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STATEMENT ON ACRYLAMIDE
COM/07/S2 - February 2007
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REQUEST FOR ADVICE ON GERM CELL MUTAGENICITY OF ACRYLAMIDE
TEXT OF LETTER FROM COM CHAIR TO HSE
Thank you for your enquiry which was received by the secretariat on the
5 January 2007. HSE has asked for an opinion on the evidence regarding
germ cell mutagenicity of acrylamide and the evidence regarding a threshold
for germ cell mutagenicity with this chemical. I have consulted with a
number of members by post and have also asked for a view from Professor
David Phillips (chair of COC) who has agreed the contents of this letter.
The need to reply to you before the 1 February 2007 COM meeting has meant
that it is not possible to consider this at a formal meeting of COM.
You provided a number of documents for members to consider. These included
a copy of the EU Risk Assessment Document. A Submission from Polyelectrolyte
Producers Group May 2006: Acrylamide: Recent Scientific Data relating
to carcinogenicity, mutagenicity and human exposure. You also submitted
7 published references selected by HSE. (References 1-7, see end of this
letter). The secretariat drafted a briefing note for COM members, who
also had access to the evaluation from the Polyelectrolyte producers and
references 1-7.
I give below agreed answers to the questions you have raised:
i) Does the new evidence confirm that acrylamide is a germ cell
mutagen?
There is overwhelming evidence in the EU RAR that acrylamide is a male
germ cell mutagen. The additional references submitted support this
conclusion.1,2,7 The possibility exists that acrylamide is
also a female germ cell mutagen.
ii) Can a threshold be identified for the end point?
No. The mechanism for acrylamide induced germ cell mutagenicity is
not fully understood. There is evidence to show that metabolism of acrylamide
to glycidamide, a DNA reactive epoxide, is a key step in the in-vivo
mutagenic responses to acrylamide. There is no evidence to support a
threshold mechanism for acrylamide or glycidamide induced mutagenicity
available in the submitted papers. The default approach recommended
by COM is to assume no threshold for what appears to be a clastogenic
mode of action. (http://www.advisorybodies.doh.gov.uk/com/comivm.htm).
The submitted references which evaluated dosimetry for mutagenic response
of acrylamide can neither prove nor disprove a threshold.1,3
It is noted that the submitted data is consistent with a linear dose-response
for mutagenicity.3
iii) Is there sufficient evidence to show that both somatic and
germ cell mutagenicity are dependent upon metabolism of acrylamide to
its epoxide glycidamide?
There is evidence from the EU RAR for DNA binding in germ cells following
dosing of rodents with acrylamide. An abolition of acrylamide induced
MN formation DNA damaging effects was noted in CYP2E1 mice which lack
the ability to metabolise acrylamide to glycidamide.5 These data taken
with a review of existing germ cell mutagenicity data7 suggest that
glycidamide is a critical metabolite in the in-vivo mutagenicity of
acrylamide including the germ cell mutagenicity.
iv) Is there sufficient evidence to show that humans metabolise
acrylamide to glycidamide to a lesser extent than rodents (with humans
< rats < mice)? In view of iii) and iv) what can be said about
risks to human health?
Fennell showed that overall AUC values for glycidamide formation in
humans and rats from absorbed acrylamide were similar.6 The rate constants
for acrylamide and glycidamide reaction with haemoglobin reported in
this paper were slightly higher in humans compared to rats. Paulsson
et al reported a higher level of acrylamide metabolism and protein adduction
in mice compared to rats.4 Overall mice metabolise acrylamide to a greater
extent than humans, but rats appear to be relatively similar to humans
regarding extent of metabolism. Its not possible to extrapolate these
data to predict mutagenic risk to humans. The default COM approach in
such situations where there is insufficient information to allow a conclusion
regarding a threshold approach to risk assessment is to assume a no
threshold approach to risk assessment.
v) Assuming that a threshold for germ cell mutagenicity is not supported,
what are the views of the committee concerning the use of a toxicological
reference point or dose descriptor on the dose-response relationship
as a basis for assessment of risks (calculation of Margins of Exposure)
taking into account interspecies differences in metabolism? In this
regard, it is noted that the Allen paper derives a toxicological reference
point (claimed to be a threshold for mutagenicity) from combining the
dose-response relationship for somatic cell mutagenicity and that for
germ cell mutagenicity. As the data appear to indicate that acrylamide
is a more "potent" germ cell mutagen than a somatic cell mutagen,
how valid is this approach? Are there any robust dose-response data
for germ cell mutagenicity of acrylamide (in the totality of the available
database) from which to identify a dose descriptor to use for risk assessment
purposes? What are the uncertainties involved in such an approach?
COM members cautioned the dose-response modelling undertaken by Allen
et al1, and considered that the interpretation of the results of the
modelling was problematic. COM members agreed it was too premature to
derive any conclusions regarding genotoxic potency on the basis of this
paper.
I would therefore consider there are too many uncertainties with regard
to extrapolation of the available mutagenicity data on acrylamide for
risk assessment, particularly as acrylamide (and glycidamide) seem to
be clastogenic in both somatic and germ cells. Any attempt should take
into account the genotoxic effect on the most sensitive cell, ie early
spermatozoa. The default recommendation from COM is to assume no threshold.
I hope the answers we have provided are useful to HSE in its consideration
of acrylamide. Please do not hesitate to contact me or the secretariat
if you have any further questions.
February 2007
COM/07/S2
References
1. Allen B et al Regulatory Toxicology and Pharmacology, 41, 6-27, 2005.
2. Marchetti F et al, Environmental and Mol Mutagen, 30, 410-417, 1997.
3. Abramsson-Zetterberg L et al Mutation Research, 535, 215-222, 2003.
4. Paulsson B et al Mutation Research, 516, 101-111, 2002.
5. Ghanayem B et al Mutation Research, 578, 284-297, 2005.
6. Fennell TR et al Toxicological Science, 84, 1-13, 2005.
7. Favor J and Shlelby MD. Mutation Research, 580, 21-30, 2005.
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