A) Threshold vs. Non-threshold Effects
One of the main problems with using the threshold concept is
that the term “threshold” has several different connotations. Therefore, with regard to their ability to
provide the basis for having a separate methodology for cancer, they must be
considered individually:
- No Observable or Measurable Effect. Whether or not it is a continuous measure of an individual effect or the frequency of occurrence of a health outcome in a population, there are limits to what can be measured or inferred accurately. Typically, this means “not statistically significant”. A limit of detection doesn’t mean there is no effect at all, but it does usually indicate that whatever effect there may be is pretty small. For some people, that is good enough. However, the limitations on what is observable apply to both cancer and noncancer endpoints, so a “measurement threshold” cannot serve as the basis for a distinction.
- A Threshold Parameter. A threshold parameter is a theoretical construct that may be added to any mathematical model. For example, adding a threshold parameter to a linear model yields the “Hockey Stick” model:
Even though there is no theoretical basis for a "absolutely no-response" threshold, models with threshold parameters
often fit observed data reasonably well for both cancer and noncancer effects.
- One-Hit Theory. It is often argued that there is no threshold for genotoxic carcinogens because one molecule might cause the mutation that results in a tumor. Other effects require more than one molecule, and therefore it is supposed that there must be a threshold. Supposedly, there are one hit theories for other effects too. With a little imagination, maybe all of them. For example, one molecule of lead or mercury might prevent a synapse (a neural connection in the brain) from developing, or one molecule of arsenic may add to the oxidative damage that occurs from other sources. So, one-hit theory doesn’t really serve as the distinction either.
B) Stochastic vs Non-stochastic Effects
The use of statistical models, along with the misguided
Copenhagen Interpretation of statistical distributions, has led the notion that
while cancer is probabilistic or stochastic, other effects are
deterministic. But, the same line of reasoning can always be
applied to effects other than
cancer. The formation of a DNA adduct
than leads to a mutation is no more probabilistic than the formation of a
protein adduct that causes the protein to be dysfunctional. Receptor-ligand theory will allow the frequency
of occupation of the receptor based on the concentration of the chemical. For an individual receptor, the same equation
can be used to predict the probability of occupation at any given time. If the ligand affects neuronal function in
some way, application of the Copenhagen Interpretation would allow the
estimation of a probabilistic “intelligence state”. No dichotomy here either.
C) Expert Opinion vs Informed Public Opinion
The Safety Assessment paradigm that forms the basis of
noncancer assessment is a product of a different tradition than the Redbook
paradigm that underlies cancer risk assessment.
In a sense, this dichotomy is as old as the hills. The safety assessment paradigm relies on the
judgment of the Platonic philosopher king toxicologist who decides on behalf of
the public what is best for them. By
formally explicating the decision process, the Redbook paradigm offers the
democratic alternative. There is
probably room for both. There are many
different molecules, both natural and man-made, in the environment. The ability of chemists to detect them has
steadily increased over the last century.
A public debate cannot be had over every one. But, if a debate does break out, the time to
switch paradigms has surely arrived – carcinogen or not.
D) Rational vs. Irrational
Not all decision processes are rational. In fact, perhaps most decisions are
reflexive. The Safety Assessment
paradigm is clearly irrational. It is
presumed that whatever level is labeled as acceptable or safe can be
attained. This may be true for man-made chemicals like
pesticidess and food additives that require prior government approval to be
used legally. However, for naturally
occurring toxic elements practical limitations are bound to arise. The Risk Assessment Paradigm isn’t
necessarily rational either. If a
predetermined risk standard (i.e. one in a million) is used to identify an
acceptable level of exposure, an impractical result will often be
obtained. But, at least the Risk
Assessment Paradigm can be rational. For
example, if a quantitative risk assessment is used as part of a cost-benefit
analysis, the risk is rationed against the cost of avoiding it. Perhaps avoiding a carcinogen is worth more
than avoiding an IQ point loss. Then
again, maybe not.
Harmonization
In conclusion, having a totally different process for the
evaluation of carcinogens is not really justifiable. That fact has led to efforts to “harmonize”
the two paradigms. Since that is not
even remotely possible, harmonization means one of the paradigms has to die. You might think that because the Redbook
Paradigm is more versatile (i.e. a quantitiative risk assessment may justify
the use of a level as a management technique), it would be the better
choice. But since that would require
authority to be shared, not everyone agrees. So, c) is the correct answer.
References
Barnes DG and Dourson ML (1988). Reference Dose (RfD): Description and Use in
Health Risk Assessments. Regul Pharmacol Toxicol 8:471-486. Also at http://www.epa.gov/IRIS/rfd.htm
National Research Council (1983). Risk Assessment
in the Federal Government. National Academy Press, Washington, DC.
United States Environmental Protection Agency (1986).
Guidelines for Carcinogen Risk Assessment. Federal
Register 51(185):33992-34003.
Official Soundtrack
Post Note
Thesis Post #17. Regulatory toxicology thread, leading into the nasty stuff.
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