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Progressing from alternatives
assessment to de novo green chemistry Hans Plugge and Longzhu Q. Shen
3E Company, Bethesda, MD and Yale University, New Haven, CT
Since the publication of “A Framework to Guide Selection of
Chemical Alternatives” by the National Academy of Sciences in
2014, there has been ample discussion regarding the proper role
of hazard and risk assessment in the regulatory process. Hazard
assessment appears favored by consumers and hence retailers,
which are driving the process of wholesale removal of any level of
all hazardous chemicals from consumer products. Obviously this
impacts the supply chain where industry and formulators are
continually struggling with the question of how much of a level of
a certain chemical is acceptable. Industry has favored a risk
assessment approach where not only the health effects but also
the exposure, are taken into account.
De novo design of green chemicals aims at designing chemicals
with a priori lesser (health) effects while maintaining functionality.
In contrast alternatives assessment examines the library of
existing chemicals to select alternatives while maintaining
functionality. Retaining functionality is paramount, because
without similar functionality, one just makes a poor substitution.
Alternatives assessment is the process by which one evaluates
either (or both) the hazard and risk inherent to chemical exposure
scenarios. Until very recently such assessments were based on
classical toxicology (read animal) studies supported by
mechanistic in vitro studies. The amount of data available for
certain chemicals has exploded since the arrival on the scene of in
vitro and enzyme based assay data such as ToxCast and Tox21
leading up to the science of toxicogenomics. Integration of
classical, in vitro and enzyme data has led to the “construction” of
Adverse Outcome Pathways, which theoretically allow for
extrapolation of enzyme data to organism (human) impact.
Notwithstanding the great progress made in recent years only a
very limited number of chemicals are covered by these advanced
methodologies. In addition their use as the basis for regulatory
action is rather unsettled.
Data analytics are continually improving and big data approaches
lead to more and more data interpretation approaches. However,
still large data gaps remain: at most 5% of the chemical universe
has a full set of toxicological data. Filling the data gaps thus
remains an important task. Methods ranging from technical
expertise/ experience based methodologies such as Read-Across
to sophisticated QSAR models have been used. None of these
methodologies are perfect – estimates of accuracy range from
barely exceeding 50% to 80% in very circumscribed conditions.
These same datasets (and gaps in them) drive the Green
Chemistry design, which is aimed at minimizing the inherent
hazard and preserving the functionality. Computational chemistry
and cheminformatics are used to derive probabilistic models for
design guidelines. Feedback loops and advances in methodologies
propel the continual improvement in accuracy of the predicted
characteristics, something which aids (the reliability) of both
alternatives assessment and de novo green design.
All of these data can be used to derive a (preliminary) hazard
assessment, used to eliminate the not-so-green outliers. The
original compound/product then enters a risk assessment phase
where exposure considerations are taken into account. Green
design is aimed at minimizing hazard, thus exposure plays a lesser
role. However, risk=hazard*exposure, thus increased chemical
exposure may make a slightly more green chemical impose a
higher risk, especially during alternatives assessment. Such a risk
assessment is then followed by a regulatory analysis as to whether
PMN/SNURs (Pre Manufacturing Notices/ Significant New Use
Rules) are necessary for this product, and what documentation is
required under current and future regulations, including TSCA and
REACH. Interim usage to retain the current chemical in commerce
may be applied for while a better chemical is designed de novo via
green chemistry principles.
The final phase involves a complete sustainability assessment.
Included is a full blown life cycle assessment incorporating the
cradle to grave impacts from production to disposal of a product.
Engineering performance examines and documents the full range
of functionality. Economics do play a role: alternatives whether
designed de novo or not, do need to maintain a certain level of
economic balance, which includes the cost of reengineering
existing facilities. A final regulatory analysis follows.
Alternatives assessment is a short term (10-20 year) solution.
During that time period the predictive methodologies should
improve sufficiently that most of the chemical library might be
redesigned de novo using green chemistry principles.
