A regulative regime for the safety of chemicals in zone of life has been rapidly established
on the basis of the advance of toxicology and related science. Especially, the application
of
risk analysis based on the toxicology has facilitated scientific decisions and administrative
actions for the security of chemical safety.
However, their decisions and actions on safety issues have not always gained social
consensus. One of the reasons was the impertinent in the practical use of scientific
knowledge
to cope with issues of health and environment which are in need of administrative
actions,
that is to say, the inappropriateness of decision making by “the regulatory science”.
Regulatory Science
Regulatory science is an effective science to justify the decision making processes
for
administrative actions. Particularly, in the safety assessments of chemicals, it is
requisite as a theoretical concept to complement the uncertainty of scientific knowledge
so
that the decision of administrative actions can be adequate in both science and society.
So as to reduce the uncertainty of scientific knowledge, it is important to improve
the
quality of the bridge introducing products of science to society, although regulatory
science is available as the bridge.
From the viewpoint of the contribution of regulatory science to regulatory decisions,
regulatory science possesses mainly three functions. The first is to provide tools
to
produce data. The second is to assess submitted data. This process involves many stages
of
evaluation, from direct assessment of data to more indirect appraisal of response
or impact
in society. The third is discussing how to consider and how to balance various factors
for
regulatory decisions. All three functions are indispensable to the optimal introduction
into
society of a new product of science, such as discovered substances, tools and technologies
as well as knowledge and information.
Therefore, the regulatory science is just an indispensable domain to effectively apply
risk
analysis.
Risk Analysis
Risk analysis based on toxicology is defined as a process consisting of three components,
namely risk assessment, risk management and risk communication (WHO/FAO, 1995).
Of risk analysis, risk assessment is a scientific procedure to assess the risk level
or to
infer the risk profile, that is to say, it is the scientific evaluation of known or
potential adverse health effects resulting from human exposure to chemical hazards.
This
assessment includes not only quantitative risk assessment but also qualitative expressions
of risk and an indication of the attendant uncertainties.
Risk management is the process of weighing policy alternatives, decision-making and
action
taking, that is to say, the process of devising means to accept, minimize or reduce
assessed
risks and to select and execute appropriate options. Risk communication is an interactive
process of exchanging information and views on risk among risk appraiser, risk managers,
and
other concerned parties.
Risk Assessment
Risk assessment of adverse health effects in human from exposure to a particular agent
is
performed on the basis of scientific data mostly derived from toxicological studies
on the
agent. Its process is composed of four main steps; hazard identification, hazard
characterization (or dose-response assessment), exposure assessment and risk
characterization. However, there are several issues of uncertainty in the scientific
knowledge of chemical risk assessment assessed on the basis of animal-tests as follows
(WHO/FAO, 1995) (IPCS, 2004, 2009);
1) Uncertainties in hazard identification aiming at the identification of potential
adverse
effects associated with exposure to the agent. Data of toxicity tests (single dose
toxicity
tests, repeated dose toxicity tests, reproductive and developmental studies and genotoxicity
tests) are used in this step.
2) Uncertainties in hazard characterization relating to the qualitative and quantitative
evaluation of the adverse effects associated with exposure to the agent. Animal data
derived
from dose-response studies, toxicokinetic studies and mechanical studies are used
to predict
adverse effects of the agent in human.
3) Uncertainties in exposure assessment indicating the qualitative and quantitative
evaluation of the intake (daily intake, duration of intake, mode of intake), distribution,
metabolism, excretion, and their specific differences. Characteristics of exposed
population
such as population with large amount of intake or population of high susceptibility
are
examined in this step.
4) Uncertainties in risk characterization being the final step to integrate hazard
identification, hazard characterization and exposure assessment into an estimation
of the
adverse effects occurring in a target population.
Risk characterization for the agent gives practically an answer to the questions regarding
to (1) A level of exposure considered to present minimal or no risk for health effects
(LOAEL: lowest observed adverse effect level to NOAEL: no observed adverse effect
level
extrapolation), (2) Possibility of an appearance of reaction and its mechanism in
human, and
(3) Relationship between dose (or intake) and toxic degree in human (dose-response
relationships).
To minimize or reduce uncertainties in risk analysis, hazard characterization is available
for final risk analysis. An introduction of genotoxic data into evaluation of carcinogenic
risk assessment is cited as an example. As other instance, corrections of a safety
factor or
uncertainty factor for establishment of the acceptable daily intake/tolerable daily
intake
(ADI/TDI) and the reference dose/reference concentration (RfD/RfC) are tested by using
data
from in vivo kinetics (absorption, distribution, metabolism, excretion) and knowledge
of
reaction mechanism (IPCS, 2009).
In the WHO/IPCS guidance (2012), considerations in the application of uncertainty
factors
for immunotoxicity data are individually presented as uncertainty factors of intraspecies,
interspecies and database (in some instances, adding matrix factor, use and time factor)
for
immunosuppression, immunostimulation, sensitization (allergic response) and autoimmunity.
However, the application of each uncertainty factor is too insufficient to be good
predictors for subsequent clinical data or epidemiological studies so far.
Immunotoxicity Risk Assessment for Chemicals
In the 1974, from a standpoint of preventive medicine, the author began to feel keenly
the
necessity of the risk assessment to evaluate individually the toxicity of such main
biofunction as brain-nerve function, immunofunction and endocrine function. First,
the
author began to aim at systematizing and giving each toxicological science an assured
status, and further advocated each as brain-neurotoxicology, immunotoxicology, and
endocrinotoxicology. These denominations and concept of biofunctional toxicology in
the 1974
are the first in Japan.
Of each toxicological science, immunotoxicology has made great advancements ever since.
Currently, immunotoxicology is recognized as a mature sub discipline of toxicology,
and has
reached the state at which information on hazard can be applied to risk assessment
with the
careful consideration of available guidance.
Up to now, there are the two major international guidance documents on immunotoxicity
risk
assessment: One is ICH S8 Guideline for human pharmaceuticals and the other is the
IPCS/WHO
Guidance for chemicals.
In March 2012, the World Health Organization (WHO)/ International Programme on Chemical
Safety (IPCS) provide a harmonized guidance for immunotoxicity risk assessment for
chemicals
(Guidance for Immunotoxicity Risk Assessment for Chemicals, 2012). The WHO guidance
presents
how information obtained by immunotoxicity assessment may be applied for risk assessment
in
the population. This guidance is the first document published as immunotoxicity risk
assessment for chemicals up to now.
The aim of the WHO/IPCS harmonization project document is to facilitate international
harmonization of immunotoxicity risk assessment, that is to say, to harmonize global
approaches to chemical risk assessment, including by increasing knowledge and agreement
on
basic risk assessment principles; developing international guidance documents on specific
issues; and enhancing the practical use of risk assessments globally.
The guidance states that immunotoxicity risk assessment should be performed according
to
the same principal approaches as applied in risk assessment for other toxicological
end-points, because the immune system or each type of immunotoxicity manifests many
special
aspects that need specific consideration in risk assessment. Furthermore, the guidance
recommends that a weight of evidence approach is most suited for risk assessment of
immunotoxicity, and that the approach should include clinical and epidemiological
information, equally as information from animal experiments and other information.
Immunotoxicity risk assessment of chemicals is an evaluation of the potential for
unintended effects of chemical exposure on the immune system. These effects manifest
as
following principal types of immunotoxicity: immunosuppression involving infection
and
carcinogenesis etc, immunoaccentuation involving sensitization and autoimmunity, or
immunostimulation. Such immune dysregulation may lead to many different types of illnesses.
Included among them are illnesses that are associated with a dysfunctional immune
system,
such as infections, inflammatory diseases, allergic diseases, autoimmune diseases,
etc,
although all of them are not induced by chemical exposure.
For instance, exposure to xenobiotics is associated with immunosuppression manifesting
the
reduction of resistance to infections, development of autoimmune disease and
hypersensitivity responding directly as allergen or enhancing the induction of allergic
sensitization. Risk associated with immunostimulation is relatively difficult of the
determination.
With the latest advance of immunology, a number of novel immunocompetent cells that
play a
part in the regulatory mechanisms of cellular immunity, humoral immunity, inflammation
and
autoimmunity are being found out through characteristic analysis. They include T cell
subsets such as Th1, Th2, Th17, Tfh, Treg, NKT, macrophage and dendritic cell. Furthermore,
the advance in immunology is producing new knowledge about findings of pattern recognition
receptors responsible for innate immunity such as TLRs, RIG-1Rs, NLRs, dectin-1; and
further
about the regulation of immune system cell differentiation and immune response by
nuclear
receptors including AhR, PPARs, RARs, RXR, RORs, GR and VDR. As the latest knowledge,
there
are miRNA and epigenetic factors that play important roles in gene regulation, and
introduction of “omics” techniques into immunotoxicology.
Thus, the up-to-date knowledge and information on novel cells and functional molecular
in
immunity, which are increasing and accumulating by leaps and bounds, have raised awareness
that they should/must be comprehensively surveyed, regulated and applied to immunotoxicology
and further immunotoxicity risk assessment, although such processes are complicated.
Unfortunately, however, the current application is insufficient in the practical stage
of
clinical and environmental immunotoxicity risk assessment. Especially in clinical
field,
there is currently a lack of adequate standardization for immune monitoring tests
during
clinical trials in immune safety issues and a lack of specific immunotoxicity biomarkers
to
improve the immune-safety of chemical agent. Most of means used for clinical immunotoxicity
risk assessment are those for immunosuppression, and there is little reference to
the
assessment of immunostimulatory and immunomodulatory compounds, because of lack of
the good
risk assessment models for detecting their compounds that can translate to clinical
risk
assessment.
Therefore, there is a need to identify the current state and quality of the science
assessing risk assessment models for immunomodulatory effects or immunostimulatory
effects
in the principal types of immunotoxicity as described above, as well as a need to
identify
research gaps and to update the current guidance.
From these points of view, regulatory science is an indispensable discipline to improve
the
quality of the immunotoxicology and further immunotoxicity risk assessment, and also
to give
each immunotoxicological science an assured status.
Particularly, under the existing conditions being flooded with uncertainty, it is
important
that the up-to-date knowledge in immunology and toxicology is applied to immunotoxicology
and immunotoxicity risk assessment, and the uncertainty of scientific knowledge is
complemented, and further public consensus is gained on the basis of a theoretical
concept
and an adequate judgment in regulatory science.
Conclusion
The first guidance has been just defined for immunotoxicity risk assessment for chemicals
(WHO/IPCS, 2012), but it admits of no doubt that it is insufficient in the level of
practical application. It is not till now for the author to feel that immunotoxicity
risk
assessment may be started along the right lines. After this, it is necessary that
accumulating useful scientific products will be comprehensively surveyed and adequately
assessed for subsequent decision-making from the standpoint of regulatory science
so as to
be able to contribute toward society.