Toxicological Testing
Whether the potentially marketable chemical is a drug, a
pesticide, a food additive, or an industrial chemical, toxicology studies done
for the purpose of getting government approval are conducted to meet guidelines
that are directed by regulatory policy. Studies for drugs and food additive are
designed to get FDA approval, while studies for pesticides and industrial
chemicals are done to get EPA approval. As
a result, it is pretty much known exactly how the results are going to be used
before the study is ever done. Some
scientific reasoning presumably goes into the design of the guidelines, but
once that is done, special permission is required to do something that is not
by the book (e.g. USFDA, 2007, USEPA, 2015).
But not all toxicology is like that. In particular, studies on “unintentional”
chemicals that are not governed by premarket approval regulations are usually far less
structured. Even if the same testing
guidelines are used, it is often not possible to predict the impact that a
study will have on any action the government may take. For
one thing, it will depend on what is possible.
Therefore, the science of and policy for unintentional chemicals do not
necessarily move in concert.
Science-Policy
The White House has an Office of Science and Technology
Policy (OSTP). The primary
mission of OSTP is as follows:
The mission of the Office of
Science and Technology Policy is threefold; first, to provide the President and
his senior staff with accurate, relevant, and timely scientific and technical
advice on all matters of consequence; second, to ensure that the policies of
the Executive Branch are informed by sound science; and third, to ensure that
the scientific and technical work of the Executive Branch is properly
coordinated so as to provide the greatest benefit to society.
In short, the primary function of OSTP is to provide
scientific information to federal decision makers.
The US Environmental Protection Agency has an
Office of Science Policy (OSP) that at first glance seems to have a similar
mission. But instead of “informing
policy”, OSP seeks to incorporating
ORD science and technology into regulatory and non-regulatory actions taken by
the agency. It oversees the Office of Research and
Development (ORD) that is responsible for most of the scientific research
conducted by the agency. But, ORD also
is responsible for what the agency refers to a Human Health Risk Assessment
that is directly involved in formulating agency regulatory policy. Here, it is hard to distinguish the science
from the policy; instead the subject becomes hyphenated “science-policy” where
the technical jargon and the regulatory jargon are inextricably
intertwined. The primary reason for this is simple: Ever
since its inception, the EPA has primarily relied on a decision making regimen
(The Safety Assessment Paradigm) that was designed for premarket approval that
dictates how scientific information will be used. When EPA changed the terminology associated
with the Safety Assessment Paradigm in 1986 (e.g. the ADI became the RfD), one
of the reasons was because different programs were doing safety assessments in
different ways (Barnes and Dourson, 1986, see section 1.2.2.2.4.):
In addition to occasionally
selecting different critical toxic effects, Agency scientists have reflected
their best scientific judgments in the final ADI by adopting factors different
from the standard factors. For example, if the toxic endpoint for a chemical in
experimental animals is the same as that which has been established for a
related chemical in humans at similar doses, one could argue for an SF of less
than the traditional 100. On the other
hand, if the total toxicologic data base is incomplete, one could argue that an
additional SF should be included, both as a matter of prudent public policy and
as an incentive to others to generate the appropriate data.
Since the use of the safety assessment paradigm is justified
as a matter of statute and agency policy, it is actually not unreasonable for
different programs to do safety assessments somewhat differently. For example an extra safety factor for
inadequate data may make sense for a chemical subject to premarket approval
(e.g. a pesticide or a chemical released in to the environment)), but it may
not for a naturally occurring element like arsenic or oxygen. Furthermore, for some regulatory decisions,
the Safety Assessment Paradigm may not be a good fit at all.
Dehyphenation
In theory, the solution is simple. If Safety Assessment Paradigm isn’t working,
do a risk assessment instead. Well,
actually no, since the EPA has called the Safety Assessment Paradigm “risk
assessment” for the last 30 years, let’s say we need a “risk analysis”
instead. The point is the same: instead
of a regulatory decision that takes the form of an acceptable level of exposure, the
assessment needs to deliver information about what the risks are.
The broken cog in the risk analysis wheel is pretty well recognized
within the agency; while exposure assessment has improved tremendously over the
last 30 years, dose-response modeling has gone almost nowhere (EPA, 2012):
Although dose-response analysis is
an integral part of human health risk assessment, it has been decades since
there have been any major fundamental changes in how dose-response is
characterized. The combination of increased demands on risk assessment and the
recent explosion of scientific knowledge presents unique opportunities to
modernize the practice of dose-response analysis. This has been echoed in
several NRC recommendations to advance dose-response analyses, particularly in
the areas of increasing the throughput of chemical assessments, characterizing
uncertainty and variability, quantifying incremental risk and addressing
susceptibility. During the October 2010
Human Health Risk Assessment Colloquium, risk managers indicated that advancing
dose-response analysis would be useful for their decision making needs.
The most obvious reason why dose-response analysis has gone
stagnant is that the current noncancer and cancer EPA guidelines both discourage
it. So, part of the solution is to
revise the guidelines so dose-response analysis is welcomed. But there is a fundamental underlying cause that needs to be overcome – the
toxicology testing that goes into scripted regulatory approval processes are often
designed by toxicologists for toxicologists. A quantitative risk analysis changes all that. The value of a study will depend on its
information value rather than it’s conformity to protocol. In addition, since a technocratic decision
process is being replaced by a democratic one, many regulatory players in
academia and the federal government will have less control over the decision
process. That’s the inevitable result when
the public gets more information.
Therefore, when they realize that their ox is being gored, complaints
about the unreliability of modeling from the powers that be are just as sure to
follow.
The other science-policy obstacle is that most chemicals
worthy of quantitative risk assessment have gained their notoriety from human
epidemiological studies. Yet, most human
studies are not designed with dose-response characterization in mind. This is also attributable to decades of
quantitative malaise. In the Safety
Assessment Paradigm, statistical significance is often equated with regulatory
significance. For a dose response
analysis more weighty evidence is needed.
Because informing regulatory decision is the main purpose for the
conduct of many epidemiological studies, establishing a regulatory market for
studies that can establish a biological gradient is prerequisite to actually
getting them.
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
USEPA (2012). Human
Health Risk Assessment. STRATEGIC
RESEARCH ACTION PLAN 2012-2016. EPA 601/R-12/007
USEPA (2015). Harmonized Test
Guidelines.
Official Post Soundtrack
Post Notes
Thesis Post #41. Introductory thesis for a Public Health Risk Analysis thread.
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