Richard A. Manderville talks
with ScienceWatch.com and answers a few questions
about this month's Fast Breaking Paper in the field of
Agricultural Sciences.
Article Title: Ochratoxin A: An overview on
toxicity and carcinogenicity in animals and
humans
Authors: Pfohl-Leszkowicz,
A;Manderville
, RA
Journal: MOL NUTR FOOD RES
Volume: 51
Issue: 1
Page: 61-99
Year: JAN 2007
* CNRS, Lab Genie Chim, UMR 5503, INPT,UPS,INP,ENSA
Toulouse, F-31326 Auzeville Tolosane, France.
* CNRS, Lab Genie Chim, UMR 5503, INPT,UPS,INP,ENSA
Toulouse, F-31326 Auzeville Tolosane, France.
* Univ Guelph, Dept Chem, Guelph, ON N1G 2W1, Canada.
(addresses have been truncated)
Why do you think your paper is highly
cited?
Our paper is highly cited because it is a recent review on ochratoxin A
(OTA) and includes 504 references. OTA is a fungal toxin (mycotoxin) and is
a concern for the food industry. Over the past 30 years, 31,684 references
dealing with mycotoxins have been published, according to PubMed. Many
researchers are interested in developing analytical techniques for
detection of mycotoxins in food and in establishing their mechanism(s) of
toxicity.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
"The data
published in our review suggests
that DNA damage and carcinogenicity
should be used to establish
acceptable intake levels of OTA
from human food sources."
Our paper represents a synthesis of knowledge and is based on the
publications of many researchers in the field. Also included in the review
are recent findings from the Manderville and Pfohl-Leszkowicz laboratories
dealing with DNA damage caused by OTA.
Would you summarize the significance of your paper in
layman's terms?
OTA is a fungal toxin that is present in grains, cereal, wine, beer, and
other food products. It is a kidney carcinogen in male rats and causes a
kidney disease in pigs. It may also be a cause of human kidney
carcinogenesis.
In this review evidence is presented that supports the DNA-damaging
activity of OTA. It is proposed that ochratoxin A undergoes metabolism in
the body to form reactive intermediates that attach to the DNA bases. This
generates a DNA adduct, which, in general, is known to contribute to human
carcinogenesis.
Currently, a provisional tolerable weekly intake level of OTA has been set
at 100 ng/kg body weight, as established by the Joint FAO/WHO Expert
Committee on Food Additives in 2001, which uses kidney disease in pigs as
an endpoint. However, the acceptable intake levels of OTA are debated
because of the growing concern of OTA as a human carcinogen. The data
published in our review suggests that DNA damage and carcinogenicity should
be used to establish acceptable intake levels of OTA from human food
sources.
How did you become involved in this research, and were
there any problems along the way?
I am a chemist and I was interested in establishing how OTA reacts with
DNA. Published evidence suggested that OTA undergoes oxidation in the body
to form DNA adducts, but no structural evidence was published. My
laboratory examined the oxidative properties of OTA and characterized an
adduct resulting from attachment of OTA to deoxyguanosine. This adduct has
been used by my collaborator, Dr. Annie Pfohl-Leszkowicz of the Ecole
Nationale Supérieur Agronomique in Toulouse, France, to determine
whether it is formed in animal tissue.
Maintaining funding for this project has been a problem. Other researchers
have been unable to detect DNA adduct formation by OTA, so a great deal of
negative evidence for DNA adduction by OTA has been published. However,
much of the negative evidence has been published by researchers at food
companies, or researchers funded by food companies, so a conflict of
interest may be present.
Where do you see your research leading in the
future?
Once we have established unequivocal evidence for DNA adduction by OTA in
animal tissue, my laboratory will be carrying out experiments to determine
the biological impact of the OTA-DNA adduct. This will involve the
synthesis of a DNA strand containing the adduct. This strand can then be
used as a substrate for DNA polymerase and DNA repair enzymes. Our
laboratory will also seek to measure the mutagenicity of the OTA-DNA adduct
in human cells through research collaboration. Structural studies of the
OTA-DNA adduct in duplex DNA would then be carried out here at the
University of Guelph.
Do you foresee any social or political implications for
your research?
The findings from our studies do indeed have social and political
implications. OTA is present in human food products and it is not easily
removed. Agencies that place acceptable intake levels for mycotoxins may
have to assess our data to establish intake levels for OTA. If levels
become more restrictive, this could become costly for the food industry.
Because OTA is in cereal and grain products, people will want to know if it
is safe to eat these products. The general public should be made aware that
the levels in these products are extremely low and are well below the
levels needed to induce carcinogenesis in animal models.
Dr. Richard A. Manderville
Associate Professor of Chemistry
Departments of Chemistry and Toxicology
University of Guelph
Guelph, Ontario, Canada