19 research outputs found
A new sighting study for the fixed concentration procedure to allow for gender differences
The fixed concentration procedure (FCP) has been proposed as an alternative to the median lethal
concentration (LC50) test (organisation for economic co-operation and development (OECD) test guideline
[TG] 403) for the assessment of acute inhalation toxicity. The FCP tests animals of a single gender (usually
females) at a number of fixed concentration levels in a sequential fashion. It begins with a sighting study that precedes
the main FCP study and is used to determine the main study starting concentration. In this paper, we propose
a modification to the sighting study and suggest that it should be conducted using both male and female
animals, rather than just animals of a single gender. Statistical analysis demonstrates that, when females are more
sensitive, the new procedure is likely to give the same classification as the original FCP, whereas, if males are more
sensitive, the new procedure is much less likely to lead to incorrect classification into a less toxic category. If
there is no difference in the LC50 for females and males, the new procedure is slightly more likely to classify into
a more stringent class than the original FCP. Overall, these results show that the revised sighting study ensures
gender differences in sensitivity do not significantly impact on the performance of the FCP, supporting its use as
an alternative test method for assessing acute inhalation toxicity
A statistical evaluation of the effects of gender differences in assessment of acute inhalation toxicity
Acute inhalation toxicity of chemicals has conventionally been assessed by the median lethal concentration
(LC50) test (organisation for economic co-operation and development (OECD) TG 403). Two new methods,
the recently adopted acute toxic class method (ATC; OECD TG 436) and a proposed fixed concentration procedure
(FCP), have recently been considered, but statistical evaluations of these methods did not investigate
the influence of differential sensitivity between male and female rats on the outcomes. This paper presents an
analysis of data from the assessment of acute inhalation toxicity for 56 substances. Statistically significant differences
between the LC50 for males and females were found for 16 substances, with greater than 10-fold differences
in the LC50 for two substances. The paper also reports a statistical evaluation of the three test
methods in the presence of unanticipated gender differences. With TG 403, a gender difference leads to a
slightly greater chance of under-classification. This is also the case for the ATC method, but more pronounced
than for TG 403, with misclassification of nearly all substances from Globally Harmonised System (GHS) class 3
into class 4. As the FCP uses females only, if females are more sensitive, the classification is unchanged. If males
are more sensitive, the procedure may lead to under-classification. Additional research on modification of the
FCP is thus proposed
Novel in vitro and mathematical models for the prediction of chemical toxicity
The
focus
of
much
scientific
and
medical
research
is
directed
towards
understanding
the
disease
process
and
defining
therapeutic
intervention
strategies.
Whilst
the
scientific
basis
of
drug
safety
has
received
relatively
little
attention,
despite
the
fact
that
adverse
drug
reactions
(ADRs)
are
a
major
health
concern
and
a
serious
impediment
to
development
of
new
medicines.
Toxicity
issues
account
for
~21%
drug
attrition
during
drug
development
and
safety
testing
strategies
require
considerable
animal
use.
Mechanistic
relationships
between
drug
plasma
levels
and
molecular/cellular
events
that
culminate
in
whole
organ
toxicity
underpins
development
of
novel
safety
assessment
strategies.
Current
in
vitro
test
systems
are
poorly
predictive
of
toxicity
of
chemicals
entering
the
systemic
circulation,
particularly
to
the
liver.
Such
systems
fall
short
because
of
1)
the
physiological
gap
between
cells
currently
used
&
human
hepatocytes
existing
in
their
native
state,
2)
the
lack
of
physiological
integration
with
other
cells/systems
within
organs,
required
to
amplify
the
initial
toxicological
lesion
into
overt
toxicity,
3)
the
inability
to
assess
how
low
level
cell
damage
induced
by
chemicals
may
develop
into
overt
organ
toxicity
in
a
minority
of
patients,
4)
lack
of
consideration
of
systemic
effects.
Reproduction
of
centrilobular
&
periportal
hepatocyte
phenotypes
in
in
vitro
culture
is
crucial
for
sensitive
detection
of
cellular
stress.
Hepatocyte
metabolism/phenotype
is
dependent
on
cell
position
along
the
liver
lobule,
with
corresponding
differences
in
exposure
to
substrate,
oxygen
&
hormone
gradients.
Application
of
bioartificial
liver
(BAL)
technology
can
encompass
in
vitro
predictive
toxicity
testing
with
enhanced
sensitivity
and
improved
mechanistic
understanding.
Combining
this
technology
with
mechanistic
mathematical
models
describing
intracellular
metabolism,
fluid-‐flow,
substrate,
hormone
and
nutrient
distribution
provides
the
opportunity
to
design
the
BAL
specifically
to
mimic
the
in
vivo
scenario.
Such
mathematical
models
enable
theoretical
hypothesis
testing,
will
inform
the
design
of
in
vitro
experiments,
and
will
enable
both
refinement
and
reduction
of
in
vivo
animal
trials.
In
this
way,
development
of
novel
mathematical
modelling
tools
will
help
to
focus
and
direct
in
vitro
and
in
vivo
research,
and
can
be
used
as
a
framework
for
other
areas
of
drug
safety
science
Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing
Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or refining the use of animals, and (3) recommendations for future work in this area
Alternative (non-animal) methods for cosmetics testing: current status and future prospects2010
Reducing the number of fish in bioconcentration studies with general chemicals by reducing the number of test concentrations
Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison of Route-Specific Systemic Toxicity and Hazard Classifications Under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative ‘under-classification’ to 1%, but increased the relative ‘over-classification’ to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of \u3e2000 mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements
Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison of Route-Specific Systemic Toxicity and Hazard Classifications Under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative ‘under-classification’ to 1%, but increased the relative ‘over-classification’ to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of \u3e2000 mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements