The 1986 EPA Cancer Risk Assessment Guidelines
While the 1986 Guidelines mention the importance of weight of
the evidence evaluations, the issue is brought up in a one page discussion that
gives almost no guidance as to how they are to be done. It is stipulated that results of the
evaluation will be stored in categories similar to those used by IARC. The presumption seems to be that a
statistical significance test will settle the matter. Until the next set of “finalized” guidelines
were issued in 2005, this proved to be a matter of substantial debate. The main issue that arose was this: How a
chemical may cause cancer came to be regarded as being as being at least as important
as the “Delaney” question of whether or not it can cause cancer at all.
The 2005 EPA Cancer Risk Assessment Guidelines
The 2005 Guidelines have a far more lengthy discussion of
Weight of the Evidence. The guidelines
adopt a slightly modified version of the Hill criteria to structure the evaluations. In
fact, they do this twice. The first time
is for the same purpose as the IARC or 1986 evaluations, where the goal is to
determine whether the chemical should be identified as a carcinogen or not. The second time is when is in the context of
a discussion of potential alternative modes of action. Tree-wise, the most pertinent section of the
guidelines is section 2.4.3.3. Consideration
of the Possibility of Other Modes of Action:
The possible involvement of more
than one mode of action at the tumor site should be considered. Pertinent
observations that are not consistent with the hypothesized mode of action can
suggest the possibility of other modes of action. Some pertinent observations
can be consistent with more than one mode of action. Furthermore, different
modes of action can operate in different dose ranges; for example, an agent can
act predominantly through cytotoxicity at high doses and through mutagenicity
at lower doses where cytotoxicity may not occur.
If there is evidence for more than
one mode of action, each should receive a separate analysis. There may be an
uneven level of experimental support for the different modes of action.
Sometimes this can reflect disproportionate resources spent on investigating
one particular mode of action and not the validity or relative importance of
the other possible modes of action. Ultimately, however, the information on all
of the modes of action should be integrated to better understand how and when
each mode acts, and which mode(s) may be of interest for exposure levels
relevant to human exposures of interest.
You might think that the weight of the evidence narrative
that follows such careful examination would embrace the possibility of multiple
possible interpretations of the body of evidence where each potential mode
becomes a node on the tree. For example,
you might have one node that stipulates that there is no causal relationship, a
second node that supposes that genotoxicity is responsible, and a third node
that supposes that increased cell proliferation is responsible for increased
tumor incidence. But, that’s not what
the guidelines recommend. Instead, they
keep the IARC-like categories that simply grade whether or not the chemical
should be considered to be carcinogenic.
The mode of action evaluation is folded into the category of Not Likely to Be Carcinogenic to Humans:
This descriptor is appropriate when
the available data are considered robust for deciding that there is no basis
for human hazard concern. In some instances, there can be positive results in
experimental animals when there is strong, consistent evidence that each mode
of action in experimental animals does not operate in humans. In other cases,
there can be convincing evidence in both humans and animals that the agent is
not carcinogenic.
The problem with this tactic is this: In order to argue that
the risk is “unlikely” one must essentially conduct a risk assessment, so
excluding regulatory scrutiny on the basis of evidential grading is
premature. Even if the conclusion is
correct, a probability tree would be much better at laying out the real argument.
Otherwise, the obvious question to ask
is “How unlikely is it?”.
WoE Becomes a Buzzphrase
Since 2005, there has been a proliferation of guidelines for
both generating and using weight of the evidence (WoE) evaluations for a range
of different purposes. Evidence-based Medicine
uses a WoE process to evaluate individual study quality. WoE guidelines issues by the EPA (2011) lay
out a process for evaluating potential mechanisms of action involving hormonal regulation. A more interesting development is the use of WoE
for environmental assessments. Suter and
Cormier (2011) describe a process that integrates epidemiology and risk
assessment by treating them as
complimentary processes. They also
differentiate between “weighting evidence” a la evidence based medicine vs “weighing
evidence” where the strength of a hypothesis is evaluated. They also discuss the possibility of
enumerating evidential weight:
However, it must be recognized that
the weights do not have natural units and cannot be naturally added or
averaged. For example, if you assign a
weight of 2 for strength of a piece of evidence and 4 for quality, those scores
are numerical but not quantitative. If you sum them to obtain an overall weight
of six for the evidence, it may impart a sense of rigor, but it is still a
qualitative score. Therefore, qualitative weights are better expressed by
symbolic systems such as the scale, +++, ++, +, 0,−, −,−−−, commonly used in
causal assessments.
The counterargument is this:
Precisely because the weights aren’t natural, they can be construed or
reverse-engineered as necessary. In
other words, If summing numerical weights doesn’t yield a proper assessment,
then perhaps the numerical assignments need to be changed so they do.
Suter and Cormier (2011) also discuss the idea of “Building
a Case” for environmental risk assessments. In the same vein, Lutter et al (2015) have suggested using “Hypothesis-based weight of the evidence” for chemical risk assessments in general. Both of
these suggestions embody the notion of a probability tree. But, neither of them convey the main advantage
of a tree in assimilating scientific information: It is not necessary to prove
one hypothesis to the exclusion of all others.
Instead competing hypotheses can share space on the same probability
tree, where their probability is proportional to their evidential weight (make
it so). Perhaps, at some time in the future one of
the hypotheses will drive the others to extinction. In the mean time, risk assessments and decisions can still be
made.
References
Lutter et al (2015). Improving Weight of Evidence Approaches to Chemical Evaluations. Risk Anal 35:186-192.
Suter, GW and Cormier SM (2011). Why and how to combine evidence in environmental assessments: Weighing evidence and building cases. Science of the Total Environment 409:1406–1417.
Suter, GW and Cormier SM (2011). Why and how to combine evidence in environmental assessments: Weighing evidence and building cases. Science of the Total Environment 409:1406–1417.
USEPA (1986). Guidelines
for Carcinogen Risk Assessment. EPA/630/R-00/004
USEPA (2011). Weight-of-Evidence:
Evaluating Results of EDSP Tier 1 Screening to Identify the Need for Tier 2
Testing
Official Post Soundtrack
Post Notes
Thesis Post #25. The last in the Probability Tree thread, I think.
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