[Dioxin-l] References about threshold.

Wed, 16 Feb 2000 11:11:21 -0500

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Have you read the following

My favorite summary of the problems of TEQ and risk assessment of dioxins at
the AHR.

Reflections on Risk Assessment of Receptor-Acting Xenobiotics
Alan Poland (discovered, isolated and characterized the AHR) 

Regulatory Toxicology and Pharmacology Vol 26 41-43 1997

For those of you who may not have access to this I'll quote a few choice
sections.

Threshold and Receptor theory.

The EPA has used a linear multistage model to extrapolate from high-dose
animal data (e.g. 1-20% incidence in the chronic bioassay) to low dose in
humans, less that or equal to 1x10(6) incidence, and for carcinogenesis no
threshold is permitted. Various arguments have been advanced to rationalize
this conservative assumption. It must be noted, that for practical purposes,
it is impossible to determine the effects of very low dose levels which
effect 1 in 10 (6) human beings i.e it is not verifiable; hence it is not
really science, but a policy.

While linear extrapolation without a threshold may be an untestable policy
at EPA, in receptor pharmacology, threshold is a bedrock concept rooted in
empiricism. Neurons have a resting potential, which must be raised to a
certain threshold before the nerve will fire and conduct the impulse. If a
nerve cell responded in a linear fashion to every small quantity of
neurotransmitter leaked across the synapse, it would not make physiological
sense. Since the dawn of studying receptors-nearly 100 years ago- I am
unaware of a single instance of a drug i.e any biologically active
substance) acting upon a receptor which upon sufficient decrease in
concentration or dose does not display a no-effect level i.e a threshold.
For receptors, threshold is a universal empiricism; for risk assessment, the
absence of threshold (i.e low dose linearity) is a useful statistical
approach, a policy without verification.

On TEQ-

Cumulative effects of multiple agonists acting on the same receptor. Linear
occupancy vs efficacy model. 

A major consideration in estimating the risk of receptor acting xenobiotics
is how to calculate the cumulative effects of multiple agonists acting on
the same receptor. The approach adopted in the dioxin reassessment was to
estimate the potency of each congener relative to TCDD (i.e the Toxic
equivalency factor) by multiplying the TEF by the amount of congener and
then summing the products. This approach assumes linear a linear occupancy
model, i.e for a given response each congener occupies the same fraction of
receptor. This is a simplifying assumption, but incorrect. We know that
among xenobiotics acting on the AH receptor (for dioxins) and on the
estrogen receptor, there are partial agonists, compounds which never produce
the maximal response and which can antagonize full agonists. For each
congener, the biological activity is a function of the intrinsic efficacy of
the drug, it's concentration, and the receptor concentration. Receptor
concentration varies two to three orders of magnitude among cell
types.....efficacy has been determined for the beta adrenergic agonist but
never for soluble receptors. Thus the additivity TEF approach is not some
approximation estimate; it is a sheer guess into the unknown.

..............................

My favorite paper for destroying the threshold theory is George Lucier's
paper using PCR- enhanced analysis of expression of P450 mRNA.  I recall (I
think) that the paper was EHP (Env Health Perspec) but I don't recal the
year, maybe 3 - 5 years ago at a guess.

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Have you read the following My favorite summary of the 
problems of TEQ and risk assessment of dioxins at the AHR. Reflections on 
Risk Assessment of Receptor-Acting Xenobiotics Alan Poland (discovered, 
isolated and characterized the AHR) 
Regulatory Toxicology and Pharmacology Vol 26 41-43 
1997 For those of you who may not have access to this I'll quote a few 
choice sections. Threshold and Receptor theory. The EPA has used a 
linear multistage model to extrapolate from high-dose animal data (e.g. 1-20% 
incidence in the chronic bioassay) to low dose in humans, less that or equal to 
1x10(6) incidence, and for carcinogenesis no threshold is permitted. Various 
arguments have been advanced to rationalize this conservative assumption. It 
must be noted, that for practical purposes, it is impossible to determine the 
effects of very low dose levels which effect 1 in 10 (6) human beings i.e it is 
not verifiable; hence it is not really science, but a policy. While 
linear extrapolation without a threshold may be an untestable policy at EPA, in 
receptor pharmacology, threshold is a bedrock concept rooted in empiricism. 
Neurons have a resting potential, which must be raised to a certain threshold 
before the nerve will fire and conduct the impulse. If a nerve cell responded in 
a linear fashion to every small quantity of neurotransmitter leaked across the 
synapse, it would not make physiological sense. Since the dawn of studying 
receptors-nearly 100 years ago- I am unaware of a single instance of a drug i.e 
any biologically active substance) acting upon a receptor which upon sufficient 
decrease in concentration or dose does not display a no-effect level i.e a 
threshold. For receptors, threshold is a universal empiricism; for risk 
assessment, the absence of threshold (i.e low dose linearity) is a useful 
statistical approach, a policy without verification. On 
TEQ- Cumulative effects of multiple agonists acting on the same 
receptor. Linear occupancy vs efficacy model. 
A major consideration in estimating the risk of receptor acting 
xenobiotics is how to calculate the cumulative effects of multiple agonists 
acting on the same receptor. The approach adopted in the dioxin reassessment was 
to estimate the potency of each congener relative to TCDD (i.e the Toxic 
equivalency factor) by multiplying the TEF by the amount of congener and then 
summing the products. This approach assumes linear a linear occupancy model, i.e 
for a given response each congener occupies the same fraction of receptor. This 
is a simplifying assumption, but incorrect. We know that among xenobiotics 
acting on the AH receptor (for dioxins) and on the estrogen receptor, there are 
partial agonists, compounds which never produce the maximal response and which 
can antagonize full agonists. For each congener, the biological activity is a 
function of the intrinsic efficacy of the drug, it's concentration, and the 
receptor concentration. Receptor concentration varies two to three orders of 
magnitude among cell types.....efficacy has been determined for the beta 
adrenergic agonist but never for soluble receptors. Thus the additivity TEF 
approach is not some approximation estimate; it is a sheer guess into the 
unknown. .............................. My favorite paper for 
destroying the threshold theory is George Lucier's paper using PCR- enhanced 
analysis of expression of P450 mRNA.&nbsp; I recall (I think) that the paper 
was EHP (Env Health Perspec) but I don't recal the year, maybe 3 - 5 years 
ago at a guess. </BODY></HTML>

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