Day 038 - 19 Oct 94 - Page 14

     
     1        detailed explanation and justification for the dose scaling
     2        practice.  It is more a matter of -----
     3
     4   MR. JUSTICE BELL:  Come back to that, if you wish, later, but
     5        what I had not understood was that the dose which was used
     6        was in any way related to some kind of calculation between
     7        the difference in size and the difference in life-span
     8        between, for instance, say, a typical laboratory mouse or
     9        rat and a typical man or woman.
    10
    11        I thought they just chose the high doses and, indeed, on
    12        occasions may have kept increasing them until they get a
    13        reaction or in search of a reaction.  The multiplier then
    14        comes in as a safety factor, much as, for instance, bridges
    15        are designed to carry, whatever it is, four times the
    16        greatest weight they are ever expected to carry?
    17        A.  Yes.  I do not think considerations of similarities or
    18        differences between humans and rodents are typically
    19        incorporated in the ways in which doses are chosen.  The
    20        factors, nominal factors of ten, say, between laboratory
         rodents and humans, and a factor of ten nominally
    22        accounting for the variation in human population are
    23        adjustments and safety factors typically applied to the
    24        results of the tests rather than to the initial design of
    25        the doses.
    26
    27        The way in which doses are typically chosen in long-term
    28        feeding studies is they are chosen by looking at the
    29        results of short-term feeding studies (often called range
    30        finding studies) in which animals are exposed to what are
    31        thought to be a range of relatively high fixed doses on a
    32        daily basis.  They search for what is customarily referred
    33        to as a maximum tolerated dose.  The maximum tolerated does
    34        is typically taken to be the highest dose to which the
    35        animals are exposed which produce some reduction in
    36        expected weight gain, but do not otherwise provoke gross
    37        pathological symptoms, such as diarrhoea or cancer.
    38
    39        The practice then, in a long-term feeding study, is to have
    40        a control group with the food but no test dose; the highest
         dose group that receive the maximum tolerated dose; and
    42        then usually two intermediate doses, perhaps a tenth of the
    43        maximum tolerated dose and a hundredth or a tenth and a
    44        twentyth, or some intermediate scaling.
    45
    46        So, the ways in which doses are determined for tests
    47        typically depends upon the reaction of the animal to the
    48        compound in short-term tests.
    49
    50   Q.   That was my understanding exactly.  The factor of a 100, 
    51        once you got a result, then comes in later in deciding 
    52        what, if any, number of milligrams per kilogram of body 
    53        weight or parts per million are to be allowed to be added
    54        to food?
    55        A.  That is correct.
    56
    57   MR. MORRIS:  Would you like to expand on the differences between
    58        the typical laboratory sample of animals and the relevance
    59        for the human population, other factors that point out
    60        serious difficulties in transposing results from one to the