Adequate Uncertainty Factor for Exposure Limit

Thu Oct 19 08:47:08 EST 1995

Lawrence Segal (am879 at FreeNet.Carleton.CA) wrote:
: I am currently reviewing information concerning a proposed occupational
: exposure limit for an industrial chemical.  The substance is a
: non-genotoxic carcinogen, which has been tested in both mouse and rat
: chronic/onco studies.  In males of both species, statistically significant
: increases in liver adenomas/carcinomas were observed at exposure levels of
: 75 ppm.  The company that manufactures the substance is proposing a TWA
: occupational exposure limit of 3 ppm.  This provides a 25-fold
: uncertainty factor applied to the LOEL in the rodent studies.  The company
: considers this to be an adequate safety factor, because the liver tumours
: were benign, there was no significant increase in mortality at 75 ppm
: relative to control, and the latency period was long.  

-I think that an adequate safety margin could depend on the mechanism
of action of the non-genotoxic carcinogen, eg is it a peroxisomal
proliferator?  If this is the case, then there is a considerable body
of evidence to show that such a chemical would not be expected to be a
carcinogen in man.  A safety margin could then be set based on inter
and intra species sensitivities (eg 10x for each based on animal NOEL)
plus any additional factors that could modify this based on
metabolism, etc.

If the mechanism is unknown, and you are basing your comment re
non-genotoxicity on the fact that it is negative in an appropriate
(and validated) battery of STT's, then one must conclude that the
chemical could possibly  be carcinogenic in man under appropriate
exposure conditions. However, non-genotoxic carcinogens are considered
to have a threshold.   In any this case I believe a 25x factor is too
low, and as previously mentioned, the default figure is usually 100x,
but with additional safeguards to take into account the uncertainly
over the mechanism of action, eg an additional 10x.  You would have to
be in full agreement that the chemical is non-genotoxic rather than
sex specific.

Paul Whitehead BSc DABT

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