Day 039 - 20 Oct 94 - Page 75


     
     1
     2   Q.   Then we find monkeys?
     3        A.  Yes.
     4
     5   Q.   Something called cynomogus monkeys, whatever they may be?
     6        A.  Yes.
     7
     8   Q.   Then may we read the conclusion, Comments, on the
     9        right-hand side on page 17.  This is JECFA, who shortly go
    10        to recommend an ADI of 0.5 mg/kg:  "Studies have been
    11        conducted that provide additional information on the
    12        proliferative changes observed in the forestomach of rats
    13        fed BHA.  No new studies on the effect of BHA on the
    14        stomach and oesophagus of species that do not have a
    15        forestomach, e.g., pigs or monkeys, were conducted.  The
    16        data show that continuous exposure of the rat forestomach
    17        to 2% BHA in the diet for 6-12 months is necessary to
    18        produce squamous cell carcinoma.  The data also show that
    19        the induction of mild hyperplasia can occur at levels of
    20        0.125% of BHA in the diet but not at a level of 0.1% BHA.
    21        After reevaluating the data in pigs, it was concluded that
    22        the evidence that BHA produces hyperplasia in the esophagus
    23        of the pig is questionable.  Moreover, these presumptive
    24        effects in pigs were reported to occur at levels of BHA
    25        significantly higher than those that produced the confirmed
    26        effects in the rat forestomach.  Considering the absence of
    27        any significant adverse effects in two dog studies, it was
    28        concluded that further investigations in animals without
    29        forestomachs are not required.  The human relevance of the
    30        rat studies, while inherently questionable because the
    31        target tissue in the rat has no human counterpart, cannot
    32        readily be ignored.  Based on the dose dependence and
    33        reversibility of the lesions produced in the rat, discussed
    34        previously in the 1986 monograph ... and since confirmed by
    35        more recent studies, it was concluded that an ADI can be
    36        established."
    37
    38        Now that I have read that, Dr. Millstone, do you still
    39        assert that the ADI proposed by this body was irresponsibly
    40        high?
    41        A.  Oh, I certainly do and I would be happy to go through
    42        that paragraph sentence by sentence and indicate precisely
    43        where my doubts and concerns lie, if you would like me to
    44        do that?
    45
    46   Q.   I think you had better do it because then we can put this
    47        away until tomorrow.
    48        A.  OK.  "Studies have been conducted", OK.   No new
    49        studies on the effect of species that do not have a stomach
    50        were conducted.  Now, clearly, the initial tumours reported 
    51        by Ito et al in the rats were in rat forestomachs. 
    52        Elsewhere in the body of this document they state that the 
    53        tissue in the humans which most closely resembles the rat
    54        forestomach is the oesophagus, and imply elsewhere that it
    55         -- several things; firstly, it is important to look at
    56        species that do not have forestomachs and that, insofar as
    57        we are looking for lesions that might be triggered by BHA
    58        in tissue similar to the forestomach, the oesophagus would
    59        be the place to look, but studies in species that do not
    60        have forestomachs were not conducted.  "No new studies were

Prev Next Index