]]]]]]]]       U.S. Expected to Lift Ban On Cyclamate     [[[[[[[
              Sweetener Harmless, Most Experts Say
                       By Malcolm Gladwell
                  Washington Post Staff Writer

         [From The Washington Post, 16 May 1989, p. A1:6]

            [Kindly uploaded by Freeman 10602PANC]

   Federal health officials, who  banned the artificial sweetener
cyclamate 20 years ago in the  midst of one of the biggest health
scares of  the 1960s,  are now  widely expected  to reapprove it,
possibly  this year.   Once  accused of  causing  everything from
bladder cancer to birth defects,  cyclamate is now widely thought
to be harmless.
   ``I have no reluctance in saying that with cyclamate we made a
mistake,'' said Robert Scheuplein,  acting director of the office
of toxicological  services for the  FDA's Center  for Food Safety
and Applied Nutrition.
   A group of  monkeys at the  National Cancer Institute provides
evidence of the mistake.  Each of them has been fed the amount of
cyclamate that would sweeten 30 cans of diet soda every day, five
days a week, for the past 17 years.
   In February, the  institute issued its  first progress report:
the monkeys are doing just fine.
   After two decades of  legal and regulatory controversy, scores
of cancer  and toxicology  studies and  heated scientific debate,
the jury on cyclamate is in.
   The  agency's reversal  on cyclamate  promises  to add  to the
growing  public  debate  about  how  government  health officials
evaluate  potential health  risks.   According to  scientists and
industry  officials  involved in  the  controversy,  the evidence
exonerating cyclamate was  available years ago  and the fact that
the  agency took  two decades  to concede  its mistake  shows how
large  a  role  politics  can  play  in  decisions  presented  as
   Even some government officials concede that the long and often
bizarre  story of  the chemical  is  an example  of how  a system
designed to separate real from imagined risks broke down.
   Cyclamate was one  of the world's  most widely used artificial
sweeteners when, in the late 1960s, its safety became a matter of
public concern.  In 1969, following  the completion of a study by
a  New  York laboratory  showing  that some  rats  with cyclamate
pellets implanted in  their bladders were  developing tumors, the
FDA restricted  the sale  of the  chemical.  The  following year,
under pressure from Congress, the agency banned it entirely.
   From the beginning,  the ban was  controversial.  Referring to
the ``farcical  progress'' of  the cyclamate  veto ``bandwagon,''
the  British   scientific  journal  Nature   ridiculed  that  FDA
decision,  calling the  evidence  indicting cyclamate  ``about as
solid as candy floss.''
   One problem, for example:  The method of surgically implanting
cyclamate  pellets in  rats  -- as  opposed  to feeding  them the
chemical -- was one the National Academy of Sciences had rejected
that same year as not analogous  to the way humans are exposed to
   Over the next few years, 10 more experiments were conducted on
rats, seven on mice, one on  hamsters, one on beagles, and two on
monkeys -- all in  an attempt to replicate  the original New York
study.  None could.  The scientist  who headed up the one damning
experiment renounced  it.  Numerous  countries that  had followed
the U.S. lead on banning cyclamate reapproved it.
   The FDA, however, stood firm.   In 1980, seven years after the
manufacturer  of   cyclamate,  Abbott   Laboratories,  filed  for
reapproval  of  cyclamate,  the  agency  emphatically  denied the
request.  Only  today, seven  years after  Abbot filed  again for
reapproval, after two  dozen long-term cancer  studies, more than
70  experiments looking  for  genetic damage,  hundreds  of other
toxicological studies, and exhaustive and positive reviews of the
chemical  by  the  National  Cancer  Institute  and  the National
Academy  of  Sciences,  is the  FDA  apparently  comfortable with
reapproving the chemical.
   According  to many  of the  scientists and  industry officials
involved with  cyclamate, the  FDA's long  delay in acknowledging
the  new evidence  raises troubling  questions  about the  way in
which the agency assesses suspected carcinogens.
   One concern is  over the way  that politics --  not science --
appeared to play the lead role in the evaluation of cyclamate.
   ``The matter was taken out of the hands of the scientists here
and handled by attorneys.'' said  Scheuplein of the agency's 1980
decision  not to  reapprove the  sweetener.  ``Meetings  were not
held.  Things were  not pursued.  Work was  not done.  The people
who were involved at the time were inadequate to the job.''
   ``It was just  politics,'' said Elizabeth  Weisberger, the now
retired  assistant  director  for  chemical  carcinogens  at  the
National Cancer Institute.  ``Once the  decision was made, no one
wanted to reverse it.  It would have meant a loss of face.''
   In  a  strongly  worded  letter  to  the  FDA  after  the 1980
decision, the American Statistical Association said the arguments
used   to    reject   cyclamate   amounted    to   an   ``extreme
misrepresentation of our professional methodology'' and routinely
used  methods  ``foreign  to everything  that  is  taught  in the
statistics profession.''
   ``We   strongly  encourage   you   to  have   the  appropriate
professionals prepare  a new  statement that  correctly expresses
the statistical principles that are involved in this issue,'' the
latter  said.   ``This  new  statement  is  needed  to  avoid the
ridicule  of  knowledgeable scientists  including  those  in your
is theirs]''
   The  group's  arguments  centered  on  interpretation  of what
statisticians  call ``p''  values, a  measure of  the probability
that an experimental result could have happened by chance and not
because of the thing being tested, cyclamate in this case, alone.
The p value is  calculated from the size  of the experimental and
control groups.   Typically scientists  do not  accept results as
statistically significant  if there is  greater than  a 5 percent
chance that the observed differences  between two groups could be
a chance occurrence.
   In  the 1980  cyclamate decision,  however, the  FDA routinely
interpreted  as  significant  experiments  with  high  p  values,
including one study with  very few tumors where  the chances of a
spontaneous tumor development was 20 percent.
   What the agency's actions  reflected, according to many within
the  scientific   and  regulatory   community,  is   the  extreme
conservatism that public and  congressional pressure has demanded
from the FDA on issues involving cancer risk.
   According to the FDA's congressional mandate, for example, the
agency is not allowed  to approve any substance  that is known to
cause  cancer  in animals.   The  effect of  this,  though rarely
invoked explicitly by the agency, has  been to turn mouse and rat
studies into a ``gold standard'' for carcinogenicity, even though
new scientific  evidence has  increasingly cast  doubt on whether
giving mice or  rats massive doses  of a chemical  is actually an
effective way of  predicting the cancer-causing  potential of the
same compound in humans.
   In the case  of cyclamate, many  scientists and regulators say
that holding the sweetener to  such a standard made it impossible
to overturn the FDA's prior decision to ban.

      [The following is not part of the original article.]

Edith Efron.  The Apocalyptics: How Environmental Politics
   Controls  What  We  Know  About  Cancer.   New  York:  Simon &
   Schuster, Inc., 1984.
William R. Havender.  Of Mice and Men: The Benefits and
   Limitations  of  Animal  Cancer  Tests.   New  York:  American
   Council On Science and Health, August 1984.
Lester B. Lave, et al.  ``Information Value of the Rodent
   Bioassay'',  Nature  336,  p.   631-633  (15  December  1988).
   (``Tests for human carcinogens using lifetime rodent bioassaysays
   are expensive, time-consuming and give uncertain results.  For
   most chemicals such tests are not cost-effective.'')

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