friendly and publicly acces‐
sible so ware tools which promote reliable
computer‐based es ma on methods for the
regulatory assessment of chemicals, including
industrial chemicals under the scope of
REACH. Examples include toxtree, toxmatch
and DART.
step.
In the fourth step, further
refinement selected the biomarkers
known to be directly related to liver
toxicity and cell death performed by
Ingenuity Pathway Analysis.
This
func onal analysis step led to the
final 32 biomarkers of hepatocellular
toxicity. The last step was the mul ‐
variate predic on model construc‐
on based on the final 32 genes.
Courtesy of Cheng et al., (2011)*.
Cheng, F., Theodorescu, D., Schul‐
man, I.G. & Lee, J.K. In vitro tran‐
scriptomic predic on of hepatotoxi‐
city for early drug discovery. J Theor
Biol 29, 29 (2011).
11
Summary of available in silico systems for toxicity predic ons
Table2:
System name
Short descrip on
Predicted endpoints
In silico techniques or computa onal
Classical QSAR ap‐
proaches
Correlate structural or property descriptors of
compounds with biological ac vi es
QSARs for various endpoints
published.
approaches are mediated through
DEREK for Windows
Knowledge (rule)‐based expert system
Muta/Carc/Skin Sens/Irrit and
more (>40)
MCASE (CASE, CA‐
SETOX)
Machine‐learning approach to iden fy molecular
fragments with a high probability of being associat‐
ed with an observed biological ac vity
Available modules:
TOPKAT
TOPKAT employs cross‐validated QSTRj models for
assessing various measures of toxicity; each mod‐
ule consists of a specific database
Muta/Carc/Repr/Acute Tox/
Skin Sens/Irrit/Env and more.
OncoLogic
Knowledge‐based expert system, mimicking the
decision logic of human experts
Carc
Lazar
Derives predic ons from toxicity data by searching
the database for compounds that are similar with
respect to a given toxic ac vity
Muta/Carc/Hepato Tox/Env
MDL QSAR
QSAR modeling system to establish structure‐
property rela onships, create new calculators and
generate new compound libraries
Muta/Carc/hERG inhib/Acute
Tox
ToxScope
ToxScope correlates toxicity informa on with
structural features of chemical libraries, and cre‐
ates a data mining system
Muta/Carc/Irrit/Hepato Tox/
Repr and more
HazardExpert
Knowledge (rule)‐based expert system
Muta/Carc/Irrit/SkinSens/
Immuno Tox/Neuro Tox
COMPACT
COMPACT is a procedure for the rapid iden fica‐
on of poten al carcinogenicity or toxici es medi‐
ated by CYP450s
Carc and P450‐mediated toxici‐
es
PASS
On the basis of the comparison of new structures
with structures of well‐known biological ac vity
profiles by using MNAo structure descriptors
Mul ple endpoints
Cerius2
Molecular modeling so ware with a ADME/Tox
tool package provides computa onal models for
the predic on of ADME proper es
ADME/Hepato Tox
Tox boxes
Modules generated by a machine‐learning ap‐
proach implemented in a fragment‐based Ad‐
vanced Algorithm Builder (AAB)
Muta/Acute Tox/Carc and more
MetaDrug
Assessment of toxicity by genera ng networks
around proteins and genes (toxicogenomics
pla orm)
>40 QSAR models for ADME‐
Tox proper es
DICAS
Cascade model with the capability to mine for local
correla ons in datasets with large number of
a ributes
Carc
CADD
Computer‐aided drug design (CADD) by mul ‐
dimensional QSARs applied to toxicity‐relevant
targets
Receptor‐ and CYP450‐
mediated toxici es, Endo Dis‐
rup.
CSGeno Tox
QSTR‐based package employing electrotopological
state indexes, connec vity indexes and shape
indices
Muta
Admensa Interac ve
QSAR‐based system primarily for ADME
op misa on
Cardio Tox
PreADMET
Calcula on of important descriptors and neural
network for the construc on of predic on system
Muta/Carc
BfR decision support system
Rule‐based system using physicochemical proper‐
es and substructures
Irrit and corrosion
Bioclipse
A free and open source workbench. Has a variety of
modules for similarity searches, structural alerts
and QSARs. It has an extensible architecture.
h p://www.bioclipse.net/decision‐support
Muta/Carc/Nuclear Recep/
others
the use of computer so ware pro‐
grammes. Numerous commercially
available and free web‐based pro‐
grammes for toxicity predic on are
Muta/Carc/Repr/Irrit/Hepato
Tox/MTD/BD/Acute Tox/ and
more
available; some are listed here,
adapted from Muster et al., (2008)*.
Available modules:
In silico predic on of chemical liabili‐
es such as adverse effects and
toxicity is a poten ally important
approach in reducing costs and
animal tes ng by complemen ng or
replacing in vitro and in vivo liability
models.
*Muster, W. et al. Computa onal
toxicology in drug development.
Drug Discov Today 13, 303‐10 (2008)
12
Toxtree predicts various kinds of toxic
effect by applying decision trees such as the
Cramer classifica on scheme, the Verhaar
scheme, the BfR rulebases for irrita on and
corrosion, and the Benigni‐Bossa scheme for
mutagenicity and carcinogenicity, and the
START rulebase for persistence and biodegra‐
dability. Toxmatch generates quan ta ve
measures of chemical similarity. These can be
used to compare datasets and to calculate
similarity between compounds.
DART
(Decision Analysis by Ranking Techniques)
was developed to make ranking methods
available to scien fic researchers. DART is
designed to support the ranking of chemicals
according to their environmental and toxico‐
logical concern. The JRC is also developing a
web‐based inventory of (Q)SAR models (the
JRC QSAR Model Database) which will help to
iden fy relevant (Q)SARs for chemicals under‐
going regulatory review. The JRC QSAR Model
Database provides informa on on QSAR mod‐
els and will enable any proponent of a (Q)SAR
model to submit this informa on by means of
a QSAR Model Repor ng Format (QMRF). The
in silico tools developed by the JRC are freely
available at (h p://ihcp.jrc.ec.europa.eu/
our_labs/computa onal_toxicology/
qsar_tools/qsar‐tools). In addi on, the EC‐
funded FP7 project “OpenTox” is developing
an Open Source‐based, predic ve toxicology
framework that provides a unified access to
toxicological data and (Q)SAR models (h p://
www.opentox.org/). OpenTox provides tools
for the integra on of data, for the genera on
and valida on of (Q)SAR models for toxic
effects, libraries for the development and
integra on of (Q)SAR algorithms, and scien‐
fically sound valida on rou nes. The OECD
also has a QSAR Toolbox to make this technol‐
ogy readily accessible, transparent, and less
demanding in terms of infrastructure costs.
Version 2.3 is currently available and intended
to be used by governments, chemical industry
and other stakeholders in filling gaps in (eco)
toxicity data needed for assessing the hazards
of chemicals. The US FDA Center for Drug
Evalua on and Research (CDER) uses compu‐
ta onal models to help evaluate toxici es of
drugs and drug‐related substances, such as
precursors, degradants, and contaminants.
Its current focus of research is developing a
paradigm for using the results of more than
one computa onal toxicology program for
any one endpoint. Using different predic on
paradigms together may give the best overall
predic on as none of the currently commer‐
cially available computa onal tools have all
necessary func onali es; none of them have
100% coverage, sensi vity, and specificity;
and all of the programmes have some unique
features (i.e., they are not completely over‐
lapping) in their strategies.
Conclusions
Hartung & Hoffmann (2009)* suc‐
cinctly summarised in silico tools as
having “... a bright future in toxicolo‐
gy. They add the objec vity and the tools to appraise our toolbox. They help to combine various approaches in more intelligent ways than a ba ery of tests”. It is evident that
the requirements for reducing ani‐
mal tes ng in REACH and similar
legisla on elsewhere in the world,
together with rapid technological
progress and economic incen ves,
are the main drivers for promo ng
The role of computa onal methods is to
increase predic on based on exis ng
knowledge. In silico methods have the poten‐
al to ra onalise the drug/chemical discovery
process and increase its produc vity but have
only recently been applied in toxicity predic‐
on, so quan ta ve analysis is less mature in
toxicology compared with similar uses in
target design and pharmacology. Part of the
explana on is that toxicity is thought of as a
mul factorial process compared to pharma‐
cological effects, which are mostly due to the
interac on of a drug with only a single target.
The current repertoire of computa onal tools
are not sufficiently predic ve to match clinical
trial data in the case of pharmaceu cal devel‐
opment nor are they capable of modelling
complex toxicological endpoints like organ
toxici es (e.g. liver and kidney), cardiac safety
(torsade de pointes, TdP), and teratogenicity
with a high degree of certainty.
the use of in silico or computa onal
approaches. Computa onal toxicol‐
ogy has yet to fulfil its full poten al,
and it is s ll the case that regular
usage of computa onal toxicology is
mainly the preserve of drug develop‐
ment laboratories, yet legisla on is
requiring increasing numbers of
chemicals to be tested for their
toxicity.
The poten al economic
savings are real and substan al with
the increased use of in silico ap‐
proaches but are indirect by chan‐
nelling resources into more promis‐
ing candidates and minimising the
occurrence of costly withdrawals
further downstream in the develop‐
ment process. QSAR‐based compu‐
ta onal approaches are now used
extensively around the world by
‘….quan ta ve analysis is less mature in toxicolo‐
gy compared with similar uses in target design and pharmacology’ regulatory agencies as an adjunct to
safety assessment and so reduce the
requirement for large numbers of
animals for costly in vivo tes ng. It
is likely that in silico methods will be
More novel approaches are required with
be er integra on of in silico and in vitro tech‐
nologies. High‐quality datasets for these
more complex toxicological endpoints are s ll
not really available. Even experimental stud‐
ies on large datasets to derive ADME‐Tox
proper es is inaccessible. For predic ve
QSAR modelling, the limi ng factors involve
assurance and transparency of the experi‐
mental data used to build the training data
set and knowledge of what exactly is being
modelled for the users of the QSAR model.
Some forums such as QSAR world (h p://
www.qsarworld.com/),
www.opentox.org,
and www.openqsar.com are making an effort
to collect these datasets as an open reposito‐
ry for chemoinforma cs data as well as
toolkits for models and descriptors e.g. CDK‐
Taverna. Extrac on of all relevant data from
different sources and structured storage to
enable automated data mining and analysis is
essen al to furthering progress in the predic‐
on of toxicity using in silico techniques.
used increasingly for the direct
replacement of test data, as relevant
and reliable models become availa‐
ble, and as experience in their use
becomes more widespread.
*Hartung, T. & Hoffmann, S. Food for
thought ... on in silico methods in
toxicology. ALTEX 26, 155‐66 (2009).
13
BisphenolA:theissuethatjustwontgoaway!
Bisphenol A, or BPA, is by now one of the most
researched chemicals in existence. In rela on
to food safety, BPA is regulated as a food con‐
tact material under Commission Regula on (EU)
No 10/2011 on plas c materials and ar cles
intended to come into contact with food. It was
first evaluated for this use over twenty five
years ago by the EU Scien fic Commi ee on
Food (SCF) who set a Tolerable Daily Intake
(TDI) for BPA of 0.05 mg per kg body weight.
The SCF reassessed the chemical in 2002 and
maintained their TDI of 0.05 mg per kg body
weight and since that me the safety of BPA
has been assessed by a number of na onal and
interna onal organisa ons including the Euro‐
pean Union (in the context of Council Regula‐
on (EEC) No. 793/93 on the evalua on and
control of exis ng substances), the European
Food Safety Authority (EFSA), the United States
Food and Drug Administra on (US‐FDA), Health
Canada, the French Agency for Food, Environ‐
mental and Occupa onal Health and Safety
(ANSES) and the World Health Organisa on.
BPAinourenvironment
BPA is a building block or mono‐
mer in the synthesis of polycar‐
bonate plas cs which are widely
used in many household items
including plas c bo les, tableware
(plates, mugs, plas c utensils,
etc.), storage containers, plas c
furniture and CDs. BPA is also a
component of epoxy resins which
have a variety of applica ons
including the protec ve coa ngs
and linings for food and beverage
cans and in dental materials.
The focus on the safety of BPA reflects increas‐
ing concerns about the its poten al adverse
health effects, par cularly based on recent
studies using novel tes ng approaches. BPA is
known to have oestrogen‐like proper es and
has been characterised as an endocrine‐ac ve
substance or endocrine‐disruptor which may
affect physical, neurological and behavioural
development. Regulatory bodies including the
EFSA and the US‐FDA have however concluded
that current low levels of human exposure to
BPA do not present a risk, based on the results
of the standard toxicity studies that are normal‐
ly applied for tes ng the safety of chemicals. In
2010, EFSA commented on reports of BPA‐
related effects of possible toxicological rele‐
vance, in par cular biochemical changes in
Bisphenol A (BPA) brain, immune func on and enhanced suscep ‐
bility to breast cancer, but considered that the
reported studies had many shortcomings. EFSA
concluded therefore that no new toxicological
study could be iden fied which would call for a
revision of the exis ng TDI. Exposure es mates
for the European popula on, including infants
and young children, indicate that these are
below the TDI.
In the light of the uncertain es iden fied in the EFSA opinion, the European Union prohibited the
manufacture and sale of BPA‐based infant feeding bo les, from March 2011 (manufacture) and June
2011 (sale) respec vely. This followed a similar ban by the Canadian Government in 2008, while in
2010 Denmark introduced a temporary ban on BPA in all food contact materials for young children.
In 2011, France proposed dra legisla on banning BPA in all food container products intended for
children under three years of age from 2013 and from all food packaging from 2014. The French
proposed ban has however been the subject of objec ons from a number of other European Mem‐
ber States on the grounds that the dra French law represents an internal barrier to trade. Despite
this, the French move has been followed by Belgium, who indicated in March of this year its inten‐
on to ban the use of BPA in materials in contact with foods intended for infants and young children
under three years of age. Most recently, Sweden has announced a similar ban on such products and
may introduce similar measures for toys and childcare ar cles.
So far, the European Commission has not signalled any inten on to introduce a European‐wide ban
on use of BPA in all food contact materials for young children, in line with the exis ng or proposed
measures in Denmark, France, Belgium and Sweden. EFSA has announced that it will undertake a full
re‐evalua on of the human risks associated with exposure to BPA through the diet by May 2013,
focussing in par cular on exposure of vulnerable groups such as pregnant women and young chil‐
dren. Should EFSA conclude, based on the available evidence of the adverse health effects of BPA,
that current levels of human exposure to BPA may present a risk to health, in contrast to its earlier
opinions, it is likely that the European Commission will move to harmonise legisla on on the use of
this controversial chemical in food contact materials in the EU members states.
Note, this informa on has been previously published in the FSAI Newsle er of July‐August, 2012 14
Member’scontributions
PARTICIPATING IN ‘YOUR’ NEWSLETTER
MembersContributions
The commi ee of the Irish Society of Toxicology have a cons tu onal obliga on to maintain a website
and to produce a newsle er on an annual basis. In this regard, and conscious of avoiding the develop‐
ment of a ‘top‐down’ culture, we have decided that ac ve par cipa on by the membership is not only
highly desirable, but essen al to maintaining a dynamic and relevant Society. Therefore, the ethos of
the IST newsle er shall be that it is by the members, for the members. To facilitate this par cipa on,
we ac vely encourage our members to submit ar cles concerning their own research, relevant topics of
interest, forthcoming events, travel and study opportuni es etc., to either the secretary of the Society
at [email protected], or to the webmaster at [email protected]. The Com‐
mi ee’s editorial board would be delighted to hear from you.
Would you like to contribute to
the website? We would love to
hear from you.
RTIfurtherdetails
“we have decided that ac ve par cipa on by the membership is not only highly desirable, but essen al to maintaining a dynamic and relevant Society” RegisterofToxicologistsinIreland
WHAT IS THE REGISTER?
OBJECTIVES OF THE REGISTER
In response to the need for interna onal harmo‐
nisa on and mutual recogni on of qualifica ons,
the Register of Toxicologists in Ireland (RTI) was
established in 2003 under the auspices of the
Irish Society of Toxicology. By iden fying profes‐
sional toxicologists with suitable qualifica ons
and experience, it is intended that the RTI fosters
competence in prac ce and makes publicly avail‐
able authorita ve sources of informa on on
toxicological ma ers. The a ainment of registra‐
on is seen as a significant milestone in a career
in toxicology and will become increasingly desira‐
ble for career progression. The designa on
Member of the Register of Toxicologists in Ire‐
land (MRTI) is subject to review every five years
of the member’s con nuing engagement and
prac ce in toxicology. Members of the RTI gain
automa c membership of the EUROTOX Register
of Toxicologists (ERT).
The objec ves of the Ins tu on, which is a pro‐
fessional body linked to the ERT, is:
I.
to recognise experienced scien sts who are
ac vely engaged in the mul ‐disciplinary
field of toxicology.
II.
to ensure that registered toxicologists ob‐
serve and maintain high standards of pro‐
fessional competence and ethical conduct.
III.
to ensure the descrip on “Registered Toxi‐
cologist” or the use of ini als or le ers
having a similar significance is confined to
persons who have sa sfied the Ins tu on
of their professional competence and expe‐
rience.
Further details on the require‐
ments for Registra on and the
Applica on process can be ac‐
cessed on the IST website at
h p://
www.toxicologyireland.com/
irtreg.html
.
15
2012Conference&AGM
Programme TheToxicologyofChemical
Mixtures
10:00 – 10:30
Registra on & Refreshments
The risk assessment of chemicals has
10:30 – 10:45
Dr. John Moriarty, IST President. Welcome & Introduc on
been, and con nues to be, largely
10:45 – 11:30
Prof. Dr. Andreas Kortenkamp, University of London
Mixture risk assessment – is it necessary and feasible?
performed on an individual chemical
11:30 – 12:15
basis. However, it has been accept‐
ed for some
12:15 – 12:45
environmental exposures to chemi‐
Dr. Thomasina Barron, DAFM.
Challenges in the risk assessment of mul ple pes cide exposures
cals occur in a complex milieu where
co‐exposures to other chemicals is
12:45 – 14:00
the rule rather than the excep on.
14:00 – 14:45
Lunch
Dr. Thomas Backhaus, University of Gothenburg
The threshold of toxicological concern (TTC) ‐ a suitable tool for mixture
risk assessment and ranking?
Chemical safety is tradi onally as‐
sessed in laboratory studies with
14:45 – 15:15
single chemicals even though a
Prof. James Heffron, University College Cork.
Assessing toxicant interac on in vitro: organic solvents
chemical’s toxicity can be influenced
15:15 – 15:45
by other chemicals during simultane‐
15:45 – 16:15
ous exposure because of the cocktail
effect.
Prof. Alan Boobis, Imperial College London
Emerging issues and future priori es in risk assessment
me that human and
Coffee
Dr. Craig Sla ery University College Dublin
When mixed signals combine ‐ Synergis c effects of immunosuppressive
agents on epithelial cells
Undoubtedly, the logis cal
challenges faced when tes ng the
16:15 – 16:45
toxicity of combina ons of chemicals
have obviated the need for a more
structured approach to the risk
assessment.
The ‘State of the Art Report on
Mixture Toxicity’ which was carried
out at the behest of the European
Commission by the Universi es of
Gothenburg and London was pub‐
lished in 2009 and concluded that all
relevant research to date has unam‐
biguously showed that the cocktail
effect of environmental chemical
combina ons is more toxic than the
individual toxici es of each chemical.
The report has advocated the gener‐
a on of regulatory guidelines for the
assessment of chemical mixtures,
not only for assessing the impact on
human health, but also the impact
on ecosystem structure and func‐
on. The regulatory system of the
EU can facilitate the genera on of
appropriate guidelines that cover
both human health and environmen‐
tal protec on.
16
Prof. Michael Ryan, University College Dublin